AU3895401A - Nitric ester derivatives and their use in the treatment of gastrointestinal tumours - Google Patents

Description

AUSTRALIA

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

Invention Title: NITRIC ESTER DERIVATIVES AND THEIR USE IN THE TREATMENT OF GASTROINTESTINAL TUMOURS S S 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 S* 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 Scanr 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 Sthe urinary bladder and manifests itself with a sudden.

and urgent stimulus to urinate. Urge incontinence is

S

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, Pharmaological Reviews, 1993, 45, 253-308: reduced detrusor activity, 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 o 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 Lowering 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 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 important 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 case, as in the first approach described above, severe side effects of a hypontensive 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 -N0 2 or their salts, where: "A R(COX) t where t is an integer 0 or 1; e. X O, NH, *NRe 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

112 4

R

*R IA :1

F

(LAa) 33 (Lb) where:

R

115 is H, a linear or whenever possible branched C 1 -c 3 alkyl;

RI

1 6 has the same meaninas as orwhn TT i Hi can'be benzyl;

RII

1

R

11 2 and R 113 are ecaual or different one from the other and are hydrogen, linear or whenever possible branched C 1

-C

6 alkyl or cl-c 6 alkoxy, or Cl, F, Br; R14is R 1 1 1 or bromine; preferred are the compounds where R II 1

RI

1 2 and R1 are H, and R 1 13 is C1 and R 1 1 3 is in the ortho position *to NH; R 11 5 and R 1 1 6 are H, X is equal to 0, and Xis (CH 2

-C

2 -0) 2 I.

C

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

*0~*The compounds preferred are those where X =0; II~ A) c-hosen- from the following: :where, when t R is Ra Ria C- 3a where R 2 and Rja are H, 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; preferably R 2 a is H, alkyl has from 1 to 4 C atoms, R3a -is H; Ri a is chosen from II Aa) -I2-

(IIV)

S*

S S

S

C-,

(VI)

4 S 4

CH

'3 0N H3C

MX

0 where meanings are as follows: in the comoounds of formula residue of ketoorofen: RIIII is H, SRIII 3 where RIII3 contains from 1 to- 4 C linear or whenever oossible branched C atoms; RIII2 is H, hydroxy; preferred are the compounds where R III and RII2 are H, R3a is H, and R 2 a is methyl, X 0; in the compounds of formula (XXI), residue of carprofen: 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 C 1

-C

6 alkyl, a C-Cg carboxyalkyl, a

C-C

6 alkanoyl, optionally substituted with halogen, benzyl or halobenzyl, benzoyl or halobenzoyl; Rxxi is H, halogen, hydroxy, CN, a CI-Cg alkyl optionally containing OH groups, a C 1 -Cg alkoxy, acetyl, benzyloxy, SR.i 2 where Rx2 is a C -C 6 aliyl; a perfluoroalkyl having from 1-3 C atoms, a C -C 6 carboxyalkyl optionally containing O.H groucs, N0 2 sulpharnoyl, dilalkyl sulohamoyl with the alkyl having from 1 to 6 C atoms, or difluoroalkcylsulphonyl with the alkyl having from 1 to 3 C acoms; Rxxi' is halogen, CN, a C 1

-C

6 alky! conzaining one or mor OHgroosa 1

-C

6 alkoxy, acetyl, aceztamido, benzy'oxy,

SR

1 1 1 3 is as above defined, a perfluor.alkyl having from 1 to i5 C atoms, hydroxy-, a carboxyalkyl having f rom 1 to 6 C atoms, N0 2 amino, a mono- or dialkylamino having from 1 to 6 C atoms, suiphamoyl, a dialkyl suipDhamoyl having from 1 to 6 C atoms, or difluoroalkylsul- ::phamoyl as above defined; or R~x jointly with Rxi is an alkylene dioxy having from 1 to 6 C atoms; *preferred are the comrounds where Rxi is H, the connecting bridge is at position 2, Rxx is H, Rxxj 1 is chlorine and is in the pare position to nitrogen;

R

3 a i-S H, R 2 a is methyl and X is 0; in the comoounds of formula (XXXV) residue of thiaprofenic acid: Ar is phenyl, hydroxyphenyl optionally mono- or po lysubstituted 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, cyclopentyl o-he~xyi o-heptyi, heeor], Ore ferably Enienvyl, :rloocionally conta:iinc OH, pyridyl; the preferred comounds of orla(XXXV) are those where Ar is phenyl, Ra i-s H, R2 s methyl and X is 0; nthe comnounds of formula (T7) residue -of suorofen, the preferred, where R 3 a H, R 2 a CH 3 and X =0; in the compounds of formula (VI), of which the preferred, indoprof en, when R 2 a. is CH 3 or indobuf en, when R2. is eo'ual to H- and R 3 a CH 3 and X 0 in th co*u ffoml VI) -in the compounds of formula (VII), of which the preferred, fetodoac, when R3a R2a H and in the compounds of formula (VII, rsdeo om~ whna R2a HI{ and X 0; in the compounds of f or-mula residue of ftoirbi (TllXfY)

/JN

q

(TIXX)~)

*l a

N

-I

H

a a a. (TXXX) 1) a. a I a sa, j a. a a..

a a a.

(XYX)

0

KE

01/ IjX (qV II -c -jdU 3qm uj.

0 X'VL N \0 *H4Ce wher th ennsar sflos whe *Ia otis-HC3_~- ti -on spa noroSn a-ehlS-4 ezprn (,-jy_;ie7 acti acd4rfre :,adX=0 whe reiu (XX otis4:(O -OH s n as bemorfn 4.z oei--c~ caip e fere isX=0**a H ~a CL resiue (YXX) is known as CS-670: 2- (2-oxo-lcyclohexylideneme chyl)phenyllp roopion c acid, when the radical is -CH(CH)-COOH;; preferred R~ H, Ra CH3~ and X 0; residue (XrXXII) derives L m hekown Demedolac which contains roup -CHCOOH, Dreferred R2a R3a 14 and X 0; -when residue (XXXIII). is saturated with -CH2COOH it is known- as pyrazolac: 4-(4-chlorohenyl)-l--(4-fluorophenyl) 3-pyrazolyl acid derivatives; preferred RRa R3a H and X 0; when residue (XXXVI) is saturated with -CH(CH3) -COO- Sit is known as zaltoprofen. When the residue is satura- :ted with a ydroxy or amine group or the acid salts, the compounds are known as dibenzothiepin -derivatives.

Preferred Ra= H, Ra= CH3 and X 0; -when' residue (XXXVII) is CH2-COOH it derives from the I' known mof ezolac z 3,4 -:di (p-methoxyphenyl isoxazol 5- ace-- 0, ':tic acid; preferred are R2a Rja H, t 1 X= 0.

SGroup IIIA) where t =i RIVd

IV

RIVdi where: RIVd and RIVdl are at least one H and the other a linear or whenever possible branched Ci-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 RIVdI jointly form a methylene group; RIV has the following meaning: 0 0000 0eS@

SB

0 0 OSS 6 0000 @0 0* S @6 S. S @0 S. @0 0 0

S

S

6SSS 0 0 e.g.

0060 5050 0 @550 00 500* 0 @0 05 S0

R.

IXV-3-).

(11) R iv-LiZcm=) where the comp~ounds of group lIIA) have the following meanings: in the comonds of f-:ormula (MI Rvi is an alk-vl havina _F 0m 0 6 C atoms, a cycloalkyl havina from 3 to 7 C atoms, an alcoxyrnethyi havina from 1 to 7 C atoms, a tr-ifluoroalkyl having from 1 to 3 C azoms, vinyl, ethynyl, halogen, an alkoxy havinig 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 alkyithiomethyloxy with the alkyl having from 1 to 7 C atoms, an alkylmethyithio -with the alkyl having from 1 Co 7 C atoms, cyano, difluoromethylthio, a substituted phenyl- or phenylalkyl with the alkyl having from 1 to 8 C atoms; preferably RIV..II is CH 3 0, RIvd is H and RIvdl is CH 3 and is known as the residue of 'naproxen; *X =NH{ and X1is equal to (g)4or (CH 2

CH

2 O) 2 also loref erred is the same compound where X is equal to 0; 00.

-in the preferred compounds of formula for which the residue of loxoorof en has been shown, RIVd is H and RIVdi is- G{ 3 X NH or 0 and X 1 is equal to (.CH 2 4 or :00..0 00. CCH 2

CH

2 O) 2; in the compounds of formula RIVIIIis a C 2 alkyl, even branched when possible, a

C

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

-C

2 alkyl; preferred is the compound where Riv- 111 is CH 3

CH-CH

2

CH

3 and Rivd Rid is C-1 3 a coiPoound known as the residue of' ibunrofen; X N-H ard is eqrual to (C2)4_or (0CrH 2 O) 2 also Dref errled is the same compound where X =0; *Group IV A)

CHC

cai: Ix-3 (IV A) where A =RCOO, t 1, of whi-ch the residue of the knowti indome~zhacil has been shown.

*Group V A) chosen from the following: -V Aa) fenamates chosen from the following, whar-e 1

NHCH

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

CH-

3 (V Aa3) (V Aa4) (V AaS) H 3C C1 of nif lutnic acid, where t 1 V Ab), derivatives CF3 (v Abi) V Ac) COX 2 inhibitors, where t 0 and R is as follows: N SO 2

CH

3 0 Y, V Ac

NO-

2 (V Adl) N 0 CH3 (V Ac2) 0 0 sF

CHI-

s

SH

(V AC4) 3H 3 (V -V Ad) derivatives of diuretics whien t 1 and R is as f ollows: 00 NH2 H 3 (V Ad) (V AdA) V Ae) derivatives of diuretics wh en t 0 and R i s as f ollows: (V Ael) H o0 3 S=O y Hi

CH

c- 3 0 3 N I (V Ae2)

NN

N-N

(V Ae3) 0/0 0/l0 HN NH-SN NlN 0 0 (V Ae) 000 0 *.oo HNA'

NH

o. (V .000 H N 3 N 0. 00 L a~j (V Ae6) 0 NH 0/0 HO NHc (V Ae8) 0 0 0 HN N NH

N-

CH3

C

(V Ae9)

S

S*

S S 55 *5

S

S

*.SS

(V Aell) 0 0 0 (V AeI-2) S. S

SS

*S

where tihe meanIng Z2: crouc V A) as 01±0ll-W5: in compounc s (v reslc' c: erifenam.Lc acid, 2- ((2-ohenviezhy1)a~ninolbefizoi'c ac~, has been shown; in comioouncs (V Aa2) r-ne residue of flufenarric acid, 2- (trif-cuoromer-hlY) phenll -amlnoj .enzoic acid, has been shown; in compounds (V Aa3) the residue or meclofenamic.

