US3654291A - Certain 3-amino-2(1h)-pyridones - Google Patents

Certain 3-amino-2(1h)-pyridones Download PDF

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US3654291A
US3654291A US876059A US3654291DA US3654291A US 3654291 A US3654291 A US 3654291A US 876059 A US876059 A US 876059A US 3654291D A US3654291D A US 3654291DA US 3654291 A US3654291 A US 3654291A
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pyridone
amino
mixture
methyl
nitro
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Bruce E Witzel
Tsung-Ying Shen
Patricia M Graham
Robert L Clark
Arsenio A Pessolano
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Merck and Co Inc
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Merck and Co Inc
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/61—Halogen atoms or nitro radicals
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/70—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/73—Unsubstituted amino or imino radicals
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/84—Nitriles
    • C07D213/85—Nitriles in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom

Definitions

  • This invention relates to a novel class of compounds.
  • a class of compounds useful in the treatment of inflammation which also exhibit potent analgesic and antipyretic activity. More particularly the invention is concerned with amino-substituted pyridones, pyridinethione's, hydroxypyridines, and mercaptopyridines.
  • novel pyridones and pyridines of the invention have the following structural formulas:
  • L may be 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 arloweralkyl such as benzyl and substituted benzyl, phenethyl, phenylhexyl, etc.); aryl (preferably phenyl) or substituted phenyl (such as tolyl, halophenyl, hydroxyphenyl, anisyl, etc.); hydroxyalkyl (preferably hydroxyloweralkyl such as hydroxyethyl, hydroxypropyl, etc.); amino; dialkylamino (preferably diloweralkylamino); dialkylaminoalkyl
  • L may be hydrogen; alkyl (preferably loweralkyl 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 arloweral'kyl such as benzyl and substituted benzyl, phenethyl, phenylhexyl, etc.); aryl (preferably phenyl) or substituted phenyl (such as tolyl, halophenyl, anisyl, hydroxyphenyl etc.); hydroxyalkyl (preferably hydroxyloweralkyl such as hydroxymethyl, hydroxyethyl, hydroxypropyl, etc.) alkyla
  • arylthio such as phenyl-' thio; aralkylthio such as benzylthio; acylamino (preferably loweracylamino such as formylamino, acetylamino, etc.); hydroxyalkyl (preferably hydroxyloweralkyl such as hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, etc.); acyl (preferably loweracyl such as forrnyl, acetyl, propionyl, butyryl, etc.); and including benzoyl; alkenyl (preferably lower alkenyl such as vinyl, allyl, methallyl, etc.); alkynyl (preferably lower alkynyl such as ethynyl, methylbutynyl, propynyl, etc.); halogen (fiuoro, bromo, iodo, chloro
  • this invention relates to the class of chemical compounds of Formulas I and II wherein L is hydrogen, alkyl or aryl; F is hydrogen or acyl, X is O; and R (T R (T and R (T is alkyl, halogen, trihaloalkyl, alkylsulfinyl, alkylsulfonyl or alkylthio.
  • the compounds of the invention are of value in the treatment of arthritic and dermatological disorders or like conditions responsive to anti-inflammatory drugs. In general they are indicated for a Wide variety of conditions Where one or more of the symptoms of inflammation, fever and pain are manifested. Included within this category are diseases such as rheumatoid arthritis, osteo arthritis, gout, infectious arthritis and rheumatic fever. As indicated above the compounds of the invention also possess a useful degree of analgesic and anti-pyretic activity.
  • the compounds of the invention may be administered orally, topically, parenterally, by inhalation spray or rectally in formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
  • parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.
  • the compounds of the invention are effective in the treatment of humans.
  • compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, colouring agents and preserving agents in order to provide a pharmaceutically elegant and palatable preparation. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for manufacture of tablets.
  • excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example maize starch, or alginic acid; binding agents, for example starch, gelatine or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gas tro-intestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate above or with a wax may be employed.
