SMOKING SUPPRESSION
United States Patent 3622676
A method of treating the habit of tobacco smoking by suppressing the pleasure associated with the taste of smoke is disclosed in which a bis-(B-di-lower alkylaminoethyl) disulfide composition is administered over a period of several days to generate a feeling of distaste and discomfort when smoking.
Application Number:
04/777461
Publication Date:
11/23/1971
Filing Date:
11/20/1968
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Export Citation:
Assignee:
Drucker, William Anthony (Washington, CT)
, Maibach Howard Ira (Kentfield, CA)
, Maibach Howard Ira (Kentfield, CA)
Primary Class:
Other Classes:
514/813
International Classes:
A61K45/00; A61K27/00
Field of Search:
424/325 260/583EE
Other References:
chem. Abstracts, Sec. 6861 (d), Vol. 47 (1953) .
Chem. Abstracts, Sec. 17149 (b), Vol. 50 (1956) .
Chem. Abstracts, Sec. 13212 (i), Vol. 51 (1957) .
Smoking & Health (U.S.E.P.O.) pp. 354-355 (1964).
Primary Examiner:
Rosen, Sam
Parent Case Data:
This application is a continuation-in-part application of abandoned application Ser. No. 236,414 filed Nov. 8, 1962, and of copending application Ser. No. 342,227 filed Feb. 3, 1964.
Claims:
I claim
1. A method of suppressing the desire to smoke tobacco and the satisfaction derived therefrom which comprises orally administering to a smoker prior to smoking a composition comprising a compound selected from bis-(B-di-lower alkylaminoethyl) disulfide and the therapeutically active acid addition salts thereof in a dosage per kilo of body weight from 0.1 to about 15 milligrams.
2. A method according to claim 1 in which the compound is bis-(B-diethylaminoethyl) disulfide.
3. A method according to claim 1, in which the compound is in dosage unit form of from 100 to about 1000 milligrams.
1. A method of suppressing the desire to smoke tobacco and the satisfaction derived therefrom which comprises orally administering to a smoker prior to smoking a composition comprising a compound selected from bis-(B-di-lower alkylaminoethyl) disulfide and the therapeutically active acid addition salts thereof in a dosage per kilo of body weight from 0.1 to about 15 milligrams.
2. A method according to claim 1 in which the compound is bis-(B-diethylaminoethyl) disulfide.
3. A method according to claim 1, in which the compound is in dosage unit form of from 100 to about 1000 milligrams.
Description:
This invention relates to pharmaceutical preparations useful in suppressing the habit of smoking tobacco and to an aversion treatment for suppressing such habit. More particularly, the invention relates to therapeutic compositions such as tablets, capsules, powders, liquids and the like comprising a member selected from the group consisting of bis-(B-di-lower alkylaminoethyl) disulfide and the therapeutically useful addition salts thereof. The invention is also concerned with methods of inhibiting the desire to smoke by the internal administration of said disulfides and salts thereof.
Among the objects of the present invention is the production of therapeutic compositions comprising bis-(B-di-lower alkylaminoethyl) disulfide or the therapeutically useful acid addition salts thereof which may be utilized in curbing the tobacco habit, or at least in diminishing the amount of smoking, such substances producing disagreeable symptoms and signs in the smoker or one who is exposed to tobacco smoke within substantial periods of time after suitable dosages of such substances have been administered.
Other and further objects and advantages, including methods of inhibiting the desire to smoke by the administration of the aforementioned disulfides and by the utilization of the herein described pharmaceutical preparations, will appear from the more detailed description set forth hereinafter, it being understood that such more detailed description is given by way of illustration and explanation only, and not by way of limitation, since various changes therein may be made by those skilled in the art without departing from the scope and spirit of the present invention.
In accordance with the present invention, it has been found that, after the administration of suitable dosages of bis-(B-di-lower alkylaminoethyl) disulfide or the therapeutically useful acid addition salts thereof, there are produced strong and very disagreeable symptoms such as occasional vomiting, belching, a general state of ill-being, or a jittery, nervous condition coupled with an unpleasant, nauseating taste and similar sensations in the mouth and nose of a smoker or one who is exposed to tobacco smoke. The consequence of this aversion treatment is an unpleasant conditioned reflex to smoking.
