WO1992004021A1

WO1992004021A1 - Method for providing improved analgesic effect

Info

Publication number: WO1992004021A1
Application number: PCT/US1991/006398
Authority: WO
Inventors: James Vincent Sorrentino
Original assignee: Richardson Vicks Inc.
Priority date: 1990-09-11
Filing date: 1991-09-09
Publication date: 1992-03-19
Also published as: CA2090234C; IE913185A1; CA2090234A1; MA22277A1; KR930701994A; AU662297B2; AU8538491A; MX9101045A; PT98919A; JPH06500784A

Abstract

A method for providing improved analgesic and/or anti-inflammatory effect by administering a safe and effective amount of a composition comprising a naphthalene derivative along with a sympathomimetic amine.

Description

METHOD FOR PROVIDING IMPROVED ANALGESIC EFFECT

TECHNICAL FIELD

The present invention relates to a method for providing improved analgesic and/or anti-inflammatory effect by administering a safe and effective amount of a composition comprising a naphthalene derivative aiong with a sympathomimetic amine.

BACKGROUND OF THE INVENTION

Inflammation, or the "inflammatory response", is the result of complex interconnected physiological events, including increased vascular permeability, fluid accumulations, and the migration of a cnanging population of inflammatory cells into the inflamed area. The clinical manifestations of inflammation include swelling (edema), increased local temperature, erythema, and pain. The inflammatory response can be triggered by any of a numcer of causative factors, including certain bacteria, radiation, hypersensitivity to chemical agents, arthritis-like conditions, and the like. The inflammatory response is generally believed to be a primary defense mechanism in the body, but, unchecked, can become excessive and can result in functional impairment.

The use of non-steroidal anti-inflammatory, anti-pyretic and analgesic drugs, especially the salicylates, which include aspirin and aspirin derivatives, 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, and the like.

While pain is incapable of precise definition due to its basically subjective nature, it can generally be said that the term refers to feelings of distress or suffering caused by stimulation of specialized nerve endings. A great variety of drugs have been developed to reduce pain in man and other animals; some directed to eliminating pain at its source, and others directed to blocking the perception of pain by the brain. Among the latter group of drugs that are designed to block the sensation of pain, are the analgesics, which generally relieve pain without causing unconsciousness. Analgesics can be further classified into two main categories: opioid analgesics, including morphine, codeine, levorphanol, and the morphine-like analgesics merperidine, and methadone; and antipyretic analgesics, such as aspirin, ibuprofen, phenacetin, acetaminophen, phenylbutazone, and indomethacin.

Although the precise pharmacological action of these analgesics is uncertain, there are certain effects which readily distinguish the opioid analgesics from the antipyretics. In particular, the antipyretics are weak analgesics, with much of their effect in the peripheral nervous system, so that behavioral changes do not usually occur. Generally, these analgesics relieve only pain originating from muscles, joints, tendons and fasciae, and are ineffective against deep visceral pain. However, the opioid analgesics are quite effective against all types of pain, with broad-based action in the central nervous system. Aside from potent analgesia, the opioids, also known as narcotics, often produce effects on mood and other behavioral changes. Perhaps the most notable side effect of opioid analgesics is the fact that their repeated use is associated with tolerance, as well as psychic and physical dependence.

Naproxen ((+)-2-(6α-methoxy-naphthyl) propionic acid), a nonsteroidal 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.

The use of naproxen, as well as other of the newer non-steroidal anti-inflammatory agents (i.e., excluding aspirin, acetaminophen and phenacetin) in the preparation of cough/cold pharmaceutical compositions containing sympathomimetic amines, has been disclosed in, for example, U.S. Patent 4,552,899 to Sunshine et al. issued November 12, 1985.

Surprisingly, the present inventor has found that selected compositions comprising certain naphthalene derivatives in combination with sympathomimetic amines provide improved analgesic and/or anti- inflammatory effect. SUMMARY OF THE INVENTION

The present invention relates to a method of eliciting a sustained, enhanced analgesic response in a human or lower animal in need of such treatment, comprising administering to such human or lower animal a safe and effective amount of a composition comprising:

a) from about 10% to about 95% of a carboxylic acid represented by the following formula:

R¹ is alkyl having up to 6 carbon atoms, cycloalkyl having from 3 to 7 carbon atoms, alkoxymethyl having up to 7 carbon atoms, trifluoromethyl, vinyl, ethynyl, halo (iodo, bromo, chloro or fluoro) alkoxy having up to 6 carbon atoms, difluoromethoxy, alkoxymethoxy having up to 7 carbon atoms, alkylthiomethyloxy having up to 7 carbon atoms, alkylthio having up to 6 carbon atoms, alkoxymethylthio having up to 7 carbon atoms, cyano difluoromethylthio, phenyl or alkyl substituted phenyl having up to 8 carbon atoms; one of R² and R³ is hydrogen, the other being methyl, ethyl or difluoromethyl or R² or R³ together are methylene; and R⁴ 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; and b) from about 5% to about 90% of one or more of a sympathomimetic amine.

