IL31133A - New pyridone and pyridine derivatives,their preparation and pharmaceutical compounds containing them - Google Patents

Description

jiT B niiiiin i"a i6 nn^in ninpn »©am ,fn.on , τ 'β «·.»«-.ST•SIm.SS aaCS-aS5«-S3··S3·■SS·»SO«-5S—SS"-- New pyridone and pyridine sulfide derivativeB, their preparation and pharmaoeutioai compounds containing them MERCK & CO., INC- la - This invention relates to preparations for treating inflammation which contain as an active ingredient a compound having one of the structures I or II: ¾2 β II in which ' 1 ^ is hydrogen i lower alkyl . phenyl ar-lower alkyl halogen lower alkoxy amino dilower lkylamino diloweralkylamino loweralkyl nitro loweralkylsulfonyl phenylsulfonyl or triphenylmethyl R-, is hydrogen . loweralkyl loweralkenyl hydroxy amino loweralkynyl phenyl □ubotitutod phenyl ar-loweralky1 ar-loworalkony1 benzamido loweralkanoylamino carbobenzoxyamino carb- loweralkoxyamino benzylidineamino phenylureido aminoloweralkyl loweralkylamino lower alkyl diloweralkylamino lower alkyl loworalkanoyl lower alkyl carboxyloweralkyl hydroxyloweralkyl cyanoloweralkyl or 2'-quinolyl R-j is hydrogen or loweralkyl R4 and 5 are the same or different hydrogen loweralkyl phenyl halogen trihalo-loweralkyl loweralkoxy amino cyano culfamoyl loworalkyl-culfamoyl diloweralky1-sulfamoyl hydroxy mercapto lower alkylthio lower alkylsulfinyl lower alkylsulfonyl carbamoyl carboxy aulfo or phenylsulfonyl Rg is oxygen or sulfur R7 is ORg or SRg in which Rg is loweralkanoyl or loweralkyl benzyl nitrobenzyl lower alkylbenzyl halobenzyl aminobenzyl lower alkylaminobenzyl lower alkoxybenzyl methylenedioxybenzyl group o and [A] is carbocylic or heterocyclic aryl s-tteh—es comprised from the phenyl 11,755 31133/2 - 4 - . thienyl pyridyl or furyl and is linked to the 3 or 4 position. More specifically also, this invention relates to certain novel active compounds which are contained in the above preparations.

In the past, a standard treatment of inflammation has been to administer various compounds of the steroid class. These had the great disadvantage of affecting the calcium in the bones after prolonged administration".

Recently,* certain non-steroid drugs have been, introduced · which eliminate, to a large extent, this deficiency. How- ever, there' still remains the problem of certain other side I effects such as haematological disorders and irritations in i 1 the gastro intestinal tract. There is, therefore, a need t for new compounds for the treatment of inflammation which will further reduce the side effects experienced on chronic administration.

We have found that inflammation can be treated advantageously with the class of compounds known generical- ly as 3- or 4-phenyl-2- [1H] -pyridone including the parent compound of each series, namely, 3- or 4-pheny1-2- [1H] - pyridone. Treatment of inflammation with this class Of com- pounds shows less side effects than with prior drugs while retaining excellent effectiveness.

The novel compounds according to the invention are those . of either the structures I or II above, with the various substituents having the definitions given above, wherein the group is always linked to the' 3-position of the heterocyclic ring;with the added provisos that when is phenyl, R. gen and when R is loweralkyl, R, is other than hydrogen.

The preparation of the compounds of this inven-tion are described in the Flow Sheet for 3-phenyl-2- [1H] -pyridone compounds. The reactions described operate equally for the 4-phenyl compounds. In general, a 3- or 4-amino-pyridine is diazotized in the presence of benzene or a sub-stituted benzene. The resultant 3-phenylpyridine is then oxidized to the corresponding N-oxide. The N-oxide can be converted by one of two methods into the 3-phenyl-2- [1H] -pyridone. In the first, the N-oxide is heated with lower alkanoic anhydride which results in the formation by re-arrangement of 2-acyloxy 3- or 4-phenylpyridine which upon acid or preferably basic hydrolysis gives the 3- or 4-phenyl- 2- [1H] -pyridone . Alternatively, the N-oxide is treated with chlorinating agent which again, by rearrange-ment, produces corresponding 2-chloropyridine which also upon hydrolysis gives the 3- or 4-phenyl-2 [1H] -pyridone . The 2-chloro-3-phenylpyridine oxide is also prepared by direct oxidation of 2-chloro-3-phenylpyridine . The 3- or 4-phenyl- 2 [1H] -pyridones (Compound VI in the Flow Sheet) may be converted to the corresponding 3- or 4-pheriylthio-pyridones by treatment with phosphorus pentasulfide . The 3- or 4-pheny1-2 [1H] -pyridones of Compound VI may be con-verted to the 1-substituted 3- or 4-pheny1-2 [1H] -pyridones of Compound IX by the action of alkylating agents. Certain other compounds to be used in the method of this invention, namely, the 3-phenylalkoxy or alkylthiopyridines (Compound XI) are prepared from the 2-chloropyridines by use of the sodium alcoholate or thioalcoholate . When 3- or 4- (nitro-phenyl) -pyridones are prepared, the nitro group can be re-duced to the amino rou and this can be used via a Sand- meyer type reaction, to prepare halo, cyano, raercapto, etc., derivatives.

The Flow Sheet also shows an alternate method of making the 3- or 4-phenyl-2 [1H] -pyridones which is the oxi-dation of the corresponding 3- or 4-phenylpiperidones . It should be noted that the reactions shown in the Flow .Sheet are numbered with numbers corresponding to the Examples which follow in this specification and which illustrate these reactions.

Other methods have been known in the literature for the preparation of 3- or 4-phenyl-2 [1H] -pyridones . A 3-or 4-amino 2-halogenopyridine can be diazotized in the pres-ence of a benzene to get Compound VII, directly, nitro ben-zenes can be heated with pyridines at very elevated tempera-tures to produce 3- or 4-phenylpyridines . An open chain sub-stituent on a benzene compound can be cyclized to form the pyridone ring or a piperidone ring which can be oxidized as described above to the 3- or 4-phenyl-2 [III] -pyridone. A 3- or 4-phenylpyridine 2-sulfonic acid, upon fusion with caustic, gives a 3- or 4-pheny1-2 [1H] -pyridone . An alpha pyrone can be treated with ammonia to give a 3- or 4-pheny1-2 [1H] -pyridone . 3- or 4-phenylpyridines can be hydroxylated directly in the vapor phase. 3- Or 4-pheny1 2-aminopyridines can be diazotized and the diazo compound hydrolyzed to give a 3- or 4-pheny1-2 [III] -pyridone . The N-oxides (Compound IV) can be rearranged under the influence of light to give the 3-phenyl-2- [1H] -pyridones. The 1-s ubstituted-3- or 4-phenyl-2 [1H] -pyri-dones (Compound IX) can be prepared by the direct oxidation of the corresponding 3- or 4-phenyl N-pyridinium compounds.

These various preparations generally are not as practical 4· in the Flow Sheet, being either highly specialized in what compounds can be used or being methods which give poorer yields or for other inherent weaknesses.

In the treatment of inflammation by 3-phenyl-2 tlH] -pyridones , the medicament may be administered orally, intravenously or applied topically. It c n be used with any ordinary pharmaceutical carrier. In formulations, it can be pressed into shaped dosage forms, such as pills or tablets, or be encapsulated or dissolved in isotonic solu-tion for I.V. use or made into ointments for topical use.

