DE3044568C2 - - Google Patents

Description

The invention relates to 5- (pyridinyl) -2 (1H) pyridinones, which are useful as cardiotonic agents, as well as their preparation.

In US Pat. Nos. 40 04 012 and 40 72 746, 3-amino- (or cyano) -5- (pyridinyl) -2 (1H) -pyridinones are described as cardiotonic agents and, as intermediate compounds, the corresponding 3-carbamyl compounds, which are alternative be referred to as 1,2-dihydro-2-oxo-5- (pyridinyl) nicotinamides, which by reaction with a reagent capable of converting the carbamyl group to the amino group, e.g. B. by heating with an alkali metal hypohalite, are converted into the corresponding 3-amino compounds. A preferred embodiment of these compounds is 3-amino-5- (4-pyridinyl) -2- (1H) -pyridinone, which is generally known under the name amrinone and alternatively as 5-amino- [3,4′-bipyridine] - 6 (1H) -on. One method described for the preparation of the 3-cyano-5- (pyridinyl) -2 (1H) pyridinones, which are alternatively referred to as 1,2-dihydro-2-oxo-5- (pyridinyl) nicotinonitriles, is the reaction of α - (Pyridinyl) - β - (dialkylamino) acrolein with α- cyanoacetamide. US Pat. No. 4,072,746 describes 3-Q-5- (pyridinyl) -2 (1H) -pyridinones, where Q is hydrogen, halogen, lower alkylamino, di (lower alkyl) amino and NHAc, where Ac is lower alkanoyl or lower carbalkoxy.

The 3-unsubst.-5- (pyridinyl) -2 (1H) -pyridinones (Q = H) were by heating the corresponding 3-cyano compounds with aqueous sulfuric acid, the first being the 3-carboxylic acids, d. H. 1,2-dihydro-2-oxo-5- (pyridinyl) nicotinic acids, are formed, which are then decarboxylated. For this was 1,2-dihydro-2-oxo-5- (pyridinyl) nicotinic acids no cardiotonic activity shown.

The invention relates to the compounds of formula I.

wherein
Q denotes hydrogen, amino, cyano, lower alkylamino, di (lower alkyl) amino, lower acylamino, bromine or carboxy,
R is methyl or ethyl and
PY unsubstituted 4- or 3- or 2-pyridinyl
means, and the acid addition salts or cationic salts thereof.

The compounds of formula I are useful as cardiotonic agents, such as by pharmacological Standard evaluation methods is determined. The Compounds of formula I, wherein Q is carbamyl and cyano and where Q is hydrogen can be converted into the corresponding compounds, where Q is amino or halogen. The connections of the formula I, in which Q is halogen, can be converted into the corresponding 3- [Mono- or di (lower alkyl) amino] compound converted will. Preferred embodiments are those of the formula I in which Q is hydrogen, amino or cyano, PY 4-pyridinyl or 3-pyridinyl, R₁ hydrogen and R is methyl or ethyl. Particularly preferred embodiments are

1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) nicotinonitrile (Formula I wherein Q = CN; R₁ = H; PY = 4-pyridinyl and R = methyl);
3-amino-6-ethyl-5- (4-pyridinyl) -2 (1H) -pyridinone (Formula I, wherein Q = NH₂; PY = 4-pyridinyl; and R = ethyl);
3-amino-5- (4-pyridinyl) -6-methyl-2 (1H) -pyridinone (Formula I, wherein Q = NH₂; PY = 4-pyridinyl; and R = methyl);
6-methyl-5- (4-pyridinyl) -2 (1H) pyridinone (Formula I, wherein PY = 4-pyridinyl; and R = methyl); and
6-ethyl-5- (4-pyridinyl) -2 (1H) -pyridinone (Formula I, wherein PY = 4-pyridinyl; and R = ethyl)

or the pharmaceutically acceptable acid addition salts thereof. Of these particularly preferred embodiments found that they have significantly higher cardiotonic activity have as the corresponding, known des-alkyl compounds, 3-Amino-5- (4-pyridinyl) -2 (1H) -pyridinone, which as Amrinone is known; 1,2-dihydro-2-oxo-5- (4-pyridinyl) nicotinonitrile and 5- (4-pyridinyl) -2 (1H) pyridinone.  

The compounds of formula I as defined above can be obtained by a method which comprises

• (a) Reaction of a compound of formula III wherein R₃ and R₄ are each lower alkyl, with malonamide to form a compound of formula I, wherein Q is carbamyl, or
• (b) Reacting either a compound of Formula III above or Formula IV with α- cyanoacetamide to produce a compound of formula I wherein Q is cyano;
  if desired, partial hydrolysis of a compound of formula I, wherein Q is cyano, to give a corresponding compound, wherein Q is carbamyl;
  if desired, reacting a resulting compound of formula I, wherein Q is carbamyl, with a reagent which converts carbamyl to amino to produce the corresponding compound, wherein Q is amino;
  if desired, reacting a resulting compound of formula I, wherein Q is amino, with 1 or 2 mole equivalents of a lower alkylating agent to obtain the corresponding compound, wherein Q is lower alkylamino or di (lower alkyl) amino;
  if desired, reacting a resulting compound of formula I, wherein Q is amino, with a low acylating agent to produce the corresponding compound, wherein Q is low acylamino;
  if desired, hydrolysis of a compound of formula I, wherein Q is cyano, to give the corresponding compound, wherein Q is carboxy;
  if desired, heating a resulting compound of formula I, wherein Q is carboxy, with a mixture of concentrated sulfuric acid and concentrated nitric acid to obtain the corresponding compound, wherein Q is nitro, which compound, where Q is nitro, is then reduced to a compound to get where Q is amino;
  if desired, heating a resulting compound of formula I, wherein Q is cyano or carboxy, with an aqueous mineral acid to give the corresponding compound, wherein Q is hydrogen;
  if desired, bromination of a resulting compound of formula I wherein Q is hydrogen to produce a compound wherein Q is bromine;
  if desired, reacting a resulting compound of formula I, wherein Q is hydrogen, with halogen to produce the corresponding compound, wherein Q is halogen; and
  Reaction of a compound of the formula I obtained, in which Q is halogen, with a lower alkylamine or a di (lower alkyl) amine to prepare a corresponding compound in which Q is lower alkylamino or di (lower alkyl) - is amino; and
  if desired, converting a free base obtained into an acid addition salt or converting a obtained compound into a cationic salt thereof.

The 1-PY-2- [di- (low- alkyl) amino] ethenyl lower alkyl ketone of the formula III

wherein R₃ ind R₄ each represent lower alkyl and one is preferred Is methyl and PY and R are those given in formula I. Can have meanings by reacting a PY-methyl low alkyl ketones of the formula

PY-CH₂-C (= O) -R (II)

With Di (lower alkyl) formamide di (lower alkyl) acetal produced will. These compounds of formula III or above whose acid addition salts are new compounds.  

The invention also relates to a cardiotonic composition to increase heart contractility, taking this composition a pharmaceutically acceptable carrier and as an active component an effective amount of a cardiotonic of the invention Contains 2 (1H) pyridinones of formula I or a pharmaceutical acceptable acid addition salt or cationic Salt of it.

One can have cardiac contractility in a patient who has a such treatment requires increasing through a process that the administration of an effective amount of an invention cardiotonic 2 (1H) -pyridinones of formula I or one pharmaceutically acceptable acid addition salt or cationic Salt thereof to such a patient.

The term "lower alkyl" used here as meaning from "lower alkyl" to lower alkylamino or di (low alkyl) amino as a meaning for Q means alkyl radicals with 1 to 6 carbon atoms, which are straight or branched can be, e.g. B. methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, n-amyl, n-hexyl and the like.

The term "low acyl" as used herein, e.g. B. as in the 3- (lower-acylamino) substituent in the compounds of formula I (Q = lower-acylamino) means alkanoyl radicals having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, and having substituents selected from hydroxy, Acetoxy or propionoxy including the straight and branched chain residues, e.g. B. Formyl, acetyl, propionyl (n-propanoyl), butyryl (n-butanoyl), isobutyryl (2-methyl-n-propanoyl), caproyl (n-hexanoyl), hydroxyacetyl, α -hydroxypropionyl, β -hydroxypropionyl, α - Acetoxypropionyl, propionoxyacetyl, β- acetoxypropionyl and α- acetoxybutyryl.

The compounds of formulas I and III are both in the free Base form usable and in the form of acid addition salts. The acid addition salts are simply a convenient form of application; in practice, the use of the salt form is inherent beyond the use of the base shape. The acids which are used to prepare the acid addition salts can preferably include those that are combined with the free base pharmaceutically acceptable salts deliver, d. H. Salts, their anions for the animal organism relatively harmless in pharmaceutical doses of the salts so that the good ones inherent in the free base (I) cardiotonic properties due to side effects of the anions not be affected. In the practical implementation the invention, it is appropriate to change the shape of the free Base to apply; however, suitable are pharmaceutically acceptable Salts in the scope of the 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, benzenesulfonic acid, p-toluenesulfonic acid, Cyclohexylsulfamic acid, quinic acid and the like, which the Hydrochloride, sulfate, phosphate, sulfamate, acetate, citrate, Lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexyl sulfamate or quinate.

The acid addition salts of the basic compound (I or III) are made either by dissolving the free base in  aqueous or aqueous-alcoholic solution or other suitable Solvents containing the appropriate acid and isolating the salt by evaporating the solution or by reaction of the free base and acid in an organic Solvent, in which case the salt directly separates, or can be obtained by concentrating the solution can.

Although pharmaceutically acceptable salts of the basic compound I are preferred, all acid addition salts are in the scope of the invention. All acid addition salts are useful as sources for the form of the free base, itself if the special salt as such is only an intermediate is desired, for example if the salt is only for the purpose cleaning or identification was made, or if it as an intermediate in the manufacture of a pharmaceutical acceptable salt is used by ion exchange.