acidi, 2 [(2,6-dichloro-3-methylphefl) aminlo]benzoic acid, has been shown; in compounds (V Aa4) the residue of mefanamic acid, 3-dimethyiphenyl) amino] benzoic acid, has been shown; in compounds (V Aa5) the residue of tolfenamic acid, 2- ((3chloro-2-methypheny)aminolbeflzoic acid, has been shown; in compounds (V Abi) the residue of niflumic acid, 2-4f (trifluoromethyl)phenyl aminlo] -3-pyridine carboxylic acid, has been shown; -in compounds (V Al) Rvacl attached to the oxygen atom in position 2 of the benzene ring of N-(4-flitrophenyl)metha-nsulphonamide can be phenyl or cycloeXa-le- When Rvaci is phenyl the residue is Tihat- of nimesulide; in comoounds (V Ac2) the residue ofz 3-zformylamfiP.o-7 mechlsu- oyl-min-6-henocy-H-ibezoyrn-4one has been shown; in comooundS (V Ac3) the atom X, thnat links the raci- Cal 2 ,4-difluoroth2-ophenyl to position 6 of the indanone' rngZo the residue 5methanesulrfonamido- 1 -'naanone can be sulfur or oxygen; in compounds (V Ac4) the residue of celecoxib (4-methyiphenyl) (trifluoromethyl)PYrazo-ilI benzensuiphonamide, has been shown; in compounds (V AcS) the residue of 6-[2-(3-ethy- 2,3-dihydro-thiazolyl) thio-5S-methafesuphonamido- 3

H

isobenzonfuran-1-one has been shown.

to 9* in compounds (V Adi) the residue of bumetanide 3- (Aminosulforlyl) (butylamino) -4-phefloxybenzoic acid has been shown; *too in compounds (V Ad.2) the residue of ticrynafen [2,3- Dichloro-4- (2-thienylcarbolYl) -phenoxy] acetic acid has .been -shown; -in compounds (V Ad3) the residue of ethacrynic acid 2 3 -Dichloro 4 (methyleneioxobutyl)pheny) cei acid, has been shown;in compou-nds (V Ad4) the rsde of piretarilde 3- (AminosulfonyiV 4prhenoxy-5(1pyrrolidinyl)bezi acid has been shown.

in COrocunds (V Aed) the resA.>z of zirioamide (3ac, 4 C, 7a, 7 au) 3 -(Ami_4no s u Ioho,-v I -4c n 1c- -(oc t.a idro 4,7-e-n-H-sino 2-l ez has been shown.

incomounds(v Ae2) the residu- of r-orsemide Met-hvlethyl) amnino] carbonyll 4- (3 -me--hylahenyl) aminoj -3pyrinesulfonamide has been shown; -in comoounds (V Ae3) the residue of azosemide 2-Choro-S- CiH-tetrazol-5-yl) (2-thienylmethyl) amino] benzensulPhonamide has been shown; in comrvounds (V Ae4) the residue of bendroflumethiazide 3,4-Dihydro-3- (phenyl -methyl) (trifluoromethyl) 2 H-1,2,4-benzothiadiazine-7-.sulfonar~de 1,1dioxide has been shown;L 5 -in compounds (V Ae5) the 'residue of hirohoiaid z-clro-2-Clr-,-iho2-,2,benzotothadiazine~7ufnmd Vsoot so0 ulonmie ,1dioxide has been shown; -in comnounds (V Ae7) the residue of mehydrohiroiazide Gor-hor-c,4-dihyro-H1,4-benzdothiadiazine-7- 12,4-eztidaie7sulfonami~de 1,1-diox-ide hasbenso; been shown; in compounds (V Ae8) the residue of chiorthalidone 2-Chloro-5-(2,3-dihydro-1-hydroxy-3-oxo-lH-isoindol-lyl)benzensulf.Lonamide has been shown; in compounds (V Ae9) the residue of Indainamide 3- (Aminosulfonyl)-4-chloro-N- (2,3-dihydro-2-methyl-1Hindol-l-yl)benzamide has been shown; in compounds (VAe1O) the residue of metolazone 7- Chloro-l,2,3,4-tetrahydro-2-methyl-3- (2-methyiphenyl) 4-oxo-6-auinazolinesulfonamide has been shown; -in compounds (V Aell) the residue of quinetazone 7- Chloro- 2-ethyl-l1, 2, 3, 4 -tetrahydro-4 -oxo- 6-quinazol ine sulfonamide has been shown; -in *compounds- (V Ael2) the residue of furosemide (Aiinosulfonyl) -4-chloro-2- C((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 from 2 to S carbon atoms, or an optionally substituted cycloalkylene having from 5 to 7 carbon atoms; CI 2-G (CHf) 2 n3 where n 3 is an integer from 0 t~o 3; H-2 0- COOH CH 2 UNU2

-(CH-C

2 -H-f-)j where Rf-H H n nf is an integer from 1 to 6, peeal rm2 tofral 4;m2to4 n GoVAwhere t~ 1,, 3 adn sa itgrfo o6 2 1 (Ia) 6ocoo 2 nI nI S* where: RI is group OCOR3; where R3 is methyl, ethyl or a linear

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 alcol havingle from i1 to 4 C ato m s; a linear or whenever possible hetebr anched perfluoroalkyl having from can be aromatic, for example trifluoromettally hydrogenated, containing one or 32 more heteroatoms independently chosen from 0, N and S; i2 l s 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 (C 1 4)alkylamino;- Rand R 2 jointly are the dioxymethylene group, with the proviso that when X NE-, 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 NH, R, is acetoxy, preferably at position 3 or 4, most preferably in the ortho position to Co. X1is 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-nitifoxyethyl) -benzamide, 4-acetoxy-N- (2-nitroxyethyl) -benza- *mide, 3 -ace toxy-N- (5 -ni troxypenthyl) benzamide, 2-acetoxy-N- (5-nitroxypenthyl) -benzamide, N-2- (nitroxyethyl) -2-propionoxybenzamide, 2-acetoxy-2-nitroxyethylbenzoate, 2-acetoxy-N- (cis -2 -nitroxy'cyclohexyl) benzamide, 2-acetoxy-4-chloro-N- (2-nitroxyethyl) -benzamide, N- (2 -nitroxyethyl) 2- (4 -thiazolindinyl) carbonl- ~yloxy) -benzamide hydrochloride, 2-nicotinoyloxy-N (2nitroxyethyl) -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.

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 N0 2 or their salts, where: 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, o R 113 o H o o 3 116 where:

R

115 is H, a linear or whenever oossible branched C 1 -c 3 alkyl; RI6has the same meanings as R 1 1 5 or when RTT 5 is H it can be benzyl; RIII, R 112 and R 1 1 3 are eaual or di-Z:ferent one from the other and are hydrogen, linear or whenever possible branched C 1

-C

6 alkyl or Cl-C 6 alkoxy, or Cl, F, Br; R14is R 111 or bromine; preferred are the compounds where R 1 1 1

R

1 1 2 arnd 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 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-(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) c-hosen-from the following: where, when t R is

R

2 a RIa Cwhere R2a and 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, R 3 a -is H; Rla is chosen from II Aa)

(TT)

o R

OI

(~XE)

R

(Iv) C 6H

Q\

(XXXv)

(VI)

(VIII)

CIX)

HG 3 C/ CHi '3 0N C -2 where meanings are as follows: in the comoounds of formula residue of ketoorofen: RIII1 is H, SR 1 11 3 where RII 1 3 contains from 1 to- 4 C linear or whenever possible branched C atoms; RIII2 is H, hydroxy; preferred are the compounds where RI 1 and RIII2 are H, R3a is H, and R 2 a is methyl, X 0; r. in the compounds of formula (XXI), residue of carprof en: Rxxio is H, a linear or whenever possible branched alkyl having from 1 to 6 carbon atoms, a C1-C 6 alkoxycarbonyl bound to a C 1

-C

6 alkyl, a Cf-C 6 carboxyalkyl, a

C

1

-C

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

-C

6 alkyl optionally containing OH groups, a CI-C 6 alkoxy, acetyl, benzyloxy, SRxxi2 where Rxxi 2 is a Ci-C 6 alkyl; a perfluoroalkyl having from 1-3 C atoms, a C 1

-C

6 carboxvalkyl opionally containing O-H groups, NO, sulphamoyl, dialkyl sulohamoyl with the alkyl having from 1 to 6 Caos or diEfluoroalk'ylsulphonyi with the alkyl having f rom 1 to 3 C atoms; Rxi is halogen, CN, a C 1

-C

6 alkyl1 conztaining one or mor OHgropsa 1

-C

6 alkoxy, acetyl, acetamido, benz- Yloxy,

SR

1 1 1 3 is as above defined, a perfluoroalkyl having from 1 to j C atoms, hydroxy-, a carboxyalkyl having f rom 1 to 6 C atoms, NO 2 amino, a mono- or dialkylamino ha- OV, ving from 1 to 6 C atoms, suiphamoyl, a dialkyl SU1~ha- *0 moyl having from 1 to 6 C atoms, or difluoroalkylsulphamoyl as above defined; or Rxx 1 jointly with Rxxil is 0 an alkylene dioxy having from 1 to 6 C atoms; preferred are. the compounds where RxYdo is H, the connecting bridge is at position 2, Rxx 1 is H, is chlorine and is in the para position to nitrogen; R H

R

3 a iHR 2 a is methyl and X is 0; -in the comoounds of formula (XXXv) residue of thiaprof enic acid: Ar is phenyl, hydrox-yphenyl option ally mono- or Dolysubstituted with halogen, an alkanoyl or alkoxy having from 1 to 6 C atoms, a tlrialalkyl having :rom 1-6 C atoms, preferably from 1-3 C atoms, cyclopentyl o-hexyl o-heptyl, herercaryL, preferably thienyl, furyl optionally conla-nin. OH, pyridyl; the preferred compounds of formula (XXXV) are those where Ar is phenyl, R 3 a is H, R -s methyl and X is O; -in te compounds of formula residue -of suorofen, the preferred, where R 3 a H, R 2 a =CH 3 and X 0; in the compounds of formula (VI), of which the preferred, indoprofen, when R2a is CH 3 or indobufen, when R2a is eaual to H and Ra CH and X 0; o* 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,

SR

2 a CH3 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- TT lxnY) D H L q: C~ m I I LG j0oa 0 XcCI

ECN

whr th ennsar.sflo whe .Ia cotis.HC3 CO- ti -on spa *roen a-ehl*-l ezp--n 23bp-iie 7 acti acd prfre R 2a1--,adX 0 whe re iu.X X o t i s -H O- t s ):0f as be**rfn iez(~)oxpn2ael cd ~e fere is X. ,RR =C 2a 3a.

residue (XXXT) i s knownz as CS- 6 70: 2 oxo cyclohexylidenemethyl)phenylj c--ror ai, hnoh radical is -CP(C-H 3 i)-COOH; oreferred

R

2 a H, R 3 a CH 3 and X =0; residue (XXXII) derives from the known pemedolac which contains group -CH 2 COOH, ore-"'erred

R

2 a R 3 a =H and X 0; when residue (XXXIII), is saturated with -CH 2 COOH it i s known-as pyrazolac: 4- (4-chlorophenyl) (4-f luorophenryl) 3 -pyrazolyl acid derivatives; preferred :o: oo*

R

2 a R 3 a H and X 0; oo..o. when residue (XX.XVI) is saturated with -CH(CH 3 -Cooit is known as zaltoprof en. When the residue is satura- 5 ted with a hydroxy or amine group or the acid salts, 0 o 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 -acetic .acid; preferred are R 2 a R 3 a t X =0.