The standard pharmaceutical ingredients normally used in pharmaceutical formulations can be used in formulating these compounds. Inflammation is treated by the administration from 0.5 to 30 milligrams of the compound per kg. body weight per day. An example of the above class is the simple unsubstituted 3-phenyl-2 [1H] -pyridone which should be ad-ministered in a dosage range of from 2 to 15 mg./kg. of body weight/day. The 3-pheny1-2 [1H] -pyridone is effective at -30 milligrams per kilogram in rats. The patients used in this treatment may be either animal or human since all warm-blooded species are subject to the ills of inflammation.

FLOW SHEET - (Cont'd) VI XI VIII Reactions 1. Addition of or to amyl nitrite with or without an inert solvent, followed by heat. Amyl nitrite can be replaced by other organic solvent-soluble nitrosating agents. 2. Oxidation in an inert solvent. H2°2 a Pre^erre^ agent. 2a. Oxidation is an inert solvent (e.g. acetic acid) with peracetic acid. 3. (a) Heating with a lower alkanoic anhydride in an inert atmosphere. Acetic anhydride preferred. (b) Hydrolysis, usually by contact with water, also in presence of alkali or acid. 4. (a) Heating with a chlorinating agent, such as PCI,, in an inert solvent. (b) Hydrolysis, usually by cone. base.

. Heating with a dehydrogenating agent such as with palladium on charcoal in an inert atmosphere. 6. Reaction with a strong base, e.g. NaH in an inert atmos- phere, followed by addition of an alkylating agent such as an aliphatic tosylate, sulfate or aliphatic halide. 7. Heating with strong base (e.g., NaOH) and an unsaturated organic compound such as acrylonitrile or an a-haloacid derivative such as chloroacetic acid. (The latter proce- dure is described in J. Am. Chem. Soc. 71, 1949, p. 390.) l-Carboxymethyl-3-phenyl-2-pyridone , m.p. 93-96°C. , may be prepared by this procedure. 8. Reaction with a strong base such as NaH in an inert atmosphere, followed by heating with iodobenzene or a substituted iodobenzene. 9. Stirring at low temperatures, preferably cold with an N-halo amino compound. 11. Heating with P2S5 ^n the aksence of 0H' ketone or amino groups in the molecule) . 12. Heating with a metal alkoxide or other alcoholate. 13. Heating with a metal mercaptide.

Our invention can be illustrated by the following examples.

EXAMPLE 1 A. 3-Aminopyridine (39 g.) in 1.5 1. of anhydrous benzene is treated with amyl nitrite (68 g.) and the result-ing mixture heated slowly to 81°C. and kept overnight at this temperature. The solution is decanted from some tar which has precipitated, and the excess benzene removed in vacuo. Distillation of the residue yields 3-phenyl-pyridine (38 g.; 59%), b.p. 102-105.5° (2.5 mm.) as a yellow oil.

Similarly, when 4-amino pyridine is used in the above example in place of 3-amino pyridine, there is ob— tained 4-phenylpyridine .

B. Similarly, when the benzene in Part 1A is replaced by toluene, anisole, benzoriitrile , nitrobenzene, fluorobenzene , benzotrifluoride , naphthalene, o-, m- , and p-xylenes, o-, m- , and p-dichlorobenzenes , hydroquinone dimethyl ether, veratrole, resorcinol dimethyl ether, biphenyl, thiophene , furan or thiazole, the corresponding substituted phenylpyridines , 3-(o-, m- , and p-irethy¾»!_½nyl)-pyridines, 3-(o-, m- , and p-methoxyphenyl) -pyridines , 3-(o-, m- , and p-cyanophenyl) -pyridines , 3-(o-, m- and p- / nitrophenyl) -pyridines , 3-(o-, m-, and p-fluorophenyl) -pyridines, 3-(o-, m-, and p-trifluoromethylphenyl) -pyridines , 3- (a- and (3-na th l) - ridines , 3*-(o,m-, m,p. ο,ο'-, ο,ρ- 4r φ m,m ' - , and o,m' -dimethylphenyl) -pyridines , 3-(o,m-, m,p-, ο,ο'-, ο,ρ-, m,m,- and o,m'-dichlorophenyl) -pyridines, 3-(o,m-, m,p-, ο,ο'-, ο,ρ-, and m,m'- and o,m'-dimethoxy-phenyl) -pyridines , 3-(o-, m-, and p-biphenylyl) -pyridines , 3- (2-thienyl) -pyridines , 3-(2' and 3 ' -furyl) -pyridines , and 3-(2'-, 4'- and 5 * -thiazolyl) -pyridines are obtained after separation of isomers via fractional distillation and/or column and vapor-phase chromatography.

C. 3-Aminopyridine (39 g.) in 1.5 1. of anhydrous chlorobenzene is treated with amyl nitrite (68 g.) as described in (A) above. Distillation of the concentrated reaction mixture yields 35.4 g. of the three isomers, b.p. 110-130° at ca. 2.5 mm. The fraction boiling 110-113°C. at ca. 2.5 mm. consists of 11.5. of nearly one component material; I.R., N.M.R., U.V. and T.L.C on this and on products derived from this indicate the o-isomer. The other isomers are isolated from the higher boiling fractions via purification of their picrates, followed by regeneration of the free bases. When 4-aminopyridine is used in place of 3-aminopyridine in the above procedure, the corresponding 4-phenylpyridines are obtained.

D. In cases where the benzene-substitute is a solid, an inert co-solvent is used and the amount of benzene-substitute reduced. Also, the phenylpyridines listed in (A) above are obtained by coupling a substituted aniline, as o-chloroaniline , with pyridine via the above procedure, and separating the isomeric a- , 0- and μ- pyridines, to give the desired 3- (substituted phenyl) -pyridine .

E. When 5-amino-2-picoline is used in place of 3-aminopyridine in procedure (A) above, 6-methyl-3-phenyl) - 4·' pyridine is obtained. Similarly, when 5-amino-3-picoline , 3-amino-4-picoline 5-amino-2-chloropyridine , 3-amino-5- chloropyridine , 3-amino-4-chloropyridine , 5-amino-2-methoxypyridine , 3-amino-5-methoxypyridine , 3-amino-4-methoxypyridine, 5-amino-2-nitropyridine, 3-amino-5-nitro-pyridine, 3-amino-4-nitropyridine , 5-amino-2-ethoxypyridine , 3-amino-5-ethoxypyridine , 3-amino-4-ethoxypyridine , 5- amino-2-ethylpyridine , 3-amino-4-ethylpyridine , 5-amino-2-phenethyl, 3-amino-4-phenethylpyridine , 5-amino-2-fluoro-pyridine, 5-amino-2- (methylsulfonyl) -pyridine , 3-amino-4- (methylsulfonyl) -pyridine, 5-amino-2- (phenylsulfonyl) -pyridine, 5-arnino-3-chloro-2-phenoxy-pyridine , 5-amino-2-methoxy-4-picoline , and 3-amino-5-phenyl-4-picoline are used in place of 3-aminopyridine in the same procedure, 5-methyl-3-phenylpyridine , 4-methyl-3-phenylpyridine , 6-chloro- 3-phenylpyridine, 5-chloro-3-phenylpyridine , 4-chloro- 3-phenylpyridine , 6-methoxy- 3-phenylpyridine, 5-methoxy-3-phenylpyridine , 4-methoxy- 3-phenylpyridine , 6-nitro- 3-phenylpyridine , 5-nitro-3-phenylpyridine , 4-nitro-3-phenylpyridine, 6-ethoxy-3-phenylpyridine , 5-ethoxy-3-phenylpyridine , 4-ethoxy-3-phenylpyridine , 6-ethyl-3-phenylpyridine, 4-ethyl-3-phenylpyridine , 6-phenethyl-3-phenylpyridine, 4-phenethyl- 3-phenylpyridine , 6-fluoro-3-phenylpyridine, 6-methylsulfonyl-3-phenylpyridine , 4-methylsulfonyl-3-phenylpyridine , 6-phenylsulfonyl-3-phenylpyridine, 5-chloro-6-phenoxy-3-phenylpyridine , 6-methoxy-4-methy1-3-phenylpyridine and 3 , 5-diphenyl-4-methylpyridine are obtained.