The bis-(B-di-lower alkylaminoethyl) disulfides that are operable herein may be represented by the formula:
wherein R represents a lower alkyl radical, straight or branch chained, with from one to six carbon atoms. Typical of such lower alkyl radicals, which may be the same or different with respect to the four possible positions indicated in the above formula, are methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl and the like. Of the foregoing possible disulfides, bis-(B-diethylaminoethyl) disulfide is preferred.
The dosage unit forms of the present invention may be formulated in accordance with conventional practices well-known in the art. In general, they are prepared by formulating the therapeutically active bis-(B-di-lower alkylaminoethyl) disulfide or acid addition salts thereof with the required nontoxic, pharmaceutical carriers. Such carriers include those commonly employed in pharmaceutical practice and comprise, for example, in the case of orally ingestible solid dosage unit forms, diluents, binders, lubricants, disintegrators, flavors and the like. In the case of orally ingestible liquid dosage unit forms, said carriers comprise water, edible oils, alcohol, glycol, colors, flavors, sweeteners, suspending agents, surfactants, preservatives and the like. In the case of injectables, including solutions and suspensions, said carriers comprise the commonly employed parenteral fluids such as Water for Injection, U.S.P., vegetable oils, e.g., peanut oil, sesame oil and the like.
In accordance with this invention, the aforementioned pharmaceutical preparations suitably comprise from about 100 to about 1000 milligrams of bis-(B-di-lower alkylaminoethyl)-disulfide or the therapeutically active acid additional salts thereof per dosage unit form, although from about 150 to about 750 milligrams per dosage unit form is preferred. The liquid compositions suitably comprise from about 1 to about 300 milligrams of said active ingredients per milliliter and, preferably, from about 10 to about 150 milligrams per milliliter. The process of this invention involves the administration of such dosage units from 1 to 4 times daily depending upon the age, weight and condition of the subjects to be treated. Expressed differently, the dosage per kilo of body weight of the subject treated may advantageously vary from about 0.1 to about 15 milligrams and, preferably, from about 5 to about 10 milligrams of the active ingredient. The preferred route of administration is by oral ingestion and, preferably, the dosage is taken in the form of a tablet or capsule.
The following examples serve to illustrate the invention:
EXAMPLE 1
Preparation of bis-(B-diethylaminoethyl) disulfide and its hydrochloride.
A solution of 1125 g. (6.65 mole) of B-diethylamino-ethylmercaptan hydrochloride in 4 liters of water is treated with a solution of 540 g. (13.5 mole) of sodium hydroxide in 2 liters of water. The basic solution is treated slowly with 770 g. (6.76 mole) of a 30 percent solution of hydrogen peroxide, while the temperature is maintained at less than 25° C. by the use of a cooling bath.
The reaction mixture is stirred for one hour and the oily product is extracted with ether. The ether solution is dried with anhydrous magnesium sulfate. After filtration, the ether is distilled in vacuo. The product remains as an oil and weighs 859 g., 96 percent of the theoretical yield of bis-B-diethylaminoethyl) disulfide.
The oily product is dissolved in 750 mil. of isopropyl alcohol. This solution is treated with a solution of 233 g. (6.4 mole) of hydrogen chloride in 1 liter of isopropyl alcohol. After standing for 2 hours in an ice bath, the precipated product is filtered. Recrystallization from methyl alcohol gives 878 g. of the dihydrochloride salt, m.p. 217° - 219° C.
EXAMPLE 2
Preparation of bis-(B-dimethylaminoethyl) disulfide and its hydrochloride.
Using the same procedure as in example 1 except that an equivalent quantity of B-dimethylaminoethyl mercaptan is used in place of B-diethylaminoethyl mercaptan, bis-(B-dimethyl-aminoethyl) disulfide and its dihydrochloride salt are obtained.
