"5-(PYRIDINIL)-2(1H)-PYRIDINONES USEFUL AS CARDIOTONIC AGENTS AND THEIR PREPARATION.

Description

; Here ι INDUSTRY. DUMWtftClDAY AND AREA 176 | MQD. r - 4B NOT > / 114 8 7 4 0 MINISTRY OF TRADE AND CRAFT INDUSTRY DG Ρ. I. - CENTRAL PATENT OFFICE PATENT FOR INDUSTRIAL INVENTION N………p…..ù:., . / …n…^…… I! this patent is granted for the invention subject to the application below specified: -'V Λ N. 1 JP A\3* Zi Γι 1L With Prov U p 1 ί ' ? 6 21 R fi Q, 1 5 t· ; ι rn Who:m:i ' 1 7 8 6 IT 01. IN Λ INV. DES, s τ e: rlimc In f ; ι; five . SEE YORK '1 · Y0 9C IJ . 0 . TO . S − ( Ρ I f? ICIN ! U ~ ? ( 1 H ) − Ρ IS IO IN Ο NI USEFUL WITH f CARDIOTOnic AGENTS AND THEIR I '·; f 6 WHERE ϊ THE ONE . GEORGE YC Lr ! 1. ESU t E RICHARD f VERE TT f'HILION DONALD IRFDERICL f'AGF ORTORITA CUF ARE YOU? J 0 5 Γ <> 1' 0 TALKAJR . USA Ρ V , !| 1? f ))). N. 97 504 OF ?ó NINE. SRI 19'-), N. 175100 OF ?fi fi. 7 0 1 9 '5 0 , N » 1 ');; , . A 01 PEL ?C OCTOBER 19 8 0 f l. τ f ) υ . DII. 6 NOVEO'UÌF 1 9 ?. 0 Rome, li........................1 T^ · ' · P. 1985..... Register A Protocol No. 56218 A / QQ MINISTRY OF INDUSTRY, COMMERCE AND CRAFTS Provincial Office of Industry, Commerce and Crafts of Milan COPY OF THE VE UBALE OF DEPOSIT BEH INDUSTRIAL PATENT FOR INVENTION In the year 1980 on the twenty-fifth day of the month of November the STERLING DRUG INC. pill. jjofilgjxx of American nationality £224^2- | n New York, New York,USA. x ersi ostro; Via through an agent U [international trust Patents 1 ηκ. C. GREGORJ and with domicile for legal purposes in Milan - Via Dogana 1 at the office of the agent. presented to me, the undersigned: - Stamped application for the granting of a patent for an industrial invention having for T 1 T OL O 5-(PlRIDINIL)-2(1H)-PYRIDINONES USEFUL AS CARDIOTONIC AGENTS AND THEIR PREPARATION. Inventors designated 1) George Yohe LESHER; 3) Donald Frederick PAGE ; 2)l?ichard Everett PPILION; A) Chester Joseph OPALKA.JR. Priority 1 of the patent application in: U SA No. 97504 of November 26, 1379; No.135100 of 28 March 1980; of October 50, 1980; of November 6, 1980. accompanied by: - Description in duplicate of 99 pages of writing - Letter of appointment - (ιτχ,»:£Χ'Χ]@χίχχ • Priority document and Italian translation (reserve) - Authorization or deed of transfer, (reservation) - Act of designation of the inventor. - Proof of payment on postal account no. 00668004 in the name of the Tax and Concession Registry Office Rome of L. 188,500.- issued by the Post Office of Milan 32 on 6.8.1979 n. 058 Revenue stamp of L. 2,000. The application, descriptions and drawings listed above have been signed by the applicant and stamped with the office stamp. vX'· ,- < » Tb THE DEPOSITOR. OFFICER R Peter Messico For a true copy of the original, please contact the Director (Salvatore Ravalli) THE HEAD OF THE PATENT OFFICE IRaoUDSolellìl d / 6531> On the MINISTRY OF INDUSTRY, COMMERCE AND CRAFTS 6 21 8 A / 80 Central Patent Office - ROME the Company: STEKLING DRUC INC. (a corporation organized and existing under the laws of the state of Delaware, USA) UJUO.AM!L / ~No / 2τηέ0 niubi .....-..-..min located at: 90 Park Avenue, New York, New York, USA. of US nationality through agent and domiciliary PATENT OFFICE ι ; ING. C. GREGORJ, Milan, Via Dogana 1 - requests a patent certificate for an industrial invention having: for title: « 5-(PYRIDINIL)~2( 1H)-PYRXDXN0NI USEFUL WITH CARDIOTONIC AGENTS AND THEIR PREPARATION.” Inventors: 1)George Yohe LESHER, , at: RD 1,Box 268,Miller Road,East Greenbush, New York,U$A; 2) Richard Everett PHILION .a: Edgewood Drive, Averill Park, New York, USA; 3)Donald Prederick PAGE at: 121, Alvo Street, East Greenbush, New York, USA; d)Chester Joseph OPALKA,JR., a: 1331 Angelo Drive, Castleton, New York,USA all of US nationality. PRIORITY OF PATENT APPLICATION IN No. 97SO4 of 26 November 1979; No.139100 of £8 March 1980; of £0 October 1980; V' USA ........ of November 6, 1980. The following documents are attached to this document I. - Description in duplicate. xjtxfitBfltgniQixxx xm x jtavoiBxinxduplaz 3. - Letter of appointment. - Reference / stxpoz.oouraLgenexx rale 4. - Attention to payment of the required taxes. δ. - Revenue stamp of L. 2,000. 6. - Act of designation of the inventor. 7. - Priority document with Italian translation (reservation) o.- Deed of assignment (reservation.) Milan, there , 4 / 65315 G' / G Description of the invention entitled: 5-(PYRIDINIL)-2(1H)—PIEIDJNONE USEFUL AS CARDIOTONIC AGENTS AND THEIR PREPARATION. in the name of: STERLING DRUG INC. at: 90 Park Avenue, New York, New York, USA of American nationality and domiciled by choice, registered in Milan, Via Dogana l, at the office of the Patent Attorney Eng. C. Gregorj Dep. the 2 f F' 1 : !F' No. $6 / 1 the / F Fi SUMMARY Amended description (art. 49 DPR ￎﾷ. 330 / 1979) application filed on 10,2. 1-R 1-3-[unsubstituted amino, cyano, carbamoyl, halogen, alkyl(lower)amino, di-(lower alkyl)amino, acyl(lower)aminocarboxy or lower carbalkoxy]-6-(lower alkyl)-5-(pyridinyl)2(1H)-pyridinones or their pharmaceutically acceptable cationic or acid addition salts are useful as cardiotonic agents, where R 1 represents hydrogen, lower alkyl or lower hydroxyalkyl. 1-R -3-amino-6-(lower alkyl)-5-(pyridinyl)-2(1H)pyridinones are prepared by hydrolyzing the corresponding 3-cyano-compounds to yield the corresponding 3-carbamyl compounds and reacting the latter with a reagent capable of converting the carbamyl to an amino. The 1-R 1-3-cyano-6-(lower alkyl)-5(pyridinyl)-2(1H)-pyridinones are prepared with Γ· ¢.. a process in which one reacts with di-(pyridinylmethyl)alkyl(lower)ketones with dimethylformamide di-(lower)alkyl to obtain 1-(pyridinyl)-2-(dimethylamino)ethenyl alkyl(lower) ketone and reacting said ketone with NR.j-O-cyanoacetamide to produce the 1R^-3-cyano6-(lower alkyl)"5-(pyridinyl)-2(1H)-pyridinones. The conversions are also shown: of the 3-cyanocompounds to the 3-H and 3-carboxy-compounds; of the 3-H compounds to the 3-halo-compounds; of the 3-halo-compounds to the 3-mono-(lower alkyl)-or di(lower alkyl)-amino] compounds; of the 3-aminocompounds to the 3-acyl(lower)amino or 3-mono-(lower alkyl)-or di-(lower alkyl)amino] compounds; and of the 3-carboxycompounds to the 3-carbethoxy-compounds. DESCRIPTION The present invention relates to 5-(pyridinyl)-2(1H)-pyridinones useful as cardiotonic agents and to their preparation. U.S. Patent Nos. 4,004,012 and 4,072,746 show 3-amino(or cyano)-5-(pyridinyl)-2(1H)-pyridinones as cardiotonic agents and the corresponding 3-carbamyl compounds, alternatively called 1,2-dihydro-2-oxo-5-(pyridinyl)nicotinamides, as intermediates, which are converted to the corresponding 3-amino compounds by reaction with a reagent capable of converting carbamyl to an amino, for example by heating with an alkali metal hypohalide. A preferred embodiment of these compounds is 3-amino-5-(4-pyridinyl)-2(1H)pyridinone, now generically known as 3-amino-5-(4-pyridinyl)-2(1H)pyridinone, alternatively called 5-amino-3,4-t-pyridinone-3-6(1H)one. A suitable method for preparing 3-cyano-5(pyridinyl)-2(1H)-pyridinones, also called 1,2-dihydro2-oxo-5-(pyridinyl)nicotinonitriles, is the reaction of alpha-(pyridinyl)-beta-(dialkylamino)acrolein with alpha-cyanoacetamide. U.S. Patent 4,072,746 also shows 3-0-5-(pyri dini 1)-2-(-1 H)pyridinones where Q represents hydrogen, halogen, alkyl(lower)amino, di-(lower)alkyl)amino and NHAc where Ac represents lower alkanoyl or lower carbalkoxy. The 3-unsubstituted-5-(pyridinyl)-2-(1H)-pyridinones, (Q=H) were prepared by heating the corresponding 3-cyano-compounds with aqueous sulfuric acid, first forming the acids 3- carboxylic acids, i.e. 1,2-dihydro-2-oxo-5-(pyridinyl)nicotinic acids, which are then decarboxylated. For the said 1,2-dihydro-2-oxo-5-(pyridinyl)nicotinic acids II.· no cardiotonic activity is detected. The present invention lies in the compounds having the formula I R / \zAo where Q is hydrogen, amino, CN, carbamoyl, halogen, alkyl(lower)amino, di-(lower)alkylamino, acyl(lower)aminocarboxy, or lower carbalkoxy, R^ represents hydrogen, lower alkyl, or lower hydroxyalkyl; R^ represents lower alkyl, and PY represents 4-03-02-pyridinyl or 4-03-02-pyridinyl having 1 or 2 lower alkyl substituents, or pharmaceutically acceptable cationic or acid addition salts of such compounds. The compounds of formula I are useful as cardiotonic agents as determined by standard pharmacological evaluation procedures. The compounds of formula I where Q represents carbamoyl and CN and where Q represents hydrogen are also useful as intermediates for the preparation of the corresponding compounds where Q represents amino and halogen, respectively.Compounds of formula I where Q represents halogen are also useful as intermediates for the preparation of the corresponding 3-[mono- or di-(alkyl)lower)amino]-compounds. Preferred embodiments are those of formula I where O represents hydrogen, amino or CN, PY represents 4-pyridinyl or 3-pyridinyl, R^ represents hydrogen and R represents methyl or ethyl. Particularly preferred embodiments are 1,2-dihydro6-methyl-2-oxo-5-(4-pyridinyl)nicotinotrile (i where O is CN, R is Η, PY is 4-pyridinyl and R is methyl), 3-amino6-ethyl-5-(4-pyridinyl)-2(1H)pyridinone (I where Q is NH^, R is H, PY is 4-pyridinyl and R is ethyl), 3-aminopyridinyl)-6-methyl-1-2(1H)pyridinone (I where Q is NH^, R is H, PY is 4-pyridinyl and R is methyl), 6-methyl-5-(4-pyridinyl)-2(1H)pyridinone (i where R is H, py is 4-pyridinyl and R is methyl) and 6-ethyl-5-(4-pyridinyl)-2(1H)-pyridinone(1 where R^ is H, PY is 4-pyridinyl and R is ethyl), or pharmaceutically acceptable acid addition salts of these compounds. These particularly preferred embodiments have been found to have a significantly higher cardiotonic activity than the corresponding known non-alkylated compounds, namely 3-amino5-(4-pyridinyl)-2(1H)pyridinone known as amrinone, I, 2-dihydro-2.-oxo-5-(4-pyridinyl)nicotinonitrile and 5- (4“pir i of ni. 1)-2-(1H)-pir i of none. A compound of formula I as defined above can be prepared by a process which includes: a, reaction of a compound of formula RR NCH=CC(==O)-R ' III PY where R^ and R^ each represent lower alkyl, with malonamide to produce a compound of formula I where Q is carbamyl, or b. the reaction of a compound having the above formula III or having the formula RC-CH-CHO « » PY IV with NR^-o-cyanoacetamide to prepare a compound of formula I wherein Q is CN, partially hydrolyzing, if desired, a compound of formula I so obtained wherein Q is CN to obtain the corresponding compound wherein Q is carhamyl, reacting, if desired, a compound of formula I obtained in the above manner wherein Q is carbamyl with a reagent capable of converting carbamyl to amino to produce the corresponding compound wherein Q is amino; by reacting, if desired, a compound of formula 1 obtained in the above manner where Q is amino with 1 or 2 molar equivalents of a lower alkylating agent to afford the corresponding compound where Q is alkyl, respectively.(lower)amino or di-(lower alkyl)amino; reacting, if desired, a compound of formula I obtained as above where Q is amino with a lower acylating agent to produce the corresponding compound where Q is acyl(lower)amino; hydrolyzing, if desired, a compound of formula I obtained as above where Q is CN to obtain the corresponding compound where Q is carboxyl; heating, if desired, a compound of formula I obtained as above where Q is carboxyl with a mixture of concentrated sulfonic acid and concentrated nitric acid to obtain the corresponding compound where Q is nitro, said compound where Q is nitro being subsequently reduced to obtain the compound where Q is amino; heating, if desired, a compound of formula I obtained as above where Q is CN or Carboxyl with an aqueous mineral acid to obtain the corresponding compound where Q is hydrogen,. U f' F ί (esterifying, if desired, with a lower carboxyl group a compound of formula I obtained as above where Q is carboxyl to obtain the corresponding compound where Q is lower carboxyl, reacting, if desired, a compound of formula I obtained as above where R.