WO2007087215A2 - N-acetyl-cysteine and its derivatives as an antitussive - Google Patents

N-acetyl-cysteine and its derivatives as an antitussive Download PDF

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Publication number
WO2007087215A2
WO2007087215A2 PCT/US2007/001278 US2007001278W WO2007087215A2 WO 2007087215 A2 WO2007087215 A2 WO 2007087215A2 US 2007001278 W US2007001278 W US 2007001278W WO 2007087215 A2 WO2007087215 A2 WO 2007087215A2
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zinc
alkyl
compound
antitussive
composition
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PCT/US2007/001278
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French (fr)
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WO2007087215A3 (en
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Roger Berlin
Alexandra Kropotova
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Wyeth
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    • 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
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/14—Antitussive agents

Definitions

  • the present invention relates to the prevention and/or treatment of respiratory conditions. Specifically, the invention relates to the novel use of N-acetyl-cysteine and its derivatives as an antitussive for administration to mammals.
  • N-acetyl-L-cysteine a preferred active ingredient in the method claimed in the present invention, has been used as a component in topical cosmetic compositions, a mucolytic, a corneal vulnerary and an antidote to acetaminophen poisoning (The Merck Index, (1989) 11th Edition, p.14).
  • European Patent Application 219 455, issued to Fabbro, published Apr. 22, 1987 discloses a dermatological and skin cosmetic, topical, pharmaceutical composition containing N-acetyl-L-cysteine as the active constituent. The composition is disclosed as being useful for the prevention and treatment of sunburn and for increasing the speed of skin pigmentation bronzing.
  • U.S. Patent No. 3,184,505 issued to Martin et al. on May 18, 1965, discloses a process for the production of N-acetyl-cysteine and its use as a mucolytic agent.
  • Dextromethorphan is a well-known non-opioid antitussive agent which is employed in a number of cough/cold remedies which are presently commercially available. While it is recognized as both safe and effective when used as directed, episodic and sporadic abuse has been reported due to its hallucinogenic properties when ingested in excess. The primary psychological symptoms of dextromethorphan abuse have been identified as euphoria, increased perceptual awareness, altered time perception, feelings of floating, tactile hallucinations, visual hallucinations, auditory hallucinations, visual disturbances, paranoia, and disorientation (see Archives of Family Medicine. Vol. 8, No. 2, March 1999). Objects of the Present Invention
  • the present invention relates to a method of suppressing coughing in a mammal through the administration of a safe and effective amount of n-acetyl-cysteine and/or a derivative thereof to such mammal.
  • alkyl means an unsubstituted carbon-containing chain which may be straight, branched or cyclic, preferably straight or branched, more preferably straight; saturated, monounsaturated (i.e., one double or triple bond in the chain), or polyunsaturated (i.e., two or more double bonds in the chain; two or more triple bonds in the chain; one or more double and one or more triple bonds in the chain), preferably saturated.
  • pharmaceutically-acceptable means that drugs, medicaments or inert ingredients which the term describes are suitable for ingestion by humans and other mammals without undue toxicity, incompatibility, instability, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio.
  • safe and effective amount means an amount of compound or composition sufficient to significantly induce a positive modification in the condition to be treated, but low enough to avoid serious side effects (at a reasonable benefit/risk ratio), within the scope of sound medical judgment.
  • the safe and effective amount of the compound or composition will vary with the particular condition being treated, the age and physical condition of the patient being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, the specific compound or composition employed, the particular pharmaceutically-acceptable carrier utilized, and like factors within the knowledge and expertise of the attending physician.
  • the present invention relates to a method of suppressing coughing in a mammal through the administration of a safe and effective amount of an active compound.
  • active compound means a compound having the structure below or a pharmaceutically-acceptable salt thereof.
  • R 1 is selected from the group consisting of 0 and a C 1 -C 18 alkyl, preferably C 1 -C 7 , more preferably C 1 -C 3 , more preferably still C 1 alkyl.
  • R 2 is selected from the group consisting of 0, -H, C 1 -C 18 ,
  • R 2 is preferably a C 1 -C 18 alkyl, more preferably C 1 -C 7 , more preferably C 1 -C 3 , more preferably still C 1 .
