US20050187253A1 - Medicinal kit to quit tobacco consumption comprising central cannabinoid receptor antagonist - Google Patents

Medicinal kit to quit tobacco consumption comprising central cannabinoid receptor antagonist Download PDF

Info

Publication number
US20050187253A1
US20050187253A1 US11/113,864 US11386405A US2005187253A1 US 20050187253 A1 US20050187253 A1 US 20050187253A1 US 11386405 A US11386405 A US 11386405A US 2005187253 A1 US2005187253 A1 US 2005187253A1
Authority
US
United States
Prior art keywords
compound
nicotine
active principle
tobacco consumption
pharmaceutically acceptable
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US11/113,864
Inventor
Jean Blanchard
Francois Menard
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sanofi Aventis France
Original Assignee
Sanofi Aventis France
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sanofi Aventis France filed Critical Sanofi Aventis France
Priority to US11/113,864 priority Critical patent/US20050187253A1/en
Publication of US20050187253A1 publication Critical patent/US20050187253A1/en
Abandoned legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/34—Tobacco-abuse

Definitions

  • the present invention relates to a novel use of an antagonist of the central cannabinoid receptors, known as the CB1 receptors. More particularly, the invention relates to the use of a kit comprising CB1-receptor antagonist for helping to quit tobacco consumption.
  • N-piperidino-5-(4-chloro-phenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide referred to hereinbelow as compound A, of formula: the pharmaceutically acceptable salts thereof and the solvates thereof are disclosed in European patent EP-[lacuna] 656 354 and by M. Rinaldi-Carmona et al. (FEBS Lett., 1994, 350, 240-244) as being CB 1 central-receptor antagonists.
  • compound A and its salts which are central cannabinoid receptor antagonists, may be used to treat appetite disorders, in particular as anorexigenic agents, and in the treatment of disorders associated with the use of psychotropic substances.
  • international patent application WO 99/00119 discloses the use of central cannabinoid receptor antagonists to treat craving disorders, i.e. to control the desire for consumption, in particular for consumption of sugars, carbohydrates, alcohol or drugs and more generally of appetizing ingredients.
  • compound A the pharmaceutically acceptable salts thereof and the solvates thereof help in quitting tobacco consumption and are useful in the treatment of nicotine dependence and/or in the treatment of the symptoms of withdrawal from nicotine.
  • compound A makes it possible to observe, in nicotine consumers such as tobacco smokers, a total or partial abstinence from tobacco, with early or delayed onset. Furthermore, the symptoms of withdrawal from nicotine are very substantially attenuated or even eliminated, and the weight gain after quitting tobacco consumption is reduced or nonexistent.
  • the present invention relates to the use of N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-pyrazole-3-carboxamide, a pharmaceutically acceptable salt thereof or a solvate thereof for the preparation of medicinal products that are useful for helping to quit tobacco consumption, in the treatment of nicotine dependence and/or in the treatment of the symptoms of withdrawal from nicotine.
  • compound A a pharmaceutically acceptable salt thereof or a solvate thereof may also be used, in combination with another active principle, for the preparation of medicinal products that are useful for helping to quit tobacco consumption, in the treatment of nicotine dependence and/or in the treatment of the symptoms of withdrawal from nicotine.
  • compound A may be combined
  • compound A For its use as a medicinal product, compound A, a pharmaceutically acceptable salt thereof or a solvate thereof, alone or in combination with another active principle, must be formulated as a pharmaceutical composition.
  • a subject of the present invention is also pharmaceutical compositions containing, in combination, N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide, a pharmaceutically acceptable salt thereof or a solvate thereof and another active principle, the other active principle being a compound that is useful for helping to quit tobacco consumption and/or that is useful in the treatment of nicotine dependence and/or in the treatment of the symptoms of withdrawal from nicotine.
  • the said other active principle is preferably chosen from:
  • the active principle in the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal, local or rectal administration, may be administered in unit administration form, as a mixture with conventional pharmaceutical supports, to animals and human beings.
  • the unit administration forms that are suitable comprise oral forms such as tablets, gel capsules, pills, powders, granules, chewing gums and oral solutions or suspensions, sublingual and buccal administration forms, aerosols, implants, local, transdermal, subcutaneous, intramuscular, intravenous, intranasal or intraocular administration forms and rectal administration forms.
  • the active principle(s) is(are) generally formulated in dosage units.
  • the dosage unit contains 0.5 to 300 mg, advantageously from 5 to 60 mg and preferably from 5 to 40 mg per dosage unit, for daily administrations, one or more times a day.
  • the dosage which is appropriate to each patient is determined by the doctor according to the mode of administration, the age, the weight and the response of the said patient.
  • a wetting agent such as sodium lauryl sulfate may be added to the micronized or non-micronized active principle(s) and the whole may be mixed with a pharmaceutical vehicle such as silica, starch, lactose, magnesium stearate, talc or the like.
  • a pharmaceutical vehicle such as silica, starch, lactose, magnesium stearate, talc or the like.
  • the tablets may be coated with sucrose, various polymers or other suitable materials or alternatively they may be treated such that they have sustained or delayed activity and such that they continuously release a predetermined amount of active principle.
  • a preparation in the form of gel capsules is obtained by mixing the active principle(s) with a diluent such as a glycol or a glycerol ester and by incorporating the mixture obtained into soft or hard gel capsules.
