AU764127B2

AU764127B2 - Nitric ester derivatives and their use in the treatment of gastrointestinal tumours

Info

Publication number: AU764127B2
Application number: AU38954/01A
Authority: AU
Inventors: Francesco Sannicolo'; Piero Del Soldato
Original assignee: Nicox SA
Current assignee: Nicox SA
Priority date: 1996-09-04
Filing date: 2001-04-27
Publication date: 2003-08-14
Anticipated expiration: 2017-09-02
Also published as: AU3895401A

Description

AUSTRALIA

Patents Act 1990 COMPLETE SPECIFICATION STANDARD PATENT Applicant: SNICOX S.A.

Invention Title: NITRIC ESTER DERIVATIVES AND THEIR USE IN THE TREATMENT OF GASTROINTESTINAL TUMOURS The following statement is a full description of this invention, including the best method of performing it known to me/us: NITRIC ESTER DERIVATIVES AND THEIR USE IN THE TREATMENT OF GASTROINTESTINAL TUMOURS The present invention relates to new medicaments to be useful in the treatment of urinary disorders in the treatment of gastrointestinal tumours. Urinary disorders are generally grouped in one single functional pathology class and are characterized by several symptoms, including changes in micturition (like for example incontinence), changes in urinary output (like for example polyuria, oliguria, anuria), changes in the appearance of urine (like for example hematuria), edema (like for example anasarca), pain (like for example bladder pain).

The invention relates to new compounds having superior efficacy in the treatment of some forms of urinary incontinence (anti-incontinence 'compounds) or edema (diuretics) and which appear to be well tolerated by the body.

In particular, it is known that urinary incontinence car-n be considered a disorder of micturition control resulting from a lesion or dysfunction of the lower urinary tract. In particular, the urinary bladder smooth muscle called detrusor muscle and the internal (smooth muscle) and external (striated muscle) urethral sphincters are involved.

See for example Ferguson D. and Christopher Urinary bladder function and drug development, Trends in Pharmacological Sciences, 1996, 17, 161-165. This publication reports that there are various types of incontinence characterised by different causes and symptoms. In particular, the following can be mentioned: stress incontinence, which is the discharge of small amounts of urine due to increased intraabdominal pressure caused, for example, by cough or an effort. Stress incontinence is due to a change in vesicourethral angle and relaxation of the urethral sphincter muscle. Stress incontinence is frequent in women, particular multipara women.

urge incontinence, which is the inability to control the urinary bladder and manifests itself with a sudden.

and urgent stimulus to urinate. Urge incontinence is due to intermittent contraction of the urinary bladder muscle for no apparent cause (detrusor instability) or caused by interstitial cystitis or other inflammatory phenomena which lead to urinary bladder hyperexcitability. It seems that changes in urinary bladder innervation are present in all these cases; incontinence from urinary bladder overdistention, which occurs in case of chronic urinary retention due to obstructive causes. The urinary bladder never empties completely, resulting in continous discharge of small amounts of urine.

total incontinence, which is a complete lack of urinary bladder control due to inability of controlling the sphincters. It is the result-of severe neurologic damages.

In the known art, the available therapies are based on three different approaches, see for example the above publication and Anderson Pharmacology of lower urinary tract smooth muscles-and- penile erectile tissues, Pharnatological Reviews, 1993, 45, 253-308: reduced detrusor activity, S- changed sensory nervous transmission, changed urethral resistance.

According to the first approach, detrusor contraction -is stimulated by the parasympathetic system and acetylcholine is the main mediator. Therefore, anticholinergic agents are used to reduce vesical hyperactivity. However, these are effective but of limited use due to the systemic anticholinergic side effects including for example dry mouth,-constipation and tachycardia. Taking into account that vesical irritability is often associated with urinary bladder obstructive disease, the administration of anticholinergic agents risks triggering an acute urinary retention crisis.

Another pharmacological approach to reduce detrusor activity includes the use of medicaments which help opening potassium channels or calcium antagonists which relax the smooth muscle. However, there are disadvantages such as a marked hypotensive action due to a nonspecific vasodilator effect produced by these agents.

An additional pharmacological measure to reduce detrusor activity consists of the use of prostaglandin synthesis inhibitors -which were tested in some detrusor hyperactivity and enuresis cases with promising results but giving major side effects. Their use is based on the fact that numerous prostaglandins were found to be synthesised in the urinary bladder following nervous stimulation and some of them seem to act as mediators of detrusor contraction. Additionally, some prostaglandines may be involved in severe urge incontinence and vesical hyperactivity events during some inflammatory disease of the urinary tract.

Therefore, nonsteroidal anti-inflammatory drugs are potentially useful in 1owering the urinary bladder excitability threshold, and are thus effective in cases of detrusor instability. Unfortunately, they have the disadvantage of being little tolerated at active doses, especially in the gastrointestinal tract.

Likewise, NO synthetase enzyme inhibitors can prevent hyperexcitability of the urinary bladder and hyperalgesia resulting from inflammatory events such as interstitial cystitis; see Rice Topical spinal administration of a nitric oxide synthase inhibitor prevents the hyperreflexia associated with a rat model of persistent visceral pain, Neuroscience Letters, 1995, 187, 111-114. However, there are currently no agents of this type which can be used therapeutically due to a relative nonspecificity of their pharmacological profile.

The second approach, which consists of changing sensory o nervous transmission (whenever urinary incontinence results from lesions of the nervous system), includes the use of drugs which act on neurotransmission, for example gamma-aminobutyric acid (GABA), or peptides, or purines, which are Simportant neurotransmitters in the urinary tract.

Studies are also known which use capsaicin for intravesical instillation with sometimes satisfactory results. However, this treatment has limited clinical applications due to its transient effect, which, in addition, can be obtained only by local use.

The third approach considers the fact that muscle tone in the urethra is mediated by different neurotransmission systems, including for example the adrenergic system, by stimulation of a-receptors, a-agonist medicaments, which increase the pressure borne by the urethra, are used to change urethral resistance sometimes with satisfactory results.

However, the use of these compounds involves some risks, as in the case of urinary bladder obstructive disease where even alpha-antagonists are used. In these cases a sphincter hyperactivity is observed, which prevents regular urinary bladder voiding causing urgeincontinence. Also in this ca- -se, as in the first approach described above, severe side effects of a hypontensiye type related to the a-antagonistic activity in the cardiocirculatory system are observed.

To increase urethral resistance in women with stress incontinence, an oestrogen based therapy which was found to be efficacious in increasing intraurethral pressure and in changing the structure of mucous membrane, vessel and connective, is used. Good results were observed combining treatment with a-agonists with oestrogen treatment. However, the well known side effects which occur when oestrogen treatment is used must be reported.

So far, commercial pharmaceutical preparations resolve the problem only in a limited number of cases. However, they generally cause side effects, even somewhat severe.

The applicant has unexpectedly and surprisingly found that the particular classes of compounds described below can be beneficially used in the treatment of gastrointestinal tumours, as they exhibit a pharmacological profile superior to that of the known preparations used for this type of disease.

In one aspect, the present invention provides the use of compounds, or their compositions, having the following general formula for the treatment of gastrointestinal tumours:

A-X

1

-NO

2 or their salts, where: -A R(COX) t where t is an integer 0 or 1; X 0, NH, NRC where Ric is a linear or branched alkyl having from 1 to 10 C atoms; R is chosen from the following groups: Group I where t 1, R R

II

2

R

NH

T141 (Aa) (LAb) where:

R

115 is H, a linea- or whenever cossible b ranched C 1 -c 3 alkyl;

R

11 6 has the same meanings as R 115 or when R 1

T

5 is H it can be benzyl;

RII

1

R

1 1 2 and R 1 1 3 are equal or different one from the other and are hydrogen, linear or whenever possible branched C 1

-C

6 alkyl or Cj-C 6 alkoxy, or Cl, F, Br; R14is R 11 1 or bromine; preferred are the compounds where RIII, R 1 1 2 and R 1 1 4 are H, and R 1 1 is Cl and R 1 1 is in the ortho posit.ion to NH; R 1 1 5 and R 1 1 6 are H, X is equal to 0, and

X

1 is C2H20; (I Ab) is the residue of 2-U[2-methyl-3-(trifluoro- *methyl) phenyl] amino] 3-pyridinecarboxylic acid and when -COOH is present it is known as flunixin.

The compounds preferred are those where X =0; II~ A) chosen- from the following: ;where, when t R is Ra Ria Cwhere R 2 a and R 3 a are H, a linear or whenever possible branched substituted or non-substituted Cl-C 1 2 alkyl, allyl, with the proviso that when one of the two is allyl the other is H; piceferably R 2 a is H, alkyl has from 1. to 4 C atoms, Ra -is H; Ri a is chosen from II Aa) Ri (rr) R6

S-

(XG~v)

(VI)

C H 2

(VIII)

H 3C

/C

CH

'3 0N 0 C -2 where meanings are as follows: in the comoounds of formula residue of ketoprofen: RIIII is H, SRIII3 where RI 1 1 3 contains from 1 to-4 C linear or whenever possible branched C atoms; II2 is H, hydroxy; preferred are the compounds where RjjI and RII2 are H, R3a is H, and R 2 a is methyl, X 0; in the compounds of formula (XXI), residue of carpro- S* fen: Rxxio is H, a linear or whenever possible branched alkyl having from 1 to 6 carbon atoms, a CI-C 6 alkoxycarbonyl bound to a CI-C 6 alkyl, a C--C 6 carboxyalkyl, a

C

1

-C

6 alkanoyl, optionally substituted with halogen, benzyl or halobenzyl, benzoyl or halobenzoyl; Rx i is H, halogen, hydroxy, CN, a CI-Cg alkyl optionally containing OH groups, a C 1

-C

6 alkoxy, acetyl, benzyloxy, SRxi 2 where Rxi2 is a C -C 6 alkyl; a perfluoroalkyl having from 1-3 C atoms, a C 1

-C

6 carboxyalkyl optionally containing OH groups, NO 2 sulphamoyl, dialkyl sulphamoyl with the alkyl having from 1 co 6 C atoms, or difluoroalk-ylsulphonyl with the alkyl having from 1 to 3 C atoms; Rxxil is halogen, CN, a C 1

-C

6 alkyl containing one or more OH groups, a C 1

-C

6 alkoxy, acetyl, acetamido, benzyloxy,

SRIII

3 is as above defined, a perfluoroalkyl having from 1 to 3 C atoms, hydroxy-, a carboxyalkyl having from 1 to 6 C atoms, NO 2 amino, a mono- or dialkylamino having from 1 to 6 C atoms, sulphamoyl, a dialkyl sulphamoyl having from 1 to 6 C atoms, or difluoroalkylsulphamoyl as above defined; or Rxx i jointly with Rxxil is an alkylene dioxy having from 1 to 6 C atoms; preferred are the compounds where Rxio is H, the connecting bridge is at position 2, Rxx i is H, Rxxil is chlorine and is in the para position to nitrogen;

R

3 a i s H, R 2 a is methyl and X is O; in the compounds of formula (XXXV), residue of thiaprofenic acid: Ar is phenyl, hydroxyphenyl optionally mono- or polysubstituted with halogen, an alkanoyl or alkoxy having from 1 to 6 C atoms, a trialalkyl having rrom 1-6 C atoms, preferably from 1-3 C atoms, cyclopentyl o-hexyl o-heptyi, hpeeroaryl, preferably thienyl, furyl optionally contai-ing OE, pyridyl; the preferred comoounds of formula (XXXV) are those where Ar is phenyl, R 3 a is H, R 2 a is methyl and X is O; in the comoounds of formula (II) residue -of suprofen, the preferred, where R 3 a H, R 2 a CH 3 and X 0; in the comDounds of formula (VI), of which the preferred, indoprofen, when R2a is CH 3 or -indobufen, when R 2 a is ecual to H and R 3 a CH 3 and X =O; C in the compounds of formula (VIII), of which the preferred, etodolac, when R3a R 2 a H and X O; in the compounds of formula (VII), of which the preferred, fenoprofen, when R3a H,

R

2 a CH 3 and X 0; in the compounds of formula (III), of which the preferred, fenbufen, when R 3 a R2a H and X O; in the compounds of formula residue of tolmetin, when R 3 a R 2 a H and X O; in the comoounds of formula residue of flurbi-

(ITIXXX)

(IXX~)

4' *4*0 *4*q 4 4 444*44 -l

H

4 .4 (TXXX) .4 4 I A 4 I 44 4 ~4 4, 4* 414 444 4 *4 4' .444 4 (XXx) 0

JH

(er~r (qv II -0 L- j uzr boad HE a

N

H. S

C

S.0 aceti acd peere R.XV3 JI) n X=0 whee thesimenings are a n follows:OH t i '=I as berrnoorofen: dibenz oxepin-2-acet~ic acid, nreferred is X 0, R 2 a H, R 3 a 3 -residue (XXXT) is known as CS-670: 2 -[4-(2-oxo-p.

cyclohexylidenemechyl)phenyl] oroc on -c acid, when the radical is -CP(CH 3 )-COOH; Preferred R 2 a R 3 a CH 3 and X 0; -residue (XXXII) derives from the known oemedolac which contains group -CH 2 COOH, Dreferred R 2 a R3a H and X 0; when residue (XXXIII). is saturated with -CH 2 COOH it is known- as pyrazolac: 4- (4-chiorohelyl) (4-f luorophenyl)3-pyrazolyl acid derivatives; preferred R2a =R 3 a H and X 0; -when residue (XXJCVI) is saturated with -CH(CH -COOit is known as zaltoprofen. When the residue is saturated with a hydroxy or amine group or the acid salts, *..the compounds are known as dibenzothiepin -derivatives.

Preferred R2a H, R3a CH 3 and X 0; *see wheni' residue (XXXVII) is CH 2 -COOH it derives from the known mofezolacz 3, 4 di (p-methoxyphenyl) isoxazol-S -ace- *0 1. tic -acid; preferred are R2a R 3 a t X 0.

*Group IIIA) where t 1, RIVd RIv C RVd 1 where: RIVd and RIVdl are at least one H and the other a linear or whenever possible branched C 1

-C

6 al kyl, preferably C 1 and C 2 or difluoroalkyl with the alkyl having from 1 to 6 C atoms, preferred is C 1 or RIVd and RIVdi jointly form a methylene group; RIV has the following meaning:

R.I

000 900 00 0 0.:

R.

(in) wnere the comnoumds of group lIIA) have the following meanings: in the comoou-nds of formula R is an alkvl hav ino f 0m I 0 6 C atoms, a cycloalkyl having from 3 to 7 C atoms, an alcoxyrnethyl having fromn 1 to 7 C atoms, a tr-ifluoroalkyl having from 1 to 3 C a~ioms, vinyl, ethynyl, halogen, an alkoxy having from 1 to 6 C atoms, a difluoroalkoxy with the alkyl having from 1 to 7 C atoms, an alkoxymethyloxy having from 1 to 7 C atoms, an alkylthiomethyloxy with the alkyl having from 1 to 7 C atoms, an alkylmethylthio -with the alkyl ha-ving from 1 Co 7 C atoms, cyano, difluoromethylt-hio, a substituted phenyl- or 0 phenylalkyl with the alkyl having from 1 to 8 C atoms; 000.

preferably RIV-II is CH 3 O, RIVd is H and RIVdl is CH 3 0.0 0 and is known as the residue of naproxen; *X NIH and X 1 is equal to (Cg 2 4 or (CH 2

CH

2 O) 2 also 0 0 0 0 0pref erred is the same compound where X is equal to 0; -in the oreferred compounds of formula for which 0: 0.the residue of loxoorofe-n has been shown, RIvd is H and 0 RIVdi is- CH- 3 X NHl or 0 and X 1 is equal to (.CH 2 4 or :000** 00. 0(CH 2

CH

2 0) 2' -in the comiDounds of formula RIV-III is a C 2

-C

3 alkyl, even branched when possible, a

C

2 and C 3 alkyloxy, allyloxy, phenoxy, phenvlthio, a cycloalky! having from 5 to 7 C atoms, optionally substituted at position 1 by a Cj-C 2 alkyl; preferred is the compound where Riv-iii is

CH

3

CH-CH

2

CH

3 and RIvd iH, RIvdi is C,; 3 a comoound known as the residue of ibunrofen; X= and is ea-ual to (CH o r (C 2

O)

2 also orefer-red is the same compound where X o *Group IV A)

~C

(IV A) where A =RCOO, t =1 of whi-ch the residue of the knowh indome-zhacin has been shown.

*Group V A) chosen from the following: -V Aa) fenamates chosen from the following, where z

NHCH

2 CHCl- 0 (V Aal) (V Aa2) cl (V Aa3)

N\

CH 3 CH 3 (V Aa4) (V AaS) H3 CC -V Ab) derivatives of niflurnic acid, where t 1: CF 3 N Nil (v Abi) -V AC), COX 2 inhibitors, where t o and R is as f ollows: N SO 2

CH

3 0 Y RVAl

S.

(V Acl) 0H

H

Nr 0 (V Ac2) 0 H-

NF

5 0 Ac3iJ

F

(V AC4)

S\

0 /0 CH 3f (V -V Ad) derivatives of diuretics when t 1 and R is as f ollows: 0 0 (V Adi) 0 (V Ad2) HG2 H3 cj 41c (V Ad3) N SN2 0 0 0 (V Ad4) V Ae) derivatives of diuretics wh en t 0 and R i s as f ollows: H- N- -1 (V Ael) S S

S.

H 1 0

HCH

NNJ4 (V Ae2)

N

\N NH

N-N

(V Ae3) 0/0 00 :aN F 3C

H

(V Ae4) 0 0 00 (V AeS) 00 0 0

HNH

(V Ae6) 0 0 0 *H N Y, T*.

(V Ae7) 0 NH 0/0 HO

N

Ic (V Ae8) 0 HN N

NH

N

I

CH

2

C

(V Ae9) (V Aell)

H

K0

COGH

(V AeI2) where tihe ma ng c- oup V A) as =01llows: in comoounc s (V -al) Ices-,_ c:z enlfenamlc acid, 2- ((2-p~henvle~hyl)am-flnobefizo~c aci, has been snown; in comoounds (V Aa2) trhe res-idue of flurenam.ic acid, 2- t[3-(tril luoromc,.fyl)Pflnyll-amrn2oizenzoic acid, has been shown; in compounds (V Aa3) the residue of meclofenamicacid, 2- (2,6-dictloro-3-methylphel) aminlo)benlzoic acid, has been shown; in compounds (V Aa4) the residue of mefanamic acid, 2 (2,3 -dime thylpheny) aminlo]benlzoic acid, has been 0* 0 shown; in compounds (V Aa5) the residue of tolfenamic acid, 2- C((a-chloro-2-methylphenyl) amino] benzoic acid, has 0000 been shown; in compounds (V Abi) the residue of niflumic acid, 2- -t(3 (trif luoromethyl) phenlyl amino] 3-pyridinle carboxylic acid, has been shown; -in compounds (V Al) Rvaci attached to the oxygen atom in position 2 of t.he benzene ring of N- (4nitrophenyl)methansulphonamide can be pnenyl or cycloexa-le- When Rvacl is phenyl the residue Is Tihat of nimesuJlide; in comoounds (V Ac2) Lhe residue of 3---ormylamfino- 7 me hylsulfoflylan- -hoPhenoY!-be zpoyra One has been shown; in comnounds (V Ac3) the atom X, Llhan links the radical 2 ,4-difluorothiophenyl to position 6 of the indanone-ring ofE the residue 5 -methanesul-Folamido-i-ri-danone can be sulfur or oxygen; in compounds (V Ac4) the residue of" (4-methylphelyl) (trifluoromfethyl)PYrazollyll benzensuipholamide, has been shown; in compounds (V Ac5) the residue of 6-[2-(3-ethyl- 2,3-dihydro-thiazolyl) thio..5-methafesu1phonamido- 3

H

isobenzonfural-ofle has been shown.

