WO2012016314A1

WO2012016314A1 - Arachidonic acid-derived coxib analogue-substituted compounds for use in treating pain

Info

Publication number: WO2012016314A1
Application number: PCT/BR2011/000275
Authority: WO
Inventors: André AUGUSTO GOMES FARACO; Janetti Nogueira De Francischi; Rafael Machado Rezende; Patrícia PAIVA LIMA; Webster Glayser Pimenta Dos Reis
Original assignee: Universidade Federal De Minas Gerais - Ufmg
Priority date: 2010-08-04
Filing date: 2011-08-04
Publication date: 2012-02-09
Also published as: BRPI1003050B1; WO2012016314A9; BRPI1003050A2

Abstract

The present invention describes the production of arachidonic acid-derived coxib analogue-substituted compounds and salts thereof for use in treating pain. Furthermore, the invention relates to pharmaceutical compositions containing arachidonic acid-derived coxib analogue-substituted compounds, salts thereof and pharmaceutically acceptable excipients for use in treating pain. The painkillers comprised by the invention can be used alone or in combination with other painkillers, for relieving slight, moderate or severe pain.

Description

AQUAQUIDONIC ACID DERIVATIVE COMPOUNDS REPLACED WITH PAIN TREATMENT ANALOGS

FIELD OF INVENTION

The present invention describes the production of arachidonic acid derivative compounds substituted with coxib analogs and their salts for treating pain. The invention further comprises pharmaceutical compositions containing arachidonic acid derivative compounds substituted with coxib analogs, their pharmaceutically acceptable salts and excipients for the treatment of pain.

The analgesics comprised by the invention may be used alone or in combination with other analgesics to relieve mild, moderate or severe pain.

TECHNICAL STATE

Traditional non-steroidal anti-inflammatory drugs, the prime example of which is aspirin, are one of the most widely used drug groups in the world (Vane JR, Botting RM (1998). Int J Tissue React. 20 (1): 3-15).

Among them, they stand out in Brazil besides aspirin, diclofenac, meloxicam, indomethacin, among many others. Such drugs, which are now identified by the acronym "NSAIDs", generally have three pharmacological properties common to each of them: anti-inflammatory, analgesic and antipyretic properties. The antiinflammatory property includes, for example, reduction of swelling; analgesia is related to the relief of mild to moderate pain, usually associated with inflammation, and the anti-thermal property is related to fever reduction.

Although synthesized and launched on the German consumer market in 1897, the way aspirin acts as an anti-inflammatory, analgesic and antipyretic drug only began to be unraveled since the 1970s, the most emblematic record of which is found in the journal Nature. by Professor John Vane of England in 1971. (Vane JR (2000). The fight against rheumatism: from willow bark to COX-1 sparing drugs. Journal of Physiology and Pharmacology 51 (4): 573-586. Vane JR (1971). Inhibition of prostaglandin synthesis as a mechanism of action for aspirin like drugs. Nature New Biology 231: 232-235).

In the aforementioned work, aspirin has been shown to inhibit prostaglandin synthesis, a group of compounds endogenously formed during inflammation that is now known to be primarily responsible for the onset of inflammation and inflammatory pain. The target of the action of aspirin and its pharmacological correlates in the body comprises a family of enzymes called cyclooxygenases (COXs), present in virtually all cells of the body, that transform a normally inactive cell membrane component into substances with broad biological activity. , called "prostaglandins". Aspirin and analogues, therefore, when interacting with COXs, inhibit prostaglandin synthesis, whose functional consequence varies according to the cell type involved.

Unlike during inflammation, prostaglandins are continuously synthesized in the body at low concentrations, contributing to the maintenance of homeostasis, especially in the gastrointestinal tract, and kidneys. They are also produced by platelets, being called in this case thromboxanes. When cell damage or alteration occurs, prostaglandins are synthesized in increasing amounts, depending on the degree of injury, leading to the appearance of inflammatory signs and symptoms. Therefore, it is the increase of prostaglandins at the inflammation site that will cause the deleterious effects associated with it.