Other pharmaceutically acceptable salts of the compound of Formula I are such cationic salts derived from strong inorganic or organic bases, e.g. B. sodium hydroxide, Potassium hydroxide, trimethylammonium hydroxide, for production the corresponding 1- or N-cationic salt, e.g. B. the sodium, potassium, trimethylammonium salt, d. H. the cationic ion is at the 1- or N-position of the 2 (1H) - Pyridinone ring bound.

The molecular structures of the compounds of the formulas I and III were determined based on the studies by Infrared spectrum, nuclear magnetic resonance spectrum and Mass spectrum and by matching the calculated and found values for elemental analysis.

The invention will be described in general in the following, thus the specialist in the field of pharmaceutical Chemistry can work after that.  

The production of the as raw material serving 1-PY-2- (dimethylamino) -ethenyl-low- alkyl ketones (III) by reacting PY-methyl-low alkyl ketone (II) with dimethylformamide di (lower alkyl) - acetal is carried out by mixing the reaction components in the presence or absence of a suitable solvent. The reaction is expedient at room temperature, d. H. about 20 to 25 ° C, carried out or by heating the reactant to about 100 ° C, preferably in an aprotic solvent, expediently hexamethylphosphoramide, because of the method used to manufacture the PY-methyl-lower alkyl ketones, as in Example A-1 further is given below. Other suitable solvents include Tetrahydrofuran, dimethylformamide, acetonitrile, ether, benzene, Dioxane and the like. The reaction can also be carried out without a solvent, preferably using an excess Dimethylformamide di (lower alkyl) acetal can be carried out. This procedure is shown in the examples below A-1 to A-12 explained.

The PY-methyl-lower-alkyl- ketones (II) are generally known compounds which are characterized by known methods can be produced (e.g. as indicated in: Rec. Trav. chim., 72, 522 [1953]; U.S. Patent 31 33 077; Bull. Soc. Chim., 1968, 4132; Chem. Abstrs., 79, 8539h [1973]; Chem. Abstrs., 81, 120, 401a [1974]; J. Org. Chem., 39, 3834 [1974]; Chem. Abstrs., 87, 6594q [1977]; J. Org. Chem., 43, 2286 [1978]).

The reaction of 1-PY-2- (dimethylamino) -ethenyl-lower alkyl ketone (III) with α- cyanoacetamide to form 1,2-dihydro-2-oxo-5-PY-6-R-nicotinonitrile ( I, where Q = CN) is preferably carried out by heating the reactants in a suitable solvent in the presence of a basic condensing agent. The reaction is expediently carried out using an alkali-lower alkoxide, preferably sodium methoxide or ethoxide, in dimethylformamide. In the practice of the invention, the reaction was carried out in refluxing dimethylformamide using sodium methoxide. Alternatively, methanol and sodium methoxide or ethanol and sodium ethoxide can be used as the solvent or basic condensing agent; however, a longer heating time is then required. Other basic condensing agents and solvents include sodium hydride, lithium diethylamide, lithium diisopropylamide and the like in an aprotic solvent, e.g. B. tetrahydrofuran, acetonitrile, ether, benzene, dioxane and the like. This method is explained below in Examples B-1 to B-5.

Alternatively, the preparation of 1,2-dihydro-2-oxo-5-PY-6-nicotinonitrile by heating a 1-PY-2- (R₃R₄-amino) -äthenyl-lower alkyl ketone (III) in an aqueous alkaline medium, e.g. B. aqueous sodium or potassium hydroxide solution to form the corresponding α -PY- β -R- β - oxopropionaldehyde (IV), and reactions of (IV) with α- cyanoacetamide.

Alternatively, the 1,2-dihydro-2-oxo-5-PY-6-R-nicotinamide (I, Q = carbamyl) directly by reaction of 1-PY-2- (R₃R₄-amino) -äthenyl-lower alkyl ketone of the formula III be made with malonamide.

The partial hydrolysis of 1,2-dihydro-2-oxo-5-PY-6-R- nicotinonitrile (I, Q = cyano) for the production of 1,2-dihydro-2- oxo-5-PY-6-R-nicotinamide (I, Q = carbamyl) is made by heating the same (I, Q = cyano) with concentrated sulfuric acid carried out. Although the reaction is convenient and preferred by heating the reactants on a steam or oil bath at about 90 to 100 ° C, the  Temperature range for the reaction from about 70 to 120 ° C vary. This procedure is further below in the examples C-1 to C-5 explained in more detail.

The conversion of 1,2-dihydro-2-oxo-5-PY-6-R-nicotinamide (I, Q = carbamyl) to 3-amino-5-PY-6-R-2 (1H) -pyridinone (I, Q = amino) is obtained by reacting the same (I, Q = carbamyl) with a reagent capable of converting carbamyl to amino, e.g. B. an alkali metal hypohalite or lead tetraacetate, carried out. This reaction is made convenient by heating an aqueous mixture containing an alkali metal hypohalite, preferably sodium hypobromite or hypochlorite, and contains the compound I (Q = carbamyl), followed by acidification the reaction mixture, preferably with an aqueous Mineral acid, e.g. B. hydrochloric acid. The reaction can be carried out from about 40 to 100 ° C, preferably 70 to 100 ° C will. This procedure is further below in the examples D-1 to D-5.

Alternatively, the 3-amino-5-PY-6-R-2 (1H) pyridinone (I, Q = amino) are prepared by heating 5-PY-6-R- 2 (1H) -pyridinone with a mixture of nitric acid and Sulfuric acid to produce 3-nitro-5-PY-6-R-2 (1H) - pyridinone and direct reduction of the 3-nitro compound for the preparation of 3-amino-5-PY-6-R-2 (1H) -pyridinone (I, Q = amino).  

The conversion of 1,2-dihydro-2-oxo-5-PY-6-R-nicotinonitrile (I, Q = cyano) in 5-PY-6-R-2 (1H) pyridinone (I, Q = Hydrogen) is carried out by heating the compound I (Q = cyano), as above, with an aqueous mineral acid, preferably 50% sulfuric acid, initially for formation a compound of formula I (Q = carboxy), and then that Heating continued for an extended period of time, after which the 3-carboxylic acid is decarboxylated to form of I (Q = hydrogen). This procedure is in below Examples E-1 to E-5 explained in more detail.

The reaction of 5-PY-6-R-2 (1H) -pyridinone (I, Q = hydrogen) with bromine to produce the corresponding 3-bromo Compound (I, Q = bromine) is carried out by mixing the reactant in a suitable inert Solvent under the reaction conditions, with a preferred one Solvent is acetic acid. The reaction is Conveniently carried out at room temperature or by heating the reactant to a temperature up to about 100 ° C.

In this way, the inventive bromination Compound of formula I are prepared with Q = Br.

Anyone can inert solvent can be used, e.g. B. dimethylformamide, Chloroform, acetic acid and the like. This method is explained further below in Examples F-1 to F-7.

The reaction of 3-bromo-5-PY-2 (1H) -pyridinone (I, Q = Bromine) with a lower alkylamine to generate the corresponding 3- (low- Alkylamino) -5-PY-6-R-2 (1H) -pyridinones (I, Q = lower alkylamino)  is carried out by heating the reactants in an autoclave at about 110 to 180 ° C, preferably about 145 to 165 ° C, and preferably in a suitable solvent, e.g. B. water, dimethylformamide, dioxane, 1,2-dimethoxyethane and the like or mixtures thereof. This process continues Examples G-1, G-2, G-4, G-5, G-6, G-7 below explained in more detail.

An alternative method of manufacture according to the invention of 3- [mono- (lower alkyl) amino] -5-PY-6-R- 2 (1H) -pyridinone involves the reaction of the corresponding 3-amino compound with 1 mol equiv. one low alkylating agent.

A preferred method of making 3-dimethyl amino-5-PY-6-R-2 (1H) pyridinone (I, Q = dimethylamino) carried out by reaction of 3-amino-5-PY-6-R-2 (1H) - pyridinone (I, Q = amino) with a mixture of formaldehyde and Formic acid. This reaction is made convenient by heating the 3-amino compound to reflux with an excess of each formaldehyde, preferably in aqueous solution, and Formic acid, preferably more than twice the molar Excess used by everyone is carried out. This The procedure is below in Example G-3 explained in more detail.

The acylation of 3-amino-5-PY-6-R-2 (1H) -pyridinone (I, Q = amino) for the preparation of the corresponding 3- (low-acylamino) - Compound (I, Q = low acylamino) is carried out by reaction of I (Q = amino) with a low acylating agent, e.g. B. a low acyl halide, preferably that Chloride, a low acyl anhydride and the like are preferred in the presence of an acid acceptor. The acid acceptor is a basic substance, which is preferably freely water-soluble  Forms by-products from the reaction product are easily removable, including z. B. sodium hydroxide, Potassium hydroxide, sodium carbonate, potassium carbonate, sodium alkoxides, Potassium alkoxides, sodium amide and the like. The reaction is preferably in the presence of a suitable solvent, which is inert under the reaction conditions, d. H. a solvent such as low alkanol, acetone, Dioxane, dimethylformamide, dimethyl sulfoxide, hexamethylphosphoramide, or a mixture of the solvents, e.g. Legs Mixture of water and methylene dichloride or chloroform. The reaction is generally carried out at a temperature between about 10 and 150 ° C, preferably about 20 to 25 ° C, performed. This procedure is shown in the examples below H-1 to H-6 explained in more detail.

Hydrolysis of 1,2-dihydro-2-oxo-5-PY-6-R-nicotinonitrile (I, Q = Cyano) for the preparation of 1,2-dihydro-2- oxo-5-PY-6-R-nicotinic acid (I, Q = carboxy) is useful by heating this nicotinonitrile on the steam bath an aqueous mineral acid, preferably 50% sulfuric acid, carried out. This procedure is described below in the Examples I-1 to I-5 explained in more detail.  