*-in compounds (v Adi) the residue of bumetanide 3- (Aminosulfony.) (butylamino) -4-phenoxyber1zoic acid has been shown; -in compounds (V Ad2) the residue of ticrynaf en (2,3- Dichloro-4- (2-thienylcarbonyl) -phenoxy) acetic acid has .been -shown; -in comnounds (V Ad3) the residue of ethacrylic acid 2 3 -Dichloro 4 (2methyleneoxobutyl)pheoyIaei acid, has been showmn; in comoounds (V Ad4) the 'residue of pireta-nide 3- (Aminosulfoflyl) -4-tahenoxy- 5 Cl-pyrroliditnyl)befizoic acid has been show-,.

in compIounds (V Ae!) the rsd f rpmd 3o 4 ,7-mer-ano-2H-isoindo±2-yl)benza-i 6e has been shown.

in comnounds (V Ae2) the residu=e of= torsemide Me t hyle thyl) ami no] carbonyl] 4- me -_hylohenyl) amri no -3 pyrinesulfonamide has been shown; -in compoounds (V Ae3) the residue of azosemide 2-Chia- (iH-tetrazo1-5-yl) (2 -thienvlmethyl) arrino]-benzensulphonamide has been shown; in cotTnounds (V Ae4) the residue of bendroflumethiazide 3, 4-Dihydro-3 (phenyl -methyl) 6- (trif luoromethyl) 2 H-1,2,4-benzothjadjazjne-7-sulfonamiLde* 1, 1dioxide has been shown; S -in comounds (V Ae) the residue of chior~cothiazide 1, 2,S G-Chloro2h-l24badiazine-7-su-Le 1,1onamide hasbeen shown; in comoounds (V Ae8) the residue of chiorthalidone 3-dihydro-1-hydroxy-3-oxo-IE-iSoifdol-1yl)benzensulfonamide has been shown; 2-n comoounds* (V Ae9) the residue of Indapamide 3- (Aminosulfonyl)-4-chloro-N-(2,3-dihydro-2-methyl-iHindol-1-yl)benzamide has been shown; in compounds (VAe1Q) the residue of metolazone 7- Chloro-l,2,3,4-tetrahydro-2--methyl- 3 (2-methyiphenyl) 4-oxo-6-cruinazolinesulfolamiude has been shown; in compounds (V Aell) the residue of quinetazone 7- Chloro 2 -ethy 2, 3, 4tetrahydro4 oxo-6 quinazol inesulfonamide has been shown; -in 'compounds- (V Ael2) the residue of furosemide (Aminosulfonyl) -4-chloro-2- (2-furanylmethyl) amino) benzoic acid has been shown.

xin formula A-X 1 -N0 2 is a bivalent connecting bridge 0. chosen from the following:

-YO

where Y is a linear or whenever possible branched C 1

-C

20 alkylene, preferably having from 2 to 5 carbon atoms, or an optionally substituted cycloalkylene having from 5 to 7 carbon atoms; 2C )i where n3is an integer from 0 to 3; H 0- 2 COOH CH 2

(CH

2

-CH-.CH

2 -0)1 fI *where nf' is an integer from 1 to 6, preferably from 2: to 4;

(CH-CH

2 -O)nf Rif where R. f H, CH 3 and nf is an integer f rom 1 to 6, preferably from 2 to 4; and G roup VIA), where t 1, 2 1 (Ia)

COR

3 coo (R (R 2 nI nI (Ib) where:

R

1 is group OCOR 3 where R 3 is methyl, ethyl or a linear 3 or branched C 3

-C

5 alkyl, or the residue of a single-ring heterocycle having 5 or 6 atoms which can be aromatic, partially or totally hydrogenated, containing one or more heteroatoms independently chosen from O, N and S;

R

2 is hydrogen, hydroxy, halogen, a linear or whenever possible branched alkyl having from 1 to 4 C atoms, a linear or whenever possible branched alcoxyl having from 1 to 4 C atoms; a linear or whenever possible branched perfluoroalkyl having from 1 to 4 C atoms, for example trifluoromethyl, nitro, amino, mono- or 32 di (Cl 4 )alkylamino; Rand R 2 jointly are the dioxyrnethylene group, with the proviso that when X NH, then X 1 is ethylene and R= H; R 1 cannot be OCOR 3 at position 2 when R 3 is.

methyl; nI being an integer from 0 to 1; preferably in Ia) X is equal to 0 or NEl, R, is acetoxy, preferably at position 3 or 4, most preferably in the ortho position to Co. X 1 is ethylene or (CH 2

CH

2

O)

2 R2is Hydrogen or lialogen, most preferred are the following A X 1

-NO

2 compounds: 3-acetoxy-N-(2-litffoxyethyl) -benzamide, 4-acetoxy-N- (2-nitroxyethyl) -benzamide, 3 -ace toxy-N- (5 -ni troxypenthyl) -benzamide, 2-acetoxy-N- (5-nitroxypenthyl) -benzamide, N-2- (nitroxy- :::*ethyl) -2-propionoxybenzamide, 2-acetoxy-2-flitroxyethylbenzoate, 2-acetoxy-N- (cis-2-nitroxycyclohexyl) benzamide, 2-acetoxy-4-chloro-N- (2-nitroxyethyl) -benzamide, N- (2-nitroxyethyl) (4-thiazolindinyl) carbonl- *.:yloxy) -benzamide hydrochloride, 2-nicotinoyloxy-N- (2nitroxyethyl) -benzamide, 2-acetoxy-75-nitroxypeflthylbenzoate; preferably in Ib) R 3

CH

3 nI 0; X is equal to 0, X 1 is ethylene; in this case Ib) is the residue of acetylsalicylsalicylic acid.

In a further aspect there is provided use of compounds having the following general formula for the preparation of medicaments for the treatment of gastrointestinal tumours:

A-X

1

-NO

2 or their salts, where: -A R(COX) t where t is an integer 0 or 1; X 0, NH, NRic where Ric is a linear or branched alkyl having from 1 to 10 C atoms; R is chosen from the following groups: S: Group I where t 1,

R

RII

3 S* IL2 "o R116 RIIIb (LAb) where:

R

115 is H, a linear or whenever possibDle branched c 1

-C

3 alkyl;

R

1 1 6 has the same meanings as RIT 5 or when RTTS is H it can be benzyl;

RI

13

R

11 an d R 11 are eaual or dif-ferent one from the other and are hydrogen, linear or whenever Dossible branched C 1 -C6 alkyl or Ci-C 6 alkoxy, or Cl, F, 1Br; R14is RI1or bromine; preferred are the compounds where R 1 1 1

R

1 1 2 and R1 :are H, and R 1 1 3 is Cl and R 1 1 3 is in the ortho position to NH; RII 5 and R 1 1 6 are H, X is equal to 0, and xi is (CH2-CH2-O)2; (I Ab) is the residue of 2-[2-methyl-3-(trifluoromethyl) phenyl] amino] -3 -pyridinecarboxylic acid and when -COOH is present it is known as flunixin.

The compounds preferred are those where X =0; *II A) chosen-from the following: where, when t R is R 2 a R la 3a where R aand R 3 a are LI, a linear or whenever possible branched substituted or non-substituted C 1

-C

1 2 alkyl, allyl, with the proviso that when one of the two is allyl the other is H; prceferably R 2 a is H, alkyl has from 1 to 4 C atoms, R3a -is H; Ria is chosen from II Aa)

-LI)

MmI)

R

*C H (:fl (XG)av

(VI)

4*4* 4.

4 4* 4 *4 *4 4 4 4 444444 4 4 /V2 4. 4 4 44 4 44 H 3C

CH

0N where meanings are as follows: in the comoounds of formula residue of ketoprofen: RIIII is H, SRIII 3 where RI 11 3 contains from 1 to- 4 C linear or whenever possible branched C atoms; RIII2 is H, hydroxy; preferred are the compounds where RIMII and RIII2 are H, R 3 a is H, and R 2 a is methyl, X 0; in the compounds of formula (XXI), residue of carprofen: Rio is H, a linear or whenever possible branched alkyl having from 1 to 6 carbon atoms, a Cl-C 6 alkoxycarbonyl bound to a C -Cg alkyl, a C--C 6 carboxyalkyl, a

C

1

-C

6 alkanoyl, optionally substituted with halogen, benzyl or halobenzyl, benzoyl or halobenzoyl; R;i is H, halogen, hydroxy, CN, a C 1

-C

6 alkyl optionally containing OH groups, a C 1

-C

6 alkoxy, acetyl, benzyloxy, SR-xi 2 where Rxxi2 is a CI-C 6 alkyl; a perfluoroalkyl having from 1-3 C atoms, a CI-C 6 carboxyalkyl ootionally cont-aining OH groups, NO, sulphamoyl, dialkyl sulphamoyl with the alkyl having from 1 Co 6 C atoms, or difluoroalkylsulphony1 with the alkyl having from 1 to 3 C atoms; Rxi is halogen, CN, a C 1

-C

6 alkylI conctaining one or more OHi groups, a C 1

-C

6 alkoxy, acetyl, acetamido, benzyloxy,

SR

1 1 1 3 is as above defined, a perfluoroalkyl having from 1 to j C atoms, hydroxy-, a carboxyalkyl having from 1 to 6 C atoms, NO 2 amino, a mono- or dialkylamino having f rom 1 to 6 C atoms, suiphamoyl, a dialkyl sul-pha moyl having from 1 to 6 C atoms, or difluoroalkylsulphamoyl as above defined; or Rxxi jointly with Rxxil is 9 an alkylene dioxy having from 1 to 6 C atoms; preferred are. the comrpounds whrere Rxx 0 o is H, the connecting bridge is at position 2, RP 1 is H, Rx; is chlorine and is in the para position to nitrogen;

R

3 a is H_ R 2 a is methyl and X is 0; -in the comoounds of formula (xxxv) residue of thiaprofenic acid: Ar is phenyl, hydrox-yphenyl optionally mono- or- p0 lysubstituted with halogen, an alkanoyl or alkoxy having from 1 to 6 C atoms, a t-rialalkyl having -rom 1-6 C atoms, preferably from 1-3 C atoms, cyclopencyl o-hexy o-heptyl, he-arcaryl, preferably chienyl, furyl oocionally conta:-ing OE, pyridyl; the oreferred compounds of formula (XXXV) are those where A- is phenyl, R 3 a is H, R 2 a is methyl and X is O; tne compounds of formula residue -of suprofen, the preferred, where R 3 a H, R 2 a CH 3 and X 0; in the comoounds of formula (VI), of which the preferred, indoprofen, when R2a is CH 3 or X= 0; of which the preferred, etodolac, when R 3 a R2a H and S. X 0; in the compounds of formula (VII), of which the preferred, fenoprofen, when R 3 a H, o R 2 a CH 3 and X 0; in the compounds of formula (III), of which the preferred, fenbufen, when R 3 a R2a H and X 0; in the compounds of formula residue of tolmetin, when R 3 a R 2 a H and X O; in the compounds of formula residue of flurbiorof en, When R3a R 2

C

3 r-x=0 I I Ab): ~ITa) H C 3 -In (YxXXf UI) E C 7 0 i0i O I 0 0z 0 00 where the mea-nings are as follow s: hn ia cnais-GCH-COOu it is known as pranoprofen: a-methyl-5H- benzooyr-an (2,3-b]Oyr2-Jdife-7 acetic acid; preferred R 2 a H, R a=CL- and X 0; -when residue (XXX) contains -CH (CG 3 )-COOH-- ;t is5 Ic-iow as bermnoorofen: dibenz oxeoin-2-acer-c acid, oreferred is X 0, Ra 14H, R Cresidue XJXI) is known as CS-670: 2-[4-(2-oxo-lcyclohexy1ideneme hyl) phenylj roci on ic acid, when the radical is -CH'(C 3 )-COOH; oreferred

R

2 a H, Rja CH 3 and X 0; residue (XXXII) derives from the known Demedolac which contains group -CH 2 COOH, oreferred R 2 a R3a H and X 0; when residue (XXXIII). is saturated with -CH 2 COOH it is known- as pyrazolac: 4-(4-chlorophenyl) -l-(4-fluorophenyyl)3-pyrazolyl acid derivatives; preferred

R

2 a R 3 a H and X 0; when residue (XXXVI) is saturated with -CH(CH 3

)-COO-

it is known as zaltoprofen. When the residue is saturated with a hydroxy or amine group or the acid salts, the compounds are known as dibenzothiepin -derivatives.

Preferred R2a H, R3a CH 3 and X 0; when' residue (XXXVII) is CH 2 -COOH it derives from the known mofezolacz 3,4 7di (p-methoxyphenyl) isoxazol 5 acetic acid; preferred are R 2 a R 3 a H, t 1, X 0.

Group IIIA), where t 1, RIVd RIV C

RI

RIVd where: RIVd and RIvdi are at least one H and the other a linear or whenever possible branched C 1

-C

6 alkyl, preferably C.

and C 2 or difluoroalkyl with the alkyl having from 1 to 6 C atoms, preferred is C 1 or RIVd and RIVdi jointly form a methylene group; RIV has the following meaning: CCx where the comoounds of group have the following meanilngs: in the comocu-nds of formula Rii is an alkyl having f rom I to 6 C aos cycloalkyl having fLrdm 3 to 7 C atoms, an alcoxymnethyl having from 1 to 7 C atoms, a trifluoroalkyl having from 1 to 3 C at oms, vinyl, ethynyl, halogen, an alkoxy naviffg from 1 to 6 C atoms, a difluoroalkoxy with the alkyl having from 1 to 7 C atoms, an alkoxyrnethyloxy having from 1 to 7 C atoms, an alkylthiomethyloxy with the alkyl having f rom 1 to 7 C atoms, an alkylmethylthiJo vwith the alkyl having from 1 Co 7 C atoms, cyano, difluoromethylt-kio, a substituted phenyl- or phenylalkyl with the alkyl having from 1 to 8 C atoms; preferably RIV 1 1 I is CH 3 O, RIVd is H and RIVdi is CH 3 and is known as the residue of naproxen; X =NIH and X 1 is equal to (Cg 2 4 or (CHCHO; also preferred is the same compound where X is equal to 0; in the Dreferred compounds of formula for which the residue of loxoorofe-n has been shown, RIVd is H and RIvdl is CH3 X NH or 0 and X 1 is equal to (CH 2 4 or

(CH

2

CH

2 0) 2; in the comoounds of formula RIV-IIr is a C 2 alkyl, even branched when possible, a C 2 a-nd C 3 alkyloxcy, allyloxcy, phenoxy, phenylthio, a cycloalkyl having from 5 to 7 C atoms, optionally substituted at position 1 by a C 1

-C

2 alkyl; preferred is the compound where Riv-iri is CH 3

CH-CH

2 and Riva P, iv 1 is C, a conpoounci known as the residue of ibu-irofen; X H and X, is equal to or(CFT- 2

CH

2 0) 2 also preferred is the sameco- Dound where X =0; *Group) IV A) CH 3 0CHZ1 (IV A) where A =RCOO, t =1, ot whi-ch the residue of the kcnown indornetzhacin has been shown.

*Group V A) chosen from the following: -V Aa) fenamaues chosen from the followinlg, whe2re z

/NHCH-

2

CH

2 (V AaJJ)

CF

3 (V Aa2) *.cl CH 3 *c 1 (V Aa3) I NH

CH

3

CH-

3 (V Aa4) (V Aa5) H3 CC -V Ab), derivatives of niflunic acid, where c. 1: CF 3 N NH (V Abi) -V Ac), COX 2 inhibitors, where t 0 and R is as f ol lows: N SO 2

CH

3 0 Y RVAl a a.

NO

2 (V Ac uN 0 0

H

(V Ac2)

NF

F

(V Ac3) CH CH 2 3

S\

0 /0 CH 3 (V V Ad) derivatives of diuretics who"n t 1 and R is as f ollows: 0 0

I

0 00 I(V Ad2) HH 2 j H3C (V Ad3)

NH

0 0 0 (V Ad4) V Ae) derivatives of diuretics when t 0 and R is as f ollows:

H

a a I. a. 'a a a a (V Ael) a. a.

H I o 3 y 3

CH

(V M2)

NN

N

7 JlNH

N=N

(V Ae3) 00 0 H N 3C

H

(V Ae4) 0 0 0 0

HNAN

(V 0 0 '0 (V Ae6) *0 .00 0 0

HNH

(V Ae7) 0 NH 0 0

N"

(V Ae8) 0 0 0 HN ~NH (V Ae9) 9 a a..

H b (V AeLi3) a a.

COOH

H 0 2Nx 0 0 (V A&1-2) where The mea7, nq Li cr-our V A) as follows: in comoounds (v aai) tihe res_'cu'_ cf enfenamlc acid, 2- ((2-oheniviezhyI)a.inolben-zo-"c acJz_, 'nas been' sh~own; -in comoounds (V Aa2) Lhe residue~ of flu-Fenamj.-c acid, 2-t[3-(urif- uoromec*hy)oe-y1]-amnoj'elzo1c acid, has been shown; in compounds (v Aa3) the residue of meclofenamic acid, 2- [(2,6-dictiloro-3-methypheny) ainlo)benzoic acid, has been shown; in compounds (V Aa4) the residue of mefanamic acid, 2- 3-dimethylphenyl) amino] belzoic acid, has been shown; -in compounds (V Aa5) the residue of-l tolfenamic acid, 2- (3-chloro-2-methylphenyl)amiflo]benzoic acid, has been shown; .see 0006- in compounds (v AI,1) the residue of niflumic acid, (trif luoromethyli phenylaminlo] -3-pyridine carboxylic acid, has been shown; in compounds (V Acl)Rvacl attLached to the oxygen atom in position 2 of the benzene ring of N-.(4-rnitrophenyl)methansulphonamide can be phenyl or cycloexa-ne.

When 1 Pvacl is phenyl the residue is zhat of nimesulide; in compounds (V Ac2) Lhe residue of 3-formylamino-7me Chylsu onyain -6opheno4H !be zooyan4or)e has been shown; in compoands (V Ac3) the atom X4 that links the radical 2,4-difluorothophelyj to position 6 cf: the indanone ring o-f the re sidue 5 -methanesulrFofamido-i-g-aanone can be sulfur or oxygen; incomounds (V Ac4) the residue of celecoxib (4-methylphenyl) (trifluoromfethyl)pyrazollylI benzensuiphonamide, has been shown; 06 -in compounds (V Ac5) the residue of 6-[2-(3-ethyl- 2 ,3-dihydro-thiazolyl) thio-5-methanesulphonamido- 3

H-

~isobenzonfuranl-ofle has been shownl.

in compoundas (v Adi) the residue of burnetanide 3- *ee.: 0 (Aminosulfonyl) (butylano) 4 -phefloxybenzoic acid has been shown; 6@O@ -in compounds (v Ad2) the residue of ticrynafen [2,3- Dichloro-4- (2-thienylcarbonl) -phenoxyl acetic acid has been -shown; in comoounds (V Ad3) the residue of ethacrynic acid [2,3 -Dichloro-4- 2 -methyleneoxobutyl) pheoylaei acid, has been shown; in comoounds (V Ad4) the residue of piretanide 3- (Aminosulfoly 1 4 -ohenoxy5-(1-pyrrolidinyl)b-zi acid has been shown.