  • a diluent such as a glycol or a glycerol ester
  • a preparation in the form of a syrup or elixir may contain the active principle(s) together with a sweetener, preferably a calorie-free sweetener, methylparaben and propylparaben as antiseptics, and also a flavor enhancer and a suitable colorant.
  • a sweetener preferably a calorie-free sweetener, methylparaben and propylparaben as antiseptics, and also a flavor enhancer and a suitable colorant.
  • the water-dispersible powders or granules may contain the active principle(s) as a mixture with dispersants or wetting agents, or suspending agents such as polyvinylpyrrolidone or polyvidone, as well as with sweeteners or flavor enhancers.
  • suppositories which are prepared with binders that melt at the rectal temperature, for example cocoa butter or polyethylene glycols.
  • Aqueous suspensions, isotonic saline solutions or sterile injectable solutions which contain pharmacologically compatible dispersants and/or solubilizing agents, for example propylene glycol or butylene glycol, are used for parenteral administration.
  • pharmacologically compatible dispersants and/or solubilizing agents for example propylene glycol or butylene glycol
  • a co-solvent for example an alcohol such as ethanol or a glycol such as polyethylene glycol or propylene glycol, and a hydrophilic surfactant such as polysorbate 80.
  • the active principle can be dissolved with a triglyceride or a glycerol ester.
  • Patches in multilaminar form or with a reservoir in which the active principle is in alcoholic solution may be used for transdermal administration.
  • the active principle(s) may also be formulated in the form of microcapsules or microspheres, optionally with one or more supports or additives.
  • the active principle(s) may also be in the form of a complex with a cyclodextrin, for example ⁇ -, ⁇ - or ⁇ -cyclodextrin, 2-hydroxypropyl- ⁇ -cyclodextrin or methyl- ⁇ -cyclodextrin.
  • a cyclodextrin for example ⁇ -, ⁇ - or ⁇ -cyclodextrin, 2-hydroxypropyl- ⁇ -cyclodextrin or methyl- ⁇ -cyclodextrin.
  • implants which are useful in the case of chronic treatments and which may be used are implants. These implants may be prepared in the form of an oily suspension or in the form of a suspension of microspheres in an isotonic medium.
  • compound A is administered orally, as a single dosage intake per day.
  • compound A, a pharmaceutically acceptable salt thereof or a solvate thereof and the other active principle combined may be administered simultaneously, separately or sequentially to help in quitting tobacco consumption.
  • sequential use means the successive administration of the first compound of the composition according to the invention, in one pharmaceutical form, followed by the second compound of the composition according to the invention, in a different pharmaceutical form.
  • the time elapsed between the administration of the first compound of the composition according to the invention and the administration of the second compound of the same composition according to the invention generally does not exceed 24 hours.
  • compositions comprising either only one of the compounds constituting the composition according to the invention or the combination of both compounds, which may be used in the various types of uses described above, may be suitable, for example, for oral, nasal, parenteral or transdermal administration.
  • two different pharmaceutical forms may be intended for the same administration route or for a different administration route (oral and transdermal or oral and nasal or parenteral and transdermal, etc.).
  • the invention thus also relates to a kit for helping to quit tobacco consumption, containing compound A and another active principle for helping to quit tobacco consumption, in which the said compound A and the said active principle are in separate compartments and in packaging which may be identical or different, and are intended to be administered simultaneously, separately or sequentially.
  • the said active principle is preferably chosen from:
  • the invention also relates to a method for helping to quit tobacco consumption, which consists in administering to a nicotine consumer a therapeutically effective amount of compound A, a pharmaceutically acceptable salt thereof or a solvate thereof.
  • Compound A administered at a dose of 0.3 mg/kg and 1 mg/kg reduces, in a statistically significant manner, the number of nicotine injections to rats which have learnt to self-administer nicotine intravenously.
  • a double-blind study was carried out with individuals who smoked more than 15 cigarettes a day and who showed symptoms of nicotine dependence.
  • the patients received 40 mg of compound A per day for 10 weeks, including 2 weeks before the start of the period of withdrawal from tobacco.
  • a greater level of withdrawal was observed in the treated group than in the group receiving a placebo, in particular during the last 4 weeks of treatment.
  • the withdrawal from tobacco was confirmed by weekly measurement of the levels of carbon monoxide exhaled and of cotinine in the plasma.
  • Micronized compound A 5.00 mg Corn starch 51.00 mg Lactose monohydrate 99.33 mg Polyvidone 4.30 mg Sodium lauryl sulfate 0.17 mg Crosslinked sodium carboxymethylcellulose 8.50 mg Purified water: qs for wet granulation Magnesium stearate 1.70 mg For a filled No. 3 opaque white gel 170 mg capsule containing
  • Micronized compound A 20.00 mg Corn starch 51.00 mg Lactose monohydrate 84.33 mg Polyvidone 4.30 mg Sodium lauryl sulfate 0.17 mg Crosslinked sodium carboxymethylcellulose 8.50 mg Purified water: qs for wet granulation Magnesium stearate 1.70 mg For a filled opaque white gel capsule containing 170 mg
  • Micronized compound A 30.00 mg Corn starch 80.00 mg 200 mesh lactose monohydrate 252.00 mg Povidone K 30 12.00 mg Crosslinked sodium carboxymethylcellulose 20.00 mg Sodium lauryl sulfate 2.00 mg Magnesium stearate 4.00 mg Purified water: qs For a finished tablet containing 400 mg

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Biomedical Technology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Addiction (AREA)
  • Psychiatry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

The invention relates to the use of a medicinal kit comprising N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide for helping to quit tobacco consumption.