*GrouuD IIIA) where t =1, R IVd RIV C- RIVdl 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 RIVdi jointly form a methylene group; RIV has the following meaning: (11) (inT) where the comuounds of group have the following meanings: in the comoounds of formula (11): TVII is an alkyl having f rom I. to 6 C atoms, a cycloalkyl having f~rom 3 to 7 C atoms, an alCoxyrnethyl having from 1 to 7 C atoms, a triffluoroalkyl having from 1 to 3 C aiorns, 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 alkoxymethyloxy having from 1 to 7 C atoms, an alkyithiomethyloxy with the alkyl having from 1 to 7 C atoms, an alkylmethyithiao -with the alkyl having fErom 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-I 1 is CH 3 O, RIVd is H and RIVdi is CR 3 and is known as the residue of naproxen; or (C.Has X=NH and X 1 is equal to org2 4C 2

CH

2 0) 2 as preferred is the same compound where X is equal to 0; -in the oreferred compounds of formula WX, for which the residue of loxoprofL-n has been shown, R~v is H and *d :RIVdi is- CH- 3 X NH or 0 and X 1 is equal to (CH29 4 or

(CH

2

CH

2 O) 2; in the comoounds of formula RIVrIIr 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 at~oms, ootionally substituted 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 Rrvd Rivd 1 is C' 3 4 a conpooud known as the residue of ibu-rofen; X NH and X; is eiaul to

(CH

2 4 or (CF12Ca 2 2 also oreferred is the same com- Dound where X 0; GrouD IV A) CEI O Cir (IV A) where A RCOO, t 1, of which the residue of the knowhi indome-hacin has been shown.

Grouo V A) chosen from the following: V Aa) fenamates chosen from the following, where 1

NHCH

2

CH

2 (V Aal) NH -QNi CF 3 (V Aa2)

CH

3 NH Cl (V Aa3) (V Aa4) (V AaS) H 3C V Ab) derivatives of nif lumic acid, where L=1 CF3 a (V Abi) V Ac),i COX inhibitors, where t 0 and R is as f ol lows: N SO 2

CH

3 0 I RV R

NO,

(V Acl)

H

N 0 o

H

0 .0 CH 3 (V AM2

N

CHI-

77.

(V AM3 H- (V Ac4) CH C-H- 2 3 IZ

S

CHI (V V Ad) derivatives of diuretics wh-en t =1 and R is as f ollows: 0 *.2 NH f.

3 (V Adi) (V Ad3) (V AdA4) I. V Ae) deriva~ives of diureti cs when1 t 0 and R is as f ollows:

KN

(V Ael) H 0 HGC N I* 3 s=0 I y H

C

LIM

3 0 N (V Me2)

CL/

N

7

JNH

N N (V Ae3) (V Ae4) 00 0/0 cl NH (v

HN

CI.

(V Ae6) 0 0

HN

S, 3 cl

H

(V Ae7) 0 II NH 0 0 (V Ae8) 0 0 0 H NNH CH3 (V Ae9) (V Aeli) 0 (V AcI2) where The rnea7,Ing -L crouc V P- A aS: follows: in como~ounds (V aa) res~d'c cz: enfenamlc acd, 2- ((2-ohenvietihyl)am-inojbenzoi-c acid_, has been shown; in comiDounds (V PAa2) Lhe residu-_ of flufenamnic acid, 2- ([3-(uirifl-luorom-E'hyl)chenvl) -amr:iojbe-nzoic acid, has been shown; in comipounds (v Aa3) the residue of meclofenamic acid, 2- [(2,6-diclhiloro-3-methylphenyl) amino] benlzoic acid, has been shown; in compounds (v Aa4) the residue of: mefanamic acid, 2- C 3-dimethyliphenyl) amino] benzoic acid, has been shown; -in compo unds (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, 2-1 (trifluoromethyl)phenyll amino]-3-pyridine carboxylic acid, has been shown; in compounds (V Ac1)Rvaci attached to the oxygen atom in position 2 of the benzene ring of N-.(4flitrophenyl)metharnsulphonamide can be oh enyl or cycioexa-ne.

When Rvacl is phenyl the residue is zihat of nimesulide; in comcounds (V Ac2) the resicu of 3-zor-mylamr-0n 7 mechylsulfl-oyamio6phenoxy-4 lbez~~pyan-one has been shown; in comooulas (V Ac3) the atom X, th-at links the radical 2,4-difluorothiophelyl to positilon 6 of the indanone ring o' -he residue S-methafesulofamio!iinaao can be sulfur or oxygen; in comoounds (V Ac4) the residue of: celecoxib 4- (4-methylpheflyl) (trifluoromfethyl)pyrazollylI benzensuiphonamide, has been shown; in compounds (V Ac5) the residue of 6-[2-(3-ethyl- 2,3-dihydro-thiazolyl) thio-5-methanesulphonamido- 3

H-

isobenzonfuran-].-ofle has been shown.

in compounds (V Adi) the residue of bumetanide 3- *000 (Aminosuif any1) (butylamino) 4 -phenoxybenzoic acid 0 0*00 has been shown; in compounds (V Ad2) the residue of ticrynafen [2,3- Dichloro-4- (2-thienylcarbonyl) -phenoxy) acetic acid has 0 s-been -shown; -in comoounds (V Ad3) the residue of ethacrynic acid 2 3 -Dichloro4 ethyl ne-i o obut~pheoyIaei acid, has been shown; in compounds (V Ad4) the residue of piretanide 3- (Aminosulfonyl) 4 -ohenoxy541lpyrrolidinyl)benzoi acid has been shown, -in COMIDOunds (V Ael) the OFifi of rioamide (3aca, a, 7 a, 7acz) -3 (Am4inosu2_ohorwv!) -Iccor-o-N- (ocz-aidr..

4,-eao2-sirdl2y~ez- has been shown.

in comp~ounlds (v Ae2) tine residue Of t-orsernideN-(- Methylethyl) amino] carbonyll 4- (3-re-_ylohenyl) amino] -3pyrinesulfonamide has been shown; -in cotnoounds (V Ae3) the residue of azosemide 2-Chforo-S tetrazol -S yl)-4 -thienvlmethyl) arinol benzensulphonamjide has been shown; in conmounds (V Ae4) the residue of bendrof lumethiazide 3,4-Dihydro-3- (phenyl-rnethyl) (trifluoromethyl) 2 H-1,2,4-benzothiadiazine-7..sulfonarLde 1,1dioxide has been shown; -in compounds (V Ae5) the residue of chiorothiazide dioxide has been shown; -in Compounds (V AeG) the residue of hydrochiorotiazide 6-Choro-3,4-dihydro-2H-1,2,4-bnzot-hiadiazine-7sulfonarride 1,1-dioxide has been shown; in comptounds (V Ae7) the residue of methylciothiazide (6-Chloro-3-(chloromethy)-3,4-dhydro-2-meuhyl-2H- 1, 2 ,-benzothiadiazine-7sulfonamide i, i-dioxide has been shown; -in compounds (V Ae8) uhe residue of chlorthalidone 3-dihydro-1-hydroxy-3-oxo-A-E-isoindol-lyl~benzensulfonamide has been shown; in comoounds (V Ae9) the residue of Indapamide 3- (Aminosulfonyl)-4-chloro-N-(2,3-dihydro-2-methyl-1Hindol-1-yl)benzamide has been shown; in compounds (VAelO) the residue of metolazone 7- Chloro-1, 4- tetrahydro- 2-methyl 3-(2 -methylphenyl) 4--oxo-6'-auinazolinesulfonamide has been shown; in compounds (V Aell) the residue of quinetazone 7- *Chloro- 2-ethyl- 1, 2,3, 4-tetrahydro-4-oxo-6-quinazolinesulfonamide has been shown; *-in .compounds- (V Ael2) the residue of furosemide (Aminosulfonyl) -4-chloro-2- (2-furanylmethyl) amino) benzoic 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;

(CH)

2 n3 where n 3 is an integer from 0 Lo 3; H 0- 2-C2 2U

-(CHC

2

-H-H

2 o)rf whereR HC an nf is an integer f rom 1 to 6, peeal rm2 preferably from 2 to 4; and Group VIA), where t 1, 0 2 1 (la)

COR

3 coo 2n1 2 (R (R 2 n. I (Ib) where: R1 is group OCOR 3 where R3 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 di (Cl 4 )alkylamino; Rand R 2 jointly are the dioxymecihylene group, with the proviso that when X NEl-, then xiis 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 Nil, R 1 is acetoxy, preferably at position 3 or 4, most preferably in the ortho position to Co. X1is ethylene or (CH 2

CH

2

O)

2

R

2 is Hfydrogen or Ifalogen, most preferred are the :following A X 1

-NO

2 compounds: 3-acetoxy-N-(2-nitffoxyethyl) -benzamide, 4-acetoxy-N- (2-nitroxyethyl) -benza- *mide, 3 -ace toxy-N- (5 -ni troxypent hyl) 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) -benzamide, N- (2-nitroxyethyl) (4-thiazolindinyl) carbonyloxy) -benzamide hydrochloride, 2-nicotinoyloxy-N- (2nitroxyethyl) -benzamide, 2 -ace Coxy-5 -nitroxypenthyibenzoate; preferably in Ib) R 3

CH

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

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-X

1

-NO

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

R

S112

II

(LAa) (L~b) where:

R

115 is H, a linear or whenever cossible branched 13 alkyl;

RI

1 6 has the same meanings as RI 15 or when RTTS is H it can be benzyl; RI1 R1 and R 1 1 3 are eaual or different one from the other and are hydrogen, linear or whenever possible branched C 1

-C

6 alkyl or C 1

-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 R1 o* are H, and R 1 1 3 is Cl and R 1 1 3 is in the ortho position o:to NH; RIIS and R16are H, X is equal to 0, and xiis (CH 2

-CH

2 -0) 2 o (I Ab) is the residue of 2-U(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; o o* II A) chosen- from the following: where, when t R is Ra

I'

3a where R 2 and R 3a are H, a linear or whenever oossible 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 f rom. 1 to 4 C atoms, R 3 a -is H; Ria is chosen from II Aa.) a a a

(IX

p..

R

a* a.