F. When the substituted benzenes of (B) are used in place of benzene in part (E) above, the corresponding G. 3-Amino-2-chloropyridine (5.1 g.) in 50 ml. of anhydrous benzene is added dropwise over 32 minutes to 150 ml. of benzene to which has just been added 8 ml. of i-amyl nitrite and which is held at 50-56 °C. The mixture is heated to 75°C. over 2 hours and worked up as in part (A) to give 2-chloro-3-phenylpyridine .

H. Similarly, when the benzene in the above re-action is replaced by pyridine, methylphenylsulfide or any of the benzene substitutes used in part (B) , the correspond-ing 2-chloro-3-amylpyridine is obtained. The products are mixtures of the isomeric arylpyridines and the isomers are separated by fractional distillation and/or column and vapor phase chromatography. In this way, there are obtained 2-chloro-3- (2 ' , 3 ' - and 1 -pyridino) -pyridines , 2-chloro-3- (o-, m- and p-methylthiophenyl) -pyridines , 2-chloro-3- (o- , m- and p-methylphenyl) -pyridines , 2-chloro-3- (o- , m- and p-methoxyphenyl) -pyridines , 2-chloro-3- (o- , m- and p-cyano-phenyl) -pyridines , 2-chloro-3- (o- , m- and p-nitrophenyl) -pyridines, 2-chloro-3- (o- , m- and p-fluorophenyl) -pyridines , 2-chloro-3- (o- , m- and p-trifluoromethylphenyl) -pyridines , 2-chloro-3- (a- and β-naphthyl) -pyridines , 2-chloro-3- (o ,m- , m,p-, ο,ο'-, ο,ρ-, m,m'- and o,m'-dimethylphenyl) -pyridines, 2-chloro-3- (o,m- , m,p-, ο,ο'-, ο,ρ-, m,m'- and o,m'-dichloro phenyl) -pyridines , 2-chloro-3- (o,m- , m,p-, ο,ο'-, ο,ρ-, m,m' and o,m' -dimethoxyphenyl) -pyridines , 2-chloro-3- (o- , m- and p-biphenylyl) -pyridines , 2-chloro-3- (2-thienyl) -pyridines , 2-chloro-3- (2- and 3-furyl) -pyridines , and 2-chloro-3- (21 - , 41- and 5 ' -thiazolyl) -pyridines .

EXAMPLE 2 A. 3-o-Chlorophenylpyridine (11.4 g.) in 40 ml. of glacial acetic acid is treated at 27°C. with 7 ml. of 30% hydrogen peroxide solution. The mixture is heated gently, in this case 75+2° preferred and kept overnight, during which time another 9 ml. of hydrogen peroxide is added in 6 cc. and 3 ml. portions. After cooling, solid sodium bisulfite is added in small portions as needed to destroy the excess peroxide, the mixture is concentrated to ca. one-half the volume, 75 ml. of water is added, the mixture concentrated to ca. one-third the original volume, 100 ml. of water added, and the mixture concentrated to dryness. The oil remaining is dissolved in 150 ml. of chloroform, solid anhydrous sodium carbonate is added until the mixture is basic to pH paper, the mixture is filtered, the chloroform solution boiled down to ca. 45 ml. and petroleum ether slowly added, with swirling of the chloro-form solution to a volume of ca. 250 ml. The white solid that precipitates is filtered, washed with petroleum ether and dried to give 8.4 g. 3-o-chlorophenylpyridine-N-oxide , m.p. 118-123°, I.R. 8.26μ. This material is used without further purification in part 3B.

B. Similarly, when the 3-o-chlorophenylpyridine in the above reaction is replaced by the other 3- or 4-phenyl-pyridines prepared in Example 1, the corresponding N-oxides are obtained.

C. Similarly, when 4-phenylpyridine , 4-(p-tolyl)-pyridine, 4- (i-propylphenyl) -pyridine , 4- ( 3-biphenylyl) -pyridine, 4- (p-chlorophenyl) -pyridine , 4- (p-bromophenyl) -pyridine, 4- (o-methoxyphenyl) -pyridine , 4- (m-methoxyphenyl ) - - - - - - - pyridine, 4-(ο-, m- or p-nitrophenyl) -pyridine , are used in the procedure of part (A) , the corresponding 4-phenyl-pyridine oxides are obtained.

EXAMPLE 3 3-Phenylpyridine-N-oxide (9.2 g.) and of acetic anhydride are heated in an oil-bath to 153°C., (bath temperature), under a nitrogen atmosphere, the stirred mixture kept eleven hours at this temperature, allowed to cool to room temperature, and the dark mixture added slowly to a stirred ice-water mixture (250 ml.) covered with ca.. 50 ml. of ether. After solidification of the oily mixture occurs, the solid is filtered, washed well with water and ether, and dried to give 7.7 g. of tan, nearly pure solid. Recrystallization from dimethyl-sulfoxide followed by recrystallization from chloroform (darco) yields white crystals, m.p. 225-227°C, of 3-phenyl 2 [1H] -pyridone.

B. 3- (o-Chlorophenyl) -pyridine-N-oxide (4.1 g.) and acetic anhydride (10 ml.) are heated, under nitrogen, in an oil bath to 146+2° (bath temperature) and maintained on this temperature for ca. eleven hours. On cooling, the mixture is added to a stirred ice-water mixture (80 ml.), and the resultant oil taken up in chloroform. The chloro-form is removed in vacuo , the residue dissolved in 60 ml. methanol, 7 ml., water and 2 ml. saturated aqueous sodium bicarbonate added, the mixture refluxed ca. 15 minutes, the mixture made neutral with 2.5 hydrochloric acid, the solvents removed, and the residue partitioned between chloroform-water. The chloroform layer is dried, stripped of solvent, and the residue recrystallized from benzene to yield 635 mg. white 3- (o-chlorophenyl) -2- [1H] -pyridone , m.p. 203.5-207°.

C. Alternately, the acetic anhydride may be stripped iri vacuo directly and the methanol-bicarbonate treatment used immediately.

