Specifically the present invention concerns nitroxyderivatives of non-steroidal anti- inflammatory compounds, which are able to inhibit selectively the enzyme COX-2.

It is well known that non-steroidal anti-inflammatory drugs are widely used as analgesics, antipyretics and in the treatment of pathologies that have an inflammatory origin. As known, the use of NSAIDs is limited by serious side-effects at gastrointestinal and renal levels andbyhaemorrhagic complications that appear after prolonged treatments with these drugs.

The inflammatory process originates from the activation of two isoforms of the enzyme cyclooxygenase (COX), which are involved in the activation of a series of biochemical processes, known as arachidonic acid cascade. In this series of biochemical processes the formation of metabolites, such as for example pro-algogenic and inflammatory prostaglandins and leukotrienes, takes place. The two isoforms of the enzyme cyclooxygenase are identified as cyclooxygenase-1 or COX-1 and cyclooxygenase-2 or COX-2 respectively (Annu. Rev. Pharmacol. Toxicol. 1998 38, 97-120). The COX-1 constitutively expressed in gastrointestinal, renal tissues or at endothelial level, plays a primary role in physiological phenomena, and at gastric mucosa level promotes the formation of the protective prostanoids involved in the gastric cytoprotection. The COX-2 produced after inflammatory stimuli represents the form of the enzyme cyclooxygenase responsible for the production of inflammatory and pro-algogenic prostanoids. Moreover, the COX-2 activates a series of factors that maintain and amplify the inflammatory process.

The NSAIDs present on the market inhibit both the isoforms, both the COX-1 and COX-2, provoking a decrease in the production of protective prostanoids, and therefore the appearance of the aforementioned side-effects. In order to obviate these inconveniences, drugs that inhibit selectively COX-2 without inhibiting substantially COX-1 have been proposed. Among the COX-2 inhibitor drugs, celecoxib, rofecoxib,

etc. , can be mentioned. (Drugs of Future 1998,23 (12) 1287-1296). It has been found that the use of these drugs is not exempt from side-effects, in particular those affecting gastrointestinal (Gastroenterology 1997,112, 645-648), renal levels and above all those concerning the cardiovascular apparatus (JAMA 2001; 286,954-959). Especially for what concerns the side-effects at gastrointestinal level, the delay that these drugs cause in the cicatrisation of pre-existent gastric ulcers, can be mentioned. Furthermore, in the presence of gastritis provoked by H. pylory, and in general in the presence of an inflammatory state affecting the gastrointestinal tract (IBD), the use of the known COX-2 inhibitors can facilitate the onset of ulcers (J. Clin. Gastroenterol. 2002 34, 451-453). Another drawback of these drugs is that the analgesic activity is not optimal.

The need was felt to have available drugs showing an improved COX-1/COX-2 pharmacological performance, and being able to inhibit both the activity and expression of the enzyme COX-2 without presenting the aforesaid side-effects.

The Applicant has surprisingly and unexpectedly found drugs that are able to solve the aforementioned technical problem.

An object of the present invention is the use of compounds of formula (I) or salts thereof with an anti-inflammatory activity that are able to inhibit selectively the enzyme COX-2 without inhibiting substantially the enzyme COX-1, without showing side- effects, in particular at gastrointestinal, renal levels, and without damaging the cardiovascular apparatus: <BR> <BR> <BR> <BR> R-TI-B-Cco-N (o) s<BR> <BR> <BR> <BR> <BR> (I) wherein R-TI-is a radical deriving from a non steroidal anti-inflammatory drug of formula R- TIOH or R-TIH wherein R is defined hereunder, T, is CO or X, wherein X is O, S, N (RIC) wherein Ric is H or a linear or branched Cl-C5 alkyl ; c0 is an integer equal to 0 or 1; s is an integer equal to 1 or 2, preferably 2; B is a bivalent linker of formula (III) - TB-X2-TBI- (III) wherein TB and TBI are equal or different and are CO or X wherein X is as defined above; X2 is a bivalent bridging group and is selected from the following compounds: a)

wherein: nl and n2 are integers 0 or 1 ; R2and R3 are independently selected from H or CH3; b)