^ is hydrogen with an alkylating agent of the formula R'-An wherein R* is lower alkyl or lower hydroxyalkyl and An is an anion of a strong inorganic acid or an organic sulfonic acid to prepare the corresponding compound wherein R^ is R*, reacting, if desired, a compound of formula I obtained as above wherein Q is hydrogen with a halogen to produce the corresponding compound wherein Q is halogen, reacting, if desired, a compound of formula I obtained as above wherein Q is halogen with a lower alkylamine or a di-(lower alkyl)-amine to produce a corresponding compound wherein Q is alkyl(lower)-amino or di(lower alkyl)-amino, respectively, and converting, if desired, a free base obtained as above to an acid addition salt thereof, or converting a compound obtained as above to a cation salt thereof. A PY-methyl(lower alkyl)ketone of the formula PY-CH-C(=O)-R(11) can be reacted with di(lower alkyl)formamido di-(lower alkyl)acephalic to produce 1-ΡΥ-2-Γdi-(lower alkyl)aminojetanyl alkyl(lower)ketone of the formula III RR ICH ^CC(=O)-R PY III wherein R and R each represent lower alkyl and one preferably represents methyl and PY, R, R 1 and R* have the meanings indicated with respect to formula I. Said Hpix (idinyl)-2-[di(lower alkyl)aminojeteryl lower alkyl ketones] having the above formula III wherein PY and R have the meanings indicated with respect to formula I, or acid addition salts thereof, are novel compounds according to one aspect of the present invention. The present invention also provides a cardiotonic composition for enhancing cardiac contractility, said composition comprising a pharmaceutically acceptable carrier and, as its active component, an effective amount of a cardiotonic 1R 1-3-Q-5-PY-6-R-2(1H)-pyridinone having the formula I wherein R 1, Q 2, PY and R 3 are each as defined in formula I, or a pharmaceutically acceptable cationic or acid addition salt of such compound. Cardiac contractility may be increased in a patient requiring such treatment by a process comprising administering to said patient an effective amount of a cardiotonic 1-1^-3-0-5-PY-6-P-2(1H)-pyridinone having the formula I wherein , Q, PY and R are each defined as in the formula X, or a pharmaceutically acceptable cationic or acid addition salt of said compound, . The term lower alkyl as used herein for example as meaning R, as one of the meanings of R, as meaning lower alkyl in alkyl(lower)amino or di-(lower)alkylamino, as meaning O or as substituent for PY in formula I, means alkyl groups having from 1 to 6 carbon atoms which may be structured as linear or branched chains and of which methyl, ethyl, n-propyl, isopropyl, n-butyl, sec,buyl, isobutyl, n-amyl, n-hexyl, and the like are illustrative examples. The term lower hydroxyalkyl as used here, for example as one of the meanings of R in formula I, means hydroxyalkyl groups having from 2 to 6 carbon atoms and having their α-rosyl group and their free valence bond (or linking bond) on different carbon atoms, and illustrative examples of which are 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 2-hydroxy-2-methylpropyl, 2-hydroxy-1,1-dimethylethyl, 4-hydroxybutyl, 5-hydroxypentyl, 6-hydroxyhexyl and the like. Illustrative examples of PY in formula I where PY is 4-3- or 2-pyridinyl having 1 or 2 lower alkyl substituents, are as follows: 2-methyl-4-pyridinyl, 2,6-dimethyl-4-pyridinyl,3-methyl 4-pyridinyl, 2-methyl-3-pyridinyl, 6-methyl-3-pyridinyl (alternatively called 2-methyl-5-pyridinyl), 4-methyl-2-pyridinyl, 6-methyl-2-pyridinyl, 2,3-dimethyl-4-pyridinyl, 2,6-dimethyl-4-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 and the like. The term “lower acyl” as used herein, for example, as in the 3-(acyl(lower)amino)-substituent in compounds of formula 1 (Q is acyl(lower)amino), means alkanoyl groups having from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms, and having substituents selected from hydroxyl, acetoxy, or propionoxy, including the straight-chain and branched-chain groups of which formyl, acetyl, propionyl(n-propanoyl), bupropyryl(n-butanoyl), isobutyryl(2-methyl-n-propanoyl), caproyl(n-hexanoyl), hydroxyacetyl, α-hydroxypropionyl, β-hydroxypropionyl, α-acetoxypropionyl, propionoxyacetyl, β-acetoxypropionyl, α-acetoxypropionyl, α-acetoxypropionyl, α-acetoxypropionyl, and the like are illustrative examples. The compounds having formulas I and III are useful in both free base form and acid addition salt form and both forms are within the scope of the present invention, Acid addition salts are simply a more convenient form for use, and in practice the use of the salt form virtually corresponds to the use of the free base form. Acids that may be used to prepare acid addition salts preferably include those acids that produce, when combined with the free base, pharmaceutically acceptable salts—that is, salts in which the anions are relatively harmless to the animal organism at pharmaceutical doses of the salts, so that the beneficial cardiotonic properties of the free base(s) are not marred by side effects attributable to the anions.In the practice of the present invention it is convenient to use the free base form; however, suitable pharmaceutically acceptable salts within the scope of the present invention are those derived from mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and sulfamic acid; and organic acids such as acetic acid, citric acid, lactic acid, tartaric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulphonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, quinic acid, and the like, respectively, yielding the hydrochloride, sulfate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfarrenate, and ΰ-quinate. Acid addition salts of said basic compound (I or III) are prepared by dissolving or the liquid base in aqueous / aqueous-alcoholic solution or other suitable solvents containing the appropriate acid and isolating the salt by evaporation of the solution, or by reacting the free base and the acid in an organic solvent, in which case the salt separates directly or can be obtained by concentrating the solution. While pharmaceutically acceptable salts of said basic compound (I or III) are preferred, all acid addition salts are contemplated by the present invention. All acid addition salts are useful as sources of the free base form even if the particular salt itself is desired only as an intermediate, such as when the salt is formed solely for purification or identification purposes or when it is used as an intermediate in the preparation of a pharmaceutically acceptable salt by ion-exchange processes. Other pharmaceutically acceptable salts of the said compound of formula I are those cationic salts derived from strong inorganic or organic phases, e.g. sodium hydroxide, potassium hydroxide, trimethylammonium hydroxide, to obtain the corresponding 1- or N-cationic salt, e.g. the sodium, potassium or trimethylammonium salt respectively, i.e. the cationic ion being attached to the 1- or N-position of the 2(1H)-pyridinonic ring. The molecular structures of compounds having formulas I and III have been assigned based on data obtained from infrared, nuclear magnetic resonance, and mass spectra; and by matching values ​​calculated and found in the case of elemental analysis. The method for realizing and exploiting the present invention will now be described in general terms below so as to enable a person skilled in the field of medicinal chemistry to implement and employ the invention itself. The preparation of 1-PY-2-(dimethylamino)ethenyl alkyl(lower)ketone(II) by reacting PY-methyl alkyl(lower)ketone(II) with dimethylformamido di-(lower)alkyl acetal is carried out by mixing the reactants in the presence or absence of a suitable solvent. The reaction is conveniently carried out at normal room temperature, i.e., about 20-25°C, or by heating the reactants to about 100°C, preferably in a practical solvent, suitably hexamethylphosphoramide in view of the method used to prepare PY-methyl alkyl(lower)ketone, as noted below in Example A-1. Other suitable solvents include tetrahydrofuran, dimethylformamide, acetonitrile, ether, benzene, dioxane, and the like. Furthermore, the reaction can be carried out without using any solvent, preferably using an excess of di-(lower alkyl)acephalic dimethylioramide. This procedure is further illustrated in Examples A-1 through A-17 below. Intermediates consisting of PY-methyl alkyl(lower)ketones(II) are generally known compounds which are prepared by known methods [e.g. as given in Ree. trav. chem. 72 » 522 (1953); U.S. Pat. 3,133,077(5-12-64); Bull. Soc. Chim 1968, 4132; Chem. Abstrs. 79 8539h (1973); Chem. Abstrs. 81_ , 12O.4O1a(1974) ΐ J. Org. Chem. 39 , 3834 (1974; Chem. Abstrs,87 / 6594q (1977);J. Org. Chem. 43 2286(1978)]. r The reaction of 1-ργ-2-(dimethylamino)ethenyl alkyl(lower)ketone(III) with NR^a-cyanoacetamide to produce 1-1^-1,2-dihydro-2-oxo-5-RY-6-Rnicotinonitrile (l where 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 oxide, preferably sodium methoxide or ethoxide, in dimethylformamide. In the practice of the present invention, the reaction has been carried out in dimethylformamide heated to reflux, using sodium methoxide. Alternatively, methanol and sodium methoxide or ethanol and sodium ethoxide can be used as the solvent and basic condensing agent, respectively; However, a longer heating period is required. Other basic condensing agents and solvents include sodium hydride, lithium diethylamide, lithium diisopropylamide, and the like, in an aprotic solvent, such as tetrahydrofuran, acetonitrile, ether, benzene, dioxane, and the like. This process is further illustrated below in Examples B-1 through B-21. Alternatively, the preparation of 1R^-1,2dihydro-2-oxo-5-PY-6-R,-nicotinonitrile can be carried out by heating a 1-PY-2-(RR amino)ethenyl alkyl(lower)ketone (III) in an aqueous alkaline medium, e.g., aqueous sodium or potassium hydroxide solution, to produce the corresponding alpha-PY-beta-R-beta-oxopropionaldehyde (IV) and reacting (IV) with NR^-alpha-cyanoacetamide. Alternatively, 1,2-dihydro-2-oxo-5-PY-6-R-nicolamide (1, Q is carboxylic acid and R^ is hydrogen) can be prepared directly by reacting 1-PY-2(RR amino) ethenyl alkyl(lower)ketone of formula III with malonamide. Partial hydrolysis of TR^-1,2-dihydro-2-oxo 5-PY-6-R-nicotinonitrile (I where Q is CN) to produce 1,2-Dihydro-2-oxo-5-PY-6-R-nicotinamide (I where Q is carbamate) is made by heating it (I where Q is CN) with concentrated sulfuric acid. Although the reaction is conveniently and preferably carried out by heating the reactants on a steam or oil bath to about 90-100°C, the temperature range for the reaction can be from about 70 to 120°C. This procedure is further illustrated later in Examples C-1 through C-2. C— 21, The conversion of ,2-dihydro-2-oxo-5-PY-6R-nicotinamide (I where Q is carbamyl) to 1R^-3amino-5-ΡΥ—6-R-2(1H)-pyridinone (1 where Q is amino) is accomplished by reacting said nicotinamide (I where Q is carbamyl) with a reagent capable of converting carbamyl to amino, such as an alkali metal hypohalide, lead tetraacetate, and so on. This reaction is conveniently carried out by heating an aqueous mixture containing an alkali metal hypohalide, preferably sodium hypobromite or sodium hypochlorite, and I where Q is carbamyl, then acidifying the reaction mixture preferably with an aqueous mineral acid, such as hydrochloric acid. The reaction may be carried out at a temperature between about 40°C and 100°C, preferably at a temperature between ?0°C and 100°C. This procedure is further illustrated below in Examples I>-1 through D— 21. Alternatively, 1-R -3-amino- 5-PY-6-R-2(1H)-pyridinone (I, Q is amino) can be prepared by heating 5-FY-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-PY6-R-2(1H)-pyridinone, Q is amino and Ρ Ί ​​is hydrogen^ or by first alkylating (see next paragraph) the 3-nitro-compound to afford 1-R-S-nitro-SPY-6-R-2(1H)-pyridinone and reducing the 3-nitro-compound to afford 1-R l-3-amino-5-PY-6-R-2(lH)-pyridinone (I, Q is amino and R^ is lower alkyl or lower hydroxyalkyl). Alternatively, compounds of formula I wherein R^ represents lower alkyl or lower hydroxyalkyl may be prepared by reacting the corresponding compounds of formula I unsubstituted at the 1-position where hydrogen is with a lower hydroxyalkyl or lower alkyl ester of an inorganic acid or an organic sulfonic acid, preferably in the presence of an acid acceptor. The conversion of 1-R^I,2-dihydro-2-oxo-5-PY6-P-nicotillone trile{ I, Q and G1 ) to 1P^-ò-PY-G-R2(1H)-pyridinone(1, Q is hydrogen) is effected by heating compound 1 where Q is CN as above with an aqueous mineral acid, preferably 50 / 1 sulfuric acid, with formation first of I where Q is carboxyl and then continuously heating for a longer period of time, with the result that the 3-carboxylic acid is decarboxylated to yield compound I where Q is hydrogen. This procedure is further illustrated below in examples E-1 through E-21. The reaction of 1-R5-PY-6-R-2(IH)-pyridinone (I, Q is hydrogen) with halogen to produce the corresponding 3-halo compound (I» Q is halogen) is carried out by mixing the reactants in a suitable solvent inert under the reaction conditions, a preferred solvent being acetic acid. The reaction is conveniently carried out at room temperature or by heating the reactants to temperatures up to about 100°C. Preferred halogens are bromine and chlorine. Any inert solvent may be used, such as dimethylformamide, chloroform, acetic acid, and the like. This process is further illustrated below in Examples E-1 through F-22. 