JPS6159625B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides 5-pyridinyl-
This invention relates to 2(1H)-pyridinones and their production method.

U.S. Pat. Also named -oxo-5-(pyridinyl)nicotinamide; this compound can be converted by reacting with a reagent capable of converting the carbamoyl group to an amino group (e.g., by heating with an alkali metal hypohalite). 3-amino compound] is disclosed. Preferred specific examples of these compounds are 3-amino-5-(4pyridinyl)-2(1H)-
Pyridinone, now known by its common name amrinone, is also named 5-amino-[3,4'-bipyridinone]-6(1H)-one. 3- disclosed in the above patent
Cyano-5-(pyridinyl)-2(1H)-pyridinone [or 1,2-dihydro-2-oxo-5-
(pyridinyl)nicotinonitrile] One of the methods for producing α-(pyridinyl)-β
-(dialkylamino)acrolein and α-cyanoacetamide. US patent
4072746 is also 3-Q-5-(pyridinyl)-2
(1H)-Pyridinone (wherein Q is hydrogen, halogen, lower alkylamino, di(lower alkyl)amino) and NHAc (wherein Ac is lower alkanoyl or lower carbalkoxy) are also disclosed.

3-Unsubstituted-5-(pyridinyl)-2(1H)-pyridinone (Q=H) is first converted into a 3-carboxylic acid compound, i.e., 1,2- by heating the corresponding 3-cyano compound with an aqueous sulfuric acid solution. It was produced by generating dihydro-2-oxo-5-(pyridinyl)nicotinic acid and decarboxylating it.
No inotropic effect has been disclosed for this 1,2-dihydro-2-oxo-5-(pyridinyl)nicotinic acid.

This invention is based on the general formula (wherein Q means hydrogen, amino, cyano, carbamoyl, halogen, lower alkylamino, di(lower alkyl)amino, lower acylamino, carboxy or lower carbalkoxy, R ₁ means hydrogen or lower alkyl, R is lower alkyl and PY means 4-, 3- or 2-pyridinyl or 4-, 3- or 2-pyridinyl having 1 or 2 lower alkyl substituents; Pharmaceutically acceptable acid addition salts or cationic salts. Compounds of the above general formula are useful as cardiotonic agents as determined by standard pharmacological testing methods.
Compounds of the general formula where Q is carbamoyl and cyano or Q is hydrogen are useful as intermediates for the preparation of the corresponding compounds where Q is amino and halogen, respectively. Compounds of the general formula in which Q is halogen are also useful as intermediates for the production of the corresponding 3-[mono- or di(lower alkyl)amino] compounds. Preferred compounds are those in which Q is hydrogen, amino or cyano;
PY is 4-pyridinyl or 3-pyridinyl, R ₁ is hydrogen, and R is methyl or ethyl. Particularly preferable specific examples include 1,
2-dihydro-6-methyl-2-oxo-5-
(4-pyridinyl)nicotinonitrile (and Q
is CN, R ₁ is H, PY is 4-pyridinyl, R is methyl), 3-amino-6-ethyl-5-(4-pyridinyl)-2(1H)-pyridinone (and Q is
NH ₂ , R ₁ is H, PY is 4-pyridinyl, R is ethyl), 3-amino-5-(4-pyridinyl)-6-
Methyl-2(1H)-pyridinone (where Q is
NH ₂ , R ₁ is H, PY is 4-pyridinyl, R is methyl), 6-methyl-5-(4-pyridinyl)-2
(1H)-pyridinone (where R ₁ is H, PY is 4-pyridinyl, and R is methyl) and 6-ethyl-5-
(4-pyridinyl)-2(1H)-pyridinone (
, R ₁ is H, PY is 4-pyridinyl, and R is ethyl), or a pharmaceutically acceptable acid addition salt thereof. Particularly preferred embodiments of these are the corresponding known des-alkyl compounds, namely:
3-Amino-5-(4-
pyridinyl)-2(1H)-pyridinone, 1,2-
Dihydro-2-oxo-5-(4-pyridinyl)
Nicotinonitrile and 5-(4-pyridinyl)-
It was found that the inotropic effect was significantly higher than that of 2(1H)-pyridinone.

The production of the compound of the above general formula (wherein Q, R ₁ , R and PY have the same meanings as above) is as follows: (a) General formula (In the formula, R ₃ and R ₄ each mean lower alkyl, R and PY have the same meanings as above) are reacted with malonamide, and Q
or (b) produce a compound of the general formula in which N-R ₁ is carbamoyl;
- reacting with α-cyanoacetamide to produce a compound of the general formula in which Q is cyano; optionally, partially hydrolyzing the resulting compound of the general formula in which Q is cyano, in which Q is carbamoyl; Obtaining the corresponding compound; optionally reacting the obtained compound of the general formula in which Q is carbamoyl with a reagent capable of converting the carbamoyl group into an amino group to produce the corresponding compound in which Q is amino If desired, the resulting compound of the general formula in which Q is amino is reacted with 1 or 2 molar equivalents of a lower alkylating agent to form a corresponding compound in which Q is lower alkylamino or di(lower alkyl)amino, respectively. Optionally, the obtained compound of the general formula where Q is amino is reacted with a lower acylating agent to produce the corresponding compound where Q is lower acylamino; Hydrolyzing the compound of the general formula in which Q is cyano to obtain the corresponding compound in which Q is carboxy; optionally, the resulting compound of the general formula in which Q is carboxy is treated with concentrated sulfuric acid and concentrated nitric acid. heating with the mixture to give the corresponding compound where Q is nitro, and then reducing this compound where Q is nitro to give the compound where Q is amino; optionally the resulting Q is cyano or carboxy Heating a compound of the general formula where is with an aqueous mineral acid solution to obtain the corresponding compound where Q is hydrogen; optionally, the resulting compound of the general formula where Q is carboxy is esterified with a lower alkanol to obtain Q is lower carbalkoxy; optionally, the resulting compound of the general formula in which R ₁ is hydrogen is converted into a compound of the general formula R'-An, where R' is lower alkyl or lower hydroxyalkyl. and An represents an anion of a strong inorganic acid or an organic sulfonic acid) to form the corresponding compound in which R ₁ is R′; optionally, the resulting Q A compound of the general formula in which Q is hydrogen is reacted with a halogen to form a corresponding compound in which Q is a halogen; optionally, the resulting compound of the general formula in which Q is a halogen is reacted with a lower alkylamine or a di(lower alkyl)amine to give the corresponding compounds in which Q is lower alkylamino or di(lower alkyl)amino, respectively; and optionally converting the resulting free base into its acid addition salt; or The resulting compound is converted into its cationic salt.

This can be carried out by a method characterized by the following.

PY with the general formula PY-CH ₂ -C(=O)-R()
-When methyl lower alkyl ketone is reacted with di(lower alkyl) formamide di(lower alkyl) acetal, the general formula (In the formula, R ₃ and R ₄ are each lower alkyl, preferably methyl, and PY and R each have the same meanings as above.) Lower alkyl ketones can be produced. 1-pyridinyl)-2-[di(lower alkyl)amino]ethenyl/lower alkyl ketone compound of the above general formula (in the formula, RY and R
(as defined for the general formula) or its acid addition salts are also novel compounds and are encompassed by the present invention.

The present invention also provides a pharmaceutically acceptable carrier and, as an active ingredient, an effective amount of 1-R ₁ -3-Q-5-PY-6-R-2 (1H) having a cardiotonic effect.
- a cardiotonic agent for increasing cardiac contractility containing pyridinone (wherein R ₁ , Q, PY and R are each as defined in the general formula) or a pharmaceutically acceptable acid addition salt or cation salt thereof; Compositions are also provided.

In patients requiring treatment to increase cardiac contractility, an effective amount of the general formula 1-
R ₁ -3-Q-5-PY-6-R-2(1H)-pyridinone (where R ₁ , Q, PY and R are each as defined in the general formula) or a pharmaceutically acceptable acid addition thereof Cardiac contractility can be increased in such patients by a method consisting of administering a salt or cationic salt.

In this specification, for example, as the definition of R in the general formula, as one of the definitions of R ₁ , as the "lower alkyl" in lower alkylamino or di(lower alkyl)amino as the definition of Q, or as a substituent of PY. The term "lower alkyl" used as ``lower alkyl'' means an alkyl group having 1 to 6 carbon atoms which may be in either a straight or branched chain configuration. Examples of lower alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-
Examples include butyl, sec-butyl, t-butyl, isobutyl, n-amyl, n-hexyl, and the like.

Examples of PY of the general formula when PY is 4-, 3- or 2-pyridinyl having 1 or 2 lower alkyl substituents are 2-methyl-4-pyridinyl, 2,6-dimethyl-4- pyridinyl, 3
-Methyl-4-pyridinyl, 2-methyl-3-pyridinyl, 6-methyl-3-pyridinyl (also named 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.

As used herein, the term "lower acyl" has a substituent selected from hydroxy, acetoxy or propionoxy, for example, in the 3-lower acylamino substituent in a compound of the general formula (Q is acylamino). A linear or branched chain having 1 to 6 carbon atoms, which may be
Preferably 1 to 4 alkanoyl groups, such as formyl, acetyl, propionyl (n-propanoyl), butyryl (n-butanoyl), isobutyl (2-methyl-n-propanoyl), caproyl (n-hexanoyl), hydroxyacetyl, α −
It means hydroxypropionyl, β-hydroxypropionyl, α-acetoxypropionyl, propionoxyacetyl, β-acetoxypropionyl, α-acetoxybutyryl, and the like.

Compounds of general formula and are useful in both free base and acid addition salt forms, both of which are within the scope of this invention. Acid addition salts are simply the more convenient form to use; as a practical matter, use of the salt form is essentially equivalent to use of the base form. Acids that can be used in the preparation of acid addition salts include salts that are pharmaceutically acceptable when combined with the free base, i.e., the anion of which is relatively harmless to living organisms at the pharmaceutical dosage of the salt; Preferred are acids that yield salts in which the beneficial cardiotonic properties inherent in () are not compromised by side effects due to the anion. While it is convenient in the practice of this invention to employ the free base form, suitable pharmaceutically acceptable salts within the scope of this invention include mineral salts such as hydrochloric, sulfuric, phosphoric and sulfamic acids. acids; and acetic acid, citric acid, lactic acid, tartaric acid, metal sulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p
- Those derived from organic acids such as toluenesulfonic acid, cyclohexylsulfamic acid, and quinic acid. In addition, these acids are hydrochloride, sulfate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, This produces p-toluenesulfonate, cyclohexylsulfamate and quinate.