wherein: Yl is-CH2-CH2-(CH2) n2-or-CH=CH-(CH2) n2-, wherein n2'is an integer from 0 to 10, and n2 and R2 are as above defined; c)

wherein: n4 is an integer from 1 to 20 and n5 is an integer from 0 to 20, R4 and R4 Rs and Rs are independently selected from H, CH3, OH, NH2, NHCOCH3, COOH; when the bond between the CA and CB carbons is a double bond R4 and R or R4'and R5 are absent; d)

wherein:

nIX is an integer from 0 to 10, preferably from 1 to 5; nIIX is an integer from 1 to 10, preferably from 1 to 5; RTIX, RTIX', RTIIX, RTIIX', are the same or different, and are H or straight or branched Ci- C4-alkyl, preferably RTIX, RTIX', RTIIX, RTIIX' are H; Y3 is a saturated, unsaturated or aromatic heterocyclic ring having 5 or 6 atoms, containing one or more heteroatoms selected from nitrogen, oxygen, sulphur, and selected from:

preferably Y3 are : (Y1), having the two free valences in ortho position to the nitrogen atom, (Y4), (Y10) ; C is the bivalent radical-TC-Y-wherein : Te is CO or X, wherein X is as above defined;

Y is a bivalent radical having the following meaning: e) an alkylenoxy group-R'O-wherein R'is linear or when possible branched C l-C 20, alkylene preferably having from 2 to 6 carbon atoms, or a cycloalkylene having from 5 to 7 carbon atoms, in the cycloalkylenic ring one or more carbon atoms can be substituted b y h eteroatoms, t he r ing c an h ave s ide c hains o f R't ype w herein R'is a s above defiend ; f)

wherein m is an integer from 1 to 6, preferably from 1 to 4, Rif is H or CH3; g)

wherein n3 is an integer from 0 to 3 and n3'is an integer from 1 to 3; with the proviso that: when T, is CO then TB is X wherein X is as defined above; when T, is X wherein X is as defined above, then TB is CO; when c0 is 1, Te is CO when TBI is X wherein X is as above defined; when c0 is 1, Tc is X wherein X is as above defined, when TBI is CO; when c0 is 0, To has the only meaning of O ; the radical R, deriving from the non steroidal anti-inflammatory drugs o f formula R- TIOH, when T, is CO, or R-TlH, when T, is X, is selected from:

in formula (Ia) : Rl is H or-OCOR3 wherein R3 is methyl, ethyl or linear or branched C3-Cs alkyl, R2 is H, hydroxy, halogen atom, nitro, amino, mono-or di-(C,-C4) alkylamino, linear or when possible branched C-C4 alkyl, linear or branched when possible C-C4 alkoxy, a linear or when possible branched C-C4 perfluoroalkyl, for example trifluoromethyl; with the proviso that in formula (Ia) Rland R2 cannot contemporaneously be H, preferably when Rl is H, R2 is OH; - when Ri is-OCOCH3 in position 2 and R2 is hydrogen, la) represents the residue of acetylsalicylic acid; - when R, is H and R2 is OH in position to 2, la) represents the residue of salicylic acid; in formula (Ib) : nI is an integer equal to 0 or 1; Ri, R2 and R3 are as defined above; - when R3 is CH3, nI is 0, the compounds of formula Ib) is the residue of acetylsalicylsalicylic acid; wherein in formula (Ic) : M is CH or N ; R6 is H, CH3, an halogen atom preferably Cl,; R4 is H, CF3, CH3 or an halogen atom preferably Cl,; R5 is H, an halogen atom preferably Cl;

- when M is CH, R6 and R5 are H, R4 is CF3, (Ic) is the residue of flufenamic acid; - when M is CH, R6 and R5 are Cl, R4 is CH3, (Ic) is the residue of meclofenamic acid; - when M is CH, R6 and R4 are CH3, R5 is H, (Ic) is the residue of mefenamic acid; - when M is CH, R6 is CH3, R5 is H, R4 is Cl, (Ic) is the residue of tolfenamic acid; - when M is N, R6 and R5 are H, R4 is CF3, (Ic) is the residue of niflumic acid; - when M is N, R6 is CH3, R5 is H, R4 is CF3, (Ic) is the residue of flunixin ;

wherein RFI and RF2 are independently selected from H or Cl, Br, F, RG is hydrogen or, Ci-Ce linear or branched alkyl, preferably RG is methyl; when RF1 and RF2 are Cl and RG is hydrogen the compound of formula (IIa) represents the residue of dichlophenac ;

