NITROXYDERIVATIVES HAVING ANTIINFLAMMATORY, ANALGESIC AND ANTITHROMBOTIC ACTIVITY

Abstract: Organic or inorganic salts of compounds of general formula: A - X1 - N(O)z for use as medicaments having anti-inflammatory, analgesic and antithrombotic activity, wherein A is R(COXu)t wherein t is 0 or 1; u is 0 or 1 and X is O, NH, NR1c wherein R1c us a C1-C10 alkyl and R is, for example, (Ia) wherein R1 is acetoxy, preferably in ortho position with respect to -CO- and R2 is hydrogen or acetylsalicylsalicylic acid derivatives; and X1 is the formula (B), Y being a ring containing at least one salified nitrogen atom.

Description: NITROXYDERIVATIVES HAVING ANTIINFLAMMATORY. ANALGESIC AND ANTITHROMBOTIC ACΗVITY * * * * * * The present invention relates to new products having anti -inflammatory, analgesic and antithrombotic activity. Specifically it relates to cyclo-oxygenase (COX) inhibitors . It is known that the anti -inflammatory and antithrombotic efficacy of NSAIDs (Non steroid antiinflammatory drugs) , also known as FANS (non steroid antiinflammatory drugs) , but especially their tolerability, seem to be considerably affected by their inhibitory activity of the cyclo-oxygenase (COX) both in the inflammatory site and in the healthy tissue. See for example FASE3 Journal 1, 89, 1987; Bioch. Biophys . Acta 1083, 1, 1991. The drawback of these products is that they are toxic, as already described in USP 5,861,426. Nitroderivative compounds, described in said patent, are also known, have an high efficacy in the cyclooxygenase inhibition and a low toxicity. However these compounds show some drawbacks connected to the chemical-physical and structural characteristics of the molecules themselves, these latter being highly lipophilic and therefore having a poor solubility in water. It is well known that the solubilization process is decisive for absorption and interaction with the effector. The poor solubility generally involves a variable and unpredictable efficacy whereby it is difficult to set a correct posology. In practice it is necessary to administer higher doses in order to contain the above mentioned variabilities. The drawback is the risks of a higher incidence of side effects. Another disadvantage bound to the poor solubility of the nitroderivatives of said patent application is that they are difficult to be formulated. It is well known that the solubility in water of a molecule is one of the most important properties affecting the pharmacokinetic and pharmacodynamic processes. For example for parenteral administration, particularly by intravenous route, drugs must be formulated in solutions. In order to increase solubility, when it is unsatisfactory for these uses, the choice of suitable solvents and/or excipients is therefore critical, for example, among the latter, surfactants, etc., can be mentioned. This can lead to drawbacks from the toxicological point of view connected to the excipient tolerability,- besides there are other drawbacks for example in the intravenous formulation which, as well known, must not cause haemolysis or incompatibility with blood constituents. Besides it is necessary to notice that it is well known that surfactants and apolar solvents can be irritant. See for example J. Pharm. Science 72, 1014, 1983. Experiments carried out by the Applicant, wherein 0.1% Tween 80 and 1% dimethylsulphoxide have been used to suspend the nitroxy derivatives of the antiinflammatory compounds described in the patent application WO 95/30641 have shown that these substances were irritant towards the gastric mucous membrane . It has unexpectedly been found that the derivatives of the present invention, differently from the above mentioned compounds of the prior art, can be solubilized without using the substances commonly used in the pharmaceutical technique to obtain solutions or suspensions, maintaining or even improving the activity of the prior art nitroxy derivatives. A further advantage of the compounds of the present invention is that it is possible to avoid adding to the formulation the excipients, such as for example those above mentioned, which cause or can induce irritant effects. The antiinflammatory products described in the present application have an high cyclo-oxygenase inhibiting activity combined with low toxicity and pharmacokinetic good responses, and have furthermore a better systemic absorption degree. This is quite surprising and unexpected since the factors affecting the FANS antiinflammatory and antithrombotic efficacy depend on various parameters whereby it is not possible to foresee a priori the pharmacokinetics, for example the absorbed product fraction, the pharmacodynamic activity, the toxicity and the COX inhibiting properties and most of all, no assumptions can be made to predict or limit the response variability. An object of the present invention are compounds or organic or inorganic salts of compounds of general formula: A - X L - N(0) z for use as medicaments, specifically as antiinflammatory and antithrombotic agents, wherein: z is an integer and is l or 2, preferably 2; A = R(COX u ) t and wherein t is an integer 0 or 1; u is 0 or 1 ,- X = 0, NH, NR lc wherein R lc is a linear or branched C^C^ alkyl ; wherein: nIX is an integer between 0 and 3 , preferably 1 ; nllX is an integer between l and 3, preferably l; R-Tix/ E-Tix- R TH R TIIX < / equal to or dif ferent from each other , are H or linear or branched C x -C 4 alkyl ; preferably R-. IX , R τIx . , Y is a ring containing at least one salifiable nitrogen atom; preferably Y is an heterocyclic ring, saturated or unsaturated or aromatic, having preferably 5 or 6 atoms and containing at least one or two nitrogen atoms, preferably one or two nitrogen atoms,- R is selected from the following groups Grouo I) wherein t = 1 and u = l lb) IC) ■ c.) IC.) IC,) wherein : R λ is the OCOR 3 group; wherein R 3 is methyl, ethyl or linear or branched C 3 -C 3 alkyl, or the residue of a heterocycle with a single ring having 5 or 6 atoms which may be aromatic, partially or totally hydrogenated, containing one or more hetero-atoms independently selected from 0, N and S; R 2 is hydrogen, hydroxy, halogen, a linear or when possible branched Ci-C 4 alkyl, a linear or when possible branched Ci-C 4 alkoxyl; a linear or when possible branched C 1 -C 4 perfluoroalkyl, for example trifluoromethyl; nitro, amino, mono- or di- (C-- 4 ) alkylamino; nl is an integer 0 or 1; preferably in the compounds of formula la) X is equal to 0 or NH, R. is acetoxy, preferably in ortho position with respect to -CO-, R 2 is hydrogen; in X x R- lx = R TIX ,= R τIIX = R mx - = H ' n ι x = n nx = 1 and Y is an aromatic ring having 6 atoms, containing one nitrogen atom, said aromatic ring having the two free valences in position 2 and 6. Preferably in the compounds of formula lb) R 3 = CH 3 , nl = 0, X is equal to 0, X x is as above defined for la) ; in this case lb) is the residue of the acetylsalicylsalicylic acid. The compounds Ic) of formula Ic are the 5-amino salicylic acid derivatives (5-amino-2-hydroxybenzoic acid) , for example mesalamine, when the valence is saturated with -COOH. In the compounds of formula lc 2 ) at least one of the two carboxyl groups is reacted for obtaining the invention compounds. When both carboxyl groups react, bifunctional compounds are obtained. When the two valences are saturated with -COOH, the compound known as olsalazine is obtained. When one of the two valences instead of -COOH is saturated with -CONHCH 2 -CH 2 -COOH, the compound is known as balsalazide, wherein -OH which is in ortho position in the same aromatic ring is substituted with H. The compounds of formula IC 3 ) are known as sulphalazine: 