-in cornpournds (V Ael) the res riocamnide (3acy,, Cy, 7 L, 7 aa) 3- (Aminosulohovlj -CnIorO -N -(oc *aidro 47 -retano-2H-isoindol 2 y) benz~a--'d=- has been shown.

n comoounds (v Ae2) the residu=_ of Lorsemide Methylethyl) amiino] carbonyl] 4 Cj (3 -me--nylohenyl) amino] -3 pyrinesulfonamide has been shown; -in corrrounds (V Ae3) the residue of azosernide 2-Chfo- (lH- tetrazol -5S-yl) -4 (2 -thi en--vmethy1) amrinol benzensulpDhonanmide has been shown; in comDounds (V Ae4) the residue of bendroflumethiIazide 3,4-Dihydro-3 (phenyl-methyl) (trif luoromethyl) 2 H- 1, 2, 4-benzothiadiazine- 7 -sulf onamide 11 dioxide has been shown; -in compounds (V AeS) the residue of chiorothiazide G-Chloro-2H-1,2,4-benzothadiazine-7sufonamide 1,1dioxide has been shown; -in compounds (V Ae6) the residue of hydrochiorotiazide 6-Chloro-3, 4-dihydro-2H-1, 2, 4-banzothiadiazine-7sulfonamiude 1,1-dioxide has been shown; in compounds (V Ae7) the residue of" methylciothiazide (6-Chloro-3-(chloromethy)-3,4dihydro-2-mehyl-2HI- 1,2, 4-benzothiadiazine-7-sulfonamide i, i-dioxide has been shown; -in comoounds (V Ae8) TIhe residiue of chiorthalidone 3-dihydro-1-hydroxy-3-oxo-lH-isoildol-lvl)benzensulfLonamide has been shown'; in comoounds (V Ae9) the residue of Indaoamide 3- (Aminosulfonyl)-4-chloro-N- (2,3-dihydro-2-methyl-lHindol-l-yl)benzamide has been shown; in compounds (VAelO) the residue of retolazone 7- Chloro-1,2, 3, 4 -tetrahydro- 2-methyl 3 (2 -methyiphenyl) 4-oxo-6-cniinazolinesulfonamide has been shown; in compounds (V Aell) the residue of quinetazone 7- Chloro-2-ethyl-1, 2, 3, 4-tetrahydro-4-oxo-6-quinazoli-nesulfonamide has been shown; -in .compounds- (V Ael2) the residue of furosemide (Aminosulfonyl) -4-chloro-2- CI (2-furanylmethyl) amino] benzoic acid has been shown.

Xin formula A-X 1 -N0 2 is a bivalent connecting bridge chosen from the following:

YO

where Y is a linear or whenever possible branched C 1

-C

20 alkylene, preferably having f rom 2 to 5 carbon atoms, or an optionally substituted cycloalkylene having .:rom 5 to 7 carbon atoms;

(CH

2 n3 where n 3 is an integer from 0 to 3; H UNU2 where nf' is an integer from 1. to 6, preferably from 2;to 4; Rif where Rif H, CH 3 and nf is an integer f rom 1 to 6, preferably from 2 to 4; and Group VIA), where t =1, 0 2 1 (la)

COR

3 coo 2 1 (R (R nI 1nl (Ib) where:

R

1 is group OCOR 3 where R 3 is methyl, ethyl or a linear or branched C 3

-C

R

2 is hydrogen, hydroxy, halogen, a linear or whenever possible branched alkyl having from 1 to 4 C atoms, a linear or whenever possible branched alcoxyl having from 1 to 4 C atoms; a linear or whenever possible branched perfluoroalkyl having from 1 to 4 C atoms, for example trifluoromethyl, nitro, amino, mono- or di (C- 4 alkylamino; Rand R 2 jointly are the dioxymethylene group, with the proviso that when X NEH, then xiis ethylene and R2=H; R 1 cannot be OCOR 3 at position 2 when R 3 is.

methyl; nI being an integer from 0 to 1; preferably in Ia) X is eq-ual to 0 or NIH, R 1 is acetoxy, preferably at position 3 or 4, most preferably in the ortho position to Co. is ethylene or (CH 2

CH

2

O)

2

R

2 is Hfydrogen or hialogen, most preferred are the :following A X 1 V0 2 compounds: 3-acetoxy-N-(2-nit~oxyethyl) -benzamide, 4-acetoxy-N- (2-nitroxyethyl) -benzamide, 3-acetoxy-N- (5-nitroxypenthyl) -benzamide, 2-acetoxy-N- (5-nitroxypenthyl) -benzamide, N-2- (nitroxyethyl-)-2-propionoxybenzamide, 2-acetoxy-2-nitroxyethylbenzoate, 2-acetoxy-N- (cis -2 -nitroxycyclohexcyl) benzamide, 2-acetoxy-4-chloro-N- (2-nitroxyethyl) -benzamide, N- (2-nitroxyethyl) (4-thiazolindinyl) carbonlyloxy) -benzamide hydrochloride, 2-nicotinoylo'cy-N- (2nitroxyethyl) -benzamide, zoate; preferably in Tb) R 3

CH

In a still further aspect there is provided a method for the treatment of gastrointestinal tumours comprising administering to a patient in need of such treatment a compound having the general formula: A-Xi-NO 2 or their salts, where: -A R(COX) t where t is an integer 0 or 1; X 0, NH, -NRli where RIC is a linear or branched alkyl having from 1 to 10 C atoms; R is chosen from the following groups: Group I where t i, R* M 112

TIA

R

-c R 's I I 6

II

(IAa) (LMb) where:

R

115 is H, a linear or whenever oossible branched i3 alkyl;

RI

1 6 has the same meanings as R-or- when R,,S is H it can be benzyl;

RI

11

R

1 1 2 and R 1 1 3 are equal or different one from the other and are hydrogen, linear or whenever possible branched Ci-C 6 alkyl or Cj-C 6 alkoxy, or Cl, F, Br; R14is R 1 1 1 or bromine; preferred are the compounds where R 1 1 1

R

1 1 2 and R 1 1 4 :are H, and R 1 1 3 is Cl and R 1 1 3 is in the ortho position to NH; RIIS and RI 1 6 are H, X is equal to 0, and xiis (CH 2

-CH

2 -0) 2 (I Ab) is the residue of 2-[[2-rnethyl-3-(trifluoromethyl) phenyl) amino] -3-pyridinecarboxylic acid and when -COOH is present it is known as flunixin.

The compounds preferred are those where X 0; *II A) chosen- from the following: where, when t 1, R is

R

2 a RIa Cwhere R 2 and Rja are H, a linear or whenever oossible branched substituted or non-substituted Cl-C 1 2 alkyl, allyl, with the proviso that when one of the two is allyl the other is H; prceferably R 2 a is H, alkyl has from 1. to 4 C atoms, R3a -is H; Rla is chosen from II Aa) S.

S

SS

S.

(TT)

R.

rx

R

XDC:I

R

CrI Q~(IV) Az xyG-V)

(VI)

C R 2

(VIII)

(Ix) H 3 C-0

CH

'3 0N 0 C 2 wh~ere meanings are as follows: in the comoounds of' formula (TV) residue of ketoorof en:

R

1 1 1

I

1 is H, SR 1 1 1 3 where -R 1 1 1 3 contains from 1 to- 4 C linear or whenever oossible branched C atomis; is H, hydroxy; preferred are the comDounds where RIII, and R 1 1 1 2 are H, R3a is H, and R 2 a is methyl, X 0; -in the compounds of f ormula (XXI), residue of caz-pro- Rxxj is H, a linear or whenever possible brainched alkyl having from 1 to 6 carbon atoms, a Cl-C6 alkoxy-.

:'.0..carbonyl bound to a C 1

-C

6 alkyl, a CI--C 6 carboxyalkyl, a

C

1

-C

6 alkanoyl, optionally substituted with halogen, benzyl or halobenzyl, benzoyl or halobenzoyl; is H, halogen, hydroxy, CN, a Ci-C6 alkyl optionally containing OH groups, a C 1

-C

6 alkoxy, acetyl, benzyl- O~Y ~-W2where is a C 1

-C

6 alkyl; a Derfluoroalkyl having fLrom 1-3 C atoms, a C 1 -C carboxyalkyl optionally containing O14 grouos, NO 2 suinharnoyl, dialkyl sulphamoyl with the alkyl having r"rom 1 Lo 6 C atoms, or difluoroalkylsulphony. with the alky! having from 1 to 3 C atoms; R.i is halogen, CN, a C 1

-C

6 alky. conaining one or more OH groups, a C 1

-C

6 alkoxy, acetyl, ace~amido, benzyloxy,

SR

1 1 1 3 is as above defined, a perfluoroalkyl having from I to 5 C atoms, hydroxy, a carboxyalkyl having f rom 1 to 6 C atoms, NO 2 -amino, a mono- or dialkylamino ha.- *:ving from 1 to 6 C atoms, suiphamoyl, a dialkyl sulhamoyl having from 1 to 6 C atoms, or difluoroalkylsulphamoyl. as above defined; or R~x jointly with Rxx 1 is alkylene dioxy having from 1 to 6 C atoms; preferred are the compounds where Rxi is H, the connecting bridge is at position 2, Rxx is H4, Rxx 1 is V*690 chlorine and is in the para. position to nitrogen; R 3 a i- H_ R 2 a is methyl and X is 0; -in the compounds of formula (XXXV) residue of thiaprofenic acid: Ar is phenyl, hydroxyphenyl optionally mono- or Dolysubstituted with halogen, an alkanoyl or alkoxy having from 1 to 6 C atoms, a trialalkyl having zrom 1-6 C atoms, preferably from 1-3 C atoms, cyclopentyl c-*exyl o-heptyl, herercary, preferably thieny, ury opionally conai.ing OH, pyridyl; the preferred compounds of formula (XXXV) are those where Ar is phenyl, R 3a is H, R2a is methyl and X is O; in the compounds of formula residue -of suorofen, the preferred, where R 3 a H, R 2 a CH3 and X 0; in the comoounds of formula (VI), of which the preferred, indoprofen, when R2a is CH 3 or indobufen, when R 2 a is equal to H and R 3 a CH3 and X 0; in the compounds of formula (VIII), of which the preferred, etodolac, when R 3 a 2 H and S X O; in the compounds of formula (VII), of which the preferred, fenoprofen, when R 3 a H,

R

2 a CH 3 and X 0; do 0 0 in the compounds of formula-(III), of which the preferred, fenbufen, when R 3 a R2a H and X 0; in the compounds of formula residue of tolmetin, when R 3 a R 2 a H and X 0; in the compounds of formula residue of flurbiorof an, whben R3 E R 2 cz ar A 0; II Ab) NC

I

(UX

*68 0 x~.I H 3C 7

N\

*F

I'

wher th ennsar sflos whe 9@a otis-C(H)CoHi i nw sp norfn a-ehl5-l bezprn(,-bp*-d-e7 acti acd.rfre.Ra=H OadX=0 whe reiu otis i M w as be orfn .iezC~ )oei--c~caioe f ered s X= 0 R~ Cx Ra =Oi) residue XXXI_-) iJs known as CS-670: 2 4 2ool cy clohexylideneme -hy1)phenyllprooc-on -c acid, when the radical is -Ci-(cH 3 -COOH; oref erred R 2 a Rja CHij and X =0; -residue (XXXII) derives f'rom the known oemedolac which contains group -CH 2 COOH, Drer"'erred R 2 a =R 3 a =H and X 0; when residue (XXXIII). is saturated with -CH 2 COOH it is known- as pyrazolac: 4- (4-chiorothenyl) luoro- 0 0 0 pherryl) 3-pyrazolyl acid derivatives; preferred o R2a =R3a H and X 0; -when residue (XXXVI) is saturated with -CH(CH 3

-COO-

it is known as zaltoprof en. When the residue is saturao 0..:ted with a hydroxy or amine group or the acid salts, the compounds are known as dibenzothiepin -derivatives.

Preferred R2a H, R~a CH 3 and X 0; -when' residue (XXXVII) is CH 2 -COOH it derives from the o ~known mofezolac 3, 4 di (p-methoxyphenyl) isoxazol- acetic-acid; preferred are R 2 a R 3 a H, t 1, X =0.

*Group IIIA), where t =1 RVd RIv C- RIVdi where: RIVd and RIVdl are at least one H and the other a linear or whenever possible branched C 1

-C

6 alkyl, preferably C 1 and C 2 or difluoroalkyl with the alkyl having from 1 to 6 C atoms, preferred is C 1 or RIvd and RIVdl jointly form a methylene group; RIV has the following meaning: 9

(II)

II)

where the compounds of group IIIA) have the following meanings: in the comoounds of formula (II): Rri Isa alkyl having f rom I L~o 6 C atoms, a cycloalkyl having from 3 to 7 C atoms, an alcoxymethyl having from 1 to 7 C aztoms, a trif-uoroalkyl having from 1 to 3 C atoms, vinyl, ethynyl, halogen, an alkoxy .naving frm1t Caos adluoroelkoxy with the alkyl having from 1 to 7 C atoms, an alkoxyrnethyloxy having from 1 to 7 C atoms, an alkyithiomethyloxy with the alkyl having f rom 1 to 7 C atoms, an alkylmethylthi, -with the alkyl ha-ving j"from 1 Co 7 C atoms, cyano, difluoromethyithia, a substituted phenyl- or phenylalkyl with the alkyl having from 1 to 8 C atoms; preferably RIv-II is CH 3 O, RIVd is H and RIVdl is CH3, and is known as the residue of naproxen; X NTH and X1is equal to 2 4 or (CH 2

CH

2

O)

2 also p~referred is the same compound where X is equal to 0; in the Dref erred compounds of formula WX) for which the residue of loxoprof en has been shown, R~v is H and RIvdl is- CH 3 X NHL or 0 and Xi is equal to (.CH 2 4 or

(CH

2

CH

2 O) 2' in the comoounds of formula RIv 1

I

1 I is a C 2

-C

5 alkyl, even branched when possible, a

C

2 and c 3 alkyloxcy, allyloxy, phenoxy, phenylthio, a cycloalkyl having from 5 to 7 C azioms, optionally substituted at position 1 by a C 1

-C

2 alkyl; preferred is the compound where Rjv-III is CH 3

CH-CH

2 CH 3 and Rrvd F, R Ivd 1 is C- 3 a coirnou-ia known a5 the residue of ibu-profen; X NUH and is equal to or,' (CH2{rC1 2

O)

2 also oreferred is' the same cornound where X 0; *Group IV A) 3j (IV A) where A =RCOO, t =1, at whi-ch the residue of the knowti indornezhacin has been show-n.

*Group V A) chosen from the following: -V Aa) fenamaces chosen from the following, where

NHCH-

2

CH-

2 (V Aal) NEl

CF

3 (V Aa2) ci CH 3

NH~

(V Aa3)

CH

3 CH- 3 (V Aa4) (V AaS) H3 CC -V Ab), derivatives of nif lurnic acid, where L 1: CF 3 N NE (V Abi) -V Ac), COX 2 inhibitors, where t 0 and R is as f ollows: a.

a R V Acl N0 2 (V Ard)

H

N 0 0 0 y (V Ac2) N* F 0 0.

H:L

F

(V Ac3) 2 3 0 S- N C3 1 (V -V Ad) derivatives of d±uretics when t 1 and R is as f ollows: 0 0 (V Adl) 0 (V Ad2) (V Ad3) NHi 0 0 0 (V Ad4) V Ae) derivatives of diuretics whnt =0 and R is as f ollows: 0 0 H N N (V Ael) H to 3 N.

C

3 0 (V Ae N N N N (V Ae3) 0 0 0 0 H NN HN S NH H N (V Ae) 0 0 0 H N -IsNH kz! Il (V Ae6) 0 0 o00 (V Ae7) 0 NH 0 0 HO (V Ae) 0 0 0 HN

NH

N

CH

2 cl (V Ae9) <9 a.

a.

a. a a.

a. .a a a a. a

H

C

H (V Aell) a a a a.

COCH

H 0 0 0 Ci (V AeI2) where The rean~ng Z2OU cu V A) L- as -01lOWS: ip. comoouncs (v Th rs zeo en'.:namlc acid 2- ((2-ohenvierhy1)a,-inolbenzoic acic, has been showni; in comoounds (V Aa2) the residue of flufenamic acid, 2- [(3-(r-rif'luorom-echy1)oheny]-amnoi"-elzoic acid, has been shown; in comp~ounds (v Aa3) the residue of meclofenamic acid, 2- C (2,6-dichiloro-3-methylphenyl) aminlo)benlzoic acid, has been shown; in compounds (V Aa4) the residue o:-l mefanamic acid, 2- 3-dimethylphenyl) amino]lbenlzoic acid, has been shown; 0. to in compounds (V Aa5) the residue of tolfenamic acid, 2- ((3-chloro-2-methylphelyl) amino] benzoic acid, has *been shown; in compounds (V Abi) the residue of nif lumic acid, 2 (trit luoromethyl) phenyl]. amino] -3 -pyridine carboxylic acid, has been shown; -in compounds (V Adl) Rvacl attached to the oxygen atom in position 2 of the benzene ring of N-(4-nicrophenyl)metha-nsulphonamide can be phnenyl or cycloexa-rne.

When Rvaci is phenyl the residue is zhat of nimesulide; in compounds (V Ac2) the residue of 3-formylamino- 7 me thylsul foyl iaorniflheox-y-noY!-be z~oyan-one has been shown; -in compoundas (V Ac3) the atom X. tha links the radi- Cal 2 ,-difluorouhiophelyl to posi~iol 6 of the indanone .ring of residue can be sulfur or oxygen; in compounds (V Ac4) the residue of celecoxib (4-methylphenyl) (trifluoromfethyl)pyrazol--ll benzensuiphonamide, has been shown; 9:00- in compounds (V Ac5) the residue of 6-[2-(3-ethyl- 2,3-dihydro-thiazo1yl) thio-5-methafeu1phonamido- 3

H-

S. isobenzoffuran-1-one has been shown.

-in compounds (V Adi) the residue of bumetanide 3- (Aminosulfonyl) (butylamino) -4-phenoxybeflzoic acid has been shown; -in compounds (V Ad2) the residue of ticrynafen [2,3- Dichloro-4- (2-thienylcarbolyl) -phenoxy) acetic acid has -been -shown; in compounds (V Ad3) the residue of ethacry-nic acid 3 -Dichloro- 4- 2 -me thvlene-1 -oxobutyl) phenoxy) ace t c acid, has been showrn; in como~ounds (V Ad4) the residue of pireta-nide 3 -(Ami no su 1fony 1) 4- phenoxy 5- (1l-pyrrol idinyl) ben zo ic acid has been shown.

-in Co~mcurnds (V Ael) the residue= z:rioamride (3ac', a, 7c', 7 ac) 3- (AM ino s uloho nv'_ icl0ro N- (oc La id ro 4, 7 -recan-2Hisoindo-2-y)bena-4de has been shown.

in com:counds (v Ae2) the residue o torsernide N- C(I- Mi !hvlethy)anolcarbony!I4. (3 -methylheny1) amino] -3pyrinesulfonamide has been shown; -in comptounds (V Ae3) the residue of azosernide 2-Chic- (lH-tetrazol-s-yl) (2-thienvimethyl) amino] benzensulphonamide has been shown; -in corcpoukds (V Ae4) the residue of bendroflumethiazide 3,4-Dihydro-3- (phenyl-methyl) (trif luoromethyl) -211-1, 2,4-benzothiadiazine-7-sulfonamide 1,1- 000.

6-Chloro-2H-1,2,4-benzothjadiazine-7-sulfonahide 1,1- 0 00 dioxide has been shown;in cotroounds (V Ae6) the r esidue of hydrochiorotiazide 6-Chloro-3, 4-dihydro-2H-1, 2, 4-benzothiadiazilesulfonamde 1,1-dioxide has been shown; in comnoimds (V Ae7) the residue off met-hyiciothiazide (G-Chloro-3-(chloromethyl) -3,4-di-hydro-2-methyl-2H- 1, 2 ,4-benzothiadiazine-7-sulfonami de 1,1-dioxide has been shown; in comoouncis (V Ae8) he residue of chiorthalidone 2-Chloro-S-(2,3-dj-hyoro-l-hydroxy-3-oxo-l--soJifdol-lvl)benzensulf-onamide has been show-n; i n comoounds (V Ae9) the resizaue of Indaoamide 3- (Aminosulfonyl)-4-chloro-N-(2,3-dihydro-2-methyl-lHindol-1-yl)benzamide has been shown; in compounds (VAe1O) the residue of metolazone 7- Chloro-1,2,3,4-tetrahydro-27-methyl- 3 (2-methylphenyl) 4-oxo-6-a~uinazolinesulfonamide has been shown; -in compounds (V Aell) the residue of quinetazone 7sulfonamide has been shown; -in compounds- (V Ae12) the residue of furosemide (Aminosulfonyl) -4-chloro-2- [(2-furanylmethyl) amino] benzoic acid has been shown.

