MXPA97010494A - Composite (s) -2- (6-methyoxythhyl) propionate of tris (hydroxymethyl) methylamonium which has analgesic, anti-piretica, anti-arthritic and anti-inflammatory activities improved; process to prepare it, pharmaceutical composition that contain it and use - Google Patents
Composite (s) -2- (6-methyoxythhyl) propionate of tris (hydroxymethyl) methylamonium which has analgesic, anti-piretica, anti-arthritic and anti-inflammatory activities improved; process to prepare it, pharmaceutical composition that contain it and useInfo
- Publication number
- MXPA97010494A MXPA97010494A MXPA/A/1997/010494A MX9710494A MXPA97010494A MX PA97010494 A MXPA97010494 A MX PA97010494A MX 9710494 A MX9710494 A MX 9710494A MX PA97010494 A MXPA97010494 A MX PA97010494A
- Authority
- MX
- Mexico
- Prior art keywords
- compound
- hydroxymethyl
- tris
- methoxynaphthyl
- inflammatory
- Prior art date
Links
- 230000003110 anti-inflammatory Effects 0.000 title claims abstract description 39
- 230000000202 analgesic Effects 0.000 title claims abstract description 24
- 238000000034 method Methods 0.000 title claims description 19
- 230000002456 anti-arthritic Effects 0.000 title claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 8
- XBDQKXXYIPTUBI-UHFFFAOYSA-M propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 title description 5
- 239000007983 Tris buffer Substances 0.000 title description 2
- 239000002131 composite material Substances 0.000 title 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 56
- 230000001754 anti-pyretic Effects 0.000 claims abstract description 32
- 239000003814 drug Substances 0.000 claims abstract description 31
- DRDCQJADRSJFFD-UHFFFAOYSA-N Tris-Hydroxymethyl-Methyl-Ammonium Chemical compound OC[N+](C)(CO)CO DRDCQJADRSJFFD-UHFFFAOYSA-N 0.000 claims abstract description 24
- LENZDBCJOHFCAS-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 claims abstract description 10
- 230000001684 chronic Effects 0.000 claims abstract description 10
- 239000002221 antipyretic Substances 0.000 claims abstract description 9
- 239000000126 substance Substances 0.000 claims abstract description 9
- XQMPFCWHEKIBNV-VIFPVBQESA-N (2S)-2-(6-methoxynaphthalen-1-yl)propanoic acid Chemical compound OC(=O)[C@@H](C)C1=CC=CC2=CC(OC)=CC=C21 XQMPFCWHEKIBNV-VIFPVBQESA-N 0.000 claims abstract description 8
- 206010003246 Arthritis Diseases 0.000 claims abstract description 6
- 238000006386 neutralization reaction Methods 0.000 claims abstract description 4
- -1 tris (hydroxymethyl) methylammonium compound Chemical class 0.000 claims description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 10
- 206010039073 Rheumatoid arthritis Diseases 0.000 claims description 9
- 238000002360 preparation method Methods 0.000 claims description 9
- 206010061218 Inflammation Diseases 0.000 claims description 8
- 230000004054 inflammatory process Effects 0.000 claims description 8
- 208000002193 Pain Diseases 0.000 claims description 7
- 230000036407 pain Effects 0.000 claims description 7
- XBDQKXXYIPTUBI-UHFFFAOYSA-N propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 230000037396 body weight Effects 0.000 claims description 5
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- 206010037660 Pyrexia Diseases 0.000 claims description 3
- 238000006243 chemical reaction Methods 0.000 claims description 3
- 230000027950 fever generation Effects 0.000 claims description 3
- BAVYZALUXZFZLV-UHFFFAOYSA-O methylammonium Chemical compound [NH3+]C BAVYZALUXZFZLV-UHFFFAOYSA-O 0.000 claims description 3
- 238000009835 boiling Methods 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 235000019260 propionic acid Nutrition 0.000 claims description 2
- 230000002917 arthritic Effects 0.000 claims 1
- 238000001816 cooling Methods 0.000 claims 1
- 229960003940 Naproxen sodium Drugs 0.000 abstract description 61
- CDBRNDSHEYLDJV-FVGYRXGTSA-M naproxen sodium Chemical compound [Na+].C1=C([C@H](C)C([O-])=O)C=CC2=CC(OC)=CC=C21 CDBRNDSHEYLDJV-FVGYRXGTSA-M 0.000 abstract description 59
