DE2059358A1 - Pyridone and thiopyridone derivatives, which are useful as anti-inflammatory agents - Google Patents

Description

The present invention relates to new 3-substit. 2-pyridones and -thiopyridones and processes for preparing these compounds. It also becomes a treatment procedure described in that of 2-pyridones and thiopyridones a novel class of remedies and therapeutic agents' is made use of. The compounds according to the invention show anti-inflammatory activity and provide a method of treating inflammation. They also exhibit effective levels of antipyretic and analgesic activity.

Much research has been done over the past two decades - to find anti-inflammatory remedies to develop. As a result of this research, many new remedies have been synthesized, most of them 11-oxygenated Fregnan series steroids.

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It has been found that the structure of the 3-substit. 2-Fyxddone and -Thiopyridone according to the invention has no Steroids are valuable anti-inflammatory agents.

The present invention relates to new chemical compounds which contain a phenyl or substituted phenyl radical which is linked via a carbon or heteroatom bond to the 3-position of a 2-PyridOn or a 2-Thiopyridon-Binges.

The present invention also relates to a new method of treating inflammation by means of therapy Means, according to humans or animals, * such as horses, dogs, cats, sheep, etc., a 3 ~ substit.-2-pyridone or 3-substit. 2-thiopyridone compound is administered, which is the in the Pig. I and II corresponds to the structural formulas shown.

-X J ^ rT E

II

Herein mean:

Ar is any benzoloid or non-benzoloid aromatic-like structure (preferably phenyl) that includes one or contains more H substituents which can be in any position of the ring;

B hydrogen, alkyl (preferably lower alkyl, such as Methyl, xthyl, propyl, etc.), halogen (such as fluorine, chlorine »

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Bromine us «), hydroxy, alkoxy (preferably lower alkoxy, such as methoxy, ethoxy, propoxy, etc.), haloalkyl (preferably halo germ iedrigalkyl, such as fluoromethyl, trichloromethyl, trifluoromethyl, etc.), aryl (preferably Phenyl, naphthyl, substituted phenyl such as hydroxyphenyl, halophenyl, alkoxyphenyl etc.), nitro, Amino, acylamino (such as acetylamino, etc.), alkylamino, (preferably lower alkylamino such as! Ethylamino »ethylamino, etc.) or dialkylamino (preferably M-lower alkylamino, such as dimethylamino, diethylamine, etc.);

E 'hydrogen or alkyl (preferably lower alkyl, such as Methyl, ethyl, propyl, etc.);

X -CH ₂ -,

-CHpCHp-. ■

-CE-CH-, -C = C-,

-NH- or

-NE "-; . Hydrogen, alkyl (preferably lower alkyl, such as Methyl, ethyl, propyl, etc.). Alkenyl (preferably lower alkenyl such as vinyl, allyl, methallyl, etc.), alkynyl (preferably lower alkynyl, such as ethynyl, methyl, butynyl etc.), aralkyl (preferably Am-lower alkyl such as benzyl etc.), aryl (preferably phenyl or substituted phenyl such as hydroxyphenyl, halophenyl, Anisyl, etc.), hydroxyalkyl (preferably hydroxy-lower alkyl, such as hydroxyethyl, hydroxypropyl, etc.), aminoalkyl (preferably amino-lower alkyl, such as aminomethyl, aminoethyl, etc.) or dialkylaminoalkyl (preferably

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preferably di-lower alkylamino lower alkyl, such as diethylaminoethyl etc.); and

B "alkyl (preferably lower alkyl, such as methyl, ethyl, etc.)» aralkyl (preferably am lower alkyl, such as
Benzyl, etc.) or acyl (such as acetyl, etc.).

The more preferred compounds for a method of treating inflammation and for use in therapeutic Agents include those compounds of structural formulas I and IX, in which:

Ar phenyl; B hydrogen, alkyl, halogen, hydroxy, alkoxy, Haloalkyl, nitro, amino, alkylamino or

Dialkylamino; B ^{1 is} hydrogen; -CH-CH-, -O-

■?

0 0. .

-S- or -HH-; and hydrogen, alkyl, aralkyl, aryl or Li alkylaminoalkyl.

109824? 22-57

12671.

Most preferred compounds for treating inflammation and for use as therapeutic agents include those compounds of Structural Formula III :

in which means: X -CH-CH-,

III

or

-HH-.

The present invention also relates to a new class of chemical compounds of structural formulas IV and V:

B <

IV

-Z- £ ksjl · B

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in which mean:

Ar any benzoloid or non-benzoloid, aromatic-like structure (preferably phenyl), the one or contains more R substituents which are in any • Can be in position on Sing; '

B hydrogen, alkyl (preferably lower alkyl, such as methyl, ethyl, propyl, etc.) »halogen (such as fluorine, chlorine, Bromine etc.), hydroxy, alkoxy (preferably lower alkoxy, such as methoxy, ithoxy, propoiy etc. *.), haloalkyl (preferably halo-lower alkyl such as fluoromethyl, trichloromethyl, trifluoromethyl etc.), aryl (preferably Phenyl, naphthyl, substituted phenyl, such as hydroxy-. phenyl, halophenyl, alkoxyphenyl etc.), nitro, Amino, acylamino (such as acetylamino, etc.), alkylamino (preferably lower alkylamino such as methylamino, ethylamino etc.) or dialkylamino (preferably di-lower alkylamino such as dimethylamino, diethylamino etc.);

B ^{1 is} hydrogen or alkyl (preferably lower alkyl, such as methyl, ethyl, propyl, etc.);

Z -CH ₂ -,

-CH ₂ CH ₂ -, "". · '

-CH-CH-, -C = C-,

-NH- or -NO"-}

IL hydrogen, alkyl (preferably lower alkyl, such as

Methyl, ethyl, propyl, etc.), alkenyl (preferably lower alkenyl such as vinyl, allyl, methallyl, etc.), alkynyl (preferably lower alkynyl, such as ethynyl, methylbutynyl, etc.), aralkyl (preferably am-lower alkyl, such as benzyl etc.), aryl (preferably phenyl or substituted phenyl, such as hydroxyphenyl, halophenyl, Anisyl, etc.), hydroxyalkyl (preferably hydroxy-lower alkyl, such as hydroxyethyl, hydroxypropyl, etc.),

2 ^ / ^ 25 7

Aminoalkyl (preferably amino-lower alkyl, such as amino- ■ methyl »aminoethyl , etc.) or dialkyl amino alkyl (preferably di-lower alkylamino-lower alkyl, such as ΒΙΑ thylaminoethyl, etc.); and

E "alkyl (preferably lower alkyl, such as methyl, ethyl etc.), aralkyl (preferably ar-lower alkyl such as benzyl etc.) or acyl (such as acetyl etc.).

The more preferred compounds of the present invention include those compounds of Structural Formulas IV and

V, in which mean:

Ar phenyl j ■

B hydrogen,. '.

Alkyl, halogen, hydroxy, alkoxy, haloalkyl, nitro, amino, alkylamino or

Dialkylamino *} B * hydrogen; Z -CHg-, _c

-CH-CH-, -O- or

-HH-; and R ₄ . Hydrogen, alkyl, aralkyl, aryl or dialkylaminoalkyl.

The most preferred compounds of the present invention include those compounds of Structural Formula VI:

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₁₂₆₇₁

VI

in which means:
Z -CH ₂ -,

-CH-CH-,, '

-O- or

-NH-.

ft

It is well known in the pharmacological art that non-toxic acid addition salts of pharmacologically active Amine compounds differ in terms of their effectiveness, indistinguishable from their free bases. The expediency of the salts results only from consideration the solubility.

The amines according to the invention can easily be converted into their non-toxic ones by customary methods belonging to the prior art Acid addition salts are converted. The non-toxic salts according to the invention are those salts the acid component of which is pharmacologically acceptable at the intended dosages; belong to such salts those made from hydrochloric acid, hydrobromic acid, sulfuric acid, Nitric acid, phosphoric acid, methanesulfonic acid, Acetic acid, propionic acid, oxalic acid, glycolic acid, lactic acid, salicylic acid, etc.

The person skilled in the art is also familiar with the following; Best in the practical implementation of the present

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can be used to find:

Ar for haphthyl;

£ in the meaning of alkenyl (preferably lower alkenyl, such as vinyl, allyl, etc.) »acyl (such as acetyl, propionyl, benzoyl, etc.), cyano, carboxy, carbalkoxy (preferably carbo-lower alkoxy, such as carbomethoxy, carbethoxy, etc.) · carbamyl, dialkylsulfamyl (preferably di-lower alkylsulphamyl, such as bimethylsulphamyl), acyloxy (such as acetoxy, propionoxy etc.), mercapto, alkylthio (preferably lower alkylthio, such as methyltMo, itylthio etc.), alkylsulphonyl (preferably lower alkylsulphonyl, such as methylsulphonyl), alkylsulphinyl , such as methylsulfinyl), ßulfonamido, sulfinazaido, alkylaminoalkyl (preferably lower alkylamino-lower alkyl, such as methylaminomethyl, xthylaminomethyl, etc.), hydroxyalkyl (preferably hydroxy-lower alkyl, such as hydroxy methyl, lower hydroxyethyl, lower hydroxyethyl, lower hydroxyethyl, methoxyethyl, hydroxyalkyl, such as methoxyalkyl, methyl, hydroxyalkyl, such as methoxyalkyl, such as methoxyalkyl, such as methoxyalkyl, such as methoxyalkyl, hydroxy-lower-lower alkyl, such as methylaminomethyl, lower-alkyl, such as methylaminomethyl, lower alkyl, such as methylaminomethyl, lower-alkyl, preferably methylaminomethyl, lower-alkyl, hydroxy-lower-alkyl, preferably methylaminomethyl, lower alkyl, such as methylaminomethyl, lower-alkyl, preferably lower-alkylamino-lower-alkyl (preferably methylaminomethyl, Xthylaminomethyl, hydroxy-alkyl, hydroxy-alkyl, e.g. Ithoxypropyl etc.), mercaptoalkyl (preferably mercapto lower alkyl such as Merca ptomethyl, Marcaptoäthyl etc.), Alkylmexcaptoalkyl (preferably Niedrigalkylmercaptoniedrigalkyl as Meiäiylmercaptomethyl, Ithylaercaptoäthyl, Äthylmercaptopropyl etc.), aralkyl (such as benzyl, phenethyl, etc., etc.), aryloxy or aralkoxy; and

