WO1999032425A1 - Analgesic naproxene trometamonic salt - Google Patents

Abstract

The chemical compound (s)-2-(6-methoxynaphtyl)propionate of tris(hydroxymethyl)methylamonium, called TROMETOXAN of the present invention and which has the chemical structure of formula (I) is the result of a neutralization reaction between (s)-2-(6-methoxynaphtyl)-propionic acid and tris(hydroxymethyl)methyl amine. Said compound has improved analgesic, antipyretic, anti-inflammatory properties in chronical rheumatoid arthritis. Amongst possible applications, it can be used in the pharmaceutic industry and its use in the medical field, said fields requiring substances with efficient therapeutical properties to improve or alleviate diseases related to pain and inflammatory troubles in general. TROMETOXAN is a highly efficient compound in comparison with the anti-inflammatory and anti-pyretic activity of the chemical compound called Naproxen, according to an experimental study carried out on rodents and has minor toxicity and reduced ulcerogenic activity with respect to sodic naproxen.

Description

 ANALGESIC NAPROXEN TROMETAMONIC SALT

TECHNICAL FIELD OF THE INVENTION

The present invention relates to an optically active isomer of the novel chemical compound, (s) -2- (6- methoxynaphthyl) propionate of tris (hydroxymethyl) methylammonium, which exhibits analgesic, anti-pyretic, anti-inflammatory activities in chronic and anti rheumatoid arthritis -inflammatory improved compared to the pharmaceutical activities of naproxen sodium (Naproxen). Also, the invention relates to the process for preparing said compound, pharmaceutical composition containing it and uses in the treatment of pain and inflammatory disorders in general; which makes it a compound of great commercial expectation in the pharmaceutical industry and of great therapeutic application in the medical field.

INTRODUCTION

The chemical compound of the present invention is a tromethammonium salt derived from (s) -6- (methoxynaphthyl) -propionic acid, which has the following chemical structure of formula (I):

whose chemical name is (s) -2 - (6-methoxynaphthyl) propionate from tris (hydroxymethyl) methylammonium, referred to as TROMETOXAN where appropriate.

TROMETOXAN is the result of a neutralization reaction between the (s) -2- (6-methoxynaphthyl) propionic acid and tris (hydroxymethyl) methyl amine, followed by crystallization in a suitable solvent by using standard techniques known by subject matter experts Said chemical compound was subjected to a series of experimental studies and tests where its characterization was completely determined by elemental analysis, nuclear magnetic resonance imaging (NMR), infrared and mass spectroscopy. Likewise, the chemical compound TROMETOXAN has improved analgesic, anti-pyretic, anti-arthritic and anti-inflammatory activities compared to the pharmaceutical activities typical of sodium naproxen, in addition to presenting less ulcerogenic activity and being less toxic. These analyzes were carried out by means of a comparative experimental study in rodents, between the compound of the present invention and the -2- (6-methoxynaphthyl) -propionic acid (s), commercially known as Naproxen. Both the characterization and the analgesic, anti-pyretic activities,

improved anti-arthritic and anti-inflammatory compound

TROMETOXAN are shown in the examples below

describe.

BACKGROUND OF THE INVENTION

-2- (6-methoxynaphthyl) propionic acid (s) and methods

for their preparation are described in patent applications

Americans with Nos. of Series 694,771 and 741,858 from the

1967, said active principle known as Naproxen is included among the substances that have activities

anti-inflammatory, analgesic and anti-pyretic; his main

Therapeutic use is the treatment of rheumatoid arthritis and other degenerative forms that have phlogistic characteristics.

On the other hand, tris (hydroxymethyl) methyl amine is a well-known organic amino base, which does not have

anti-inflammatory or pharmaceutical activity per se. The

derivative obtained by combining these two

Compounds is the main object of the present invention.

Related state of the art documents

with the present invention, they are mentioned below with the

purpose of including them only as references.

US Patents Nos. 3,651,106; 3,787,580; 3,803,245; 3,828,038; 3,896,157; 3,975,432; 3,978,116; 4,051,233 and 4,097,674, whose owner is Syntex Corp., as well as Patents 3,720,708; 4,550,191; 4,922,010; 5,093,361; 5,145,993; 5,179,208 and 5,286,902 describe different methods of preparing the (s) -2- (6-methoxynaphthyl) propionic acid, as well as its derivatives and the corresponding amides, esters, hydroxamic acids and addition salts thereof, by substitution and hydrolysis reactions; pharmaceutical compositions containing them, which have analgesic, anti-pyretic and anti-inflammatory activities. US Patents Nos. 3,904,683; 4,246,193; 4,395,571; 4,399,284; 4,423,244; 4,515,811; 4,546,201; 4,865,770 and 5,229,280 describe processes for the resolution of D and / or L enantiomers of sodium naproxen.

Patent No. 3,896,157 and divisional applications thereof, mention that the addition salts are prepared by conventional techniques using pharmaceutically acceptable non-toxic bases including metal salts, such as sodium, potassium, calcium, aluminum and the like; as well as organic amino salts, such as triethylamine, 2-dimethylamino ethanol, 2-diethylamino ethanol, lysine, arginine, histidine, caffeine, procaine, N-ethylpiperidine, hydrabamine and the like. Particularly this document describes esters or derivatives of Naproxen which includes substituents in the naphthenic ring and / or in the alpha position of the propyl acid, which is not a priority of the present invention.