Description

  • This application is a continuation of U.S. application Ser. No. 10/203,077, filed Oct. 15, 2002, now allowed, which was the National Stage of International application No. PCT/FR01/00,356, filed Feb. 7, 2001; which claims the benefit of priority of French Patent Application No. 00/01,682, filed Feb. 9, 2000, all of which are incorporated herein by reference in their entirety.
  • The present invention relates to a novel use of an antagonist of the central cannabinoid receptors, known as the CB1 receptors. More particularly, the invention relates to the use of a kit comprising CB1-receptor antagonist for helping to quit tobacco consumption.
  • Families of compounds having affinity for the cannabinoid receptors have been disclosed in several patents and patent applications, in particular European patent application EP-[lacuna] 576 357, which discloses pyrazole derivatives, and patent application WO 96/02248 which discloses in particular benzofuran derivatives.
  • More particularly, N-piperidino-5-(4-chloro-phenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide, referred to hereinbelow as compound A, of formula:
    Figure US20050187253A1-20050825-C00001
    the pharmaceutically acceptable salts thereof and the solvates thereof are disclosed in European patent EP-[lacuna] 656 354 and by M. Rinaldi-Carmona et al. (FEBS Lett., 1994, 350, 240-244) as being CB1 central-receptor antagonists.
  • It is disclosed that compound A and its salts, which are central cannabinoid receptor antagonists, may be used to treat appetite disorders, in particular as anorexigenic agents, and in the treatment of disorders associated with the use of psychotropic substances. Furthermore, international patent application WO 99/00119 discloses the use of central cannabinoid receptor antagonists to treat craving disorders, i.e. to control the desire for consumption, in particular for consumption of sugars, carbohydrates, alcohol or drugs and more generally of appetizing ingredients.
  • It has now been found that compound A, the pharmaceutically acceptable salts thereof and the solvates thereof help in quitting tobacco consumption and are useful in the treatment of nicotine dependence and/or in the treatment of the symptoms of withdrawal from nicotine.
  • Thus, the administration of compound A, a pharmaceutically acceptable salt or solvate thereof makes it possible to observe, in nicotine consumers such as tobacco smokers, a total or partial abstinence from tobacco, with early or delayed onset. Furthermore, the symptoms of withdrawal from nicotine are very substantially attenuated or even eliminated, and the weight gain after quitting tobacco consumption is reduced or nonexistent.
  • According to one of its aspects, the present invention relates to the use of N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-pyrazole-3-carboxamide, a pharmaceutically acceptable salt thereof or a solvate thereof for the preparation of medicinal products that are useful for helping to quit tobacco consumption, in the treatment of nicotine dependence and/or in the treatment of the symptoms of withdrawal from nicotine.
  • According to the present invention, compound A, a pharmaceutically acceptable salt thereof or a solvate thereof may also be used, in combination with another active principle, for the preparation of medicinal products that are useful for helping to quit tobacco consumption, in the treatment of nicotine dependence and/or in the treatment of the symptoms of withdrawal from nicotine.
  • For example, compound A may be combined
      • with nicotine, a nicotine agonist or a partial nicotine agonist, or
      • with a monoamine oxidase inhibitor (MAOI),
      • or with any other active principle which has demonstrated its efficacy in helping to quit tobacco consumption, for example an antidepressant such as bupropion, doxepine, nortriptyline or an anxiolytic agent such as buspirone, or clonidine.
  • For its use as a medicinal product, compound A, a pharmaceutically acceptable salt thereof or a solvate thereof, alone or in combination with another active principle, must be formulated as a pharmaceutical composition.
  • Thus, a subject of the present invention is also pharmaceutical compositions containing, in combination, N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide, a pharmaceutically acceptable salt thereof or a solvate thereof and another active principle, the other active principle being a compound that is useful for helping to quit tobacco consumption and/or that is useful in the treatment of nicotine dependence and/or in the treatment of the symptoms of withdrawal from nicotine. The said other active principle is preferably chosen from:
      • nicotine, a nicotine agonist or a partial nicotine agonist, or
      • a monoamine oxidase inhibitor (MAOI),
      • or any other active principle which has demonstrated efficacy in helping to quit tobacco consumption, for example an antidepressant such as bupropion, doxepine, nortriptyline or an anxiolytic agent such as buspirone, or clonidine.
  • In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal, local or rectal administration, the active principle, alone or in combination with another active principle, may be administered in unit administration form, as a mixture with conventional pharmaceutical supports, to animals and human beings. The unit administration forms that are suitable comprise oral forms such as tablets, gel capsules, pills, powders, granules, chewing gums and oral solutions or suspensions, sublingual and buccal administration forms, aerosols, implants, local, transdermal, subcutaneous, intramuscular, intravenous, intranasal or intraocular administration forms and rectal administration forms.
  • In the pharmaceutical compositions of the present invention, the active principle(s) is(are) generally formulated in dosage units. The dosage unit contains 0.5 to 300 mg, advantageously from 5 to 60 mg and preferably from 5 to 40 mg per dosage unit, for daily administrations, one or more times a day.
  • Although these dosages are examples of average situations, there may be particular cases in which higher or lower dosages are appropriate, and such dosages also form part of the invention. According to the usual practice, the dosage which is appropriate to each patient is determined by the doctor according to the mode of administration, the age, the weight and the response of the said patient.
  • When a solid composition in the form of tablets is prepared, a wetting agent such as sodium lauryl sulfate may be added to the micronized or non-micronized active principle(s) and the whole may be mixed with a pharmaceutical vehicle such as silica, starch, lactose, magnesium stearate, talc or the like. The tablets may be coated with sucrose, various polymers or other suitable materials or alternatively they may be treated such that they have sustained or delayed activity and such that they continuously release a predetermined amount of active principle.
  • A preparation in the form of gel capsules is obtained by mixing the active principle(s) with a diluent such as a glycol or a glycerol ester and by incorporating the mixture obtained into soft or hard gel capsules.
  • A preparation in the form of a syrup or elixir may contain the active principle(s) together with a sweetener, preferably a calorie-free sweetener, methylparaben and propylparaben as antiseptics, and also a flavor enhancer and a suitable colorant.
  • The water-dispersible powders or granules may contain the active principle(s) as a mixture with dispersants or wetting agents, or suspending agents such as polyvinylpyrrolidone or polyvidone, as well as with sweeteners or flavor enhancers.