- 230000001225 therapeutic Effects 0.000 abstract description 16
- CMWTZPSULFXXJA-VIFPVBQESA-N Naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 abstract description 13
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- 231100000419 toxicity Toxicity 0.000 abstract description 13
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- YVWMPILNFZOQSZ-UHFFFAOYSA-N 2-methoxy-2-naphthalen-1-ylpropanoic acid Chemical compound C1=CC=C2C(C(C)(C(O)=O)OC)=CC=CC2=C1 YVWMPILNFZOQSZ-UHFFFAOYSA-N 0.000 description 3
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Abstract
The chemical compound (s) -2- (6-methoxynaphthyl) propionate of tris (hydroxymethyl) methylammonium, called TROMETOXAN, of the present invention, which has the chemical structure of formula (I): is the result of a neutralization reaction between the acid (s) -2- (6-methoxynaphthyl) -propionic acid and the tris (hydroxymethyl) methyl amine. Said compound presents analgesic, anti-pyretic, anti-inflammatory activities in improved chronic rheumatoid and anti-inflammatory arthritis. Among its applications are commercial uses related to the Pharmaceutical Industry and is used particularly in the field of medicine, said fields require materials with effective therapeutic applications to improve or alleviate the diseases related to pain and inflammatory disorders in general. Likewise, TROMETOXAN is shown to be a highly effective compound compared to the anti-inflammatory and anti-pyretic activity of the chemical compound known as Naproxen, through an experimental study conducted in rodents, in addition to having less toxicity and less ulcerogenic activity than naproxen sodium (Naproxe
Description
COMPOUND (S) -2- (6-METHYOXYTHHYL) PROPIONATE OF TRIS (HYDROXYMETHYL) METHYLAMONIUM WHICH HAS ANTI-PATHETIC, ANTI-PIRATE, ANTI-ARTHRITIC AND ANTI-INFLAMMATORY ACTIVITIES IMPROVED; PROCESS TO PREPARE IT, PHARMACEUTICAL COMPOSITION 5 THAT CONTAINS IT AND USES OF THE SAME
TECHNICAL FIELD OF THE INVENTION The present invention relates to an optically active isomer of the novel chemical compound, tris (hydroxymethyl) methylammonium (s) -2- (6- # 10-methoxynaphthyl) propionate, which has analgesic, anti-pyretic activities, anti-inflammatory in improved chronic rheumatoid and anti-inflammatory arthritis compared to the pharmaceutical activities of naproxen sodium (Naproxen). A) Yes
Also, the invention relates to the process for preparing said compound, a pharmaceutical composition that contains it and uses in the treatment of pain and inflammatory disorders in general; what makes it a compound of great commercial expectation in the pharmaceutical industry and
2nd great therapeutic application in the field of medicine.
INTRODUCTION The chemical compound of the present invention is a tro-ammonium salt derived from propionic acid (s) -6- (methoxynaphthyl) -25, which has the following chemical structure of formula (I)
whose chemical name is (s) -2- (6-methoxynaphthyl) propionate of tris (hydroxymethyl) methylammonium, called TROMETOXAN in what comes. TROMETOXAN is the result of a neutralization reaction between (s) -2- (6-methoxynaphthyl) propionic acid and tris (hydroxymethyl) methyl amine, followed by crystallization in a suitable solvent by using standard techniques known to the subject matter experts. Said chemical compound was subjected to a series of studies and experimental tests where its characterization was completely determined by elemental analysis, nuclear magnetic resonance (NMR), infrared and mass spectroscopy. Likewise, the chemical compound TROMETOXAN presents improved analgesic, anti-pyretic, anti-arthritic and anti-inflammatory activities in comparison with the pharmaceutical activities of naproxen sodium, besides having 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 acid (s) -2- (6-methoxynaphthyl) -propionic, commercially known as Naproxen. Both the characterization and the improved analgesic, anti-pyretic, anti-arthritic and anti-inflammatory activities of the TROMETOXAN compound are shown in the examples that are described below.