2-hydroxy-5- [ (2-pyridinylamino) sulphonyl] phenyl] azo] benzoic acid when the free valence is saturated with -COOH. The preferred Ic) compounds have X = 0 and u = 1 ; Group II) wherein t = l, u = 1 lib) wherein : R IIS is H, a linear or branched when possible C 1 -C 3 alkyl ; R II6 has the same meaning as R IIB , or when R IIS is H it may be benzyl ; R i n R ι i 2 an< i m can independently be hydrogen, a linear or when possible branched alkyl or a linear or when possible branched C x -C 6 alkoxy, or Cl, F, Br ; R II4 is R IX1 or bromine; the compounds wherein R ιτι , R II4 are hydrogen and R II2 and R II3 are chlorine in ortho position with respect to NH are preferred; R II5 and R II6 are H, X is equal to O, and X x is as above defined for the compounds of formula la) ; lib) is the residue of the 2- [ (2-methyl-3- (trifluoro- methyl) henyl] amino] -3-pyridincarboxylic] acid and when the -COOH group is present the compound is known as flunixin; Group III) wherein t = 1, u = 1 and R is wherein : R 2a and R 3a are H, a linear or when possible branched, substituted or non-substituted, C x -C 12 alkyl or allyl, with the proviso that when one of the two is allyl, the other is H; preferably R 2a is H, C^C, alkyl, R 3a is H; R la is selected from (U) iW) (XXXV) (vi: (VII) (VIII) (IX) (X) (Ill) HID) R-ι a corresponds to the following formulas: (II: (XXX) (XX I ) (xxxir; ( XXIIX) (XXiVL) ( U) wherein the meanings are the following: when R la is as defined in formula (IV), Ketoprofen residue: R IIX1 is H, SR III3 wherein R III3 contains from 1 to 4 C atoms, linear or branched when possible,- R III2 is H, hydroxy; preferred are the compounds wherein R XII1 and R III2 are H, R 3a is H, and R 2a is methyl, X = 0; when R la is as defined in formula (XXI) , carprofen residue: R- ^ i o is H, a linear or when possible branched alkyl having from 1 to 6 C atoms, a Ci-Cg alkoxycarbonyl bound to a alkyl, C x -C 6 carboxyalkyl , Ci-Cg alkanoyl, optionally substituted with halogens, benzyl or halobenzyl, benzoyl or halobenzoyl; is H, halogen, hydroxy, CN, alkyl optionally containing OH groups, alkoxy, acetyl, benzyloxy, alkyl; -C-, perfluoroalkyl ; - C 6 carboxyalkyl optionally containing OH groups, N0 2 , amino ,- sulphamoyl, di -alkyl sulphamoyl with alkyl, or difluoroalkylsulphonyl with -C 3 alkyl; alkyl containing one or more OH groups, C : -C 6 alkoxy, acetyl, acetamido, benzyloxy, SR :::3 being R..- 3 as above defined, perfluoroalkyl, hydroxy, C-C 6 carboxyalkyl, N0 2 , amino, mono- or di-alkyl -amino C.-C 6 ; sulphamoyl, di-alkyl sulphamoyl or di-fluoroalkyklsulphamoyl as above defined; or R^ together with alkylene dioxy; preferred are the compounds wherein R ^io is H, the linking bridge is in position 2, R^ is H, R ^ ^ is chlorine and is in para position with respect to nitrogen; R 3a is H, R 2a is methyl and X is 0; when R la is as defined in the formula (XXXV) , residue of the tiaprofenic acid: Ar is phenyl, hydroxyphenyl optionally mono- or poly-substituted with halogen, alkanoyl and alkoxy, Cj-Cg trialkyl, preferably cyclopentyl, cyclohexyl cy- cloheptyl, heteroaryl, preferably thienyl, furyl optionally containing OH, pyridyl; the preferred compounds of (XXXV) are those wherein Ar is phenyl, R 3a is H, R 2a is methyl and X is 0; when R la is as defined in formula (II) , suprofen residue, of which the preferred one has been shown, wherein R 3a is H, R 2a is methyl and X = 0, as described and obtained in USP 4,035,376 herein incorporated by reference; when R la is as defined in formula (VI) , R is the residue of indoprofen when R 2a = H and R 3a = CH 3 ; of indobufen when R 2a is equal to H and R 3a = C 2 H 5/ - X = 0, as described and obtained according to USP 3,997,669 herein incorporated by reference,- when R la is as defined in formula (VIII) , R is the residue of etodolac when R 2a = R 3a = H and X = 0, as described in and obtained according to USP 3,843,681 herein incorporated by reference; when R la is as defined in formula (VII) , R is the residue of fenoprofen when R 3a = H, R 2a = CH 3 and X = 0, as described in and obtained according to USP 3,600,437 herein incorporated by reference,- when R la is as defined in formula (III) , R is the residue of fenbufen when R 2a = R 3a = H and X = 0, as described in and obtained according to USP 3,784,701 herein incorporated by reference; when R la is as defined in formula (IX) , R is the residue of flurbiprofen when R 3a = H, R 2a = CH 37 X = O; when R la is as defined in formula (X) R is the residue of tolmetin when R 2a = R 3a = H, X = 0, as described in and obtained according to FR 1,574,570 herein incorporated by reference . group HID) R la corresponds to the following formulas: - Ilia) , when R 2a = H and R 3a = CH 3 the residue of pranopro- fen is obtained: o.-methyl-5H- [l] benzopyrano- [2 , 3-b] pyri- din-7-acetic acid; in the preferred compound R 2a = H, R 3a = CH 3 , u = l and X = 0: (XXX) , when R 2a = H and R 3a = CH 3 the bermoprofen residue is obtained: dibenz [b, f] oxepin-2-acetic acid; in the preferred compound R 2a = H, R 3a = CH 3 , u = 1 and X = 0. (XXXI) , when R 2a = H and R 3a = CH 3 , R is the radical of the compound CS-670: 2- [4- (2-oxo-l-cyclohexylidene methyl) phenyl] propionic acid; the preferred compound has R 2a = H, R 3 a = CH 3 , u = 1 and X = O; (XXXII) , when R 2a = R 3a = H the Pemedolac residue is obtained; the preferred compound has R 2a = R 3a = H, u = 1 and X = 0; (XXXIII) , when R 2a = R 3a = H the pirazolac residue is obtained: derivatives of the 4- (4-chlorophenyl) -l- (4- fluorophenyl) -3-ρyrazolic acid; the preferred compounds have R 2a = R 3a = H, u = 1 and X = O. (XXXVI) , when R 2a = H, R 3a = CH 3 , the zaltoprofen residue is obtained; when the residue is saturated with an hydr- oxyl or aminic group, or with the carboxylic function the compounds are known as dibenzothiepin derivatives,- in the preferred compounds R 2a = H, R 3a = CH 3 , u = 1 and X = O. (XXXVII), when R 2a = R 3a = H the mofezolac residue is obtained: 3 , 4-di (p-methoxyphenyl) isoxazol -5 -acetic acid when the residue is CH 2 -COOH; in the preferred compounds R 2a = R 3a = H, t = 1 and X = 0; (XII), when R 2a = R 3a = H the bromfenac residue is obtained: 2-amino-3 - (4-bromobenzoyl) benzeneacetic acid,- the preferred compounds have u = l, t = 1, X = 0, R 2a = R 3a = H; or t = 0; In the group IV) wherein t = 1 , u = l, R is R IVd R IV - C - R IVdl wherein : R ιvd and R ιvdl are at least one H and the other a linear or branched when possible alkyl from C x to C 6 , preferably and C 2 , or difluoroalkyl with the alkyl having from 1 to 6 C atoms, C j _ is preferred, or R ιvd and R ιvdl form together a methylene group; R IV has the following meaning: ( ID (X) (HI) wherein the compounds of group IV) have the following meanings: in formula (II) H is C--C 6 alkyl, C 3 -C 7 cycloalkyl, C^C-, alkoxymethyl, C^C, trifluoroalkyl, vinyl, ethynyl, halogen, alkyl, C^C, alkoxymethyloxy, alkylthiomethyloxy with the Ci-C, alkyl, alkyl methylthio with the C^C, alkyl, cyano, difluoromethylthio, phenyl- or phenylalkyl substituted with the Ci-Cβ alkyl; preferably R iv- ii is CH 3 0-, R ιvd is H and R ιvdl is CH 3 , and is known as naproxen residue,- X = O and X 1 is as above defined for la) ; in formula (X) , of which the loxoprofen residue has been shown, described in USP 4,161,538 herein incorporated by reference, the compounds are preferred wherein R ιvd is H and R ιvdl is CH 3 , X = 0 and x is as above defined for la) ; in formula (III) : R ιv-ιι. is a C 2 -C 5 alkyl, optionally branched when possi - bile, C 2 and C 3 alkyloxy, allyloxy, phenoxy, phenylthio, cycloalkyl from 5 to 7 C atoms, optionally substituted in position l with a C^C j alkyl; the compound in which R lV-111 is CH 3 \ CH-CH 2 - / CH, and R ιvd = H, R Ivdl is CH 3 , is preferred, a compound known as ibuprofen residue,- X = 0 and X x is as above defined for la) ,- Group V) (IX) (IV) (V) (III) (II) Group VΞ) (X) (XI) (en) * Ϊ"Y * ( XX I) In group V), the compounds have the following meanings: when R is the formula (II) , R Vll is H or a linear or branched when possible C 1 -C 4 alkyl ; vn -i s R Vll , or a linear or branched when possible Cj-C 4 alkoxy,- Cl , F, Br,- the position of R Vll-ι being ortho, or meta, or para; the residue of the known Ketorolac is preferred, wherein R Vll and R Vll .