R

C H Q)

C

6 5 c s

(XXDY)

(VT)

C R 2

(VIII)

p

C*

CH

0N H 3C Wx o C 2 where meanings are as follows: in the comoounds of formula residue of ketoorofen:

R

I I I I is H, SRIII3 where R 111 3 contains from 1 to- 4 C linear or whenever Dossible branched C atoms; R is Ii, hydroxy; preferred are the comounds where RI and RIII2 are H, R3a is H, and R 2 a is methyl, X 0; in the compounds of formula (XXI), residue of carprofen: Rxio is H, a linear or whenever possible branched alkyl having from 1 to 6 carbon atoms, a C 1

-C

6 alkoxy-.

carbonyl bound to a C 1

-C

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

SC

1

-C

6 alkanoyl, optionally substituted with halogen, benzyl or halobenzyl, benzoyl or halobenzoyl; Rxx i is H, halogen, hydroxy, Na C 1

-C

6 alkyl optionally containing OH groups, a C 1

-C

6 alkoxy, acetyl, benzyloxy, SRcxi 2 where Pcxi2 is a C -C 6 alkyl; a oerfluoroalkyl having from 1-3 C atoms, a C -C 6 carboxyalkyl optionally conr-aiping OH groups, NO 2 sulohanoYl, dialkyl sulohamoyl wich Lhe alkyl having fErom 1 L.o 6 Caos or difluoroalkylsulphonyl with the alkyl having From 1 to 3 C acoms; R)Cx 1 is halogen, CN, a CK-C 6 alky! conrcaining 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 j 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 suloha.moyl having from 1 to 6 C atoms, or difluoroalkylsulphamoyl as above defined; or P,,cx jointly with Rxxi 1 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 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 compounds of formula (XXXV) residue of thiaprof enic acid: Ar is phenyl, hydroxyphenyl. optionally mono- or polysubstituted with halogen, an alkanoyl. or alkoxy having from 1 to 6 C atoms, a crialalkyl having :Irom 1-6 C atoms, preferably from 1-3 C atoms, CYClopentyl o-hexyl o-heptyl, he:eroary!, preferably thienvy, fury oopionally conca.inc OH, pyridyl; the preferred compounds of formula (XXXV) are those where Ar is phenyl, R 3 a is H, R 22 is methyl and X is O; in Ene compounds of formula residue -of suorofen, the preferred, where R 3 a H, R 2 a CH 3 and X 0; in the compounds of formula (VI), of which the preferred, indoprofen, when R2a is CH 3 or o indobufen, when R2a is eaual to H and R3a CH 3 and X 0; in the compounds of formula

(VIII),

of which the preferred, etodolac, when R 3 a R2a H and X 0; in the compounds of formula (VII), of which the preferred, fenoprofen, when R3a H, V000

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 0; in the compounds of formula residue of flurbi- (-EI XY) (Tv' I I pj"2 uzj ~LM'b~oad 0 FL a 3* *H

C\

whr th mennsae.sflos whe otis-C(H)CoHi i nw sp noroen **ehlS-1 ezpra 23bp-iie7 whee rhesimenings arean follows:3)-OO t s cn 44s noo rno n r -e thyl-5H I' e zo yran-2 [2,3t bc acidi le f erred is X 0, R 2 a H, R 3 a residue (XX) is known as CS-670: 2-4-(2-oxoij_ cyclohexylidenemeuhyl)phenyl] croionoic acid, when the radical is -CP(CH 3 )-COOH; oreferred

R

2 a H, Rja

CH

3 and X 0; residue (XXXII) derives from the known pemedolac which contains group -CH 2 COOH, Dreferred R 2 a Rja H and X 0; when residue (XXXIII). is saturated with -CH 2 COOH it is known- as pyrazolac: 4-(4-chiorohenyl)-1- (4-fluoropherryl)3-pyrazolyl acid derivatives; preferred SR2a R3a 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, R 3 a 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 R 3 a H, t 1, X 0.

Grouo IIIA), where t 1, RIVd RIV C

RI

RIVdl 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, prefer red is C 1 or RIVd and RIVdi jointly form a methylene group; RIv has the following meaning: 0

R

whr th.*nud f ru IA av h olwn gs in th.o o Ln s of r a (I RriII is an alkyl having f rom I. t o 6 C atoms, a cycloalkyl having f rom 3 to 7 C atoms, an alcoxymethyl having from 1 to 7 C atoms, a t-rif-uoroalkyl having from 1 to 3 C acorns, vinyl, ethynyl, halogen, an alkoxy haviffg from 1 to 6 C atoms, a d~fluoroalkoxy with the alkyl having f rom 1 to 7 C atoms, an alkoxyrnethyloxy having from 1 to 7 C atoms, an alkyithiomethyloxy with the alkyl having from I. to 7 C atoms, an alkylmethylthiJo -with the alkyl ha-ving Zfrom 1 Co 7 C atoms, cyano, difluoromethylt-hio, a substituted phenyl- or phenylalkyl with the alkyl having from 1 to 8 C atoms; pref erably RIV-II is CH 3 O, RIVd is H and RIVdl is CH 3 and is known as the residue of naproxen; *X =N"M and X 1 is equal to 2 4 or (CH 2

CH

2 O) 2 also pref erred is the same compound where X is equal to 0; -in the Dre-rerred compounds of formula MX, for which the residue of loxoprof en has been shown, RIVd is H and :RIVdi is- CH 3 X =NE- or 0 and X 1 is equal to (.CH 2 4 or

(CH

2

CH

2 O) 2' in the comoounds of formula (III)

RIV

1 1 xI is a C 2 -CS alkyl, even branched when possible, a

C

2 and c 3 alkyloxcy, allyloxy, 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-ill is CH 3

CH-CH

2 CH 3 and Rfvd R 1 vd~ is C,; 3 a comuournd known as the residue ofL- ibuorofen; X N-I and is ecj.ial ro (H),or (CFI 2 (dO) 2 also preferred is the same compound where X =0; Group) IV A) j3 CH. C 3 0j 04- 2 (IV A) where A =RCOO, t 1, of whi-ch the residue of the knowh indornehacin has been shown.

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

NHCH

2

CH

2 (V Aal) CF 3 (V Aa2) ci CH 3 (V Aa3) 9 .9 CH 3 H 3 (V Aa4) (V Aa5) H3 CC -V Ab), derivatives of nif lumic acid, where L 1 CF 3 N NH (V Abl) -V Ac), COX 2 inhibitors, where t 0 and R is as f ollows: N S0 2

CH

3 0

NO

2 (V Acd)

H

N 0 o

H

(V Ac2) (V Ac3)

H

(V AC4) CH C~H 2 3 S0 0

O\/

IS-M

13 1- (V V Ad) derivatives of d -uretics when t 1 and R is as f Ollows: S S S. S.

S S

S

(V Adi) (V Ad2)

HGC

3 0 c~j (V Ad3) NH2 UN 2 0 0 0 (V AdA) V Ae) derivatives of diuretics when t =0 and R is as f ollows:

H

(V Ael) H 0a 3 H 0- (V Pe 2) o: 00C N N H

NN

H NIN" NH )aNN (V Ae3) 00 (V Ae)

S.

S.

*S

H N' cl (V Ae6) S S SS 0 0 H NA

H

(V Ae7) 0 I il' NH 0/0 HO

NH

(V Ae8) 0 0 0 HN

N

CH

2 (V Ae9) a H N, (V Ael I)

COOH

(V AeI-2) where The meaning in croup V A) is as follOws: in comoouncs (V resic' of enfenamic acid, 2- ((2-ohenvlethyl)aniinolbenzoic acid, has been shown; in comDounds (V Aa2) the residue of flufenam.ic acid, 2-[f3-(E-rif'luorome ch yl)Phenyl-am-noelZoic acid, has been shown; in compounds (V Aa3) the residue of meclofenamic acid, 6-dichi oro-3-methylhenyl) amino] belZoic acid, has been shown; in compounds (V Aa4) the residue o: 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, (trif luoromethyl) phenyl amino] -3 -pyridine carboxylic acid, has been shown; in compounds (V A )Rvacl attached to the oxygen atom in position 2 of the benzene ring of N-(4-nitrophenyl) methansuiphonamide can be phenyl or cycloexa-ne.

When Rvaci is phenyl the residue is That of nimesulide; in comoounds (V Ac2) the residue of 3-formylamino-7me thylsul onl 2am Ifno -phefoy- I-be zvAyrari-4 -one has been shown; in comnounds (V Ac3) LEhe atom X, Lthaz links the radical 2,4-difluorothiophelyl to position 6 of the indanone'ring of th.e residue 5-methnfesulronamido-1-iflnanone can be sulfur or oxygen; in comDoulds (V Ac4) the residue ofE celecoxib 4- (4-methylphenyl) (trifluoromethyl)pyrazoi--yl] benzensuiphonamide, has been shown; 0:00- in comp~ounds (V Ac5) the residue of 6-[2-(3-ethyl- 2,3-dihydro-thiazolYl) thio-5-methanesu1phofamido- 3

H-

isobenzonfuran-l-ofle has been shown.

-in compounds (V Adi) the residue of bumetanide 3- (Aninosulfonyl) (butylamino) -4-phenoxybeflzoic acid fees has been shown; -in compounds (V Ad.2) the residue of ticrynafen [2,3- Dichloro-4- (2-thienylcarbonyl) -phenoxyl acetic acid has -been -shown; -in cornDounds (V Ad3) the residue of ethacrynic acid (2..3-Dichloro-4- 2 -methvlene-1-oxobutyl)phenoxyI acetic acid, has been shown; in comoounds (V Ad4) the residue of pireta-nide 3- (Aminosulfony!) 4 -phenoxy-5- (1-pyrrolidinyl)beflzoic acid has been shownj.

-in conTpolzds (V Ae!) the resid' f romd 3o a, 7a, 7 acz) 3 -(Am ino su1-1o honv 1) c bloaro -N (o c ,aj dr o 4, 7 -re~ano-2isoindo12-y)ben,a--de has been shown.

in com-oounds (v Ae2) the residue off torsernide Mi thyl ethyl) amino] carbonyl 14 C[(3 -met hyl1Dhenyl) amino] -3pyrinesulfonamide has been shown; -in cornoounds (V Ae3) the residue off azosernide 2-Chio- (1H-tetrazo1-5-yl) -thienvlmethyl) amrino]-benzensulphonamide has been shown; -in com~ounds (V Ae4) the residue of bendroflumethiazide 3, 4-Dihydro-3 (phenyl -methyl) 6- (trif luoro methyl) -2H-J, 2,4-benzothiadiazine-7-sulfonamide 1, 1dioxide has been shown; -in Conmounds (V AeS) the residue of chiorothiazide G-Chloro-2H-1,2,4-benzothiadiazine-7..sulfonamde 1,1- *dioxide has been shown; -in compounds (v Ae6) the r~esidue of hydrochlorotia- 0. zide 6-Chloro-3, 4-dihydro-2H-1, 2,4-benzothiadiazine-7sulfonarmide 1,1-dioxide has been shown; in compounds (V Ae7) the residue of methylothiazide (6-Chloro-3-(choromethy)3,4-dihydro-2-methyl-2H- 1, 2 ,4-benzothiadiazine-7sulfonam.ide 1,1-dioxide has been shown; in comoounds (V Ae8) he residue of chlorthalidone 3-dihydro-1-hydroxy-3-oxo-lH-i-soindol-lvl)benzensulflonamide has been shown; i n comoounds (V Ae9) r-he resildue 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-l,2,3,4-tetrahydro-2--methyl-3- (2-methyiphenyl)- 4-oxo-6-cruinazolinesulfonamide has been shown; in compounds (V Aell) the residue of qtinetazone 7- Chloro-2 -ethyl-l1, 2, 3, 4 tetrahydro- 4-oxo- 6-quinazol iesulfonamide has been shown; -in 'compounds- (V Ae12) the residue of furosemide (Aminosulfonyl) -4-chloro-2- C((2-furanylmethyl) amino] benzoic 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, preferably having from 2 to 5 carbon atoms, or an optionally substituted cycloalkylene having :rom 5 to 7 carbon acoms;

-(CH)

2 n.3 where n 3 is an int~eger from 0 to 3; H COOHi CH 2 UNU2 0 where nf' is an integer f rom 1 to 6, preferably f rom 2.

to 4; 1 2 Rif where R3.f 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 (la)

COR

3 coo 2 nI R I nI (Ib) where: S• 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

C.