D. When the substituted pyridine oxides from Example 2 are used in place of 3- (o-chlorophenyl) -pyridine oxide in the above reaction, the corresponding 2[1H]-pyridones: 3-(o-, m- and p-methylpheny])-2 [1H] -pyridines , 3- (m- and p-chlorophenyl) -2 [1H] -pyridones , 3-(o-, m- and p-methoxyphenyl) -2 [1H] -pyridones , 3-(o-, m- and p-cyanophenyl) -2 [1H] -pyridones , 3-(o-, m- and p-nitrophenyl) -2 [1H] -pyridones , 3-(o-, m- and p-fluorophenyl) -2 [1H] -pyridones , 3-(o-, m- and p-trifluoromethylphenyl) -2 [1H] -pyridones , 3-a- and p-naphthyl-2 [1H] -pyridones , 3- (o,m-dimethylphenyl) -2 [1H] -pyridone , 3- (m,p-dimethylphenyl) -2 [1H] -pyridone , 3- (o,o 1 -dimethylphenyl) -2 [III] -pyridone , 3- (o,p-dimethylphenyl) -2 [1H] -pyridone, 3- (m,m' -dimethylphenyl) -2 [1H] -pyridone , 3- (o,m' -dimethylphenyl) -2 [1H] -pyridone , the corresponding dichloro and dimethoxy phenyl pyridones, 3-(o-, m- and p-biphenylyl) -2 [1H] -pyridones , 3- (2 '-thienyl)-2 [1H] -pyridone, 3- (2'-furyl)-2 [1H] -pyridone , 3- (3· -furyl)-2'[lH] -pyridone, 3- (2'-thiazolyl)-2 [1H] -pyridone , 3- ( '-thiazolyl)-2 [1H] -pyridone, 3- (5'-thiazolyl) -2 [1H] -pyridone, 6-methyl-3-phen 1-2 [1H] -pyridone, -methyl-3-phenyl-2 [1H] -pyridone, 4-methyl-3-phenyl-2 [1H] -pyridone, 6,5- and 4-chloro-3-phenyl-2 [1H] -pyridones , 6,5- and 4-methoxy-3-pheny1-2 [1H] -pyridones , 6,5- and 4-nitro-3-pheny1-2 [1H] -pyridones , 6,5- and 4-ethoxy-3-pheny1-2 [1H] -pyridones , 6- and 4-ethyl-3-phenyl-2 [1H] -pyridones , 6- and 4-phenethyl-3-phenyl-2 [1H] -pyridones , 6-fluoro- 3-phenyl-2 [1H] -pyridone , 6- and 4-methylsulfonyl-3-phenyl-2 [III] -pyridones , 6-phenylsulfonyl-3-phen l-2 [1H] -pyridone , -chloro-6-phenoxy-3-phenyl-2 [1H] -pyridone , 6-methoxy-4-methyl-3-phenyl-2 [1H] -pyridone , 4-methyl-3,5-diphenyl-2 [1H] -pyridone, and the corresponding 3-substituted-phenyl derivatives of the above compounds are obtained.

E. In the above cases, the inductive effects of the substituents on the phenyl and pyridine rings help determine the course of the rearrangement, and in some cases some of the corresponding 5-phenyl-2 [1H] -pyridones are obtained. The isomers are separated by recrystalliza-tion and column chromatography techniques.

EXAMPLE 4 Λ. 2-Methyl-5-phenylpyridine-N-oxide (1 g.), phosphorous pentachloride (1.2 g.) and dry chloroform (10 ml.) are refluxed on the water-bath for 1 hour. Ice with potassium carbonate. The chloroform layer is separated, dried (CaC^), and concentrated to yield crude 2-chloro-3-phenyl-6-methylpyridine .

B. Basic hydrolysis of this compound yields 6-methyl-3-phen l-2 [1H] -pyridone. and % Pd/C (0.5 g.) are mixed intimately, covered with a nitrogen atmosphere and placed in a metal-bath set at 270°C. The mixture is kept 8 hours, cooled, the residue extracted several times with boiling chloroform, the solvent removed and the residue chromatographed on a silica gel column us-ing an acetone-ether (V/vO-50%) system as eluant, yielding 3-pheny1-2 [1H] -pyridone.

EXAMPLE 6 l-Methyl-3-phenyl-2 [1H] -pyridone A. To a stirred suspension of 0.87 grams of 50% NaH (0.018M) is added at 5° under nitrogen 3.08 grams (0.018M) of 3-phenyl-2 [1H] -pyridone. The reaction is allowed to stir for 1/2 hour at room temperature and is then cooled to 5° and 2.84 grams (0.020M) of methyl iodide is added. The reaction mixture is stirred for 3 hours at room temperature and is then concentrated in vacuo . The residue is extracted between methylene chloride and water containing a little hydrochloric acid. The combined methylene chloride extracts are dried over sodium sulfate and concentrated. The residue is recrystallized from methylene chloride and hexane to give 1.9 grams of 1-methyl- - - - m 35- ° B. Similarly, when other alkyl halides such as ethyl bromide, butyl bromide, propyl bromide, etc. are used in place of methyl iodide in the above example, the corres-ponding 1-alkyl-3-pheny1-2 [1H] -pyridones are obtained.

C. Similarly, when allyl bromide, methally-chloride and crotyl chloride are used in place of methyl iodide in the above example, there is obtained l-allyl-3-phenyl-2 [1H] -pyridone, 1- (methallyl) -3-phenyl-2 [1H] -pyridone and l-crotyl-3-phenyl-2 [1H] -pyridone.

D. When benzyl chloride, o-chlorobenzyl chloride, m-chlorobenzyl chloride, p-chlorobenzyl chloride, o-methylbenzyl chloride, m-methylbenzyl chloride, p-methyl-benzyl chloride, o-fluorobenzyl chloride, m-fluorobenzyl chloride, p-fluorobenzyl chloride, o-methoxybenzyl chloride, m-methoxybenzyl chloride, p-methoxybenzyl chloride, penta-fluorobenzyl bromide, 3 , 4-dichlorobenzyl chloride or 3 , 4-dimethoxybenzyl chloride is used in place of methyl iodide, the corresponding l-arylmethyl-3-phenyl-2 [1H] -pyridones are obtained.

E. When cinnamyl bromide is used in place of methyl iodide, there is obtained l-cinnamyl-3-phenyl-2 [1H] -pyridone.

F. When propargyl bromide is used in place of methyl iodide, there is obtained l-propargyl-3-phenyl-2 [1H] -pyridone.

G. When methyl iodide is replaced in the above procedure by 2-chloroethylamihe , N-methyl-2-chloroethyl-amine, N,N-dimethyl-2-chloroethylamine, N-ethyl-2-chlorb-ethylamine, N,N-diethyl-2-chloroethylamine , N-(2-chloro-ethyl) -piperidine or 3-chloropropylamine , the corres- H. When methyl iodide is replaced with chlor-acetone, l-chloropropan-2-one and phenacyl chloride in the above procedure, the corresponding l-acylmethyl-3-phenyl-2 [1H] -pyridone is obtained.

I. When methyl iodide is replaced with 2-bromo-ethanol or 2-bromopropanol in the above procedure, the corres-ponding 1-hydroxyalkyl-pyridone is obtained.

EXAMPLE 7 A mixture of 0.02 moles of 3-pheny1-2 [1H] -pyridone and 0.02 moles of acrylonitrile is warmed with 0.1 gram of solid sodium hydroxide on a steam bath until reaction occurs. When the exothermic reaction subsides, the reaction mixture is heated on the steam bath for one hour, then cooled. The residue is taken up in chloroform, washed with water and the chloroform extract dried over sodium sulfate and concentrated. Chromatography of the residue on 400 grams of silica gel and elution with ether-petroleum ether (0-70%) gives l-(2-cyano-ethyl)-3-phenyl-2 [1H] -pyridone.

EXAMPLE 8 A. Sodium 3-phenyl-pyridone To a suspension of 0.87 grams of 50% NaH (0.018 m.) in 100 mis. of dry benzene is added 3.08 grams (0.018 m.) of 3-phenyl-2 [III] -pyridone. The reaction mixture is heated at 35 °C. for 6 hours and allowed to stir at room tempera-ture overnight. The benzene was then evaporated in vacuo leaving a residue of sodium 3-phenyl-pyridone.