__ are H, and A = R (A being the group of the formula A-X 1 -N0 2 ) and t = 0 ; when R is the formula (V) , of which the residue of the known tenidap has been mentioned, as described and obtained in USP 4,556,672 herein incorporated by reference,- in these compounds of formula (V) A = R and t = 0, when R is the formula (VII) , of which the residue of the known tenoxicam has been mentioned, A is RCO, t = l u = 0 or A is R and t = 0, as described and obtained in DE 2,537,070 herein incorporated by reference; when R is the formula (IX) , wherein A = R and t = 0, or A = RCO with t = 1 and u = 0, the residue of the known piroxicam has been indicated, as described and obtained in USP 3,591,584 herein incorporated by reference,- when R is the formula (III) wherein A = RCOO, t = 1 and u = 0 or 1 ; or t =0 and A= R, of which the residue of the known nabumetone has been indicated, as described and obtained in USP 4,061,779 herein incorporated by reference,- when R is the formula (IV) wherein A = RCOO, t = 1 and u = l, of which the indomethacin residue has been indicated, as described and obtained in USP 3,161,654 herein incorporated by reference; when R is the formula (X) , the residue X is known as meloxi- cam,- the preferred compounds are those wherein A = RCO, t = 1 and u = 0 ; when R is the formula (XI) the residue is known as ampiroxicam when the end group is -CH (CH 3 ) OCOC 2 H s ; the preferred compounds have A = RCO, t = l and u = 0 ,- when R is the formula (XIII) and the valence is saturated with H the residue derives from lornoxicam,- the preferred compounds have A = RCO, t = 1 and u = 0 ,- when R is the formula (XXXX) and the valence is saturated with H the compound known as paracetamol is obtained, as described and obtained in USP 2,998,450 herein incorporated by reference ; when R is the formula (XXXXI) and the valence is saturated with H the compound known as Tramadol is obtained, as described and obtained in USP 3,652,589; the preferred compounds according to the present invention obtainable with the radicals corresponding to the formulas (XXXX) and (XXXXI) have A= RCO, t = 1 and u = 0. Y in the above mentioned X λ formula contains one or two nitrogen atoms in the ring, and preferably selected from the following : (Y9) (Y10 ) (Yn ) ( YX2) (Y13) (ϊi4) ( Y15) The preferred of Y is Y12 (pyridyl) substituted in position 2 and 6. The bonds can be also in non symmetric position, for example Y12 (pyridyl) can be substituted also in position 2 and 3; Yl (pyrazol) may be 3 , 5-disubstituted. The X : precursors, wherein the oxygen free valence is saturated with H and the free valence of the end carbon is saturated either with a carboxylic or hydroxyl group, are commercially available products or are obtainable with methods known in the prior art . The compounds containing R of group I) of the type la) are described in the patent WO 92/01668 wherein the preparation methods are also described. This patent is herein incorporated by reference. The type lb) compounds are for example prepared by using the method shown in The Merck Index, XI ed., 1989, pag. 16, No. 95 for the residue of the acetyl - εalicylsalicylic acid. The changes of the compounds of formula lb) may be obtained by applying the processes mentioned in the patent WO 92/01668. Compounds Ic) of the Ic class, in which the radical is a 5-amino salicylic acid derivative (5-amino-2-hydroxybenzoic acid) known as mesalamine, when the starting radical contains -COOH, are prepared by reduction of the m-nitrobenzoic acid with * Zn powder and HC1 (see H. Weil et al . , Ber. 55B, 2664 (1922)), or by electrolytic reduction: Le Guyader, Peltier, Compt. Rend. 253, 2544 (1961). These publications are herein incorporated by reference. The starting radical Ic 2 ) , when it contains -COOH, is known as olsalazine: 3 , 3 ' -azabis (6 -hydroxybenzoic) acid; and it is prepared according to EP 36,636 or USP 4,528,367, both herein incorporated by reference. The Ic 3 ) compounds are prepared according to USP 2,396,145 herein incorporated by reference. Equivalent compounds to Ic , Ic 2 ) and Ic 3 ) contain the substituents mentioned in the above references. The compounds wherein R is of the group II) are described in the patents WO 94/04484 and USP 3,558,690 wherein the preparation methods are also described. These patents are herein incorporated by reference. The starting compound of lib) , when the valence is saturated with -COOH (flunixin) , is obtained according to USP 3,337,570 and USP 3,689,653, both herein incorporated by reference. The compounds containing the substituents mentioned in the previous patents are equivalent to flunixin. The compounds wherein R is of group III) are described and obtained with the processes mentioned in the following patents : patent application PCT/EP/93 03193; for the compounds of formula (IV) see also USP 3,641,127; for the compounds of formula (XXI) see also USP 3,896,145; for the compounds of formula (IX) residue of flurbiprofen see also USP 3,755,427; for the compounds of formula (II) see also USP 4,035,376; for the compounds of formula (VI) see also USP 3,997,669; for the compounds of formula (VIII) see also USP 3,843,681; for the compounds of formula (VII) see also USP 3,600,437; for the compounds of formula (III) see also USP 3,784,701. All the above mentioned patents are herein incorporated by reference . The processes for preparing the compounds of class HID) are the following: The residue Ilia) is obtained by preparing the acid compound according to USP 3,931,205, the valence is saturated with -CH (CH-J -COOH. The compounds containing the substituents mentioned in the above patent are equivalent to pranoprofen. The residue (XXX) is prepared through the compound with the -CH (CH 3 ) -COOH group (bermoprofen) according to USP 4,238,620 herein incorporated by reference. Other equivalent products are described in the above mentioned patent . The residue (XXXI) is prepared starting from the corresponding -CH(CH 3 ) -COOH acid according to USP 4,254,274. Equivalent compounds are described in the same patent . The residue (XXXII) is prepared according to EP 238,226 herein incorporated by reference, when the valence is saturated with -CH 2 -COOH. Equivalent products are reported in said patents as substituted 1, 3,4, tetrahydropyrane [3,4-b] indol- l-acetic acids. The residue (XXXHI) is prepared from pirazolac and the valence is saturated with -CH 2 -COOH, as mentioned in EP 54,812 herein incorporated by reference. Equivalent products are described in said patent. The residue (XXXVI) is prepared according to UK 2,035,311 herein incorporated by reference, starting from zaltoprofen and having the -CH(CH 3 ) -COOH end group. Equivalent products are described in said patent. The preparation process of the residue (XXXVII) is obtained starting from mofezolac and is prepared according to EP 26,928. Equivalents products are reported in the same patent. The compounds in which R is of the group IV) are described in the British patent application 2,283,238, wherein also the preparation methods are indicated; this patent is herein incorporated by reference. In the group IV) the compounds can also be obtained: for the compounds of formula (II) using USP 3,904,682; the compounds of formula (X) according to USP 4,161,538, the compounds of formula (III) according to USP 3,228,831. These patents herein mentioned are here incorporated by reference. In the group V) the compounds can also be obtained: for the compounds of formula (II) using USP 4,089,969 herein incorporated by reference,- the compounds of formula (V) can be obtained according to USP 4,556,672 herein incorporated by reference. The residue (X) is prepared according to the German patent 2,756,113. Equivalent products are described in said patent . The residue (XI) is prepared according to EP 147,177, herein incorporated by reference, starting from ampiroxicam having the -CH (CH 3 ) OCOOC 2 H 5 end group. Equivalent products are described in said patent. The residue (XII) is prepared according to J. Med. Chem., vol. 27 n. 11, Nov. 1984, Walsh et Al . "Antiinflammatory Agents. 