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 (Cl 1 4 alkyl amino; Rand R 2 jointly are the dioxymethylene group, with the proviso that when X NH, then xiis ethylene and P= H; R, 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 acetoxy, preferably at position 3 or 4, most preferably in the ortho position to Co. X1is ethylene or (CH 2

CH

2

O)

2 R2is Hydrogen or ffalogen, most preferred are the following A X 1 -N0 2 compounds: 3-acetoxy-N-(2-nitfoxyethyl) -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) -benzamide, N- (2 -nitroxyethyl) 2- (4 -thiazolindinyl) carbonyloxy) -benzamide hydrochloride, 2-nicotinoyloxy-N- (2nitroxyethyl) -benzamide, 2-acetoxy 7 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.

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.

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, -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)me- I thansulphonamide can be phenyl or cycloexane. When Rvaci S*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 product 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) (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-l-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 Adi) 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 S[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 saidpatent can be used, too.

In compounds (V Ael) the residue of tripamide (3ar, 4a, 7a,7aa)-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) (trifluoromethyl) -2H- 1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide was substituted according to the present invention, has too.

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.

In compounds (V Ae7) the residue of methyclothiazide (6-Chloro-3- (chloromethyl) -3,4-dihydro-2-methyl-2H-

S

1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide was substituted according to the present invention, has been shown.

6 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- Aminosulfonyl)-4-chloro-N-(2,3-dihydro-2-methyl-H1-indol- 1-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 acid was substituted according to the present inven- 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 IA 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 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.

°ooooo 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;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: 0 2 1 (Ia)

OR

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

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, 101 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 Ta) 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~ferred are the following A X, NO 2 compounds: 3-acetoxy-N- (2-nitroxyethyl) -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) -benzamide,- N- (2-nitroxyethyl) (4-thiazolindinyl) carbonyloxy) -benzamide hydrochloride, 2-nicotinoyloxy-N- (2-nitroxyethyl) -benzamide, preferably in Tb) R 3

CH

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

The processes to obtain the compounds which contain R in group VT 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 Dicyclohexylcarbodiimide 5.6 g

CH

2 C1 2 200 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: CO CH

CH

3 0 2

COO

SCH ONO b 2 Preparation of NO-Flufenamic (NO-F) 3-Hydroxybenzylnitrate 6 g *,Flufenamic acid 13 g Dicyclohexylcarbodiimide 9.5 g

CH

2

C

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 C1 2 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 80 for flufenamic-NO.

The 1 H NIVR analysis (CDCl 3 200 MHz) gave the- following data: (2H1, 6.9 (1H1, 7.4 (10H1, in); 8.2 (1H1, dd).

The product obtained- has the formula: .CH

ONGO

C0 0

I{H

*CF 3 Preparation of No-Nimesulide (NO-M) Preparation of the brominated derivative N- (2 -PHENOXY-4 -NITRO) PHENYL] (6-BROMO)H-EXANOYLMETHANE-

SULPHONAMIDE

4,85 g 6-Bromohexanoylchloride (23 inmol) was added dropwise to a mixture kept at 0 0 C of 7 g nimesulide (23 rnmol) 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 inmol) and 3 ml triethylamine (22 minol) 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 Spoint 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 g) 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 (CDC13) 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 lh (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 I 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

S*

*5 a

S

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 ID Indomethancin 10_ 4 M 10 38.5 1E Naproxen 5-10_ 4 M 10 15.2 IF Nimesulide 10-4 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_ M 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.

i*"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 111 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 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.

112 %0 0 0 0000 0 0 0 0.

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 asdescribed 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 S 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 doqs 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 pressure. 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 .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 0~Se S. S *SS 6 S. S 9

S

0 S e@ 0@ 0 05 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 con- 115 nected 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 acid-10 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 helicoidal 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.

117 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 M 10 29.0 NO-M 10 4 M 0 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) Tn vivn castrointestinal safety studies Forty Sprague Dawley rats randomly divided into 4 groups day for 4 days according to the weighing about 300 g were and orally treated twice a following experimental scheme: 1. Controls: carboxymethyl cellu-lose 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.

o.

o Examples 18-18A and 18-B (comparison) Studies of nitroxvsynthetase 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 nitroxy 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 a 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.

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

It will be clearly understood that, although a number S" 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.

S.

oe o• e 121

Claims (2)

1. Use of compounds, or their compositions, having the following general formula for the treatment of gastrointestinal tumours: A-X 1 -N0 2 or their salts, where: R(COX)t where t. is an integer 0 or 1; X 0, NH, -NRilc where RIC is a linear or branched alkyl having from 2. to 10 C atoms; R is chosen from the following groups: Group I A) where t 1, R113 R T, (XAa) r3 3 N (T-kb) 122 where: RIIS is H, a linear or whenever possible branched C 1 -c 3 alkyl; R 1 1 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 different 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 RII 1 or bromine; Preferred are the compounds where R 1 R 1 1 andR 11 11211 .are H, and R 1 1 is Cl and R 1 1 is in the ortho position 11 113 to NH; R 1 1 5 and R16are H, X is equal to 0, and *X 1 is C2H20; (I Ab) is the residue of 2-V(2-methyl-3-(trifluoro- methyl) phenyl]I amino] 3-pyri dine carboxyli c 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 C- A a where R 2 and R 3 a are H, a linear or whenever Dossible 123 branched substituted or non-substituted C 1 -C 1 2 alkyl, allyl, with the proviso that when one of the two is al lyl the other is H; preferably R2a is H, alkyl has from 2. to 4 C atoms, R3a -is H; Ria is chosen from II Aa) -L2- (IV) (V 124 QcCV) (VI) c H 2 0N H 3 C WX 125 where meanings are as -follows: in tihe comoou-nds ofE formula (IV) residue of ketooro- f en: -RI1is H, SR 1 1 1 3 where -RII 1 3 contains from 1 to- 4 C linear or whenever nossible branched C atoms; *R1112 is H, hydroxy; pref erred are the compounds 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 formula (XXT) residue of carpro- f en: Rxi is H, a linear or whenever possible branched alkyl having from 1 to 6 carbon atoms, a C 1 -C 6 alkoxy- *.**carbonyl bound to a C 1 -C6 alkyl, a Cj--C6 carboxyalkyl, a C 1 -C6 alkanoyl, op~ionaJlly substi-tuted with halogen, benzyl or halobenzyl, benzoyl or halobenzoyl; is H, halogen, hydroxy, CN, a Ci-C6 alkyl optional- ly containing OH groups, a C 1 -C 6 alkoxy, acetyl, benzyl- ox-y, S 2 where Rxx- 2 is a Cl-C 6 alk-yl; a Derfluoroal- kyl having from 1-3 C atoms, a C 1 carboxvalkyl oPtiO- 126 nally containing OH groups, NO, SUl~harnoyl, dialkyl sulphamoyl with the alkyl having from 1 to 6 C atoms, or dificuoroalk'/lsulphony1 with the alkyl having from 1 to 3 C atoms; R)Ci is nalogen, CN, a C 1 alkyl containing one or more OH groups, a C 1 -C 6 alkoxy, ace~yl, acezamido, benz- yloxy, SR 1 1 1 3 is as above defined, a perfluorQalkyl having from 1 to j C atoms, hydroxy-, a carboxyalkyl having from 1