International Patent Application PCT / US91 / 06398 with publication number WO 92/04021, describes a method for providing an improved analgesic effect by synergistic activity between the combination of a Naproxen derivative, salts and esters thereof with a sympathomimetic amine . He also mentions on page 6, lines 14-29 the definition of the term "pharmaceutically acceptable salts" from non-toxic bases, including inorganic and organic bases. However, this document does not explicitly refer to the use of tris (hydroxymethyl) methyl amine, used in this invention, nor does it describe that by reacting this organic amino base with the (s) -2- (6- methoxynaphthyl) propionic acid a novel compound with unexpected pharmaceutical activities and applications would originate.

On the other hand, US Patent No. 5,093,361, recently granted, is a clear example of the need to find novel chemical compounds with improved therapeutic properties, despite belonging to the group of Naproxen-derived compounds.

The importance of the present invention, unlike what is described in the prior art documents mentioned above, lies in the technical characteristics of the invention itself, as well as in the additional advantages derived from it. thereof, which are described in more detail below.

The present invention describes a novel, non-steroidal, non-salicylate chemical compound, which is a quaternary ammonium salt of Naproxen, that is, it is a tro-ethammonium salt derived from propionic acid (s) -6- (methoxynaphthyl), whose Analgesic, anti-pyretic, antiarthritic and anti-inflammatory activities are more highly effective than those shown by naproxen sodium, in addition to presenting less ulcerogenic activity and being less toxic.

Likewise, the fundamental part of the process of obtaining the TROMETOXAN compound is the importance of introducing a methylammonium ion into the general molecule, resulting in a substance more soluble in water and in organic solvents. The effect of this property is that the compound will have a greater bioavailability, which makes the required therapeutic doses lower and, therefore, the side reactions are reduced.

Therefore, none of the processes for obtaining derivatives of the -2 (6-methoxinaphthyl) propionic acid (s) described in the prior art documents would be relevant with respect to the procedure for obtaining the TROMETOXAN compound.

The chemical compound of this invention has a high therapeutic value in the treatment of various conditions. inflammatory such as in the skin, eyes, respiratory tract, bones and internal organs, as well as in dermatitis, allergic reactions and rheumatoid arthritis; and in some cases in which the conditions include pain, pyrexia and pruritis accompanied by inflammation, this compound is useful for relieving the associated effects, as well as the main condition of the damage.

Due to the great importance of these compounds in the pharmaceutical field, countless ways have been described for their preparation, most of them are procedures that involve long periods of time to get the product of interest, some with low yields global in the percentage of production and others where they include many stages or that involve the management of toxic and / or dangerous products.

In view of the aforementioned, the authors of the present invention have been given the task of finding a process to produce a compound with great therapeutic application as an analgesic, anti-pyretic, anti-arthritic and anti-inflammatory agent compared to those other compounds used in the pharmaceutical industry, commercially known, as is the case in particular with Naproxen.

Thus, as in the present invention, the preparation process, pharmaceutical composition and uses are disclosed. Therapeutics of a novel chemical compound called TROMETOXAN, with analgesic, anti-pyretic, anti-inflammatory activities in improved chronic and anti-inflammatory rheumatoid arthritis, with lower ulcerogenic activity and lower toxicity than naproxen sodium.

BRIEF DESCRIPTION OF THE DRAWINGS

Other objects, particularities and advantages of the invention will be apparent from the following detailed description, of the preferred embodiments, of the appended claims and of the accompanying drawings, wherein:

Figure 1 graphically depicts the nuclear magnetic resonance (f ^ NMR) study of the tris (hydroxymethyl) methylammonium compound (s) -2- (6- methoxynaphthyl) propionate, called TROMETOXAN;

Figure 2 is a graphical representation of the infrared spectrum, I.R. (KBr) of the same compound;

Figure 3 is a graphic representation of the ¹³ C analysis of the same compound;

Figure 4 graphically depicts the mass spectrum of the same compound;

Figure 5 represents a graph of the stretching means' induced by intraperitoneal acetic acid in unmedicated mice (control) and medicated orally with various doses of naproxen sodium and TROMETOXAN;

Figure 6 shows the anti-pyretic effect of TROMETOXAΝ and sodium naproxen at a dose of 6.25 mg / kg in both cases, orally in mice, to which they were applied

a lysate of Eschrichia coli;

Figure 7 shows the anti-pyretic effect at doses of 12.5 mg / kg under the conditions of Figure 6;

Figure 8 shows the anti-pyretic effect at doses of

50 mg / kg under the conditions of Figure 6;

Figure 9 shows the anti-pyretic effect at doses of 100 mg / kg under the conditions of Figure 6;

Figure 10 shows the anti-inflammatory effect of

TROMETOXAΝ and sodium naproxen at a dose of 6.25 mg / kg in both cases, orally in mice, after administration of 0.03 ml of 0.5% suspension BCG with Freund's adjuvant for 13 days;

Figure 11 shows the anti-inflammatory effect a

dose of 12.5 mg / kg under the conditions of figure 10; Figure 12 shows the anti-inflammatory effect at doses of 50 mg / kg under the conditions of Figure 10;

Figure 13 shows the anti-inflammatory effect at doses of 100 mg / kg under the conditions of Figure 10;

Figure 14 shows the relationship of edema found with the treatment based on TROMETOXAN and sodium naproxen at several doses, after the application of 0.2 ml of carrageenan; Y

Figure 15 graphically depicts acute mortality in mice dosed orally with sodium naproxen on a logarithm / probability scale.

