DE2055513A1 - Fertilize anti-inflammatory Pyndonverbin - Google Patents

Description

Patent Attorneys 205551

Dr. Fng. Walter Abitz
Dr. Dieter F. Morf
Dr. Hans-A. Browns

Munich 86, Pienzeneuerstr. 28

November 11, 1970 13 241

MERCK & CO., INC.
126 East Lincoln Avenue, Rahway, NJ, V.St.A.

Anti-inflammatory pyridone compounds

The present invention relates to a novel class of compounds and, moreover, to a class of compounds which are useful in treating inflammation and also powerful analgesic and antipyretic Show effectiveness. In particular, the invention relates to amino-substituted pyridones, pyridinethiones, hydroxypyridines and mercaptopyridines.

The novel pyridones and pyridines according to the invention have the following structural formulas:

Formula I.

and

109821/2251

Herein: L denotes hydrogen; Alkyl (preferably lower alkyl, such as methyl, ethyl, propyl, etc.); Alkenyl (preferably lower galkenyl such as vinyl, allyl, methallyl, etc.); Alkynyl 'preferably lower alkynyl, such as ethynyl, methylbutynyl, PrQpinyl etc.); Aralkyl (preferably Am-lower alkyl, such as Benzyl and substituted benzyl, phenylethyl, phenylhexyl etc.); Aryl (preferably phenyl) or substituted phenyl (e.g. tolyl, halophenyl, hydroxyphenyl, anisyl, etc.); Hydroxyalkyl (preferably hydroxy lower alkyl, such as hydroxyethyl, Hydroxypropyl etc.); Amino, dialkylamino (preferably dinledrigalkylamino); Dialkylaminoalkyl (preferably Di-lower alkylamino-lower alkyl, such as diethylaminoethyl, etc.); Carboxyalkyl (preferably carboxy-lower alkyl, such as carboxymethyl, Carboxyethyl, carboxypropyl, etc.); Alkylaminoalkyl (preferably lower alkylamino lower alkyl); Haloalkyl (preferably halo-lower alkyl, such as tri fluorine thy I, etc.); Alkylamino such as methylamino; Ethylamino, etc .; Alkylamidoalkyl (preferably lower alkylamido lower alkyl, such as acetamidoethyl etc.); Hydroxy; N-alkanoyl-alkylaminoalkyl, such as N-acetylmethylaminoethyl; N-alkyl-N-alkyl-aminoalkyl, such as N-ethyl-N-methylaminopropyl; Aralkenyl (preferably am-lower alkenyl such as styryl, phenylpropylenyl, phenylbutylenyl, etc.); Alkoxy; a heterocyclic radical, such as puryl, tetrahydropyranyl, thienyl, Pyridyl, thiazolyl, imidazolyl, thiadiazolyl, oxazolyl and substituted derivatives thereof, etc .;

P each hydrogen or acyl, such as formyl, acetyl, propionyl, Butyryl, benzoyl, etc .; Alkoxycarbonyl such as methoxycarbonyl, etc .; X oxygen or sulfur;

Z is hydrogen, alkyl or aryl such as phenyl, etc .; R ,, Rp and R-, each haloalkyl (preferably halo-lower alkyl, such as triohlomethyl, tri fluorine thy 1 etc.); Alkylthio (preferably lower alkylthio such as methylthio, ethylthio, butylthio, _] pentylthio, etc.); Alkylsulfinyl (preferably lower alkylsulfinyl, such as methylsulfinyl, ethylsulfinyl, propylsulfinyl, pentylaulfinyl, etc.); 'alkylsulfonyl (pre-

109821/2251
- 2 -

preferably lower alkylsulfonyl, such as methylsulfonyl, Ä'fchylsulfonyl, Butylsulfonyl etc.); Hydroxy, sulfonamido; Sulfo; Carboxyalkyl (preferably carboxy-lower alkyl such as carboxymethyl, carboxyethyl, carboxybutyl, etc.); Alkoxy (preferably Lower alkoxy such as methoxy, ethoxy, butoxy, etc.); Lower alkenyloxy such as allyloxy; Carbalkoxy (preferably Carbo-lower alkoxy, e.g. carbomethoxy, carbopropoxy, carbobutoxy etc.) j. Alkoxyalkyl (preferably lower alkoxy-lower alkyl, e.g. methoxymethyl, methoxyethyl, ethoxymethyl etc.); Arylthio such as phenylthio; Aralkylthio such as benzylthio; Acylamino (preferably lower acylamino, such as formylamino, Acetylamino etc.); Hydroxyalkyl (preferably hydroxy-lower alkyl, such as hydroxymethyl, hydroxyethyl, hydroxypropyl, Hydroxybutyl etc.); Acyl (preferably lower acyl, such as formyl, acetyl, propionyl, butyryJ. Etc.) including Benzoyl with the proviso that if a single radical R stands for acyl, the other two radicals R have a different meaning must have as alkyl; Alkenyl (preferably lower alkenyl such as vinyl, allyl, methallyl, etc.); Alkynyl (preferably lower alkynyl, such as ethynyl, propynyl, methylbutynyl Etc.); Alkyl (preferably lower alkyl such as methyl, ethyl, propyl, butyl, etc.); Nitro; Cycloalkyl, such as cyclopropyl, Cyclobutyl etc.); Carbamoyl and substituted Carbamoyl, such as N-mono- and dialkyl- and aryl-substituted Carbamoyl; with the proviso that if an individual radical R is alkyl or nitro, the two remaining radicals R are one must have a meaning other than hydrogen; or hydrogen with the proviso that at least one radical R is a must have a meaning other than hydrogen.

The compounds according to the invention, which in the treatment of inflammation and related pain and fever are useful have the following structural formulas

109821/2251

Formula II

/ Ti ^ X

and

XZ

Herein: L denotes 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, propynyl, etc.); Aralkyl (preferably am-lower alkyl, such as benzyl or substituted benzyl, phenylethyl, phenylhexyl, etc.); Aryl (preferably phenyl) or substituted phenyl (such as tolyl, halophenyl, anisyl, hydroxyphenyl etc.); Hydroxyalkyl (preferably hydroxy lower alkyl such as hydroxymethyl, hydroxyethyl, hydroxypropyl, etc.); Alkylaminoalkyl such as methylaminomethyl, etc .; Carboxyalkyl (preferably carboxy-lower alkyl such as carboxymethyl, carboxyethyl, carboxypropyl, etc.); Amino; Dialkylamino such as dimethylamino, etc .; Haloalkyl (preferably halo-lower alkyl such as trifluoromethyl etc.); Alkylamino such as methylamino, ethylamino, etc .; Dialkylaminoalkyl, e.g. B. dimethylaminoethyl, diethylaminoethyl etc .; Hydroxy; Alkoxy; Alkylamidoalkyl (preferably lower alkylamido lower alkyl such as acetamidoethyl, etc.); N-alkanoyl-alkylaminoalkyl, such as N-acetyl-methylaminoethyl; N-alkyl-N-alkyl-aminoalkyl, such as N-ethyl-N-methylaminopropyl; Aralkenyl (preferably am lower alkenyl, such as styryl, phenyl

109821/2251

ORlQiNAL INSPECTED

propylenyl, phenylbutylenyl etc.); a heterocyclic radical such as furfuryl, tetrahydropyranyl, thienyl, pyridyl or substituted derivatives thereof; P each is hydrogen or acyl such as formyl, acetyl, propionyl, butyryl, benzoyl, etc .; X oxygen or sulfur;
Z is hydrogen, alkyl or aryl, such as phenyl; T ₁ , Tp and T ^ each haloalkyl (preferably halo-lower alkyl, such as tri chlorine thyl, tri fluorine thy 1 etc.); Alkylthio (preferably lower alkylthio such as methylthio, ethylthio, butylthio, pentylthio, etc.); Alkylsulfinyl (preferably lower alkylsulfinyl such as methylsulfinyl, ethylsulfinyl, propylsulfinyl, pentylsulfinyl, etc.); Alkylsulfonyl (preferably lower alkylsulfonyl, such as methylsulfonyl, ethylsulfonyl, butylsulfonyl, etc.); Hydroxy; Sulfonamido; SuIfo; Carboxyalkyl (preferably carboxy-lower alkyl such as carboxymethyl, carboxyethyl, carboxybutyl, etc.); Alkoxy (preferably lower alkoxy such as methoxy, ethoxy, butoxy, etc.); Carbalkoxy (preferably carbon leatherrigalkoxy, e.g. carbomethoxy, carbopropoxy, carbobutoxy, etc.); Alkoxyalkyl (preferably lower alkoxy-lower alkyl, for example methoxymethyl, methoxyethyl, ethoxypropyl, etc.); Arylthio such as phenylthio; Aralkylthio such as benzylthio; Acylamino (preferably lower acylamino such as formylamino, acetylamino, etc.); Hydroxyalkyl (preferably hydroxy lower alkyl such as hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, etc.); Acyl (preferably lower acyl such as formyl, acetyl, propionyl, butyryl, etc.); including benzoyl; Alkenyl (preferably lower alkenyl such as vinyl, allyl, methallyl, etc.); Alkynyl (preferably lower alkynyl such as ethynyl, methylbutynyl, propynyl, etc.); Halogen, (fluorine, bromine, iodine, chlorine); Alkyl (preferably lower alkyl such as methyl, ethyl, propyl, butyl, etc.); Nitro; Hydrogen; Amino; Cyano; Cycloalkyl (preferably cyclone lower alkyl such as cyclopropyl or cyclobutyl etc.); Carbamoyl or substituted carbamoyl, such as N-mono- or

- 5 -9821/2251

Dialkyl or aryl substituted carbamoyl.