All percentages and ratios used herein are by weight unless otherwise indicated. DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a method of eliciting a sustained, enhanced analgesic response in a human or lower animal in need of such treatment, comprising administering to such human or lower animal a safe and effective amount of a composition comprising a naphthalene derivative, preferably a 2-(5'-substituted-2'-naphthyl)-acetic acid derivative, and salts and esters thereof along with a sympathomimetic amine.

The naphthalene derivatives 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:

In the above formula,

R¹ is alkyl having up to 6 carbon atoms, cycloalkyl having from 3 to 7 carbon atoms, alkoxymethyl having up to 7 carbon atoms, trifluoromethyl, vinyl, ethynyl, halo (iodo, bromo, chloro or fluoro) alkoxy having up to 6 carbon atoms, difluoromethoxy, alkoxymethoxy having up to 7 carbon atoms, alkylthiomethyloxy having up to 7 carbon atoms, alkylthio having up to 6 carbon atoms, alkoxymethyl thio having up to 7 carbon atoms, cyano difluoromethylthio, phenyl or alkylsubstituted phenyl having up to 8 carbon atoms;

one of R² and R³ is hydrogen, the other being methyl, ethyl or difluoromethyl or R² or R³ together are methyl ene;

R⁴ 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-cycloalkyl ethyl having from 5 to 10 carbon atoms, 3-cyclopentyl ethyl having from 5 to 10 carbon atoms, 3-cyclopentylpropyl, 3-cyclohexylpropyl, benzyl, 2-phenylethyl or 3-phenylpropyl. Preferably, the 6'-substituent (represented by R¹ 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 R² and R³ is hydrogen and the other is methyl; and R⁴ is hydrogen, methyl, ethyl, propyl, isopropyl, butyl, pentyl, isopentyl, hexyl, 2-hexyl, isohexyl, heptyl, isoheptyl, octyl, isooctyl, nonyl, isononyl, decyl, isodecyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, cyclopentyl or cyclohexyl.

The term "alkyl" refers to and includes branched and 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. The term "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.

The term "cycloalkyl" refers to cyclo hydrocarbon groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

The term "alkoxy" refers to straight or branched chain alkyl ether groups such as methoxy, ethoxy, 2-propoxy, butoxy, 3-pentoxy and the like.

The term "alkoxymethyloxy" refers to methyl ether groups substituted with one alkoxy group (defined above) such as methoxymethyloxy, ethoxymethloxy, isopropoxymethyloxy and the like.

The term "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.

The term "alkylthiomethyloxy" refers to methyl ether groups substituted with an alkylthio group (defined above) such as methylthiomethyloxy, 2-propylthiomethyloxy, pentylthiomethloxy and the like.

The term "alkylthiomethylthio" as used herein denoted methylthio ether groups substituted with an alkylthio group such as methylthiomethylthio, ethylthiomethylthio and the like. The term "alkoxymethylthio" refers to methylthio ether groups substituted with an alkoxy group such as methoxymethylthio, ethoxymethylthio, 2-propoxymethylthio and the like.

The term "aryl" refers to phenyl, or o-, m- and/or p- alkylsubstituted phenyl derivatives such as phenyl, o-tolyl, m-tolyl, p-tolyl, o-ethyl phenyl, m-ethylphenyl, p-ethylphenyl, xylyl and the like.

The term "cycloalkylmethyl" refers to cycloalkyl substituted methyl groups such as cyclopropylmethyl, cyclobutylmethy, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, and the like. The term "2-cycloalkylethyl" refers to an ethyl group substituted at the 2-position with a cycloalkyl group such as 2-cyclopropylethyl, 2-cyclobutylethyl, 2-cyclopentylethyl, 2-cyclohexylethyl and 2-cycloheptylethyl.

