US3466377A - Aralkyl aliphatic sulfoxide oral,parenteral and rectal dosage units for pain,fever and inflammation - Google Patents

Aralkyl aliphatic sulfoxide oral,parenteral and rectal dosage units for pain,fever and inflammation Download PDF

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US3466377A
US3466377A US569054A US3466377DA US3466377A US 3466377 A US3466377 A US 3466377A US 569054 A US569054 A US 569054A US 3466377D A US3466377D A US 3466377DA US 3466377 A US3466377 A US 3466377A
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sulfoxide
benzyl
oral
pain
fever
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Clifford H Shunk
Tsung-Ying Shen
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Merck and Co Inc
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Merck and Co Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides

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  • This invention relates to a method of treating inflammation in its varying manifestations, utilizing novel antiinflammatory compositions containing an aralkyl alkyl sulfoxide.
  • novel compositions exhibit potent analgesic and antipyretic activity and, therefore, this invention also relates to analgesic and antipyretic methods and compositions. More particularly, this invention is concerned with the use of benzyl methyl sulfoxide as the active therapeutic ingredient in the herein described methods and compositions.
  • Benzyl methyl sulfoxide and the related aralkyl sulfoxides of this invention represent a new milestone in the continuing search for potent, low toxicity, anti-inflammatory agents.
  • These sulfoxides provide a unique structureactivity relationship which not only has resulted in high anti-inflammatory, antipyretic, and analgesic potency, but also appear to exhibit a biological profile quite different from the salicylates and phenylbutazone.
  • a disease condition symptomatically evidenced by pain, fever and inflammation, either as essential or concomitant phenomena of the disease
  • a pharmaceutically acceptable composition containing a therapeutically effective amount of an aralkyl sulfoxide, such as benzyl methyl sulfoxide.
  • an aralkyl sulfoxide such as benzyl methyl sulfoxide.
  • R represents alkyl of from 1 to about 16 carbon atoms, preferably, of from 1 to about 4 carbons, such as methyl, ethyl, propyl and butyl, cycloloweralkyl such as cyclopentyl and cyclohexyl, loweralkenyl, haloloweralkenyl, haloloweralkyl, or nitroloweralkyl.
  • R represents hydrogen, halo, loweralkyl, nitroloweralkyl, or loweralkylsulfoxyl.
  • X and Y are hydrogen, halo, nitro, or loweralkyl.
  • Loweralkyl and loweralkenyl means groups of from 1 to about 3 carbons, and halo refers to chloro and bromo.
  • a preferred embodiment of this invention is a method of treating a disease which is symptomatically character- 3,466,377 Patented Sept. 9, 1969 ized by pain, fever and/ or inflammation which comprises the administration in dosage unit form of between about 0.01 and 5 gm. of a benzyl methyl sulfoxide per day. On a kilogram basis, it is preferred to utilize between about 0.5 mg./kg. and 70 mg./kg. per day to a patient of the aralkyl hydrocarbyl sulfoxides of this invention.
  • compositions in dosage unit form which comprise from about 5 to 500 mg, and preferably from 25 to 250 mg, of an aralkyl hydrocarbyl sulfoxide of the above formula.
  • Benzyl methyl sulfoxide, in oral dosage unit form, comprising about 25 to about 500 mg. is a preferred pharmaceutical composition of this invention.
  • the aralkyl hydrocarbyl sulfoxide active ingredient of the compositions of this invention demonstrates significant anti-inflammatory analgesic and antipyretic properties.
  • anti-inflammatory activity of a high order of potency was shown for benzyl methyl sulfoxide against carrageenan edema, using the method set forth in Proc. Soc. Exp. Biol. Med. 3: 544 (1962).
  • the minimum dose required for dependable demonstration of anti-inflammatory activity was about 3 mg./kg.
  • This compound is also a potent analgesic, as has been shown by antinociceptive testing by the infiammed foot technique of Randall & Selitto, Arch. Int. Parmacodyn.
  • benzyl methyl sulfoxide is a potent analgesic.
  • the sulfoxides of this invention as exemplified by benzyl methyl sulfoxide, exhibit potent antipyretic activity in yeast induced fever tests.
  • Benzyl methyl sulfoxide was demonstrated to have antipyretic activity at dosages as low as 6.25 mg./kg.
  • anti-inflammatory, analgesic and antipyretic activity can be demonstrated for other active sulfoxide ingredients of this invention, e.g.
  • benzyl ethyl sulfoxide benzyl propyl sulfoxide, benzyl butyl sulfoxide, benzyl t-butyl sulfoxide, benzyl decyl sulfoxide, benzyl dodecyl sulfoxide, benzyl nonyl sulfoxide, benzyl hexyl sulfoxide, benzyl isobutyl sulfoxide, benzyl isopropyl sulfoxide, benzyl octyl sulfoxide, benzyl 1,2dichlorovinyl sulfoxide, p-chlorobenzyl 1,2-dichlo-rovinyl sulfoxide and the like.
  • novel sulfoxide compositions of this invention exercise anti-inflammatory, analgesic and antipyretic activity. In general they are indicated for a wide variety of conditions where one or more of the symptoms of inflammation, fever and pain are manifested.
  • compositions may be in a form suitable for oral use, for example, as tablets, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, colouring agents and preserving agents in order to provide a pharmaceutically elegant and palatable preparation.
  • Tablets contain the active sulfoxide ingredient in admixture with nontoxic p-harmaceutically acceptable excipients which are suitable for manufacture of tablets.
  • excipients may be, for example, inert diluents, for example calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example maize starch, or alginic acid; binding agents, for example starch, gelatine or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastro-intestinal tract and thereby provided a sustained action over a longer period.