The following examples are intended to explain the invention in more detail, without restricting them.

Output connections A. 1-PY-2- (dimethylamino) ethenyl lower alkyl ketones A-1. 1- (4-pyridinyl) -2- (dimethylamino) ethenyl methyl ketone

A mixture containing 20 g of (4-pyridinyl) methyl methyl ketone [alternatively named as 1- (4-pyridinyl) -2-propanone] and Containing 30 cm³ of hexamethylphosphoramide was mixed with 65 cm³ of dimethylformamide diluted dimethylacetal, and the resulting The mixture was heated to reflux for 30 minutes. In thin layer chromatography (TLC) there was one spot, which indicated the completion of the reaction. (At a another attempt, the reaction appeared after 30 min at room temperature to be finished.) The reaction mixture was under reduced pressure using a rotary evaporator and evaporated to a pressure of about 20 nPa, and it a crystalline residue of 24 g resulted. The residue was determined by continuous chromatographic extraction Alumina (about 150 g) using reflux boiling chloroform as eluent. To The extract was heated in vacuo for 1½ hours to remove the chloroform remove, using a light yellow, crystalline material, 23.2 g of 1- (4-pyridinyl) -2- (dimethylamino) ethenyl methyl ketone, alternatively referred to as 4-dimethylamino-2- (4- pyridinyl) -3-buten-2-one remained.

The above preparation can be carried out using other solvents instead of hexamethylphosphoramide, e.g. B. dimethylformamide, acetonitrile or others, above specified, or in the absence of a solvent; however Hexamethylphosphoramid was used appropriately, because (4-Pyridinyl) methyl methyl ketone expediently together as a mixture was made with hexamethylphosphoramide as from following manufacture emerges:  

To a stirred solution, which 70 cm³ freshly distilled Diisopropylamine and 200 cm³ of tetrahydrofuran were included at 0 ° C under nitrogen dropwise over 20 min 210 cm³ 2.4 M n-butyllithium added to n-hexane, and the reaction mixture was stirred at about 0 to 5 ° C for about 35 min. To the cold solution were added dropwise over a period of time 90 cm³ of dry hexamethylphosphoramide (none Change in temperature) and the resulting light yellow Solution was stirred for 15 minutes. The cold solution was added to 0 ° C a solution of 50 cm³ 4-picoline in 150 cm³ dry Tetrahydrofuran was added for 15 min and stirring was continued Continue for 30 min at 0 ° C. Then there was a mixture, which Contained 50 cm³ of dry ethyl acetate and 150 cm³ of tetrahydrofuran, added over 15 min (the temperature rose from 0 ° to about 6 ° C), and the resulting mixture was at 20 min 0 ° C stirred. The ice bath was then removed and stirring continued for a further 90 min, after which the temperature of the reaction mixture rose to about 25 ° C. The reaction mixture was then cooled in an ice bath and became 60 cc Acetic acid was added over a period of about 30 minutes. The tetrahydrofuran was removed using a rotary evaporator distilled off in vacuo. The remaining mixture was diluted with 400 cc of water, and the aqueous mixture was successively with two 250 cc portions of isopropyl acetate and extracted three 80 cc portions of chloroform. The solvents were distilled off under reduced pressure, and there was obtained about 137 g of a mixture which was mainly from the desired product and hexamethylphosphoramide duration. Another approach has been used the same amounts performed as above, except that after the addition of 60 cm³ of glacial acetic acid, the mixture with only Diluted 200 cm³ of water, the phases separated and the aqueous Phase was extracted with five 100 ml portions of chloroform. The chloroform extract was washed with brine, and that  Chloroform was distilled off in vacuo. The remaining one Mixture of the desired ketone and hexamethylphosphoramide was combined with the above 137 g of the same mixture, and the combined mixture was distilled under reduced pressure and gave the following fractions:

I. 63 g, bp 110 to 112 ° C at 5.3 nPa;
II. 59 g of light yellow oil, bp. 113 to 115 ° C at 4 nPa; and
III. 69 g light yellow oil, bp. 115 to 118 ° C at 3.3 nPa.

Examination of Fraction III by NMR showed that it was from a 2: 3 mixture (weight) of (4-pyridinyl) methyl methyl ketone and hexamethylphosphoramide. The acid addition salts of 1- (4-pyridinyl) -2- (dimethylamino) ethenyl methyl ketone are conveniently made by adding to a mixture of 5 g of 1- (4-pyridinyl) -2- (dimethylamino) ethenyl methyl ketone the appropriate acid is added in about 100 ml of aqueous methanol will, e.g. B. methanesulfonic acid, conc. Sulfuric acid, conc. Phosphoric acid, up to a pH of about 2 to 3, which After partial evaporation, the mixture cooled down considerably and that failed salt, e.g. B. dimethanesulfonate, sulfate or phosphate, is collected. The acid addition salt is also useful prepared in aqueous solution by adding to water Stirring molar equivalent amounts of 1- (4-pyridinyl) each 2- (dimethylamino) -äthenylmethylketon and the suitable acid, e.g. As lactic acid or hydrochloric acid can be added to the Monolactate or monohydrochloride salt in aqueous solution to manufacture.

A-2. 1- (4-pyridinyl) -2- (dimethylamino) ethyl ethyl ketone

An 87.5 g (4-pyridinyl) methyl ethyl ketone [alternatively as 1- (4-pyridinyl) -2-butanone] and 160 cm³ of hexamethylphosphoramide containing mixture was 100 g Diluted dimethylformamide dimethylacetal, and the resulting Mixture was under nitrogen at room temperature during Stirred for 45 min. The methanol formed in the reaction became  distilled off in vacuo using a rotary evaporator, and the remaining material was reduced Pressure distilled to give two fractions, one boiling at 45 to 80 ° C at 0.66 nPa and a second at 90 fraction boiling up to 95 ° C under 0.66 nPa. After the TLC Analysis showed predominantly only one spot for each Fraction, the two fractions were combined (135 g) and taken up in 600 cm³ of chloroform. The resulting solution was washed with two 300 cc portions of water, and that Water was back extracted with three 100 cc portions of chloroform. The combined chloroform solution was over anhydrous Dried sodium sulfate and by continuous Extraction chromatography on 300 cm³ of aluminum oxide Use of refluxing chloroform as the eluent cleaned. The chloroform was distilled off in vacuo and gave a red oil that was in when standing overnight crystallized in an ice bath. The crystalline material was dissolved in carbon tetrachloride, cyclohexane was added and the mixture cooled to give 64 g of the resulting yellow, crystalline product, 1- (4-pyridinyl) -2- (dimethylamino) ethyl ethyl ketone. The mother liquor became by continuous extraction chromatography on aluminum oxide using refluxing chloroform as eluent another 11 g of crystalline product receive.

The above intermediate (4-pyridinyl) methyl ethyl ketone was as follows in a mixture with hexamethylphosphoramide received: To a 200 cm³ tetrahydrofuran and 70 cm³ Diisopropylamine containing mixture were under nitrogen at 0 to 5 ° C 210 cm³ 2.4 N n-butyllithium in n-hexane, and the resulting mixture was stirred for 30 minutes. Then were 90 cm 3 of hexamethylphosphoramide were added over the course of 10 minutes and then the mixture was stirred for 15 minutes. Then during one  Duration of 15 min a solution of 48 cm³ 4-picoline placed in 150 cm³ of tetrahydrofuran, and then was Stirred for 30 min at about 0 ° C. The ice / acetone bath, which the Reaction mixture cooled, was passed through a dry ice / acetone Bath was replaced and the reaction mixture was added in the course a mixture of 75 cm³ of ethyl propionate in one given the same volume of tetrahydrofuran. The reaction mixture was then allowed to warm to room temperature for about 90 minutes and then heated to about 35 ° C for 30 minutes. The mixture was then cooled in an ice / acetone bath and 60 cc of glacial acetic acid were added over 30 minutes. The resulting, light yellow Suspension was diluted with 200 cc of water. The mixture was extracted with three 150 cc portions of ethyl acetate, and the ethyl acetate extract was washed back with brine. The extract was heated in vacuo to add the ethyl acetate remove, and the residue was again in ethyl acetate added. The solution was washed with water and then heated in vacuo to remove the ethyl acetate, then was the residue heated in vacuo at 50 ° C for about 30 min and gave 100 g of a light yellow oil. The light yellow oil was combined with appropriate samples, which in two further operations were obtained, and then in vacuo distilled and gave a fraction of 256 g, bp 85 bis 105 ° C at 0.66 to 1.33 nPa. The NMR spectrum of this fraction showed that it was a mixture of (4-pyridinyl) methyl ethyl ketone and hexamethylphosphoramide in a molar ratio from 1: 1.55, i.e. H. 35% or 0.35 x 256 = 90 g this ketone.

A-3. 1- (4-pyridinyl) -2- (dimethylamino) -ethenyl-n- propyl ketone

An 80 g (4-pyridinyl) methyl n-propyl ketone [alternatively as 1- (4-pyridinyl) -2-pentanone] and 46 cm³ of hexamethylphosphoramide containing mixture was 250 cm³  Diluted acetonitrile. 90 cm 3 of dimethylformamide were added to the mixture. Given dimethylacetal and the resulting reaction mixture was heated on a steam bath for 90 min and then under vacuum at about 2.6 nPa for removal volatile materials including methanol, acetonitrile and distilled hexamethylphosphoramide. The remaining residue was diluted with ethyl acetate and washed with water. The combined, aqueous washing liquids were washed with five 150 cc portions of ethyl acetate extracted. The United Ethyl acetate solutions were washed with brine, over anhydrous sodium sulfate, filtered and dried Evaporated dry. The residue crystallized on standing in a freezer. The crystalline product was with Slurried cyclohexane, filtered and overnight at 30 ° C dried and gave as a yellow, crystalline product 97 g 1- (4-pyridinyl) -2- (dimethylamino) -ethenyl-n-propyl ketone, Mp 48 to 50 ° C.

