DE3044568A1 - 5- (PYRIDINYL) -2 (1H) -PYRIDINONE, WHICH ARE USEFUL AS CARDIOTONIC AGENTS, AND THEIR PRODUCTION - Google Patents

Description

Case 3678/53
10 / My

STERLING DRUG INC., New York / USA

5- (Pyridinyl) -2 (1H) -pyridinones, which are called cardiotonic Means are useful as well as their manufacture

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

In U.S. Patents 4,004,012 and 4,072,746, cardiotonic Means 3-amino (or cyano) -5- (pyridinyl) -2 (1H) -pyridinone described and alc Zv / ischenverbindungen the corresponding 3-carbamyl compounds, which can alternatively be used as 1,2-dihydro-2-oxo-5- (pyridinyl) nicotinamides are referred to by reaction with a reagent responsible for conversion of the carbamyl group in the amino group is capable, e.g. by Heating with an alkali metal hypohalite, can be converted into the corresponding 3-amino compounds. A preferred one The embodiment of these compounds is 3-amino-5- (4-pyridinyl) -2- (iH) -pyridinone, that generally under dsm na-

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men amrinone and alternatively as 5-Amiui .- [3.4 ^t -bipyridin] -6 (iH) -one is designated. A method described for the preparation of the 3-cyano-5- (pyridinyl) -2 (iH) -pyridinones, which are alternatively referred to as 1,2-dihydro-2-oxo-5- (pyridinyl) -nicotinonitrile, is the reaction of cc- (pyridinyl) -ß- (dialkylamino) -acrolein with cc-cyanoacetamide. US Pat. No. 4,072,746 describes 3-Q-5- (pyridinyl) -2 (iH) -pyridinones, where Q is hydrogen, halogen, lower-alkylamino, di- (lower-alkyl) -amino and NHAc, where Ac is lower alkanoyl or lower carbalkoxy.

The 3-unsubF-c.-5- (pyridinyl) -2 (iH) -pyridinones (Q = H) were by heating the corresponding 3-cyano compounds with aqueous sulfuric acid, the 3-car ~ acidic acids, i.e. 1,2-dihydro-2-oxo-5- (pyridinyl) nicotinic acids, which are then decarboxylated. For this 1,2-dihydro-2-oxo-5- (pyridinyl) nicotinic acid was used no cardiotonic activity shown.

The invention relates to the compounds of formula I.

PY. ^ o. ^ Q

(D

where mean:

Q hydrogen, amino, cyano, carbamyl, halogen, lower-alkylamino, di- (lower-alkyl) -amino, lower-acylamino, Carboxy or lower carbalkoxy;

R _{1 is} hydrogen, lower alkyl or lower hydroxyalkyl;

R is lower-alkyl and

PY 4- or 3- or 2-pyridinyl or 4- or 3- or 2-pyridinyl with one or two lower alkyl substituents,

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or the pharmaceutically acceptable acid addition salts or cationic salts thereof. The compounds of Formula I are useful as cardiotonic agents as determined by standard pharmacological evaluation methods. The compounds of formula I wherein Q is carbamyl and cyano and wherein Q is hydrogen are also useful as intermediates in the preparation of the corresponding ones. Compounds in which Q is amino or halogen. The compounds of formula I wherein Q is halogen are also useful as intermediates in the preparation of the corresponding 3- [mono- or di- (lower-alkyl) -amino] -compounds. Preferred embodiments are those of the formula I 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 preferred embodiments are

1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) nicotinonitrile (formula I where Q = CN; R ₁ = H; PY = 4-pyridinyl and R = methyl);

3-Amino-e-ethyl-5- (4-pyridinyl) -2 (1H) -pyridinone (formula I, in which Q = NH ₂ ; R ₁ = H; PY = 4-pyridinyl; and R = ethyl);

3-Amino-5- (4-pyridinyl) -6-methyl-2 (1H) -pyridinone (Formula I where Q = NH ₂ ; R ₁ = H; PY = 4-pyridinyl; and R = methyl);

6-methyl-5- (4-pyridinyl) -2 (1H) -pyridinone (formula I, in which R ₁ = H; PY = 4-pyridinyl; and R = methyl); and

6-Ethyl-5- (4-pyridinyl) -2 (1H) -pyridinone (Formula I, wherein R ₁ -H; PY = 4-yridinyl; and R = ethyl) or the pharmaceutically acceptable acid addition salts thereof. These particularly preferred embodiments have been found to have a significantly higher cardiotonic activity than the corresponding, known de-alky compounds, 3-amino-5- (4-pyridinyl) -2 (1H) -pyridinone, than Ararinon is known; 1,2-dihydro-2-oxo-5- (4-pyridinyi) -nicotinonitrile and 5- (4-pyridinyl) -2 (1H) -pyridinone.

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

(a) Reaction of a compound of formula III

R ₃ R ₄ NCH = CC (= 0) -R (III)

PY

wherein R _{1 and R 4 are} each lower alkyl, with malonamide to form a compound of the formula I _: wherein Q is carbamyl, or

(b) Reaction of either a compound of the above formula III or of the formula IV

R-C-CH-CHO (IV)

II t

0 PY

with N-R ^ -cc-cyanoacetamide to produce a compound of formula I wherein Q is cyano;

if desired, partial hydrolysis of a obtained compound of the formula I, in which Q is cyano, to obtain a corresponding compound in which Q is carbamyl is;

if desired, reaction of a compound obtained of formula I wherein Q is carbamyl with a reagent that causes the conversion of carbamyl to amino for instant generation the corresponding compound wherein Q is amino;

if desired, reaction of a compound obtained of the formula I, in which Q is amino, with 1 or 2 molar equivalents of a lower-alkylating agent to obtain the corresponding compound in which Q is lower-alkylamino or di- (lower-alkyl) -amino is;

if desired, reaction of a compound of the formula I obtained, in which Q is amino, with a lower acylating agent to produce the corresponding compound wherein Q is lower acylamino;

if desired, hydrolysis of a compound obtained of formula I in which Q is cyano to obtain the corresponding compound in which Q is carboxy;

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if desired, heating an elevated connection

of the formula I, in which Q is carboxy, with a mixture of con-

k _iK> Schute L SCL ^ rv

centered sulfonic acid / and concentrated nitric acid for Obtaining the corresponding compound in which Q is nitro, this compound in which Q is nitro, then reduced to obtain a compound wherein Q is amino;

if desired, heating a compound of the formula I obtained, in which Q is cyano or carboxy, with an aqueous solution Mineral acid to give the corresponding compound, wherein Q is hydrogen;

if desired, esterification of a compound of the formula I obtained, in which Q is carboxy, with a lower alkanol to obtain the corresponding compound in which Q is lower carbalkoxy;

if desired, reaction of a compound of the formula I obtained, in which FL is hydrogen, with an alkylating agent of the formula R ¹ -An, in which R ^{1 is} lower-alkyl or lower-hydroxyalkyl and An is an anion of a strong inorganic acid or an organic sulfonic acid, for Preparation of the corresponding compound in which R "is R ';

if desired, reaction of a compound of formula I obtained, wherein Q is hydrogen, with halogen to produce the corresponding compound wherein Q is halogen;

if desired, 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 produce one corresponding compound in which Q is lower-alkylaraino or di- (lower-alkyl) -amino; and

if desired, transfer of a free one obtained Base into an acid addition salt or conversion of a obtained one Compound into a cationic salt thereof.

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304456a -.11 -

One can use a PY-methyl-lower-alkyl-'ketone of the formula PY-CH ₂ -C (= O) -R (II) with di- (lower-alkyl) -formamide-di- (lower-alkyl) -acetal convert to produce the 1-PY-2- [di- (lower-alkyl) -amino] -ethenyl-lower-alkyl-ketone of the formula III

R ₃ R ₄ NCH = C-CC = O) -K (III)

PY

in which R, and R each denote lower-alkyl and aine is preferably methyl and PY, R, R ^ and R ¹ have the meanings given for formula I. These 1- (pyridinyl) -2- [di- (lower-alL / l) -amino] -ethenyl-lower-alkyl-ketones of the above formula III, in which PY and R have the meanings given for formula I, or their acid addition salts are novel compounds according to a feature of the present invention.

The invention also relates to a cardiotonic composition for increasing cardiac contractility, said composition comprising a pharmaceutically acceptable carrier and, as the active component, an effective amount of a cardiotonic 1-R ₁ -3-Q-5-PY-6-R-2 (iH) - pyridinons of formula I wherein R., Q, PY and R are each as defined in formula I, or a pharmaceutically acceptable acid addition salt or cationic salt thereof.

One can increase cardiac contractility in a patient in need of such treatment by a process which involves the administration of an effective amount of a cardiotonic 1-R ₁ -3-Q-5-PY-6-R-2 (1H) -pyridinone of Formula I wherein R ₁ , Q, Pt and R are each as defined in Formula I, or a pharmaceutically acceptable acid addition salt or cationic salt thereof, to such a patient.

The term "lower-alkyl" used here, for example as a meaning of R, as one of the meanings of FL _t as a meaning

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3044S68

of "lower-alkyl" in lower-alkylyrri.no or di- (lower-alkyl) -amino as a meaning for Q or as a substituent for PY in formula I, denotes alkyl radicals with 1 to 6 carbon atoms, which can be straight or branched chain, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, n-amyl, n-hexyl ¹ JUId the like.

The term "lower hydroxyalkyl" used here, for example as one of the meanings for R ₁ in formula I, denotes hydroxyalkyl radicals with 2 to 6 carbon atoms which have their hydroxy group and their free valence bond (or connecting bond) on different carbon atoms, e.g. 2-hydroxyethyl , 2-hydroxypropyl, 3-hydroxypropyl, 2-H} ^r hydroxy-2-toethylpropyl, 2-hydroxy-1, 1-dimethyla thy 1,4-hydroxybutyl, 5-hydroxypentyl, 6-hydroxyhexyl and the like.

Examples of PY in formula I, in which PY is a 4-, 3- or 2-pyridinyl with one or two lower-alkyl substituents, are the following: 2-methyl-4-pyridinyl, 2,6-dimethyl-4-pyridinyl, 3-methyl-4-pyridinyl, 2-methyl-3-pyridinyl, 6-methyl-3-pyridinyl (alternatively referred to as 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 ,? -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- ^ · - pyridinyi, 2,6-di-n-hexyl-4-pyi * idinyl and the like.

The term "lower acyl" as used herein, e.g. 3- (lower-acylamino) -Su.bstituenten in the compounds of Formula I (Q = lower acylamino), means Alkanoyj.reste with 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, and with substituents selected from hydroxy, acetoxy or propionoxy including the straight - and branched -

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chain radicals, e.g. formyl, acetyl, propio:. ^ /]. (n-propanoyl), Butyryl (n-butanoyl), isobutyryl (2-methyl-n-proparioyl), Caproyl (n-hexanoyl), hydroxyacetyl, cc-hydroxypropionyl, ß-hydroxypropionyl, a-acetoxypropionyl, propionoxyacetyl, β-acetoxypropionyl, α-acetoxybutyryl and the like.

The compounds of the formulas I and III can both be used in the free base form and in the form of the acid addition salts and both forms are within the scope of the invention. The acid addition salts are simply a more convenient application; in practice, the use of the salt form runs inherently to the use of the base form. The acids used to make the acid addition salts preferably include those which, when combined with the free base, form pharmaceutically acceptable salts deliver, i.e. salts, the anions of which are relatively harmless for animal urgeism in pharmaceutical doses of the salts are, so that the free base (I) inherent, good cardiotonic properties by side effects of the anions not be affected. In practicing the invention, it is convenient to use the shape of the free To apply base; however, suitable pharmaceutically acceptable salts within 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 Hydrochloride, sulfate, phosphate, sulfamate, acetate, citrate. Lactate, tartrate, methanesulphonate, ethanesulphonate, henzenesulphonate, p-Toluenesulfonate, Cyclohexylsulfamat or Chinat result.

The acid addition salts of the basic compound (I or III) have been produced either by dissolving the free bas ^ in

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aqueous or aqueous L ^ -alcoholic solution or other suitable Solvents containing the appropriate acid and isolating the salt by evaporating the solution or by the reaction of free brine and acid in an organic one Solvent, in which case the salt separates out directly, or can be obtained by concentrating the solution can.

Although pharmaceutically acceptable salts of the basic compound (I or III) are preferred, all acid addition salts are within the scope of the invention. All saxir addition salts are useful as sources of the free base form, even when the particular salt as such is only an intermediate is desired, for example, when the salt was formed for purification or identification purposes only, or when it is used as an intermediate in the manufacture of a pharmaceutically acceptable salt by ion exchange.