Because of the mode of action, aspirin and its analogs, when used to inhibit prostaglandin synthesis in inflammation, have beneficial effects, alleviating inflammation. However, these beneficial effects are also accompanied by unpleasant effects related to the stomach and kidneys, for example, in which case they are called side or adverse effects.

From the 1990s onwards, knowledge about the mechanism of action of NSAIDs began to change, and it was demonstrated for the first time that there was a possibility of finding different types. of cyclooxygenases in the different cells of the body which, however, produced the same known prostaglandins (Fu Ji-Yi, Masferrer JL, Seibert K, Raz A, Needleman P (1990). The induction and suppression of Prostaglandin H2 synthase (cyclooxygenase) in human monocytes The Journal of Biological Chemistry 265 (28): 16737-6740).

Cyclooxygenases (COXs) were now identified as 1 and 2, or constitutive and induced, respectively, and type 2 was found to be the major form of COX present in inflamed cells, while COX 1 was found in all cells. " normal ". Pharmacologists soon deduced that drugs that only inhibit COX 2 could be developed, thus not affecting the necessary synthesis of prostaglandins involved in normal body function due to COX 1.

Next, the first selective drugs for COX 2 were synthesized, the group of which was called "coxibes" (selective cyclooxygenase 2 inhibitors), which were rapidly introduced to the world market from 1999, including Brazil (Penning, TB; Talley, JJ; Bertenshaw, SR; Carter, JS; Collins, PW; Docter, S.; Granite, MJ; Lee, LF; Malecha, JW; Miyashiro, JM; Rogers, RS; Rogier, DJ; Yu, SS ; Anderson, GD; Burton, EG; Cogburn, JN; Gregory, SA; Koboldt, CM; Perkins, WE; Seibert, K.; Veenhuizen, AW; Zhang, YY; Isakson, PC 1997. Synthesis and biological evaluation of the 1 , 5-Diarylpyrazole class of cyclooxygenase-2 inhibitors: Identification of 4- [5- (4-Methylphenyl) -3- (trifluoromethyl) -1H-pyrazol-1-y1] benzenesulfonamide (SC-58635, Celecoxib) J. Med Chem., 40: 1347-1365, Chan CC, Boyce S, Brideau C, Charleson S, Cromlish W, Ethier D, Evans J, Ford-Hutchinson AW, Forrest MJ, Gauthier JY, Gordon R, Gresser M, Guay. Kargman S Kennedy B Leblanc Y L Eger S, Mancini J, O ^{^} Neill GP, Ouellet M, Patrick D, Percival MD, Perrier H, Prasit P, Rodger I, Tagari P, Therien M, Vickers P, Wang Z, Webb J, Wong E, Xu LJ, Young RN, Zamboni R, Riendeau D, 1999. Rofecoxib [Vioxx, MK-0966; 4- ^{(4'-Methylsulfonylphenyl)} -3-phenyl-2- (5H) -furanone]: a potent and orally active cyclooxygenase-2 inhibitor. Pharmacological and Biochemical profiles. Journal of Pharmacology and Experimental Therapeutics 290: 551-560). The first selective COX 2 inhibitors marketed were celecoxib and rofecoxib, released by the Food and Drug Administration (FDA) for use in the chronic treatment of rheumatoid arthritis and osteoarthritis. These compounds were a bestseller, followed in Brazil by etoricoxib, valdecoxib, and more recently lumiracoxib, the latter being introduced in 2005. (Shi S, Klotz U. (2008). 2 inhibitors Eur. J. Clin. Pharmacol 64 (3): 233-252). Other coxibs for veterinary use were also developed.