Acid addition salts of the above basic compounds (or) can be prepared by dissolving the free base in an aqueous or aqueous alcoholic solution or other suitable solvent containing a suitable acid and isolating the salt by evaporation of the solution; It is produced by reacting an acid with an organic solvent in an organic solvent. In the latter case, the salt precipitates out immediately or can be obtained by concentration of the solution.

Although pharmaceutically acceptable salts of the basic compound(s) are preferred, all acid addition salts are within the scope of this invention. For example, when salts are produced solely for purification or fixation purposes, or when used as intermediates in the production of pharmaceutically acceptable salts by ion-exchange methods, the salts themselves may be All acid addition salts are useful as a source of the free base form, even if only as a base form is desired.

Other pharmaceutically acceptable salts of compounds of general formula are cationic salts derived from strong inorganic or organic bases such as sodium hydroxide, potassium hydroxide, trimethylammonium hydroxide, etc., where these bases are combined with the corresponding 1 - or N-cationic salts (eg, sodium, potassium, or trimethylammonium salts, respectively). That is,
The cation ion is the 1- of the 2(1H)-pyridinone ring.
or attached to the N-position.

The general formula and the molecular structure of the compound were determined based on evidence obtained by infrared, nuclear magnetic resonance and mass spectra, and agreement between calculated and observed values of elemental analysis.

The details of the practice and use of this invention are described in more detail below to enable those skilled in the art of pharmaceutical chemistry to make and use the same.

The production of 1-PY-2(dimethylamino)ethenyl lower alkyl ketone () by the reaction of PY-methyl lower alkyl ketone () with dimethylformamide di(lower alkyl) acetal involves the reaction of both reactants with appropriate It is carried out by mixing in the presence or absence of a solvent. The reaction may be carried out at room temperature, i.e., about 20-25°C, or by introducing the reactants in a preferably neutral solvent, conveniently as described in Example A-1 below. It is conveniently carried out in hexamethylphosphoramide by heating to a temperature of up to about 100° C. due to the method used for the preparation of ketones. 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 of dimethylformamide di(lower alkyl)acetal. This method is further described in Example A below.
-1 to A-3.

The intermediate PY-methyl lower alkyl ketone (
(1953); U.S. Patent 3133077 (5-12-64), Bull.
Sco.Chim. 1968 , 4132; Chem.Abstrs. 79 , 8539h
(1973); Chem.Abstrs. 81 , 120401a (1974);
J.Org.Chem. 39 , 3834 (1974); Chem.Abstrs.
87 , 6594q (1977); J.Org.Chem. 43 , 2286
(1978)].

1-R ₁ -1,2- by reaction of 1-PY-2-(dimethylamino)ethenyl lower alkyl ketone () with N-R ₁ -α-cyanoacetamide
Dihydro-2-oxo-5-PY-6-R-nicotinonitrile (where Q=CN) is prepared by heating both reactants in a suitable solvent in the presence of a basic condensing agent. is preferable. This reaction is conveniently carried out in dimethylformamide using an alkali lower alkoxide, preferably sodium methoxide or ethoxide. In the practice of this invention, this reaction was carried out with sodium methoxide at refluxing dimethylformamide. Alternatively, methanol and sodium methoxide or ethanol and sodium ethoxide can be used as the solvent and basic condensing agent, respectively. However, in this case a longer heating time is required. Other basic condensing agents and solvents include condensing agents such as sodium hydride, lithium diethylamide, lithium diisopropylamide, and approach solvents such as tetrahydrofuran, acetonitrile, ether, benzene, dioxane, and the like. This method is illustrated in Examples B-1 to B-4 below.

Also, 1,2-dihydro-2-oxo-5-
PY-6-R-nicotinamide (where Q=carbamoyl, R=H) is produced directly by reacting 1-PY-2-( _R3R4amino )ethenyl _lower alkyl ketone () with malonamide. be able to.

1-R ₁ -1,2-dihydro-2-oxo-5
-PY-6-R-1,2-dihydro- by partial hydrolysis of nicotinonitrile (where Q=cyano)
The preparation of 2-oxo-5-PY-6-R-nicotinamide (where Q = carbamoyl) is carried out by heating the starting material (where Q = cyano) with concentrated sulfuric acid. This reaction is conveniently and preferably carried out by heating the reactants in a steam or oil bath to a temperature of about 90-100°C, although the temperature range for this reaction extends from 70-120°C. This method is further illustrated in Examples C-1 to C-3 below.

1-R ₁ -1,2-dihydro-2-oxo-5
-PY-6-R-nicotinamide (where Q=carbamoyl) to 1-R ₁ -3-amino-5-PY-
The conversion to 6-R-2(1H)-pyridinone (where Q = amino) is this (where Q = carbamoyl)
is carried out by reacting with a reagent capable of converting carbamoyl groups to amino groups (eg alkali metal hypohalites, lead tetraacetate). This reaction involves heating an aqueous mixture containing an alkali metal hypohalite (preferably hypobromic acid or sodium hypochlorite) and the compound (Q=carbamoyl), and then heating the reaction mixture. Preferably an aqueous mineral acid solution (e.g. hydrochloric acid)
This is conveniently carried out by acidification. This reaction is carried out at about 40-100℃, preferably 70-100℃.
It can be carried out at a temperature of °C. This method is further illustrated in Examples D-1 to D-3 below.

Alternatively, 1-R ₁ -3-amino-5-PY-
6-R-2(1H)-pyridinone (,Q=amino) is 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 is produced and this 3-nitro compound is directly reduced to 3-amino-5-PY-6-R-2(1H)-pyridinone (,Q=amino, R ₁ = H) or by first alkylating the 3-nitro compound (see next section) to produce 1-R ₁ -3-nitro-5-
Producing PY-6-R-2(1H)-pyridinone,
Next, this 3-nitro compound is reduced to 1-R ₁ −
It can also be produced by producing 3-amino-5-PY-6-R-2(1H)-pyridinone (, Q = amino, R ₁ = lower alkyl or lower hydroxyalkyl).

In addition, a compound in which R ₁ =lower alkyl or lower hydroxyalkyl in the general formula, a corresponding 1-unsubstituted compound in which R ₁ =H in the general formula,
It can be prepared by reaction with a lower alkyl or lower hydroxyalkyl ester of a strong inorganic or organic sulfonic acid, preferably in the presence of an acid acceptor.

1-R ₁ -1,2-dihydro-2-oxo-5
-PY-6-R-nicotinonitrile (,Q=cyano) to 1-R ₁ -5-PY-6-R-2 (1H)
- For conversion to pyridinone (,Q=H), the compound () where Q=cyano is heated with an aqueous mineral acid solution, preferably 50% sulfuric acid to first form the compound () where Q=carboxy, and then heated is continued for a longer time to decarboxylate the 3-carboxylic acid, and Q=H
This is done by producing a compound (). This method is further illustrated in Examples E-1 to E-3 below.

The production of the corresponding 3-halo compound (,Q=halogen) by reaction of 1- _R1-5 -PY-6-R-2(1H)-pyridinone (,Q=H) with a halogen involves This is carried out by mixing in a suitable solvent that is inert under the reaction conditions (the preferred solvent is acetic acid). The reaction is conveniently carried out at room temperature or by heating the reactants to a temperature of up to about 100°C.

Preferred halogens are bromine or chlorine. Any inert solvent can be used, such as dimethylformamide, chloroform, acetic acid, etc. This method is further illustrated in Examples F-1 to F-2 below.

The corresponding 1-R ₁ -3- by reaction of 1-R ₁ -3-halo-5-PY-2(1H)-pyridinone (,Q=halogen) with a lower alkylamine or di(lower alkyl)amine (lower alkylamino)-5-PY-6-R-2(1H)-pyridinone-
(, Q = lower alkylamino) or 1-R ₁ -
3-[di(lower alkyl)amino]5-PY-2
The production of (1H)-pyridinone-[,Q=di(lower alkyl)amino] is carried out by combining the reactants in an autoclave, preferably in a suitable solvent (e.g., water, dimethylformamide, dioxane, 1,2-dimethoxyethane). etc., or mixtures thereof) in approx.
This is carried out by heating to a temperature of 110-180°C, preferably about 145-165°C. This method is further illustrated in Examples G-1 to G-3 below.

Another method for producing 1- _R1-3 [mono- or di(lower alkyl)amino]5-PY-6-(lower alkyl)-2(1H)-pyridinone according to the present invention is as follows:
This method involves reacting the corresponding 3-amino compound with 1 or 2 molar equivalents of a lower alkylating agent.

1-R ₁ -3-dimethylamino-5-PY-6-
A preferred method for producing R-2(1H)-pyridinone (,Q=dimethylamino) is 1-R ₁ -3-amino-5-PY-6-R-2(1H)-pyridinone (,Q=amino) is carried out by reacting with a mixture of formaldehyde and formic acid. In this reaction, the 3-amino compound is added in excess,
This is conveniently carried out by refluxing with formaldehyde (preferably an aqueous solution thereof) and formic acid, preferably in molar excess of at least two times.
This method is further illustrated in Example G-3 below.