The NSAIDs of formulas R-TlOH and R-TlH, mentioned above, are commercially available compounds or can be prepared according to the known methods described in the prior art, for example, in"The Merck Index"12a Ed. (1996), herein incorporated by reference. Example of anti-inflammatory compounds for use in the present inventions are: Aspirin, Salicylic acid, Mesalamine, Acetylsalicylsalicylic acid, 5-amino- acetylsalicylic acid, Flunixin, Ketorolac, Tolfenamic acid, Niflumic acid, Mefenamic acid, Meclofenamic acid, Flufenamic acid, Enfenamic acid, Etodolac, Pirazolac, Tolmetin, Bromefenac, Fenbufen, Mofezolac, Diclofenac, Pemedolac, Sulindac, Indomethacin, Suprofen, Ketoprofen, Tiaprofenic acid, Fenoprofen, Indoprofen, Carprofen, Naproxen, Loxoprofen, Ibuprofen, Pranoprofen, Bermoprofen, CS-670, Zaltoprofen, Flurbiprofen, Tenoxicam, Piroxicam, Meloxicam, Lornoxicam, Tenidap, Paracetamol and Salacetamide.

Example of precursor compounds of the bivalent radical B of formula (III), wherein the free valences of TB and TBI can be saturated with OH or H, for use in the present

invention are: penicillamine, N-acetylpenicillamine, cysteine, N-acetylcysteine, aspartic acid, gallic acid, ferulic acid, gentisic acid, citric acid, caffeic acid, dihydrocaffeic, p- coumaric acid, vanillic acid, dihydroxymaleic acid, glycolic acid, lactic acid, fumaric acid, 3-3'-thiodipropionic acid, p-coumaric alcohol, 4-hydroxyphenethylalcohol, conyferyl alcohol Compounds of the present invention which have one or more asymmetric atoms can exist as the optically pure enantiomers, pure diastereoisomers, mixture of enantiomers, mixture of diastereoisomers, racemic mixtures of enantiomers, diasteroeisomeric racemates o r m ixtures o f d iastereoisomeric r acemates. It i s t o b e u nderstood t hat t he present invention anticipates and includes within its scope all such isomers or mixtures thereof.

Compounds of the inventions comprise a carbon-carbon double bond may exist as E or Z isomers, it is to be understood that the present invention anticipates and includes within its scope all such isomers or mixtures thereof.

The methods to prepare the compounds of formula (I) are described in patent applications WO 00/51988, WO 00/61537 and WO 00/61541, signed by the Applicant.

The compounds according to the present invention, when at least a functional group salifiable with acids is present, for example an amino group, can be transformed into the corresponding salts. For example a method to form salts is the following: when in the molecule one basic nitrogen atom is present, it is reacted in organic solvent as, for instance, acetonitrile, tetrahydrofuran, with an equimolecular amount of the corresponding organic or inorganic acid. Examples of organic acids are: oxalic, tartaric, maleic, succinic, citric, trifluoroacetic acids. Examples of inorganic acids are: nitric, hydrochloric, sulphuric, phosphoric acids.

The compounds object of the present invention are formulated in the corresponding pharmaceutical compositions, even at delayed release, for parental, oral and topic use, as for example inhalatory, suppository, transdermal, enema use, according to the well known methods in the art, together with the usual excipients; see for example the volume"Remington's Pharmaceutical Sciences", 15a Ed.

The amount on molar basis of the active principle in these formulations is generally the same, or lower, in comparison with that of the corresponding precursor drug.

The daily administrable doses are those of the precursor drugs, or in the case lower. The daily doses can be found in the publications of the field, such as for example in"Physician's Desk Reference".

