US3928624A - Phenol compounds in treating pain, fever and inflammation - Google Patents

Phenol compounds in treating pain, fever and inflammation Download PDF

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US3928624A
US3928624A US464003A US46400374A US3928624A US 3928624 A US3928624 A US 3928624A US 464003 A US464003 A US 464003A US 46400374 A US46400374 A US 46400374A US 3928624 A US3928624 A US 3928624A
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aminomethyl
compound
butyl
inflammation
mixture
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Jr Edward J Cragoe
Everett M Schultz
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Merck and Co Inc
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/13Amines
    • A61K31/135Amines having aromatic rings, e.g. ketamine, nortriptyline
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C37/00Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
    • C07C37/62Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by introduction of halogen; by substitution of halogen atoms by other halogen atoms

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  • ABSTRACT The invention relates to a method of treating inflam- (gl.2 mation employing certain aminomethylphenol [58] Field s I 260/570 9 pounds and to pharmaceutical compositions thereof.
  • R is, C loweralkyl, such as propyl, isopropyl, sec-butyl, t-butyl, t-amyl and the like, but especially t-butyl and isopropyl and R is halogen, such 'as chloro, bromo, fluoro and iodo, andespecially iodo and chloro, in a non-toxic pharmaceutically acceptable carrier. Also included are their non-toxic pharmaceutically acceptable salts, suchas hydrochloric, hydrobromic, hydroiodic, sulfuric, methanesulfonic, isethionic acid and thelike. Salts may also be prepared from the alkali metal bases such as sodium hydroxide, potassium hydroxide and the like.
  • the non-toxic pharmaceutical carrier may be, for example, either a solid or a liquid.
  • exemplary of solid carriers are lactose, corn starch, gelatin, talc, sterotix, stearic acid, magnesium stearate, terra alba, sucrose, agar, pectin and acacia.
  • exemplary of liquid carriers are peanut oil, olive oil, seasame oil, propylene glycol, glycerine, ethanol and water.
  • the carrier or diluent may include a time delay material such as glyc- H eryl monostearate or glyceryl distearate alone or with a WHX.
  • compositions may take the form of tablets, capsules, powders, troches or lozenges, prepared by standard pharmaceutical techniques.
  • a liquid carrier is used, the preparation may be in the form ofa soft gelatin capsule, a syrup, an aqueous solution or aliquid suspension.
  • Suppositories may be prepared in a conventional manner by mixing the compounds of this invention with a suitable nonirritating excipient which is solid at room temperature, but liquid at the rectal temperature.
  • suitable nonirritating excipient which is solid at room temperature, but liquid at the rectal temperature.
  • Such materials are cocoa butter and polyethylene glycol.
  • compositions will contain the active ingredient in an amount of from about 0.1 mg. to 50 mg. per kg. body weight per day (5 mg. to 3.5 g. per patient per day), preferably from about 1 mg. to 15 mg. per kg. body weight per day (50 mg. to l g. per patient per day).
  • the aminomethylphenols are used as topical anti-inflammatory agents and are particularly effective in topical treatment of dermatological disorders and like conditions, such as dermatitis (actinic, atopic, contact, eczematoid, seborrheic and stasis), dermatitis herpetiformis, lichen planus, neurodermatitis, intitrigo, lichen simplex chronicus, and pruritus, as well as for topical treatment of inflammation of the respiratory and intestinal mucosa such as allergic rhinitis, bronchitis, bronchial asthma, bronchiectasis, colitis and the like.
  • dermatological disorders and like conditions such as dermatitis (actinic, atopic, contact, eczematoid, seborrheic and stasis), dermatitis herpetiformis, lichen planus, neurodermatitis, intitrigo, lichen simplex chronicus, and pruritus, as well as for topical treatment of inflammation of the respiratory
  • These aminomethylphenols are ordinarily administered in the form of a pharmaceutical composition comprising the active compound in combination with a pharmacologically acceptable carrier adapted for topical administration.
  • topical pharmaceutical compositions may be in the form of a-cream, ointment, gel or aerosol formulation adapted for application to the skin for treatment of dermatoses; or it may be in the formof a solution, suspension or aerosoLadapted for topical spray application to respiratory passages for treatment of nasal allergies, bronchial inflammation, and the like; or in the form of suppositories or enclosed in enteric capsules for treatment of intestinal inflammations.