DETAILED DESCRIPTION OF THE INVENTION

The chemical compound TROMETOXAN of formula (I), is

- obtained by means of the chemical reaction that can be illustrated as follows:

(A) (B) (I) wherein the compound represented by the formula (A) corresponds to -2- (6-methoxynaphthyl) propionic acid; the compound of formula (B) is tris (hydroxymethyl) methyl amine, and the compound of formula (I) corresponds to a tromethammonium salt derived from Naproxen, whose chemical name is (s) -2- (6-methoxynaphthyl) propionate of tris (hydroxymethyl) methyl ammonium, called TROMETOXAN. The compounds of the formulas (A and B) and the procedures for their preparation have been previously described in the prior art. The objects and advantages are presented below which are derived from this invention.

An object of the present invention is to provide a process for preparing the tris (hydroxymethyl) methylammonium compound (s) -2- (6-methoxynaphthyl) -propionate, which is a quaternary ammonium salt derived from Naproxen, said compound is obtained by means of a neutralization reaction of the (s) -2- (6-methoxynaphthyl) propionic acid with tris (hydroxymethyl) methyl amine, which has unexpectedly specific therapeutic properties superior to the activities of sodium naproxen.

Another objective of the invention is to provide a compound with improved analgesic, anti-pyretic, anti-inflammatory activities in chronic rheumatoid arthritis and anti-inflammatory compared to sodium naproxen. An additional advantage in the process of obtaining the compound TROMETOXAN, is to introduce a methylammonium ion into the general chemical molecule.

Also provided in the present invention are pharmaceutical compositions containing the chemical compound TROMETOXAN in a therapeutically effective amount or amounts to treat or relieve conditions of pain and / or inflammations in general. Likewise, as its therapeutic uses with analgesic, anti-pyretic, anti-inflammatory activities in chronic rheumatoid arthritis and improved anti-inflammatory. Another additional advantage still of greater importance of the compound TROMETOXAN, is that it has lower ulcerogenic activity and less toxicity than naproxen sodium; being therefore used in the treatment of disorders, which include, but are not limited to inflammation, pain and pyrexia in mammalian animals, including man. For example, inflammatory conditions of the skeletal muscular system, as well as the treatment of conditions characterized by inflammation, such as rheumatism, concussion, laceration, arthritis, bone fracture, post-traumatic conditions and gout.

The preferred way of applying the present invention is by orally administering the chemical compound of formula (I), where a therapeutically effective amount is provided at a convenient daily unit dose regimen to an individual suffering from pain and / or inflammatory conditions in general, said regimen can be adjusted in accordance with the degree of affliction. Generally, a daily unit dose of from 2.5 mg to 100 mg of the active compound per kilogram of individual weight is employed. Preferably 3.0 mg / kg.

The preparation of a pharmaceutical composition that includes the chemical compound TROMETOXAN, can be carried out by using standard techniques well known to those skilled in the art in combination with any of the pharmaceutically acceptable carriers described in the state of the art, including but not limited to starch, glucose, lactose, sucrose, gelatin, malt, rice, wheat flour, chalk, silica gel, magnesium stearate, sodium stearate, talc of glyceryl monostearate, sodium chloride, glycerol, propylene glycol, water, ethanol and the like. These compositions take the pharmaceutical form of solutions, suspensions, tablets, pills, capsules, powders and prolonged release formulation and the like. The above description and the following examples are intended to illustrate particular ways of carrying out the invention and should not be considered as limiting the scope of protection thereof.

EXAMPLES

Example 1 Obtaining the compound (s) -2- (6-methoxynaphthipropionate of tris (hydroxymethyl) methylammonium

An amount of 347.3 gr (1.5 mol) of propionic methoxynaphthyl acid was dissolved in 1200 ml of hot methanol. On the other hand, an amount of 181.5 gr (1.5 mol) of tromethamine was dissolved in 2000 ml of hot methanol. The methoxynaphthyl propionic acid solution was poured onto the tromethamine solution and allowed to boil for 3 minutes. The solution mixture was cooled in an ice bath at 5 ° C, it was filtered and allowed to air dry. 500 grams of the tris (hydroxymethyl) methylammonium compound (s) -2- (6-methoxynaphthyl) propionate were obtained, with a yield of 94 percent yield. If the optically active methoxynaphthyl propionic acid is taken as the starting point, the compound TROMETOXAN is obtained as a single enantiomer and, therefore, optically active. This feature is recommended according to the Federal Drug Administration of the United States of America (FDA).

Each of the optical isomers of the tromethammonium salt is included in the present invention. In some instances, one enantiomer may exhibit greater analgesic, anti-pyretic and anti-inflammatory activity than the other enantiomer.

Any commercial solvent that is inert to the reactants can be used in this reaction. Suitable solvents may include, but are not limited to hydrocarbon solvents, such as methanol, toluene, benzene, xylene, cyclohexane; ethers such as diethyl ether, tetrahydrofuran, tetrahydropyran, dimethoxyethane and the like. Preferably using methanol.