The most preferred compound used herein is (+)-2-(6α-methoxy- 2-napthyl) propionic acid, and salts and esters thereof.

The term "pharmaceutically acceptable 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 ami nes , substituted ami nes i ncluding natural ly occurri ng substi tuted amines, cyclic amines and basic ion exchange resins, such as triethylamine, tripropyl amine, 2-dimethylaminoethanol, 2-diethylamino- ethanol, lysine, arginine, histidine, caffeine, procaine, N-ethylpip- eridine, hydrabamine, choline, betaine, ethyl enedi amine, glucosamine, methylglycamine, theobromine, purines, piperazine, piperidine, poly- amine resins and the like.

When one of R² and R³ is hydrogen and the other is methyl or difluoromethyl, 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.

The optical isomers can be resolved by conventional means, such as selective biological degradation or by the preparation of dias- tereo-isomeric salts of the naphthalene derivative with an optically active amine base such as cinchonidine and separating the diastereoisomers by fractional crystallization. The separated diastereoisomeric salts are then acid cleaved to yield the respective optical isomer.

These compounds are fully disclosed in U.S. Patent 3,904,682 to Fried et al. issued September 9, 1975 and in U.S. Patent 3,998,966 to Fried et al. issued December 21, 1976, both incorporated by reference herein, as having anti-inflammatory, analgesic and anti-pyretic activities and as being useful in the treatment and elimination of inflammation, such as rheumatism, concussion, laceration, arthritis, bone fractures, post-traumatic conditions, and gout.

Sympathomimetic amines are a well-known class of drugs which activate adrenergic receptors. These drugs are fully described in Respiratory Pharmacology and Therapeutics, Ziment, W.B., Saunders & Company (1978), pp. 316-339, which is incorporated by reference herein. Drugs that are particularly preferred for use herein are those which are known to stimulate the alpha adrenergic receptors. The sympathomimetic amines useful herein include pseudoephedrine, phenylpropanolamine, phenylephrine and ephedrine, their pharmaceutically acceptable salts, and mixtures thereof.

Preferably, the pharmaceutical compositions of the present invention comprise the naphthalene derivative and sympathomimetic amine in a ratio of naphthalene derivative:sympathomimetic amine of from about 200:1 to about 1:1, preferably from about 50:1 to about 1:1 and most preferably from about 10:1 to about 1:1.

Various oral dosage forms can be used, including such solid forms as tablets, gelcaps 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, tablet triturates, enteric-coated, sugar-coated, film-coated or multiple compressed, containing suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, preservatives and flow-inducing agents.

Liquid oral dosage forms include aqueous and nonaqueous solutions, 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. Specific examples of pharmaceutically acceptable carriers and excipients that may be used to formulate oral dosage forms, are described in U.S. Patent 3,903,297, Robert, issued September 2, 1975, incorporated by reference herein. Techniques and compositions for making solid oral dosage forms are described in Marshall, "Solid Oral Dosage Forms," Modern Pharmaceutics, Vol. 7, (Banker and Rhodes, editors), 359-427 (1979), incorporated by reference herein. Techniques and compositions for making tablets (compressed and molded), capsules (hard and soft gelatin) and pills are described in Remington's Pharmaceutical Sciences (Arthur Osol, editor), 1553-1593 (1980), incorporated herein by reference.

In preparing the liquid oral dosage forms, the active component is incorporated into an aqueous-based orally acceptable pharmaceutical carrier consistent with conventional pharmaceutical practices. An "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 microcrystalline 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. While the amount of water in the compositions of this invention can vary over quite a wide range depending upon the total weight and volume of the active component and other optional non-active ingredients, 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.

Although water itself may make up the entire carrier, typical liquid formulations preferably contain a co-solvent, for example, propylene glycol, glycerin, sorbitol solution and the like, to assist solubilization and incorporation of water-insoluble ingredients, such as flavoring oils and the like into the composition. In general, therefore, the 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.