Other pharmaceutically acceptable salts of the compound of Formula I are those cationic salts derived from strong ones inorganic or organic bases, e.g. sodium hydroxide, potassium hydroxide, trimethylammonium hydroxide, to generate of the corresponding. 1- or N-cationic salt, e.g. the sodium, potassium, trimethylammonium salt, i. 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 IZI were determined on the basis of the investigations by Infrared spectrum, nuclear magnetic resonance spectrum and Mass spectrum as well as by agreement of the calculated and found values for the elemental analysis.

The invention will be described in general below, so that the expert in your field of pharmaceutical chemistry can then pi "work.

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The production of the 1-PY-2- (dimethylamine ») - äthenyl-lower alkyl-ketone (III) by reaction of PY-methyl-lower 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 expediently carried out at room temperature, i.e. etvre. 20 to 25 ° C, carried out or by heating the reactants down to about 100 ° C, preferably in an aprotic solvent, expediently hexamethylphosphoramide, because of the method used to 'produce the PY-methyl-lower-alkyl-ketone, as in Example A-1 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 of dimethylformamide di - (lower alkyl) acetal. This procedure is illustrated in Examples A-1 through A-17 below.

The PY-methyl-lower alkyl ketones (II) used as intermediates are generally known compounds which are prepared by known methods [for example as indicated in: Rec.trav.chim 72, 522 (1953); U.S. Patent 3,133,077; Bull.Soc.Chim. 1968 , 4132; Chem. Abstrs. 79: 8539h (1973); Chem. Abstrs. 8 ±, 120, 401a (1974); J.Org.Chem. 3-9, 3834 (1974); Chem. Abstrs. 87: 6594q (1977); J.Org.Chem. 43,, 2286 (1978)].

The reaction of 1-PY-2- (dimethylamino) -ethenyl-lower-alkylctvtons (III) with NR ^ -a-cyanoacetamide to form the 1-R ^ - 1,2-dihydro-2-oxo-5-PY- SR 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 zv / square under Ver \. ^r he, d \ mr; an alkali-low-alkoxide,

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preferably sodium methoxide or alkoxide, in dimethylformamide carried out. In carrying out the invention was the reaction is carried out in refluxing dimethylformamide using sodium methoxide. Alternatively you can Methanol and sodium methoxide or ethanol and sodium ethoxide as solvents or basic "condensation agents uses white; .'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., tetrahydrofuran, acetonitrile, ether, benzene, dioxane, and the like. This procedure is described below in Examples B-1 to B-21.

Alternatively, the preparation of 1-R ^ -i, 2-dihydro-2 »oxo-5-PY-6-nicotinonitrile by heating a 1-PY-2- (R, R ^ - amino) ~ ethhenyl ~ lower alkyl ketone (III) in an aqueous alkaline medium, e.g. aqueous sodium or potassium hydroxide solution, take place to the corresponding a-PY-ß-R-ßoxopropionaldehyde Form (IV), and reaction of (IV) with N-R ^ -a-cyanoacetamide.

Alternatively, the 1,2-dihydro-2-oxo-5-PY - ^ - R-nicotinamide (I, Q = carbamyl and R ₁ = ¥ hydrogen) can be obtained directly by reaction of 1-PY-2- (R, R ^ -amino) -ethenyl-lower-alkyl-ketone of the formula III can be prepared with malonamide.

The partial hydrolysis of 1-R ₁ -I, 2-dihydro-2-oxo-5-PY-6-R-nicotinonitrile (I, Q = cyano) to produce 1,2-dihydro-2-oxo-5- PY-6-R ~ nicotinamide (I, Q = carbamyl) is carried out by heating the same (I, Q = cyano) with concentrated sulfuric acid. Although the reaction bsi suitably and preferably by heating the Reaktionsteilnelimer on a Daapf- or oil bath about 90 to 100 ⁰ C performed v / LRD, can e'er

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Temperature range for the reaction from about 70 to 120 ° C vary. This procedure is further illustrated in Examples C-1 through C-21 below.

The conversion of 1-R ₁ -I, 2-dihydro-2-oxo-5-PY-6-R-nicotinamide (I, GUCarbamyl) to 1-R ₁ -3-araino-5-PY-6-R- 2 (iH) -pyridirxone (I, Q = amino) is carried out by reacting the same (I, Q = carbamyl) with a reagent capable of converting carbamyl to amino, for example an alkali metal hypohalite or lead tetraacetate. This reaction is expediently carried out by heating an aqueous mixture which contains an alkali metal hypohalite, preferably sodium hypobromite or hypochlorite, and the compound I (Q = carbamyl), and then acidifying the reaction mixture, preferably with an aqueous mineral acid, e.g. hydrochloric acid. The reaction may be from about 40 to 100 ⁰ C, preferably 70 to 100 ⁰ C is performed. This procedure is described below in Examples D-1 through D-21.

Alternatively, the 1-R ₁ -3-amino-5-PY-6-R-2 (iH) -pyridinone (Ί, Q = amino) can be prepared by heating "5-PY-6-R-2 (iK ) -pyridinone with a mixture of nitric acid and sulfuric acid to produce 3-nitro-5-PY-6-R-2 (iH) -pyridinone and either direct reduction of the 3-nitro compound to produce 3-amino-5-PY- 6-R-2 (1H) -pyridinone '(I, Q is amino and R is hydrogen) or -. ^ waxed alkylation (. cf. the next section) ,, the 3-nitro compound to produce 1-R ₁ -3 -Nitro-5-PY-6-R-2 (iH) -pyridinone and reduction of the nitro compound to produce 1-R ₁ -3-Amino-5-PY-6-R.-2 (iH) -pyridinone ( I, Q = amino and R ₁ - lower alkyl or lower hydroxyalkyl).

Alternatively, the compounds of the formula I in which R ^ low-alkyl or low-hydroxyalkyl are by reaction of the corresponding i-unsubstituiertori

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Compounds of the formula I in which R _{1 is} hydrogen with a lower-alkyl or lower-hydroxyalkyl ester of a strong inorganic acid or an organic sulfonic acid, preferably in the presence of an acid acceptor.

The conversion of 1-R ..- 1 ^ -

nitrile (I, Q ^ cyano) in 1-R ^ -5-PY-6-R ~ 2 (iH) -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 the formula I (Q = carboxy), and then heating is continued for a longer period of time, after which the 3-carboxylic acid is decarboxylated to form of I (Q = hydrogen). This procedure is below in the examples E-1 to E-21 explained in more detail.

The reaction of 1-R ₁ -S-PY-SR-Zi1H) -pyridinone (I, Q = hydrogen) with halogen to produce the corresponding 3-halogen compound (I, Q = halogen) is carried out by mixing the reactants in a suitable one inert solvent under the reaction conditions, a preferred solvent being acetic acid. The reaction is expediently carried out at room temperature or by heating the reactants to a temperature of up to about 100 ^° C.

Preferred halogens are bromine and chlorine. Any inert solvent can be used, e.g. dimethylformamide, Chloroform, acetic acid and the like. This Vtc driving is explained in more detail below in Examples F-1 to F-22.

The reaction of 1-R ₁ -3-halo-5-PY-2 (1H) -pyridinone. (I, Q = halogen) with a lower-alkylamine or a di- (lower-alkyl) -amine to produce the corresponding 1- R ₁ ~ 5- (r.iec ^I r :: 3-alkylamino) -5-PY-6-R-2 (1H) -pyridinones (I, ü = --- ni edr ic- alkyl amino) or des 1 -R ₁ -3- [di- (lower-alkyl) -aminoJ-5-PY-

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2 (iH) -pyridir.Dns [I, Q = di- (lower-alkyl) -amino] is carried out by heating the reactants in an autoclave at about 110 to 180 ⁰ C, preferably about 145 to 165 ° C, and preferably in a suitable solvent, for example water, dimethylformamide, dioxane, 1,2-dimethoxyethane and the like. Or mixtures thereof. This procedure is explained in more detail below in Examples G-1, G-2, G-3 through G-7, G-9 through G-19, and G-21 through G-23.

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

A preferred method for the preparation of 1-R "-3-dimethylamino-5- ^p Y-6-R-2 (iH) -pyridinone (I, Q = dimethylamino) is carried out by reacting 1-R., - 3- Amino-5-PY-6-R-2 (iH) -pyridinone (I, Q = amino) with a mixture of formaldehyde and formic acid. This reaction is expediently carried out by heating the 3-amino compound to reflux with an excess of formaldehyde, preferably in aqueous solution, and formic acid, preferably more than twice the molar excess of each A ^ being used. This procedure is detailed in Examples G-3, G-8, and G-20 below.

The acylation of'i-R ₁ -3-amino-5-PY-6-R-2 (1H) -pyridinone (I _t Q = amino) to produce the corresponding 3- (lower-acylamino) compound (I, Q = low acylamino) is carried out by reacting I (Q = amino) with a low acyl halide, for example a low acyl halide, preferably the chloride, a low acyl anhydride and the like, preferably in the presence of an acid acceptor . The acid acceptor is a basic substance, which preferably wast; or-

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■ - 20 -

Forms soluble by-products which are easily separable from the reaction product, including, for example, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium alkoxides, potassium alkoxides, sodium amide and the like. The reaction is preferably carried out in the presence of a suitable solution which is inert under the reaction conditions, ie a solvent such as low-alkanol, acetone, dioxane, dimethylformamide, dimethyl sulfoxide, hexaraethylphosphoramide, or a mixture of solvents, for example a mixture of water and methylene dichloride or chloroform. The reaction is generally conducted at a temperature between about 10 and 150 ⁰ C, preferably about 20 to 25 ° C is performed. This procedure is further illustrated in Examples H-1 through H-17 below.

The hydrolysis of 1-R ^ -1,2-dihydro-2-oxo-5-r ⁾ Y-6-R-nicotinonitrile (I, Q = cyano) to produce iR ^ -1,2-dihydro-2- oxo-5-PY-6-R-nicotinic acid (I, Q = carboxy) is expediently carried out by heating this nicotinonitrile on the steam bath with an aqueous mineral acid, preferably 50? 6 sulfuric acid. 1 to 1-21 explained in more detail.

The esterification of 1-R ^ -1,2-dihydro-2-oxo-5-PY ~ 6-R-nicotinic acid (I, Q = carboxy) to produce lower-alkyl-1-R ,, - 1 ^ -dihydro-Z-oxo-S-PY-ö-R-nicotir.at (I, Q = low-carbalkoxy) is carried out by heating the acid (I, Q = carboxy) with a lower-alkanol at about 25 to 150 ⁰ C, preferably about 50 to 100 ⁰ C, preferably in the presence of a suitable solvent, such as excess uiedrig alkanol and in the presence of an acid catalyst, for example a strong inorganic acid or an organic sulfonic acid, such as hydrochloric acid, sulfuric acid, methanesulfonic acid, p-Toluenesulfonic acid and the like. This method is further explained in Examples J-1 to .1-19.

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

A. 1-PY-2- (dimethylamino) -ethenyl-lower-alkyl-ketones

A-11 1- (4-pyridinyl) -2- (dimethylamino) ethenyl methyl ketone

A mixture containing 20 g of (4-Pyrldiiiyl) -methylethylketon [alternatively named as 1- (4-pyridinyl) -2-propanone] and 30 cm of hexamethylphosphoramide was used with 65 cm of dimethylformamide dimethylacetal and the resulting mixture was refluxed for 30 minutes. In thin layer chromatography (TLC) showed a single spot indicating completion of the reaction. (At a In another attempt, the reaction appeared to have ended after 30 min at room temperature.) The reaction mixture was under evaporated under reduced pressure using a rotary evaporator and a pressure of about 15 mm, and as a crystalline residue of 24 g resulted. The residue was εη by continuous chromatographic extraction Purified alumina (about 150 g) using refluxing chloroform as the eluant. To The extract was heated in vacuo for 1 1/2 h to remove the chloroform, leaving a light yellow, crystalline material, 23.2 g of 1- (4-pyridinyl) -2- (dimethylamino) -ethenylmethyl ketone, alternatively referred to as 4-dimethylamino-2 ~ (/ -: - pyridinyl} -3-buten-2-one, remained.