1-R ₁ -3-amino-5-PY-6-R-2
The preparation of the corresponding 3-(lower acylamino) compound (,Q=lower acylamino) by acylation of (1H)-pyridinone (,Q=amino)
This is carried out by reacting the amino compound () with a lower acylating agent (eg, lower acyl halide, preferably chloride, lower acyl anhydride, etc.), preferably in the presence of an acid acceptor. Acid acceptors are basic substances that preferably form freely water-soluble by-products that are easily separable from the products of the reaction, including, for example, sodium hydroxide,
Includes potassium hydroxide, sodium carbonate, potassium carbonate, sodium, alkoxide, potassium alkoxide, sodium amide, etc. The reaction can be carried out using a suitable solvent that is inert under the reaction conditions, such as lower alkanols, acetone, dioxane, dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide, or one solvent, such as water and methylene chloride or chloroform. Preferably, the reaction is carried out in the presence of a mixture of two or more solvents, such as a mixture with. This reaction is generally carried out at about 10-150°C, preferably about 20-25°C.
It is carried out at a temperature of This method is further illustrated in Examples H-1 and H-2 below.

1-R ₁ -1,2-hydro-2-oxo-5-
1-R ₁ -1,2-dihydro-2-oxo-5-PY-6-R-nicotinic acid (,Q=carboxy) by hydrolysis of PY-6-R-nicotinonitrile (,Q=cyano) The preparation is conveniently carried out by heating the nicotinonitrile with an aqueous mineral acid solution, preferably 50% sulfuric acid, in a steam bath. This method is further illustrated in Example I-1 below.

1-R ₁ -1,2-dihydro-2-oxo-5
1-R ₁ -1,2-dihydro-2-oxo-5-PY-6-R-lower alkyl nicotinic acid (, Q = lower Carboalkoxy) is prepared by using an acid (,Q=carboxy) preferably in a suitable solvent (e.g., excess lower alkanol) and an acid catalyst (e.g., hydrochloric acid, sulfuric acid, metalsulfonic acid, p-toluenesulfonic acid, etc.). from about 25 to 150 °C, preferably from about 50 to
This is done by heating to a temperature of 100°C.
This method is further illustrated in Example J-1 below.

The following examples further illustrate the invention without limiting it.

In addition, in the following examples, in general formula ()
Compounds in which PY corresponds to 4-pyridinyl or substituted 4-pyridinyl will be explained.
Compounds in which is 3- or 2-pyridinyl or substituted 3- or 2-pyridinyl can be produced in a similar manner, and similar pharmacological effects can be expected.

The equivalence of the 4-pyridinyl group and 3- or 2-pyridinyl in the target compound is also clear from the disclosure of Japanese Patent Publication No. 32630/1989, which was filed by the applicant. That is, in the above publication, various 4-, 3-, or 2-pyridinyl groups are bonded to the 5-position of compounds in which a hydrogen atom is bonded in place of the lower alkyl group at the 6-position in the general formula () of the present invention. Compounds are shown and shown to be equivalent with respect to their synthesis and pharmacological action, regardless of the position of pyridinyl substitution.

Therefore, it will be clear to those skilled in the art that 3- or 2-pyridinyl compounds can be prepared based on the description of 4-pyridinyl compounds in the examples below.

Example A 1-PY-2-(dimethylamino)ethenyl
Lower alkyl ketones A-1: 1-(4-pyridinyl)-2-(dimethylamino)ethenyl methylketone-4-(pyridinyl)methyl methylketone [or 1-(4-
A mixture containing 20 g of pyridinyl)-2-propanone and 30 c.c. of hexamethylphosphoramide was diluted with 65 c.c. of dimethylformamide/dimethylacetal, and the resulting mixture was refluxed for 30 minutes. TLC analysis showed a single spot, indicating the reaction was complete (in another run, the reaction appeared to be complete after 30 minutes at room temperature). The reaction mixture was evaporated under reduced pressure using a rotary evaporator at a pressure of about 15 mm to obtain a crystalline residue in the amount of 24 g. This residue was purified by successive chromatographic extractions on alumina (approximately 150 g) using refluxing chloroform as eluent. After 1.5 hours, the extract was heated under vacuum to remove chloroform, and 23.2 g of 1
-(4-pyridinyl)-2-(dimethylamino)ethenyl methylketone, or alternatively 4-dimethylamino-2-(4-pyridinyl)-3
-Buten-2-one remained as a pale yellow crystalline material.

The above preparation can also be carried out using other solvents instead of hexamethylphosphoramide, such as dimethylformamide, acetonitrile or others listed above, or in the absence of a solvent, but the preparation examples below As can be seen from (4-
Since pyridinyl)methyl methylketone is conveniently prepared in a mixture with hexamethylphosphoramide, preference is given to using hexamethylphosphoramide.

A mixture containing 70 c.c. of freshly distilled diisopropylamine and 200 c.c. of tetrahydrofuran was heated to 0°C.
While stirring under nitrogen, 210 c.c. of a 2.4M n-hexane solution of n-butyllithium was added dropwise over 20 minutes. The reaction mixture was stirred at about 0-5°C for about 35 minutes. To this cold solution, 90 c.c. of dry hexamethylphosphoramide was added dropwise over 10 minutes (no temperature change) and the resulting pale yellow solution was stirred for 15 minutes. 0
Add dry tetrahydrofuran to this cold solution at 150 °C.
A solution of 50 c.c. of 4-picoline in cc was added dropwise over 15 minutes and stirring was continued for 30 minutes at 0°C. A mixture containing 50 c.c. of dry ethyl acetate and 150 c.c. of tetrahydrofuran was then added over 15 minutes (temperature rose from 0°C to approximately 6°C) and the resulting mixture was heated at 0°C for 20 minutes.
Stir for a minute. The ice bath was then removed and stirring continued for an additional 90 minutes, during which time the temperature of the reaction mixture rose to approximately 25°C. The reaction mixture was then cooled in an ice bath and to it was added 60 c.c. of acetic acid over about 30 minutes. Tetrahydrofuran was removed under vacuum using a rotary evaporator. The remaining mixture was diluted with 400 c.c. of water and the aqueous mixture was sequentially extracted twice with 250 c.c. of isopropyl acetate and three times with 80 c.c. of chloroform. The solvent was distilled off under reduced pressure to obtain about 137 g of a mixture mainly consisting of the desired product and hexamethylphosphoramide. Another experiment using the same amount
After addition of 60 c.c. of glacial acetic acid, the mixture was diluted with only 200 c.c. of water and, after phase separation, the aqueous phase was extracted five times with 100 ml each of chloroform. After washing the chloroform extract with saline,
Chloroform was removed in vacuo. The resulting target mixture of ketone and hexamethylphosphoramide was combined with 137 g of the same mixture above, and the combined mixture was distilled under reduced pressure to obtain the following fraction. :
63g, bp110-112℃/4mm; : Slight yellow oil 59
g, bp113-115℃/3mm;: slightly yellow oil 69
g, bp115-118℃/2.5mm. Examination of the fraction by NMR showed that it consisted of a 2:3 mixture by weight of (4-pyridinyl)methyl methylketone and hexamethylphosphoramide.

The acid addition salt of 1-(4-pyridinyl)-2-(dimethylamino)ethenyl methyl ketone is prepared by adding 1-(4-pyridinyl)-2-(dimethylamino)ethenyl methylketone in approximately 100 ml of aqueous methanol.
Adding a suitable acid such as methanesulfonic acid, concentrated sulfuric acid or concentrated phosphoric acid to a mixture of 5 g of 2-(dimethylamino)ethenyl methyl ketone until the pH is about 2-3 and cooling the mixture after partial evaporation; It is conveniently prepared by collecting the precipitated salts, eg dimethane sulfonate, sulfate, phosphate, respectively. In addition, an equimolar amount of 1-
It can also be done by adding (4-pyridinyl)-2-(dimethylamino)ethenyl methylketone and a suitable acid, such as lactic acid or hydrochloric acid, with stirring to produce the monolactate or monohydrochloride, respectively, in aqueous solution. , acid addition salts are conveniently prepared in aqueous solution.

A-2: 1-(4-pyridinyl)-2-(dimethylamino)ethenyl ethyl ketone (4-pyridinyl)methyl ethyl ketone [alternative nomenclature: 1-(4-pyridinyl)-2-butanone] 87.5 g and hexamethylphosphoramide
The mixture containing 160 c.c. was diluted with 100 g of dimethylformamide dimethyl acetal and the resulting mixture was stirred at room temperature under nitrogen for 45 minutes. The methanol produced by the reaction is distilled off under vacuum using a rotary evaporator, and the remaining substances are distilled under reduced pressure to produce two fractions, one with a boiling point of 45-80℃/0.5mm and one with a boiling point of 90-80℃/0.5mm.
A fraction of 95°C/0.5mm was obtained. Since TLC analysis mainly showed only one spot for each fraction, both fractions were combined (135 g) and dissolved in 600 c.c. of chloroform. The resulting solution was washed twice with 300 c.c. each of water, and the water was back extracted three times with 100 c.c. each of chloroform.
The combined chloroform solution was dried over anhydrous sodium sulfate and purified by continuous extraction chromatography on 300 c.c. of alumina using refluxing chloroform as eluent. The chloroform was removed in vacuo to give a red oil. This crystallized when left overnight in an ice bath. This crystalline material was dissolved in carbon tetrachloride, cyclohexane was added, the mixture was cooled and 64 g of the desired 1-(4-
pyridinyl)-2-(dimethylamino)ethenyl
Ethyl ketone was obtained as a yellow crystalline product. From the mother liquor, a separate 11 g
of crystalline product was obtained.