B . 1, 3-Diphenyl-2 [1H] -pyridone The sodium 3-phenyl-pyridone from above (0.018 m.), copper (0.003 m.) are mixed with mechanical stirring and heated at 155° under nitrogen for six hours. The reaction mixture is allowed to cool to room temperature overnight and the mixture then extracted well with chloroform. The chloroform extracts are washed with water, dried over sodium sulfate and concentrated. Chromatography of the residue on 500 grams of silica gel and elution with ether-petroleum ether (0-75%) gives 1 , 3-diphenyl-2 [1H] -pyridone .

C. Similarly, when substituted iodo benzenes, ex. 2-iodonitrobenzene , 3-iodonitrobenzene-4-iodonitrobenzene are used in place of iodo benzene in the above example, the corresponding 1- (substituted aryl) -3-phenyl-2 [1H] -pyridones are obtained.

EXAMPLE 9 3-Phenyl-l- (2 ' -quinolyl) -2 [1H] -pyridone A. 2-Bromo-3-phenyl-pyridine A mixture of 0.1 moles of 3-phenyl-2 [1H] -pyridone and 0.15 moles of phosphorous tribromide are heated for 3 hours at 180°. The reaction mixture is cooled, decomposed in ice water, made alkaline with sodium hydroxide and extracted well with ether. The combined ether extracts are dried over sodium sulfate and concentrated in vacuo to yield 2-bromo-3-phenyl-pyridine .

B. 3-Pheny1-1 (2 '-quinolyl) -2 [111] -pyridone A mixture of 0.02 moles of quinoline-N-oxide and 0.022 moles of 2-bromo-3-phenyl-pyridine are heated on the steam bath for 8 hours. The reaction mixture is cooled, taken up in water containing a little hydrochloric acid and washed with ether. The aqueous layer is made alkaline with tassium carbon te s uti d x chloroform. The combined chloroform extracts are dried over potassium carbonate and concentrated to yield 3-phenyl-1- (21 -quinoly.0-2 [1H] -pyridone.

C. Similarly, when 2-picoline-N-oxide , 3-picoline-N-oxide or 4-picoline-N-oxide is used in place of quinoline-N-oxide in the above procedure, there is obtained 3-phenyl-l- [21 - (6 ' -methylpyridyl) ] -2 [ 1H] -pyridone , 3-phenyl-l- [2 '- (5 '-methylpyridyl) ] -2 [1H] -pyridone, and 3-phenyl-1- [2'- (4 ' -methylpyridyl) ]-2 [ 1H] -pyridone .

' EXAMPLE 10 A solution of chloramine is prepared by treating at 0°C. 65 ml. of a 1.93 m. neutral sodium hypochlorite solution (0.125 m.) with 20 mis. of 1.84 m. NH^OH (0.375 m.). The above mixture is allowed to stand for one hour in an ice-salt bath and then 0.125 m. of sodium 3-phenyl-pyridone is added. The reaction mixture is stirred overnight at 0-10°C. and. is then continuously extracted with ether for 24 hours. The ether extracts are dried over sodium sulfate and concentrated to yield l-amino-3-phenyl-2 [1H] -pyridone .

EXAMPLE 11 l-Hydroxy-3-phenyl-2 [1H] -pyridone A. 2-Chloro-3-phenyl-pyridine-N-oxide 0.2 Moles of 2-chloro-3-phenyl-pyridine is treated with 25 mis. of glacial acetic acid and 22 mis. of 40% peracetic acid. The temperature of the reaction mix-ture is kept at 70 °C. for 3 hours. The reaction mixture is concentrated, extracted with chloroform and the chloroform extracts concentrated to yield 2-chloro-3-phenylpyridine-N- B. 0.01 Moles of 2-chloro-3-phenyl-pyridine-N-oxide and 20 mis. of acetic anhydride are heated for 3 hours at 130-140°. The reaction mixture is then concen-trated in vacuo to yield crude l-hydroxy-3-phenyl-2 [1H] -pyridone .

EXAMPLE 12 A. A mixture of 0.02 moles of 3-phenyl-2 [1H] -pyridone and 0.025 moles of phosphorus pentasulfide is heated for 6 hours at 160°C. The reaction mixture is then poured into 100 ml. of hot water, cooled and the 3-phenyl-2- [1H] -thiopyridone collected by filtration. Chromatography on 400 gm. of silica gel and elution with ether-petroleum ether (0-90%) gives 3-phenyl-2 [1H] -thiopyridone . M.p. 229-237°.

B. Similarly, when the other substituted pyridines are used in place of 3-phenyl-2 [1H] -pyridone in the above example, the corresponding 2 [1H] -thiopyridones are obtained.

EXAMPLE 13 A. 2-Methoxy-3-pheny1-pyridine A mixture of 0.01 moles of 2-chloro-3-phenyl-pyridine, 0.01 moles of sodium methoxide and 50 cc . of dry dimethylformamide are heated, at 60° for 2 hours. The re-action mixture is concentrated iri vacuo , taken up in chloroform and washed with water. The chloroform extract is dried over sodium sulfate and concentrated. The residue is chromatographed on 250 gms. of silica gel. Elution with ether-petroleum ether (0-75%) gives 2-methoxy-3-phenyl- B. Similarly, when the other substituted 2-chloro-3-phenyl-pyridines are used in place of 2-chloro-3-phenyl-pyridine, the corresponding 2-methoxy phenyl-pyridines are obtained. When other alkoxides such as sodium ethoxide or propoxide, sodium phenolate, sodium o- or p-chlorophenolate or p-methoxyphenolate , sodium alloxide, crotoxide, or methalloxide , sodium propargoxide , sodium benzoxide, chlorbenzoxide or methoxybenzoxide , sodium cinnamoxide, sodium 2-aminoethoxide , 2-amino-propoxide, 2-dimethylaminoethoxide , 3-dimethylaminopropoxide , methylaminoethoxide or sodium methoxyethoxide or ethoxy-propoxide are used in place of sodium methoxide, such as-in the above example, the corresponding alkoxyphenyl-pyridines are obtained. The alkoxides are prepared by adding 0.01 mole of the alcohol in 20 cc. dry DMF to 0.01 moles of NaH in 30 cc . dry DMF, and stirring 1 hour.

EXAMPLE 14 The procedure of Example 13 is followed except that sodium methyl mercaptide is used instead of sodium methoxide. There is obtained the corresponding 2-methyl-thio-3-phenyl-pyridine . When other mercaptides such as the sodium salts of benzylmercaptan, o-nitrobenzylmercaptan, m-nitrobenzylmercaptan, o-methylbenzylmercaptan , m-methyl-benzylmercaptan, p-methylbenzylmercaptan, 2 , 4-dimethyl-benzylmercaptan, 3 , 4-dimethylbenzylmercaptan, o-chloro-benzylmercaptan, m-chlorobenzylmercaptan, p-chlorobenzyl-mercaptan, 2 , 4-dichlorobenzylmercaptan, 3 , 4-dichlorobenzyl-mercaptan, 2 , , 5-trichlorobenzylmercaptan , 2-chloro-5-nitrobenzylmercaptan, 5-amino-2 , 4-dichlorobenzylmercaptan , benzylmercaptan, 3-amino-4-methoxybenzylmercaptan, o-methylaminobenzylmercaptan, p-methbxybenzylmercaptan, 4-methoxy-3-nitrobenzylmercaptan, 3 , 4-dimethoxybenzyl-mercaptan, 3 , 4-methylenedioxybenzylmercaptan are used in place of the methyl mercaptide, the corresponding 2-sulfide is obtained.