-YO

where Y is a linear or whenever possible branched C 1

-C

20 alkylene, preferably having from 2 to 5 carbon atoms, or an optionallv substituted cycloalkylene having :rom 5 to 7 carbon atoms; (CHi 2 n3 where n3is an integer from 0 to 3; H 0- 2 UNU2 whr-f is ac 2 cH-n itge roo)o ,prfrbl rm 0 2 where Rf H H n nf is an integer f rom 1 to 6, peeal rm2 tofral 4;m2to4 n *Group VIA), where t =1, 2 1 (Ia)

COR

3 (R R 1 (Ib) where:

R

1 is group OCOR 3 where R 3 is methyl, ethyl or a linear or branched C 3

-C

R

2 is hydrogen, hydroxy, halogen, a linear or whenever possible branched alkyl having from 1 to 4 C atoms, a linear or whenever possible branched alcoxyl having from 1 to 4 C atoms; a linear or whenever possible branched perfluoroalkyl having from 1 to 4 C atoms, for example trifluoromethyl, nitro, amino, mono- or li (C, 1 4 )alkylamino; Rand R 2 jointly are the dioxymethylene group, with the proviso that when X =Nil, then xiis ethylene and P= H; R 1 cannot be OCOR3 at position 2 when R 3 is methyl; nI being an integer f rom 0 to 1; preferably in Ia) X is equal to 0 or NH, R 1 is acetoxy, preferably at position 3 or 4, most preferably in the ortho position to CO. X 1 is ethylene or (CH 2

CH

2

O)

2

R

2 is Hy~drogen or hialogen, most preferred are the following A X 1

-NO

2 compounds: 3-acetoxy-N-(2-nitffoxyethyl) -benzamide, 4-acetoxy-N- (2-nitroxyethyl) -benzamide, 3-acetoxy-N- (5-nitroxypenthyl) -benzamide, 2-acetoxy-N- (5-nitroxypenthyl) -benzamide, N-2- (nitroxyethyl) -2-propionoxybenzamide, 2-acetoxy-2-nitroxyethylbenzoate, 2-acetoxy-N- (cis-2-nitroxycyclohexyl) benzamide, 2-acetoxy-4-chloro-N- (2-nitroxyethyl) -benzainide, N- (2-nitroxyethyl) ((4-thiazolindinyl)carbonyloxy)-benzamide hydrochloride, 2-nicotinoyloxyN(2nitroxyethyl) -benzamide, 2-acetoxy-- zoate; preferably in Ib) R 3

CH-

In V Aa): in compounds (V Aal) the residue of enfenamic- acid, 2-[(2-phenylethyl)amino]benzoic acid, where COOH was substituted according to the present invention, has been shown.

This can be prepared according to the Indian patents 103.066 and 114.805, herein incorporated by reference. Equivalent products containing various substituents as described in said patents can be used, too.

In compounds (V Aa2) the residue of flufenamic acid, 2- [[3-(trifluoromethyl)phenyl]-amino] benzoic acid, where COOH was substituted according to the present invention, has been shown.

This can be prepared according to Wilkinson's article, Finar, J.Chem.Soc. 1948, 32, herein incorporated by reference. Any equivalent product containing various substituents as described in said article can be used, too.

In compounds (V Aa3) the residue of meclofenamic acid, 2-[(2,6-dichloro-3-methylphenyl)amino]benzoic acid where COOH was substituted according to the present invention, has been shown.

This can be prepared according to the German patent DE 1.149.015 and USP 3.313.848 herein incorporated by reference. Any equivalent product containing various substituents as described in said patents -can be used, too.

In compounds (V Aa4) the residue of mefenamic acid, 2-[(2,3-dimethylphenyl)amino] benzoic acid where COOH was substituted according to the present invention, has been shown.

This can be prepared according to the Belgian patent 605.302, herein incorporated by reference. Any equivalent product containing various substituents as described in said patent can be used, too.

S* In compounds (V Aa5) the residue of tolfenamic acid, 2-[(3-chloro-2-methylphenyl)amino] benzoic acid where COOH was substituted according to the present invention, has been shown.

This can be prepared according to patent USP 3.313.848, *D -herein incorporated by reference. Any equivalent product containing various substituents as described in said patent can be used, too.

In V Ab): in compounds (v Abl) the residue of niflumic acid, 2-[[3-(trifluoromethyl)phenyl]amino]-3-pyridine carboxylic acid, where COOH was substituted according to the present invention, has been shown.

This can be prepared according to patent USP 3.415.834, herein incorporated by reference. Any equivalent product containing various substituents as described in said patent can be used, too.

In V Ac): in compound (V Acl)Ryvac attached to the oxygen atom in position 2 of the benzene ring of N-(4-nitrophenyl)methansulphonamide can be phenyl or cycloexane. When Rvacl is phenyl the residue is that of nimesulide.

This can be prepared according to patent USP 3,840,597 herein incorporated by reference. Any equivalent pro- "duct containing various substituents as described in said patent can be used, too.

In compounds (V Ac2) the residue of 3-formylamino- 7-methylsulfonylam-ino-6-phenoxy-4H-1-bezopyran-4-one was substituted according to the present invention, has been shown.

This can be prepared according to patent DE 3834204 herein incorporated by reference. Any equivalent product containing various substituents as described in said patent can be used, too.

In compounds (V Ac3) the atom X, that links the radical 2,4-difluorothiophenyl to position 6 of the indanone ring of the residue 5-methanesulfonamido-1-indanone can be sulfur or oxygen.

This can be prepared according to WO 9413635 herein incorporated by reference. Any equivalent product containing various substituents as described in said patent_can be used, too.

In compounds (V Ac4) the residue of celecoxib 4-[5(4methylphenyl) -3-(trifluoromethyl)pyrazol-l-yl] benzensulphonamide was substituted according to the present invention, has been shown.

This can be prepared according to patent WO 9427980 herein incorporated by reference. Any equivalent product containing various substituents e.g. WO 9515315- 318 as described in said patents can be used, too.

In compounds (V Ac5) the residue of 6-[2-(3-ethyl-2,3dihydro-thiazolyl)thio-5-methansulphonamido-3H-isobenzonfuran-1-one was substituted according to the present invention,, has been shown.

This can be prepared according to patent WO 9623786 herein incorporated by reference. Any equivalent product containing various substituents as described in said patent can be used, too.

In compounds (V Adl) the residue of bumetanide 3-(Aminosulfonyl)-5-(butylamino)-4-phenoxybenzoic acid was substituted according to the present invention, has been shown.

This can be prepared according to patent USP 3,806,534 herein incorporated by reference. Any equivalent product containing various substituents as described in said patent can be used, too.

In compounds (V Ad2) the residue of ticrynafen [2,3- Dichloro-4-(2-thienylcarbonyl)-phenoxy]acetic acid was substituted according to the present, has been shown.

This can be prepared according to patent USP 3,758,506 herein incorporated by reference. Any equivalent product containing various substituents as described in said patent can be used, too.

In compounds (VAd3) the residue of ethacrynic acid [2,3-Dichloro-4-(2-methylene-l-oxobutyl)phenoxy]acetic acid was substituted according to the present invention, has been shown.

This can be prepared according to patent USP 3,255,241 herein incorporated by reference. Any equivalent product containing various substituents as described in said patent can be used, too.

In compounds (V Ad4) the residue of piretanide 3-(Aminosulfonyl)-4-phenoxy-5-(1-pyrrolidinyl)benzoic acid was substituted according to the present invention, has been shown.

This can be prepared according to patent USP 4,010,273 herein incorporated by reference. Any equivalent product containing various substituents as described in said patent can be used, too.

In compounds (V Ael) the residue of tripamide (3aa, 4a, 7a,7a) -3-(Aminosulphonyl)-4-chloro-N-octaidro-4,7-methano-2H-isoindol-2-yl)benzamide was substituted according to the present invention, has been shown.

This can be prepared according to patent JP 73 05, 585 herein incorporated by reference. Any equivalent product containing various substituents as described in said patent can be used, too.

In compounds Ae2) the residue of torsemide N- [[(1-Methylethyl)amino]carbonyl]4-[(3-methylphenyl)amino]-3-pyrinesulfonamide was substituted according to the present invention, has been shown.

This can be prepared according to patent USP 4,018,929 herein incorporated by reference. Any equivalent product containing various substituents as described in said patent can be used, too.

In compounds (V Ae3) the residue of azosemide 2-Chloro- 5-(1H-tetrazol-5-yl)-4-[(2-thienylmethyl)amino]benzensulphonamide was substituted according to the present invention, has been shown.

This can be prepared according to patent USP 3,665,002 herein incorporated by reference. Any equivalent product containing various substituents as described in said patent can be used, too.

In compounds (V Ae4) the residue of bendroflumethiazide 3,4-Dihydro-3- (phenyl-methyl)-6-(trifluoromethyl)-2H- 1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide was substituted according to the present invention, has been shown.

This can be prepared according to patent USP 3,392,168 herein incorporated by reference. Any equivalent product containing various substituents as -described in said patent can be used, too.

In compounds (V Ae5) the residue of chlorothiazide 6- Chloro-2H-1,2,4-benzothiadizine-7-sulfonamide 1,1-dioxide was substituted according to the present invention, has been shown.

This can be prepared according to patent USP 2,809,194, USP 2,937,169 herein incorporated by reference. Any equivalent product containing various substituents as described in said patent can be used, too.

In compounds (V Ae6) the residue of hydrochlorotiazide 6-Chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide was substituted according to the present invention, has been shown.

This can be prepared according to patent DE 1,163,332, USP 3,043,840 herein incorporated by reference. Any equivalent product containing various substituents as described in said patent can be used, too.

0 In compounds (V Ae7) the residue of methyclothiazide (6-Chloro-3-(chloromethyl) -3,4-dihydro-2-methyl-2H- 1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide was substituted according to the present invention, has been shown.

This can be prepared according to patent Close et al., J.Am. Chem. Society 82, 1132 (1960) herein incorporated by reference. Any equivalent product containing various substituents as described in said patent can be used, too.

In compounds (V Ae8) the residue of chlorthalidone 2- Chloro-5-(2,3-dihydro-1-hydroxy-3-oxo-1H-isoindol-1yl)benzensulfonamide was substituted according to the present invention, has been shown.

This can be prepared according to patent USP 3,055,904 herein incorporated by reference. Any equivalent product containing various substituents as described in said patent can be used, too.

In compounds (V Ae9) the residue-of Indapamide 3-LAminosulfonyl)-4-chloro-N-(2,3-dihydro-2-methyl-JB-indoll-yl)benzamide was substituted according to the present invention, has been shown.

This can be prepared according to patent USP 3,565,911 herein incorporated by reference. Any equivalent product containing various substituents as described in said patent can be used, too.

In compounds (V AelO) the residue of metolazone 7-Chloro-1,2,3,4-tetrahydro-2-nethyl-3-(2-methylphenyl)-4oxo-6-quinazolinesulfonamide was substituted according to the present invention, has been shown.

This can be prepared according to patent USP 3,360,518 herein incorporated by reference. Any equivalent product containing various substituents as described in said patent can be used, too.

In compounds (V Aell) the residue of quinetazone 7-Chloro-2-ethyl-1,2,3,4-tetrahydro-4-oxo-6-quinazolinesulfonamide was substituted according to the present invention, has been shown.

This can be prepared according to patent USP 2,976,289 herein incorporated by reference. Any equivalent product containing various substituents as described in said patent can be used, too.

In compounds (V Ael2) the residue of furosemide nosulfonyl) -4-chloro-2- (2-furanylmethyl)amino] benzoic acid was substituted according to the present invention, has been shown.

This can be prepared according to patent USP 3,058,882 herein incorporated by reference. Any equivalent product containing various substituents as described in said patent can be used, too.

The processes for obtaining the compounds which contain R from groups I A IV A are described in patent application WO 95/30641 herein incorporated by reference.

The processes for preparing the compounds of class V A are those described above in application wo 95/30641.

It has been surprisingly found by the Applicant that, meaningfully, the products of the invention do not show reduced pharmacological activity compared to precursors. Conversely, they have a wider pharmacological range of action, since a synergy between the cyclooxigenase inhibiting effect and the myorelaxing effect related to the opening of potassium channels and/or release of nitric oxide, was unexpectedly observed in the lower urinary tract. The products of the invention exhibit a higher safety and do not induce tachyphylaxis.

The applicant found that in addition to treatment of urinary incontinence the products of the invention carry out a pharmaco-therapeutic activity in diverse appropriate experimental models, as described below: articular inflammation (musculoskeletal disease) in rats; see Winter C. et al., Caraggeenin-induced edema o0f in hind paw of the rat as an assay for antiinflammatory drugs, Proceedings of the Society for Experimental Biology and Medicine 1962, 111, 544-47; respiratory disease for example bronchospasm from bradykinin in Guinea pigs (Del Soldato P. et al., The anesthetized Guinea pig as a versatile pharmacological test object, Jour. of Pharmacological Methods, 1981 279-285); vascular disease, such as re-stenosis induced in rats (Role of kinins and nitric oxide in the effects of anigiotensin converting enzyme inhibitors on neointima formation, Fahry-RD et al., CIRC-RES. 72/6 (1202- 1210)1983); gynaecological and obstetrical diseases: as shown in hyperexcitability states in rat isolated myometrium (Izumi H. et al., Gestational changes in L-arginine-induced relaxation of pregnant rat and nonpregnant myometrial contractility, Am. J. Obstet.

Gynecol., 1993, 169, 1327-1337); blood platelet aggregation in women in a pre-eclampsia condition (Janes Sl et al., Flow cytometric detection of circulating activated platelets and platelet hyperresponsiveness in pre-eclampsia and pregnancy, Clin.

Science, 86, 731-739, 1994).

intestinal tumours, such as for example in experimental adenocarcinoma in rats (Dubois R. et al., Increased cyclooxigenase-2 levels in carcinogen -induced rat colonic tumors, Gastroenterology, 110,1259-1262, 1996) Therefore, based on the experimental results obtained the above products may be therapeutically useful in the following diseases, in addition to urinary incontinence: musculoskeletal disease of an inflammatory nature: group V A; respiratory disease, for example bronchitis, in particular asthma, etc.: compounds of the groups from I A to V A; gynaecological and obstetricial diseases, including premature delivery, pre-eclampsia and dysmenorrhoea: groups from I A to V A and, additionally, the comopounds from group VI A as defined below;e: vascular disease such as re-stenosis: compounds from groups I A to VI A; gastrointestinal tumour: compounds from groups from I A to VI A.

The compounds in group VI A, where t 1, include the 100 following: 2 1 (la)

OR

S

is group COR3; where R 3 is methyl, ethyl or a linear or 2 n 1l (Ib) .eb a c e C3where: or totally hydrogenated, containing one or more heteroatoms independently chosen from O, N and S; R is hydrogen, hydroxy, halogen, a linear or whenever possi- 2 .2 ble branched alkyl having from 1 to 4 C atoms, a linear or whenever possible branched alcoxyl having from 1 to 4 C atoms; a linear or whenever possible branched perfluoroalkyl having from 1 to 4 C atoms, for example trifluoromethyl, nitro, amino, mono-or di (Cl 4 )alkylamino; R1and R 2 jointly are the dioxymethylene group, with the proviso that when X NH, then X 1 is ethylene and R 2 H; R 1 cannot be OCOR 3 at position 2 when R 3 is methyl; fT being an integer from 0 to 1; preferably in Ia) X is equal to 0 or NH, R, is acetoxy, preferably at position 3 or 4, most preferably in the ortho position to CO. X, is ethylene or (CH 2

CH

2

O)

2

R

2 is hydrogen or halogen, most pr~f erred are the following A X, NO 2 compounds: 3-acetoxy-N- (2-nitroxyethyl) -benzamide, 4-acetoxy-N- 0%.(2-nitroxyethyl) -benzamide, 3-acetoxy-N- (5-nitroxypenthyl) benzamide, 2-acetoxy-N- (5-nitroxypelthyl) -benzamide, N-2- (nitroxyethyl) -2-propionoxybenzamide, 2-acetoxy-2-nitroxyethylbenzoate, 2-acetoxy-N- (cis-2-nitrOXycyclohexyl) benzaide,2-acetoxy-4-chloro-N- (2-nitroxyethyl) -benzamide,- N- (2-nitroxyethyl) (4-thiazolindinyl) carbonyloxy) -benzamide hydrochloride, 2-nicotinoyloxy-N- (2-nitroxyethyJ-) -benzamide, 2-acetoxy-5-nitroxypethyl1benzoate; 0 preferably in Tb) R 3

CH-

3 nI 0; X is equal to 0, X, is ethylene; in this case Tb) is the residue of acetylsalicylsalicylic acid.

The processes to obtain the compounds which contain R in group VI A are described in patent WO 95/30641 herein in- 102 corporated by reference.

The examples below are intended as an explanation not a limitation of the present invention.

EXAMPLES

Examples -1,2,3 and from 1A to 1F (comparison) Chemical synthesis The following compounds were prepared: NO-indomethacin NO-flufenamic NO-nimesulide

(NO-M),

NO-Naproxen (NO-N).

Preparation of NO-Indomethacin

(NO-I)

3-Hydroxybenzylnitrate 9.5 g Indomethacin 7.4 g SDicyclohexylcarbodiimide 5.6 g

CH

2 C12 200 ml were reacted and the solution was allowed to react overnight at zoom temperature, concentrated to a small volume and filtered. The filtrate was dried and passed through a column containing gel by using chloroform/ethyl acetate 14:1 as an eluting system. A head fraction was thus separated and purified by chromatography using a 2-mm silica plate. Each plate was run three times in a mobile phase made up of cyclohexane/ethyl acetate 6:1.

A yield of 85% was obtained of indomethacin-NO in group 103 IV A where R is residue (IV) of indomethacin; t 1; X 0 and X 1 is the connecting bridging, shown after YO, where n3 0, and having the general formula: I S- CH 3

CHO

3 0 CH 2 CCOO

CHONO

2 2 Preparation of NO-Flufenamic (NO-F) 3-Hydroxybenzylnitrate 6 g Flufenamic acid 13 g Dicyclohexylcarbodiimide 9.5 g

CH

2 C1 2 150 ml Ethyl ether 50 ml were reacted and it was allowed to react overnight, concentrated to a small volume and dicyclohexylurea was filtered.

The filtrate was dried and passed through a column-containing silica by using CH 2 C12 as an eluant. A head fraction was thus separated. This fraction was purified by chromatography using a 2-mm silica plate and a cyclohexane/ethyl acetate 6:1 system. Each plate was run three consecutive times. The 104 head fraction was recovered by extraction: with ethyl ether.

The ethereal extract was brought to dryness and gives a yellow oil and a yield of 801 for flufenamic-NO.

The 1 H NIVR analysis (CDCl 3 200 MHz) gave the- following data: (2H, 6.9 (1H, 7.4 (10H, in); 8.2 (1H, dd).

