Classifications

• • 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
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
• • 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
  • A61K31/16—Amides, e.g. hydroxamic acids
  • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
• • 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
• • 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
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
  • A61K31/52—Purines, e.g. adenine
• • 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
  • A61K31/60—Salicylic acid; Derivatives thereof
• • 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
  • A61K31/60—Salicylic acid; Derivatives thereof
  • A61K31/618—Salicylic acid; Derivatives thereof having the carboxyl group in position 1 esterified, e.g. salsalate
  • A61K31/621—Salicylic acid; Derivatives thereof having the carboxyl group in position 1 esterified, e.g. salsalate having the hydroxy group in position 2 esterified, e.g. benorylate

Definitions

• This invention relates to processes for relieving pain in animals and is more particularly concerned with proccesses for relieving protopathic pain in humans.
• compositions used for the suppression of protopathic pain are the salicylates such as sodium salicylate, aspirin, and salicylamide; the acetanilids such as acetophenetidin, acetyl-p-aminophenol and acetanilid; and the narcotics such as morphine, codeine and the like.
• the presently used salicylates and acetanilids do not provide a sufficient depth of analgesia to be fully effective.
• prolonged use of the more analgesic narcotics, such as codeine or morphine may lead to narcotic addiction.
• corticosteroids also used in such circumstances, may give rise to undesirable side-effects, so profound as to necessitate discontinuance of the medication.
• the present invention is based on the unexpected finding that 3,4-dimethylbenzamide exhibits analgesic activity when administered to the animal organism. Oral administration of dosage quantities of the compound to humans gives beneficial relief of protopathic pain without gastric distress or observable toxic, sedative, or hypotensive side-effects.
• the invention sought to be patented resides in the concept of a method of mitigating protopathic pain in humans which comprises the oral administration of 3,4- dimethylbenzamide to a person suffering from protopathic pain, the average daily dose administered being in the range 0.5 to 3.0 grams.
• analgesic effect potentiated, but it was lengthened in duration.
• the analgesia of the compounds was evaluated as compared to placebos administered to the same group of patients.
• analgetic effects lasting from 8 to 15 hours were observed.
• protopathic analgesic effects of 3,4-dimethylbenzamide have also been combined with the different analgesic effects of the narcotic derivatives related to opium such as codeine, morphine and meperidine. This combination provides analgesic protection against intense pains having both protopathic and epicritic components.
• 3,4-dimethylbenzamide lowers the body temperature in pyrexic rats when tested by the method of Boxhill et al., J. A. Ph. A., 47, 479 (1958).
• the response to the administration of 3,4-dimethylbenzamide is much more rapid than that of aspirin or salicylamide.
• This antipyretic effect was studied in humans; two pyretic patients suffering from nonspecific fevers had their temperature return to normal within three hours after the oral administration of 500 milligrams of 3,4- dimethylbenzamide.
• 3,4-dimethylbenzamide was administered to two series of hypertensive patients.
• the first series of 30 patients had severe hypertension with average blood pressures of 230/126 millimeters and had been under careful observation as hypertensives prior to the study.
• 3,4-dimethylbenzamide was administered orally to each patient in doses of 250 milligrams, four times a day. At the end of one month, these patients showed no average reduction in blood pressure and hence no hypotensive response to 3,4-dimethy1benzamide.
• the patients having less severe hypertension with an average blood pressure of I00 millimeters the administration of 3,4 dimethylbenzamide caused no significant decrease in blood pressure. This lack of hypertensive activity is of great value, since this material can be used routinely and safely as an analgesic or in combination with other analgesics without causing undesirable changes in blood pressure.
• 3,4-dimethylbenzamide can be administered alone or in combination with the other analgetics. It may be administered by mouth in aqueous suspension or solutions, more conveniently in solid form via capsules and tablets.
• aqueous suspension or solutions more conveniently in solid form via capsules and tablets.