Once the tris (hydroxymethyl) methylammonium tris (-2) methoxynaphthyl) propionate compound (s) was obtained by the procedure described above, it was subjected to a series of studies and tests, where its Molecular Weight of 351 grams / mol and its melting point of approximately 170-172 ° C was determined.

The results of the Elemental Analysis are shown below:

Calculated for CisHzsNOe: 61.53% C; 7.12% H; 3.99% N; 27.35% 0. Expected 61.62% C; 7.09% H; 4.0% N, 27.29% 0.

Referring again to the figures, the results obtained from the nuclear magnetic resonance analysis (H ^ NMR) of the TROMETOXAN, shown in Figure 1, whose maximum values (peaks or crests) are the most significant are: 1.39 (d.) , 3.40 (s.), 3.60 (q.), 3.85 (s.), 7.11 (dd), 7.24 (d.), 7.44 (dd), 7.66 (bd), 7.69 (s.) And 7.73 (d. ).

The values shown in Figure 2 of 3303, 1631, 1604, 1556 and 1070 cm ^"1 are the result of infrared spectroscopy, IR of the

TROMETOXAN at a certain percentage of transmittance,% T, with respect to a number of waves, # 0 (cm ^"1 ).

The result of the ^U C analysis of the TROMETOXAN shown in Figure 3 corresponds to the following values expressed in parts per million ^, (ppm): 19.47, 47.24, 55.10, 15.69, 118.22, 125.16, 126.19, 127.09, 128.16, 128.96 , 132.83, 139.18, 156.72 and 177.73. In analysis of mass spectroscopy performed on the TROMETOXAN compound, represented in Figure 4, it shows the following values: 230 (M *) and 185 (M-C0 ₂ H).

Example 2 Analgesic activity of TROMETOXAN

60 male mice of the strain CD-1 were used, with an average weight of 36 to 43 grams.

After the acclimatization period of one week, 3 batches of 20 mice each were formed, randomly distributed. A group designated as A received treatment with TROMETOXAN and a group B received sodium naproxen and the control group received an injection of saline solution in the same volume as the previous groups. The doses were applied orally by means of a probe at a rate of 6.25, 12.5, 50 and 100 mg / kg body weight, dissolved in physiological saline solution in constant volume per kg of weight (10 ml / kg). Thirty minutes after the administration of the drugs or the vehicle, they were injected intraperitoneally with a solution of acetic acid (0.5%, 10 ml / kg) to produce a painful syndrome, which can be reduced or abolished by analgesic drugs in study. Subsequently, the number of stretches or contractions caused by the pain in the mouse, presented every 5 minutes, during a period of time was counted. 20 minutes total. Mice that did not stretch during that time were eliminated. In this experiment, no animal died or had apparent symptoms of toxicity. The therapeutic analysis to determine the comparative analgesic activity between the two drugs, was determined by an analysis of variance of two inputs, stretching response and treatment, with successive Dunnet t tests.

The results of the number of stretches due to acetic acid in mice treated with TRC-VIETOXAN, sodium naproxen and in the control group (untreated) are presented in Tables 1 to 9, and where the means and standard deviations of these values are presented in the form of frequency bars in Figure 5, which corresponds to the dose (D) of the analgesics TROMETOXAN (T) and sodium naproxen (N) in (mg / kg) in relation to the number of contractions every 5 minutes, No C / 5 min, in addition to the values of the mean (X) and effective dose (SD) of the control group (GT).

Statistical analysis comparing the means of the number of stretches revealed that there were no significant differences (P> 0.05) due to the effect of the drugs with respect to the control group. When comparing the effects of both drugs, no difference was found for any better effect between the drugs (P = 0.084), with the exception of TRCMETOXAN at a dose of 100 mg / kg (P = 0.05), nor was it possible to detect an effect due to the increase in the dose (P = 0.23). TABLE 1. Application of naproxen sodium at a dose of 6.25 mσ / kσ orally.

Contractions every 5 min.

CUADRO 2. Aplicación de naproxeno sódico a dosis de 12.5 mg/kg vía oral.

TABLE 2. Application of naproxen sodium at a dose of 12.5 mg / kg orally.

Contractions every 5 min.

CUADRO 3. Aplicación de naproxeno sódico a dosis de 50.0 mg/kσ vía oral.

TABLE 3. Application of naproxen sodium at a dose of 50.0 mg / kg orally.

Contractions every 5 min.

CUADRO 4. Aplicación de naproxeno sódico a dosis de 100 g/kq vía oral.

TABLE 4. Application of naproxen sodium at a dose of 100 g / kg orally.

Contractions every 5 min.

CUADRO 5. Aplicación de TROMETOXAN a dosis de 6.25 mg/kq vía oral.

TABLE 5. Application of TROMETOXAN at a dose of 6.25 mg / kg orally.

Contractions every 5 min.

CUADRO 6. Aplicación de TROMETOXAN a dosis de 12.5 m^g/k^g vía oral .

TABLE 6. Application of TROMETOXAN at doses of 12.5 m ^g / k ^g orally.

Contractions every 5 min.

CUADRO 7- Aplicaf-ión de TROMETOXAN a dosis de 50.0 mq/kq

TABLE 7- Application of TROMETOXAN at a dose of 50.0 mq / kq

orally .

Contractions every 5 min.

CUADRO 8. Aplicación de TROMETOXAN a dosis de 100 mg/kg vía oral.