In the preferred aspects, the present invention relates to that class of chemical compounds of the formulas I and II in which L is hydrogen, alkyl or aryl; P is hydrogen or acyl; X oxygen; and the radicals R ₁ (T ₁ ), R ₃ (T ₂ ) and R, (T 1) are alkyl, halogen, trihaloalkyl, alkylsulfinyl, alkylsulfonyl or alkylthio.

Representative of the preferred compounds according to the invention, as denoted by formulas I and II are the following:

b) 5-Amino-4-methyl-2 _i / rH7-pyridone

c) 3-Amino-5-methyl-2 _i / TH7-pyridone

d) 5-Amino-5-chloro-2 / TH7-pyridone

e) 3-Amino-4-t-butyl-2 ₍ / TH7 - pyridone

f) 5-Amino-4-methyl-6-t-butyl-2 ^ TH7-pyridone

g) 5-Amino-5,6-dimethyl-2 ₁ / TH7-pyridone h) 3-Amino-4,5-dimethyl-2 _i / rH7-pyridone i) 5-Amino-4-ethyl-2 / lH7- pyridon

J) 3-Amino-6-ethyl-5-methyl-2 ₍ / rHy%) yridone

k) 3-Amino-6-sec-butyl-2 </ TH / ^r -pyridone

1) 5-Amino-6-ethyl-2 £ rH7-pyridone

• m) 5-Amino-6-methyl-2 _i / rH7-pyridone

n) 3-Amino-5-t-butyl-2 ^ rH7-pyridone

o) 5-Amino-4-t-butyl-2 / TH7 "-pyridone

p) j5-Amino-5-n-propyl-2 / ΓH7-pyridone

q) 6-Amino-4-methyl -P./jE/- pyridone

r) 4-Amino-5-ethyl-2 ^ TH7-pyridone

s) 2- (N, N-bis-acetylamino) -4-methyl-2 ₍ / rH7-pyridone

t)> amino-4,5,6-

u) 5-amino-4,6-

- 6 -109821 / 22S1

To other representative compounds within the scope of the invention include the following:

3-Amino -5-methy 1 sulphony 1 -S ^ / TH ^ -pyridon 5-Amino-3-methylthio-2 _i / TH7-pyridone 3-Amino-4-ethyl-5-methylsulfinyl-2 ^ rH7-pyridon 5-methylthio-4-ethyl-3-amino-2 ^ rH7-pyridon 4-t-butyl-5-cyano-3-amino-2 ^ rK £ / ^r -pyridone 5-bromo-4-ethyl -> amino-2 ^ TH7-pyridone 5-chloro-3-amino-6-methyl-2 / ^ rH7-pyridone 6-methyl-5-amino-3-trifluoromethyl-2 ^ TH7-pyridone 3-acetyl-5- amino-6-raethyl-2 / TH / ^r _pyridon 5-amino-3-13-hydroxyethyl-6-methyl-2 / TH7 ^r -pyridone

5-methylsulfinyl-4-ethyl-5-aπlino-2 / ΓH7-pyridone 5-methoxy-1,6-dimethyl-3-amino-2 / ΓH7-pyridone, 5-carbamyl-4-methyl-; 5-amino-2 _< / rH7 - pyridon 4-carboxymethyl-5-amino-2 ^ TH / ^r -pyridon ^ -t-butyl-l-methyl-J-amino ^ / Tl ^ -pyridon 4-t-butyl-3-amino- l-phenyl-2 ₍ / rH7-pyridone 5-ethyl- ^ - amino-l-tetrahydropyranyl-2 ^ TH7-pyridone

5-ethyl-5-amino-2-pyridinethione 6-benzylthio-3-ainino-2 _i / ΓH7-pyridone 5-amino-5-ethyl-2-methoxypyridine 5-fluoro-4-methyl-5-amino-2 _ί / TH7-pyridone

The substituted pyridones and pyridines according to the invention have a high degree of anti-inflammatory, analgesic and antipyretic activity. They are valuable in the treatment of arthritic and dermatological disorders or similar conditions that are responsive to anti-inflammatory drugs. In general, they are recommended for a wide variety of conditions in which

109821/2251 _ _? i original inspiectsd

one or more of the symptoms inflammation, fever and Pain occur. Such diseases as rheumatoid arthritis, osteoarthritis, Gout, contagious arthritis, and rheumatic fever. As stated above, the compounds of the invention have also exhibit useful levels of analgesic and antipyretic activity.

For these purposes, the compounds according to the invention can be used orally, locally, parenterally, by inhalation sprays or Administered rectally in preparations containing conventional, non-toxic, pharmaceutically acceptable carriers, excipients and vehicle included. The term "parenteral" as used here includes subcutaneous injections, intravenous, intramuscular, or intrasternal injection or infusion methods. Except for the treatment of Warm-blooded animals, such as mice, rats, horses, dogs, cats, etc., are the compounds according to the invention in the Treatment of humans effective.

The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, e.g. as tablets, lozenges, rhombuses, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules or syrups or elixirs. Compositions intended for oral use can be prepared according to any of the methods for preparing pharmaceutical compositions known in the art, and such compositions may contain one or more other ingredients, namely sweeteners, flavorings, coloring agents and preservatives, with them results in a pharmaceutically pleasant and tasty preparation. Tablets contain the active ingredient in admixture with non-toxic, pharmaceutically acceptable carriers which are suitable for the tablet manufacturer.

109821/2251

Position are suitable. These carriers can, for example, be inert diluents such as calcium carbonate, sodium carbonate, Lactose, calcium phosphate or sodium phosphate; Granulating agent and disintegrants, for example corn starch or alginic acid; Binders, e.g. starch, gelatin or Acacia; and lubricants such as magnesium stearate, stearic acid or talc, be. The tablets may not be coated or they may be coated by known methods around their To delay disintegration and absorption in the gastrointestinal tract and thereby for a lasting effect over a longer period of time to worry about. For example, a delay material such as glyceryl monostearate or glyceryl distearate can be used (see above) or these can be used together with a wax.

Preparations for oral use can also be used as hard gelatin capsules, in which the active ingredient is mixed with an inert, solid diluent, e.g. calcium carbonate, Calcium phosphate or kaolin, is mixed, or presented as soft gelatin capsules, in which the active ingredient is mixed with water or an oil medium, e.g. arachid oil, peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active substances mixed with carriers necessary for the production of aqueous suspensions are suitable. Such carriers are suspending agents, e.g. Sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, Sodium algenate, polyvinylpyrrolidone, gum tragacanth and gum acacia. Dispersing or Wetting agents can be naturally occurring phosphatides, e.g. lecithin, or condensation products of an alkylene oxide with fatty acids, e.g. polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain, aliphatic alcohols, e.g. heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters,

109821/2251

A *

which are derived from fatty acids and a hexitol, such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters, those of fatty acids and Hexitanhydrides are derived, e.g. polyoxyethylene sorbitan ' monooleat, be. The aqueous suspensions mentioned can also one or more preservatives, e.g. ethyl or n-propyl-p-hydroxy-benzoate, one or more coloring agents Agents, one or more flavoring agents and one or more sweeteners, such as sucrose, saccharin or sodium or Calcium cyclamate.