3. Synthesis and Pharmacological Evaluation of 2-ami- no-3-benzoylphenylacetic Acid and Analogues", herein incorporated by reference. Equivalent products are described in said publication. The residue (XIII) is prepared starting from lornoxicam, wherein the valence is saturated with H. It is prepared according to GB 2,003,877. Equivalent products are described in said paten . Generally the connection between A and X. is, as seen, of ester or amidic type (NH or NR 1C , as defined in X) when R is of groups I, II, HI, IV and V. All well known synthesis routes for forming such bonds may be used to form said connection. In the case of esters of groups I, II, HI and IV, and for the compounds of group V ending with a carboxylic function, the most direct synthetic route to obtain the corresponding nitroxyderivatives of the present invention involves : a) reaction of the acyl chlorides R-CO-C1 with halogen alcohols of the H0-X 1Z -C1, HO-X lz -Br, H0-X 1Z -I type, wherein X 1Z is X x as above defined without the oxygen atom, in the experimental conditions of the prior art, and isolation of compounds of formula R-CO-0-X lz -Cl (Br, I) . The above products can also be obtained by reaction of the sodium or potassium salts of said R-CO-OH acids with dihalogen derivatives of general formula X 1Z C1 2 , X lz Br 2 or b) The above products are transformed into the final products by reaction with AgN0 3 in acetonitrile, according to what known in the prior art . The general schemes are the following: R-CO-Cl+HO-X lz -Br * R-C0-0-X lz -Br + AgN0 3 > A-X 1 N0 2 wherein X x = X 12 0. R-CO-ONa + Br 2 X lz * . R-CO-0-X lz -Br + AgN0 3 > A-X 1 N0 2 wherein X x = X 1Z 0. In the case of amides the synthetic sequence involves the reaction of the same acyl chlorides RCOCl with aminoalcohols of general formula NH 2 -X 1Z -0H, NHR 1C -X 1Z -0H to give amides of general formula : R-CO-NH-X lz -OH and R-CO-NR lc -X lz -OH according to known methods . The reaction of said amides with halogenating agents such as for example PC1 5 , PBr 3 , S0C1 2 etc. leads to halogen derivatives of general formula: R-C0-NH-χ. z -Br (CD and R-C0-NR 1C -X. z -Br (CD . The latter by reaction with AgN0 3 in acetonitrile, according to known methods in the prior art, lead to the final products A-X.-N0 2 . The synthesis scheme is the following: PC1 5 R-C0-C1 + NHR 1C -X 12 -0H * R-CO-NR :c -X lz -OH » R-C0-NR 1C -X 1Z -C1 + AgN0 3 * R-C0-NR 1C -X 1Z -0N0 2 wherein X 1Z 0 is X : _ c) An alternative route to the synthesis through steps a) and b) above is the reaction of the acid sodium or potassium salts with the nitric esters of halogeno- alcohols of general formula: N0 2 -0-X lz -Cl(Br,I) to give directly the nitroxy derivatives of the invention. The reaction scheme is the following: R-CO-ONa + Br-X lz -ON0 2 » R-CO-0-X lz -ON0 2 wherein X 1Z 0 is X . Synthetic routes similar to those above described are used for the products of group v, for example tenoxicam and piroxicam, wherein a dihalogen derivative of formula Br 2 X lz is reacted with the corresponding enolates . The products obtained are then transformed into the compounds of the invention by reaction with AgN0 3 in acetonitrile according to the above reported reaction scheme. The scheme is herein reported for the piroxicam of formula IX of group V. Group V products, such as tenoxicam and piroxicam, wherein the antiinflammatory reactive function is an hydroxyl, can be also reacted with an acyl chloride of formula C1C0-X 1Z -Q X wherein Q r is Cl, Br, I, OH. When Q τ = OH, the hydroxyl is substituted with an halogen as above described before the final nitration reaction with AgN0 3 . Nitration is carried out as above described. In order to obtain the compounds of formula A-X-^NO, acyl chlorides of formula R-COC1 are reacted with HX-X 1Z -0H, wherein R, X and X 1Z have the above mentioned meanings, in the experimental conditions described in the prior art. The obtained alcohols are reacted with sodium nitrite in a solvent, for instance constituted of a mixture of water with tetrahydrofuran in the presence of hydrochloric acid. The reaction is described in the prior art. The general scheme is the following: R-COC1 + HX-X lz -OH --→ R-C0-X-X 1Z -0H + NaN0 2 --→ A-X- . -N0 The compounds according to the present invention are transformed into the corresponding salts by reaction in organic solvent such as for example acetonitrile and tetrahydrofuran with an equimolecular amount of the corresponding organic or inorganic acid. Examples of suitable organic acids are: oxalic, tartaric, maleic, succinic, citric acid. Examples of suitable inorganic acids are: nitric, hydrochloric, sulphuric, phosphoric acid. Another object of the invention is that it has surprisingly been found that the invention products containing 0N- (0) z groups are able to exert also an inhibiting effect of the inflammation induced by liposaccharide (LPS) and therefore are usable in septic shock. This is surprising, since it is well known that generally antiinflammatories do not meaningfully change the nitrosynthetase activity induced by lipopolysaccharides in the rat and therefore they cannot be used in septic shock. The compounds of the present invention can be used as antiinflammatory drugs or for the therapy and prophylaxis of cardiovascular diseases and of those pathologies wherein cellular hyperproliferation plays an important pathogenetic role. It must be understood that when the compounds of the various groups contain at least one asymmetric carbon, the products can be used in racemic form or as single isomers. It is indeed well known that in the therapeutic uses of the invention generally an isomeric form is more active than the others. When the compounds present cis/trans isomers, they can be used in this separated form or in admixture. The pharmaceutical formulations of the compounds according to the present invention contain the same dose of the antiinflammatory precursor products, or lower. The pharmaceutical formulations can be given by os or parenterally and can be prepared according to well known processes in the prior art. See the volume "Remington's Pharmaceutical Sciences". The following Examples are given for illustrative purposes but are not limitative of the present invention. EXAMPLE 1 Synthesis of 2-acetylbenzoic acid 6- (nitroxymethyl) -2-pyri- dinylmethyl ester chlorhvdrate (NCX 4050) of formula: s tart ing f rom the acetylsal icyl ic acid ( f ormula F1A) and 2 , 6 bi s - ( hydroxymethyl ) pyridine ( f ormula FIB ) ( F1A) ( FIB; A) -Synthesis of 2 , 6 -bis- (chloromethyl) pyridine To thionyl chloride (11.6 ml, 158 mmoles), cooled at 0°C, 2, 6 -bis- (hydroxymethyl) pyridine (4 g, 28 mmoles) is very slowly