However, the FDA in the United States and ANVISA (National Agency for

Health Surveillance) in Brazil prohibited the sale of rofecoxib and valdecoxib (FUNK, C.D .; FITZGERALD, G.A. COX-2 inhibitors and cardiovascular risk. J. Cardiovasc. Pharmacol. 50: 470-479, 2007).

Withdrawal of these drugs from the market was mainly due to the risk of cardiovascular disease, such as heart attack and sudden death (DIEPPE, PA et al. Lessons from the withdrawal of rofecoxib. Br. Med. J. 329: 867-8, 2004. SARAIVA, JFK COX-2 Cardiovascular Risk: Molecular Effect or Class Dependent? Phaoenix Integrated Communication, São Paulo: 1-5, 2007).

Francischi et al (2002) demonstrated that celecoxib and rofecoxib were excellent analgesics in a standard model of inflammation and inflammatory pain, the carrageenan model injected into rat paws. In this work, it was observed that these compounds presented analgesic activity in the same range of doses used in humans, a behavior peculiar to drugs that traditionally belong to the group of aspirin, which generally require higher doses in this type of animal, considering the same experimental model. It was also observed that in comparison with the traditional NSAIDs used to study the analgesic effect, indomethacin and piroxicam, the pain relief was greater with the tested coxibes, which was called "hypoalgesia" in the mentioned work. Moreover, only at the highest doses used did the anti-inflammatory effect appear. (Francischi JN, CT Keys, Moura ACL, Lima AS, Rocha OA, Ferreira-Alves DL, Bakhle YS (2002). Selective inhibitors of cyclooxygenase-2 (COX-2) induce hypoalgesia in a rat paw model of inflammation. Br J Pharmacol 137: 837-844).

Subsequently, France et al. (2006) demonstrated that a selective COX 1 inhibitor (compound (SC560) did not cause hypoalgesia, and that an opioid antagonist prevented the development of hypoalgesia induced by three coxibs used (celecoxib, rofecoxib, and experimental compound SC236)). In addition, morphine tolerant animals also had no hypoalgesia if also treated with celecoxib (France DS, Ferreira-Alves DL, Duarte ID, Ribeiro MC, Rezende RM, Bakhle YS, Francischi JN (2006). hypoalgesia induced by inhibitors of cyclooxygenase-2 in rat paws treated with carrageenan (Neuropharmacology 51: 37-43).

Taken together, these results suggested that efficient analgesia associated with coxib use was due to the release of endogenous opioids.

More recently, peripheral or centrally used opioid antagonists in rats have been shown to block celecoxib hypoalgesia, as described in the following work (Correa, JD; Paiva-Lima, P .; Rezende, RM; Dos Reis, WP; Ferreira-Alves, DL; Bakhle, YS; Francischi, J. Peripheral mu-, kappa and delta-opioid receptors mediate the hypoalgesic effect of celecoxib in a rat model of thermal hyperalgesia Life Sci. 2010, 86: 951-956); (Rezende, RM. A new mechanism of action to explain the central analgesic actions of celecoxib: involvement of endogenous opioid and cannabinoid systems. 2010. Thesis defended at the postgraduate course in biological sciences: physiology and pharmacology. ICB / UFMG, Belo Horizonte, MG).

Literature data have shown that cannabinoid receptor activation leads to the synthesis and release of endogenous opioids (Corchero J, Avila MA, Fuentes JA, Manzaneres J, 1997. Delta 9-tetrahydrocannabinol increases prodynorphin and proenkephalin gene expression in the spinal cord of the rat Life Sciences 61: L39-L43). Ibrahim et al. (2005) demonstrated beta-endorphin release by keratinocytes from rat skin after activation CB2 (cannabinoid agonist) receptor activity in rat paw (Ibrahim MM, Forreca F, Lai J, Albrecht PJ, Rice FL, Khodorova A, Davar G, Vanderah TW, HP Mata, Malan TP Jr, 2005. CB2 cannabinoid receptor activation produces antinociception by stimulating peripheral release of endogenous opioids (Proc Natl Acad Sci 102 (8): 3093-3098).

