WO2008128832A1

WO2008128832A1 - Nitroderivatives of non-peptidic renin inhibitors for the treatment of cardiovascular, renal and chronic liver disease, inflammations and metabolic syndrome

Info

Publication number: WO2008128832A1
Application number: PCT/EP2008/053267
Authority: WO
Inventors: Nicoletta Almirante; Stefano Biondi; Ennio Ongini
Original assignee: Nicox S.A.
Priority date: 2007-04-18
Filing date: 2008-03-19
Publication date: 2008-10-30

Abstract

Non-peptidic renin inhibitors nitroderivatives of general formula (I) : A1- (Xa-ONO2) j wherein A1 is selected from the group consisting of formula (Ia), (Ib), (Ic), Id), (Ie) and (If). They can be employed for treating or preventing cardiovascular, renal and chronic liver diseases, inflammatory processes and metabolic syndrome.

Description

NITRODERIVATIVES OF NON-PEPTIDIC RENIN INHIBITORS FOR THE TREATMENT OF CARDIOVASCULAR, RENAL AND CHRONIC LIVER DISEASE, INFLAMMATIONS AND METABOLIC SYNDROME

The present invention relates to nitroderivatives of non-peptidic renin inhibitors, pharmaceutical compositions containing them and their use for the treatment or prophylaxis of cardiovascular, renal and chronic liver diseases, inflammatory processes and metabolic syndrome. Renin is a proteolytic enzyme which is predominantly released into the blood from the kidney. It cleaves its natural substrate, angiotensinogen, releasing the decapeptide, angiotensin I. In turn this is cleaved by the converting enzyme (ACE) in the lung, kidney and other tissues to the octapeptide angiotensin II, which has an effect on blood pressure. Angiotensin II raises blood pressure both directly by causing arteriolar constriction and indirectly by stimulating release of the sodium- retaining hormone aldosterone from the adrenal gland causing a rise in extracellular fluid volume.

The activity of the renin-angiotensin system can be manipulated pharmacologically by the inhibition of the activity of renin (renin inhibitors) , or by the inhibition of the angiotensin converting enzyme (ACE inhibitors) or by blockade of angiotensin II receptors (angiotensin II receptor blockers) .

Renin inhibitors have been developed as agents for control of hypertension, congestive heart failure, and hyperaldosteronism. Inefficient absorption, high first-pass metabolism and biliary excretion have constituted an obstacle to the clinical development of this group of drugs. The insufficient oral activity are due to their peptidomimetic character. WO 01/35961 describes methods of treating and/or preventing vascular diseases where nitric oxide insufficiency is a contributing factor by administering a therapeutically effective amount of at least one antioxidant, or a pharmaceutically acceptable salt thereof, and at least one of isosorbide dinitrate and isosorbide mononitrate, and, optionally, at least one nitrosated angiotensin-converting enzyme inhibitor, nitrosated beta- adrenegic blocker, nitrosated calcium channel blocker, nitrosated endothelin antagonist, nitrosated angiotensin II receptor antagonist, nitrosated renin inhibitor, and/or at least one compound used to treat cardiovascular diseases.

WO 2005/023182 describes novel nitrosated and/or nitrosylated cardiovascular compounds or pharmaceutically acceptable salts thereof, and novel compositions comprising at least one nitrosated and/or nitrosylated cardiovascular compound, and, optionally, at least one nitric oxide donor and/or at least one therapeutic agent. The nitrosated and/or nitrosylated cardiovascular compounds are selected from: aldosterone antagonists, angiotensin II antagonists, calcium channel blockers, nitrosated and/or nitrosylated endothelin antagonists, hydralazine compounds, neutral endopeptidase inhibitors and renin inhibitors.

WO 2006/093864 describes compositions and kits comprising at least one cardiovascular compound and at least one nitric oxide enhancing group, or pharmaceutically acceptable salts thereof, and, optionally, at least one nitric oxide enhancing compound and/or at least one therapeutic agent. The cardiovascular compounds are angiotensin II antagonists, aldosterone antagonists, endothelin antagonists, hydralazine compounds, neutral endopeptidase inhibitors and renin inhibitors . The nitric oxide enhancing groups are nitroxides and/or heterocyclic nitric oxide donors.

The need was felt to have available new renin inhibitors with good oral bioavailability and long duration of action. It has been so surprisingly found that nitroderivatives of renin inhibitors of a non-peptidic nature have a significantly improved overall profile as compared to the compounds above mentioned both in term of wider pharmacological activity and enhanced tolerability . In particular, it has been recognized that the non- peptidic renin inhibitors nitroderivatives of the present invention exhibit an anti-inflammatory, antithrombotic and antiplatelet activity and can be furthermore employed for treating or preventing congestive heart failure, coronary diseases, left ventricular dysfunction and hypertrophy, cardiac fibrosis, myocardial ischemia, stroke, atherosclerosis, restenosis post angioplasty, renal ischemia, renal failure, renal fibrosis, glomerulonephritis, renal colic, ocular and pulmonary hypertension, glaucoma, systemic hypertension, diabetic complications such as nephropathy, vasculopathy and neuropathy, peripheral vascular diseases, liver fibrosis, portal hypertension, metabolic syndromes, erectile dysfunction, complications after vascular or cardiac surgery, complications of treatment with immunosuppressive agents after organ transplantation, hyperaldosteronism, lung fibrosis, scleroderma, anxiety, cognitive disorders.

Object of the present invention are, therefore, non- peptidic renin inhibitors nitroderivatives of general formula (I) and pharmaceutically acceptable salts or stereoisomers thereof:

A¹- (Xa-ONO₂) j (D wherein : j is an integer equal to 1, or 2

A¹ is selected from the group consisting of formula (Ia), (Ib), (Ic), (Id), (Ie) and (If) :

wherein Ni is -NH-, -N-, when Ni is -N-, it is bound to one group - X_a-ONO₂; R¹ can be

(A) R¹ is aryl when R² is tetrazolyl or imidazolyl each of which may be substituted by Ci-₆alkoxy-Ci_₆alkoxy-Ci- 6alkyl, Ci-₆alkoxy-Ci-₆alkyl, aryloxy-Ci-εalkyl, heterocyclyloxy-Ci-_δalkyl, or

(B) R¹ is aryl when X is -0-CH-R^5-CO-NR⁶; or

(C) R¹ is aryl when Z is -alk-NR⁶ where alk is Ci-εalkylene, and n is 1; or

(D) R¹ is aryl which is substituted by 1-4-acetamidinyl-Ci- εalkyl, acyl-Ci-ealkoxy-Ci-εalkyl, (N-acyl) -Ci-εalkoxy-Ci-

₆alkylamino, Ci-εalkoxy, Ci-_δalkoxy-Ci-_δalkoxy, Ci- 6alkoxy-Ci-₆alkoxy-Ci-₆alkyl, Ci-₆alkoxy-Ci-₆alkyl, (N-Ci- εalkoxy) -Ci-ealkylaminocarbonyl-Ci-_δalkoxy, (N-Ci-

₆alkoxy) -Ci-ealkylaminocarbonyl-Ci-_δalkyl, Ci_₆alkoxy-Ci- 6alkylcarbamoyl, Ci-ealkoxy-Ci-_δalkylcarbonyl, Ci-

₆alkoxy-Ci-₆alkylcarbonylamino, 1-

Ci-₆alkoxy-Ci-₆alkylimidazol-2-yl, 2-

Ci-₆alkoxy-Ci-₆alkyl-4-oxoimidazol-l-yl, l-Ci-εalkoxy-Ci- ₆alkyltetrazol-5-yl, Ci-βalkyl, (N-Ci-βalkyl) -Ci-εalkoxy- Ci-6alkylcarbamoyl, (N-Ci-βalkyl) -Ci-6alkoxy-Ci-

₆alkylcarbonylamino, (N-Ci-βalkyl) -Ci-εalkoxy- carbonylamino, (N-Ci-βalkyl) -C_o-βalkylcarbonylamino-Ci- εalkoxy, (N-Ci-βalkyl) -C_o-βalkylcarbonylamino-Ci-_δalkyl,

(N-Ci-₆alkyl) -Ci-εalkyl sulphonylamino-Ci_₆alkoxy, (N-Ci- ₆alkyl) -Ci-_δalkylsulphonyl-amino-Ci-_δalkyl, Ci- _δalkylamidinyl, Ci-ealkylaminocarbonyl-Ci-_δalkoxy, di-Ci- ₆alkylaminocarbonyl-Ci-₆alkoxy, Ci_₆alkylaminocarbonyl- Ci-₆alkoxy-Ci-₆alkyl, Ci-ealkylaminocarbonyl-Ci-_δalkyl,

Ci-ealkylaminocarbonylamino-Ci-_δalkoxy, Ci-

₆alkylaminocarbonylamino-Ci-₆alkyl, di-Ci-

₆alkylaminocarbonyl-Ci-₆alkyl, Ci_₆alkylamino-C₂-₆alkoxy, di-Ci-₆alkylamino-C₂-₆alkoxy, Ci-ealkylamino-Ci-ealkyl, di-Ci-ealkylamino-Ci-_δalkyl, Ci-₆alkylcarbamoyl, di-Ci- _δalkylcarbamoyl, Co-βalkylcarbonylamino-Ci-_δalkoxy, C₀- ₆alkylcarbonylamino, C_o-βalkylcarbonylamino-Ci-_δalkyl, Ci-ealkylcarbonyloxy-Ci-_δalkoxy, Ci_₆alkylcarbonyloxy-Ci- ₆alkyl, Ci-₆alkylsulphonyl, Ci_₆alkylsulphonyl-Ci- εalkoxy, Ci-ealkylsulphonyl-Ci-_δalkyl, Ci-

₆alkylsulphonylamino-Ci-₆alkoxy, Ci-εalkylsulphonylamino -Ci-εalkyl, carbamoyl, carbamoyl-Ci_₆alkoxy, carbamoyl- Ci-εalkyl, carboxy-Ci_₆alkoxy, carboxy-Ci_₆alkoxy-Ci- ₆alkyl, carboxy-Ci-εalkyl, cyano, cyano-Ci_₆alkoxy, cyano-Ci-₆alkyl, C₃-₆cycloalkylcarbonylamino-Ci-₆alkoxy,

C₃-₆ cycloalkylcarbonylamino-Ci-_δalkyl, cyclopropyl-Ci- εalkyl, 0,N-dimethylhydroxylamino-Ci-₆alkyl, halogen, hydroxy-C2-εalkoxy-Ci-εalkoxy, hydroxy-C2-6alkoxy-Ci-

₆alkyl, hydroxy-Ci-₆alkyl, (N-hydroxy) -Ci- ealkylaminocarbonyl-Ci-_δalkoxy, (N-hydroxy) -Ci-

₆alkylaminocarbonyl-Ci-₆alkyl, (N- hydroxy) aminocarbonyl-Ci_₆alkoxy, (N- hydroxy) aminocarbonyl-Ci-_δalkyl, 2-oxooxazolidinyl-Ci- ₆alkoxy, 2-oxooxazolidinyl-Ci-6alkyl, O-methyloximyl-Ci- εalkyl or trifluoromethyl; or

(E) R¹ is aryl which is substituted by 3- acetamidomethylpyrrolidinyl 3-Ci-₆alkoxy-Ci_₆alkyl- pyrrolidinyl, 3, 4-dihydroxypyrrolidinyl, 2,6-dimethyl morpholinyl, 3, 5-dimethylmorpholinyl, dioxanyl, dioxolanyl, 4, 4-dioxothiomorpholinyl, dithianyl, dithiolanyl, 2-hydroxymethylpyrrolidinyl, 4- hydroxypiperidinyl, 3-hydroxypyrrolidinyl, imidazolylalkoxy, imidazolylalkyl, 2- methylimidazolylalkoxy, 2-methylimidazolylalkyl, 3- methyl- [1,2,4] -oxadiazol-5-ylalkoxy, 5-methyl- [1,2,4]- oxadiazol-3-ylalkoxy, 3-methyl- [1,2,4] -oxadiazol-5- ylalkyl, 5-methyl- [ 1, 2, 4 ] oxadiazol-3-ylalkyl, 4- methylpiperazinyl, 5-methyltetrazol-l-ylalkoxy, 5- methyltetrazol-1-ylalkyl, morpholinyl, [1,2,4]- oxadiazol-5-ylalkoxy, [1,2,4] -oxadiazol-5-ylalkyl, oxazol-4-ylalkoxy, oxazol-4-ylalkyl, 2-oxo-

[ 1, 3] oxazinyl, 2-oxooxazolidinyl, 2-oxoimidazolidinyl, 2-oxopyrrolidinyl, 4-oxopiperidinyl, 2- oxopyrrolidinylalkoxy, 2-oxopyrrolidinylalkyl, 2- oxotetrahydro-pyrimidinyl 4-oxothiomorpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, pyrrolyl,

[1,2,4] triazol-1-ylalkoxy, [1,2,4] triazol-4-ylalkoxy, [1, 2, 4] triazol-1-ylalkyl, [ 1, 2, 4 ] triazol-4-ylalkyl, tetrazol-1-ylalkoxy, tetrazol-2-ylalkoxy, tetrazol-5- ylalkoxy, tetrazol-1-ylalkyl, tetrazol-2-ylalkyl, tetrazol-5-ylalkyl, thiazol-4-ylalkoxy, thiazo-4- ylalkyl, thiomorpholinyl; or (F) R¹ is heterocyclyl, optionally substituted, in particular as specified under (D) or (E) , in particular benzo [ 1, 3] dioxoyl, benzofuranyl, benzoxazolyl, dihydrobenzofuranyl, 3, 4-dihydro-2H- benzo [1,4] oxazinyl, dihydro-3H-benzo [1,4] oxazinyl, dihydro-2H-benzo [1,4] thiazinyl, 2, 3-dihydroindolyl, dihydro-lH-pyrido [2, 3-b] [ 1, 4 ] oxazinyl, 1,1- dioxodihydro-2H-benzo [1,4] thiazinyl, indazolyl, indolyl, [ 1, 5] naphthpyridyl, oxazolyl, 2-oxoazepanyl, 3-oxo-4H-benzo [ 1, 4 ] oxazinyl, 2-oxobenzoxazolyl, 3-oxo- 4H-benzo [1, 4] thiazinyl, 2- oxodihydrobenzo [e] [ 1, 4 ] diazepinyl, 2- oxodihydrobenzo [d] [ 1, 3] oxazinyl, 2-oxodihydro-lH- quinazolinyl, 4-oxodihydroimidazolyl, 2-oxo-l,3- dihydroindolyl, l-oxo-3H-isobenzofuranyl, 2- oxopiperidinyl, 2-oxo-lH-pyrido [2, 3-b] [ 1, 4 ] oxazinyl, 1-oxopyridyl, 2-oxotetrahydrobenzo [e] [ 1, 4 ] diazepinyl, 4-oxo-3H-thieno [2 , 3-d] pyrimidinyl, 5-oxo-4H- [ 1, 2, 4 ] triazinyl, phthalazinyl, pyrazolyl, IH- pyrrolizinyl, lH-pyrrolo [2, 3-b] pyridyl, pyrrolyl, tetrahydroquinoxalinyl, tetrahydropyranyl, triazinyl, or 1, 1, 3-trioxodihydro-2H-lλ benzo [1,4] thiazinyl;

R² is phenyl or a heterocyclyl which is linked via a C atom, each of which radicals may be substituted by 1-4-Ci- ₆alkanoyl, Ci-6-alkoxy, Ci-6alkoxy-Ci_6alkoxy, Ci_6alkoxy-Ci- ₆alkyl, Ci_6alkoxycarbonylamino, Ci-εalkyl, Co- ₆alkylcarbonylamino, Ci-6alkylenedioxy, Ci-6alkylsulphanyl, Ci-βalkylsulphonyl, optionally N-mono- or N, N- di-Ci-6- alkylated amino, optionally N-mono- or N, N- di-Ci-6- alkylated carbamoyl, , optionally esterified carboxy, cyano, cyano-Ci-6alkyl, C3-scycloalkyl, halogen, hydroxy-Ci-6alkyl, nitro, oxide, oxo, trifluoromethyl, trifluoromethoxy or optionally N-Ci-εalkylated piperazinyl-Ci-6-alkyl; R³ is hydrogen, -OH, -0-, Ci-εalkoxy or CVεalkenyloxy, with the proviso that when R³ is -0-, it is bound to one group - Xa-ONO₂;