added. The obtained solution is left under stirring for 2 hours at room temperature, then the thionyl chloride in excess is evaporated at reduced pressure. The obtained residue is treated with chloroform and evaporated again at reduced pressure to eliminate the thionyl chloride residues. The crude product is treated with chloroform and washed with water. The organic phase is anhydrified with sodium sulphate and dried obtaining 4.81 g of the product as white solid having m.p. = 76°-78°C. B) -Synthesis of 2-acetylbenzoic acid 6- (chloromethyl) -2 -me- thylpyridinyl ester To a solution of salicylic acid (1.6g, 8.88 mmoles) in N,N' -dimethylformamide (20 ml) and under stirring sodium et- hylate (0.64 g, 8.88 mmoles) is added. After 30 minutes the obtained solution is added to a solution of 2 , 6-bis- (chloromethyl) pyridine (4.72 g, 26.81 mmoles) in N, N' -dimethylforma- mide (20 ml) . The solution is left at room temperature for 7 days, under stirring, then is diluted with ethyl ether and washed with water. The separated organic phases are anhydrified with sodium sulphate and the solvent is evaporated at reduced pressure. The reaction crude product is purified by chromatography on silica gel by eluting with n-hexane/ethyl acetate 7/3. 1.7 g of the product as yellow oil are obtained. - MR (200MHz) (CDC1 3 ) : 8.10(lH,d); 7.74 (lH,t); 7.57(lH,t); 7.42(lH,d); 7.33(2H,m); 7.11(lH,d); 5.42(2H,s); 4.67(2H,s); 2.41 (3H, S) . C) -Synthesis of 2 -acetylbenzoic acid 6- (nitroxymethyP -2- me- thylpyridinyl ester To a solution of 2-acetylbenzoic acid 6- (chloromethyl) -2- methylpyridinyl ester (1.5 g, 4.7 mmoles) in acetonitrile (20 ml) maintained under stirring, silver nitrate is added (1.3 g, 7.65 mmoles). The solution is heated to 80°C, maintaining it sheltered from light, under stirring for 30 hours. The formed silver chloride is filtered, the solvent is evaporated. The reaction crude product is purified by silica gel chromatography by eluting with n-hexane/ethyl acetate 7/3. 1.2 g of product as yellow oil are obtained. 'H-NMR (200MHz) (CDC1 3 ) : 8.10(lH,d); 7.74(lH,t); 7.57(lH,t); 7.42(lH,d); 7.33(2H,m); 7.11 (1H, d) ; 5.60(2H,s); 5.42(2H,s); 2 . 41 ( 3 H , s ) . D) -Synthesis of 2-acetylbenzoic acid 6 - (nitroxymethyl) -2- methylpyridmyl ester hydrochloride To a solution of 2-acetylbenzoic acid 6- (nitroxymethyl) - 2 -methylpyridmyl ester (l g, 2.88 mmoles) in ethyl acetate (20 ml) cooled at 0°C, a solution of ethyl acetate/HCl 5M is added by dropping under stirring. It is left for one hour at 0°C, then the temperature is let reach room values . The formed precipitate is filtered and washed with ethyl ether. 900 mg of solid product are obtained. Elementary analysis Calculated C 50.21% H 3.95% N 7.31% Cl 9.26% Found C 50.23% H 3.97 ? N 7.29% Cl 9.20% EXAMPLE 2 Synthesis of 2-acetylbenzoic acid 6- (nitroxymethyl) -2 -pyri * dinylmethyl ester nitrate (NCX 4051) of formula: starting from the 2-acetylbenzoic acid 6- (nitroxymethyl) -2- methylpyridinyl ester, isolated at step C) of the previous Example 1. Synthesis of 2-acetylbenzoic acid 6- (nitroxymethyl) -2-methyl- pyridinyl ester nitrate To a solution of 2-acetylbenzoic acid 6- (nitroxymethyl) - 2-methylpyridinyl ester (1 g, 2.88 mmoles) in acetonitrile (10 ml) cooled at 0°C, a solution of 65% nitric acid (0.2 ml) in acetonitrile (2 ml) is added by dropping under stirring. It is left for 2 hours at 0°C, then the temperature is let reach room values . The formed precipitate * is filtered and washed with ethyl ether. 1 g of solid product is obtained. Elementary analysis Calculated C 46.95% H 3.69% N 10.26% Found C 46.99% H 3.72% N 10.22% EXAMPLE 3 Synthesis of the (S) -6-methoxy-o.-methylnaphthaleneacetic acid 6- (nitroxymethyl) -2 -pyridinylmethyl ester hydrochloride of formula : starting from naproxen (formula F3A) and 2, 6-bis- (hydroxymethyl) pyridine (formula FIB) (F3A) (FIB) The compound is synthetized following the procedure repeorted in Example 1. Yield 38%. Elementary analysis Calculated C 58.25% H 4.88% N 6.47% Cl 8.19% Found C 58.29% H 5.00% N 6.44% Cl 8.11% EXAMPLE 4 Synthesis of the f S) -6-methoxy-α-methylnaphthaleneacetic acid 6- (nitroxymethyl) -2 -pyridinylmethyl ester nitrate of formula: The compound is synthetized following the procedure reported in Example 2. Yield 42%. Elementary analysis Calculated C 54.88% H 4.60% N 9.15% Found C 54.91% H 4.65% N 9.10% EXAMPLE 5 Synthesis of the 2-fluoro-o.-methyl- (1 ,.1'biphenyl) -4-acetic acid 6- (nitroxymethyl) -2 -pyridinylmethyl ester hydrochloride of formula: starting from flurbiprofen (Formula F5A) and 2 , 6-bis- (hydroxymethyl) pyridine (formula FIB) (F5A) (FIB) The compound is synthetized following the procedure reported in Example 1. Yield 35%. Elementary analysis Calculated C 59.12% H 4.51% N 6.29% Cl 7.93% F 4.25% Found C 59.17% H 4.55% N 6.21% Cl 7.91% F 4.22% EXAMPLE 6 Synthesis of the 2-fluoro-a-methyl- (l , l'biphenyl) -4 -acetic acid 6- (nitroxymethyl) -2 -pyridinylmethyl ester nitrate of formula : The compound is synthetized following the procedure reported in Example 2. Yield '39%. Elementary analysis Calculated C 55.79% H 4.26% N 8.91% F 4.01% Found C 55.83% H 4.30% N 88 ! F 4.00% EXAMPLE 7 Synthesis of the 1- (4-chlorobenzoyl) -5-methoxy-2-methyl-lH-in- dol-3-acetic acid 6 - (nitroxymethyl) -2 -pyridinylmethyl ester hydrochloride of formula: starting from indomethacin (Formula F7A) and 2,6- bis- (hydroxymethyl) yridine (formula FIB) H (F7A) (FIB) The compound is synthetized following the procedure reported in Example l. Yield 41%. Elementary analysis Calculated C 55.71% H 4.13% N 7.53% Cl 12.65% Found C 55.73% H 4.16% N 7.49% Cl 12.64%s EXAMPLE 8 Synthesis of 1- (4-chlorobenzoyl) -5-methoxy-2-methyl-lH-indol- 3-acetic acid 6- (nitroxymethyl) -2 -pyridinylmethyl ester nitrate of formula: The compound is synthetized following the procedure reported in Example 2. Yield 35%. Elementary analysis Calculated C 53.18% H 3.95% N 9.58% Cl 6.04% Found C 53.20% H 4.41% N 9.56% Cl 6.01% EXAMPLE 9 (comparative) Preparation of 1- (4-chlorobenzoyl) -5-methoxy-2-methyl-lH-in- dol-3-acetic acid 3- (nitroxymethyl) phenyl ester of formula: wherein the precursor drug is indomethacin (formula F7A) . a) -Synthesis of 1- (4-chlorobenzoyl) -5-methoxy-2-methyl-lH-in- dol-3-acetic acid 3- (formyl) phenyl ester To a solution of 3-hydroxybenzaldehyde (g 8.30) and trie- thylamine (g 0.824) in methylene chloride (200 ml), cooling at a temperature in the range -5°C-0°C indomethacin in the form of the corresponding acylchloride (g 16.50) is added under stirring. It is still maintained under stirring for 15 minutes, then water (100 ml) is added and the phases are separated. The aqueous phase is recovered and extracted with methylene chloride (300 ml) . The organic phases are joined together, washed with a 5% Na 2 C0 3 solution, the organic phase is anhydrified with sodium sulphate obtaining the expected compound . b) -Synthesis of 1- (4-chlorobenzoyl) -5-methoxy-2-methyl-lH-in- dol-3-acetic acid 3 - (hydroxymethyl) phenyl ester The compound isolated in the previous step (g 1.9) is dissolved in ethyl acetate (100 ml) in the presence of palladium 5% on carbon (g 0.290) with the 50% of humidity. The mixture is hydrogenated at room temperature and hydrogen pressure of about 2.5 atm, under stirring. After 12 hours the catalyst is removed by filtration under vacuun, washing with ethyl acetate (200 ml) . The organic phases are joined together and washed with a 5% sodium bicarbonate solution and water. It is anhydrified with magnesium sulphate. It is filtered under vacuum and evaporated at reduced pressure obtaining the expected compound. c) -Synthesis of 1- (4-chlorobenzoyl) -5-methoxy-2-methyl-lH-in- dol-3-acetic