BACKGROUND OF THE INVENTION The acid (s) -2- (6-methoxynaphthyl) propionic acid and methods for its preparation are described in the US patent applications with serial nos. 694,771 and 741,858 since 1967, said active principle known as Naproxen. it is included among the substances that have anti-inflammatory, analgesic and antipyretic activities; Its 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 has no anti-inflammatory or pharmaceutical activity per se. The derivative obtained by the combination of these two compounds is the main object of the present invention. The documents of the state of the art related to the present invention are mentioned below for the purpose of including them only as references. U.S. Patent 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, owned by the company 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 5,286,902 disclose different processes for the preparation of the (s) -2- (6-methoxynaphthyl) propionic acid, as well as their derivatives and the corresponding amides, esters, hydroxamic acids and addition salts thereof, by means of substitution and hydrolysis reactions.; pharmaceutical compositions containing them, which present analgesic, anti-pyretic and anti-inflammatory activities. U.S. Patent 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 j5 of D and / or L enantiomers of naproxen sodium. Patent No. 3,896,157 and divisional applications thereof, mention that the addition salts are prepared by conventional techniques using non-toxic pharmaceutically acceptable 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
Naproxen derivatives which includes substituents on the naphthenic ring and / or on the alpha position of 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 (s) -2- (6-methoxynaphthyl) propionic acid a novel compound with unexpected pharmaceutical activities and applications was originated. On the other hand, US Pat. 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 compounds derived from Naproxen. The importance of the present invention, unlike that described in the aforementioned documents of the prior art, lies in the technical characteristics of the invention itself, as well as in the additional advantages derived therefrom, which are described in more detail then. The present invention discloses a novel, non-spheroidal, non-salicylate chemical compound, which is a quaternary ammonium salt of Naproxen, that is, it is a tro-ammonium salt derived from (s) -6- (methoxynaphthyl) ropionic acid, Analgesic, anti-pyretic, anti-arthritic and anti-inflammatory activities are more highly effective than those shown by naproxen sodium, in addition to having less ulcerogenic activity and being less toxic. Likewise, the fundamental part of the process of obtaining the compound TROMETOXAN, lies in 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 higher bioavailability, which means that the therapeutic doses required are lower and, therefore, the side reactions are reduced. Therefore, none of the processes for obtaining derivatives of the acid (s) -2- (6-methoxynaphthyl) propionic described in the documents of the state of the art would be relevant with respect to the procedure for obtaining the compound TROMETOXAN. The chemical compound of this invention has a high therapeutic value in the treatment of various inflammatory conditions 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 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, many ways have been described for their preparation, most of them are procedures that involve long periods of time to get to obtain 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 handling 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 in comparison with those other compounds used in the industry pharmaceutical, commercially known, as is the case in particular of Naproxen. Thus, as in the present invention is disclosed the process of preparation, pharmaceutical composition and therapeutic uses of a novel chemical compound called TROMETOXAN, with analgesic, anti-pyretic, anti-inflammatory activities in chronic rheumatoid arthritis and anti-inflammatory improved, with lower activity ulcerogenic and lower toxicity than naproxen sodium.
BRIEF DESCRIPTION OF THE DRAWINGS Other objects, features and advantages of the invention will be apparent from the following detailed description, from the preferred embodiments, from the appended claims and from the accompanying drawings, wherein: Figure 1, graphically represents the nuclear magnetic resonance (H1RMN) study of the tris (hydroxymethyl) methylammonium compound (s) -2- (6-methoxynaphthyl) propionate, termed TROMETOXAN; Figure 2 is a graphic representation of the infrared spectrum, I.R. (KBr) of the same compound; Figure 3 is a graphic representation of the 13C analysis of the same compound; Figure 4 graphically represents the mass spectrum of the same compound; Figure 5 represents a graph of the means of stretching induced by intraperitoneal acetic acid in untreated (control) mice and orally medicated with several doses of naproxen sodium and TROMETOXAN; * Figure 6 shows the antipyretic effect of TROMETOXAN and naproxen sodium at a dose of 6.25 mg / kg in both cases, orally in mice, to which a lysate of Eschrichia coli was applied; Figure 7 shows the anti-pyretic effect at a dose of 12.5 mg / kg in the conditions of Figure 6; Figure 8 shows the antipyretic effect at a dose of 50 mg / kg in the conditions of Figure 6; # 10 Figure 9 shows the anti-pyretic effect at a dose of 100 mg / kg in the conditions of Figure 6; Figure 10 shows the anti-inflammatory effect of
TROMETOXAN and naproxen sodium at a dose of 6.25 mg / kg in both cases, orally in mice, after
administration of 0.03 ml of BCG in 0.5% suspension with Freund's adjuvant for 13 days; Figure 11 shows the anti-inflammatory effect at doses of 12.5 mg / kg in the conditions of Figure 10; Figure 12 shows the anti-inflammatory effect at 20 doses of 50 mg / kg in the conditions of Figure 10; Figure 13 shows the anti-inflammatory effect at a dose of 100 mg / kg in the conditions of Figure 10; Figure 14 shows the relationship of the edema found with the treatment based on TROMETOXAN and naproxen sodium at various doses, after the application of 0.2 ml of carragemna; and FIG. 15 graphically depicts acute mortality in orally dosed mice with naproxen sodium on a logarithm / probability scale.