Oily suspensions can be prepared by suspending the active ingredient in a vegetable oil, for example arachid oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as a liquid paraffin. The oily suspensions can contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweeteners such as those noted above and flavoring agents can be added to provide a palatable oral preparation. These agents can be preserved by adding an antioxidant such as ascorbic acid. .

Dispersible powders and granules, which are suitable for the production of an aqueous suspension by adding water, provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more Preservatives ready. Suitable dispersing. or wetting agents and suspending agents are for example those already mentioned above. Additional carriers, e.g., sweeteners, flavors, and coloring agents, can also be used to be available.

The pharmaceutical agents according to the invention can also be in the form of oil-in-water emulsions. The oily phase can be a vegetable oil, for example olive oil or arachid oil, or a mineral oil, such as liquid paraffin or mixtures of these substances. Suitable emulsifying agents are of course 10982172251

- 10 -

Occurring gums, e.g. acacia gum or tragacanth gum, naturally occurring phosphatides, e.g. soybean lecithin, and esters of partial esters derived from fatty acids and hexithydrides, e.g., sorbitan monooleate, and condensation products of the above-mentioned partial esters with ethylene oxide, e.g. polyoxyethylene sorbitan monooleate, in "Question. The emulsions may also contain sweeteners and flavorings.

Syrups and elixirs can be mixed with sweeteners, e.g. B. glycerin, Sorbitol or sucrose. Such preparations can also contain a demulgent, a preservative and flavor and dyes. The pharmaceutical agents may be in the form of a sterile, injectable preparation, e.g. a sterile, injectable, aqueous or oily suspension. This suspension can according to the known Prior art methods using those suitable dispersing or wetting agents and suspending agents, which have been mentioned above. The sterile, injectable preparation can also be a sterile, injectable one Solution or suspension in a non-toxic, parenterally acceptable diluent or solvent, e.g. a solution in 1,5-butanediol. To decent vehicles and Solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. Besides that For example, sterile, solid oils are conventionally employed as the solvent or suspending medium. For this purpose each is any soft, solid oil can be used, e.g. synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid, use in the manufacture of injectable preparations.

The compounds of the invention can also be in the form of Suppositories can be administered for rectal administration of the medicinal product. These funds can be made by the remedy is mixed with a suitable, non-irritating vehicle that will solidify at ordinary temperatures but at The rectal temperature is fluid and therefore melts in the rectum and releases the remedy. Such substances are cocoa butter

and polyethylene glycols.
■ 109821/2251

11-

For local use are creams, ointments, jellies, solutions or suspensions, etc., which are anti-inflammatory Means included, used.

Dosage levels on the order of 20 mg up to 7 g per day are useful for treating the conditions indicated above. For example, inflammation can be effectively treated and antipyretic and analgesic efficacy is revealed when about 0.3 to 100 mg of the compound each kg body weight per day are administered. Advantageously, about 2 mg to about 50 mg per kg of body weight are administered, and especially a dosage of from about 4 mg to about 20 mg / kg per day gives very good results.

The amount of the active ingredient that can be combined with the carriers to make up a single dosage form depends on the value being treated and the particular mode of administration. For example, a preparation intended for oral administration to humans can contain 5 mg to 5 g of the active ingredient compounded with a suitable and appropriate amount of carrier material, which is from about 5 to about 95 % of the total Means may vary, included. Dosage unit forms generally contain from about 25 mg up to about 500 mg of the active ingredient.

It will be understood, however, that the particular dose level for any particular patient will depend on a variety of factors, e.g. B. the effectiveness of the particular compound used, the age, the body weight, the general state of health, the sex, the diet, the duration of administration, the route of administration, the rate of excretion; the combination of remedies and the severity of the particular disease the therapy is being applied to.

- 12 -

10982 1/22 51

An expedient method for the preparation of the inventive Compounds, as illustrated in Flow Scheme I, generally encompasses the oxidation of a pyridine (A) to the corresponding N-oxide (F). The N-oxide can be converted into the 2- ^ TH7-Pyridone can be converted by using it with a lower Alkanoic anhydride is heated, which leads to the formation of the 2-Acyloxy-pyridins leads, which is acidic, neutral or Basic hydrolysis gives the 2 / 1H7-pyridone (E). The nitration des pyridone (E) leads to the corresponding nitropyridone (D). The nitropyridone (D) can be in an alternative way by amination of the pyridine (A) to form the aminopyridine (B). The aminopyridine (B) can to an amlno-nitropyridine (C) are nitrated, which then becomes the nitropyridone (D) is diazotized, or on the other hand also initially converted into the pyridone (E) and then with formation of nitropyridine (D) are nitrated. The reduction of the nitropyridine (D) leads to the production of the aminopyridone (H) according to the invention. The person skilled in the art is familiar with the fact that the pyridones can be converted into the corresponding thiopyridones (L) by treatment with agents such as phosphorus pentasulphide. 1-substituted aminopyridones can be made by the nitropyridones (D) in an inert atmosphere with a strong base, such as sodium hydride, around the 1-nitrogen atom activate, be implemented. The addition of a suitable alkylating agent etc. results in the formation of the corresponding one N-substituted material (N). By reducing the nitro group the aminopyridone (M) is then obtained.

Flow scheme II

The enol ethers and thioethers of the pyridones according to the invention are prepared in a number of different possible ways, e.g. by alkylation with diazoalkanes, alkylation or arylation of the silver salts and displacement of a halopyridine with an alkoxide (or AroxJLd) or alkyl mercaptide

109821/2251

13 241.

(or aryl mercaptide).

For example, a 2-halonitropyridine (T) is produced by halogenating the nitropyridone (D). The reaction with a metal alkoxide (aryl oxide) or metal alkyl mercaptide (aryl mercaptide) gives the nitropyridine of the formula (R). The reduction of the nitropyridine leads to the aminopyridine (S). N-acylation of the primary amine using, for example, an acid anhydride gives the acyl-substituted amines of formula (T). The cleavage of the enol ether or thioether using, for example, boron tribromide leads to the preparation of the pyridones and thiopyridones of the formula (X). The NI-substituted derivatives of the compound (X) are prepared according to the teachings of the flow scheme I ₁ which lead to the formation of the compound (Z).

- 14 -109821/2251

241

. fs

FLOW SCHEME I

R.
(1-3)

(1-3

(1-3), NO.

(A)

NH

2 B)

(1-3

R,

N /

Ψ (P)
O

(1-3

NO.

(E)

H (D)

(1-3

2
(L)

H (H)

(N)

(M)

The symbols L, · 'R ₁ , "R ₂ , R, have the" meanings given above,

- 15 -

109821/2251

HiGu-AL INSPECTED

241

/ Λ

FLOW SCHEME II

Ri

NO

(D)

al

N \ ρ

XZ

(W)

(1-3)

-NH.

XZ (S)

'(1-3)

/ P

(X)

(1-3

The symbols L, - R, X, Z and P have - the meaning given above- · services. 10 9821 / 22S1

. 16 - ORJQJNAL iN3PECTE0

In the following examples, the invention is not limited to procedures for the preparation of the invention Connections illustrated.

example 1 Preparation of 2-Amino-4-ethylpyridine

0.8 m of 4-ethylpyridine is added to a stirred suspension of freshly prepared sodium amide (from 24 g of sodium) in 90 ml of dimethylaniline / prepared according to the procedure according to Organic Reactions, Volume I /, and the mixture obtained is slowly increased heated to about 155 ° C. After the evolution of hydrogen has slowed down noticeably, the reaction is allowed to continue for 5 hours and then cooled. The mixture is treated with 160 ml of 5% sodium hydroxide solution and extracted with benzene. The benzene extracts are dried and concentrated in vacuo, and the oily residue is crystallized in a fractionated manner from ether petroleum ether. 2-Amino-4-ethylpyridine is obtained.

If you use other alkylpyridines, such as the picolines, propylpyridines, 3- or 4-t-butylpyridine, 2,3-dimethylpyridine, 3,4-dimethylpyridine, 3,5,6-trimethylpyridine, 4,5,6-trimethylpyridine, the methy1-ethylpyridines, 2-n-butylpyridine, etc., as described above, treated, the corresponding α-aminopyridine is obtained.