  • For rectal administration, use is made of suppositories which are prepared with binders that melt at the rectal temperature, for example cocoa butter or polyethylene glycols.
  • Aqueous suspensions, isotonic saline solutions or sterile injectable solutions which contain pharmacologically compatible dispersants and/or solubilizing agents, for example propylene glycol or butylene glycol, are used for parenteral administration.
  • Thus, to prepare an aqueous solution for intravenous injection, it is possible to use a co-solvent, for example an alcohol such as ethanol or a glycol such as polyethylene glycol or propylene glycol, and a hydrophilic surfactant such as polysorbate 80. To prepare an oily solution for intramuscular injection, the active principle can be dissolved with a triglyceride or a glycerol ester.
  • Patches in multilaminar form or with a reservoir in which the active principle is in alcoholic solution may be used for transdermal administration.
  • The active principle(s) may also be formulated in the form of microcapsules or microspheres, optionally with one or more supports or additives.
  • The active principle(s) may also be in the form of a complex with a cyclodextrin, for example α-, β- or γ-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin or methyl-β-cyclodextrin.
  • Among the sustained-release forms which are useful in the case of chronic treatments and which may be used are implants. These implants may be prepared in the form of an oily suspension or in the form of a suspension of microspheres in an isotonic medium.
  • Preferably, compound A is administered orally, as a single dosage intake per day.
  • According to another aspect of the invention, compound A, a pharmaceutically acceptable salt thereof or a solvate thereof and the other active principle combined may be administered simultaneously, separately or sequentially to help in quitting tobacco consumption.
  • The expression “simultaneous use” means the administration of the compounds of the composition according to the invention in one and the same pharmaceutical form.
  • The expression “separate use” means the administration, at the same time, of the two compounds of the composition according to the invention, each in a separate pharmaceutical form.
  • The expression “sequential use” means the successive administration of the first compound of the composition according to the invention, in one pharmaceutical form, followed by the second compound of the composition according to the invention, in a different pharmaceutical form.
  • In the case of this “sequential use”, the time elapsed between the administration of the first compound of the composition according to the invention and the administration of the second compound of the same composition according to the invention generally does not exceed 24 hours.
  • The pharmaceutical forms, comprising either only one of the compounds constituting the composition according to the invention or the combination of both compounds, which may be used in the various types of uses described above, may be suitable, for example, for oral, nasal, parenteral or transdermal administration.
  • Thus, in the case of a “separate use” and of a “sequential use”, two different pharmaceutical forms may be intended for the same administration route or for a different administration route (oral and transdermal or oral and nasal or parenteral and transdermal, etc.).
  • The invention thus also relates to a kit for helping to quit tobacco consumption, containing compound A and another active principle for helping to quit tobacco consumption, in which the said compound A and the said active principle are in separate compartments and in packaging which may be identical or different, and are intended to be administered simultaneously, separately or sequentially. The said active principle is preferably chosen from:
      • nicotine, a nicotine agonist or a partial nicotine agonist, or
      • a monoamine oxidase inhibitor (MAOI),
      • or any other active principle which has demonstrated efficacy in helping to quit tobacco consumption, for example an antidepressant such as bupropion, doxepine, nortriptyline or an anxiolytic agent such as buspirone, or clonidine.
  • According to another of its aspects, the invention also relates to a method for helping to quit tobacco consumption, which consists in administering to a nicotine consumer a therapeutically effective amount of compound A, a pharmaceutically acceptable salt thereof or a solvate thereof.
  • The effects of compound A were studied in rats on a model which predicts the effects on nicotine dependence: the self-administration of nicotine according to W.T. Corrigal and al. Psychopharmacology, 1989, 99, 473-478.
  • Compound A, administered at a dose of 0.3 mg/kg and 1 mg/kg reduces, in a statistically significant manner, the number of nicotine injections to rats which have learnt to self-administer nicotine intravenously.
  • Thus, the positive effects of compound A were observed on these two models.
  • A double-blind study was carried out with individuals who smoked more than 15 cigarettes a day and who showed symptoms of nicotine dependence. The patients received 40 mg of compound A per day for 10 weeks, including 2 weeks before the start of the period of withdrawal from tobacco. A greater level of withdrawal was observed in the treated group than in the group receiving a placebo, in particular during the last 4 weeks of treatment. The withdrawal from tobacco was confirmed by weekly measurement of the levels of carbon monoxide exhaled and of cotinine in the plasma.
    • EXAMPLE 1 Gel Capsule Containing a 5 mg Dose of Compound A
  • Micronized compound A  5.00 mg
    Corn starch 51.00 mg
    Lactose monohydrate 99.33 mg
    Polyvidone  4.30 mg
    Sodium lauryl sulfate  0.17 mg
    Crosslinked sodium carboxymethylcellulose  8.50 mg
    Purified water: qs for wet granulation
    Magnesium stearate  1.70 mg
    For a filled No. 3 opaque white gel   170 mg
    capsule containing
    • EXAMPLE 2 Gel Capsule Containing a 10 mg Dose of Compound A
  • Micronized compound A 10.00 mg
    Corn starch 51.00 mg
    Lactose monohydrate 94.33 mg
    Polyvidone  4.30 mg
    Sodium lauryl sulfate  0.17 mg
    Crosslinked sodium carboxymethylcellulose  8.50 mg
    Purified water: qs for wet granulation
    Magnesium stearate  1.70 mg
    For a filled No. 3 opaque white gel   170 mg
    capsule containing
    • EXAMPLE 3 Gel Capsule Containing a 20 mg Dose of Compound A
  • Micronized compound A 20.00 mg
    Corn starch 51.00 mg
    Lactose monohydrate 84.33 mg
    Polyvidone  4.30 mg
    Sodium lauryl sulfate  0.17 mg
    Crosslinked sodium carboxymethylcellulose  8.50 mg
    Purified water: qs for wet granulation
    Magnesium stearate  1.70 mg
    For a filled opaque white gel capsule containing   170 mg
    • EXAMPLE 4 Tablet Containing a 10 mg Dose of Compound A
  • Micronized compound A  10.00 mg
    Corn starch  50.00 mg
    200 mesh lactose monohydrate 211.50 mg
    Hydroxypropylmethylcellulose 6 cP  9.00 mg
    Sodium carboxymethylstarch  15.00 mg
    Sodium lauryl sulfate  1.50 mg
    Magnesium stearate  3.00 mg
    Purified water: qs
    For a finished tablet containing   300 mg
    • EXAMPLE 5 Tablet Containing a 30 mg Dose of Compound A
  • Micronized compound A  30.00 mg
    Corn starch  80.00 mg
    200 mesh lactose monohydrate 252.00 mg
    Povidone K 30  12.00 mg
    Crosslinked sodium carboxymethylcellulose  20.00 mg
    Sodium lauryl sulfate  2.00 mg
    Magnesium stearate  4.00 mg
    Purified water: qs
    For a finished tablet containing   400 mg