R⁴ is Ci-6alkoxy, Ci-δalkoxy-Ci-δalkoxy, optionally N-mono- or N, N-di-Ci-Cεalkylated amino, optionally N-mono- or N,N-di- Ci-Cεalkylated amino-Ci-εalkoxy, optionally N-Ci-εalkylated Ci-δalkoxycarbonylamino-Ci-δalkoxy, CVs-cycloalkyloxy, C3-8- cycloalkyloxy-Ci-6alkoxy, -OH, -0-, hydroxy-C₂-6alkoxy, hydroxy-CVβalkoxy-Ci-δalkoxy, heterocyclyl-Ci-6alkoxy, heterocyclyloxy, heterocyclyloxy- Ci-εalkoxy or oxo, with the proviso that when R⁴ is -0-, it is bound to one group -X_a-ONθ2;

R⁵ is acyl, CVsalkenyl, Ci-εalkyl, aryl-Ci-₆alkyl or hydrogen;

R⁶ is acyl, CVsalkenyl, Ci-βalkyl, aryl-Ci-₆alkyl or hydrogen;

R⁷ is Ci-_δalkoxycarbonyl-Ci-_δalkyl, Ci-βalkyl, carboxy-Ci- ₈alkyl or hydrogen;

W is oxygen, methylene or difluoromethylene;

X is a bond, oxygen or sulphur, where the bond originating from an oxygen or sulphur atom leads to a saturated C atom of group Z or to R¹, or a group >CHR⁵, >CHOR⁶, -0-C0-, >C0, >C=NOR⁷, -O-CHR⁵-, -O-CHR⁵-CO-NR⁶;

Z is Ci-εalkylene, C₂-salkenylene, hydroxy-Ci-εalkylidene, -0- , -S-, -0-AIk-, -S-AIk-, -AIk-O-, -AIk-S- or -AIk-NR⁶-, where AIk denotes Ci-εalkylene; and where a) if Z is -O-Alk or -S-AIk, then X is -CHR⁵; and b) if X is a bond, then Z is C₂-salkenilene, -AIk-O- or AIk-S-; n is 1 or, if X is -0-C0- or -O-CHR⁵-CO-NR⁶-, 0 or 1;

wherein :

Ni is -NH- or -N-; when Ni is -N-, it is bound to one group

- Xa-ONO₂; R¹ is unsubstituted or substituted aryl, unsubstituted or substituted mono- or bicyclic heterocyclyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl-alkyl, unsubstituted or substituted mono- or bicyclic heterocyclyl-alkyl, unsubstituted or substituted cycloalkyl-alkyl, or acyl;

R² is unsubstituted or substituted alkyl, unsubstituted or substituted aryl, unsubstituted or substituted mono- or bicyclic heterocyclyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl-alkyl, unsubstituted or substituted mono- or bicyclic heterocyclyl-alkyl or unsubstituted or substituted cycloalkyl-alkyl, with the proviso that if L is methylene (-CH₂-), oxy (-O-), thio (-S-) or unsubstituted (-NH-) or substituted imino, R² is selected from one of these mentioned groups and (as additional alternative) from hydrogen;

R³ is hydrogen, unsubstituted or substituted alkyl, substituted or unsubstituted aryl, unsubstituted or substituted heterocyclyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl-alkyl, unsubstituted or substituted heterocyclyl-alkyl, unsubstituted or substituted cycloalkyl-alkyl, or, if L is oxy, thio or unsubstituted or substituted imino, has one of the meanings just mentioned or is unsubstituted or substituted alkylcarbonyl, unsubstituted or substituted arylcarbonyl (aroyl) , unsubstituted or substituted heterocyclylcarbonyl (heterocycloyl) , unsubstituted or substituted cycloalkylcarbonyl, etherified carboxy, carbamoyl, N-mono- or N, N-di-substituted amino-carbonyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted heterocyclylsulfonyl or substituted or unsubstituted cycloalkylsulfonyl, sulfamoyl or N-mono- or N, N-di- substituted amino-sulfonyl;

R⁴ is hydrogen -O- or -OH with the proviso that when R⁴ is -0- it is bound to one group -Xa-ONO₂; L is a bond, methylene (-CH₂-) , oxy (-O-) , thio (-S-) or unsubstituted (-NH-) or substituted imino, with the proviso that if L is a bond then R³ is one of the moieties mentioned for R³ other than substituted alkyl; or R³ and R⁴ which then is -O- together with L which then is methylene and the carbon to which R³-L- and R⁴ are bound form a substituted or unsubstituted ring annealed to an unsubstituted or substituted aryl, unsubstituted or substituted heterocyclyl or unsubstituted or substituted cycloalkyl, thus forming a spiro compound of the formula 1, or R³ and R⁴ together with L form oxo (=0), thioxo (=S) or unsubstituted or substituted imino (=NH) ; T is methylene or methylene monosubstituted by alkyl, carbonyl (-C(=O)-) or thiocarbonyl (-C(=S)-;

wherein

Ni is -N- or -NH-; when Ni is -N-, it is bound to one group - Xa-ONO₂;

R is C₂-₈~alkenyl, Ci-₈-alkyl, C₂-₈~alkynyl, Co-₈-alkyl- carbonyl-amino-Ci-8-alkyl, Cs-s-cycloalkyl-Co-salkyl, Ci-8- alkyl-sulfonyl-Ci-8-alkyl, optionally N-mono- or N,N-di-Ci-8- alkylated carbamoyl-Co-8-alkyl, optionally O-Ci-s-alkylated carboxyl-Co-βalkyl, optionally N and/or N' mono-, di- or tri-Ci-8-alkylated ureido-Ci-s-alkyl or heterocyclylcarbonyl- Co-8-alkyl, each of said radicals may be substituted, preferably by 1-4 Ci-salkoxy, Ci-salkoxy-Ci-salkoxy, Ci- ₈alkoxycarbonyl- (N-Ci-salkyl) -amino, Ci-8-alkyl-sulfanyl, aryl-Co-βalkoxy, which is optionally substituted by 1 or 2 aryl or Ci-s-alkoxy radicals, aryl-amino, cyano, C3-8- cycloalkoxy, halogen, heterocyclyl- Co-salkyl, heterocyclyl- Co-salkoxy, heterocyclyl-Co-salkyl-amino, heterocyclyl- carbonyl, hydroxyl, -O-, optionally N-mono- or N,N-di-Ci-8~ alkylated amino, optionally N-mono- or N, N-di-Ci-s-alkylated carbamoyl-Co-8alkyl, optionally N-mono- or N,N-di-Ci-8~ alkylated carbamoyloxy, optionally N-mono- or N,N-di-Ci-8~ alkylated sulfamoyl, optionally N-arylated or N- heterocyclyl-substituted carbamoyl, oxo, trifluoromethoxy or trifluoromethyl , with the proviso that when R is -O-, it is bound to one group -X_a-ONθ2; R¹ is aryl or heterocyclyl;

R² is acenaphthyl, cyclohexyl, diazinyl, furyl, imidazolyl naphtyl, oxadiazolyl, oxazolyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyrrolyl, oxopyridinyl, tetrazolyl thienyl or triazolyl, each of said radicals may be substituted by 1-3 Ci-salkanoyloxy-Ci-salkyl, C₂-salkenyloxy, Ci-salkoxy, Ci-salkoxy-Ci-salkoxy, Ci-salkoxy- Ci-salkoxy-Ci- galkyl, Ci-s-alkoxy-Ci-salkyl, Ci-8-alkoxycarbonyl, Ci- salkoxycarbonyloxy-Ci-salkyl, Ci-8-alkyl, carboxy-C_x-s-alkyl, Ci-salkoxy-Ci-salkylsulfanyl, Ci-8-alkylsulfanyl, Ci-8~ alkylsulfanyl-Ci-8-alkoxy, Ci-8-alkylsulfanyl-Ci-salkoxy-Ci-s- alkyl, Ci-salkylsulfanyl-Ci-8-alkyl, cyano, cyano-Ci-8-alkyl, C3-8cycloalkyl-Co-6-alkoxy-Ci_8-alkoxy, Ci_6alkoxy-Co-6alkyl-C3- scycloalkyl-Co-βalkoxy-Ci-salkyl, Cs-scycloalkyl-Co-βalkoxy- Ci- 8-alkyl, halo-Ci-8-alkyl, halogen, hydroxy-Ci-8-alkyl, hydroxyl, -O-, oxide, trifluoromethoxy or trifluoromethyl groups, or a Ci-s-alkylenedioxy group, and/or by an Ll-Tl- L2-T2-L3-T3-L4-T4-L5-U radical; Ll, L2, L3, L4 and L5 are each independently a bond, Ci-salkylene, C₂-salkenylene or C₂-8alkynylene, C3-scycloalkene or are absent, with the proviso that when R² is -O-, it is bound to one group -X_a~ ONO₂ ; Tl , T2, T3 and T4 are each independently (a) a bond, or are absent, or are one of the groups

(b) -CH(OH)-

(c) -CH(OR⁶)-

(d) -CH(NR⁵R⁶) - (e)-CO- (f) -CR⁷R⁸

(g) -0- or -NR⁶ (h) -S(0)o-2- (i) -SO₂NR⁶ (j) -NR⁶SO₂-

(k) -CONR⁶

(1) -NR⁶CO-

(m) -0-C0- (n) -CO-O-

(o) -0-CO-O-

(p) -0-CO-NR⁶

(q) -N(R⁶) -CO-N(R⁶) -

(r) -N (R⁶) -CO-O- (s) pyrrolidinylene, piperidinylene or piperazinylene

(t) -C(R¹¹) (R¹²)-, where the bonds starting from (b) - (t) lead to a saturated or aromatic carbon atom of the adjacent group if the bond starts from a heteroatom, and where not more than two (b)-(f) groups, three (g) - (h) groups and one

(i)-(t) group are present;

R³ is hydrogen, hydroxyl, Ci-salkoxy or C2-salkenyloxy;

R⁴ is hydrogen, C2-salkenyl, Ci-salkoxy, Ci-salkoxy-Ci-salkyl, Ci-salkoxy-Ci-salkoxy, Ci-salkyl, optionally (N-Ci-salkyl) -Ci-8- alkoxycarbonyl-amino-Ci-8alkoxy, optionally (N-Ci-s-alkyl) -

Ci-salkylcarbonyl-amino-Ci-s-alkoxy, optionally (N-mono- or N, N-di-Ci-8-alkyl) -amino-Ci-salkoxy, benzyl, C3- scycloalkyloxy, Cs-scycloalkyloxy-Ci-salkoxy, heterocyclyl-Co-

₈alkoxy, heterocyclyloxy-Ci-salkoxy, hydroxy, -0-, with the proviso that when R² is -0-, it is bound to one group -X_a~

ONO₂; hydroxy-Ci-salkoxy-Ci-salkoxy, hydroxy-Ci-salkyl, oxo or a R^4a-Zl-Xl- group where R^4a is

(a) H-

(b) Ci_₈alkyl-

(c) C₂-₈alkenyl- (d) hydroxy-Ci-salkyl-

(e) polyhydroxy-Ci-salkyl-

(f) Ci-₈alkyl-O-Ci_₈alkyl-

(g) aryl- (h) heterocyclyl-

(i) arylalkyl-

(j) heterocyclylalkyl-

(k) aryloxyalkyl-

(1) heterocyclyloxyalkyl- (m) (R⁵,R⁶)N- (CH₂) 1-3-

(n) (R⁵,R⁶)N-

(0) Ci-₈alkyl-S (0) 0-2- (p) aryl-S (0)o-2-

(q) heterocyclyl-S (O) o-2^~ (r) HO-SO₃- or salts thereof

(s) H₂N-C(NH)-NH-

(t) -NC- and the bonds starting from (n) - (t) lead to a carbon atom of the adjacent group and this carbon atom is saturated if the bond starts from a heteroatom;

Zl

(a) is a bond, is absent, or is one of the groups

(b) -Ci-salkylene-

(c) -C₂-salkenylene- (d) -0-, -N(R¹¹) -,-S (0)o-2-

(e)-CO- f) -0-C0-

(g) -0-CO-O-

(h) -0-CO-N(R¹¹) - (D-N(R¹¹J-CO-O-

(j) -CO-N(R¹¹)-

(k) -N(R¹¹J-CO-

(1) -N(R¹¹) -CO-N(R¹¹) - (m) -CH ( OR⁹ ) - and the bonds starting from (d) and (f)-(m) lead to a carbon atom of the adjacent group and this carbon atom is saturated if the bond starts from a heteroatom; Xl

(a) is a bond, is absent, or is one of the groups

(b) -0- (c)-N(R¹¹)- (d) -S(O) 0-2- (e)- (CH₂)i-3-; or R³ and R⁴ in formula (Ic) together are a bond;

R⁵ and R⁶ are each independently hydrogen, Ci-salkyl, C2- galkenyl, aryl-Ci-salkyl or acyl, or, together with the nitrogen atom to which they are bonded, are a 5- or 6- membered heterocyclic ring which may contain an additional nitrogen, oxygen or sulphur atom or a -SO- or -SO2- group, and the additional nitrogen atom may optionally be substituted by Ci-salkyl radicals;

R⁷ and R⁸, together with the carbon atom to which they are bonded, are a 3-7-membered ring which may contain one or two -0- or -S- atoms or -SO- or -SO2- groups;

R⁹ is hydrogen, Ci-salkyl, Ci-salkoxy-Ci-salkyl, acyl or arylalkyl;

R¹⁰ is carboxyalkyl, alkoxycarbonylalkyl, alkyl or hydrogen;

R¹¹ is hydrogen or Ci-salkyl;

R¹² is hydrogen or Ci-salkyl; Q is ethylene or is absent (formula Ic) or is ethylene or methylene (formula Id) ;

U is hydrogen, Ci-salkyl, cyano, optionally substituted C₃_₈-cycloalkyl, aryl, or heterocyclyl;

W is oxygen or sulphur;

X is a bond, oxygen or sulphur, or is a XCH-R¹¹, >CHOR⁹,

-O-CO-, >CO, >C=NOR ,10 -O-CHR¹¹- or -O-CHR^-CO-NR⁹- group and the bond starting from an oxygen or sulphur atom leads to a saturated carbon atom of the Z group or to

R¹;

Z is Ci-salkylene, CVsalkenylene, hydroxy-Ci-salkylidene, -O-, -S-, -O-alk-, -S-alk-, -alk-O-, -alk-S- or -alk- NR⁹-, where alk is Ci-salkylene; and where

(a) if Z is -O- or -S-, X is XCH-R¹¹ and either R² contains an L1-T1-L2-T2-L3-T3-L4-T4-L5-U substituent or R⁴ is a substituent other than hydrogen as defined above;

(b) if Z is -O-alk- or -S-alk-, X is XCH-R¹¹ ; and

(c) if X is a bond, Z is CVsalkenylene, -alk-O- or -alk- S-; n is 0 or 1, m is 0 or 1;

wherein Ni is -N- or -NH-; when Ni is -N-, it is bound to one group - Xa-ONO₂; R¹ can be

(A) R¹ is aryl when R² is tetrazolyl or imidazolyl each of which may be substituted by Ci-salkoxy-Ci-salkoxy-Ci- galkyl, Ci-salkoxy-Ci-salkyl, aryloxy-Ci-salkyl, heterocyclyloxy-Ci-salkyl, or

(B) R¹ is aryl when X is -0-CH-R^5-CO-NR⁶; or

(C) R¹ is aryl when Z is -alk-NR⁶ where alk is Ci-salkylene, and n is 1 ; or

(D) R¹ is aryl which is substituted by 1-4-acetamidinyl-Ci- galkyl, acyl-Ci-salkoxy-Ci-salkyl, (N-acyl) -Ci-salkoxy-Ci- 8alkylamino, Ci-salkoxy, Ci-salkoxy-Ci-salkoxy, Ci- salkoxy-Ci-salkoxy-Ci-salkyl, Ci-salkoxy-Ci-salkyl, (N-Ci- salkoxy) -Ci-salkylaminocarbonyl-Ci-salkoxy, (N-Ci-

₈alkoxy) -Ci-salkylaminocarbonyl-Ci-salkyl, Ci-salkoxy-Ci- galkylcarbamoyl, Ci-salkoxy-Ci-salkylcarbonyl, Ci- galkoxy-Ci-₈alkylcarbonylamino, 1-

Ci-₈alkoxy-Ci-₈alkylimidazol-2-yl, 2- Ci-₈alkoxy-Ci-₈alkyl-4-oxoimidazol-l-yl, 1-Ci-salkoxy-Ci- galkyltetrazol-5-yl, Ci-salkyl, (N-Ci-salkyl) -Ci-salkoxy- Ci-salkylcarbamoyl, (N-Ci-salkyl) -Ci-salkoxy-Ci-