The above intermediate (4-pyridinyl) methyl n-propyl ketone was as follows in a mixture with hexamethylphosphoramide obtained: To a stirred solution of 70 cm³ of diisopropylamine in 200 cm³ of tetrahydrofuran were added under nitrogen at about 0 ° C (using an ice bath) 210 cm³ 2.4 N n-butyllithium given for 20 min, and the resulting mixture was stirred at about 0 ° C for 30 min, and to the mixture 90 cm 3 of hexamethylphosphoramide were stirred for 10 minutes was given, and the resulting mixture was further Stirred for 10 min. Then 45 cc became 4-picoline in 140 cc Tetrahydrofuran added dropwise over 15 to 20 minutes. The resulting dark orange-brown solution was 30 min Stirred at 0 ° C and then dropwise over a period of time from 18 min a solution of 68 cm³ ethyl butyrate in 68 cm³ Tetrahydrofuran treated, the temperature of -8 ° +8 to 10 ° C rose. The reaction mixture was removed from the ice bath  removed and allowed to warm to room temperature for 75 min. The The reaction mixture was cooled again and it was added dropwise 60 cm³ of glacial acetic acid were added over 15 min. A light yellow, solid matter separated out and gave a suspension. The suspension was diluted with water and with two 200 cc Proportions of ethyl acetate extracted. The ethyl acetate extract was washed with three 100 cc portions of brine, over anhydrous Dried sodium sulfate and evaporated in vacuo and gave 107 g of a mixture consisting mainly of (4-pyridinyl) methyl n-propyl ketone and hexamethyl phosphoramide. The mixture obtained in this operation was mixed with appropriate Mixtures in two additional operations were obtained, combined, and the combined mixtures were distilled under vacuum and gave as the main fraction with Kp. 80 to 90 ° C at 0.26 nPa a mixture consisting of 80 g (4-pyridinyl) methyl n-propyl ketone and 46 g hexamethyl phosphoramide.

If one works according to the procedure described in example A-2, however, using a molar equivalent amount the appropriate PY-methyl-lower alkyl ketone (II) instead of (4-pyridinyl) methyl ethyl ketone, the corresponding 1-PY-2- (dimethylamino) -ethenyl-lower alkyl ketone of Examples A-4 to A-17.

A-4. 1- (3-pyridinyl) -2- (dimethylamino) -ethyl methyl ketone using (3-pyridinyl) methyl methyl ketone.
A-5. 1- (2-pyridinyl) -2- (dimethylamino) -ethyl methyl ketone using (2-pyridinyl) methyl methyl ketone.
A-6. 1- (4-pyridinyl) -2- (dimethylamino) -ethenyl isopropyl ketone using (4-pyridinyl) methyl isopropyl ketone.
A-7. 1- (4-pyridinyl) -2- (dimethylamino) -ethenyl-n-butyl ketone using (4-pyridinyl) methyl-n-butyl ketone.
A-8. 1- (4-pyridinyl) -2- (dimethylamino) ethenyl isobutyl ketone using (4-pyridinyl) methyl isobutyl ketone.
A-9. 1- (4-pyridinyl) -2- (dimethylamino) -ethenyl tert-butyl ketone using (4-pyridinyl) methyl tert-butyl ketone.
A-10. 1- (4-pyridinyl) -2- (dimethylamino) -ethenyl-n-pentyl ketone using (4-pyridinyl) methyl-n-pentyl ketone.
A-11. 1- (3-pyridinyl) -2- (dimethylamino) ethyl ethyl ketone using (3-pyridinyl) methyl ethyl ketone.
A-12. 1- (2-pyridinyl) -2- (dimethylamino) -ethenyl-n-hexyl ketone using (2-pyridinyl) methyl-n-hexyl ketone.

Compounds according to the invention B. 1,2-dihydro-6- (methyl or ethyl) -2-oxo-5-PY-nicotinonitrile B-1. 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) - nicotinonitrile alternatively as 1,6-dihydro-2-methyl-6-oxo Designated [3,4'-bipyridine] -5-carbonitrile

To a mixture containing 23 g of 1- (4-pyridinyl) -2- (dimethylamino) ethyl methyl ketone and 11 g of α- cyanoacetamide dissolved in 400 cm 3 of dimethylformamide was added 14 g of sodium methoxide with stirring and the resulting reaction mixture was placed in an oil bath heated under gentle reflux for 1 h. TLC analysis indicated that no starting material was contained in the reaction mixture, which was then concentrated in vacuo on a rotary evaporator to a volume of approximately 80 cm³. The concentrate was treated with about 160 cc of acetonitrile and the resulting mixture was stirred on a rotary evaporator with heating to homogeneity and then cooled. The crystalline product was collected, rinsed successively with acetonitrile and ether and dried overnight at 55 ° C. and gave 28 g of a brown, crystalline product, namely the sodium salt of 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) - nicotinonitrile, the presence of cyano being confirmed by IR analysis. A portion of 8 g of this sodium salt was dissolved in 75 cm 3 of hot water, the aqueous solution was treated with decolorizing charcoal, filtered, and the filtrate was again treated with decolorizing charcoal and filtered, and the filtrate was acidified to pH 3 with 6 N hydrochloric acid by dropwise addition . The acidic mixture was diluted with ethanol and cooled; the crystalline product was collected, dried, recrystallized from dimethylformamide water and dried and gave 3.75 g of 1,2-dihydro-6-methyl-2-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 to a mixture of 2 g of 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) nicotinonitrile in about 40 ml aqueous methanol the appropriate acid, e.g. B. methanesulfonic acid, conc. Sulfuric acid, conc. Phosphoric acid, to a pH of about 2 to 3 added, the mixture strongly after partial evaporation cooled and the precipitated salt is collected, e.g. B. that Dimethanesulfonate, sulfate or phosphate. The acid addition salt can also be conveniently prepared in aqueous solution, by adding molar equivalents to water with stirring each 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) nicotinonitrile and the appropriate acid, e.g. B. lactic acid or hydrochloric acid, are added to produce the monolactate or monohydrochloride salt (mp. <300 ° C) in aqueous solution.

B-2. 6-ethyl-1,2-dihydro-2-oxo-5- (4-pyridinyl) nicotinonitrile

Alternatively referred to as 2-ethyl-1,6-dihydro-6-oxo [3,4′-bipyridine] -5-carbonitrile, mp. <300 ° C., 11.6 g, was analogous to that in Example B- 1 described method prepared using 20 g of 1- (4-pyridinyl) -2- (dimethylamino) - ethyl ethyl ketone, 8.4 g of α- cyanoacetamide, 16.2 g of sodium methoxide and 250 cm³ of dimethylacetamide (as a solvent instead of dimethylformamide).

Analogous to the process described in Example B-2, but using a molar equivalent amount of the suitable 1-PY-2- (dimethylamino) -ethenyl-lower-alkyl-ketone (III) instead of 1- (4-pyridinyl) -2- (dimethylamino) ethyl ethyl ketone and the suitable α- cyanoacetamide, the corresponding 1,2-dihydro-2-oxo-5-PY-6-R-nicotinonitriles of Examples B-3 to B-5 can be obtained.

B-3. 1,2-Dihydro-6-methyl-2-oxo-5- (3-pyridinyl) nicotinonitrile using 1- (3-pyridinyl) -2- (dimethylamino) ethylenyl methyl ketone and α- cyanoacetamide.
B-4. 1,2-dihydro-6-methyl-2-oxo-5- (2-pyridinyl) nicotinonitrile using 1- (2-pyridinyl) -2- (dimethylamino) ethylenyl methyl ketone and α- cyanoacetamide.
B-5. 6-ethyl-1,2-dihydro-2-oxo-5- (3-pyridinyl) nicotinonitrile using 1- (3-pyridinyl) -2- (dimethylamino) - ethyl ethyl ketone and α- cyanoacetamide.

C. 1,2-dihydro-6- (methyl or ethyl) -2-oxo-5- (pyridinyl) - nicotinamide C-1. 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) - nicotinamide alternatively as 1,2-dihydro-2-methyl-o-oxo Designated [3,4'-bipyridine] -5-carboxamide

A 9.0 g of 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) nicotinonitrile and 45 cm³ conc. Mixture containing sulfuric acid was heated to 100 ° C for 30 minutes using an oil bath. The hot reaction mixture was added to 200 cm³ of ice and the resulting mixture is cooled in an ice / acetone bath. To the cold solution was carefully dropwise about 150 cc Given 28% ammonium hydroxide. The resulting one Mixture containing precipitate was dissolved in an ice / acetone Bath cooled for about 30 minutes. The precipitate was then collected, rinsed successively with water and acetonitrile, dried well and recrystallized by hot in 130 cm³ Water (at the boiling point) was dissolved, 30 cm³ of acetic acid were added, treated with decolorizing carbon and filtered has been. The filtrate was concentrated and diluted with acetonitrile. The mixture was kept in ice for about 30 minutes. The resulting crystalline material was collected and revealed  8.35 g of a yellow-brown, crystalline material. This material was made with the same material as another Operation was obtained, united, and the united 13.5 g were in 500 cm³ of dimethylformamide at the boiling point dissolved, the hot mixture filtered and the filtrate in one Chilled ice bath. The crystalline precipitate was collected rinsed with acetone and dried at 100 ° C over P₂O₅ for 14 h and by IR and NMR analysis it was found that still some dimethylformamide was included. The 10.5 g leather-colored, crystalline product was in 75 cc hot acetic acid dissolved, treated with 50 cm³ of water and then to a volume of 300 cm³ diluted with acetone. The resulting mixture which contained some crystals was grown in about 45 min Chilled ice bath. The resulting, light yellow-brown, crystalline Product was collected, first at 55 ° C and then at 110 ° C dried to the last faint smell of acetic acid to remove, and gave 9.2 g of 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) nicotinamide, m.p. <300 ° C.