EXAMPLE 15 A mixture of 0.01 moles of 1- (2-cyanoethyl) -3-phenyl-2 [1H] -pyridone , 50 ml. of acetic acid and 50 ml. of 10% sulfuric acid is refluxed for 4 hours. The reaction mixture is then concentrated, poured- into water and extracted well with chloroform. The combined chloroform extracts are dried over sodium sulfate and concentrated to give 1- (2-carboxyethyl) -3-pheny1-2 [1H] -pyridone .

EXAMPLE 16 A mixture of 0.01 moles of 1- (2-hydroxyethyl) -3-phenyl-2 [1H] -pyridone and 25 cc. of concentrated hydro-chloric acid is heated in a sealed tube for 60 hours at 120°. The reaction mixture is cooled and then concentrated in vacuo to yield 1- (2-chloroethyl) -3-phenyl-2 [1H] -pyridone .

The following examples illustrate the intercon-version or introduction of functional groups after prepara-tion of the phenyl pyridone nucleus.

EXAMPLE 17 -Chloro-3-phenyl-2 [1H] -pyridone 3-Phenyl-2 [1H] -pyridone (3.08 g.) and N-chloro- (25 ml.) for 28 hours under a nitrogen atmosphere. Solu- tion gradually occurs. After cooling, the mixture is filtered to remove succinimide, the filtrate diluted with ca. 20 more ml. CH2C12, washed with water (2 x ca. 50 ml.) , dried over magnesium sulfate, filtered, concentrated to 3.2 g. tan solid. Recrystallization from benzene (concen-trating to ca. 40 ml. hot) yields 815 mg. very pale pink cotton-like crystals, m.p. 157.5-159°, of 5-chloro-3-phenyl- 2 [1H] -pyridone .

EXAMPLE 18 -Dimethylamino-3-phen l-2 [1H] -pyridone -Chloro-3-phenyl-2 [1H] -pyridone (1 g.) in anhydrous dimethylformamide (50 ml.) is saturated with dimethylamine , and the resultant mixture heated in a lined stainless-steel bomb for several hours. The solvent is removed in vacuo, the residue distributed between chloro-form and water, the chloroform layer dried, solvent stripped, and the residue chromatographed on a silica gel column using a methanol-methylene chloride eluent (v/vO-100% MeOH) to yield the title compound.

EXAMPLE 19 3-p-Hydroxyphenyl-2 [1H] -pyridone 3-p-Methoxyphenyl-2 [1H] -pyridone (2 g.) is added to a stirred 10 g. portion of pyridine-hydrochloride at 188°. A dry nitrogen atmosphere is maintained. The mixture is kept 20 minutes, allowed to cool, then added to 45 g. of ice. The crude product is collected, dried and recrystallized to yield the title compound.

Similarly, when the o- and m-methoxyphenyl-pyridones are substituted for the p-isomer in the above reaction, the corresponding o- and m-hydroxy analogs are obtained.

EXAMPLE 20 3- (p-Aminophenyl) -2 [1H] -pyridone 3- (p-Nitrophenyl) -2 [1H] -pyridone (1 g.) in warm dioxane (50 ml.) is reduced under a hydrogen atmosphere in the presence of 0.3 g. 5% Pd/C. The mixture is filtered, the cake washed well with warm dioxane, the combined filtrates concentrated to residue, the residue recrystallized to yield title compound.

Alternately, when the dioxane solution is treated with anhydrous ethereal-hydrogen chloride solution, the hydrochloride precipitates. When the corresponding o- , and m-nitrophenyl-pyridones are used in the above reduction the o- and m-aminophenyl-pyridones are obtained.

EXAMPLE 21 3- (p-Dimethylaminophenyl) -2 [1H] -pyridone 3- (p-Nitrophenyl) -2 [1H] -pyridone (1 g.) in methanol (100 ml.) containing glacial acetic acid (1 ml.) and 37% formaldehyde solution ( 3 ml . ) is reduced in the presence of Raney nickel (1/4 tsp.) under a hydrogen atmos-phere. The mixture is filtered, the cake washed with methanol, and the combined filtrates concentrated to a residue. Chromatography on an alumina column using a methanol-methylene chloride system (V/vO-100%) yields the title compound.

When the o- and m-nitro isomers are used in place of the p-isomer in the above reduction, the corresponding o- and m-dimethylaminophenyl-2-pyridones are obtained.

EXAMPLE 22 oyl 3- (p-Carbany-cdophenyi) -2 [1H] -pyridone 3- (p-Cyanophenyl) -2 [1H] -pyridone (5 g.) is added to a stirred ice-cold portion of concentrated sulfuric acid (20 g.) and the mixture stirred overnight, added to ice-water, the crude product collected, dried and recrystallized to yield the title compound. When the o- and m-cyanophenyl-pyridones are used in the above reaction, the corresponding o- and m-carbamidophenyl isomers are obtained.

EXAMPLE 23 3- (p-Carboxyphenyl) -2 [1H] -pyridone 3- (p-Cyanopheny1-2 [1H] -pyridone (1 g.) in 30 ml. of a 1:1 mixture of glacial acetic acid - 20% hydrochloric acid is heated for twelve hours, the solvent removed in vacuo , the residue partitioned between chloroform and nearly saturated sodium bicarbonate solution, the bicar-bonate solution filtered and acidified, the precipitate collected, dried and recrystallized to yield the title compound.

When the o- and m-cyanophenyl-pyridones are used in the above reaction, the corresponding o- and m-carboxy-phenyl isomers are obtained.

EXAMPLE 24 l-Methyl-3-phenyl-2 [ III] -pyridone-5-sulfonic acid When l-meth l-3- hen l-2 III -v ridone is treated ι..

German Patent 601,896, there is obtained l-methyl-3-phenyl-2 [1H] -pyridone-5-sulfonic acid.

EXAMPLE 25 3-Phenyl-5-triphenylmethyl-2 [IH] -pyridone 3-Phenyl-2 [IH] -pyridone (3 g.) and trityl chloride (3 g.) are intimately mixed and heated at ca. 250° in a metal-bath for 30 minutes, the reaction mixture cooled, and 60 ml. of boiling ethanol added, the solid filtered, washed with fresh ethanol, and recrystallized to give the title compound.

EXAMPLE 26 -Amino-3-phenyl-2 [IH] -pyridone When 5-nitro-3-pheny1-2 [IH] -pyridone is reduced under the conditions described in Example 20 above, the title compound is obtained.

When the 4- and 6-nitro isomers are used in place of the 5-nitro compound, the corresponding 4- and 6-amino-3-phenyl-2 [IH] -pyridones are obtained.

EXAMPLE 27 -Dimethylaminomethyl-3-phenyl-2 [IH] -pyridone -Methyl-3-pheny1-2 [IH] -pyridone (0.01 m.) and N-bromosuccinimide (0.01 m.) in carbon tetrachloride (250 ml.) are refluxed under irradiation for ca. 15 mins. (occasionally a trace of benzoyl peroxide is necessary to initiate reaction) , cooled, filtered, and the filtrate concentrated in vacuo to a residue.

The residue is taken up in dimethylformamide , ssel sealed and heated the solvent removed in vacuo , and the residue chromatographed on an alumina column using a methanol-methylene chloride system (V^v 0-100%) as eluent to yield the title compound.

Similarly, when the corresponding 4- and 6-methyl isomers are used in the above process, the corres-ponding 4- and 6-dimethylaminomethyl isomers are obtained.