99.9to 6 C atoms, N0 2 -amino, a mono- or dialkylamino ha- 9*999:ving f rom 1 to 6 C atoms, suiphamoyl, a dialkyl sulpha- moyl having from 1 to 6 C atoms, or difluoroalkylsul- phamoyl as above defined; or P-cx jointly with Rxxil is an alkylene dioxy having from 1 to 6 C atoms; preferred are the compounds whrere Rxxio is H, the 'eee.. connecting bridge is at position 2, Rxx is H, Rxxj 1 is chlorine and is in the para position to nitrogen; is Ra is methyl and X is 0; -in the comuounds -of formula (XXXV) residue of thia- profenic acid: Ar is phenyl, hydroxyphenyl optionally mono- or po lysubstituted with halogen, an alkanoyl or alkoxy having from 1 to 6 C atoms, a trialalkyl having :-rom 1-6 C atoms, preferably from 1-3 C atoms, cyclo- 127 pentyl o-hexyl o-heptyl, he:rcaryl, preferably thienyl, furyl optionally containing OH, pyridyl; the preferred compounds of formula (XXXV) are those where Ar is phenyl, R 3 a is H, R 2 is methyl and X is O; n the compounds of formula residue -of suoro- fen, the preferred, where R 3 a H, R 2 a C 3 and X 0; in the compounds of formula (VI), of which the preferred, indoprofen, when R 2 a is CH 3 or Sindobufen, when R2a is equal to H and R 3 a CH 3 and g.. .X 0; in the compounds of formula (VIII), of which the preferred, etodolac, when R3a R2a H and X 0; in the compounds of formula (VII), of which the preferred, fenoprofen, when R3a H, R2a C and X O; in the compounds of formula (III), of which the preferred, fenbufen, when R3a R2a H and X O; in the compounds of formula residue of tolmetin, when R3a R2a H and X O; in the compounds of formula residue of flurbi- in the compounds of formula residue of flurbi- 128 Orof en, when R R 2 L n c=0 11 Ab) 1Th NCN C. I7F 0YT 1 129XX (X)xVI) 3a 7 V wh r hSe n ns.r s f l o s whe .Ia cotis.HC3-O-.Iiti nw sp no..en -l ezprn (,-lyiie 7 aceti acd prfre Ra' H Ra C-,adX 0 whnrsde:X)cotis-.-'C3)CO ti -'w ibn b**S*xei cel cdTDe fer ed s X 0 R~ R a Oi) 130 -residue (XJ(XI) is known as CS-670: 2 4 2ooj cyclohexylicienemechyl) phenyl] propi oni-c acid, when the radical is -CH(CH 3 )-COOH; pref erred R 2 a R 3 a CH 3 and X 0; residue (XXXII) derives from the kn own 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-chiorophenyl) (4-f luoro- pher-yl) 3 -pyrazolyl acid derivatives; preferred **R 2 a R3 a H and X 0; -when residue (xXVI) 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 R2a H, R3a C3and X 0; -when' residue (XXXVII) is CH -COOH it derives from the known mofezolacL 3, 4 -di (p-methoxyphenyl) isoxazol-5 -ace- :tic -acid; preferred are R 2 a =R 3 a t X =0. *Group) IIIA), where t 1*, RIVd RIv C- RIVdl 131 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: C. CC C C (IIT) *CC. C. C C C CC iv-uI7 where the comnounds of group lIIA) have the following meanilngs: in the comoounds of formula 132 RIVII is an alkyl havi ng f rom 1 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 azoms, vinyl, ethynyl, halogen, an alkoxy haviffg from 1 to 6 C atoms, a difluoroalkoxy with the alkyl having from 1 to 7 C atoms, an alkoxymethyloxy having from 2. to 7 C atoms, an alkyithiomethyloxy with the alkyl having from 1 to 7 C atoms, an alkylme- thylthio, -with the alkyl ha-ving fErom 21 Co 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 CH 3 Q, RIvd is H and RIVdi is CE 3 *and is known as the residue of naproxen; X NTH 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 orefcerred compounds of formula MX), for which residue of loxoorofen has been shown, RIVd is H and R~~d i s- CH X NE or 0and Xis equal to (CH 2 or (CH 2 CH 2 O) 2' in the compounds of formula RIV-III is a C 2 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 C 1 -C 2 alkyl; preferred is the compound where Riv.III is CH 3 CH-CH 2 CH 3 and RIvd ,R~d is Ci 3 a comnoouni known as the re- sidue of ibunrof en; x NH-- an~d is ecTual to (H -or (Cfl"C 2 O) 2 also ureferrled is the same com- pound where X =0; *Groua IV A) O 0 CH~ 3 j (IV A) where A RCOO, t =1, :of whi-ch the residue of the lcnowt indome-zinacin has been shown. *Groupn V A) chosen from the following: -V Aa) fenamates chosen from the following, where =I 134 NHCH- 2 CH2 (V Aal) -NH CF 3 (V Aa2) a Cl CH 3 NH--/ cl (V Aa3) a. a. a. CH 3 CH 3 (V Aa4) (V AaS) H3 CC -V Ab), derivatives of nit lurnic acid, where t 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, V Ac NO 2 (V Acl) 136 N 0 0 H CH 3 (V Ac2) *1 N *CHI- Ac3) H (V AC4) 137 CH CH 2 3 0 O\ 3H I (V V Ad) derivatives of diuretics when t i and R is as f ollows: 0 0 0 0 0 00 0 0 000000 0 00. 0 0000 (V Adl) 0 (V Ad2) 00 *000 00 0 0* 00 H C. 3 0 (V Ad3) 138 NH 2 0 0 0 (V Ad4) V Ae) derivatives of dijuretics wmhen t 0 and R is as f ollows: (V Ael) H I o 3 S~ I N H CH c~rl 3 0N3 (V Ae2) 139 s NH N" NH N=N (V Ae3) 0/0 0/0 H N NH- N" F 3C H (V Ae4) 0 0 00 H N) NH 0 m* 0 a* 00 0 0 Ae6) 00 0 0 CO N H (V Ae7) 140 0 NH 0\/0 HO f I (V Ae8) 0 0 0 N ~NH CH 2 (V Ae9) H N. 0O*S 9. 9 0 S .95. Se S. p CS C S .9 69 9 S 0 (V AeUl) *get 9C*9 9*SR C 0@*S C S. S S. 00 COOH H 0 0 0 (V Ael-2) 141 where the meaning Ln croup V A) is as 01 1 0lws: in cornDounds (V a'al) r-*he residue c_ enfenamlc acid, 2- ((2-phenvle~hyl )aminolbenzoic acid_, has-been shown; in comDounds (V Aa2) tEne residue of flufenarrnic acid, 2 [3 (tri I'uorome chy1) phenyl I aminoljbenzoic ac id, has been shown; in compounds (V Aa3) the residue of meclofenamic acid, 6-dich-loro-3-methylphenyl) amino) benzoic acid, has been shown; in compounds (V Aa4) the residue of mefanamic acid, 3-dimethy1~heny1) amino) benzoic acid, has been shown; in compounds (V Aa5) the residue of tolfenamic acid, 2 C (3 -chloro- 2-methylpheny1) amino) benzoic acid, has been shown; *-in compounds (V Abi) the residue of nif lumic acid, 2--t (trif luoromethyl) phenyl]. amino] -3-pyridine car- boxylic acid, has been shown; -in compounds (V Adl) vac. attached to the oxygen atom in position 2 of the benzene ring of N-.(4-nitro- phenyl)methansulphonamide can be phenyl or cyc1oexne- When Rvaci is phenyl the residue is t.hat of nimesulide; in comnounds (V Ac2) the residue ofE 3-for-mylamfino- 7 142 methlsu-:Lonyamio-6phenxy-H-1bezoyrn-4one has been shown; -in comDounds (V Ac3) the atom X. thaZ links the radi- cal 2..4-difluorothiophenyl to position 6 of the indano- ne ring of- the residue 5 -methane sulf onamido i--ifldanone can be sulfur or oxygen; in compounds (V Ac4) the residue of celecoxib (4-methyiphenyl) (trifluoromethyl)pyrazol-1-yl] ben- zensuiphonamide, has been shown; -in compounds (V Ac:5) the residue of 6- (3-ethyl- 2,3-dihydro-thiazoly.) thio-5-methanesu1phoflamido- 3 H- isobenzonfurai-l-one has been shown. -in compounds (V Adi) the residue of bumetanide 3- (Aminosulfonyl) -5-(butylamino) -4-phenoxybeflzoic 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; 00 0.: in compoounds (V Ad3) the residue of ethacrynic acid 2 3 -Dichloro- 4 2 -methy~lee--oxobutyl) phenoxy] acetic acid, has been shown; in compounds (V Ad4) the residue of piretariide 3- (Aminosulfonyl) -4-phenoxy-S (1-pyrrolidinyl)be-izoic 143 acid has been shown. in comoun~ds (V Ael) the reside *7rcmje(3c 4 a, 7cf, 7 a) (Amnosui-phonvy,) chlor-o-N- (octaidro 4, 7 -rneano-2H-isoildoi-2-yl)benz--'de has been shown. -in comnounds (v Ae2) the residue of Lorsemide Meth-vlethyl) amino] carbonyl] 4- -me-hyl-ohenyl) amino] -3- pyrinesulfonamide has been shown; -in Comptounds (V Ae3) the residue of azosemide 2-Chio- (J.H-tetrazol-5-y1) C(2-thienylmethyl) aminol-ben- zensulpmhonamide has been shown; in cotflounds (V Ae4) the residue of bendrof lume- thiazide 3, 4-Dihydro-3- (phenyl-rnethyl) (trifluoro- dioxide has been shown; -in compounds (V AeS) the residue of chiorothiazide 6-Chloro-2H-1, 24benzothd dijfln..7sulfonamide 1,1- dioxide has been shown;L n comounds (V AeE) the residue of hydrochiorotia- zide 6-Chloro-3,4dihydro212, benzothiadiazine-7. **sulfonlamide 1,1-dioxide has been shown; in coonmds (V Ae7) the residue of methylothiazide (6-Chloro-3-(chloromethyl) -3,4-dihydro-2-met hyl-2H- l, 2 4 -benzothiadiazine-7-sulfonarride 1,1-dioxide has 144 been shown; in COMDounds (V Ae8) the residue of chiorthalidone 2-Chloro-5-(2,3-dihydro-1-hydroxy-3-oxo-lE-isoindol-i- yl~benzensulfonamide has been shown; in comnounds- (V Ae9) the residue of Indaoamide 3- (Arinosulfonyl)-4-chloro-N- (2,3-dihydro-2-methyl-1H- indol-1-yl)benzamide has been shown; in compounds (VAelO) the residue of ietolazone 7- Chloro-1,2,3,4-tetrahydro-Z-methyl-3- (2-methyiphenyl) 4-oxo-6-auinazolinesulfonamide has been shown; in compounds (V Aell) the residue of quinetazone 7- Chloro-2-ethyl-i, 2,3, 4-tetrahydro-4-oxo-6-quinazoline- sulfonamide has been shown; -in 'compounds- (V Ae12) the residue of furosemide (Aminosulfonyl) -4 -chloro-2- (2-f uranylmethyl) 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, preferably having from 2 to S carbon atoms, or an optionally substituted cycloalkylene having from 5 to 7 carbon atoms; 145 CH 2 -(CH 2 ZL3 where n3is an integer from 0 to 3; H UMJ2 Swhere 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, 146 2 1 (Ia) COR coo (R (R 2nI 1 n .(Ib) where: R1 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 j 4 )alkylamino; R 1 and R 2 jointly are the dioxymethylene group, with the proviso that when X NHl, then X1is ethylene and R= H; R 1 cannot be OCOR 3 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 ace- toxy, preferably at position 3 or 4, most preferably in the ortho position to Co. X1is ethylene or (CH 2 CH 2 O) 2 R 2 is Hydrogen or Ifalogen, 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) 2- (4 -thiazolindinyl) carbon- -benzamide hydrochloride, 2-nicotinoyloxy-N- (2- nitroxyethyl) -benzamide, 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-X 1 -N0 2 or their salts, where: R(COX)t where t is an integer 0 or 1; X 0, NH!, -NRjC where Ric is a linear or branched alkyl having f rom 1 to 10 C atoms; R is chosen from the following groups: *Group I where t =1, ~I i R 1 (I-Aa) (!Ab) 149 where: R 115 is H, a linear or whenever oossible branched C 1 -c 3 alkyl; RI 1 has the same meanings as R3 or when RTT 5 is H it can be benzyl; R 111 R 1 1 2 and R 1 1 3 are equal or ai::ferent 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 1 1 4 is R 11 1 or bromine; %:pref erred are the compounds where R 1 R 1 1 andR .99.