TABLE 8. Application of TROMETOXAN at a dose of 100 mg / kg orally.

Contractions every 5 min.

CUADRO 9. Número, media γ desviación estándar de estiramientos en el grupo testigo después de la aplicación intraperitoneal de ácido acético.

TABLE 9. Number, mean γ standard deviation of stretching in the control group after intraperitoneal application of acetic acid.

Contractions every 5 min.

Ej emplo 3

Ex emplo 3

TROMETOXAN anti-pyretic activity

After an acclimatization period of one week, 3 batches of 20 male mice of the strain CD-1, each were randomly formed. The mice had an average weight of 31 to 40 grams. Group A received treatment with TROMETOXAN, group B received sodium naproxen and the control group received saline injection in the same volume as the previous groups. Rectal temperature was recorded using a digital thermometer three times to obtain basal body temperature. A 0.2 ml dose of bacterial detritus lysate, inactivated from Escherichia coli, was then applied. which produces hypertemia in mice, which can be reduced or abolished by the administration of the anti-pyretic drugs under study; upon registering a temperature of 41 ° C, the above-mentioned drugs were administered orally, at doses of 6.25, 12.5, 50 and 100 mg / kg, and the temperature was quantified every 15 minutes until 6 hours and the next day. No animal showed toxicity symptoms during the experiment.

The therapeutic analysis to determine the comparative antipyretic activity between the temperature curves of the two drugs was determined by analysis of variance of _d o _s in _t ra _d as, graphing the results in the Origin program for Windows.

_T he results of measurements of _I m _pe rature rectally in mice receiving Fscherichia coli lysate and treated with TROMETOXAN, naproxen sodium and the control group (untreated) are given in Tables 10 to 18. The middle and Standard deviations of these values are presented in Figures 6 to 9, which correspond to the measurements of the temperature (MT) in relation to the temperature in degrees Celsius (T ° C), during the application (I) of the lysate of E. coli until the temperature measurement one day later (T + ld). The symbols used to plot the curves correspond to -M- TROMETOXAN, - • - sodium naproxen and - A- control, for each of the concentrations of 6.25, 12.5, 50 and 100 mg / kg, in figures 6, 7, 8 and 9, respectively.

Statistical analysis comparing the means of measuring the rectal temperature in mice revealed that there were significant differences (P <0.05) due to the effect of the drugs with respect to the control group. When comparing the effects between both drugs, a better effect of TROMETOXAN was found with respect to sodium naproxen. TABLE 10. Anti-pyretic effect of TROMETOXAN at a dose of 6.25 mg / kg.

* A suspension of cellular debris from Escherichia coli was used.

** The temperature of each animal was taken three times and an average of them was obtained. TABLE 11. Anti-pyretic effect of naproxen sodium at a dose of 6.25 mg / kg.

* A suspension of cellular debris from Escherichia coli was used.

** The temperature of each animal was taken three times and an average of them was obtained. TABLE 12. Anti-pyretic effect of TROMETOXAN at a dose of 12.5 mg / kg.

* A suspension of cellular debris from Escherichia CQli was used.

** The temperature of each animal was taken three times and an average of them was obtained. TABLE 13. Anti-pyretic effect of naproxen sodium

at a dose of 12.5 mg / kg.

* A suspension of cellular debris from Escherichia coli was used.

** The temperature of each animal was taken three times and an average of them was obtained. TABLE 14. Anti-pyretic effect of TROMETOXAN at a dose of 50 mg / kg.

* A suspension of cellular debris from Escherichia coli was used.

** The temperature of each animal was taken three times and an average of them was obtained. TABLE 15. Anti-pyretic effect of naproxen sodium at a dose of 50 mg / kg.

* A suspension of cellular debris from Escherichia coli was used.

** The temperature of each animal was taken three times and an average of them was obtained. TABLE 16. Anti-pyretic effect of TROMETOXAN at a dose of 100 mg / kg.

* A suspension of cellular debris from Escherichia coli was used.

** The temperature of each animal was taken three times and an average of them was obtained. TABLE 17. Anti-pyretic effect of naproxen sodium at a dose of 100 mg / kg.

* A suspension of cellular debris from Escherichia coli was used.

** The temperature of each animal was taken three times and an average of them was obtained. TABLE 18. Pyretic effect of an inactivated Escherichia coli lysate.

* A suspension of cell debris was used

Escherichia coli.

** The temperature of each animal was taken three times and an average of them was obtained.

*** Dead mice. Ex emplo 4

Anti-inflammatory activity in chronic rheumatoid arthritis of TROMETOXAN

After an acclimatization period of one week, it

⁵ formed 3 batches of 20 male mice of the CD-1 strain, each, distributed randomly. The mice had an average weight of 25 to 40 grams. Group A received treatment with TROMETOXAN, group B received treatment with sodium naproxen and the control group received the injection of saline solution in the same volume as the previous groups. The drugs were administered orally at doses of 6.25, 12.5, 50 and 100 mg / kg body weight, dissolved in saline (0.9%) in constant volume per kg of weight (10 ml / kg). Subsequently he administered in the plantar bearing ⁵ right hind limb of the mouse an amount of 0.03 ml of 0.5% suspension of BCG, prepared in mineral oil with Freund 's adjuvant. Said BCG suspension causes chronic arthritis in the mouse, which can be reduced by the anti-inflammatory drugs under study. The treatment was continued for 13 days (additionally the limb volume was measured on alternate days). After that time, the mice were sacrificed and their right limbs were weighed. The calculation of the percentage of inflammation inhibition in chronic rheumatoid arthritis was obtained using the comparative difference in weight with the left limb. Additionally, they were processed according to routine methods.

joints for histopathological examination.