  • Formulations for oral use may also be presented as hard gelatine capsules wherein the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatine capsules wherein the active ingredient is mixed with water or an oil medium, for example arachis oil, peanut oil, liquid paraffin or olive oil.
  • an inert solid diluent for example calcium carbonate, calcium phosphate or kaolin
  • water or an oil medium for example arachis oil, peanut oil, liquid paraffin or olive oil.
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturallyoccurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols,
  • aqueous suspensions may also contain one or more preservatives, for example ethyl, or npropyl, p-hydroxy benzoate, one or more colouring agents, one or more flavouring agents and one or more sweetening agents, such as sucrose, saccharin, or sodium or calcium cyclamate.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid parafiin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard parafiin or cetyl alcohol.
  • Sweetening agents, such as those set forth above, and flavouring agents may be added to provide a palatable oral preparation.
  • These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • a dispersing or wetting agent e.g., kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol,
  • the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oils, or a mineral oil, forexample liquid parafiin or mixtures of these.
  • Suitable emulsifying agents may be naturally-occurringgums, for example gum acacia gum tragacanth, naturally-occurring phosphatides, for example soya bean lecithin, and esters of partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan mono-oleate.
  • the emulsions may also contain sweetening and flavouring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavouring and colouring agents.
  • the pharmaceutical compositions may be in the form of a sterile injectable preparation, for example as a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting .agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3- butane diol.
  • a non-toxic parenterally-acceptable diluent or solvent for example as a solution in 1,3- butane diol.
  • acceptable vehicles and solvents that may be employed are water, Ringers solution and isotonic sodium chloride solutionl'In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic monoor diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectibles.
  • the compounds of this invention may also be ad ministered in the form of suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing-the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials are cocoa butter and polyethylene glycols.
  • creams, ointments, jellies, solutions or suspensions etc. containing the anti-inflammatory agents are employed.
  • Dosage levels of the order of 20 mg. to 7 grams per day are useful in the treatment of the above indicated conditions.
  • inflammation is effectively treated and anti-pyretic and analgesic activity manifested by the administration from about .3 to 100 milligrams of thecompound per kilogram of body weight per day.
  • Advantageously from about 2 mg. to about 50 mg. per kilogram of body weight and especially from about 4 mg. to about 20 mg./kg. per daily dosage produce highly effective results.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • a formulation intended for the oral administration of humans may contain from 5 mg. to 5 grams of active agent compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about percent of the total composition.
  • Dosage unit forms will generally contain between from about 25 mg. to about 500 mg. of active ingredient.
  • the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion; drug combination and the severity of the particular disease undergoing therapy.
  • a convenient method for the preparation of the compounds of the invention as illustrated in Flow Sheet I involves, in general, oxidation of a pyridine (A) to the corresponding N-oxide (F).
  • the N-oxide may be converted to the 2-H H]-pyridone by heating with lower alkanoic anhydride which results in the formation of the Z-acyloxy pyridine which upon acid, neutral, or basic hydrolysis gives the 2[1 H]-pyridone (E).
  • Nitration of the pyridone (B) will result in the corresponding nitropyridone (D).
  • the nitropyridone (D) may be prepared in an alternative manner by amination of the pyridine (A) to produce the aminopyridine (B').
  • the aminopyridine (B) may be either nitrated to produce an aminonitropyridine (C) which is then diazotized to the nitropyridone (D) or alternatively the aminopyridine is initially converted to the pyridone (E) and then nitrated to produce the nitropyridine (D). Reduction of the nitropyridine (D) will result in the preparation of the aminopyridone (H) of the invention.
  • the pyridones may be readily converted to the corresponding thiopyridones (L) by treatment with agents such as phosphorous pentasulfide.
  • lsubstituted aminopyridones may be prepared 'by reacting the nitropyridones (D) with a strong base such as sodium hydride in an inert atmosphere to activate the l-nitrogen. Addition of an appropriate alkylating agent, etc.; results in the production of the corresponding N-substituted material (N). Reduction of the nitro group then yields the aminopyridone (M).