  • R 3 is selected from the group consisting of -H 1 and C 1 -C 18 alkyl, preferably -H.
  • R 3 is preferably a CrCi 8 alkyl, more preferably C 1 -C 7 , more preferably C 1 -C 3 , more preferably still C 1 .
  • R 4 is a C 1 -C 18 alkyl; preferably C 1 -C 7 ; more preferably C 1 -C 3 ; more preferably still C 1 .
  • both R 1 and R 2 are 0 and the carbonyl carbon and the sulfur adjacent R 1 and R 2 , respectively, are covalently bonded to form a cyclic ring. Otherwise, both R 1 and R 2 are other than 0.
  • Preferred pharmaceutically-acceptable salts of the active compound include, but are not limited to, sodium, potassium, magnesium, calcium, lithium, rubidium, strontium, aluminum, boron, silicon and zinc salts of the active compound.
  • the present invention relates to a method of suppressing coughing in a mammal through the administration of a safe and effective amount of an active compound having the structure
  • compositions of the present invention should provide a patient with a dose of the active ingredient ranging from about 0.01 g. to about 12 g. per day.
  • a dose of the active ingredient ranging from about 0.01 g. to about 12 g. per day.
  • such dose should range from about 0.1 g. to about 6 g. on the same basis. More preferably, such dose should range from about 0.2 g. to about 4 g. on the same basis.
  • Most preferably, such dose should be about 1.0 g per day. Dosing should preferably be accomplished every 4-8 hours, preferably every 6 hours.
  • zinc salts are included within the claimed compositions.
  • the presence of zinc salts offers at least two benefits.
  • Zinc salts are also known to reduce the odor that may be associated with N-acetyl-cysteine and its derivatives.
  • U.S. Patent No. 5,296,500 issued March 22, 1994 to Hillebrand, zinc complexes with malodorous H 2 S which may be formed as trace amounts as the active compound decomposes. The action of zinc renders the compositions of the present invention substantially odorless.
  • the zinc salt is selected from the group consisting of zinc oxide, zinc chloride, zinc acetate, zinc stearate, zinc ascorbate, zinc citrate, zinc picolinate, zinc transferrin, zinc aspartate, zinc glycinate, zinc alaninate, zinc lysinate, zinc leucinate, zinc valinate, zinc oleate and sulfate; more preferably zinc oxide, zinc ascorbate, zinc gluconate and zinc chloride.
  • compositions within this embodiment of the present invention preferably comprise from about 0.001 % to about 10% of a zinc salt, more preferably from about 0.01% to about 5%, more preferably still from about 0.01% to about 0.5%.
  • treatment will employ the use of a pharmaceutical composition
  • a pharmaceutical composition comprising the active compound and a pharmaceutically-acceptable carrier.
  • pharmaceutically-acceptable carrier means one or more compatible solid or liquid filler diluents or microencapsulating substances which are suitable for administration to a human or other mammal.
  • Pharmaceutically- acceptable carriers must be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the human or other mammal being treated.
  • a safe and effective amount of carrier is from about 50% to about 99.99%, preferably from about 99.9% to about 80%, more preferably from about 98% to about 95%, of the composition.
  • compositions of the present invention may be made into a wide variety of product types, including solid and liquid dosage forms. These dosage forms include, but are not limited to tablets, caplets, liquid-filled soft capsules, suppositories, solutions and syrups. Conventional carriers and excipients may be used in the practice of the invention to produce the pharmaceutical compositions claimed herein.
  • compositions of the present invention may employ liquid carrier vehicles such as those disclosed in U.S. Patent No. 5,563,177, issued on October ⁇ , 1996 to Popli et al. and U.S. Patent No. 5,749,579, issued on June 2, 1998 to Singh et al.
  • compositions of the present invention may also comprise other active ingredients.
  • additional active ingredients for the treatment of respiratory conditions may be present.
  • NSAISDs non-steroidal anti-inflammatory drugs
  • decongestants decongestants
  • mucolytics mucolytics
  • acetaminophen acetaminophen and other antitussives.
  • Decongestants which may be useful in the compositions of the present invention include pseudoephedrine and phenylephrine.
  • Mucolytics which may be useful in the compositions of the present invention include guaifenesine, ambroxol and bromhexine.