Among the compounds of the invention the following ones are preferred: (S)-N-acetyl- [a-methyl-4- (2-methylpropyl) benzeneacetyl] ysteine 4-nitrooxybutyl ester having formula:

(IVC) <BR> trans-3-[4-[2-fluoro-α-methyl(1,1'-biphenyl)-4-acetyloxy]-3 -methoxyphenyl]-2- propenoic acid 4- (nitrooxy) butyl ester, having formula: (vIc) (S)-N-acetyl-[2-fluoroamethyl (1, 1'-biphenyl) +acetyl] cysteine 4- (nitrooxy) butyl ester having formula :

2-fluoro-a-methyl [1, 1'-biphenyl]-4-acetic acid 6- (nitrooxymethyl)-2-methylpyridyl ester having formula : (S) -6-methoxy-a-methyl-2-naphtaleneacetic acid 6- (nitrooxymethyl)-2- methylpyridyl ester having formula:

trans-3- [4- [6-methoxy-a-methyl-2-naphtaleneacetyloxy]-3-methoxyphenyl]- 2- propenoic acid 4- (nitrooxy) butyl ester having formula: (XIII) (S, S)-N-acetyl-S- (6-methoxy-a-methyl-2-naphtaleneacetyl) cysteine 4- (nitrooxy) butyl ester having formula : (XIVC) 2- [ (2, 6-dichlorophenyl) amino] benzene acetic acid 6- (nitrooxymethyl)-2- methylpyridyl ester hydrochloride having formula: (XVf) trans-3- [4-a-methyl-4- (2-methylpropyl) benzoyl acetate]-3-methoxyphenyl]-2- propenoic acid 4- (nitrooxybutyl) ester having formula :

trans-3- [4-acetylbenzoyloxy]-3-methoxyphenyl]-2-propenoic acid 4- (nitrooxybutyl) ester having formula:

(XVIIII) (S) -6-methoxy-a-methyl-2-naphtaleneacetic acid-3-[4-(3-nitrooxypropyl)-1- piperazinyl] propyl ester dihydrochloride having formula :

(XIXC) 2-fluoro-a-methyl- [l, l'-biphenyl]-4-acetic acid-3- [4- (3-nitrooxypropyl)-1- piperazinyl] propyl ester dihydrochloride having formula:

(S)-3-enzoyl-a-methyl-benzeneacetic acid-3- [4- (3-nitrooxypropyl)-l- piperazinyl] propyl ester dihydrochloride having formula 2- [ (2, 6-dichlorophenyl) amino] benzeneacetic acid-3- [4- (3-nitrooxypropyl)-l- piperzinyl] propyl ester dihydrochloride having formula : 5-benzoyl-2, 3-dihydro-3H-pyrrole [ 1, 2-a] pyrrole-l-carboxylic acid-3- [4- (3- nitrooxypropyl)-1-piperazinyl] propyl ester dihydrochloride having formula: a-methyl-4- (2-methyl-propyl) benzeneacetic acid-3- [4- (3-nitrooxypropyl)-l- piperazinyl] propyl ester dihydrochloride having formula: (XXIVC) (S)-6-methoxy-a-methyl-2-naphtaleneacetic acid-3- [4- (3-nitroxypropyl)-l- piperidinyl] propyl ester hydrochloride having formula :

(S)-3-benzoyl-a-methyl-benzeneacetic acid-3- [4- (3-nitrooxypropyl)-l- piperidinyl] propyl ester hydrochloride having formula :

(XXVIC) 2- [ (2, 6-dichlorophenyl) amino] benzeneacetic acid-3- [4- (3-nitrooxypropyl)-l- piperidinyl] propyl ester hydrochloride having formula :

(XXVIIC) 5-benzoyl-2,3-dihydro-3H-pyrrole [1, 2-a] pyrrole-1-carboxylic acid-3- [4- (3- nitrooxypropyl)-1-piperidinyl] propyl ester hydrochloride having formula:

(XXVI) Surprisingly, the compounds of the invention can inhibit substantially selectively COX-2 without showing a marked inhibitory effect on COX-1. These results are even more surprising if it is considered the fact that the precursors are not selective COX-2 inhibitors. Moreover, even the same compounds of the invention but without the presence of the bivalent linker-B-of formula (III) have resulted non-selective towards the COX-2. See the comparative examples.

Furthermore, the compounds of the present invention do not present any side- effect at gastric, cardiovascular and renal levels, and at the same time they also show a good analgesic activity.