4.35 The reaction of 1-R 1-3-halo-5-PY-2(1H)-pyridinone (I, Q is halogen) with an alkyl(lower)amine or a di(lower)alkyl)amine to produce the corresponding 1-1-alkyl(lower)amino)--5-PY~6_R-2(1H)-pyridinone (I, Q is alkyl(lower)amino) or Ί —R—3—-E<3i —(lower)alkyl)amino]-5-PY-2(1H)pyridinone [I, Q is di-(lower)alkyl)amino] is carried out by heating the reactants in an autoclave to about 110—180°C, preferably about 145— 165°C and preferably in a suitable solvent, e.g., water, dimethylformamide, dioxane, 1,2-cimethoxyethane, and the like, or mixtures thereof. This process is further illustrated below in Examples G-1, G-2, G-3 to G-7, G-9 and G-19, and G-21 to G-23. Another aspect of the process of the present invention for preparing 1—R^—3-[mono— or di—(lower alkyl)amino]-5-PY-6-(lower alkyl)-2(1H)pyridinone comprises the reaction of the corresponding 3-amino compound with one or two molar equivalents of a lower alkylating agent. A preferred method for the preparation of 1—R^—3—dimet:yl—amino—5—PY—6—R—2( 1 H)-pyridinone( I, Q is dimethylamino) is carried out by reacting 1-R 1-3-amino-5-PY-6-R-2(lH)-pyridin.one(l, Q is amino) SO with a mixture of Idei forms and formic acid This reaction is conveniently carried out by heating the 3-amino compound under reflux with an excess of each formaldehyde, preferably an aqueous solution, and formic acid, preferably a more than twofold molar excess of each. This procedure is further illustrated below in Examples G-3, G-8, and G-20. The acylation of 1-R^-3-amino-5-PY-6—R-2(1H)pyridinone (1, Q is amino) to produce the corresponding 3-(lower acyl)amino-compound (i, Q is lower acyl)amino) is carried out by reacting compound I where Q is amino with a lower acylating agent, e.g., a lower acyl halide, preferably chloride, a lower acyl anhydride, and the like, preferably in the presence of an acid acceptor. The acid acceptor is a basic substance, which preferably forms freely water-soluble byproducts that can be easily separated from the reaction product. Such a basic substance includes, for example, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium alkoxy(s), potassium oxides, sodium amide, and the like. The reaction is preferably carried out in the presence of a suitable solvent that is inert under the reaction conditions, for example, a solvent such as a lower alkanol, acetone, dioxane, dimethylformamide, dimethyl sulfoxide, hexamethylphosphoramide, or a mixture of solvents, such as a mixture of water and methylene dichloride or chloroform. The reaction is generally carried out at a temperature between about 10°C and about 150°C, preferably about 20-25°C. This process is further illustrated later in examples H-1 through H-17. Hydrolysis of 1-Rp1,2-dihydro-2—oxo—5-PY6-R-nicotinonitrile(I, Q is CN) to yield acid 1- R.pl,2-dihydro-2-oxo-5-PY~6~R-nicotinic acid (1,Q is carboxyl) is conveniently carried out by resecising said nicotinonitrile on a steam bath with an aqueous mineral acid, preferably 50% sulfuric acid. This procedure is further illustrated later in Examples 1-21 through 1-22. Esterification of 1-Rp1,2-dihydro-2-oxo-5-PY“6-R-nicotinic acid (1, Q is carboxyl) to produce (lower) alkyl 1-Rp1,2-dihydro-2-oxo-5-PY-6-R-nicotinate (1, Q is lower carboxyl) is carried out by heating the acid (1, Q is carboxyl) with a lower alkanol at a temperature of about 25°C to 150°C, preferably in the presence of a suitable solvent, e.g., excess lower alkanol, and in the presence of an acid catalyst, e.g., a strong inorganic acid or an organic sulfonic acid, such as hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid and the like. This process is further illustrated below in Examples J-1 through J-19. The following examples will further illustrate the present invention without however limiting it to them. A. 1—PY-2—(DIMETHYLAMINO)ETHENYL ALKYL(LOWER) KETONES A-1· 1-(4-PYRIDINIL)-2-(dimethylamino)ethenyl methyl ketone-_A mixture containing 20 g of (4-pyridinyl)methyl methyl ketone (also called 1-(4-pyridinyl)-2-propanone) and 30 ml of hexamethylphosphoramide was diluted with 65 ml of dimethylformamido dimethylacetal and the resulting mixture was heated under reflux for 30 minutes. Analysis by thin-layer chromatography (TLC) showed a single spot, thus indicating completion of the reaction (in another run the reaction appeared complete after 30 minutes at room temperature). The reaction mixture was evaporated under reduced pressure using a rotary evaporator at a pressure of approximately 15 mm, resulting in a crystalline residue weighing 24 grams. The residue was purified by continuous chromatographic extraction on alumina (approximately 150 grams) using refluxed chloroform as the eluent. After 1.5 hours, the extract was risen and evaporated under vacuum to remove the chloroform, leaving a light yellow crystalline material. 23.2 grams of 1-(4—pyridinium1)-2-(dimethylamino)ethenyl methyl ketone, also called 4-dimethylamino-2-(4-pyridinium1)-3-buten-2-one. The above preparation may be carried out using other solvents in place of hexamethylphosphoramide, for example, dimethylformamide, acetonitrile, or other solvents mentioned above, or it may be carried out in the absence of solvent; however, hexamethylphosphoramide has been used conveniently because (4-pyridinyl)methyl methyl ketone has been obtained very conveniently in the form of an asf II' ί' I mixture together with hexamethylphosphoramide, as shown by the following preparation: to a stirred solution containing 70 ml of freshly distilled diisopropylamine and 200 ml of tetrahydrofuran at 0°C under a nitrogen atmosphere, 210 ml of a 2.4 M solution of n-butyllithium in n-hexane were added dropwise over a period of 20 minutes, and the reaction mixture was stirred for about 35 minutes at about 0–5°C. To the cold solution, 90 ml of dry hexamethylphosphoramide was added dropwise over a period of 10 minutes (no change in temperature), and a resulting light yellow solution was stirred for 15 minutes. To the cold solution, which was at 0°C, a solution of 50 ml of 4-picoline in 150 ml of dry tetrahydrofuran was added over a period of 15 minutes, and stirring was continued for 30 minutes at 0°C. Then, a mixture containing 50 cc of dry ethyl acetate and 150 cc of tetrahydrofuran was added over a period of 15 minutes (the temperature was raised from 0° to about 6°C) and the resulting mixture was stirred for 20 minutes at 0°C. The ice bath was then removed and stirring continued for another 90 minutes, resulting in an increase in the temperature of the reaction mixture to about 25°C. The reaction mixture was then cooled in an ice bath and / or <i si sono aggiunti 60 cc di acido acetico nel corso un periodo circa 30 minuti. il tetraidrofurano è stato eliminato mediante distillazione usando evaporatore rotativo che operava sotto vuoto. la restante miscela stata diluita con 400 acqua e la acquosa estratta in successione 2 porzioni da 250 isopropilacetato 3 80 cloroformio. i solventi stati eliminati pressione ridotta ottenimento 137 g una miseelei consisteva principalmente del prodotto desiderato esametilfosforamide. un’altra prova le stesse quantità effettuata modo suddetto, differenza però dopo l’aggiunta glaciale solo 200 acqua, fasi state separate fase 5 100 mi l’estratto cloroformio lavato soluzione salina il chetone esametilfosforamide combina i suddetti grami della stessa mescolanza ϊ combinata distillata delle seguenti frazioni: i. 63 g.,p.e. 110-112°c. a 4 mm,; ii. 59 g. olio colore giallo pallido, p.e. 113-115°c mm.; xxi. 69 pallido,p.e. 115-118°c 2,5 mm. un esame frazione iii nmr ha mostrato essa consiste rapporto 2:3 peso (4—piridinil)-metil metil ed sali addizione acidi 1-(4-piridinil)2-(dimetil-amino)etenil vengono preparati convenientemente aggiungendo ad grammi 1-(4-piridinil)-2-(dimetil—amino)etenil metanolo acquoso l’acido appropriato, esempio metansolfonico, solforico concentrato od fosforico sino ph 2-3, raffreddando bruscamente parziale evaporazione raccogliendo sale precipitato sarà rispettivamente, esempio, dimetansolfonato, solfato o fosfato. inoltre, viene preparato agitazione, molari equivalenti ciascuno 1-(4—piridinil)-2-(dime!il— 'ί γ [ ' ί t.s'iii no) ί.·ΐ · .· j ί dell’acido lattico cloridrico, ìn preparare rispettivamente monolattato oppure monocloridrato. a-2. - 1-(4-piridinil)-2-(dimetilamino)etenil etilchetone- una contenente 87,5 (4-piridini1)metil etil chetone[detto anche 1-(4piridinil)-2-butanoneje 160 esameti1posforami— de dimetilformamido dimetil acefale risultante agitata atmosfera azoto alla temperatura ambiente normale per 45 formatosi dalla reazione vuoto materiale rimasto come residuo distillato due frazioni, bollente 45-8o°c 0,5 mm seconda 90-95°c dopo analisi cromato gitfica su strato sottile prevalentemente un'unica macchia ogni frazione, frazioni combinati? (135 g) θ riprese 600 lavata 300 l'acqua controestratta essiccata presenza sodico anidro pino ficaia cromatografia estrazione continua allumina eluente riscaldato riflusso. dando rosso cristallizzato stando riposo durata notte bagno ghiaccio. cristallino disciolto tetracloruro carbonio, aggiunto cicloesano raffreddata 64 giallo, cioè 1-(4-piridinil)-2-(dimetilamino)etenil chetone. altri 11 ottenuti dalle acque madri operando l’uso riflusso quale eluente. suddetto intermedio costituito (4-piridinil)metil ottenuto seguente; 70 diisopropi.lam.ina 0-5°c 210 2,4 n n-butil~litio n-esano poi aggiunti, nell’arco 10 minuti„ facendo seguire agitazione 15 poi,nell*arco minuti aggiunta 48 4-picolina 150 tetraidrofurano, 0°c, ghiaccio acetone raffreddante sc&ituito secco 20 75 etilpropionato par^volume tetraidrofurano. poi lasciata riscaldare 90 riscaldata 35°c successivamente nell'arco sospensione pétllido acqua. etilacetato l’estratto sottoposto controlavaggio salina. ί. eliminare 1'etilacetato ripreso nuovamente etilacetato. l’etilacetato, riscaldamento 50°c pallido. l’olio pallido dato combinato corrispondenti campioni dttenuti altre prove 256 avente punto ebollizione 85-1o5°c 0,5-1,0 lo spettro questa era p-piridinil)metil rispettivo molare 1:1,55, 35% ovvero 0,35 x ~ detto chetone, a-3. 1-{4 -piridinil)-2-(dimetilamino)etenil n-propilchetone- (4piridinil)metil n-propil 1-(4piridinil)-2-pentanone] 46 acetoni trilealla acetale vapore materiali volatili fra cui metanolo, acetonitri diluito metilacetato lavaggi combinati estratti le soluzioni combinate lavate saline, essiccate pre enza sodio anidro, filtrate fatte evaporare secchezza. mentre rimaneva congelatore. disperso cicloesano, filtrato essiccato 3o°c produrre, forma 97 1-(4-piridinil)-2-(dimetilamino) eteni1 p.f. 48-5o°c. n-propìl seguente: ad 70cc d.iisopropilamina t et raidro furano o°c(impiego ghiaccio) 2,4n n-butillitio effettuando tale e- ’30 0°c; io esametil fosforamide altri 15-20 gocce 140 arancione scuro bruno 0°c trattata 18 consistente 68 etilbutirrato tetraidrofurano; salita -8°0 +8-10°c. tolta dal ghiaccio· normaleyf>over 75 minutes. The reaction mixture was again cooled and glacial acetic acid was added dropwise over 15 to 60 cc. minutes. A pale yellow solid separated, giving a suspension. The suspension was diluted with water and extracted with two 200 cc portions of ethyl acetate. The ethyl acetate extract was washed with three 100 cc portions of brine, dried over anhydrous sodium sulfate, and evaporated in vacuo to yield 107 g of a mixture consisting essentially of (4-pyridinyl)methyl n-propyl ketone and hexamethylphosphoramide. The mixture obtained in this run was combined with corresponding mixtures obtained in two other runs and the combined mixtures were distilled under vacuum to produce, as the major fraction having a boiling point of 8O-9O°C at 0.2 mm, a mixture consisting of 80 g of (4-pyridinyl) methyl n-propyl ketone and 46 grams of hexamethylphosphoramide. By following the procedure described in Example A-2, but using an equivalent molar amount of the appropriate PY-methyl alkyl(lower)ketone (11) in place of (4-pyridinyl)methyl ethyl ketone, the possibility of obtaining the corresponding 1-PY-2(dimethylamino)ethylphenyl alkyl(lower)ketones of Examples A-4 through A-17 is contemplated. A-4» 1-(3-pyridinyl)-2-(dimethylamino)ethenyl methyl ketone using (3-pyridinyl)methyl methyl ketone. A-5. 1-(2-Pyridinyl)-2-(dimethylamino)ethenyl methyl ketone using (2-pyridinyl)methyl methyl ketone. A-6. 1-(4_pyridinyl)-2-(dimethy1amino)et eni1 isopropyl ketone using (4-pyridinyl)methyl isopropyl ketone. A-7. 1-(4-pyridinyl)-2-(dimethylamino)ethenyl n-butyl ketone using (4-pyridinyl )meth:n-butyl ketone, A-8. i-(4~pyridinyl)~2-{dimethylamino)ethenyl isobutyl ketone using (4-pyridinyl)methy1 isobutyl ketone. A-9. 1-(4-Pyridinyl)-2~(dimethylamino)etheni1 tert.butylketone using (4-pyridinyl)methyl tert.butyl ketone. A-10. 1-(4-Pyridinyl)-2-(dimethylamino)ethenyl npentylketone using (4-pyridinyl)methyl n-pentylketone. A-11· 1-(2-methyl1-4-pyridini1)-2-(dimethylamino)— ethenyl ethyl ketone using (2-methyl1-4-pyridini1) methyl ethyl ketone. A-12. 1—(5-methyl1-2-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-(dimethy1-amino) ethenyl methyl ketone using (4,6-dimethyl-2-pyridinyl)methyl methyl ketone. A-16. 1-(6-Methyl-2-pyridinyl)-2-(dimethylamino)ethenyl isopropylhetone using (6-methyl-2-pyridinyl) methyl isopropylhetone, A-17. 