  • Formulations for oral use may also be presented as hard gelatine capsules wherein the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatine capsules wherein the active ingredient is mixed with an oil medium, for example arachis oil, liquid paraffin or olive oil.
  • an inert solid diluent for example calcium carbonate, calcium phosphate or kaolin
  • an oil medium for example arachis oil, liquid paraffin or olive oil.
  • Aqueous suspensions contain the active aralkyl hydrocarbyl sulfoxides in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethyl cellulose, methyl cellulose, hydroxypropylmethyl cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol, for example polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydr
  • the said aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more colouring agents, one or more fiavouring agents and one or more sweetening agents, such as sucrose, saccharin, or sodium or calcium cyclamate.
  • preservatives for example ethyl, or n-propyl, p-hydroxybenzoate
  • one or more colouring agents for example ethyl, or n-propyl, p-hydroxybenzoate
  • one or more colouring agents for example ethyl, or n-propyl, p-hydroxybenzoate
  • one or more colouring agents for example ethyl, or n-propyl, p-hydroxybenzoate
  • colouring agents for example ethyl, or n-propyl, p-hydroxybenzoate
  • one or more fiavouring agents such as sucrose, saccharin, or sodium
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid parafiin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol.
  • Sweetening agents, such as those set forth above, and fiavouring agents may be added to pro vide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • a dispersing or wetting agent e.g., glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, g., g., g., g., g., g., g., sorbitol, g., sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, gly
  • the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oils, or a mineral oil, for example liquid paraffin or mixtures or these.
  • Suitable emulsifying agents may be naturally occurring gums, for example gum acacia or gum tragacanth, naturally occurring phosphatides, for example soya bean lecithin, and esters of partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and fiavouring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and fiavouring and colouring agents.
  • the pharmaceutical compositions may be in the form of a sterile injectable preparation, for example as a sterile injectable aqueous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenternally acceptable diluent or solvent, for example as a solution in 1,3-butane diol.
  • compositions of this invention may also be in the form of suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable nonirritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable nonirritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable nonirritating excipient are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials are cocoa butter and polyethylene glycols.
  • compositions may be tableted or otherwise formulated so that for every 100 parts by weight of the composition there are present between 5 and parts by weight of the active ingredient and preferably between 25 and 85 parts by weight of the active ingredient.
  • the dosage unit form will generally contain between about mg. and about 500 mg. of the active ingredient of the formula stated above.
  • compositions of this invention can be administered orally, parenterally, and rectally.
  • parenteral as used herein includes subcutaneous injection, intravenous, intramuscular, or intrasternal injection or infusion techniques.
  • the dosage regimen in carrying out the methods of this invention is that which insures maximum therapeutic response until improvement is obtained and thereafter is the minimum effective level which gives relief.
  • the dosages are those that are therapeutically effective in the treatment of inflammation, pain and fever.
  • the daily dose can be between about 0.5 mg./ kg. and 70 mg./kg., bearing in mind, of course, that in selecting the appropriate dosage in any specific case, consideration must be given to the patients weight, general health, age and other factors which may influence response to the drug.
  • compositions of this invention will generally be administered in dosage units of between 5 and 500 mg. of active ingredient.
  • Preferred compositions for ease of administration are in oral dosage unit form, e.g., tablets or capsules, containing between 25 and 500 mg. of a sulfoxide of this invention.
  • EXAMPLE 1 A mixture of 250 parts of benzyl methyl sulfoxide and 25 parts of lactose is granulated with suitable water, and to this is added 100 parts of maize starch. The mass is passed through a 16 mesh screen. The granules are dried at a temperature below 60 C. The dry granules are passed through a 16 mesh screen, and mixed with 3.8 parts of magnesiumstearate. They are then compressed into tablets suitable for oral administration.
  • the benzyl methyl sulfoxide used in the foregoing example may be replaced by 25, 100 or 500 parts of benzyl methyl sulfoxide, benzyl propyl sulfoxide, benzyl isopropyl sulfoxide, benzyl n-butyl sulfoxide, benzyl isobutyl sulfoxide, benzyl t-butyl sulfoxide, benzyl ethyl sulfoxide, benzyl dodecyl sulfoxide, 2-chlorobenzyl methyl sulfoxide, u-methane sulfoxyl benzyl methyl sulfoxide, and the like sulfoxides of this invention to produce tablets suitable for oral administration as an anti-inflammatory,
  • antipyretic and/or analgesic according to the method of this invention.