The compounds of the present invention can be used for the treatment of diseases having an inflammatory origin, osteoarthritis, rheumatoid arthritis, dysmenorrhea, pain, fever, and for the treatment and/or the prevention of troubles caused by high levels of COX-2.

The following examples have an illustrative purpose for the invention, and not a limitative one.

EXAMPLES EXAMPLE 1 Synthesis of (S)-6-methoxy-a-methyl-2-naphtaleneacetic acid, 3- [4- (3-nitrooxypropyl)- 1-piperazinyl]-propyl ester dihydrochloride (nIX) A) Synthesis of (S) -6-methoxy-a-methyl-2-naphtaleneacetic acid, 3-bromopropyl ester To a solution of 1,3-dibromopropane (2.42 ml) in DMF (50 ml) a suspension of naproxen sodium salt (2g, 7.93 mmoles) in DMF (50 ml) was added in small portions and the suspension was kept under stirring at room temperature for 24 hours. Then, water (200 ml) was added to the suspension, and the organic phase was extracted by ethyl ether (100 ml x 3). The reunited organic phases were anydrified and the solvent was evaporated at reduced pressure. The crude product of reaction was purified by

chromatography on silica gel eluting with hexan/ethyl acetate (9/1 v/v) to give 2. 15g of (S)-6-methoxy-a-methyl-2-naphtaleneacetic-3-bromopropyl ester.

B) Synthesis of (S)-6-methoxy-a-methyl-2-naphtaleneacetic acid-3- [4- (3-chloropropyl)- 1-piperazinyl] propyl ester To a solution of (S)-6-methoxy-a-methyl-2-naphtaleneacetic acid-3-bromopropyl ester (1.5 g, 4.3 mmoles) in THF (20 ml) at 40 °C, a solution of N- (3- chloropropyl) piperazine dihydrochloride (lg, 4.3 mmoles), synthesized as described in the example 1A hereinafter reported, in THF (25 ml), DMF (20 ml) and triethylamine (TEA) (2 ml) was added. The resulting solution was heated at 55 °C for 24 hours. Then the solution was cooled and extracted by ethyl ether; the reunited organic phases were washed with water, dried over Na2S04 and filtered. The solvent was evaporated at reduced pressure and the residue was purified by chromatography on silica gel eluting with ethyl acetate/TEA (10/0.4 v/v) to give 0.725 g of (S)-6-methoxy-a-methyl-2- naphtaleneacetic acid-3- [4- (3-chloropropyl)-l-piperazinyl] propyl ester.

'H NMR (CDC13) : 7.67 (3H, m); 7.39 (1H, dd); 7.11 (2H, m); 4.11 (2H, m); 3.9 (3H, s); 3.85 (1H, q); 3.56 (2H, t); 2.42-2. 21 (12H, m); 1.90 (2H, m); 1.70 (2H, m); 1.56 (3H, d).

C) Synthesis of (S)-6-methoxy-a-methyl-2-naphtaleneacetic acid-3- [4- (3- nitrooxypropyl)-1-piperazinyl] propyl ester To a solution of (S)-6-methoxy-a-methyl-2-naphtaleneacetic acid-3- [4- (3- chloropropyl)-1-piperazinyl] propyl ester (0.7 g, 1.6 mmoles) in acetonitrile (50 ml) AgN03 (0.545 g, 3.2 mmoles) was added and the solution was heated at 60 °C kept away from light for 24 hours. Salts were filtered, the solvent was evaporated, and the obtained crude product was purified by chromatography on silica gel eluting with ethyl acetate/TEA (10/0.4 v/v) to give (S)-6-methoxy-a-methyl-2-naphtaleneacetic acid- 3- [4- (3-nitroxypropyl)-l-piperazinyl] propyl ester (0.1 g).

'H NMR (CDC13) : 7.67 (3H, m); 7.39 (1H, dd); 7.11 (2H, m); 4.5 (2H, t); 4.11 (2H, m); 3.9 (3H, s); 3.85 (1H, q); 3.56 (2H, t); 2. 42- 2. 21 (12H, m); 1.90 (2H, m); 1.70 (2H, m); 1.56 (3H, d).

