U.S. patent number 3,928,624 [Application Number 05/464,003] was granted by the patent office on 1975-12-23 for phenol compounds in treating pain, fever and inflammation.
This patent grant is currently assigned to Merck & Co., Inc.. Invention is credited to Edward J. Cragoe, Jr., Everett M. Schultz.
United States Patent |
3,928,624 |
Cragoe, Jr. , et
al. |
December 23, 1975 |
Phenol compounds in treating pain, fever and inflammation
Abstract
The invention relates to a method of treating inflammation
employing certain aminomethylphenol compounds and to pharmaceutical
compositions thereof.
Inventors: |
Cragoe, Jr.; Edward J.
(Lansdale, PA), Schultz; Everett M. (Ambler, PA) |
Assignee: |
Merck & Co., Inc. (Rahway,
NJ)
|
Family
ID: |
23842128 |
Appl.
No.: |
05/464,003 |
Filed: |
April 25, 1974 |
Current U.S.
Class: |
514/655 |
Current CPC
Class: |
C07C
37/62 (20130101); A61K 31/135 (20130101); C07C
37/62 (20130101); C07C 39/27 (20130101) |
Current International
Class: |
C07C
37/62 (20060101); A61K 31/135 (20060101); C07C
37/00 (20060101); A61K 031/135 () |
Field of
Search: |
;424/330 ;260/570.9 |
References Cited
[Referenced By]
U.S. Patent Documents
Primary Examiner: Friedman; Stanley J.
Attorney, Agent or Firm: Anderson, Jr.; Stanley E. Monaco;
Mario A. Westlake, Jr.; Harry E.
Claims
What is claimed is:
1. 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:
##SPC2##
wherein R is C.sub.3-7 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 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.
Description
SUMMARY OF THE INVENTION
This invention relates to the use of aminomethylphenols containing
halogen and alkyl substituents as medicinal agents. These compounds
exhibit anti-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 result, a great many new drugs
have been synthesized. Most of these have been steroids of the
11-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
This invention is directed to the use of known aminomethylphenol
compounds as anti-inflammatory agents. The invention is also
directed to pharmaceutical compositions employing these compounds.
These compounds and their method of preparation are generally known
from German publication Ser. No. 2,163,908, filed Dec. 22,
1971.
The treatment of inflammation in accordance with the method of the
present invention is accomplished by topically, orally, rectally or
parenterally administering to patients the aminomethylphenols of
the following formula: ##SPC1##
Wherein R is C.sub.3-7 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, and especially iodo and chloro, in a non-toxic
pharmaceutically acceptable carrier. Also included are their
non-toxic pharmaceutically acceptable salts, such as hydrochloric,
hydrobromic, hydroiodic, sulfuric, methanesulfonic, isethionic acid
and the like. 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 glyceryl monostearate or
glyceryl distearate alone or with a wax.
Several pharmaceutical forms of the therapeutically useful
compositions can be used. For example, if a solid carrier is used,
the compositions may take the form of tablets, capsules, powders,
troches or lozenges, prepared by standard pharmaceutical
techniques. If a liquid carrier is used, the preparation may be in
the form of a soft gelatin capsule, a syrup, an aqueous solution or
a liquid 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; that is, 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 1 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 form of a
solution, suspension or aerosol adapted 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 90
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 system selected
should be such as to obtain maximum partitioning of the active
compound from the vehicle to the skin. The thickening agent,
preferably hydroxyethyl 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.
A preferred topical 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 60.degree.C, 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-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 for a period of approximately 15 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 illustration:
EXAMPLE 1
A mixture of 250 parts of 2-aminomethyl-4-t-butyl-6-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
60.degree.C. 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-butyl-6-chlorophenol, 3
parts of the calcium salt of lignin sulfonic acid and 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.
2-Aminomethyl-4-t-butyl-6-iodophenol is used in place of the
6-chlorophenol compound in the above example to obtain a suspension
suitable for oral administration.
EXAMPLE 3
A mixture of 250 parts of 2-aminomethyl-4-isopropyl-6-chlorophenol,
200 parts of maize starch and 30 parts of alginic acid is mixed
with a sufficient quantity of 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.
Similar results are obtained by employing
2-aminomethyl-4-isopropyl-6-iodophenol in place of the ethylamino
compound in the above example.
EXAMPLE 4
A mixture of 500 parts of 2-aminomethyl-4-t-amyl-6-iodophenol, 60
parts 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 16-mesh screen, mixed with 5 parts of
magnesium stearate and compressed into tablet form suitable for
oral administration.
Similar results are obtained by employing
2-aminomethyl-4-t-amyl-6-chlorophenol in place of the allylamino
compound in the above example.
EXAMPLE 5
1. Tablets -- 10,000 scored tablets for oral use, each containing
500 mg. of active ingredient are prepared from the following
ingredients:
Gm. 2-aminomethyl-4-propyl-6-chlorophenol 5000 Starch, U.S.P. 350
Talc, U.S.P. 250 Calcium stearate 35
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 100 mg. of active ingredient are also prepared by
substituting 100, 250, 500 and 1000 gm. for 2500 gm. 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:
Gm. 2-Aminomethyl-4-t-butyl-6-iodophenol 2000 Methylparaben, U.S.P.
7.5 Propylparaben, U.S.P. 2.5 Saccharin sodium 12.5 Glycerin 3000
Tragacanth powder 10 Orange oil flavor 10 F.D. & C. orange dye
7.5 Deionized water, q.s. to 10,000 ml.
EXAMPLE 6
Gel Formulation
0.1 mg. disodium edetate
1.30 mg. of purified H.sub.2 O
300 mg. isopropanol
26 mg. hydroxypropyl cellulose
q.s.a.d. 1 gm. propylene glycol
1.09 mg. 2-aminomethyl-4-t-butyl-6-bromophenol hydrochloride
EXAMPLE 7
Ointment Formulation
50 mg. wool alcohols B.P.
150 mg. amichol C
350 mg. wax white Be square 170/175.degree.C
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 20.degree.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 of 95% ethanol (25 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. 241.degree.-242.degree.C.
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-t-amyl-6-chlorophenol hydrochloride.
EXAMPLE 9
2-Aminomethyl-4-isopropyl-6-iodophenol hydrochloride
Step 1: 2-Iodo-4-isopropylphenol
4-Isopropylphenol (27.2 g., 0.20 mole) is dissolved in acetic acid
(100 ml.). Iodine 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-iodo-4-isopropylphenol (26
g.), m.p. 137.degree.-140.degree.C (15 mm).
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-Iodo-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 20.degree.C. The solution
is stirred for 2.5 hours and then added to 300 ml. of water. The
crude solid is collected (18 g.) and refluxed in ethanol (25
ml.)-hydrochloric acid (10 ml.) 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-isopropyl-6-iodophenol hydrochloride (7 g.),
m.p. 211.degree.-212.degree.C, dec.
Analysis: Calc.: C, 36.66; H, 4.62; N, 4.28; Found: C, 36.51, H,
4.54, N, 4.14.
EXAMPLE 10
2-Aminomethyl-4-t-amyl-6-iodophenol hydrochloride
Step 1: 2-Aminomethyl-4-t-amylphenol hydrochloride
A mixture of 4-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 stirred at
20.degree.C 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 (100 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
(17 g.), m.p. 191.degree. -192.degree.C.
Analysis: Calc.: 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 -10.degree.C. The solid that separates is
crystallized from ethanol -- 12 N hydrochoric acid (1:10) to obtain
2-aminomethyl-4-t-amyl-6-iodophenyl hydrochloride (4.15 g.), m.p.
203.degree.-204.degree.C, dec.
Analysis: Calc.: C, 40.53; H, 5.38; N, 3.94; Found: C, 40.77; H,
5.31; N, 3.97.
* * * * *