The above preparation can be carried out using other solvents in place of hexamethylphosphoramide, e.g., dimethylformamide, acetonitrile, or others, above indicated, or in the absence of a solvent; however, hexamethylphosphoramide was appropriately used because (4-Pyridinyl) -methylinethy! Ketone expediently together as a mixture with Hexamethylphüsphoramiü was produced, as from the following manufacturing process:

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To a stirred solution containing 70 cnr freshly distilled diisopropylamine and 200 cnr tetrahydrofuran was added at 0 ⁰ C under nitrogen was added dropwise during 20 min 210 cm ^ added 2.4 M n-butyllithium in η-hexane, and was about 35 Reaktiorsmischung stirred min at about 0 to 5 ° C. To the cold solution, 90 cm of dry hexamethylphosphoramide (no change in temperature) was added dropwise over a period of 10 minutes, and the resulting pale yellow solution was stirred for 15 minutes. A solution of 50 cm 4-picoline in 150 cm dry tetrahydrofuran was added to the cold solution at ^{0 ° C. over the course of 15 minutes and stirring was continued at 0} ° C. for 30 minutes. Then a mixture became what

'S ^

50 cnr dry ethyl acetate and 150 cnr tetrahydrofuran was added over 15 minutes (the temperature rose from 0 ° to about 6 ° C.) and the resulting mixture was stirred ^{at 0 ° C. for 20 minutes.} The ice bath was then removed and stirring continued for an additional 90 minutes after which the temperature of the reaction mixture rose to about 25 ° C. The reaction mixture was then cooled in an ice bath and 60 cm of acetic acid was added over a period of about 30 minutes. The tetrahydrofuran was distilled off in vacuo using a rotary evaporator. The remaining mixture was diluted with 400 cm of water and the aqueous mixture was extracted successively with two 250 cm portions of isopropyl acetate and three 80 cm portions of chloroform. The solvents were distilled off under reduced pressure, and about 137 g of a mixture consisting mainly of the desired product and hexamethylphosphoramide were obtained. A further approach was carried out using the same amounts as above, with the exception that after the addition of 60 cnr glacial acetic acid the mixture was reduced to only 55%

^ .00 cnr of water diluted, the phases separated and the aqueous Phase was extracted with five 100 ml portions of chloroform. The chloroform extract was washed with saline and the

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Chloroform was distilled off in vacuo. The remaining 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 to give the following fractions: I. 63 g; . Kp bis.112 110 ⁰ C at 4 mm;

II. 59 g of light yellow oil, boiling point 113 to 115 ^° C. at 3 mm; and III. 69 g of light yellow oil, b.p. 115 to 118 ° C. at 2.5 mm. Examination of fraction III by NMR showed that it was composed of a 2: 3 mixture (weight) of (4-pyridinyl) methylene ethyl ketone The acid addition salts of 1- (4-pyridinyl) -2- (dimethylamine) -ethenylmethyl ketone are expediently prepared by adding to a mixture of 5 g of 1- (4-pyridinyl) -2- (dimethylamino ) -äthenylmethylketon in eti-ra 100 ml of aqueous methanol, the appropriate acid is added, for example methanesulfonic acid, concentrated sulfuric acid, concentrated phosphoric acid, up to a pH of about 2 to "3", the mixture is strongly cooled and after partial evaporation the precipitated salt, for example dimethanesulfonate, sulfate or phosphate, is collected. The acid addition salt is also advantageously prepared in aqueous solution by adding molar equivalent amounts of 1- (4-pyridinyl) -2- (dimethy? amino) - to water with stirring. Ethyl methyl ketone and the appropriate acid, e.g. lactic acid or hydrochloric acid, are added, to produce the monolactate or monohydrochloride salt in aqueous solution.

A-2 1- (4-pyridinyl) -2- (dimethylamino) -äthenylät hy! Ketone

A mixture containing 87.5 g of (4-pyridinyl) methyl ethyl ketone [alternatively referred to as 1- (4-pyridinyl) -2-butanone] and 160 enr ⁵ hexamethylphosphoramide was diluted with 100 g of dimethylforaamide dimethylacetal and the resulting mixture was dissolved under nitrogen stirred at room temperature for 45 min. 'C ^ 2 methanol formed in the reaction v / ur-

130035 / 0.450

ORiGiNAL INSPECTEB

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de distilled off in vacuo using a rotary evaporator and the remaining material was distilled under reduced pressure and gave two fractions, one boiling at 45 to 80 ° ^{C. at 0.5 mm and a second boiling at 90 to 95 °} C. below 0.5 mm Fraction. TLC analysis showed predominantly only one spot for each fraction, the two fractions were combined (135 g) and taken up in 600 cnr chloroform. The resulting solution was washed with two 300 cm portions of water and the water was back extracted with three 100 cm portions of chloroform. The combined chloroform solution was dried over anhydrous sodium sulfate and purified by continuous extraction chromatography on 300 cm alumina using refluxing chloroform as the eluent. The chloroform was distilled off in vacuo to give a red oil which crystallized upon standing in an ice bath overnight. The crystalline material was dissolved in carbon tetrachloride _t it cyclohexane was added and the mixture cooled to give 64 g of the resulting yellow, crystalline product, 1- (4-pyridinyl) -2- (dimethylamino) -äthenyläthy! Ketone. A further 11 g of crystalline product were obtained from the mother liquor by continuous extraction chromatography on aluminum oxide using refluxing chloroform as the eluent.

The above intermediate (4-pyridinyl) -methylethy] ketone was in a mixture with hexaraethylphosphoramide as follows obtained: To a 200 cnr tetrahydrofuran ^ nd 70 cnr Mixture containing diisopropylamine were heated under nitrogen

ο "5

at 0 to 5 C 210 csr 2,4N n-butyllithium in n-hexane and the resulting mixture was stirred for 30 min. Then vmrden for 10 minutes 90 cm "hexamethylphosphoramide was added and then the mixture was stirred PY min. Then, during egg

130035 / 0A50

■ ζ

A solution of 48 cm 4-picoline in 150 cm tetrahydrofuran was added over a period of 15 minutes and the mixture was then stirred ^{at about 0 ° C. for 30 minutes.} The ice / acetone bath, which cooled the reaction mixture, was replaced by a dry ice / acetone bath, and a mixture of 75 cm of ethyl propionate in an equal volume of tetrahydrofuran was added to the reaction mixture over the course of 20 minutes. The reaction mixture was then allowed to warm to room temperature for about 50 minutes and then warmed to about 35 ° C for 30 minutes. The mixture was then cooled in an ice / acetone bath and 60 cm of glacial acetic acid was added over 30 minutes. The resulting, bright

■ 7.

yellow suspension was diluted with 200 cnr v / water. The mixture was extracted with three 150 cm portions of ethyl acetate and the ethyl acetate extract was backwashed with brine. The extract was heated in vacuo to remove the ethyl acetate and the residue was again dissolved in ethyl? _L acetate added. The solution was washed with water and then heated in vacuo to remove the ethyl acetate to, then the residue in vacuo at 50 ⁰ C for about 30 min and was heated gave 100 g of a light yellow oil. The light yellow oil was combined with corresponding samples, which were obtained in two further operations, and then distilled in vacuo and gave a fraction of 256 g, b.p. 65 to 105 ° C. at 0.5 to 1.0 mm. The JJMR spectrum of this fraction showed that it was a mixture of (4-pyridinyl) methyl ethyl ketone and hexamethylphosphoraride in a molar ratio of 1: 1.55, ie 35% or 0.35 × 256 = 90 g of this ketone.

A-3 1- (4-pyridinyl) -2- (dimethylamine) -ätlenyl-n- propyl ketone

iSine 80 g (4-pyridinyl) ~ methyl-n-propyl ketone [alternatively as 1- (4-Pyriäinyi) -2 ~ pentanone referred to] and 46 cm Hexamathylphojphorairäd containing- ITi λr.hung vairde with 250 ren *

130035/0450

ORIGINAL INSPECTED COPV

Acetonitrile diluted. To the mixture vurder 90 cnr dimethylformamide dimethylacetal was added and the resulting reaction mixture was heated on a steam bath for 90 minutes and then distilled under vacuum at about 2 mm to remove volatile materials including methanol, acetonitrile and hexamethylphosphoramide. The remaining pulp was diluted with ethyl acetate and washed with water. The combined, aqueous washing liquids were extracted with five 150 cm portions of ethyl acetate. The combined ethyl acetate solutions were washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The residue crystallized on standing in a freezer. The crystalline product was slurried with cyclohexane, filtered and dried overnight at 30 ° C. and gave 97 g of 1- (4-pyridinyl) -2- (dimethylamino) -ethenyl-n-propyl ketone, melting point 48 bis, as a yellow, crystalline product 50 ⁰ C.

The above intermediate (4-pyridinyl) -methyl-n-propy! Ketone was obtained in a mixture mix hexamethylphosphoramide as follows: To a stirred solution of 70 cui diisopropylamine in 200 cnr tetrahydrofuran were added under nitrogen at about ⁰ ° C. (use of an ice bath) 210 cm ^J ?., 4N n-butyl lithium was added for 20 min and the resulting mixture was ^{stirred for 30 min at about 0} ° C. and 90 cm of hexamethylphosphoramide were added to the mixture with stirring for 10 min, and the resulting mixture was v / stirred for a further 10 min. Then 45 cnr of 4-picoline in 140 carbons of tetrahydrofuran was added dropwise over 15 to 20 minutes. The resulting dark orange-brown solution was stirred for 30 min at 0 ⁰ C and then treated dropwise over a period of 18 min a solution of 68 cnr ethyl butyrate in 63 cirr ⁵ tetrahydrofuran, the temperature from -8 ° to +8 to 10 ⁰ C rose. The reaction mixture was from the Eir.bad

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removed and allowed to warm to room temperature for 75 min. That

The reaction mixture was cooled again and there were ΐΓΟρΐβη-χ

60 cnr glacial acetic acid was added wisely over 15 minutes. A light yellow solid separated out and gave a suspension. The suspension was diluted with water and extracted with two 200 cm portions of ethyl acetate. The ethyl acetate extract was washed with three 100 cubic centimeters of brine, dried over anhydrous sodium sulfate and evaporated in vacuo to give 107 g of a mixture consisting mainly of (4-pyridinyl) methyl-n-propyl ketone and hexamethylphosphoramide. The mixture obtained in this operation was combined with corresponding mixtures which were obtained in two further operations, and the combined mixtures were distilled under vacuum and resulted as the main fraction with a boiling point of 80 to 90 ^° C. at 0.2 mm, a mixture consisting of 80 g (4-pyridinyl) -raethyl-n-propyl ketone and 46 g hexamethylphosphoramide.

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

A-4. 1- (3-Pyridiny1) -2- (dimethylamino) -äthenylme thylketon using (3-pyridinyl) methyl ethyl ketone.

A-5. 1- (2-pyridinyl) -2- (dimethylamino) -ethenylmethyl-ketone using (2-pyridinyl) methyl ethyl 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-butyiketone using (4-pyridinyl) -methyl-n-butylketcr ⁱ ..

AS. 1- (4-pyridinyl) -2- (dimethyamino) -ethenylisobutyl-ketori with preconditioning of ( ^? ! -Pyrldir.yl) -methylisobutylket-yne.

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~ 28 -

A-9. 1- (4-pyridinyl) -2- (dimethylamino) -ethenyl-tert-butyl ketone using (4-pyridinyl) methyl tert-butyl ketone.

A-OK. 1- (4-pyridinyl) -2- (dimethylamine ») -ethenyl-n-pentyl ketone using (4-pyridinyl) methyl n-pentyl ketone.

A-11. '(- (2-Methyl-4-pyridinyl) -2- (dimethylamino) -ethenylethylketone using (2-methyl-4-pyridinyl) -ine thy la thy Ike t ο η.

A-12. 1- (5-methyl-2-pyridinyl) -2- (dimethylamino) -äthe- nylmethylke lon using (5-methyl-2-pyridinyl) -methylmethylketon.

A-13 · 1 ~ (5-ethyl-2-pyridinyl) -2- (dimethylamine) -etheny] ethyl ketone using (5-ethyl-2-pyridinyl) methyl ethyl ketone.

A-14. 1 - (3-Py2 * idinyl) -2- (dimethylamino) - ethenyl ketone using (3-Pyi'idinyl) methyl ethyl ketone.

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

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

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

B. 1-R ₁ -I, 2-dihydro-D- (lower alkyl) -2-OXO-S-PY

nitrile ____

B-1,1,2-dihydro-6 • methyl-2-oxo-5- (4-pyridinyl) nicotinonitrile

alternatively alT'Tröyy

[3 ^ '- bipyridinj-S-carbonitrile

To a 23 g of 1 ™ (4 - pyridinyl) -2- (dimethylamino) -ethenylraethyl ketone and 11 g a ~ Cyaiioacetani.id, dissolved in 400 cm "* Di-

130035/0450

methylformamide, containing mixture were 14 g with stirring Sodium methoxide was added and the resulting reaction mixture was refluxed gently in an oil bath Heated for 1 h. TLC analysis indicated no starting material was contained in the reaction mixture, which was then vacuumed on a rotary evaporator to volume

• z

of about 80 cm. The concentrate was treated with about 160 cn acetonitrile and the resulting mixture was stirred on a rotary evaporator with heating until homogeneous 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-methy1-2-OXO-S- (^ -pyridinyl) nicotinonitrile, the presence of cyano being confirmed by IR analysis. A portion of 8 g of this sodium salt was dissolved in 75 cnr 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 with 6N hydrochloric acid by dropwise addition to a pH of 3. The acid ο mixture was diluted with ethanol and cooled; The crystalline product was collected, dried, recrystallized from Dimethylformainid water and dried, yielding 3.75 g 1> 2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) -nicotinonitrile, m.p.,> 300 ⁰ C.