• the following non-limiting series of formulations are illustrative of the proportions of ingredients required per 1000 tablets to give tablets suitable for oral administration:
• FORMULATION B The ingredients were mixed, granulated, dried, and then pressed into tablets.
• FORMULATION F Grams 3,4-dimethylbenzamide 250 Aspirin 300 Phenacetin 150 Caffeine 30 Carbowax 20 Starch 100 The formulation was mixed and pressed into tablets.
• the amount of 3,4-dimethylbenzamide in each dosage form depends on the frequency of administration, the intensity of the pain being treated, and the total daily amount of the therapeutic agents that it is desired to have administered.
• the average daily dose for a human adult falls in the range 0.5 to 3.0 grams, preferably in the range 1.0 to 2.0 grams, when administered alone or in conjunction with the analgesics.
• the average daily dose is usually administered in divided doses, the dosage form conveniently containing 0.25 or 0.50 gram of 3,4-dimethylbenzamide.
• Example 1 Preparati0n of 3,4-Dz'm thylb nzonitrile Slowly heat to 225-230 degrees with stirring 27.75 grams of 4-bromo-o-xylene, 14.85 grams of cuprous cyanide, and 1.20 grams of pyridine. When the initial reaction is substantially complete as evidenced by the disappearance of the foam and the brown color of the reaction mixture, the reaction mixture is maintained at 230-232 degrees for an additional 3 hours and then cooled. Toluene is added and the mixture filtered. The precipitate is washed with hot toluene. The filtrate and wash liquors are combined and the toluene removed by evaporation. The residue is flash distilled under vacuum, 148-152 degrees at 54 millimeters. The 3,4-dimethylbenzonitrile thus obtained is recrystallized from ethanol to a melting point of 648-66 degrees.
• Example 2 Preparation of 3,4-Dimethylbenzamia'e Via the Acid 3,4-dimethylbenzonitrile is hydrolyzed in 75 milliliters of 10 percent aqueous sodium hydroxide solution containing 10 milliliters of ethanol by refluxing for 8 hours. The reaction mixture is cooled, diluted, and filtered. The filtrate, the sodium salt of 3,4-dimethylbenzoic acid, is neutralized with hydrochloric acid. The free acid is separated and recrystallized from aqueous alcohol to a melting point of 166-168 degrees.
• 3,4-dimethylbenzoyl chloride is slowly added to concentrated ammonia. solution.
• the reaction mixture is maintained at 10-15 degrees for one hour.
• the mixture is then filtered and the cake washed with cold water at 5-10 degrees.
• the product, 3,4-dimethylbenzamide is obtained in 97 percent yield and has a melting point range of 111.5-112.5 degrees.
• Example 3-Preparali0n of 3,4-Dimethylbenzamide by Oxidation of the Nitrile A flask equipped for heating and cooling is charged with 30 milliliters of ethanol and 33 grams of 30 percent hydrogen peroxide and its contents adjusted to pH 10 with sodium hydroxide. To this solution is added 10 grams of 3,4-dimethylbenzonitrile and the reaction mixture maintained at 48-50 degrees for 3 hours. The reaction mixture is then cooled to ice temperature and filtered. The precipitate is washed with ice water and then dried to yield 3,4-dimethylbenzamide having a melting point range of 111-113 degrees in 96 percent yield.
• the method of mitigating protopathic pain in animals which comprises the oral administration of 3,4- dimethylbenzarnide to an animal having protopathic pain.
• the method of mitigating protopathic pain in humans which comprises the oral administration of dosage units of 3,4-dimethylbenzamide to a person suffering from protopathic pain.
• dirnethylbenzamide to a person suffering from protopathic pain, the average daily dosage administered being in the range 0.5 to 3.0 grams.
• the method of mitigating protopathic pain in humans which comprises the oral administration of 3,4- dimethylbenzamide to a person suffering from protopathic pain, the average daily dose administered being in the range 1.0 to 2.0 grams.
• the method of mitigating protopathic pain in humans which comprises the oral administration of 3,4- dimethylbenzamide in divided doses to a person suffering from protopathic pain, the average daily dose administered 5 being in the range 1.0 to 2.0 grams.

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• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Emergency Medicine (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

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Cited By (6)

• 0
  • BE BE618035D patent/BE618035A/xx unknown
• 1961
  • 1961-05-26 US US112776A patent/US3086911A/en not_active Expired - Lifetime
  • 1961-10-06 GB GB36035/61A patent/GB926584A/en not_active Expired
• 1962
  • 1962-03-09 FR FR890571A patent/FR1815M/fr not_active Expired

Non-Patent Citations (1)

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