E. meaning aralkenyl (preferably am-lower alkonyl, such as phenylpropenyl, fnenylbutenyl, etc.); and

H ^{1 has} the meaning of alkenyl (preferably üüedrigalkenyl, such as vinyl, allyl, metalallyl, etc.), alkynyl

(preferably lower alkynyl, such as ithynyl, methylbutynyl, etc.), aryl (preferably phenyl or substituted phenyl, such as! polyl, halophenyl, anisyl, etc.), Aminoalkyl. (Preferably amino lower alkyl, such as amino * methyl, aminoethyl etc.), dialkylaminoalkyl (preferably M-lower alkylamino-lower alkyl, such as Siäthylamino- *

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ethyl etc.) or aralkenyl (preferably am-lower alkenyl such as phenylpropenyl, phenylbutenyl etc.).

The compounds of formulas VII and VIII

-CH-CH j ^ Lr / -B

VII

VIII

in which Ar, fi and IL have the meanings given above, can occur as geometric isomers. For example, 3-styryl-2ZiI / pyridon in an ice form, in which the .Aryl ring and the pyridone ring on the same side of the double bond stand, and are in a trans form in which the aryl ring and the pyridone ring are on opposite sides Sides of the double bond. It goes without saying that the various geometric isomers of the formulas VII and VIII fall within the scope of the present invention.

E are representative compounds of the present invention the following:

3-phenoxy-2 / iH / pyridone

3- (p-chlorophenoxy) -2 / IH / pyridone 3- (p-nitrophenoxy) -1 / 3H7pyridon 3-2R Benzy1- H / pyridone

1-methyl-3-phenoxy-2 / IB7 pyridone 4-methyl-3-phenoxy-2ZiH7pyridone eis-3-styry1-2ΖΪS7pyridone

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trans-3-styryl-2Zi2 / pyridone 5- (N-phenylbenzamido) -2 / iS / pyridone 3-anilino-2/ ³ / H7pyridone trans-3- (o-chlorostyryl) -2ΖΪ27pyridone 1- (ß-dimethylaminopropyl ) -5-anilino-2Ziss7pyridoJi

5- (o-methylanilino) -2 / iB7 pyridone

1-Ac e ty 1-3 - "b enzyl-S / ^ HTpyri don 1-phenyl-3-benzyl-2 / ia7pyridone

1-dimethylaminoethyl-3-pii.eno3cy-2Zifl7pyi ^> idon *

3-Piienoxy-2Zi27tliiopyildon. . ■

3- (o-Tolyloxy) -2ZiS7thiopyridon 3- (p-Ki tro "b enzoy 1) - 2 / Ϊ aZthiopyri don 3- (p-fluorotyryl) -2 / ^: TB7thiopyridone 3- (p-chlorophenyl sulfonyl) - S / iH / pyri do 3- (phenylsulfinyl) - ^2/3 I E7pyridon

"It is further understood that the compounds according to the invention can exist in various tautomeric structures, in particular when E _x . Stands for H, for example as:

^ L

10982 U 2257

Here Z stands for -X- ^ rT R. These tautomeric connec- *

fertilizers also fall within the scope of the present invention.

A preferred embodiment of the present invention is a method of treating a disease that is symptomatic is characterized by pain, fever and / or inflammation and will be treated according to this treatment method about 5 to 500 mg of the pyridone or thiopyridone compound administered daily in a unit dosage form. On a kilogram basis, about 0.5 mg / kg to 70 mg / kg de day of the pyridones or thiopyridones according to the invention used.

In view of the fact that the novel compounds of the present invention are anti-inflammatory, analgesic and exert antipyretic activity, they are im generally indicated for a wide variety of conditions in mammals where one or more of the symptoms Inflammation, fever, and pain occur. Examples of such conditions are rheumatic diseases, e.g. B. rheumatoid arthritis, osteoarthritis and other degenerative Joint disease, psoriatic arthritis, viral column stiffening, Gout and rheumatic fever; B. tendinitis, periathritis and periostitis; acute muscular rheumatism, e.g. B. sciatica and the like; the treatment of pain after fractures, of pain and inflammation associated with dental surgery and the like, conditions of human diseases and animal diseases showing the above symptoms and the use of an anti-inflammatory, analgesic and / or antipyretic pharmaceutical Demand means.

You inventive compounds can be used in one for

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oral use suitable form, e.g. B. as tablets, aqueous or oily suspensions, dispersible powders or grains, Bnulaionen, hard or soft capsules or syrups or elixirs. Compositions intended for oral use may be made vegetables by any method known in the literature for the manufacture of pharmaceutical compositions, and such compositions may contain one or more compositions, namely, sweeteners, flavorings, colors and preservatives to provide a pharmaceutically acceptable and palatable preparation. Contain mixtures which are non-toxic to the active pyridone and thiopyridone ingredient in admixture with pharmaceutically-acceptable carriers suitable for the manufacture of tablets ■ i, piping carrier can, for example, inert diluents, eg. B. calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; Granulating and loosening agents, e.g. B. corn starch or alginic acid; Binders, e.g. B. starch, gelatin or acacia; and lubricants, e.g. B. magnesium stearate, stearic acid or talc. The tablets can be uncoated, or they can be coated by known methods in order to delay their disintegration and their absorption in the gastrointestinal tract .and thereby for. to ensure a lasting effect over a longer period of time.

Approaches for oral use can also be called hard "

Gelatin capsules are offered in which the active ingredient is mixed with an inert, solid diluent, e.g. B. Calcium carbonate, calcium phosphate or kaolin, is mixed, or they can be offered as soft gelatin capsules in which the active ingredient is mixed with an oil medium, z. B. arachid oil, liquid paraffin or olive oil is mixed.

Aqueous solutions containing the active pyridones and thiopyri-

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done, form a further embodiment of the present invention. If desired, the carrier can, the _# are suitable for aqueous suspensions be used. These carriers are suspending agents, e.g. B. Sodium carboxymethyl cellulose, methyl cellulose, hydroxypropylmethyl cellulose, sodium alginate, polyvinylpyrrolidone ,. Gum tragacanth and acacia; The dispersants or wetting agents can be naturally occurring phosphatides, e.g. B. lecithin; or condensation products' of an alkylene oxide with fatty acids, e.g. B. polyoxyethylene stearate; or condensation products of ethylene oxide with long-chain aliphatic alcohols, e.g. B. heptadecaethyleneoxy-cetanol; or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol, e.g. B. polyoxyethylene sorbitol monooleate; or condensation products of ethylene oxide with partial esters derived from fatty acids and hexyl anhydrides, e.g. B. Polyoacyäthylensorbitan monooleate be. Said aqueous suspensions can also contain one or more preservatives, e.g. B. ethyl or n-propyl p-hydroxy-benzoate, one or more colorants, one or more flavorings and one or more sweeteners such as sucrose.

Oily suspensions can be created by suspending the active Ingredient in a vegetable oil, e.g. B. arachid oil, olive oil, sesame oil or coconut oil, or in a mineral oil, like liquid paraffin. You oily suspensions can use a thickener, e.g. B. beeswax, Hard paraffin or cetyl alcohol, sweeteners such as those mentioned above, and flavorings can be added to provide a tasty preparation to be taken orally · These agents can be added by adding a Antioxidant, such as ascorbic acid, can be preserved.

In dispersible powders and grains, which are suitable for the preparation of an aqueous suspension by adding water

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are suitable} is the active ingredient mixed with. a dispersing or wetting agent} suspending agent or one or more preservatives. Suitable dispersing or wetting agents and suspending agents are for example those already mentioned above. Other carriers, ζ. B. sweeteners, flavorings and dyes, can also be present.

The compounds according to the invention can also be used in Torrn of Oil-in-water emulsions are present. The oily phase can be a vegetable oil, ζ. B. olive oil or arachid oil, or a, Mineral oil, 2. B. liquid paraffin or mixtures of- " same, be. Suitable emulsifying agents can be the naturally occurring gums, e.g. B. acacia gum or tragacanth gum, naturally occurring phosphatides, ζ. B. Soybean lecithin, and esters of partial esters derived from fatty acids and hexanhydrides ^ ζ. B. sorbitan monooleate, -and condensation products of said partial esters with ethylene oxide, z. B. polyoxyethylene sorbitan monooleate, be. The emulsions can also contain sweeteners and flavorings.