₈alkylcarbonylamino, (N-Ci-salkyl) -Ci-salkoxy- carbonylamino, (N-Ci-salkyl) -C_o-βalkylcarbonylamino-Ci- salkoxy, (N-Ci-salkyl) -C_o-βalkylcarbonylamino-Ci-salkyl,

(N-Ci-salkyl) -Ci-salkyl sulphonylamino-Ci-salkoxy, (N-Ci- galkyl) -Ci-salkylsulphonyl-amino-Ci-salkyl, Ci- galkylamidinyl, Ci-salkylaminocarbonyl-Ci-salkoxy, di-Ci- 8alkylaminocarbonyl-Ci-₈alkoxy, Ci-salkylaminocarbonyl- Ci-salkoxy-Ci-salkyl, Ci-salkylaminocarbonyl-Ci-salkyl,

Ci-salkylaminocarbonylamino-Ci-salkoxy, Ci-

₈alkylaminocarbonylamino-Ci-salkyl, di-Ci-

₈alkylaminocarbonyl-Ci-₈alkyl, Ci_₈alkylamino-C₂-₈alkoxy, di-Ci-₈alkylamino-C₂-₈alkoxy, Ci-salkylamino-Ci-salkyl, di-Ci-salkylamino-Ci-salkyl, Ci-salkylcarbamoyl, di-Ci- galkylcarbamoyl, Co-salkylcarbonylamino-Ci-salkoxy, C₀- 6alkylcarbonylamino, C_o-βalkylcarbonylamino-Ci-salkyl, Ci-salkylcarbonyloxy-Ci-salkoxy, Ci-salkylcarbonyloxy-Ci- galkyl, Ci-salkylsulphonyl, Ci-salkylsulphonyl-Ci-

₈alkoxy, Ci-salkylsulphonyl-Ci-salkyl, Ci- βalkylsulphonylamino-Ci_₈alkoxy, Ci-salkylsulphonylamino -Ci-salkyl, carbamoyl, carbamoyl-Ci-salkoxy, carbamoyl- Ci-salkyl, carboxy-Ci-salkoxy, carboxy-Ci-salkoxy-Ci- galkyl, carboxy-Ci-salkyl, cyano, cyano-Ci-salkoxy, cyano-Ci-salkyl, C₃_₈cycloalkylcarbonylamino-Ci-salkoxy, C₃-₈ cycloalkylcarbonylamino-Ci-salkyl, cyclopropyl-Ci- 8alkyl, 0,N-dimethylhydroxylamino-Ci-salkyl, halogen, hydroxy-C₂-₈alkoxy-Ci-salkoxy, hydroxy-C₂-salkoxy-Ci- galkyl, hydroxy-Ci-salkyl, (N-hydroxy) -Ci-

₈alkylaminocarbonyl-Ci-₈alkoxy, (N-hydroxy) -Ci-

₈alkylaminocarbonyl-Ci-₈alkyl, (N- hydroxy) aminocarbonyl-Ci-salkoxy, (N- hydroxy) aminocarbonyl-Ci-₈alkyl, 2-oxooxazolidinyl-Ci-

₈alkoxy, 2-oxooxazolidinyl-Ci-₈alkyl, O-methyloximyl-Ci- βalkyl or trifluoromethyl; or

(E) R¹ is aryl which is substituted by 1-4 3- acetamidomethylpyrrolidinyl 3-Ci-₈alkoxy-Ci-salkyl- pyrrolidinyl, 3, 4-dihydroxypyrrolidinyl, 2,6-dimethyl morpholinyl, 3, 5-dimethylmorpholinyl, dioxanyl, dioxolanyl, 4, 4-dioxothiomorpholinyl, dithianyl, dithiolanyl, 2-hydroxymethylpyrrolidinyl, 4- hydroxypiperidinyl, 3-hydroxypyrrolidinyl, imidazolylalkoxy, imidazolylalkyl, 2- methylimidazolylalkoxy, 2-methylimidazolylalkyl, 3- methyl- [1,2,4] -oxadiazol-5-ylalkoxy, 5-methyl- [1,2,4]- oxadiazol-3-ylalkoxy, 3-methyl- [1,2,4] -oxadiazol-5- ylalkyl, 5-methyl- [ 1, 2, 4 ] oxadiazol-3-ylalkyl, 4- methylpiperazinyl, 5-methyltetrazol-l-ylalkoxy, 5- methyltetrazol-1-ylalkyl, morpholinyl, [1,2,4]- oxadiazol-5-ylalkoxy, [1,2,4] -oxadiazol-5-ylalkyl, oxazol-4-ylalkoxy, oxazol-4-ylalkyl, 2-oxo-

[ 1, 3] oxazinyl, 2-oxooxazolidinyl, 2-oxoimidazolidinyl,

2-oxopyrrolidinyl, 4-oxopiperidinyl, 2- oxopyrrolidinylalkoxy, 2-oxopyrrolidinylalkyl, 2- oxotetrahydro-pyrimidinyl 4-oxothiomorpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, pyrrolyl, [1,2,4] triazol-1-ylalkoxy, [1,2,4] triazol-4-ylalkoxy, [1,2,4] triazol-1-ylalkyl, [1,2,4] triazol-4-ylalkyl, tetrazol-1-ylalkoxy, tetrazol-2-ylalkoxy, tetrazol-5- ylalkoxy, tetrazol-1-ylalkyl, tetrazol-2-ylalkyl, tetrazol-5-ylalkyl, thiazol-4-ylalkoxy, thiazo-4- ylalkyl, thiomorpholinyl; or

(F) R¹ is heterocyclyl, optionally substituted, in particular as specified under (D) or (E) , in particular benzo [ 1, 3] dioxoyl, benzofuranyl, benzoxazolyl, dihydrobenzofuranyl, 3, 4-dihydro-2H- benzo [1,4] oxazinyl, dihydro-3H-benzo [1,4] oxazinyl, dihydro-2H-benzo [1,4] thiazinyl, 2, 3-dihydroindolyl, dihydro-lH-pyrido [2, 3-b] [ 1, 4 ] oxazinyl, 1,1- dioxodihydro-2H-benzo [1,4] thiazinyl, indazolyl, indolyl, [ 1, 5] naphthpyridyl, oxazolyl, 2-oxoazepanyl, 3-oxo-4H-benzo [ 1 , 4 ] oxazinyl, 2-oxobenzoxazolyl, 3-oxo- 4H-benzo [1, 4] thiazinyl, 2- oxodihydrobenzo [e] [ 1, 4 ] diazepinyl, 2- oxodihydrobenzo [d] [ 1, 3] oxazinyl, 2-oxodihydro-lH- quinazolinyl, 4-oxodihydroimidazolyl, 2-oxo-l,3- dihydroindolyl, l-oxo-3H-isobenzofuranyl, 2- oxopiperidinyl, 2-oxo-lH-pyrido [2, 3-b] [ 1, 4 ] oxazinyl, 1-oxopyridyl, 2-oxotetrahydrobenzo [e] [ 1, 4 ] diazepinyl, 4-oxo-3H-thieno [2, 3-d] pyrimidinyl, 5-oxo-4H-

[ 1 , 2 , 4 ] triazinyl, phthalazinyl, pyrazolyl, IH- pyrrolizinyl, lH-pyrrolo [2, 3-b] pyridyl, pyrrolyl, tetrahydroquinoxalinyl, tetrahydropyranyl, triazinyl, or 1, 1, 3-trioxodihydro-2H-lλ⁶benzo [ 1, 4 ] thiazinyl;

R² is phenyl, naphthyl, acenaphthyl, cyclohexyl, pyridyl, pyrimidinyl, pyrazinyl, oxopyridinyl, diazinyl, triazolyl, thienyl, oxazolyl, oxadiazolyl, thiazolyl, pyrrolyl, furyl, tetrazolyl or imidazolyl, where the radicals are substituted by 1-3 C₂-galkenyloxy-Ci-galkyl, Ci-galkoxy-Ci- galkyl, Ci-g-alkoxy-Ci-galkylamino-Ci-g-alkyl, Ci-galkoxy-Ci-g alkylsulphanyl-Ci-salkyl, Ci-salkoxy-Co-salkyl-Cs-gcycloalkyl- CO-δalkoxy-Ci-salkyl, Ci-galkyl, Ci-salkylsulphanyl-Ci-galkoxy- Ci-salkyl, Ci-galkylsulphanyl- Ci-galkyl, Ci-galkylsulphonyl-

Ci-slkoxy-Ci-salkyl, C₃_₈cycloalkyl-Co-salkoxy-Ci-galkoxy-Ci- galkyl, Cs-gcycloalkyl-Co-salkoxy- Ci-salkyl, optionally halogen-substituted Ci-salkoxy-Ci-salkoxy-Ci-salkyl, or

(oxygen-heterocyclyl) -Co-₈alkoxy-Ci_₈alkyl, and may, in addition to the aforementioned substituents, also be substituted by a maximum of 4 halogen;

R³ is hydrogen, -OH, -O-, Ci-salkoxy or C2-salkenyloxy, with the proviso that when R³ is -O-, it is bound to one group - Xa-ONO₂;

R⁴ is optionally halogen and/or hydroxyl-substituted Ci- ₈alkyl optionally halogen and/or hydroxyl-substituted Ci- galkoxy-Ci-8alkyl, optionally N-mono- or N,N-di-Ci- Cgalkylated amino-Ci-galkyl, N-mono- or N, N-di-Ci-galkylated optionally or is optionally hydroxy-substituted amino-Co- ₈alkylcarbonyl-Ci-₈alkyl, hydroxy-Co-salkylcarbonyl- Co- galkyl, Ci-galkoxy-Co-salkylcarbonyl- Co-galkyl, optionally N- d-8-alkylated d-salkoxycarbonylamino-d-salkyl, optionally N-Ci-s-alkylated-Ci-s-salkoxy-Ci-s-alkylamino-Ci-salkyl, optionally N-Ci-s-alkylated or optionally halogen- substituted Ci-salkylcarbonylamino-Ci-salkyl, cyano- Ci- galkyl, optionally N-Ci-salkylated or optionally halogen- substituted C₃-₈-cycloalkyl-C_o-₈alkylcarbonylamino-Ci-salkyl, optionally N-Ci-s-alkylated hydroxy-Ci-salkylamino- Ci-salkyl, heterocyclylcarbonyl- Co-salkylamino-Ci-salkyl, Ci- ₈alkoxycarbonylamino- Ci-salkyl, optionally N-Ci-s-alkylated or optionally halogen-substituted heterocyclyl-Co- ₈alkylcarbonylannino-Ci-₈alkyl, C₃_₈cycloalkyl- Co-salkyl, C₃- scycloalkyloxy-Ci-salkyl, heterocyclyl-Co-8- (optionally hydroxy-substituted) alkyl, optionally N-Ci-salkylated heterocyclyl-Co-salkylamino-Co-salkylcarbonyl-Co-salkyl, Ci- ₈alkylsulphonyl-Ci-8alkyl, C2-salkinyl, heterocyclyl-C2- galkinyl, optionally N-mono- or N, N-di-Ci-s-alkylated amino- C2-8alkinyl, N-mono- or N, N-di-Ci-s-alkylated aminocarbonyl- C₂-₈alkinyl, heterocyclylcarbonyl-Co-salkyl or heterocyclyloxy-Ci-salkyl; and where

(a) if Y is -O- and R²> is not para-Ci-salkyl- substituted phenyl, then R⁴ may additionally also be hydrogen, and

(b) if Y is oxo, then R" is absent;

R is acyl, C₂-salkenyl, Ci-salkyl, aryl-Ci-salkyl or hydrogen;

R⁶ is acyl, C₂-salkenyl, Ci-salkyl, aryl-Ci-salkyl or hydrogen;

R⁷ is Ci-salkoxycarbonyl-Ci-salkyl, Ci-salkyl, carboxy-Ci- ₈alkyl or hydrogen; X is a bond, oxygen or sulphur, where the bond originating from an oxygen or sulphur atom leads to a saturated C atom of group Z or is a group >CHR⁵, >CHOR⁶, -0-C0-, >C0, >C=NOR⁷, -O-CHR⁵-, -O-CHR⁵-CO-NR⁶;

Y is -0-, oxo or a bond;

Z is Ci-salkylene, C₂-salkenylene, hydroxy-Ci-salkylidene, -0- , -S-, -0-AIk-, -S-AIk-, -AIk-O-, -AIk-S- or -AIk-NR⁶-, where AIk denotes Ci-salkylene; and where a) if Z is -O-Alk or -S-AIk, then X is -CHR⁵; and b) if X is a bond, then Z is CVsalkenylene, -AIk-O- or - AIk-S-; n is 1 or, if X is -0-C0- or -O-CHR⁵-CO-NR⁶-, is 0 or 1;

wherein

Ni is -N- or -NH-; when Ni is -N-, it is bound to one group - Xa-ONO₂; R¹ can be

(B) R¹ is aryl when X is -0-CH-R^5-CO-NR⁶; or

(C) R¹ is aryl when Z is -alk-NR⁶ where alk is Ci-salkylene, and n is 1 ; or (D) R¹ is aryl which is substituted by 1-4-acetamidinyl-Ci- galkyl, acyl-Ci-salkoxy-Ci-salkyl, (N-acyl) -Ci-salkoxy-Ci- ₈alkylamino, Ci-salkoxy, Ci-salkoxy-Ci-galkoxy, Ci- salkoxy-Ci-salkoxy-Ci-salkyl, Ci-galkoxy-Ci-galkyl, (N-Ci- ₈alkoxy) -Ci-salkylaminocarbonyl-Ci-salkoxy, (N-Ci-

₈alkoxy) -Ci-galkylaminocarbonyl-Ci-galkyl, Ci-salkoxy-Ci- galkylcarbamoyl, Ci-galkoxy-Ci-galkylcarbonyl, Ci- galkoxy-Ci-₈alkylcarbonylamino, 1-

Ci-₈alkoxy-Ci-₈alkylimidazol-2-yl, 2-

Ci-8alkoxy-Ci-8alkyl-4-oxoimidazol-l-yl, 1-Ci-galkoxy-Ci- galkyltetrazol-5-yl, Ci-galkyl, (N-Ci-salkyl) -Ci-salkoxy- Ci-salkylcarbamoyl, (N-Ci-salkyl) -Ci-salkoxy-Ci-

₈alkylcarbonylamino, (N-Ci-salkyl) -Ci-salkoxy- carbonylamino, (N-Ci-salkyl) -C_o-βalkylcarbonylamino-Ci- ₈alkoxy, (N-Ci-salkyl) -C_o-βalkylcarbonylamino-Ci-salkyl, (N-Ci-salkyl) -Ci-salkyl sulphonylamino-Ci-salkoxy, (N-Ci- ₈alkyl) -Ci-salkylsulphonyl-amino-Ci-salkyl, Ci- galkylamidinyl, Ci-salkylaminocarbonyl-Ci-salkoxy, di-Ci- ₈alkylaminocarbonyl-Ci-₈alkoxy, Ci-salkylaminocarbonyl- Ci-galkoxy-Ci-galkyl, Ci-galkylaminocarbonyl-Ci-galkyl,

Ci-salkylaminocarbonylamino-Ci-salkoxy, Ci- galkylaminocarbonylamino-Ci-galkyl, di-Ci- galkylaminocarbonyl-Ci-galkyl, Ci_₈alkylamino-C₂-₈alkoxy, di-Ci-₈alkylamino-C₂-₈alkoxy, Ci-galkylamino-Ci-galkyl, di-Ci-galkylamino-Ci-galkyl, Ci-galkylcarbamoyl, di-Ci- galkylcarbamoyl, Co-salkylcarbonylamino-Ci-salkoxy, C₀- ₆alkylcarbonylamino, C_o-βalkylcarbonylamino-Ci-galkyl,

Ci-salkylcarbonyloxy-Ci-salkoxy, Ci-galkylcarbonyloxy-Ci- galkyl, Ci-galkylsulphonyl, Ci-salkylsulphonyl-Ci-

₈alkoxy, Ci-galkylsulphonyl-Ci-galkyl, Ci-

₈alkylsulphonylamino-Ci_₈alkoxy, Ci-galkylsulphonylamino -Ci-galkyl, carbamoyl, carbamoyl-Ci-salkoxy, carbamoyl-