Acid addition salts of 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) -nicotinonitrile are expediently prepared by adding to a mixture of 2 g of 1,2-dihydro-6-methyl-2-oxo -5- (4-pyridinyl) nicotinonitrile in about 40 ml of aqueous methanol the appropriate acid, for example methanesulfonic acid, conc. Sulfuric acid, conc. Phosphoric acid, to a pH of about 2 to 3 .v \ j ^; e _; -; ühon, --lie mixture after partial / cicttr evaporation stniv:

130035/0450

BAD ORIQ! NAL

304A568

cooled and the precipitated salt is collected, e.g. the dimethanesulfonate, sulfate or phosphate. The acid addition salt can also expediently be prepared in aqueous solution by adding molar equivalent amounts of to water with stirring each 1, Z-dihydro-e-methyl ^ -oxo-S- (4-pyridinyl) nicotinonitrile and the appropriate acid, e.g. lactic acid or hydrochloric acid, are added to prepare the monolactate or monohydrochloride salt in aqueous solution.

B-2. 6-ethyl-1,2-dihydro-2-oxo-5-PY-nicotinonitrile > alternatively referred to as 2-ethyl-1,6-dihydro-6-oxo - [?. 4'-bipyridine] -5-carbonitrile, Melting point> 500 ° C., 11.6 g were prepared analogously to the method described above in Example BT using 20 g of 1- (4-pyridinyl) -2- (dimethylamine) -ethenylethyl ketone, 8.4 g of α-cyanoacetamide , 16.2 g sodium methoxide and 250 cnr dimethylacetamide (as a solvent instead of dimethylformamide).

B-3 · 1 »2-dihydro-2-oxo-6-n-propyl-5- (4-pyridinyl) nicotinonitrile _>

alternatively as 1,6-dihydro-6-oxo-2-n-propyl- [3,4'-bipyridine] -5-carbonitrile Designated, mp 232 to 234 ° C, 9.9 g, was prepared analogously to the method described above in Example B-1 using 85 g of 1- (4-pyridinyl) -2- (dimethylamino) -ethenyl-n-propylke tone, 36.5 g of a-cyanoacetamide, 50 g Sodium methoxide and 800 cnr dimethylacetamide.

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

Alternatively, 2-dimethyl-6-oxo- (3,4 -'- bipyridine) -5-carbonitrile referred to as 1, 6-dihydro-1, mp. 245 to 248 ⁰ C, was gi 32.3 analogously to the above in Method described in Example B-1 prepared using 42.5 g of 1- (4-pyridinyl) -2 ~ (dimeth3 "amino) -ethenyl methyl ketone, 23.5 g of N-methyl ~ a-cya.noacetamide, 6.7 g of sodium mexhoxide, 400 ml of methanol and a reflux time of 2 hours.

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- ■ 31 -

Analogous to the procedure described in Example B-2, but using a molar equivalent amount of the appropriate one 1-PY-2- (dimethylamino) -ethenyl-lower-alkyl-ketone (III) instead of 1- (4-pyridinyl) -2- (dimethylamino) -ethenylethyl ketone and the appropriate N-R ^ -a-cyanoacetamides, the corresponding 1-R ^ -1,2-dihydro-2-oxo-5-PY-6-R-nicotinonitrile of Examples B-5 to B-21 can be obtained.

B-5. 1,2-Dihydro-6- methyl-2-oxo-5- (3-pyridinyl) nicotinonitrile using 1- (3-pyridinyl) -2- (dimethyl ~ amino) -äthenylmethylketon and cc-Cyar.cacetamid.

B-6. 1,2-Dihydro-6-methyl-2-oxo-5- (2- pyridinyl) nicotinonitrile using 1- (2-pyridinyl) -2- (dimethylamino) -ethenylmethyl ketone and cc-cyanoacetamide.

B-7. 1,2-dihydro-6-isopropyl-2-oxo-5- (4-pyridinyl) nicotinonitrile using 1- (4-pyridinyl) -2- (dime thylami no) -äthenylisopropylketon and a-Cyanoacetainid.

B-8. 6-n -Butyl-1,2-dihydro-2-OXO-5- (4-pyridinyl) nicotinonitrile using 1- (4-pyridinyl) -2- (dimethylamino) -ethenyl-n-butyl ketone and α-cyanoacetamide.

B-9. 1,2-dihydro-6-isobutyl-2-oxo-5- (4-pyridi.nyl) -nicutinonitrile using 1- (4-pyridinyl) -2- (dimethylamino) -ethenylisobutylketone and α-cyanoacetamide.

B-10. 1, 2-0 ^ 7 (^ 0-2-0X0-5- (4-pyridinyl) -6-tert-butylnicotinonitrile using 1- (4-pyridinyl) -2- (dimethylamino) -ethenyl-tert-butyl ketone and α-cyanoacetamide.

B-11. 1,2-dihydro-2-oxo-6-n -pentyl-5- (4-pyridinyl) nicotinonitrile using 1- (4-pyridinyl) -2- (dimethylamino) -ethenyl-n-pentyl ketone and α-cyanoacetamide.

B-12. 6-ethyl-1 _f 2-dihydro-5- (2-methyl-4-pyridinyl) -2-oxonicotinonitrile using 1- (2-methyl-4-pyridinyl) -2- (dimethylamino) -ethenylethyl ketone and a- Cyanoacotamide.

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B-13. 1,2-DIhydro-6-methyl-5- (5-methyl-2-pyridinyl) -2-oxonicotinonitrile using 1- (5-methyl-2-pyridinyl) -2- (dimethylamine) -ethenylraethyl ketone and α-cyanoacetamide.

B-14. 6-ethyl-5- (5-ethyl-2-pyridinyl) -1,2-dihydro-2-oxonicotinonitrile using 1- (5-ethyl-2-pyridinyl) -2- (dimethylamine) -äthenyläthylketon ui; d a-cyanoacetamide.

B-15 x 6-ethyl-1,2-dihydro-2-oxo-5- (3-pyridinyl) nicotine nitrile using 1- (3-pyridinyl) -2- (dimethylamino) -ethenylethyl ketone and α-cyanoacetamide.

B-16. 1,2-dihydro-5- (4,6-dimethyl-2-pyridinyl) -6-methyl-2-oxonicotinonitrile using 1- (4,6-dimethyl-2-pyridinyl) -2- (dimethylamine) -ethenylmethyl ketone and α-cyanoacetamide.

B-17. 1,2-dihydro-6-isopropyl-5- (6-methyl-2-pyridinyl) -2-oxo-nicotinonitrile using 1- (6-methyl-2-pjTidinyl) -2- (dimethylamine) -ethenyl isopropyl ketone. and α-cyanoacetamide.

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

B-19. 6-ethyl-1,2-dihydro-1- (2-hydroxyethyl) -2-OXO-5- (4-pyridinyl) nicotinonitrile using 1- (4-pyridinyl) -2- (dimethylamino) -ethenylethyl ketone and N- (2-hydroxyethyl) -a-cyanoacetamide.

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

B-21. 1,6-Diethyl-1,2-dihydio-2-oxo-5 ~ (4-pyridinyl) nicotinonitrile using 1- (4-pyridinyl) -2- (dimethylamino) -ethenylethylketone and N-ethyl-a-cyanoacetamide.

C. 1-R ₁ -I, 2-dihydro-6- (lower alkyl) -2-oxo-5- (pyridinyl) nicotinamides

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COPV

3QU568

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

alternatively referred to as 1, Z-yy [3,4'-bipyridine] -5 ~ carboxamide

A 9.0 g of 1, Z-dihydro-e-methyl-Z-oxo ^ - (4-pyridinyl) nicotinonitrile and 45 cnr conc. The mixture containing sulfuric acid was ^{heated for 30 min at aux 10O 0} C using an oil bath. The hot reaction mixture was added to 200 cm of ice and the resulting mixture was cooled in an ice / acetone bath. To the cold solution was carefully added about 150 cubic meters of 28% ammonium hydroxide dropwise. The resulting mixture, containing a precipitate, was chilled in an ice / acetone bath for about 30 minutes. The precipitate was then collected, rinsed successively with water and acetonitrile, dried well and recrystallized by dissolving in 130 cm hot water (at the boiling point), adding 30 carbons of acetic acid, treating with decolorizing charcoal and filtering. The filtrate was concentrated and diluted with acetonitrile. The mixture was kept in ice for about 30 minutes. The resulting crystalline material was collected to give 8.35 g of a tan crystalline material. This material was combined with the same material obtained in a different operation and the combined 13.5 g was dissolved in 500 cnr dimethylformamide in the Si.edehitze, the hot mixture filtered and the filtrate cooled in an ice bath. The crystalline precipitate was collected, rinsed with acetone and for 14 h at 100 ⁰ C over P? 5 ° and dried by IR and NMR analysis it was determined that something was contained dimethylformamide. The 10.5 g buff-colored, crystalline product was dissolved in 75 cubic centimeters of hot acetic acid, treated with 50 cubic centimeters of water and then diluted to a volume of 300 cubic meters with acetone. The resulting mixture, which contained some crystals, was chilled in an ice bath for about 45 minutes. The resulting, light yellow-brown, crystalline.

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Product was collected, ^{dried first at 55 0} C and then at 110 ⁰ C to remove the last faint odor of acetic acid, yielding 9.2 g of 1,2-dihydro-6-methyl-2-oxo-5- ( 4-pyrid3nyl) nicotinamide, m.p.> 3CO ⁰ C

C.

Acid addition salts of 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) nicotinamide are conveniently prepared by adding to a mixture of 5 g of 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) nicotinamide in about 100 ml of aqueous methanol the appropriate acid, e.g. methanesulfonic acid, conc. Sulfuric acid, conc. Phosphoric acid, added to a pH of about 2 to 3, the mixture 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 expediently be prepared in aqueous solution by adding molar equivalent amounts of in each case to water with stirring 1,2-Dihydro-6-methyl-2-oxo-5- (4-pyridinyl) -nicotinamide and the appropriate acid, e.g. lactic acid or hydrochloric acid, be added to the monolactate or mono hydro chloride salt to be prepared in aqueous solution.

C-2. 6-ethyl-1,2-dihydro-2-oxo-5- (4-pyridinyl) nicotine amide

alternatively 1,6-'dihydro-2-ethyl-6-oxo- [3> 4'-bipyridine] -5-carboxamide called

A portion of 40 g of 6-ethyl-1,2-dihyiro-2-oxo-5- (4-pyridinyl) -nicotinonitrile was concentrated to 170 cm-. ⁵ Given sulfuric acid, after which the temperature rose to about 70 ⁰ C. The reaction mixture was poured into a preheated to about 90 ⁰ C Ö: bad dipped and then kept about 40 min between 95 and 105 ⁰ C. The hot reaction mixture was then era in a 800 'cast ^one ice beaker containing. The mixture was stirred and then placed in an ice / acetone bath, to the cold mixture was added dropwise with stirring 650 cnr * 28? Oi ^: es Amrno-

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ORIGINAL INSPECTED

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hydroxide was added and the temperature to about 46 ⁰ C

■ 3 increase. About 300 cubic meters of ice were added to the mixture with stirring and stirring continued for about 15 minutes. The precipitate was collected with three 150 cm 'portions Rinsed with water, dried in the air for 2 h, slurried with a little acetonitrile, filtered and the solid several Days dried at 55 ° C and gave 39.5 g of product. The solid was stirred well with 300 cnr * water, filtered and dried to give 38 g of crystalline product, 6-ethyl-1,2-dihydro-2-oxo-5- (4-pyridinyl) nicotinamide. A 14.3 g portion of this product was further purified by being in 40 cnr hot acetic acid dissolved, the hot solution filtered

and the filtrate was diluted to 180cc with absolute ethanol, after which crystals formed. The hot mixture was allowed to cool. The light tan, crystalline product was collected at 110 ⁰ C over P2O, - for about 15 h dried, yielding 11.7 g of 6-ethyl-1,2-dihydro-2-oxo-5- (4-pyridinyl) nicotinamide , M.p.> 300 ^° C.

C-3. 1,2-dihydro-2-oxo-6-n ~ propyl-5- (4-pyridinyl) -

.nicotinamide

alternatively 1,6 - dihydro-6-ojco-2-n-propyl- [3,4'-bipyridinj-5-carboxamide called, melting point> 300 ° C, 10.5 g, was analogous to the method described in Example C-2 using 30.7 g of 1 ^ -dihydro ^ -oxo-ö-n-propyl ^ - (4-pyridinyl) -nicot.onitrile and 130 cnr concentrated sulfuric acid.

When following the procedure described in Example C-2, but using a molar equivalent amount of the suitable 1-R ^ -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-nicotinann.de of Examples C-4 to C ~ 21 are obtained.

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

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

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

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

C-8. 1 ^ -Dihydro-e-isobutyl - ^ - oxo - ^ - (4-pyridinyl) nicotinamide.

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

C-10. 1,2-dihydro-2-oxo-6-n -pentyl-5- (4-pyridinyl) nicotinamide.