The product obtained-has the formula: C H 2O N O 2 _C0 0

CF

*':Preparation of No-Nimesulide (NO-M) Preparation of the brominated derivative N (2 -PHENOXY 4 -N ITRO) PHENY L 6 -B ROM0) H EXAN OY LME THANE

SULPHONAMIDE

4,85 g 6-Bromohexanoylchloride (23 minol) was added dropwise to a mixture kept at 0 0 C of 7 g nimesulide (23 mmol) and 6.4 ml triethylamine (46 minol) in dichloromethane ml) After stirring- for one hour at 0 0 C, a thin layer chromatography analysis (eluant: toluene/ethyl acetate 9:1) showed that unreacted nimesulide was still present. 1 g acyl chloride (4,7 mnrol) and 3 ml triethylamine (22 inmol) were 105 added to the reaction mixture, the temperature was allowed to rise to room temperature and the reaction mixture was stirred overnight. A chromatographic control showed that the reaction was complete. The reaction mixture was treaced with water (50 ml), the organic phase was then washed three times with water (50 ml for each washing), then with diluted NaCH then dried over anhydrous sodium sulphate Solvent evaporation at reduced pressure left a yellow solid residue which was ground twice with two portions of ethyl ether (50 ml each). The air-dried solid was 8.3 g, which corresponds to a yield of 74% and exhibited a melting point of 980C.

Preparation of NO-Nimesulide

(NO-M)

N- (2-PHENOXY-4-NITRO) PHENYL]-N-(6-NITROXY)HEXANOYLMETHANE-

SULPHONAMIDE

A solution of 4 g N-[(2-phenoxyl-4-nitro)phenyl]-N-(6bromo)hexanoyl-methanesulphonamide (8.24 mmol) and 2.8 g silver nitrate (16.48 mmol) in anhydrous acetonitrile ml) was reacted with stirring for 2 days. Then 1 g of silver nitrate (6 mmol) was then added and stirring was continued for another day. The precipate was removed by filtration and the solvent was evaporated from the filtrate at reduced pressure. The residue was dissolved in a mixture of 106 equal proportions of ethyl acetate and isopropyl ether and stirred for a few minutes with chromatographic-grade silica gel (5 The solid was removed by filtration and the filtrate of the solvent was removed at reduced pressure. The residue was a yellow oil which solidified in time (2.6g) The solid was ground with ethyl ether and dried, and exhibited a melting point of 960C.

The 1 H NMR spectrum (CDC1 3 showed the following signals: 8.05 (1 H, 7.62 (2 H, 7.48 (2 H, 7.32 (1 H, m); 7.08 (2 H, 4.40 (2 H, 3.40 (3 H, 2.24 (2 H, t); 2.18 (3 H, 1.70 (4 H, 1.45 (2 H, m).

Preparation of compound NO-Naproxen

(NO-N)

Compound NO-Naproxen was prepared according to Example Ih (Example 1) in patent WO 95/30641.

Pharmacological tests The products were administered in a suspension of carboxymethyl cellulose in in-vivo experiments, while they were dissolved in dimethylsulphoxide in-in-vitro studies.

The same vehicle used in the corresponding treatment groups was always used for control groups.

The acute toxicity was roughly determined administering an oral dose of 50 mg/kg of substance to groups of 10 mice.

107 Death rate and appearance of toxic symptoms were evaluated in a period of 14 days from dosing: no toxic effects were observed at the dose administered.

Contraction -inhibiting activity in isolated rat detrusor Male Wistar rats weighing 200 to 300 g were used. The method used is described by Zhou Q. et al. (1995) (see Example 13). After sacrificing the rats by cervical displacement the urinary bladder was isolated and horizontal strips of detrusor muscle about 2 mm wide and about 5 mm long were obtained from the median region. The strips were placed in baths for isolated organs containing Krebs liquid and subjected to a 1 g tension. Tension variations during the test were measured isometrically by using a pressure transducer connected to a polygraph. The inhibitory effect of a pre-treatment with the test derivatives on contraction induced by 40 mM KC1 was determined versus drugs having an opening potassium channel activity (cromakalin, nicorandil) nitroderivatives (nitroglycerin, nicorandil) and antiinflammatories (indomethacin,- naproxen, nimesulide). The results are shown in Table 1.

108 Table 1 Example Product No. of Inhibitests tion% 1A comparison Cromakalim 10_ M 10 33.3 1B Nitroglycerin 10_ M 10 28.7 1C Nicorandil 10_, M 10 26.4 1D Indomethancin 10_4 M 10 38.5 1E Naproxen 5-10_ 4 M 10 15.2 1F Nimesulide 104 M 10 41.8 1 NO-I 10_ 4 M 10 46.3 2 NO-N 5-10_ 4 M 10 31.3 3 -NO-M 10_4M 10 48.1 All new nitroderivatives (Examples 1 to 3) proved to be more active than the products used as comparison.

Examples 4-5 and 4A-4C (comparison) In vivo studies in normal urinary bladder of conscious rats Cystometrograms of conscious rats were determined according to the method described by Howe B.B et al. (1995) (see Example 9).

Male Wistar rats weighing about 500 g were used. The rats were anaesthetised with- Nembutal. After opening their abdomen and exposing their urinary bladder, a catheter filled with physiological solution was implanted in the urinary bladder and caused to emerge from the back of the animals.

The abdominal muscle and skin were then sutured. 48 hours 109 after surgery the animals were placed in metabolic cages and the catheters were connected to a perfusor which perfused 0.18 ml/min of a physiological solution into the urinary bladder, and to a pressure transducer in order to measure intravesical pressure. After stabilisation for 60 minutes, the animals were orally treated with the test products and urination frequency was than measured during 4 hours after dosing. Table 2 shows the results obtained expressed as a ratio versus the baseline frequency recorded before dosing (IC interval between contractions).

Table 2 Example Treatment No. of IC treated/IC tests baseline 4 A Controls 8 1.05 4 B comparison Flufenamic 8 1.42 acid 5 mg/kg_ 4 NO-F 5 mg/kg 8 1.62 4 C comparison Indomethacin 8 1.34 mg/kg NO-I 5 mg/kg 8 1.48 Both new derivatives (Examples 4-5) proved to be more active than the products used as comparison.

Examples 5-6 and 5A-5B (comparison) In vivo studies in normal urinary bladders of anaesthetised rats Sprague Dawley rats weighing about 300 g were ran- 110 domly divided into 4 groups and orally treated twice a day for 4 days according to the following experimental scheme: 1. Controls: 0.5% carboxymethyl cellulose 2. Indomethacin 3 mg/kg 3. NO-I 3 mg/kg 4. NO-F 5 mg/kg 18 hours after the last treatment, the effects on the urinary bladder voiding reflex were evaluated using the method described by Maggi C.A. et al., Prostanoids modulate reflex micturition by acting through capsaicin-sensitive afferents, European Journal of Pharmacology, 105-112, 1988.

The animals were anaesthetised with urethane, the urinary bladder was prepared for intraluminal pressure measurement. After a stabilisation period with an empty urinary bladder, this was progressively filled with a physiological solution by slow infusion (0.046 ml/min). A contraction of the urinary bladder was observed upon reflex triggering.

The volume- of physiological solution and intraluminal pressure required to evoke the reflex (volume and pressure thresholds) were measured. Table 3 shows the pressure and volume threshold values after treatment, calculated considering 100 the values obtained in control animals. All tested products increased this threshold and can, therefore, be ll considered useful in case of detrusor instability.

Table 3 Example Treatment No. of Pressure Volume animals threshold threshold A Controls 10 100 100 B Indomethacin 10 190 198 NO-1 10 223 226 6 NO-F 10 203 205 Examples 7-8 (7A-7D as comparison) In vitro studies in unstable urinary bladder The vesical hypertrophy model secondary to urethral o* obstruction in rats described by Malmgren A. et al.: Cystometrical evaluation of bladder instability in rats with intravesical outflow obstruction, The Journal of Urology, 1987, 137, 1291-1294, was used in order to evaluate the effect of the drugs on hyperactive vesical muscle.

Male Sprague Dawley rats weighing about 250 g were used. In order to obtain partial urethral obstruction, therats were anaesthetised with Nembutal and the urinary bladder and urethra were exposed by abdominal incision. A ligature was made around the urethra in the presence of an intraluminal cannula with 1 mm diameter. After suturing the abdominal wall the animals were stabulated for 6 weeks in order for vesical hypertrophy to start.

C.

C*

The in vitro experiments were conducted with the parallel use of strips obtained from normal rats and rats with vesical hypertrophy.

The in vitro urinary bladder strips were prepared as described above and the inhibition induced by the drugs on contraction induced by 1/7 Hz electrical stimulation lasting 1 msec., an above maximal voltage, produced by two platinum electrodes, was measured.

The following table shows the percentage of contraction induced by electrical stimulus in normal and hypertrophic urinary bladders in the presence of the test drugs.

Table 4 Example Product/Tissue No. of tests Contraction 7 A Cromakalim 10- 6 6 50.5 M (normal) 7 B Cromakalin 10- 6 6 35.7 M (hypertrophic) 7 C Indomethacin 10-6 6 78.2 M (normal) 7 D Indomethacin 10- 6 6 76.3 M (hypertrophic) 7 NO-I 10 6 6 61.5 M (normal) 8 NO-I 10 6 6 40.3 M (hypertropic) Differently from indomethacin, the products with an opening of potassium channel activity and the new compounds were found to be more active in inhibiting hypertrophic uri- 113 nary bladder contraction than normal urinary bladder.

Examples 9-10 and from 9A to 9B (comparison) In vivo studies in normal urinary bladder of conscious dogs The cystometrogram of conscious dogs was determined in accordance with the method described by Howe B. B. et al., ZENECA ZD 6169: a NOVEL KATP Channel opener with in vivo selectivity for urinary bladder, Journal of Pharmacology and Experimental Therapeutics, 274, 884-890, 1995.

Female Beagle dogs with urinary bladder catheterised through the urethra by operating in sterile conditions, were used. Catheters were connected to a perfusor which perfused into the urinary bladder a physiological solution and to a pressure transducer in order to measure intravesical pressu- •re. After 15 minute stabilisation, a 30 ml bolus of physiological solution was perfused into the urinary bladder in order to measure increased intravesical pressure and a series of smaller boluses were then perfused until spontaneous S. contractions were observed. After a period of contraction stabilisation, contracting activity was monitored for minutes. The animals were then treated orally with the test products and urination frequency was then measured during 4 hours following dosing in control rats and treated rats.

Table 5 shows the results obtained expressed as a ratio ver- 114 abe.

a.

a

S

a S@ C a* a

C.

C. se a a

C

S

C

Ca C

S.

sus the baseline frequency recorded before dosing (IC interval between contractions).

Table Examples Treatment No. of IC treated/IC animals baseline 9 A comparison Controls 5 1.03 9 B comparison Cromakalim 5 1.48 mg/kg 9 C comparison Flufenamic 5 1.42 acid 3 mg/kg 9 NO-F 3 mg/kg 5 1.76 9 D comparison Indomethacin 5 1.25 3 mg/kg 10 NO-I 3 mg/kg 5 -1.43 Examples 11-12 and 11A-11D (comparison) Relaxing effect in pig urethral smooth muscle The method described by Werkstr6m et al., Factors involved in the relaxation of female pig urethra evoked by electrical field stimulation, British Journal of Pharmacology, 116, 1599-1604, 1995, was used for sample preparation.

Samples of urethra were removed from female pigs about 6 months old.

The urethra was opened longitudinally and samples of smooth muscle about 1x2x6 mm in size were removed from an area about 4 mm below ureteral orifices. The samples of smooth muscle were placed in baths for isolated organs, incubated at 37 0 C and subjected to a 10 mN tension and connected to a force transducer for measuring mechanical activity. After a period of balancing of about 60 minutes, the prepared samples were exposed to Krebs solution without Ca+ to' determine the highest relaxation level. Normal tone was then restored by adding Krebs solution. The relaxation effects of the test derivatives were then measured. The test was repeated two consecutive times for each prepared sample in order to evaluate any tachyphylaxis effects. The table below shows the relaxation percentages obtained following the two treatments with each test product, expressed considering 100% the highest relaxation determined by the medium without Ca Table 6 Example Product No. of Relaxation Relaxation tests 1 2 11 A Indometha- 6 1.0 1.2 cin 10 5

M

11 NO-I 10 5 M 6 39.3 37.2 11 B Flufenamic 6 12.2 13.2 5

M

12 NO-F 10 5 M 6 45.8 52.1 11 C Nitrogl ce- 6 32.1 7.3 rin 10 M 11 D L-arginine 6 22.7 12.2 5

M

The results show that, while drugs with an anti-inflammatory activity such as indomethacin were practically inactive except for flufenamic acid which has itself a myorela- 116 xing activity, and conventional NO donors, such as nitroglycerin and arginine, were active but induced tachyphylaxis, the new derivatives which are an object of the invention were active and did not induce any tachyphylaxis.

Examples 13-15 and 13A-13B (comparison) Relaxing activity on vessel smooth muscle Male Wistar rats weighing 200 to 300 g were used. The method used is described by Zhou Q. et al. The-inhibitory mechanism of nicorandil in isolated rat urinary bladder and femoral artery, European Journal of Pharmacology, 153-159, 1995. After sacrifing the rats by cervical displacement, the femoral arteries were isolated for the preparation of heli- S•coidal strips about 1x15 mm in size, from which the endothelium was removed. The prepared strips were placed in baths for isolated organs containing Krebs liquid and subjected to a weight of 0.5 g. Tension variations during the test were :isometrically measured by means of a pressure transducer connected to a polygraph. The inhibitory effect of a treatment with the test derivatives on contractions induced by 3 x 10-5 M phenylephrine versus reference preparations having a potassium channel opening activity and/or NO donors was measured.

The results are included in Table 7.

Table 7 Example Product No. of Inhibition tests 13 A comparison Cromakalim 10 54.1 3x10 7

M

13 B comparison Nicorandil 10 32.6 6

M

13 NO-I 10 4 M 10 22.2 14 NO-N 5-10 4 M 10 29.0 NO-M 10 4 M -10 19.5 All new compounds proved to be less active than Cromakalin and Nicorandil, even used at higher concentrations, then those shown in specific models (see for example Table 6).

Example 16-17 and 16A-16B (comparison) In vivo gastrointestinal safety studies Forty Sprague Dawley rats weighing about 300 g were randomly divided into 4 groups and orally treated twice a day for 4 days according to the following experimental scheme: 1. Controls: carboxymethyl cellulose by weight): ml/kg) 2. Indomethacin 3 mg/kg 3. NO-I 3 mg/kg 4. NO-F 5 mg/kg 118 Eighteen hours after the last treatment the rats were sacrified to determine any gastrointestinal damage. No gross changes were observed in the gastroenteric tract of control animals.

In the animals treated with indomethacin ulceration was observed in the stomachs and, additionally, the intestines of most animals (7/19) and in some cases (3/10) even diffuse adherences. In the group treated with NO-I, only gastric ulcers were observed in 1 animal, and in the group treated with NO-F one animal with a gastric ulcer and an animal with a duodenal ulcer were found.

Examples 18-18A and 18-B (comparison) Studies of nitroxysynthetase activity The nitroxy-sinthetase inhibiting activity induced by lipopolisaccharide (LPS) was determined in rat neutrofils after administration of any of the test compounds and compared with that obtained after treatment with the suspending vehicle alone carboxymethyl cellulose, 5 ml/kg) and a product used as comparison. Briefly, Wistar rats fasted for 24 hours before treatment received one of the test compounds mg/kg) intraperitoneally or the vehicle LPS (5 mg/kg) intravenously (caudal vein).

Four hours later the animals were sacrified. Blood was 119 collected for neutrofil isolation.

The enzymatic activity was determined according to the method described by Assreuy J. et.al. Feedback inhibition of nitric oxide sinthase activity- by nitric oxide, British Journal of Pharmacology, 883-837, 1993.

As shown in Table 8, the test product was found to be very effective in inhibiting fitroxy sinthetase compared to the group treated with the vehicle alone and differently from the reference flufenamic.

Table 8 EXAMPLE COMPOUND DOSE NITROXY-SYNTHE- (mg/kg/i.p.) TASE ACTIVITYa 18 A Vehicle 100 18 B Flufenamic 10 98 18 NO-F 10 63 Sa percentage compared to the group treated with the vehicle alone.

Conclusions from the whole tests The derivatives of the invention were found to be active in several tests aimed at determining the potential pharmacological activity controlling urination.

It should also be noted that the derivatives of the invention were also found to be effective in a broader series of tests than that in which each reference drug was found to be active, confirming the hypothesis that these derivatives are endowed with a superior overall pharmacolo- 120 gical activity in controlling urinary incontinence.

Furthermore, the derivatives of the invention were found to be better tolerated than the reference products.

They appeared to be less harmful to the stomach than the corresponding anti-inflammatory agents and less hypotensive than the standard agents with vasorelaxing activity.

The combined characteristics mentioned above make the products of the invention superior to the reference agents.

o Throughout this specification and the claims, the words "comprise", "comprises" and "comprising" are used in *a non-exclusive sense, except where the context requires o otherwise.

It will be clearly understood that, although a number cc of prior art publications are referred to herein, this reference does not constitute an admission that any of these documents forms part of the common general knowledge in the art, in Australia or in any other country.

oe Example 19 In vivo assay of the inhibiting activity of precancerous cell formation by the compounds of the invention.

Aberrant crypt foci (ACF) are preneoplastic lesions that have been consistently observed in a number of experimental models of colon carcinogenesis. Moreover, ACF are present in the mucosa of human colon cancer, where they have been suggested to be precursor lesions from which adenomas and carcinomas develop.

Since ACF express mutations in the apc gene abd the ras oncogene, these lesions have been considered early markers of colon cancer development.

The compounds assayed in this test were the following: 2-(acetyloxy)benzoic acid 3-(nitrooxymethyl)phenyl ester.

The compound was prepared according to ex. 1 of WO 00/44705 (NO-Asp-l).

Aspirin.

Male wistar rats (weight 200-250 g) were randomised into n. 3 groups of 8-9 animals each at the beginning of the experiment.

Colonic adenocarcinoma was induced by sequential S treatment injection) with trinitrobenzene sulfonic acid (TNBS) and azoxymethane (AOM) according to the experimental model of D'argenio et Al., Gastroenterology 110, 1727-1734 1996.

The test drugs were dissolved in DMSO diluted in carboxymethylcellulose.

The treated groups were administered, respectively, with a daily dose of aspirin (10 mg/Kg) and with an equimolar dose (18 mg/Kg) of NO-Asp-l.

The control group was administered with the vehicle.

The treatment with TNBS and AOM lasted 28 days. Oral drug administration was continued. Six weeks after the end of the experiment the animals were sacrificed by an overdose of 121a pentobarbital. Laparatomy was then performed with the whole colon excision.

After flushing with 0.9% saline, the colon was tied at both ends with a silk suture and filled with 10% phosphatebuffered formalin (pH After 2 hours the colon specimen was opened by cutting along the mesenteric border and pinned flat. Colon mucosa was then dipped into formalin.

After this treatment and rinsing from formalin, tissues were stained with 0.2% methylene blue in 0.9% saline. After minutes the tissues were recovered and the number of ACF in the entire colon specimen, using a dissecting microscope at magnification. ACF were clearly identified as abnormally dilated crypts, with multiple adjacent crypts, often appearing to be contiguous.

Administration of TNBS and AOM in the control group resulted in the development of widespread precancerous cells formation in the distal colon.

Data are reported in Table wherein the number of ACF.

cells developed in the colon of the animals of the control group was assumed to be 100%. The Table shows that NO-Asp-1 is more effective than aspirin in preventing colon neoplastic lesion.

Table 9 In vivo- inhibition of precancerous cell formation by NO-Asp-l and aspirin in an experimental model of colon Adenocarcinoma Compound Dose (mg/Kg) Precancerous cell Number to the control group) Vehicle 100 NO-Asp-l 18 Aspirin 10 121b Example 19 In vitro assay of the antiproliferative activity of the compounds of the invention in cancerous cells.

Example 19A Human adenocarcinoma (HT29) cells taken from colon affected by cancerous process were transferred into plates with 24 wells containing a cellular culture medium formed by of foetal bovine serum, penicillin (50 U/ml), streptomycin mg/ml) and PEG 400 (polyethylenglycol).