1-(2-pyridinyl)-2-(dimethylamino)ethenyl n-hexylketone using (2-pyridinyl)methyl n-hexylketone. B. 1—R —1,2—DIHYDRO—6—(LOWER ALKYL)2—OXO—5—py—nicotinonitriles Bl. - 1,2-Dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile, also called 1,6-dihydro-2methyl-6-oxo-[3,4'-bipyridin-S-S-carbonitrile., -To a mixture containing 23 grams of 1-(4-pyridinyl)2-(dimethylamino)ethenyl methyl ketone and 11 grams of alpha-cyanoacetamide dissolved in 400 cc of dimethylformamide was added with stirring 14 g of sodium methoxide and the resulting reaction mixture was heated in an oil bath under gentle reflux for 1 hour. Analysis by thin-layer chromatography showed no starting material in the reaction mixture which was then concentrated under vacuum in a rotary evaporator to a volume of about 80 cc. The concentrate was treated with approximately 160 cc of acetonitrile and the resulting mixture was stirred in a rotary evaporator with heating until homogeneous and then cooled* The crystalline product was collected, washed successively with triacetone and ether, and dried overnight at 55°C, yielding 28 grams of a light brown crystalline product, namely the sodium salt of 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile, the presence of CN being confirmed by infrared analysis. An 8-g portion of the said sodium salt was dissolved in 75 cc of hot water, the aqueous solution was treated with decolorizing charcoal, filtered, the filtrate was again treated with decolorizing charcoal and filtered, and the filtrate was acidified with 6N hydrochloric acid solution by dropwise addition to a pH of 3. The acidic mixture was diluted with ethanol and cooled. The crystalline product was collected dried, recrystallized from dimethylformamide-water, and dried to yield 3.75 grams of 1,2-dihydro-6-methyl2-oxo-5-(4-pyridinyl)nicotinonitrile, mp ^*300°C. Acid addition salts of 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile are conveniently prepared by adding to a mixture of 2 grams of 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile in about 40 ml of aqueous methanol the appropriate acid, e.g., methicillin-sulfonic acid, concentrated sulfuric acid, or concentrated phosphoric acid, to a pH of about 2-3, rapidly cooling the mixture after partial evaporation, and collecting the precipitated salt, e.g., dimethanesulfonate, sulfate, or phosphate, respectively. Furthermore, the acid addition salt is conveniently prepared in aqueous solution by adding to water with stirring equivalent molar amounts of each of 1,2-dihydro—6—methyl—2—oxo-5—(4—pyridinyl)nicotinonitrile and the appropriate acid, e.g., lactic acid or hydrochloric acid to prepare the monolactate or monohydrochloride, respectively, in aqueous solution. B-2. - 6-Ethyl~1,2-dihydro-2-oxo-5-PY-nicot inori trile, also called 2-ethyl-1,6-dihydro-6~oxo [3,4'-bipyridire]-5-carbonitrile, mp, >300°C., 11.6 g. was prepared following the procedure described above in Example B-1 using 20 g of 1—(4—pyridyl)—2—(dimethylamino)ethenyl ethyl ketone, 8.4 g. of alpha-cyanoacetamide, 16.2 g of sodium methoxide and 250 cc of dimethylacetamide (as solvent instead of dimethylformamide). B-3. ​​—1,2—Dihydro—2—oxo—6—n—propyl—5—(4—pyridinyl)nicotinonitrile, also called 1,6-dihydro-6oxo—2—n—propyl—[3,4 '-bipyridin|-5-carbonitril e, mp 232-234°C, 9.9 g, was prepared following the procedure described above in Example B-1 with the use of 85 g of 1-(4-pyridinyl)-2-(dimethylaminoy-ethenyl n-propyl ketone, 36.5 g of alpha-cyanoacetamido, 50 g of sodium methoxide and 800 cc of dimethylacetamide. B-4·-Ί, 2—Dihydro-1,6-dimethyl-2-oxo-5-(4-»pyridinyl)nicotinonitrile, also called 1,6-dihydro1,2-dimethyl-6-oxo-(3,4*· bipyridin)-5-carbonitrile, mp 245-248°C, 32.3 g; was prepared following the procedure described above in Example B-1 using 42.5 g of 1-(4-pyridinyl)-2(dimethylamino)ethenyl methyl ketone, 23.5 g of N-methyl-alpha-cyanoacetamide, 6.7 grams of sodium methoxide, 400 ml of methanol, and a reflux period of 2 hours. Following the procedure described in Example B-2, but using an equivalent molar amount of the appropriate 1-PY-2-(dimethylamino)ethenyl alkyl(lower)ketone(III) in place of 1-(4-pyridinyl)-2-(dimethylamino)ethenyl)ethyl-ketone and the appropriate cN-R-alpha-cyanoacetamide, the possibility of obtaining the corresponding 1-1^-1,2-dihydro-2-oxo-5-PY~6-R-nicotinonitriles of examples B-5 to Β-2Ί, B-5. 1,2-Dihydro-G-mi t yl-2-o;so-5-(3-pyridinyl)nicotinonitrile, using 1~(3-pyridini1)-2-(dimethyl amino)ethenyl methyl ketone and a-cyanoacetamide. B-6. Ί,2-hydro-6-methyl-2-oxo-5-(2-pyridinyl)nicotinonitrile, using 1-(2-pyridinyl)-2-(dimethylamino)ethenyl methyl ketone and α-cyanoacetamide. B-7· 1 » 2-Dihydro-6-isopropyl-2-oxo-5-(4-pyridinyl)nicotinotrile, using 1-(4-pyridinyl)-2-(dimethylamino)ethenyl isopropyl ketone and a-cyanoacetamide. B-8* 6-n-Butyl-1 12-dihydro-2-oxo-5-(4-pyridinyl) nicotinonitrile, using 1-(4-pyridinyl)-2-(dimethylamino)ethenyl n-butylketone and a-cyanoacetamide. B-9 · 1,2-Di idLco-6-isobuti 1-2-oxo-5-(4-pyridinyl )nicotinonitrile, using 1-(4-pyridinyl)-2-(dimethyl-amino)ethenyl isobutyl ketone and a-cyanoacetamide, B-10. 1 t2-Dihydro-2-oxo-5-(4-pyridinyl)-6-tert.butylnicotinonitrile, us andò 1-(4-pyridinyl)-2(dimethylamino)ethenyl tert.butylketone or α-cyanoacetamide. B-1 1· 1 » 2-Dihyd.ro-2-oxo-6-n-pentyl-5-(4-pyridinyl)nicotinonitrile, using 1-(4-pyridinyl)-2(dimethyl-amino)ethenyl n-pentylketone and a-cyanoacetamide. Β-1 2. 6-Ethy.1—1,2-dihydro-5~(2-methyl-4-pyridinyl)2- ox ο nicoti η ο ni tri 1 e, us went 1 - ( 2-methyl-4-pyr idinyl ) - 2-(dimethylamino)ethenyl ethyl ketone and α-cyanoacetamido. B— 13. 1,2-Dihydro-6-metyl1-5-(5-methy1-2-pyridinyl)2-oxonicotlnonitrile, using 1-(5-methyl-2-pyridinyl)2-(dimethylamino)ethenyl methylketone and a-cyanoacetamide. B-14· 6-Ethyl-1-5-(5-ethyl-2-pyridinyl)-1,2-dihydro2-oxoneheptinonitrile, using 1-(5-ethyl-2-pyridinyl)2-(dimethylamino)ethenyl ethyl ketone and α-cyanoacetamide. B-15 · Ethyl-1,2-dihydro-2-oxo~5-(3-pyridinyl) nicotinonitrile, using 1-(3-pyridinyl)-2-dimethclamino) ethenyl. ethyl ketone and a-cyanoacetamide. B-16 1,2-Dihydro-5-(4,6-dimethyl)2-pyridinyl)-6methyl 1-2-oxonicotinoni.tri 1 e, using 1-(4,6-dimethyl2-pyridinyl)-2-(dimethylamino)ethenyl methyl ketone and α-cyano-acetamide. B-17· 1 » 2-Pyhydro-6-isopropy1-5-(6-methyl1-2-pyridinyl)-2-oxo-nicotinonitrile, using 1-(6-methyl-2pyridinyl)-2-(dimethylamino)ethenyl isopropyl ketone and a-cyanoacetamide. B-18· -1.2-Dii.dro~Gn-hexyl-2-oxo-5-(2-Pyridimi)ni cot inones tri le.using 1-(2-pyri dini1)-2-(dimethy1amino)ethenyl n-hexylketone and a-cyanoacetamide r B-1 . C—Ethyl—1,2-dihydro-Ί(2-hydroxyethyl)-2o ss o- 5- ( 4-pyr i. dini 1 ) nicoti non it: ri 1 ef using 1-'^-pyridini 1)-2-(dimethylamino)etenyl 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 methylhexane and N-ethyl-α-acetamide. B-21. 1,6-PethylI-1,2-dihydro~2-oxo-5-C4~pyridini1)nicotinonitrile, using l-(4-pyridinyl)-2-(dimethylamino)etenyl ethyl ketone and N-ethyl-a-cyanoacetamide. C. 1_R -1,2—DIIDR0—6—(INTERNAL ALKYL)-2-0SSO— 5- (PYRIDINIL)NICOTINAMIDES C,-1. 1,2-Dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinamide, also called 1,2-dihydro-2-methyl-6-oxo[3,4'-bipyridinyl]-5-carboxamide.- A mixture containing 9.0 grams of 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile and 45 ml of concentrated sulfuric acid was heated to 100°C for minutes using an oil bath. The hot reaction mixture was added to 200 ml of ice, and the resulting mixture was cooled in an ice / acetone bath. Approximately 150 ml of 28% ammonium hydroxide was carefully added dropwise to the cold solution. The resulting mixture containing a precipitate was cooled in an ice / acetone bath for approximately 30 minutes. The precipitate was then collected, washed successively with water and acetonitrile, dried thoroughly, and recrystallized by dissolving it in 130 ml of hot (boiling) water, adding 30 ml of acetic acid, treating with decolorizing charcoal, and filtering. The filtrate was concentrated and diluted with acetonitrile; the mixture was kept on ice for about 30 minutes. The resulting crystalline material was collected, yielding 8.35 g of reddish-brown crystalline material. This material was combined with the same material obtained from another run, and the combined 13.5 g were dissolved in 500 ml of dimethylformamide at its boiling point; the hot mixture was filtered, and the filtrate was cooled in an ice bath. The crystalline precipitate was collected, washed with acetone and dried for 14 hours at 100°C over P„0 c 2 5 and by infrared analysis and nuclear magnetic resonance analysis was found to still contain dimethylformamide. F ' ί ί The 10.5 grams of yellow-brown crystalline product were dissolved in 75 cc of hot acetic acid, treated with 50 cc of water, and then diluted to a volume of 300 ml with acetone. The resulting crystalline mixture was cooled in an ice bath for approximately 45 minutes. The resulting light reddish-brown crystalline product was collected and dried, first at 55°C and then at 110°C to remove the last faint odor of acetic acid, to yield 9.2 grams of 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinil-1)nicotinamide, mp >300°C. Acid addition salts of 1,2-dihydro-6-methyl-1-2-oxo-5-(4-pyridinyl)nicotinamide are conveniently prepared by adding 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, e.g. methanesulfonic acid, concentrated sulfuric acid or concentrated phosphoric acid, to a pH of about 2-3, cooling the mixture sharply after partial evaporation and collecting the precipitated salt, e.g. dimethanesulfonate, sulfate or phosphate, respectively. Furthermore, the acid addition salt is conveniently prepared in aqueous solution by adding to water, with stirring, equivalent molar amounts of each of 1,2-dihydro-6-methyl-2-oxo-5-(4pyridinyl)nicotinamide and the appropriate acid, e.g., lactic acid or hydrochloric acid, to prepare the monolactate or monohydrochloride in aqueous solution, respectively. C—2,— 6—Ethyl-1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinonitrile, also called 1,6-dihydro-2-ethyl-6-oxo[3,4'-bipyridinyl]-5-carboxamide~ A 40 g portion of 6-ethyl-1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinonitrile was added to 170 ml of concentrated sulfuric acid and the temperature was then raised to about 70°C. This reaction mixture was immersed in an oil bath preheated to about 90°C and then held at a temperature between 95°C and 105°C for about 40 minutes. The hot reaction mixture was then poured into a beaker containing 800 ml of ice. The mixture was stirred and then placed in an ice / acetone bath. 650 cc of 28% ammonium hydroxide was added dropwise to the cold mixture while stirring; the temperature then rose to approximately 46°C. Approximately 300 cc of ice was added while stirring, and stirring was continued for approximately 15 minutes.The pref [' f precipitate was collected, washed with three 150 cc portions of water, air dried for 2 hours, clarified with acetonitrile, filtered and the solid dried for several days at 55°C to yield 39.5 g of product. The solid was stirred well with 300 ml of water, filtered, and dried to yield 38 g of a crystalline product consisting of 6-ethyl-1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinamide. A 14.3 g portion of this product was further purified by dissolving it in 40 ml of hot acetic acid, filtering the hot solution, and diluting the filtrate to 180 ml with absolute ethanol, which formed crystals. The hot mixture was allowed to cool. The light reddish brown crystalline product was collected and dried at 110°C on P 2°5 P 61' for about 15 hours to obtain 11.7 g of 6-ethyl-1,2-dihydro2-oxo-5-(4-pyridinyl)nicotinamide, mp )>300°C. C~3. 1,2-Dihydro-2-oxo-6-n-propyl-5-(4-pyridinyl)nicotinamide, also called 1,6-dihydro-6-oxo2-η-ρΓθρί1-[3,4*-1φίΓί<3ίηϋ]-5-εβτόθ55&>ηίά6, mp >300°C, 10.5 g., was prepared following the procedure described in example C—2 using 30.7 g of 1,2—dihydro—2—oxo—6—n—propyl—5—(4—pyri— (Dinyl)nicotinonitrile and 130 cc of concentrated sulfuric acid. By following the procedure described in Example C-2, but employing an equivalent molar amount of the appropriate 1-R 1-1,2-dihydro-2-oxo-5-PY-6-R-nicotinonitrile (where 0 is CN) in place of 6-ethyl-1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinonitrile, the possibility of obtaining the corresponding 1,2-dihydro-2-oxo-5-PY-6-R-nicotinamides of Examples C-4 through C-21 is contemplated. C-4. 1,2-Dihydro-6-methyl-2-oxo-5-(3-pyridinel)~ nicoti —inamide. C-5. 1,2-Dihydro-6-methyl-2-oxo-5-(2-pyridxnyl)nicotinamide. C-6. 1 r2-Dihydro~6-isopropyl-2-oxo-5-(4-pyridinyl) nicotinamide. C-7. 6-n-Butyl-1,2-dihydro-2-oxo-5-(4-pyridinilini cotinamide. C-8. 1,2-Dihydro-G-isobuty1-2-oxo-5-C4-pyridinyl) nicotinamide. C-9. 1,2-Dihydro-2-oxo-5-(4-pyridinyl)-6-tert. butynicotinamide. C—10. 1, 2-i>ihydro-2-o xo-6-η-ρ ent yl-5-(4-pyridines 1 ) nicotinamide. C-11. 