Applying antagonist of central cannabinoid receptor for preparing drugs designated for relief in smoking ceasing

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention proposes applying N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazol-3-carboxamide or its salt for manufacturing a medicinal agent used for treatment of nicotine dependence and/or symptoms of nicotine withdrawal syndrome and a method for help in ceasing using tobacco. The claimed compound is known as antagonist of central cannabinoid receptors and agent used for treatment of disorders associated with using psychoactive substances. Indicated compounds are effective with respect to complete or partial tobacco abstinence with elimination of attenuation of nicotine withdrawal syndrome and patients show reduced weight loss or its absence.

EFFECT: valuable medicinal properties of antagonist.

3 cl, 5 ex

 

The present invention relates to a new use of an antagonist of Central cannabinoid receptors, known as SV receptors. More specifically the invention relates to the use of antagonist SW receptors for preparation of medicinal products that are useful to assist with cessation of tobacco use.

Family of compounds having affinity for cannabinoid receptors, are described in several patents and patent applications, in particular in the application for the European patent EP-[space] 576357, which describes pyrazole derivatives, and the patent application WO 96/02248, which describes, in particular, derivatives of benzofuran.

In particular, N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide, which is further referred to as the compound a, the formula

its pharmaceutically acceptable salt and solvate described in European patent EP-[space] 656354 and .Rinaldi-Carmona et al (FEBS Lett., 1994, 350, 240-244) as antagonists of the Central SW receptors.

Described that the compound and its salts, which are antagonists of the Central cannabinoid receptor, can be used to treat disorders associated with the presence of appetite, in particular as anorectic agents, in the treatment of disorders associated with the use of psychotropic substances is STV. Further, international patent application WO 99/00119 discloses the use of an antagonist of Central cannabinoid receptors for the treatment of disorders associated with addiction, that is for the traction control to consumption, particularly the consumption of sugars, carbohydrates, alcohol or drugs, and in more General terms - stimulating the appetite ingredients.

Now found that the compound And its pharmaceutically acceptable salt and solvate help in the cessation of tobacco use and useful in the treatment of nicotine addiction and/or in the treatment of symptoms of the syndrome of nicotine.

Thus, the introduction of the compound And its pharmaceutically acceptable salt or MES make it possible to observe the consumers of tobacco, such as Smoking tobacco, full or partial abstinence from tobacco with early or delayed start. Further, the symptoms of the syndrome nicotine is very significantly reduced or even eliminated, and the weight loss after stopping tobacco use is reduced or does not exist.

In accordance with one aspect of the present invention relates to the use of N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide, its pharmaceutically acceptable salt or MES for preparation of medicinal products that are useful to aid in the cessation of circulation the Oia tobacco, in the treatment of nicotine dependence and/or treating the symptoms of the syndrome of nicotine.

In accordance with the present invention the compound And its pharmaceutically acceptable salt or MES can also be used in combination with another active principle for the preparation of medicinal products that are useful to aid in the cessation of tobacco use in the treatment of nicotine dependence and/or treating the symptoms of the syndrome of nicotine.

For example, the connection And can be combined:

with nicotine agonist nicotine or partial agonist nicotine, or

with a monoamine oxidase inhibitor (MAOI), or

- any other active principle which has demonstrated its effectiveness in helping to quit tobacco consumption, for example an antidepressant such as bupropion, doxepin, nortriptyline, or tranquilizer, such as buspirone, or clonidine.

For use as a medicinal product the compound And its pharmaceutically acceptable salt or MES, single or in combination with other active early, should be incorporated into pharmaceutical compositions.

Thus, an object of the present invention are also pharmaceutical compositions containing combinations of N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide, E. what about the pharmaceutically acceptable salt or MES and other active principle, and this is another active principle is a compound that is useful to aid in the cessation of tobacco use and/or which is useful in the treatment of nicotine dependence and/or treating the symptoms of the syndrome of nicotine. Specified other active principle preferably chosen from:

- nicotine agonist nicotine or partial agonist nicotine, or

- monoamine oxidase inhibitor (MAOI), or

- any other active principle, which has been demonstrated to aid in the cessation of tobacco consumption, for example, antidepressant such as bupropion, doxepin, nortriptyline, or tranquilizer, such as buspirone, or clonidine.

In the pharmaceutical compositions of the present invention for oral, sublingual, transdermal, intramuscular, intravenous, subcutaneous, local or rectal introduction of the active principle, one or in combination with other active early, can be introduced animals and people in the standard form of administration, mixed with conventional pharmaceutical carriers. Usable standard form of introduction include oral forms such as tablets, gelatin capsules, pills, powders, granules, chewing gum and oral solutions or suspensions, sublingual and transbukkalno forms of administration, aerosols, implants is s, local, transdermal, subcutaneous, intramuscular, intravenous, intranasal or intraocular forms of administration and rectal forms of administration.