EXAMPLE 3
Preparation of bis-(B-diethylaminoethyl) disulfide maleate.
By using a solution of 765.6 g. (6.6 moles) of maleic acid in isopropyl alcohol in place of the solution of hydrogen chloride in example 1, bis-(B-diethylaminoethyl) disulfide maleate is obtained.
EXAMPLE 4
A capsule containing 700 mg. of bis-(B-diethyl-aminoethyl) disulfide dihydrochloride is orally ingested after each of three meals daily by a smoker weighing approximately 132 lbs. who averages 30- 40 cigarettes a day. During the second and third day of such administration, a bad-tasting sensation is noticed in the mouth upon smoking. After the third day, two such capsules are taken after meals thrice daily, resulting in an increased severity of symptoms upon smoking such as nausea, jitteriness, bad-taste and general ill-being. As a result, smoking is reduced to about 5 cigarettes a day. After the fifth day, three such capsules are taken after meals thrice daily. Thereafter, the obnoxious symptoms so worsen upon each attempt to smoke that the desire to smoke substantially ceases.
EXAMPLE 5
Two capsules each containing 350 mg. of bis-(B-di-ethylaminoethyl) disulfide dihydrochloride is orally ingested before breakfast and before lunch. Within 24 hours, a foul tasting sensation is noticed in the mouth of a smoker weighing about 140 lbs. who averages 60 cigarettes a day when he attempts to smoke a cigarette.
Among the objects of the present invention is the production of therapeutic compositions comprising bis-(B-di-lower alkylaminoethyl) disulfide or the therapeutically useful acid addition salts thereof which may be utilized in curbing the tobacco habit, or at least in diminishing the amount of smoking, such substances producing disagreeable symptoms and signs in the smoker or one who is exposed to tobacco smoke within substantial periods of time after suitable dosages of such substances have been administered.
Other and further objects and advantages, including methods of inhibiting the desire to smoke by the administration of the aforementioned disulfides and by the utilization of the herein described pharmaceutical preparations, will appear from the more detailed description set forth hereinafter, it being understood that such more detailed description is given by way of illustration and explanation only, and not by way of limitation, since various changes therein may be made by those skilled in the art without departing from the scope and spirit of the present invention.
In accordance with the present invention, it has been found that, after the administration of suitable dosages of bis-(B-di-lower alkylaminoethyl) disulfide or the therapeutically useful acid addition salts thereof, there are produced strong and very disagreeable symptoms such as occasional vomiting, belching, a general state of ill-being, or a jittery, nervous condition coupled with an unpleasant, nauseating taste and similar sensations in the mouth and nose of a smoker or one who is exposed to tobacco smoke. The consequence of this aversion treatment is an unpleasant conditioned reflex to smoking.
The bis-(B-di-lower alkylaminoethyl) disulfides that are operable herein may be represented by the formula:
wherein R represents a lower alkyl radical, straight or branch chained, with from one to six carbon atoms. Typical of such lower alkyl radicals, which may be the same or different with respect to the four possible positions indicated in the above formula, are methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl and the like. Of the foregoing possible disulfides, bis-(B-diethylaminoethyl) disulfide is preferred.
The dosage unit forms of the present invention may be formulated in accordance with conventional practices well-known in the art. In general, they are prepared by formulating the therapeutically active bis-(B-di-lower alkylaminoethyl) disulfide or acid addition salts thereof with the required nontoxic, pharmaceutical carriers. Such carriers include those commonly employed in pharmaceutical practice and comprise, for example, in the case of orally ingestible solid dosage unit forms, diluents, binders, lubricants, disintegrators, flavors and the like. In the case of orally ingestible liquid dosage unit forms, said carriers comprise water, edible oils, alcohol, glycol, colors, flavors, sweeteners, suspending agents, surfactants, preservatives and the like. In the case of injectables, including solutions and suspensions, said carriers comprise the commonly employed parenteral fluids such as Water for Injection, U.S.P., vegetable oils, e.g., peanut oil, sesame oil and the like.
