Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
  • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Definitions

• compositions containing 2-(6'-substituted-2'-naphthyl)-acetic acid deri vatives for the treatment of respiratory disorders
• the present invention relates to novel methods of using certain napthalene derivatives, preferably certain 2-(6'-substituted-2'-naphthyl)-acetic acid derivatives and salts and esters thereof in the treatment, management or mitigation of cold, cold-like and/or flu symptoms.
• the common cold although not usually a serious illness, is a highly prevalent, discomforting and annoying infliction.
• the term "common cold” is applied to minor respiratory illnesses caused by a variety of different respiratory viruses. While rhinoviruses are the major known cause of common colds, accounting for approximately 30 percent of colds in adults, viruses in several other groups are also important. While immune responses occur, and infection with some respiratory tract viruses therefore could be prevented by a vaccine, development of a polytypic vaccine to cover all possible agents is impractical. Thus, the problem of controlling acute upper respiratory disease presents complex challenges, and the long-desired discovery of a single cure for the common cold is an unrealistic expectation.
• Influenza infection generally includes fever, often of sudden onset and persisting for several days, and with great severity; generalized aches and pains; fatigue and weakness; and chest discomfort.
• Exemplary prior art formulations for treatment of cough, cold, cold-like and/or flu symptoms and the discomfort, pain, fever and general malaise associated therewith generally contain an analgesic
• non-steroidal anti-inflammatory drugs to combat inflammation and attendant pain is accepted medical practice.
• the non-steroidals are commonly employed to relieve pain and inflammation associated with, for example, bursitis, arthritis, headache and the like.
• drugs of the non-narcotic analgesic class of drugs are aspirin, acetaminophen, ibuprofen and naproxen.
• Aspirin, acetaminophen and ibuprofen have heretofore been included as the pain reliever and fever-reducing component in conventional cough/cold multi-symptom alleviating compositions.
• These commercially marketed products generally contain in addition to aspirin, acetaminophen or ibuprofen, one or more antihistaminics, decongestants, coughsuppressants, antitussives and expectorants.
• Naproxen ((+)-2-(6 methoxy-2-naphthyl) propionic acid), a non- steroidal anti-inflammatory drug (NSAID), became available in the U.S. for the treatment of rheumatoid arthritis in 1976. Naproxen has been further indicated for osteoarthritis, tendonitis and bursitis, ankylosing spondylitis and acute gout. Additional indications include mild to moderate pain and primary dysmenorrhea. Naproxen has also been demonstrated to have less severe gastrointestinal and central nervous system adverse effects than aspirin.
• NSAID non- steroidal anti-inflammatory drug
• Such symptoms as used herein refer to coryza, nasal congestion, upper respiratory infections, allergic rhinitis, otitis, sinitis, etc.
• the present invention relates to a method for eliciting an enhanced response in the treatment of cough, cold, cold-like and/or flu symptoms in a human or lower animal in need of such treatment, comprising administering to such mammaliam organism in need of such treatment a symptom relieving, analgesically and anti-inflammatorily effective amount of a specific naphthalene derivative within the first 24 hours of the discovery of the onset of symptoms.
• the present invention relates to methods for the treatment of cold, cold-like, flu and flu-like symptoms by administration of a safe and effective amount of a napthalene derivative, preferably a 2-(6'- substituted-2'-naphthyl)-acetic acid derivative, and salts and esters thereof.
• a napthalene derivative preferably a 2-(6'- substituted-2'-naphthyl)-acetic acid derivative
• salts and esters thereof are administered to a mammalian organism for the treatment of cough, cold, cold-like and/or flu symptoms within the first 36 hours of the discovery of the onset of said symptoms.
• the compounds of this invention are the carboxylic acids and carboxylic acid esters represented by the following formula, and the pharmaceutically acceptable salts of the carboxylic acids represented by the following formula:
• R 1 is alkyl having up to 6 carbon atoms, cycloalkyl having from 3 to 7 carbon atoms, al koxymethyl having up to 7 carbon atoms, trifluoromethyl, vinyl, ethynyl, halo (iodo, bromo, chloro or fluoro) alkoxy having up to 6 carbon atoms, difluoromethoxy, al koxymethoxy having up to 7 carbon atoms, alkyl thiomethyloxy having up to 7 carbon atoms, alkylthio having up to 6 carbon atoms, alkoxymethylthio having up to 7 carbon atoms, cyano difluoromethylthio, phenyl or alkylsubstituted phenyl having up to 8 carbon atoms;
• R 2 and R 3 is hydrogen, the other being methyl, ethyl or difl uoromethyl or R 2 or R 3 together are methylene;