Active(s) beginning(a) in the pharmaceutical compositions of the present invention is usually prepared(s) in the form of dosage units. The unit dosage contains from 0.5 to 300 mg, more useful - from 5 to 60 mg, and preferably from 5 to 40 mg per unit dosage for daily introduction of one or more than one time per day.

Although these dosages are examples of common situations, there may be special cases when suitable are higher or lower dosage, and such dosages are also part of the invention. In accordance with usual practice, the dosage that is appropriate for each patient is determined by the physician in accordance with the method of administration, age, weight and response of the specified patient.

When preparing a solid composition in tablet form, wetting agent, such as sodium lauryl sulfate, may be added to the micronized or namiranian active start(s), and all of this can be mixed with a pharmaceutical carrier, such as silicon dioxide, starch, lactose, magnesium stearate, talc or the like. Tablets can be coated with sucrose, various polymers or other suitable materials, or alternative, they can be made so that they have a prolonged or delayed activity and so that they continuously release a specified number of active principle.

The drug is in the form of gelatin capsules are prepared by mixing the active(s) are started(started) with a diluent such as a glycol or ether of glycerin and incorporating the resulting mixture into soft or hard gelatin capsules.

The drug is in the form of a syrup or elixir may contain the active(s) beginning(a) together with a sweetener, preferably low-calorie sweetening ingredient, methyl paraben and propyl paraben as antiseptics, as well as an intensifier of taste and aroma and a suitable dye.

Dispersible in water powders or granules can contain the active(s) beginning(a) in a mixture with dispersing or wetting agents, or suspendresume agents such as polyvinylpyrrolidone or polyvidone, and together with sweetening substances or intensifiers taste and aroma.

For rectal injection use suppositories which are prepared with binders, melting at a temperature in the rectum, for example, cocoa butter or polyethylene glycols.

Aqueous suspensions, isotonic saline solutions or sterile injectable solutions which contain pharmacologically with the compatible dispersing agents and/or solubilizing agents, for example propylene glycol or butyleneglycol, are used for parenteral administration.

Thus, preparation of 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 prigotovit oily solution for intramuscular injection, the active principle can be dissolved in triglyceride or ester of glycerin.

The patch in a multilayer form or reservoir, in which the active principle is in an alcohol solution, can be used for transdermal administration.

Active(s) beginning(a) can also be prepared in the form of the drug in the form of microcapsules or microspheres, possibly with one or more than one carrier or additive.

Active(s) beginning(a) also may be represented by(s) in the form of a complex with a cyclodextrin, for example α-, βor γ-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin or methyl-β-cyclodextrin.

To form slow release, which is suitable in the case of treatment of chronic diseases and which can be used include implants. Such implants can be prepared in the form of an oil suspension or in the form of SSP is nsii microspheres in an isotonic environment.

Preferably, the compound a is administered orally, the dosage once a day.

In accordance with another aspect of the invention, the compound And its pharmaceutically acceptable salt or MES and other active principle, combined with him, combined, can be introduced simultaneously, separately or sequentially to aid in the cessation of tobacco use.

The expression “simultaneous application” means the administration of compounds of the composition according to the invention in the same pharmaceutical form.

The expression “separate use” means the introduction at the same time two compounds of the composition according to the invention, in which each connection is a separate pharmaceutical form.

The expression “consistent application” means the introduction of a sequentially first compound of the composition according to the invention in the same pharmaceutical form, and then the second connection of the composition according to the invention in a different pharmaceutical form.

In the case of this “sequential injection” the time elapsing between the introduction of the first compound of the composition according to the invention and introduction of the second connection arrangement, typically less than 24 hours.

Pharmaceutical form containing or only one of the compounds constituting the composition, or a combination of both compounds, the cat is which can be used in various types of applications, as described above, may be suitable, for example, for oral. nasal, parenteral or transdermal administration.

So, in the case of separate application and consistent application of two different pharmaceutical forms can be intended for the same route of administration or different routes of administration (oral and transdermal, or oral and nasal, or parenteral, and transdermal and so on).

The invention thus relates also to a kit to aid in the cessation of tobacco consumption, containing the compound a and other active principle to aid in the cessation of tobacco consumption, where the specified connection and specified the active principle are in separate offices and packaging, which may be the same or different, and are intended for simultaneous, separate or sequential administration. The specified active principle preferably chosen from:

- nicotine agonist nicotine or partial agonist nicotine, or

- monoamine oxidase inhibitor (MAOI), or

- any other active principle, which has been demonstrated to aid in the cessation of tobacco use, such as antidepressant such as bupropion, doxepin, nortriptyline, or tranquilizer, such as buspirone, or clonidine.