  • EXAMPLE 3 A mixture of 250 parts of benzyl butyl sulfoxide, 200 parts of maize starch and 30 parts of alginic acid is mixed with a suflicient quantity of a 10% aqueous paste of maize starch, and granulated. The granules are dried in a current of warm air and the dry granules are then passed through a 16-mesh screen, mixed with 6 parts of magnesium stearate and compressed into tablet form to obtain tablets suitable for oral administration.
  • EXAMPLE 4 A mixture of 500 parts benzyl decyl sulfoxide, 60 parts of maize starch and 20 parts of gum acacia is granulated with a sufficient quantity of water. The mass is passed through a 12-mesh screen and the granules are dried in a current of warm air. The dry granules are passed through a l6-mesh screen, mixed with 5 parts of magnesium stearate and compressed into tablet form suitable for oral administration.
  • aralkyl hydrocarbyl sulfoxides of this invention are produced by well-known techniques, such as oxidation of the corresponding sulfide with dilute sodium periodate or hydrogen peroxide. These methods are more fully set forth in Synthetic Organic Chemistry, John Wiley & Sons, Inc., New York, pages 801-803 (1953), and by the following examples.
  • EXAMPLE 6 Benzyl bis-methyl sulfoxide A solution of 16.6 g. of sodium metaperiodate in 250 ml. of water is added, with stirring and cooling to 0-5 C., to a solution of 7.0 g. of benzyl bis-methyl sulfide in 250 ml. of methanol and stirring is continued at 0-5 for 14 hours. The mixture was filtered, and the filtrate is extracted with 3 x 200 m1. of methylene chloride. The extract is dried over magnesium sulfate and concentrated under reduced pressure at 25 to give 7.9 g. of oil which crystallizes on standing. The solids are recrystallized from methanol-ether solution to give 2.43 g. of product, M.P.
  • EXAMPLE 7 Benzyl 1,1-dimethyl-2-nitroethyl sulfoxide Utilizing the method of Example 5 but employing 8.1 g. of benzyl 1,1-dimethyl-2-nitroethyl sulfoxide in place of the 2-chlorobenzyl methyl sulfide, there is obtained benzyl 1,1-dimethyl-2-nitroethyl sulfoxide.
  • EXAMPLE 8 a-Chlorobenzyl methyl sulfoxi'de Utilizing the method of Example 5 but employing 6.2 g. of a-chlorobenzyl methyl sulfide in place of the 2- chlorobenzyl methyl sulfide, there is obtained a-chlorobenzyl methyl sulfoxide.
  • a method of treating a disease exhibiting at least one of the symptoms of pain, fever, and inflammation which comprises the oral, parenteral or rectal administration in unit dosage form of a pharmaceutically acceptable composition containing a therapeutically effective amount of a compound having the following formula:
  • R is a member selected from the group consisting of alkyl of from 1 to 16 carbon atoms, cyclolower alkyl, loweralkenyl, haloloweralkyl, nitroloweralkyl, and lowersulfoxyl; and X and Y are members selected from. the group consisting of hydrogen, halo, nitro, and loweralkyl, wherein loweralkyl and loweralkenyl mean from 1 to 3 carbons, and halo refers to chloro and bromo.
  • a method of treating a disease, exhibiting at least one of the symptoms of pain, fever and inflammation which comprises the oral, parenteral or rectal administration in dosage unit form of a therapeutically effective amount of benzyl methyl sulfoxide.
  • composition is in a parenteral dosage unit form suitable for oral administration.
  • composition is in a parenteral dosage unit form suitable for oral administration.
  • composition is in a dosage unit form suitable for parenteral administration.
  • composition is in a dosage unit form suitable for parenteral administration.
  • a pharmaceutical composition in oral dosage unit form comprising an oral pharmaceutical carrier vehicle and between about 25 and 250 mg. of benzyl methyl sulfoxide.
  • a method of treating a disease exhibiting at least one of the symptoms of pain, fever, and inflammation which comprises the oral, parenteral or rectal administration in unit dosage form of a pharmaceutically acceptable composition containing a therapeutically effective amount of a compound having the following formula:
  • R is a member selected from the group consisting of alkyl of from 1 to 4 carbon atoms, cyclopentyl, cyclohexyl, lower alkenyl, haloloweralkenyl, haloloweralkyl, and nitrolo-weralkyl; R is a member selected from the group consisting of hydrogen, haloloweralkyl, nitroloweralkyl, and loweralkylsulfoxyl; and X and Y are members selected from the group consisting of hydrogen, halo, nitro, and loweralkyl, wherein loweralkyl and lower alkenyl mean from 1 to 3 carbons, and halo refers to chloro and bromo.
  • a pharmaceutical composition in oral, parenteral or rectal dosage unit form comprising an oral, parenteral or rectal pharmaceutical carrier vehicle and between about 5 and 500 mg. of a compound having the following formula:
  • R is a member selected from the group consisting of alkyl of from 1 to 4 carbons, cyclopentyl, cyclohexyl, lower alkenyl, haloloweralkenyl, haloloweralkyl, nitroloweralkyl, and loweralkylsulfoxyl; and X and Y are members selected from the group consisting of hydrogen, halo, nitro, and loweralkyl, wherein loweralkyl and loweralkenyl mean from 1 to 3 carbons, and halo refers to chloro and bromo.
  • R is a member selected from the group con sisting of alkyl of from 1 to 16 carbon atoms, cycloloweralkyl, loweralkenyl, haloloweralkenyl, haloloweralkyl, and nitroloweralkyl; R isa member selected from the group consisting of hydrogen, haloloweralkyl, nitroloweralkyl, and loweralkylsulfoxyl; and X and Y are members selected from the group consisting of hydrogen, halo, nitro, and loweralkyl, wherein loweralkyl and loweralkenyl mean from 1 to 3 carbons, and halo refers to chloro and bromo.
  • composition of claim 12 wherein said compound is benzyl methyl sulfoxide.
  • composition of claim 12 in oral dosage unit form 14.
  • composition of claim 12 in parenteral dosage unit form 15. The composition of claim 12 in parenteral dosage unit form.
  • R' is a member selected from the group consisting of hydrogen, haloloweralkyl, nitroloweralkyl and lower alkylsulfoxyl;