The compounds tested have been the following: 2-(acetyloxy)benzoic acid 3-(nitrooxymethyl)phenyl ester.

The compound was prepared according to ex. 1 of WO 00/44705 (NO-Asp-l).

2-(acetyloxy)benzoic acid 4-(nitrooxymethyl)phenyl ester The compound was prepared according to ex. 3 of WO 00/44705 (NO-Asp-2).

2-(acetyloxy)benzoic acid 2-(nitrooxymethyl)phenyl ester The compound was prepared according to ex. 2 of WO 00/44705 (NO-Asp-3).

Aspirin.

i. After 24 hours a portion of the plates was inoculated with the tested compounds dissolved in the carrier (PEG 400).

96 hours after the inoculation of the compounds the cellular growth was measured by haemocytometer. The results, reported in Table 10, are expressed as percentage of the cellular proliferation with respect to the controls.

The obtained results show that the compounds of the invention are much more effective in inhibiting the proliferation of the cancerous cells with respect to the corresponding native compound.

e 121c Table Activity in vitro on the proliferation of cancerous cells Treatment Concentration Proliferation Vehicle 1 00 Aspirin 500 100 NO-Asp-l 300 NO-Asp-2 10 0' NO-Asp-3 20 Example 19B r r In this experiment flurbiprofen (4-nitrooxy)butyl ester (NO-flurbiprofen) and flurbiprofen, as reference compound, were used.

Flurbiprofen (4-nitrooxy)butyl ester was obtained according to Ex. 1 of WO 94/12463.

HT-29 and HCT-15 human colon adenocarcinoma cell lines (American Type Culture Collection) were grown as monolayers in McCoy 5A medium and RPMI 1640 respectively, and supplemented with 10% foetal calf serum (FCS), penicillin (50 U/ml) and streptomycin (50 mg/ml). Cells were seeded at a density of million cells/100 cm 2 culture dish and incubated at 37 0 C in

CO

2 and 90% relative humidity. Single-cell suspensions were obtained by tripsinization (0.05% trypsin/EDTA), and cells were counted using a hemacytometer.

121d Viability was determined by the tryptan blue dye exclusion method.

The compounds under test were dissolved in dimethyl sulfoxide (DMSO) solutions. All compounds were added to the culture medium before plating. Final DMSO concentration was adjusted in all media to 1% w/v.

A control group was run by adding the the cells a same quantity of DMSO.

NO-flurbiprofen reduced the number of HT-29 cells in the culture more effectively than flurbiprofen. Similar results were obtained with HCT-15 cells.

48 hours after incubation with the compounds, the cells were counted using a hemacytometer. Table 11reports the results obtained, expressed as percentage of cellular hrowth with respect to the control group.

Table 11 Activity in vitro on the proliferation of cancerous cells Treatment Concentration Growth at 48 hours Vehicle 100 Flurbiprofen 500 NO-Flurbiprofen 500 121e

Claims

1. Use of compounds, or their compositions, having the following general formula for the treatment of gastrointestinal tumours A-X 1 -NO 2 or their salts, where: -A R(COX) t where t is an integer 0 or 1; X O, N NRIC where RIc is a linear or branched alkyl having from 1 to 10 C atoms; R is chosen from the following groups: Group I where t 1, -RII3 113 C-" 116 (IAa) H (Lb) 122 where: R 115 is H, a linear or whenever possible branched C 1 -c 3 alkyl; R 1 T 6 has the same meanings as RT or when RTT 5 is H it can be benzyl; RII 1 R 1 1 2 and R 1 1 3 are equal or dia:e-rent one from the other and are hydrogen, linear or whenever possible branched C 1 -C 6 alkyl or Cj-C 6 alkoxy, or Cl, F, Br; R 114 is RII 1 or bromine; Preferred are the compounds where RI 1 1 R 1 1 2 and R1 are H, and R 11 is Cl and R 11 is in the ortho position to NH; R 115 and R 1 1 6 are H, X is equal to 0, and Xi is (CH 2 -CH 2 -0) 2 (I Ab) is the residue of 2-[U2-methyl-3-(trifluoro- me thyl) phenylJ amino] -3-pyr idine carboxyl ic acid and when -COOH is present it is known as flunixin. The compounds pref erred are those where X =0; *II A) chosen- from the following: where, when t R is R 2 a Ria C- 3a where R 2 a and R 3 a are H, a linear or whenever possible 123 branched substituted or non-substitutLed Cl-C 1 2 alkyl, allyl, with the proviso that when one of the two is allyl the other is H; preferably R2a is H, alkyl has from 1 to 4 C atoms, R 3 a -is H; Ria is chosen from II Aa) (TT) p R C H Q( (vx) 124 Ai -C H -7 C 2 H *CH *3 H c i** DO 125 0 where meanings are as follows: in the comoounds of formula residue of ketopro- fen: RIIII is H, SR 11 13 where R 111 3 contains from 1 to-4 C linear or whenever oossible branched C atoms; RI112 is H, hydroxy; preferred are the compounds where RII and RII2 are H, R3a is H, and R 2 a is methyl, X 0; in the compounds of formula (XXI), residue of carpro- eo fen: Rocio is H, a linear or whenever possible branched alkyl having from 1 to 6 carbon atoms, a C 1 -Cg alkoxy- carbonyl bound to a Ci-Cg alkyl, a C,--C 6 carboxyalkyl, a S" C 1 -C 6 alkanoyl, optionally substituted with halogen, benzyl or halobenzyl, benzoyl or halobenzoyl; Rx i is H, halogen, hydroxy, CN, a Ci-C 6 alkyl optional- ly containing OH groups, a CI-C 6 alkoxy, acetyl, benzyl- oxy, SRxi 2 where RPxi 2 is a Cl-C 6 alkyl; a perfluoroal- kyl having from 1-3 C atoms, a CI-C 6 carboxyalkyl optio- 126 nally containing OH groups, NO 2 sulphamoyl, dialkyl sulphamoyl with the alkyl having from 1 to 6 C atoms, or difluoroalkylsulphonyl with the alkyl having from 1 to 3 C atoms; Rxxil is halogen, CN, a C 1 -C 6 alky! containing one or more OH groups, a C 1 -C 6 alkoxy, acetyl, acetamido, benz- yloxy, SRIII 3 is as above defined, a perfluoroalkyl having from 1 to 3 C atoms, hydroxy-, a carboxyalkyl having from 1 to 6 C atoms, NO 2 amino, a mono- or dialkylamino ha- ving from 1 to 6 C atoms, sulphamoyl, a dialkyl sulpha- moyl having from 1 to 6 C atoms, or difluoroalkylsul- phamoyl as above defined; or Rxx i jointly with Rxxil is a**n alkylene dioxy having from 1 to 6 C atoms; preferred are the compounds where Rxxio is H, the connecting bridge is at position 2, Rxx i is H, Rxxil is chlorine and is in the para position to nitrogen; R 3 a i H,_R 2 a is methyl and X is 0; -in the compounds -of formula (XXXV), residue of thia- profenic acid: Ar is phenyl, hydroxyphenyl optionally mono- or polysubstituted with halogen, an alkanoyl or alkoxy having from 1 to 6 C atoms, a trialalkyl having from 1-6 C atoms, preferably from 1-3 C atoms, cyclo- 127 pentyl o-hexyl o-heptyl, heceroaryl', preferably thienyl, furyl optionally containing OH, pyridyl; the preferred compounds of formula (XXXV) are those where Ar is phenyl, R3a is H, R 2 a is methyl and X is 0; in the compounds of formula residue -of suoro- fen, the preferred, where R3a H, R 2 a CH 3 and X 0; in the compounds of formula (VI), -of which the preferred, indoprofen, when R 2 a is CH 3 or indobufen, when R 2 a is eaual to H and R 3 a CH3 and in the compounds of formula (VIII), of which the preferred, etodolac, when R3a R2a H and S X 0; in the compounds of formula (VII), of which the preferred, fenoprofen, when R3a H, R2a CH 3 and X O; e So in the compounds of formula (III), of which the preferred, etodolacbuf, when R3a R2a H and X 0; in the compounds of formula (VII), residue of olmein, S of which the preferred, fenoprofen, when R^a H, when R2 a HCH and X 0; in the compounds of formula residue of flurbi- in the compounds of formula.(III), of which the preferred, fenbufen, when R 3 a R2a H and X 0; in the compounds of formula residue of tolmetin, when R 3 a R^a H and X 0; in the compounds of formula residue of flurbi- 128 lorof enr, When R R C: 3 an.-x 0; I! Ab): ITa) (XXX1 ii) 129 (xx~x-N H C 7 whr th mennsae.sflos whe .Ia cotis-HC sknw sp norfn ehlS-l .ezprn(,-~y-d-e7 acti acid prfrrdRa' 0 0- ndX 0 whe reiu..X otan C'-(F 3) .CO CIw asba.....:diez xpn2-cri ai ,p e f er e sX =0 C ,R a O3 130 -residue (XXXI) is known as CS-670: 2 -[4-(2-oxo-j_ cyclohexylidenemed-iyl)phenylj proo4ioni-c acid, when the radical is -CH(CH3)-COOH; preferred R 2 a Rja CH 3 and X 0; residue (XXXII) derives from the known nemedolac which contains group -CH 2 COOH, Qref":erred R 2 a R 3 a=H and X 0; when residue (XXXIII). is saturated with -CH 2 COOH it is known- as pyrazolac: 4-(4-chlorohelyl) luoro- phen-yl) 3-pyrazolyl acid derivatives; preferred R 2 a =R3a H and X 0; -when residue (XXXVI) is saturated with -CH(CH 3 -COO- is known as zaltoprofen. When the residue is satura- ted with a hiydroxy or amine gro up or the acid salts, the compounds are known as dibenzothiepin -derivatives. Preferred R2a H, R 3 a CH 3 and X 0; when' residue (XXXVII) is CH 2 -COOH it derives from the known mofezolacz 3, 4 di (p-methoxyphenyl) isoxazol-5 -ace- :tic-acid; preferred are R2a R 3 a t ,X =0. *Group IIIA), where t =1 RIVd I RIVdi 131 where: RIVd and RIVdl are at least one H and the other a linear or whenever possible branched C 1 -Cg alkyl, preferably C 1 and C 2 or difluoroalkyl with the alkyl having from 1 to 6 C atoms, preferred is C 1 or RIVd and RIVdl jointly form a methylene group; RIV has the following meaning: R IV--i (11) (m) where the compounds of group IIIA) have the following meanings: in the comoounds of formula (II): 132 RIvII is an alkyl having from 1 to 6 C atoms, a cycloalkyl having from 3 to 7 C atoms, an alcoxymethyl having from 1 to 7 C atoms, a trifluoroalkyl having from 1 to 3 C acoms, vinyl, ethynyl, halogen, an alkoxy having from 1 to 6 C atoms, a difluoroalkoxy with the alkyl having from 1 to 7 C atoms, an alkoxymethyloxy having from 1 to 7 C atoms, an alkylthiomethyloxy with the alkyl having from 1 to 7 C atoms, an alkylme- thylthio -with the alkyl having from 1 to 7 C atoms, cyano, difluoromethylthio, a substituted phenyl- or phenylalkyl with the alkyl having from 1 to 8 C atoms; preferably RIVyII is CH 3 0, RIVd is H and RIVdl is CH 3 and is known as the residue of naproxen; X NH and X 1 is equal to (ClK 2 4 or (CH 2 CH 2 0) 2 also preferred is the same compound where X is equal to O; in the preferred compounds of formula for which the residue of loxoprofen has been shown, RIVd is H and RIvd is- CH3, X NH or 0 and X 1 is equal to (CH 2 4 or (CH 2 CH20)2; in the comoounds of formula (III): RIV-II I is a C 2 -C5 alkyl, even branched when possible, a C 2 and C 3 alkyloxy, allyloxy, phenoxy, phenylthio, a cycloalkyl having from 5 to 7 C atoms, optionally sub- 133 stituted at position 1 by a C1-C 2 alkyl; preferred is the compound where RiViiij is CH 3 CH-CH 2 CH 3 and RIvd F, R~vdl is CW 3 a comnoound known as the re- sidue of ibu-prof en; X N-1 and i-s equal to or (Cfl2cHr 2 O) 2 also prefer-red is the same Com- pound where X =0; Grouo IV A) ~CH (IV A) where A =RCOO, t 1, .been of whi-ch the residue of the knowf indornezhacin has be shown. *GrouiD V A) chosen from the following: -V Aa) fenamates chosen from the following, wher-e =I 134 NHCH 2 CH- 2 (V Aal1) (V Aa2) cl CH 3 (V Aa3) *H CH 3 CH* 3 (V Aa4) 135 6: NHP (V AaS) H 3C C1 -V Ab), derivatives of nif luntic acid, where t 1 CF 3 N N H (V Abl) -V Ac), COX 2 inhibitors, where t =0 and R is as f ol- lows: N SO 2 CH 3 0 Y, V Ac S S. S N02 (V Acl) 136 N 0 o H (V Ac2) (V Ac3) H:L (V Ac4) 137 CH CI 2 3 y S CH 3 (V V Ad) derivatives of diuretics when t =1 and R is as f ollows: 00 (V Adi) H 3 C- (V Ad3) 138 NH 2 0 00 (V Ad4) V Ae) derivatives of diuretics when t 0 and R is as follows: a a a a H N 'j, (V Ael) H IO 3 HC3 CH. 3 0 a. aa*. a. a a a. (V P2) 139 N 7 NH N-N (V AeS) 0/0 00// HA SNI NH F 3C H (V Ae4) 0 0 0 0 Cal N (V Ae6) 0 0 0 0 -l N' CI H (V Ae6) 140 0 NH 0 H 0H HO I I (V Ae8) (V Aeg) 0@ 0 0Oe S 0000 SO S. 9 0@ 0 0 S. 0@ SO S S S H N_~ H N C. (V Aeli1) 0 see 000S 5*55 0 S S S @5 C OOHH 0 0 cl (V Ael 2) 141 where the meaning in group V A) is as follows: in compounds (V Aal) :eresid'e of enfenamic acid,

2- ((2-lhenviethyl)a:,inolbenzoi-c ac~a, has-been shown; in comp~ounds (V Aa2) t-ne- residue of flufenamic acid, 2- Ctrif'luoromer-hyl)-phenyl] -amino:,obenzoic acid, has been shown; in compounds (V Aa3) the residue of meclofenamic acid, 2- C 6-dich-loro-3-methylphenyl) amino) benlzoic acid, has been shown; in compounds (V Aa4) the residue ofE mefanamic acid,

3-dimethylphenyl) amino] benzoic acid, has been *.shown; in compounds (V Aa5) the residue of tolfenamic acid, 2 C (3 -chl oro- 2 -me thylphenyl) amino b en zo ic acid, has been shown; *-in compounds (V Abi) the residue of niflumic acid, 2--t (trif luoromethyl) phenyll amino] -3-pyridine car- boxylic acid, has been shown; -in compounds (V Acl) Rvacl attached to the oxygen atom in position 2 of the benzene ring of N-.(4-nitro- phenyl)rnethansulphonamide can be phenyl or cycloexane- When Rvacl is phenyl the residue is that ofE nimesulide; in comounds (V Ac2) the residue o-f 3-formylamfifo- 7 142 mechylsul'onyl amin2o-6 -Phenoxy- 4 H- !-bezoyran-4 -oneha been shown; -in comDounds (V Ac3) the atom X. that links the radi- cal 2,4-difluoroth.opheflyl to position 6 of the indano- ne ring of the residue S5-methanesul f onamido 1-naoe can be sulfur or oxygen; -in comiDounds (v Ac4) the residue o-f celecoxib (4-methyiphelyl) (trifluoromethyl)pyrazol-1-yl] ben- zensuiphonamide, has been shown; -in compounds (V AcS) the residue of 6-(2-(3-ethyl- 2,3-dihydro-thiazolyl) thio-5-methanesu1pholamido- 3 I- isobenzonfuran-1-ole has been shown. *-in compounds (V Adi) the residue of bumetanide 3- (Aminosulfonyl) (butylamino) -4-phenoxyberizoic acid has been shown; -in compounds (V Ad2) the residue of ticrynafen [2,3- Dichloro-4- (2-thienylcarbollyl) -phenoxy] acetic acid has *been -shown; in comp~ounds (V Ad3) the residue of ethacrynic acid 2 3 -Dichloro- 4 2 methyeneioxobutyl) phenoxyl acei acid, has been shown; in compounds (V Ad4) the residue of piretanide 3- (Aminosulfonyl) 4 -phenoxy-5- 1-pyrrolidinyl)benzoic 143 acid has been shown. in COMDOcunds (V Ael) the res ff-r;an-de(3c= 4 c, 7 L, 7aci) 3- (AminosulphonvI) chloro (oc Zajdr-o. 4,7-eao2 -sidl2ylbna-d has been shown. in compoounds (V Ae2) the residue off torsernide Methvlethyl) amino) carbonyl]