The fit is accordance with another aspect of the invention also relates to a method of assistance in stopping tobacco use, at which the consumer of nicotine administered is a therapeutically effective amount of the compound And its pharmaceutically acceptable salts or its MES.

The effects of the compounds As studied on rats, a model that predicts the effects on nicotine dependence: a self-introduction of nicotine in accordance with W.T.Comgal and al. Psychopharmacology, 1989, 99, 473-478.

The compound a, administered at doses of 0.3 and 1 mg/kg reduces statistically significant, the number of nicotine injections to rats that have learned to introduce nicotine intravenously.

Thus, the positive effects of the compounds was observed on these two models.

Double-blind study was conducted with individuals who smoked more than 15 cigarettes per day and who showed symptoms of nicotine addiction. Patients received 40 mg of compound a day for 10 weeks, including 2 weeks before the beginning of the syndrome of tobacco. In the group that was treated, observed a higher level of abstinence compared with placebo group, in particular, in the last four weeks of treatment. The syndrome of tobacco was confirmed by weekly measurement of the levels of exhaled carbon monoxide and cotinine in plasma.

Example 1: gelatin capsules containing a dose of a compound And 5 mg:

Micronized compound And 5,00 mg

Corn starch 51,00 mg

Monohydrate lactose 99,33 mg

Polyvidone 4,30 mg

Sodium lauryl sulfate, 0.17 mg

Cross-linked sodium carboxymethylcellulose 8,50 mg

Purified water: as required

for wet granulation

Magnesium stearate 1.70 mg

For a full opaque white gelatin capsules No. 3, containing 170 mg

Example 2: a gelatin capsule containing a dose of a compound And 10 mg:

Micronized compound And 10,00 mg

Corn starch 51,00 mg

Monohydrate lactose 94,33 mg

Polyvidone 4,30 mg

Sodium lauryl sulfate, 0.17 mg

Cross-linked sodium carboxymethylcellulose 8,50 mg

Purified water: as required

for wet granulation

Magnesium stearate 1.70 mg

For a full opaque white gelatin capsules No. 3, containing 170 mg

Example 3: a gelatin capsule containing a dose of a compound And 20 mg:

Micronized compound And 20,00 mg

Corn starch 51,00 mg

Monohydrate lactose 84,33 mg

Polyvidone 4,30 mg

Sodium lauryl sulfate, 0.17 mg

Cross-linked sodium carboxymethylcellulose 8,50 mg

Purified water: as required

for wet granulation

Magnesium stearate 1.70 mg

For a full opaque white gelatin capsules containing 170 mg

Example 4: a tablet containing a dose of a compound And 10 mg:

ekranizirovannoy connection And 10,00 mg

Corn starch 50,00 mg

The lactose monohydrate 200 mesh 211,50 mg

The hypromellose 6 SDR 9,00 mg

Sodium carboximetilkrahmal 15,00 mg

Sodium lauryl sulfate 1.50 mg

Magnesium stearate 3,00 mg

Purified water: as required

For tablets, the end containing 300 mg

Example 5: a tablet, containing 30 mg dose of compound A:

Micronized compound And 30,00 mg

Corn starch 80,00 mg

The lactose monohydrate 200 mesh 252,00 mg

Povidone K 30 12,00 mg

Crosslinked carboxymethylcellulose sodium 20,00 mg

Sodium lauryl sulfate 2.00 mg

Magnesium stearate 4,00 mg

Purified water: as required

For tablets, the end containing 400 mg

1. The use of N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide, its pharmaceutically acceptable salt or MES for preparation of medicinal products that are useful to aid in the cessation of tobacco use in the treatment of nicotine dependence and/or treating the symptoms of the syndrome of nicotine.

2. Pharmaceutical composition to aid in the cessation of tobacco consumption, for the treatment of nicotine dependence and/or to treat the symptoms of the syndrome nicotine containing an effective amount of N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide, its pharmaceutical is Eski acceptable salt or MES.

3. The way aid in the cessation of tobacco use, treatment of nicotine addiction and/or treatment of symptoms of the syndrome nicotine at which the consumer of nicotine administered is a therapeutically effective amount of N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide, its pharmaceutically acceptable salt or MES.



 

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3 ex, 1 tbl

FIELD: medicine, pharmacy.

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24 cl, 1 tbl, 10 ex

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