The 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 cough suppressant 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, ammonium chloride, N-acetylcysteine and bromhexine, ambroxol, their pharmaceutically acceptable salts; and an antihistamine such as chlorpheniramine brompheniramine, dexchlorpheniramine, dexbrompheniramine, triprolidine, doxylamine, tripelennamine, cyproheptadine, carbinoxamine, bromodiphenhydramine, phenindamine, pyrilamine, azatadine, their pharmaceutically acceptable salts, as well as the non-sedating antihistamines which include acrivastine, AHR-11325, phenindamine, astemizole, azelastine, cetirizine, ebastine, ketotifen, lodoxamide, loratidine, levocabastine, mequitazine, oxatomide, setastine, tazifylline, temelastine, and terfenadine, their pharmaceutically acceptable salts: all of these components, as well as their acceptable dosage ranges are described in the following: U.S. 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, which are incorporated by reference herein. Also useful are bronchodilators such as theophylline and albuterol. A highly preferred optional component is caffeine, which is preferably present at a level of from about 10% to about 50%.

Other optional ingredients well known to the pharmacist's art may also be included in amounts generally known for these ingredients, for example, 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.

METHOD OF TREATMENT

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, expectorant and/or antihistamine required per dose, stability, release characteristics and other pharmaceutical parameters.

Usually from about 1 mg/kg to about 50 mg/kg per day, preferably from about 2 mg/kg to about 30 mg/kg per day and most preferably from about 3 mg/kg per day to about 20 mg/kg per day of the pharmaceutical composition is administered as described herein. This amount can be given in a single dose, or, preferably, in multiple (two to six) doses repeatedly or sustained release dosages over ^fehe course of treatment. Generally, 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 ba taken, as with any drug, in some individuals to prevent adverse side effects.

The fol l owing exampl es i l l ustrate embodiments of the subject invention wherei n both essenti al and optional ingredients are combined . EXAMPLE I

A soft gelatin capsule composition for oral administration is prepared by combining the following ingredients:

Ingredient Amount

Naproxen 200 mg

Pseudoephedrine HCl 30 mg

Triturate active ingredients and q.s. with lactose to selected capsule size.

Administration of two of the above capsules to a human in need of treatment provides improved analgesic and/or anti-inflammatory effect.

EXAMPLE II

Ingredient Amount

Naproxen 200 mg

Astemizole 10 mg

Pseudoephedrine HCL 30 mg

Glyceryl guaiacolate 100 mg

Triturate active ingredients and q.s. with lactose to selected capsule size.

EXAMPLE III

A liquid composition for oral administration is prepared by combining the following ingredients:

Ingredient % W/V

Naproxen 6.667

Pseudoephedrine HCl 0.200

Alcohol (95%) 25.000

Propylene Glycol 25.000

Sodium Citrate 2.000

Citric Acid 0.250

Liquid Sugar 70.000

Glycerin 7.000

Colorants 0.008

Flavor 0.500

Water, Purified QS 100.000 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 HCI are added sequentially and dissolved with agitation. The glycerin and liquid sugar are then added. In a seperate container the colorance are added to purified water (approximately 0.5% of the final batch volume). This colorance solution is then added to the first batch container. In a seperate 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.

Administration of 30 ml to a human in need of treatment provides improved analgesic and/or anti-inflammatory effect.

EXAMPLE IV

Ingredient % W/V

Naproxen 6.667

Pseudoephedrine HCI 0.200

Chlorpheniramine Maleate 0.013

Alcohol (95%) 25.000

Propylene Glycol 25.000

Sodium Citrate 2.000

Citric Acid 0.250

Liquid Sugar 70.000

Glycerin 7.000

Colorants 0.008

Flavor 0.500

Water, Purified QS 100.000

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 HCI and chlorpheniramine maleate are added sequentially and dissolved with agitation. The glycerin and liquid sugar are then added. In a seperate container the colorance are added to purified water (approximately 0.5% of the final batch volume). This colorance solution is then added to the first batch container. In a seperate 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.

Administration of 30 ml to a human in need of treatment provides improved analgesic and/or anti-inflammatory effect. EXAMPLE V

Ingredient % W/V

Naproxen 6.667

Pseudoephedrine HCI 0.200

Chlorpheniramine Maleate 0.013

Dextromethorphan HBr 0.100

Alcohol (95%) 25.000

Propylene Glycol 25.000

Sodium Citrate 2.000

Citric Acid 0.250

Liquid Sugar 70.000

Glycerin 7.000

Colorants 0.008

Flavor 0.500

Water, Purified QS 100.000

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 HCI and chlorpheniramine maleate are added sequentially and dissolved with agitation. The glycerin and liquid sugar are then added. In a seperate container the colorance are added to purified water (approximately 0.5% of the final batch volume). This colorance solution is then added to the first batch container. In a seperate 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.