DETAILED DESCRIPTION OF THE INVENTION The TROMETOXAN chemical compound of formula (I) is obtained by the chemical reaction that can be illustrated as follows:
(A) (B) (I) wherein the compound represented by the formula (A) corresponds to the acid (s) -2- (6-methoxynaphthyl) propionic acid; the compound of formula (B) is tris (hydroxymethyl) methyl amine, and the compound of formula (I) corresponds to a salt of tromethamium 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 processes for their preparation have been previously described in the prior art. Below are the objects and
advantages that derive from this invention.
It is an object of the present invention to provide a process for preparing the tris (hydroxymethyl) ethylammonium compound (s) -2- (6-methoxynaphthyl) propionate, which is a quaternary ammonium salt derived from Naproxen, said
The compound is obtained by a neutralization reaction of (s) -2- (6-methoxynaphthyl) propionic acid with tris (hydroxymethyl) methyl amine, which has unexpectedly specific therapeutic properties superior to those
^ activities of naproxen sodium. Ifr 10 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 naproxen sodium. 15 An additional advantage in the process of obtaining the compound TROMETOXAN, is to introduce an ion of jJ methylammonium in 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 alleviate pain conditions and / or inflammations in general. Also, as its therapeutic uses with analgesic, anti-pyretic, anti-inflammatory activities in chronic rheumatoid arthritis and anti-inflammatory 25 improved.
Another additional advantage of the TROMETOXAN compound is that it has less ulcerogenic activity and less toxicity than naproxen sodium; it is 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 muscle 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 supplying the chemical compound of formula (1) / wherein 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 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 employing 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 limiting 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, lozenges, capsules, powders and prolonged release formulation and the like. The above description and the following examples are intended to illustrate particular modes of carrying out the invention and should not be considered as limiting the scope of protection thereof.
EXAMPLES Example 1 Preparation of tris (hydroxymethyl) methylammonium compound (s) -2- (β-methoxynaphthyl) propionate An amount of 347.3 g (1.5 mol) of methoxynaphthyl propionic acid was dissolved in 1200 ml of hot methanol. On the other hand, an amount of 131.5 g (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 warm to boiling for 3 minutes. The mixture of solutions was cooled in an ice bath at 5 ° C, filtered and allowed to air dry. 500 grams of tris (hydroxymethyl) methylammonium compound (s) -2- (6-methoxynaphthyl) propionate were obtained, yielding 94 percent yield. If the optically active methoxynaphthylpropionic acid is taken as starting point, the TROMETOXAN compound is obtained as a single enantiomer and, therefore, optically active. This characteristic is recommended according to the Federal Administration of Drugs of the United States of North America (FDA). Each of the optical isomers of the trometamonium salt is included in the present invention. In some instances an enantiomer may exhibit greater
--1 > 5 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 compound (s) -2- (6-25-methoxynaphthyl) propionate of tris (hydroxymethyl) methylammonium was obtained, by the procedure described above, it was subjected to a series of studies and tests, where its Molecular Weight was determined. 351 grams / mol and its melting point of approximately 170-172 ° C. The results of the Elemental Analysis are shown below:
Calculated for C? 8H25N06: 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, one can observe the results obtained from the nuclear magnetic resonance analysis (ft'-NMR) of the TROMETOXAN, shown in figure 1, whose maximum values (peaks or ridges) 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, 3303, 1631, 1604, 1556 and 1070 arf1 are the result of infrared spectroscopy, I.R. of the TROMETOXAN to a certain percentage of transmittance,% t, with respect to a number of waves, # 0 (cm-1). The result of the analysis ^ C 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 the mass spectroscopy analysis performed on the TRQMETOXAN compound, represented in figure 4, it shows the following values: 230 (M *) and 185.