C-11. 6-ethyl-1,2-dihydro-5- (2-methyl-4-pyridinyl) -2-oxonicotinamide.

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

C-13. 6-ethyl-5- (5-ethy3-2-pyridinyl) -1,2-dihydro-2-oxo ni c ο tinami d.

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

C-15. 1,2-dihydro-6-methyl-5- (4,6-diinsthyl-2-pyridium nyl) -2-oxonicotinamide.

C-16. 1,2 ~ Dihydro-6-isopropyl-5- (6-methyl-2-pyridinyl) -2-oxonicotinamide.

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

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

C-19. 6-ethyl ~ 1,2-dihydro-1- (2-hydroxyethyl) -2-oxo-5- ( Z | -pyridinyl) -nico tinamide.

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

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3Q44568

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

D. 1-R ₁ -3-Amino-6- (lower alkyl) -5-PY-2 (1H) -pyridinone D-1 • 5-Amino-6-methyl-g- (4-pyridinyl) -2 (1H) -pyridino n alternatively called 5-amino-2-methyl- [3,4'-bipyridin] -6 (1H) -one "

To a solution containing 13 grams of sodium hydroxide in 250 cubic meters of water was added 12 grams of 1 ^ -dihydro-e-methyl ^ -oxo ^ - (4-pyridinyl) nicotinamide and the resulting mixture was heated on a steam bath to dissolve. A further 250 cm of water were added to the solution and the resulting solution was ^{cooled to about 35 °} C. with stirring, after which some crystals separated out. The mixture was strongly chilled in an ice bath and a total of 4.0 cubic meters of bromine was added dropwise, dissolving after about 3 cubic meters of bromine was added. The mixture was stirred in the cold for an additional 10 minutes and then heated on a steam bath for 45 minutes. The reaction mixture was then concentrated to about half its volume, cooled in an ice bath and treated with 6N hydrochloric acid until the pH was about 8. The resulting crystalline product was collected, rinsed twice with water and once with acetone and dried to give 7.3 g of material. The 7.3 g was treated with 20 cnr water and the insoluble, amorphous material was filtered off. The filtrate was concentrated to dryness and the resulting crystalline material was recrystallized from dimethylformamide / water and gave 3.8 g of 3-amino-6-methyl-5- (4-pyridinyl) -2 (1H) -pyridinone, m.p. 300 ⁰ 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 5-amino-6-methyl-5- (4-pyridinyl) -2 (1 H) - pyridinone in ot './ a 40 ml of aqueous methanol the ^ eoi

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Acid, e.g. methanoulfonic acid, conc. Sulfuric acid, conc. Phosphoric acid, except for a pH of about 2 to 3, the mixture is strongly cooled after partial evaporation and that precipitated salt is collected. e.g. dimethanesulfonate or sulfate or phosphate. The acid addition salt can also be useful be prepared in aqueous solution by adding no! equivalent amounts of 3-amino-6-methyl-5- (4-pyridinyl) -2 (iH) -pyridinone to V / water with stirring and the appropriate acid, e.g., lactic acid or hydrochloric acid, can be added to produce the monolactate or monohydrocarbon salt in aqueous solution.

D-2. 5-Amino-6-ethyl-5- (4-pyridinyl) -2 (iU) -pyridinone , alternatively called 5-amino-2-ethyl- [3,4 ^I -bipyridin] -6 (1H) -one, m.p. .> 30O ⁰ C, 8.8 g, was prepared analogously to the method described in Example D-1, but using 10.0 g of 6-ethyl-1,2-dihydro-2-oxo-5- (4- pyridinyl) nicotinamide, 8.8 g sodium hydroxide, 300 enr water, 3> 0 enr bromine and recrystallization from dimethylformamide-isopropyl alcohol.

D-3 · 3-Amino-6-n-propyl-5- (4-pyridinyl) -2 (1H) -pyridinone alternatively as 5-amino-2-n-propyl- [3,4'-bipyridine] ~ 6 (1H) -one.

To an 8.5 g of 1,2-dihydro-2-oxo-6-n-propyl-5- (4-pyridinyl) nicotinamide and the stirred mixture containing 95 enr of water became a solution of 1.32 g of sodium hydroxide at room temperature given in 6 enr water. The resulting slurry was cooled in an ice bath, stirred for 10 min and carm by adding dropwise 22 cm of 13.1 tiger aqueous Sodium hypochlorite treated over a period of 3 minutes. Dissolution occurred and stirring was continued for 50 minutes without cooling. The resulting solution was at 15 ° C 27% aqueous sodium hydroxide was added. The reaction mixture wi-.r & e 1] i on one. Danpibad box etv / a 60 bic

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Heated 70 ° C, and let the solution wui-de slowly treated with 14 cnr glacial acetic acid over a period of 5 min, after which a yellow-brown precipitate separated out. The mixture was stirred for 5 minutes, the precipitate was collected, washed with warm water and dried over PoOc. It turned out

3 3

12 g of product which was dried, 100 cm Dim & fchylxormamid and 80 cnr umkriWallisiert water and incubated overnight at 95 ⁰ C over P ₂ ⁰ ^; 9 »5 g of 3-amino-6-n-propyl-5- (4-pyridinyl) -2 (1H) -pyridinone, melting point 200 to 202 ° C., were obtained.

If one works according to the procedure described in Example D-1, but using a molar equivalent amount of the appropriate 1-R ₁ -I ^ -dihydro ^ -oxo-S-PY-eR-nicotinamide (I, Q = carbamyl) instead of 1, 2-Dihydro-6-methyl ~ 2-oxo-5- (4-pyridinyl) -nicotinamide, the corresponding 1-R ₁ -3-amino-5-PY-6-R-2 (iH) - pyridinones of Examples D-4 to D-21 can be obtained.

D-4. 3-Amino-6-methyl-5- (3-pyridinyl) -2 (1H) -pyridinorL. D-5. 3 ~ Amino-6-methyl-5- (2-pyridinyl) -2 (1 H) -pyridines. D-6. 3-Amino-6-isopropyl-5- (4-pyridinyl) -2 (1H) -pyridi-

3-Amino-6-n-butyl-5- (4-pyridinyl) -2 (1H) -pyridinone. 3-Amino-6-isobutyl-5- (4-pyridinyl) -2 (1H) -pyridinone. 3-Amino-6-tert-butyl-5- (4-pyridinyl) -2 (IH) -

3-Amillo-6-n -pentyl-5- (4-pyridinyl) -2 (III) -pyridi

D-7.

D-8.

D-9.
pyridinoη -

D-10
non.

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

D-12. 3-Amino-6-methyl-5- (5-methyl-2-pyridinyl) -2 (1H) pyridinone.

D-13. 3-Ars.ino-6-ethyl ~ 5- (5-ethyl-2-pyridinyl) -2 (1H) pyridinor.

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D-14. 3-Aminu-e-ethyl-5- (3-pyridinyl) -2 (1 H) -pyridinone.

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

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

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

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

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

D-20. 3-Amino-1-ethyl-δ-methyl-S- (4-pyridinyl) -2 (1H) pyridinone.

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

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

A mixture of 5.3 g of 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) nicotinonitrile and 30% strength sulfuric acid was heated to about 195 ° C., gently refluxed for 24 hours heated, cooled and added to ice. The aqueous mixture was added by adding conc. brought to pH 8 aqueous sodium hydroxide solution. The resulting precipitate (product plus NapSO ^) was treated with chloroform and the chloroform solution filtered. The filtrate was concentrated to remove the chloroform in vacuo and the resulting crystalline residue was recrystallized from Methylendichlon'd / ether and dried for 4 h at 75 ⁰ C to yield 4.1 g of 6-methyl-5- (4-pyridinyl) - 2 (IH) -pyridinone, mp 287-288 ° C.

Acid addition salts of 6-ethyl 1- (4-pyridinyl) -2 (1H) -pyridinone are expediently produced by adding to a

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mixture of 5 έ 6-methyl-5- (4-pyridinyl) -2 (iH) -pyridinone in about 100 ml of aqueous methanol the appropriate acid, e.g. methanesulfonic acid, conc. Sulfuric acid, conc. Phosphoric acid, until a pH of about 2 Ms 3 is added, the mixture is strongly cooled after partial evaporation and the precipitated Salt is collected, e.g. dimethanesulfonate or sulfate or Phosphate. The acid addition salt can also conveniently be prepared in aqueous solution by adding to water Stir molar equivalent amounts of 6-methyl-5- (4-pyridinyl) -2 (1H) -pyridinone each time and the appropriate acid, e.g. lactic acid or hydrochloric acid, can be added to the monolactate or to produce monohydrochloride salt in aqueous solution.

E-2. e -ethyl-5- (4-pyridinyl) -2 (1H) -pyridinone

alternatively 2-ethyl- [3,4 · -bipyridin) -6 (1H) -one called.

A 9 g of 6-ethyl-1,2-dihydro-2-oxo-5- (4-pyridinyl) nicotinonitrile and 50 ml of conc. The mixture containing sulfuric acid was heated with stirring ^{at 200 ° C. for 24 h, cooled to about 40 °} C. and quenched in 200 ml of ice-water. After the aqueous solution with conc. Ammonium hydroxide had been made basic, the deposited solid was collected, recrystallized from 70 ml of isopropyl alcohol and dried at 60 ° C. in vacuo to give 3 g of 6-ethyl-5- (4-pyridinyl) -2 (1H) -pyridinone, mp 226 to 228 ⁰ C. A zveite yield of 0.4 g., mp. 225-227 ⁰ C, .wurde obtained ml by concentration of the filtrate to about 20.

E-3. 6-n-Propyl-5- (4-pyridinyl) -2 (1H) -pyridinone , alternatively referred to as 2- (n-propyl) - [3,4'-bipyridin] -6 (1H) -one, m.p. 179 to 180 ^° C., 3.4 g, was prepared according to the method described in Example E-2, but using 10 g of 1,2-dihydro-6-n-propyl-2-oxo-5- (4-pyridinyl ) -nicoti- nonitrile, 42.5 cnr 85? '> iger sulfuric acid and Unkr.iGt3.11iGr. ~.:. v? n. from methylene dichloride ether obtained.

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If one works analogously to the process described in Example E-2, but instead of 6-ethyl-1 _f 2-dihydro-2-oxo-5- (4-pyridinyl) nicotinonitrile a molar equivalent amount of the corresponding 1-R ₁ -I , 2-Dihydro-2-oxo-5-PY-6- (lower-alkyl) -nicotinonitrile is used, the iR ^ -5-P ^ - 6- (lower-alkyl) -2 (iH) -pyridinones of Examples E -4 to E-21 can be obtained.

E-4. 6-methyl-5- (3-pvridinyl) -2 (IH) -pyridinone.

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

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

E-7. 6-Isobutyl-5- (4- pyridinyl) -2 (1H) -pyridinone.

E-8. 5- (4-pyridinyl) -6-tert-butyl-2 (1H) -pyridinone.

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

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

E-11. 6-ethyl-5- (3-pyridinyl) -2 (iH) -pyridinone.

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

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

E-14. 1-ethyl-e-methyl-S- (4-pyridinyl) -2 (1H) -pyridinone.

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

E-16. 6-Methy1-5- (2-pyridinyl) -2 (1H) -pyridinone.

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

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

E-19. e-Methyl-5- (4,6-dimethyl-2-pyridinyl) -2 (1H) -pyridinone.

E-20. 6-Isopropyl-5- (6 ~ aethyl-2-pyridinyl) -2 (1H) -pyridino oru

E-21. 6-ri-hexyl-5- (° "pyridinyl) -2 (iH) -pyridinone.

F. 1 -R. | -3-Halo-e- (lower-alkyl) -5-PY-2 (1 H) -pyridinone F-1. ^ -Bromo-S-methyl - ^ - (4-pyridinyl) -2 (1H) -pyridinone, alternatively called 5-bromo-2-methyl- [3 »4'-bipyridin] -6 (1H) -one.

130035 / 0A5G

To a stirred solution of 80 g 6-methyl-5- (4-pyridinyl) -2 (IH) -pyridinone in 1 1 of acetic acid, which is heated to 65 ⁰ C, was added dropwise during 25 min 69 g of bromine in 50 * cnr Given acetic acid. The reaction mixture was stirred for an additional 30 minutes, cooled to room temperature and filtered to collect the crystalline precipitate. The precipitate was dried and suspended in 1,500 cubic meters of water. To the vigorously stirred suspension, 25 cm of 2854 ammonium hydroxide was added dropwise, after which a white, creamy precipitate separated out. The solid was collected and dried in vacuo at 90 ⁰ C to give 101 g of 3-bromo-6 ~ iaethyl-5- (4-pyridinyl) -2 (IH) -pyridinone, mp. 252-254 ° C A sample of 15g [was dissolved in 200cc hot acetic acid and filtered. The filtrate was concentrated in vacuo, diluted with methanol and the resulting white crystalline precipitate was collected, while 16 h in vacuo at 100 G ⁰ dried, yielding 9.8 g of the product 252, mp. To 254 ° C.