Claims (3)

1. A kit for helping to quit tobacco consumption, containing N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide, a pharmaceutically acceptable salt thereof or a solvate thereof and another active principle for helping to quit tobacco consumption, in which the N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide, a pharmaceutically acceptable salt thereof, a solvate thereof and the said active principle are in separate compartments and in packaging which may be identical or different and are intended to be administered simultaneously, separately or sequentially.
2. The kit as claimed in claim 1, containing N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide, a pharmaceutically acceptable salt thereof or a solvate thereof and nicotine, a nicotine agonist or a partial nicotine agonist.
3. The kit as claimed in claim 1, containing N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide, a pharmaceutically acceptable salt thereof or a solvate thereof and a monoamine oxidase inhibitor.
US11/113,864 2000-02-09 2005-04-25 Medicinal kit to quit tobacco consumption comprising central cannabinoid receptor antagonist Abandoned US20050187253A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US11/113,864 US20050187253A1 (en) 2000-02-09 2005-04-25 Medicinal kit to quit tobacco consumption comprising central cannabinoid receptor antagonist

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
FR0001682A FR2804604B1 (en) 2000-02-09 2000-02-09 USE OF A CENTRAL CANNABINOID RECEPTOR ANTAGONIST FOR THE PREPARATION OF USEFUL DRUGS TO FACILITATE THE STOPPAGE OF TOBACCO CONSUMPTION
FR00/01682 2000-02-09
US10/203,077 US6930122B2 (en) 2000-02-09 2001-02-07 Use of central cannabinoid receptor antagonist for preparing medicines designed to facilitate smoking cessation
PCT/FR2001/000356 WO2001058450A2 (en) 2000-02-09 2001-02-07 Use of central cannabinoid receptor antagonist for preparing medicines designed to facilitate smoking cessation
US11/113,864 US20050187253A1 (en) 2000-02-09 2005-04-25 Medicinal kit to quit tobacco consumption comprising central cannabinoid receptor antagonist