Example 2 5 Analgesic activity of TROMETOXAN
Sixty male mice of strain CD-1 were used, with an average weight of 36 to 43 grams. ^ After the acclimation period of one week, 10 groups of 20 mice were randomly distributed. One group designated A was treated with TROMETOXAN and one group B received naproxen sodium and the control group received an injection of saline in the same volume as the previous groups. The doses are
applied orally by means of a probe at a rate of 6.25, 12.5, 50 and 100 mg / kg of body weight, dissolved in physiological saline in constant volume per kg of weight (10 ml / kg). Thirty minutes after the administration of the drugs or the vehicle, they were injected via
intraperitoneal solution of acetic acid (0.5%, 10 ml / kg) to produce a painful syndrome, which can be reduced or abolished by the analgesic drugs under study. Subsequently the number of stretches or contractions caused by pain in the mouse was counted,
presented every 5 minutes, for a total time of 20 minutes. The mice that did not stretch during that time were eliminated. In this experiment, no animal died or showed 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 entries, response of stretches and treatment, with successive t tests of Dunnet. The results of the number of stretches due to acetic acid in mice treated with TRQMETOXAN, naproxen sodium 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 to way of frequency bars in Figure 5, which corresponds to the dose (D) of the analgesics TROMETOXAN (T) and naproxen sodium (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 (DE) of the control group (GT). The 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 in any better effect between the drugs (EMD .084), with the exception of TROMETOXAN at a dose of 100 mg / kg (P = 0.05), and no effect was detected. due to the increase in dose (P = 0.23).
TABLE 1. Application of naproxen sodium at a dose of 6.25 mg / kg orally. Contractions every 5 min.
TABLE 2. Application of naproxen sodium at a dose of 12.5 mg / kg orally. #
Contractions every 5 min.
15 20 25 TABLE 3. Application of naproxen sodium at a dose of 50.0 mg / kg orally. Contractions every 5 min.
TABLE 4. Application of naproxen sodium at a dose of 100 mg / kg orally. Contractions every 5 min.
TABLE 5. Application of TROMETOXAN at a dose of 6.25 mg / kg orally, Contractions every 5 min.
TABLE 6. Application of TROMETOXAN at a dose of 12.5 mg / kg orally. Contractions every 5 min.
TABLE 7. Application of TROMETOXAN at a dose of 50.0 mg / kg orally. Contractions every 5 min.
TABLE 8. Application of TROMETOXAN at a dose of 100 mg / kg orally. Contractions every 5 min.
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TABLE 9. Number, mean and standard deviation of stretches in the control group after intraperitoneal application of acetic acid.
Contractions every 5 min.
Example 3 Anti-pyretic activity of TROMETOXAN
After a one-week acclimation period, 3 batches of 20 male CD-1 strain mice, each one, were randomly formed. The mice had an average weight of 31 to 40 grams. Group A received treatment with TROMETOXAN, group B received naproxen sodium and the control group received saline injection in the same volume as the previous groups. The rectal temperature was recorded by a digital thermometer on three occasions to obtain the basal body temperature. Then, a dose of 0.2 ml of lysate of bacterial detritus, inactivated of Escherichia coli, was applied, which produces hypertemia in the mice, which can be reduced or abolished by the administration of the antipyretic drugs under study; when a temperature of 41 ° C was recorded, the 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 following day. No animal showed symptoms of toxicity during the experiment.
The therapeutic analysis to determine the comparative antipyretic activity between the temperature curves of the two drugs was determined by means of the variance analysis of two entries, plotting the results in the Origin for Windows program. The results of measurements of rectal temperature in mice that received a lysate of Escherichia coli and treated with TROMETOXAN, naproxen sodium and in the control group (without treatment) are presented in tables 10 to 18. The means and standard deviations of those values are presented in figures 6 to 9, which correspond to the measurements of temperature (MT) in relation to temperature in degrees Celsius (T ° C), during the application (I) of the E lysate. coli until the temperature measurement one day later (T + ld). The symbols used to graph the curves correspond to -M - TROMETOXAN, - • - naproxen sodium 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. The statistical analysis comparing the measurement means of 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 naproxen sodium.
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* A suspension of cellular detritus of Escherichia coli was used. ** The temperature of each animal was taken three times and obtained
an average of them.
TABLE 11. Anti-pyretic effect of naproxen sodium
* at a dose of 6.25 mg / kg.
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* A suspension of cellular detritus of Escherichia coli was used. ** The temperature of each animal was taken three times and obtained
an average of them.
TABLE 12. Anti-pyretic effect of TROMETOXAN at a dose of 12.5 mg / kg.
* A suspension of cellular detritus of Escherichia coli was used. ** The temperature of each animal was taken three times and an average was obtained.
TABLE 13. Anti-pyretic effect of naproxen sodium at a dose of 12.5 mg / kg.
* A suspension of cellular detritus of Escherichia coli was used. ** The temperature of each animal was taken three times and an average was obtained.
TABLE 14. Anti-pyretic effect of TROMETOXAN at a dose of 50 mg / kg.
* A suspension of cellular detritus of Escherichia coli was used. ** The temperature of each animal was taken three times and an average was obtained.