Acid addition salts of 3-bromo-6-methyl-5- (4 ~ pyridinyl) ~ 2 (1H) -pyridinones are expediently 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 the appropriate acid, e.g. methanesulfonic acid, conc. Sulfuric acid, conc. Phosphoric acid, added to a pH of about 2 to 3, the mixture strongly cooled after partial evaporation and that precipitated salt is collected, z.3. the dimethanesulfonate or sulfate or phosphate. The acid addition salt can also can advantageously be prepared in aqueous solution by adding molar equivalent amounts of 3-bromo-6-methyl-5- (4-pyridinyl) -2 (iH) -pyridinone to water with stirring and the appropriate acid, e.g., lactic acid or hydrochloric acid, can be added to the Production of the monlactate or monohydrochloride salt in aqueous solution.

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F-2. 3-chloro-6-methyl - ^ - (4-pyridinyl) -2 (1H) -pyridinone, alternatively called 5-chloro-2-methyl- [3,4 ^f -bipyridin] -6 (1H) -one

An 18.6 g of 6-methyl-5- (4-pyridinyl) -2 (1H) -pyridine and 200 ml of acetic acid-containing mixture, which is heated on a steam bath, is passed in chlorine for 4 hours treated. After the reaction mixture has reached room temperature Allowed to cool, the solid is collected, washed with ether and dried. The solid is in water dissolved, the aqueous solution is mixed with 2N aqueous potassium hydroxide solution neutralized and the mixture cooled. The deposited solid is collected, washed with water, dried and recrystallized from ethanol to give 3-chloro-6-methyl-5- (4-pyridinyl) -2 (1H) -pyridinone.

If you work according to the method described in Example F-1 or F-2, but instead of 6-methyl-5- (4-pyridinyl) -2 (1H) -pyridinone a molar equivalent amount of the corresponding 1-R ₁ -6- (lower-alkyl) -5-PY-2 (iH) -pyridinones and bromine or chlorine are used, the corresponding 1-R _-1 -3-bromo- (or chlorine) -6- (lower-alkyl) -5 -PY-2 (1H) -pyridinones of Examples F-3 to F-22 can be obtained.

F-3. 3-chloro-6-ethyl-5- (4-pyridinyl) -2 (1H) -pyridinone.

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

F-5. 3-chloro-6-n-propyl-5- ( ^z : -pyridinyl) -2 (1 H) -pyridinone.

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

F-7. 3-Bromo-6-ii ~ butyl-5- (4-pyridinyl) -2 (1H) -pyridine n.

F-8. 5-chloro-6-isobutyl-5- (4-pyridinyl) -2 (1H) -pyridinone.

P-9. 3-Bromo-5- (4-pyridinyl) -6-tert-butyl-2 (1H) pyridinone.

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

F-11. 3-Bromo-6-ethyl-5- (2-methyl-4-pyridinyl) -2 (1H) -pyridinone «

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F-12. 3 -Chlor-6-ethyl-.5- (3-pyridinyl) -2 (iH) -pyridinone.

F-13. 3-chloro-1, e-dimethyl-S- (4-pyridinyl) -2 (1H) -pyridinone.

F-14. 3-chloro-6-ethyl-1- (2-hydroxyethyl) -5- (4-pyridinyl) -2 (1rf) -pyridinone.

F-15. S-chloro-S-methyl-S- (4-pyridinyl) -2 (1H) -pyridinone.

P-16. 3-Bromo-i, e-diethyl-5- (4-pyridinyl) -2 (1H) -pyridinone.

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

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

F-19. S-bromo-e-e-fchyl-S- (5-ethyl-2-pyridinyl) -2 (1H) -pyridinone.

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

F-21. 3-Bromo-6-isopropyl-5- (6-methyl-2-pyridinyl) -2 (1H) -pyridinone.

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

G. 1-R ₁ -3- [mono- or di- (lower-alkyl) -amino] -5-PY-6- (lower; -alkyl) -2 (1H) -pyridinones

G-1. e-Methyl-S-methylamino-S- (4-pyridinyl) -2 (1H) » pyridinone

alternatively referred to as 2-methyl-5-methylamino- [3 »4 ^f bipyridin] -6 (1H) -one.

A mixture containing 19 g of 3-bromo-6-methyl-5- (4-pyridinyl) -2 (1H) -pyridinone, 250 cnr 70% aqueous methylamine, 60 rag copper bronze and 60 mg copper (II) sulfate, was Treated 48 h at 160 ° C in the autoclave. The crystalline mass was taken up with warm, aqueous methanol and filtered the mixture and collected the product. The solid (6 g) plus a larger portion (1 g), which by Ein narrow the matter liquor and diluting it with methanol was dissolved in a small amount of acetic acid, filtered and. the filtrate is diluted with water. The resulting

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The resulting crystalline precipitate was collected, washed well with water and dried overnight at 90 ° C. to give 5.1 g of 6-methyl-3-methylamino-5- ( ^z- t-pyridinyl) -2 (1H) -pyridinone, m.p. 270 to 275 ° C (decomp.) · This preparation can also be carried out as described above using a molar equivalent amount of 3-chloro-6-methyl-5- (4-pyridinyl) -2 (IH) -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 expediently prepared by adding to a mixture of 5 g of 6-methyl-3-methylamino-5 ~ (4-pyridinyl) -2 (1H) -pyridinone in about 100 ml of aqueous methaxiol die suitable acid, e.g. B. methanesulfonic acid, conc. Sulfuric acid, conc. Phosphoric acid, added to a pH of about 2 to 3, the mixture strong after partial evaporation cooled and the precipitated salt, e.g. dimethanesulfonate or sulfate or phosphate, is collected. The acid addition salt can also be conveniently prepared in aqueous solution by adding mol-equivalent amounts to water with stirring each of 6-methyl-3-methylamino-5- (4-pyridinyl) -2 (iH) -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 (1 H) -pyridinone

alternatively referred to as 5-ethylamino-2-methyl- [3,4'-bipyridine] -6 ( 'IH) -CN, mp. 250 ⁰ C, 1.6 g, was described method according to the in Example G-1, but using 16.5 g of 3-bromo-6-methyl-5- (4-pyridinyl) -2 (1H) -pyridinone, 110 cnr of ethylamine, 15 cnP of water, 30 mg of copper bronze, 30 mg of copper (II) - sulfate, treat in the autoclave at 150 ⁰ C during. 45 h and recrystallization twice from acetonitrile.

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G-3. e-

pyridinone

alternatively 5- (dimethylamino) -2-methyl [3,4'-bipyridin] -6 (1H) -one called

To a stirred solution containing 20 g of 3-amino-6-methyl-5- (4-pyridinyl) -2 (1H) -pyridinone dissolved in 200 cnr formic acid, 20 cnr of a 37 % formaldehyde solution given. The reaction mixture was refluxed for 1 hour and 45 minutes, heated to dryness in vacuo, and the residue was taken up in methylene dichloride. The methylene dichloride solution was washed with saturated aqueous sodium bicarbonate solution and filtered. The filtrate was dried over anhydrous sodium sulfate, filtered and the solvent was distilled off in vacuo, giving 14 g of yellow, crystalline solid. The solid was dissolved in 250 cm hot methylene dichloride, the hot solution was treated with decolorizing charcoal and filtered, and the filtrate was concentrated to almost dryness in vacuo and then treated with acetonitrile. The resulting mixture of crystalline material and acetonitrile was cooled and the solid collected and dried to give 10.5 g of a yellow crystalline product which contained a trace of impurity (determined by TLC). The solid was dissolved in chloroform solution and trace contamination by filtering the chloroform solution through a 2 1/2 inch silica gel column. removed. The resulting product (10.5 g) was dissolved in methylene dichloride, the solution was diluted with isopropyl alcohol and concentrated in vacuo and strongly cooled. The precipitate was collected and dried at 80 ⁰ C to yield 9.0 g of 6-meth \ l-3- (dimethylamino) -5- (4-pyridinyl) -2 (IH) -pyridinone, Fp.223 to 225 ° C .

Following the procedure described in Example G-I or G-2, , but using a molar equivalent amount of

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suitable 1 - ^ - 3-BrOm (or chloro) -5-PY-6 - «. lower-alkyl) 2 (1H) -pyridinone and the suitable lower-alkylamine or di- (lower-alkyl) -amine instead of 3 -Bromo-5-methyl-5- (4-pyridinyl) -2 (1H) -pyridinone, the 1-R ₁ -3- [Mono- or di- (lower-alkyl) -amino] -5-PY- 6- (lower-alkyl) -2 (1 H) pyridinones of Examples G-4 Ms ^ G-23 can be obtained.

G-4. δ-Ethyl ^ -methylamino-S- (4-pyridinyl) -2 (1H) pyridinone.

G-5. S-methylamino-S-methyl ^ - (3-pyridinyl) -2 (1H) pyridinone.

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

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

G-8. δ-n-Butyl ^ -dimethylamino ^ - (A-pyridinyl) -2 (1H) pyridinone.

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

G-10. 3-methyl-amino-5- (4-pyridinyl) -β-tert-butyl-2 (1H) -pyridinone.

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

G-12. 6-ethyl-3-diethylamino-5- (2-methyl-4-pyridinyl,) 2 (1H) -pyridinone.

G-13- 6-Ethyl-3r-ethylamino ~ 5- (3-pyridinyl) -2 (1H) -pyridinone.

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

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

G-16. 1-Ethyl-ü-ynethyl ^ -methylaniino ^ - (4-pyridinyl) 2 (1H) -pyridinone.

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

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

G-19. 3-Ä ^; hylamino-6-methyl-5- ^ -methyl ^ -pyridinyl) 2 (1H) -pyridinone.

G-20. 6-ethyl-5- (5-ethyl-2-pyridinyl) -3-dimethylainino-2 (i H) pyridinone.

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

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

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

H. 1-R ₁ -3 (low-acylamino) -6- (lower-alkyl) -5-PY ~ 2 (1H) - pyridinone

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

alternatively N-M, 2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) J-acetamide called

One 10.1 g of 3-amino-6-methyl-5- (4-pyridinyl) -2 (1H) -pyridinone, The mixture containing 5.7 g of acetic anhydride and 120 ml of pyridine is heated on a steam bath for 1 hour and then cooled calmly. The deposited product is collected, washed with ether, dried and recrystallized from dimethylformamide and gave 3-acetylino-6-methyl-5- (4-pyridinyl) -2 (1H) -pyridinone.

Acid addition salts of 3-acetylamino-6-methyl-5- (4-pyridinyl) -2 (1H) -pyridinone v / ground expediently prepared by adding to a mixture of 5 g of 3-acetylamino-6-methyl-5- (4-pyridinyl) -2 (1H) -pyridinone in about 100 ml of aqueous methanol the appropriate acid, e.g. Hethanesulfonic acid, conc. Sulfuric acid, conc. Phosphoric acid, the mixture is added to a pH of about 2 to 3 ° C

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strongly cooled after partial evaporation and the precipitated Salt is collected, e.g. the dimethanesulfonate or sulfate or phosphate. The acid addition salt can also expediently be prepared in aqueous solution by adding to water under Stir molar equivalent amounts of 3-acetylamino-6-methyl-5- (4-pyridinyl) -2 (iH) -pyridinone in each case and the appropriate acid, e.g., lactic acid or hydrochloric acid, may be added to the monolactate or monohydrochloride salt in aqueous solution to manufacture.

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

To a stirred mixture containing 20.1 g of 3-amino-6-methyl-5- (4-pyridinyl) -2 (1H) -pyridinone and 300 ml of pyridine are added dropwise at room temperature over a period of about A Sia. 16.5 g of 2-acetoxypropanoyl chloride are added and the resulting mixture is cooled in an ice bath. The product which separates out is collected, washed with ether, dried, recrystallized from methanol, washed successively with ethanol and ether and dried, giving 3- [2- ^ lcetoxy) propanoylamino] -6-methyl-2 (1H) -pyridinone.

If you work analogously to the procedure described in Example H-1 or H-2, but instead of 3-amino-6-methyl-5- (4-pyridinyl) -2 (1H) -pyridinone and / or acetic anhydride or 2- Acotoxypropanoyl chloride molar equivalent amounts of the corresponding 1-R ₁ -3 ~ amino-5-PY-6- (lower-alkyl) -2 (1H) -pyridinone and / or suitable nisdrig-acylating agents used, so the 3- (low- Acylarnino) -5-PY-6- (lower-alkyl) -2 (1H) -υ-rridine of Examples H-3 to HI? can be obtained.

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

HA. 6-methyl ~ 3-propionylamino-5- (3-pyridinyl) -2 (1H) -pyridinone »

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

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

H-7. 3-Formylamino-6-isobutyl-2-oxo-5- (4 - pyridinyl) nicotinic acid or -2 (1H) pyridinone.