In addition, the FAAH (Fatty Acid Hydrolase) inhibitor, which is involved in endogenous cannabinoid metabolism (Cravatt BF, Gianq DK, Mayfield SP, Boger DL, Lerner RA, Gilula NB, was administered to the central nervous system of rats). 1996. Molecular characterization of an enzyme that degrades neuromodulatory fatty acids (Nature 384 (6604): 83-87). This same inhibitor, URB597, administered subcutaneously ½ h before celecoxib, dose-dependently prevented the onset of hypoalgesia (Rezende, RM. A new mechanism of action to explain celecoxib's central analgesic actions: involvement of opioid and cannabinoid systems 2010. Thesis defended at the postgraduate course in biological sciences: physiology and pharmacology (ICB / UFMG, Belo Horizonte, MG).

One way to check if there was an important COX 2 inhibitor component for the hypoalgesic action of celecoxib was to use OSU03012, a chemical analogue devoid of COX 2 inhibitory activity (JOHNSON, AJ; SMITH, LL; ZHU, J. et al. The novel celecoxib derivative, OSU03012, induces cytotoxicity in primary CLL cells and transformed B-cell lymophoma cell line via the caspase-and Bcl-2-independent mechanism Blood v. 105 n.6, p 2504-2509. 2005; ZHU, J. From the Cyclooxygenase - 2 Inhibitor Celecoxib to a Novel Class of 3-Phosphoinositide-Dependent Protein Kinase-1 Inhibitors Cancer Research, v. 64. pp. 4309-4318. Jun, 2004; , JE et al Celecoxib analogues disrupt Akt signaling, which is commonly activated in primary breast tumors (Breast Cancer Research, v. 7, 5. p. 796 - 807, 2005).

In fact, both centrally and peripherally injected OSU03012 caused hypoalgesia similar to that observed after celecoxib administration, which served as important evidence that inhibition of COX 2 does not specifically contribute to the hypoalgesic effect observed after administration.

Patent application PI 0802850-8 reports the use of compound OSU 03012 and its derivatives for the treatment of painful conditions in mammals (human and veterinary use), and supports the argument that the hypoalgesic mechanism of coxibs does not involve COX inhibition. -2.

US5760068, US5466823, US5563165 describe classes of pyrazolyl benzene sulfonamides compounds, or pharmaceutically acceptable salts thereof for use in treating inflammation and related disorders. EP0418845 describes new pyrazole derivatives and their pharmaceutically acceptable salts with antiinflammatory, analgesic and antithrombotic activity.

However, none of the above patents describe the coxib derivatives derived from this application, as well as their use as an analgesic.

Even though undesirable effects on certain medications are rare, it is still important to maintain scientific research on new classes of drugs aimed at treating pain patients, as exemplified by patients who become tolerant to morphine analgesic. Thus, for patients with chronic painful pathologies, an alternative treatment may mean improved quality of life and consequent reduction in the occurrence of comorbidities.

The coxib derivatives discussed in this application may be used alone or in combination with other analgesics to treat mild, moderate or severe pain, in which other proven analgesics have not had the desired effect. DETAILED DESCRIPTION OF TECHNOLOGY

The present invention describes the production of arachidonic acid derivative compounds substituted with coxib analogs and their salts for treating pain, having the following structural formula:

where R is selected from the group comprising:

The invention further comprises pharmaceutical compositions containing arachidonic acid derivative compounds substituted with coxib analogs, their pharmaceutically acceptable salts and excipients for the treatment of pain.

Standard compositions may be liquid, solid or semi-solid.

The liquid preparations may be in the form of solution, syrup, elixir, suspension, emulsion, tincture or enema. The semisolids in the form gels, ointments, creams or pastes and solids in the form of capsules, tablets, dragees or lozenges.