WHAT IS CLAIMED IS:

Claims

Cl aims

1. The use of a composition comprising:

a) from 10% to 95% of a carboxylic acid represented by the following formula:

R¹ is alkyl having up to 6 carbon atoms, cycloalkyl having from 3 to 7 carbon atoms, alkoxymethyl 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, alkylthiomethyloxy having up to 7 carbon atoms, alkylthio having up to 6 carbon atoms, alkoxymethyl thio having up to 7 carbon atoms, cyano difluoromethylthio, phenyl or alkyl substituted phenyl having up to 8 carbon atoms; one of R² and R³ is hydrogen, the other being methyl, ethyl or difluoromethyl or R² or R³ together are methylene; and R⁴ 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-cycl oalkyl ethyl 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; and b) from 5% to 90% of one or more of a sympathomimetic amine; for producing a medicament for eliciting a sustained, enhanced analgesic response in a human or lower animal in need of such treatment.

2. A medicant for eliciting a sustained, enhanced analgesic response in a human or lower animal in need of such treatment comprising: a) from 10% to 95% of a carboxylic acid represented by the following formula:

R¹ is alkyl having up to 6 carbon atoms, cycloalkyl having from 3 to 7 carbon atoms, alkoxymethyl having up to 7 carbon atoms, trifluoromethyl, vinyl, ethynyl. halo (iodo, bromo. chloro or fluoro) alkoxy having up to 5 carbon atoms, difluoromethoxy. al koxymethoxy having up to 7 caroon atoms, alkylthiomethyloxy having up to 7 carbon atoms, alkylthio having up to 5 carbon atoms, alkoxymethylthio having up to 7 carbon atoms, cyano difluoromethylthio, phenyl or alkylsubstituted phenyl having up to 8 carbon atoms; one of R² and R³ is hydrogen, the other being methyl, ethyl or difluoromethyl or R² or R³ together are methylene; and R⁴ 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: and b) from 5% to 90% of one or more of a sympathomimetic amine.

3. The medicament of Claim 1 or 2 wherein said acetic acid derivative is 2-(6α-methoxy-2-napthyl) propionic acid and pharmaceutically-acceptable salts and esters thereof and is administered at a level of from 100 mg to 2000 mg., preferably from 50 mg to 2000 mg.

4. The medicament of Claim 3 wherein saiα sympathomimetic amine is selected from the group consisting of pseudoephedrine, phenylpro panolamine. pnenyleohrine and eohedrine. mixtures thereof or pharmaceutically acceptable salts thereof.

5. The medicament of Claim 4 wherein the ratio of naphthalene derivative to sympathomimeti c amine ranges from 200:1 to 1:1.

6. The medicament of Claim 5 wherein said pharmaceutical medicament further comprises at least one other active component selected from the group consisting of an antihistamine, cough suppressant and expectorant and mixtures thereof.

7. The medicament of Claim 6 wherein said active component is an cough suppressant, preferably said cough suppressant is selected from the group consisting of dextromethorphan, chlophedianol. caroetapentane. caramiphen. noscaoine, diohenhydramine. codeine. hydrocodone. nydromorphone, fominoben. mixtures thereof or pharmaceutically acceptable salts thereof.

8. The medicament of Claim 6 wherein said active component is a antihistamine, preferably said antihistamine is selected from the group consisting of chlorpheniramine brompheniramine, dexchlorpheniramine, dexbromphreniramine. triprolidine. doxylamine, tripelennamine, cyproheptadine, carbinoxamine. bromodiphenhydramine. phenindamine, pyrilamine. azatadine. acrivastine, AHR-11325, phenindamine, astemizole. azatadine. azelastine, cetirizine. eoastine, ketotifen. lodoxamide. loratidine, levocabastine, mequitazine. oxatomide. setastine. tazifylline. temelastine, and terfenadine. mixtures thereof or pharmaceutically acceptable salts thereof.

9. The medicament of Claim 5 wherein said active component is an expectorant, preferably said expectorant is an expectorant or mucolytic such as glyceryl guaiacolate. terpin. ammonium chloride. N-acetylcysteine and promhexine, ambroxol. mixtures thereof or pharmaceutically acceptable salts thereof.