  • Antitussives which may be useful in the compositions of the present invention include diphenhydramine, dextromethorphan and chlophendianol.
  • NSAIDs which may be useful in the compositions of the present invention include the non-steroidal anti-inflammatory agents.
  • the variety of compounds encompassed by this group are well-known to those skilled in the art.
  • non-steroidal anti-inflammatory agents useful in the composition of the present invention include, but are not limited to the oxicams, such as piroxicam, isoxicam, tenoxicam and sudoxicam; the salicylates, such as aspirin, disalcid, benorylate, trilisate, safapryn, solprin, diflunisal, and fendosal; the acetic acid derivatives, such as diclofenac, fenclofenac, indomethacin, sulindac, tolmetin, isoxepac, furofenac, tiopinac, zidometacin, acematacin, fentiazac, zomepiract, clidanac, oxepinac, and felbinac; the fenamates, such as mefenamic, meclofenamic, flufenamrc, niflumic, and tolfenamic acids; the propionic
  • An antitussive syrup formulation was prepared in accordance with the following procedure.
  • the example illustrates a formulation containing 125 milligrams of N- acetyl-L-cysteine per 5 ml of the formulation.
  • the PEG 1450 is introduced into a flask and melted at 50°-60°degree C. and 62.5 ml of propylene glycol is added with stirring.
  • the N-acetyl-L-cysteine is then dissolved in the mixture.
  • the sodium carboxymethylcellulose is dispersed in glycerin, and in a third flask, the sodium benzoate and sodium saccharin are dissolved in 60 ml of purified water.
  • the sodium carboxymethylcellulose dispersion is added to the third flask and stirred for at least 30 minutes or until the preparation becomes thick.
  • the thick preparation is added to the bulk in the first flask.
  • To the first flask is then added the sorbitol solution and the corn syrup with continuous stirring.
  • the menthol is then dissolved in 12.5 ml of propylene glycol and added to the bulk.
  • the citric acid is dissolved in 10 ml water and added to the bulk.
  • the flavors and coloring are added and then purified water is added in an amount to create 500 ml. of the final formulation

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Abstract

The present invention relates to a method of suppressing coughing in a mammal through the administration of a safe and effective amount of N-acetyl-cysteine, or its derivatives, to such mammal.

Description

THE USE OF N-ACETYL-CYSTEINE AND ITS DERIVATIVES AS AN
ANTITUSSIVE
Technical Field
The present invention relates to the prevention and/or treatment of respiratory conditions. Specifically, the invention relates to the novel use of N-acetyl-cysteine and its derivatives as an antitussive for administration to mammals.
Background of the Invention
N-acetyl-L-cysteine, a preferred active ingredient in the method claimed in the present invention, has been used as a component in topical cosmetic compositions, a mucolytic, a corneal vulnerary and an antidote to acetaminophen poisoning (The Merck Index, (1989) 11th Edition, p.14). For example, European Patent Application 219 455, issued to Fabbro, published Apr. 22, 1987, discloses a dermatological and skin cosmetic, topical, pharmaceutical composition containing N-acetyl-L-cysteine as the active constituent. The composition is disclosed as being useful for the prevention and treatment of sunburn and for increasing the speed of skin pigmentation bronzing. U.S. Patent No. 3,184,505, issued to Martin et al. on May 18, 1965, discloses a process for the production of N-acetyl-cysteine and its use as a mucolytic agent.
Dextromethorphan is a well-known non-opioid antitussive agent which is employed in a number of cough/cold remedies which are presently commercially available. While it is recognized as both safe and effective when used as directed, episodic and sporadic abuse has been reported due to its hallucinogenic properties when ingested in excess. The primary psychological symptoms of dextromethorphan abuse have been identified as euphoria, increased perceptual awareness, altered time perception, feelings of floating, tactile hallucinations, visual hallucinations, auditory hallucinations, visual disturbances, paranoia, and disorientation (see Archives of Family Medicine. Vol. 8, No. 2, March 1999). Objects of the Present Invention
It is therefore an object of the present invention to provide an effective method of suppressing coughing in a mammal through the administration of a safe and effective composition.
It is further an object of the invention to provide a method of suppressing coughing while avoiding the administration of opioids and/or other compounds which may be subject of abuse.