4- C(3 -methylphenyl) amnino] -3- pyrinesulfonamide has been shown; -in comptounds (V Ae3) the residue off azosernide 2-Chlo- (lH-tetrazol-5-yl) C(2-thieivlmethyl) atino]-ben- zensulphonamide has been shown; -in conmounds (V Ae4) the residue of bendrof lume- :::thiazide 3,4-Dihydro-3 (phenyl-Tm-ethyl) (trif luoro- methyl) -2H-1, 2,4-benzothiadiazine-7-sulfona~de' 1,1- dioxide has been shown; -in compounds (V AeS) the residue of chiorothiazide dioxide has been shown;L in ~lcompounds (v Ae6) the residue of hydrochiorotia- zide 6 -Chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7- sulfonamide 1,1-dioxide has been shown; in Comnounds (V Ae7) the residue of methyiclothiazide (G-Chloro-3-(chloromethy)34dihydro-2met hyl-2H- 1, 2 4 -benzothiadiazine.7-sulfonami de 1,1-dioxide has 144 been shown; in comoounds (V Ae6) the residue of chiorthalidone (2,3-dihydro- -hydroxy-3-oxo-lH-isoindol-1- yl)benzensulfonamide has been shown; in comoounds (V Ae9) the residue of Indapamide 3- (Aminosulfonyl)-4-chloro-N- (2,3-dihydro-2-methyl-H- indol-1-yl)benzamide has been shown; in compounds (VAe1O) the residue of metolazone 7- Chloro-1,2,3,4-tetrahydro-Z-methyl-3- (2-methyiphenyl) 4-oxo-6- aujnazolinesulfonamide has been shown; in compounds (V Aell) the residue of quinetazone 7- Chloro-2-ethyl-1,2,3,4-tetrahydro-4-oxo-6-quinazolifle- sulfonamide has been shown; in compounds- (V Ael2) the residue of furosemide (Aminosulfonyl) -4-chloro-2- ((2-furanylmethyl) amino] ben- zoic acid has been shown. X 1 in formula A-X 1 -N0 2 is a bivalent connecting bridge chosen from the following: YO where Y is a linear or whenever possible branched C 1 -C 20 alkylene, preferably having from 2 to S carbon atoms, or an optionally substituted cycloalkylene having from 5 to 7 carbon atoms; 145 -(cH 2 r13 where n 3 is an integer from 0 to 3; H 2 0- UN2 where nf' is an integer from 1 to 6, Preferably from 2. to 4; (CH-CH 2 -o)i-f Rif .where Rif H, CH 3 and nf is an integer f rom i to 6, preferably from 2 to 4; and *Group VIA), where t 1, 146 0 2 1 (Ia) COR 3 Coo 2 nI nI (Ilb) Swhere: R 1 is group OCOR 3 where R 3 is methyl, ethyl or a linear or branched C 3 -C 5 alkyl, or the residue of a single-ring heterocycle having 5 or 6 atoms which can be aromatic, partially or totally hydrogenated, containing one or more heteroatoms independently chosen from O, N and S; R 2 is hydrogen, hydroxy, halogen, a linear or whenever possible branched alkyl having from 1 to 4 C atoms, a linear or whenever possible branched alcoxyl having from 1 to 4 C atoms; a linear or whenever possible branched perfluoroalkyl having from 1 to 4 C atoms, for example trifluoromethyl, nitro, amino, mono- or 147 di (Cl 1 -)alkylamino; R 1 and R 2 jointly are the dioxymethylene group, with the proviso that when X NIH, then X1is ethylene and R= H; R 1 cannot be OCOR 3 at position 2 when R 3 is methyl; nI being an integer from 0 to 1; preferably in Ia) X is equal to 0 or Ni, R 1 is ace- toxy, preferably at position 3 or 4, most preferably in the ortho position to CO. X 1 is ethylene or (CH 2 CH 2 O) 2 R 2 is Hydrogen or hialogen, most preferred are the following A XI -NO 2 compounds: 3-acetoxy-N-(2-nitfoxy- ethyl) -benzamide, 4-acetoxy-N- (2-nitroxyethyl) -benza- mide, 3 -ace toxy-N- (5 -ni troxypenthyl) benzamide, 2-ace- toxy-N- (5-nitroxypenthyl) -benzamide, N-2- (nitroxy- *SSSethyl) -2=propionoxybenzamide, 2-acetoxy-2-nitroxy- ethylbenzoate, 2-acetoxy-N- (cis -2 -nitroxycyclohexyl) benzamide, 2-acetoxy-4-chloro-N- (2-nitroxyethyl) -benza- mide, N- (2 -nitroxyethyl) 2- (4 -thiazolindinyl) carbon- yloxy) -benzamide hydrochloride, 2-nicotinoyloxy-N- (2- nitroxyethyl) -benzamide, 2-acetoxy-- zoate; preferably in Ib) R 3 CH 3 nI 0; X is equal to 0, X 1 is ethylene; in this case Ib) is the residue of acetylsalicylsalicylic acid. 148 2. Use of compounds having the following general formula for the preparation of medicaments for the treatment of gastrointestinal tumours: A-XI-NO 2 or their salts, where: -A R(COX)t where t is an integer 0 or 1; X O, NH, NRIC where RiC is a linear or branched alkyl having from 1 to 10 C atoms; R is chosen from the following groups: Group I where t 1, 113 FTISI Is K 116I~ (IAa) (TAb) 149 where: RII 5 is H, a linear or whenever possible branched CI-C 3 alkyl; RII 6 has the same meanings as RII 5 or when RII 5 is H it can be benzyl; RII 1 RII 2 and R II3 are equal or different one from the other and are hydrogen, linear or whenever possible branched C 1 -Cg alkyl or C 1 -Cg alkoxy, or Cl, F, Br; RII 4 is RII 1 or bromine; preferred are the compounds where RII 1 R 1 1 2 and R I4 are H, and R 113 is Cl and R 1 1 3 is in the ortho position to NH; RII 5 and R 11 6 are H, X is equal to 0, and X 1 is (CH 2 -CH 2 -O) 2 (I Ab) is the residue of 2-[[2-methyl-3-(trifluoro- methyl) phenyl] amino] -3 -pyridinecarboxylic acid and when -COOH is present it is known as flunixin. The compounds preferred are those where X 0; II A) chosen. from the following: where, when t 1, R is 2a Rla C 3a where R2a and R 3 a are H, a linear or whenever possible 150 branched substituted or non-substituted C 1 -C 1 2 alkyl, allyl, with the proviso that when one of the two is allyl the other is H; preferably R2a is H, alkyl has from 1 to 4 C atoms, R 3 a -is H; Ria is chosen from II Aa) -l I) (rr) H. N 1 /-I 151 (VI) C 2H (VI]I) 0 0* (II) HC 3 CH '3 0 N 152 0 C 2 where meanings are as follows: in the compounds of' formula (IV) ,residue of ketooro- fen: -FI1is H, SR 1 1 1 3 where-RII 1 3 contains from 1. to- 4 C linear or whenever possible branched C atomns; R is H, hydroxy; *preferred are the compounds where RII 1 1 and R 1 1 1 2 are R3a is H, and R 2 a is methyl, X 0; -in the compounds of formula (XXT) residue of carpro- Rxi is H, a linear or whenever possible branched alkyl having from 1 to 6 carbon atoms, a Ci-C 6 alkoxy-. carbonyl bound to a C,-C 6 alkyl, a C,.f-C 6 carboxyalicyl, a C-C 6 alkanoyl, optionally substituted with halogen, benzyl or halobenzyl, benzoyl or halobenzoyl; Rxiis H, halogen, hydroxy, CN, a Ci-C 6 alkyl optional- ly containing OH groups, a C 1 -C 6 alkoxy, acetyl, benzyl- oxy, SR~ 2 where R-x- 2 is a Ci-C 6 alkyl; a perfluoroal- kyl having from 1-3 C atoms, a Ci-C 6 carboxyalkyl optio- 153 nally containing OH groups, NO 2 sulphamoyl, dialkyl sulphamoyl with the alkyl having from 1 to 6 C atoms, or difluoroalkylsulphonyl with the alkyl having from 1 to 3 C atoms; Rxxil is halogen, CN, a C 1 -C 6 alky! containing one or more OH groups, a C 1 -C 6 alkoxy, acetyl, acetamido, benz- yloxy, SR 1 1 1 3 is as above defined, a perfluoroQlkyl having from 1 to 3 C atoms, hydroxy, a carboxyalkyl having from 1 to 6 C atoms, NO 2 amino, a mono- or dialkylamino ha- ving from 1 to 6 C atoms, sulphamoyl, a dialkyl sulpha- moyl having from 1 to 6 C atoms, or difluoroalkylsul- phamoyl as above defined; or Rxxi jointly with Rxxil is an alkylene dioxy having from 1 to 6 C atoms; preferred are the compounds where Rxxio is H, the connecting bridge is at position 2, Rxx i is H, Rxxil is chlorine and is in the para position to nitrogen; R3a i R 2 a is methyl and X is O; in the compounds -of formula (XXXV), residue of thia- profenic acid: Ar is phenyl, hydroxyphenyl optionally mono- or polysubstituted with halogen, an alkanoyl or alkoxy having from 1 to 6 C atoms, a trialalkyl having from 1-6 C atoms, preferably from 1-3 C atoms, cyclo- 154 pentyl c-hexyl o-heptyl, hezercaryl, preferably thienyl, furyl optionally. con:a in..nc OH, pyridyl; the preferred compounds of formula (XXXV) are those where Ar is phenyl, R 3 a is H, R 2 a is methyl and X is O; n the compounds of formula residue -of suDro- fen, the preferred, where R 3 a H, R 2 a CH3 and X 0; in the compounds of formula (VI) of which the preferred, indoprofen, when R 2 a is CH 3 or indobufen, when R 2 a is equal to H and R3a CH3 and X 0; S. in the compounds of formula (VIII), of which the preferred, etodolac, when R 3 a R 2 a H and X 0; in the compounds of formula (VII), of which the preferred, fenoprofen, when R3a H, R 2 a C 3 and X 0; in the compounds of formula (III), of which the preferred, fenbufen, when R 3 a R2a H and X 0; in the compounds of formula residue of tolmetin, when R 3 a R 2 a H and X 0; in the compounds of formula residue of flurbi- 155 ~rof a-r, when R R 2 cL 3 an,-X 0; "3a 2 I I Ab) H C (xxXX N. (xxxf ii) 156 0% 0 wher th.ennsar.sflos whee rhesimeningsare a n follows: Co tiS Clw as bermocrofen: dibenz [b,fJl oxepin-2-ace~ic acid, pre- ferred is X 0, R2a H, R3a O3 157 -residue (YXXI is knjown as CS-670: 2 (2-oxo-li cy clohexylidenemeuhyl)phenyl1prooi-onic acid, when the radical is -CH(C-H 3 )-COOH; oreferred R 2 a H, R3a CH 3 and X =0; -residue (XXXII) derives from the known Demedolac which contains group -CH 2 COOH, oreferred R 2 a =R 3 a H and X 0; -when residue (XXXIII). is saturated with -CH 2 COOH i t is. known-- as pyrazolac: 4- (4-chiorophenyl) (4-f luoro- pherryl) 3-pyrazolyl acid derivatives; preferred R 2 a R3a H and X =0; -when residue (XXXVI) is saturated with -CH(CH 3 -COO- it is known as zaltoprofen. When the residue is satura- ted with a hydroxy or amine gro up or the acid salts, the compounds are known as dibenzothiepin -derivatives. Preferred R2. H, R 3 a CH 3 adX=0 -when, residue (XXXVII) is CH 2 -COOH it derives from the known mofezolacz 3, 4 di (p-methoxyphenyl) isoxazol-5 -ace- tic-acid; preferred- are R2a R 3 a H, t 1, X =0. *Grourp IIlA), where t 1, RIVd RIV C- RIVdl 158 where: RIVd and RIvdl are at least one H and the other a linear or whenever possible branched C 1 -Cg alkyl, preferably C 1 and C 2 or difluoroalkyl with the alkyl having from 1 to 6 C atoms, preferred is C 1 or RIvd and RIvdl jointly form a methylene group; RIV has the following meaning: (II) where the compounds of group IIIA) have the following meanings: in the comoounds of formula (II): 159 Rii i s an alkyl having f rom i to 6 C atoms, a cycloalkyl having from 3 to 7 C atoms, an alcoxyrnethyl having -from 1 to 7 C atoms, a t-rifluoroalkyl having from 1 to 3 C aorns, vinyl, ethynyl, halogen, an alkoxy naviffg from 1 to 6 C atoms, a aifrluoroalkoxy with the alkyl having from 1 to 7 C atoms, an alkoxymethyloxy having from 1 to 7 C atoms, an alkylthiomethyloxy with the alkyl having from 1 to 7 C atoms, an alkylme- thylthiJo -with the alkyl ha-ving fLrom 1 to 7 C atoms, cyano, difluoromethylt-hio, a substituted phenyl- or phenylalkyl with the alkyl having from 1 to 8 C atoms; preferably RIv-II is C11 3 0, RIVd is H and RIVdl is CH 3 and is known as the residue of naproxen; X NH{ and X 1 is equal to (Cg 2 4 or (CH 2 CH 2 O) 2 also preferred is the same compound where X is equal to 0; -in the ureferred compounds of formula for which the residue of loxoorofen has been shown, R~v is H and R~vdiis- CH- 3 X NH or 0 and X 1 is equal to (.CH 2 4 or (CH 2 CH 2 0) 2' in the compounds of formula RIvx 1 1 I is a C 2 alkyl, even branched when possible, a C 2 a-nd C 3 alkyloxcy, allyloxy, phenoxy, phenylthio, a cycloalkyl having from 5 to 7 C atoms, optionally sub- 160 stituted at position 1 by a C 1 -C 2 alkyl; preferred is the compound where RIV-III is CH 3 CH-CH 2 CH 3 and RIVd H, RIdl is CH 3 a compound known as the re- sidue of ibuprofen; X NH: and X, is ecual to (CH2) 4 or (CC2CH 2 0) 2 also preferred is the same com- pound where X 0; Group IV A) N 3 H1 (IV A) where A RCOO, t 1, of which the residue of the known indomethacin has been shown. Group V A) chosen from the following: V Aa) fenamates chosen from the following, where t 1 161 NH-CH 2 CH 2 (V Aa 1) (V Aa2) a a. a. a CH I 3 Cl (V Aa3) CH 3 CH 3 (V Aa4) 162 (V Aa5) H 3C V Ab) derivatives of niflurmic acid, where t =1: CF3 (V Abl) V Ac),i COX 2 inhibitors, where t 0 and R is as f ol lows: N S0 2 CH 3 0 Y, V Ac N0 2 (V Adl) 163 N 0 s H CH (V Ac2) 6i NF 0 (VFC~ (V AC4) 164 CH CH 2 3 y S CH3 (V -V Ad) derivatives of di-,uretics whien t =1 and R is as f ollows: 0 0 IW2 H NH *3 *0 I (V Adi) 0 (V Ad) 165 NH 0 0 0 (V Ad4) -V Ae) deri-vatives of diuretics whn;, t =0 and R is as follows: H 0 .0 H21 (V Ael) H to 3 ICy CH 3 (V Ae2) 166 N 7 NH N N (V Ae3) 00 HNA NNH FC H (V Ae4) :I H N I- NH HNH i (V Ae6) 0\ 0 /0 .iS (V Ae7) 167 0 NH 0\/O HO N (V Ae8) 0 0 0 HN N NH N (V Ae9) 9 0@@e S@ 5 0 S *SSS SO 05 0 S. S 0 55 S. 55 S S S 0 (V Ael 1) *0 5050 S 55 S. HN~ 0 0 0 CI (V Ael-2) 168 where the meaing in crouc V A) is as :ollows: in comoounds (V aal) rhe resid's c' enfenamic acid, 2- [(2-Dhenviethyl)aminobenzoic acid, has-been shown; in comiounds (V Aa2) Eri residue oz flufenarnic acid, 2- Ctrifluoromec chyl) o'henyl] -ani nobenzoic acid, has been shown; in compounds (V Aa3) the residue of meclofenamic acid, 2- 6-dich-loro-3-methylphenyl) amino] benlzoic acid, has been shown; in compounds (V Aa4) the residue of mefanamic acid, 2- 3-dimethyiphenyl) amino] benzoic acid, has been shown; in compounds (V Aa5) the residue of tolfenamic acid, 2- [(-3-chloro-2-methylphenyl) amino] benzoic acid, has been shown; in compounds (V Abi) the residue of niflumic acid, 2 [3 (trifluoromethyl) phenyl amino] 3 -pyridine car- :boxylic acid, has been shown; in compounds (V A) Rvacl attached to the oxygen atom in position 2 of the benzene ring of N-(4-fitro- phenyl)methansulphonamide can be phenyl or cycloexa-ne. When Rvaci is phenyl the residue is that of nimesulide; in comnounds (V Ac2) the residue of 3-formylamino-7- 169 me thylsul-foryamio phenoxy-4H-!bezopyran- 4 -one has been shown; -in comoouflds (V Ac3) the atom X 4 that links the radi- Cal 2,4-difluorothophelYl to position 6 of the indano- ne ring of the residue

5-methanesulr-foamido-i-Z--1Qanone can be sulfur or oxygen; in comnounds (V Ac4) the residue of celecoxib (4-methylp~henyl) (trifluoromfethyl)pyrazol-1-yl] ben- zensuipholamide, has been shown; -in compounds (V AcS) the residue of.

6-[2-(3-ethyl. 2,3-dihydro-thiazolyl) thio-5-methaneSU1phonamido- 3 H- isobenzonfural-1-one has been shown. *-in compounds (V Adi) the residue of bumetanide 3- (Aminosulfonyl) -5-(butylamilo) -4-phefloxybenzoic acid has been shown; -in compounds (V Ad2) the residue of ticrynafen [2,3- Dichloro-4- (2-thienylcarbonyl) -phenoxyl acetic acid has -been -shown; in compounds (V Ad3) the residue of ethacryflic acid 3 -Dichloro- 4- 2 -methylene oxobutyl) phenoxy] acetic acid, has been shown; in compounds (V Ad4) the residue of piretaflide 3 (Aminosulf ofyl) -4 -phe±oxy- 5 (1-pyrrolidir1yl) benzoic 170 acid has been shown. in Cor-Pocunds (V Aed) the OFsA~ ot ripamide (3ac, 4 ce, 7ar, 7 ace) 3- (Am ino s u!oho nl) 4c hl oro N- (oc ta i do 7 -retano-2iisoindo2y)beza- &d has been shown. -in compounds (V Ae2) the residue o~f torsernide Me thyl ethyl)amino] carbonyl]1 4- C (3 -me~hy1Dohenyl) amino] -3 pyrinesulfonamide has been shown; -in con-mounds (V Ae3) the residue of, azosemide 2-Chfo. (I-q-tetrazol -5 -yl) -4 (2 -thienylmethyl) amino] ben- zensuliohonamide has been shown; -in compounds (V Ae4) the residue of bendroflume- thiazide 3,4-Dihydro-3- (phenyl-methyl) (trifluoro- methyl) -2H-1, 2, 4 -benzothiadiazine-