The treatment during the 13 days did not produce apparent toxicity

according to the administered doses, which was evaluated by appearance

general, behavior and weight of animals.

The therapeutic analysis to determine the anti ^¬ inflammatory activity in chronic rheumatoid arthritis was determined by a two-way analysis of variance of the quantitative variables of

weight and volume of the limbs.

The results of the measurements of the inflamed members with the BCG suspension, treated with TRC-YEE-TOXAN, sodium naproxen and in the control group (without treatment) are presented in tables 19 to 27. The measurements and standard deviations of those Values are presented in Figures 10 to 13, which correspond to the measurements of the member width (mam) in relation to the size of the member width in millimeters (mm). The symbols used to graph these results are the same as those used in Figures 6 to 9.

Statistical analysis of the comparison of the measurements of the widths of the experimental members revealed that there were significant differences (P <0.05) due to the effect of the drugs with respect to the control group. When the effects between both drugs were compared, a better effect of TROMETOXAN was found with respect to sodium naprαxen at a level of 93% (P = 0.069), at a dose of 6.25 mg / kg. TABLE 19. Treatment with TROMETOXAN 6.25 mg / k ^g. Measurements on alternate days of the width of the member (mm).

CUADRO 20. Tratamiento con naproxeno sódico 6.25 mg/kg. Mediciones en días alternos del ancho del miembro (mm)

TABLE 20. Treatment with naproxen sodium 6.25 mg / kg. Measurements on alternate days of member width (mm)

CUADRO 21. Tratamiento con TROMETOXAN 12.5 mg/kg. Mediciones en días alternos del ancho del miembro ⁽mm⁾ .

TABLE 21. Treatment with TROMETOXAN 12.5 mg / kg. Measurements on alternate days of the width of the member ⁽ mm ⁾ .

CUADRO 22. Tratamiento con naproxeno sódico 12.5 mg/kg. Mediciones en días alternos del ancho del miembro (mm) .

TABLE 22. Treatment with sodium naproxen 12.5 mg / kg. Measurements on alternate days of the width of the member (mm).

CUADRO 23. Tratamiento con TROMETOXAN 50 mg/kg. Mediciones en días alternos del ancho del miembro (mm) .

TABLE 23. Treatment with TROMETOXAN 50 mg / kg. Measurements on alternate days of the width of the member (mm).

CUADRO 24. Tratamiento con naproxeno sódico 50 mg/kg. Mediciones en días alternos del ancho del miembro (mm) .

TABLE 24. Treatment with naproxen sodium 50 mg / kg. Measurements on alternate days of the width of the member (mm).

CUADRO 25. Tratamiento con TROMETOXAN 100 mg/kg. Mediciones en días alternos del ancho del miembro ⁽mm⁾

TABLE 25. Treatment with TROMETOXAN 100 mg / kg. Measurements on alternate days of member width ⁽ mm ⁾

CUADRO 26. Tratamiento con naproxeno sódico 100 mg/kg. Mediciones en días alternos del ancho del miembro (mm) .

TABLE 26. Treatment with naproxen sodium 100 mg / kg. Measurements on alternate days of the width of the member (mm).

CUADRO 27. Grupo Testigo. Mediciones en días alternos del ancho del miembro (mm)

TABLE 27. Witness Group. Measurements on alternate days of member width (mm)

E-iemolo 5 Actividad anti-inflamatoria del TROMETOXAN

E-iemolo 5 Anti-inflammatory activity of TROMETOXAN

After an acclimatization period of one week, 3 batches of 20 male mice of strain CD-1 were formed, each randomly distributed. The mice had a weight of about 30 to 42 grams. Group A received treatment with the compound of the present invention, TROMETOXAN, group B received treatment with sodium naproxen and the control group received saline injection in the same volume as the previous groups. In each of the two experimental cases the analgesic compounds were administered orally, at a dose of 6.25, 12.5, 50 and 100 ^m 9 / k body weight, one hour later the carrageenan suspension was injected (1% weight / volume in physiological serum with a total volume of 0.2 ml). This carrageenan injection was applied in the plantar aponeurosis of the right hind limb of the mice to cause an inflammatory response, which can be reduced or abolished by the anti-inflammatory drugs under study. After a period of 3 hours the mice were sacrificed and the inflammation of the anteroposterior edema was measured with a micrometer (Vernier). The thickness of the edema of the injected limb was determined by comparison with the thickness of the other non-injected limb. During the course of the experiment, no animal died or had apparent symptoms of toxicity. The therapeutic analysis to determine the comparative anti-inflammatory activity among pharmaceutical compounds was based on an analysis of variance of two entries, response of edema and treatment, with successive

Dunnet t tests.

The results of the measurements of the limbs inflamed with carrageenan, treated with TROMETOXAN, sodium naproxen and in the control group (untreated), are presented in Tables 28 to 36. The standard measurements and deviations of the

Edemas produced are presented as frequency bars in Figure 14, which corresponds to the dose of the drugs in milligrams per kilogram of body weight, D (mg / kg), in relation to the size of the thickness of the edema in millimeters (mm ). The white bars correspond to the edema treated with TROMETOXAN (E / T) and the bars with stripes correspond to the edema treated with sodium naproxen (E / N). The upper lines correspond to the mean (X) and effective dose (ED) of the edema in the control group (E-GT).