Example 2 Preparation of 2-Amino-4-ethyl-3-nitropyridine

To an ice-cold, stirred mixture of the 2-amino-4-ethylpyridine (0.19 m) of Example 1 in concentrated sulfuric acid (120 ml) are 15 * 2 ml of concentrated nitric acid in

30 ml of sulfuric acid given in the course of about 1.3 hours, 109821/225 1

- ■ 17 - '

the temperature of the mixture being kept below 6 ^° C. After warming to room temperature the mixture is slowly heated to 92 ⁰ C, held for 3 hours at this temperature, cooled und'dann to 2 1 of ice added. The mixture is then made basic with concentrated ammonium hydroxide. The mixture obtained is extracted with chloroform, the chloroform is removed in vacuo and the residue is distilled with steam. The distillate is collected until the vessel is empty of further volatile isomers. Extraction of the distillate with methylene chloride gives 2-amino-4-ethyl-3-nitropyridine.

Extraction of the vessel residue with chloroform gives crude 5-nitro isomer, which is purified by column chromatography. Alternatively, the crude material is extracted with dilute sulfuric acid, filtered and the residue collected.

If you have other alkylated 2-aminopyridines, such as 2-amino-6-ethylpyridine, 2-amino-4,5- or 6-methylpyridine, 2-amino-4-propylpyridine, 2-amino-4,5-dimethylpyridine, 2-amino-5 # 6-dimethylpyridine, 2-amino-4,5,6-trimethylpyridine, 2-amino-4,6-dimethyl-5-ethylpyridine, S-Amino-δ-pentylpyridine, 2-amino-6-methyl-5-propylpyridine etc., as described above, nitrided, one obtains the

corresponding amino-nitro-alkylpyridines.

If, for example, the 2-amino-4-ethylpyridine in the above is replaced by the following connections:

2-amino-5-methylpyridine
2-amino-4,5,6-trimethylpyridine
2-amino-4-ethyl-5-fluoropyridine
2-amino-5-ethyl-6-trifluoromethylpyridine,

you get:

- 18 109821/2251

2-amino-3-nitro-5-methylpyridine
2-Amino-3-nitro-4,5,6-trimethylpyridine, 2-amino-3-nitro-4-ethyl-5-fluoropyridine or 2-amino-3-nitro-5-ethyl-6-trifluoromethylpyridine.

Example 3

Production of 4-ethyl-3-nitro-2 _< £ TH7'-pyridone

To a stirred solution of 2-amino-4-ethyl-3-nitropyridine (0.032 m) of Example 2 in a sulfuric acid (9 mL) -water (90 ml) mixture at 5 ⁰ C, a concentrated aqueous solution of 2 , 4 g (0.033 m) of sodium nitrite added, while the 'temperature is maintained by external cooling below 10 ⁰ C. the mixture is allowed to warm to room temperature, heated to 45 ⁰ C, cools down, filtered to wäsch't the collected product with water and dried to give 4-ethyl-3-nitro-2 ^ TH7-pyridone. Recrystallization gives the pure material.

If the sulfuric acid solution of the 5-nitro isomer (Example 2) is used, 4-ethyl-5-nitro-2 _< / TH / -pyridone is obtained.

If the nitro-aminopyridine of Example 2 or the aminopyridines of Example 1, as described above, is diazotized Λ, will give the corresponding alkyl-nitro-pyridone and Alkylpyridone.

Example 4 Production of 4-t-butylpyridine-N-oxide

To a stirred solution of 27 g (0.2 m) of 4-t-butylpyridine in 100 ml glacial acetic acid at 33 ⁰ C are added 25 ml of 30 # aqueous hydrogen peroxide, and the resulting mixture is heated to about 75 ⁰ C. Another 30 ml of j50 # Lgen peroxide will be added

109821/2251

added, and the reaction mixture is heated overnight, cooled and solid sodium bisulphite added to the destroy excess peroxide. The mixture is then concentrated in vacuo to a residue. It becomes chloroform added, and the mixture is stirred with anhydrous sodium carbonate until all traces of acetic acid are neutralized have been. The mixture is then filtered and the chloroform solution is concentrated in vacuo to a golden yellow oil, which, when left to stand, crystallizes into a hygroscopic, white, waxy solid called 4-t-butylpyridine-N-oxide is identified.

If the alkylpyridine starting materials of Example 1 are treated as described above, the corresponding ones are obtained Alkyl pyridine N-oxides.

If, for example, the alkylpyridines, such as the picolines, 3-propylpyridine, 3-t-butylpyridine, 2,3-dimethylpyridine, 3,4-dimethylpyridine, 3,5,6-trimethylpyridine, 4,5,6-trimethylpyridine, methylethylpyridines, 2-n-butylpyridine, 5-methylpyridine, 4-ethyl-5-fluoropyridine, 5-ethyl-6-trifluoromethylpyridine, etc., instead of in the reaction described above of 4-t-Butylpyr.idin used, one obtains the corresponding N-oxides.

Example 5

Preparation of 4-t-butyl-2 ₁ / TH7'-pyridone

A mixture of the 4-t-butylpyridine-N-oxide from Example 4 (12 g, 0.08 m) with 35 ml of acetic anhydride is stirred and boiled under gentle reflux for 18 hours (nitrogen atmosphere). After cooling, the mixture is added to 300 ml of ice water . Solid sodium bicarbonate is then added to make the mixture basic and the mixture is cooled

109821/2251 " ²⁰ "

and filtered. 4-t-Butyl-2 / TH_7-pyridone is obtained. Extra product is obtained by extracting the aqueous mother liquors with chloroform. Recrystallization from acetone yields pure material (mp. 139 to 140.5 ⁰ C).

An alternative method can be used to produce the pyridone, by the N-oxide with sulfuryl chloride (or an equivalent compound) to form the 2-chloropyridine is implemented. The corresponding pyridone is obtained by hydrolyzing the chlorine group.

Example 6

Preparation of 4-t-butyl-5-nitro-2 / TH7-pyridone

Obtained to a cooled solution of 1.5 g (0.01 m) of Example 5 from 4-t-Butylpyridons in 15 rnl of concentrated sulfuric acid at ice-bath, 0.9 ml (0.01 m) of concentrated nitric acid in the course of about J > Q minutes added dropwise. The solution is allowed to warm to room temperature overnight and then 250 ml of ice water are added in small portions. The solution is then filtered, washed with water and dried. A pale yellow solid is obtained. etc. The nuclear magnetic resonance analysis, a 5-nitro shows to 5-nitro-isomer ratio of about 4: To 1. Recrystallization from ether obtained 4-t-butyl-5-nitrö-2 ^ TH7-pyridone (m.p. 140-144 ⁰ C).

If the pyridones of Examples J> and 5 are nitrided as described above, the corresponding nitropyridones are obtained.

For example, if you use the 4-t-butylpyridone in the above-described Function by replacing the following connections:

109821/2251

5-methyl-2 / TH7-pyridone

you get:
5-methyl-> nitro-2 _i / rH / ^r -pyridone

Example 7

Production of 5-bromo-4-ethyl-3-nitro-2 _i / TH / ^r -pyridone

To a stirred mixture of 0.06 m 4-ethyl-5-nitro-2 _i / rH7'-pyridone in 100 ml of chloroform and 100 ml of acetic acid at 2 ⁰ C, a chloroform (20 ml) solution of 9.6 g (0.06 m) bromine added over the course of 75 minutes while the temperature
below 5 ⁰ C is kept. After the addition, the mixture is allowed to warm to room temperature overnight. The mixture is concentrated in vacuo, the residue is triturated with dilute sodium bicarbonate solution and the 5-bromo-4-ethyl-j5-nitro-2 _< / TH / ^r -pyridone is collected.

It should be noted that N-bromosuccinimide can be used in place of bromine in the reactions described above, the mixture being heated in chloroform until the
Succinimide precipitation is complete.

The treatment of the pyridones of Examples JJ, 5 and 6 according to the process described above leads to the formation of the corresponding 3- (or 5-) bromopyridones.

- 22 -

109821/2251

»3

Example 8

Production of 5-methylthio-4-ethyl-; 5-nitro-2 / TH7-pyridone

0.05 m of 5-bromo-4-ethyl-3-nitro-2 £ TH7-pyridone are added to a mixture of copper methyl mercaptide (from 0.05 m of copper) in 50 ml of 2,4-lutidine, and the resulting mixture is added Boiled under reflux for 20 hours. After removing the lutidine in vacuo, the residue is taken up in chloroform, washed with dilute ammonium hydroxide and water, dried and then concentrated in vacuo to a residue. Chromatography of the residue on an alumina column using a methanol-methylene chloride system (v / v 0-15 % methanol) as the eluent gives

If you use other mercaptides, e.g. B. copper ethyl, propyl, -butyl- etc. mercaptide, used in place of the copper methyl mercaptide in the above example, gives this corresponding alkyl mercaptopyridone.