10. The medicament of any of the preceding Claims which further comprises from 50 to 100 mg of caffeine.

11. A method of eliciting a sustained, ennanced analgesic response in a numan or lower animal in need of such treatment. comprising administering to such numan or lower animal a safe and effective amount of a composition comprising:

a) from apout 10% to about 95% of a carboxylic acid represented by the following formula:

R¹ is alkyl naving up to 6 carbon atoms, cycloalkyl naving from 3 to 7 carbon atoms, alkoxymethyl naving up to carbon atoms, trifluoromethyl. vinyl, etnynyl. nalo (iodo. bromo. chloro or fluoro) alkoxy naving up to 5 carbon atoms, difluoromethoxy, alkoxymethoxy naving up to 7 carbon atoms, alkylthiomethyloxy naving up to 7 carbon atoms, alkylthio having up to 6 carbon atoms, alkoxymethylthio naving up to 7 carbon atoms, cyano difluoromethylthio, phenyl or alkylsubstituted phenyl having up to 8 carbon atoms; one of R² and R³ is hydrogen, the other being methyl, ethyl or difluoromethyl or R² or R³ together are methylene; and R⁴ is nydrogen. alkyl naving up to 22 carbon atoms, unsaturated alkyl naving up to 22 carbon atoms, cycloalkyl naving from 3 to carbon atoms, cycloalkylmethyl naving from 2 to carbon atoms, cycloalkylmethyl naving from 4 to 9 carbon atoms. 2-cycloalkylethyl naving from 5 to 10 carbon atoms. 3-cyclopentylethyl having from 5 to 10 carbon atoms. 3-cyclopentylpropyl. 3-cyclohexylpropyl. benzyl, 2-pnenylethyl or 3-phenylpropyl: and b) from apout 5% to aoout 90% of one or more of a sympathomimetic amine.

12. A method according to .Claim llwnerein said acetic acid derivative is 2-(6α-methoxy-2-napthyl) propionic acid and pnarmaceuticallyacceptable salts and esters thereof.

13. A method according to Claim 12 which comprises administering from about 100 mg to about 2000 mg of said 2-(6β-methoxy-2-naphthyl) propionic acid.

14. A method according to Claim 13 wherein said sympathomimetic amine is selected from the group consisting of pseudoephedrine, phenyl-propanol amine, phenylephrine and ephedrine, mixtures thereof or pharmaceutically acceptable salts thereof.

15. A method according to Claim 14 wherein the ratio of naphthalene derivative to sympathomimetic amine ranges from about 200:1 to about 1:1.

16. A method according to Claim 15 which comprises from about 50 mg to about 2000 mg of said pharmaceutical composition.

17. A method according to Claim 16 which comprises from about 100 mg to about 2000 mg of said pharmaceutical composition.

18. A method according to Claim 15 wherein said pharmaceutical composition further comprises at least one other active component selected from the group consisting of an antihistamine. cough suppressant and expectorant and mixtures thereof.

19. A method according to Claim 18 wherein said active component is a cough suppressant.

20. A method according to Claim 18 wherein said active component is an antihistamine.

21. A method according to Claim 18 wherein said active component is an expectorant

22. A method according to Claim 19 wherein said cough suppressant is selected from the group consisting of dextromethorphan. chlophedianol. carbetapentane, caramiphen, noscapine. diphenhydramine, codeine, hydrocodone, hydromorphone, fominoben, mixtures thereof or pharmaceutically acceptable salts thereof.

23. A method according to Claim 20 wherein said antihistamine is selected from the group consisting of chlorpheniramine brompheniramine, dexchlorpheniramine, dexbromphreniramine, triprolidine, doxylamine, tripelennamine, cyproheptadine, carbinoxamine, bromidiphenhydramine, phenindamine, pyrilamine, azatadine, acrivastine, AHR-11325, phenindamine, astemizole, azatadine, azelastine, cetirizine, ebastine, ketotifen, lodoxamide, loratidine, levocabastine, mequitazine, oxatomide, setastine, tazifylline, temelastine, and terfenadine, mixtures thereof or pharmaceutically acceptable salts thereof.

24. A method according to Claim 21 wherein said expectorant is an expectorant or mucolytic such as glyceryl guaiacolate, terpin, ammonium chloride, N-acetylcysteine and bromhexine, ambroxol, mixtures thereof or pharmaceutically acceptable salts thereof.

25. A method according to Claim 12 which further comprises from about 50 to about 100 mg of caffeine.

26. A method according to Claim 23 which further comprises from about 50 to about 100 mg of caffeine.

27. A method according to Claim 14 which further comprises from about 50 to about 100 mg of caffeine.