acid 3- (chloromethyl) phenyl ester To a mixture formed by the compound isolated in the previous step (g 1.85) and thionyl chloride (ml 5.5), maintained under stirring, dimethylformamide (ml 0.5) is added at room temperature and left under stirring for one hour. At the end the thionyl chloride is evaporated at reduced pressure at a bath temperature lower than 40°C. The so obtained crude solid product is purified by crystallization with isopropyl ether (ml 30) . A solid is isolated which is dried under vacuum at room temperature, obtaining the expected compound. d) -Synthesis of the 1- (4-chlorobenzoyl) -5-methoxy-2-methyl - lH-indol-3 -acetic acid 3 - (nitroxymethyl) phenyl ester A solution of the compound isolated in the previous step (1.4 g) in acetonitrile (ml 8) is treated under stirring, sheltered from light and at room temperature with AgN0 3 (g 0.9) . It is heated at reflux for two hours and then cooled at room temperature and AgN0 3 (g 1.2) is added. It is filtered under vacuum, the precipitate (silver salts) is washed with acetonitrile. The organic phase is evaporated under vacuum at a bath temperature lower than 40°C. The obtained crude product is crystallized from isopropyl ether. The process global yield is 34%. By analyzing the final product by chromatography on thin layer of silica gel, using as eluent hexane/ethyl acetate 7/3, an unitary stain is obtained, m.p. 115-117°C. 'H-NMR ( CDC1-J : 7.70 (2H, d) , 7.49 (2H, d) , 7.42 (1H, t) , 7.14-7.06 (4H, m) , 6.90 (1H, d) , 6.70 (1H, dd) , 5.42 (2H, s) , 3.93 (2H, s), 3.86 (3H, s) 2.48 (3H, s). EXAMPLE 10 (comparative) Synthesis of the 1- (4-chlorobenzoyl) -5-methoxy-2 -methyl -lH-in- dol-3 -acetic acid 4-nitroxγbutyl ester To a solution of indomethacin (5.04 g, 14 mmoles) in chloroform (50 ml) at room temperature i-chloro-4-butanol (1.4 ml, 14 mmoles), N,N' dicyclohexylcarbodii ide (2.87 g, 14 mmoles) and 4-dimethylaminopyridine (0.11 g, 0.09 mmoles) are added. The mixture is maintained under stirring at room temperature for 6 hours. The solid is filtered and the organic phase is washed with water, separated, dried with sodium sulphate and finally evaporated under vacuum. The obtained residue is purified by column chromatography (eluent n-hexane- /ethyl acetate 9/1) . An yellow-coloured oily residue (5.2 g) , corresponding to 4-chlorobutyl ester of the indomethacin is isolated. 5 g of the compound (11 mmoles) are dissolved in acetonitrile (25 ml) and treated with silver nitrate (3.8 g, 22 mmoles) . The mixture is let reflux in the dark for 48 hours. After cooling, the solid residue is filtered and the solvent is evaporated under vacuum. The obtained residue is purified by column chromatography (eluent n-hexane/ethyl acetate 9/1) . At the end an oil (4.2 g) is isolated. 'H-NMR (CDC1 3 , ppm): 7.65 (2H, m) ; 7.45 (2H, m) ; 6.95 (1H, d) ; 6.84 (1H, d) ; 6.66 (1H, dd) ; 4.10 (2H, t) ; 3.82 (3H, s) ; 3.65 (2H, s) ; 3.35 (2H, t) ; 2.39 (3H, s) ; 1.80 (4H, m) . EXAMPLE 11 Solubility tests Solubility tests in water of the salts of the l-(4- chlorobenzoyl) -5-methoxy-2-methyl-lH-indol-3-acetic acid 6- (nitroxymethyl) -2 -pyridinylmethyl ester (Ex. 7 and 8) by comparison with the l- (4-chorobenzoyl) -5-methoxy-2-methyl-lH- indol-3 -acetic acid 3- (nitroxymethyl) phenyl ester (Ex. 9) and with the 1- (4-chlorobenzoyl) -5-methoxy-2-methyl-lH-indol-3- acetic acid 4-nitroxybutyl ester have been carried out. Said solubility tests have been effected by adding, at room temperature, in a 50 ml flask, 5 g of the substance and then bringing to volume with water. The compounds according to the invention completely dissolve, therefore they show a solubility equal to at least 100 mg/ml. The comparative compounds under the same conditions are unsoluble. EXAMPLE 12 Example 11 has been repeated with the compounds from 1 to 6. All the compounds result soluble in water under the same conditions of the previous Example. EXAMPLE 13 Synthesis of 2- f (2 , 6-dichlorophenyl) aminobenzeneacetic acid 6- (nitroxymethyl) -2-pyridinylmethyl ester hydrochloride of formula: starting from 2- [ (2 , 6 -dichlorophenyl) aminobenzeneacetic acid sodium salt (formula) and 2 , 6-bis - (hydroxymethyl) pyridine (F9A) 1F1B) A) -Synthesis of 2- \ (2.6 -dichlorophenyl) aminobenzene acetic acid 6- (chloromethyl) -2 -methylpyridinil ester To a solution of 2, 6-bis- (chloromethyl) pyridine (3.83 g, 21.75 mmoles), prepared as described in Example 1 A, in N,N'- dimethyl formamide (20 ml) , under stirring, a solution of 2- [ (2, 6-dichloro phenyl) amino] benzene acetic acid sodium salt (3.04 g, 9.54 mmoles) in N,N' -dimethylformamide (25 ml) is added dropwise. The solution is stirred at room temperature for one day, then it is diluted with ethyl acetate and washed with water. The organic phases are recovered and anhydrified with sodium sulphate. The solvent is then evaporated under a reduced pressure. The crude reaction product is purified by chromatography on a silica gel column, eluted with n-hexane/ ethyl acetate 8/2. 2.88 g of the product are obtained as a white solid. Yield 69% 'HNMR (200MHz) (CDC1 3 ) : 7.66 (1H, t); 7.41 (1H, d) ; 7.33 (1H, d) ; 7.27 (1H, d) ; 7.18 ( 2H, m) ; 6.97 (2H, dd) ; 6.81 (1H, s) ; 6.57 (1H, d) ; 5.3 (2H, s); 4.62 (2H, s); 3.93 (2H, s) . B) -Synthesis of 2- I (2.6 -dichlorophenyl) aminobenzene acetic acid 6- (nitroxymethyl) -2 -methyl pyridinyl ester To a stirred solution of 2- [ (2, 6 -dichlorophenyl) aminobenzene acetic acid 6- (chloromethyl) -2 -methylpyridinil ester (2.438 g, 5.59 mmoles) in 90 ml of acetonitrile is added silver nitrate ( 2.19 g, 12.89 mmoles). The solution is further stirred for 30 hours at 80°C maintaining it sheltered from light. The formed silver chloride is filtered and the solvent evaporated. The crude reaction product is purified by silica gel column chromatography, eluted with n-hexane/ethyl acetate 7/3. 1.2 g of the product in the form of a yellow oil are obtained. Yield 46%. X H NMR (200MHz) (CDCl 3 ) : 7.69 (1H, dd) ; 7.33 (1H, d) ; 7.25 (1H, m) ; 7.23 (2H, m) ; 7.16 ( 1H, dd) ; 6.98 (2H, m) ; 6.82 (1H, s) ; 6.57 (1H, d) ; 5.49 (2H, s) ; 5.31 (2H, s) ; 3.94 (2H, s). C) -Synthesis of 2- \ (2 , 6 -dichlorophenyl) aminobenzene acetic acid 6- (nitroxymethyl) -2-methyl pyridinyl ester hydrochloride To a solution of 2- [ (2, 6-dichlorophenyl) aminobenzene acetic acid 6- (nitroxymethyl) -2 -methylpyridinil ester (0.400 g, 0.86 mmoles) in ethyl acetate (6 ml), cooled at 0 °C, a solution of HC1/ ethyl acetate 3M (0.6 ml) is added dropwise under stirring, the reaction mixture is stirred for one hour at 0 °C, then is warmed up to room temperature. The formed precipitate is filtered and washed with ethyl ether. 0,310 g of solid product are obtained. Yield 73%. Elementary analysis Calculated: C 50.58% H 3.63% N 8.42% Cl 21.32% Found C 50.62% H 3.66% N .40% Cl 21.02% EXAMPLE 14 Synthesis of 2- [J 2 , 6-dichlorophenyl) aminobenzene acetic acid 6- (nitroxymethyl) -2-methyl pyridinyl ester nitrate of formula: starting from 2- [ (2, 6-dichlorophenyl) aminobenzene acetic acid 6- (nitroxymethyl) -2 -methylpyridinil ester, obtained in step B) of the previous example 13. Synthesis of 2- I " (2 , 6-dichlorophenyl) aminobenzene acetic acid 6- (nitroxymethyl) -2-methyl pyridinyl ester nitrate To a solution of 2- [ (2 , 6-dichlorophenyl) aminobenzene acetic acid 6- (nitroxymethyl) -2 -methylpyridinil ester (0.760 g, 1.65 mmoles) in acetonitrile (6 ml), cooled at 0 °C, a solution of nitric acid (65%) (0.150 ml) in acetonitrile (2 ml) is added dropwise, under stirring. The reaction mixture is stirred one hour at 0 °C, then is warmed up to room temperature. The formed precipitate is filtered and washed with ethyl ether. 