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WO1999032425A1 - Sel trometamonique du naproxene analgesique - Google Patents

Sel trometamonique du naproxene analgesique Download PDF

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Publication number
WO1999032425A1
WO1999032425A1 PCT/MX1998/000059 MX9800059W WO9932425A1 WO 1999032425 A1 WO1999032425 A1 WO 1999032425A1 MX 9800059 W MX9800059 W MX 9800059W WO 9932425 A1 WO9932425 A1 WO 9932425A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
tris
trometoxan
inflammatory
hydroxymethyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/MX1998/000059
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English (en)
Spanish (es)
Inventor
Angel Guzman Sanchez
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Laboratorios Columbia S A De C V
Original Assignee
Laboratorios Columbia S A De C V
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from MXPA/A/1997/010494A external-priority patent/MXPA97010494A/xx
Application filed by Laboratorios Columbia S A De C V filed Critical Laboratorios Columbia S A De C V
Priority to AU17858/99A priority Critical patent/AU1785899A/en
Publication of WO1999032425A1 publication Critical patent/WO1999032425A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
    • C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C215/04—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated
    • C07C215/06—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic
    • C07C215/10—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic with one amino group and at least two hydroxy groups bound to the carbon skeleton

Definitions

  • 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.
  • 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):
  • 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.
  • Therapeutic use is the treatment of rheumatoid arthritis and other degenerative forms that have phlogistic characteristics.
  • tris (hydroxymethyl) methyl amine is a well-known organic amino base, which does not have
  • 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.
  • 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.
  • esters or derivatives of Naproxen which includes substituents in the naphthenic ring and / or in the alpha position of the propyl acid, which
  • 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.
  • 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.
  • 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.
  • TROMETOXAN a novel chemical compound called TROMETOXAN
  • analgesic anti-pyretic
  • anti-inflammatory activities in improved chronic and anti-inflammatory rheumatoid arthritis, with lower ulcerogenic activity and lower toxicity than naproxen sodium.
  • 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 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 TROMETOXA ⁇ and sodium naproxen at a dose of 6.25 mg / kg in both cases, orally in mice, to which they were applied
  • Figure 7 shows the anti-pyretic effect at doses of 12.5 mg / kg under the conditions of Figure 6;
  • FIG. 8 shows the anti-pyretic effect at doses of
  • Figure 9 shows the anti-pyretic effect at doses of 100 mg / kg under the conditions of Figure 6;
  • FIG. 10 shows the anti-inflammatory effect of
  • TROMETOXA ⁇ 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
  • 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.
  • 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.
  • 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 are also provided in the present invention.
  • 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.
  • disorders include, but are not limited to inflammation, pain and pyrexia in mammalian animals, including man.
  • 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.
  • 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.
  • compositions 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 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.
  • one enantiomer may exhibit greater analgesic, anti-pyretic and anti-inflammatory activity than the other enantiomer.
  • 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.
  • TROMETOXAN at a certain percentage of transmittance,% T, with respect to a number of waves, # 0 (cm "1 ).
  • mice of the strain CD-1 were used, with an average weight of 36 to 43 grams.
  • mice After the acclimatization period of one week, 3 batches of 20 mice each were formed, randomly distributed.
  • 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).
  • 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).
  • mice of the strain CD-1 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.
  • mice 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).
  • mice 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
  • 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.
  • 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
  • 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.
  • 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
  • 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).
  • TROMETOXAN 6.25 mg / kg in mice that received the dose of carragenin in the right limb— (0.2ml)
  • TROMETOXAN 12.5 mg / kg in mice that received the dose of carragenin in the right limb (0.2ml).
  • mice were dosed ue g carrageenan right member (0-2ml).
  • TROMETOXAN 100 mg / kg in mice that received the dose of carragenin in the right limb ( 0.2ml ) .
  • mice of strain CD-1 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.
  • 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.
  • 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.
  • mice 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
  • 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.
  • 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).
  • mice 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
  • TROMETOXAN chronic rheumatoid: With low doses of 6.25 mg / kg, TROMETOXAN is more effective than naproxen sodium.
  • TROMETOXAN has lower ulcerogenic activity than naproxen sodium.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne le composé chimique (s)-2-(6-méthoxynaphtyl)propionate de tris(hydroxyméthyl)méthylamonium, dénommé TROMETOXAN qui présente la structure de la formule (I). Ce composé est obtenu par une réaction de neutralisation entre l'acide (s)-2-(6-méthoxynaphtyl)-propionique et la tris(hydroxyméthyl)méthyle amine. Ce composé présente des propriétés analgésiques, antipyrétiques, anti-inflammatoires dans les cas d'arthrite rhumatoïde chronique et une activité anti-inflammatoire améliorée. Ce composé présente un grand intérêt pour les applications de l'industrie pharmaceutique et plus précisément dans le secteur médical, où il peut être utilisé à des fins thérapeutiques pour soigner et soulager la douleur et l'inflammation. Ainsi, une étude expérimentale réalisée chez le rongeur a mis en évidence une efficacité supérieure du TROMETOXAN par rapport aux activités anti-inflammatoires et antipyrétiques du composé chimique connu comme le Naproxen, ainsi qu'une moindre toxicité et une moindre activité ulcérogène que le naproxène sodique.
PCT/MX1998/000059 1997-12-19 1998-12-16 Sel trometamonique du naproxene analgesique Ceased WO1999032425A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU17858/99A AU1785899A (en) 1997-12-19 1998-12-16 Analgesic naproxene trometamonic salt

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
MXPA/A/1997/010494A MXPA97010494A (en) 1997-12-19 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
MX9710494 1997-12-19

Publications (1)

Publication Number Publication Date
WO1999032425A1 true WO1999032425A1 (fr) 1999-07-01

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PCT/MX1998/000059 Ceased WO1999032425A1 (fr) 1997-12-19 1998-12-16 Sel trometamonique du naproxene analgesique

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AU (1) AU1785899A (fr)
WO (1) WO1999032425A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4033816A (en) * 1973-06-18 1977-07-05 The Upjohn Company Process for inhibiting platelet aggregation
GB2059768A (en) * 1979-09-27 1981-04-29 Ilona Kahan Water-soluble derivatives of non-steroidal anti-inflammatory agnets and a process for the production thereof
US5183829A (en) * 1991-09-27 1993-02-02 Applied Analytical Industries, Inc. Oral liquid compositions of non-steroidal anti-inflammatory drugs

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4033816A (en) * 1973-06-18 1977-07-05 The Upjohn Company Process for inhibiting platelet aggregation
GB2059768A (en) * 1979-09-27 1981-04-29 Ilona Kahan Water-soluble derivatives of non-steroidal anti-inflammatory agnets and a process for the production thereof
US5183829A (en) * 1991-09-27 1993-02-02 Applied Analytical Industries, Inc. Oral liquid compositions of non-steroidal anti-inflammatory drugs

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DATABASE WPI Section Ch Week 8406, Derwent World Patents Index; Class B05, AN 84-031960, XP002099349 *
GU L ET AL: "Preformulation salt selection. Physical property comparisons of the tris(hydroxymethyl)aminomethane (THAM) salts of four analgesic/anti- inflammatory agents with the sodium salts and the free acids", PHARMACEUTICAL RESEARCH, vol. 4, no. 3, 1987, pages 255 - 7, XP002099348 *

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