Statistical analysis comparing the measurements of the widths of the experimental members revealed that there were significant differences (P <0.05) due to the effect of the drugs with respect to the control group. When the effects between Arab drugs were compared, a better effect of TRCMETOXAN was found with respect to sodium naproxen, at a dose of 100 mg / kg (P <0.05). TABLE 28

TROMETOXAN 6.25 mg / kg in mice that received the dose of carragenin in the right limb— (0.2ml)

CUADRO 29

TABLE 29

Naproxen sodium 6.25 mg / kg in mice that received the dose of carragenin in the right limb (Q ₁ 2ml).

CUADRO 30

TABLE 30

TROMETOXAN 12.5 mg / kg in mice that received the dose of carragenin in the right limb (0.2ml).

CUADRO 31

TABLE 31

_N sodium aproxeno 13.05 g / kg and mice were dosed ue ^g carrageenan right member ^(0-2ml).

CUADRO 32

TABLE 32

TROMETOXAN 50 mg / kg in mice that received the dose of carragenin in the right limb (Q-2ml) _t ,

CUADRO 33

TABLE 33

_U aproxeno sodium 50 mg / kg in mice gue recibierpp. the dose of carrageenan in the right limb (Q _t 2ml) _f ,

CUADRO 34

TABLE 34

TROMETOXAN 100 mg / kg in mice that received the dose of carragenin in the right limb ⁽ 0.2ml ⁾ .

CUADRO 35

TABLE 35

Naproxen sodium 100 mg / kg in cπie mice received the dose of carragenin in the right limb— (0.2ml)

CUADRO 36. Grupo Testigo.

TABLE 36. Witness Group.

_R atons who received an injection of carra ^g enina in the right limb ⁽ 0.2ml ⁾ .

99/32425

99/32425

60

TABLE 36 Group or Testi ^g.

_Rato nes q _ι , _{ι «} received. ^ Rum an invention <* carrijiqenina

. => p _< ->! right member (0-2 lt

Ejemplo 6 _Evaluación del efecto tóxico del TROMETOXAN en ratones

Example 6 _E evaluation of the toxic effect of TROMETOXAN in mice

After an acclimatization period of one week, 2 batches of male mice of strain CD-1, weighing 20 to 36 grams, were randomly distributed. The drugs under study, TROMETOXAN and naproxen sodium, were administered orally, suspended in acacia gum prepared in water at the time of use, at varying concentrations and administered in cbp volumes.

In the case of TROMETOXAN, doses of 800, 1000, 1250, 1560, 2000 and 2500 mg / kg per day were administered, dividing the dose into two or more doses as needed, and in the case of sodium naproxen, doses of 100, 200, 300, 400, 500, 600, 700 and 800 mg / kg. One more lot was used as a witness and received only the vehicle.

The overdose of any non-steroidal anti-inflammatory induces ulcers and irritative gastritis that are inherent to its mechanism of action, but which varies in intensity and speed of presentation with respect to the agent used.

After drug administration, the mice were observed every hour on the day of the administration and every 3 days during the subsequent 14 days, in order to record the number of deaths and symptoms caused by intoxication. The dead and surviving mice were subsequently subjected to

autopsy.

The toxicity analysis of TROMETOXAN compared to that of sodium naproxen, was determined by performing mortality curves vs. dose and time, using a logarithm / probability analysis included in the Origin for Windows package and based on the postulated by Lichfield & Wilcoxon.

An attempt was made to induce oral toxicity with naproxen sodium and TROMETOXAΝ in mice (10 mice per dose), using other doses of 100, 500, 1000, 1500, 2000 and 2500 mg / kg. From the dose of 1500 mg the TROMETOXAΝ could not be completely dissolved, but it was administered with the purpose of dissolving it in the mouse. Νo it was possible to induce mortality with TROMETOXAΝ, even at doses of 2500 mg / kg, since this represents a dose of 175 g / human subject (70 kg), it was considered irrelevant to continue with larger doses.

The toxicity results (% of mortality) that were presented by the administration of the naproxen sodium drug The initial doses are shown in Table 37. These toxicity results were plotted on a logarithm / probability scale according to the Litchfield & Wilkinson postulate in Figure 15, where sodium naproxen shows a lethal dose 1 (DLl) of 110 mg / kg and a lethal dose 50 (LD50) of 520 mg / kg, in relation to the base 10 logarithm (Log 10) of the doses administered in (mg / kg) with respect to the probability (P) of occurring events of mortality caused by the toxic effect of naproxen sodium. The symbols used to plot the curves correspond to -------- sodium naproxen and linear regression (R).

TABLE 37. Toxicity values for naproxen sodium in mice dosed orally.

Ej emplo 7

Ex emplo 7

Ulcerogenic activity of TROMETOXAN

For the ulcerogenic phase, an average of

35 to 40 mice that were continuously administered 100 mg / kg of TROMETOXAN or sodium naproxen, twice daily, orally in acacia gum and subsequently 3 to 5 mice were sacrificed by barbiturate overdose every third day, until finishing with the group. Necropsy lesions were classified as: unchanged, moderate gastric irritation and

severe

The results of ulcerogenic activity of the drugs are presented in Table 38, which details the number and percentage of mice that presented ulceration or evidence of gastric irritation, with the constant medication of the drugs.