The intermediate (4-pyridinyl)methyl ethyl ketone used above was obtained as a mixture with hexamethylphosphoramide as follows.
A 2.4 N n-hexane solution of n-butyllithium is added to a mixture containing 200 c.c. of tetrahydrofuran and 70 c.c. of diisopropylamine under nitrogen at 0-5°C.
210 c.c. was added and the resulting mixture was stirred for 30 minutes. 90 c.c. of hexamethylphosphoramide was then added over 10 minutes and the mixture was stirred for 15 minutes. Then 4-picoline 48 in tetrahydrofuran 150 c.c.
cc solution was added over 15 minutes and stirred at about 0°C for 30 minutes. The ice/acetone bath cooling the reaction mixture was replaced with a dry ice/acetone bath, and a mixture of 75 c.c. of ethyl propionate and the same volume of tetrahydrofuran was added to the reaction mixture over 20 minutes. The reaction mixture was then allowed to warm to room temperature over about 90 minutes and then to about 35° C. for 30 minutes. The mixture was then cooled in an ice/acetone bath and to it was added 60 c.c. of glacial acetic acid over 30 minutes. The resulting yellow suspension was diluted with 200 c.c. of water. 150 each of this mixture
Extracted three times with cc of ethyl acetate, and the ethyl acetate extract was backwashed with brine. The extract was heated under vacuum to remove ethyl acetate, and the residue was dissolved in ethyl acetate. The solution was washed with water and heated in vacuo to remove ethyl acetate, and the residue was heated in vacuo to 50° C. for about 30 minutes to obtain 100 g of a pale yellow oil. This pale yellow oil was combined with corresponding samples from two further production runs and then vacuum distilled to yield 256 g of a bp 85-105°C/0.5-1.0 mm fraction. The NMR spectrum of this fraction showed that it was a mixture of (4-pyridinyl)methyl ethyl ketone and hexamethylphosphoramide in a molar ratio of 1:1.55, respectively. That is, the amount of ketone produced is 35%, or 0.35×256
= 90g.

A-3: 1-(4-pyridinyl)-2-(dimethylamino)ethenyl n-propyl ketone: 80 g of (4-pyridinyl)methyl n-propyl ketone [alternative nomenclature is 1-(4- pyridinyl)-2
-pentanone] and 46 c.c. of hexamethylphosphoramide was diluted with 250 c.c. of acetonitrile. 90 c.c. of dimethylformamide/dimethylacetal was added to this mixture, and the resulting reaction mixture was heated in a steam bath for 90 minutes and then vacuum distilled at approximately 2 mm to remove volatiles containing methanol, acetonitrile, and hexamethylphosphoramide. Removed sexual substances. Dilute the remaining residue with ethyl acetate,
Washed with water. The combined water washes were extracted with 5 x 150 c.c. of ethyl acetate. The combined ethyl acetate solution was washed with brine, dried over anhydrous sodium sulfate,
Filtered and evaporated to dryness. The residue crystallized while standing in the freezer. The crystalline product was slurried with cyclohexane, filtered, and dried overnight at 30°C to yield 97 g of 1-(4-pyridinyl)-2-(dimethylamino)ethenyl n-propyl ketone. m.
p.48-50°C was obtained as a yellow crystalline product.

The intermediate (4-pyridinyl)methyl/n-propyl ketone used above was obtained as a mixture with hexamethylphosphoramide in the following manner. To a stirred solution of 70 c.c. of diisopropylamine in 200 c.c. of tetrahydrofuran was added 2.4Nn of n-butyllithium under nitrogen at about 0°C (using an ice bath).
- Add 210 c.c. of hexane solution over 20 minutes, stir the resulting mixture at about 0° C. for 30 minutes, and add 90 c.c. of hexamethylphosphoramide to this mixture with stirring.
was added over 10 minutes and the resulting mixture was added for another 10 minutes.
Stir for a minute. Then 45 c.c. of 4-pyricone in 140 c.c. of tetrahydrofuran was added dropwise over 15-20 minutes. The resulting dark orange-brown solution was stirred at 0°C for 30 minutes and then mixed with 68 c.c. of butyl butyrate and 68 c.c. of tetrahydrofuran.
A solution consisting of was added dropwise over 18 minutes. The temperature rose from -8°C to +8-10°C. The reaction mixture was removed from the ice bath and allowed to warm to room temperature over 75 minutes. The reaction mixture was recooled and 60 c.c. of glacial acetic acid was added dropwise to it over 15 minutes. A slightly yellow solid precipitated out to form a suspension. The suspension was diluted with water and extracted with 2 x 200 c.c. of ethyl acetate. This ethyl acetate extract was washed with 3 x 100 c.c. of saline solution,
Dry over anhydrous sodium sulfate, evaporate in vacuo,
107 g of a mixture consisting mainly of (4-pyridinyl)methyl/n-propyl ketone and hexamethylphosphoramide was obtained. The resulting mixture was combined with the corresponding mixtures from two other experiments, and the combined mixture was vacuum distilled to obtain the main fraction b.
A mixture consisting of 80 g of (4-pyridinyl)methyl/n-propyl ketone and 46 g of hexamethylphosphoramide with a p. of 80-90°C/0.2 mm was obtained.

B 1-R ₁ -1,2-dihydro-6-((lower alkyl)-2-oxo-5-PY-nicotinonitriles B-1 1,2-dihydro-6-methyl-2-oxo-5 -(4-pyridinyl)nicotinonitrile, also named 1,6-dihydro-2-methyl-6-oxo-[3,4'-bipyridine]-5-carbonitrile. Dissolved in 400 c.c. of dimethylformamide. To a mixture of 23 g of 1-(4-pyridinyl)-2-(dimethylamino)ethenyl methyl ketone and 11 g of α-cyanoacetamide was added 14 g of sodium methoxide with stirring, and the resulting reaction mixture was heated under gentle reflux. Heated in an oil bath for 1 hour.
TLC analysis showed no starting material in the reaction mixture. This reaction mixture was heated to about 80 c.c. in a rotary evaporator.
It was concentrated in vacuo to a volume of . Approximately 160 c.c. of this concentrate.
of acetonitrile and the resulting mixture was stirred with warming on a rotary evaporator until homogeneous, then cooled. The crystalline product was collected, washed sequentially with acetonitrile and ether, and dried overnight at 55°C to yield 28 g of tan crystalline product, i.e. 1,2
-dihydro-6-methyl-2-oxo-5-(4
-pyridinyl) nicotinonitrile sodium salt was obtained. The presence of cyano groups was confirmed by IR analysis. Take 8g of this sodium salt and add 75c.c. of boiling water.
This aqueous solution is treated with decolorizing charcoal and filtered, the liquid is treated again with decolorizing charcoal and filtered, and the liquid is
Acidified to PH3 by dropwise addition of 6N hydrochloric acid. This acidic mixture was diluted with ethanol and cooled. The crystalline product was collected, dried, recrystallized from dimethylformamide-water and dried to yield 3.75 g of 1,2-
dihydro-6-methyl-2-oxo-5-(4-
pyridinyl) nicotinonitrile, mp>300°C.

1,2-dihydro-6-methyl-2-oxo-
The acid addition salt of 5-(4-pyridinyl)nicotinonitrile is prepared by mixing 2 g of 1,
2-dihydro-6-methyl-2-oxo-5-
A mixture of (4-pyridinyl)nicotinonitrile with a suitable acid, such as methanesulfonic acid, concentrated sulfuric acid,
Conveniently prepared by adding concentrated phosphoric acid to a pH of about 2-3, cooling the mixture after partial evaporation, and collecting the precipitated salts, e.g. dimethane sulfonate, sulfate, phosphate, respectively. . Also,
An acid addition salt is an equimolar amount of 1,2-dihydro-6 in water.
-Methyl-2-oxo-5-(4-pyridinyl)
It is also conveniently prepared in aqueous solution by adding nicotinonitrile and a suitable acid, such as lactic acid or hydrochloric acid, with stirring to form the monolactate or monohydrochloride salt, respectively, in aqueous solution.

B-2 6-ethyl-1,2-dihydro-2-oxo-5-PY-nicotinonitrile, or 2-
Ethyl-1,6-dihydro-6-oxo-[3,
4′-Bipyridine]-5-carbonitrile, mp>
300°C, 11.6g was prepared according to the method of Example B-1 above, and 20g of 1-(4-pyridinyl)-2-
(dimethylamino)ethenyl ethyl ketone, 8.4
g of α-cyanoacetamide, 16.2 g of sodium methoxide and 250 c.c. of dimethylacetamide (as a solvent in place of dimethylformamide)
manufactured using.

B-3 1,2-dihydro-2-oxo-6-n
-propyl-5-(4-pyridinyl)nicotinonitrile, or 1,6-dihydro-6-oxo-
2-n-propyl-[3,4'-bipyridine]-5-
Carbonitrile, mp 232-234°C, 99g was prepared by adding 85g of 1% according to the method described in Example B-1.
-(4-pyridinyl)-2-(dimethylamino)ethenyl n-propyl ketone, 36.5 g of alpha-cyanoacetamide, 50 g of sodium methoxide and 800 c.c. of dimethylacetamide.

B-4 1,2-dihydro-1,6-dimethyl-
2-oxo-5-(4-pyridinyl)nicotinonitrile, or 1,6-dihydro-1,2-dimethyl-6-oxo-[3,4'-bipyridine]-5-
Carbonitrile, mp 245-248° C., 32.3 g was prepared according to the method described in Example B-1 above, at 42.5
Using g of 1-(4-pyridinyl)-2-(dimethylamino)ethenyl methyl ketone, 23.5 g of N-methyl-α-cyanoacetamide, 6.7 g of sodium methoxide, 400 ml of methanol and 2 hours of reflux time. Manufactured by

According to the method described in Example B-2, 1,2-
dihydro-6-methyl-5-(3-methyl-4-
pyridinyl)-2-oxonicotinonitrile (m.
p.>260°C).

C 1-R ₁ -1,2-dihydro-6-lower alkyl-2-oxo-5-(pyridinyl)nicotinamide C-1 1,2-dihydro-6-methyl-2-oxo-5-(4- pyridinyl) nicotinamide;
or 1,2-dihydro-2-methyl-6-oxo-[3,4'-bipyridine]-5-carboxamide.