6-Ethyl—1,2-dihydro-5-(2-methyl—4—pyridinyl)— I, » 2-osscni.cot inamido » C-1 2. 1,2-Dihydro-6-methy1-5-(5-methyl-2-pyridinyl)2—oxonicotinamide, C—13. 6-Ethyl-5-(5-ethyl-2-pyridinyl)-1,2-dihydro2-oxonicotinamide, C-14. 6-Ethyl-1,2-d.ihydro-5-(3-pyridinyl)-2-oxonicotinamide. C-15. 1,2-Dihydro-6-methyl-5-(4,6-dimethyl-2-pyridinyl)-2-oxonicotinamide, C-16. 1,2-Dihydro-6-isopropyl-5-(6-methyl-2-pyridinyl)2-os sonicoti nami de. C-17. 1,2-Dihydro-6-n-hexyl-2-o5so~5-(2-pyridinyl) nicotinamide. C-18. 1,2-Dihydro-1,6-dimeti l-2-o sso- 5-(4-pyr idylls l)i*i cot inamide. C-19. 6-Ethyl-1,2-thiohydro-1-(2-hydroxyethyl)-2-oxo5-(4-pyridini1)nicotinamide. C-20. 1—Ethyl—1,2-dihydro-6-jnetyl-2-oxo-5-(4pyridinyl)nicotinamide. C—21. 1,6-Diethyl-1,2-dihydro~2-oxo-5-(4-pyridinyl) nicotinamide. D. 1-R -3-AMINO-6-(LOWER ALKYL)-5-PY-2(1H) PIR IDI NONI D-1· 3-Amino-6-methyl-5-(4-pyridinol)-2-(1H)pyridinone, also called 5-amino-2-methyl-[ 3 ,,4 A tf l! f bipyridinyl]-6(1H)-onc-To a solution containing 13 g of sodium hydroxide in 250 cc of water, 12 g of 1,2-dihydro~6-methyl-2-c <sso5-(4-piridinil)nicotinamide e la risultante miscela è stata riscaldata su bagno di vapore per provocare la dissoluzione. Alla soluzione di sono aggiunti altri 250 cc di acqua e la risultante soluzione è stata raffreddata sino a circa 35°C con agitazione ed in seguito a ciò si sono seprati alcuni cristalli. The mixture was cooled rapidly in an ice bath and a total of 4.0 cc of bromine was added dropwise, resulting in dissolution after approximately 3 cc of the bromine had been added. The mixture was stirred for an additional 10 minutes while cold and then heated on a steam bath for 45 minutes. The reaction mixture was then concentrated to approximately half its volume, cooled in an ice bath, and treated with 6 N hydrochloric acid until the pH was approximately 8. The resulting crystalline product was collected, washed twice with water and once with acetone, and dried to yield 7.3 g of material. The 7.3 g was treated with 20 cc of water, and the insoluble amorphous material was filtered off. Ί ί i 3 ΐ i' ; ο ion / was concentrated to dryness. and the remaining crystalline material was recrystallized from dimethylformamide-aqueous solution to yield 3.8 g of 3-amino-6-methyl-5-(4-pyridinyl)-2(1H)pyridinone, mp >300°C. Acid addition salts of 3-amino-6-methyl-5-(4-pyridinyl)-2(1H)-pyridinone are conveniently prepared by adding to a mixture of 2 g of 3-amino-6-methyl-1-5-(4-pyridinyl)-2(1H)pyridinone in about 40 ml of aqueous methanol the appropriate acid, e.g. methanesulfonic acid, concentrated sulfuric acid or concentrated phosphoric acid, to a pH of about 2-3, rapidly cooling the mixture after partial evaporation and collecting the pre-copilated salt which is, e.g., dimethanesulfonate, sulfate or phosphate respectively. Furthermore, the acid addition salt is conveniently prepared in aqueous solution by adding to water, with stirring, equine molar amounts of each 3-amino-6-methyl-5-(4-pyridinyl)2-(1H)-pyridinone and the appropriate acid, e.g., lactic acid or hydrochloric acid to prepare the monolactate or monohydrochloride, respectively, in aqueous solution. D—2. 3-Amino-6~ethyl-5-(4-pyridinyl)-2(lH)ί,: ridin]-6(1H)-one, mp >300°C, 8.8 g was prepared following the procedure described in Example D-1 but using 10.0 g of 6-ethyl1-1,2-dihydro-2-oxo5-(4-pyridino,l)nicotinamide, 8.8 g of sodium hydroxide, 300 cc of water, 3.0 cc of bromine, and re-crystallizing from dimethylformamide-isopropyl alcohol. D-3. 3-Amino-6-n-propy1-5-(4-pyridini1)-2(1H)-pyridinone, also called 5-amino-2-n-propyl-[3,4*bipyridin]-6(1H)-one- To a stirred mixture containing 8.5 g of 1,2-dihydro-2-oxo-6-n-propyl-5(4-pridinyl)nicotinamide and 95 cc of water at room temperature was added a solution of 1.32 g of sodium hydroxide in 6 cc of water. The resulting dispersion was cooled in an ice bath, stirred for 10 minutes, and then treated by adding 22 cc of a 43.1% aqueous solution of sodium hypochlorite dropwise over a period of 3 minutes. Dissolution occurred and stirring was continued without cooling for 30 minutes. 27 ec of solution was added to the resulting solution at 15°C.35% aqueous sodium hydroxide; the reaction mixture was heated on a steam bath at about 60-70°C for 1 hour; and the hot solution was slowly treated with 14 ml of glacial acetic acid over a period of 5 minutes, after which a reddish brown precipitate separated. The mixture was stirred for 5 minutes; the precipitate was collected, washed with hot water, and dried over P„0 c. The resulting 12 g of product was recrystallized from dimethylformamide (100 cc)-water (80 cc), and the product was dried overnight at 95°C over PO to yield 9.5 g of 3-amino-Sn-propyl-5-(4-pyridini3)-2(1H)-pyridinone, mp 200-202°C. By following the procedure described in Example D-1, but using an equivalent molar amount of the appropriate 1-R 1-1,2-dihydro-2-oxo-5-PY6-R-nicotinamide(I, where O is carbamyl) in place of 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinamide, the possibility of obtaining the corresponding 1-3-amino-5-PY-6-R-2-(IH) pyridinones of Examples D-4 to D-21 is contemplated. D-4. 3-amino-6-me t i1-5-(3-pyri di ni 1)-2-(1H)pyridinone. D-5. 3-Amino-6-methyl-5-(2-pyridinyl)-2(1H)pyridinone. D-6· 3-Amino-5—- i sopropi1-5-(4-pyridinyl)-2(IH)-pyridinone. D-r7. 3-Amino-6-n-buty3-5-(4-pyridinyl)-2(1H)-pyrιό i none. D-8, 3-Amino-6-isobutyl-5-(4-pyridini1)-2(1H)-pyridinone. D-9. 3-Amino-6-tert.-butyl-5-(4-pyridinyl)-2(1H)pyridinone. D-10. 3-Amino-6-n-pentyl1-5-(4-pyridinyl)-2(1H)-pyridinone. D-11. 3-Amino-6-ethyl-5-(2-methy1-4—pyri dini1)-2(1H)pyridinone. D-12, 3-Amino-6-Tnetyl-5-( 5-methyl-2-pyridinyl)-2(lH)pyridinone. D-13. 3-Amino-6-ethyl-5-( 5-et i1-2-pyridin1)-2(IH)-pyridinone. D-14. 3-Amino-6-ethy1-5-(3-iridini1)-2(1H)iridinone. D-15. 3-Amino-6-methyl-5-(4,6-dimethyl-2-pyridiral)-2(1H)pyridinone, D-16. 3-Amino-6-i sopropy 1-5-(6-methyl 1-2-pyrxdin.yl)-2(1H)pyridinone. D-17* 3-Amino-6-n-acyl-5-(2-pyridinyl)-2(IH)-pyridinone. D-18. 3-Amino-1,6-dimethyl-5-(4-pyridinyl)~2(lH)pyridinone. D-19. 3-Amino-6-ethy1-1-(2-hydrossiethy1)-5-(4-piD-20. 3-Amino-l-ethyl-6-methyl-5-(4~pyridine1)-2(1H)pyridinone. D-21. 3-Amino-1,6-diet1-5-(4-pyridine1)-2(1 Spiridinone. E. 1-Γ< Ί -6- ('XLCHU, INF ITI OR E )~5~PY-2(1H)-FIRIDI~ NONI E-1. 6-Metxl-5-(4-pyridinil)-2(1H)-pyridinone also called 2-methyl-[3,4'-bipiridxn. ]-6(1H)-one A mixture of 5.3 g of 1,2-dihydro-6-methyl-2-oxo5-(4-pxridxnyl)nicotinonxtrile and 30 ml of 85% sulfuric acid was heated to about 195°C, then heated under blind reflux for 24 hours, cooled, and added to ice. The aqueous mixture was adjusted to a pH of 8 by the addition of concentrated aqueous sodium hydroxide solution. The resulting precipitate (product plus Na2SO4) was treated with chloroform, and the chloroform solution was filtered. The filtrate was concentrated under vacuum to remove chloroform and the resulting crystalline residue was crystallized from methylene dichloride ether and dried at 75°C for 4 hours to yield 4.1 grams of 6-methyl-5(4-pyridinyl)-2(1H)-pyridinone, mp 287-288°C. Acid addition salts of 6-methoxy-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, e.g. methanesulfonic acid, concentrated sulfuric acid or concentrated phosphoric acid, to a pH of about 2-3, cooling the mixture sharply after partial evaporation and collecting the precipitated salt, e.g. dimethanesulfonate, sulfate or phosphate, respectively. Furthermore, the acid addition salt is conveniently prepared in aqueous solution by adding to water with stirring equivalent molar amounts of each of 6-methyl-5(4-pyridinyl)-2(1H)-pyridinone and the appropriate acid, e.g. lactic acid or hydrochloric acid, to prepare the monolactate or monohydrochloride in aqueous solution, respectively. E-2. 6-Ethyl-5-(4-pyridinyl)-2(1H)-pyridinone, also called 2-ethyl-[3,4'-bipindin]-6(1H)-one- A mixture containing 9 g of 6-ethyl-1,2-dihydro-2-oxo5-(4-pyridinyl)nicotinonitrile and 50 ml of concentrated sulfuric acid was heated with stirring at 200°C for 24 hours, cooled to about 40°C and was sharply cooled in 200 ml of ice water. After the aqueous solution had now been alkaline with concentrated ammonium hydroxide, the separated solid was collected, recrystallized from isopropyl alcohol (70 µl) and dried at 60°C under vacuum to give 3 g of 6-Ethyl-5-(4-pyridinyl)-2(1H)-pyridinone, mp. 226-228°C. A second yield of 0.4 g, mp. 225-227°C, was obtained by concentrating the filtrate to about 20 ml. E-3. 6-n-Fropyl~5~(4-pyridinyl)-2(1H)-pyridinone, also called 2-(n-propyl-[3,4*-bipyridinum]-6(1H)-one, mp 179-180°C., 3.4 g., was obtained following the procedure described in Example E-2, but using 10 g of 1,2-dihydro-6-n-propyl-2-oxo-5-(4-pyridinyl)nicotinonitrile, 42.5 cc of 85% sulfuric acid and recrystallizing from methyl ether dichloride. Following the procedure described in Example E-2, but using instead of 6-ethyl-1,2-dihydro2-oxo-5-(4-pyridinyl)nicotinonitrile an equivalent molar quantity of the corresponding 1-1^--1,2-dihydro2-oxo-5-PY-6-(lower alkyl)nicotinonitrile the possibility of obtaining the 1-R.j5-PY-6~(lower alkyl)-2(1H)-pyridinones of examples E-4 to E-21 is contemplated. E-4. 6-Methyl-5-(3-pyridinyl)-2(1H)-pyridinone. E-5. 6-Isopropyl~5-(4-pyridinyl)-2(lH)-pyridinone. E-6. 6-n-Butyl 5-(4-pyridinyl)-2(1H)-pyridinone. Ε-7. 6-Isobuti1-5-(4-pyridines 1)-2( 1H)--pyridinone. ES. 5-(4-Piridini 1 )-6-terz,butyl-2( 1H)-pyridinone. E-9. 6-n-Pentyl-5-(4-pyridinil)-2(1H)~piridinone. E—10. 6-Etil-5-(2-metil-4~pyridinil)-2(1H)pyridinone, E—11. 6-Etil-5-(3-pyridinil)-2(lH)-pyridinone. E-12, 1,6-Dimethyl-5-(4-pyridinyl)-2(1H)-pyridinone. E-13. 6—Etyl—1(2-idrossietil)—5-(4—piridinil) 2(IH)-piridinone. E-14. 1-Etil-6-metil-5(4-pyridinil)-2(lH)piridinone. Ε-Ί 5. 1,6-Dietil-5-(4-piridinyl)-2(1H)-piridinone. E-16. 6-Meti1-5-(2-pyridinyl)-2(1H)-p:iridinone. E-17. 6-Methyl-5-(5-methyl-2-pyridinyl)-2(1H)pyridinone. E-18. 6—Etyl- 5^5-etil-2-piiidinil)-2( 1H)— pyridinone, E-19. 6-Meti1-5-(4,6-dimethyl-2-pyridinyl)2(1H)-pyridinone. E-20. 6-1sopropi1-5-(6-meti1-2-pyridinyl)-2(1H)pyridinone. E-21. 6-n-Esil—5-(2-pyridinil)-2(lH)~pyridinone. F. lR -3-AlogenO-6-(ALCHIL INFERIORE')~5-PY-2 ( 1H)FIRIDINONI . F-1· 3-Bromo-6-methyl-1-5-(4-pyridinyl)-2(1H)-_ pyridinone, also called 5-bromo-2-methyl-13,4'bipyridinone-6(1H)-one- To a stirred solution of 80 g of 6-methyl-5-(4-pyridinyl)-2(1H)-pyridinone in one liter of acetic acid heated to 65°C, 69 g of bromine in 50 cc of acetic acid were added dropwise over a period of 25 minutes. The reaction mixture was stirred for another 30 minutes, cooled to room temperature, and filtered to collect the crystalline precipitate. The precipitate was dried and suspended in 1500 ml of water. 25 ml of 28% ammonium hydroxide was added dropwise to the vigorously stirred suspension, after which a white creamy precipitate separated. The solid was collected and dried under vacuum at 90°C to obtain 101 grams of 3-bromo-6-methy1-5-(4—pyridini1)-2(1H)-pyridinone, A 15-gram sample was dissolved in 200 ml of hot acetic acid and filtered. The filtrate was concentrated under vacuum, diluted with methanol, and the resulting white crystalline precipitate was collected and dried at 100°C for 16 hours under vacuum, yielding 9.8 grams of the product, mp 252-254°C. Acid addition salts of 3-bromo-6-methyl-5-(4-pyridinyl)-2(1H)-pyridinone are conveniently prepared by adding to a mixture of 5 grams of 3-bromo-6-methyl-5-(4-pyridinyl)-2(1H)-pyridinone in about 100 ml of aqueous methanol, the appropriate acid, e.g., methanesulfonic acid, concentrated sulfuric acid, or concentrated phosphoric acid, to a pH of about 2-3, cooling the mixture sharply after partial evaporation, and collecting the precipitated salt, e.g., dimethanesulfonate, sulfate, or phosphate, respectively. Furthermore, the acid addition salt is conveniently prepared in aqueous solution by adding to water with stirring equivalent molar amounts of each of 3-bromo-6-methyl-5-(4-pyridinyl)-2(1H)-pyridinone and the appropriate acid, e.g., lactic acid. or hydrochloric acid, to prepare monolactate or monohydrochloride in aqueous solution respectively. Γ F-2. 3-Chloro-G-methyl-5-(4-pyridinium 1)-2(1H)pyridinone, also called 5-chloro-2-methyl-[3,4'-bipyridinium-6(1H)-one - A mixture containing 18.6 g of 6-methyl-5-(4-pyridinyl)-2(1H)-pyridinone and 200 ml of acetic acid is heated on a steam bath and treated by bubbling chlorine through it for 4 hours. After allowing the reaction mixture to cool to normal room temperature, the solid is collected, washed with ether and dried. The solid is dissolved in water, the aqueous solution is neutralized with 2N aqueous potassium hydroxide, and the mixture is cooled. The separated solid is collected, washed with water, dried, and recrystallized from ethanol to yield 3-chloro-6-raethyl"5{4-pyridinyl)-2(1H)pyridinone. Following the procedure described in example F-1 or F-2, but using instead of 6-methyl~5-(4~ pyridinyl)-2(1H)-pyridinone an equivalent molar quantity of the corresponding 1-R^-6-(lower alkyl)5-PY-2(1h)-pyridinone and bromine or chlorine, the possibility of obtaining 1-R -3-bromo-(or chlorine) is contemplated. 