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WO1994009767A1 - Novel use of pharmaceutical compositions - Google Patents

Novel use of pharmaceutical compositions Download PDF

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Publication number
WO1994009767A1
WO1994009767A1 PCT/EP1993/003001 EP9303001W WO9409767A1 WO 1994009767 A1 WO1994009767 A1 WO 1994009767A1 EP 9303001 W EP9303001 W EP 9303001W WO 9409767 A1 WO9409767 A1 WO 9409767A1
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WO
WIPO (PCT)
Prior art keywords
compound
formula
use according
composition
group
Prior art date
Application number
PCT/EP1993/003001
Other languages
French (fr)
Inventor
Philip Lea
Original Assignee
Smithkline Beecham Plc
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Filing date
Publication date
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Publication of WO1994009767A1 publication Critical patent/WO1994009767A1/en

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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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • 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
    • A61K31/12—Ketones
    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin

Definitions

  • the present invention relates to the use of napthalene derivatives for the treatment of upper respiratory tract infections, in particular the treatment management or mitigation of cold, cold-like and/or flu symptoms, pharmaceutical compositions and methods of using such compositions.
  • naphthalene derivatives are known to possess useful anti-inflammatory activity and to be suitable for use in the treatment of various rheumatic and arthritic conditions. Such compounds are known as non-steroidal anti- inflammatory drugs (NSAID's).
  • NSAID's non-steroidal anti- inflammatory drugs
  • UK Patent No. 1474377 discloses pharmaceutical compositions which comprise a compound of formula (I):
  • X is a chlorine or bromine atom or a methoxyl, methylthio or alkyl group of 1-4 carbon atoms
  • X is methyloxy or methylthio
  • R j is hydrogen and A is a -CO group.
  • the compound of formula (I) in which X is methyloxy, Y is -CHR1-CH2- where R x is hydrogen and A is -CO (4-(6-methoxy- 2-naphthyl)butan-2-one) is commercially available for the treatment of rheumatic and arthritic conditions. It has the generic name nabumetone.
  • the compounds of formula (I) provide relief from symptoms associated with colds and flu and have utility as cold and/or flu treatments in mammals, including humans.
  • Compounds of formula (I) also have potential benefit for the treatment sinus pain and in allergy, for example, hayfever. Accordingly, the present invention provides for the use of a composition comprising a compound of formula (I) for the manufacture of a medicament for the treatment of symptoms associated with colds and/or flu.
  • X is suitably a methoxyl, methylthio or methyl group. Most suitably X is a methoxyl or methylthio group.
  • Particularly suitable compounds of the formula (I) include those of the formulae (II) and (III):
  • nabumetone (4-(6-methoxy-2-naphthyl)butan-2-one) of the formula (IV):
  • the compound nabumetone has been shown to confer both analgesic and anti ⁇ pyretic properties in mammals which renders it particularly beneficial for use in the treatment of symptoms associated with colds and flu which include both pain and elevated temperature.
  • Peripherally acting compounds i.e. those that act at the site of pain, such as salicylates (eg aspirin) paracetamol, propionic acids (eg ibuprofen, naproxen, fenoprofen, ketoprofen) and indol-pyrrol acetic acids (eg indomethacin) are known to provide effective pain relief. They are also recognised antipyretics. A number of these compounds are constituents of commercially available treatments for the relief of symptoms associated with colds and flu. Certain of these analgesic/antipyretic compounds, especially aspirin and paracetamol have a rapid onset of action, which is of benefit where rapid symtomatic relief is required. Paracetamol is also not a recognised gastric irritant and shows no significant gastrointestinal related irritation. The duration of action of certain of these peripherally acting drugs, eg aspirin and paracetamol, is however relatively short.
  • salicylates eg aspirin
  • propionic acids e
  • Suitable analgesic compounds for combination with a compound of formula (I) include ibuprofen, paracetamol and aspirin.
  • Paracetamol and aspirin are relatively quick acting but of short duration compared to ibuprofen; therefore a paracetamol or aspirin/nabumetone combination which would provide both fast-acting and long lasting relief in colds and/or flu is preferred.
  • compositions of this invention comprising a compound of formula (I) in combination with a peripherally acting analgesic compound.
  • the compositions of this invention may optionally include one or more other known therapeutic agents, particularly those commonly used in cough, cold and/or flu preparations, such as, for example a decongestant (e.g. nasal decongestant), an antitussive, an expectorant or an antihistamine. These would suitably be included in amounts ranging from 1-100 mg, preferably 5-50mg.
  • Suitable nasal decongestants include the sympathomimetic amines, eg. phenylpropanolamine, ephedrine, phenylephrine, pseudoephedrine and their pharmaceutically acceptable salts.
  • Suitable antitussives include dextromethorphan, pholcodine, codeine, noscapine and their pharmaceutically acceptable salts.
  • Suitable expectorants which include mucolytics are guaphenesin, ipecacuanha, ammonium salts, bromhexine hydrochloride and acetylcysteine.
  • Suitable antihistamines include ethanolamines (e.g diphenhydramine and doxylamine), ethylenediamines (e.g. mepyramine), alkylamines (eg chlorpheniramine), piperazines and phenothiazines (e.g. promethazine).
  • ethanolamines e.g diphenhydramine and doxylamine
  • ethylenediamines e.g. mepyramine
  • alkylamines eg chlorpheniramine
  • piperazines and phenothiazines e.g. promethazine
  • a further class of antihistamines are classed as the "non-sedating" type and would typically include astemizole, terfenadine and clemastine.
  • composition comprising a compound of formula(I) in combination with one or more of a peripherally acting analgesic compound, a decongestant, an antitussive, an expectorant or an antihistamine compound.
  • compositions of the present invention are suitably administered in oral dosage forms.
  • oral dosage forms include solid forms such as tablets, powders, effervescent powders, capsules eg soft and hard gelatin capsules with either solid or liquid fill, granules and lozenges.
  • liquid forms such as syrups and suspensions are also suitable for administration.
  • Solid oral dosage forms preferably contain from 5% to 95% (w/w) more preferably from 10% to 95% (w/w) and most preferably 25% to 95% (w/w) of the active components.
  • Liquid oral dosage forms preferably contain from 1% to 50% (w/w) more preferably 1% to 25% (w/w) and most preferably 3% to 10% (w/w) of the active components.
  • each dose could provide 0.1-lOg of a compound of formula (I). More typically 0.5- lg would be given as a single dose per day alone or in combination with other analgesics (typically 200-1000mg) and/or other suggested compounds used for the symptomatic relief of colds and flu.
  • the active components are incorporated into an orally acceptable pharmaceutical carrier using standard techniques used in the art of pharmaceutical formulations.
  • the active components are admixed with a pharmaceutically acceptable carrier.
  • compositions of the invention may be included in compositions of the invention.
  • Optional ingredients include, for example, natural or artificial sweeteners, flavouring agents, colourants and other such ingredients which may for example prolong and enhance shelf life.
  • the above active combinations can be formulated into a number of both solid and liquid oral dosage forms using standard excipients and formulation technology.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Use of a composition comprising a compound of formula (I) for themanufacture of a medicament for the treatment of symptoms associated with colds and/or flu, wherein X is a chlorine or bromine atom or a methoxyl, methylthio or alkyl group of 1-4 carbon atoms; Y is a -CHR1-CH2- or -CR1=CH- group where R1 is a hydrogen atom or a methyl group and A is a -CHOH or -CO group. Compositions comprising a compound of formula (1) in combination with a peripherally acting analgesic compound and optionally a decongestant, antitussive, expectorant or antihistimine compound are also described. The preferred compound of formula (I) is nabumetone.