D) Synthesis of (S)-6-methoxy-a-methyl-2-naphthalenacetic acid-3- [4- (3- nitrooxypropyl)-1-piperazinyl] propyl ester dihydrochloride To a solution of (S)-methoxy-a-methyl-2-naphtaleneacetic acid-3- [4- (3- nitroxypropyl)-1-piperazinyl] propyl ester (0.1 g, 0.22 mmoles) in ethyl acetate cooled

in an ice bath, HCl/ethyl acetate (0.2 ml, 2.5 N) was dripped, after 1 hour the temperature of the suspension was left to return to room temperature. The solid product was filtered, washed with ethyl ether and dried up at reduced pressure.

EXAMPLE 1A Synthesis of N- (3-chloropropyl)-piperazine dihydrochloride To a solution of N-Boc-piperazine (2 g) in CH2Cl2 (40 ml) and TEA (1.8 ml), cooled at 0 °C, 3-chloro-1-bromopropane (1.3 ml) was added and the solution was heated at 50 °C for 3 hours. The solvent was evaporated at reduced pressure and the residue was dissolved in CH2C12 and washed with water. The organic phase was dried over Na2SO4 and filtered, the solvent evaporated at reduced pressure and the crude product was purified by chromatography on silica gel eluting with ethyl acetate/hexane (8/2 v/v) to obtain N'- (3-chloropropyl)-N-Boc-piperazine (1.7 g).

N'- (3-chloropropyl)-N-Boc-piperazine was dissolved in HCl/ethyl acetate (10 ml), the solution was cooled at 0 °C in an ice bath and stirred for 1 hour at 0 °C then it is left to return to room temperature. The solvent was eliminated and the residue was treated with diethyl ether and the obtained solid product was filtered and used without any further purification..

EXAMPLE Fl In vitro determination of COX-2 activity by WHMA (William Harvey Human- modified whole blood Assay) and of COX-1 activity by WBA (Whole Blood Assay) DETERMINATION OF COX-2 ACTIVITY Human bronchial epithelial A459 cells set in 96-well plates in the presence of the c ulture m edium D MEM (Dulbecco's m odified e agle's m edium), a dditivated w ith fetal bovine serum (10%) and L-glutamine (2 mM), were treated with interleukin-l for 24 hour in order to induce the expression of COX-2.

After 24 hours human blood (100 microlitres) and solutions (DMSO 0.1% v/v) of the compounds to be tested at 5 different concentrations, from 10-3 M to 10-9 M were added to the cells, and the control plates were treated with the carrier.

60 minutes after the adding of the compounds, the plates were treated with calcium ionophore A23187 (50 uM) and after 30 minutes with dichlophenac to inhibit the

enzyme COX-1 (1 mM). 15 minutes after, the cells were centrifuged and the plasma removed. The COX-2 activity of the tested compounds was determined as concentration of PGE2 present in the samples, determined by a radioimmunologic method (Amersham, Oakville, Ontario Canada). Results are reported in Table I and are expressed as the dose inhibiting 50% of COX activity (ICso).

DETERMINATION OF COX-1 ACTIVITY Aliquots (100-, tel) of venous human blood treated with heparin (19 U/ml) were transferred on a 96-well plates and treated with solutions (DMSO 0.1% v/v) of the tested compounds of concentrations from 10-3 M and 10-9 M. The control plates have been treated with the solvent (DMSO 0. 1% v/v).

60 minutes after the adding of the compounds the plates were treated with calcium ionophore A23187 (50 uM) and 30 minutes after, the plates were centrifuged (1500 Rpm, 4 °C, 5 minutes), the plasma removed and immediately frozen.

The COX-1 activity of the samples was determined as concentration of TXB2 by radioimmunologic method (Amersham, Oakville, Ontario Canada). Results, expressed as IC50s are reported, are reported in Table I.

The compounds used are the following: - Ibuprofen ; (S)-N-acetyl-S-a-methyl- [4- (2-methylpropylbenzene] acetyl) cysteine 4- nitrooxybutyl ester (NO-cys-ibuprofen), synthesized as described in WO 00/61537, example 2; - flurbiprofen ; <BR> <BR> <BR> <BR> - trans-3- [4- [2-fluoro-a-methyl- (1, 1')-biphenyl-4-acetyloxy]-3-methoxyphenyl]-2- propenoyl-4-nitrooxy) butyl ester (NO-fer-flurbiprofen), synthesized as described in WO 00/61537, example 6; - flurbiprofen 4-nitroxybutyl ester (NO-flurbiprofen), synthesized as described in WO 95/30641.