If the halopyridones of Example 7, as described above, Reacts with mercaptide, the corresponding mercaptopyridones are obtained.

Example 9

Preparation of 4-t-butyl-5-cyano-3-nitro-2 ^ TH_7-pyridone

A mixture of 0.02 m 5-bromo-4-t-butyl-3-nitro-2 / TH7 ^r -pyridone, 0.025 m copper (I) cyanide and N-methylpyrrolidone is freed from air, covered with a nitrogen atmosphere and slowly heated to l80 ⁰ C. The mixture is held at this temperature for 1/2 hours, cooled and then partitioned between chloroform-7% hydrochloric acid containing 0.025M ferric chloride. The chloroform layer is separated, dried, 109821/2251

- 23 -

filtered and concentrated in vacuo to give crude 4-t-butyl-5-cyano-3-nitro-2 ₁ / 1H7-pyridone, which is then transferred via column chromatography

graphy on silica gel using a methanol-methylene chloride system (v / v 0 to 10 % methanol) as the eluent.

If the halopyridones of Example 7, as described above, Reacts with copper (i) cyanide, one obtains the corresponding Cyahopyridone.

Example 10

Production of 4 ~ ethyl-3-amlno-2 _l / rH / ^r -pyridon

A mixture of 1.5 g of 4-ethyl-j5-riltro-2 / TH7'-pyridon, 75 ml Methanol and Raney nickel are reacted in a hydrogen atmosphere (2.81 kg / cm; 40 p.s.i.) at room temperature until until the hydrogen uptake is complete. The mixture will Filtered under nitrogen, concentrated in vacuo to an oily crust and taken up in chloroform. After filtering the chloroform is removed in vacuo. 4-Ethyl-3-amino-2 ^ TH / pyridone is obtained.

^ Palladium-on-carbon can be used in place of nickel in the described above can be used.

If you take the nitropyridones of Examples J5, 6, 8 and 9, such as described above, reduced, one obtains the corresponding aminopyridones.

Example 11

Manufacture of S-chloro - ^ - amino ^ -methyl-S / TH / '- pyridon

A stirred mixture of 0.5 g of jJ-

4.5 ml methylene chloride and 0.4 ml (0.00J ⁺ m) N-chlorosuocinimide 109821/2251

AS

is stirred at room temperature under a nitrogen atmosphere for hours and then gently under for 8 hours Refluxed '. The mixture is then diluted with fresh methylene chloride and washed with water. The methylene chloride layer is dried and concentrated to a residue. By chromatographing the material on a silica gel column using a methanol-methylene chloride system as the eluent, 5-chloro-3-nitro-4-methyl-2 / TH7-pyridone is obtained.

By reduction according to Example 10 and subsequent chromatography 5-chloro-3-amino-4-methyl-2 ^ 1H7-pyridone is obtained.

If the amines of Example 10 are treated as described above, the corresponding chlorine compounds are obtained. If you use N-bromosucoinimide, you get the bromine compounds.

Example 12

Preparation of 6-methyl-5-amino-3-trifluoromethyl-2 ₍ / TH / ^r -pyridone

A. A mixture of 6.0 g ^ -

17 g of phosphorus pentachloride and 50 ml of phosphorus oxychloride are gently heated on the steam cone overnight. The excess Phosphorus oxychloride is removed in vacuo, dry toluene is added and the residue is removed in vacuo is taken up in ether, filtered and concentrated-one receives 2-chloro-6-methylnicotinoyl chloride, which one 'used in level B.

B. A mixture of the above acid chloride (6 g), 20 g of sulfur tetrafluoride and 4 g of hydrogen fluoride is ^{heated to 120 °} C. for 17 hours in a stainless steel bomb, cooled and evacuated to a residue. The residue is treated with 2.5 N sodium hydroxide

solution cold carefully made basisoh. The mixture will 109821/2251

- 25 -

with CHCl, extracted and the chloroform removed in vacuo. Crude 2-chloro-6-methyl-3-trifluoromethylpyridine is obtained, purified by chromatography on a silica gel column will. ..

C. A stirred mixture of the above 2-chloropyridine (0.02 m), 0.021 m silver acetate and 35 ml of acetic acid is gently refluxed for 75 hours, filtered and 5 ml of hot water are added. The mixture is heated on the steam cone for 2 hours to hydrolyze the 2-acetoxy intermediate. The mixture is then concentrated in vacuo and the residue is chromatographed on a silica gel column using a methanol-methylene chloride system (v / v 0-15 % methanol) as the eluent. 6-Methyl-5-trifluoromethyl-2 _< / T "H / ^r -pyrlK3on is obtained. The material is then according to the procedure of Example 6 to form 6-methyl-5-nitro-3-trifluoro] -ethyl-2 / TH7-pyridone nitrated and reduced according to Example 10 to form 6-methyl-5-amino-3-trifluoromethyl-2 ₍ / rH / ^r -pyridone.

Example 13

Preparation of 3-acetyl-5-amino-6-methyl-2 ^ TH7'-pyridone

A slurry of 13 g of 3-cyano-6-methyl-2 ^ T "H7-pyridone in 100 ml of benzene is added and the mixture is refluxed for 5 hours. It is then poured into water-ice containing ² K) ml of acetic acid, and the pesticide is collected, dissolved in 30 ml of warm 2.5 N hydrochloric acid, filtered and made basic with ammonium hydroxide By cooling and filtering and subsequent recrystallization from ethanol, 3-acetyl-6-methyl-2j £ TH / -pyridone (Pp 201-202 ⁰ C) is obtained.

- 26 -

109821/2251

Using other Grignard reagents instead of methyl magnesium iodide used in the reaction described above, the corresponding ketone is obtained.

If you have other substituted cyanopyridones, as described above, treated, the correspondingly substituted acylpyridone is obtained. By nitriding according to the working method of the example 3-acetyl-5-nitro-6-methyl-2 ^ rH7'-pyridone is obtained. The nitro material is reduced according to Example 10 and gives 3-acetyl-5-amino-6-methyl-2 / TH7 "-pyridone.

Example 14 (

Production of 5-amino-3-a-hydroxyethyl-6-methyl-2 / rH7'-pyridone

To a mixture of 0.02 m 3-acetyl-5-amino-6-methyl-2 / TH7-pyridone in 100 ml of ethanol at 3 ⁰ C is added a solution of 0.8 g of sodium borohydride in 8 ml ethanol and 0.5 ml of water over the course of 6 minutes. The mixture is allowed to warm to room temperature and stir overnight. Then 2 ml of acetic acid are added and the solvents are removed in vacuo. By distributing the oil obtained was partitioned between methylene chloride-dilute sodium bicarbonate solution and subsequent removal of the methylene chloride in vacuo obtained 5-amino-j5-a-hydroxyethyl-6-methyl-2 ä _i / TH7-pyridone.

Example 15

Preparation of 3-acetamido-4-methyl-2 / TH7-pyridone and N- (4-Methyl-2 / TH / -pyridon-3-yl) -acetimide

A mixture of 3.0 g (0.02 m) 4-methyl-3-nitro-2 / fH7-pyridone, 100 ml acetic anhydride, 0.5 ml acetic acid and 1.0 g palladium (5 %) -on-carbon is reacted in a hydrogen atmosphere (2.81 kg / cm) at room temperature. After the theoretical amount of hydrogen has been absorbed, the mixture becomes

Ί09821 / 2251 -27-

filtered and concentrated in vacuo to about 10 g. The oil is then added to 50 ml of ice water, stirred overnight, and the aqueous mixture is concentrated in vacuo to a thick oil which solidifies on trituration with ether and gives a white solid. Fractional recrystallization from acetone gives the acetate, 3-acetamido-4-methyl-2 / TH7-pyridone (mp 218-220> ffc), and the imide, N- (4-methyl-2 ^ TH7-pyridone-3 -yl) -acetimid (m.p. 159-163 ⁰ C).