  • these topical pharmaceutical compositions containing the aminomethylphenols ordinarily include about 0.01 to 2 percent, preferably about 0.5 percent, of the active compound in admixture with 99.75 to 99.99 percent (preferably 99.90 percent) of gel vehicle comprising water, at least one organic solvent, and at least one thickening agent.
  • the water ordinarily constitutes from about 8 to 18 percent of the gel vehicle, preferably about 13 percent.
  • the organic solvent ordinarily constitutes about 60 to percent of the gel vehicle.
  • Representative solvents are ethyl alcohol, isopropyl alcohol, propylene glycol, glycerine, 2-octyldodecanol and N-methylpyrrolidine, and preferably isopropyl alcohol; propylene glycol mixtures at a ratio of 0.5 to 0.6 parts isopropyl alcohol to 1.0 parts propylene glycol.
  • the solubility of the aminomethylphenol compounds in the solvent'syiteffl selected should be such as to obtain maximum partitioning of the active compound from 1 the vehicle to the skin.
  • the thickening agent preferably hydfoxyethyl cellulose, hydroxypropyl cellulose,
  • a stabilizing agent such as disodium edetate, sodium citrate, dipotassium edetate, citric acid, and the like, in the proportion of about'"0.02 to 0.5 percent of the gel vehicle may be employed, if desired.
  • Apreferredtopical pharmaceutical composition is prepared as follows: About 2.60 g. of hydroxypropyl cellulose is added to a solution of 0.05 g. of disodium edetate in. 13.00 g. purified water while agitating the mixture and maintaining the temperature at about 60C, and the agitation is continued until the hydroxypropyl cellulose is completely dispersed and wetted. To the resulting dispersed mixture is added, with agitation, a solution containing 0.1 g. of, for example, 2 1 aminomethyl-4-t-butyl-6-fluorophenol hydrochloride dispersed in a mixture of 30.00 g. of anhydrous isopropyl :alcohol and 54.25 g. of propylene glycol. The resulting gel mixture is stirred vigorously at room temperature fora period of approximately minutes thereby forming a pharmaceutical composition adapted for the treatment of topical anti-inflammatory conditions.
  • mice ear test which -is.known to correlate well with anti-inflammatory activity in humans and is a standard test used to determine anti-inflammatory activity.
  • EXAMPLE 1 A mixture of 250 partsof 2-aminomethyl-4-t-butyl 6r bromophenol 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 60C. The dry granules are passed through a 16 mesh screen and mixed with 3.8 parts of magnesium stearate. They are then compressed into tablets suitable for oral administration- 25, 100 or 500 parts of 2-aminomethyl-4-t-butyl-6- bromophenol may be used in place of 250 parts above to produce tablets suitable for oral administration according to'the method of this invention.
  • EXAMPLE 2 A mixture of 50 parts of 2-aminomethyl-4-t-buty1-6- chlorophenol, 3 parts of the calcium salt of lignin sulfonic acidand'237 parts of water is ball-milled until the size of substantially all of the particles is less than 10 microns.
  • the suspension is diluted with a solution containing 3 parts of sodium carboxymethyl cellulose and 0.9 parts of the butyl ester of p-hydroxybenzoic acid in 300 parts of water. There is thus obtained an aqueous suspension suitable for oral administration for therapeutic purposes. 7
  • 2-Aminomethyl-4-t-butyl-6-iodophenol is used in place of the 6-chlor'ophenol compound in the above example to obtain a suspension suitable for oral administration.
  • EXAMPLE 3 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 EXAMPLE 5 1. Tablets 10,000 scored tablets for oral use, each containing 500 mg. of active ingredient are prepared from the following ingredients:
  • Capsules 10.000 two-piece hard gelatin capsules for oral use, each containing 250 mg. of active ingredient are prepared from the following ingredients:
  • Soft elastic capsules One-piece soft elastic capsules for oral use, each containing 500 mg. of active material are'prepared in the usual'manner by first dispersing the active material in sufficient corn oil to render the material capsulatable.