EXAMPLE F2 Evaluation of analgesic activity

The experiments were conducted as described by Moore et al. , J. Pharmacol.

1991,102, 198-202.

Rats weighing 20 g, were treated i. p. with acetic acid (2% w/v in saline solution pH 2.7, 10 ml/kg) and after 15 minutes the animals were treated p. o. with the tested compounds at doses as indicated in Table 2 or with the carrier (carboxymethylcellulose 0.5 % w/v; 10 ml/kg) and immediately set in single cages where the number of abdominal contractions were calculated for 30 minutes. The results reported in Table are expressed as inhibition percentage of the abdominal contractions induced by acetic acid in comparison with non-treated controls.

EXAMPLE F3 Evaluation of gastric and vascular damage The e xperiments w ere c arried o ut as d escribed i n M. N. M uscara e t a l., Br. J.

Pharmacol. 133,1314, 2001.

Rats weighing 200-250g, divided in groups of 10 animals each, were treated p. o. with the tested compounds indicated in F1 (suspended in carboxymethylcellulose 1%) at the daily doses reported in Table 3, for two weeks.

In these rats arterial hypertension was induced by adding L-NAME (N-omega-nitro-L- arginine methyl ester) in drinking water, at a concentration of 400 mg/l.

Sixteen hours after the last administration, hematic pressure was determined by cannulating femoral artery, and measured by polygraphic transductor. Later, rats were sacrificed and the gastric damage was noticed, determining the percentage of animals that presented gastric damage.

The results reported in Table 3 show that the products of the invention are well tolerated at gastric level, while celecoxib, the COX-2 inhibitor taken as reference drug, and the precursor drugs provoke gastric damage on a percentage between 80 and 100% in the animals.

Celecoxib and precursor drugs cause an elevation of pressure, while the drugs of the present invention do not influence the cardiovascular parameters.

Table 1 Evaluation of COX-1 and COX-2 activities of the compounds of the present invention, in comparison with Celecoxib, a COX-2 inhibitor, with the precursor anti-inflammatory compounds and with the corresponding nitroxyderivatives according to WO 95/30641. Compound COX-I COX-2 COX-I/COX-2 IC50 (M) ICso (M) Ratio ICso Celecoxib (cf.) 1.2 0.34 3.3 Ibuprofen (cf.) 7. 6 10-6 1. 95 10-5 0. 4 NO-cys-ibuprofen 9. 23 10-5 7.7 10-8 1198. 7 Flurbiprofen (cf.) 7. 54 10-8 1. 14 10-6 0 07 NO-fer-flurbiprofen 1. 06 10-5 3.6 10-8 294. 4 NO-flurbiprofen (cf.) 5. 25 10-7 5 10-7 1.05 Table 2 Evaluation of the analgesic activity of the compounds of the present invention in comparison with the precursor anti-inflammatory drugs and with the correspondent nitroxyderivatives according to WO 95/30641 Compound Dose % of inhibition of (mglkg) abdominal contractions Vs. controls Celecoxib (cf.) 10 0 Ibuprofen (cf.) 30 32 NO-cys-ibuprofen 60 85 Flurbiprofen (cf.) 3 25 NO-fer-flurbiprofen 20 72 NO-flurbiprofen (cf.) 20 63 Table 3 Determination of gastric damage and of cardiovascular parameters of the compounds of the present invention, in comparison with Celecoxib, with the precursor anti-inflammatory compounds and with the correspondent nitroxyderivatives according to WO 95/30641 Compound Dose % animals with Arterialpressare (mglkg) gastric damage (mmHg) Carrier-50 140 Celecoxib (cf.) 10 80 170 Ibuprofen (cf.) 30 100 160 NO-cys-ibuprofen 60 0 138 Flurbiprofen (cf.) 3 100 167 NO-fer-flurbiprofen 20 0 135 NO-flurbiprofen (cf. ) 20 30 150