Example 16

Production of 5-methylsulfinyl-4-ethyl-5-amino-2 _< / TH / ^r -pyridone

A solution of 0.012 M sodium metaperiodate in the minimum amount of water is added to a solution, cooled with ice, of 0.01 M 5-methylthio-4-ethyl-5-nitro-2 _{i (/ rH7'-pyridone in methanol-acetone} The mixture is ^{stirred until the precipitation of sodium iodate is complete below 8 °} C. The sodium iodate is then removed by filtration, the solvents are removed in vacuo, the residue is taken up in chloroform, and the chloroform solution is dried, filtered and concentrated. Crude 5-methylsulfinyl-4-ethyl-3-nitro-2 ^ jH / ^r -pyridone is obtained. The crude material is purified by recrystallization or chromatography on a silica gel column. By reducing according to Example 10, S-

Using excess periodate at elevated temperatures and subsequent chromatography gives 5-methylsulfonyl-4-ethyl-3-nitro-2 _j / TH7-pyridone. The sulfonyl is also available by using peroxide in acetic acid.

Those prepared by the procedure of Example 8 AlkylthJLopyridones result when they are reacted as described above the sulfoxide or sulfone .. For example, 5-methylthio-3-nitro-2 ^ TH7-pyridone gives 5-pyridone and the corresponding sulfone, etc.

10 9 8 2 1/2251

- 28 -

Example 17
Manufacture of jJ-

If 3-amino-6-ethyl-2 _i / TH7 ^r -pyridone is nitrated as described in Example 6 and the mixture mixed with water is neutralized with ammonium hydroxide, 3-amino-6-ethyl-5-nitro-2 is obtained ^ THj7-pyridon.

By rduction (palladium-on-carbon catalyst) this The 4-amino analogue is obtained from material at room temperature.

Example 18

Preparation of 5-methoxy-1,6-dimefchyl-3-nitro-2 _< / TH7-pyridone

A mixture of O, Oj5 m 5-bromo-l, 6-dimebhyl-35-nitro-2 / TH7-pyridone, O, O6 m sodium methoxide and methanol for 8 hours heated a sealed tube at 150 ⁰ C and then cooled. The mixture is made slightly acidic, concentrated in vacuo and the residue is chromatographed on a silica gel column using a methanol-methylene chloride system (v / v 0-20 % methanol) as the eluent. 5-Methoxy-1,6-dimethyl-; 5-nitro-2 / TH / -pyrldon are obtained. β

If sodium methoxide is replaced by other alkoxides in the reaction described above, the corresponding result is obtained Alkoxypyridone.

The corresponding reduction is obtained as in Example 10 Amino compound.

- 29 -

109821/2251

13 241

Example 19

Preparation of 5-carbamyl-4-methyl-3-nitro-2 ^ TH / ^r -pyridone

0.02 m S-Cyano - ^ - methyl - ^ - nitro-S / rHZ-pyridon are in small Add portions to 25 ml of cold, stirred sulfuric acid. The mixture is stirred for 1 hour after solution is reached and then added to crushed ice, filtered, washed well with water and dried. 5-carbamyl-4-methyl-3-nitro-2 ^ T & 7-pyridone is obtained. Reduction of this material gives the jJ-amino analogue.

Example 20

Preparation of 4-carboxymethyl-3-amino-2 / TH7-pyridone

To a mixture of 0.02 m 4-methyl-3-nitro-2 / 1H / ^r -pyridone in freshly distilled tetrahydrofuran in an ice bath, 0.042 m n-13utyllithium in hexane is added. The resulting mixture is stirred for J> 0 minutes and then slowly added to a stirred tetrahydrofuran-dry ice (excess) mixture. After 1 hour the solvent is removed in vacuo, the residue is partitioned in sodium carbonate-chloroform, the carbonate solution is filtered and neutralized with dilute hydrochloric acid. 4-carboxymethyl-3-nitro-2 ^ TH7-pyridone is obtained. The purification is carried out by chromatography of the corresponding methyl ester or by recrystallization. By reduction according to the method of Example 10, 4-carboxymethyl-3-amino-2 _< / TH / -pyridone is obtained.

Example 21

Preparation of 4-t-butyl-1-methyl-3-amino-2 ^ TH7-pyridone

ι ,

0.02 M sodium hydride dispersion is added to an ice-cold, stirred mixture of 0.02 m 4-t-butyl-3-nitro-2 ₍ / T> 17-pyridone in 80 ml dimethylformamide (nitrogen atmosphere), and

the Oemieoh is stirred cold until the hydrogen 109821/2251

development has stopped and salt formation is complete. Then 0.022 m of methyl iodide to the stirred mixture in proportions salt are added such that the temperature gehalten'wird below 10 ^0C. The mixture is then allowed to warm to room temperature overnight, 200 ml of ice water containing 1 ml of acetic acid are added, the mixture is filtered and the filtrate is extracted with chloroform. The chloroform extracts are washed with water, dried and concentrated to a residue. Chromatography (silica gel) of the residue combined with the original filter cake gives pure 4-t-butyl-1-methyl-J-nitro ^^ rHT'-pyridone. By reduction according to Example 10, the corresponding amine, ^ -amino ^ -t-butyl-1-methyl ^^ THT "- * pyridone is obtained.

Methylation is also achieved by the pyridone in ethanolic potassium hydroxide heated with excess methyl iodide will.

If you use ethyl, propyl, butyl, methallyl, 2-chloroallyl, Propargyl, benzyl, substituted benzyl, phenylethyl, 3-hydroxypropyl, 2-chloroethyl, cinnamyl, thenyl, furfuryl, substituted thenyl and furfuryl, such as 5-methylthenyl and 4; 5-diethylfurfuryl, pyridylmethyl, and substituted pyridylmethyl bromide (iodide or chloride) instead of methyl iodide Used in the above examples, the corresponding .N-substituted pyridone is obtained.

If methyl bromoacetate or bromo- or chloroacetic acid is used in the procedure with the refluxing ethanolic potassium hydroxide, the corresponding N-acetic acid or the corresponding ester is obtained. The use of a dialkylaminoalkyl halide in the above process leads to the production of the corresponding N-dialkylaminoalkyl

pyridone.

- 51 -

109821/2251

Example 22
Making ^ -t-

A. The sodium salt of ^ -t-butyl- ^ - nltro-S ^ TH ^ -pyridone is prepared by the procedure of Example 21. After the evolution of hydrogen is complete, the solvent is removed in vacuo. The salt remains as a residue.

B. 0.03 M iodobenzene and 0.8 g copper powder are added to the salt and the mixture is gently refluxed for 16 hours. The mixture is cooled, chloroform is added, the mixture is filtered and concentrated in vacuo, and the remaining material is chromatographed on a silica gel column using a methanol-methylene chloride system (v / v 0-17% methanol) as the eluent. ^ -T-Butyl - ^ - nitro-1-phenyl-S ^ 1HZ-pyridone is obtained. The reduction carried out according to Example 10 gives 3-amino-4-t-butyl-1-phenyl-2 / rH7-pyridone.

If you use substituted halobenzenes, such as iodonitrobenzene, Bromo (trifluoromethyl) benzene, (dimethylamine) iodobenzene, etc., used instead of the iodobenzene used above, one obtains the corresponding 1- (substit.-phenyl) -2 / Th / -pyridones.

Taking the pyridones of Examples 2, 5, 6, 8 and 9 as above described, converts, one obtains the corresponding l- (phenyl and -substit.-phenylJ-

example 2k

Preparation ¹ of 5-ethyl-3-amino-1-tetrahydropyranyl-2 ^ rH7-pyridone

A solution of 0.05 m 5-ethyl-3-nitro-2 _< / rH / -pyridon in 100 ml benzene, which contains enough dimethylformamide to make the solution

to let enter is with 0.2 g of anhydrous p-toluene-sulfone-109821/2251

acid and then treated with 0.3 M dihydropyran in benzene at * room temperature. The mixture is then heated for 6 hours at about 70 ⁰ C, cooled and treated with I50 ml of benzene, and the mixture is dried concentrated diluted with 0.5 $ sodium hydroxide and water (5 times), washed and concentrated in vacuo. 5-Ethyl-5-nitro-1-tetrahydropyranyl-2 ₍ / TH / -pyridone is obtained, which is then reduced in a neutral medium to S-ethyl- ^ - amino-1-tetrahydropyranyl-S / 1HT'-pyridone will.

Example 24
Manufacture of ^ -

A. 3-Nitro-6-methyl-2 / TH7'-pyridone is treated with chlorosulfonic acid by way of the method of German patent No. 601 896 in 3-nitro-6-methyl-2 ^ TH / -pyridon-5- sulfonic acid transferred. The reduction according to Example 10 gives 3-amino-6-methyl-2 _j / TH / -pyridone-5-sulfonic acid.