Syrups and elixirs can contain sweeteners, ζ. Β. Glycerine, sorbitol or sucrose. Such approaches can also contain a demulsifier, a preservative, and flavorings and colorings. The pharmaceutical compositions may be in the form of an aerobic injectable preparation, e.g. B. a sterile, injectable, aqueous suspension. This suspension can be prepared according to methods belonging to the known state of the art, using the above-mentioned suitable dispersing agents or wetting agents and suspending agents. The sterile, injectable preparation can also be a sterile, injectable solution or suspension in a non-toxic - see, parenterally compatible diluent or solvent

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solvent, ζ. B. a solution in 1,3-butanediol.

The inventive pyridones and thiopyridones can also in the form of suppositories for rectal administration of the Remedy available. The production of these fecal suppositories can be done by using the remedy with a suitable, non-irritating vehicle which is solid at ordinary temperatures but liquid at the bectal temperature is and therefore melts in the sectum and releases the remedy. Such substances are cocoa butter and polyethylene glycols.

These compounds can continue to be tabletted or in used in a different way, so that for every 100 parts by weight of the agent 5 to 95 parts by weight of the active ingredient and preferably from 25 to 85 parts by weight of the active ingredient. The dosage unit form contains generally about 100 mg to about 500 mg of the active ingredient the formula given above.

From the above discussion of the nature of the formulation it can be seen that the compounds according to the invention can be administered orally, parenterally, locally and rectally. The term parenteral includes as used herein Meaning subcutaneous injection, intravenous, intramuscular or intrasternal injection or infusion methods.

The dosage rule when carrying out the inventive The procedure is the one that ensures maximum therapeutic response until improvement is achieved, and the dosage is therefore the minimum effective concentration that will provide relief. So are the dosages in general those used in the treatment of disease states or symptoms such as inflammation, pain, and fever are therapeutically effective. In general

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The daily dose can mean between about 0.5 mg / kg . and 70 mgAg, although it should of course be borne in mind that when choosing the appropriate dosage in each specific case, the weight, the general state of health and the age of the patient and other factors which may affect the response to the remedy must be considered.

It is expected that the inventive pyridones and thiopyridones are generally administered in dosage units of 5 to 50 Ω mg of the active ingredient. Gowns because of the ease of administration are preferred are in unit dosage form for oral administration, e.g. B. as tablets or Capsules containing 25 to 500 mg of a pyridone or thiopyridone according to the invention.

The compounds according to the invention can conveniently be prepared by the following general method will.

Treatment of the 3-substituted pyridines with peroxide, like hydrogen peroxide, in an acidic medium leads to the 3-substituted pyridine-N-oxide. This can then go through Heating in the presence of an anhydride, such as acetic anhydride, can be rearranged to give the 3-substit.-2 / i ^ 7-pyridone compound (Ia). This sequence of actions can be given by the following Ventilation equation can be represented:

109824/2287

-x —- Λ?

" ^x - ² ^ - ^H

Ox — ö

The symbols Ir ₁ B and Z have the meanings given above.

By reacting the 2-pyridone compounds with a strong base, such as sodium hydride, the 1-nitrogen atom becomes activated. The addition of an aliphatic or aromatic agent, such as an aliphatic tosylate or halides, leads to the N-substituted products (Ib). The following equation illustrates this implementation:

Yes

Ib

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Here, the symbols Ar, B and X have those given above Meanings and IL has the meaning described above except hydrogen.

The 3-substit.-2 / iH /! E! Hiopyridones according to the invention can be prepared from the corresponding 5-substit.-2 / iS7 pyridones by heating with P ₂ Sc.

The reaction can be carried out on the compounds which are unsubstituted in the 1-position (Ia), and the 3-substit.-2 ^ iS7lhiopyridones (Ila), which then, if desired, N-substituted can (lib). The products can also be prepared from those compounds which are already substituted in the 1-position (Ib), and the N-substit.-thiopyridones * (lib) are obtained.

These implementations are illustrated by the following equations:

Ib B "lib

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If an R 'substituent is desired on the pyridone ring, the reactions described above can be used, starting with the appropriate starting material.

The starting materials for the present invention are either known compounds, or the process for their Production is described in the examples of this document. Appropriate instructions will be given on those known in the literature Working methods added.

The amine products according to the invention can be adjusted to the solubility ratios by methods customary in the art to improve in an intermediate way, easily in its non-toxic way Acid addition salts are converted.-The inventive Non-toxic salts include those salts which contain acid components included in the intended Dosages are pharmacologically acceptable. Such salts include those obtained from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, Phosphonic acid, methanesulfonic acid, acetic acid, Propionic acid, glycolic acid, lactic acid, salicylic acid, etc. getting produced.

Appropriately substituted, desired end products which have different R substituents can under Using appropriate reactions to convert one R group to another can be prepared. For example a nitro group can be reduced to an amino group, which can then be mono- or dialkylated. One The hydroxy compound can be obtained by demethylating a methoxy substituent or prepared by diazotizing an amino group will. A chlorine compound can be produced by diazotizing an amino group. These reactions can be carried out at any convenient stage in the synthesis.

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Ss follows a group of individual examples in which the Preparation of desired compounds according to the invention will be shown. These examples are only intended to illustrate, but not limit, the invention.

example 1

5 ~ phenoxypyridine

15 »2 g (0.16 mol) 3-hydroxypyridine and 9.0 g (0.16 mol) potassium hydroxide are heated together to 150 ° C. while a gentle stream of nitrogen is passed over it to drive off water. Then an additional 3.8 g (0.0 ^ mol) of 3-hydroxypyridine and then 47.1 g (0.30 mol) of bromobenzene and 0.40 g of copper (H) carbonate are added. The nitrogen inlet tube is replaced with an air condenser and the mixture is heated to 130 ° C for 3 hours and then to 180 ° C for 15 hours. The black mixture is diluted with 250 ml of water, made strongly alkaline (3.3 S (0.06 mol) KOH) and then distilled with steam. The distillate (about 1.7 l) is extracted with Ither, and the ethereal phase is dried with anhydrous MgSO ^ and evaporated. The residue is fractionated in a vacuum. 3-Phenoxypyridine is obtained (sp. 101 to 10 3 ° / 0.55 mm).

Example 2

5-phenoxypyridine H-oxide

A mixture containing 8.6 g (0.05 mol) of 3-enenoxypyridine, 30 ml of glacial acetic acid and 5 ml of 50% H ₂ Op is heated in an oil bath at 75 ° C. for 3 hours. Another 3.6 ml of peroxide solution is then added and heating is continued for 12 hours. The solution is concentrated in vacuo to a volume of about 10 ml, 10 ml of water are added, and the concentration is repeated. Will be again

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10 ml of water are added, and then small portions of Sodium bisulfite is added with shaking until the Starch jodid-Probβ on hydrogen peroxide turns out negative. The mixture is again concentrated to about 10 ml. The residue is mixed with 50 ml of chloroform and then with solid Treat sodium carbonate in small portions with shaking until no more carbon dioxide develops. The mixture is then dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The deficit, a viscous, yellow oil (about 9.4 g), is through Triturated with ether to crystallize and then recrystallized from a mixture of methylene chloride and ether. 3-Phenoxypyridine-N-oxide is obtained (pp. 78 to 80 °).

Example 3 3-Phenoxy-2ZiHZPyridone

A solution of 2.8 g of 3-phenoxypyridine-N-oxide in 15 ml of acetic anhydride is heated to reflux temperature for 5 hours. Most of the solvent is removed by evaporation in vacuo and the dark, oily residue is treated with 25 ml of water. The aqueous mixture is heated on the steam bath for 1 hour and then allowed to stand overnight at room temperature. The dark, organic phase partially crystallizes. The mixture is filtered and the gummy black solid on the filter washed by slurrying with acetone. A large part of the colored material is washed away by this procedure, and 1.3 g of grayish crystals remain on the filter. Recrystallization from acetone gives nan ^ -Phenoxy- ^ flTipyridon (melting point 158.5 ° to 160 ° C.).

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Example 4-3-BenzTlpyri din

10.1 g of 3-benzoylpyridine are reduced with 2.5 g of red phosphorus and ^ O ml of hydriodic acid according to the method of AE Tschitschibabin (Ber., 36, (1903) 2711). The reaction mixture is made strongly alkaline by adding concentrated sodium hydroxide solution, and the yellow oil which separates out is extracted with ether (2 × 50 ml). The combined ether extracts are washed with water (2 × 25 ml), _{dried over anhydrous MgSO x} ^ and evaporated in vacuo. The residue crystallizes in long needles. One receives 1r-Benzylpyridin (Sp. 28 to 31 °) · '

Example 5

The 3-benzylpyridine (8.5 gt 0.05 mol) is treated with acetic acid and 8.6 ml of 30 # strength aqueous hydrogen peroxide treated according to the procedure of Example 2.

Working up gives 3-benzylpyridine-N-oxide as viscous, pale yellow oil that does not crystallize can be brought. For characterization purposes converted a sample into 3-benzylpyridine-N-oxide-picrate and recrystallized from alcohol (ϊρ. 133 to 134 ° C);

Example 6

The rearrangement of 3.7 g (0.02 mol) of 3-benzylpyridine-H * oxide in 20 ml of acetic anhydride, as in Example 3, be «. wrote, performs. After hydrolysis with 25 ml of water

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you get a very dark oil that doesn’t if left standing stiffens. The water is decanted and the dark residue is taken up in methylene chloride (50 ml). The watery Solution is extracted with 25 ml of methylene chloride and the organic solutions are combined, over anhydrous MgSO ^ dried and evaporated in vacuo. The residue is a dark brown syrup, which when rubbed with a little ether results in solid material, which is transferred to a funnel made of sintered glass and slurried with Ether is washed thoroughly .. The solid is washed twice recrystallized from acetone. 3-Benzyl-2/12 / -pyridone is obtained (Pp. 160 to 161.5 °).