Related Parent Applications (2)

Application Number Title Priority Date Filing Date
US10/203,077 Continuation US6930122B2 (en) 2000-02-09 2001-02-07 Use of central cannabinoid receptor antagonist for preparing medicines designed to facilitate smoking cessation
PCT/FR2001/000356 Continuation WO2001058450A2 (en) 2000-02-09 2001-02-07 Use of central cannabinoid receptor antagonist for preparing medicines designed to facilitate smoking cessation

Publications (1)

Publication Number Publication Date
US20050187253A1 true US20050187253A1 (en) 2005-08-25

Family

ID=8846875

Family Applications (2)

Application Number Title Priority Date Filing Date
US10/203,077 Expired - Fee Related US6930122B2 (en) 2000-02-09 2001-02-07 Use of central cannabinoid receptor antagonist for preparing medicines designed to facilitate smoking cessation
US11/113,864 Abandoned US20050187253A1 (en) 2000-02-09 2005-04-25 Medicinal kit to quit tobacco consumption comprising central cannabinoid receptor antagonist

Family Applications Before (1)

Application Number Title Priority Date Filing Date
US10/203,077 Expired - Fee Related US6930122B2 (en) 2000-02-09 2001-02-07 Use of central cannabinoid receptor antagonist for preparing medicines designed to facilitate smoking cessation

Country Status (32)

Country Link
US (2) US6930122B2 (en)
EP (1) EP1257275B1 (en)
JP (2) JP2003522145A (en)
CN (1) CN1250220C (en)
AR (1) AR028505A1 (en)
AT (1) ATE292467T1 (en)
AU (1) AU781827B2 (en)
BG (2) BG110386A (en)
BR (1) BR0108126A (en)
CA (1) CA2397262C (en)
CZ (1) CZ296685B6 (en)
DE (1) DE60109903T2 (en)
DK (1) DK1257275T3 (en)
EE (1) EE04836B1 (en)
ES (1) ES2240416T3 (en)
FR (1) FR2804604B1 (en)
HU (1) HU225328B1 (en)
IL (1) IL150710A0 (en)
IS (1) IS6450A (en)
MX (1) MXPA02007766A (en)
NO (1) NO324521B1 (en)
NZ (1) NZ519924A (en)
PL (1) PL201685B1 (en)
PT (1) PT1257275E (en)
RS (1) RS50404B (en)
RU (1) RU2257207C2 (en)
SI (1) SI1257275T1 (en)
SK (1) SK284952B6 (en)
TW (1) TWI243677B (en)
UA (1) UA72783C2 (en)
WO (1) WO2001058450A2 (en)
ZA (1) ZA200205317B (en)