EXAMPLE 28 3- (p-Mercaptophenyl) -2 [1H] -pyridone The title compound is prepared from 3- (p-amino-phenyl) -2 [1H] -pyridone via the procedure of Tarbell & Fukushima for thiocresol (Org. Syn., Coll. Vol. Ill, p. 809) , but using chloroform as the organic extractant, omitting the 10% sodium hydroxide wash, and hydrolyzing the intermediate thiocarbonate under milder conditions.

The mixture is then acidified, the solvent removed in vacuo , and the residue recrystallized, using deaerated solvents to avoid disulfide formation.

When the o- and m-aminophenyl isomers are used in place of the p-isomer in the above reaction, the corres-ponding o- and m-mercapto isomers are obtained.

EXAMPLE 29 p- (2 [1H] -Pyridon-3-yl) -benzenesulfonic acid The procedure employed by Wallace (Tetrahydron Letters (1963) 1131) for benzene sulfonic acid is used. 3- (p-Mercaptophenyl-2 [1H] -pyridone is stirred at room temperature in dimethylformamide containing potassium hydroxide (1.3 M. ) under a partial oxygen atmosphere (1 atm.) for 24 hours. The mixture i.n nc.i .0 grams of anhydrous potassium carbonate in 100 mis. of chloroform is added portlonwise with stirring 0.01 moles of benzoyl 6 chloride. The reaction mixture is stirred for k hours at reflux, then 7 cooled and filtered. The filtrate is concentrated in vacuo to yield 8 l-benzamido-3-phenyl-2[lH -pyridone . 9 B. When acetyl chloride is used in place of benzoyl chloride in the above example, there is obtained l«acetamido-3-phenyl-2-(jji]- 11 pyridone · 12 Co When carbobenzoxy chloride is used in place of benzoyl 13 chloride in the procedure of part (A), l»carbobenzoxyamino-3-phen3rl lU 2LlH3—pyridone is obtained. 1$ D. When ethyl chloro ormate is used in place of benzoyl 16 chloride in the procedure of part (A), l-carbethoxyamino-3-phenyl- 17 CLH) -pyridone is obtained. 18 E. A mixture of 0.01 moles of l-amino-3-phenyl-2 JIH] - 19 pyridone and 0.01 moles of benzaldehyde is refluxed for 3 hours in 30 mis. 0 of ethanol. The reaction mixture is then concentrated to yield 1 l-benzylidineamlno-3-phenyl-2 Q.H] -pyridone. 2 F. To 0.01 moles of l-amino-3-phenyl-2 [li-Q-pyridone in 100 mis. 3 of anhydrous ether is added 0.01 moles of phenylisocyanate . The reaction k mixture is refluxed for one hour, then concentrated to yield 1-(N' -phenyl- 5. ureido)-3-phenyl-2 [in]-pyridone. 6 EXAMPLE 33 7 3-(p-Methylsulfinylphenyl)-2 CLH] -pyridone 8 3-(p-Methylmercaptophenyl)-2 flit) -pyridone !t 1 is stirred at room temperature for several days and then filtered. The 2 filtrate is concentrated in vacuo and partitioned between chloroform and 3 water. The chloroform layer is dried over sodium sulfate and the chlorals form is removed in vacuo. The residue is recrystallized to yield the £ above compound. 6 When the o- and m-methylmercaptophenyl-pyridones are used in 7 the above process, the corresponding o- and m-methylsul inylphenyl- 8 pyridones are obtained. 9 EXAMPLE 3k 3-(p-Methylsulfonylphenyl)-2 Qjij -pyridone 11 To 3-(p-Methylmercaptophenyl)-2[lHj -pyridone (1 g.) in glacial 12 acetic acid (2£ ml.) is added 30% aqueous hydrogen peroxide (2 ml.), and 13 the resultant mixture is allowed to stir several days at room temperature. lh A minimum of sodium bisulfite is added to destroy the excess peroxide.

The solvent is removed in vacuo and the residue is recrystallized to 16 give the above compound. 17 When the o- and m-methylmercaptophenyl-pyridones are used in 18 the above process, the corresponding o- and -methylsulfonylphenyl-19 2 QLH]-pyridones are obtained.

EXAMPLE 3$ ■21 The testing procedures used are essentially those of l) Winter, 22 et e]., Proo. Soc. F.xpor. Biol. Ill (196?), p. 5ΊΊ (Cnrropeon n-induced 23 Foot Inflammati n)j 2) 'M.onrlc «I, al, Am. J. Pathol. 0 (.!?!¾), p. 2) (Adjuvant Arthritis l)j and 3 ) Newbould, Brit. J. Pharmacal. 2h (19 ^), 2 p. 632 (Adjuvant Arthritis-I Γ) .

For Example* (Dosage in Mg./Kg. Body Weight) Compound Carrogeenin Proc. Adj. Arthr. I Adj.

Dose Inhibition Do3e Inhibit. Dose Inhibit. 3-Phenyl-2|lH|-pyridone 10 ■ 38 12.5 - 51 U-Phenyl-2 [IH] -pyridone 100 - 5 .7 12.5 - 55 31133/2

Claims (1)