0,600 g of the product, in the form of a solid, are obtained. Yield 70%. Elementary analysis Calculated: C 48.02% H 3.45% N 10.67% Cl 13.50% Found: C 48.06% H 3.47% N 10.66% Cl 13.60% EXAMPLE 15 Study of the inhibition effect on smooth muscle contraction and smooth muscle cell proliferation As known, contraction and/or cell proliferation of smooth muscle are important steps in the inflammation process. Smooth muscle contraction New Zealand White Rabbits (2.0-2.5 kg) were killed by cervical dislocation, cavernosal tissue (corpus cavernosus) and aorta excised. The tissue was mounted in organ baths for recording of isometric tension, according to the method described by Khan MA et al (BJU Int. 1999 84 (6) : 720-4) . Tissues were precontracted with phenylephrine (10 μM) and relaxation responses to carbachol assessed in the presence of the compound to be tested. The compound of the invention used in the assay was 2- acetylbenzoic acid 6- (nitroxymethyl) -2 -pyridinylmethyl ester hydrochloride (NCX 4050) , which synthesis is described in preceding example 1. The reference compound was 2-acetoxybenzoic acid (3- nitroxymethyl) phenyl ester of formula which synthesis is described in ex. 3 of the PCT patent application WO 97/16405 filed in the Applicant's name. Results are given in following Table 1, that showsthat the compound of the invention is more active than the reference compound in inhibiting smooth muscle contraction. Smooth muscle cell proliferation Human saphenous veins were cultured by standard explant methods (J. Cardiovasc . Pharmacol. 1999, 33(2), 204-11). Tissues were collected into sterile pots containing PBS, penicillin and streptomycin. Under sterile tissue culture conditions, tissues were cut into small pieces (approximately 1 mg weight) and placed into a standard culture medium containing 20 % fetal calf serum (FCS) for several days (medium changed every 2-4 days) . 3 H- thymidine was measured in the DNA fraction of cells cultured into 48 well plates. Cells were cultured to confluence in the medium containing 10% FCS. Cells were deprived of serum for 24 h before the addition of 10% FCS, together with different concentration of steroids. After 24 h, 3 H-thymidine was added to the cells for 4 h. Cells were washed with phosphate buffered saline and ethanol. DNA was extracted with sodium hydroxide solution and the 3 H material counted by scintillation. The data represents observations made in triplicate wells. Table 2 reports results obtained on the inhibitory effect of the tested compounds on human vascular smooth cell proliferation . The Table shows that the compound of the invention is much more active than the reference compounds. Table 1 and 2 demonstrate that the antiinflammatory activity of the compound of the invention is higher than that of the reference compound. Table 1 Table 2

Claims: CLAIMS 1. Organic or inorganic salts of compounds of general formula : A - X- - N(0) z wherein : z is an integer and is 1 or 2 ; A = R(COX u ) t and wherein t is an integer 0 or 1 ,- u is 0 or 1 ,- X = 0, NH, NR lc wherein R lc is a linear or branched C ι -C 10 alkyl . ■ ^ • TI ^nx I I *ι = - [C] nIX — Y— [C] nIlx -0- (B) TIX- RTIIX' wherein : nix is an integer between 0 and 3 ,- mix is an integer between 1 and 3 ; R- ΓIX / R- ΓIX' / R- mx R- rnx - equal to or different from each other, are H or a linear or branched C^d alkyl; Y is a ring containing at least one salifiable nitrogen atom; preferably Y is an heterocyclic ring, saturated or unsaturated or aromatic, having preferably 5 or 6 atoms and containing at least one or two nitrogen atoms,- R is selected from the following groups: Group I) wherein t = 1 and u = l Ic) ιc 3 ) wherein : R x is the OCOR 3 group,- wherein R 3 is methyl, ethyl or linear or branched C 3 -C 3 alkyl, or the residue of a heterocycle with a single ring having 5 or 6 atoms which may be aromatic, partially or totally hydrogenated, containing one or more hetero-atoms independently selected from 0, N and S; R 2 is hydrogen, hydroxy, halogen, a linear or when possible branched C-C. alkyl, a linear or when possible branched C-C. alkoxyl; a linear or when possible branched d- i perfluoroalkyl, for example trifluoromethyl ; nitro, amino, mono- or di- (C, -4 ) alkylamino; nl is an integer 0 or 1; Group II) wherein t = 1 , u = 1 lib) wherein: R IIS is H, a linear or when possible branched alkyl; R II6 has the same meaning as R II5 , or when R II5 is H it may be benzyl ; R m ' R ι i 2 and R III3 can independently be hydrogen, a linear or when possible branched Ci-Cg alkyl or a linear or when possible branched alkoxy, or Cl , F, Br,- R II4 is R„. or bromine; Group HI) wherein t = 1, u = 1 and R is R 2a I Rx. -C - R 3a wherein: R 2a and R 3a are H, a linear or when possible branched, substituted or non-substituted, C^C^ alkyl or allyl, with the proviso that when one of the two is allyl, the other is H; preferably R 2a is H, C^Q, alkyl, R 3a is H; R la is selected from ( n ) (XXI) (IV) Occcv) (VI) (VII) (IX) (X) (III) HID) R la corresponds to the following formulas Ilia) (XXX] ; xx.x i ) (XXXII) (XXXIII) ( XJVI) (in) wherein the meanings are the following: when R la is as defined in formula (IV) , Ketoprofen residue: R πι , is H, SR III3 wherein R III3 contains from 1 to 4 C atoms, linear or branched when possible; R :II2 is H, hydroxy; when R la is as defined in formula (XXI) , carprofen residue: R^,, is H, a linear or when possible branched alkyl from 1 to 6 C atoms, a Ci-Cg alkoxycarbonyl bound to a Ci-Cg alkyl, carboxyalkyl, Ci-Cg alkanoyl, optionally substituted with halogens, benzyl or halobenzyl, benzoyl or halobenzoyl ,- R^ is H, halogen, hydroxy, CN, Ci-Cg alkyl optionally containing OH groups, alkoxy, acetyl, benzyloxy, SR---. i2 wherein R---. i2 is -Cg alkyl; C- L -C J perfluoroalkyl; carboxyalkyl optionally containing OH groups, N0 2 , amino ; sulphamoyl, di- alkyl sulphamoyl with alkyl, or di- fluoroalkylsulphonyl with C 3. -C, alkyl; R-- 3 -- 1. is halogen, CN, C-C 6 alkyl containing one or more OH groups, C L -C S alkoxy, acetyl, acetamido, benzyloxy, SR III3 being as above defined, perfluoroalkyl, hydroxy, C--C 3 carboxyalkyl, N0 2 , amino, mono- or di-alkyl-amino C--C 6 ; sulphamoyl, di- alkyl sulphamoyl or di-fluoroalkylsulphamoyl as above defined,- or R- ^ .. together with R -αtll is a C 3 -C 6 alkylene dioxy; when R la is as defined in the formula (XXXV) , residue of the tiaprofenic acid: Ar is phenyl, hydroxyphenyl optionally mono- or poly-substituted with halogen, alkanoyl and alkoxy, C^ trialkyl, preferably C α -C 3 , cyclopen- tyl, cyclohexyl cycloheptyl, heteroaryl, preferably thienyl, furyl optionally containing OH, pyridyl; when R la is as defined in formula (II) , suprofen residue, wherein R 3a is H, R^ is methyl and X = O; when R la is as defined in formula (VI) , R is the residue of indoprofen when Rj a = H and R 3a = CH 3 and of indobufen when ^ is equal to H and R 3a = C 2 H 5 ; X = O; when R la is as defined in formula (VHI) , R is the residue of etodolac when R^ = R 3a = H and X = 0; when R la is as defined in formula (VII) , R is the residue of fenoprofen when R 3a = H, R^ = CH 3 and X = O ; when R- a is as defined in formula (III) , R is the residue of fenbufen wherein R-, a = R 3a = H and X = 0; when R la is as defined in formula (IX) , R is the residue of flurbiprofen when R 3a = H, R 2a = CH 3 , X = O; in the compounds of formula (X) R is the residue of tolmetin when R^ = R 3a = H, X = 0; in the group HID) R la corresponds to the following formulas : Ilia) , when R 2a = H and R 3a = CH 3 the residue of pra- noprofen is obtained: o.