Example 7 3-AnilinoT> yridine

A. N- (5-pyridyl ^ anthranilic acid

A mixture containing 4.1 g of anthranilic acid, 6.3 6 3-bromopyridine, Containing 4 g of anhydrous potassium carbonate, 200 mg of copper powder and 25 ml of nitrobenzene is refluxed for 3 hours heated. The black mixture is cooled, treated with 200 ml of water and then with ether (2 × 50 ml) extracted. Acidification of the aqueous phase with acetic acid immediately gives a dark precipitate, which can be removed by filtration is collected and washed thoroughly with water and ethanol. This solid is then circulated from ethanol metallized. N- (3-pyridyl) anthranilic acid is obtained (M.p. 237-238 ° C).

B. 3-anilinopyridine

4.0 g of N- (3-pyridyl) anthranilic acid are placed in a metal bath According to Wood, heated to 250 ° C until the development of COn subsides (about 3/4 hour). The temperature will

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then increased to 290 to 295 ° C in the course of 1/4 hour and kept in this area for several minutes. Man then allowed to cool to room temperature »The residue is dissolved in dilute hydrochloric acid (concentrated ECl, 5 mlj water, 10 ml) and the solution becomes brief heated with 0.5 g of charcoal and filtered under the action of gravity, and the dark green filtrate becomes while drilling and cooling with ice to an excess of 2.5 »aqueous sodium hydroxide (JO ml) added dropwise. The precipitated, greenish, amorphous solid is filtered off ^ collected and washed thoroughly with vase and sublimed in vacuo. 3-anilinopyridine is obtained (melting point 140 ° -141 ° C.).

Example 8 N-3-pyrid.vlbenzanilide

A solution of 1.70 g (.0.010 mol) of 3-anilinopyridine in Given 10 ml of dimethylformamide. The addition is carried d of air and moisture (dry nitrogen is flushed out via the Beaktanten) for 35 minutes at tree temperature with stirring and exclusion. The mixture is then stirred for an additional 60 minutes at tree temperature under nitrogen. The mixture is then cooled by immersion in an ice bath and a solution of 1.69 g (0.012 mol) of benzoyl chloride in 10 ml of dry dimethylformamide is added dropwise over 35 minutes with constant stirring. When the addition is complete, the mixture is stirred for 16 hours at tree temperature under nitrogen.

The reaction mixture is poured into a mixture of 125 ml of ither, Poured 1.0 ml of acetic acid and 200 ml of ice water. The layer

" ²⁵ " 108824/2257

12671

th are separated, and the aqueous phase becomes two more extracted with ither. The extracts will be combined washed with water and dried over anhydrous MgSO ^. The dried extracts of it are in a vacuum evaporated to dryness and the residue triturated with ether. The crystalline amide is obtained, which is as follows is recrystallized: It is dissolved in the minimum amount of boiling methanol, and the solution becomes hotter Action of gravity filtered and diluted with Ither. After standing overnight in the cold one wins fine, white needles of N-3-pyridylbenzanilide (mp. 158 to 159 ° C).

Example 9

-Phenylbenzamido) -pyridine-1- »oxide

To a solution of 550 mg of N-3-pyridylbenzanilide in 2 ml of glacial acetic acid, which is kept in an oil bath at 70 ° C., 0.20 ml of 50% aqueous H ₂ O _{2 are added} . An additional 0.15 ml of peroxide solution is added after 3 hours, and then the reaction mixture is kept at 70 ° C. overnight. After the volatile material has evaporated in vacuo, the yellow, oily residue is solidified by rubbing it with ither, which contains a few drops of acetone. 460 mg of a creamy white solid are obtained, which is recrystallized from acetone / JLther, and j- (N-phenylbenzene aido) -pyridine-1-oxide (melting point 151 to 152 ° C.) is obtained.

Example 10

3- (N-Phenylbenzamido) -2ZiH7Pyridone

871 ing 3- (N-phenylbenzamido) -pyridine-1-oxide are dissolved in 5 ml acetic anhydride, and the solution is divided for 5 hours

109824/2267

Bückfluss "cooked The main mass of the solvent is evaporated in vacuo and the black oily pike stand _f is treated with 7.5 ml of water for 1 hour on the steam bath. The oil is extracted with methylene chloride and the solution is dried over anhydrous MgSO ^ and evaporated in vacuo. The residue is a thick, black rubber that is rubbed in with JLther / acetone. A dark, gray-brown solid (295 mg) is obtained. The solid material is auskristaiiisiert from Kethanol / acetone, leather brown colored crystals (100 mg; Pp about 221-229 ° C with decomposition..) Apply, and then, from ethanol lisiert umkristal- *. Pure 3- (N-phenylbenzamido) -2 / ^: iH / ^r pyridone (pp. 217 to 222 ° C.) is obtained.

Be it game 11 5-anilino-2 / riS7pyridon

435 ^m S 3- (N-Phenylbenzamido) -22i27pyridon are in a. Suspended mixture of 3 ml of 2.5 ° aqueous NaOH and 12 ml of water, and the mixture is heated to reflux temperature for 4 hours. Undissolved pesticide is removed by filtering the hot reaction mixture under the action of gravity. The piltrate is adjusted to a pH of about 6 with dilute HCl and allowed to cool down. The precipitated, pale green, shiny, crystalline plague is collected by filtration on the pump and washed thoroughly with water and then recrystallized from acetone (about 5 ml) , 5 ° C).

Example 12 β-phenyl-q-3-pyridyl acrylic acid

The procedure of J.A. T. Beard and A. B. Katritzky (Bee. Trav. Chim, 78, (1959) 592) is followed. the

'" ²⁷ " 1Q982W2257

The reaction temperature is about 110 to 120 ° C. and the total reaction time is 100 hours. You will dark solution treated with a solution of 6 g of sodium hydroxide in 300 ml of water, and the whole is vacuumed up to volume of about 25 J & l evaporated to remove pyridine. Of the The residue is diluted with water up to a volume of 125 ml diluted, and the solution is filtered through a pad of glass wool to remove some dark, insoluble material, and the filtrate is acidified with acetic acid. The precipitated, buff-colored solid is filtered off collected, washed thoroughly with water and then recrystallized from ethanol. Β-Phenyl-α-3-pyridyl- is obtained. acrylic acid (melting point 231 to 234 ° C. with decomposition).

Be i s ρ i e 1 15 trans-5-styryl pyridine

The decarboxylation of ß-phenyl-α-3-pyridyl acrylic acid is carried out by heating 3 g of the compound in a Wood metal bath at 250 ° C. until the development of COp ceases (about 1 hour). Then, the temperature in the course of 10 minutes to 280 is increased to 235 ° C and held for a few minutes in this area, and then allowed to cool to tree temperature.

The dark residue is taken up in 150 ml of ether and the solution is made up of a small amount of insoluble material filtered off and then extracted with 120 ml of 2N HCl. The aqueous extract is washed with 50 ml of ether and then made basic by adding ammonia. The separated, dark brown oil is washed with ether (1 χ 150 ml; 1 χ 50 ml), and the essential solution is over dried anhydrous magnesium sulfate, briefly with 0.2 g Treated Darco, filtered and evaporated in vacuo. Of the

- 28 -

109824/2257

¹ ! I ¹¹ I ¹¹ '! · '" ^{: Ί} Ij! ΠΙ'β'Τ

The residue is triturated with cyclohexane and the pesticide is collected by filtration and rinsed thoroughly with cyclohexane washed. Recrystallization from cyclohexane gives pure trans-3-styrylpyridine (melting point 78 to 79 ° C.).

Example 14-

trans »S-styrylpyridine-IT-oxide

The working method of A. B. Katritzky and A. M. Monro (J. Chem. Soc, (1958) 150) using 3 ml of acetic acid, 0.75 ml of 30% strength hydrogen peroxide and 906 mg " trans -3-styryl pyridine followed. By working up as described, trans-3-Styrylpyri'din-N-oxide is obtained as dark brown oil that cannot be made to crystallize. The product is characterized by conversion to trans-5-styrylpyridine-N-oxide-picrate (bp. 186 to 190 ° C.).

Example 15 trans -5-styryl-2i / is7pyridone

The rearrangement of trans-5-styrylpyridine-F-oxide is according to { Example 3 carried out. 1.87 g of trans-3-styrylpyridine-N-oxide are dissolved in 10 ml of acetic anhydride, and the The solution is boiled under Bückfluas for 5 hours. By Removing most of the solvent in vacuo leaves a black, oily residue; this will treated with 20 ml of water and the mixture is heated on the steam bath for 1 hour. Hardens on cooling the oil turns into an aphwarous, sticky solid that penetrates through Filter collect and wash thoroughly with water and then by slurry with acetone. At this When working, a pale-green, crystalline residue (390 mg) remains on the filter, which comes from the minimum

- 29 -

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read amount of methanol is recrystallized. Han receives trana-3-styryl-2zil7pyridone (bp 261-265 ° C).

Example 16

The working method of FH Clarke, GA FeIock, GB Silvexmann and CH. Vatnick (<?. Org. Chem. 27, (1962) 533) applied. A mixture of 21.4 g of 3-pyridine aldehyde, 27 »2 g of phenylacetic acid, 20.2 g of triethylamine and 160 ml of acetic anhydride is stirred under reflux for 2 hours. The dark solution obtained is then allowed to cool to 90.degree. C. and 100 ml of cold water are added dropwise over a period of about 10 minutes at such a rate that the temperature remains> 90.degree. The solution is filtered hot, the filter is washed with 50 ml of water, and the washed solutions combined with the filtrate are set aside to cool.