Acid addition salts of 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) - nicotinamide are conveniently manufactured by to a mixture of 5 g 1,2-dihydro-6-methyl-2-oxo-5- (4- pyridinyl) nicotinamide in about 100 ml of aqueous methanol suitable acid, e.g. B. methanesulfonic acid, conc. Sulfuric acid, conc. Phosphoric acid, added to a pH of about 2 to 3, the mixture was strongly cooled after partial evaporation and the precipitated salt is collected, e.g. B. the dimethanesulfonate or sulfate or phosphate. The acid addition salt can also be conveniently prepared in aqueous solution, by adding molar amounts of each to water with stirring 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) nicotinamide and the appropriate acid, e.g. B. lactic acid or hydrochloric acid, are added to the monolactate or monohydrochloride salt to produce in aqueous solution.  

C-1a

1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) nicotinamide also directly by reaction of 1- (4-pyridinyl) -2- (dimethylamino) - Ethenyl methyl ketone made with malonamide: For one stirred suspension containing 100 g of 1- (4-pyridinyl) -2- (dimethylamino) - ethenyl methyl ketone with 132 g malonamide in 900 ml dimethylformamide contained, became a mixture of 24 g for 5 minutes Sodium hydride dispersed in 24 g mineral oil added. The The resulting reaction mixture was placed on a steam bath Nitrogen is heated, followed by an after about 15 minutes Reaction with vigorous development of dimethylamine and precipitation of the product with resulting foam formation. Heating was stopped and a further 200 ml of dimethylformamide added. Heating the stirred reaction mixture continued on a steam bath for about 2.5 hours and then was cooled to room temperature. The resulting one crystalline precipitate was collected from water recrystallized and dried to give 35 g of 1,2-dihydro-6- methyl-2-oxo-5- (4-pyridinyl) nicotinamide, mp <300 ° C. The chemical structure is confirmed by the following NMR data:

C-2. 6-ethyl-1,2-dihydro-2-oxo-5- (4-pyridinyl) nicotinamide alternatively, 1,6-dihydro-2-ethyl-6-oxo- [3,4′-bipyridine] - Called 5-carboxamide

A portion of 40 g of 6-ethyl-1,2-dihydro-2-oxo-5- (4-pyridinyl) - nicotinonitrile was concentrated to 170 cm³. Given sulfuric acid, after which the temperature rose to about 70 ° C. The reaction mixture was immersed in an oil bath preheated to about 90 ° C and then held between 95 and 105 ° C for about 40 minutes. The hot reaction mixture was then poured into an 800 cc ice poured beaker poured. The mixture was stirred and then placed in an ice / acetone bath. To the cold mixture 650 cm³ of 28% ammonium hydroxide was added dropwise with stirring added, after which the temperature is raised to about 46 ° C rise. About 300 cc of ice was added to the mixture with stirring and stirring continued for about 15 minutes. The Precipitation was collected with three 150 cc portions Rinsed water, air dried for 2 h, with a little acetonitrile slurried, filtered and the solid several Dried at 55 ° C for days and gave 39.5 g of product. The solid was stirred well with 300 cm³ of water, filtered and dried and gave 38 g of crystalline product, 6-ethyl-1,2- dihydro-2-oxo-5- (4-pyridinyl) nicotinamide. A share of 14.3 g of this product was further purified by washing it in 40 cm³ of hot acetic acid dissolved, the hot solution filtered and diluted the filtrate to 180 cm³ with absolute ethanol after which crystals formed. The hot mix was allowed to cool. The light yellow-brown, crystalline product was collected and at 110 ° C over P₂O₅ for about Dried for 15 h and gave 11.7 g of 6-ethyl-1,2-dihydro-2-oxo 5- (4-pyridinyl) nicotinamide, m.p. <300 ° C.

When working according to the procedure described in Example C-2, however, using a molar equivalent amount of suitable 1,2-dihydro-2-oxo-5-PY-6-R-nicotinonitrile (I, Q = cyano) instead of 6-ethyl-1,2-dihydro-2-oxo-5- (4- pyridinyl) nicotinonitrile, the corresponding 1,2-dihydro 2-oxo-5-PY-6-R-nicotinamides of Examples C-3 bis C-5 can be obtained.  

C-3. 1,2-dihydro-6-methyl-2-oxo-5- (3-pyridinyl) nicotinamide.
C-4. 1,2-dihydro-6-methyl-2-oxo-5- (2-pyridinyl) nicotinamide.
C-5. 6-ethyl-1,2-dihydro-5- (3-pyridinyl) -2-oxo nicotinamide.

D. 3-Amino-6- (methyl or ethyl) -5-PY-2 (1H) pyridinones D-1. 3-amino-6-methyl-5- (4-pyridinyl) -2 (1H) pyridinone alternatively 5-amino-2-methyl- [3,4′-bipyridine] - 6 (1H) -on called

To a 13 g sodium hydroxide in 250 cm³ of water containing Solution, 12 g of 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) - Nicotinamide added, and the resulting mixture was on a Steam bath heated for dissolution. The solution was added another 250 cm³ of water, and the resulting solution was cooled to about 35 ° C with stirring, after which some Say goodbye to crystals. The mixture was in an ice bath heavily chilled, and it was dropped overall 4.0 cc of bromine was added, with dissolution occurring after about 3 cm³ of bromine were added. The mixture was further 10 minutes stirred in the cold and then heated on a steam bath for 45 min. The reaction mixture was then reduced to about half of its volume, cooled in an ice bath and with Treated 6N hydrochloric acid until the pH was about 8. The The resulting crystalline product was collected twice rinsed with water and once with acetone and dried and gave 7.3 g of material. The 7.3 g were treated with 20 cm³ of water, and the insoluble, amorphous material was filtered off. The filtrate was evaporated to dryness, and the resulting crystalline material was made from dimethylformamide Water recrystallized to give 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-5- (4-pyridinyl) -2 (1H) - pyridinone in about 40 ml of aqueous methanol  Acid, e.g. B. methanesulfonic acid, conc. Sulfuric acid, conc. Phosphoric acid, added to a pH of about 2 to 3, the mixture is strongly cooled after partial evaporation and that precipitated salt is collected, e.g. B. dimethanesulfonate or Sulfate or phosphate. The acid addition salt can also be useful be prepared in aqueous solution by adding water molar amounts of 3-amino-6- each with stirring methyl-5- (4-pyridinyl) -2 (1H) pyridinone and the appropriate Acid, e.g. As lactic acid or hydrochloric acid, are added to Production of the monolactate or monohydrochloride salt in aqueous solution.

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

Alternatively called 5-amino-2-ethyl- [3,4′-bipyridine] -6 (1H) -one, Mp. <300 ° C, 8.8 g, was analogous to that described in Example D-1 Process made, but using 10.0 g of 6-ethyl-1,2-dihydro-2-oxo-5- (4-pyridinyl) nicotinamide, 8.8 g sodium hydroxide, 300 cm³ water, 3.0 cm³ bromine and recrystallization from dimethylformamide isopropyl alcohol.

If you follow the procedure described in Example D-1 works, but using a molar equivalent amount the appropriate 1,2-dihydro-2-oxo-5-PY-6-R-nicotinamide (I, Q = carbamyl) instead of 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) nicotinamide, so the corresponding 3-Amino-5-PY-6-R-2 (1H) -pyridinones of Examples D-3 bis D-5 can be obtained.

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

E. 6- (methyl or ethyl) -5-PY-2 (1H) pyridinones E-1. 6-methyl-5- (4-pyridinyl) -2 (1H) pyridinone alternatively 2-methyl- [3,4′-bipyridine] -6 (1H) -one called

A mixture of 5.3 g of 1,2-dihydro-6-methyl-2-oxo-5- (4- pyridinyl) nicotinonitrile and 30 cm³ 85% sulfuric acid was heated to about 195 ° C., heated slightly to reflux for 24 h, chilled and added to ice. The aqueous mixture became by adding conc. aqueous sodium hydroxide solution to pH 8 brought. The resulting precipitate (product plus Na₂SO₄) was treated with chloroform and the chloroform solution filtered. The filtrate was used to remove the chloroform concentrated in vacuo, and the resulting crystalline The residue was recrystallized from methylene dichloride / ether and dried at 75 ° C for 4 h to give 4.1 g of 6-methyl-5- (4- pyridinyl) -2 (1H) pyridinone, mp 287-288 ° C.

Acid addition salts of 6-methyl-5- (4-pyridinyl) -2 (1H) - Pyridinones are conveniently made 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. B. Methanesulfonic acid, conc. Sulfuric acid, conc. Phosphoric acid, is added to a pH of about 2 to 3, the mixture after partial evaporation, it is strongly cooled and the failed Salt is collected, e.g. B. dimethanesulfonate or sulfate or Phosphate. The acid addition salt can also be useful in aqueous solution can be prepared by adding water under Stir molar amounts of 6-methyl-5- (4- pyridinyl) -2 (1H) pyridinone and the appropriate acid, e.g. B. Lactic acid or hydrochloric acid can be added to make the monolactate or to produce monohydrochloride salt in aqueous solution.  

E-2. 6-ethyl-5- (4-pyridinyl) -2 (1H) pyridinone alternatively 2-ethyl- [3,4′-bipyridine] -6 (1H) -one called

A 9 g of 6-ethyl-1,2-dihydro-2-oxo-5- (4-pyridinyl) nicotinonitrile and 50 ml conc. Mixture containing sulfuric acid was heated at 200 ° C. with stirring for 24 h, cooled to about 40 ° C. and quenched in 200 ml of ice water. after the aqueous solution with conc. Ammonium hydroxide made basic the separated solid was collected from 70 ml of isopropyl alcohol recrystallized and at 60 ° C in a vacuum dried and gave 3 g of 6-ethyl-5- (4-pyridinyl) -2 (1H) - pyridinone, mp 226-228 ° C. A second yield of 0.4 g, Mp. 225 to 227 ° C, was concentrated to approximately by evaporation of the filtrate Get 20 ml.