6-(lower alkyl)-5-PY-2(1H)-pyridinones of examples F-3 through F-22. F-3. 3-Chloro-6-ethyl-5-*(4-pyridinyl)-2( 1]l)-piII! I' ! GIC υ iì t Vi: Ϊ it ridinone. F-4. 3_chloro-6-methy1-5"(3-pyridinyl)-2(1H)-pyridinone. F-5. 3-Chloro-6-n-propy1-5-(4-pyridinyl)-2(IH)pyridinone. F-6· 3-Bromo-6-isopropy1-5-(4—pyridinyl)-2(QH)pyridinone. F-7. 3-Bromo-6-n-butyl-5-(4-pyridini1)-2(1H)pyridinone. F-8. 3-Chloro-6-isobutyl-5-(4-pyridinyl)-2(1H)pyridinone. F-9 3-Bromo-5-(4—pyr ì dini1)-6-tert »-but 1-2(1H)pyridinone. F—10. 3-C 1orο-6-η-ρenti1-5-(4-pyri d ini1)—2(1H)— pyridinone. F-11· 3-Bromo-6-eti1-5-(2-methyl-4-pyridinyl)2(1H)-pyridinone. F-12, 3-Cloro-6-eti1-5-(3-pyridinyl)-2(1H)-pyridinone. F-13. 3-Cloro-1,6-dimethyl-5^4-pyridinyl)-2(1H)-pyri dinone, F-14. 3-Cloro-6-eti1-1-(2-i drossieti1)-5-(4pyridini1)-2(1H)-piri dinone. F-15. 3-Cloro-6-methyl-5-(4-pyridinyl)-2(lH)-pyridinone F-16. 3—Bormo-1 >6-diethyl-5-(4-pyridinyl)~2(lH)pyridinone. F-17. 3-Bromo-6-methyl-5(2-pyridinyl)-2( 1H)~pyridinone. F—18. 3-Bromo-6-methyl-5~(5-methyl-2-pyridinyl)2(1H)-pyrid inone· F-19. 3-Bromo-6-eti1-5-(5~ethyl-2-pyridinìl)-2{1H)pyridinone. F—20. 3-Cloro-6-methyl-5-(4,6-dimethyl-2-pyridinyl)2(1H)-pxridinone. F-21. 3-Bromo-6-isopropi1-5-(6-methyl-2-pyridinyl)2(1H)-pyridinone. F-22. 3-Clorο-6-n-esii-5-(2-pirxd ini1)-2(1H)-pir idinone. G. 1—R3-[MONO—0 DI(ALCHIL INFERIORE)AMINOj-5PY—6—(ALCHIL INFERIORE)—2{1H)—PYRIDINONI» G—1. 6-Methyl-3-methoxylamino-5-(4-pyridinyl)-2(1H)pyridinone, also called 2-methyl-5-methoxylamino-[3,4-bipyridino]-6-0H)-one- A mixture containing 19 grams of 3-bromo-6-methyl-5-(4-pyridinyl)-2(1H)pyridinone, 250 cc of 70% aqueous methylamine, 100 mg of copper bronze, and 60 mg of cupric sulfate was autoclaved at 160°C for 48 hours. The crystalline mass was taken up with hot aqueous methanol and the mixture was was filtered to collect the product. The solid (6 grams) plus another portion (1 gram) obtained by concentrating the mother liquors and diluting with methanol was dissolved in a small amount of acetic acid, filtered, and the filtrate was diluted with water. The resulting crystalline precipitate was collected, washed thoroughly with water, and dried at 90°C overnight to yield 5.1 grams of 6-methyl-3-methylamino-5(4-pyridinyl)-2(1H)-pyridinone, mp 270-275°C with decomposition. This preparation was also carried out in the above manner using an equivalent molar amount of 3-chloro-6-methyl-1-5-(4-pyridinyl)-2(1H)pyridinone in place of 3-bromo-6-methyl-5-(4-pyridinyl)2(1H)-pyridinone. Acid addition salts of 6-methyl-3-methylamino-5-(4-pyridinyl)-2(1H)-pyridinone are conveniently prepared by adding to a mixture of 5 grams of 6-methyl-1-3-methylamino-5-(4-pyridinyl)-2(1H)pyridinone in about 100 ml of aqueous methanol the appropriate acid, e.g., methanesulfonic acid, concentrated sulfuric acid, or concentrated phosphoric acid, to a pH of about 2-3, cooling the mixture sharply after partial evaporation, and collecting the precipitated salt, e.g., dimethanesulfonate, sulfate, or phosphate, respectively. Furthermore, the acid addition salt is conveniently prepared in aqueous solution by adding to water with stirring equivalent molar amounts of each of 6-methyl-3-methylamino-5-(4-pyridinyl)2(1H)-pyridinone and the appropriate acid, e.g. lactic acid or hydrochloric acid to prepare the monolactate or monohydrochloride respectively in aqueous solution, G—2· 3-Ethylamino-6-methyl-5-(4-pyridinyl)-2(1H)pyridinone, also called 5-ethylamino-2-methyl-[3,4*bipyridinone]-6(1H)-one, mp 250°C., 1.6 g was prepared following the procedure described in example G-1, but using 16.5 g of 3-bromo-6-methyl-5-(4-pyridinyl)-2(1H)-pyridinone, 110 cc of ethylamine, 15 cc of water, 30 milligrams of copper bronze, milligrams of cupric sulfate, treating in an autoclave at 150°C for 45 hours and recrystallizing twice from acetonitrile. G-3. 6-Methyl-3-(dimethylamino)-5-(4-pyridinyl)2(1H)-pyridinone, also called 5-(dimethyl-amino)-2methyl-[3,4*-bipyridinone]-6(1H)-one- To a stirred solution containing 20 g of 3-amino-6-methyl-5~(4-pyridinyl)-2(1H)-pyridinone dissolved in 200 cc of formic acid, 20 cc of a 37% formaldehyde solution were added dropwise with stirring and at 1 eb over a period of 5 minutes. The reaction mixture was heated to reflux for 1 hour and 45 minutes, heated under vacuum to dryness, and the residue was dissolved in methylene dichloride. The methylene dichloride solution was washed with saturated aqueous sodium bicarbonate solution and filtered. The filtrate was dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation, yielding 14 grams of a yellow crystalline solid. The solid was dissolved in 250 ml of hot methylene dichloride.The hot solution was treated with bleaching charcoal and filtered, and the filtrate was concentrated under vacuum to dryness and then treated with acetonitrile. The resulting mixture of crystalline material and acetonitrile was cooled, and the solid was collected and dried, yielding 10.5 g of a yellow crystalline product containing a trace impurity (indicated by thin-layer chromatography). The solid was dissolved in chloroform solution, and the trace impurity was removed by filtering the chloroform solution through an ί gel column. 2.5 inch (6.35 cm) silica. The resulting product (10.5 grams) was dissolved in dimethylene dichloride, the solution was diluted with isopropyl alcohol and concentrated under vacuum and then cooled rapidly. The precipitate was collected and dried at 80°C to yield 9.0 grams of 6-methyl-1-3-(dimethylamino)5-(4-pyridinyl)-2(1H)-pyridinone, mp 223-225°C. By following the procedure described in Examples G-1 and G-2, but using in place of 3-bromo-6-methyl-5-(4-pyridinyl)-2(1H)-pyridinone an equivalent molar amount of the appropriate 1R^-3-bromo(or chloro)-5-PY-6-(lower alkyl)-2(1H)-pyridinone and the appropriate lower alkylamine or di(lower alkyl)amine, the possibility of obtaining the 1R^-Cmono- or di-(lower alkyl)amino3-5-PY-6-(lower alkyl)-2(1H)-pyridinones of Examples G-4 through G-23 is contemplated. G—4. 6-Ethy1-3-methy1 amino-5-(4-pyri dini1)-2(1H)pyri dini none;. G-5. 3-Methylamino-6-methy1-5-(3-pyridinyl)-2(1H)-pyridinone. G-6. 3-n-Propi1amino-6-n-prop i1-5-(4-pyr i dini1 ) 2(IH)-pyridinone. G-7. 3-Metilamino-6-isopropil-5-(4~piridinil)G-β. 6-n-Butyl-3-dimetilamino-5-(4-piridinil)2(1H)-piridinone» G-9. 3-n-Bxiti lamino-6-i sobuti1-5-(4-pyridinyl)2(1H)-piri dinone. G—10» 3-Metilami.no~ 5-(4-piridinil )-6-t_era.butil-2(1H)-piridinone. G-11 3-Isopropyl-amino-6-n~pentyl-5-(4-piridini1)-2(1H)-pyridinone, GE. 6-Etil—3—dietylamino-5-(2—metil-4—pi ridinil) 2-( m)-piri dinone. G-13. 6-Etyl-3-ethylamino~5~(3-pyridinyl)--2(lH)— pyridinone. G-14. 3-Methylamino-1′6-dimeti1-5-(4-pyridinyl)2(1H)-pyridinone. G-15 6-Ethyl-3-ethylamino-1-(2-idros3Ìetil)-5(4-piridini1)-2(1H)-piridinone. G-16. 1-Etyl-6-methyl-3-methylamino-5-(4—pyridinyl) 2 ( m)—pyridinone. G-17. 1,6-Dietll~3-methylamino-5-(4~pyridinyl)2(1H)—pyridinone. G-18. 3-n-Esylamino—6-meti1-5-(2-pyridinyl)— 2(1H)-pyridinone G-19. 3-Etilamino-6-metil-5-(5-metil-2-pyridinil) 2(1H)-pyridinone. G-20. 6-Etyl-5-(5-etil-2-piridinyl)~3-dimetil:τίϊηο-2(1H)-piridinone. G-21. 3-Diisopropylamino-6-meti1-5-(4,6dimethyl -2-pyridinyl)-2(1H)-pyridinone. G—22. 3-Etylamino-6-isopropyl-5-(6-meti1-2piridinil)-2(lH)-piridinone. G-23. 3-Met i1amino-6-n-es i1-5-(2-pirid ini1)2 ( 1H)-piridinone. H. 1-R -3-(ACIL (INFERIORE)AMINO)—6-(ALCHIL INFERIORE)->PY-2(IH)- PYRIDINONI H-1 · 3-Acetylamino-6-methyl-5-(4-pyridinyl)2(1H)-pyridinone, also called N-[1,2-dihydro6-methyl-1—2—oxo-5-(4-pyridinyl]acetamide. A mixture containing 10.1 g of 3-amino-6-methyl-5-(4-pyridinyl)-2(1H)-pyridinone, 7 g of acetic anhydride and 120 ml of pyridine is heated on a steam bath for one hour and then allowed to cool. The separated product is collected, washed with ether, dried and recrystallized from dimethyl-1-pyridinone to obtain 3-acetylamino-6-methyl-5-(4-pyridinyl)-2(1H)-pyridinone. 3-Acetylamino acid addition salts— 6-methyl-5-(4-pyridinyl)-2(1H)-pyridinone is conveniently prepared by adding to a mixture of 5 grams of 3-acetylamino-6-methyl-5-(4-pyridinyl)2-(1H)-pyridinone in about 100 ml of aqueous methanol ....... 70 UF (· ( C ι the big C; the appropriate acid, e.g., methanesulfonic acid, concentrated sulfuric acid, or concentrated phosphoric acid, to a pH of about 2-3, cooling the mixture sharply after partial evaporation and collecting the precipitated salt, e.g., dimethanesulfonate, sulfate, or phosphate, respectively. Furthermore, the acid addition salt is conveniently prepared in aqueous solution by adding to water, with stirring, equivalent molar amounts of each of 3-acetylamino-6-methyl-5(4-pyridinyl)-2(1H)-pyridinone and the appropriate acid, e.g., lactic acid or dihydrodiic acid to prepare the monolactate or monohydrochloride, respectively, in aqueous solution. H-2. 3-[2-Acetoxy)propanoylamino]-β-methyl-1-2(1H)-pyridinone- To a stirred mixture containing 20.1 g of 3-amino-6-methyl-1-5-(4-pyridinol)-2(1H)-pyridinone and 300 ml of pyridine at room temperature, 16.5 grams of 2-acetoxypropanoyl chloride are added dropwise over a period of about 1 hour, and the resulting mixture is cooled in an ice bath. The resulting product is collected, washed with ether, dried, recrystallized from methanol, washed successively with ethanol and ether, and dried with 1H: obtaining 3-Γ2-acetoxy)-propanoylamino]-6-methyl2(1H)-pyridine, By following the procedure described in Examples H-1 or H-2 but using in place of 3-amino-6methyl-5-(4-pyridinyl)-2(1H)-pyridinone and / or acetic anhydride or 2-acetoxypropanoyl chloride, equivalent molar amounts of the corresponding 1-R^-3-amino-5-PY-6-(lower alkyl)-2(1H)-pyridinone and / or appropriate lower acylating agents, the possibility of obtaining the 3-(acyl(lowerhexamino)-5-PY-6-(lower alkyl)-2(1H)-pyridinones of Examples H-3 to H-17 is contemplated. H-3. 3-Acetylamino-6-ethi1-5-(4-pyridinii)-2(1 non papyrus. H-4. 6—Methy1—3—propyloniamino-5-(3-pyridinyl)2(1H)-pyridinone. H-5. 3-Bu t ilriamino-6-n-propy1-5-(4-pyridini1)2(1H)-pyridinone. H-6. 6-n-Butyl-3-aethylamino-5-(4-pyridinyl)-2(1H)pyridinone. H-7· 3-formylamino-6-isobutyl-2-oxo-5(4-pyridinyl)-2(H)-pyridinone. H-8. 3-Aceti1amino-6-n-pent i1-5-(4-pyri dini1)2(lH)-pyridinone, H-9 3-f2-(Acetossi)propanoylamino3-6-ethyl-5-(2e methyl—4-pyridinyl)-2-(1H)-pyridinone. H-1 0. 6-Eth 1-3-propionium no- 5-(3-pyridinyl)2(1H)-pyridinone. H-11. 3-Acetylamino-1,6-dimethyl-2-osso-5-(4-pyridinyl)-2(lH)-pyridinone. H-1 3-Acety1-6-ethy1-1(2-hydrosyethyl)-5-(4pyridinyl)-2(lH)-pyridinone. H—13· 1,6-Diethyl-3-propionylamino-5-(4-pyridinyl)2(lH)-pyridinone. Η—14. 3-A ceti1amino-6-methyl 1-5-(2-pyridine1)-2(1H)pyridinone. H-15·6-Ethy 1-5-( 5-ethy 1-2-pyridine 1 )-3-formyl-am.ino-2 ( 1H ) -p iride none. H-1 3-Acetylamino-6-methyl-5"(4,6-dimethyl-2~pyridinyl)-2(1H)-pyridinone. H-17· 3-A cetylamino-6-ne s i1-5-(2-pyridine1)- 2(1H)pyridinone. I. 1-R-1,2-Dihydro-6-(LOWER ALCHYL)-20SS0-5-PY-NIC0TINIC ACID 1-1· 1,2-Dihydro-6-methyl-2-oxo-5-(4-pyridinyl) nicotinic acid, also called 1,6-dihydro-2-methyl-6-oxo [3,4'-bipyridinyl-S-carboxylic- A 30-gram portion of 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl) nicotinonitrile was added, with stirring, to a hot solution containing 220 cc of water U Η· 1 , '' he,. and 145 cc of concentrated sulfuric acid. The reaction mixture was heated to reflux for 7 hours (approximately 122°C) and then allowed to stand for a weekend at room temperature. It was then diluted with water, cooled in an ice bath, and treated, dropwise and with stirring, with ammonium hydroxide until neutral pH was achieved. The resulting crystalline precipitate was collected, washed successively with three 100-cc portions of water, several times with acetone, then with ether, and dried at 80°C. The crystalline material was dispersed with 200 cc of chloroform and 200 cc of methanol for 30 minutes and the mixture was concentrated under vacuum to a volume of 150 cc. The crystalline product was collected and dried at 95°C over P 20^, obtaining approximately 24 grams of product. A 10 g sample of the product was heated with 200 cc of water to incipient boiling, the mixture was cooled and the solid was collected and dried at 80°C to obtain g of 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinic acid, mp ^26O°C, By following the procedure described in Example 1-1, but using in place of 1,2-dihydro-6-methyl-274-oxo-5-(4-pyridini-1)-nicotinonitrile an equivalent molar quantity of the corresponding 1-RYj-1,2-dihydro-2-oxo-5-PY-6-(lower alkyl)™* cotinonitrile, the possibility of obtaining the 1-R -1,2-dihydro-2-oxo-5-PY-6-(lower alkyl)nicotinic acids of Examples 1-2 to 1-21 is contemplated. 1-2. 6-Ethyl-1,2-dihydro-2-oxo-5-(4~pyridinyl)-nicotinic acid. 1-3 · 1 ^-dihydro-ó-methyl^-oxo-S-tS-pyridini1)-nicotinic acid · 1—4* 1,2-Dihydro-2-oxo-6-n-propyl-5-(4-pyridinyl)-ni cotinico acid. 1-5· 1,2-Dihydro-2-oxo-6-isopropyl-5(4-pyridini1)nicotinic acid. 1-6. 