*are H, and R 1 1 3 is Cl and R 1 1 3 is in the ortho position. to NH; RII 5 and RI 1 6 are H, X is equal to 0, and 999999X 1 is (CH 2 -CH 2 -0) 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 R is R 2 a Ria C- 3a where R 2 and Rja 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) R P. R ;C T /2 R (IV) (V) 151 Ai OcGav) (VI) C H 2 (VIII) (II) a. a a. a. H CH '3 0 152 where meanings are as follows: in the comoounds of formula residue of ketopro- f en: R 111 I 1 is H, SR 1 1 1 3 where- RI 1 1 3 contains from 2. to- 4 C linear or whenever Dossible branched C atomns; R is H, hydroxy; *pref erred are the comoounds where RIII, and RII 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: Pxxi is H, a linear or whenever possible branched alkyl having from 1 to 6 carbon atoms, a C 1 -C 6 alkoxy- carbonyl bound to a C 1 -C 6 alkyl, a C,--CG carboxyalkyl, a 1 -c 6 alkanoyl, op~ionally substitutedwih algn benzyl or halobenzyl, benzoyl or halobenzoyl; Rxxd is H, halogen, hydroxy, CN, a Ci-C6 alkyl optional- ly containing OH groups, a C 1 -C 6 alkoxy, acetyl, benzyl- oxySR- where is a C-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; Rxxi is halogen, CN, a C 1 -Cg alkyl 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 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 Rx 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; R 3 a i s 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 Irom 1-6 C atoms, preferably from 1-3 C atoms, cyclo- 154 pentyl o-hexyl o-heptyl, he:ercaryl, preferably thienyl, furyl optionally containinc 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; in the compounds of formula residue -of suoro- fen, the preferred, where R 3 a 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 CH3 or indobufen, when R2a is equal to H and R 3 CH3 and 0* X 0; in the compounds of formula (VIII), of which the preferred, etodolac, when R 3 a R 2 a H and *SS* X 0; 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 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 nrof en, wh.-en R3 RH 2 CH 3 ar: 0; I I Ab) NCc (xxx) @0 X-XaI I 156 (X..xxvL) 0a 0* *0 whnreiu (XXXX7onansEE)-'C! 3 when iia cotan -c(1 3 O it isClonoswra as berrnoorofen: dibenz oxepin-2-acetic acid, pre- f erred is X 0, R 2 a H, R 3 a O3 157 resdue XX) is known as CS-670: 2 [4-(2ooi cy clohexylidenememiy1)phery1] prooionic acid, when the radical is -C-(CH-IYCOOH; orefez-red R 2 a Rja CH 3 and X 0; -residue (XXXII) derives from the known uemedolac which contains group CH 2 COOH, prefrerred 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) (4-f luoro- pheriyl) 3-pyrazoly. acid derivatives; preferred R 2 a R 3 a H and X 0; -when residue (XJCCVI) 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 R 2 a H, R 3 a CH 3 and X 0; -when'l 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 RIv C RIVdl 158 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 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 R .T whr th oS.nso ru II)hv h olwn me.n **s in th coouSso frua(I 159 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 atoms, 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, difluoromethylt-hio, a substituted phenyl- or phenylalkyl with the alkyl having from 1 to 8 C atoms; preferably RIVII is CH30, RIVd is H and RIVdl is CH 3 and is known as the residue of naproxen; X NH and X 1 is equal to (CT 2 4 or (CH 2 CH20) 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 RIvdl is- C H 3 X NH or O and X 1 is equal to (CH2) 4 or (CH 2 CH 2 0)2; in the compounds of formula (III): RIV-III is a C 2 -C 5 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- 160 stituted at position 1 by a C 1 -C 2 alkyl; preferred is the compound where Riv 111 i is CH 3 CH-CH 2 -CH 3 and RIVd R~d is C;1a compound known as the re- sidue of ibuorof en; x NH and is ecrual to (H2,-or (CF1 2 (7r 2 0) 2 also preferred is the same corn- pound where X =0; *Group IV A) 3 ~CH (IV A) where A =RCOO, t 1, ot which the residue of the knowi indome-zhacin has been shown. *Group V A) chosen from the following: -V Aa) fenamates chosen from the following, where z-- 161 NHCH 2 CH 2 (V Aal) CF 3 (V Aa2) *cl CH 3 C]. (V Aa3) (V Aa4) 162 (V Aa5) H3 CC V Ab), derivatives of niflumic acid, where t 1: (V Abi) V Ac), COX 2 inhibitors, where t =0 and R is as f ol- lows: N S0 2 C8 3 0 Y, V Ac N0 2 (V Acl) 163 0 0 H N 00 CH H (V Ac2) N F F H *3 (V Ac4J 164 CH CH F 2 3 y S CHI 3 (V -V Ad) derivatives of dluretics whien t =1 and R is as f ollows: 0 0 S 0* 0 0~ 0 (V Adi) 00 00 0 *l (V Ad) 165 NH C N 2 0 0 0 (V AdA) V Ae) derivatives of diuretics when t =0 and R is as f ollows: S. S S 5 S S *S S. S S (V Ael) S. *5*S H I o 3 S= CL-I 3 0 N,3 (V Ae2) 166 s N N)-""NH N N (V Ae3) 0\\ H Nl- sl*- NH )aN F 3 C H (V Ae4) H N NH cl (V 0 0 0 s H N NH cl aN H (V Ae6) 0 0 0 0 (V Ae7) 167 0 HH N N C H I (V Ae9) H NN CH HN N H C (V AelO) S. 0 S 0.55 5@ @0 4 65 S S S. 55 0 0 S S 0 *.0S (V Aeli) H 1- 0 6004 S 05 0 S S *5 0 0 (V AeI-2) 168 where the meaning in group V A) is za follows: in compounds (V a,-al) cle rsedu c enfenamic acid, 2-((2-phenvier-hy1)amino] benzoc acL-, nas-been snown; in comDounds (V Aa2) the residue of flufenamic acid, 2- [(3-(tri fluoromel hy1 )pyhefnyly -a mino jbenzoic acid, has been shown; in compounds (V Aa3) the residue of meclofenamic acid, 2- 6 dich-loro-3-methyphenyl) 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 (trif luoromethyl) phenyl I amino 3 -pyridine car- :boxylic acid, has been shown; in compounds (V Ad)Rvac1 attached to the oxygen atom in position 2 of the benzene ring of N-(4-flitro- phenyl) methansuiphonamide can be ph enyl or cycoexane- When Racl is phenyl the residue is that of nimesulidel in compounds (V Ac2) the residue of 3-formylamino-7- 169 me thylsul-fonylarifo-6 phenoy-4H- ibe zopyran 4 -one has been shown; -in comnou1rds (V Ac3) the atom X 4 that links the radi- cal 2,4-difluorothl4ophelyl to position 6 of the iridano- ne ring of: the residue 5-methanesulfofamido-1-ilndaflone can be sulfur or oxygen; in comoounds (V Ac4) the residue of celecoxib (4-methyiphenyl) (trifluoromethyl)pyrazol-l-yl) ben- zensulphonamide, has been shown; -in compounds (V Ac5) the residue of. 6-[2-(3-ethyl- 2,3-dihydro-thiazolYl) thio-5-mfethaflesulphonamido- 3 H- isobenzonfuran-1-one has been shown. *-in compounds (v Adi) the residue of bumetanide 3- (Aminosulfonyl) (butylamino) -4-phenoxybenzoic 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 compoounds (V Ad3) the residue of ethacry-nic acid 2 3 -Dichloro 4 2 -methyleneloxobutyl)phenoxylacetic acid, has been shown; in compounds (V Ad4) the residue of pireta-nide 3- (Aminosulfonyl) -4-phenoxy-5- (1-pyrrolidinyl)benzoic 170 acid has been shown-. in c~tompoads (V Aed) the re S'-4 oF tripamide 4 CY, 7a, 7 aac) 3- (Am ino s u pho nv 4C hlo0ro N- (o c La idro 4 7 -mr-eano-2!i-isoindo-2-yl)berza- d has been shown. in compounds (V Ae2) the residue o~f torsernide Me thyl ethyl) amino] carbonyl] 14- (3 -me thylohenyl) amino] -3 pyrinesulfonamide has been shown; -in cornoonds (V Ae3) the residue of azosem-ide 2-Chlo- ro- 5- (I-H-tetrazol 5 yl) -4 (2 -thiJenvmethyl) amino] ben- zensulphonarijde has been shown; -in cot~ounds (V Ae4) the residue of bendroflume- thiazide 3, 4- Dihydro 3- (phenyl -me thyl) 6- (tri fluoro methyl) -2H-l1, 2 4-benzothiadiazine- 7 -sufonamid~e1- dioxide has been shown; -in compounds (V Ae5) the residue of chiorothiazide 6-Chloro-2H-l,24benzothiadiazine7.sulfonamide ill- dioxide has been shown;L in compounds (v Ae6) the residue of hydrochiorotia- zide 6-Chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7- su.onaid 1,1-dioxide has been shown; in compuounds (V Ae7) the residue of methyiclothiazide (G-Chloro-3-(choromethy)34d4hydro2methyl12H- 1, 2 4-benzothiadiazine-7-sulfonami-,de 1,1-dioxide has 171 been shown; in comoounds (V Ae8) the residue of chiorthalidone 2-Chloro-5-C(2.3-dihydro-l-hydroxy-3-oxo-lH-isoindol-l yl)benzensulfonamide has been shown; in comoounds' (V Ae9) the residue of Indapamide 3- (Aminosulfonyl)-4-chloro-N-(2,3-dihydro-2-methy'-iH- indol-1-yl)benzanide has been shown; in compounds (VAe1O) the residue of metolazone 7- Chloro-l,2-,3,4-tetrahydro-2--methyl-3- (2-methyiphenyl) 4-oxo-6--cruinazolinesulfonamide has been shown; in compounds (V Aell) the residue of quinetazone 7- O.. Chloro-2-ethyl-1,2,3,4-tetrahydro-4-oxo-6-quinazoline- 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 iJs 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 farom 5 to 7 carbon atoms; 172 (H2 u i3 where n 3 is an integer from 0 to 3; H COO(l li2 wher .f I i nitgrfo o6 rfrbyfr 2 to 4; (CH-CH Rif where R, f 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 *1 I n (Ib) where: 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 174 di (C 1 4 alkylamino; R 1 and 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 R3is. methyl; nI being an integer from 0 to 1~; preferably in Ia) X is equal to 0 or NH, 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 R2is Hiydrogen or lialogen, most preferred are the following A X 1 -N0 2 compounds: 3-acetoxy-N-(2-nitffoxy- 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- ethyl.)-2-propionoxybenzamide, 2-acetoxy-2--nitroxy- ethylbenzoate, 2-acetoxy-N- (cis-2-nitroxycyrclohexyl) benzamide, 2-acetoxy-4-chloro-N- (2-nitroxyethyl) -benza- mide, N- (2-nitroxyethyl) ((4-thiazolindiflyl)carbon- yloxy) -benzamide hydrochloride, 2-nicotinoyloxy-N-(2- nitroxyethyl) -benzamide, 2-acetoxy-IS-nitroxypelthyilben- 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. 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-INO 2 or their salts, where: R(COX)t where t is an integer 0 or 1; X 0, NH, -NRI 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 113 R 116 S* a a a a a a a. a. (IAa) (Ilkb) 176 where: R 1 1 5 is H, a linear or whenever possible branched C 1 -c 3 alkyl; R 11 6 has the same meanings as RI or- when RT T r 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 C 1 -C6 alkyl or C 1 -C 6 alkoxy, or Cl, F, Br; R 1 14 is R 1 1 1 or bromine; preferred are the compounds where RII 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 R16are H, X is equal to 0, and *x 1 is H2H20; (I Ab) is the residue of 2-[U2-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 C- 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, R3a -is H; Ria is chosen from II Aa) R C H *1 *(N 178 S AA\ A(r (VI) -C H -2 1111 I/ V C 2 H (V=II) (Ix *Se. 9 9 HC 3 CH '3 0N 179 2 (IIC where meanings are as follows: in the compou-nds formula residue of ketooro- f en: -RIII 1 is H, SR' 1 1 1 3 where ,RII 1 3 contains from 1 to- 4 C linear or whenever possible branched C atomns; R12is H, hydroxy; pref erred are the comDounds; where R 11 1 1 and R 1 1 1 2 are H, R3 a is H, and Ra is methyl, X 0; -in the compounds of formula (XXT) residue of carpro- fen: Rxi is H, a linear or whenever possible bra nched alkyl having from 1 to 6 carbon atoms, a C 1 -C 6 alkoxy-. carbonyl bound to a C 1 -C 6 alkyl, a Cj--C6 carboxyalkyl, a C 1 -C6 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 Cl-C 6 alkoxy, acetyl, benzyl- oxy, SR.