1,2-dihydro-6-methyl-2-oxo-
A mixture containing 9.0 g of 5-(4-pyridinyl)nicotinonitrile and 45 c.c. of concentrated sulfuric acid was heated at 100°C using an oil bath.
heated for 30 minutes. The hot reaction mixture was poured into 200 c.c. of ice and the resulting mixture was cooled in an ice/acetone bath. Approximately 150 c.c. of 28% ammonium hydroxide was carefully added dropwise to this cold solution. The resulting mixture containing the precipitate was cooled in an ice/acetone bath for approximately 30 minutes. Collect the precipitate, wash sequentially with water and acetonitrile, dry thoroughly, dissolve in 130 c.c. of hot water (near boiling), add 30 c.c. of acetic acid, treat with decolorizing charcoal,
Recrystallization was carried out by filtration. The solution was concentrated, diluted with acetonitrile, and the mixture was kept on ice for about 30 minutes. The resulting crystalline material was collected to yield 8.35 g of tan crystalline material. This material was combined with the same material from another run, a total of 13.5 g dissolved in 500 c.c. of boiling dimethylformamide, the hot mixture filtered and the liquid cooled in an ice bath. The crystalline precipitate was collected, washed with acetone and dried over P ₂ O ₅ at 100 °C for 14 h.
According to its IR and NMR analysis, it was found that it still contained some dimethylformamide. 10.5 g of this pale yellow crystalline product was dissolved in 75 c.c. of hot acetic acid, treated with 50 c.c. of water and 300 c.c. of acetone.
diluted to an amount of The resulting mixture containing some crystals was cooled in an ice bath for about 45 minutes. The precipitated light tan crystalline product was collected and heated first at 55°C and then at 110°C.
℃ to completely remove the faint odor of acetic acid, 9.2 g of 1,2-dihydro-6-methyl-2
-Oxo-5-(4-pyridinyl)nicotinamide, mp>300°C was obtained.

1,2-dihydro-6-methyl-2-oxo-
The acid addition salt of 5-(4-pyridinyl)nicotinamide is prepared by adding 5 g of 1,
2-dihydro-6-methyl-2-oxo-5-
A suitable acid, such as methanesulfonic acid, concentrated sulfuric acid, or concentrated phosphoric acid, is added to a mixture of (4-pyridinyl)nicotinamide until the pH reaches about 2-3, and the mixture is cooled after partial evaporation, and the precipitated salts, such as They are conveniently prepared by collecting dimethane sulfonic acid, sulfate, and phosphate, respectively. Also,
The acid addition salt in an aqueous solution is prepared by adding an equimolar amount of 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinamide to water with stirring and a suitable acid (e.g., lactic acid or hydrochloric acid). ) to prepare the monolactate or monohydrochloride in aqueous solution.

C-2 6-ethyl-1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinamide,
or 1,6-dihydro-2-ethyl-6-oxo-[3,4'-bipyridine]-5-carboxamide. 40 g of 6-ethyl-1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinonitrile was added to 170 c.c. of concentrated sulfuric acid. This brings the temperature to about 70
The temperature rose to ℃. The reaction mixture was placed in a preheated oil bath at about 90°C and then held at 95-105°C for about 40 minutes. The hot reaction mixture was poured into a beaker containing 800 c.c. of ice, and the mixture was stirred before being placed in an ice/acetone bath. 650 c.c. of 28% ammonium hydroxide was added dropwise to the cold mixture with stirring, and the temperature rose to about 46°C. Approximately 300 c.c. of ice was added to the mixture while stirring, and stirring continued for approximately 15 minutes. The precipitate was collected, washed with 3 x 150 c.c. of water, air dried for 2 hours, then slurried with a small amount of acetonitrile, filtered and the solid was dried at 55°C for several days to yield 39.5 g of product. Ta. This solid is 300c.c.
Thoroughly stir with water, filter, dry, 38
g of crystalline product, i.e. 6-ethyl-1,2
-dihydro-2-oxo-5-(4-pyridinyl)nicotinamide was obtained. part of this product
14.3 g was dissolved in 40 c.c. of hot acetic acid for further purification, the hot solution was filtered, and the liquid was diluted with absolute ethanol to 180 c.c. to precipitate crystals. The hot mixture was allowed to cool and the pale tan crystalline product was collected and dried over P ₂ O ₅ at 110° C. for about 15 hours.
11.7 g of 6-ethyl-1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinamide,
mp>300°C was obtained.

C-3 1,2-dihydro-2-oxo-6-n
-propyl-5-(4-pyridinyl)nicotinamide, or 1,6-dihydro-6-oxo-2
-n-propyl-[3,4'-bipyridine]-5-carboxide, mp > 300°C, 10.5 g were prepared using 30.7 g of 1,
2-dihydro-2-oxo-6-n-propyl-
5-(4-pyridinyl)nicotinonitrile and 130c.c.
manufactured using concentrated sulfuric acid.

According to the method described in Example C-2, 1,2-
dihydro-6-methyl-5-(3-methyl-4-
pyridinyl)-2-oxonicotinamide (mp
>260℃).

D 1-R ₁ -3-amino-6-lower alkyl-
5-PY-2(1H)-pyridinones D-1 3-amino-6-methyl-5-(4-pyridinyl)-2(1H)-pinolidinone, or 5
-amino-2-methyl-[3,4'-bipyridine]-
6(1H)-on. Sodium hydroxide in 250 c.c. of water
1,2-dihydro-6-methyl-
12 g of 2-oxo-5-(4-pyridinyl)nicotinamide was added and the resulting mixture was heated in a steam bath to dissolve. Another 250 c.c. of water was added to this solution, and the resulting solution was cooled to about 35° C. while stirring, and a small amount of crystals precipitated. The mixture was cooled in an ice bath and a total of 4.0 cc of bromine was added dropwise; dissolution occurred after about 3 cc of bromine had been added. The mixture was stirred for an additional 10 minutes while cooling, then heated in a steam bath for 45 minutes. The reaction mixture was then concentrated to approximately half volume, cooled in an ice bath, and treated with 6N hydrochloric acid until the pH was approximately 8. The resulting crystalline product was collected, washed twice with water and once with acetone,
After drying, 7.3 g of solid was obtained. 7.3g of this with 20ml of water
cc to remove insoluble amorphous material.
The liquid was evaporated to dryness and the resulting crystalline product was recrystallized from dimethylformamide-water to give 3-amino-6-methyl-5-(4-pyridinyl)-2.
(1H)-pyridinone, mp>300°C, 3.8g was obtained.

This acid addition salt of 3-amino-6-methyl-5-(4-pyridinyl)-2(1H)-pyridinone is
A mixture of 2 g of 3-amino-6-methyl-5-(4-pyridinyl)-2(1H)-pyridinone in about 40 ml of aqueous methanol is treated with a suitable acid, such as methanesulfone, until the pH is about 2-3. It is conveniently prepared by adding the acid, concentrated sulfuric acid, concentrated phosphoric acid, cooling the mixture after partial evaporation, and collecting the precipitated salts, such as dimethane sulfonate, sulfate, and phosphate, respectively. In addition, to produce an acid addition salt in an aqueous solution state, an equimolar amount of 3-amino-6-methyl-5-(4-pyridinyl)-2 is added to water with stirring.
This is conveniently carried out by adding (1H)-pyridinone and a suitable acid, such as lactic acid or hydrochloric acid, to prepare the monolactate or monohydrochloride acid, respectively, in aqueous solution.

D-2 3-amino-6-ethyl-5-(4-pyridinyl)-2(1H)-pyridinone, or 5-
Amino-2-ethyl-[3,4'-bipyridine]-6
(1H)-one, mp>300°C, 8.8g is Example D
-1, except that 10.0 g of 6-ethyl-1,2-dihydro-2-oxo-5
-(4-pyridinyl)nicotinamide, 8.8 g sodium hydroxide, 300 cc. water, 3.0 cc. bromine and dimethylformamide - prepared using recrystallization from isopropyl alcohol.

D-3 3-amino-6-n-propyl-5-
(4-pyridinyl)-2(1H)-pyridinone, or 5-amino-2-n-propyl-[3,4'-bipyridin]-6(1H)-one. 8.5g of 1, at room temperature
2-dihydro-2-oxo-6-n-propyl-
To a stirred mixture containing 5-(4-pyridinyl)nicotinamide and 95 c.c. of water was added a solution of 1.32 g of sodium hydroxide in 6 c.c. of water. The resulting slurry was cooled in an ice bath, stirred for 10 minutes, and then added with 22 c.c. of 13.1% sodium hypochlorite aqueous solution.
The solution was added dropwise over a period of minutes. Dissolution occurred.
Stirring was continued for 30 minutes without cooling. obtained
Add 27c.c. of 35% aqueous sodium hydroxide solution to the solution at 15℃.
was added, the reaction mixture was heated in a steam bath to about 60-70° C. for 1 hour, and the warm solution was slowly treated with 14 cc. of glacial acetic acid over 5 minutes, causing a precipitate to separate out. After stirring the mixture _for 5 minutes, the precipitate was collected, washed with warm water, and dried over _P2O5 . The resulting 12 g of product was recrystallized from dimethylformamide (100 c.c.)-water (80 c.c.) and dried overnight at 95° C. over P ₂ O ₅ to yield 9.5 g of 3-amino- 6-n-propyl-
5-(4-pyridinyl)-2(1H)-pyridinone,
mp200-202°C was obtained.

According to the method described in Example D-1, 3-amino-6-methyl-5-(3-methyl-4-pyridinyl)-2(1H)-pyridinone hydrate (4:1),
(mp234~235℃).

E 1-R _1-6 (lower alkyl)-5-PY-2
(1H)-pyridinone E-1 6-methyl-5-(4-pyridinyl)-2
(1H)-pyridinone, or 2-methyl-[3,
4′-Bipyridine]-6(1H)-one. 5.3 g of 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile and 30 g of 85% sulfuric acid
The mixture with cc was heated to about 195°C and gently refluxed for 24 hours, then cooled and poured onto ice. This aqueous mixture was dissolved by addition of concentrated aqueous sodium hydroxide solution.
I set it to PH8. The deposited precipitate (product + Na ₂ SO ₄ ) was treated with chloroform, and the chloroform solution was filtered. The solution was concentrated in vacuo to remove chloroform, and the resulting crystalline residue was recrystallized from methylene dichloride-ether and dried at 75°C for 4 hours to obtain 4.1
g of 6-methyl-5-(4-pyridinyl)-2
(1H)-pyridinone, mp 287-288°C was obtained.