Examples of excipients include methylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, carboxymethylcellulose, polymers derived from acrylic and methacrylic acid, polyethylene glycols, solid vaseline, solid paraffin, lanolin, vegetable oils, mineral oil, cetyl alcohol, sterile alcohol, cetostearyl alcohol, glyceryl monostearate, of cetyl esters, nonionic and anionic self-emulsifying wax and sodium lauryl sulfate, for semi-solid dosage forms.

Binders, disintegrants, diluents, lubricants, surfactants such as cellulose, lactose, starch, mannitol, magnesium stearate, talc, colloidal silicon dioxide, magnesium oxide and kaolin for solid preparations.

For liquid dosage forms solubilizers and surfactants such as glycerine, propylene glycol and sucrose may be used.

Excipients may also contain minor amounts of additives as substances that increase the isotonicity and chemical stability of preservatives, chelators and stabilizers. Examples of such substances include phosphate buffer, bicarbonate buffer and Tris buffer, thimerosal, m- or o-cresol, formalin, benzyl alcohol, parabens, EDTA, BHA, BHT; in addition to sweeteners, colorings and flavorings.

Such compositions may be administered intramuscularly, intravenously, topically, orally, by inhalation or as devices that may be implanted or injected.

The present invention may be better understood by the following non-limiting examples of technology:

EXAMPLE 1: SYNTHESIS OF ARAQUIDONOIL-CLECOXIBE (AACX)

Based on data available in the literature, it was postulated that celecoxib would need to generate an endogenous metabolite with the participation of FAAH, which would be ultimately responsible for the activation of cannabinoid receptors, culminating in the release of beta-endorphin at the inflammation site. Although FAAH metabolizes anandamide, when reagents (in this case, celecoxib and arachidonic acid) are in higher concentrations than FAAH can act in reverse, ie synthesize the product (Deutsch DG; Ueda N; Yamamoto S. The fatty acid amide hydrolase (FAAH). 2002 Prostaglandins Leukot Essent Fatty Acids; 66 (2-3): 201 -10.). Thus, celecoxib administered via the icv (intracerebroventricular) route and the other reagent, arachidonic acid (AA) would have increased CNS concentrations due to the carrageenan-induced inflammatory process. Thus, both celecoxib and AA could be combined by the action of FAAH, forming a new product capable of activating cannabinoid receptors, similar to what happens after endogenous synthesis of anandamide. Based on the endogenous cannabinoid molecule anandamide and 2-arachidonyl glycerol, which are formed by the combination of arachidonic acid (AA) with ethanolamine or glycerol, respectively, arachidonoyl celecoxib was synthesized (Figure 1). Therefore, it was assumed that this metabolite would be responsible for the antinociceptive effects of celecoxib through agonist action on the cannabinoid system, culminating in the development of hypoalgesia.

For the synthesis of the compound arachidonoyl celecoxib were added in a moisture-free system (balloon coupled to a calcium chloride tube and under magnetic stirring, 100 mg (0.25 mmol) celecoxib, and 20 ml anhydrous acetone.) , the solution obtained by mixing 100 mg (0.33 mmol) of arachidonic acid and 68 mg of dicycloexylcarbodiimide (0.33 mmol) in anhydrous acetone (20 mL) was continued. The reaction was carried out by means of CCD (eluent: hexane / ethyl acetate 7: 3 v / v; developers: iodine and 15% w / v ethanolic sulfuric acid solution, followed by heating in an oven). Acetone was added to the obtained residue, which led to the formation of a precipitate, filtered and the filtrate concentrated in a rotary evaporator, again yielding a residue which was purified by CCS. was eluted 7: 3 with hexane / ethyl acetate to give 100 mg (0.15 mmol) of a viscous oil.

The product was characterized by IR (Figure 2) and hydrogen ( ¹ H) (Figure 3) and carbon nuclear magnetic resonance spectra. thirteen ( ¹³ C) (Figure 4).