H-8. 3-acetylamino-6-n -pentyl-5> - (4-pyvidinyl) -2 (1H) -pyridinone.

H-9. 3- [2- (A.cetoxy) -propanoylamino] -6 ~ ethyl-5- (Z-methyl-4-pyridinyl) -2 (1H) -pyridinone.

H-10. 6-ethyl-3-propionylaniino-5- (3-pyridinyl) -2 (1H) pyridinone.

H-11. 3-acetylamino-1,6-dimethyl-2-oxo-5- (4-pyridinyl) -2 (1H) -pyridinone.

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

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

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

H-15. 6-Ethyl-5- (5-ethyl-2-pyridinyl) -3-formylamino-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 -I, 2-dihydro-6- (lower-alkyl) -2-oxo-5-PY-nicotine-

1-1. 1,2-Dihydro-6-methyl-2-oxo-5- (4-pyridinyl) -n icotinic acid

alternatively as 1,6-dihydro-2-methyl-6-oxo- [3,4'-bipyridine] -5-carboxylic acid designated

A portion of 30 g of 1,2-dihydro ~ 6 ~ niethyl-2-oxo-5- (4-pyridinyl) -niootinonitrile v / urde with stirring to a hot,

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220 cnr Wassex and 145 cm conc. Given a solution containing sulfuric acid. The reaction mixture was 7 h (about 122 ⁰ C) heated to reflux and then allowed to stand over the weekend at room temperature. It was then diluted with water, cooled in an ice bath and treated dropwise with stirring with ammonium hydroxide until neutral pH. The resulting crystalline precipitate was collected, washed successively with three 100 cnr servings water and several times with acetone and then washed with ether and at 80 ⁰ C. The crystalline material was slurried with 200 cn chloroform and 200 cn methanol for 30 minutes and the mixture concentrated in vacuo to a volume of 150 cm- '. The crystalline product was collected and ^{dried at 95 °} C. over P ₂ ⁰ 5 and gave about 24 g of product. A sample of 10 g of the product was heated to the beginning of boiling with 200 cm of water, the mixture was cooled and the solid material was collected and ^{dried at 80 °} C. and gave 9 g of 1,2-dihydro-6-methyl-2-oxo-5 - (4-pyridyl) nicotinic acid, mp> 260 ^0C.

If one analogously to the procedure described in Example 1-1 works, but instead of 1,2-dihydro-6-methyl-2 ~ oxo-5- (4-pyridinyl) nicotinonitrile a molar equivalent amount of the corresponding 1-R ^ -1,2-dihydro-2-oxo-5-PY-6- (lower-alkyl) nicotinonitrile used, the 1-R ..- 1, 2-dihydro-2-oxo-5-PY-6- (lower-alkyl) -nicotinic acids can be used of Examples 1-2 to 1-21 can be obtained.

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

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

1-4. 1,2-Dihydro- ^ - oxo-6-n-px-opyl-5- (4-pyridinyl) nicotinic acid.

1-5. 1,2-Dihydro-2-o>: o ~ 6-isopropyl-5- (4 ~ pyridinyl) nicotinic acid.

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1-6. 6-: i-Butyl-1,2-dihydro-2-0X0-5- (4-pyridinyl) nicotinic acid .

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

■ 1-3. 1,2-Dihydro-2-oxo-5- (4-pyridinyl) -6-tert-butylnicotinic acid.

1-9. 1 ^ -Dihydro ^ -oxo-ö-n-pentyl-S- (4-pyridinyl) nicotinic acid.

1-10. 6-ethyl-1,2-dihydro-5- (2-methyl-4-pyridinyl) -2-oxonicotinic acid.

1-11. 6-ethyl-1,2-dihydro-2-oxo-5- (3-pyridinyl) nicotinic acid .

1-12. 1,2-Dihydro-i, e-dimethyl-1-oxo-S- (4-pyridinyl) nicotinic acid.

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

1-14. 1-Ethyl-1,2 ^ x1 ^^ - 6-11 ^ 1 ^ 1-2-0X0-5- (4-pyridinyl) nicotinic acid.

1-15. 1,6-diethyl-1,2-dihydro-2-oxo-5- (4-pyridiryl) nicotinic acid.

1-16. 1,2-dihydro-6-methyl-2-oxo-5- (2-pyridinyl) nicotinic acid .

1-17. 1,2-dihydro-6-methyl-5- (5-methyl-2-pyridinyl) -2-oxonicotinic acid.

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

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

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

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

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J. Lower-alkyl-iR ^ e-C-lower-alkylJ-1, 2-dihydro-2-oxo-5- PY-nicotinate ~ ■

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

A 4 g portion of 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) nicotinic acid is heated in 200 cm of refluxing ethanol with 1 g of methanesulfonic acid 'for 1Ch. That Excess ethanol is distilled off in vacuo and the residue is recrystallized from dimethylformamide and yielded Ethyl-1,2-dihydro-6-methyl-2-oxo-5- (A-pyridinyl) nicotina.t as methanesulfonic acid salt. The salt is in warm water dissolved and the solution made basic with excess aqueous potassium carbonate solution. The solid that separates out is collected, dried, recrystallized from isopropyl alcohol and dried to give ethyl 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) nicotinate.

Acid addition salts of ethyl 1,2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) nicotinate are expediently prepared by adding to a mixture of 5 g of ethyl 1,2-dihydro-6-methyl-2 ~ GXO-5- (4-pyridinyl) nicotinate in about 100 ml of aqueous methanol the appropriate acid, e.g. methanesulfonic acid, conc. Sulfuric acid, conc. Phosphoric acid, to a pH of about 2 to 3 is added, the mixture is strongly cooled after partial evaporation and the precipitated salt is collected, e.g. the Dimethanesulfonate or sulfate or phosphate. The acid addition salt can also expediently be prepared in aqueous solution by adding molar equivalents to water with stirring Amounts of ethyl 2-dihydro-6-methyl-2-oxo-5- (4-pyridinyl) nicotinate in each case and the appropriate acid, 7.B. Lactic acid or hydrochloric acid, to be added to the monolactate or. To produce monohydrochloride salt in aqueous solution.

If you work analogously to the method described in Example J-1, but instead of 1,2-dihydro-6-methyl-2-oxo-5-

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(4-pyridinyl, / - nicotinic acid and ethanol mol-equivalent amounts of the suitable 1-R ₁ -I, 2-dihydro-2-oxo-5-PY-6- (lower ^ alkyl) ~ nicotinic acid and lower alkanol used, so can the lower-alkyl-1 - ^ - 1,2-dihydro-2-oxo-5-PY-6- (lower-alkyl) nicotinates of Examples J-2 to J-19 can be obtained.

J-2. M ° .thyl 1,2-dihydro-6-methyl-2-oxo-5- ( ^z ) -pyridinyl) nicotinate.

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

J-4. n-Propyl-1,2-d: .hydro-6-methyl-2-oxo-5- (3-pyridinyl) nicotinate.

J-5. Ethyl 1,2-dihydro-2-oxo-6-n-propyl-5- (4-pyridinyl) nicotinate.

J-6. Isopropyl 1,2-dihydro-2-oxo-6-isopropyl-5- (4-pyridinyl) nicotinate.

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

J-8. Ethyl 1,2-dihydro-6-isobutyl-2-oxo-5- (4-pyi-idynyl) nicotinate.

J-9. Methyl 1 ^ -dihydro ^ -oxo-S- (4-pyridinyl) -6-tert-butyl nicotinate.

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

J-11. n-Butyl-6-ethyl-1,2-dihydro-5- (2-methyl ~ 4-pyridinyl) -2-oxonicotinate.

J-12. Ethyl 6-ethyl-1,2-dihydro-2-oxo-15- (3-pyridinyl) nicotinate.

J-13. Ethyl-1,2-dihydro-1, e-dimethyl ^ -oxo-. · "- (4-pyridinyl ) nicotinate.

J-14. Ethyl-6-ethyl-- | , 2-dihydro-1- (2-hydroxyethyl) -2-. oxo-5- (4-pyridinyl) nicotinate.

J-15 ethyl-1,6-diethyl-1,2-dihydro-2-oxo-5- (4-pyridinyl) - nicotinate.

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J-16. n-Hexyl 1,2-dihydro-6-methyl-2-oxo-5- (2-pyridinyl) nicotinate. ·

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

J-18. Ethyl 1,2-dihydro-6-methyl-5- (4,6-dimethyl-2-pyridinyl) -2-o ^: onicotinate.

J-19. Ethyl 1,2-dihydro-6-n-hexyl-2-oxo-5- (2-pyridinyl) ■ nicotinate.

The usefulness of the compounds of formula I or their salts as cardiotonic agents is demonstrated by their effectiveness demonstrated in standard pharmacological test procedures, e.g. that a considerable increase in contractile force in the isolated feline atria (atria) and papillary Muscle process is caused and a significant increase in cardiac contractile force in the anesthetized dog procedure with little or minimal change heart rate and blood pressure. Find detailed descriptions of these test procedures U.S. Patent 4,072,746.

When tested by the isolated cat auricular and papillary muscle methods mentioned above, the compounds of Formula I at doses of 3, 10 or 30 µg / ml show a considerable increase, ie greater than 25%, in papillary muscle strength and a considerable increase , ie, greater than 25%, in right atrial force while causing only a small percentage increase (about one third or less than the percentage increase in right atrial force or capillary muscle force) in right atrial rate. In addition, it has been found that the 6- (lower-alkyl) compounds of the formula I are unexpectedly significantly more active than cardiotonics when tested by this method, in comparison with the corresponding, known ones

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6-des (lower alkyl) compounds. It was also found that 3 some of them, e.g. those where Q in Formula I is carbamyl and bromine, are active as cardiotonics while the corresponding 6-des- (lower-alkyl) -compounds are only known as intermediates, not that they are cardiotonic Properties Laben.

The markedly higher cardiotonic activity of the 6- (lower-alkyl) -compounds compared to the corresponding, known 6-unsubstituted compounds is illustrated by the following comparisons of the test results which were obtained when using the above-mentioned method of the isolated cat atria and papillary muscles: The percentage Increases in papillary muscle strength and right atrial strength for 3-amino-6-methyl-5 ~ (4-pyridinyl) -2 (1H) -pyridinone were found to be 96% and 75%, respectively, when tested at 10 ^ ug / ml, compared with the corresponding increases of 109 + 11.3% and 49.9 + 8.4% for 3-amino-5- (4-pyridinyl) -2 (iH) -pyridinone (amrinone), which at 100 µg / ml was tested, ie with a dose ten times higher. The percentage increases in papillary muscle strength and right atrial strength for 3-aluino-6-ethyl-5- (4-pyridinyl) -2 (1H) -pyridine were found to be 53% and 37% in the test 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 jig / ml, ie ten times the dose; the percent 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) nicotinonitriles were found to be 45% and 5% for the 6-methyl compound and 107% and 79% for the 6-ethyl compound when tested at 3 µg / ml, compared with corresponding increases of 65% and 15%. for the well-known 6-dealkyl-1,2-dihydro-2-oxo-5- ( ^Zl -pyridinyl) -nicotinonitrile at 30 / ig / ml, ie ten times the dose. The percentage increases in papillüro:

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Muscle strength and right atrial strength for 1,2-dihydro-6-methyl ~ 2-oxo-5- (4-pyridinyl) -nicotinonitrile were found to be 135% and 102% in the 10 µg / ml test, while the corresponding known 6-desmethyl compound at 10 ^ ug / ml was inactive. The percent increase in papillary muscle strength and right atrial strength for 6-methyl-3-methylamino-5- (4-pyridinyl) -2 (1H) -pyridinone was found to be 68% and 41% in the 30 µg / ml test, compared to corresponding ones Increases of 64% and 39% for the well-known 3-methylamino-5- (4-pyridinyl) ~ 2 (iH) -pyridinone when tested at 100 ^ g / ml, i.e. more than three times the dose.

Examples of cardiotonic-active compounds of the formula I, in which Q is carbamyl and halogen, while the corresponding, known 6-des- (lower-alkyl) compounds are only known as intermediates and not as cardiotonic agents are: 1,2- Dihydro-6-methyl-2-oxo-5- (4-pyridinyl) nicotinamide; in the in vitro test of the cat atrial and papillary muscle tests, the percentage increases in papillary muscle strength and right atrial strength were found to be 35% and 35%, respectively 22% were at 30 µg / ml and 87% and 37%, respectively, at 100 µg / ml; 6-ethyl-1,2-dihydro-2-oxo-5- (4-pyridinyl) -nicotinamide, when tested by the same method showed percentage increases in papillary muscle strength and right atrial strength of 29% and 7% at 100 jig / ml and 89 or 2½% at 300 ig / ml; and 3-bromo-6-methyl-5- (4-pyridinyl) -2 (iH) -pyridinone shows percentage increases in papillary muscle strength and right atrial strength of 87% and right atrial strength, respectively, in the aforementioned in vitro test of the cat atrium and the papillary muscles 99% at 1.0 mg / ml and 107% or 53% at 10 / Ag / ml.