  • FLOW SHEET II The enol-ethers and thioethers of the pyridones of this invention are prepared via a number of alternative routes including alkylation with diazoalkanes, alkylation or arylation of the silver salts and displacement of a halopyridine with an alkoxide (or aroxide) or alkylmercaptide (or arylmercaptide).
  • a 2-halonitropyridine is prepared by halogenation of the nitropyridone (D).
  • Reaction with a metal alkoxide aryloxide ,or metal alkylmercaptide (arylmercaptide) produces the nitropridine of the Formula R.
  • Reduction of the nitropyridine results in the aminopyridine (S).
  • N-acylation of the primary amine using, for example, an acid anhydride produces the acyl-substituted amines of the Formula W.
  • Cleavage of the enol-ether or thioether employing, for example, borontribromide results in the preparation of the pyridones and thiopyridones of the Formula X.
  • the N-1 substituted derivatives of 7 compound (X) are prepared in accordance with the teachings of Flow Sheet I resulting in the production of compound (Z).
  • alkylpyridines such as the picolines, propylpyridine, 3 or 4-t-butylpyridine, 2,3-dimethylpyridine, 3,4-dimethylpyridine, 3,5,6-trimethylpyridine, 4,5,6-trimethylpyridine, the methyl-ethylpyridines, Z-n-butylpyridine, etc. are treated as above, the corresponding tut-aminopyridine is obtained, respectively.
  • alkylated Z-aminopyridines such as 2- amino-6-ethylpyridine, 2-amino-4,5-or 6-methylpyridines, 2-amino-4-propylpyridine, 2-amino-4,S-dimethylpyridine, Z-amino-5,6-dimethylpyridine, 2-amino-4,5,6 trimethylpyridine, 2 amino 4,6 dimethyl 5 ethylpyridine, 2 amino 6 pentylpyridine, 2 amino 6 methyl- S-propylpyridine, etc. are nitrated as above, the corresponding amino-nitro-alkylpyridines are obtained.
  • alkylpyridines such as the picolines, 3-propylpyridine, 3-t-butylpyridine, 2,3-dimethylpyridine, 3,4-dimethylpyridine, 3,5,6-trimethylpyridine, 4,5,6-trimethylpyridine, the methylethylpyridines, 2-nbutylpyridine, S-methylpyridine, 4-ethyl-5-fluoropyridine, 5-ethyl-6-trifiuorornethylpyridine, etc. are employed in the above reaction in place of 4-t-butylpyridine the corresponding N-oxides are obtained.
  • pyridone As an alternative method of preparing the pyridone one may react the N-oxide with sulfuryl chloride (or equivalent) to obtain the 2-chloropyridine. Hydrolysis of the chloro group yields the corresponding pyridone.
  • N-bromosuccinirnide may be used in place of bromine in the above reactions with the mixture being heated in chloroform until succinimide precipitation is complete.
  • the chloroform layer is separated, dried, filtered and concentrated in vacuo to crude 4-t-butyl-5-cyano-3-nitro-2[1H]-pyridone which is then purified via column chromatography on silica gel., using a methanolmethylene chloride system (v./v. 010% methanol) as eluant.
  • Palladium on carbon may be used in place of nickel in the above procedure.
  • a stirred mixture of the above 2-chloropyridine (0.02 m.), silver acetate (0.021 m.) and acetic acid (35 ml.) is refluxed gently for 75 hours, filtered, hot water (5 ml.) added, and the mixture heated on the steam cone for two hours to hydrolyze the 2-acetoxy intermediate.
  • the mixture is then concentrated in vacuo, and the residue chromatographed on a silica gel column using methanol-methylene chloride system (v./v. 0-15 methanol) as eluant to yield 6-methyl-3-trifluoromethyl- 2[lH]-pyridone.
  • Example 6 The material is then nitrated according to the procedure of Example 6 to yield 6-methyl-5-nitro- 3-trifluoromethyl-2[1H]-pyridone and reduced according to Example 10 to produce 6-methyl-S-amino-B-trifluoromethyl-2 1H] -pyridone.