The product separates out of the solution as brown needles, which are collected by filtration and washed with 50 ml of 50 # iger Acetic acid and 200 ml water. Recrystallization from about 350 ml of ethanol gives cis-ß-carboxy-3-stilbazole (M.p. 194-195 ° C).

B ice ρ i el 17

cis-3-stilbazole

1113 g of cis-ß-carboxy-3-etilbazole are used in small portions in the course of about 15 minutes to a stirred suspension of 1.2 g of copper chromite in 25 ml of quinoline, which by Immersion in an oil bath kept at 230 ° C is added. Stirring is then added for an additional 30 minutes at 230 continued up to 235 ° C. The mixture is cooled, fil-

' * ° "' 109824/2257

triturated and distilled in vacuo. Han receives pure cis-3-stilbazole (pp. 111 to 113 ° C / 0.65 mm).

Example 18 ei s ~

If one follows the procedure of Example 14- but Using 1.8 g of cis-3-stilbazole, cis-3-ßtyrylpyridine-N-oxide is obtained.

Example 19 *. *

The procedure of Example 15 is followed using eis-3-styrylpyridine-N-oxide. The entire product, which is isolated after digestion with hot water, is a black gum (2.0 g) which is then chromatographed on silica gel. The column is developed with methylene chloride and eluted with methylene chloride / methanol (40: 1 v / v) to give cie ~ 3-styryl-2 / ^: ili7pyridone.

Example 20

ft-phenylethylpyridine

To a solution of 0.2 m 3-styrylpyridine in 40 ml of methanol 0.2 g of platinum oxide catalyst are added. This mixture is then with hydrogen at room temperature under one Pressure reduced by 2.81 kg / cm (40 lb / in.). The EeakfcLonsmixture is then filtered through a filtercel pad and concentrated to dryness. 3-Phenylethylpyridine is obtained.

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Example 21

3-phenylethylpyridine-N-oxide

If the procedure of Example 5 is followed, but an equimolar amount of 3-phenylethylpyridine is used one 3-phenylethylpyridine-N-oxide.

Example 22 3-Phenylethyl-2 £ lg7pyridon

The procedure of Example 6 is followed using 3-phenylethylpyr * idine-N-oxide. The product obtained is 3-phenylethyl-2 ^ Wpyridoa. .

Example 23 3-phenylethinylpyridine

To a cooled solution of ELs with 11 ml of bromine in 50 ml of carbon tetrachloride, a solution of 0.20 mole is added 3-Styrylpyridin in MO ml of carbon tetrachloride was added dropwise with vigorous Eühren. The solution is then decanted off any gummy by-products and evaporated under reduced pressure at 40 ° C. Crude 3- (α, β-dibromophenylethyl) pyridine is obtained.

The crude dibromide is powdered to 20 g in 30 ml of t-butyl alcohol in a stream of nitrogen over 30 minutes Potassium hydride in vigorously stirred under reflux boiling t-butyl alcohol (100 ml) containing 1 g of hydroquinone added. When the addition is complete, the solution becomes stirred and refluxed for 1 1/2 hours, diluted with 100 ml of ether and removed from an amorphous, black Filtered off solid. The filtrate is treated with water

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wash and the aqueous phase extracted twice with Ither The combined ethereal solutions are washed with water, .dry and evaporated to dryness in vacuo. The residue is then distilled. 3-Phenyläthinylpyridin is obtained.

Example 24 3-Phenyläthinylpyridin ~ y- »03cid

By following the procedure of Example 14 but i

an equimolar amount of 3-phenylethinylpyridine is used » 3-Phenyläthinylpyridin-H-oxide is obtained.

Example 25 3-Phenylethinyl-2Z ^ a7pyridone

The procedure of Example 15 is followed using the 3-phenylethinylpyridine H-oxide. The product is a black gum which is then chromatographed on a silica gel column using methylene chloride / methanol (50: 1 v / v). 3H ^ enyläthinyl-2 / ia7pyridon is obtained. |

Be i s P i e 1 26

A slurry of 0.2 moles of 3-bromo-2Z ^ gTpJrAdOn, 0.22 Mol of copper (I) thiophenol and 120 ml of 2,4-lutidine becomes 24 Heated to 155 oi * 165 ° C for hours. The lutidine will removed by distillation under reduced pressure, and the residue is taken up in 400 ml of 10% aqueous sodium hydroxide. The unwanted material is filtered through filtration removed. The tiltrate is extra-

- 33 -

109824/2257.

hiert, and the aqueous solution is concentrated with Hydrochloric acid brought to pH 7. The resulting mixture is continuously treated with chloroform for 24 hours extracted. The chloroform extracts are combined and concentrated in vacuo. The residue is dissolved in chloroform and on an aluminum column using Chromatographyert chloroform as eluent. You get 3-phenylthio-2 ^ g7pyridone.

Example 27 3-Phenylsulfinyl-2 / iS7py: ridon

O j 25 mol of 3-phenyltMo ~ 2 /? Üä7pyridon with 100 ml of glacial acetic acid mixed, and 28.3 g (0.25 mol) of hydrogen peroxide are added as a JO ^ ige, aqueous solution. The addition takes place in proportions with drilling, and the reaction mixture is then boiled for 4 hours under reflux and cooled, and the glacial acetic acid is removed under reduced pressure. 3-Phenyl8ulfinyl-2ZT17pyridone is obtained.

Example 28

3-Pheny 1 sulphonyl-2ZiB7pyridone

If the procedure described above is followed but 0.50 mol of hydrogen peroxide is used, the product is obtained 3-phenylsulfonyl-2 / iS7pyridone.

- 34 -

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ar

Production of N-substituted products * Example 29 "

k ■ '' Ii m ni ι μ Μ *

1- (2-propynyl) -trans-5- (o -chlorostyryl) -2 / iS7pyridone

5 »75 S trans ^ -Co-Chlorstyi ^ O- ^ ilL ^ pyridon, which in 100 ml Dimethylformamide are dissolved with 1.25 S sodium hy & rid offset. This mixture is warmed to 4-5 ° C for 2 1/2 hours and cooled with ice. The mixture of heaps is then mixed with 3.57 S 1-bromine ~ 2-propyne and then at Stirred at room temperature for 10 hours. 200 ml of "ice water" are added and then 3 ml of 2.5N HOl. The pesticide is then filtered and washed with ice water. The product is recrystallized. Pure 1- (2-propynyl ) -trans-3- (o-chlorostyryl) -2Z? lB7pyridone.

b. <If one uses an equimolar set of the reactants of the below • the table shown instead of 1-bromo-2-propyne in the If the procedure described above is used, the corresponding N-substituted product is obtained.

Methyl iodide, 2-butenyl bromide, 4-pentenyl bromide, methallyl bromide ¹ , 1-brom-3-pentyne, benzyl chloride, ■ phenylethyl bromide, 1-bromo-3-phenyl-2 -propene, hydropathy 1-bromide, ß-diethylaminoethyl bromide, aminopropyl bromide or methylaminopropyl bromide d.

- 35--

109824/2257

c. If the procedure described above is followed, but an equimolar amount of the 2-pyridones according to the invention and 2-thiopyridones (with the exception of 3-anilinopyridones) used, the corresponding 1-substit. 2-pyridone and 2-thiopyridone products are obtained.

1-phenyl-trans-3- (o-chlorostyryl) -2 / iH / ^r pyridone

d. 0.025 m of trans-3- (o-chlorostyryl) -2 / i_l7pyridon, which are dissolved in 100 ml of benzene, are mixed with 1.25 6 sodium hydride. The reaction mixture is heated with stirring to about 45 ° C. for 8 hours and then kept at room temperature for 15 hours. The mixture is then centrifuged and the gel-like N-sodium compound is dried in an Abderhalden apparatus. The mixture is then added to 5 il iodobenzene and 0.3 g of copper metal and rapidly for 35 minutes at 120 - heated 2 ° C. Then let it slowly cool to room temperature. Dry chloroform is then added to a volume of about 50 ml. It is then stirred, filtered, and the filter cake is washed with chloroform. The chloroform is evaporated to dryness and the residue is chromatographed on 300 g of silica gel using ether-petroleum ether (10-80 %). 1-Phenyl-trans-3- (o-chlorostyryl) -2ZiH / -pyridone is obtained.

e. The 3-substituted-2Zia7Pyridones according to the invention and 3-substit.-2 / W "thiopyridones (with the exception of the 3-A * iilin-opyridone) in the desired,

• 1-Phenyl-3-substit.-2 / iIiZpyridone and 1-Phenyl-3-substit.-2ZiS7thiopyridone are converted.

f. If you have an equimolar amount of a substituted iodobenzene compound (such as p-chloroiodobenzene or p- * nitroiodobenzene) used instead of iodobenzene, the corresponding N- (substit.-phenyl) product is obtained.

-36- 109824/22 57

G. If the 3- (N-substit.-anilino product is desired, the following working methods can be used:

1. If only one R "substituent is desired (no R., - substituent), Examples 7-10 can be followed and the desired R "substituent in Example 8 can be followed to be introduced. Such substituents can be those of example 29b.

2. If only one E ^ substituent is desired (no R "substituent), Examples 7-10 can be followed and an acyl substituent can be used as H "im. Example 8 can be introduced. Then they can. Examples 29a, b or 29d, f can be followed to get the desired one R ^ group to be introduced. The acyl (R'-O- group then becomes removed according to example 11.