In the infrared spectrum of the arachidonoylcoxib derivative, the characteristic bands of both celecoxib molecule and arachidonic acid are observed. In addition to these, it is possible to observe a characteristic band of the NH stretch of the sulfonamide group attached to the arachidonic acid carbonyl group. In the ¹³ C and ¹ H NMR spectrum it is possible to observe the existence of the characteristic carbon and hydrogen signals of the arachidonoyl and celecoxib groups. In addition, a paramagnetic displacement of carbonyl carbon and sulfonamide hydrogen from the arachidonoyl and benzenesulfonamide groups, respectively, is observed.

EXAMPLE 2: ANALGESIC ACTIVITY

Test 1: Model of carrageenan-induced hyperalgesia in rats

AACX-induced hypoalgesia was measured following intracerebroventricular (icv) and intraplantar (ipl) administration in carrageenan-injected rats. (Di Rosa, M. (1972). Biological properties of the carrageenan. J. Pharm. Pharmac. 24: 89-102. Vinegar R, Truax JF, Selph JL, Johnston PR, Venable AL, McKenzie KK (1987). Pathway to carrageenan-induced inflammation in the hind limb of the rat (Fed. Proc. 46: 118-126).

Araquidonoyl celecoxib (AACX; 5.5, 11, 22 and 44 pg icv or 50, 80, 100 and 300 pg ipl) was administered 30 min (icv) or 5 min (ipl) before carrageenan injection (CG, 250 pg / paw) in the rat paw. The contralateral paw received only sterile physiological saline (SAL). The arachidonoyl celecoxib compound (AACX, figure 1) induced hypoalgesia both when administered via icv (Figures 5a and 5b) and intraplantar (Figures 5c and 5d).

The effect of selective cannabinoid receptor antagonists CB1 (AM 251) and CB2 (SR 144528) and naltrexone (non-selective opioid receptor antagonist) on centrally administered AACX (Araquidonoyl celecoxib) induced hypoalgesia was evaluated. Selective cannabinoid receptor antagonists (10 pg) were administered icv 30 min before arachidonoyl celecoxib (AACX; 22 pg). Carrageenan (GC, 250 pg / paw) was injected intraplantar 30 min after compound. The contralateral paw received only sterile physiological saline (SAL) (Figures 6a, 6b, 7a and 7b). Naltrexone (4 pg) was administered icv 30 min before arachidonoyl celecoxib (AACX; 22 pg). Carrageenan (GC, 250 pg / paw) was injected intraplantar ½ h after compound. The contralateral paw received only sterile physiological saline (SAL) (Figures 8a and 8b).

Through the analysis of Figures 6 (a and b), 7 (a and b) and 8 (a and b) it was observed that the hypoalgesic effect produced by centrally administered AACX was prevented by antagonist CB1 (AM 251).

Figure 9 shows that the CB2 receptor (SR 144528) and opioid receptor (naltrexone) antagonists totally reversed the peripherally induced hypoalgesia induced by arachidonoyl celecoxib. Figure 10 shows, through the immunohistochemically labeled beta-endorphin area, the effect of arachidonoyl celecoxib on the presence of this opioid in the skin epithelium taken from the inflammation site. This method showed that local administration of carrageenan caused increased synthesis of betaendorfin in the adjacent epithelium and that intra-plantarly injected AACX caused acute release (reduction of immunostaining in the epithelium of the paw skin) of local beta-endorphin.

BRIEF DESCRIPTION OF THE FIGURES

Figure 1: Structure of arachidonoyl celecoxib.

Figure 2: Arachidonoyl celecoxib IV spectrum

Figure 3: Hydrogen (H) nuclear magnetic resonance spectrum of arachidonoyl celecoxib compound

Figure 4: Thirteen ( ¹³ C) carbon magnetic resonance spectrum of the arachidonoyl celecoxib compound

Figure 5 A: AACX-induced hypoalgesia (arachidonoyl celecoxib) administered via icv in rats. Measurement performed on the right paw of the animals.