When analogous to the procedure described in Example E-2 works, but instead of 6-ethyl-1,2-dihydro-2-oxo-5- (4-pyridinyl) nicotinonitrile a molar equivalent amount of corresponding 1-R₁-1,2-dihydro-2-oxo-5-PY-6- (methyl or ethyl) nicotinonitrile used, so the 1-R₁-5-PY- 6- (methyl or ethyl) -2 (1H) pyridinones of Examples E-3 bis E-5 can be obtained.

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

F. 3-Halogen-6- (methyl or ethyl) -5-PY-2 (1H) pyridinones F-1. 3-bromo-6-methyl-5- (4-pyridinyl) -2 (1H) pyridinone alternatively 5-bromo-2-methyl- [3,4′-bipyridine] - 6 (1H) -on called

To a stirred solution of 80 g of 6-methyl-5- (4-pyridinyl) - 2 (1H) -pyridinone in 1 l acetic acid, which is heated to 65 ° C , 69 g of bromine in 50 cm 3 were added dropwise over 25 minutes Given acetic acid. The reaction mixture became more Stirred for 30 min, cooled to room temperature and filtered, to collect the crystalline precipitate. The precipitation was dried and suspended in 1500 cm³ of water. To the strongly stirred suspension were dropwise 25 cm³ 28% Ammonium hydroxide added, after which a white, creamy Precipitation farewell. The solid was collected and in Vacuum dried at 90 ° C and gave 101 g of 3-bromo-6-methyl 5- (4-pyridinyl) -2 (1H) pyridinone, mp 252-254 ° C. A 15 g sample was dissolved in 200 cc hot acetic acid and filtered. The filtrate was concentrated in vacuo with methanol diluted, and the resulting white, crystalline precipitate was collected, dried in vacuo at 100 ° C for 16 h and gave 9.8 g of the product, mp. 252-254 ° C.

Acid addition salts of 3-bromo-6-methyl-5- (4-pyridinyl) - 2 (1H) pyridinones are conveniently prepared by adding to a Mixture of 5 g of 3-bromo-6-methyl-5- (4-pyridinyl) -2 (1H) - pyridinone in about 100 ml of aqueous methanol Acid, e.g. B. methanesulfonic acid, conc. Sulfuric acid, conc. Phosphoric acid, added to a pH of about 2 to 3, the mixture is strongly cooled after partial evaporation and that precipitated salt is collected, e.g. B. the dimethanesulfonate or sulfate or phosphate. The acid addition salt can also be conveniently prepared in aqueous solution by Water with stirring molar amounts of 3-bromo 6-methyl-5- (4-pyridinyl) -2 (1H) pyridinone and the appropriate one Acid, e.g. As lactic acid or hydrochloric acid, are added to Production of the monolactate or monohydrochloride salt in aqueous solution.  

F-2. 3-chloro-6-methyl-5- (4-pyridinyl) -2 (1H) pyridinone alternatively 5-chloro-2-methyl- [3,4′-bipyridine] - 6 (1H) -on called (intermediate)

An 18.6 g of 6-methyl-5- (4-pyridinyl) -2 (1H) pyridinone and Mixture containing 200 ml of acetic acid on a steam bath is heated by introducing chlorine for 4 h treated. After the reaction mixture is brought to room temperature was allowed to cool, the solid is collected with Ether washed and dried. The solid is in water dissolved, the aqueous solution is with 2 N aqueous potassium hydroxide solution neutralized and the mixture cooled. The isolated one Solid is collected, washed with water, dried and recrystallized from ethanol and results 3-chloro-6-methyl-5- (4-pyridinyl) -2 (1H) pyridinone. This connection has, as the hydrochloride, a mp. of 286 to 288 ° C (dec.).

If you follow the procedure described in Example F-1 or F-2 works, but instead of 6-methyl-5- (4-pyridinyl) - 2 (1H) -pyridinone a molar equivalent amount of the corresponding 6- (methyl or ethyl) -5-PY-2 (1H) pyridinone and bromine or Chlorine used, the corresponding 3-bromo (or chlorine) -6- (methyl or ethyl) -5-PY-2 (1H) -pyridinone of the examples F-3 to F-7 can be obtained.

F-3. 3-chloro-6-ethyl-5- (4-pyridinyl) -2 (1H) -pyridinone (Zw.).
F-4. 3-chloro-6-methyl-5- (3-pyridinyl) -2 (1H) -pyridinone (Zw.).
F-5. 3-chloro-6-ethyl-5- (3-pyridinyl) -2 (1H) -pyridinone (Zw.).
F-6. 3-chloro-6-methyl-5- (4-pyridinyl) -2 (1H) pyridinone (Zw.).
F-7. 3-bromo-6-methyl-5- (2-pyridinyl) -2 (1H) -pyridinone) (Zw. = Intermediate).

G. 3- [Mono- or -Di- (lower alkyl) amino] -5-PY-6- (methyl or ethyl) -2 (1H) pyridinones G-1. 6-methyl-3-methylamino-5- (4-pyridinyl) -2 (1H) - pyridinone alternatively as 2-methyl-5-methylamino- [3,4′- bipyridine] -6 (1H) -one

A mixture containing 19 g of 3-bromo-6-methyl-5- (4-pyridinyl) - 2 (1H) -pyridinone, 250 cm³ 70% aqueous methylamine, 60 mg Contained copper bronze and 60 mg copper (II) sulfate Treated in an autoclave at 160 ° C for 48 h. The crystalline Mass was taken up with warm, aqueous methanol and filter the mixture and collect the product. The solid (6 g) plus another portion (1 g), which by concentration the mother liquor and dilution with methanol was dissolved in a small amount of acetic acid, filtered and the filtrate diluted with water. The emerging crystalline precipitate was collected, well with Washed water and dried overnight at 90 ° C and gave 5.1 g of 6-methyl-3-methylamino-5- (4-pyridinyl) -2 (1H) - pyridinone, mp 270-275 ° C (dec.). This manufacture can can also be performed using as described above a molar equivalent amount of 3-chloro-6-methyl 5- (4-pyridinyl) -2 (1H) pyridinone instead 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 to a mixture of 5 g of 6-methyl-3-methylamino-5- (4-pyridinyl) - 2 (1H) -pyridinone in about 100 ml of aqueous methanol suitable acid, e.g. B. methanesulfonic acid, conc. Sulfuric acid, conc. Phosphoric acid, up to a pH of about 2 to 3 added, the mixture strongly after partial evaporation cooled and the precipitated salt, e.g. B. Dimethanesulfonate or sulfate or phosphate is collected. The acid addition salt can also be conveniently prepared in aqueous solution be by adding molar amounts to water with stirring each of 6-methyl-3-methylamino-5- (4-pyridinyl) -2 (1H) - pyridinone and the appropriate acid, e.g. B. lactic acid or Hydrochloric acid, are added to produce the monolactate or monohydrochloride salt in aqueous solution.  

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

Alternatively as 5-ethylamino-2-methyl- [3,4′-bipyridine] -6 (1H) - on, mp. <250 ° C, 1.6 g, was according to that in Example Method described G-1, but using 16.5 g of 3-bromo-6-methyl-5- (4-pyridinyl) -2 (1H) -pyridinone, 110 cc ethylamine, 15 cc water, 30 mg copper bronze, 30 mg Copper (II) sulfate, treating in an autoclave at 150 ° C during 45 h and twice recrystallization from acetonitrile.

G-3. 6-methyl-3- (dimethylamino) -5- (4-pyridinyl) -2 (1H) - pyridinone alternatively 5- (dimethylamino) -2-methyl- [3,4′-bipyridine] - 6 (1H) -on called

To a stirred, 20 g 3-amino-6-methyl-5- (4-pyridinyl) - Containing 2 (1H) -pyridinone, dissolved in 200 cm³ of formic acid Solution were added dropwise with stirring over the course of 5 min 20 cm³ of a 37% formaldehyde solution. The The reaction mixture was heated under reflux for 1 h and 45 min. heated to dryness in vacuo and the residue in methylene dichloride added. The methylene dichloride solution was washed with saturated aqueous sodium bicarbonate solution and filtered. The filtrate was over anhydrous sodium sulfate dried, filtered and the solvent in vacuo distilled off and gave 14 g of yellow, crystalline solid. The solid was dissolved in 250 cc hot methylene dichloride, the hot solution was treated with decolorizing carbon and filtered and the filtrate in vacuo almost to dryness concentrated and then treated with acetonitrile. The resulting one Mixture of crystalline material and acetonitrile was cooled and the solid collected and dried and gave 10.5 g of a yellow, crystalline product, the one Contained trace contamination (determined by TLC). The Solid was dissolved in chloroform solution and the trace Contamination by filtering the chloroform solution through removed a 6.35 cm silica gel column. The resulting Product (10.5 g) was dissolved in methylene chloride, which Solution diluted with isopropyl alcohol and concentrated in vacuo  and strongly chilled. The precipitate was collected and dried at 80 ° C. and gave 9.0 g of 6-methyl-3- (dimethylamino) - 5- (4-pyridinyl) -2 (1H) pyridinone, mp 223 bis 225 ° C.

According to the procedure described in Example G-1 or G-2, however, using a molar equivalent amount of suitable 3-bromo (or chlorine) -5-PY-6- (methyl or ethyl) - 2 (1H) pyridinones and the appropriate lower alkylamine or Di- (lower alkyl) amines instead of 3-bromo-6-methyl-5- (4- pyridinyl) -2 (1H) -pyridinone, the 3- [mono- or Di- (lower alkyl) amino] -5-PY-6- (methyl or ethyl) -2 (1H) - pyridinones of Examples G-4 to G-7 can be obtained.