3. If both R "- and R, - substituents, but unequal, are desired, Examples 7 "through 10 can be followed and the desired R "substituent can be introduced in Example 8. The R ^ substituent becomes then introduced by Examples 29a, b or 29d, f.

4. If both R "and" R ^ substituents, but the same, If desired, Example 29c can be followed using 2 moles of reactant. .

" ^37t 101824/2217

3ί

Manufacture of! Dhiopyridones Example 30

trans-3- (o-chlorostyryl) -2 / iH7thiopyridone

A. B- (o ~ chlorophenyl) -q-3-pyriaylacrylic acid

The procedure of JA (D. ♦ Beard and AE Katritzky (Hec. Trav. Chim., 78, (1959) 592) is followed, a total reaction time of 88 hours and a temperature of 120 to 125 ° C being used. By working up in the usual way, some dark, oily by-product is obtained, which is removed by extraction with 50 ml of ether before acidifying the aqueous phase with acetic acid is recrystallized from ethanol to give Q- (o-chlorophenyl) -a-3-pyridyl acrylic acid (ip. 258 to 242 ° C. [with decomposition)] J

B. trans -3 (2'-chlorostyryl) pyridine

The decarboxylation of ß- (o-chlorophenyl) -a-3-pyridyl acrylic acid (2.3 g) is carried out according to Example 15. The dark, oily residue is treated with 100 ml of ether and filtering the solution from a small amount of insoluble material over anhydrous magnesium sulfate dried and evaporated in vacuo. The residue (1.7 g) is dissolved in 10 ml of nitrobenzene, a few iodine crystals are added and the solution is then refluxed for 20 minutes.

The cooled reaction mixture is diluted with 100 ml of ether and extracted with 80 ml of 2.5N hydrochloric acid. the aqueous phase is washed with 50 ml of ether and then through

109824/2257

12671 2053358

dropwise addition of concentrated ammonia alkaline made. The separated, brown oil is extracted with ether (2 × 50 ml), and the combined extracts are dried and evaporated. Pure trans isomer becomes isolated by way of its crystalline hydrochloride salt; when all of the crude oil (1.5 g) is in A'ther solution (about 50 ml) is treated with ethereal hydrogen chloride, you get 1.8 g (78 #) of the light buff, solid hydrochloride (ip. 198 to 204- ° C). By recrystallization the crude solid from methanol / ether gives trans-3- (o-chlorostyryl) pyridine hydrochloride (Pp. 203-211 ° C). "'

C. trans-B-Co-

The conversion of trans-3- (o-chlorostyryl) -pyridine (750 mg) is carried out according to Example 14 in 2 ml of acetic acid with 0.3 al 'Performed hydrogen peroxide and then with an additional 0.22 ml hydrogen peroxide after 3 hours. The solution is held at 75 to 80 ° C for 18 hours. By working up in the usual way, about 950 mg of trans-3 ~ (o-chlorostyryl) pyridine N-oxide is obtained as an oil.

D. trans -3- (o- (3hlorstyryl) -2 ^ H7pyridone

The N-oxide (525 mgj 2.3 mmol) is dissolved in 5 ml · acetic anhydride dissolved, and the solution is refluxed for 7 hours. By removing most of the solvent by evaporation in vacuo, and duroh digestion of the remaining, dark oil with 10 ml of water during , 1 hour on the steam bath - you get a black, gummy precipitate. The water is decanted and the rubber is rubbed with a little acetone. The thus obtained, yellow, crystalline. The solid is collected by filtration, washed thoroughly with acetone, air dried and "recrystallized from methanol. Trans-3-

- 39 -

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12671

(o-chlorostyryl-2Zi £ 7pyridione (pp. 188 to 191 ° C.

E. trans-J-io-chlorostyryl ^ ZWthiopyridone

0.11 mol of trans-3- (o-chlorostyryl) -2Z ^ B7p * yridone ⁱⁿ 75 ^{ml of} dry pyridines are mixed with 0.058 mol of phosphorus pentasulfide suspended in 75 ml of dry pyridine. The reaction mixture is refluxed for 1/2 hour. The pyridine is removed in vacuo and the residue pumped dry for several hours at room temperature. The residue is extracted in a Soxhlet apparatus with 1500 ml of benzene and the benzene is then evaporated to dryness. The residue is recrystallized from methanol. Trans-3- (o-chlorostyryl) -2ZiS7- · thiopyridone is obtained.

If one uses an equimolar amount of the pyridones according to the invention used in the procedure described above, the corresponding ihiopyridones are obtained.

The following representative examples illustrate the interconversion of functional groups that can be accomplished at different stages in the manufacture of the final products.

Example 51

3- (p-aminophenoxy) -2 / 1H7 pyridone

, A mixture of 0.01 moles of pure 3- (p-Mtrophenoxy-2ZiH7-pyridone in methanol-dioxane (1: 1) (about 200 ml)

with hydrogen at room temperature (2.81 kg / cm) in the presence of 1.0 g of palladium (10%) - converted to carbon. The mixture is filtered, the cake \ d.rd well with methanol washed, the! "filtrate is evaporated in vacuo, and the

- 40 -

109824/2257

The residue is chromatographed on a silica gel column using a methanol-methylene chloride system (v / v 0 to 30 % methanol) as the eluent. 3- (p-aminophenoxy) -2Z? IS7pyridone is obtained.

Example 52

Ί - Benzyl-3- (p-methyl-aminophenoxy) -2Z? IS7pyridon

A mixture of 0.05 m 1-benzyl-3- (p-aminopheno: sgO ~ 2 / is7pyridon and 20 ml of methyl formate are added for 18 hours | heated to reflux temperature · Unreacted methyl formate is removed under reduced pressure. The oily residue is dissolved in benzene and extracted with dilute hydrochloric acid to remove any unreacted 1-bericyl-3- (p-aminophenoxy) -2 / 327pyridone. After washing with water, the benzene extract is dried over anhydrous sodium sulfate, filtered and concentrated. 1-Benzyl-3- (p-formylaainophenoxy) * 2Z'ia7-pyridone is obtained.

By reducing this amide in ethyl ether with an excess of lithium aluminum hydride and isolating the product in the usual manner, 1-benzyl-3- (p-methylaminophen-. Oxy) -2 / T27pyridone is obtained. .

Example 33 '

1 -Hethyl-3- (p-dimethylaminophenoay) -2Z? I27thiopyridone

A solution of 0.005 mol of 1-methyl-3- (p-aitropheno3cy) -2Zi.ii7thiopyridon and 1.6 ml of 37% iormaldehyde in 50 ml of methanol is poured over 0.5 g of palladium (5 J under a hydrogen pressure of 2 , 95 kg / 6m ² hydrogenated until 5 equivalents of hydrogen have been absorbed

109824/2267

HZ-

are. The catalyst is filtered off and the ill occurred Vacuum evaporated · The Hi c reads and is in absolute alcohol dissolved) with hydrogen chloride gas, and then to dryness evaporated. Han "receives 1-methyl-3- (p ~ dimethylaminophenoxy) -2Z3S7tliiopyridon,

Example 34,. ■

3- (p-Hydroxyphenoxy) -

A mixture of 0.2 mol of 3- (p-aminophenoxy) -2Z'iil7pyridon, 600 ml of water and 25 ml of concentrated sulfuric acid is cooled to 10 ° 0, and a «solution of 0.21 mol of sodium nitrite in the minimum amount of water is gradually added. If the presence of free, nitrous acid can be detected (starch-iodide paper), the addition is interrupted and the diazotization mixture is allowed to warm to room temperature and then heated on a steam bath until no more nitrogen is evolved. The mixture is cooled, extracted well with chloroform, the combined chloroform layers are dried and concentrated to a residue, and 300 ml of methanol plus 0.5 ml of concentrated sulfuric acid are added. The mixture is heated gently for several hours, concentrated in vacuo to remove most of the methanol, and extracted with chloroform. The chloroform is dried, filtered and concentrated down to a back wall. Chromatographing the residue on a silica gel column using an ether-petroleum ether system (v / v 0 to 100 % ether) as the eluent gives 3- (p-hydroxyphenoxy- 2ZiB7-pyridone.

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¹²⁶⁷¹ ° 2053358

Example 55

3- (p-chlorophenoxy) pyridine

To 0.014 mol of 5- (p-aminophenoxy) -pyrioin _> the in 125 al. 80? & Lger hydrochloric acid are suspended and cooled to 0 ° 0, a solution of 1.17 6 sodium nitrite in 15 ml of water is added dropwise. After about 10 minutes, a solution of 8.42 g of Xupfer (I) chloride in 200 ml of 50% hydrochloric acid is added in portions and stirred for 15 hours. The reaction mixture is then poured onto ice water and extracted with chloroform. This is dried over sodium sulfate and concentrated in vacuo to a solid which is chromatographed on silica gel. 5- (p-Chlorophenoxy) pyridine is obtained by eluting with Xther petroleum ether (15 to 25 #).