Description

- i -
Novel Use of Pharmaceutical Composition..
The present invention relates to the use of napthalene derivatives for the treatment of upper respiratory tract infections, in particular the treatment management or mitigation of cold, cold-like and/or flu symptoms, pharmaceutical compositions and methods of using such compositions.
Certain naphthalene derivatives are known to possess useful anti-inflammatory activity and to be suitable for use in the treatment of various rheumatic and arthritic conditions. Such compounds are known as non-steroidal anti- inflammatory drugs (NSAID's).
UK Patent No. 1474377 discloses pharmaceutical compositions which comprise a compound of formula (I):
Figure imgf000003_0001
(I)
wherein X is a chlorine or bromine atom or a methoxyl, methylthio or alkyl group of 1-4 carbon atoms; Y is a -CHRi-CE - or -CRι=CH- group where Rj is a hydrogen atom or a methyl group and A is a -CHOH or -CO group, and a pharmaceutically acceptable carrier.
In compounds of formula (I) suitably X is methyloxy or methylthio, Rj is hydrogen and A is a -CO group. The compound of formula (I) in which X is methyloxy, Y is -CHR1-CH2- where Rx is hydrogen and A is -CO (4-(6-methoxy- 2-naphthyl)butan-2-one) is commercially available for the treatment of rheumatic and arthritic conditions. It has the generic name nabumetone.
We have now found that the compounds of formula (I) provide relief from symptoms associated with colds and flu and have utility as cold and/or flu treatments in mammals, including humans. Compounds of formula (I) also have potential benefit for the treatment sinus pain and in allergy, for example, hayfever. Accordingly, the present invention provides for the use of a composition comprising a compound of formula (I) for the manufacture of a medicament for the treatment of symptoms associated with colds and/or flu.
In compounds of formula (I) for use in the present invention, X is suitably a methoxyl, methylthio or methyl group. Most suitably X is a methoxyl or methylthio group. Particularly suitable compounds of the formula (I) include those of the formulae (II) and (III):
Figure imgf000004_0001
(II)
Figure imgf000004_0002
(HI) wherein Rj and A as defined in relation to formula (I). Most suitably R^ is a hydrogen atom and A is a CO group. Thus a particularly suitable compound of the formula (II) is the compound nabumetone (4-(6-methoxy-2-naphthyl)butan-2-one) of the formula (IV):
Figure imgf000004_0003
(IV)
The compound nabumetone has been shown to confer both analgesic and anti¬ pyretic properties in mammals which renders it particularly beneficial for use in the treatment of symptoms associated with colds and flu which include both pain and elevated temperature.
It will be appreciated that when compounds of formula (I) are administered to mammals, conversion of the active metabolite takes place within the liver and thus the active metabolites of compounds of formula (I) will be included within the scope of this patent.
Compounds of formula (I), when administered to humans are believed to be slow to act, but remain in the blood stream for prolonged periods, and because of this long duration they are particularly effective. An inherent long duration of action is of particular benefit in drug therapy since it obviates the need for frequent dosing or sustained release formulations.
Peripherally acting compounds i.e. those that act at the site of pain, such as salicylates (eg aspirin) paracetamol, propionic acids (eg ibuprofen, naproxen, fenoprofen, ketoprofen) and indol-pyrrol acetic acids (eg indomethacin) are known to provide effective pain relief. They are also recognised antipyretics. A number of these compounds are constituents of commercially available treatments for the relief of symptoms associated with colds and flu. Certain of these analgesic/antipyretic compounds, especially aspirin and paracetamol have a rapid onset of action, which is of benefit where rapid symtomatic relief is required. Paracetamol is also not a recognised gastric irritant and shows no significant gastrointestinal related irritation. The duration of action of certain of these peripherally acting drugs, eg aspirin and paracetamol, is however relatively short.
It would therefore be particularly beneficial if compounds of formula (I) which are effective for long periods were combined with fast acting analgesic compounds, in particular with compounds which have a rapid onset, but a short duration of action.