Summary of the invention
The present invention relates to a method of suppressing coughing in a mammal through the administration of a safe and effective amount of n-acetyl-cysteine and/or a derivative thereof to such mammal.
Detaiied Description of the invention
As used herein, "alkyl" means an unsubstituted carbon-containing chain which may be straight, branched or cyclic, preferably straight or branched, more preferably straight; saturated, monounsaturated (i.e., one double or triple bond in the chain), or polyunsaturated (i.e., two or more double bonds in the chain; two or more triple bonds in the chain; one or more double and one or more triple bonds in the chain), preferably saturated.
As used herein, "pharmaceutically-acceptable" means that drugs, medicaments or inert ingredients which the term describes are suitable for ingestion by humans and other mammals without undue toxicity, incompatibility, instability, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio.
As used herein, "safe and effective amount" means an amount of compound or composition sufficient to significantly induce a positive modification in the condition to be treated, but low enough to avoid serious side effects (at a reasonable benefit/risk ratio), within the scope of sound medical judgment. The safe and effective amount of the compound or composition will vary with the particular condition being treated, the age and physical condition of the patient being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, the specific compound or composition employed, the particular pharmaceutically-acceptable carrier utilized, and like factors within the knowledge and expertise of the attending physician.
As used herein, all percentages are by weight unless otherwise specified.
Active Compound
The present invention relates to a method of suppressing coughing in a mammal through the administration of a safe and effective amount of an active compound. As used herein, "active compound" means a compound having the structure below or a pharmaceutically-acceptable salt thereof.
Figure imgf000004_0001
R1 is selected from the group consisting of 0 and a C1 -C18 alkyl, preferably C1 -C7, more preferably C1 -C3, more preferably still C1 alkyl.
R2 is selected from the group consisting of 0, -H, C1 -C18,
Figure imgf000004_0002
preferably -H and, C1 -C18 alkyl, more preferably -H. In one embodiment, R2 is preferably a C1 -C18 alkyl, more preferably C1 -C7, more preferably C1 -C3, more preferably still C1. R3 is selected from the group consisting of -H1 and C1 -C18alkyl, preferably -H. In one embodiment, R3 is preferably a CrCi8 alkyl, more preferably C1 -C7, more preferably C1 -C3, more preferably still C1.
R4 is a C1 -C18 alkyl; preferably C1 -C7; more preferably C1 -C3; more preferably still C1.
In another embodiment, both R1 and R2 are 0 and the carbonyl carbon and the sulfur adjacent R1 and R2, respectively, are covalently bonded to form a cyclic ring. Otherwise, both R1 and R2 are other than 0.
Preferred pharmaceutically-acceptable salts of the active compound include, but are not limited to, sodium, potassium, magnesium, calcium, lithium, rubidium, strontium, aluminum, boron, silicon and zinc salts of the active compound.
In a specific embodiment, the present invention relates to a method of suppressing coughing in a mammal through the administration of a safe and effective amount of an active compound having the structure
Figure imgf000005_0001
Compositions of the present invention should provide a patient with a dose of the active ingredient ranging from about 0.01 g. to about 12 g. per day. Preferably, such dose should range from about 0.1 g. to about 6 g. on the same basis. More preferably, such dose should range from about 0.2 g. to about 4 g. on the same basis. Most preferably, such dose should be about 1.0 g per day. Dosing should preferably be accomplished every 4-8 hours, preferably every 6 hours.
Zinc Salts
In an embodiment of the present invention, zinc salts are included within the claimed compositions. The presence of zinc salts offers at least two benefits. First, it has been disclosed that certain zinc salts possess antiviral properties and can reduce the duration of the common cold in humans. In particular, the reader is directed to U.S. Patent Nos.4,956,385; 5,002,970; 5,095,035; 5,409,905 and Re 33,465 issued to George A. Eby, III . Zinc salts are also known to reduce the odor that may be associated with N-acetyl-cysteine and its derivatives. According to the disclosure of U.S. Patent No. 5,296,500, issued March 22, 1994 to Hillebrand, zinc complexes with malodorous H2S which may be formed as trace amounts as the active compound decomposes. The action of zinc renders the compositions of the present invention substantially odorless.