6-methyl-5-(4-pyridinyl)-2
The acid addition salt of (1H)-pyridinone is 6-methyl-
5-(4-pyridinyl)-2(1H)-pyridinone 5
A suitable acid, such as methanesulfonic acid, concentrated sulfuric acid, or concentrated phosphoric acid, was added to a mixture of g and about 100 ml of aqueous methanol until the pH was about 2-3, and the mixture was cooled after incomplete evaporation to precipitate. It is conveniently prepared by collecting salts such as dimethane sulfonate, sulfate, phosphate, respectively. In addition, acid addition salts in an aqueous solution state can be produced by adding equimolar amounts of 6-methyl-5-(4-pyridinyl)-2(1H)-pyridinone and a suitable acid, such as lactic acid or hydrochloric acid, to water with stirring. This is conveniently carried out by preparing the monolactate or monohydrochloride, respectively, in aqueous solution.

E-2 6-ethyl-5-(4-pyridinyl)-2
(1H)-pyridinone, or 2-ethyl-[3,
4′-Bipyridine]-6(1H)-one. A mixture of 9 g of 6-ethyl-1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinonitrile and 50 ml of concentrated sulfuric acid was heated to 200° C. for 24 hours with stirring,
It was cooled to about 40°C and quenched in 200ml of ice water. This aqueous solution was made basic with concentrated ammonium hydroxide,
The precipitated solid was collected, recrystallized from isopropyl alcohol (70 ml), dried under vacuum at 60°C, and
g of 6-ethyl-5-(4-pyridinyl)-2
(1H)-pyridinone, mp 226-228°C was obtained.
When the liquid is concentrated to about 20 ml, 0.4 g of product,
mp225-227°C was obtained.

E-3 6-n-propyl-5-(4-pyridinyl)-2(1H)-pyridinone, or 2-(n-propyl)-[3,4'-bipyridin]-6(1H)-one, mp179 ~180°C, 3.4 g was prepared according to the method described in Example E-2 except that 10 g of 1,2-
dihydro-6-n-propyl-2-oxo-5-
(4-pyridinyl)nicotinonitrile, 42.5cc
Prepared using recrystallization from 85% sulfuric acid and methylene dichloride-ether.

F 1-R ₁ -3-halo-6-(lower alkyl)-
5-PY-2(1H)-pyridinone F-1 3-bromo-6-methyl-5-(4-pyridinyl)-2(1H)-pyridinone, or 5-
Bromo-2-methyl-[3,4'-bipyridine-6
(1H)-on. 6 in 1 of acetic acid heated to 65°C
To a stirred solution of 80 g of -methyl-5-(4-pyridinyl)-2(1H)-pyridinone was added dropwise over 25 minutes 69 g of bromine in 50 c.c. of acetic acid. The reaction mixture was stirred for an additional 30 minutes, then cooled to room temperature and
A crystalline precipitate was collected. This precipitate was dried and suspended in 1500 c.c. of water. When 25 c.c. of 28% ammonium hydroxide was added dropwise to this vigorously stirred suspension, a white creamy precipitate separated. This solid was collected and dried under vacuum at 90°C to produce 101 g of 3-bromo-6-methyl-5-(4-pyridinyl)-2.
(1H)-pyridinone, mp 252-254°C was obtained. A 15 g sample of this product was dissolved in 200 c.c. of hot acetic acid,
passed. The solution was concentrated in vacuo, diluted with methanol, and the resulting white crystalline precipitate was collected and incubated at 100 °C for 16
Vacuum drying for 9.8g of product, mp252~
Obtained 254°C.

The acid addition salt of 3-bromo-6-methyl-5-(4-pyridinyl)-2(1H)-pyridinone is prepared by preparing the acid addition salt of 3-bromo-6-methyl-5-(4-pyridinyl)- in about 100 ml of aqueous methanol. A suitable acid, such as methanesulfonic acid, concentrated sulfuric acid, concentrated phosphoric acid, is added to a mixture of 5 g of 2(1H)-pyridinone until the pH is about 2-3, and the mixture is cooled after partial evaporation.
It is conveniently prepared by collecting the precipitated salts, such as the dimethane sulfonate, sulfate, and phosphate salts, respectively. In addition, to produce an acid addition salt in an aqueous solution state, an equimolar amount of 3-bromo-6-methyl-5-(4-pyridinyl)-2 is added to water with stirring.
This is conveniently carried out by adding (1H)-pyridinone and a suitable acid, such as lactic acid or hydrochloric acid, to prepare the monolactate or monohydrochloride, respectively, in aqueous solution.

F-2 3-chloro-6-methyl-5-(4-pyridinyl)-2(1H)-pyridinone, or 5-
Chloro-2-methyl-[3,4'-bipyridine]-6
(1H)-on.

18.6 g of 6-methyl-5-(4-pyridinyl)-2(1H)-pyridinone and 200 g of acetic acid heated in a steam bath.
ml of the mixture was treated by bubbling it with chlorine for 4 hours. After the reaction mixture was allowed to cool to room temperature, the solid was collected, washed with ether, and dried.
This solid was dissolved in water, the resulting aqueous solution was neutralized with a 2N aqueous potassium hydroxide solution, and the mixture was cooled. The precipitated solid was collected, washed with water, dried, and recrystallized from ethanol to obtain 3-chloro-6-methyl-5(4-pyridinyl)-2(1H)-pyridinone.

G1- _R1-3 [mono- or di-(lower alkyl)amino]-5-PY-6(lower alkyl)-
2(1H)-pyridinone G-1 6-methyl-3-methylamino-5-
(4-pyridinyl)-2(1H)-pyridinone, or 2-methyl-5-methylamino-[3,4'-bipyridin]-6(1H)-one. 19g of 3-bromo
6-Methyl-5-(4-pyridinyl)-2(1H)-
Pyridinone, 70% aqueous methylamino solution, 250 c.c.
A mixture of 60 mg copper bronze and 60 mg cupric sulfate was heated to 160° C. for 48 hours in an autoclave.
The product was recovered by dissolving the crystalline material with a warm aqueous solution of methanol and filtering the resulting mixture. The mother liquor was concentrated and diluted with methanol to obtain a solid (6
g) and others (1 g) were dissolved in a small amount of acetic acid and filtered, and the solution was diluted with water. The resulting crystalline precipitate was collected, thoroughly washed with water, and dried in one liquid at 90°C to give 5.1 g of 6-methyl-3-methylamino-5.
-(4-pyridinyl)-2(1H)-pyridinone, m.
p.270-275°C (decomposition) was obtained. This method consists of 3-
Bromo-6-methyl-5-(4-pyridinyl)-2
Equimolar amount of 3-chloro-6-methyl-5-(4-pyridinyl)-2 instead of (1H)-pyridinone
The same procedure can be carried out using (1H)-pyridinone.

The acid addition salt of 6-methyl-3-methylamino-5-(4-pyridinyl)-2(1H)-pyridinone is prepared by adding 5 g of 6-methyl-3-methylamino-5-
(4-pyridinyl)-2(1H)-pyridinone approx.
A suitable acid such as methanesulfonic acid, concentrated sulfuric acid or concentrated phosphoric acid is added to 100ml aqueous methanol solution until the pH is about 2-3, and after partial evaporation the mixture is cooled and the precipitated salt, e.g. dimethanesulfone, respectively, is added. Conveniently produced by collecting acid salts, sulphates, phosphates. Alternatively, equimolar amounts of 1-(4-pyridinyl)-2-(dimethylamino)ethenyl methyl ketone and a suitable acid, such as lactic acid or hydrochloric acid, are added to water with stirring to form monolactate or monohydrochloride, respectively. Also by preparation in aqueous solution, acid addition salts are conveniently prepared in aqueous solution.

G-2 3-ethylamino-6-methyl-5-
(4-pyridinyl)-2(1H)-pyridinone or 5-ethylamino-2-methyl-[3,4'-bipyridin]-6(1H)-one, mp250°C, 1.6 g
was prepared according to the method of Example G-1, but in this case 16.5 g of 3-bromo-6-methyl-5-
(4-pyridinyl)-2(1H)-pyridinone, 110
cc of methylamine, 15 c.c. of water, 30 mg of copper bronze and 30 mg of cupric sulfate were heated to 150° C. for 45 hours in an autoclave and recrystallized twice from acetonitrile.

G-3 6-methyl-3-(dimethylamino)-5
-(4-pyridinyl)-2(1H)-pyridinone, or 5-(dimethylamino)-2-methyl-[3,
4′-Bipyridine]-6(1H)-one. 20g of 3-
Amino-6-methyl-5-(4-pyridinyl)-2
To a solution obtained by dissolving (1H)-pyridinone in 200 c.c. of formic acid, 20 c.c. of a 37% formaldehyde solution was added dropwise with stirring over 20 minutes. 1 of the reaction mixture
Reflux for 45 minutes and heat to dry under vacuum. The residue was dissolved in methylene dichloride. The resulting methylene dichloride solution was washed and filtered with a saturated aqueous solution of sodium bicarbonate. The solution was dried over anhydrous sodium sulfate, filtered and the solvent was evaporated under vacuum to give 14 g of a yellow crystalline solid. The solids were dissolved in 250 c.c. of hot methylene dichloride, the resulting hot solution was treated with decolorizing charcoal, filtered and concentrated under vacuum to near dryness.
It was then treated with acetonitrile. cooling the resulting mixture of crystalline material and acetonitrile;
Collect and dry the solids to yield a yellow crystalline product with trace amounts of impurities (as shown by TLC)
10.5g was obtained. The solids were dissolved in a chloroform solution and passed through a 21/2 inch silica gel column to remove trace amounts of impurities from the chloroform solution.
The resulting product (10.5 g) was dissolved in methylene dichloride and the solution was diluted with isopropyl alcohol and then concentrated under vacuum and cooled. The precipitate was collected and dried at 80°C to give 6-methyl-3-(dimethylamino)-5-(4-pyridinyl)-2(1H)-
9.0 g of pyridinone (mp 223-225°C) was obtained.