Example 36

By following the procedures of Examples 1 to 35, but using the appropriate raw materials, one can manufacture the following products:

- 43 -

109824/2257

product

Raw material

Way of working

3- (p-riethylpheno: ^ -) - 2 / iH / pyridon

3- (p-hydroxyphenoxy) -2 / iH7pyridone 3- (p-iTitrophenoxy) -2 / il7pyridone 3- (o-Ni trophenoxy) -2 / jiH7pyri dön

3- (p-Trifluoromethylphenoxy) -2ZiH7-pyridone

35- (p-biphenyloxy) -2 / iS7 pyridone

3- (Ei, !!! ¹ , p-trimethoxyphenoxy) -2 /? IB7-pyridone

3- (o-aminophenoxy) -2 / Ϊ SZpyridon

1-phenyl-3- (p-methylaminophenoxy) -2 / 1By pyridon

1- (ß-Diiaethylaminoäthyl) -3- (p- dime thy laminophenoxy) - 2 / Ϊ HTpyri don

3- (ο, ο'-dichlorophenoxy) -2ZiS7pyridon 3- (o-tolyloxy) -2 / i§7 pyridone 1-Methy 1-3-phenoxy-2 / iiB7 pyridone 1-methallyl-3-phenoxy-2- / i27pyridone 1- (3-pentynyl) -3-phenoxy-2 / iH7-pyridone 1-phenyl-3- (p-nitrophenoxy) -2 / ϊ§7-pyridone

1- (p-chlorophenyl) -3- (p-ethy! Phenoxy)

in

3- (p-Methy! Phenoxy) pyridine

3- (p-chlorophenoxy) pyridine

3- (p-HethoxyphenoxjO-pyi ^> idin

3- (p-aminophenoxy) -2 / 107 pyridone

3- (p-nitrophenoxy) pyridine

3- (o-nitrophenoxy) pyridine

3- (p-Trifluoromethylphenoxy) pyridine

3- (p-biphenyloxy) pyridine

3- (m, ni ', p-trimethoxyphenoxy) pyridine

3- (o-Nit rophenoxy) -2 / ig7pyri don

1-phenyl-3- (ppyridone

1- (ß-Dimethylaminoethyl) -3- (p-nitro phenoxy) -2ZiS7pyridon

3- (o, o'-dichlorophenoxy) pyridine

3 ~ (o-tolyloxy) pyridine

3-phenoxy-2 / iiH7pyridone

3-Phenoxy-2-Zi57pyridone

3-phenoxy- 2 /? I SZpy ri don

3- (p-Hi trophenoxy) - 2ZiJ7pyri don

- 3- (p-Methylphenoxy) -2ZiJ7pyridon

Examples 1 to 3

Examples 1 to 3

Examples 1 to 3 Example y \

Examples 1 to 3

Examples 1 to 3

Examples 1 to 3

Examples 1 to 3 Examples 1 to 3

Example 31 Example 32

- Example 33

Examples 1 to 3 Examples 1 to 3 Example 29b, c Example 29b, c Example 29b, c Example 29d,

Example 29f

CD Ol CO

ca cn co

product

Raw material

Way of working

y pyriaon

1- (β-A: ninoethyl) -3-pneno: xy-2ZW-pyridone

1 - (ß- Bim e tny laminoä thy 1) - 3-phenoxy / 3S7i

4-methyl-3-phenoxy-

6-methyl- 3- (ρ- chi pyridon

1-Benzyl-3- (p-chlorobenzyl) pyridone

ι 3- (p-2? rifluoromethylbenzyl) -2iiij ^ - pyridone 1-methallyl-3- (p-phenylbenzyl) -

y pyiidoa

ο 1- (ß-Dxmeth.ylaminoäthyl) -5- (p ~ tlbl) 2 ^? TBid

i-Benzyl-3- (p-nitrop3ienylethyl) - ^ S ^ id

3-Plieiioxy- 2Z? Ii! 7pyri don

4-methyl-3-pb.enoxypyri din
6-methyl-3- (p-chloroplienosy) pyridine

J- (p-chlorobenzyl) pyridine

3- (p-5Brif luoxmethylbenzyl) pyridine

3- (p-phenylbenzyl) pyridine

35- (pM.trobenzyl) -2 / i27pyridone
3- (p-Methosybenzyl) pyridine

3- (p- CJhlorplieny läthyl) -py ri din
3- (p-Hitrophenylätnyl) -pyri din

trans -3 (p-Kitros tyryl) pyridine
ice-3-. (p-Hi trostyryl) pyridine

Example 29b, c

Example 29b, c

- Example 29b, c

Examples 1 to 3 Examples 1 to 3

Examples 4 to 6, 31b, c

Examples 4 to 6

Examples 4 to 6, 29b, c

Examples 29d, e, 33

Examples M- to 6, 29b, c

Examples 20 to

Examples 20 to 22, 1

Examples 12 through Examples 16 through

Product

Raw material

Way of working

1- (ß-Dimethyl aainoethyl) - 3- (pmetlioxystyryl ) -2/5 B / pyridone

3- (p-hydroxystyryl) - 2 / iE7 pyridone

3- (p-Bimethylaminostyryl) -2 / ΪΗ7-pyridone

1-Benzy1-57 (p-trifluoromethylstyryl) -2 / iE / pyridone

i-methyl-3- (p-nitrophenylthio) -2ZW-pyridone

1-methyl-3- (p-nitroanilino) -2ZW-pyridone

5 -. (O-Methylanilino) -2ZWpyridone

1 - (ß-Dime tiwlaminoäthyl) - 3- (H-phenyl benz ami do; - 2 / Δ H7pyri don

3- (N-Ac etyl-p-nitroanilino) - _ »Pyridon ^ - (p-chlorophenylethinyl) -2Z? IS7 ", Pyridon

- 2ΖΪ W'thiopyri don

o * -Methyl-3-phenoxy- 2 / ÄE7ühl opyri don "^ -Benzyl-2 / iB7thiopyri don 3-benzoyl-3- (p-methoxystyryl) pyridine

3- (p-Amino styryl) -2Z? IS7pyxi don

3- (p-Hitrostyryl) -2 / il7pyridone

3- (p-Trifluoromethylstyryl) pyridine 3- (p-Ni trophenylthio) -2 / ^ BTpyridone 3- (p-38itroanilino) pyridine

3- ( o-Me thy lanilino) -pyri din

3-anilinopyridine

3- (N-Phenylbenzamido) -2Z] iS? Pyridone 3- (p-nitroanilino) pyridine
p-C3ilorphenyl- (3-pyi ^> idyl) -acetylen 4-Methyl- 3-PlIeJ ¹ OXyPy ^ i <&&

3-phenoxy-2ZiS7pyridone
4-Methy 1- 3-phenoxy-3-benzyl-2 /? 12 / ^ir pyridone
3-benzoyl

Examples 12 to 29b, c

Examples 12 to 19, · <»

Examples 12 to 19, 33

Examples 12 to 19, 29b, c

Examples 26, 29b, c

Examples 7 to 10, 29a, b,

Examples 7 to Examples 7 to Examples 29a, b

Examples 7 to Examples 23 to

Examples 1 to 3" _m to
CD 29b, c cn
£ O example 30th E. * TlI *
CO example 30th E ' cn example 30th E- OO example 3Q E.

Product i

Raw material

Way of working

3- (IT-phenyll3enzamido) -2 / fiH / thiopyridone

3-anilino-2ZiH7 ^r thiopyridon trans- 3- styryl- 2Z? Lg7tni opyri don cis-3-styryl-2Zi ^ tliiopyridon 3-phenylätliyl-2 /? LS7tliiopyridon 3-phenyläthinyl-2 /? TH7tniopyrid7thio-3-yridon-phenylthio-3-phenylthio-3- Phenylsulfinyl-2 / iS7thiopyridon 3-Phenyls olfonyl-2ZiE7thiopyridon

1 '- (2-propynyl) -trans-3- (o-chlorostyryl ^ - ^ ST'thiopyridone

1-phenyl-trans-3- (o-chlorostyryl) -2 / ^; ) B / thiopyridone

1 _i 4-dimethyl-3-pneno: xy-2 / ^: ES7thiopyridone 3- (N-phenyrbenzamido) -2 ^ BZpyridone Example 30 E.

Example 30 E.

Example 30 E.

Example 30 E.

Example 30 E.

Example 30 E.

Example 30 E.

Example 30 E.

Example 30 E.

Example 30 E.

Example 30 E. 1,4-Dimethyl-3-phenoxy-2 / 3S7-pyridone Example 30. E.

trans-3-styr / 1-2Zia7pyridone

cis -3-styryl-2ZPLS7 pyridone

3-pnenylethyl-2 / iB7pyridone

3-Pheny la thiny 1-2 / Ϊ S7py ri don

3-phenylthio-2 /? Ts7pyridone

3-pnenylsulfinyl-2 / ^: ia7pyridone

3-phenylsulfonyl-2 ^ iH7pyridone

1- (2-propynyl) -trans -3- (o-cliloretyryl) -2 / ia7pyridone

1-Plienyl-trans-3- (o-chlorostyryl) -2Z? Li7pyridn

12671.

The following examples are representative of those according to the invention Middle.

Example 37

A mix of 25> 100 or 500 parts of trans-3- (o-chlorostyryl-2 / ili7pyridon and 25 parts of lactose is granulated with the appropriate amount of water, and to this are added 100 parts corn starch given. The mass is poured through a 16-mesh sieve. The grains are at a Dried at a temperature below 60 ° C. The dry kernels are poured through a '16 mesh sieve, and mixed with 3 »8 parts of magnesium stearate. You will then compressed into tablets suitable for oral administration.

Example 38

A mixture of 50 parts of 3-JPkenoxy-2 / ig7pyridon, 3 Parts of the calcium salt of ligninsulphonic acid and 237 parts of water are ground in the ball mill for so long until the size of virtually all particles of the sulfone is less than 10 microns. The suspension is with a Diluted solution containing 3 parts of sodium carboxymethyl cellulose and 0.9 parts of the butyl ester of p-hydroxy-benzoic acid contains 3QO parts of water .. This gives an aqueous one Suspension suitable for oral administration for therapeutic purposes.