-methyl-5H- [1] benzopyran- [2, 3-b] pyridin-7-acetic acid; (XXX) , when R^ = H and R 3a = CH 3 the bermoprofen residue is obtained: dibenz [b, f] oxepin-2-acetic acid; (XXXI), when R 2a = H and R 3a = CH 3 , R is the radical of the compound CS-670: 2- [4- (2-oxo-l- cyclohexylidenmethyl) phenyl] propionic acid; (XXXII) , when R ja = R 3a = H the Pemedolac residue is obtained; (XXXIII) , when R 2a = R 3a = H the pirazolac residue is obtained: 4- (4-chlorophenyl) -l- (4-fluorophenyl) -3- pyrazolic acid; (XXXVI) , when R-, a = H, R 3a = CH 3 , the zaltoprofen residue is obtained; when the residue is saturated with an hydroxyl or aminic group or with the carboxylic function the compounds are known as dibenzothiepin derivatives; (XXXVII) , when R 2a = R 3a = H the mofezolac residue is obtained: 3 , 4-di (p-methoxyphenyl) isoxazol-5-acetic acid; (XII) , when R 2a = R 3a = H the bromfenac residue is obtained: 2-amino-3- (4-bromobenzoyl) benzeneacetic acid; in group IV) wherein t = l, u = l, R is Ri di wherein: R ιvd and R ιvdl are at least one H and the other a linear or branched when possible alkyl from C, to C 6 , preferably C x and C 2 , or difluoroalkyl with the alkyl having from 1 to 6 C atoms, C x is preferred, or R τvd and R^.^ form together a methylene group; R JV has the following meaning: iv— x (ID (X) wherein: in formula (II) R iv-i i is alkyl, C 3 -C 7 cycloalkyl, trifluoroalkyl, vinyl, ethynyl, halogen, Cj-Cg alkoxy, difluoroalkoxy with the C L -C 7 alkyl, Cj-C, alkoxymethyloxy, alkylthiomethyloxy with the C-C 7 alkyl, alkyl methylthio with the C^C, alkyl, cyano, difluoromethylthio, phenyl- or phenylalkyl substituted with the alkyl; formula (X) , loxoprofen residue; in formula (III) R iv - ϋ i is a C 2 -C 3 alkyl, optionally branched when possible, C 2 and C 3 alkyloxy, allyloxy, phenoxy, phenylthio, cycloalkyl having from 5 to 7 C atoms, optionally substituted in position 1 with a C j -C, alkyl; Grout) V) (VII) (IV) (V) (III) (II) Group VEl (X) (XI) (xm) ( XXX) (XXXXI) oup v) , when R is the formula (II) , R vii is H or a linear or branched when possible C 1 -C 4 alkyl; R vu- ι is Rvϋ or a linear or branched when possible C x -C 4 alkoxy; Cl, F, Br; the position of R vi i- ι being ortho, or meta, or para; when R is the formula (V) , A = R and t = 0; when R is the formula (VII) , A is RCO, t = 1 u = 0 or A is R and t = 0 ; when R is the formula (IX) , A = R and t = 0, or A = RCO with t = l and u = 0; when R is the formula (HI) A = RCOO, t = l and u = 0 or l; or t = 0 and A = R; when R is the formula (IV) , A = RCOO, t = 1 and u = 1; when R is the formula (X) , it is the residue of meloxicam; when R is constituted of the formula (XI) , it is known as ampiroxicam when the end group is -CH(CH 3 )OCOC 2 H 5 ; when R is the formula (XIII) and the free valence is saturated with H, the residue is that of lomoxicam; when R is the formula (XXXX) and the valence is saturated with H, the compound is known as paracetamol; when R is the formula (XXXXI) and the valence is saturated with H, the residue is known as tramadol . 2. Salts according to claim 1, wherein in the compounds of formula A-X--N(O)-. z is 2 and nix and nllX in the formula (B) of X- are integers equal to 1 and rIX , Rj K . , !!„„, R- rnx - are equal to H. 3. Salts according to claims l and 2, wherein in the compounds of formula A-X 1 -N(0) z R, X, u and t of the formula A = R(COX u ) t , and Y in formula (B) of X 17 have the following meanings: when R is selected from Group I), in the compounds of formula la) X is equal to 0 or NH, R. is acetoxy, preferably in ortho-position with respect to -CO-, R 2 is hydrogen,- in X 1 R-. IX = R-Ti- RTII = R-ΓIIX- = H n rχ = n ιιχ = 1 and Y is an aromatic ring having 6 atoms, containing a nitrogen atom, said aromatic ring having the two free valences in position 2 and 6; in the compounds of formula lb) R 3 = CH 3/ nl = 0, X is equal to 0, X x is as above defined for la) ; in this case lb) is the residue of the acetylsalicylsalicylic acid,- in the compounds of formula lc) X = 0 and u = l; when R is selected from Group II) , in the formula Ha R II1 # R are hydrogen and R II2 and R II3 are chlorine in ortho-position with respect to NH; R πs and R II6 are H, X is equal to 0, and X x is as above defined for the compounds of formula la) ; when R is selected from Group III) , when R la is as defined in formula (IV) , R Ilτι and R III2 are H, R 3a is H, and R-j a is methyl, X = 0; when R la is as defined in formula (XXI) , R^,- is H, the linking bridge is in position 2, R xκi is H, R^. is chlorine and is in para position with respect to nitrogen; when R la is as defined in the formula (XXXV) , Ar is phenyl, R 3a is H, R 2a is methyl and X is 0; R 3a is H, R 2a is methyl and X is 0; when R la is as defined in the formula IHa) , R 2a = H, R 3a = CH 3 , u = l and X * = 0; when R la is as defined in the formula (XXX) R 2a = H, R 3a = CH 3 , u = 1 and X = 0; when R la is as defined in the formula (XXXI) , R^ = H, R 3a = CH 3 , u = l and X = 0; when R la is as defined in the formula (XXXII) , R 2a = R 3a = H, u = 1 and X = 0; when R la is as defined in the formula (XXXIII) , R a = R 3a = H, u = l and X = 0; when R la is as defined in the formula (XXXVI) , R 2a = H, R 3a = CH 3 , u = l and X = 0; when R la is as defined in the formula (XXXVII) , R 2a = R 3a = H, t = 1 and X = 0; when R la is as defined in the formula (XII), R 2a = R 3a = H, U = 1, t = 1, X = O, R_ a = R 3a = H; or t = 0 when R is selected from Group IV) , when R IV is the formula (II), R iv --i = CH 3 0-, R Jvd = H and R Ivdl = CH 3 , X = 0 and X. is as above defined for la) ; when R IV is the formula (X), R tvd = H, R ιvdl = CH 3 , X = 0 and X x is as above defined for la) ; when R IV is the formula (HI) , R iv- iii is CH 3 \ CH-CH 2 - / CH 3 and R ιvd = H, R ιvdl is CH 3 , X = 0 and X x is as above defined for la) ,- when R is selected from Group V, when R is the formula (II) , R vii and R vii-1 are H, and A = R; when R is the formula (X) , A = RCO, t = 1 and u = 0; when R is the formula (XI) , A = RCO, t = l and u = 0; when R is the formula (XIII) , A = RCO, t = 1 and u = 0; when R corresponds to the formula (XXXX) or (XXXXI) , A= RCO, t = 1 and u = 0. Salts according to claims 1-3, wherein Y in formula (B) of Xi contains one or two nitrogen atoms in the ring and is selected from the following: (Y7) (YS) ( γ ι) (Y2) (Y3) (Y4) (Y5) (Y6) (Y9) (Y o) (Yll) C^ ) C n3 > (Y1 ) (Y15) 5. Salts according to claim 4, wherein the preferred radical Y of formula (B) of X__ is Y12 (pyridyl) substituted in position 2 and 6. 6. Salts according to claims 1-5, wherein the organic acids are selected from the following: oxalic, tartaric, maleic, succinic, citric acids and the inorganic acids from nitric, hydrochloric, sulphoric, phosphoric acids. 7. Salts according to claims 1-6, wherein R in formula A = R(COX u ) c is selected among those of Group I) and Group IV) . 8. Salts according to claims 1-7 for use as medicaments. 9. Use of salts according to claim 8 for the preparation of drugs having an aniinflammatory activity. 10. Use of salts according to claim 8 for the preparation of drugs for the antithrombotic therapy. 11. Use of salts according to claim 8 for the preparation of drugs having an analgesic activity. 12. Use of salts according to claim 8 for the preparation of drugs for the septic shock therapy. 13. Pharmaceutical formulations for oral and parenteral use containing as active principles the salts of claims 1-7. 14. Compounds of formula A - X. - N(0) z according to claims 1-8.

Inventors: BENEDINI FRANCESCA, DEL SOLDATO PIERO, BENEDINI, FRANCESCA, DEL SOLDATO, PIERO
Applicants: BENEDINI FRANCESCA, DEL SOLDATO PIERO, NICOX SA, BENEDINI, FRANCESCA, DEL SOLDATO, PIERO, NICOX S.A.
Application year: 2000
Main classification: C07D213
IPC codes: A61K31, A61P7, A61P29, C07D213, C07D401