  • Aqueous suspension An aqueous suspension for oral use containing in each 5 ml., 1 gm. of active ingredient is prepared from the following ingredients:
  • Finely powdered N-hydroxymethyl-2-chloroacetamide (6.15 g., 0.05 mole) is added gradually with stirring at about C. The mixture is stirred for 2.5 hours additionally and then is poured into 300 ml. of cold water. The gum that separates is extracted with ether. The ether extract is washed with water and with salt brine, dried with magnesium sulfate and evaporated to dryness. The residue is refluxed in a mixture of95% ethanol ml.) and 12 N hydrochloric acid (10 ml.) for 2.5 hours.
  • Step 2 2 Aminomethyl-4-isopropyl-6-iodophenol hydrochloride 2-lodo-4-isopropylphenol (13.1 g., 0.05 mole) is dissolved in a mixture of acetic acid (50 ml.) and 96% sulfuric acid (5 ml.) and powdered N-hydroxymethyl- 2-chloroacetamide (6.15 g., 0.05 mole) is added during 10 minutes with stirring at 20C. The solution is stirred for 2.5 hours and then added to 300 ml. of water.
  • the crude solid is collected 1 8g.) and refluxed in ethanol (25 ml.)rhydro chlo,ric acid (110ml) for 2 hours.
  • the solid (7.5 g.) that separates on cooling; namely, 2- aminomethyl-4-isopropyl-6-iodophenol hydrochloride, is purified by crystallization from ethanol 12 N hydrochloric acid (7:3) to obtain 2-aminomethyl-4-isopropyl6-iodophe'nol hydrochloride (7 g.), m.p. 211-2l2C, dec.
  • the oily residue is dissolved in a mixture of 12 N hydrochloric acid ml.) and ethanol (100 ml.). The mixture is refluxed for 7 hours. The mixture then is evaporated to dryness under reduced pressure. The residue is triturated with dry-ether to obtain a sticky white solid that is dissolved in hot ethanol (50 ml.) and precipitated in the cold by addition of ether (800 ml.). The solid is then crystallized 'from ethanol 12 N hydrochloric acid (1:10) to obtain 2-aminomethyl-4-t-amylphenol hydrochloride (1? g.), m.p. 191 492C.
  • Step 2 2-Aminomethyl-4-t-amyl-6-iodophenol hydrochloride
  • 2-Aminomethyl-4-t-amylphenol hydrochloride (4.6 g., 0.02 mole) is dissolved in water (15 ml.) and a solution of iodine monochloride (3.28 g.) in water (5 ml.) is added. The mixture is kept for 3 hours and then cooled to 10C. The solid that separates is crystallized from ethanol 12 N hydrochoric acid (1:10) to obtain Z-aminomethyl-4-t-amyl--iodophenyl hydrochloride (4.15 g.), m.p. 203204C, dec.
  • a method of treating a condition exhibiting at least one of the symptoms of pain, fever and inflammation which comprises the administration to a patient in need of such treatment a therapeutically effective amount of a compound of the formula:
  • R is C,, loweralkyl and R is halogen, or the non-toxic pharmaceutically acceptable salt thereof.

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Abstract

The invention relates to a method of treating inflammation employing certain aminomethylphenol compounds and to pharmaceutical compositions thereof.

Description

United States Patent Cragoe, Jr. et a]. Dec. 23, 1975 [5 PHENOL COMPOUNDS IN TREATING [56] References Cited PAIN, FEVER AND INFLAMMATION UNITED STATES PATENTS [75] Inventors: Edward J. Cragoe, Jr., Lansdale; 2,220,835 11/1940 Bruson et al 260/5709 Everett M. Schultz, Ambler, both of 3,082,113 3/1963 Hemwali 260/5706 Pa. Primary Examiner-Stanley J. Friedman [73] Asslgnee' Merck & Rahway Attorney, Agent, or Firm-Stanley E. Anderson, In; [22] Filed: Apr. 25, 1974 Mario A. Monaco; Harry E. Westlake, Jr.
[211 App]. No.: 464,003
ABSTRACT The invention relates to a method of treating inflam- (gl.2 mation employing certain aminomethylphenol [58] Field s I 260/570 9 pounds and to pharmaceutical compositions thereof.