Figure 5 B: AACX (arachidonoyl celecoxib) induced hypoalgesia administered via icv in rats. Measurement performed on the left paw of the animals. Figure 5 C: AACX (arachidonoyl celecoxib) -induced hypoalgesia after intraplantar administration, difference between the values obtained in the right and left paws of rats.

Figure 5 D: AACX (arachidonoyl celecoxib) induced hypoalgesia following intraplantar administration to the left paw of rats.

Figure 6 A: Effect of AM 251 on induced hypoalgesia following icv administration of AACX (arachidonoyl celecoxib). Measurement performed on the right paw.

Figure 6 B: Effect of AM 251 on induced hypoalgesia following icv administration of AACX (arachidonoyl celecoxib). Measurement performed on the left paw. Figure 7 A: Effect of SR 144528 on induced hypoalgesia following icv administration of AACX (arachidonoyl celecoxib). Measurement performed on the right paw.

Figure 7 B: Effect of SR 144528 on induced hypoalgesia following icv administration of AACX (arachidonoyl celecoxib). Measurement performed on the left paw.

Figure 8: Effect of naltrexone on AACX (arachidonoyl celecoxib) induced hypoalgesia following icv administration in rats. (A and B)

Figure 9: Effect of SR 144528 and naltrexone on AACX (arachidonoyl celecoxib; 100 pg) -induced hypoalgesia following i.pl administration in rats (paw variation).

Figure 10: Evidence of β-endorphin release from the skin epithelium of the paws of rats treated with arachidonoyl celecoxib (AACX; 100 pg / 50 μΙ). Reversal of this effect by CB2 cannabinoid receptor antagonist (SR; 50 pg / 50 μΙ) is also presented.

Claims

1. PROCEDURE FOR OBTAINING AQUAQUIDONIC ACID DERIVATIVE COMPOUNDS REPLACED WITH COXIBLE ANALOGS

characterized by comprising the following steps:

(a) Addition to a moisture-free system of 70 to 150 mg of coxibe dissolved in 20 ml of anhydrous acetone and 70 to 150 mg of aracdonic acid and 40 to 80 mg of dicycloexylcarbodiimide dissolved in 20 ml of anhydrous acetone, b) Magnetic stirring for 10 hours ;

c) Solvent removal and addition of acetone;

d) Filtration of the precipitate formed;

e) Concentration of the resulting filtrate;

d) Purification of the concentrate by chromatographic methods.

2. AQUIDONIC ACID DERIVATIVE COMPOUNDS REPLACED WITH COXIBLE ANALOGS, characterized in that they have the following structural formula:

where R is selected from the group comprising:

Substituted AQUIDONIC ACID DERIVATIVE COMPOUNDS WITH COXIBLE ANALOGUE according to claim 2, characterized in that they are used as analgesics to relieve mild, moderate or severe pain derived from musculoskeletal disorders of inflammatory origin or other origins.

AXYCHRONIC ACID DERIVATIVE COMPOUNDS REPLACED WITH COXIBLE ANALOGUE according to claims 2 and 3, characterized in that they are used alone or in combination with other analgesics.

5. PHARMACEUTICAL COMPOSITION, characterized in that it comprises coxib derivatives having the following structural formula:

where R is selected from the group comprising:

at least one physiologically acceptable pharmaceutical excipient or adjuvant.

PHARMACEUTICAL COMPOSITION according to Claim 5, characterized in that it is administered by oral, subcutaneous, intramuscular, intravenous, intraperitoneal, subcutaneous, transdermal canal or as devices which may be implanted or injected.

7. USE OF ARAQUIDONIC ACID DERIVATIVE COMPOUNDS REPLACED WITH COXIBLE ANALOGS, characterized by being in the preparation of analgesic and anti-inflammatory drugs.