Families Citing this family (42)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2804604B1 (en) * 2000-02-09 2005-05-27 Sanofi Synthelabo USE OF A CENTRAL CANNABINOID RECEPTOR ANTAGONIST FOR THE PREPARATION OF USEFUL DRUGS TO FACILITATE THE STOPPAGE OF TOBACCO CONSUMPTION
US6462237B1 (en) * 2001-06-14 2002-10-08 Usv Limited Cyclodextrin stabilized pharmaceutical compositions of bupropion hydrochloride
US7662650B2 (en) 2001-08-13 2010-02-16 Finisar Corporation Providing photonic control over wafer borne semiconductor devices
EP1487436A4 (en) 2002-03-08 2009-06-03 Signal Pharm Inc Combination therapy for treating, preventing or managing proliferative disorders and cancers
NZ534757A (en) 2002-03-12 2006-07-28 Merck & Co Inc Substituted amides
AU2003215024B2 (en) 2002-03-26 2008-02-21 Merck Sharp & Dohme Corp. Spirocyclic amides as cannabinoid receptor modulators
JP2005531520A (en) 2002-03-28 2005-10-20 メルク　エンド　カムパニー　インコーポレーテッド Substituted 2,3-diphenylpyridines
AU2003223510B2 (en) 2002-04-12 2008-05-08 Merck Sharp & Dohme Corp. Bicyclic amides
US6825209B2 (en) 2002-04-15 2004-11-30 Research Triangle Institute Compounds having unique CB1 receptor binding selectivity and methods for their production and use
DE60316829T2 (en) 2002-08-02 2008-07-10 Merck & Co., Inc. SUBSTITUTED FURO [2,3-B] PYRIDINE DERIVATIVES
JP2006510597A (en) 2002-09-27 2006-03-30 メルク　エンド　カムパニー　インコーポレーテッド Substituted pyrimidines
US7129239B2 (en) 2002-10-28 2006-10-31 Pfizer Inc. Purine compounds and uses thereof
US7247628B2 (en) 2002-12-12 2007-07-24 Pfizer, Inc. Cannabinoid receptor ligands and uses thereof
EP1575901B1 (en) 2002-12-19 2012-10-10 Merck Sharp & Dohme Corp. Substituted amides
US7329658B2 (en) 2003-02-06 2008-02-12 Pfizer Inc Cannabinoid receptor ligands and uses thereof
US7176210B2 (en) 2003-02-10 2007-02-13 Pfizer Inc. Cannabinoid receptor ligands and uses thereof
US7268133B2 (en) 2003-04-23 2007-09-11 Pfizer, Inc. Patent Department Cannabinoid receptor ligands and uses thereof
US7145012B2 (en) 2003-04-23 2006-12-05 Pfizer Inc. Cannabinoid receptor ligands and uses thereof
US20040224963A1 (en) * 2003-05-09 2004-11-11 Pfizer Inc Pharmaceutical composition for the prevention and treatment of nicotine addiction in a mammal
US20040224962A1 (en) * 2003-05-09 2004-11-11 Pfizer Inc Pharmaceutical composition for the treatment of obesity or to facilitate or promote weight loss
WO2004113320A1 (en) * 2003-05-20 2004-12-29 The University Of Tennessee Research Foundation Cannabinoid derivatives, methods of making, and use thereof
US7232823B2 (en) 2003-06-09 2007-06-19 Pfizer, Inc. Cannabinoid receptor ligands and uses thereof
WO2005044785A1 (en) * 2003-10-30 2005-05-19 Merck & Co., Inc. Aralkyl amines as cannabinoid receptor modulators
NZ580387A (en) 2004-07-12 2011-06-30 Cadila Healthcare Ltd Tricyclic pyrazole derivatives as cannabinoid receptor modulators
US20060025448A1 (en) 2004-07-22 2006-02-02 Cadila Healthcare Limited Hair growth stimulators
ES2435790T3 (en) 2004-12-03 2013-12-23 Intervet International B.V. Substituted piperazines as CB1 antagonists
KR20080097426A (en) * 2006-01-18 2008-11-05 쉐링 코포레이션 Cannabinoid Receptor Modulators
WO2007121687A1 (en) * 2006-04-26 2007-11-01 Institute Of Pharmacology And Toxicology Academy Of Military Medical Sciences P.L.A. China 4-methyl-1h-diaryl pyrazole derivatives and their uses as medicament
CN101062919B (en) * 2006-04-26 2012-08-15 中国人民解放军军事医学科学院毒物药物研究所 4-methyl-1H-diaryl pyrromonazole derivative and medicament usage thereof
US20070287734A1 (en) * 2006-06-09 2007-12-13 Auspex Pharmaceuticals, Inc. Preparation and utility of substituted pyrazole compounds with cannabinoid receptor activity
RU2455981C2 (en) * 2006-06-16 2012-07-20 Теракос, Инк. Treatment of obesity with antagonists of muscarinic receptor m1
AU2007312233B2 (en) * 2006-10-20 2012-09-20 Abbvie B.V. Micellar nanoparticles of chemical substances
US20100197564A1 (en) * 2007-04-19 2010-08-05 Schering Corporation Diaryl morpholines as cb1 modulators
WO2009005646A2 (en) * 2007-06-28 2009-01-08 Schering Corporation Substituted piperazines as cb1 antagonists
EP2170847A2 (en) * 2007-06-28 2010-04-07 Intervet International BV Substituted piperazines as cb1 antagonists
EP2095814A1 (en) * 2008-02-26 2009-09-02 Wolfgang J. Kox Nicotine withdrawal supported by medication
WO2010018856A1 (en) * 2008-08-13 2010-02-18 持田製薬株式会社 Prophylactic/ameliorating or therapeutic agent for cannabinoid receptor-related disease
RU2533224C2 (en) * 2010-07-21 2014-11-20 Мапикс Эс.Эй.Ар.Эл. Method of treating psychoactive substance dependence, alcohol and nicotine addiction and medication for treatment of psychoactive substance dependence, alcohol and nicotine addiction
WO2013068371A1 (en) 2011-11-08 2013-05-16 Intervet International B.V. Soft chewable dosage form compositions of cannabinoid receptor type 1 (cb-1) antagonists
WO2014181357A1 (en) * 2013-05-09 2014-11-13 Council Of Scientific & Industrial Research Novel pyrazole derivatives with silicon incorporation
US10897925B2 (en) 2018-07-27 2021-01-26 Joseph Pandolfino Articles and formulations for smoking products and vaporizers
US20200035118A1 (en) 2018-07-27 2020-01-30 Joseph Pandolfino Methods and products to facilitate smokers switching to a tobacco heating product or e-cigarettes

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5624941A (en) * 1992-06-23 1997-04-29 Sanofi Pyrazole derivatives, method of preparing them and pharmaceutical compositions in which they are present
US5780051A (en) * 1992-04-02 1998-07-14 Dynagen, Inc. Methods and articles of manufacture for nicotine cessation and monitoring nicotine use
US6344474B1 (en) * 1997-01-28 2002-02-05 Sanofi-Synthelabo Use of central cannabinoid receptor antagonists for regulating appetence
US6930122B2 (en) * 2000-02-09 2005-08-16 Sanofi-Aventis Use of central cannabinoid receptor antagonist for preparing medicines designed to facilitate smoking cessation