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US569054A 1966-08-01 1966-08-01 Aralkyl aliphatic sulfoxide oral,parenteral and rectal dosage units for pain,fever and inflammation Expired - Lifetime US3466377A (en)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4064178A (en) * 1975-05-19 1977-12-20 Ppg Industries, Inc. Bis(4-chlorophenyl)methyl methyl sulfoxide
US4103031A (en) * 1976-06-30 1978-07-25 Ppg Industries, Inc. Control of plant pests with bis(4-chlorophenyl)methyl methyl sulfoxide
US4117168A (en) * 1976-07-07 1978-09-26 Ppg Industries, Inc. Antifungal di(aryl)methyl alkyl sulfones
US5167846A (en) * 1990-02-05 1992-12-01 Ciba-Geigy Corporation Sulfoxides of bisthiomethylated and tristhiomethylated phenols

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3196184A (en) * 1962-04-02 1965-07-20 Proeter & Gamble Company Sulfoxonium compounds
US3288860A (en) * 1965-03-30 1966-11-29 Procter & Gamble Alkali metal salts of sulfinyl carbanions and alkali metal alkanesulfenates, processes for their preparation and reactions thereof with alkyl halides

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3196184A (en) * 1962-04-02 1965-07-20 Proeter & Gamble Company Sulfoxonium compounds
US3288860A (en) * 1965-03-30 1966-11-29 Procter & Gamble Alkali metal salts of sulfinyl carbanions and alkali metal alkanesulfenates, processes for their preparation and reactions thereof with alkyl halides

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4064178A (en) * 1975-05-19 1977-12-20 Ppg Industries, Inc. Bis(4-chlorophenyl)methyl methyl sulfoxide
US4067909A (en) * 1975-05-19 1978-01-10 Ppg Industries, Inc. Novel di(aryl)methyl alkyl sulfones
US4103031A (en) * 1976-06-30 1978-07-25 Ppg Industries, Inc. Control of plant pests with bis(4-chlorophenyl)methyl methyl sulfoxide
US4117168A (en) * 1976-07-07 1978-09-26 Ppg Industries, Inc. Antifungal di(aryl)methyl alkyl sulfones
US5167846A (en) * 1990-02-05 1992-12-01 Ciba-Geigy Corporation Sulfoxides of bisthiomethylated and tristhiomethylated phenols

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NL6710628A (enrdf_load_stackoverflow) 1968-02-02
BE702103A (enrdf_load_stackoverflow) 1968-01-31

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