Preferably, the zinc salt is selected from the group consisting of zinc oxide, zinc chloride, zinc acetate, zinc stearate, zinc ascorbate, zinc citrate, zinc picolinate, zinc transferrin, zinc aspartate, zinc glycinate, zinc alaninate, zinc lysinate, zinc leucinate, zinc valinate, zinc oleate and sulfate; more preferably zinc oxide, zinc ascorbate, zinc gluconate and zinc chloride.
Compositions within this embodiment of the present invention preferably comprise from about 0.001 % to about 10% of a zinc salt, more preferably from about 0.01% to about 5%, more preferably still from about 0.01% to about 0.5%.
Pharmaceutical Compositions
In a preferred embodiment, treatment will employ the use of a pharmaceutical composition comprising the active compound and a pharmaceutically-acceptable carrier. The term "pharmaceutically-acceptable carrier", as used herein, means one or more compatible solid or liquid filler diluents or microencapsulating substances which are suitable for administration to a human or other mammal. Pharmaceutically- acceptable carriers must be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the human or other mammal being treated. A safe and effective amount of carrier is from about 50% to about 99.99%, preferably from about 99.9% to about 80%, more preferably from about 98% to about 95%, of the composition.
Variations in formulation of these carriers will result in a wide variety of products which fall within the scope of the present invention. The pharmaceutical compositions of the present invention may be made into a wide variety of product types, including solid and liquid dosage forms. These dosage forms include, but are not limited to tablets, caplets, liquid-filled soft capsules, suppositories, solutions and syrups. Conventional carriers and excipients may be used in the practice of the invention to produce the pharmaceutical compositions claimed herein.
For example, the pharmaceutical compositions of the present invention may employ liquid carrier vehicles such as those disclosed in U.S. Patent No. 5,563,177, issued on October δ, 1996 to Popli et al. and U.S. Patent No. 5,749,579, issued on June 2, 1998 to Singh et al.
The pharmaceutical compositions of the present invention may also comprise other active ingredients. For example, additional active ingredients for the treatment of respiratory conditions may be present. These may include, but shall not be limited to, non-steroidal anti-inflammatory drugs (NSAISDs), decongestants, mucolytics, acetaminophen and other antitussives.
Decongestants which may be useful in the compositions of the present invention include pseudoephedrine and phenylephrine. Mucolytics which may be useful in the compositions of the present invention include guaifenesine, ambroxol and bromhexine. Antitussives which may be useful in the compositions of the present invention include diphenhydramine, dextromethorphan and chlophendianol.
NSAIDs which may be useful in the compositions of the present invention include the non-steroidal anti-inflammatory agents. The variety of compounds encompassed by this group are well-known to those skilled in the art. For detailed disclosure of the chemical structure, synthesis, side effects, etc., of non-steroidal anti-inflammatory agents, reference may be had to standard texts, including Anti-inflammatory and Anti-Rheumatic Drugs, K. D. Rainsford, Vol. Nil, CRC Press, Boca Raton, (1985), and Anti-inflammatory Agents, Chemistry and Pharmacology, 1, R. A. Scherrer, et al., Academic Press, New York (1974).
Specific non-steroidal anti-inflammatory agents useful in the composition of the present invention include, but are not limited to the oxicams, such as piroxicam, isoxicam, tenoxicam and sudoxicam; the salicylates, such as aspirin, disalcid, benorylate, trilisate, safapryn, solprin, diflunisal, and fendosal; the acetic acid derivatives, such as diclofenac, fenclofenac, indomethacin, sulindac, tolmetin, isoxepac, furofenac, tiopinac, zidometacin, acematacin, fentiazac, zomepiract, clidanac, oxepinac, and felbinac; the fenamates, such as mefenamic, meclofenamic, flufenamrc, niflumic, and tolfenamic acids; the propionic acid derivatives, such as ibuprofen, naproxen, benoxaprofen, flurbiprofen, ketoprofen, fenoprofen, fenbufen, indoprofen, pirprofen, carprofen, oxaprozin, pranoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen, and tiaprofenic; and the pyrazoles, such as phenybutazone, oxyphenbutazone, feprazone, azapropazone, and trimethazone. Mixtures of these non-steroidal anti-inflammatory agents may also be employed, as well as the pharmaceuticalfy-acceptable salts and esters of these agents.