Ci-galkyl, carboxy-Ci-salkoxy, carboxy-Ci-salkoxy-Ci- galkyl, carboxy-Ci-galkyl, cyano, cyano-Ci-galkoxy, cyano-Ci-galkyl, C₃-₈cycloalkylcarbonylamino-Ci-galkoxy, C₃-₈ cycloalkylcarbonylamino-Ci-salkyl, cyclopropyl-Ci- galkyl, O, N-dimethylhydroxylamino-Ci-salkyl, halogen, hydroxy-C₂-₈alkoxy-Ci_8alkoxy, hydroxy-C2-salkoxy-Ci- galkyl, hydroxy-Ci-salkyl, (N-hydroxy) -Ci- galkylaminocarbonyl-Ci-salkoxy, (N-hydroxy) -Ci-

₈alkylaminocarbonyl-Ci-₈alkyl, (N- hydroxy) aminocarbonyl-Ci-salkoxy, (N- hydroxy) aminocarbonyl-Ci-salkyl, 2-oxooxazolidinyl-Ci- 8alkoxy, 2-oxooxazolidinyl-Ci-8alkyl, O-methyloximyl-Ci- salkyl or trifluoromethyl; or

(E) R¹ is aryl which is substituted by 1-4 3- acetamidomethylpyrrolidinyl 3-Ci-₈alkoxy-Ci-salkyl- pyrrolidinyl, 3, 4-dihydroxypyrrolidinyl, 2,6-dimethyl morpholinyl, 3, 5-dimethylmorpholinyl, dioxanyl, dioxolanyl, 4, 4-dioxothiomorpholinyl, dithianyl, dithiolanyl, 2-hydroxymethylpyrrolidinyl, 4- hydroxypiperidinyl, 3-hydroxypyrrolidinyl, imidazolylalkoxy, imidazolylalkyl, 2- methylimidazolylalkoxy, 2-methylimidazolylalkyl, 3- methyl- [1,2,4] -oxadiazol-5-ylalkoxy, 5-methyl- [1, 2, 4] - oxadiazol-3-ylalkoxy, 3-methyl- [1,2,4] -oxadiazol-5- ylalkyl, 5-methyl- [ 1, 2, 4 ] oxadiazol-3-ylalkyl, 4- methylpiperazinyl, 5-methyltetrazol-l-ylalkoxy, 5- methyltetrazol-1-ylalkyl, morpholinyl, [1,2,4]- oxadiazol-5-ylalkoxy, [ 1, 2, 4 ] -oxadiazol-5-ylalkyl, oxazol-4-ylalkoxy, oxazol-4-ylalkyl, 2-oxo- [ 1, 3] oxazinyl, 2-oxooxazolidinyl, 2-oxoimidazolidinyl, 2-oxopyrrolidinyl, 4-oxopiperidinyl, 2- oxopyrrolidinylalkoxy, 2-oxopyrrolidinylalkyl, 2- oxotetrahydro-pyrimidinyl 4-oxothiomorpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, pyrrolyl,

[1,2,4] triazol-1-ylalkoxy, [1,2,4] triazol-4-ylalkoxy,

[1,2,4] triazol-1-ylalkyl, [1,2,4] triazol-4-ylalkyl, tetrazol-1-ylalkoxy, tetrazol-2-ylalkoxy, tetrazol-5- ylalkoxy, tetrazol-1-ylalkyl, tetrazol-2-ylalkyl, tetrazol-5-ylalkyl, thiazol-4-ylalkoxy, thiazo-4- ylalkyl, thiomorpholinyl; or (F) R¹ is heterocyclyl, optionally substituted, in particular as specified under (D) or (E) , in particular benzo [ 1, 3] dioxoyl, benzofuranyl, benzoxazolyl, dihydrobenzofuranyl, 3, 4-dihydro-2H- benzo [1,4] oxazinyl, dihydro-3H-benzo [1,4] oxazinyl, dihydro-2H-benzo [ 1 , 4 ] thiazinyl, 2, 3-dihydroindolyl, dihydro-lH-pyrido [2, 3-b] [ 1, 4 ] oxazinyl, 1,1- dioxodihydro-2H-benzo [1,4] thiazinyl, indazolyl, indolyl, [ 1, 5] naphthpyridyl, oxazolyl, 2-oxoazepanyl, 3-oxo-4H-benzo [ 1 , 4 ] oxazinyl, 2-oxobenzoxazolyl, 3-oxo- 4H-benzo [1, 4] thiazinyl, 2- oxodihydrobenzo [e] [ 1, 4 ] diazepinyl, 2- oxodihydrobenzo [d] [ 1, 3] oxazinyl, 2-oxodihydro-lH- quinazolinyl, 4-oxodihydroimidazolyl, 2-oxo-l,3- dihydroindolyl, l-oxo-3H-isobenzofuranyl, 2- oxopiperidinyl, 2-oxo-lH-pyrido [2, 3-b] [ 1, 4 ] oxazinyl,

1-oxopyridyl, 2-oxotetrahydrobenzo [e] [ 1, 4 ] diazepinyl,

4-oxo-3H-thieno [2 , 3-d] pyrimidinyl, 5-oxo-4H-

[ 1, 2, 4 ] triazinyl, phthalazinyl, pyrazolyl, IH- pyrrolizinyl, lH-pyrrolo [2, 3-b] pyridyl, pyrrolyl, tetrahydroquinoxalinyl, tetrahydropyranyl, triazinyl, or 1, 1, 3-trioxodihydro-2H-lλ⁶benzo [1,4] thiazinyl;

R^2' is C₂-8alkenyloxy-Ci-salkyl, Ci-salkoxy-Ci-salkyl, Ci-8- alkoxy-Ci-salkylamino-Ci-8-alky1, Ci-salkoxy-Ci-s alkylsulphanyl-Ci-salkyl, Ci-salkoxy-Co-salkyl-Cs-scycloalkyl- C0-8alkoxy-Ci-salkyl, Ci-salkyl, Ci-salkylsulphanyl-Ci-salkoxy- Ci-salkyl, Ci-salkylsulphanyl- Ci-salkyl, Ci-salkylsulphonyl- Ci-slkoxy-Ci-salkyl, C₃_₈cycloalkyl-Co-salkoxy-Ci-salkoxy-Ci- galkyl, Cs-scycloalkyl-Co-salkoxy- Ci-galkyl, optionally halogen-substituted Ci-galkoxy-Ci-galkoxy-Ci-galkyl, or

(oxygen-heterocyclyl) -Co-galkoxy-Ci-galkyl;

R^2" is halogen;

R^4' is a) optionally halogen and/or hydroxy-substituted Ci- ₈alkyl optionally halogen and/or hydroxy-substituted Ci- ₈alkoxy-Ci_8alkoxy, optionally N-mono- or N,N-di-Ci- Csalkylated amino-Ci-salkoxy, optionally N-Ci-salkylated Ci- salkoxy-Ci-salkylamino-Ci-salkoxy, optionally N-mono- or N,N- di-Ci-salkylated amino-Co-salkylcarbonyl-Ci-salkoxy, hydroxyl- Co-salkylcarbonyl-Co-salkoxy, Ci-salkoxy-Co-salkylcarbonyl-Co- ₈alkoxy, Ci-Csalkylcarbonylamino-Ci-salkoxy, cyano-Ci-salkoxy, C3-scycloalkylCo-8alkoxy, heterocyclyl-Co-salkoxy, optionally N-Ci-salkylated heterocyclyl-Co-salkylamino-Co-salkylcarbonyl- Co-βalkoxy, Ci-salkylsulphonyl-Ci-salkoxy, C₂-salkinyloxy, heterocyclyl-C₂-8alkinyloxy optionally N-mono- or N,N-di-Ci~ Csalkylated amino-C₂-salkinyloxy, N-mono- or N,N-di-Ci~ Csalkylated aminocarbonyl-C₂-salkinyl-oxy, heterocyclylcarbonyl-Co-salkoxy, optionally N-mono- or N,N- di-Ci-salkylated amino-Ci-salkyl, optionally N-Ci-salkylated- Ci-salkoxy-Ci-salkylamino-Ci-salkyl, optionally N-mono- or N, N-di-Ci-salkylated and optionally hydroxyl-substituted aminoCo-salkylcarbonyl-Co-salky, optionally N-Ci-salkylated heterocyclyl-Co-βalkylamino-Co-salkylcarbonyl-Co-salkyl, optionally halogen- or hydroxyl-substituted Ci-salkoxy-Ci- galkyl, optionally halogen- and/or hydroxy- substituted Ci- galkyl, optionally N-Ci-salkylatedhydroxy-Ci-salkylamino-Ci- galkyl, heterocyclylcarbonyl-Co-galkyl, heterocyclylcarbonyl-Co-galkylamino-Ci-galkyl, heterocyclyl- Ci-galkyl, Ci-galkoxycarbonylamino-Ci-galkyl, optionally halogen-substituted hetrocyclyl-Co-salkylcarbonylamino-Ci- galkyl, optionally halogen-substituted C3_8cycloalkyl-Co- ₈alkylcarbonylamino-Ci-₈alkyl or optionally halogen- substituted Ci-salkylcarbonylamino-Ci-salkyl; or additionally (b) is hydroxy, -0- with the proviso that when R⁴ is -0- it bounds the group -X_a-0N0₂, if R²' is not Ci_₈alkyl;

R⁵ is acyl, C₂-salkenyl, Ci-salkyl, aryl-Ci-salkyl or hydrogen;

R⁶ is acyl, Ci-salkoxy-Ci-salkyl, Ci-salkyl or aryl-Ci-salkyl or hydrogen;

R⁷ is Ci-salkoxycarbonyl-Ci-salkyl, Ci-salkyl, carboxy-Ci-

₈alkyl or hydrogen;

X is a bond, oxygen or sulphur, where the bond originating from an oxygen or sulphur atom leads to a saturated C atom of the group Z or is a group >CHR⁵, >CHOR⁶, -0-C0-, >C0,

>C=NOR⁷, -O-CHR⁵-, or -O-CHR⁵-CO-NR⁶;

Z is Ci-salkylene, C₂-salkenylene, hydroxy-Ci-salkylidene, -O-

, -S-, -0-AIk-, -S-AIk-, -AIk-O-, -AIk-S- or -AIk-NR⁶-, where AIk denotes Ci-salkylene; and where a) if Z is -O-Alk or -S-AIk, then X is -CHR⁵; and b) if X is a bond, then Z is C2-salkenylene, -AIk-O- or - AIk-S-; m is 0 , 1 , 2 ; n is 1 or, if X is -0-C0- or -O-CHR⁵-CO-NR⁶-, is 0 or 1; and the salts thereof, preferably the pharmaceutically acceptable salts thereof;

X_a is equal to -X_b-Y_a~ wherein X_b is -CO- or -COO-;

Y_a is a bivalent radical having the following meaning: a)

- straight or branched C1-C20 alkylene, preferably C1-C10, being optionally substituted with one or more of the substituents selected from the group consisting of: halogen atoms, hydroxy, -ONO2 or T_a, wherein T_a is

-OC(O) (Ci-Cio alkyl)-ONO₂ or -0(Ci-Ci₀ alkyl) -ONO₂;

- cycloalkylene with 5 to 7 carbon atoms into cycloalkylene ring, the ring being optionally substituted with side chains T_b, wherein T_b is straight or branched alkyl with from 1 to 10 carbon atoms, preferably CH₃; b)

wherein n⁰ is an integer from 0 to 20, and n¹ is an integer from 1 to 20; d)

wherein : n¹ is as defined above and n² is an integer from 0 to 2; X_c = -OCO- or -COO- and R₂ is H or CH₃; e)

wherein : n¹, n²,R₂ and X_c are as defined above; Y_b is -CH₂-CH₂- or -CH=CH-(CH₂;

wherein : n¹ and R₂ are as defined above, R3 is H or -COCH₃; with the proviso that when Y_a is selected from the bivalent radicals mentioned under b) -f) , the -ONO₂ group is linked to a - (CH₂) n¹ group; g⁾

wherein X_d is -0- or -S-, n³ is an integer from 1 to 6, preferably from 1 to 4, R₂ is as defined above; h)

wherein : n⁴ is an integer from 0 to 10; n⁵ is an integer from 1 to 10;

R₄, R₅, Rε, R7 are the same or different, and are H or straight or branched Ci-C₄ alkyl, preferably R₄, R₅, Re, R7 are H; wherein the -ONO₂ group is linked to

wherein n⁵ is as defined above;

Y_c is an heterocyclic saturated, unsaturated or aromatic 5 or 6 members ring, containing one or more heteroatoms selected from nitrogen, oxygen, sulfur, and is selected from the group consisting in:

The term "C1-C20 alkylene" as used herein refers to branched or straight chain C1-C20 hydrocarbon, preferably having from 1 to 10 carbon atoms such as methylene, ethylene, propylene, isopropylene, n-butylene, pentylene, n-hexylene and the like.

The term "C1-C10 alkyl" as used herein refers to branched or straight chain alkyl groups comprising one to ten carbon atoms, including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl, octyl and the like.

The term "cycloalkylene" as used herein refers to ring having from 5 to 7 carbon atoms including, but not limited to, cyclopentylene, cyclohexylene optionally substituted with side chains such as straight or branched (Ci-Cio) - alkyl, preferably CH₃.

The term "heterocyclic" as used herein refers to saturated, unsaturated or aromatic 5 or 6 members ring, containing one or more heteroatoms selected from nitrogen, oxygen, sulphur, such as for example pyridine, pyrazine, pyrimidine, pyrrolidine, morpholine, imidazole and the like .

Another aspect of the present invention provides the use of the compounds of formula (I) in combination with at least a compound used to treat cardiovascular disease selected from the group consisting of: aldosterone antagonists, angiotensin II receptor blockers, ACE inhibitors, HMGCoA reductase inhibitors, beta-adrenergic blockers, alpha-adrenergic antagonists, sympatholytics, calcium channel blockers, endothelin antagonists, neutral endopeptidase inhibitors, potassium activators, diuretics, vasodilators, antithrombotics such as aspirin. Also it is contemplated the combination with nitrosated compounds of the above reported compounds.

Suitable aldosterone antagonists, angiotensin II receptor blockers, ACE inhibitors, HMGCoA reductase inhibitors, beta-adrenergic blockers, alpha-adrenergic antagonists, calcium channel blockers, potassium activators, diuretics, vasodilators and antithrombotics are described in the literature such as The Merck Index (13^th edition) .

Suitable nitrosated compounds are disclosed in WO 98/21193, WO 97/16405, WO 98/09948, WO 2004/105754, WO 2004/106300, WO 2004/110432, WO 2005/011646, WO 2005/053685, WO 2005/054218.

The administration of the compounds above reported can be carried out simultaneously or successively.

The present invention also provides pharmaceutical kits comprising one or more containers filled with one or more of the compounds and/or compositions of the present invention and one or more of the compounds used to treat cardiovascular diseases reported above.

As stated above, the invention includes also the pharmaceutically acceptable salts of the compounds of formula (I) and stereoisomers thereof.

Examples of pharmaceutically acceptable salts are either those with inorganic bases, such as sodium, potassium, calcium and aluminium hydroxides, or with organic bases, such as lysine, arginine, triethylamine, dibenzylamine, piperidine and other acceptable organic amines . The compounds according to the present invention, when they contain in the molecule one salifiable nitrogen atom, can be transformed into the corresponding salts by reaction in an organic solvent such as acetonitrile, tetrahydrofuran with the corresponding organic or inorganic acids. Examples of organic acids are: oxalic, tartaric, maleic, succinic, citric acids. Examples of inorganic acids are: nitric, hydrochloric, sulphuric, phosphoric acids. Salts with nitric acid are preferred.

The compounds of the invention which have one or more asymmetric carbon atoms can exist as optically pure enantiomers, pure diastereomers, enantiomers mixtures, diastereomers mixtures, enantiomer racemic mixtures, racemates or racemate mixtures. Within the object of the invention are also all the possible isomers, stereoisomers and their mixtures of the compounds of formula (I) .

Preferred compounds are those of formula (I) wherein Y_a has the following meaning: a) straight or branched Ci-Cio alkylene being optionally substituted with one or more of the substituents selected from the group consisting of: halogen atoms, hydroxy, -ONO2 or T_a, wherein T_a is -OC(O) (Ci-Cio alkyl)-ONO₂ or -0(Ci-Ci₀ alkyl) -ONO₂; b)

wherein n is 0 or 1, n¹ is 1 ; with the proviso that the -ONO₂ group is linked to - (CH₂) _n ^x group; g⁾

wherein X_d is -0- or -S-, n is 1 and R₂ is H;

The following are preferred compounds according to the present invention:

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As mentioned above, object of the present invention are also pharmaceutical compositions containing at least a compound of the present invention of formula (I) together with non toxic adiuvants and/or carriers usually employed in the pharmaceutical field.