- 2 where Rx- 2 is a Ci-C6 alkyl; a oerfluoroal- kyl having from 1-3 C atoms, a C 1 -C 6 carboxyalkyl ootiO- 180 nally cont-aining OH groups, NO. sui-pharnoyl diLky su1lhamoyl with the alkyl having r-'rom 1 Co 6 C atoms, or dif-'luoroalkylsulphonyl with the alkyl having From 1 to 3 C atoms; Rxi is halogen, CN, a C 1 -C 6 alkyl con~aining one or mor OHgro~sa 1 -C 6 alkoxy, acetyl, acezamido, benz- yloxy, SR 1 1 1 3 is as above defined, a perfluoroalkyl having from 1 to j C atoms, hydroxy-, a carboxyalkyl having f rom 1 to 6 C atoms, NO 2 amino, a mono- or dialkylamino ha- S ving from 1 to 6 C atoms, suiphamoyl, a dialkyl suipDha- 806SO S. r moyl having from 1 to 6 C atoms, or difluoroalkylsul- *SSphamoyl as above defined; or Rxx jointly with R~xi is alkylene dioxy having from 1 to 6 C atoms; *0 ofo. preferred are the compounds whrere Rxi is H, the connecting bridge is at position 2, Rxx is H, Rx~ is chlorine and is in the para position to nitrogen; R 3 a 1-s H ,R 2 a is methyl and X is 0; -in the comnounds -of formula (XXXV) residue of thia- prof enic acid: Ar is phenyl, hydroxyphenyl optionally mono- or po lysubstituted with halogen, an alkanoyl or alkoxy having from 1 to 6 C atoms, a trialalkyl having :rom 1-6 C atoms, preferably from 1-3 C atoms, CYc1lo 181 pentyl o -'-exyl I -heptyl, he7=rcary preferably thienyl, -fury! oocionally containinc OH, pyridyl; the pref-errea comoounds of foml XXXV) are those whe~ ~is henl, 3 aisH Ra is methyl and X is 0; ni thne compounds of formula (11) residue -of sunro- fen, the preferred, where R 3 a H, R 2 a =CH 3 and X =0; in the comnounds of formula (VI), -of which the preferred, indoprof en, when R 2 a is CH 3 or indobuf en, when Ra is equal to Hi and Ra =H 3 and 0; in the compounds of formula (VIII), of which the preferred, etodolac, when R3a =R2a =H and X =0; -in the compounds of formula (VII), of which the preferred, fenoprofen, when R 3 a =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 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 f lurbi- 182 £8l (TT FXX) -I H- (TXXXT I u u 'uao~z (Xxlavi) 31 *3 0j wh r th me n nsa e a ol w whe EIa otis-HC3 CO ti nw spa :whee r~esimenings arean follows:')COH tiSknw as berrnoorofen: dibenz oxepin-2-acetic acid, pre- ferred is X 0, R 2 a H, R 3 a Cl3 184 reidu (XXI)is nown as CS-670: 2 -f4-(2-oxo-l- cy clohexylidenemehyl) phen-yli Droo2oni c acid, when the radical is -CF(CH 3 )-COOH; preferred R 2 a R 3 a =C14 3 and X 0; residue (XXXII) derives from the known oemedolac which contains group -CH 2 COOH, pDrercerred R 2 a R3a H and X 0; -when residue (XXXIII). is saturated with -CH 2 COOH it is known- as pyrazolac: 4- (4-chioroohenyl) luoro- phen-yl) 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 zaltoprof en. When the residue is satura- .ted with a hydroxy or amine gro up or the acid salts, the compounds are known as dibenzothiepin -derivatives. Pref erred R 2 a 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 R 2 a =R3a t X =0. *Group IIIA), where t =1 RIvd RIv C- RVd 1 185 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, pref erred is C 1 or RIVd and RIVdi jointly form a methylene group; RIV has the following meaning: a a a a R. 1.V-L (11) (T7) where the como~ounds of group IIA) have the following meafllings: in the comoounds of -formula 186 RI 1 I 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 t-rifluoroalkyl having from 1 to 3 C atoms, 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 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 ha-ving from 1 Co 7 C atoms, cyano, difluoromethylthio, a substituted phenyl- or phenylalkyl with the alkyl having from 1 to 8 C atoms; t preferably RIV. 11 is CH 3 O, RIVd is H and RIVdl is CH, and is known as the residue of naproxen; X NIH and X 1 is equal to (C 2 4 or (CH CH 2 O 2 also preferred is the same compound where X is equal to 0; -in the preferred compounds of formula WX), for which :0the residue of loxoprofe-n has been shown, RIVd is H- and R0.dR is- CH 3 X NH or 0 and Xis equal to (C or (CH 2 CH 2 0) 2' in the commounds of formula (III) RIV-III is a C 2 -C 5 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- 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 Rjvd H, RIvdi is CW 3 oou1 nona h e sidue of ibunrofen; X NH-- and X. is earual to 2 4 or(CCH 2 O 2 also porefer'red is the same Corn- oound where X =0; *Group IV A) *.cc_ 3j *(IV A) where A =RCOO, t 1, of which the residue of the know-i indornethacin has been shown. *Group) V A) chosen from the following: -V Aa) fenamates chosen from the following, where =I 188 NHCH 2 C 2 (V Aa 1) (V Aa2) .55. (V Aa3) S NE~ CH 3 CH 3 (V Aa4) 189 (V Aa5) H3 CC V Ab), derivatives of niflumic acid, where t 1 (V Abl) V Ac), COX, inhibitors, where t 0 and R is as f ol lows: N SO 2 CH 3 0 V Acl (V Ac].) N0 2 (V Ac2) (V Ac3) S S *5 H: L- (V Ac4) 191 CH C 2 0 0I N/N (V -V Asd) derivatives of duretics when~ t 1 and R is as f ollows: i .r c (V Adl) (V Ad2) (V Ad3) 192 (V AdA) V Ae) derivatives of diuretics whezn t 0 and R is as f ollows: H 9 9 99* 9 9* C. 9 9* 9 *9 9 a 9 (V Ael) H 0 3 S=- N- C3 (V MAe) 193 S~ N N 7 JNH N=N (V Ae3) 0/0 00// H N NH :iaN F 3C H (V Ae4) 0 ,0 0/0 S. CXXN (V AeS) 0 00 NH' (V Ae6) 0 0 0 0 H N S 3C I I (V Ae7) 194 0 NH 00 HO 0 (V Ae8) 0 0 0 HN S~ N N CH 2 C (V Ae9) 9 '-CX 3 (V Aell) COCH H 04 H N- 0 0 (V Ael 2) 195 where the meaning iln group V -is as follows: in comoounds (V :Ial) _he rs~ice enfenamic acid, 2- [(2-ohenvier-hy1)am-inolbenzoic aihas been shown; in comuounds (v Aa2) the residue of f1uffenamic acid, 2- ((3-(triffluoromer-hyl)oheny1] -am-_nolbenzoic acid, ha s been shown; in compounds (V Aa3) the residue or meclofe-namic acid, 2- C(2, 6-dich-loro-3-methylphenyl) amino] benzoic acid, has been shown; in compounds (V Aa4) the residue of mefanamic acid, 2 3 -dime thyiphenyl) amino] benzoic acid, has been shown; -in compounds (V Aa5) the residue of tolf enamic acid, 2- ((3-chloro-2-methylphenyl) amino] benzoic acid, has been shown; in compounds (V Abi) the residue of nif lumic acid, 2 (3 (trif luoromethyl) phenyl] amino] -3 -pyridine car- boxylic acid, has been shown; -in compounds (V Acl)Ravaci attached to the oxygen atom in position 2 of the benzene ring of N--(4-nitro- pheny1)methansulphonamide can be phenyl or cycioexane- When Rvaci is phenyl the residue is that nimesulide; in comoounds (V Ac2) the residue of7 3-formylaminO- 7 196 me thylsulonylaian -lPhnoxy4H-!be zpyan 4 -one has been shown; in comnourlds (V Ac3) thne atom X, th-at links the radi- cal 2,4-difluorothopheflyl to position 6 of the indano- ne ring of" the residue 5-methanesulifonamido-1-i-flpcanone can be sul-fur or oxygen; in compounds (V AC4) the residue of celecoxib (4-methyiphenyl) (trif luoromfethyl)pyrazol-1-yl] ben- zensuiphonamide, has been shown; -in compoounds (V Ac5) the residue of 6-[2-(3-ethyl- 2,3-dihydro-thiazolyl) thio-5-~methanesu1phonamido- 3 H- isobenzonfuran-l-ole has been shown. -in compounds (v Adi) the residue of bumetanide 3- (Aminosulfonyl) (butylamino) -4-phenoxybenzoic 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 ethacrylic acid 2 3 -Dichloro- 4 2 -methiene-ioxobutyl)phenoxyI aceti acid, has been shown; in compounds (V Ad4) the residue of pireta-nide 3- (Aminosulfonyl) -4-ohenoxy-5- (l-pyrrolidinyl)ben-zoic 197 acid has been shown. -in comolnds (V Aed) the res'_'e o= tripamide (a~ CY, 7 c, 7aca) 3- (Aminosulphonvl) cflloro (Octaidro 4, 7 -met-a:io2-isoindo12..yl)benz de has been shown. n compounds (v Ae2) the residue of torsemide N-((i Methyl ethyl) amino] carbonyJ. 1 4- [(3-methylohenyl) amino] -3- pyrinesulfonamide has been shown; -in comptounds (V Ae3) the residue of azosernide 2-Chfo- (1H-tetrazol-5-yl) C(12-thienvlmethyl) amino] ben- zensulphonatnide has been shown; -in contmounds (V Ae4) the residue of bendroflume- :thiazide 3, 4-Dihydro-3- (phenyl-methyl) (trifluoro- methyl) -2-,,-eztidizn--ufnmd 1,1- dioxide has been shown; -in Conpounds (V AeS) the residue of chiorothiazide 6-Clloro-2H-1,2,4-benzothtiadiazine-7-sulfonamide 1,1- dioxide has been shown;- -in compiounds (V Ae6) the residue of hydrochiorotia- *zide 6-Chloro-3, 4-dihydro--2H-1, 2,4 -benzothiadiazine-7- sulfoniamide 1,1-dioxide has been shown; in complounds (V Ae7) the residue of methyiclothiazide 6 -Chloro-3-(chorometh 13,4dhydro2methy12H 1,2, 4 -benzothiadiazine-7-sulfonamiLde 1,1-dioxide has 198 been shown; in comoounds (V Ae8) h residue of chiorthalidone 2-Chloro-5-C(2,3-dihydro-l-hydroxy-3-oxo-IIE-isoindol-l- vljbenzensulfonamide has been shown; in comDounds (V Ae9) the residue of Indapamide 3- (Aminosulfonyl)-4-chloro-N-C2,3-dihydro-2-methyl-lH- indol-l-yl)benzamide has been shown; in compounds (VAe1O) the residue of metolazone 7- Chloro-1,27,3,4-tetrahydro-Z--methyl-3- (2-methyiphenyl) 4-oxo-6-aruinazolinesulfonamide has been shown; 0 V in compounds (V Aell) the residue of quinetazone 7- Chloro-2 -ethyl 2, 3,4-tetrahydro-4-oxo-6-quinazol..ne- sulfonamide has been shown; -in 'compounds- (V Ael2) the residue of furosemide (Aminosulfonyl) -4-chloro-2- ((2-furarlylmethyl) 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 CH~ -0- H 1- 2 n3 where n 3 is an integer from 0 to 3; H COOR H H2 )xf *2 whr** sa nee o 1t ,pe rbyfrm2 to 4; L 1.I~ f .where Rf=H H n nf is an integer f rom 1 to 6, peeal rm2 tofral 4;m2to4 n Gru VI).hr 200 0 2 1 (Ia) COR 3 (R (R 2 n 1 nIl (Ib) (h) where: R1 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 201 di (C 1 4 )alkylamino; R 1 and R 2 jointly are the dioxyrnethylene group, with the proviso that when X NEl, then X 1 is ethylene and R2=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 NHl, R 1 is ace- toxy, preferably at position 3 or 4, most preferably in the ortho position to CO. X1is ethylene or (CH 2 CH 2 O) 2 R 2 is Hydrogen or h1alogen, most preferred are the following A X 1 -NO 2 compounds: 3-acetoxy-N-(2-nitf'oxy- 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- 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) 2- (4 -thiazolindinyl) carbon- yloxy) -benzamide hydrochloride, 2-nicotinoyloxy-N- (2- nitroxyethyl) -benzamide, 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