TABLE 15. Anti-pyretic effect of naproxen sodium at a dose of 50 mg / kg.
* A suspension of cellular detritus of Escherichia coli was used. ** The temperature of each animal was taken three times and an average was obtained.
TABLE 16. Anti-pyretic effect of TROMETOXAN at a dose of 100 mg / kg.
* A suspension of cellular detritus of Escherichia coli was used. ** The temperature of each animal was taken three times and an average was obtained.
TABLE 17. Anti-pyretic effect of naproxen sodium at a dose of 100 mg / kg.
* A suspension of cellular detritus of Escherichia coli was used. ** The temperature of each animal was taken three times and an average was obtained.
TABLE 18. Pyrétic effect of a lysate of w - Escherlchla. coll inactivated.
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* A suspension of cellular debris was used
Escherichia coli ** The temperature of each animal was taken three times and an average was obtained. 25 *** Dead mice.
Example 4 * Anti-inflammatory activity in chronic rheumatoid arthritis of TROMETOXAN After a period of acclimation of one week, 5 batches of 20 male mice of strain CD-1, each, were randomly distributed. The mice had an average weight of 25 to 40 grams. Group A received treatment with TROMETOXAN, group B received treatment with naproxen sodium and the control group received
the injection of saline 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 of body weight, dissolved in saline (0.9%) in constant volume per kg of weight (10 ml / kg). Later it was administered in the
plantar bearing of the right rear extremity of the mouse an amount of 0.03 ml of 0.5% suspension of BCG, prepared in mineral oil with Freund's adjuvant. This suspension of BCG causes chronic arthritis in the mouse, "^^ Tá" which can be reduced by anti-inflammatory drugs
under study. The treatment was continued for 13 days
(In addition, the volume of limbs was measured on alternate days). After that time, the mice were sacrificed and their right limbs were weighed. The percentage calculation of inflammation inhibition in arthritis
Chronic rheumatoid was obtained by the comparative difference in weight with the left extremity. In addition, §P were processed according to routine methods the joints for histopathological examination. The treatment during the 13 days did not produce apparent toxicity according to the doses administered, which was evaluated by the general appearance, behavior and weight of the animals. The therapeutic analysis to determine the anti-inflammatory activity in chronic rheumatoid arthritis was determined by means of an analysis of variance of two inputs of the quantitative variables of
weight and volume of the extremities. The results of the measurements of the inflamed limbs with the suspension of BCG, treated with TROMETOXAN, naproxen sodium and in the control group (without treatment) are presented in tables 19 to 27. The measurements and standard deviations of these values are presented in the table below. in figures 10 to 13, which correspond to the measurements of the width of the member (mam) in relation to the size of the width of the member in jm millimeters (mm). The symbols used to graph these results are the same as those used in figures 6 to 9.
The 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 with respect to naproxen was found25 sodium at the 93% level (P = 0.069), at the dose of 6.25 mg / kg.
TABLE 19. Treatment with TROMETOXAN 6.25 mg / kg.
Measurements on alternating days of limb width (mm) TABLE 20. Treatment with naproxen sodium 6.25 mg / kg.
F Measurements on alternate days of member width (mm)
F 10 15 20 25 TABLE 21. Treatment with TROMETOXAN 12.5 mg / kg.
F Measurements on alternate days of member width (mm)
F 10 15 20 25 TABLE 22. Treatment with naproxen sodium 12.5 mg / kg. Measurements on alternating days of the limb width (mm).
#
15 20
TABLE 23. Treatment with TROMETOXAN 50 mg / kg. Measurements on alternating days of limb width (mm) TABLE 24. Treatment with naproxen sodium 50 mg / kg.