The daily dose of active ingredient that should be administered can be a single dose or it can be an effective amount divided into several smaller doses that are to be administered throughout the day. The dosage regimen and administration frequency for treating the mentioned diseases with the compound of the invention and/or with the pharmaceutical compositions of the present invention will be selected in accordance with a variety of factors, including for example age, body weight, sex and medical condition of the patient as well as severity of the disease, route of administration, pharmacological considerations and eventual concomitant therapy with other drugs. In some instances, dosage levels below or above the aforesaid range and/or more frequent may be adequate, and this logically will be within the judgment of the physician and will depend on the disease state.

The compounds of the invention may be administered orally, parenterally, rectally or topically, by inhalation or aerosol, in formulations eventually containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles as desired. Topical administration may also involve the use of transdermal administration such as transdermal patches or iontophoresis devices. The term "parenteral" as used herein, includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.

Injectable preparations, for example sterile injectable aqueous or oleaginous suspensions may be formulated according to known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent. Among the acceptable vehicles and solvents are water, Ringer's solution and isotonic sodium chloride. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono or diglycerides, in addition fatty acids such as oleic acid find use in the preparation of injectables. Suppositories for rectal administration of the drug can be prepared by mixing the active ingredient with a suitable non-irritating excipient, such as cocoa butter and polyethylene glycols. Solid dosage forms for oral administration may include capsules, tablets, pills, powders, granules and gels. In such solid dosage forms, the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as in normal practice, additional substances other than inert diluents, e.g. lubricating agents such as magnesium stearate. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.

Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art, such as water. Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavouring and the like.

The compounds of the present invention can be synthesized as follows.

Synthesis procedure

1. The compound of general formula (I) as above defined

A¹- (Xa-ONO₂) j

(D wherein:

A¹ and j are as above defined; X_a is -X_b-Y_a~ wherein X_b is - CO- and Y_a is as above defined, can be obtained by a process comprising:

Ia. reacting a compound of formula B¹ with a compound of formula (Ilia) in the molar ratio 1:1 or 1:2 dependent on value of the integer j in the general formula (I) :

B¹ + HOOC-Ya-ONO₂ ( I l i a ;

wherein Y_a is as above defined; B¹ has the same meaning as

A¹ with Ni equal to -NH- and, if in A¹ a group -0- is linked to -X_a-ONθ2, then in B¹ this group corresponds to -OH; in presence of a condensing agent like dicyclohexylcarbodiimide (DCC) or N, N' -carbonyldiimidazol

(CDI) or other known condensing reagents such as HATU in solvent such as DMF, THF, chloroform at a temperature in the range from -5°C to 50⁰C in the presence or not of a base as for example DMAP.

The nitric acid ester compounds of formula (Ilia) can be obtained from the corresponding alcohols of formula HOOC- Y_a-OH (HIb), that are commercially available, by reaction with nitric acid and acetic anhydride in a temperature range from -50⁰C to 0⁰C or reacting the corresponding halogen derivatives of formula HOOC-Y_a-Hal (IIIc) wherein Hal is an halogen atom preferable Cl, Br, I, that are commercially available, with AgNθ3 as already described in WO 2006/008196.

Compounds of formula B¹ wherein B¹ has formula (Ia) with Ni equal to -NH- are known compounds and can be prepared as described in WO 2006/103273.

Compounds of formula B¹ wherein B¹ has formula (Ib) with Ni equal to -NH- are known compounds and can be prepared as described in WO 2006/066896.

Compounds of formula B¹ wherein B¹ has formula (Ic) or (Id) with Ni equal to -NH- are known compounds and can be prepared as described in WO 2006/103277.

Compounds of formula B¹ wherein B¹ has formula (Ie) or (If) with Ni equal to -NH- are known compounds and can be prepared as described in WO 2006/103275. Ib. reacting a compound of formula B¹ as above defined with a compound of formula (HId) in the molar ratio 1:1 or 1:2 dependent on value of the integer j in the general formula (D :

B¹ Act-CO-Y_a-ONO₂ (HId)

wherein Y_a is as above defined; Act is an Halogen atom or a carboxylic acid activating group used in peptide chemistry as :

The reaction is generally carried out in presence of a inorganic or organic base in an aprotic polar/non-polar solvent such as DMF, THF or CH₂Cl₂ at temperatures ranging between 0°-65°C or in a double phase system H₂0/Et₂0 at temperatures ranging between 20°-40°C; or in the presence of DMAP and a Lewis acid such as Sc(OTf)₃ or Bi(OTf)₃ in solvents such as DMF, CH₂Cl₂.

The compounds of formula (HId) can be obtained as described in WO 2006/008196.

Ic. Reacting a compound of formula C¹ with a compound of formula (Ilia)

C¹ + HOOC-Y_a-ONO₂ ( I l i a ;

wherein Y_a is as above defined; C¹ has the same meaning as

A¹ with Ni equal to >N-PG wherein PG is a N-protecting group like BOC, in presence of a condensing agent like dicyclohexylcarbodiimide (DCC) or N, N' -carbonyldiimidazol

(CDI) or other known condensing reagents such as HATU in solvent such as DMF, THF, chloroform at a temperature in the range from -5°C to 50⁰C in the presence or not of a base as for example DMAP. Eventually acid hydrolysing the

N-BOC protective group as known in the literature and salifying if required.

Id. reacting a compound of formula A¹- (CO-Y_a-Hal) -, (IVa), wherein A¹, Y_a, Hal and j are as above defined, with AgNθ3 as already described. Compounds (IVa) can be obtained by reacting a compound B¹ with a compound of formula (IIIc), as above defined, in the molar ratio 1:1 or 1:2 dependent on value of the integer j in the general formula (I), with a condensing reagent such as DCC or CDI as above described.

Ie. reacting a compound of formula A¹- (CO-Y_a-OH) -, (Va), wherein A¹, Y_a and j are as above defined, with triflic anhydride/tetraalkylammonium nitrate salt in an aprotic polar/non-polar solvent such as DMF, THF or CH2CI2 at temperatures ranging between -60° and 65°C as already described. Compounds (Va) can be obtained by reacting a compound B¹ with a compound of formula (HIb), as above defined, in the molar ratio 1:1 or 1:2 dependent on value of the integer j in the general formula (I), with a condensing reagent as above described. 2. The compounds of general formula (I) as above defined wherein :

A¹ and j are as above defined; X_a is -X_b-Y_a~ wherein X_b is - C(O)O- and Y_a is as above defined, can be obtained by a process comprising:

2a. reacting a compound of formula B¹ with a compound of formula (Via) in the molar ratio 1:1 or 1:2 dependent on value of the integer j in the general formula (I) :

B¹ + ACt-CO-O-Ya-ONO₂

(Via)

wherein B¹, Act and Y_a are as above defined.

The synthesis of compounds (Via) is described in WO 2006/008196.

2b. Reacting a compound of formula C¹ with a compound of formula (Via) :

C¹ + Act-CO-O-Y_a-ONO₂

(Via)

wherein C¹, Act and Y_a are as above defined.

The reaction is generally carried out in presence of a inorganic or organic base in an aprotic polar/non-polar solvent such as DMF, THF or CH2CI2 at temperatures ranging between 0°-65°C or in a double phase system H₂O/Et2θ at temperatures ranging between 20°- 40⁰C; or in the presence of DMAP and a Lewis acid such as Sc(OTf)₃ or Bi(OTf)₃ in solvents such as DMF, CH₂Cl₂.

The synthesis of compounds (Via) is described in WO 2006/008196. Eventually acid hydrolizing the BOC protective group and salifing is required.

2c. reacting a compound of formula A^(COO-Y_a-HaI)₃ (Vila) wherein A¹, Y_a, Hal and j are as above defined, with AgNO₃ as above described.

The compounds of formula (Vila) can be obtained by reacting a compound B¹ with a compound of formula Act-CO-O-Y_a-Hal (VIIb) in the molar ratio 1:1 or 1:2 dependent on value of the integer j in the general formula (I) .

The reaction is generally carried out in presence of an inorganic or organic base in an aprotic polar/non-polar solvent such as DMF, THF or CH₂Cl₂ at temperatures ranging between 0°-65°C as above described.

Compounds (VIIb) are commercially available or can be synthesized as already described in WO 2006/008196.

Claims

1. A compound of general formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof:

A¹- (Xa-ONO₂) j (D wherein : j is an integer equal to 1, or 2 ;

A¹ is selected from the group consisting of formula (Ia), (Ib), (Ic), (Id), (Ie) and (If):

wherein Ni is -NH-, -N-, when Ni is -N-, it is bound to one group - Xa-ONO₂; R¹ can be

(G) R¹ is aryl when R² is tetrazolyl or imidazolyl each of which may be substituted by Ci-₆alkoxy-Ci_₆alkoxy-Ci- εalkyl, Ci-₆alkoxy-Ci-₆alkyl, aryloxy-Ci-εalkyl, heterocyclyloxy-Ci-_δalkyl, or

(H) R¹ is aryl when X is -0-CH-R^5-CO-NR⁶; or (I) R¹ is aryl when Z is -alk-NR⁶ where alk is Ci-εalkylene, and n is 1; or (J) R¹ is aryl which is substituted by 1-4-acetamidinyl-Ci- 6alkyl, acyl-Ci-₆alkoxy-Ci-₆alkyl, (N-acyl) -Ci-εalkoxy-Ci- 6alkylamino, Ci-εalkoxy, Ci-_δalkoxy-Ci-_δalkoxy, Ci- 6alkoxy-Ci-₆alkoxy-Ci-₆alkyl, Ci-₆alkoxy-Ci-₆alkyl, (N-Ci- ₆alkoxy) -Ci-ealkylaminocarbonyl-Ci-_δalkoxy, (N-Ci-

₆alkoxy) -Ci-εalkylaminocarbonyl-Ci-εalkyl, Ci_₆alkoxy-Ci- ₆alkylcarbamoyl, Ci-εalkoxy-Ci-εalkylcarbonyl, Ci-

₆alkoxy-Ci-₆alkylcarbonylamino, 1- Ci-₆alkoxy-Ci-₆alkylimidazol-2-yl, 2-

Ci-6alkoxy-Ci-6alkyl-4-oxoimidazol-l-yl, 1-Ci-εalkoxy-Ci- ₆alkyltetrazol-5-yl, Ci-εalkyl, (N-Ci-εalkyl) -Ci-εalkoxy- Ci-6alkylcarbamoyl, (N-Ci-εalkyl) -Ci-εalkoxy-Ci-

₆alkylcarbonylamino, (N-Ci-εalkyl) -Ci-₆alkoxy- carbonylamino, (N-Ci-εalkyl) -C_o-βalkylcarbonylamino-Ci-

₆alkoxy, (N-Ci-εalkyl) -C_o-βalkylcarbonylamino-Ci-_δalkyl, (N-Ci-εalkyl) -Ci-εalkyl sulphonylamino-Ci_₆alkoxy, (N-Ci- ₆alkyl) -Ci-ealkylsulphonyl-amino-Ci-ealkyl, Ci- _δalkylamidinyl, Ci-ealkylaminocarbonyl-Ci-_δalkoxy, di-Ci- ealkylaminocarbonyl-Ci-_δalkoxy, Ci_₆alkylaminocarbonyl-

Ci-₆alkoxy-Ci-₆alkyl, Ci-ealkylaminocarbonyl-Ci-_δalkyl,

Ci-₆alkylaminocarbonylamino-Ci-₆alkoxy, Ci-

₆a1kylaminocarbonylamino-Ci-₆aIky1, di-Ci-

₆alkylaminocarbonyl-Ci-₆alkyl, Ci-εa1kylamino-C₂-εalkoxy, di-Ci-₆alkylamino-C₂-₆alkoxy, Ci-_δalkylamino-Ci-_δalkyl, di-Ci-ealkylamino-Ci-_δalkyl, Ci-₆alkylcarbamoyl, di-Ci- _δalkylcarbamoyl, Co-βalkylcarbonylamino-Ci-_δalkoxy, C₀- ₆alkylcarbonylamino, C₀-εa1kylcarbonylamino-Ci-εalkyl, Ci-ealkylcarbonyloxy-Ci-_δalkoxy, Ci-εalkylcarbonyloxy-Ci- εalkyl, Ci-εalkylsulphonyl, Ci_₆alkylsulphonyl-Ci-

₆alkoxy, Ci-εalkylsulphonyl-Ci-εalkyl, Ci-

₆alkylsulphonylamino-Ci-₆alkoxy, Ci-εalkylsulphonylamino -Ci-εalkyl, carbamoyl, carbamoyl-Ci_₆alkoxy, carbamoyl- Ci-εalkyl, carboxy-Ci-₆alkoxy, carboxy-Ci_₆alkoxy-Ci- εalkyl, carboxy-Ci-εalkyl, cyano, cyano-Ci-₆alkoxy, cyano-Ci-εalkyl, C₃_₆cycloalkylcarbonylamino-Ci-εalkoxy, C₃-₆ cycloalkylcarbonylamino-Ci-εalkyl, cyclopropyl-Ci- εalkyl, 0,N-dimethylhydroxylamino-Ci-εalkyl, halogen, hydroxy-C₂-₆alkoxy-Ci-₆alkoxy, hydroxy-C₂-₆alkoxy-Ci-

₆alkyl, hydroxy-Ci-₆alkyl, (N-hydroxy) -Ci-

₆alkylaminocarbonyl-Ci-₆alkoxy, (N-hydroxy) -Ci-

₆alkylaminocarbonyl-Ci-₆alkyl, (N- hydroxy) aminocarbonyl-Ci-₆alkoxy, (N- hydroxy) aminocarbonyl-Ci-₆alkyl, 2-oxooxazolidinyl-Ci-

₆alkoxy, 2-oxooxazolidinyl-Ci-₆alkyl, O-methyloximyl-Ci-

₆alkyl or trifluoromethyl; or

(K) R¹ is aryl which is substituted by 3- acetamidomethylpyrrolidinyl 3-Ci-₆alkoxy-Ci_₆alkyl- pyrrolidinyl, 3, 4-dihydroxypyrrolidinyl, 2,6-dimethyl morpholinyl, 3, 5-dimethylmorpholinyl, dioxanyl, dioxolanyl, 4, 4-dioxothiomorpholinyl, dithianyl, dithiolanyl, 2-hydroxymethylpyrrolidinyl, 4- hydroxypiperidinyl, 3-hydroxypyrrolidinyl, imidazolylalkoxy, imidazolylalkyl, 2- methylimidazolylalkoxy, 2-methylimidazolylalkyl, 3- methyl- [1,2,4] -oxadiazol-5-ylalkoxy, 5-methyl- [1,2,4]- oxadiazol-3-ylalkoxy, 3-methyl- [1,2,4] -oxadiazol-5- ylalkyl, 5-methyl- [ 1, 2, 4 ] oxadiazol-3-ylalkyl, 4- methylpiperazinyl, 5-methyltetrazol-l-ylalkoxy, 5- methyltetrazol-1-ylalkyl, morpholinyl, [1,2,4]- oxadiazol-5-ylalkoxy, [1,2,4] -oxadiazol-5-ylalkyl, oxazol-4-ylalkoxy, oxazol-4-ylalkyl, 2-oxo- [ 1, 3] oxazinyl, 2-oxooxazolidinyl, 2-oxoimidazolidinyl, 2-oxopyrrolidinyl, 4-oxopiperidinyl, 2- oxopyrrolidinylalkoxy, 2-oxopyrrolidinylalkyl, 2- oxotetrahydro-pyrimidinyl 4-oxothiomorpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, pyrrolyl, [1, 2, 4] triazol-1-ylalkoxy, [ 1, 2, 4 ] triazol-4-ylalkoxy, [1,2,4] triazol-1-ylalkyl, [1,2,4] triazol-4-ylalkyl, tetrazol-1-ylalkoxy, tetrazol-2-ylalkoxy, tetrazol-5- ylalkoxy, tetrazol-1-ylalkyl, tetrazol-2-ylalkyl, tetrazol-5-ylalkyl, thiazol-4-ylalkoxy, thiazo-4- ylalkyl, thiomorpholinyl; or