  • EXAMPLE 16 Preparation of 5-methylsulfinyl-4-ethyl-3-amino-2[1H]- pyridone To an ice-cooled solution of 5-methylthio-4-ethyl-3- nitro-2[lH]-pyridone (0.01 m.) in methanol-acetone is added a solution of sodium metaperiodate (0.012 m.) in a minimum of Water. The mixture is stirred below 8 C. until precipitation of sodium iodate is completed.
  • alkylthiopyridones prepared via the procedure of Example 8, yield the sulfoxide or sulfone when reacted as above.
  • 5-methylthio-3-nitro-2[1H]-Pyridone yields S-methylsulfinyl-3-nitro-2l1H]-pyridone and the corresponding sulfone, etc.
  • Methylation is also achieved via heating the pyridone in ethanolic potassium hydroxide with excess methyliodide.
  • substituted halobenzenes such as iodonitrobenzene, bromo-(trifiuoromethyl)-benzene, (dimethylamino)iodobenzene, etc. are used above in place of iodobenzene, the correspondingly l-(substituted phenyD-Z [1H]-pyridones are obtained.
  • EXAMPLE 23 Preparation of 5-ethyl-3-amino-l-tetrahydropyranyl- 2[1H]-pyridone
  • a solution of 5-ethyl-3-nitro-2[1H]-pyridone (0.03 m.) in benzene ml.) containing enough dimethylformamide for solution is treated with anhydrous p-toluenesulfonic acid (0.2 g.), followed by dihydropyran (0.3 m.) in benzene at room temperature. The mixture is then heated at ca. 70 C.
  • EXAMPLE 25 Preparation of 5ethyl-3amino-2-pyridinethione
  • a mixture of 5-ethyl-3-amino-2[1H]-pyridone (0.02 m.), phosphorous pentasulfide (1.9 g.) and pyridine (35 ml.) is refluxed gently for 3 hours, the mixture concentrated in vacuo and the residue partitioned between chloroform-water.
  • the chloroform layer is dried, filtered and concentrated in vacuo to a residue and the residue chromatographed on a silica gel column using a methanolmethylene chloride system (v./v. 28% methanol) as eluant to yield -ethyl-3-amino-2-pyridinethione.
  • EXAMPLE 26 Preparation of 6-benzylthio-3-amino-2[1H]-pyridone A mixture of 3-nitro-6-chloro-2[1H]-pyridone (13 g.), benzylmercaptan (13 g.), triethylamine (15 ml.) and benzene (150 ml.) in a stainless steel bomb is heated at 170 C. for 8 hrs. The mixture is allowed to cool, the benzene and excess reagents allowed to evaporate in the hood draft and the residue distributed between chloroform-water, filtered, and the chloroform layer concentrated in vacuo to 6-benzyl-thio-3-nitro-2[1H]pyridone. Reduction yields 6-benzylthio-3-amino 2 1H] pyridone.
  • EXAMPLE 27 Preparation of 3-amino5-ethyl-2-methoxypyridine (A) A mixture of 3-nitro-5-ethyl-2[1H]-pyridone (0.04 m.), phosphorous pentachloride (0.02 m.) and phosphorous oxychloride ml.) is heated on the steam cone for 3 hrs. The mixture is cooled, added to crushed ice (100 ml.), basified to pH 8 with ammonium hydroxide, and the aqueous mixture extracted with chloroform. The chloroform extracts are dried and concentrated in vacuo to 2- chloro-3nitro-S-ethylpyridine.
  • EXAMPLE 29 Preparation of 4-t-butyl-1,3-diamino-2[1H]-pyridone
  • the sodium salt of 4-t-butyl-3-nitro-2[1H]-pyridone (from Example 22A) is added to a cold chloramine solution prepared from 0.02 m. sodium hypochlorite solution via the procedure of Hoegerle and Erlenmeyer, Helv. 39 1207 (1956) and allowed to stir cold overnight. Concentration of the chloroform solution obtained by continuous extraction of the reaction mixture yields l-amino- 4-t-butyl-3-nitro-2[1H]pyridone.