H 1-R ₁ -3(lower acylamino)-6-(lower alkyl)-5-PY-2(1H)-pyridinone H-1 3-acetylamino-6-methyl-5-
(4-pyridinyl)-2(1H)-pyridinone, or N-[1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)]acetamide.
A mixture containing 10.1 g of 3-amino-6-methyl-5-(4-pyridinyl)-2(1H)-pyridinone, 5.7 g of acetic anhydride and 120 ml of pyridine was heated on a steam bath for 1 hour and then cooled. did. The separated product was collected, washed with ether, dried and recrystallized from dimethylformamide to give 3-acetylamino-6-methyl-5-(4-pyridinyl)-
2(1H)-pyridinone was obtained.

3-acetylamino-6-methyl-5-(4-
The acid addition salt of 3-acetylamino-6-methyl-5-(4-pyridinyl)-2 in about 100 ml of aqueous methanol is
A suitable acid, such as methanesulfonic acid, concentrated sulfuric acid or concentrated phosphoric acid, is added to a mixture of 5 g of (1H)-pyridinone until the pH is about 2-3, the mixture is cooled after partial evaporation, and the salt precipitates, For example, they are conveniently prepared by collecting the dimethane sulfonate, sulfate, and phosphate salts, respectively. In addition, an equimolar amount of 3-acetylamino-6-methyl-
Also by adding 5-(4-pyridinyl)-2(1H)-pyridinone and a suitable acid, such as lactic acid or hydrochloric acid, with stirring to prepare the monolactate or monohydrochloride, respectively, in aqueous solution. Acid addition salts are conveniently prepared in aqueous solution.

H-2 3-[2-(acetoxy)propanoylamino]-6-methyl-2(1H)-pyridinone.
Add 16.5 g of 2-acetoxypropanoyl chloride to a mixture of 20.1 g of 3-amino-6-methyl-5-(4-pyridinyl)-2(1H)-pyridinone and 300 ml of pyridine and stir at room temperature for about 1 hour. while dripping. The resulting mixture is cooled on an ice bath. The separated product was collected and washed with ether,
Drying, recrystallization from methanol, subsequent washing with ethanol and ether and drying yields 3-[2-(acetoxy)-propanoylamino]-6-methyl-2(1H)-pyridinone.

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

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

H-15 6-ethyl-5-(5-ethyl-2-pyridinyl)-3-formamino-2(1H)-pyridinone.

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

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

I 1-R ₁ -1,2-dihydro-6-(lower alkyl)-2-oxo-5-PY-nicotinic acid I-1 1,2-dihydro-6-methyl-2-oxo-5-(4 -pyridinyl)nicotinic acid, or 1,6-dihydro-2-methyl-6-oxo[3,4'-bipyridine]-5-carboxylic acid. 30 g of 1,2-dihydro-6-methyl-2-oxo-5
-(4-pyridinyl)nicotinonitrile in 200 c.c. of water.
and 145 c.c. of concentrated sulfuric acid with stirring. The reaction mixture was refluxed (approximately 122°C) for 7 hours and left at room temperature over the weekend. It was then diluted with water, cooled on an ice bath, and ammonium hydroxide was added dropwise with stirring until a neutral pH was reached.
The resulting crystalline precipitate was collected, washed successively with 100 c.c. of water each time, and several times with acetone and then ether, and dried at 80°C. The crystalline material was slurried with 200 c.c. of chloroform and 200 c.c. of methanol for 30 minutes and the resulting mixture was concentrated under vacuum to a volume of 150 c.c. The crystalline product was collected and dried over P ₂ O ₅ at 95° C. to give approximately 24 g of product. Add 10 g of product sample to 200 c.c. of just-boiled water.
The resulting mixture was cooled, the solids were collected and dried at 80°C to give 9 g of 1,2-dihydro-6
-Methyl-2-oxo-5-(4-pyridinyl)
Nicotinic acid, mp>260°C was obtained.

J 1-R ₁ -6-(lower alkyl)-1,2-dihydro-2-oxo-5-PY-lower alkyl nicotinic acid J-1 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl)-ethyl nicotinate, 4 g of 1,2-dihydro-6-methyl-2-
Oxo-5-(4-pyridinyl)nicotinic acid 1
refluxing ethanol with 1 g of methanesulfonic acid
Heated at 200 c.c. for 18 hours. Excess ethanol was removed by evaporation in vacuo and the residue was recrystallized from dimethylformamide to give 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinic acid as the methanesulfonate salt. Obtained ethyl. The salt was dissolved in warm water and made basic using excess potassium carbonate aqueous solution. The separated solids were collected and dried, recrystallized from isopropyl alcohol and dried to obtain ethyl 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinate.

1,2-dihydro-6-methyl-2-oxo-
Ethyl 5-(4-pyridinyl)nicotinate acid addition salt is prepared in a mixture of 5 g of ethyl 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinate in about 100 ml of aqueous methanol. Add a suitable acid, such as methanesulfonic acid, concentrated sulfuric acid or concentrated phosphoric acid, until the pH is about 2-3, cool the mixture after partial evaporation, and dissolve the precipitated salts, such as dimethanesulfonate, sulfate, respectively. , conveniently produced by collecting phosphate salts.
Alternatively, equimolar amounts of ethyl 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinate and a suitable acid, such as lactic acid or hydrochloric acid, are added to water with stirring, and each Acid addition salts have also been conveniently prepared in aqueous solution by preparing the lactate or monohydrochloride salts in aqueous solution.

The usefulness of the compound of general formula, or a salt thereof, as a cardiotonic agent is demonstrated by its effectiveness in standard pharmacological test methods, such as producing a significant increase in contractile force in tests of isolated feline atrial and papillary muscles;
This is demonstrated in studies in anesthetized dogs by producing a significant increase in cardiac contractile force with little or minimal changes in heart rate and blood pressure. Details of these test methods are described in US Pat. No. 4,072,746.

When tested in the isolated feline atrial and papillary muscle test method described above, compounds of the general formula when tested at doses of 3, 10 or 30 μg/ml produced a significant (>25%) increase in papillary muscle strength. Produces a significant (greater than 25%) increase in right atrial force, but only a very small percentage increase in right atrial heart rate (approximately 1/3 or less percent increase in right atrial force or papillary muscle strength) There was found. Furthermore, the general formula 6-
Lower alkyl compounds were unexpectedly found to be significantly more active as cardiotonic agents when tested in comparison to corresponding prior art 6-des(lower alkyl) compounds by this test method. . It has also been found that some of these compounds, such as those in the general formula in which Q is carbamoyl or bromo, are effective as cardiotonic agents, whereas the corresponding 6-des (lower alkyl) compounds It has no cardiotonic properties and is only indicated as an intermediate.

The significant improvement in cardiotonic activity of 6-lower alkyl compounds compared to the corresponding previously known 6-unsubstituted compounds is demonstrated by a comparison of the following test data obtained using the isolated feline atrial and papillary muscle test method described above. It is shown by. 3-amino-6-methyl-5-(4
-pyridinyl)-2(1H)-pyridinone was found to increase the papillary muscle strength and right atrial force by 96% and 74% when tested at 10 μg/ml. In comparison, 3-amino-5-(4-pyridinyl)-2
The corresponding increases for (1H)-pyridinone (anrinone) were 109±11.3% and 49.9±8.4% when tested at 100 μg/ml, or 10 times the dose. The rate of increase in papillary muscle strength and right atrial force for 3-amino-6-ethyl-5-(4-pyridinyl)-2(1H)-pyridinone tested at 3 μg/ml 53
% and 37%, compared to 3-
The corresponding increases for amino-5-(4-pyridinyl)-2(1H)-pyridinone were 54.1 ± 5.3% and 33.6 ± 4.4 when tested at 30 μg/ml, or 10 times the dose.
It was %. 1,2-dihydro-6-methyl-2
- Rate of increase in papillary muscle strength and right atrial force with oxo-5-(4-pyridinyl)nicotinonitrile and 6-ethyl-1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinonitrile is 3μ
45% and 51% 6-methyl compounds when tested in g/ml
%, 6-ethyl compound is 107% and 79%,
The prior art 6-desalkyl compound, namely 1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinonitrile, had a corresponding increase rate of 30 μg/ml, i.e., when tested at a 10-fold higher dose.
It turned out to be 65% and 15%. When tested with 10 μg/ml of 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile, the increase in papillary muscle strength and right atrial force was 135%.
102%, whereas the corresponding 6-desmethyl conventional compound was found to be inactive at 10 μg/ml. 6-methyl-3″-methylamino-5
-(4-pyridinyl)-2(1H)-pyridinone increased the papillary muscle strength and right atrial force by 68% and 41% when tested at 30 μg/ml, whereas the conventional 3-methylamino-5-( 4-Pyridinyl)-2(1H)-pyridinone was found to have a corresponding increase of only 64% and 39% when tested at 100 μg/ml, ie more than three times the dose.

Corresponding prior art 6-des (lower alkyl)
A representative example of a compound of the general formula where Q is carbamoyl or halogen that is effective as a cardiotonic agent, even though the compound is not a cardiotonic agent and is shown only as an intermediate, is 1,2-dihydro6-methyl-2
-Oxo-5-(4-pyridinyl)nicotinamide, which increases the rate of increase in papillary muscle strength and right atrial force when tested in the in vitro cat atrial and papillary muscle tests.
35% and 22% at 30 μg/ml and 100 μg/ml, respectively.
6-ethyl-
1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinamide, which was 29% and 7% at 100 μg/ml and 89% and 29% at 300 μg/ml, respectively, when tested by the same method. ); and 3-
Bromo-6-methyl-5-(4-pyridinyl)-2
(1H)-pyridinone, which was tested in the same in vitro cat atrial and papillary muscle assay at 1.0μ
87% and 99% respectively at g/ml and 107 at 10 μg/ml
% and 58% increase in papillary muscle strength and right atrial power).