(L) R¹ is heterocyclyl, optionally substituted, in particular as specified under (D) or (E) , in particular benzo [ 1, 3] dioxoyl, benzofuranyl, benzoxazolyl, dihydrobenzofuranyl, 3, 4-dihydro-2H- benzo [1,4] oxazinyl, dihydro-3H-benzo [1,4] oxazinyl, dihydro-2H-benzo [1,4] thiazinyl, 2, 3-dihydroindolyl, dihydro-lH-pyrido [2, 3-b] [ 1, 4 ] oxazinyl, 1,1- dioxodihydro-2H-benzo [ 1 , 4 ] thiazinyl, indazolyl, indolyl, [ 1, 5] naphthpyridyl, oxazolyl, 2-oxoazepanyl, 3-oxo-4H-benzo [ 1 , 4 ] oxazinyl, 2-oxobenzoxazolyl, 3-oxo- 4H-benzo [1, 4] thiazinyl, 2- oxodihydrobenzo [e] [ 1, 4 ] diazepinyl, 2- oxodihydrobenzo [d] [ 1, 3] oxazinyl, 2-oxodihydro-lH- quinazolinyl, 4-oxodihydroimidazolyl, 2-oxo-l,3- dihydroindolyl, l-oxo-3H-isobenzofuranyl, 2- oxopiperidinyl, 2-oxo-lH-pyrido [2, 3-b] [ 1, 4 ] oxazinyl, 1-oxopyridyl, 2-oxotetrahydrobenzo [e] [ 1, 4 ] diazepinyl, 4-oxo-3H-thieno [2 , 3-d] pyrimidinyl, 5-oxo-4H-

R² is phenyl or a heterocyclyl which is linked via a C atom, each of which radicals may be substituted by 1-4-Ci- ₆alkanoyl, Ci-₆-alkoxy, Ci-₆alkoxy-Ci_₆alkoxy, Ci_₆alkoxy-Ci- ₆alkyl, Ci_₆alkoxycarbonylamino, Ci-εalkyl, Co- ₆alkylcarbonylamino, Ci-εalkylenedioxy, Ci-εalkylsulphanyl, Ci-βalkylsulphonyl, optionally N-mono- or N, N- di-Ci-₆- alkylated amino, optionally N-mono- or N, N- di-Ci-6- alkylated carbamoyl, , optionally esterified carboxy, cyano, cyano-Ci-₆alkyl, Cs-scycloalkyl, halogen, hydroxy-Ci-₆alkyl, nitro, oxide, oxo, trifluoromethyl, trifluoromethoxy or optionally N-Ci-εalkylated piperazinyl-Ci-₆-alkyl;

R³ is hydrogen, -OH, -0-, Ci-εalkoxy or C₂-₆alkenyloxy, with the proviso that when R³ is -0-, it is bound to one group - Xa-ONO₂;

R⁴ is Ci-₆alkoxy, Ci-₆alkoxy-Ci_₆alkoxy, optionally N-mono- or N, N-di-Ci-Cεalkylated amino, optionally N-mono- or N,N-di- Ci-Cεalkylated amino-Ci-εalkoxy, optionally N-Ci-εalkylated Ci-ealkoxycarbonylamino-Ci-_δalkoxy, C₃_₈-cycloalkyloxy, C₃-₈- cycloalkyloxy-Ci-₆alkoxy, -OH, -0-, hydrOXy-C₂-₆alkoxy, hydroxy-C₂-εalkoxy-Ci-εalkoxy, heterocyclyl-Ci-₆alkoxy, heterocyclyloxy, heterocyclyloxy- Ci-εalkoxy or oxo, with the proviso that when R⁴ is -0-, it is bound to one group -X_a-0N0₂;

R⁵ is acyl, C₂-salkenyl, Ci-εalkyl, aryl-Ci-₆alkyl or hydrogen;

R⁶ is acyl, C₂-salkenyl, Ci-εalkyl, aryl-Ci-₆alkyl or hydrogen;

R⁷ is Ci-ealkoxycarbonyl-Ci-_δalkyl, Ci-βalkyl, carboxy-Ci- ₈alkyl or hydrogen;

W is oxygen, methylene or difluoromethylene;

X is a bond, oxygen or sulphur, where the bond originating from an oxygen or sulphur atom leads to a saturated C atom of group Z or to R¹, or a group >CHR⁵, >CHOR⁶, -0-C0-, >C0, >C=N0R⁷, -O-CHR⁵-, -O-CHR⁵-CO-NR⁶; Z i s Ci-6al kylene , C₂-sal kenylene , hydroxy-Ci-6al kyl idene , -O- , --SS--,, --00--AAIIkk--,, --SS--AAIIkk--,, --AAIIkk--OO--,, --AAiI:k-S- or -AIk-NR-, where AI k denotes Ci-εal kylene ; and where c) if Z is -O-Alk or -S-AIk, then X is -CHR⁵; and d) if X is a bond, then Z is C₂-salkenilene, -AIk-O- or - AIk-S-; n is 1 or, if X is -0-C0- or -O-CHR⁵-CO-NR⁶-, 0 or 1;

wherein :

Ni is -NH- or -N-; when Ni is -N-, it is bound to one group

- Xa-ONO₂;

R¹ is unsubstituted or substituted aryl, unsubstituted or substituted mono- or bicyclic heterocyclyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl-alkyl, unsubstituted or substituted mono- or bicyclic heterocyclyl-alkyl, unsubstituted or substituted cycloalkyl-alkyl, or acyl;

R² is unsubstituted or substituted alkyl, unsubstituted or substituted aryl, unsubstituted or substituted mono- or bicyclic heterocyclyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted aryl-alkyl, unsubstituted or substituted mono- or bicyclic heterocyclyl-alkyl or unsubstituted or substituted cycloalkyl-alkyl, with the proviso that if L is methylene (-CH₂-), oxy (-0-), thio (-S-) or unsubstituted (-NH-) or substituted imino, R² is selected from one of these mentioned groups and (as additional alternative) from hydrogen;

R⁴ is hydrogen -O- or -OH with the proviso that when R⁴ is -O- it is bound to one group -Xa-ONO₂; L is a bond, methylene (-CH₂-) , oxy (-0-) , thio (-S-) or unsubstituted (-NH-) or substituted imino, with the proviso that if L is a bond then R³ is one of the moieties mentioned for R³ other than substituted alkyl; or R³ and R⁴ which then is -0- together with L which then is methylene and the carbon to which R³-L- and R⁴ are bound form a substituted or unsubstituted ring annealed to an unsubstituted or substituted aryl, unsubstituted or substituted heterocyclyl or unsubstituted or substituted cycloalkyl, thus forming a spiro compound of the formula 1, or R³ and R⁴ together with L form oxo (=0), thioxo (=S) or unsubstituted or substituted imino (=NH) ;

T is methylene or methylene monosubstituted by alkyl, carbonyl (-C(=O)-) or thiocarbonyl (-C(=S)-;

wherein

Ni is -N- or -NH-; when Ni is -N-, it is bound to one group - Xa-ONO₂;

R is C₂-₈~alkenyl, Ci-₈-alkyl, C₂-₈~alkynyl, Co-₈~alkyl- carbonyl-amino-Ci-₈-alkyl, Cs-s-cycloalkyl-Co-salkyl, Ci-₈- alkyl-sulfonyl-Ci-₈-alkyl, optionally N-mono- or N,N-di-Ci-₈- alkylated carbamoyl-Co-₈-alkyl, optionally O-Ci-s-alkylated carboxyl-Co-βalkyl, optionally N and/or N' mono-, di- or tri-Ci-₈-alkylated ureido-Ci-s-alkyl or heterocyclylcarbonyl- Co-₈-alkyl, each of said radicals may be substituted, preferably by 1-4 Ci-salkoxy, Ci-salkoxy-Ci-salkoxy, Ci- ₈alkoxycarbonyl- (N-Ci-salkyl) -amino, Ci-₈-alkyl-sulfanyl, aryl-Co-βalkoxy, which is optionally substituted by 1 or 2 aryl or Ci-s-alkoxy radicals, aryl-amino, cyano, C₃-₈- cycloalkoxy, halogen, heterocyclyl- Co-salkyl, heterocyclyl- Co-βalkoxy, heterocyclyl-Co-salkyl-amino, heterocyclyl- carbonyl, hydroxyl, -O-, optionally N-mono- or N,N-di-Ci-s- alkylated amino, optionally N-mono- or N, N-di-Ci-s-alkylated carbamoyl-Co-8alkyl, optionally N-mono- or N,N-di-Ci-8^~ alkylated carbamoyloxy, optionally N-mono- or N,N-di-Ci-8^~ alkylated sulfamoyl, optionally N-arylated or N- heterocyclyl-substituted carbamoyl, oxo, trifluoromethoxy or trifluoromethyl , with the proviso that when R is -O-, it is bound to one group -Xa-ONO₂;

R¹ is aryl or heterocyclyl;

R² is acenaphthyl, cyclohexyl, diazinyl, furyl, imidazolyl naphtyl, oxadiazolyl, oxazolyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyrrolyl, oxopyridinyl, tetrazolyl thienyl or triazolyl, each of said radicals may be substituted by 1-3 Ci-salkanoyloxy-Ci-salkyl, C₂-salkenyloxy, Ci-salkoxy, Ci-salkoxy-Ci-salkoxy, Ci-salkoxy- Ci-salkoxy-Ci- galkyl, Ci-s-alkoxy-Ci-salkyl, Ci-8-alkoxycarbonyl, Ci- ₈alkoxycarbonyloxy-Ci-8alkyl, Ci-8-alkyl, carboxy-d-8-alkyl, Ci-salkoxy-Ci-salkylsulfanyl, Ci-8-alkylsulfanyl, Ci-8~ alkylsulfanyl-Ci-8-alkoxy, Ci-8-alkylsulfanyl-Ci-salkoxy-Ci-s- alkyl, Ci-salkylsulfanyl-Ci-8-alkyl, cyano, cyano-Ci-8-alkyl, C3-8cycloalkyl-Co-6-alkoxy-Ci_8-alkoxy, Ci_6alkoxy-Co-6alkyl-C3- scycloalkyl-Co-βalkoxy-Ci-salkyl, Cs-scycloalkyl-Co-βalkoxy- Ci- 8-alkyl, halo-Ci-8-alkyl, halogen, hydroxy-Ci-8-alkyl, hydroxyl, -O-, oxide, trifluoromethoxy or trifluoromethyl groups, or a Ci-s-alkylenedioxy group, and/or by an Ll-Tl- L2-T2-L3-T3-L4-T4-L5-U radical; Ll, L2, L3, L4 and L5 are each independently a bond, Ci-salkylene, C2-salkenylene or C2-8alkynylene, C3-scycloalkene or are absent, with the proviso that when R² is -O-, it is bound to one group -X_a~ ONO₂ ; Tl , T2, T3 and T4 are each independently

(a) a bond, or are absent, or are one of the groups (b) -CH(OH)-

(c) -CH(OR⁶)-

(d) -CH(NR⁵R⁶) - (e)-CO- (f) -CR⁷R⁸

(g) -O- or -NR⁶ (h) -S(O) 0-2- (i) -SO₂NR⁶ (J)-NR⁶SO₂-

(k) -CONR⁶

(1) -NR⁶CO-

(m) -0-C0-

(n) -CO-O- (o)-O-CO-O-

(p) -0-CO-NR⁶

(q) -N(R⁶) -CO-N(R⁶) -

(r) -N (R⁶) -CO-O-

(s) pyrrolidinylene, piperidinylene or piperazinylene (t) -C(R¹¹) (R¹²)-, where the bonds starting from (b) - (t) lead to a saturated or aromatic carbon atom of the adjacent group if the bond starts from a heteroatom, and where not more than two (b)-(f) groups, three (g) - (h) groups and one (i)-(t) group are present;

R³ is hydrogen, hydroxyl, Ci-salkoxy or C₂-salkenyloxy;

R⁴ is hydrogen, C₂-salkenyl, Ci-salkoxy, Ci-salkoxy-Ci-salkyl, Ci-salkoxy-Ci-salkoxy, Ci-salkyl, optionally (N-Ci-salkyl) -Ci-8- alkoxycarbonyl-amino-Ci-salkoxy, optionally (N-Ci-8-alkyl) -

Ci-salkylcarbonyl-amino-Ci-s-alkoxy, optionally (N-mono- or N, N-di-Ci-8-alkyl) -amino-Ci-salkoxy, benzyl, C3- scycloalkyloxy, Cs-scycloalkyloxy-Ci-salkoxy, heterocyclyl-Co- ₈alkoxy, heterocyclyloxy-Ci-salkoxy, hydroxy, -0-, with the proviso that when R² is -0-, it is bound to one group -X_a~ ONO₂; hydroxy-Ci-salkoxy-Ci-salkoxy, hydroxy-Ci-salkyl, oxo or a R^4a-Zl-Xl- group where R^4a is

(a) H-

(b) Ci-₈alkyl- (c) C₂-salkenyl-

(d) hydroxy-Ci-salkyl-

(e) polyhydroxy-Ci-salkyl-

(f) Ci-βalkyl-O-Ci-βalkyl-

(g) aryl- (h) heterocyclyl-

(i) arylalkyl-

(j) heterocyclylalkyl-

(k) aryloxyalkyl-

(1) heterocyclyloxyalkyl- (m) (R⁵, R⁶)N- (CH₂) 1-3-

(n) (R⁵,R⁶)N-

(o) Ci-₈alkyl-S (O) 0-2-

(p) aryl-S (O) 0-2-

(q) heterocyclyl-S (O) o-2^~ (r) HO-SO₃- or salts thereof

(s) H₂N-C(NH)-NH-

Zl

(a) is a bond, is absent, or is one of the groups

(b) -Ci-salkylene-

(c) -C₂-salkenylene- (d) -O-, -N (R¹¹) -,-S(O) 0-2-

(e)-CO- f) -O-CO- (g) -O-CO-O- (h) -0-CO-N(R¹¹) - (i) -N(R¹¹) -CO-O- (j) -CO-N(R¹¹)- (k) -N(R¹¹J-CO- (I)-N(R¹¹J-CO-N(R¹¹)-

(m) -CH(OR⁹)- and the bonds starting from (d) and (f)-(m) lead to a carbon atom of the adjacent group and this carbon atom is saturated if the bond starts from a heteroatom; Xl

(a) is a bond, is absent, or is one of the groups

(b) -0- (c)-N(R¹¹)- (d)-S (0)o-2- (e) - (CH₂)i-3-; or R³ and R⁴ in formula (Ic) together are a bond;

R⁵ and R⁶ are each independently hydrogen, Ci-salkyl, C₂- galkenyl, aryl-Ci-salkyl or acyl, or, together with the nitrogen atom to which they are bonded, are a 5- or 6- membered heterocyclic ring which may contain an additional nitrogen, oxygen or sulphur atom or a -SO- or -SO2- group, and the additional nitrogen atom may optionally be substituted by Ci-salkyl radicals;

R⁹ is hydrogen, Ci-salkyl, Ci-salkoxy-Ci-salkyl, acyl or arylalkyl ; R¹⁰ is carboxyalkyl, alkoxycarbonylalkyl, alkyl or hydrogen;

R¹¹ is hydrogen or Ci-salkyl;

R¹² is hydrogen or Ci-salkyl;

Q is ethylene or is absent (formula Ic) or is ethylene or methylene (formula Id) ;

U is hydrogen, Ci-salkyl, cyano, optionally substituted C3-8-cycloalkyl, aryl, or heterocyclyl;

W is oxygen or sulphur;

X is a bond, oxygen or sulphur, or is a XCH-R¹¹, >CHOR⁹, -O-CO-, >CO, >C=NOR¹⁰, -O-CHR¹¹- or -O-CHR^-CO-NR⁹- group and the bond starting from an oxygen or sulphur atom leads to a saturated carbon atom of the Z group or to R¹ ;

Z is Ci-salkylene, CVsalkenylene, hydroxy-Ci-salkylidene,

-O-, -S-, -O-alk-, -S-alk-, -alk-O-, -alk-S- or -alk-

NR⁹-, where alk is Ci-salkylene; and where (a) if Z is -O- or -S-, X is XCH-R¹¹ and either R² contains an L1-T1-L2-T2-L3-T3-L4-T4-L5-U substituent or

R⁴ is a substituent other than hydrogen as defined above;

(b) if Z is -O-alk- or -S-alk-, X is XCH-R¹¹ ; and (c) if X is a bond, Z is CVsalkenylene, -alk-O- or -alk-