• R 4 is hydrogen, alkyl having up to 22 carbon atoms, unsaturated alkyl having up to 22 carbon atoms, cycloalkyl having from 3 to 7 carbon atoms, cycloalkylmethyl having from 3 to 7 carbon atoms, cycloalkylmethyl having from 4 to 9 carbon atoms, 2-cycloalkylethyl having from 5 to 10 carbon atoms, 3-cyclopentylethyl having from 5 to 10 carbon atoms, 3-cyclopentylpropyl, 3-cyclohexylpropyl, benzyl, 2-phenylethyl or 3-phenylpropyl.
• the 6'-substituent (represented by R 1 in the above formula) is methyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl, vinyl, ethynyl, fluoro, chloro, methoxy, ethoxy, methoxymethyloxy, difluoromethoxy, methylthio, ethylthio, methoxymethylthio, difluoro- methylthio or phenyl; one of R 2 and R 3 is hydrogen and the other is methyl; and R 4 is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, pentyl, isopentyl, hexyl, 2-hexyl, isohexyl, heptyl, isoheptyl, octyl, isooctyl, nonyl, isononyl, decyl, isodecyl, undecyl
• alkyl refers to and includes branched or straight chain hydrocarbons. Typical alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, tertiary-butyl, neopentyl, isopentyl, hexyl, octyl, nonyl, isodecyl, 6-methyldecyl, tridecyl, isotetradecyl, pentadecyl, isohexadecyl, heptadecyl, eicosyl, docosyl, and the like.
• unsaturated alkyl refers to unsaturated hydrocarbon groups such as vinyl, allyl, propenyl, crotyl, isopropenyl, 2-propynyl, 1-propenyl, 2-butenyl, 1,3-butadienyl, 2-pentenyl, 2-penten-4-ynyl and the like.
• cycloalkyl refers to cyclo hydrocarbon groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
• alkoxy refers to straight or branched chain alkyl ether groups such as methoxy, ethoxy, 2-propoxy, butoxy, 3-pentoxy and the like.
• alkoxymethyloxy refers to methyl ether groups substituted with one alkoxy group (defined above) such as methoxymethyloxy, e hoxymethloxy, isopropoxymethyloxy and the like.
• alkylthio refers to straight or branched chain alkylthio ether groups such an methylthio, ethylthio, propylthio. 2-propylthio, 2-butylthio, pentylthio, 3-hexylthio and the like.
• alkylthiomethyloxy refers to methyl ether groups substituted with an alkylthio group (defined above) such as methylthiomethyloxy, 2-propylthiomethyloxy, pentylthiomethloxy and the like.
• alkylthiomethylthio as used herein denoted methylthio ether groups substituted with an alkylthio group such as methylthio- methylthio, ethylthiomethylthio and the like.
• alkoxymethylthio refers to methylthio ether groups substituted with an alkoxy group such as methocymethylthio, ethoxymethylthio, 2-propoxymethylthio and the like.
• aryl refers to phenyl, or o-, m- and/or p- alkyl substituted phenyl derivatives such as phenyl, otolyl, m-tolyl, p-tolyl, o-ethylphenyl, m-ethylphenyl, p-ethylphenyl, xylyl and the like.
• cycloalkylmethyl refers to cycloalkyl substituted methyl groups such as cyclopropylmethyl, cyclobutylmethy, cyclopentyl- methy, cyclohexylmethyl, cycloheptylmethyl, and the like.
• 2-cycloalkyl ethyl refers to an ethyl group substituted at the 2-position with a cycloalkyl group such as 2-cyclopropyl ethyl, 2-cyclobutylethyl, 2-cyclopentylethyl, 2-cyclohexylethyl and 2-cyclo- heptylethyl.
• the most preferred compound used herein is (+)-2-(6'-methoxy- 2-napthyl) propionic acid, and salts and esters thereof.
• salts refers to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from nonorganic bases include sodium, potassium, lithium, ammonia, calcium, magnesium, ferrous, zinc, manganous, aluminum, ferric, manganic salts and the like.
• Salts derived from pharmaceutically acceptable organic non- toxic bases include salts of primary, secondary, tertiary and quaternary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as triethyl amine, tripropylamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, lysine, argimne, histidine, caffeine, procaine, N-ethylpiperidine, hydrabamine, choline, betaine, ethyl eneci amine, glucosamine, methylglycamine, theobromine, purines, piperazine, piperidine, polyamine resins and the like.
• basic ion exchange resins such as triethyl amine, tripropylamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, lysine, argimne, histidine, caffeine, proca
• the compounds of Formula 1 exist as pairs of enantiomorphs or optical isomers. Each enantiomorph- and mixtures thereof are included within the present invention.
• the compounds of Formula 1 which exist as pairs of enantiomorphs can be administered as racemic mixtures or they can be administered as resolved enantiomorphs. In some instances, one enantiomorph exhibits greater anti-inflammatory, analgesic and/or anti-pyretic activity than the other corresponding enantiomorph.
• the most preferred derivatives for use herein are the S(+)enantiomorphs.
• optical isomers can be resolved by conventional means, such as selective biological degradation or by the preparation of diastereo-isomeric salts of the naphthalene derivative with an optically active amine base such cinchonidine and separating the diastereoisomers by fractional crystallization. The separated diastereoisomeric salts are then acid cleaved to yield the respective optical isomer.
• oral dosage forms can be used, including such solid forms as tablets, capsules, granules, lozenges and bulk powders and liquid forms such as syrups and suspensions. These oral forms comprise a safe and effective amount, usually at least about 5% of the active component.