In accordance with this invention, the aforementioned pharmaceutical preparations suitably comprise from about 100 to about 1000 milligrams of bis-(B-di-lower alkylaminoethyl)-disulfide or the therapeutically active acid additional salts thereof per dosage unit form, although from about 150 to about 750 milligrams per dosage unit form is preferred. The liquid compositions suitably comprise from about 1 to about 300 milligrams of said active ingredients per milliliter and, preferably, from about 10 to about 150 milligrams per milliliter. The process of this invention involves the administration of such dosage units from 1 to 4 times daily depending upon the age, weight and condition of the subjects to be treated. Expressed differently, the dosage per kilo of body weight of the subject treated may advantageously vary from about 0.1 to about 15 milligrams and, preferably, from about 5 to about 10 milligrams of the active ingredient. The preferred route of administration is by oral ingestion and, preferably, the dosage is taken in the form of a tablet or capsule.
The following examples serve to illustrate the invention:
EXAMPLE 1
Preparation of bis-(B-diethylaminoethyl) disulfide and its hydrochloride.
A solution of 1125 g. (6.65 mole) of B-diethylamino-ethylmercaptan hydrochloride in 4 liters of water is treated with a solution of 540 g. (13.5 mole) of sodium hydroxide in 2 liters of water. The basic solution is treated slowly with 770 g. (6.76 mole) of a 30 percent solution of hydrogen peroxide, while the temperature is maintained at less than 25° C. by the use of a cooling bath.
The reaction mixture is stirred for one hour and the oily product is extracted with ether. The ether solution is dried with anhydrous magnesium sulfate. After filtration, the ether is distilled in vacuo. The product remains as an oil and weighs 859 g., 96 percent of the theoretical yield of bis-B-diethylaminoethyl) disulfide.
The oily product is dissolved in 750 mil. of isopropyl alcohol. This solution is treated with a solution of 233 g. (6.4 mole) of hydrogen chloride in 1 liter of isopropyl alcohol. After standing for 2 hours in an ice bath, the precipated product is filtered. Recrystallization from methyl alcohol gives 878 g. of the dihydrochloride salt, m.p. 217° - 219° C.
EXAMPLE 2
Preparation of bis-(B-dimethylaminoethyl) disulfide and its hydrochloride.
Using the same procedure as in example 1 except that an equivalent quantity of B-dimethylaminoethyl mercaptan is used in place of B-diethylaminoethyl mercaptan, bis-(B-dimethyl-aminoethyl) disulfide and its dihydrochloride salt are obtained.
EXAMPLE 3
Preparation of bis-(B-diethylaminoethyl) disulfide maleate.
By using a solution of 765.6 g. (6.6 moles) of maleic acid in isopropyl alcohol in place of the solution of hydrogen chloride in example 1, bis-(B-diethylaminoethyl) disulfide maleate is obtained.
EXAMPLE 4
A capsule containing 700 mg. of bis-(B-diethyl-aminoethyl) disulfide dihydrochloride is orally ingested after each of three meals daily by a smoker weighing approximately 132 lbs. who averages 30- 40 cigarettes a day. During the second and third day of such administration, a bad-tasting sensation is noticed in the mouth upon smoking. After the third day, two such capsules are taken after meals thrice daily, resulting in an increased severity of symptoms upon smoking such as nausea, jitteriness, bad-taste and general ill-being. As a result, smoking is reduced to about 5 cigarettes a day. After the fifth day, three such capsules are taken after meals thrice daily. Thereafter, the obnoxious symptoms so worsen upon each attempt to smoke that the desire to smoke substantially ceases.
EXAMPLE 5
Two capsules each containing 350 mg. of bis-(B-di-ethylaminoethyl) disulfide dihydrochloride is orally ingested before breakfast and before lunch. Within 24 hours, a foul tasting sensation is noticed in the mouth of a smoker weighing about 140 lbs. who averages 60 cigarettes a day when he attempts to smoke a cigarette.