S-; n is 0 or 1, m is 0 or 1;

wherein

Ni is -N- or -NH-; when Ni is -N-, it is bound to one group

- Xa-ONO₂;

R¹ can be

(G) R¹ is aryl when R² is tetrazolyl or imidazolyl each of which may be substituted by Ci-salkoxy-Ci-salkoxy-Ci- galkyl, Ci-salkoxy-Ci-salkyl, aryloxy-Ci-salkyl, heterocyclyloxy-Ci-salkyl, or

(H) R¹ is aryl when X is -0-CH-R^5-CO-NR⁶; or

(I) R¹ is aryl when Z is -alk-NR⁶ where alk is Ci-salkylene, and n is 1 ; or

(J) R¹ is aryl which is substituted by 1-4-acetamidinyl-Ci- galkyl, acyl-Ci-salkoxy-Ci-salkyl, (N-acyl) -Ci-salkoxy-Ci- 8alkylamino, Ci-salkoxy, Ci-salkoxy-Ci-salkoxy, Ci- salkoxy-Ci-salkoxy-Ci-salkyl, Ci-salkoxy-Ci-salkyl, (N-Ci- 8alkoxy) -Ci-salkylaminocarbonyl-Ci-salkoxy, (N-Ci-

Ci-₈alkoxy-Ci-₈alkylimidazol-2-yl, 2-

Ci-₈alkoxy-Ci-₈alkyl-4-oxoimidazol-l-yl, 1-Ci-salkoxy-Ci- galkyltetrazol-5-yl, Ci-salkyl, (N-Ci-salkyl) -Ci-salkoxy- Ci-salkylcarbamoyl, (N-Ci-salkyl) -Ci-salkoxy-Ci-

₈alkylcarbonylamino, (N-Ci-salkyl) -Ci-salkoxy- carbonylamino, (N-Ci-salkyl) -C_o-βalkylcarbonylamino-Ci- 8alkoxy, (N-Ci-salkyl) -C_o-βalkylcarbonylamino-Ci-salkyl, (N-Ci-salkyl) -Ci-salkyl sulphonylamino-Ci-salkoxy, (N-Ci- galkyl) -Ci-salkylsulphonyl-amino-Ci-salkyl, Ci- galkylamidinyl, Ci-salkylaminocarbonyl-Ci-salkoxy, di-Ci- 8alkylaminocarbonyl-Ci-₈alkoxy, Ci-salkylaminocarbonyl- Ci-salkoxy-Ci-salkyl, Ci-salkylaminocarbonyl-Ci-salkyl,

Ci-salkylaminocarbonylamino-Ci-salkoxy, Ci- salkylaminocarbonylamino-Ci-salkyl, di-Ci-

₈alkylaminocarbonyl-Ci-₈alkyl, Ci_₈alkylamino-C₂-₈alkoxy, di-Ci-₈alkylamino-C₂-₈alkoxy, Ci-salkylamino-Ci-salkyl, di-Ci-salkylamino-Ci-salkyl, Ci-salkylcarbamoyl, di-Ci- galkylcarbamoyl, Co-salkylcarbonylamino-Ci-salkoxy, C₀- 6alkylcarbonylamino, C_o-βalkylcarbonylamino-Ci-salkyl,

Ci-salkylcarbonyloxy-Ci-salkoxy, Ci-salkylcarbonyloxy-Ci- galkyl, Ci-salkylsulphonyl, Ci-salkylsulphonyl-Ci-

₈alkoxy, Ci-salkylsulphonyl-Ci-salkyl, Ci- salkylsulphonylamino-Ci_₈alkoxy, Ci-salkylsulphonylamino -Ci-salkyl, carbamoyl, carbamoyl-Ci-salkoxy, carbamoyl-

Ci-salkyl, carboxy-Ci-salkoxy, carboxy-Ci-salkoxy-Ci- galkyl, carboxy-Ci-salkyl, cyano, cyano-Ci-salkoxy, cyano-Ci-salkyl, C₃-₈cycloalkylcarbonylamino-Ci-salkoxy, C₃-₈ cycloalkylcarbonylamino-Ci-salkyl, cyclopropyl-Ci- galkyl, O, N-dimethylhydroxylamino-Ci-salkyl, halogen, hydroxy-C₂-₈alkoxy-Ci-salkoxy, hydroxy-C₂-salkoxy-Ci- galkyl, hydroxy-Ci-salkyl, (N-hydroxy) -Ci-

₈alkylaminocarbonyl-Ci-₈alkoxy, (N-hydroxy) -Ci-

₈alkylaminocarbonyl-Ci-₈alkyl, (N- hydroxy) aminocarbonyl-Ci-₈alkoxy, (N- hydroxy) aminocarbonyl-Ci-salkyl, 2-oxooxazolidinyl-Ci- galkoxy, 2-oxooxazolidinyl-Ci-salkyl, O-methyloximyl-Ci-

₈alkyl or trifluoromethyl; or

(K) R¹ is aryl which is substituted by 1-4 3- acetamidomethylpyrrolidinyl 3-Ci-₈alkoxy-Ci-salkyl- pyrrolidinyl, 3, 4-dihydroxypyrrolidinyl, 2,6-dimethyl morpholinyl, 3, 5-dimethylmorpholinyl, dioxanyl, dioxolanyl, 4, 4-dioxothiomorpholinyl, dithianyl, dithiolanyl, 2-hydroxymethylpyrrolidinyl, 4- hydroxypiperidinyl, 3-hydroxypyrrolidinyl, imidazolylalkoxy, imidazolylalkyl, 2- methylimidazolylalkoxy, 2-methylimidazolylalkyl, 3- methyl- [1, 2, 4] -oxadiazol-5-ylalkoxy, 5-methyl- [ 1, 2, 4 ]- oxadiazol-3-ylalkoxy, 3-methyl- [1,2,4] -oxadiazol-5- ylalkyl, 5-methyl- [ 1, 2, 4 ] oxadiazol-3-ylalkyl, 4- methylpiperazinyl, 5-methyltetrazol-l-ylalkoxy, 5- methyltetrazol-1-ylalkyl, morpholinyl, [1,2,4]- oxadiazol-5-ylalkoxy, [ 1, 2, 4 ] -oxadiazol-5-ylalkyl, oxazol-4-ylalkoxy, oxazol-4-ylalkyl, 2-oxo- [ 1, 3] oxazinyl, 2-oxooxazolidinyl, 2-oxoimidazolidinyl, 2-oxopyrrolidinyl, 4-oxopiperidinyl, 2- oxopyrrolidinylalkoxy, 2-oxopyrrolidinylalkyl, 2- oxotetrahydro-pyrimidinyl 4-oxothiomorpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, pyrrolyl,

[1,2,4] triazol-1-ylalkoxy, [1,2,4] triazol-4-ylalkoxy,

[1,2,4] triazol-1-ylalkyl, [1,2,4] triazol-4-ylalkyl, tetrazol-1-ylalkoxy, tetrazol-2-ylalkoxy, tetrazol-5- ylalkoxy, tetrazol-1-ylalkyl, tetrazol-2-ylalkyl, tetrazol-5-ylalkyl, thiazol-4-ylalkoxy, thiazo-4- ylalkyl, thiomorpholinyl; or

(L) R¹ is heterocyclyl, optionally substituted, in particular as specified under (D) or (E) , in particular benzo [ 1, 3] dioxoyl, benzofuranyl, benzoxazolyl, dihydrobenzofuranyl, 3, 4-dihydro-2H- benzo [1,4] oxazinyl, dihydro-3H-benzo [1,4] oxazinyl, dihydro-2H-benzo [1,4] thiazinyl, 2, 3-dihydroindolyl, dihydro-lH-pyrido [2, 3-b] [ 1, 4 ] oxazinyl, 1,1- dioxodihydro-2H-benzo [ 1, 4 ] thiazinyl, indazolyl, indolyl, [ 1, 5] naphthpyridyl, oxazolyl, 2-oxoazepanyl, 3-oxo-4H-benzo [ 1, 4 ] oxazinyl, 2-oxobenzoxazolyl, 3-oxo- 4H-benzo [1, 4] thiazinyl, 2- oxodihydrobenzo [e] [ 1, 4 ] diazepinyl, 2- oxodihydrobenzo [d] [ 1, 3] oxazinyl, 2-oxodihydro-lH- quinazolinyl, 4-oxodihydroimidazolyl, 2-oxo-l,3- dihydroindolyl, l-oxo-3H-isobenzofuranyl, 2- oxopiperidinyl, 2-oxo-lH-pyrido [2, 3-b] [1, 4] oxazinyl,

1-oxopyridyl, 2-oxotetrahydrobenzo [e] [ 1, 4 ] diazepinyl,

4-oxo-3H-thieno [2, 3-d] pyrimidinyl, 5-oxo-4H-

[ 1 , 2 , 4 ] triazinyl, phthalazinyl, pyrazolyl, IH- pyrrolizinyl, lH-pyrrolo [2, 3-b] pyridyl, pyrrolyl, tetrahydroquinoxalinyl, tetrahydropyranyl, triazinyl, or 1, 1, 3-trioxodihydro-2H-lλ⁶benzo [1,4] thiazinyl;

R² is phenyl, naphthyl, acenaphthyl, cyclohexyl, pyridyl, pyrimidinyl, pyrazinyl, oxopyridinyl, diazinyl, triazolyl, thienyl, oxazolyl, oxadiazolyl, thiazolyl, pyrrolyl, furyl, tetrazolyl or imidazolyl, where the radicals are substituted by 1-3 C2-8alkenyloxy-Ci_8alkyl, Ci-salkoxy-Ci- galkyl, Ci-s-alkoxy-Ci-salkylamino-Ci-s-alkyl, Ci-salkoxy-Ci-s alkylsulphanyl-Ci-salkyl, Ci-salkoxy-Co-salkyl-Cs-scycloalkyl- CO-δalkoxy-Ci-salkyl, Ci-salkyl, Ci-salkylsulphanyl-Ci-salkoxy- Ci-salkyl, Ci-salkylsulphanyl- Ci-salkyl, Ci-salkylsulphonyl- Ci-slkoxy-Ci-salkyl, C₃_₈cycloalkyl-Co-salkoxy-Ci-salkoxy-Ci- galkyl, Cs-scycloalkyl-Co-salkoxy- Ci-salkyl, optionally halogen-substituted Ci-salkoxy-Ci-salkoxy-Ci-salkyl, or (oxygen-heterocyclyl) -Co-₈alkoxy-Ci_₈alkyl, and may, in addition to the aforementioned substituents, also be substituted by a maximum of 4 halogen;

R⁴ is optionally halogen and/or hydroxyl-substituted Ci- ₈alkyl optionally halogen and/or hydroxyl-substituted Ci- galkoxy-Ci-8alkyl, optionally N-mono- or N,N-di-Ci~

Csalkylated amino-Ci-salkyl, N-mono- or N, N-di-Ci-salkylated optionally or is optionally hydroxy-substituted amino-Co- salkylcarbonyl-Ci-salkyl, hydroxy-Co-salkylcarbonyl- Co- galkyl, Ci-salkoxy-Co-salkylcarbonyl- Co-salkyl, optionally N- d-8-alkylated d-salkoxycarbonylamino-d-salkyl, optionally N-Ci-8-alkylated-Ci-8-salkoxy-Ci-8-alkylamino-Ci-8alkyl, optionally N-Ci-s-alkylated or optionally halogen- substituted Ci-salkylcarbonylamino-Ci-salkyl, cyano- Ci- ₈alkyl, optionally N-Ci-salkylated or optionally halogen- substituted C₃-₈-cycloalkyl-C_o-₈alkylcarbonylamino-Ci-salkyl, optionally N-Ci-s-alkylated hydroxy-Ci-salkylamino- Ci-salkyl, heterocyclylcarbonyl- Co-salkylamino-Ci-salkyl, Ci- ₈alkoxycarbonylamino- Ci-salkyl, optionally N-Ci-s-alkylated or optionally halogen-substituted heterocyclyl-Co-

₈alkylcarbonylannino-Ci-₈alkyl, C₃_₈cycloalkyl- Co-salkyl, C₃- scycloalkyloxy-Ci-salkyl, heterocyclyl-Co-s- (optionally hydroxy-substituted) alkyl, optionally N-Ci-salkylated heterocyclyl-Co-salkylamino-Co-salkylcarbonyl-Co-salkyl, Ci-

₈alkylsulphonyl-Ci-8alkyl, C₂-salkinyl, heterocyclyl-C₂- galkinyl, optionally N-mono- or N, N-di-Ci-s-alkylated amino- C₂-8alkinyl, N-mono- or N, N-di-Ci-s-alkylated aminocarbonyl- C₂-₈alkinyl, heterocyclylcarbonyl-Co-salkyl or heterocyclyloxy-Ci-salkyl; and where

(a) if Y is -O- and R²> is not para-Ci-salkyl- substituted phenyl, then R⁴ may additionally also be hydrogen, and (b) if Y is oxo, then R⁴ is absent;

R⁵ is acyl, C₂-salkenyl, Ci-salkyl, aryl-Ci-salkyl or hydrogen; R is acyl, CVsalkenyl, Ci-salkyl, aryl-Ci-salkyl or hydrogen;

R⁷ is Ci-salkoxycarbonyl-Ci-salkyl, Ci-salkyl, carboxy-Ci- ₈alkyl or hydrogen;

X is a bond, oxygen or sulphur, where the bond originating from an oxygen or sulphur atom leads to a saturated C atom of group Z or is a group >CHR⁵, >CHOR⁶, -O-CO-, >CO, >C=NOR⁷, -O-CHR⁵-, -O-CHR⁵-CO-NR⁶;

Y is -O-, oxo or a bond;

Z is Ci-salkylene, CVsalkenylene, hydroxy-Ci-salkylidene, -0- , -S-, -0-AIk-, -S-AIk-, -AIk-O-, -AIk-S- or -AIk-NR⁶-, where AIk denotes Ci-salkylene; and where c) if Z is -O-Alk or -S-AIk, then X is -CHR⁵; and d) if X is a bond, then Z is CVsalkenylene, -AIk-O- or - AIk-S-; n is 1 or, if X is -0-C0- or -O-CHR⁵-CO-NR⁶-, is 0 or 1;

wherein

Ni is -N- or -NH-; when Ni is -N-, it is bound to one group

- Xa-ONO₂; R¹ can be

(G) R¹ is aryl when X is -0-CH-R^5-CO-NR⁶; or (H) R¹ is aryl when Z is -alk-NR⁶ where alk is Ci-salkylene, and n is 1 ; or (I) R¹ is aryl which is substituted by 1-4-acetamidinyl-Ci- galkyl, acyl-Ci-galkoxy-Ci-galkyl, (N-acyl) -Ci-galkoxy-Ci- 8alkylamino, Ci-salkoxy, Ci-salkoxy-Ci-salkoxy, Ci- salkoxy-Ci-salkoxy-Ci-salkyl, Ci-galkoxy-Ci-galkyl, (N-Ci- 8alkoxy) -Ci-salkylaminocarbonyl-Ci-salkoxy, (N-Ci- salkoxy) -Ci-salkylaminocarbonyl-Ci-salkyl, Ci-salkoxy-Ci- galkylcarbamoyl, Ci-galkoxy-Ci-galkylcarbonyl, Ci- galkoxy-Ci-₈alkylcarbonylamino, 1-

Ci-₈alkoxy-Ci-₈alkylimidazol-2-yl, 2-

Ci-8alkoxy-Ci-8alkyl-4-oxoimidazol-l-yl, 1-Ci-salkoxy-Ci- galkyltetrazol-5-yl, Ci-salkyl, (N-Ci-salkyl) -Ci-salkoxy-

Ci-salkylcarbamoyl, (N-Ci-salkyl) -Ci-salkoxy-Ci-

₈alkylcarbonylamino, (N-Ci-salkyl) -Ci-salkoxy- carbonylamino, (N-Ci-salkyl) -C_o-βalkylcarbonylamino-Ci- 8alkoxy, (N-Ci-salkyl) -C_o-βalkylcarbonylamino-Ci-salkyl, (N-Ci-salkyl) -Ci-salkyl sulphonylamino-Ci-salkoxy, (N-Ci- galkyl) -Ci-galkylsulphonyl-amino-Ci-galkyl, Ci- galkylamidinyl, Ci-salkylaminocarbonyl-Ci-salkoxy, di-Ci- 8alkylaminocarbonyl-Ci-₈alkoxy, Ci-salkylaminocarbonyl- Ci-galkoxy-Ci-galkyl, Ci-galkylaminocarbonyl-Ci-galkyl, Ci-salkylaminocarbonylamino-Ci-salkoxy, Ci- galkylaminocarbonylamino-Ci-galkyl, di-Ci- galkylaminocarbonyl-Ci-galkyl, Ci_₈alkylamino-C₂-₈alkoxy, di-Ci-₈alkylamino-C₂-₈alkoxy, Ci-galkylamino-Ci-galkyl, di-Ci-galkylamino-Ci-galkyl, Ci-galkylcarbamoyl, di-Ci- galkylcarbamoyl, Co-salkylcarbonylamino-Ci-salkoxy, C₀-