  • EXAMPLE 3 0 A mixture of 250 parts of 3-amino-4-mcthyl-2[1H]- pyridone and 25 parts of lactose is granulated with suitable water, and to this is added parts of maize starch. The mass is passed through a 16 mesh screen. The granules are dried at a temperature below 60 C. The dry granules are passed through a 16 mesh screen, and mixed with 3.8 parts of magnesium stearate. They are then compressed into tablets suitable for oral administration.
  • the 3-amino-4-methy1-2[1H]-pyridone used in the foregoing example may be replaced by 25, 100 or 500 parts of other pyridones of this invention to produce tablets suitable for oral administration as an anti-inflammatory, antipyretic and/or analgesic according to the method of this invention.
  • EXAMPLE 31 A mixture of 250 parts of 3-amino-5-methy1-2[1H]- pyridone, 200 parts of maize starch and 30 parts of alginic acid is mixed with a suflicient quantity of a 10% aqueous paste of maize starch, and granulated. The granules are dried in a current of warm air and the dry granules are then passed through a 16-mesh screen, mixed with 6 parts of magnesium stearate and compressed into tablet form to obtain tablets suitable for oraladministration.
  • EXAMPLE 33 A mixture of 500 parts 3-amino-4,5-dimethyl-2[1H]- pyridone, 60 parts maize starch and 20 parts of gum acacia is granulated with a sufiicient quantity of water. The mass is passed through a 12-mesh screen and the granules are dried in a current of Warm air. The dry granules are passed through a l6-mesh screen, mixed with 5 parts of magnesium stearate and compressed into tablet form suitable for oral administration.
  • EXAMPLE 34 Tablets 10,000 scored tablets for oral use, each containing 500 mg. of pyridone, are prepared from the following ingredients:
  • the powdered pyridone is mixed with the starch-lactose mixture followed by the talc and calcium stearate. The final mixture is then encapsulated in the usual manner.
  • Capsules containing 10,. 25, 50, and 100 mg. of pyridone are also prepared by substituting 100, 250, 500 and 1000 gm. for 2500 gm. in the above formulation.
  • Soft elastic capsules One-piece soft elastic capsules for oral use, each containing 200 mg. of 3-amino-4-methy1-2[1H]pyridone, are prepared in the usual manner by first dispersing the powdered active material in sufiicient corn oil to render the material capsulatable.
  • aqueous suspension for oral use containing in each 5 ml., 1 gram of pyridone is prepared from the following ingredients:
  • L is hydrogen, lower alkenyl, lower alkynyl, hydroxyloweralkyl or haloloweralkyl
  • R R and R are each hydrogen, loweralkyl haloloweralkyl, or cycloloweralkyl of from 3 to 6 carbon atoms with the proviso that at least two of said terms R R or R are other than hydrogen and pharmaceutical- 1y acceptable salts thereof.
  • R R and R is hydrogen or lower alkyl with the proviso that at least two Rs must be lower alkyl.
  • a compound according to claim 1 selected from the group consisting of 3-amino-4-methyl-6-t-butyl 2[1H]- pyridone, 3-amino-5,6-dimethyl 2[1H] pyridone, 3- amino-4,5-dimethyl-2[1H]-pyridone, 3-amino-6-ethyl 5- methyl-2[1H]-pyridone, 3-amino-4,6-dimethyl 2[1H]- pyridone, and 3-amino-4,5,6-trimethyl-2[1H] -pyridone.