The following examples further describe and demonstrate the preferred embodiments within the scope of the present invention. The examples are given solely for the purpose of illustration, and are not to be construed as limitations of the present invention since many variations thereof are possible without departing from its spirit and scope.
EXAMPLE I
An antitussive syrup formulation was prepared in accordance with the following procedure. The example illustrates a formulation containing 125 milligrams of N- acetyl-L-cysteine per 5 ml of the formulation.
AMT / INGREDIENTS 500 ML
N-acetyl-L-cysteine USP 125 g Polyethylene glycol 1450, NF 5O g
Propylene glycol USP 75 ml
Glycerin, USP 25 ml
High fructose corn syrup 95 225 ml
Sorbitol solution USP 25 ml L-menthol, USP 0.12 g Citric acid, anhydrous USP . 4.5 g
Sodium benzoate, USP 0.5 g
Saccharin sodium, USP 3.5 g
Coloring and sweetener 0.515 g
Sodium carboxymethylcellulose 7MF, USP 2.5 g Artificial fruit flavor 3.6 ml
Purified water, USP QS TO 500 ml
The PEG 1450 is introduced into a flask and melted at 50°-60°degree C. and 62.5 ml of propylene glycol is added with stirring. The N-acetyl-L-cysteine is then dissolved in the mixture. In a separate flask, the sodium carboxymethylcellulose is dispersed in glycerin, and in a third flask, the sodium benzoate and sodium saccharin are dissolved in 60 ml of purified water. The sodium carboxymethylcellulose dispersion is added to the third flask and stirred for at least 30 minutes or until the preparation becomes thick. The thick preparation is added to the bulk in the first flask. To the first flask is then added the sorbitol solution and the corn syrup with continuous stirring. The menthol is then dissolved in 12.5 ml of propylene glycol and added to the bulk. The citric acid is dissolved in 10 ml water and added to the bulk. The flavors and coloring are added and then purified water is added in an amount to create 500 ml. of the final formulation
While particular embodiments of the subject invention have been described, it will be obvious to those skilled in the art that various changes and modifications of the subject invention can be made without departing from the spirit and scope of the invention. It is intended to cover, in the appended claims, all such modifications that are within the scope of the invention.

Claims

ClaimsWhat is claimed is:
1. An antitussive composition comprising a compound having the structure (I) below or a pharmaceutically-acceptable salt thereof
Figure imgf000010_0001
wherein:
R1 is C1 -C18 alkyl;
R2 is selected from, -H, C1 -C18, alkyl, and
Figure imgf000010_0002
or R1 and R2 together form a covalent bond between the carbonyl group and the sulfur atom;
R3 is selected from -H and C1 -C18 alkyl; and
R4 is a C1 -C18 alkyl.
2. The antitussive composition of Claim 1 wherein: R1 is C1 -C7alkyl;
R2 is selected from -H and C1 -C18alkyl and -COR4;
R3 is H; and
R^s a d -Cralkyl.
3. The antitussive composition of Claim 2 wherein:
R1 is C1 -C3 alkyl;
R2 and R3 are -H; and
R4 is a C1 -C7 alkyl.
4. The antitussive composition of Claim 2 wherein:
R1 and R4 are methyl; and
R2 and R3 are -H.
5. An antitussive composition as claimed in claim 1 in which the compound of structure (I) is
Figure imgf000011_0001
or a pharmaceutically-acceptable salt thereof.
6. The antitussive composition of any one of Claims 1 to 5 wherein the compound is administered to the patient in an amount ranging from about 0.01 to about 12 grams per day.
7. The antitussive composition of any one of Claims 1 to 5 wherein the compound is administered to the patient in an amount ranging from about 0.1 to about 6 grams per day.
8. The antitussive composition of any one of Claims 1 to 5 wherein the compound is administered to the patient in an amount ranging. from about 0.2 to about 4 grams per day.
9. The antitussive composition of any one of Claims 1 to 5 wherein the compound is administered to the patient in an amount of about 1 gram per day.