The ulcerogenic effect caused by TROMETOXAN compared to sodium naproxen, showed that in the case of TROMETOXAN no severe lesions were found and the percentage of moderate lesions was very low, the significant difference was in favor of TROMETOXAN using a Chi test ² (P <0.001). TABLE 38. List of lesions suggestive of gastric ulcer or irritation induced by the oral application of

TROMETOXAN or sodium naproxen in mice at doses of

100 mg / kg twice daily - orally.

comparativo entre estos dos fármacos, se puede dar a conocer en la presente invención las siguientes ventajas terapéuticas del TROMETOXAN en relación a la actividad farmacéutica del naproxeno sódico:

Comparative between these two drugs, the following therapeutic advantages of TROMETOXAN in relation to the pharmaceutical activity of sodium naproxen can be disclosed in the present invention:

1) Lower analgesic activity: with a dose of 100 mg / kg, TROMETOXAN has a better analgesic effect than naproxen sodium.

2) Superior anti-pyretic activity: with a dose of 6.25

at 100 mg / kg, the anti-pyretic effect of TROMETOXAN is better

than that of sodium naproxen, keeping the temperature below the level of the temperature sustained by sodium naproxen.

3) Better anti-inflammatory activity in arthritis

Chronic rheumatoid: With low doses of 6.25 mg / kg, TROMETOXAN is more effective than naproxen sodium.

4) Increased anti-inflammatory activity: at a dose of 50 to 100 mg / kg, TROMETOXAN inhibits inflammation more than naproxen sodium.

5) Lower toxicity: the determination of LD50 showed that with TROMETOXAN up to a dose of 2500 mg / kg maintains a

0% mortality and with naproxen sodium the LD ₅₀ was 520 mg / kg, reaching 100% mortality with doses of 800 mg / kg.

6) Lower ulcerogenic activity: TROMETOXAN has lower ulcerogenic activity than naproxen sodium. The above-mentioned advantages of the compound (s) - 2- (6-Methoxynaphthyl) propionate of tris (hydroxymethyl) methyl ammonium as an analgesic, anti-pyretic, anti-arthritic and anti-inflammatory with lower toxicity and lower ulcerogenic effect, make TROMETOXAN a pharmaceutical product of great commercial expectations in the Industry Pharmaceutical and therapeutic in the medical field, particularly in the treatment of pain and inflammatory conditions in general.

It is clear that other modifications and variations in accordance with the provisions of the present invention can be made without departing from the spirit and scope thereof, as those skilled in the art can easily observe, the invention being protected under the following claims.

Claims

1.- A compound characterized by presenting the Chemical structure of formula (I):

2. - The compound according to claim 1, selected from the group consisting of tris (hydroxymethyl) methylammonium (s) -2- (6- methoxynaphthyl) propionate. 3. - The compound according to claim 1, wherein said compound exhibits improved analgesic, anti-pyretic, anti-inflammatory activities in chronic rheumatoid arthritis and anti-inflammatory. 4.- A process for the preparation of the compound (s) -2- (6-methoxynaphthyl) propionate of tris (hydroxymethyl) methylamine, of chemical structure of formula (I), characterized in that it comprises the following steps: a) to react a mixture of solutions consisting of -2- (6- methoxynaphthyl) propionic acid, of the following formula:

and of the tris (hydroxy-methyl) methyl amine, of the formula:

in the presence of a solvent; b) heat the mixture to a boil for a period of 3 minutes; c) cooling said mixture in an ice bath at 5 ° C and d) crystallizing the final compound of formula (I):

5. - The process according to claim 4, wherein the reaction of the (s) -2- (6-methoxynaphyl) propionic acid and tris (hydroxymethyl) methyl amine, is a neutralization reaction in which a methylammonium ion is introduced into the tris (hydroxymethyl) methylammonium compound (s) -2- (6-methoxynaphthyl) propionate. 6. The process according to claim 4, wherein the solvent is methanol. 7. The process according to claim 4, characterized in that a yield of 94 percent yield of the compound (s) -2- (6- methoxynaphthyl) ropionate of tris (hydroxymethyl) methylammonium is obtained. 8.- A pharmaceutical composition comprising a therapeutically effective amount of the tris (hydroxymethyl) methylammonium compound (s) -2- (6- methoxynaphthyl) propionate in combination with a pharmaceutically acceptable carrier. 9.- The use of compound (s) -2- (6-methoxynaphthyl) - tris (hydroxymethyl) methylammonium propionate, which has Enhanced analgesic, anti-pyretic, anti-arthritic and anti-inflammatory activities, for the preparation of a medication to treat conditions of inflammation, pain and pyrexia. 10. A medicament to provide an improved analgesic, anti-pyretic, anti-arthritic and anti-inflammatory effect to a human or animal in need of such treatment, which comprises a therapeutically effective amount of the compound of formula (I), in accordance with claim 1. 11. The medicament according to claim 10, characterized in that it is delivered in a daily unit dose at a level of 3.0 mg / kg body weight, to provide an analgesic, anti-pyretic, anti-arthritic and anti-arthritic effect. Enhanced inflammatory