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Cited By (18)

* Cited by examiner, † Cited by third party
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US3835143A (en) * 1969-11-12 1974-09-10 Merck & Co Inc Certain 2(1h) pyridinethiones
US3932644A (en) * 1973-05-03 1976-01-13 Smith Kline & French Laboratories, Inc. H2 histamine receptor inhibitors
US4035374A (en) * 1973-05-03 1977-07-12 Smith Kline & French Laboratories Limited Imidazolyl alkylaminopyridone and pyridinethione compounds
US4260744A (en) * 1973-05-03 1981-04-07 Smith Kline & French Laboratories Limited Pharmacologically active compounds
US4371537A (en) * 1981-08-13 1983-02-01 The Dow Chemical Company Sulfur-substituted phenoxypyridines having antiviral activity
US4412077A (en) * 1982-03-15 1983-10-25 Sterling Drug Inc. Process for preparing 5-(lower-alkanoyl)-6-(lower-alkyl)-2(1H)-pyridinone
US4451469A (en) * 1982-12-16 1984-05-29 Sterling Drug Inc. Selected 6-alkyl-and 4,6-dialkyl-2(1H)-pyridinones as cardiotonics
US4467087A (en) * 1973-05-03 1984-08-21 Smith Kline & French Laboratories Limited 1,2,4-Triazines
US4524149A (en) * 1982-03-15 1985-06-18 Sterling Drug Inc. 5-Alkanoyl-6-alkyl-2(1H)-pyridinones, their preparation and their cardiotonic use
US4578459A (en) * 1973-05-03 1986-03-25 Smithkline & French Laboratories Limited Heterocyclic alkylaminoheterocycles
US5308854A (en) * 1990-06-18 1994-05-03 Merck & Co., Inc. Inhibitors of HIV reverse transcriptase
US5334722A (en) * 1990-07-27 1994-08-02 Imperial Chemical Industries Plc Fungicides
WO2003068230A1 (en) * 2002-02-14 2003-08-21 Pharmacia Corporation Substituted pyridinones as modulators of p38 map kinase
NL1026826C2 (nl) * 2003-08-13 2007-01-04 Pharmacia Corp Gesubstitueerde pyridinonen.
AU2007202607B2 (en) * 2002-02-14 2008-12-18 Pharmacia Corporation Substituted Pyridinones as Modulators of p38 MAP Kinase
KR100901931B1 (ko) 2002-02-14 2009-06-10 파마시아 코포레이션 Ｐ３８ ｍａｐ 키나제의 조절제로서의 치환된 피리디논
CN109311813A (zh) * 2016-04-18 2019-02-05 斯克利普斯研究院 钯催化的间位-c-h官能化的通用型配体
CN116120225A (zh) * 2023-01-06 2023-05-16 利尔化学股份有限公司 一种除去三氯吡氧乙酸乙酯中吡啶酮杂质的方法及其应用

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DE3106460A1 (de) * 1980-03-03 1982-01-28 Sandoz-Patent-GmbH, 7850 Lörrach 2(1h)-pyridinon-derivate, ihre herstellung und sie enthaltende pharmazeutische zubereitungen
US4681873A (en) * 1985-07-29 1987-07-21 Warner-Lambert Company 4-amino-3-halo-2-pyridinone nucleoside and nucleotide compounds
US5032602A (en) * 1988-12-14 1991-07-16 Bayer Aktiengesellschaft Inhibiting HMG-CoA reductase with novel substituted 2-pyridones and pyrid-2-thiones
US5164506A (en) * 1988-12-14 1992-11-17 Bayer Aktiengesellschaft Substituted 2-pyridones and pyrid-2-thiones compounds

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DE596728C (de) * 1932-10-26 1934-05-09 Chem Fab Von Heyden Akt Ges Verfahren zur Darstellung von 2-Oxy-5-aminopyridin bzw. dessen Kernsubstitutionsprodukten
DE626687C (de) * 1934-07-05 1936-09-01 Chem Fab Von Heyden Akt Ges Verfahren zur Darstellung von Alkoxyaminopyridinen