9 Claims, No Drawings PHENOL COMPOUNDS IN TREATING PAIN, FEVER AND INFLAMMATION SUMMARY OF THE INVENTION This invention relates to the use of aminomethylphenols containing halogen and alkyl substituents as medicinal agents. These compounds exhibitanti-inflammatory activity and are particularly useful as topical and systemic agents.
BACKGROUND OF THE INVENTION There has been much research carried on in the past for development of anti-inflammatory drugs. As a resuit, a great many new drugs have been synthesized. Most of these have been steroids of the ll-oxygenated pregnane series. These, while highly effective, have the drawback of causing many side effects. There has also been a concentrated effort in anti-inflammatory research in indole, indenes and phenylacetic acids among others with the result of many useful drugs. We have found that certain aminomethylphenols also are valuable anti-inflammatory agents.
DESCRIPTION AND PREFERRED EMBODIMENTS wherein R is, C loweralkyl, such as propyl, isopropyl, sec-butyl, t-butyl, t-amyl and the like, but especially t-butyl and isopropyl and R is halogen, such 'as chloro, bromo, fluoro and iodo, andespecially iodo and chloro, in a non-toxic pharmaceutically acceptable carrier. Also included are their non-toxic pharmaceutically acceptable salts, suchas hydrochloric, hydrobromic, hydroiodic, sulfuric, methanesulfonic, isethionic acid and thelike. Salts may also be prepared from the alkali metal bases such as sodium hydroxide, potassium hydroxide and the like.
.The non-toxic pharmaceutical carrier may be, for example, either a solid or a liquid. Exemplary of solid carriers are lactose, corn starch, gelatin, talc, sterotix, stearic acid, magnesium stearate, terra alba, sucrose, agar, pectin and acacia. Exemplary of liquid carriers are peanut oil, olive oil, seasame oil, propylene glycol, glycerine, ethanol and water..Similarly, the carrier or diluent may include a time delay material such as glyc- H eryl monostearate or glyceryl distearate alone or with a WHX.
Severalpharmaceutical forms-of the therapeutically useful compositions can .be used. For example, if a solid carrier is used, thecompositions may take the form of tablets, capsules, powders, troches or lozenges, prepared by standard pharmaceutical techniques. lf a liquid carrier is used, the preparation may be in the form ofa soft gelatin capsule, a syrup, an aqueous solution or aliquid suspension. Suppositories may be prepared in a conventional manner by mixing the compounds of this invention with a suitable nonirritating excipient which is solid at room temperature, but liquid at the rectal temperature. Such materials are cocoa butter and polyethylene glycol.
The active compounds are administered in an amount sufficient to treat inflammation; thatis, to reduce inflammation. Advantageously, the compositions will contain the active ingredient in an amount of from about 0.1 mg. to 50 mg. per kg. body weight per day (5 mg. to 3.5 g. per patient per day), preferably from about 1 mg. to 15 mg. per kg. body weight per day (50 mg. to l g. per patient per day).
In a particularly preferred aspect of this invention, the aminomethylphenols are used as topical anti-inflammatory agents and are particularly effective in topical treatment of dermatological disorders and like conditions, such as dermatitis (actinic, atopic, contact, eczematoid, seborrheic and stasis), dermatitis herpetiformis, lichen planus, neurodermatitis, intitrigo, lichen simplex chronicus, and pruritus, as well as for topical treatment of inflammation of the respiratory and intestinal mucosa such as allergic rhinitis, bronchitis, bronchial asthma, bronchiectasis, colitis and the like. These aminomethylphenols are ordinarily administered in the form of a pharmaceutical composition comprising the active compound in combination with a pharmacologically acceptable carrier adapted for topical administration. These topical pharmaceutical compositions may be in the form of a-cream, ointment, gel or aerosol formulation adapted for application to the skin for treatment of dermatoses; or it may be in the formof a solution, suspension or aerosoLadapted for topical spray application to respiratory passages for treatment of nasal allergies, bronchial inflammation, and the like; or in the form of suppositories or enclosed in enteric capsules for treatment of intestinal inflammations. For treatment of dermatological disorders, these topical pharmaceutical compositions containing the aminomethylphenols ordinarily include about 0.01 to 2 percent, preferably about 0.5 percent, of the active compound in admixture with 99.75 to 99.99 percent (preferably 99.90 percent) of gel vehicle comprising water, at least one organic solvent, and at least one thickening agent. The water ordinarily constitutes from about 8 to 18 percent of the gel vehicle, preferably about 13 percent. The organic solvent ordinarily constitutes about 60 to percent of the gel vehicle. Representative solvents are ethyl alcohol, isopropyl alcohol, propylene glycol, glycerine, 2-octyldodecanol and N-methylpyrrolidine, and preferably isopropyl alcohol; propylene glycol mixtures at a ratio of 0.5 to 0.6 parts isopropyl alcohol to 1.0 parts propylene glycol. The solubility of the aminomethylphenol compounds in the solvent'syiteffl selected should be such as to obtain maximum partitioning of the active compound from 1 the vehicle to the skin. The thickening agent, preferably hydfoxyethyl cellulose, hydroxypropyl cellulose,
and the like, ordinarily constitutes from 0.5 to 4.0 percent of the gel vehicle. Optionally, a stabilizing agent, such as disodium edetate, sodium citrate, dipotassium edetate, citric acid, and the like, in the proportion of about'"0.02 to 0.5 percent of the gel vehicle may be employed, if desired.