10. The antitussive composition of any one of Claims 1 to 9 further comprising a zinc salt.
11. The antitussive composition of Claim 10 wherein the zinc salt is selected from the group consisting of zinc oxide, zinc chloride, zinc acetate, zinc stearate, zinc ascorbate, zinc citrate, zinc picolinate, zinc transferrin, zinc aspartate, zinc glycinate, zinc alaninate, zinc lysinate, zinc leucinate, zinc valinate, zinc oleate and zinc sulfate.
12. The antitussive composition of Claim 10 wherein the zinc salt is selected from the group consisting of zinc oxide, zinc ascorbate, zinc gluconate and zinc chloride and mixtures thereof.
13. A method of suppressing coughing in a mammal through the administration of a safe and effective amount of a composition comprising a compound having the structure (I) below or a pharmaceutically-acceptable salt thereof ORd
O =0
R1 -C Il — NH- -CH CHo — S- -R2 (I)
wherein:
R1 is C1 -C18 alkyl;
R2 is selected from -H, C1 -C18 and
O
C R4
or R1 and R2 together form a covalent bond between the carbonyl group and the sulfur atom;
R3 is selected from -H and C1 -C18 alkyl; and
R4 is a C1 -C18 alkyl.
14. The method of Claim 13 wherein:
R1 is C1 -C7 alkyl;
R2 is selected from -H and C1 -C18 alkyl and -COR4;
R3is H; and
R4 is a C1 -C7 alkyl.
15. The method of Claimi 3 wherein:
R1 is C1 -C3 alkyl; R2 and R3 are -H; and
R4 is a C1 -C7 alkyl.
16. The method of Claim 13 wherein:
R1 and R4 are methyl; and
R2 and R3 are -H.
17. The method of claim 13 in which the compound of structure (I) is
Figure imgf000014_0001
or a pharmaceutically-acceptable salt thereof.
18. The method of any one of Claims 13 to 17 wherein the compound is administered to the patient in an amount ranging from about 0.01 to about 12 grams per day.
19. The method of any one of Claims 13 to 17 wherein the compound is administered to the patient in an amount ranging from about 0.1 to about 6 grams per day.
20. The method of any one of Claims 13 to 17 wherein the compound is administered to the patient in an amount ranging from about 0.2 to about 4 grams per day.
21. The method of any one of Claims 13 to 20 further comprising a zinc salt.
22. The method of Claim 21 wherein the zinc salt is selected from the group consisting of zinc oxide, zinc chloride, zinc acetate, zinc stearate, zinc ascorbate, zinc citrate, zinc picolinate, zinc transferrin, zinc aspartate, zinc glycinate, zinc alaninate, zinc lysinate, zinc leucinate, zinc valinate, zinc oleate and zinc sulfate.
23. The method of Claim 21 wherein the zinc salt is selected from the group consisting of zinc oxide, zinc ascorbate, zinc gluconate, zinc chloride and mixtures thereof.
24. Use of a compound of structure I or a pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 5 as an antitussive agent.
25. Use of a compound of structure I or a pharmaceutically acceptable salt as defined in any one of claims 1 to 5 in the preparation of an antitussive medicament.
PCT/US2007/001278 2006-01-23 2007-01-19 N-acetyl-cysteine and its derivatives as an antitussive WO2007087215A2 (en)

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Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
BEERS M ET AL: "Merck Manual" 1999, MERCK , WHITEHOUSE STATION, NJ , XP002436365 Section "Cough-Mucolytics" page 513, column 2, paragraph 7 - page 514, column 1, paragraph 1 *
CHALUMEAU M ET AL: "[Mucolytic agents for acute respiratory tract infections in infants: A pharmaco-epidemiological problem?]" ARCHIVES DE PEDIATRIE, vol. 9, no. 11, November 2002 (2002-11), pages 1128-1136, XP008079270 ISSN: 0929-693X *
PARFITT, K: "Martindale" 1999, PP , LONDON, UK , XP002436364 page 1053, column 2, paragraphs 3,5,6 *
VÖLKL K P ET AL: "[Therapy of respiratory tract diseases with N-acetylcysteine. An open therapeutic observation study of 2,512 patients]" FORTSCHRITTE DER MEDIZIN 30 JUN 1992, vol. 110, no. 18, 30 June 1992 (1992-06-30), pages 346-350, XP008079266 ISSN: 0015-8178 *

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