6-n-butyl-1,2-dihydro-2-oxo-5~(4-pyridinyl)-nicotinic acid. 1-7. 1,2-Dihydro-6-isobutyl-1-2-oxo-5(4-pyridinyl)nicotinic acid. 1-8. 1,2-dihydro-2-oxo-5-(4-pyridinyl)-6tert.-butiini cot ini co acid. 1-9. 1,2-Dihydro-2-oxo-6-n-pentyl-5-(4pyridinyl)nicotinic acid. 1-10. 6~ethyl-1,2-dihydro-5-(2-methyl-4-pyridinyl )-2-oxonicotinic acid. 1-11. 6-Ethyl-1,2-dihydro-2-oxo-5-(3-pyridinyl)acid 1-12. 1,?-Dihydro-1,6-dimethyl-2-oxo5-( / j-pyridinyl)nicotinic acid» 1- 13. 6-Ethyl~1,2-di.i dro-1-( 2-hydroxyethyl)t acid· 2-oxo-5-(4-pyridinyl)nicotinic acid. 1-14. 1-Ethyl-1 f2-dihydro-6-methyl-2-oxo5-(4-pyridinyl)nicotinic acid. 1-15. 1 r6-Diethyl-1 f2-dihydro-2~oxo-5-(4pyridinyl)-nicotinic acid. 1-16. 1,2-Dihydro—6-methyl-2-oxo-5—(2—pyridinyl)-nicotinic acid. 1- 17· 1,2-Dihydro-6-methyl1-5-(5-methyl2-pyridinyl)-2-oxonicot ùnic 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-dimethyl2-pyridinyl)—2-oxonicotinic acid. 1- 20. 1,2-Dihydro-6-isopropy1-5-(6-methyl2-pyridinyl)-2-oxonicotinic acid. 1-21. 1,2-Dihydro-6-n-hexyl-2-oxo-5-(2pyridinyl)nicotinic acid. J. ALKYL (LOWER) 1—R^—6—(LOWER ALKYL)— 1,2—DIHYDRO—2—OXO—5— PY-NICOTINATES. J-1. Ethyl-1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinate.- A 4 g portion of 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinic acid is heated in 200 cc of refluxed ethanol together with 1 g of methanesulfonic acid for a period of 18 hours. The excess ethanol is removed by vacuum distillation and the residue is crystallized from dimethylformamide to produce ethyl 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinate as its methanesulfonic acid salt. The salt is dissolved in hot water and the solution is made basic with excess aqueous potassium carbonate solution. The solid that separates is collected, dried, recrystallized from isopropyl alcohol and dried to produce ethyl 1,2-dihydro6-methyl-2-oxo-5-(4-pyridinyl)nicotinate. Acid addition salts of ethyl 1,2-dihydro 6-methyl-2-oxo-(4-pyridinyl)nicotinate are conveniently prepared by adding to a mixture of 5 grams of ethyl 1,2-dihydro-6-methyl-2-oxo-5(4-pyridinyl)nicotinate in about 100 ml of aqueous methanol, the appropriate acid, e.g. methane sulfonic acid, concentrated sulfuric acid or concentrated phosphoric acid to a pH of about 2-3, cooling the mixture strongly after partial evaporation and collecting the precipitated salt, e.g. dimethanesulfonate, sulfate, respectively. Γ,.;P or phosphate. Furthermore, the acid addition salt is conveniently prepared in aqueous solution by adding to water, with stirring, equivalent molar amounts of each of ethyl 1,2-dihydro-6methyl-2-oxo-5-(4-pyridinyl)nicotinate and the appropriate acid, e.g., lactic acid or hydrochloric acid to prepare the monolactate or monohydrochloride, respectively, in aqueous solution. By following the procedure described in Example J-1, but using in place of 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinic acid and ethanol equivalent molar amounts of the appropriate 1—R^—1,2-dihydro-2-oxo-5-PY-6-(lower alkyl)nicotinic acid and lower alkanol, the possibility of obtaining the lower alkyl(lower)nicotinic acid of Examples J-2 through J-19 is contemplated. J-2. Methyl 1,2-dihydro-6-methyl-2-oxo-5-ί4-pi- ridinylnicotinate. J-3. Ethyl 6-ethyl-1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinate. J-4. η-Propyl 1,2-dihydro-6-methyl-2-oxo-5-(3pyridinyl)nicotinate. J-5. Ethyl 1,2—dihydro—2—oxo—6—n—propy1—5—(4—pyridinyl)nicotinate. hrr ι n SiH;, C J-6. Isopropyl 1,2-dihydro-2-oxo-6-isopropyl-5(4-pyridinyl)nicotinate. J-7. Ethyl 6-n-butyl-1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinate. J-8. Ethyl 1,2-dihydro~6-isobutyl-2-oxo-5-(4pyridinyl)nicotinate. J-9. Methyl 1,2-dihydro-2-oxo-5-(4-pyridinyl)-6tert. butyInicotinate, J-10. Methyl 1 f2-dihydro-2-osso-6-n-pentyl-5-(4pyridinyl)nicotinato. J-11. n-Butyl 6-ethyl-1,2-dihydro-5-(2-methyl-4pyridinyl)-2-oxonicotinato. J—12. Ethyl 6-ethyl-1,2-dihydro-2-oxo-5-(3-pyridinyl)nicotinate. J-13. Ethyl 1 t2-dihydro-1 r6-dimethyl-2-osso-5-(4pyridinyl)nicotinato. J-14. Ethyl 6-ethyl-1,2-diid^ro-1-(2-hydroxyetxl )-2-osso-5-( 4-pyridinyl )nicotinato. J-15. Ethyl 1,6-diethyl-1,2-dihydro-2-oxo-5-(4pyridinyl)nicotinate. J-16. n-Esyl 1,2-dihydro-6-methyl-2-oxo-5-(2pyridinyl)nicotinate. J-17. Methyl 6-ethyl-5-(5-ethyl-2-pyridinyl)-1,2dihydro-2-os icotinalo. J—18. Ethyl 1,2-dihydro-6-methyl-5-(4,6-dimethyl-2ι 11· r J-19. Ethyl 1 12-diicb'0-6-n-esyl-2-osso-5-(2-pyriclini 1 )nicotinato. The usefulness of the compounds of formula I or their salts as cardiotonic agents is demonstrated by their efficacy in standard pharmacological test procedures, such as causing a marked increase in contractile force in the isolated feline atria and papillary muscle test and causing a marked increase in cardiac contractile force in the anesthetized dog test with little or no change in cardiac rate and blood pressure. Detailed descriptions of these test procedures appear in U.S. Patent No. 4,072,746. It has been found that, when tested by the above procedure on isolated feline atria and papillary muscle, compounds of formula I tested in doses of 3, 10, or 30 micrograms / ml, cause a marked increase, i.e., greater than 25%, in papillary muscle strength and a marked increase, i.e., greater than 25%, in right atrial strength, while at the same time causing only a low percentage increase (about 1 / 3 or less of the percentage increase in right atrial strength or papillary muscle strength) in right atrial rhythm. Uses Furthermore, the 6-(lower alkyl)-compounds of formula I were found to be unexpectedly somewhat more active as cardiotonics when tested by this procedure compared to the corresponding compounds of the prior art not having a lower alkyl at the 6-position. Furthermore, some of them, e.g. those in which Q in formula I is carbamoyl or bromine, were found to be active as cardiotonics, whereas, conversely, the corresponding compounds not having a lower alkyl at the 6-position appeared to be useful only as intermediates due to the fact that they do not exhibit cardiotonic properties. The markedly higher cardiotonic activity of the 6(lower alkyl)-compounds compared to the corresponding compounds of prior art not substituted in the 6-position is illustrated by the following comparisons of experimental data obtained using the said procedure on isolated feline atria and papillary muscle. It was found that the percentage increases in papillary muscle force and right atrial force for 3-amino-6methyl-5-(4-pyridinyl)-2(1H)-pyridÌnone were 96% and 4% when tested at 10 micrograms / ml compared to the corresponding increases of 10 ± 11.3% and 4% ± 8.4%. ?.ι | ;- Ρ ? Ο f l'i I' Inp, C, C in the case of 3-aminO"5-(4-pyridinyl)-2(1H)-pyridinone (attirinone) tested at 100 micrograms / ml, i.e. a tenfold dose; the percentage increases in papillary muscle strength and right atrial strength in the case of 3-amino-6-ethyl-5-(4-pyridinyl)-2(1H)pyridine were found to be 53% and 37% when tested at 3 micrograms / ml compared to corresponding increases of 54.1 + 5.3% and 33.6 + 4.4% for 3-amino-5-(4-pyridinyl)-2(1H)—pyridinone tested at 30 micrograms / ml, i.e. a tenfold dose; The percentage increases in papillary muscle strength and right atrial strength in the case of 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile and 6ethyl-1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinonitrile were 45% and 51% in the case of the 6-methyl compound and 107% and 79% in the case of the 6-ethyl compound when tested at 3 micrograms / ml, compared with corresponding increases of 65% and 15% in the case of the past 1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinonitrile not substituted by alkyl in the 6-position at a dose of 30 micrograms / ml i.e. a tenfold dose; the percentage increases in papillary muscle strength and right atrial strength in the case of 1,2—dii dro-f>-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile were found to be 135% and 102% F 1 Iti! ρ when tested at a dose of 10 micrograms / ml while the corresponding compound of the prior technology not methylated at the 6-position was found to be inactive at 10 micrograms / ml; the percentage increases in papillary muscle strength and right atrial strength for 6-methyl-3methylamino-5-(4-pyridinyl)-2(1H)-pyridinone were found to be 68% and 41% when tested at a dose of 30 micrograms / ml, compared to corresponding increases of 64% and 39% for the 3-methylamino-5-(4-pyridinyl)-2(1H)-pyridinone of past technology when tested at 100 micrograms / ml, i.e. more than triple the dose. Illustrative examples of compounds active as cardiotonics having the formula I, where Q is carbamoyl and halogen, while the corresponding compounds of prior art not substituted with lower alkyls in the 6-position appear only as intermediates and not as cardiotonic agents, are as follows: 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinamide which when tested in vitro on feline atria and papillary muscle showed percentage increases in papillary muscle strength and right atrial strength of respectively U l I ìi,: hi / . 35 / · and 22 / at a dose of 30 micrograms / ml and equal to 8? / and 37 / respectively and a dose of 100 micrograms / ml; 6-ethyl-1,2-dihydro-2-oxo5-(4-pyridinyl)nicotinamide which when tested with the same method showed percentage increases in papillary muscle strength and right atrial strength equal to 29% and 7% respectively at a dose of 100 micrograms / ml and 89% and 29% respectively at a dose of 300 micrograms / ml; and 3-bromo-6-methyl-5-(4-pyridinyl)-2(1H)-pyridinone which when tested in vitro on feline atria and papillary muscle showed percentage increases in papillary muscle strength and right atrial strength of 87% and 99%, respectively, at a dose of 1.0 micrograms / ml and 107% and 58%, respectively, at a dose of 10 micrograms / ml. The markedly higher cardiotonic activity of the 6-(lower alkyl)-compounds of formula I where 0 is hydrogen, compared to the corresponding compounds of prior art not substituted in the 6-position, is illustrated by the following comparisons of experimental data obtained using the said procedure on isolated feline atria and papillary muscle: the percentage increases in papillary muscle force and right atrial force in the case of 6methyl-5-(4-pyridinil)-2(1H)-pyridinone were found to be 115% and 40% when tested at a dose of 10 micrograms / ml, compared to corresponding increases of 48% and 5% respectively in the case of 5-(4-pyridinil)-2(1H)-pyridinone of prior art when tested at a dose of 100 micrograms / ml.that is, at a dose 10 times higher! The percentage increases in papillary muscle strength and right atrial strength with 6-ethyl-5-(4-pyridinyl)-2(1H)-pyridinone were found to be 106% and 50% when tested at a dose of 30 micrograms / ml compared to corresponding increases of 4% and 51% when tested at a dose of 5-(4-pyridinyl)-2(1H)-pyridinone at a dose of 100 micrograms / ml, that is, more than triple the dose. As an illustrative example of a cardiotonically active compound of formalin I where Q is carboxyl, while the corresponding compounds of prior art not substituted with lower alkyl at the 6-position are referred to only as intermediates and not as cardiotonic agents, is acid 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinic acid which when tested by means of a similar in vitro test on guinea pig atria and papillary muscle showed percentage increases in papillary muscle strength and right atrial strength of 36% and 27% respectively at a dose of 30 micrograms / ml and of 44% and 69% respectively at a dose of 100 micrograms / ml. When tested by the above procedure on anesthetized dogs, the compounds of formula I when administered intravenously in a single injection corresponding to 0.01, 0.03, 0.10, 0.30, 1.0 and / or 3.0 mg / kg caused a marked increase, i.e., greater than 25%, in cardiac contractile force or cardiac contractility with little or minimal (less than 25%) change in heart rate and blood pressure. Furthermore, the 6-(lower alkyl) compounds of formula I were found to be markedly more active as cardiotonics when tested by this procedure compared to the corresponding compounds of prior technology not substituted with lower alkyls in the 6-position, as demonstrated by the following: The percentage increase in cardiac contractile force or cardiac contractility in the case of 3-amino-6-methyl-5-(4-pyridinyl)-2(1H)pyridinone, when tested as indicated on an anesthetized dog at a dose of 1.0 milligrams / kg. Ir.g. ί kg intravenously was found to be 136% compared to 125.67 + 10.59% in the case of the corresponding compound not methylated in the 6-position, i.e. amrinone, when tested at a tenfold dose, i.e. 10 milligrams / kg intravenously; Similarly, the percentage increases in cardiac contractile force in the case of 3-amino-6-ethyl~5(4”pyridinyl)-2(1H)-pyridinone when tested with the same procedure