, Apreferredtopical pharmaceutical composition is prepared as follows: About 2.60 g. of hydroxypropyl cellulose is added to a solution of 0.05 g. of disodium edetate in. 13.00 g. purified water while agitating the mixture and maintaining the temperature at about 60C, and the agitation is continued until the hydroxypropyl cellulose is completely dispersed and wetted. To the resulting dispersed mixture is added, with agitation, a solution containing 0.1 g. of, for example, 2 1 aminomethyl-4-t-butyl-6-fluorophenol hydrochloride dispersed in a mixture of 30.00 g. of anhydrous isopropyl :alcohol and 54.25 g. of propylene glycol. The resulting gel mixture is stirred vigorously at room temperature fora period of approximately minutes thereby forming a pharmaceutical composition adapted for the treatment of topical anti-inflammatory conditions.
Various tests in animals have been carried out to show the ability of the compounds described herein to exhibit reactions that can be correlated with anti-inflammatory activity in humans. One such test used is. the mouse ear test which -is.known to correlate well with anti-inflammatory activity in humans and is a standard test used to determine anti-inflammatory activity.
The following examples are given by way of illustratron:
EXAMPLE 1 A mixture of 250 partsof 2-aminomethyl-4-t-butyl 6r bromophenol 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 60C. The dry granules are passed through a 16 mesh screen and mixed with 3.8 parts of magnesium stearate. They are then compressed into tablets suitable for oral administration- 25, 100 or 500 parts of 2-aminomethyl-4-t-butyl-6- bromophenol may be used in place of 250 parts above to produce tablets suitable for oral administration according to'the method of this invention.
EXAMPLE 2 'A mixture of 50 parts of 2-aminomethyl-4-t-buty1-6- chlorophenol, 3 parts of the calcium salt of lignin sulfonic acidand'237 parts of water is ball-milled until the size of substantially all of the particles is less than 10 microns. The suspension is diluted with a solution containing 3 parts of sodium carboxymethyl cellulose and 0.9 parts of the butyl ester of p-hydroxybenzoic acid in 300 parts of water. There is thus obtained an aqueous suspension suitable for oral administration for therapeutic purposes. 7
2-Aminomethyl-4-t-butyl-6-iodophenol is used in place of the 6-chlor'ophenol compound in the above example to obtain a suspension suitable for oral administration.
EXAMPLE 3 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.
Similar results are obtained by employing 2- aminomethyl-4 -isopropyl-6-iodophenol in place of the ethylamino compound in the above example.
EXAMPLE 4 EXAMPLE 5 1. Tablets 10,000 scored tablets for oral use, each containing 500 mg. of active ingredient are prepared from the following ingredients:
2-aminomethyl-4-propyl-6-chlorophenol 5000 Starch, U.S.P. 350 Talc, U.S.P. 250 Calcium stearate The chlorophenol is granulated with a 4% w./v. aqueous solution of methyl cellulose U.S.P. (1500 cps.). To the dried granules is added a mixture of the remainder of the ingredients and the final mixture compressed into tablets of proper weight.