1. CLAIMS 'ΐί.. Preparations for treating inflammation containing tive ingredient a compound having one of the structures I < ΙΓ in which is hydrogen, lower alkyl, phenyl · ' ar- lower alkyl. halogen^ lower alkoxy amino diloweralkylamino diloweralkylamino loweralkyl nitro ! loweralkylsulfonyl phenylsulfonyl or triphenylmethyl R, is hydrogen loweralkyl loweralkenyl hydroxy 117 V amino > loweralkynyl phenyl oubotitutod phenyl ar -loweralkyl ar-loweralken l benzamido loweralkanoylamino carbobenzoxyamino carb=loweralkoxyamino benzylidineairiino phenylureido aminoloweralkyl loweraIky1amino lower alkyl diloweralkylamino lower alkyl loweralkanoyl lower alkyl cyanoloweralkyl carboxyloweralkyl hydroxyloweralkyl or 2'-quinolyl is hydrogen or loweralkyl and are the same or different and hydrogen loweralkyl phenyl halogen trihalo-loweralkyl loweralkoxy amino lower-dialkylamino nitro 11755 cyano sulfaiuoyl rdilowcralkyl -oulfamoyl hydroxy mercapto lower alkylthio lower alkylsulfinyl lower alkylsulfonyl carbamoyl carboxy gulfo or phenylsulfonyl Rg is oxygen or sulfur R7 is ORg or SR8 in which Rp is loweralkanoyl or loweralkyl benzyl nitrobenzyl lower alkylbenzyl halobenzyl aminobenzyl lower alkylaminobenzyl lower alkoxybenzyl methylenedioxybenzyl the group of and [A] is carbocylic or heterocyclic aryl -&a«*i—*e comprised from phenyl , thiazolyl thienyl pyridyl or furyl and is linked to the 3 or 4 position. Preparations 2. Tho method- of Claim 1 in which the compound has Structure I. Preparations 3. The method- of Claim 2 in which the compound is 3-phenyl-pyridone-2. Preparations 4. Tho mothod of Claim 2 in which the compound is 4-phenyl-pyridone-2. Preparations 5. Tho mothod of Claim 2 in which the compound is 3- (p-dimethylaminophenyl) -pyridone-2. compound having one of the Structures or II II is hydrogen lower alkyl phenyl ar-lower alkyl halogen halo™ lowor-alk l lower alkoxy amino diloweralkylamino loweralkyl nitro loweralk lsulfonyl phenylsulfonyl phenoxy oulfo or triphenylmethyl is hydrogen loweralkyl loweralkenyl hydroxy amino loweralkynyl phenyl aubotitutod phenyl— ar lo oralkyl ar-loworalkonyl benzamido loweralkanoylamino carbpbenzoxyamino carb-loweralkoxyaraino benzylidineamino phenylureido aminoloweralkyl loweralkylamino lower alkyl diloweralkylamino lower alkyl lowcralkanoyl lower alkyl cyanoloweralkyl carboxyloweralkyl hydroxyloweralkyl or 2'-quinolyl 11755 3 is hydrogen or loweralkyl R^ and R^ are the same or different and are hydrogen loweralkyl phenyl halogen trihalo- loweralkyl loweralkoxy amino lower-dilalkylamino nitro cyano a-u famoyl loweralkyl' sulfamoyl diloworalkyl-oulfamoyl hydroxy mercapto lower alkylthio lower alkylsulfinyl lower alkylsulfonyl carbamoyl carboxy sul o or phenylsulfonyl Rg is oxygen or sulfur R7 is ORg or in which R is loweralkanoyl or 8 1175 loweralkyl benzyl nitrobenzyl lower alkylbenzyl halobenzyl aminobenzyl lower alkylaminobenzyl lower alkoxybenzyl methylenedioxybenzyl the group and [A] is carbocyclic or heterocyclic aryl sreeh-as comprised from/ phenyl ,thiazolyl thienyl pyridyl or furyl provided that when R^ is phenyl, is loweralkyl and when is loweralkyl, is hydrogen, and also provided that when R2 is loweralkyl, R^ is other than hydrogen. 7. A compound of Claim 6 having the Structure I. 8. A compound of Claim 7 in which R-^, Rj, j , R^, and R-. are hydrogen, Rg is oxygen and [A] is phenyl. 9. A compound of Claim 7 having the structure compound of Claim 7 having the structure 31133/2 11. A process of preparing a compound of the structure ich R1 is hydrogen lower alkyl phenyl ar- lower alkyl halogen lower alkoxy amino diioweralkylamino diloweralkylamino lower nitro .Ipweralkylsulfonyl . phenylsulfonyl or triphenylmethyl 1*2 is hydrogen loweralkyl loweralkenyl hydroxy amino loweralkynyl phenyl ar-lowor alkenyl— benzamido loweralkanoylamino carbobenzoxyami.no carb-loweralkoxyamino benzylidineamino phenylureido aminoloweralkyl loweralkylamino lower alkyl diloweralkylamino lower alkyl loworalkanoyl lower alkyl cyanoloweralkyl- carboxyloweralkyl hydroxyloweralkyl or 2'-quinolyl R^ is hydrogen or loweralkyl R^ and R-. are the same or different and are hydrogen loweralkyl phenyl halogen trihalo-loweralkyl loweralkoxy amino lower-dialkylamino nitro cyano aulfamoyl ■loweralkyl aulfamoyl diloweralkyl-aulfamoyl - . 31133/2 - 45 - hydroxy mercapto lower alkylthio lower alkylsulfinyl lower alkylsulfonyl carbamoyl carboxy sulfo or phenylsulfonyl Rg is oxygen or ; sulfur and [A] is carbocyclic or heterocyclic aryl'comprised from the group ! phenyl j thiazolyl ^ ■ : : thienyl pyridyl or -- furyl , ■ and io -Linkod to tho 3 or 4 poaition provided that when is phenyl, is lower alkyl and when is" lower alkyl, R^ is hydrogen, and also provided that when R2 is lower alkyl, is other than hydrogen, which comprises reaction of a compound of the formula with either a lower alkanoic anhydride or"a"h*alog"enat'ing" agent, followed by hydrolysis to give a compound of the structure and, if desired, substituting on the 1-nitrogen by reaction of the 1-alkali metal derivative thereof, with a halogen compound, and, if desired, converting any of said substituents R- R^, 4, R^ and Rg to another substituent, and, if desired, converting said compound to a thiopyridone by reaction with P2S5' 12. A process of preparing a compound of the Structure which R^ is hydrogen lower alkyl phenyl ar-lower alkyl halogen ■halo-lowor alkyl lower alkoxy amino diloweralkylamino diloweralkylamino lower nitro loweralkylsulfonyl phenylsulfonyl phenoxy- aulfo or triphenylmethyl R2 is hydrogen 11755 hydroxy amino loweralkynyl phenyl oubatitutod phenyl ar-lowor alkyl benzamido loweralkanoylamino carbobenzoxyamino carb-loweralkoxyamino benzylidineami.no phenylureido aminoloweralkyl loweralkylamino lower alkyl diloweralkylamino lower alkyl cyanoloweralkyl carboxyloweralkyl hydroxyloweralkyl or 2'-quinolyl is hydrogen or loweralkyl and R5 are the same or different and hydrogen loweralkyl phenyl halogen trihalo-loweralkyl loweralkoxy amino lower-dialkylamino hydroxy mercapto lower alkylthio lower alkylsulfinyl lower alkylsulfonyl carbamoyl carboxy or phenylsulfonyl Rg is oxygen or sulfur and [A] is carbocyclic or heterocyclic arylj comprised from the gOu o phenyl ■ j . i thiazolyl . thienyl , pyridyl or furyl and io linkod to tho 3 or 4 pocition provided that when x is phenyl, R3 is lower alkyl and when R^ is lower alkyl,-R3 is hydrogen, and also provided that when R2 is lower alkyl, R1 is other than hydrogen, which comprises oxidizing a compound of the formula give a compound of the structure 11755 31133/2 and, if desired, substituting on the 1-nitrogen by reaction of the 1-alkali metal derivative thereof with a halogen compound, and, if desired, converting any of said substituents R, , R_ , R. , Rr and R- to another, substituent, and, if desired, 1 3 .4 5 6 ■ < . . .-converting said compound to a thiopyridone by reaction with P2S5. 13. A process according to Claims 11 or 12 for the production of 3-phenyl-pyridone-2. 14. A process according to Claims 11 or 12 for the production of 3- (p-dimethylaminbphenyl) -pyridone-2. 15. A process of preparing a compound of the structure in which * "*·" " R^ is hydrogen lower alkyl phenyl ar- lower alkyl halogen lower alkoxy amino diloweralkylamino diloweralkylamino lower alkyl nitro loweralkylsulfonyl phenylsulfonyl oulfo or triphenylmethyl R^ is hydrogen or · loweralkyl R. and Rc are the same or different and are 1 b hydrogen loweralkyl phenyl halogen trihalo-loweralkyl loweralkoxy amino lower-dialkylamino nitro cyano aulfampyl -lowera1ky1-Bu1famoy1 diloweralkyl'-'Bulfamoyl- hydroxy mercapto lower alkylthio lower alkylsulfinyl lower alkylsulfonyl carbamoyl carboxy gulfo or phenylsulfonyl R7 is ORg or SR8 in which Rg is loweralkanoyl or benzyl nitrobenzyl lower alkylbenzyl halobenzyl aminobenzyl lower alkylaminobenzyl lower alkoxybenzyl methylenedioxybenzyl gr0Up and [A] is carbocyclic or heterocyclic aryl guoh -as comprised from/ phenyl thiazolyl thienyl pyridyl or furyl -and ia linked to the 3 or 4 pooition provided that when is phenyl, is lower alkyl and when is lower alkyl, is hydrogen, which comprises reaction of a compound of the formula with an alcoholate or thioalcbholate . 16. A process for the production of 3-(p-dimethylaminophenyl) -pyridone-2 which comprises the reductive methylation of 3- (p-nitrophenyl) -pyridone-2. For ths Applicants