Production of 3-amino-6-methy 1-2 / ΪΗ7- pyridone-5-sulfonamide

B. The sulfonic acid from step (A) is then mixed with diazomethane

(1 equivalent) transferred into the Methylester, and the ester is heated with concentrated ammonium hydroxide (aqueous) for 10 hours in a sealed glass tube to I50 C ^0. J-Nitro-δ-methyl ^^ HZ-pyridone-S-sulfonamide is obtained, which is then reduced to 3-amino-6-methyl-2 ₍ / TH7-pyridone-5-sulfonamide according to the procedure of Example 10).

If you have dimethylamine, ethylamine, etc. instead of ammonium hydroxide used in the reaction described above, the corresponding substituted sulfonamide is obtained.

- 33 -109821 / 2251

ar

Example 25 Manufacture of 5-ethyl-3-amino-2-pyrldlnäthlon

A mixture of 0.02 m of 5-ethyl-3-amino-2 LH7-pyridone, 1.9 g of phosphorus pentasulfide and 35 ml of pyridine is gently refluxed for 3 hours, the mixture is concentrated in vacuo and the residue between chloroform and water distributed. The chloroform layer is dried, filtered and concentrated in vacuo to a residue which is chromatographed on a silica gel column using a methanol-methylene chloride system (v / v 0-20 % methanol) as the eluent. 5-ethyl-j5-amino-2-pyridinethione is obtained.

The person skilled in the art is familiar with the fact that one can use the corresponding pyridinethione obtained when the pyridones listed in the above examples instead of the 5-ethyl-3-aminopyridone in the method described above is used.

Example 26

Preparation of 6-benzylthio-3-amino-2 _i / rH7-pyridone

A mixture of 13 g of I-nitro-o-chloro ^ / THZ-pyridone, 13 g of benzyl mercaptan, 15 ml of triethylamine and 150 ml of benzene is ^{heated to 170 °} C. for 8 hours in a stainless steel bomb. The mixture is allowed to cool and the benzene and excess reactants evaporate in the suction of the fume cupboard and the residue is partitioned between chloroform and water, filtered and the chloroform layer is concentrated in vacuo. 6-Benzylthio-3-nitro-2 ^ TH / ^r -pyridone is obtained. The reduction gives 6-benzylthio-

109821/2251

Example 27

He establishment of 3-amino-5-ethyl-2-methoxypyridine

A. A mixture of 0.04 m of 5-nitro-5-ethyl-2 ^ 1H7-pyridone _/ 0.02 m of phosphorus pentachloride and 20 ml of phosphorus oxychloride is heated on the steam cone for 5 hours. The mixture is cooled, added to 100 ml of crushed ice, basified to pH 8 with ammonium hydroxide, and the aqueous mixture is extracted with chloroform. The chloroform extracts are dried and concentrated in vacuo. 2-chloro-3-nitro-5-ethylpyridine is obtained.

B. The chloropyridine from step (A) and methanolic sodium methoxide (from 1.1 g of sodium and 50 ml of methanol) are refluxed together for 15 hours and concentrated in vacuo. The residue is on a silica gel column using an ether-petroleum ether system (ν / ν 0-βθ % ether) as

• Eluent is chromatographed and gives 3-nitro-5-ethyl-2-methoxypyridine. The reduction gives 3-amino-5-ethyl-2-, methoxypyrid in.

Example 28

Preparation of 3-fluorine-5-amino-4-methyl-2 / TH7-pyridon '

A. 3-Fluoro-4-methyl-pyridine is on the way on the way of working of Example 4 converted into the N-oxide.

B. To an ice-cold, stirred portion (25 ml) of sulfuryl chloride 2.5 g (0.02 m) of J-fluoro-4-methyl-pyridine-N-oxide are obtained added in small portions. Solution occurs and then a yellow solid rapidly precipitates. The mixture is left warm to room temperature and then reflux for 3 hours. The mixture is then cooled, too

• Add 200 g of ice and make it basic with ammonium hydroxide. The mixture is then extracted with ether, and the ether out

109821/2251

trains are dried and concentrated to an oil, which is chromatographed on a silica gel column using an ether-petroleum ether system (v / v 0-20 %) and 2-chloro-2-fluoro-4-methylpyridine and the 6-chloro Isomers supplies.

C. If one uses the above-mentioned 2-chloropyridine according to the procedure of Example 12 C. hydrolyzed, 2-Fliior-4-methy1-2,017-pyridone is obtained. The 5-fluoro isomer is obtained from the 6-chloropyridine.

The conversion into the amino compounds according to the invention takes place according to Examples 6 and 10 and gives 5-fluoro- "5-amino-4-methyl-2 _i / rH7-pyridone.: '

The invention is illustrated by the following examples in which all Parts are parts by weight, further illustrated.

Example 29

Production of 4-t-butyl- _{1,3-diamino-2 <} / TH7-pyridone

The sodium salt of ¹ ft-butyl-5-nitro-2 _i / rH7 ^r -pyridone (from Example 22 A) is converted into a cold chloramine solution (from 0.02 M sodium hypochlorite solution according to the method of Hoegerle and Erlenmeyer, % HeIv. Vol. 59, (1956), page 1207) given and stirred cold overnight. Concentration of the chloroform solution obtained by continuously extracting the reaction mixture gives 1-amino-4-t-butyl-3-nitro-2 ₍ / T'H7-pyridone.

On the other hand, treatment of the corresponding pyron with hydrazine according to procedures well known to the person skilled in the art also gives the same 1-aminopyridone.

I. Reduction as in Example 10 gives 4-t-butyl-l, 2-

109821/2251

Example 50

A mixture of 250 parts of 5-amino-4-methyl-2 ₍ / TH7-pyridone and 25 parts of lactose is granulated with a suitable amount of water, 100 parts of corn starch are added to this and the mass is sieved through a 16-mesh sieve . the granules are dried at a temperature below 60 ⁰ C. the dry granules are strained through a 16-mesh sieve and mixed with magnesium stearate 5.8 parts. Then, they are pressed to form suitable for oral administration, tablets.

The 5-amino-4-methyl-2 ^ TH7-pyridone used in the previous example can be replaced by 25, 100 or 500 parts of other pyridones according to the invention to produce tablets, those for oral administration as anti-inflammatory, antipyretic and / or analgesic agents according to the invention Process are suitable.

Example 31

A mixture of 50 parts of 5-amino-4-methyl-2 / 1H7-pyridone, 3 Parts of the calcium salt of ligninsulphonic acid and 237 parts of water are ground in the ball mill until the size is large practically all particles of 5-amino-4-methy 1-2, / ThT "-pyridone is less than 10 microns. The suspension is diluted with a solution containing 3 parts of sodium carboxymethyl cellulose and Contains 0.9 parts of the butyl ester of p-hydroxybenzoic acid in 300 parts of water. This gives an aqueous suspension which is suitable for oral administration is suitable for therapeutic purposes.

Example 32

A mixture of 250 parts of 5-amino-5-methyl-2 ^ TH7-pyridone,. 200 parts of corn starch and 50 parts of alginic acid is mixed with a A sufficient amount of a 10 ^ igen, aqueous corn starch paste mixed and granulated. The grains are in a hot air

109821/2251, -

3g

stream dried and the dry kernels are then screened through a 16 mesh screen, mixed with 6 parts magnesium stearate and pressed into tablets. Tablets are obtained which are suitable for oral administration.

Example 33

A mixture of 500 parts of 3-amino-4,5-dimethyl-2 £ TH7-pyridone, 60 parts of corn starch and 20 parts of acacia gum are granulated with a sufficient amount of water. The mass is passed through a 12-mesh sieve and the grains are dried in a stream of warm air. The dry grains are passed through a Ιβ mesh sieve strained, mixed with 5 parts magnesium stearate and compressed into a tablet form suitable for oral administration suitable.

Example. Jk

(1) tablets. 10,000 scored tablets for oral use, each of which contains 500 mg of pyridone are made from the following ingredients:

3-Amino-4-methyl-2 £ ni7 ^r -pyridone 5000

Starch, U.S.P. 350

Talc, U.S.P. 250

Calcium stearate 35

The powdered pyridone is mixed with a 4 # (w./v.), Aqueous Solution of methyl cellulose U.S.P. (1500 cps.) Granulated. A mixture of the remaining ingredients is added to the dried grains and the final mixture is made pressed into tablets, which have the proper Oewlcht.