7-sulf onamj-de 11 dioxide has been shown; -inl compounds (V Ae5) the residue of chiorothiazide E-Cloro-2H-124-benzothiiaazne...7..sulfonamide 1,1- dioxide has been shown; -in Compounds (V Ae6) the residue of hydrochioro-tia- zide 6-Chloro-3,4-dihydro2H12,4benzothiadiazine-7. *:sulfonamide 1,1-dioxide has been shown; in compounds (V Ae7) the residue of rethylclothiazide (6-Chloro-3-(chloromethyl) -3,4-di-hydro-2-methyl-2H!- 11, 2 4 -benzothiadiazine-7-sulfonarride 1,1-dioxide has 171 been shown; in compounds (V Ae8) the residue of chiorthalidone 2-Chloro-5-(2,3-dihydro-1-hydroxy-3-oxo-1!i-isoindol-1- yl)benzensulfLonamide has been shown; in comaounds- (V Ae9) the residue of IndaDamide 3- (Aminosulfonyl)-4-chloro-N- (2,3-dihydro-2-methyl-H- indol-1-yl)benzamide has been shown; in compounds (VAelO) the residue of metolazone 7- Chloro-1,2-,3,4-tetrahydro-2--methyl-3- (2-methyiphenyl) 4-oxo-6-cxuinazoljnesulfonamide has been shown; -in compounds (V Aell) the residue of quinetazone 7- Chloro- 2-ethyl-1, 2,3, 4 -tetrahydro- 4-oxo- 6-quinazol ine sulfonamide has been shown; -in 'compounds- (V Ael2) the residue of furosemide (Aminosulfonyl) -4-chloro-2- (2-furanylmethyl) amino) ben- zoic acid has been shown. X 1 in formula A-X 1 -N0 2 is a bivalent, connecting bridge chosen from the following: where Y is a linear or whenever possible branched C 1 -C 20 alkylene, pref erably having from 2 to 5 carbon atoms, or an optionally substituted cycloalkylene having :Crom 5 to 7 carbon atoms; 172 CH -0- 2 -(cH 2 n3 where n3is an integer from 0 to 3; H COOH C 2- (CH 2 -CH-CH 2 -o)r~f. where nf' is an integer from 1 to 6, preferably from 2: to 4; Rif where Rjf CH 3 and nf is an integer f rom 1 to 6, preferably from 2 to 4; and Group VIA), where t =1, 173 0 2 1 (la) COR 3 coo 1 2 1 nI (Ib) where: R is group OCOR3; where R 3 is methyl, ethyl or a linear or branched C 3 -C 5 alkyl, or the residue of a single-ring heterocycle having 5 or 6 atoms which can be aromatic, partially or totally hydrogenated, containing one or more heteroatoms independently chosen from O, N and S; R 2 is hydrogen, hydroxy, halogen, a linear or whenever possible branched alkyl having from 1 to 4 C atoms, a linear or whenever possible branched alcoxyl having from 1 to 4 C atoms; a linear or whenever possible branched perfluoroalkyl having from 1 to 4 C atoms, for example trifluoromethyl, nitro, amino, mono- or 174 di (C 1 4 alkylamino; R 1 and R 2 jointly are the dioxymethylene group, with the Proviso that when X NH-, then Xi is ethylene and R= H; R 1 cannot be OCOR 3 at position 2 when R 3 is. methyl; fT being an integer from 0 to 1; preferably in Ia) X is equal to 0 or NHl, R, is ace- toxy, preferably at position 3 or 4, most preferably in the ortho position to CO. X 1 is ethylene or (CH 2 CH 2 O) 2 R 2 is Hydrogen or h~alogen, most preferred are the following A X 1 -NO 2 compounds: 3-acetoxy-N-(2-nitffoxy- ethyl) -benzamide, 4-acetoxy-N- (2-nitroxyethyl) -benza- .*mide, 3 -ace toxy-,N (5 -nit roxypenthyl) benzamide, 2-ace- toxy-N- (5-nitroxypenthyl) -benzamide, N-2- (nitroxy- ethyl.)-2-propionoxybenzamide, 2-acetoxy-2-flitroxy- ethylbenzoate, 2-acetoxy-N- (cis-2-nitroxycyclohexyl) benzamide, 2-acetoxy-4-chloro-N- (2-nitroxyethyl) -benza- mide, N- (2-nitroxyethyl) ((4-thiazolindinyl)carbol- yloxy) -benzamide hydrochloride, 2-nicotinoyloxy-N-(2- nitroxyethyl) -benzamide, 2-acetoxy-75-rnitroxypenthylbel zoate; preferably in Tb) R 3 CH 3 nI 0; X is equal to 0, X 1 is ethylene; in this case Tb) is the residue of acetylsalicylsalicylic acid. 175 3. A method for the treatment of gastrointestinal tumours comprising administering to a patient in need of such treatment a compound having the general formula: A-X 1 -NO 2 or their salts, where: -A R(COX)t where t is an integer 0 or 1; X O, NH, NRcl where Ric is a linear or branched alkyl having from 1 to 10 C atoms; R is chosen from the following groups: Group I where t 1, R 1 1 3 a (IAa) Ab (!Ab) 176 where: R 115 is H, a linear or whenever possible branched C 1 -c 3 alkyl; RI 1 6 has the same meanings as RT ozr when R 115 is H -it can be benzyl; RII 1 R 112 and R 1 1 3 are equal or difrferent one from the other and are hydrogen, linear or whenever possible branched C 1 -C6 alkyl or C 1 -C 6 alkoxy, or Cl, F, Br; R 1 1 4 is R 1 1 1 or bromine; ::*,preferred are the compounds where R 1 1 1 R 1 1 2 and R1 are H, and R 11 is Cl and R 1 1 is in the ortho position. to NH; RIIS and R 1 1 6 are H, X is equal to and X 1 is H2C20; (I Ab) is the residue of 2-[C(2 -methyl 3-(trif luoro- methyl) phenyll amino) 3-pyridinecarboxylic acid and -COOR is present it is known as flunixin. The compounds preferred are those where X =0; **II A) ahosen- from the following: where, when t R is Ra I' 3a where R 2 a and R 3 a are H, a linear or whenever possible 177 branched substituted or non-substituted C 1 -C 1 2 alkyl, allyl, with the proviso that when one of the two is allyl the other is H; preferably R2a is H, alkyl has from 1 to 4 C atoms, R 3 a -is H; Ria is chosen from II Aa.) (TT) R R CL (IV) C 6 Q\ (V 178 S (cG=V) (VI) C 2H C (V=r) FLt H 3C \C/ CHI '3 0N II 179 where meanings are as follows: in the comoou-nds of formula (TV) residue of ketouro- f en: .Riiii is H, SR 1 1 1 3 where -R 1 1 1 3 contains from 1 to- 4 C linear or whenever Dossible branched C atomts; R12is H, hydroxy; preferred are the compounds where RIM 1 and R 1 1 1 2 are H, R3a is H, and R 2 a is methyl, X 0; -in the compounds; of formula (XXT) residue of carpro- fen: R-xxi is H, a linear or whenever possible braniched alkyl having f rom 1 to 6 carbon atoms, a Cl-Cg alkoxy-- carbonyl bound to a Ci-C 6 alkyl, a C,--C 6 carboxyalkyl, a CC~ CC-C 6 alkanoyl, op~iona11y substituted with halogen, benzyl or halobenzyl, benzoyl or halobenzoyl; Rmci is H, halogen, hydroxy, CN a Cl-C6 alkyl optional- ly containing OH groups, a Cl-C 6 alkoxy, acetyl, benzyl- oxy, 2 where 4 2 is a C 1 -C 6 alkcyl; a oerfluoroal- kyl having from 1-3 C atoms, a Cl-C 6 carboxyalkyl OprtiO- 180 nally containing OH groups, NO 2 sulphamoyl, dialkyl sulphamoyl with the alkyl having from 1 to 6 C acoms, or difluoroalkylsulphonyl with the alkyl having from 1 to 3 C atoms; Rxxi is halogen, CN, a C 1 -C 6 alkyl containing one or more OH groups, a C -Cg alkoxy, acetyl, acetamido, benz- yloxy, SRIII 3 is as above defined, a perfluoroalkyl having from 1 to 3 C atoms, hydroxy-, a carboxyalkyl having from 1 to 6 C atoms, NO 2 amino, a mono- or dialkylamino ha- ving from 1 to 6 C atoms, sulphamoyl, a dialkyl sulpha- y. moyl having from 1 to 6 C atoms, or difluoroalkylsul- phamoyl as above defined; or Rxx i jointly with Rxxil is an alkylene dioxy having from 1 to 6 C atoms; preferred are the compounds where Rxxio is H, the connecting bridge is at position 2, Rxx i is H, Rxxil is chlorine and is in the para position to nitrogen; R3a i s H, R 2 a is methyl and X is O; in the compounds -of formula (XXXV), residue of thia- profenic acid: Ar is phenyl, hydroxyphenyl optionally mono- or polysubstituted with halogen, an alkanoyl or alkoxy having from 1 to 6 C atoms, a trialalkyl having rrom 1-6 C atoms, preferably from 1-3 C atoms, cyclo- 181 pentyl o-hentyl, he7_=ro-ary1, preferably thienyl, -rury! oncionally concazning OH, pyridyl; the pref-rred comocunds of ror-MU"a (XXXV) are those where A-r is phenyl, Ra is H, Ra is methyl and X is 0; nthe comnounds of formula (11) residue -of sunro- ten, the pref erred, where R 3 a H, R 2 a CH 3 and X 0; in the compounds ofL formula (VI), of which the preferred, indoprofen, when R 2 a is CH 3 or indobufen, when Ra is eaual to H and Ra=CH and .X 0; in the comoounds of formula (viii), 00..of which the preferred, etodolac, when Ra= Ra H and 0:0. in the compounds of formula (VII), of which the preferred, fenopro-fen, when R3a =H, R 2 a CH 3 and X 0; -in-the compounds of formula-III), of which the preferred, fenbufen, when R 3 a R~a =H and X =0; in the compounds of formula residue of tolmetin, when R 3 a R 2 a H and X 0; in the compounds of formula (IX) residue of flurbi- 182 Dorof en, winen R3 E Ra c: 3 ant':c 0; I I Ab) n I Tla) (XXX) XY-X~l (x.XX-E ii) 183 EL_ 3(G 1/V0 N H 3C 7 whr th ennsar sflos Whe *Ia otis-HC3_O_ ti -on spa norfn ehlS-i bezprn*,-bp-Jie7 :whee tresidenings are a n follows: )_CO it:iS Clw as bermoorofen: dibenz fb,f) oxepin-2-acetic acid, pre- ferred is X 0, R 2 a H, R 3 a O3 184 residue (XXXI) is known as CS-670: 2 -[4-(2-oxo-1- cyclohexylidenemechyl)phenyl]propionic acid, when the radical is -CH(CH3)-COOH; preferred R 2 a H, R3a CH 3 and X 0; residue (XXXII) derives from the known Demedolac which contains group -CH 2 COOH, preferred R 2 a R 3 a =H and X 0; when residue (XXXIII) is saturated with -CH 2 COOH it is known- as pyrazolac: 4-(4-chlorophenyl)-1- (4-fluoro- phenyl)3-pyrazolyl acid derivatives; preferred R2a R3a H and X 0; when residue (XXXVI) is saturated with -CH(CH 3 )-COO- it is known as zaltoprofen. When the residue is satura- ted with a hydroxy or amine group or the acid salts, the compounds are known as dibenzothiepin-derivatives. Preferred R2a H, R3a CH 3 and X 0; when' residue (XXXVII) is CH 2 -COOH it derives from the known mofezolacz 3,4-di(p-methoxyphenyl)isoxazol-5-ace- tic acid; preferred are R2a R 3 a H, t 1, X 0. Group IIIA), where t 1, RIVd RIV C IVdl 185 where: RIVd and RIvd1 are at least one H and the other a linear or whenever possible branched C 1 -C 6 alkyl, preferably C 1 and C 2 or difluoroalkyl with the alkyl having from 1 to 6 C atoms, preferred is C 1 or RIvd and RIVdl jointly form a methylene group; RIV has the following meaning: a a a (11) Cx) a a R.-21 where the como~ounds of group IIA) have the following meanings: in the comooLunds of formula 186 RIV. 11 is an alkyl having f rom -I to 6 C atoms, a cycloalkyl having f rbm 3 to 7 C atoms, an alcoxymethyl flaying 'from 1 to. 7 C atoms, a trilf-uoroalky. having from 1. to 3 C atoms, vinyl, ethynyl, halogen, an alkoxy naviffg from 1 to 6 C atoms, a difliuoroalkoxy with the alkyl having from 1 to 7 C atoms, an alkoxymethyloxy having from 1 to 7 C atoms, an alkyithiomethyloxy with the alkyl having from 1 to 7 C atoms, an alkylme- chylthiJo -with the alkyl ha-ving f~rom 1 to 7 C atoms, cyano, difluoromethylthio, a substituted phenyl- or phenylalkyl with the alkyl having f rom 1 to

8 C atoms; *pref erably RIV-Il is CH 3 O, RIVd is H and RIVdl is CH 3 and is known as the residue of naproxen; X= NTI and X1 is equal to (C9) or (CH 2 CH 2 O) 2 also preferred is the same compound where X is equal to 0; in the oreferred compounds of formula MX, for which the residue of loxoorofen has been shown, RIVd is H and .:RIvdl is- CE 3 X NH or 0 and X 1 is equal to (.CH 2 4 or (CH 2 CH 2 O) 2' in the compounds of formula RIVIIIis a C 2 -C 5 alkyl, even branched when possible, a C 2 and C 3 alkyloxy, allyloxy, phenoxy, bhenylthio, a cycloalkyl having from 5 to 7 C atioms, opti onally sub- 187 stituted at position 1 by a C 1 -C 2 alkyl; preferred is the compound where Riv-iii is CH 3 CH-CH 2 CH 3 and RIvd H, RIvdl is C4 3 a conpound known as the re- sidue oE iburrofen; x and X i s eaual to (CH 2 or (C'T2Cd20) 2 also preferred is the same com- Dound where X 0; Grouo IV A) Co- 3j S(IV A) where A =RCOO, t 1, of whi-ch the residue of the knowti indome-zhacin has been shown. SGrou V A) chosen from the following: SV Aa) fenamates chosen from the following, where t I 188 NHCH 2 CH 2 (V Aa 1) ~NH /Q CF 3 (V Aa2) cl CH 3 (V Aa3) (V Aa4) 189 (V Aa5) H 3C Cl -v Ab) derivatives of nif lutmic acid, where t 1: CF 3 N NH (V Abl) -V Ac), COX 2 inhibitors, where t 0 and R is as f ol lows: N S0 2 CH 3 0 Y, V Ac N0 2 (V Adi) 190 N 0 0~ H (V Ac2) F 0 0 (V AC3) 191 CH CH 2 3 /0 CH 3 (V V Ad) derivatives of diuretics when t I and R i S as f ollows: C (V Adi) C S (V Ad2) (V Ad3) 192 0 0 0 (V AdA) V Ae) derivatives of diuretics when t =0 and R is as f ollows: H o 0 .0H NN 42 (V Ael) H 1 0 I ii H ci-i 3 0 N I3 (V Pe2) 193 N CL)/ N 7 ZNH N=N (V Ae3) HN NH FC H 3 (V Ae4) 0 0 0\ /0 00 00 03000 H N S NH HN (V Ae6) CO S 0* OS (V (V Ae7) 194 0* NH 00 N H HO (V Ae8) 0 0 S~lN HN N- CH 3 (V Ae9) I CH3 (V Aell) H N",H I 0N 0 (V Ael2) 195 where the meaning _J group V iJs as follows: in comoounds (V Aal) the es_ cue c-F enfenamic acid, 2- [(2-ohenvlet-hyl)aminolbenzoic acid', has been shown; in comoounds (v Aa2) the residue of' flufenamic acid, 2- f(3-(triffluoromechyl)phenyl] -arnino) benzoic acid, has been shown; in compounds (V Aa3) the residue of meclofenamic acid, 2- [r(2,6-dichloro-3-methylphenyl) amino] benzoic acid, has been shown; in compounds (v Aa4) the residue o- mefanamic acid, 2- (2,3-dimethylphenyl) amino] benlzoic acid, has been shown; -in compo unds (V Aa5) the residue of tolf enamic acid, 2-(--chloro-2-methylphenyl) amino] benzoic acid, has been shown; in compounds (v Al1) the residue of niflumic acid, -3 (tr ifl1uo rome thyl1) phe nyl1l aminP.o]I 3 -pyridi ne car- boxylic acid, has been shown; -in compounds (V Adl) Rvacl attached to the oxygen atom in position 2 of the benzene ring of N-.(4-flitro- phenyl)methansulphonamide can be ph enyl or cycloexale- When Rvacl is phenyl the residue is t~hat of: nimesulide; in comoounds (V Ac2) the residue of: 3-formylamino- 7 196 me thylsulzfonylarino 6 phenocy4H-!be zopyran- 4 one has been shown; in comnlounds (V Ac3) the atom X. that links the radi- Cal 2,4-difluorothl4ophelyl to position 6 of the indano- nring o- the residue can be sulfur or oxygen; in comp~ounds (V Ac4) the residue of celecoxib (4-methylphenyl) (trif luoromethyl) pyrazol-1-yl] ben- zensuiphonamide, has been shown; -in compounds (V Ac5) the residue of 6-(2-(3-ethyl- 2, 3-dihydro-thiaZOlyl) thio-5-methanesu1phonamido- 3 H- .***isobenzonfuran-l-one has been shown. -in compounds (V Adi) the residue of bumetanide 3- (Aminosulfonyl) (butylamilo) -4-phefloxybeflzoic acid has been shown; -in compounds (V Ad2) the residue of ticrynafen [2,3- Dichloro-4- (2-thienylcarbonYl) -phenoxy) acetic acid has -been -shown; -in compounds (V Ad3) the residue of ethacrynic acid 2 3 -Dichloro- 4 (2-methylene-).oxobutyl) phenoxylacei acid, has been shown; in compounds (v Ad4) the residue of pireta-nide 3 (Aminosul fonyl) 4 -henoxy-5 -(1l-pyrrolidinyl) benlzoic 197 acid has been shown. in COmoDounds (V Ael) the resizfu- of rioamide (3a,, 4 c, 7 a, 7aci) -3 -(Aminosu'ohornvi) :--chioro-N- (Octaidro- 4, 7 -metanio-2Hisoindo12..yl)benz 7 de has been shown. -n 11compTounds (V Ae2) the residue of torsemide Methylethyl) amino] carbonyl] 4- (3 -methyl-henyl) amino] -3- pyrinesulfonamide has been shown; -in cotrrounds (V Ae3) the residue of azosem-Lide 2-Chlo- (1H-tetrazol5 yl 4. -thienylmethy1) amino] ben- zensulphonamide has been shown; -in Compounds (V Ae4) the residue of bendroflume- thiazide 3, 4 -Dihydro-3 (phenyl -methyl) 6- (trif luoro methyl) -2H-1, 2 ,4-benzotiadiazine-7-sulfonamjije 1,1- dioxide has been shown; -in comopounds (V AeS) the residue of chiorothiazide -Chloro-2H-124benzothd diazne...7-.sulfonamide 1,1- dioxide has been shown;L -in compounds (V Ae6) the residue of hydrochiorotia- zide 6-Chloro-3,4-dihydro2H-24-benzothiadiazine7- sulfonamide 1,1-dioxide has been shown; in compounds (V Ae7) the residue of methylciothiazide (G-Chloro-3-(chloromethyl) -3,4-di-hydro-2-methyl-2H- 1,2, 4 -benzothiadiazine7sulfonarr-,de 1,1-dioxide has 198 been shown; in comDounds (V Ae8) he residue of chiorthalidone 2-Chloro-5-(2,3-dihydro-1-hydroxy-3-oxo-lK-soindol-l- ylfbenzensulfonamide has been shown; in comoounds (V Ae9) the resicue of Indapamide 3- (Aminosulfony1)-4-chloro-N-(2,3-dihydro-2-mehy'-lH- indol-1-yl)benzamide has been shown; in compounds (VAe1O) the residue of metolazone 7- Chloro-1,2,3,4-tetrahydro-Z-methyl- 3 (2-methyiphenyl) 4-oxo-6-cninazolinesulfonamide has been shown; O.V. in compounds (V Aell) the residue of quinetazone 7- Chloro-2 -ethyl 2,3,4-tetrahydro--oxo-6-unzl-e sulfonamide has been shown; in compounds- (V Ae12) the residue of furosemide (Aminosulfonyl)-4-chloro-2-((2-furanylmethyl)amino]ben- zoic acid has been shown. X 1 in formula A-X 1 -N0 2 is a bivalent connecting bridge ~*chosen from the following: YO where Y is a linear or whenever possible branched C 1 -C 20 alkylene, preferably having from 2 to 5 carbon atoms, or an optionally substituted cycloalkylene having from 5 to 7 carbon atoms; 199 2 n~3 where n3is an integer from 0 to 3; H 2 0- coofi CH 2 u14U2 (CH-CH-cH 2 i--o 1 where Rf=H H n nf is an integer f rom 1 to 6, peeal rm2 t 4;f r b y r m 2 t o 4 n 0 Gru VI).hr 200 2 1 (la) COR 3 coo (R (H (R2 (R n (Ib) where: *5 R 1 is group OCOR 3 where R 3 is methyl, ethyl or a linear S* or branched C 3 -C 5 alkyl, or the residue of a single-ring heterocycle having 5 or 6 atoms which can be aromatic, partially or totally hydrogenated, containing one or more heteroatoms independently chosen from O, N and S; R 2 is hydrogen, hydroxy, halogen, a linear or whenever S. possible branched alkyl having from 1 to 4 C atoms, a linear or whenever possible branched alcoxyl having from 1 to 4 C atoms; a linear or whenever possible branched perfluoroalkyl having from 1 to 4 C atoms, for example trifluoromethyl, nitro, amino, mono- or 201 di (Cl 4 )alkylamino; R 1 and R 2 jointly are the dioxyrnethylene group, with the proviso that when X NH, then xiis ethylene and R= H; RI cannot be OCOR 3 at position 2 when R 3 is methyl; nI being an integer from 0 to 1; preferably in Ia) X is equal to 0 or NH, R 1 is ace- toxy, preferably at position 3 or 4, most preferably in the ortho position to Co. X 1 is ethylene or (CH 2 CH 2 O) 2 R 2 is Hydrogen or hialogen, most preferred are the following A X 1 -NO 2 compounds: 3-acetoxy-N-(2-nitffoxy- ethyl) -benzamide, 4-acetoxy-N- (2-nitroxyethyl) -benza- mide, 3-acetoxy-N- (5-nitroxypenthyl) -benzamide, 2-ace- toxy-N- (5-nitroxypenthyl) -benzamide, N-2- (nitroxy- ethyl) -2-propionoxybenzamide, 2-acetoxy-2-nitroxy- ethylbenzoate, 2-acetoxy-N- (cis-2-nitroxycyclohexyl) benzamide, 2-acetoxy-4-chloro-N- (2-nitroxyethyl) -benza- mide, N- (2-nitroxyethyl) ((4-thiazolindinyl)carbon- :yloxy) -benzamide hydrochloride, 2-nicotinoyloxy-N- (2- nitroxyethyl) -benzamide, 2-acetoxy-.S-nitroxypernthyiben- zoate; preferably in Ib) R 3 CH 3 nI 0; X is equal to 0, X 1 is ethylene; in this case Ib) is the residue of acetylsalicylsalicylic acid. 202