at a dose of 0.03 milligrams / kg and 0.10 milligrams / kg intravenously were found to be 33% and 72%, respectively, compared to 24.67 ± 3.15% and 70.63 ± 7.85%, respectively, for the previous technology when tested at tenfold respective doses, i.e., 0.3 milligrams / kg and 1.0 mg / kg intravenously; the percentage increases in cardiac contractility in the case of 1,2-dihydro~6-methyl2-oxo-5-(4-pyridinyl)nicotinonitrile, when tested with the same procedure at doses of 0.03 milligrams / kg and 0.10 mg / kg, were found to be 49.5% and 87.5% respectively as compared to 44% and 78% respectively in the case of the corresponding compound of the previous technology not methylated at the 6-position when tested at respective hundredfold doses, i.e. 3 milligrams / kg and 3 mg / kg. ΛP, mg / kg, or compared to 24.67 + 3.15 and 70.63 + 7.85 / respectively in the case of * antrinione of the prior technology when tested at respective tenfold doses, i.e., 0.3 milligrams / kg and 1.0 milligrams / kg respectively; similarly, the percentage increases in contractile force in the case of 6-methyl1-1,2-dihydro-2-oxo5-(4-pyridinyl)nicotinonitrile when tested by this procedure at doses of 0.03 mg / kg and 0.10 mg / kg were found to be 68.5% and 135% respectively as compared to 44% and 78% respectively in the case of the non-methylated compound at the 6-position of the prior technology when tested at respective hundredfold doses, i.e., 3 mg / kg and 10 mg / kg respectively. The present invention includes within its scope a cardiotonic composition for increasing cardiac contractility, said composition comprising a pharmaceutically acceptable carrier and active component thereof, the cardiotonic consisting of 1-1^-3-O-6-(lower alkyl)5-PY-2(1H)-pyridinone of formula I or its pharmaceutically acceptable cationic or acid-addition salt. The present invention also includes within its scope a method of increasing cardiac contractility in a patient requiring such treatment, which method comprises administering to said patient an effective amount of said 1-R-3-q-6-(lower alkyl)5-PY-2(1H)-pyridinone of formula I or its pharmaceutically acceptable cationic or acid-addition salt. In clinical practice, said compound or its salt will usually be administered orally or parenterally in a wide variety of dosage forms. Solid compositions for oral administration include pastilles, tablets, pills, powders, and granules. In these solid compositions, at least one of the active compounds is mixed with at least one inert diluent such as starch, calcium carbonate, sucrose, or lactose. These compositions may also contain substances other than inert diluents, such as lubricating agents such as magnesium stearate, talc, and the like. ' Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs that contain commonly used inert diluents, such as water and liquid paraffin. In addition to inert diluents, such compositions may also contain adjuvants, such as baί» I ί ι ί; ί ίί ι < eng. C, gnants and suspension agents, as well as sweetening, flavouring, perfuming and preservative agents. According to the present invention, compounds for oral administration also include capsules of absorbable material, such as gelatin, which contain said active component with or without the addition of diluents or excipients. Preparations according to the present invention for parenteral administration include sterile aqueous, aqueous-organic, and organic solutions, suspensions, and emulsions. Examples of organic solvents or suspending agents include 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, preservative, wetting, emulsifying, and dispersing agents. The compositions may be sterilized, for example, by filtration through a bacteria-retaining filter, by incorporating sterilizing agents into the compositions, by irradiation, or by heating. They may also be produced in the form of sterile solid compositions that may also be dissolved in sterile water or some other injectable medium. Sterile labile immediately before use. The percentages of active ingredients in the above composition and method for increasing cardiac contractility can be varied to achieve a suitable dosage. The dosage administered to a particular patient is variable at the physician's discretion, according to the following criteria: The route of administration, the duration of treatment, the patient's size and condition, the potency of the active ingredient, and the patient's response to it. An effective dosage of the active ingredient can therefore only be determined by the physician, considering all of the above criteria and judging the patient's best interests.

Claims

1. CLAIMS 1) A 1-Rj-3-Q-5-PY-6~R-2(1H)-pyridinone having the formula: RR wherein O represents hydrogen, amino, CN, carbamyl, halogen, alkyl(lower)amino, di(lower)alkylamino, acyl(lower)amino, carboxyl or carbalkosine C r lower alkyl, R represents hydrogen, lower alkyl or lower hydroxyalkyl, R represents lower alkyl and PY represents 4-, 3- or 2-pyridinyl or 4-, 3- or 2-pyridinyl having one or two lower alkyl substituents, or a cationic or acid addition salt of such compound. 2) Compound according to claim 1, characterized in that R represents methyl or ethyl and FY represents 4-pyridinyl. 3) 3-Amino-6-methyl1-5(4-pyridinyl)-2(1H)-pyridinone according to claim 1. 4) 3-Amino-6-ethyl1-5-(4-pyridinyl)-2( 1H)-pyridinone according to claim 1. 5) 3-Amino-6-n-propy1-5^4-pyridini1)-2(1H)pyridinone according to claim 1. 6) 1,2~Dihydro-6-methyl~2-oxo-5-(4-pyridinyl)nicotinonitrile according to claim 1. 7) 6-Methyl-3-methylamino-5-(4-pyridinyl)-2(1H) pyridinone according to claim 1. 8) 3-Bromo-6-methyl1-5-(4-pyridini1)—2(1H)—pyridinone according to claim 1 9) 6-Ethyl-1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinonitrile according to claim 1. 10) 1,2-Dihydro-6-methyl-2-oxo-5-(4-pyridinyl) nicotinamide according to claim 1. 11) 6-Ethyl-1,2~dihydro-2-oxo-5-(4-pyridinyl) ' nicotinamide according to claim 1. * 12) 3“Ethylamino-6-methyl-:>(4-pyridinyl)~2(1H)pyridinone according to claim 1. 13) 3-Dimet x 1amino-6-met 1-5-(4-pyridini1)2(1H)-pyridinone according to claim 1. 14) 6-Methyl-5-(4-pyridindi)-2(1H)-pyridinone according to claim 1. 15) 6-Ethyl-5-(4-pyridinyl)-2(1H)-pyridinone according to claim 1, 16) 1,2-Dihydro-6-methyl-2-oxo~5-(4-pyridinyl)nicotinic acid according to claim 1. 17) Compound according to claim 1 or 2, characterized in that O represents amino CN or carbamyl, R 1 represents hydrogen, and the compound is in its free base form or is an acid addition salt thereof. 18) Compound according to claim 1 or 2, characterized in that Q is halogen, alkyl (lower) amino, di-(lower) alkyl amino or lower acylamino, 19) Compound according to claim 1 or 2, characterized in that Q represents hydrogen or carboxyl, represents hydrogen, PY represents LI Li' I' 4-or 3-pyridinyl, substituted if desired according to claim 1, and the compound is in its free base form or is an acid addition salt thereof* 20) Compound according to claim 1 or 2, characterized in that 0 is lower carbacoxyl.

21. A process for preparing a compound according to claim 1, characterized in that: a. a compound of the formula R^R^NCH = CC(=O)-R PY 111 wherein R^ and R^ each represent lower alkyl, is reacted with malonamide to produce a compound of formula I wherein O is carbamyl, or b. a compound of formula III (above) or of the formula RCC-CHO \ 0 PY IV is reacted with NR^-al-Sa-cyanoacetamide to prepare a compound of formula I wherein O is CN, partially hydrolyzing, if desired, a compound of formula I so obtained wherein O is CN to obtain the corresponding compound wherein Q is Li 1' F ' carbamyl? reacting, if desired, a compound of formula I thus obtained wherein Q is carbamyl with a reagent capable of converting the carbamyl to an amino so as to produce the corresponding compound wherein Q is amino,' reacting, if desired, a compound of formula I thus obtained,wherein Q is amino with one or two molar equivalents of a lower alkylating agent to yield the corresponding compound wherein Q is alkyl(lower) amino or di-(lower) alkyl amino, respectively, reacting, if desired, a compound of formula I thus obtained wherein Q is amino with a lower alkylating agent to yield the corresponding compound wherein Q is acyl(lower) amino; hydrolyzing, if desired, a compound of formula I thus obtained wherein O is CH to yield the corresponding compound wherein Q is carboxyl; heating, if desired, a compound of formula I thus obtained wherein Q is carboxyl with a mixture of concentrated sulfuric acid and concentrated nitric acid to yield the corresponding compound wherein Q is nitro, said compound wherein Q is nitro being subsequently reduced to yield the compound wherein O is amino; heating, if desired,a compound of formula I so obtained wherein Q is CN or carboxyl with an aqueous mineral acid to obtain the corresponding compound wherein Q is hydrogen; esterifying, if desired, a compound of formula I so obtained wherein Q is carboxyl with a lower ethanol to obtain the corresponding compound wherein < O is lower carbalkoxy; reacting, if desired, a compound of formula I so obtained wherein R^ is hydrogen with an alkylating agent of formula R—Alt wherein R 1 is lower alkyl or lower hydroxyalkyl and An is a hemion of a strong inorganic acid or an organic sulfonic acid to prepare the corresponding compound wherein R 1 is R 1; reacting, if desired, a compound of formula I so obtained wherein O is hydrogen with a halogen to obtain the corresponding compound wherein Q is halogen; and reacting, if desired,a compound of formula I thus obtained wherein Q is halogenated with an alkyl(lower)amine or a di-alkyl(lower)amine, (ί lower ore) amine so as to obtain a corresponding compound wherein Q is respectively alkyl(lower)amino or di-alkyl(lower)amino; * and converting, if desired, a free base thus obtained into an acid addition salt thereof or converting a compound thus obtained into a cationic salt thereof, 22) Process according to claim 21, characterized in that a mixture of aqueous formaldehyde and formic acid is used as the lower alkylating agent so as to obtain a compound of formula I wherein Q is dimethclamine.

23. A process according to claim 21 for producing a compound as claimed in any one of claims 17-20, and wherein R1 and R2 when present are each methyl, a process characterized in that it does not include: a. reaction of the compound of formula III with malonamide, b. reaction of the compound of formula IV with nR1-alpha-cyanoacetate amide, c. heating a compound of formula I obtained wherein Q is carboxyl with a mixture of concentrated sulfonic acid and concentrated nitric acid to obtain the corresponding compound wherein Q is nitro, the said compound wherein Q is nitro being subsequently reduced to obtain the compound wherein Q is amino, or d. the reaction of a compound of formula I obtained where R 1 is hydrogen with an alkylating agent of formula R'-An where P' is lower alkyl or lower hydroxyalkyl and An is an anion of a strong inorganic acid or an organic sulfonic acid. 24) A process for preparing a compound according to claim 1, substantially as described herein with reference to the examples. 25) Compound having the above-mentioned formula I characterised in that it is prepared by the process as claimed in any of claims 21-24. » 26) Compound according to claim 1, characterized in that it is substantially as described herein with reference to the examples. 27) A cardiotonic composition for increasing cardiac contractility characterised by comprising a pharmaceutically acceptable inert carrier and, as its active component, an effective amount of a compound as claimed in any one of claims 1-20, 25 and 26. 28) A compound characterized by having the formula III where R represents lower alkyl, R^ and R^ each represent lower alkyl, and PY represents 4- or 3- or 2-pyridinyl or 4-, 3-, or 2-pyridinyl having 1 or 2 lower alkyl substituents. 29) Compound according to claim 28 characterized in that PY represents 4-pyridinyl and R represents methyl or ethyl. 30) Compound according to claim 28 or 29, characterized in that R and R each represent methyl. 31) Process for producing a compound as claimed in any of claims 28, characterised in that (pi- h ridinyl)methylalkyl(lower)ketone of the formula PY-CH 2-C(=O)-R is reacted with di-(lower alkyl)formamido di-(lower alkyl)acetal. 32) Process for preparing a compound as claimed in claim 28, characterised in that it is substantially the same as that described herein with reference to the examples. 33) Compound according to claim 28, » characterised in that it is prepared with the process as claimed in claim 31 or 32. 34) Compound according to claim 28, characterized in that it is substantially as described herein with reference to the examples. 35) Compound according to any of claims 1-20, 25 and 26, characterized in that it increases cardiac contractility in a patient requiring such treatment. Milan, OFFICE η ui ; v ι; τ τ