The markedly higher cardiotonic activity of the 6- (lower-alkyl) compounds of the formula I, in which Q is hydrogen, compared with the corresponding known 6-unsubstituted ones

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Connections is made by comparing the test data below explains which were obtained using the test on the isolated cat atrium and papillary muscles. The percent increases in papillary muscle strength and right atrial strength for 6-methyl-5- (4-pyridinyl) -2 (iH) -pyridinone were 115% and 48% in the test with 10 ^ g / ml found compared to the corresponding * increases before. 48% or 51% for the well-known 5- (4-pyridinyl) -2 (1H) -pyridinone, tested at 100 yag / ml, i.e. ten times the dose; the percentage increases in papillary muscle strength and right atrial strength for 6-ethyl-5- (4-pyridinyl) -2 (1H) -pyridine were found with 106% and 50% in the test with 30 / Ag / ml, compared to corresponding increases of 48% and 51% for 5- (4-pyridinyl) -2 (iH) -pyridinone tested with 100 jag / ml, i.e. more than three times the dose.

As an illustration of a cardiotonically active compound of the formula I, in which Q is carboxy, while the corresponding, known 6-des- (lower-alkyl) compounds are only known as intermediates 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 atria and the papillary muscle test, percentage increases in papillary muscle strength and right atrial strength of 36% and 27% at 30 ^ g / ml and 44% and 69% .at 100yug / ml.

When tested according to the above procedure on the anesthetized dog caused compounds of the formula I when administered intravenously as a single dolus injection of 0.01, 0.03> 0.10, 0.30, 1.0 and / or 3> 0 mg / kg a significant increase, i.e. greater than 25%, cardiac contractile force or cardiac contractility with little or no change (less than 25%) heart rate and blood pressure. In addition, the 6- (lower-alkyl) compounds were found

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of formula I as significantly more active old cardiotonics in the test according to this method in comparison with the corresponding, known 6 ~ des (lower-alkyl) compounds, as by the following Explanations can be seen: The percentage increase in the cardiac contractile force or cardiac Contractility for 3-amino-6-methy 1-5-iA-pyridinyl) -2 (1H) -pyridinone when tested as indicated on the anesthetized dog at 1.0 mg / kg intravenous showed 136% compared to 12.5.67 + 10.59% for the. corresponding 6-Desme thy! connection, Amrinone, when tested at ten times the dose, i.e. at 10 mg / kg intravenously; similarly showed the percentages Increases in cardiac contractile force 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%, compared to 24.67 + 3.15% and 70.63 +, respectively 7.85% for the known amrinone in the test with ten times the corresponding J) ο s s, i.e. at 0.3 ng / kg and 1.0 mg / kg i.V .; the percentage increases in cardiac contractility for 1,2-dihydro-6-methyl-2-oxo-5- (4-pyrid.inyl) nicotinonitrile when tested by the same procedure with 0.03 mg / kg \ ind 0.10 mg / kg showed 49.5% and 87.5%, compared with 44% and 78% for the corresponding, known 6-desmethyl compound when testing with 100 times the amount of the corresponding doses, i.e. at 3 mg / kg and 10 mg / kg, or compared to 24.67 + 3.15% and 70.63 + 7.85% for the known amrinone when tested with ten times the amount of the corresponding doses, i.e. 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 when tested by this method at doses of 0.03 rag / kg and 0.10 mg / kg 68.5% or 135% compared to 44% or 78% for the corresponding, known 6-desmethyl compound when tested with the 100 times the amount of the corresponding doses, i.e. at 3 mg / kg and 10 mg / kg, respectively.

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The invention also includes within its scope a cardiotonic composition for increasing cardiac contractility and this composition comprises a pharmaceutically acceptable carrier and, as an active ingredient thereof, the cardiotonic 1-R ₁ -3-Q-6- (lower-alkyl) -5- PY-2 (1H) -pyridinone of the formula I or a pharmaceutically acceptable acid addition salt or a cationic salt thereof. The invention also encompasses the method of increasing cardiac contractility in a patient in need of such treatment, which consists in giving such a patient an effective dose of this 1-R ₁ -3-Q-6- (lower-alkyl) - 5-PY-2 (1K) -pyridinonä of the formula I or a pharmaceutically acceptable acid addition salt or cationic salt thereof is administered. In clinical practice, the compound or salt thereof will normally be administered orally or parenterally in a variety of 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 compounds mixed with at least one inert diluent, such as starch, calcium carbonate, sucrose or lactones; these compositions can also additionally. before containing substances other than the inert diluents, e.g. lubricants such as magnesium stearate, talc and the like.

Liquid compositions for oral administration include 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 include auxiliaries, such as wetting agents and suspending agents, Contains sweeteners, flavorings, fragrances and preservatives. According to the invention; include :, the

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Compounds <sur 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 injectables organic esters such as ethyl oleate. These compositions can also contain auxiliaries, such as stabilizers, preservatives, Wetting, emulsifying and dispersing agents, contain. They can be sterilized, e.g. by filtration through a bacteria retentive filter, by incorporating sterilizing agents in the compositions, by irradiation or by heating. They can also be produced in the form of sterile, solid compositions immediately before can be dissolved in sterile water or other sterile injectable medium for use.

The percentages of active ingredients in the composition and the method of increasing cardiac contractility can be varied to give appropriate dosages will. The dosage administered to a particular patient will vary depending on clinical judgment, the criteria being the type of administration, the duration of the treatment, the size and condition of the patient, the strength of the active component and the response of the Serve patient on it. An effective dosage amount of the active ingredient can therefore only be determined by the clinician who takes all criteria into account and makes the best decision for the patient.

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Claims (24)

Dr. F. Zumstein Sr. - Dr. I = I:.; - ». Srnann Dr. T-t. * <oiir.jgsbörgoif Dipl.-Phyts. R. Holrbauer - Dlpl.-T.i9. F. Kiir.g ^ OJsevi - Z3r. F. Zunmslein jun. PATENTANWÄLTE 8000 Munich 2 ■ Drauhuu & ^ lrnße 4 Telephone Sarnmel-Nr 225341 · T «jlograrnm« Zumnot - Tciiex SS9979 304A568 Case 367EV53 patent claims 1. 2 (1H) -pyridinones of the formula in which Q is hydrogen, amino, cyano, carbamyl, halogen, lower-alkylamino, di- (lower-alkyl) -amino, lower-acylamino, carboxy or lower-carbalkyl, R. hydrogen, lower-alkyl or lower-hydroxyalkyl R is lower alkyl and PY is 4-, 3- or 2-pyridinyl or 4-, 3- or 2-pyridinyl with one or two lower alkyl substituents,
as well as the acid addition salts or cationic salts thereof, 2. A compound according to claim 1, wherein R is methyl or ethyl and PY is 4-pyridinyl. 3. 3-Amino-6-methyl-5- (4-pyridinyl) -2 (iH) ~ pyridinone according to Claim 1. 4. 5-Amino-6-ethyl-5- (4-pyridinyl) -2 (1H) -pyridino ^, according to Claim 1. 5. 3-Amino-6-n-propyl-5- (4-pyridinyl) -2 (1H) -p2 / ridinone according to Claim 1. 6. 1,2-Dihydro-6-methyl-2-oxo-5- (4-pyridinyi) nicotinenitrile according to claim 1. 130035/0450 ORIGINAL INSPECTED 7. e-Methyj - ^ - methylamino-S- (4-pyridinyl) -2 (1H) -pyridinone according to claim 1. 8. 3-Erom ~ 6-methyl-5- (4-pyridinyl) -2 (1H) -pyridinone according to Claim 1. 9. 6-Ethy2-1,2-dihydro-2-oxo-5- (4-pyridinyl) nicotinonitrile according to claim 10. 1,2-Dihydro-6-raethyl-2-oxo-5- (4-pyridinyl) nicotinamide according to claim 1. 11. 6-Ethyl-1,2-dihydro-2-oxo-5- (4-pyridinyl) nicotinamide according to claim 1. 12. 3-Ethylamino-6-methyl-5- (4-pyridinyl) -2 (1H) -pyridinone according to claim 1. 13. 3-Dimethylamino-6-methyl-5- (4-pyridinyl) -2 (1H) -pyridinone according to claim 14. 6-methyl-5- (4-pyridinyl) -2 (1H) -pyridinone according to claim 1. 15. 6-Ethyl-5- (4-pyridinyl) -2 (1H) -pyridinone according to claim 16. 1,2-Dihydro-6-methyl-2-oxo-5- (4-pyridinyl) nicotinic acid according to claim 17. Process for the preparation of a compound according to claim 1, characterized in that one (a) a compound of the formula R ₃ R ₄ NCH = CC (= 0) -R (III) PY 130035/0450 COPY wherein R, and FL each mean lower alkyl, with malonamide for the preparation of a compound of the formula I in which Q is carbamyl, or (T :) either a compound of the above formula (III) or the formula R-C-CH-CHO (IV) tr ι
0, PY with NR ₁ -cc-cyanoacetamide to produce a compound of formula I wherein Q is cyano; that he if desired, a compound of the formula I obtained, in which Q is cyano, for the preparation of the corresponding Partially hydrolyzed compound wherein Q is carbamyl; that he if desired, a compound of the formula I obtained, in which Q is carbamyl, is reacted with a reagent which is carbamyl capable of converting into amino, for the preparation of the corresponding compound in which Q is amino; that he if desired, a compound of the formula I obtained, wherein Q is amino with 1 or 2 molar equiv. a lower alkylating agent for the preparation of the corresponding compound in which Q is lower-alkylamino or di- (lower-alkyl) -amino is, implements; that he if desired, a compound of the formula I obtained, in which Q is amino, with a low-ip acylating agent for Preparation of the corresponding compound in which Q is lower acylamino; that he if desired, a compound of the formula I obtained, in which Q is cyano, for the preparation of the corresponding Hydrolyzed compound wherein Q is carboxy; that he if desired, a compound of the formula I obtained, in which Q is carboxy, mic a mixture of concentrated Sulfonic acid and concentrated nitric acid for the production of the corresponding compound in which Q is nitro, heated, ν .-.: - 130035/0450 BATH ORIGINAL COPY at the compound where Q is nitro, then to the preparation reducing the compound wherein Q is amino; that he if desired, a compound of the formula I obtained, wherein Q is cyano or carboxy, with an aqueous mineral acid to produce the corresponding compound, wherein. Q is hydrogen, heated; that he if desired, a obtained lower alkanol compound of the formula I, in which Q is carboxy, for the preparation of the corresponding compound in which Q is lower-carbalkoyy, esterified; that he if desired, a compound of the formula I obtained, in which R _{1 is} hydrogen, with an alkylating agent of the formula R'-An, in which R ^{1 is} lower-alkyl or lower-hydroxyalkyl and An is an anion of a strong inorganic acid or an organic sulfonic acid, for Preparation of the corresponding compound in which R _{1 is} R ', reacted; that he if desired, a compound of the formula I obtained, wherein Q is hydrogen, reacting with a halogen to produce the corresponding compound wherein Q is halogen; and that he desiredfau Is a compound of the formula I obtained, wherein Q is halogen with a lower alkyl amine or a di (lower alkyl) amine to produce a corresponding one Compound in which Q is lower-alkylamino or di- (lower-alkyl) -amino is, implements; and that one if desired, a free base obtained into an acid addition salt converted or a compound obtained converted into a cationic salt. 18. The method according to claim 17, characterized in that the low-alkylating agent is a mixture of aqueous Formaldehyde and formic acid to produce a compound 130035/0450 Formation of formula I, in which Q is dimethylamine, is used will. 19. Cardiotonic composition to increase the cardiac contractility comprising a pharmaceutically acceptable inext carrier and an active ingredient effective dose of a compound according to any one of claims 1 to 16. 20. A compound according to any one of claims 1 to 16 for increasing cardiac contractility in a patient who needs such treatment. 21. Compound of Formula III R ₃ R ₄ NCH = CC (= 0) -R (III) PY wherein R is lower alkyl, R ₇ and R ₄ each stand for lower alkyl and PY is 4-, 3- or 2-pyridinyl or 4-, 3- or 2-pyridinyl with one or two lower-alkyl substituents. 22. A compound according to claim 21, wherein PY is 4-pyridinyl and R is methyl or ethyl. 23. A compound according to claim 20 or 21, wherein R ^ and Rl are each methyl. 24. Process for the preparation of a compound according to one of claims 20 to 22, characterized in that aass (pyridinyl) -methyl-lower-alkyl-ketone of the formula PY-CH ₂ -C (= 0) -R with di- (low- alkyl) -forir-amide-di- (lower-alkyl) -acetal is implemented. 130035/0450 ORIGINAL INSPECTED COPY