Suitable analgesic compounds for combination with a compound of formula (I) include ibuprofen, paracetamol and aspirin.
Paracetamol and aspirin are relatively quick acting but of short duration compared to ibuprofen; therefore a paracetamol or aspirin/nabumetone combination which would provide both fast-acting and long lasting relief in colds and/or flu is preferred.
According to a further aspect of the invention, there is provided a composition comprising a compound of formula (I) in combination with a peripherally acting analgesic compound. The compositions of this invention may optionally include one or more other known therapeutic agents, particularly those commonly used in cough, cold and/or flu preparations, such as, for example a decongestant (e.g. nasal decongestant), an antitussive, an expectorant or an antihistamine. These would suitably be included in amounts ranging from 1-100 mg, preferably 5-50mg.
Examples of suitable nasal decongestants include the sympathomimetic amines, eg. phenylpropanolamine, ephedrine, phenylephrine, pseudoephedrine and their pharmaceutically acceptable salts.
Examples of suitable antitussives include dextromethorphan, pholcodine, codeine, noscapine and their pharmaceutically acceptable salts.
Examples of suitable expectorants which include mucolytics are guaphenesin, ipecacuanha, ammonium salts, bromhexine hydrochloride and acetylcysteine.
Examples of suitable antihistamines include ethanolamines (e.g diphenhydramine and doxylamine), ethylenediamines (e.g. mepyramine), alkylamines (eg chlorpheniramine), piperazines and phenothiazines (e.g. promethazine).
A further class of antihistamines are classed as the "non-sedating" type and would typically include astemizole, terfenadine and clemastine.
In a further aspect of the present invention, there is provided a composition comprising a compound of formula(I) in combination with one or more of a peripherally acting analgesic compound, a decongestant, an antitussive, an expectorant or an antihistamine compound.
Compositions of the present invention are suitably administered in oral dosage forms. In particular oral dosage forms include solid forms such as tablets, powders, effervescent powders, capsules eg soft and hard gelatin capsules with either solid or liquid fill, granules and lozenges. liquid forms such as syrups and suspensions are also suitable for administration.
Solid oral dosage forms preferably contain from 5% to 95% (w/w) more preferably from 10% to 95% (w/w) and most preferably 25% to 95% (w/w) of the active components. Liquid oral dosage forms preferably contain from 1% to 50% (w/w) more preferably 1% to 25% (w/w) and most preferably 3% to 10% (w/w) of the active components.
In a typical formulation, each dose could provide 0.1-lOg of a compound of formula (I). More typically 0.5- lg would be given as a single dose per day alone or in combination with other analgesics (typically 200-1000mg) and/or other suggested compounds used for the symptomatic relief of colds and flu.
In preparing liquid oral dosage forms the active components are incorporated into an orally acceptable pharmaceutical carrier using standard techniques used in the art of pharmaceutical formulations.
In preparing solid oral dosage forms the active components are admixed with a pharmaceutically acceptable carrier.
Other optional ingredients well known in the art of pharmaceutical formulation may be included in compositions of the invention.
Optional ingredients include, for example, natural or artificial sweeteners, flavouring agents, colourants and other such ingredients which may for example prolong and enhance shelf life.
It is a further object of the present invention to provide a method of treating symptoms associated with coughs colds and/or flu in a mammal in need thereof comprising administering a symptom-relieving, effective amount of a composition comprising a compound of formula(I) or a compound of formula(I) in combination with one or more of a peripherally acting analgesic compound, a decongestant, an antitussive, an expectorant or an antihistamine compound.
The following examples illustrate compositions of the invention:
Formulation 1 mg/dose
Nabumetone lg
Paracetamol lg or Aspirin 650mg
Formulation 2 mg/dose
Figure imgf000008_0001
The above active combinations can be formulated into a number of both solid and liquid oral dosage forms using standard excipients and formulation technology.