- 38 -109821/2251

(2) capsules. 10 000 two-piece hard gelatin capsules for oral use Uses, each of which contains 250 mg of pyridone, are made from the following ingredients:

3-Amino-4-methyl-2 _/ / TH / -pyridone 2500

Lactose, U.S.P. 1000

Starch, U.S.P. 500

Talc, U.S.P. 65

Calcium stearate 25

The powdered pyridone is mixed with the starch-lactose mixture and then with the talc and calcium stearate. the The final mix is then encapsulated in the usual manner. Capsules containing 10, 25, 50 and 100 mg pyridone will be also prepared by using 100, 250, 500 or 1000 g instead of the 2500 g of the above batch.

(j5) Soft, elastic capsules. One-piece, soft, elastic capsules for oral use, each of which contains 200 mg of J5-amino-4-methyl-2 _< / TH7-pyridone, are prepared in a conventional manner by first dipping the powdered active material in sufficient corn oil to to make the material suitable for encapsulation is dispersed.

(4) Aqueous suspension. An aqueous suspension for oral use, each containing 1 g of pyridone in 5 ml, is made from made of the following components:

5-Amino-4-methyl-2 _< / rH7 ^r -pyrldon 2000 g

Methyl paraben, U.S.P. 7.5 g

Propyl Paraben U.S.P. 2.5 g

Sodium saccharin '' 12, 5 6

Sodium cyclamate - 2.5 g

Glycerin 'JOOO ml

Tragacanth powder. 10 g

Orange oil flavor '10 g

P. D. and C. orange dye T »5 E

'. deionized water, qs up to 10,000 mg

.109821 / 2251 ^ _59-

Claims (11)

241 November 11 ^ 9? *) 5513 Ho Patent application ., yi compounds of the formulas or in which: L is hydrogen, alkyl, alkenyl, alkynyl, aralkyl, aryl * hydroxyalkyl, amino, dialkylamino, dialkylaminoalkyl, carboxyalkyl, alkylaminoalkyl, haloalkyl, alkylamino, alkylamidoalkyl; Hydroxy, N-alkanoyl-alkylaminoalkyl, N-alkyl-N-alkylaminoalkyl, aralkenyl, alkoxy or a heterocyclic group;
F is hydrogen, acyl or alkoxycarbonyl; X oxygen or sulfur;
Z is hydrogen, alkyl or aryl; R ₁ , R ₂ and R _{5 in} each case haloalkyl, alkylthio, alkylsulfinyl, alky! Sulfonyl. Hydroxy, sulfonamido, SuIfο, carboxyalkyl, alkoxy, carbalkoxy, alkoxyalkyl, arylthio, aralkylthio, acylamino, hydroxyalkyl, acyl, with the proviso that if a single R stands for acyl, the other two radicals R must have a meaning other than alkyl ; Alkenyl, alkynyl, cycloalkyl, carbamoyl, N-mono-alkyl, N-dialkyl or N-aryl-substituted carbamoyl. Alkyl, alkenyloxy, nitro, with the proviso that when a one of a R is alkyl or nitro, the two other radicals R have a meaning other than hydrogen or müssenj - 40 109821/2251. ^! 13 241 Η » Hydrogen, with the proviso that at least one of the R radicals must have a meaning other than hydrogen. 2. Compounds according to claim 1 of the formula in which: L is hydrogen; P hydrogen; X oxygen; and R », Rp and R, alkyl with the proviso that when a single R stands for alkyl, the other two radicals R must have a meaning other than hydrogen. 3. Compounds according to claim 2, namely 3-amino-4-meth * yl-6-t-butyl-2, / rH7-pyridone, 3-amino-5 # 6-dimethyl-2 / TH7-pyridone, 3-amino 4,5-dimethyl-2 ^ H7-pyridone, 3-amino-6-ethyl-5-methyl-2 / ^ fH7-pyridone, 3-amino-4,6-dimethyl-2 ^ rH / ^r -pyridone or 3 -Amino-4,5,6-trimethyl-2 ₍ / TH7'-pyridone. 4. 3-Amino-4-methyl-6-t-butyl-2 ^ 1H2-pyridone according to claim 3 5. 3-Amino-5,6-dimethyl-2 ^ rH7-pyridone according to claim 3. 6. 3-Amino-4,5-dimethyl-2 _l / TH7-pyridone according to claim 3. 7. 3-Amino-4,6-dimethyl-2 ^ TH / ^r -pyridone according to claim 3. 8. Pharmaceutical preparation in dosage unit form which is useful is to be administered for anti-inflammatory, antipyretic and analgesic effects, containing per dosage unit an effective, non-toxic amount within the range of about 5 mg to about 5 g a connection of the formulas - 41 '109821/2251 or in which: L denotes hydrogen, alkyl, alkenyl, alkynyl, * aralkyl, aryl, hydroxyalkyl, amino, dialkylamino, dialkylaminoalkyl, carboxyalkyl, alkylaminoalkyl, haloalkyl, alkylamino, alkylamidoalkyli hydroxy, N-alkanoyl-alkylaminoalkyl, N-alkyl-N-alkyl -aminoalkyl, aralkenyl. Alkoxy or a heterocyclic group;
F hydrogen or acyl;
X oxygen or sulfur;
Z is hydrogen, alkyl or aryl; T ₁ , T ₂ and T, each haloalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, hydroxy, sulfonamido, sulfo, carboxyalkyl,. Alkoxy, carbalkoxy, alkoxyalkyl, arylthio, aralkylthio, Acylamino, hydroxyalkyl, acyl, alkenyl, alkynyl, halogen, cycloalkyl, carbamoyl, N-mono-alkyl, N-dialkyl or N-aryl-substituted carbamoyl «alkyl, nitro, hydrogen, Amino or cyano. 9. A pharmaceutical preparation according to claim 8 in a form suitable for oral administration. 10. Process for preparing a compound of the formula 109821/2251 - 42 - in which: R haloalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, hydroxy, sulfonamido, sulfo, carboxyalkyl, alkoxy, carbalkoxy, alkoxyalkyl, arylthio, aralkylthio, acylamino, hydroxyalkyl, acyl, with the proviso that when a single R stands for acyl , the other two radicals R must have a meaning other than alkyl; Alkenyl, alkynyl, cycloalkyl, carbamoyl, N-mono-alkyl-, N-dialkyl- or N-aryl-substituted carbamoyl, alkyl, alkenyloxy or nitro, with the proviso that when a single R is alkyl or nitro, the the two remaining radicals R must have a meaning other than hydrogen; or hydrogen, with the proviso that at least one of the radicals R must have a meaning other than hydrogen; X oxygen or sulfur, characterized in that a nitropyridone of the formula • a .NO ₂ H reduced. 11. Process for preparing a compound of the formula in which R has the meaning given above, characterized in that a compound of the formula reduced. • 109821/2251 13 241 12. Process for preparing a compound of the formula (1-3). in which R has the meaning given above, characterized in that that you get the Pyrldon of the formula converted into the corresponding thiopyridone. · Process for preparing a compound of the formula (1-3) in which R and X have the meanings given above and L is alkyl, alkenyl, alkynyl, aralkyl, aryl, hydroxyalkyl, Amino, dialkylamino, dialkylaminoalkyl, carboxyalkyl, alkylaminoalkyl, Haloalkyl, alkylamino, alkylamidoalkyl, hydroxy, N-alkanoyl-alkylaminoalkyl, N-alkyl-N-alkylaminoalkyl, aralkenyl, Alkoxy or a heterocyclic group, characterized in that the 1-nitrogen atom of a nitropyridone the formula (1-3) 109821/2251 IJ, 241 activated and then the corresponding L component under Formation of a compound of the formula (1-3) substituted, which in the reduction is the 1-substituted Aminopyridone or thiopyridone yields. 14 · Process for preparing a compound of the formula in which X is oxygen or sulfur, R has the meaning given above and Z is hydrogen or alkyl or aryl, characterized in that a nitropyridine of the formula Ri reduced. 15. Process for preparing a compound of the formula (1-3) 109 8 21/2251 in which R, X and Z have the meanings given above and F is hydrogen or acyl, characterized in that that one has the amine nitrogenator of a compound the .formula NH, acylated. 16. Process for preparing a compound of the formula (1-3) in which R, X, Z and F have the meanings given above, characterized in that the ether or Thioether of the formula splits. - 46.- 109821/2251