Significantly higher inotropic activity of 6-lower alkyl compounds of the general formula where Q is hydrogen compared to the corresponding conventional 6-unsubstituted compounds was obtained using the isolated feline atrial and papillary muscle test method described above. This is shown by the comparison of the following test data. 6-methyl-5
The increase in papillary muscle strength and right atrial force for -(4-pyridinyl)-2(1H)-pyridinone was found to be 115% and 48% when tested at 10 μg/ml. The corresponding increase rate for prior art 5-(4-pyridinyl)-2(1H)-pyridinone is 100 μg/ml, i.e. 10
When double the dose was tested, the rates were 48% and 51%. 6-ethyl-5-(4-pyridinyl)-2
The increases in papillary muscle strength and right atrial force for (1H)-pyridinone were 106% and 50% when tested at 30 μg/ml, whereas for 5-(4-pyridinyl)-2(1H)-pyridinone, The corresponding increases were found to be 48% and 51% when tested at 100 μg/ml, or 3 times more doses.

Representative examples of compounds of the general formula in which Q is carboxy, which are effective as cardiotonic agents, and the corresponding conventional 6-des (lower alkyl) compounds are not shown as cardiotonic agents but only as intermediates, include 1,
2-dihydro-6-methyl-2-oxo-5-
(4-pyridinyl)nicotinic acid, which at 30 μg/ml was 36% and 27%, respectively, when tested in similar in vitro guinea pig atrial and papillary muscle tests.
%, 100 μg/ml was found to show an increase rate of 44% and 69% in papillary muscle strength and right atrial power.

When tested using the anesthetized dog test method described above, the compounds of the general formula showed 0.01, 0.03, 0.10,
Produces only small or minimal changes (less than 25%) in heart rate and blood pressure when administered intravenously as a single bolus injection of 0.30, 1.0 and/or 3.0 mg/Kg. , produced a significant (>25%) increase in cardiac contractile force or contractility. Additionally, 6-lower alkyl compounds of the general formula are significantly more active as cardiotonic agents when tested in this test method compared to the corresponding conventional 6-des(lower alkyl) compounds, as demonstrated in the examples below. was found to be high. When tested according to this anesthesia treatment dog test method, 3
-amino-6-methyl-5-(4-pyridinyl)-
The increase in cardiac contractile force or contractility of 2(1H)-pyridinone was 136% at 1.0 mg/Kg intravenously, whereas the corresponding 6-desmethyl compound (anrinone) increased by 10 times the dose. , i.e. 10mg/Kg
Even when tested by intravenous administration, it was found to be 125.67±10.59%. Similarly, the rate of increase in cardiac contractility of 3-amino-6-ethyl-5-(4-pyridinyl)-2(1H)-pyridinone was determined to be 0.03 by the same method.
33 tested at mg/Kg and 0.10mg/Kgiv respectively
% and 72%, whereas prior art anrinone was tested at 10 times higher doses, i.e. 24.67± and 1.0 mg/Kgiv, respectively.
It was found to be 3.15% and 70.63±7.85%. Also 1,2-dihydro-6-methyl-2-oxo-
The percentage increase in cardiac contractility of 5-(4-pyridinyl)nicotinonitrile when tested in the same manner
49.5% and 87.5% at 0.03mg/Kg and 0.10mg/Kg, respectively, while the corresponding conventional 6
- Desmethyl compounds are 44% and 78%, respectively, when tested at 100 times the dose, i.e. 3 mg/Kg and 10 mg/Kg, and prior art anrinone, respectively, at 10 times the dose, i.e. 0.3
It was found to be 24.67±3.15% and 70.63±7.85% when tested at mg/Kg and 1.0 mg/Kg respectively. Similarly, the rate of increase in contractile force of 6-ethyl-1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinonitrile was determined by this method.
compared to 68.5% and 135% when tested at doses of 0.03 mg/Kg and 0.10 mg/Kg, respectively.
The corresponding conventional 6-desmethyl compounds are respectively
100 times the dose i.e. 3mg/Kg and 10mg/Kg
It was found to be 44% and 78% respectively when tested in Kg.

Acute toxicity test The compound of the present invention, 1,2-dihydro-6-
The toxicity data for methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile (compound of Example B-1) are as follows.

LD ₅₀ for male rats (oral) = 90.9 mg/Kg LD ₅₀ for female rats (oral) = 153 mg/Kg LD ₅₀ for male rats (intravenous) = 72.9 mg/Kg LD ₅₀ for female rats (intravenous) = 76.3 mg/Kg Within its scope, the present invention includes a pharmaceutically acceptable carrier and a compound of the general formula having cardiotonic properties as an active ingredient.
-R ₁ -3-Q-6-(lower alkyl)-5-PY-
2(1H)-pyridinone or a pharmaceutically acceptable acid addition salt or cation salt thereof;
Includes cardiotonic compositions for increasing cardiac contractility. The present invention also provides for administering to a patient in need of treatment to increase cardiac contractility an effective amount of the general formula
-R ₁ -3-Q-6-(lower alkyl)-5-PY-
Also encompassed within the scope is a method of increasing cardiac contractility in such a patient that comprises administering 2(1H)-pyridinone or a pharmaceutically acceptable acid addition or cation salt thereof. In clinical practice, compounds of the general formula or salts thereof are generally administered via oral or parenteral routes in a variety of dosage forms.

Solid compositions for oral administration include compressed tablets,
There are pills, powders and granules. In such solid compositions, at least one active compound is mixed with at least one inert diluent such as starch, calcium carbonate, sucrose or lactose. These compositions may further contain other substances than inert diluents, such as lubricants (eg, magnesium stearate, talc, etc.).

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing water and inert diluents conventionally used in the art such as liquid paraffin. . Besides inert diluents, such compositions can also contain adjuvants such as wetting agents and suspending agents, and sweetening, flavoring, perfuming and preservative agents. According to the invention, the composition for oral administration includes:
Capsules of absorbent material such as gelatin containing active ingredients with or without added diluents or excipients are also included.

Formulations according to the invention for parenteral administration include sterile aqueous, aqueous-organic, 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. Such compositions may also contain adjuvants such as stabilizers, preservatives, wetting agents, emulsifying agents, and dispersing agents.

Sterilization of these compositions can be accomplished, for example, by passing through a bacteria-retaining filter, by incorporating a disinfectant into the composition, or by incorporating a disinfectant into the composition.
This can be carried out by irradiation or heating. They can also be prepared in the form of sterile solid compositions which can be dissolved in sterile water or other sterile injectable media immediately before use.

The proportions of active ingredients in the compositions and methods for increasing cardiac contractility can be varied to obtain a suitable dosage. The specific dosage for a patient depends on the route of administration, duration of treatment,
It may vary according to the judgment of the physician using the weight and condition of the patient, the potency of the active ingredient, and the patient's response thereto as criteria. Therefore, the effective dosage of an active ingredient can be determined by the physician considering all criteria and using his best judgment on the patient's behalf.

Claims (1)

[Claims] 1. General formula [Wherein, Q means hydrogen, amino, cyano, carbamoyl, halogen, lower alkylamino, di(lower alkyl)amino, lower acylamino, carboxy or lower carbalkoxy, and R ₁ means hydrogen or lower alkyl. , R is lower alkyl and PY means 4-, 3- or 2-pyridinyl, or 4-, 3- or 2-pyridinyl having one or two lower alkyl substituents. (1H)-pyridinone compounds and acid addition salts or cation salts thereof. 2 R is methyl or ethyl and PY is 4-
The compound according to claim 1, which is pyridinyl. 3. The compound according to claim 1, which is 3-amino-6-methyl-5-(4-pyridinyl)-2(1H)-pyridinone. 4. The compound according to claim 1, which is 3-amino-6-ethyl-5-(4-pyridinyl)-2(1H)-pyridinone. 5 3-amino-6-n-propyl-5-(4-
2. The compound according to claim 1, which is pyridinyl)-2(1H)-pyridinone. 6. The compound according to claim 1, which is 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile. 7 6-Methyl-3-methylamino-5-(4-
2. The compound according to claim 1, which is pyridinyl)-2(1H)-pyridinone. 8. The compound according to claim 1, which is 3-bromo-6-methyl-5-(4-pyridinyl)-2(1H)-pyridinone. 9. The compound according to claim 1, which is 6-ethyl-1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinonitrile. 10 The compound according to claim 1, which is 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinamide. 11 The compound according to claim 1, which is 6-ethyl-1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinamide. 12 3-ethylamino-6-methyl-5-(4
-pyridinyl)-2(1H)-pyridinone. 13 3-dimethylamino-6-methyl-5-
The compound according to claim 1, which is (4-pyridinyl)-2(1H)-pyridinone. 14 6-methyl-5-(4-pyridinyl)-2
The compound according to claim 1, which is (1H)-pyridinone. 15 6-ethyl-5-(4-pyridinyl)-2
The compound according to claim 1, which is (1H)-pyridinone. 16 The compound according to claim 1, which is 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinic acid. 17 General formula [Wherein, Q means hydrogen, amino, cyano, carbamoyl, halogen, lower alkylamino, di(lower alkyl)amino, lower acylamino, carboxy or lower carbalkoxy, R ₁ means hydrogen or lower alkyl, R is lower alkyl and PY means 4-, 3- or 2-pyridinyl, or 4-, 3- or 2-pyridinyl having one or two lower alkyl substituents] or In the method for producing the salt, (a) General formula [In the formula, R ₃ and R ₄ each mean a lower alkyl group, and R and PY have the same meanings as above] are reacted with malonamide,
or (b) produce a compound of the general formula in which Q is carbamoyl: or ₍ b) produce a compound of the general formula
- reacting with α-cyanoacetamide to form a compound of the general formula in which Q is cyano; then optionally converting the resulting free base into its acid addition salt or converting the resulting compound into its acid addition salt; A method characterized by converting into a cationic salt. 18 A pharmaceutically acceptable inert carrier and, as an active ingredient, an effective amount of the general formula [Wherein, Q means hydrogen, amino, cyano, carbamoyl, halogen, lower alkylamino, di(lower alkyl)amino, lower acylamino, carboxy or lower carbalkoxy, R ₁ means hydrogen or lower alkyl, R is lower alkyl and PY means 4-, 3- or 2-pyridinyl or 4-, 3- or 2-pyridinyl having one or two lower alkyl substituents] and A cardiotonic composition for increasing cardiac contractility, comprising: and/or a salt thereof.