G-4. 6-ethyl-3-methylamino-5- (4-pyridinyl) -2 (1H) pyridinone.
G-5. 6-methylamino-6-methyl-5- (3-pyridinyl) -2 (1H) pyridinone.
G-6. 6-ethyl-3-ethylamino-5- (3-pyridinyl) -2 (1H) pyridinone.
G-7. 3-n-Hexylamino-6-methyl-5- (2-pyridinyl) -2 (1H) pyridinone.

H. 3- (low acylamino) -6- (methyl or ethyl) -5-PY-2 (1H) - pyridinones H-1. 3-acetylamino-6-methyl-5- (4-pyridinyl) -2 (1H) - pyridinone alternatively N- [1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl)] - called acetamide

10.1 g of 3-amino-6-methyl-5- (4-pyridinyl) -2 (1H) -pyridinone, 5.7 g acetic anhydride and 120 ml mixture containing pyridine is heated on a steam bath for 1 h and then cooled calmly. The separated product is collected with Washed ether, dried and recrystallized from dimethylformamide and gave 3-acetylamino-6-methyl-5- (4-pyridinyl) - 2 (1H) pyridinone (mp <300 ° C).  

Acid addition salts of 3-acetylamino-6-methyl-5- (4-pyridinyl) - 2 (1H) -pyridinone are conveniently prepared by adding a mixture of 5 g of 3-acetylamino-6-methyl-5- (4-pyridinyl) - 2 (1H) -pyridinone in about 100 ml aqueous methanol the appropriate Acid, e.g. B. methanesulfonic acid, conc. Sulfuric acid, conc. Phosphoric acid, added to a pH of about 2 to 3, the mixture after partial evaporation, it is strongly cooled and the failed Salt is collected, e.g. B. the dimethanesulfonate or sulfate or phosphate. The acid addition salt can also be useful be prepared in aqueous solution by adding to water Stir molar amounts of 3-acetylamino-6- methyl-5- (4-pyridinyl) -2 (1H) pyridinone and the appropriate Acid, e.g. As lactic acid or hydrochloric acid, are added to the monolactate or monohydrochloride salt in aqueous solution to manufacture.

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

To a stirred, 20.1 g of 3-amino-6-methyl-5- (4-pyridinyl) - Mixture containing 2 (1H) -pyridinone and 300 ml of pyridine at room temperature dropwise over a period of time 16.5 g of 2-acetoxypropanoyl chloride of about 1 hour, and the resulting mixture is cooled in an ice bath. The separating product is collected, washed with ether, dried, recrystallized from methanol, successively washed with ethanol and ether and dried and yielded 3- [2- (acetoxy) propanoylamino] -6-methyl-2 (1H) pyridinone.

When analogous to that described in Example H-1 or H-2 Process works, but instead of 3-amino-6-methyl-5- (4-pyridinyl) -2 (1H) pyridinone and / or acetic anhydride or 2-acetoxypropanoyl chloride molar amounts of the corresponding 3-amino-5-PY-6- (methyl or ethyl) -2 (1H) - pyridinones and / or suitable low acylating agents used, the 3- (low-acylamino) -5-PY-6- (methyl or ethyl) -2 (1H) pyridinones of Examples H-3 to H-6 be preserved.  

H-3. 3-acetylamino-6-ethyl-5- (4-pyridinyl) -2 (1H) pyridinone.
H-4. 6-methyl-3-propionylamino-5- (3-pyridinyl) -2 (1H) pyridinone.
H-5. 6-ethyl-3-propionylamino-5- (3-pyridinyl) -2 (1H) pyridinone.
H-6. 3-acetylamino-6-methyl-5- (2-pyridinyl) -2 (1H) pyridinone.

I. 1,2-Dihydro-6- (methyl or ethyl) -2-oxo-5-PY-nicotinic acids I-1. 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) - nicotinic acid Alternatively as 1,6-dihydro-2-methyl-6-oxo Designated [3,4'-bipyridine] -5-carboxylic acid

A portion of 30 g 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) - nicotinonitrile became a hot 220 cm³ water and 145 cm³ conc. Containing sulfuric acid Solution given. The reaction mixture was 7 h (about 122 ° C) heated to reflux and then over the weekend at room temperature ditched. It was then diluted with water cooled in an ice bath and added dropwise with stirring Treated ammonium hydroxide to neutral pH. The resulting crystalline precipitate was collected, successively with three 100 cc portions of water and several times with acetone and then washed with ether and dried at 80 ° C. The crystalline material was made with 200 cm³ chloroform and 200 cm³ Methanol slurried for 30 min and the mixture in vacuo concentrated to a volume of 150 cm³. The crystalline The product was collected and dried at 95 ° C over P₂O₅ and gave about 24 g of product. A 10 g sample of the product was heated with 200 cm³ of water to start boiling, which Mixture was cooled and the solid was collected and added Dried 80 ° C and gave 9 g of 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) nicotinic acid, mp <260 ° C.  

If one analogously to the method described in Example I-1 works, but instead of 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) nicotinonitrile a molar equivalent amount of corresponding 1,2-dihydro-2-oxo-5-PY-6- (methyl or ethyl) - nicotinonitrile, the 1,2-dihydro- 2-oxo-5-PY-6- (methyl or ethyl) nicotinic acids of the examples I-2 to I-5 can be obtained.

I-2. 6-ethyl-1,2-dihydro-2-oxo-5- (4-pyridinyl) nicotinic acid.
I-3. 1,2-dihydro-6-methyl-2-oxo-5- (3-pyridinyl) nicotinic acid.
I-4. 6-ethyl-1,2-dihydro-2-oxo-5- (3-pyridinyl) nicotinic acid.
I-5. 1,2-dihydro-6-methyl-2-oxo-5- (2-pyridinyl) nicotinic acid.

The utility of the compounds of formula I or their Salts as a cardiotonic agent are recognized by their effectiveness demonstrated in standard pharmacological test procedures, e.g. B. that a significant increase in contractile Strength in the isolated atria and papillary cat atria Muscle procedure is caused and a significant increase in the cardiac contractile force when anesthetizing Dog procedures with little or minimal changes heart rate and blood pressure. Find detailed descriptions of these test procedures in U.S. Patent No. 40 72 746.

When tested by the above-mentioned methods of isolated Atria and papillary muscles show the connections of the formula I in doses of 3, 10 or 30 µg / ml considerable increase, d. H. more than 25% of the papillary Muscle strength and a significant increase, d. H. more than 25%, in the right atrial strength, while only a slight one percentage increase (about a third or less than that percentage increase in right atrial or papillary Muscle strength) in the right atrial rate. In addition, it was found that the compounds Formula I unexpectedly significantly more active are considered cardiotonics when tested using this procedure compared to the corresponding, known  6-Des (lower alkyl) compounds. It was also found that some of them, e.g. B. those where Q in formula I Carbamyl and bromine is active as cardiotonics while the corresponding 6-des (lower alkyl) compounds only as Intermediates are not known to be cardiotonic Have properties.

The markedly higher cardiotonic activity of the 6- (methyl or -Ethyl) compounds compared to the corresponding, known 6-Unsubstituted compounds is identified by the following Comparisons of the test results are explained, which when used the mentioned procedure of isolated cat atriums and papillary muscles obtained: The percentage increase of papillary muscle strength and right atrial strength for 3-Amino-6-methyl-5- (4-pyridinyl) -2 (1H) pyridinone was found to be than 96% or 75% when tested at 10 µg / ml compared to the corresponding increases of 109 ± 11.3% and 49.9 ± 8.4% for 3-amino-5- (4-pyridinyl) -2 (1H) -pyridinone (amrinone), that was tested at 100 µg / ml, d. H. with a ten times higher Dose. The percentage increases in papillary Muscle strength and right atrial strength for 3-amino-6-ethyl-5- (4-pyridinyl) -2 (1H) pyridine were tested with 53% and 37% found with 3 µg / ml, compared with corresponding increases of 54.1 ± 5.3% and 33.6 ± 4.4% for 3-amino-5- (4- pyridinyl) -2 (1H) -pyridinone, tested at 30 µg / ml, i.e. H. With ten times the dose; the percentage increases in papillary muscle strength and right atrial strength for 1,2-dihydro 6-methyl-2-oxo-5- (4-pyridinyl) nicotinonitrile and 6-ethyl-1,2-dihydro-2-oxo-5- (4-pyridinyl) nicotinonitrile with 45% and 51% for the 6-methyl compound and with 107% and found 79% for the 6-ethyl compound in the test with 3 µg / ml, compared to corresponding increases of 65% and 15% for the known 6-desalkyl-1,2-dihydro-2-oxo-5- (4- pyridinyl) nicotinonitrile at 30 µg / ml, d. H. with ten times Dose. The percentage increases in papillary  Muscle strength and right atrial strength for 1,2-dihydro-6- methyl-2-oxo-5- (4-pyridinyl) nicotinonitrile was 135% and 102% found in the test with 10 µg / ml, while the corresponding known 6-desmethyl compound at 10 µg / ml was inactive. The percentage increase in papillary Muscle strength and right atrial strength for 6-methyl-3-methylamino 5- (4-pyridinyl) -2 (1H) pyridinone was 68% and 41% found in the test with 30 µg / ml, compared with corresponding Increases of 64% and 39% for the well-known 3-methylamino 5- (4-pyridinyl) -2 (1H) -pyridinone when tested with 100 µg / ml, d. H. more than three times the dose.