NL6816241A (enrdf_load_html_response) * 1967-12-01 1969-06-03

Cited By (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3835143A (en) * 1969-11-12 1974-09-10 Merck & Co Inc Certain 2(1h) pyridinethiones
US3932644A (en) * 1973-05-03 1976-01-13 Smith Kline & French Laboratories, Inc. H2 histamine receptor inhibitors
US4035374A (en) * 1973-05-03 1977-07-12 Smith Kline & French Laboratories Limited Imidazolyl alkylaminopyridone and pyridinethione compounds
US4260744A (en) * 1973-05-03 1981-04-07 Smith Kline & French Laboratories Limited Pharmacologically active compounds
US4467087A (en) * 1973-05-03 1984-08-21 Smith Kline & French Laboratories Limited 1,2,4-Triazines
US4578459A (en) * 1973-05-03 1986-03-25 Smithkline & French Laboratories Limited Heterocyclic alkylaminoheterocycles
US4371537A (en) * 1981-08-13 1983-02-01 The Dow Chemical Company Sulfur-substituted phenoxypyridines having antiviral activity
US4412077A (en) * 1982-03-15 1983-10-25 Sterling Drug Inc. Process for preparing 5-(lower-alkanoyl)-6-(lower-alkyl)-2(1H)-pyridinone
US4524149A (en) * 1982-03-15 1985-06-18 Sterling Drug Inc. 5-Alkanoyl-6-alkyl-2(1H)-pyridinones, their preparation and their cardiotonic use
US4451469A (en) * 1982-12-16 1984-05-29 Sterling Drug Inc. Selected 6-alkyl-and 4,6-dialkyl-2(1H)-pyridinones as cardiotonics
US5308854A (en) * 1990-06-18 1994-05-03 Merck & Co., Inc. Inhibitors of HIV reverse transcriptase
US5334722A (en) * 1990-07-27 1994-08-02 Imperial Chemical Industries Plc Fungicides
US7067540B2 (en) 2002-02-14 2006-06-27 Pharmacia Corporation Substituted pyridinones
KR100901931B1 (ko) 2002-02-14 2009-06-10 파마시아 코포레이션 Ｐ３８ ｍａｐ 키나제의 조절제로서의 치환된 피리디논
WO2003068230A1 (en) * 2002-02-14 2003-08-21 Pharmacia Corporation Substituted pyridinones as modulators of p38 map kinase
US20060211694A1 (en) * 2002-02-14 2006-09-21 Pharmacia Corporation, Global Patent Department Diaryl substituted pyridinones
HRP20040707B1 (hr) * 2002-02-14 2012-12-31 Pharmacia Corporation Supstituirani piridinoni kao modulatori p38 map kinaze
EA008008B1 (ru) * 2002-02-14 2007-02-27 Фармация Корпорейшн Замещённые пиридиноны в качестве модуляторов мар-киназы р38
US20070088033A1 (en) * 2002-02-14 2007-04-19 Balekudru Devadas Diaryl Substituted Pyridinones
AP1822A (en) * 2002-02-14 2008-01-30 Pharmacia Corp Substituted pyridinones as modulators of P38 MAP kinase.
AU2007202607B2 (en) * 2002-02-14 2008-12-18 Pharmacia Corporation Substituted Pyridinones as Modulators of p38 MAP Kinase
CN100486576C (zh) * 2002-02-14 2009-05-13 法玛西雅公司 作为p38map激酶调节剂的取代吡啶酮类
US20040058964A1 (en) * 2002-02-14 2004-03-25 Balekudru Devadas Substituted pyridinones
US7629363B2 (en) 2002-02-14 2009-12-08 Pfizer Inc Diaryl substituted pyridinones
NL1026826C2 (nl) * 2003-08-13 2007-01-04 Pharmacia Corp Gesubstitueerde pyridinonen.
CN109311813A (zh) * 2016-04-18 2019-02-05 斯克利普斯研究院 钯催化的间位-c-h官能化的通用型配体
CN109311813B (zh) * 2016-04-18 2023-02-28 斯克利普斯研究院 钯催化的间位-c-h官能化的通用型配体
CN116120225A (zh) * 2023-01-06 2023-05-16 利尔化学股份有限公司 一种除去三氯吡氧乙酸乙酯中吡啶酮杂质的方法及其应用

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