F Measurements on alternate days of member width (mm)
15 20 25 TABLE 25. Treatment with TROMETOXAN 100 mg / kg. Measurements on alternating days of limb width (mm) TABLE 26. Treatment with naproxen sodium 100 mg / kg. Measurements on alternating days of the limb width (mm). TABLE 27. Witness Group. Measurements on alternating days of limb width (mm) Example 5 Anti-inlamatory activity of TROMETOXAN After a one-week acclimation period, 3 batches of 20 male CD-1 strain mice, each one, were formed. random way. 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 naproxen sodium 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 doses of 6.25, 12.5, 50 and 100 mg / kg of body weight, one hour later the carrageenan suspension was injected (at 1% weight / volume in physiological saline with a total volume of 0.2 ml). This injection of carrageenan was applied in the plantar aponeurosis of the right hind limb of the mice to provoke 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 antero-posterior edema was measured with a micrometer (Vernier). The thickness of the edema of the injected extremity was determined by comparison with the thickness of the other non-injected extremity. During the course of the experiment no animals died or showed apparent symptoms of toxicity. ifP. The therapeutic analysis to determine the comparative anti-inflammatory activity between the pharmaceutical compounds was based on an analysis of variance of two inputs, edema response and treatment, with successive Dunnet t tests. The results of the measurements of the inflamed limbs with carrageenan, treated with TROMETOXAN, naproxen sodium and in the control group (untreated), are shown in tables 28 to 36. Measurements and standard deviations of the edema produced are presented in the manner of 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 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 naproxen sodium (E / N). The upper lines correspond to the mean (X) and effective dose (DE) of the edema in the control group (E-GT). 20 The 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 both drugs were compared, a better effect of TRQMETOXAN with respect to naproxen was found
sodium, at a dose of 100 mg / kg (P <0.05).
TABLE 28 f TROMETOXAN 6.25 mg / kg in mice receiving the dose of carrageenan in the right limb (0.2ml)
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TABLE 29
Naproxen sodium 6.25 mg / kg in mice that received the dose of carrageenan in the right limb (0.2ml).
TABLE 30
TROMETOXAN 12.5 mg / kg in mice that received the dose of carrageenan in the right limb (0.2ml).
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TABLE 31
Naproxen sodium 12.5 mg / kg in mice that received the dose of carrageenan in the right limb (0.2ml).
TABLE 32 F
TROMETOXAN 50 mg / kg in mice that received the dose of carrageenan in the right limb (0.2ml)
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TABLE 33
Naproxen sodium 50 mg / kg in mice that received the dose of carrageenan in the right limb (0.2ml)
TABLE 34
TROMETOXAN 100 mg / kg in mice that received the dose of carrageenan in the right limb (0.2ml)
TABLE 35
Naproxen sodium 100 mg / kg in mice that received the dose of carrageenan in the right limb (0.2ml).
TABLE 36. Witness group.
Mice that received an injection of carrageenan in the right limb (0.2ml).
Example 6 Evaluation of the toxic effect of TROMETOXAN in mice
After a one-week acclimation period, 2 batches of male mice of strain CD-1, 20 to 36 grams in weight, were randomly distributed. The study drugs, TROMETOXAN and naproxen sodium, were administered orally, suspended in acacia gum prepared in water at the time of use, at variable 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 naproxen sodium, doses were administered. 100, 200, 300, 400, 500, 600, 700 and 800 mg / kg. One more lot was used as a witness and he received only the vehicle.
The overdose of any non-spheroidal anti-inflammatory induces ulcers and irritative gastritis that are inherent to its mechanism of action, but that vary in intensity and speed of presentation with respect to the agent used.
After administration of the drugs, the mice were observed every hour during the day of administration and every 3 days during the subsequent 14 days, in order to record the number of deaths and symptoms caused by the poisoning. The killed and surviving mice were subsequently autopsied.
The toxicity analysis of TROMETOXAN compared to that of naproxen sodium 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 TROMETOXAN 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 TROMETOXAN could not be completely dissolved, but it was administered with the purpose of dissolving it in the mouse. It was not possible to induce mortality with TROMETOXAN, even at a dose of 2500 mg / kg, since this represents a dose of 175 g / human subject (70 kg), it was considered irrelevant to continue with higher doses.
The toxicity results (% mortality) that were presented by the administration of the drug naproxen sodium with the initial doses are shown in Table 37. These toxicity results were plotted on a logarithm / probability scale according to the postulate of Litchfield & amp; amp;; Wilkinson in Figure 15, where naproxen sodium shows a lethal dose 1 (DL1) of 110 mg / kg and a lethal dose 50 (LD50) of 520 mg / kg, relative to the logarithm base 10 (Log 10) of the doses administered in (mg / kg) with respect to the probability (P) of occurrence events of mortality caused by the toxic effect of naproxen sodium. The symbols used to plot the curves correspond to -M- naproxen sodium and linear regression (R).
TABLE 37. Toxicity values for naproxen sodium in mice dosed orally.
Example 7
# Ulcerogenic activity of TROMETOXAN
For the ulcerogenic phase, an average of 35 to 40 mice were used to which 100 mg / kg of TROMETOXAN or naproxen sodium were administered continuously, twice a day, orally in acacia gum and subsequently sacrificed 3 to 5 mice by barbiturate overdose each
F 10 third day, until finishing with the group. Lesions at necropsy 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 with ulceration or evidence of gastric irritation, with the constant medication of the drugs.