Examples of cardiotonic active compounds of the formula I where Q is bromine, while the corresponding ones known 6-des (lower alkyl) compounds only as Intermediates and not known as cardiotonic agents are, are: 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) - nicotinamide; in the in vitro test of the atrial and papillary Muscle test found that the percentage increases papillary muscle strength and right atrial strength 35% or 22% at 30 µg / ml and 87% or 37% at 100 µg / ml were; 6-ethyl-1,2-dihydro-2-oxo-5- (4-pyridinyl) nicotinamide, when tested according to the same method showed percentage increases papillary muscle strength and right atrial strength from 29% to 7% at 100 µg / ml and 89 or 29% at 300 µg / ml; and 3-bromo-6-methyl-5- (4-pyridinyl) -2 (1H) pyridinone in the in vitro test of the atrium and the papillary muscles percentage increases in papillary Muscle strength and right atrial strength of 87% and 99% respectively 1.0 µg / ml and 107% or 58% at 10 µg / ml.

The markedly higher cardiotonic activity of the 6- (methyl or Ethyl) compounds of the formula I in which Q is hydrogen, compared to the corresponding known 6-unsubstituted  Connections is made through the following comparisons of test data explains which of the isolated on using the test Atrial and papillary muscles were obtained. The percentage increases in papillary muscle strength and right atrial force for 6-methyl-5- (4-pyridinyl) -2 (1H) - pyridinone were 115% and 48% when tested at 10 µg / ml found compared to the corresponding increases of 48% and 51% for the known 5- (4-pyridinyl) -2 (1H) - pyridinone, tested at 100 µg / ml, i.e. H. a ten-fold dose; the percentage increases in papillary muscle strength and right atrial force for 6-ethyl-5- (4-pyridinyl) -2 (1H) - pyridine was found at 106% and 50% when tested at 30 µg / ml, compared with corresponding increases of 48% and 51% for 5- (4-pyridinyl) -2 (1H) pyridinone, tested with 100 µg / ml, i.e. H. of more than three times the dose.

As an explanation for a cardiotonic active compound of the formula I, in which Q is carboxy, while the corresponding, known 6-des (lower alkyl) compounds only as intermediates are known and not as cardiotonic agents: 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) nicotinic acid in a similar in vitro test on guinea pig auricles and the papillary muscle test percentage increases the papillary muscle strength and right atrial strength of 36% and 27% at 30 µg / ml and 44% and 69% at 100 µg / ml.

When tested according to the above procedure on the anesthetized dog caused compounds of formula I when administered intravenously as a single bolus injection of 0.01, 0.03, 0.10, 0.30, 1.0 and / or 3.0 mg / kg a significant increase, i. H. more than 25%, the cardiac contractive or cardiac Contractility with only minimal or minimal changes (less than 25%) heart rate and blood pressure. In addition, the 6- (methyl or ethyl) compounds were found  Formula I as significantly more active than cardiotonics in the test according to this procedure in comparison with the corresponding, known 6-des (lower alkyl) compounds, as by the following Explanations can be seen: The percentage increase the cardiac contractile force or cardiac Contractility for 3-amino-6-methyl-5- (4-pyridinyl) -2 (1H) - pyridinone during the test, as indicated, on the anesthetized dog at 1.0 mg / kg intravenously, showed 136% compared to 125.67 ± 10.59% for the corresponding 6-desmethyl compound, Amrinone, when tested at ten times the dose, i.e. H. at 10 mg / kg intravenously; similarly show the percentages Increases in cardiac contractile strength for 3-Amino-6-ethyl-5- (4-pyridinyl) -2 (1H) -pyridinone in the test following the same procedure at 0.03 mg / kg and 0.10 mg / kg i.v. 33% and 72%, respectively, compared to 24.67 ± 3.15% and 70.63 ± 7.85% for the known amrinone when tested ten times corresponding doses, d. H. at 0.3 mg / kg and 1.0 mg / kg IV; the percentage increases in cardiac contractility for 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) nicotinonitrile when tested according to the same procedure with 0.03 mg / kg and 0.10 mg / kg showed 49.5% and 87.5% compared to 44% and 78% for the corresponding, known 6-desmethyl compound when testing with 100 times the amount of the corresponding doses, d. H. at 3 mg / kg and 10 mg / kg, or compared to 24.67 ± 3.15% or 70.63 ± 7.85% for the known amrinone in the test with ten times the amount of the corresponding doses, i.e. H. at 0.3 mg / kg or 1.0 mg / kg. Similarly, the percentage increases in contractile force for 6-ethyl 1,2-dihydro-2-oxo-5- (4-pyridinyl) nicotinonitrile in the test using this procedure in doses of 0.03 mg / kg and 0.10 mg / kg 68.5% and 135% compared to 44% and 78% for the corresponding known 6-desmethyl compound when tested with the 100 times the amount of the corresponding doses, i.e. H. at 3 mg / kg or 10 mg / kg.  

To increase cardiac contractility in a patient in need of such treatment effective for such a patient Dose of this 5-PY-2 (1H) pyridinone of formula I or a pharmaceutically acceptable acid addition salt or cationic salt thereof.

In clinical practice, the connection or that Salt thereof is usually orally or parenterally in a variety administered by dosage forms.

Solid compositions for oral administration include compressed tablets, pills, powders and granules. In such solid compositions is at least one of the active ones Compounds mixed with at least one inert diluent, such as starch, calcium carbonate, sucrose or lactose; these compositions can also be additional Contain substances other than the inert diluents, e.g. B. lubricants such as magnesium stearate, talc and the like.

Include liquid compositions for oral administration pharmaceutically acceptable emulsions, solutions, suspensions, Syrups and elixirs which are commonly used contain inert diluents such as water and liquid Paraffin. In addition to the inert diluents, such Compositions also auxiliaries, such as wetting agents and suspending agents, Sweeteners, flavors, fragrances and preservatives, contain. According to the invention, the  Compounds for oral administration also capsules made of adsorbable Material, such as gelatin, which is the active component with or without the addition of diluents or excipients contain.

Preparations according to the invention for parenteral administration include sterile, aqueous, aqueous-organic and organic Solutions, suspensions and emulsions. Examples of organic Solvents or suspending media are propylene glycol, Polyethylene glycol, vegetable oils such as olive oil and injectable organic esters, such as ethyl oleate. These compositions auxiliaries such as stabilizers, preservatives, Wetting agents, emulsifiers and dispersants. You can be sterilized, e.g. B. by filtration through a bacteria restrained filter, by incorporating sterilizing Means in the compositions, by radiation or by heating. They can also be in the form of sterile, solid compositions are generated immediately before use in sterile water or other sterile, injectable medium can be solved.

The percentages of active ingredients in the composition and the method of increasing cardiac contractility can be varied so that suitable dosages are obtained will. That administered to a particular patient Dosage is variable, depending on the clinical assessment, where the criteria are the type of administration, the Duration of treatment, size and condition of the patient, the strength of the active component and the response of the Serve patients on it. An effective dosage amount active ingredient can therefore only be determined by the clinician who takes all criteria into account and who makes the best decision for the patient.

Claims (5)

1. 5- (pyridinyl) -2 (1H) -pyridinones of the general formula I wherein
Q denotes hydrogen, amino, cyano, lower-acylamino, N- (lower-alkyl) -amino, N- (di-lower-alkyl) -amino, bromine or carboxy,
R is methyl or ethyl and PY means unsubstituted 4-, 3- or 2-pyridinyl,
and the acid addition salts or cationic salts thereof. 2. 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) nicotinonitrile. 3. A process for the preparation of a compound according to claim 1, characterized in that in a manner known per se

• (a) a compound of the general formula III wherein R₃ and R₄ each represent lower alkyl, with malonamide to prepare a compound of formula I, wherein Q is carbamyl, or that
• (b) either a compound of formula (III) above or formula (IV) with N-R₁- α- cyanoacetamide to produce a compound of formula I, wherein Q is cyano; that he
  if desired, partially hydrolyzing a resulting compound of formula I, wherein Q is cyano, to produce the corresponding compound, where Q is carbamyl; that he
  if desired, reacting a compound of formula I obtained, wherein Q is carbamyl, with a reagent capable of converting carbamyl to amino to produce the corresponding compound, wherein Q is amino; that he
  if desired, a compound of formula I obtained, wherein Q is amino, with 1 or 2 mol equiv. a lower alkylating agent for the preparation of the corresponding compound, wherein Q is lower alkylamino or di (lower alkyl) amino; that he
  if desired, reacting a compound of formula I obtained, wherein Q is amino, with a low acylating agent to prepare the corresponding compound, wherein Q is low acylamino; that he
  if desired, hydrolyzing a resulting compound of formula I, wherein Q is cyano, to produce the corresponding compound, where Q is carboxy; that he
  if desired, heating a resulting compound of formula I, wherein Q is carboxy, with a mixture of concentrated sulfuric acid and concentrated nitric acid to produce the corresponding compound, wherein Q is nitro, the compound, wherein Q is nitro, then to prepare the compound, where Q is amino is reduced; that he
  if desired, heating a resulting compound of formula I, wherein Q is cyano or carboxy, with an aqueous mineral acid to produce the corresponding compound, wherein Q is hydrogen; that he
  if desired, a obtained compound of formula I, wherein Q is hydrogen, brominates to produce a compound, wherein Q is bromine; that he
  if desired, reacting a resulting compound of formula I, wherein Q is hydrogen, with a halogen to produce the corresponding compound, where Q is halogen; and the resulting compound of formula I, wherein Q is halogen, with a lower alkylamine or a di (lower alkyl) amine to prepare a corresponding compound, wherein Q is lower alkylamino or di (lower alkyl) - is amino, converts; and that one
  if desired, a free base obtained is converted into an acid addition salt or a compound obtained is converted into a cationic salt.

4. The method according to claim 3, characterized in that as a low alkylating agent, a mixture of aqueous formaldehyde and formic acid to produce a compound of Formula I, wherein Q is dimethylamino, is used. 5. Cardiotonic composition to increase cardiac Contractility comprising a pharmaceutically acceptable inert carrier and a compound as an active ingredient one of claims 1 or 2.