CA1056306A - Pharmaceutical compositions containing 2-naphthyl-butyric acid derivatives - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE:

A pharmaceutical composition for the treatment of inflammations, pain and pyrexia in man, containing a therapeuti-cally effective amount of a 2-naphthyl-butyric acid derivative having the formula

Description

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, , ~ .

-2-, ~ .

105~306 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.
:
~ -3-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 %).

~ .

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 .
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 --6~

.. , . :~ ' ' ~ -.
.-: :- : , - , . ... . .

``'-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

-7-,.... . . . .
:, , ~

` 1056306 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.

. - .

- ;- , - . -1~5~;3~6 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.

-,. : . , - ' ' . ~: - ~

~ `
1~56306 1~ 1 ~ . ~ ~ ~ ~
o ~ .
o~
o.
~> 0 ~D
In :
_ ~. ' a) ~ o `~ - .-h ~ O O O O O
~ _. _ _ _ _ .~ ~ ~
~ u~ D ~
~;r~ rl' . __ ~

_3 ~ 0 ` o_ :. ~ ~ O O -i 0 0 H , J ~3 t~ 00 1~ ' . ~J . 111 t~' 00 d' ~J
~_ O d'~O
_~0 ~ ' ~ ~ d 3 d' ~ 1 E-~ ~ . Ql ~ o o ~ ~ ~1 O O ~I` O O . .
~D 0~ , .. ' ~o ~o ~ ':
'. . ~.
.' ~ ~ d' h ~ O O ~1 ~I O ~
.I .~ o, o O O O
, ~ 1 - .
r~ ~ 0 ~'ul ::
~.: . .. - _ _ . ~
00' m o ', ~ ~ ~
o ~ ~rl ~ ~
~Q1 0 0 :~

., ~; 10 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 1~56306 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.

~. ~
, , ~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.

-1~563~)6 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.

~ .
: -

Claims (3)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A pharmaceutical composition useful in the treatment of inflammations, pain and pyrexia in man comprising a non-toxic pharmaceutical excipient and a therapeutically effective amount of a 2-naphthyl-butyric acid derative of the formula wherein R is a methyl radical, R1 is a hydrogen atom or a methyl radical and M is a hydrogen atom or the cation of a pharmaceutically acceptable base.

2. A pharmaceutical composition as claimed in claim 1, wherein said therapeutically effective amount is between about 100 and 500 mg.

3. A pharmaceutical composition as claimed in claim 1, or 2, wherein the 2-naphthyl-butyric acid derivative is gamma-(6-methoxy-2-naphthyl)-beta-methyl-butyric acid or a salt thereof with a pharmaceutically acceptable base.