• Solid oral dosage forms preferably contain from about 5% to about 95%, more preferably from about 10% to about 95%, and most preferably from about 25% to about 95% of the active component.
• Liquid oral dosage forms preferably contain from about 1% to about 50% and more preferably from about 1% to about 25% and most preferably from about 3% to about 10% of the active component.
• Tablets can be compressed, triturated, enteric-coated, sugarcoated, film-coated or multiple compressed, containing suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, preservatives and flow- inducing agents. Also useful are soft gelatin capsules.
• Liquid oral dosage forms include aqueous and nonaqueous solutions, emulsions, pseudo emulsions, suspensions, and solutions and/or suspensions reconstituted from non-effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, coloring agents, and flavoring agents.
• suitable solvents preservatives, emulsifying agents, suspending agents, diluents, sweeteners, coloring agents, and flavoring agents.
• aqueous-based orally acceptable pharmaceutical carrier is one wherein the entire or predominant solvent content is water.
• Typical carriers include simple aqueous solutions, syrups, dispersions and suspensions, and aqueous based emulsions such as the oil-in-water type.
• the most preferred carrier is a suspension of the pharmaceutical composition in an aqueous vehicle containing a suitable suspending agent.
• suitable suspending agents include Avicel RC-591 (a microcrys- talline cellulose/sodium carboxymethyl cellulose mixture available from FMC), guar gum and the like. Such suspending agents are well known to those skilled in the art.
• the total water content based on the weight of the final composition, will generally range from about 20 to about 75%, and, preferably, from about 20 to about 40%, by weight/volume.
• compositions of this invention preferably contain from about 5 to about 25 volume/volume percent and, most preferably, from about 10 to about 20 volume/ volume percent, of the co-solvent.
• compositions of this invention may optionally contain one or more other known therapeutic agents, particularly those commonly utilized in cough/cold preparations, such as, for example, a decongestant such as pseudoephedrine, phenyl propanol amine, phenylephrine and ephedrine, their pharmaceutically acceptable salts; an antitussive such as dextromethorphan, chlophedianol, carbetapentane, caramiphen, noscapine, diphenhydramine, codeine, hydrocodone, hydromorphone, fominoben, their pharmaceutically-acceptable salts; an expectorant or mucolytic such as glyceryl guaiacolate, terpin hydrate, ammonium chloride, N-acetylcysteine and bromhexine, ambroxol, their pharmaceutically acceptable salts; and an antihistamine such as chlorpheniramine, brompheniramine, dexchlorpheniramine, dexbromphreni
• Patent 4,783,465 to Sunshine et al. issued November 8, 1988
• U.S. Patent 4,619,934 to Sunshine et al. issued October 28, 1986
• bronchodilators such as terbutaline, aminophylline, epinephrine, isoprenaline, metaproterenol, bitoterol, theophylline and albuterol.
• a highly preferred optional component is caffeine, which is preferably present at a level of from about 10% to about 50%.
• ingredients well known to the pharmacist's art may also be included in amounts generally known for these ingredients, for e. iple, natural or artificial sweeteners, flavoring agents, colorants and the like to provide a palatable and pleasant looking final product, antioxidants, for example, butylated hydroxy anisole or butylated hydroxy toluene, and preservatives, for example, methyl or propyl paraben or sodium benzoate, to prolong and enhance shelf life.
• the amount of the pharmaceutical composition administered depends upon the percent of active ingredients within its formula, which is a function of the amount of the naphthalene derivative and any optional components such as a decongestant, cough suppressant, expectorant and/or antihistamine required per dose, stability, release characteristics and other pharmaceutical parameters.
• each individual dosage of the pharmaceutical compositions of the present invention range from about 1 mg/kg to about 25 mg/kg, preferably from about 2 mg/kg to about 15 mg/kg and most preferably from about 3 mg/kg to about 10 mg/kg.
• Typical unit dosage forms for oral administration generally comprise from about 100 mg to about 2000 mg, preferably from about 150 mg to about 600 mg and most preferably from about 150 mg to about 400 mg of the naphthalene derivative. While dosages higher than the foregoing are effective to provide relief from cough, cold-like, flu and flu-like symptoms, care must be taken, as with any drug, in some individuals to prevent adverse side effects.
• composition is administered within about 36 hours preferably about 24 hours, and, most preferably within about 12 hours of discovery of the onset of symptoms by the individual.
• the onset of symptoms generally occurs within about 36 hour after viral infection or innoculation .
• a soft gelatin capsule composition for oral administration is prepared by combining the following ingredients:
• Triturate active ingredients and q.s. with lactose to weight sufficient to fill selected capsule size Triturate active ingredients and q.s. with lactose to weight sufficient to fill selected capsule size.
• a soft gelatin capsule composition for oral administration is prepared by combining the following ingredients:
• Triturate active ingredients and q.s. with lactose to weight sufficient to fill selected capsule size Triturate active ingredients and q.s. with lactose to weight sufficient to fill selected capsule size.
• a soft gelatin capsule composition for oral administration is prepared by combining the following ingredients:
• Triturate active ingredients and q.s. with lactose to weight sufficient to fill selected capsule size Triturate active ingredients and q.s. with lactose to weight sufficient to fill selected capsule size.
• a liquid composition for oral administration is prepared by combining the following ingredients:
• the purified water (approximately 10% of the final batch volume) is poured into a batch container equipped with a lightnin' mixer.
• the sodium citrate and citric acid are added sequentially and dissolved with agitation.
• the glycerin and liquid sugar are then added.
• the colorants are added to purified water (approximately 0.5% of the final batch volume). This colorant solution is then added to the first batch container.
• the naproxen is added to the alcohol while stirring.
• the propylene glycol and flavors are added to this alcohol premix and the resulting mixture is stirred until homogeneous and then added ttr the first container.
• the remaining purified water is added to the resulting mixture and stirred.
• a liquid composition for oral administration is prepared by combining the following ingredients:
• the purified water (approximately 10% of the final batch volume) is poured into a batch container equipped with a lightnin' mixer.
• the sodium citrate, citric acid and pseudoephedrine HCl are added sequentially and dissolved with agitation.
• the glycerin and liquid sugar are then added.
• the colorants are added to purified water (approximately 0.5% of the final batch volume). This colorant solution is then added to the first batch container.
• the naproxen is added to the alcohol while stirring.
• the propylene glycol and flavors are added to this alcohol premix and the resulting mixture is stirred until homogeneous and then added to the first container.
• the remaining purified water is added to the resulting mixture and stirred.
• a liquid composition for oral administration is prepared by combining the following ingredients:
• the purified water (approximately 10% of the final batch volume) is poured into a batch container equipped with a lightnin' mixer.
• the sodium citrate, citric acid, pseudoephedrine HCl and chlorpheniramine maleate are added sequentially and dissolved with agitation.
• the glycerin and liquid sugar are then added.
• the colorants are added to purified water (approximately 0.5% of the final batch volume). This colorant solution is then added to the first batch container.
• the naproxen is added to the alcohol while stirring.
• the propylene glycol and flavors are added to this alcohol premix and the resulting mixture is stirred until homogeneous and then added to the first container.
• the remaining purified water is added to the resulting mixture and stirred.
• a liquid composition for oral administration is prepared by combining the following ingredients:
• the purified water (approximately 10% of the final batch volume) is poured into a batch container equipped with a lightnin' mixer.
• the sodium citrate, citric acid, pseudoephedrine HCl and chlorpheniramine maleate are added sequentially and dissolved with agitation.
• the glycerin and liquid sugar are then added.
• the colorants are added to purified water (approximately 0.5% of the final batch volume). This colorant solution is then added to the first batch container.
• the naproxen and dextromethorphan HBr are added sequentially to the alcohol while stirring.
• the propylene glycol and flavors are added to this alcohol premix and the resulting mixture is stirred until homogeneous and then added to the first container.
• the remaining purified water is added to the resulting mixture and stirred.

Landscapes

• Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Chemical & Material Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Emergency Medicine (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Applications Claiming Priority (2)

Publications (1)

Family

ID=24322297

Family Applications (1)

Country Status (7)

Cited By (9)

Citations (3)

• 1991
  • 1991-09-09 WO PCT/US1991/006399 patent/WO1992004022A1/en unknown
  • 1991-09-09 AU AU85059/91A patent/AU8505991A/en not_active Abandoned
  • 1991-09-10 PT PT98921A patent/PT98921A/pt not_active Application Discontinuation
  • 1991-09-10 IE IE318491A patent/IE913184A1/en unknown
  • 1991-09-10 MA MA22559A patent/MA22278A1/fr unknown
  • 1991-09-11 EG EG54191A patent/EG19841A/xx active
  • 1991-09-11 MX MX9101031A patent/MX9101031A/es unknown

Patent Citations (3)

Also Published As

Similar Documents

Legal Events