The ulcerogenic effect caused by TROMETOXAN compared to naproxen sodium, 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 shown in favor of TROMETOXAN using a
Chi2 test (P <0.001).
TABLE 38. List of lesions suggestive of gastric ulcer or irritation induced by the oral application of
TROMETOXAN or naproxen sodium in mice at a dose of 100 mg / kg twice daily, orally.
According to the results obtained in the comparative study between these two drugs, the following therapeutic advantages of TROMETOXAN can be disclosed in the present invention in relation to the pharmaceutical activity of naproxen sodium: 1) Better analgesic activity: with a dose of 100 mg / kg, TROMETOXAN presents a better analgesic effect than naproxen sodium. 2) Superior antipyretic activity: with a dose of 6.25 to 100 mg / kg, the anti-pyretic effect of TROMETOXAN is better than that of naproxen sodium, keeping the temperature below the level of the temperature maintained by naproxen sodium. 3) Better anti-inflammatory activity in chronic rheumatoid arthritis: with low doses of 6.25 mg / kg, TROMETOXAN is more effective than naproxen sodium. 4) Increased anti-inflammatory activity: at doses of 50 to 100 mg / kg, TROMETOXAN inhibits inflammation more than naproxen sodium. 5) Less toxicity: the determination of DL? 0 showed that with TROMETOXAN up to a dose of 2500 mg / kg it maintains a 0% mortality and with sodium naproxen the LD50 was 520 mg / kg, reaching 100% mortality with dose of 800 mg / kg. 6) Lower ulcerogenic activity: TROMETOXAN has less ulcerogenic activity than naproxen sodium. The aforementioned advantages of tris (hydroxymethyl) methyl ammonium compound (s) -2- (6-methoxynaphthyl) propionate as analgesic, anti-pyretic, anti-arthritic and anti-inflammatory with less toxicity and less ulcerogenic effect, make the TROMETOXAN is a pharmaceutical product with great commercial expectations in the Pharmaceutical Industry and therapeutic in the field of medicine, particularly in the treatment of pain and inflammatory conditions in general. It is evident that other modifications and variations in accordance with what is stated in the present invention can be carried out without departing from the spirit and scope of the same, as will be easily observed by those skilled in the art, the invention being protected according to the following claims.
Claims (11)
- 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. r 10
- 3. - The compound in accordance with the claim 1, wherein said compound exhibits improved analgesic, anti-pyretic, anti-inflammatory activities in chronic rheumatoid arthritis and anti-inflammatory arthritis.
- 4. A process for the preparation of tris (hydroxymethyl) methylammonium 2- (6-methoxynaphthyl) propionate compound of chemical structure of formula (I), characterized by the following steps: a) react a mixture of solutions consisting of (s) -2- (6-methoxynaphthyl) propionic acid, of the following formula: and of the tris (hydroxymethyl) methyl amine, of formula: in the presence of a solvent; b) heat the mixture to W. boiling 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 (s) -2- (6- r 10-methoxynaphthyl) propionic acid and tris (hydroxymethyl) methyl amine, is a neutralization reaction in which a methylammonium ion in the tris (hydroxymethyl) methylammonium compound (s) -2- (6-methoxynaphthyl) propionate.
- 6. The process according to claim 15, 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) propionate 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 the compound (s) -2- (6-methoxynaphthyl) -25-propionate of tris (hydroxymethyl) methylammonium, which has improved analgesic, anti-pyretic, anti-arthritic and anti-inflammatory activities, for the preparation of a medicament to treat conditions of inflammation, pain and pyrexia.
- 10. A medicament for providing an improved analgesic, anti-pyretic, anti-arthritic and anti-inflammatory effect to a human or animal in need of said treatment, comprising a therapeutically effective amount of the compound of formula (I), according to claim 1.
- 11. The medicament according to claim 10, characterized in that it is supplied in a daily unit dose at a level of 3.0 mg / kg of body weight, to provide an analgesic, antipyretic, anti-inflammatory effect. Arthritic and anti-inflammatory improved.
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU17858/99A AU1785899A (en) | 1997-12-19 | 1998-12-16 | Analgesic naproxene trometamonic salt |
PCT/MX1998/000059 WO1999032425A1 (en) | 1997-12-19 | 1998-12-16 | Analgesic naproxene trometamonic salt |
Publications (1)
Publication Number | Publication Date |
---|---|
MXPA97010494A true MXPA97010494A (en) | 1999-06-01 |
Family
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