2. Capsules 10.000 two-piece hard gelatin capsules for oral use, each containing 250 mg. of active ingredient are prepared from the following ingredients:
Gm. 2-Aminomethyl-4-t-butyl-6-bromophenol 2500 Lactose. U.S.P. 1000 Starch, U.S.P. 300 Talc, U.S.P. 65 Calcium stearate 25 The bromophenol compound is mixed with the starch lactose mixture followed by the talc and calcium stearate. The final mixture is then encapsulated in the usual manner. Capsules containing 10, 25, 50 and mg. of active ingredient are also prepared by substituting 100, 250, 500 and 1000 gm. for 2500gm. in the above formulation.
3. Soft elastic capsules One-piece soft elastic capsules for oral use, each containing 500 mg. of active material are'prepared in the usual'manner by first dispersing the active material in sufficient corn oil to render the material capsulatable.
4. Aqueous suspension An aqueous suspension for oral use containing in each 5 ml., 1 gm. of active ingredient is prepared from the following ingredients:
2-Aminoinethyl-4-t-butyl-6-iodophenol 2000 Methylparaben, U.S.P. 1 7.5
I v continued Propylparaben, USP. 2.5 Saccharin sodiumx 12.5 Glycerin I 2 3000 Ttagac'anth ow'der m Orange oil avor l0 F.D. & C. orange dye 7.5
I EXAMPLE Gel Foiniulation .0. 1 mg disodium edetate 1.39 mg'fo'f purifidH O 300mg. isopropa'nol 26mg. hydroxypropyl cellulose q.s.a.d. 1 gm. propylene gly'col V 1.09 mg. 2 aminornethyl-4t-butyl-6-bromophenol hydrochloride EXAMPLE 7 Ointment Formulation 50 mg. wool alcohols B.P.
150 mg. amichol C 350 mg. wax white Be square l70/175C q.s.a.d. 1 gm. isopropyl myristate 1.09 mg. 2-aminomethyl-4-isopropyl-6-iodophenol hydrochloride .4% citrate acid anhydrous 0.5% sodium phosphate dibasic anhydrous EXAMPLE 8 2-Aminomethyl-4-isopropyl-6-chlorophenol hydrochloride 2-Chloro-4-isopropylphenol (8.35 g., 0.05 mole) is dissolved in a mixture of acetic acid (50 ml.) and 96% sulfuric acid (5 ml.). Finely powdered N-hydroxymethyl-2-chloroacetamide (6.15 g., 0.05 mole) is added gradually with stirring at about C. The mixture is stirred for 2.5 hours additionally and then is poured into 300 ml. of cold water. The gum that separates is extracted with ether. The ether extract is washed with water and with salt brine, dried with magnesium sulfate and evaporated to dryness. The residue is refluxed in a mixture of95% ethanol ml.) and 12 N hydrochloric acid (10 ml.) for 2.5 hours. The product that separates on cooling is crystallized from ethanol 12 N hydrochloric acid (3:2) to obtain 2-aminomethyl-4-isopropyl-6-chlorophenol hydrochloride, 5.8 g., m.p. 24l242C.
Analysis: Calc.: C, 50.86; H, 6.40; N, 5.93;Found: C, 50.53; H, 6.46; N, 5.98.
Following the procedure in Example 8 above but using an equivalent amount of 2-chloro-4-t-amylphenol in place of 2-chloro-4-isopropylphenol, there is obtained an equivalent amount of 2-aminomethyl-4-tamyl-6-chlorophenol hydrochloride.
EXAMPLE 9 2-Aminomethy1-4-isopropyl-o-iodophenol hydrochloride Step 1: 2-lodo-4-isopropylphenol 4-lsopropylphenol (27.2 g., 0.20 mole) is dissolved in acetic acid (100 ml.). lodine monochloride (32.5 g., 0.20 mole) in acetic acid (50 ml.) is then added slowly. The dark mixture is refluxed for 6 hours, cooled and poured into cold water (1 l.) containing a little sodium bisulfite. The black oil that separates is extracted with ether and the extract is washed with water and salt brine and dried over magnesium sulfate. The ether is evaporated and the residue is purified by distillation to obtain 2-iod'o 4-isopropylphenol (26 g.), m.p. 137-l40C (15 mm). P 5
Analysis: Calc.: C, 41,89; H, 4.23; Found: C, 41,69; H, 4.62. Step 2: 2 Aminomethyl-4-isopropyl-6-iodophenol hydrochloride 2-lodo-4-isopropylphenol (13.1 g., 0.05 mole) is dissolved in a mixture of acetic acid (50 ml.) and 96% sulfuric acid (5 ml.) and powdered N-hydroxymethyl- 2-chloroacetamide (6.15 g., 0.05 mole) is added during 10 minutes with stirring at 20C. The solution is stirred for 2.5 hours and then added to 300 ml. of water. The crude solid is collected 1 8g.) and refluxed in ethanol (25 ml.)rhydro chlo,ric acid (110ml) for 2 hours. The solid (7.5 g.) that separates on cooling; namely, 2- aminomethyl-4-isopropyl-6-iodophenol hydrochloride, is purified by crystallization from ethanol 12 N hydrochloric acid (7:3) to obtain 2-aminomethyl-4-isopropyl6-iodophe'nol hydrochloride (7 g.), m.p. 211-2l2C, dec.
Analysis: Calc.: C, 36.66; H, 4.62; N, 4.28; Found: C, 36.51, H, 4.54,N, 4.14.
EXAMPLE l0 2-Aminomethyl-4-t-amyl-6-iodophenol hydrochloride Step 1: 2-Aminomethyl-4-t-amylphenol hydrochloride A mixture ofj4-t-amylphenol (32.8 g., 0.20 mole), N-hydroxymethyl 2-chloroacetamide (24.6 g., 0.20 mole) in acetic acid (200 ml.) and 96% sulfuric acid (20 ml.) is stirredat 20C for 12 hours and then poured into cold water (1 l.). The solid that separates is extracted with ether and the ether extract is washed with water and salt brine and evaporated to dryness. The oily residue is dissolved in a mixture of 12 N hydrochloric acid ml.) and ethanol (100 ml.). The mixture is refluxed for 7 hours. The mixture then is evaporated to dryness under reduced pressure. The residue is triturated with dry-ether to obtain a sticky white solid that is dissolved in hot ethanol (50 ml.) and precipitated in the cold by addition of ether (800 ml.). The solid is then crystallized 'from ethanol 12 N hydrochloric acid (1:10) to obtain 2-aminomethyl-4-t-amylphenol hydrochloride (1? g.), m.p. 191 492C.
Analysis: Calcf: C, 62.73; H, 8.77; N, 6.10; Found: C, 62.80; H, 8.76;N, 6.21.
Step 2: 2-Aminomethyl-4-t-amyl-6-iodophenol hydrochloride 2-Aminomethyl-4-t-amylphenol hydrochloride (4.6 g., 0.02 mole) is dissolved in water (15 ml.) and a solution of iodine monochloride (3.28 g.) in water (5 ml.) is added. The mixture is kept for 3 hours and then cooled to 10C. The solid that separates is crystallized from ethanol 12 N hydrochoric acid (1:10) to obtain Z-aminomethyl-4-t-amyl--iodophenyl hydrochloride (4.15 g.), m.p. 203204C, dec.
Analysis: Calc.: C, 40.53; H, 5.38; N, 3.94; Found: C, 40.77; H, 5.31; N, 3.97.
What is claimed is:
l. A method of treating a condition exhibiting at least one of the symptoms of pain, fever and inflammation which comprises the administration to a patient in need of such treatment a therapeutically effective amount of a compound of the formula:
wherein R is C,, loweralkyl and R is halogen, or the non-toxic pharmaceutically acceptable salt thereof.
2. The method of claim 1 wherein the compound is 2-aminomethyl-4-t-butyl-6-chlorophenol, or the hydro chloride salt thereof.
3. The method of'claim 1 wherein the compound is 2-aminomethyl-4-t-butyl-6-iodophenol, or the hydrochloride salt thereof.
drochloride salt thereof.

Claims (9)

1. A METHOD OF TREATING A CONDITION EXHIBITING AT LEAST ONE OF THE SYMPTONS OF PAIN, FEVER AND INFLAMMATION WHICH COMPRISES THE ADMINISTRATION TO A PATIENT IN NEED OF SUCH TREATMENT A THERAPEUTICALLY EFFECTIVE AMOUNT OF A COMPOUND OF THE FORMULA:
2. The method of claim 1 wherein the compound is 2-aminomethyl-4-t-butyl-6-chlorophenol, or the hydrochloride salt thereof.
3. The method of claim 1 wherein the compound is 2-aminomethyl-4-t-butyl-6-iodophenol, or the hydrochloride salt thereof.
4. The method of claim 1 wherein the compound is 2-aminomethyl-4-t-butyl-6-bromophenol, or the hydrochloride salt thereof.
5. The method of claim 1 wherein the compound is 2-aminomethyl-4-t-butyl-6-fluorophenol, or the hydrochloride salt thereof.
6. The method of claim 1 wherein the compound is 2-aminomethyl-4-t-amyl-6-chlorophenol, or the hydrochloride salt thereof.
7. The method of claim 1 wherein the compound is 2-aminomethyl-4-t-amyl-6-iodophenol, or the hydrochloride salt thereof.
8. The method of claim 1 wherein the compound is 2-aminomethyl-4-isopropyl-6-chlorophenol, or the hydrochloride salt thereof.
9. The method of claim 1 wherein the compound is 2-aminomethyl-4-isopropyl-6-iodophenol, or the hydrochloride salt thereof.
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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4029816A (en) * 1975-11-25 1977-06-14 Merck & Co., Inc. Substituted 2-aminomethyl-6-iodophenols
US4906633A (en) * 1987-05-26 1990-03-06 Ici Americas Inc. Pyrazine amides
US4910202A (en) * 1987-05-26 1990-03-20 Ici Americas Inc. Aminomethylphenolic pyrazines
US4980352A (en) * 1988-05-25 1990-12-25 Ici Americas Inc. Gem-dimethyl substituted bicyclic compounds useful as eukalemic diuretics
US5998487A (en) * 1998-04-08 1999-12-07 Colgate-Palmolive Company Anti-inflammatory and antibacterial benzyl phenol agents and their use in oral compositions
US20040198747A1 (en) * 2002-02-19 2004-10-07 Parion Sciences, Inc. Sodium channel blockers
US20040198749A1 (en) * 2002-02-19 2004-10-07 Parion Sciences, Inc. Methods of using sodium channel blockers
US6903105B2 (en) 2003-02-19 2005-06-07 Parion Sciences, Inc. Sodium channel blockers
US7745442B2 (en) 2003-08-20 2010-06-29 Parion Sciences, Inc. Methods of reducing risk of infection from pathogens
JP2012511585A (en) * 2008-12-09 2012-05-24 ユニバーシティ オブ フロリダ リサーチ ファウンデーション,インコーポレイテッド Kinase inhibitor compounds
US8669262B2 (en) 2011-06-27 2014-03-11 Parion Sciences, Inc. 3,5-diamino-6-chloro-N-(N-(4-(4-(2-(hexyl(2,3,4,5,6-pentahydroxyhexyl)amino)ethoxy)phenyl)butyl)carbamimidoyl)pyrazine-2-carboxamide
US9586911B2 (en) 2013-12-13 2017-03-07 Parion Sciences, Inc. Arylalkyl- and aryloxyalkyl-substituted epthelial sodium channel blocking compounds
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2220835A (en) * 1939-03-14 1940-11-05 Rohm & Haas Oxides of phenolic amines
US3082113A (en) * 1961-05-03 1963-03-19 Dow Chemical Co Method for improving physical properties of clays and clay-containing soils and compositions resulting therefrom

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2220835A (en) * 1939-03-14 1940-11-05 Rohm & Haas Oxides of phenolic amines
US3082113A (en) * 1961-05-03 1963-03-19 Dow Chemical Co Method for improving physical properties of clays and clay-containing soils and compositions resulting therefrom

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US4906633A (en) * 1987-05-26 1990-03-06 Ici Americas Inc. Pyrazine amides
US4910202A (en) * 1987-05-26 1990-03-20 Ici Americas Inc. Aminomethylphenolic pyrazines
US4980352A (en) * 1988-05-25 1990-12-25 Ici Americas Inc. Gem-dimethyl substituted bicyclic compounds useful as eukalemic diuretics
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