1 09824/2257

Claims (1)

Claims in which: A oxygen or sulfur; Ar any benzoloid or non-benzoloid aromatic-like Structure containing one or more E substituents that are in any Position on the bing; B hydrogen, alkyl, halogen, hydroxy, alkoxy, Haloalkyl, aryl, nitro, amino, acylamino, alkyl amino or dialkylamino; E ^{1 is} hydrogen or alkyl; Z -CH ₂ -, -CH ₂ OH ₂ -, -CH = CH-, -ΟΞΟ-, ' -WH- or -NB "-; E ^ hydrogen, alkyl, alkenyl, alkynyl, aralkyl, Aryl, ^ hydroxyalkyl, aminoalkyl or dialkylamino- alkyl and E "alkyl, aralkyl, or acyl; and their non-toxic, pharmaceutically acceptable Salts. - 49 - 109824/2257 2. Compounds according to claim 1, characterized in that A oxygen; Ar phenyl; B hydrogen, alkyl, halogen, hydroxy, alkoxy,;, haloalkyl < Nitro, amino, alkylamino or di- alkylamino; fi ¹ hydrogenj Z ■ -CH ₂ -, -CH-CH-, -O- or -NH-; .and
R ,. Hydrogen, alkyl, aralkyl, aryl or dialkyl mean aminoalkyl. 3 connections according to claim 2, characterized in that that A oxygen; Ar phenyl; B hydrogen; Δ -OtL, - »-CH-CH-, -0- or -NH-; and ' R ^ mean hydrogen. 4. Compounds according to claim 2, characterized in that that • A oxygen; Ar phenyl; B halogen; Z -CH-CH-; and IL mean hydrogen. - 50 - '109824/2267 ! 2671 5 · Connection according to claim J3, characterized in that
that Z denotes -CH = CH-, so that 3-styryl-2 / TH7pyridone results. 6. A compound according to claim 3, characterized in that
that Z means -O-, so that J5-phenoxy- 2 / J ^ / - pyridone results. 7. A compound according to claim 3, characterized in that Z -NH- means, so that 3-anilino-2 / lH7-pyridone er gives. 8. A compound according to claim 4, characterized in that B o-chlorine means that 3- (o-chlorostyryl) -2 /! EH7 pyridon results. 9. Process for preparing compounds of formula in which: Ar any benzoloid or non-benzoloid aromatic-like Structure containing one or more R substituents located in any position on the Ring ™ can be located;
B hydrogen, alkyl, halogen, hydroxy, alkoxy, haloalkyl, aryl, nitro, amino, acylamino, alkylamino or Dialkylamino;
R ^{1 is} hydrogen or alkyl; Z -CH ₂ -, —CHpCHp-, -NH- or
-NO"-; R "alkyl, aralkyl, or acyl, 109824/2257 - 51 - characterized in that one (a) a J-substituted pyridine compound of the formula 2 ^ r? B. in which the symbols Ar, B, E 'and Z have the meanings given above, in acidic media with peroxide with formation of an N-oxide compound of the formula E? B. implements and (b) rearranges said N-oxide to form the 2-pyridone. 1O _:. The method according to claim 9> characterized in that Ar phenyl; B hydrogen, alkyl, halogen, _s hydroxy, alkoxy, haloalkyl, nitro, amino, alkylamino or Dialkylamino; R ^{1 is} hydrogen; and Z -CH ₂ -, -CH = CH-, '-O- or -MH-mean. 11. The method according to claim: 1O ,, characterized in that Ar phenyl; - 52 - 109824/2257 B hydrogen; and Z -CH ₂ -, -CH = CH-, -O- or -NH-mean. 12. The method according to claim 10, characterized in that that Ar phenyl; B halogen; and · . Z -CH = CH-. I. mean. l'j>. Process according to Claim 11, characterized in that Z denotes -CH = CH-, so that J5-styryl-2 / TH7pyridone is formed. 14. The method according to claim 11, characterized in that ζ -0- means that 3-phenoxy- 2 / Te / - pyridone is formed. 15. The method according to claim 11, characterized in that that Z -NH- means, so that ^ -anilino-2 / ThJ ⁷ - a pyridon forms. 16. The method according to claim 12, characterized in that B denotes o-chlorine, so that j5- (o-chlorostyryl) -2 / TH7-pyridone is formed. 17 · Process for the preparation of compounds of the formula - 5J5 - 10-9824 / 2267 12671 pi Ir? B. in which: Ar any benzoloid or non-benzoloid, aromatic-like Structure containing one or more R substituents in any Position on the ring; B hydrogen, alkyl, halogen, hydroxy, alkoxy, Haloalkyl, aryl, nitro, amino, acylamino, Alkylamino or dialkylamino; R ^{1 is} hydrogen or alkyl; Z -CH-CH-, -NH- or
-NO"-; R ^ alkyl, alkenyl, alkynyl, aralkyl, aryl, hydroxyalkyl, Aminoalkyl or di alkyl aminoalkyl; and R "alkyl, aralkyl or acyl, characterized in that one connects the formula 1Q982A / 22S7 in which the symbols Ar, B, Ei, Z and E "have the meanings given above, with a connection of the formula in the E ,. has the meaning given above and Y Halogen means, converts 18. Process for the preparation of compounds of the formula E ' in which: Ar any benzoloid or non-benzoloid aromatic-like Structure containing one or more R substituents in any Position on the ring; B hydrogen, alkyl, halogen, hydroxy, alkoxy, Haloalkyl, aryl, nitro, amino, acylamino, * Alkylamino or dialkylamino; ™ E 'hydrogen or alkylj
Z -CH ₂ -, —CHpCHp-, -CH = CH-, -C = C-, -HH- or -NE "-j
E ^ hydrogen, alkyl, alkenyl, alkynyl, aralkyl, aryl, hydroxyalkyl, aminoalkyl or dialkylaminoalkyl; and - 55 - 109824/2257 * -r 2ÜB9358 12671 St ΔΌΌΌΟΌΟ E "alkyl, aralkyl or acyl, characterized in that one has a 2-pyridoii compound the formula _Z ^ I ^ Z β in which the symbols Ar, B, E ', Z and E _x . have the meanings given above-P, reacts with phosphorus pentasulfide. 19. The method according to claim 17! characterized, that Ar phenyl; B hydrogen, alkyl, halogen, hydroxy, alkoxy, Haloalkyl, nitro, amino, alkylamino or di- alkylamino;
E 'hydrogen;
Z -CH ₂ -, -CH = CH- ,, -O- or
™ -NH-; and E ^. Hydrogen, alkyl, aralkyl, aryl or dialkyl aminoalkyl
mean. 20. The method according to claim 18, characterized in that that Ar phenyl;
B hydrogen;
Z -CH ₂ -,
-CH-CH-, -56- 1Q982W2257 1267-. i> -O- or -KH-; and Ry, mean hydrogen. 21. The method according to claim 8 »characterized in that that Ar phenyl; B halogen; Z -CH = CH-, and R ^ mean hydrogen. 22. Pharmaceutical preparation in unit dosage form, which is suitable for administration to relieve pain, strain and / or inflammation, containing an effective, non-toxic one per dosage unit Amount within the range of about 5 to 500 mg on at least one compound of the Pormel -Z -β, -g. B. in which: A oxygen or sulfur j Ar any benzoloid or non-benzoloid aromatic-like Structure containing one or more R substituents in any Position on the ring; R is hydrogen, alkyl, halogen, hydroxy, alkoxy, haloalkyl, aryl, nitro, amino, acylamino, alkylamino or dialkylamino; - 57 - 109824/225 12671 ^{Upper Austria} R 'is hydrogen or alkyl; -.CH = CH-, -0 = 0-, -0-, -S-, -HH- or -NBiL;
E ,. Hydrogen, alkyl, alkenyl, alkynyl, aralkyl, aryl, Hydroxyalkyl, aminoalkyl or dialkylaminoalkyl; and R "is alkyl, aralkyl, or acyl; in combination with a pharmaceutical carrier. '2>. Agent according to Claim 22, characterized in that ~~ 'A is oxygen;
^, Ar phenyl; R is hydrogen, alkyl, halogen, hydroxy, alkoxy, haloalkyl, nitro, amino, alkylamino or dialkylamino;
R ^{1 is} hydrogen;
-CH = CH-,
-0-,
-S-, -S-, Q 0 -S- or -NH-; and - 58 - 10982A / 2257. R _{1 is} hydrogen; Alkyl, aralkyl, aryl or dialkyl aminoälkyl; mean. 24. Means according to claim 23, characterized in that A oxygen; • Ar phenyl; R is hydrogen; X -CH = CH-, 0 Λ Il I 0 O -S- or -NH-; and R _{1 is} hydrogen. 25. Means according to claim 23 * characterized in that A oxygen; Ar phenyl; R halogen; '* · X -CH = CH-; and R ₁ hydrogen f mean. 26. Gown according to claim 24, characterized in that X -CH = CH- means that the agent is 3-styryl-2 / TH / -pyridone contains. 27. Agent according to claim 24, characterized in that X means -0-, so that the agent is 3-phenoxy-2 / TH7- 'contains pyridon. - 59 - 109824/2257 28. Means according to claim 24, characterized in that X -NH- means, so that the agent> anilino-2- / 1H7-pyridone contains. 29. Means according to claim 24, characterized in that R o-chlorine means, so that the agent J5- (o-chlorostyryl) -2 / lH7pyridon contains. - 60 - 109824/2257