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2713225B1 (en) * 1993-12-02 1996-03-01 Sanofi Sa Substituted N-piperidino-3-pyrazolecarboxamide.
US5596106A (en) * 1994-07-15 1997-01-21 Eli Lilly And Company Cannabinoid receptor antagonists
FR2765107B1 (en) * 1997-06-26 2000-03-24 Sanofi Sa USE OF A SPECIFIC 5HT2 RECEPTOR ANTAGONIST FOR THE PREPARATION OF MEDICINES USEFUL IN THE TREATMENT OF SLEEP APNEA SYNDROME
FR2789079B3 (en) 1999-02-01 2001-03-02 Sanofi Synthelabo PYRAZOLECARBOXYLIC ACID DERIVATIVE, ITS PREPARATION, PHARMACEUTICAL COMPOSITIONS CONTAINING SAME

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5780051A (en) * 1992-04-02 1998-07-14 Dynagen, Inc. Methods and articles of manufacture for nicotine cessation and monitoring nicotine use
US5624941A (en) * 1992-06-23 1997-04-29 Sanofi Pyrazole derivatives, method of preparing them and pharmaceutical compositions in which they are present
US6344474B1 (en) * 1997-01-28 2002-02-05 Sanofi-Synthelabo Use of central cannabinoid receptor antagonists for regulating appetence
US20020128302A1 (en) * 1997-01-28 2002-09-12 Jeanne Maruani Use of central cannabinoid receptor antagonists for the preparation of drugs
US6930122B2 (en) * 2000-02-09 2005-08-16 Sanofi-Aventis Use of central cannabinoid receptor antagonist for preparing medicines designed to facilitate smoking cessation

Also Published As

Publication number Publication date
BG106946A (en) 2003-05-30
JP2010018622A (en) 2010-01-28
SK11292002A3 (en) 2003-02-04
NO20023765L (en) 2002-10-09
UA72783C2 (en) 2005-04-15
CZ296685B6 (en) 2006-05-17
CA2397262C (en) 2007-09-11
IS6450A (en) 2002-06-28
NO20023765D0 (en) 2002-08-08
EP1257275A2 (en) 2002-11-20
HUP0300237A2 (en) 2003-07-28
HK1051140A1 (en) 2003-07-25
CA2397262A1 (en) 2001-08-16
IL150710A0 (en) 2003-02-12
ATE292467T1 (en) 2005-04-15
RS50404B (en) 2009-12-31
AU781827B2 (en) 2005-06-16
FR2804604A1 (en) 2001-08-10
WO2001058450A2 (en) 2001-08-16
YU59002A (en) 2005-07-19
FR2804604B1 (en) 2005-05-27
DE60109903T2 (en) 2006-02-09
AR028505A1 (en) 2003-05-14
BR0108126A (en) 2003-01-28
EE04836B1 (en) 2007-06-15
SI1257275T1 (en) 2005-10-31
US6930122B2 (en) 2005-08-16
SK284952B6 (en) 2006-03-02
PL201685B1 (en) 2009-04-30
HU225328B1 (en) 2006-09-28
TWI243677B (en) 2005-11-21
PL358221A1 (en) 2004-08-09
PT1257275E (en) 2005-07-29
RU2002118309A (en) 2004-02-20
NZ519924A (en) 2005-01-28
CZ20022698A3 (en) 2002-11-13
BG110386A (en) 2009-09-30
AU3562001A (en) 2001-08-20
CN1250220C (en) 2006-04-12
EP1257275B1 (en) 2005-04-06
JP2003522145A (en) 2003-07-22
EE200200439A (en) 2003-12-15
CN1406128A (en) 2003-03-26
BG65856B1 (en) 2010-03-31
DK1257275T3 (en) 2005-08-08
WO2001058450A3 (en) 2002-04-25
US20030087933A1 (en) 2003-05-08
ZA200205317B (en) 2003-09-04
HUP0300237A3 (en) 2003-09-29
ES2240416T3 (en) 2005-10-16
MXPA02007766A (en) 2002-10-11
NO324521B1 (en) 2007-11-12
RU2257207C2 (en) 2005-07-27
DE60109903D1 (en) 2005-05-12

Similar Documents

Publication Publication Date Title
US6930122B2 (en) Use of central cannabinoid receptor antagonist for preparing medicines designed to facilitate smoking cessation
US6344474B1 (en) Use of central cannabinoid receptor antagonists for regulating appetence
US8088827B2 (en) Use of irbesartan for the preparation of medicinal products that are useful for treating pulmonary hypertension
US20050182089A1 (en) Pharmaceutical composition comprising a monoamine neurotransmitter re-uptake inhibitor and an N-methyl-D-aspartate (NMDA) receptors antagonist
MXPA01010904A (en) Use of saredutant and the pharmaceutically acceptable salts thereof to produce medicaments used to treat or prevent mood disorders, adjustment disorders or mixed anxiety-depression disorders.
EP0884054B9 (en) Fixed-dose association of an angiotensin-converting enzyme inhibitor and of a calcium channel antagonist for the treatment of cardiovascular illnesses
HK1051140B (en) Use of central cannabinoid receptor antagonist for preparing medicines designed to facilitate smoking cessation
MXPA06008113A (en) Pharmaceutical composition comprising a monoamine neurotransmitter re-uptake inhibitor and an n-methyl-d-aspartate (nmda) receptors antagonist

Legal Events

Date Code Title Description
STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION