Note: Descriptions are shown in the official language in which they were submitted.
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The present invention is concerned with the use as
anti-inflammatory, analgestic and antipyretic agents, of deriva-
tives of 2-naphthyl-butyric acid of the general formula I :
~ CH2 CH/ 2 ~COOM (I)
RO
in which R is a methyl radical
Rl is a hydrogen atom or a methyl radical
and M is a hydrogen atom or the cation of a pharmaceutic-
ally acceptable inorganic or organic base.
The fact that the compounds of general formula (I) pos-
sess the above-mentioned pharmacological properties is unexpected
and surprising because :
(1) Similar compounds having a propionic or pentanoic side chain
instead of a butyric side chain are inactive in the pharma-
cological tests considered here : this is true particularly
of delta-(6-methoxy-2-naphthyl)-delta-oxo-pentanoic acid
and beta-(6-methoxy-2-naphthyl)-propionic acid ;
; (2) In the butyric chain series, the compounds carrying a hydro-
xyl group instead of an OR group in the 6-position of the
naphthalene nucleus are also inactive, particularly gamma-
(6-hydroxy-2-naphthyl)-gamma-oxo-butyric acid and gamma-(6- -
hydroxy-2-naphthyl)-ga~ma-ethyl-butyric acid, as well as
those having a substituent in the gamma-position, particular-
ly the above-mentioned acids and, in addition, gamma-(6-
methoxy-2-naphthyl)-gamma-ethyl-butyric acid, gamma-(6-
methoxy-2-naphthyl)-beta-methyl-gamma-ethyl-butyric acid.
(3) The same is true of acids having structures close to those
of the 2-naphthyl-butyric acids according to the present
invention, for example : gamma-(6-methoxy-2-naphthyl~-gamma-
ethyl-beta-carboxymethyl-butyric acid, gamma-(6-methoxy-2-
naphthyl)-gamma-propyl-beta-carboxymethyl-butyric acid,
, ~ .
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2-(7-methoxy-4-oxo-1,2,3,4-tetrahydro-2-phenanthryl)acetic
`~ acid, 2-(1-ethyl-7-methoxy-4-oxo-1,2,3,4-tetrahydro-2-phenan-
` ~ thryl)-acetic acid, 2-(1-propyl-7-methoxy-4-oxo-1,2,3,4-
tetrahydro-2-phenanthryl)-acetic acid, gamma-(6-methoxy-2-
naphthyl)-gamma-ethyl-beta-carbethoxy-methyl-butyric acid,
2-methyl-2-~(6-methoxy-2-naphthyl)-methyl~-cyclopropane-
carboxylic acid, 2-methyl-2-~1-(6-methoxy-2-naphthyl)-propyl~
cyclopropane-carboxylic acid, 2-methyl-2-~1-(6-methoxy-2-
naphthyl)-butyl~-cyclopropane-carboxylic acid, gamma-(6-
methoxy-2-naphthyl)-gamma-ethyl-beta-carboxymethyl-butyric
anhydride and the like.
The derivatives of 2-naphthyl-butyric acid used accord-
ing to the present invention are known, such as, for example,
gamma-(6-methoxy-2-naphthyl)-butyric acid (prepared by M. GHOSAL,
J. Org, Chem. 25, (1960), 1856-59) and gamma-(6-methoxy-2-naph-
thyl)-beta-methyl-butyric acid (prepared by R.A. BAXTER, W.L.
NORRIS and D.S. MORRIS, J. Chem. Soc. 1949, 95-98) however,
literature makes no mention of any pharmacological activity what-
soever.
These salts of 2-naphthyl-butyric acids of the general
formula (I) can be prepared in conventional manner by neutrali-
zation of the acid with an appropriate non-toxic and pharmaceu-
tically acceptable inorganic or organic base. The cation of the
inorganic base may a metallic cation (for example Na+, K+, Cà++,
Mg++, Cu++), while the cation of the organic base originates
from a pharmaceutically-inactive base or from a pharmaceutically-
active base such as can be used, for example, as a vasococonstric-
tor, bronchodilator, antitussive, antihistaminic, antibiotic,
bactericide, anthelmintic, anaesthetic, sedative or respiratory
~0 analeptic examples of these organic bases include ethanolamine,
arginine, lysine, caffein, procaine, piperazine, 2-amino-2-
thiazoline, and the like.
:
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By way of example, the following salts of gamma-(6-
methoxy-2-naphthyl)-beta-methyl-butyric acid can be prepared as
described hereunder :
1. Sodium salt.
70 g. of the free acid are introduced into 50 ml. of
g5% ethanol and neutralized with a solution of 10.96 g. sodium
hydroxide in 200 ml. water. The reaction medium is extracted
twice with 100 ml. toluene and the aqueous phase is evaporated
under reduced pressure (20 mm. Hg.). The resulting pasty residue
is suspended in 300 ml. isopropanol, in which it crystalizes.
The product is filtered off and dried. 71 g of the desired
sodium salt (yield 92.6% of theory) are thus obtained.
Decomposition point : 235-241C.
Analysis : calc. Na 8.21% C 68.57% H 6.07%
found 8.29% 68.46% 6.08%
2. Potassium salt.
2.28 g of potassium hydroxide (0.039 mole) are added to
a suspension of 10 g. acid (0.039 mole) in 50 ml. water. After
complete dissolution, water is evaporated. The oily residue is
dissolved in 50 ml. of 95% ethanol. 200 ml. ethyl ether are then
added. A white precipitate is formed which is separated by
filtration and washed with ethyl ether. 8.3 g. of the potas-
sium salt are obtained (yield : 71.9 %~.
Melting point : 248-258C.
Analysis : calc. C 64.92 % H 5.79 %
found 64.80 % 5.84 %
3. Copper salt.
A solution of 7.07 g. cupric acetate (0.039 mole) in
50 ml. water is added to a suspension of 10 g. acid in 50 ml.
water. The desired salt is obtained as a blue green precipitate.
It is filtered, washed with ethanol and dried. 10 g. of the
cupric salt are thus obtained (yield 88.7 %).
~ .
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Decomposition point : 155-260C.
Analysis : calc. C 66.5 % H 5.93 %
found 66.4 % 6.00 %
4. Calcium salt.
A solution of 1.55 g. sodium hydroxide in 100 ml. water
is added to a suspension of 10 g. acid in 100 ml. water. A
solution of 2.85 g. calcium chloride (0.026 mole) in 100 ml.
water is added to the resulting solution of the sodium salt. m e
desired calcium salt is obtained as a precipitate. It is filter-
ed, washed with alcohol and dried. 8.75 g. of the calcium salt
are thus obtained (yield 81.0 %).
Decomposition point : 190C.
Analysis : clac. C 69.3 % H 6.14 %
found 69.3 % 6.12 %
5. 2-amino-2-thiazoline salt.
3.6 g. (0.035 mole) 2-amino-2-thiazoline and 100 ml.
water are added to a solution of 9.1 g. (0.035 mole) acid in
50 ml. of 95 % ethanol. The solvents are removed by distillation
under reduced pressure. The residue is recrystallized from 200
ml of a 50/50 mixture of ethanol and ethyl ether. The desired
salt is obtained as white crystals, which are separated by fil- -
tration and dried. 8.85 g. of the 2-amino-2-thiazoline salt are
.. ; ,
thus obtained (yield 70.2 %.
Melting point : 150-156C.
Analysis : calc. C 63.39 %H 6.72 % N 7.78 %
found 63.44 % 6.78 %7.75 %
6. Piperazine double salt.
A solution of 3.76 g (0.0194 mole) piperazine in 50 ml.
ethanol is added at room temperature to a solution of 10 g. acid
(0.039 mole) in 50 ml. of 95 % ethanol. The salt precipitates.
The mixture is left to stand for 48 hours. ~hen, 200 ml. ethanol
; ~ are added to the mixture, which is heated to reflux and filtered
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.
on "NORIT"* The piperazine salt crystalliæes on cooling. After
filtering and drying, 11 g. of the piperazine salt are thus
obtained (yield 93.3 %).
Melting point : 144-157C.
Analysis : calc. C 71t76 % H 7.64 % N 4.65 %
found 72.06 % 7.70 % 4.67 %
Pharmacoloqical tests.
The compounds of general formula (I) have pharmacologic-
al activity as is shown by the tests given below, in which use
is made of gamma-(6-methoxy-2-naphthyl)-butyric acid (Product A),
gamma-(6-methoxy-2-naphthyl)-beta-methyl-butyric acid ~product B)
and sodium gamma-(6-methoxy-2-naphthyl)-beta-methyl-butyrate
(product C).
a. Anti-inflammatory action.
W anti-erythema test (S.S. ADAMS, J.Pharm.Pharmacol.
12,(1960),251).
,
Principle: the activity of the substance is tested for its
inhibiting power towards slight inflammation occurring in the
form of an erythema caused in the guinea-pig by W light.
Method : albino guinea-pigs of from 300 to 500 g. body weight -
are shaved and depilated on the abdomen the day before the tests
and arranged in groups of six.
The W radiation is emitted by an HBO 200 ("Osram")*
lamp mounted in a casing. A mask placed over the guinea-pig
allows only three small round holes, each of 6 mm. diameter, to
be exposed. The guinea-pigs are exposed for 30 seconds at a
fixed distance of 10 cm. from the lamp (5 cm. from the casing).
Reading is effected after 2 hours.
Under these conditions, the control animals all have an
erythema of a rating "3" (1 for each of the 3 holes) in accor-
dance with the following principle :
0 = No erythema
* trademarks
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0.5 = pink zone with undefined edges
1 = pink or red zone with sharp edges.
The products tested are administered orally at the rate
of 4 ml.~kg., 1 hour before exposure and a second time just after
exposure (4ml. represents the volume in which each dose is ad-
ministered in the form of a solution of the product in the
9/~ isotonic serum or suspended in 10% gum arabic.
The product tested has a protective actlon if the total
erythema rating (sum of the ratings for each of the holes) is
equal to or lower than 1.5 (reduction of the erythema by 50%)~
The number of animals protected is thus counted for each dose.
The result is expressed as an effective dose (ED 50), which is
the dose providing a reduction of at least 50% of the erythema
in 50% of the guinea pigs.
` " b. Analqesic activity.
Randall and Selitto test (Arch.Int.Pharmacodyn,III,
(1957),409),
principle: the pressure to be applied to a normal paw and to
an inflamed paw in the same animal (rat) to produce a painful
reaction is me~sured. The variation of these two pressure thre-
sholds occuring in the same animal through the influence of the
product being tested is evaluated. An analgesic product has
the effect of raising the level of these thresholds.
Method: the apparatus used is that of Ugo Basile, Milan, which
is an apparatus for measuring analgesia for rats'paws.~ The rats
; are arranged in groups of ten- and subjected thre~ times to in-
creasing pressure. The rats then haue a stable reaction at the
.,; . . .
increasing pressure (reaction threshold different for the normal
paw and for the inflamed paw). ~he product to be tested is
administered orally.
The rise of the.threshold for the two paws is studied
during the hours following the administration of the different
doses. The different thresholds for the normal paw and
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:, , ~
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for the inflamed paw remain constant in the control
animals.
The dose of the product tested (in mg./kg. of animal)
- which raises the threshold of painful reaction by at least 40%
in relation to that of the control animals is sought.
c. ~L~,
C. Winder test (J.Pharmacol.Exp.Therap,138,(1962),405).
Principle: The reduction of rectal temperature of rats previous-
ly injected with a pyrogenic product is measured.
Method : Male Wistar rats are used which have a body weight of
from 125 to 150 g. and which are arranged into random groups of
ten.
17 hours before the test, the rats are injected subcutane-
ously (per kg. of animal) with 10 ml. of dried medical beer yeast
in the form of a 15% suspension in a 0.9/ solution of sodium
chloride (as pyrogenic agent). The rats are kept fasting. At
the moment of the test, the rectal temperature of the animals is
checked three times in succession at intervals of 30 minutes,
a determined-dose of the product to be tested is then adminis-
tered orally in the form of a solution in a volume of water of10 ml./kg. Every hour after ingestion, the rectal temperature
of the different groups is measured, both in the control rats
and in the tested rats.
; The active dose is that which brings about the same lower-
, ing of temperature as is found when, in a parallel test, 15 mg.
aminophenazone per kg. of animal is administered (aminophenazone
is the standard reference substance for this activity).
d. Toxicity.
The lethal dose of the product to be tested, which is
administered intraperitoneally, is measured in conventional manner
in mice 24 hours after administration. The dose is expressed in
mg. (and in mM)/kg. of animal.
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The results of these four tests are given in the
following Table, which also includes the results obtained with
comparison anti-inflammatory, analgesic and antipyretic compounds,
namely, phenylbutazone (4-butyl-1,2-diphenyl-3,5-pyrazolidine-
dione), aminophenazone (4-dimethylamino-2,3-dimethyl-1-phenyl-3-
pyrazolin-5-one) and aspirin (acetylsalicylic acid), respective-
ly.
The first numerical value is given in mg./kg., and that
in brackets is given in millimoles/kg.
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1~56306
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1~563V6
Additional analqesia test with_phenyl~benæo~uinone.
An intraperitoneal injection of an aqueous solution of
phenyl-p-benzoquinone produces pain in the animal (female mouse
of about 22 g. body weight), which stretches itself until the
rear paws are extended. These extensions are counted over a
determined period of time (about 20 minutes) and the number thus
obtained for the treated animals is compared with that obtained
for the control animals
The product studied is administered 30 minutes before
the injection of phenyl-p-benzoquinone.
In this test, product (B) and product (C) are administe-
red orally at a dosage of 50 mg./kg. of animal. Product (B) is
in the form of a 10 % suspension in gum arabic and product (C)
is in the form of a normal aqueous solution. The results obtain-
ed are as follows :
T A B L E II
test compoundNumber of -% of protection (reduction
stretchesof number of stretches)
Control 138
Product (B) 68 50 %
Product (C) 43 68 %
Clinical tèsts.
The analgesic acti~ity of product (C) has been clinically
verified and compared with that of a known analgesic, glaphenine
(2,3-dihydroxy-propyl ~-(7-chloro-4-quinolyl)-anthranilate).
The tests were carried out as follows : Product (C)
and the mentioned reference substance are orally administered
in double blind at the rate of 3 capsules of 200 mg. per day
during 10 days to patients suffering generally from subacute or
chronic rheumatism.
The effect of the administration of each of the products
on each "symptom" (pain, painful irradiation) has been
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appreciated in a global subjective way, after tratment, and the
global results have been estimated as very good, good, moderate
or nil. The results are given in the following Table. For each
symptom and for each tested product, the number of patients is
given, whose global results have been estimated as very good,
good, moderate or nil.
T A B L E III
P a i n Painful irradiation
Results product C reference product C reference
Very good 3 1 3
Good 5 3 5 3
Moderate 3 4 3 3
Nil 1 4 1 4
From the results given this Table, it can be seen that
product C relieves the suffering of the patients in a more dis-
tinct and significative way than does the reference product.
Thus, for both the symptoms taken into consideration, product C
gives for 8 patients results that are qualified to be at least
"good", whereas for the reference product this result is reached
only in the case of 4 patients.
Tolerance.
Preliminary studies carried out on monkeys have shown
; that product (C) was well tolerated. This was confirmed by
- studies made on patients.
a) ~l~nica~_toleE3nce.
2 patients out of 12 in each series have shown slight
reactions in the form of headache, nausea, gastralgia.
b) B_QloglC--l-t-o-l-eE3-nc---
No significative difference appeared from the statisticalstudies of the data collected before and after treatment (600 mg.
per day, during 10 days) on the following parameters : globular
counting and leucocytic formula, speed of sedimentation, azote-
mia, 0 & T transaminase, glycemia, uricemia, cholesterolemia.
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~OS63~)6
The derivatives of 2-naphthyl-butyric acid used
according to the present invention can be administered orally in
solid or liquid form, for example in the form of tablets, pills,
sugar-coated pills, gelatine capsules, solutions, syrups or the
like. Similarly, they may be administered parenterally in
pharmaceutical forms known for this method of administration,
for example, aqueous or oily emulsions, suspensions or solutions.
For rectal administration, the products of the present invention
are generally used in the form of suppositories,
The pharmaceutical forms, such as injectable solutions,
injectable suspensions, tablets, drops or suppositories are
prepared by the conventional methods used by pharmacists. The
compounds of the present invention are mixed with a non-toxic,
pharmaceutically acceptable solid or liquid vehicle and optional-
ly with a dispersing agent, a disintegrating agent, a lubricant,
a stabilizing agent or the like. If desired, preservatives,
sweetening agents, coloring agents and the like may also be added.
Similarly, the solid or liquid pharmaceutical vehicles
used for the formulation of these medicaments are well known to
those skilled in the art. Solid pharmaceutical excipients for
the preparation of tablets or capsules include, for example,
starch, talc, calcium carbonate, lactose, sucrose, magnesium
stearate and the like.
The percentage of active product in the pharmaceutical
preparaticns may vary within very wide limits, depending on the
conditions of use and particularly depending upon the requency
of administration.
Human dosage is of the order of 1.2 g. per day but may
be from 1 to 2 g. per day.
B~ way of example, a formulation is given below for
tablets :
Product A (B or C) 200 mg.
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Maize starch 83 mg.
Lactose 32 mg.
Polyvinylpyrrolidone8 mg.
Magnesium stearate2 mg.
325 mg.
and a formulation for capsules :
Product A (B or C)200 mg.
Lactose 45 mg.
"Aerosil"* (standard)2.5 mg.
Magnesium stearate2.5 mg.
For one capsule (size 2) 250 mg.
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