Claims

Claims
1. Use of a composition comprising a compound of formula (I) for the manufacture of a medicament for the treatment of symptoms associated with colds and/or flu
Figure imgf000009_0001
(I) wherein X is a chlorine or bromine atom or a methoxyl, methylthio or alkyl group of 1-4 carbon atoms; Y is a -CHRi-CB - or -CRι=CH- group where Ri is a hydrogen atom or a methyl group and A is a -CHOH or -CO group.
2. Use according to claim 1, wherein the compound of formula (I) is nabumetone.
3. Use according to claim 2, wherein the composition comprises a compound of formula (I) in combination with a peripherally acting analgesic compound.
4. Use according to claim 3, wherein the analgesic compound is a salicylate, propionic acid, or paracetamol, or an indol-pyrrol acetic acid.
5. Use according to claim 4, wherein the analgesic compound is aspirin, ibuprofen or paracetamol.
6. Use according to any one of the above claims, additionally comprising a decongestant, antitussive, expectorant or antihistamine.
7. Use according to claim 6, wherein the composition is in solid or liquid oral dosage form.
8. A pharmaceutical composition comprising a compound of formula (I), as defined above or a compound of formula (I) in combination with one or more of a peripherally acting analgesic compound, a decongestant, an antitussive, an expectorant or an antihistamine compound and a pharmaceutically acceptable carrier.
9. A pharmaceutical composition for use in the treatment of symptoms associated with colds and/or flu, which comprises a compound of formula
(I), as defined above and a pharmaceutically acceptable carrier.
10. A method of treating symptoms associated with coughs colds and/or flu in a mammal in need thereof comprising administering a symptom- relieving, effective amount of a composition comprising a compound of formula (I), as defined above or a compound of formula (I) in combination with one or more of a peripherally acting analgesic compound, a decongestant, an antitussive, an expectorant or an antihistamine compound.
PCT/EP1993/003001 1992-10-31 1993-10-25 Novel use of pharmaceutical compositions WO1994009767A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB929222849A GB9222849D0 (en) 1992-10-31 1992-10-31 Novel use of pharmaceutical compositions
GB9222849.3 1992-10-31

Publications (1)

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WO1994009767A1 true WO1994009767A1 (en) 1994-05-11

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997004808A1 (en) * 1995-07-28 1997-02-13 The Procter & Gamble Company Compositions containing analgesics and antihistamines and methods for treating respiratory disorders

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1474377A (en) * 1973-09-11 1977-05-25 Beecham Group Ltd Naphthalene derivatives

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1474377A (en) * 1973-09-11 1977-05-25 Beecham Group Ltd Naphthalene derivatives

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
D. ANDJELKOVIC ET AL.: "The influence of nabumetone and naproxen on the contraction of guinea-pig bronchial muscle.", EUR. J. PHARMACOL., vol. 183, no. 6, 1990, pages 2404 *
E.A. BOYLE ET AL: "Nabumetone(BRL 14777, 4-[6-methoxy-2-naphthyl]-butan-2-one) a new anti-inflammatory agent", J. PHARM. PHARMACOL., vol. 34, no. 9, 1982, pages 562 - 569 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997004808A1 (en) * 1995-07-28 1997-02-13 The Procter & Gamble Company Compositions containing analgesics and antihistamines and methods for treating respiratory disorders

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