₆alkylcarbonylamino, C_o-βalkylcarbonylamino-Ci-galkyl, Ci-salkylcarbonyloxy-Ci-salkoxy, Ci-galkylcarbonyloxy-Ci- galkyl, Ci-galkylsulphonyl, Ci-salkylsulphonyl-Ci- ₈alkoxy, Ci-galkylsulphonyl-Ci-galkyl, Ci- salkyl sulphonyl amino -Ci_₈alkoxy, Ci-s a lkyl sulphonyl ami no -Ci-salkyl, carbamoyl, carbamoyl-Ci-salkoxy, carbamoyl- Ci-salkyl, carboxy-Ci-salkoxy, carboxy-Ci-salkoxy-Ci- galkyl, carboxy-Ci-galkyl, cyano, cyano-Ci-salkoxy, cyano-Ci-salkyl, C₃-₈cycloalkylcarbonyl amino -Ci-salkoxy, C₃-₈ cycloalkylcarbonylamino-Ci-salkyl, cyclopropyl-Ci- 8alkyl, 0,N-dimethylhydroxylamino-Ci-salkyl, halogen, hydroxy-C₂-₈alkoxy-Ci-salkoxy, hydroxy-C₂-salkoxy-Ci- galkyl, hydroxy-Ci-galkyl, (N-hydroxy) -Ci-

₈alkylaminocarbonyl-Ci-₈alkoxy, (N-hydroxy) -Ci- galkylaminocarbonyl-Ci-galkyl, (N- hydroxy) aminocarbonyl-Ci-salkoxy, (N- hydroxy) aminocarbonyl-Ci-galkyl, 2-oxooxazolidinyl-Ci- salkoxy, 2-oxooxazolidinyl-Ci-galkyl, O-methyloximyl-Ci- βalkyl or trifluoromethyl; or

(J) R¹ is aryl which is substituted by 1-4 3- acetamidomethylpyrrolidinyl 3-Ci-₈alkoxy-Ci-salkyl- pyrrolidinyl, 3, 4-dihydroxypyrrolidinyl, 2,6-dimethyl morpholinyl, 3, 5-dimethylmorpholinyl, dioxanyl, dioxolanyl, 4, 4-dioxothiomorpholinyl, dithianyl, dithiolanyl, 2-hydroxymethylpyrrolidinyl, 4- hydroxypiperidinyl, 3-hydroxypyrrolidinyl, imidazolylalkoxy, imidazolylalkyl, 2- methylimidazolylalkoxy, 2-methylimidazolylalkyl, 3- methyl- [1,2,4] -oxadiazol-5-ylalkoxy, 5-methyl- [1,2,4]- oxadiazol-3-ylalkoxy, 3-methyl- [1,2,4] -oxadiazol-5- ylalkyl, 5-methyl- [ 1, 2, 4 ] oxadiazol-3-ylalkyl, 4- methylpiperazinyl, 5-methyltetrazol-l-ylalkoxy, 5- methyltetrazol-1-ylalkyl, morpholinyl, [1,2,4]- oxadiazol-5-ylalkoxy, [1,2,4] -oxadiazol-5-ylalkyl, oxazol-4-ylalkoxy, oxazol-4-ylalkyl, 2-oxo- [ 1 , 3 ] oxazinyl, 2-oxooxazolidinyl, 2-oxoimidazolidinyl, 2-oxopyrrolidinyl, 4-oxopiperidinyl, 2- oxopyrrolidinylalkoxy, 2-oxopyrrolidinylalkyl, 2- oxotetrahydro-pyrimidinyl 4-oxothiomorpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, pyrrolyl, [1,2, 4] triazol-1-ylalkoxy, [1, 2, 4] triazol-4-ylalkoxy,

(K) R¹ is heterocyclyl, optionally substituted, in particular as specified under (D) or (E) , in particular benzo [ 1, 3] dioxoyl, benzofuranyl, benzoxazolyl, dihydrobenzofuranyl, 3, 4-dihydro-2H- benzo [ 1, 4 ] oxazinyl, dihydro-3H-benzo [1, 4] oxazinyl, dihydro-2H-benzo [1,4] thiazinyl, 2, 3-dihydroindolyl, dihydro-lH-pyrido [2, 3-b] [ 1, 4 ] oxazinyl, 1,1- dioxodihydro-2H-benzo [1,4] thiazinyl, indazolyl, indolyl, [ 1, 5] naphthpyridyl, oxazolyl, 2-oxoazepanyl, 3-oxo-4H-benzo [ 1, 4 ] oxazinyl, 2-oxobenzoxazolyl, 3-oxo- 4H-benzo [1, 4] thiazinyl, 2- oxodihydrobenzo [e] [ 1, 4 ] diazepinyl, 2- oxodihydrobenzo [d] [ 1, 3] oxazinyl, 2-oxodihydro-lH- quinazolinyl, 4-oxodihydroimidazolyl, 2-oxo-l,3- dihydroindolyl, l-oxo-3H-isobenzofuranyl, 2- oxopiperidinyl, 2-oxo-lH-pyrido [2, 3-b] [ 1, 4 ] oxazinyl, 1-oxopyridyl, 2-oxotetrahydrobenzo [e] [ 1, 4 ] diazepinyl, 4-oxo-3H-thieno [2, 3-d] pyrimidinyl, 5-oxo-4H-

[ 1, 2, 4 ] triazinyl, phthalazinyl, pyrazolyl, IH- pyrrolizinyl, lH-pyrrolo [2, 3-b] pyridyl, pyrrolyl, tetrahydroquinoxalinyl, tetrahydropyranyl, triazinyl, or 1, 1, 3-trioxodihydro-2H-lλ⁶benzo [1,4] thiazinyl; R^2' is C₂-₈alkenyloxy-Ci-₈alkyl, Ci-salkoxy-Ci-salkyl, Ci_s- alkoxy-Ci-salkylamino-Ci-₈-alky1, Ci-salkoxy-Ci-s alkylsulphanyl-Ci-salkyl, Ci-salkoxy-Co-salkyl-C₃-scycloalkyl-

C0-8alkoxy-Ci-₈alkyl, Ci-salkyl, Ci-salkylsulphanyl-Ci-salkoxy- Ci-salkyl, Ci-salkylsulphanyl- Ci-salkyl, Ci-salkylsulphonyl-

Ci-slkoxy-Ci-salkyl, C₃-scycloalkyl-Co-salkoxy-Ci-salkoxy-Ci- galkyl, Cs-scycloalkyl-Co-salkoxy- Ci-salkyl, optionally halogen-substituted Ci-salkoxy-Ci-salkoxy-Ci-salkyl, or

(oxygen-heterocyclyl) -Co-salkoxy-Ci-salkyl;

R^2" is halogen;

R^4' is a) optionally halogen and/or hydroxy-substituted Ci- ₈alkyl optionally halogen and/or hydroxy-substituted Ci- salkoxy-Ci-salkoxy, optionally N-mono- or N,N-di-Ci- Csalkylated amino-Ci-salkoxy, optionally N-Ci-salkylated Ci- salkoxy-Ci-salkylamino-Ci-salkoxy, optionally N-mono- or N,N- di-Ci-salkylated amino-Co-salkylcarbonyl-Ci-salkoxy, hydroxyl- Co-salkylcarbonyl-Co-salkoxy, Ci-salkoxy-Co-salkylcarbonyl-Co- salkoxy, Ci-Csalkylcarbonylamino-Ci-salkoxy, cyano-Ci-salkoxy, C₃_₈cycloalkylCo-₈alkoxy, heterocyclyl-Co-salkoxy, optionally N-Ci-₈alkylated heterocyclyl-Co-salkylamino-Co-salkylcarbonyl- Co-βalkoxy, Ci-salkylsulphonyl-Ci-salkoxy, C₂-salkinyloxy, heterocyclyl-C₂-₈alkinyloxy optionally N-mono- or N,N-di-Ci^~ Csalkylated amino-C₂-salkinyloxy, N-mono- or N,N-di-Ci^~ Csalkylated aminocarbonyl-C₂-salkinyl-oxy, heterocyclylcarbonyl-Co-salkoxy, optionally N-mono- or N,N- di-Ci-salkylated amino-Ci-salkyl, optionally N-Ci-salkylated- Ci-salkoxy-Ci-salkylamino-Ci-salkyl, optionally N-mono- or N, N-di-Ci-salkylated and optionally hydroxyl-substituted aminoCo-salkylcarbonyl-Co-βalky, optionally N-Ci-salkylated heterocyclyl-Co-salkylamino-Co-salkylcarbonyl-Co-salkyl, optionally halogen- or hydroxyl-substituted Ci-salkoxy-Ci- galkyl, optionally halogen- and/or hydroxy- substituted Ci- galkyl, optionally N-Ci-salkylatedhydroxy-Ci-salkylamino-Ci- galkyl, heterocyclylcarbonyl-Co-galkyl, heterocyclylcarbonyl-Co-galkylamino-Ci-galkyl, heterocyclyl- Ci-galkyl, Ci-galkoxycarbonylamino-Ci-galkyl, optionally halogen-substituted hetrocyclyl-Co-salkylcarbonylamino-Ci- galkyl, optionally halogen-substituted C3_8cycloalkyl-Co- ₈alkylcarbonylamino-Ci-₈alkyl or optionally halogen- substituted Ci-galkylcarbonylamino-Ci-galkyl; or additionally (b) is hydroxy, -O- with the proviso that when R⁴ is -O- it bounds the group -X_a-ONθ2, if R²' is not Ci-galkyl;

R⁵ is acyl, C2-galkenyl, Ci-galkyl, aryl-Ci-salkyl or hydrogen;

R⁶ is acyl, Ci-galkoxy-Ci-galkyl, Ci-galkyl or aryl-Ci-salkyl or hydrogen;

R⁷ is Ci-galkoxycarbonyl-Ci-galkyl, Ci-galkyl, carboxy-Ci- salkyl or hydrogen;

X is a bond, oxygen or sulphur, where the bond originating from an oxygen or sulphur atom leads to a saturated C atom of the group Z or is a group >CHR⁵, >CHOR⁶, -O-CO-, >CO, >C=NOR⁷, -O-CHR⁵-, or -O-CHR⁵-CO-NR⁶;

Z is Ci-salkylene, C2-salkenylene, hydroxy-Ci-salkylidene, -O- , -S-, -0-AIk-, -S-AIk-, -AIk-O-, -AIk-S- or -AIk-NR⁶-, where AIk denotes Ci-salkylene; and where a) if Z is -O-Alk or -S-AIk, then X is -CHR⁵; and b) if X is a bond, then Z is C2-salkenylene, -AIk-O- or -

AIk-S-; m is 0 , 1 , 2 ; n is 1 or, if X is -0-C0- or -O-CHR⁵-CO-NR⁶-, is 0 or 1 ; and the salts thereof, preferably the pharmaceutically acceptable salts thereof; X_a is equal to -X_b-Y_a- wherein X_b is -CO- or -COO-; Y_a is a bivalent radical having the following meaning: a)

-OC(O) (Ci-Cio alkyl)-ONO₂ or -0(Ci-Ci₀ alkyl)-ONO₂;

wherein n is an integer from 0 to 20, and n is an integer from 1 to 20; d)

wherein : n¹ is as defined above and n² is an integer from 0 to 2; X_c = -OCO- or -COO- and R₂ is H or CH₃;

wherein : n¹, n²,R₂ and X_c are as defined above; Y_b is -CH₂-CH₂- or -CH=CH- (CH₂) _n ²-;

wherein: n¹ and R₂ are as defined above, R3 is H or -COCH₃; with the proviso that when Y_a is selected from the bivalent radicals mentioned under b) -f) , the -ONO₂ group is linked to a - (CH₂J_n ¹ group; g)

wherein : n⁴ is an integer from 0 to 10; n⁵ is an integer from 1 to 10;

R₄, R₅, Rε, R7 are the same or different, and are H or straight or branched Ci-C₄ alkyl, preferably R₄, R₅, Re, R7 are H; wherein the -ONO2 group is linked to

wherein n⁵ is as defined above;

2. A compound of general formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof according to claim 1, wherein Y_a is a bivalent radical having the following meaning: a ) straight or branched Ci-Cio alkylene being optionally substituted with one or more of the substituents selected from the group consisting of: halogen atoms, hydroxy, -ONO2 or T_a, wherein T_a is -OC(O) (Ci-Cio alkyl)-ONO₂ or -0(Ci-Ci₀ alkyl) -ONO₂; b)

wherein n⁰ is 0 or 1, n¹ is 1 ; with the proviso that the -ONO₂ group is linked to - (CH₂J_n ¹ group ; g)

wherein XH i s -0- or -S - , n³ i s 1 and R₂ i s H .

3. A compound according to claims 1-2, selected from the group consisting of compounds of formula from (1) to (143) .

4. A compound of general formula (I) according to claims 1- 3 for use as a medicament.

5. Use of a compound according to claims 1-3 for preparing a drug having anti-inflammatory, antithrombotic and antiplatelet activity.

6. Use of a compound according to claims 1-3, for preparing a drug that can be employed in the treatment or prophylaxis of cardiovascular, renal and chronic liver diseases, inflammatory processes and metabolic syndrome.

7. Use of a compound according to claims 1-3, for preparing a drug that can be employed in the treatment or prophylaxis of congestive heart failure, coronary diseases, left ventricular dysfunction and hypertrophy, cardiac fibrosis, myocardial ischemia, stroke, atherosclerosis, restenosis post angioplasty, renal ischemia, renal failure, renal fibrosis, glomerulonephritis, renal colic, ocular and pulmonary hypertension, glaucoma, systemic hypertension, diabetic complications such as nephropathy, vasculopathy and neuropathy, peripheral vascular diseases, liver fibrosis, portal hypertension, metabolic syndrome, erectile dysfunction, complications after vascular or cardiac surgery, complications of treatment with immunosuppressive agents after organ transplantation, hyperaldosteronism, lung fibrosis, scleroderma, anxiety, cognitive disorders.

8. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of general formula (I) or a salt or stereoisomer thereof according to claims 1-3.

9. A pharmaceutical composition according to claim 8 in a suitable form for the oral, parenteral, rectal, topic and transdermic administration, by inhalation spray or aerosol or iontophoresis devices.

10. Liquid or solid pharmaceutical composition for oral, parenteral, rectal, topic and transdermic administration or inhalation in the form of tablets, capsules and pills eventually with enteric coating, powders, granules, gels, emulsions, solutions, suspensions, syrups, elixir, injectable forms, suppositories, in transdermal patches or liposomes, containing a compound of formula (I) or a salt or stereoisomer thereof according to claims 1-3 and a pharmaceutically acceptable carrier.

11. A pharmaceutical composition comprising a compound of general formula (I) according to claims 1-3, at least a compound used to treat cardiovascular disease and a pharmaceutically acceptable carrier.

12. Pharmaceutical composition according to claim 11 wherein the compound used to treat cardiovascular disease is selected from the group consisting of: aldosterone antagonists, angiotensin II receptor blockers, ACE inhibitors, HMGCoA reductase inhibitors, beta-adrenergic blockers, alpha-adrenergic antagonists, sympatholytics, calcium channel blockers, endothelin antagonists, neutral endopeptidase inhibitors, potassium activators, diuretics, vasodilators, antithrombotics such as aspirin or nitrosated compounds thereof.

13. A pharmaceutical kit comprising a compound of general formula (I) as defined in claim 1, a compound used to treat cardiovascular disease as combined preparation for simultaneous, separated or sequential use for the treatment of cardiovascular disease.

14. A pharmaceutical kit according to claim 13 wherein the compound used to treat cardiovascular disease is selected from the group consisting of: aldosterone antagonists, angiotensin II receptor blockers, ACE inhibitors, HMGCoA reductase inhibitors, beta-adrenergic blockers, alpha- adrenergic antagonists, sympatholytics, calcium channel blockers, endothelin antagonists, neutral endopeptidase inhibitors, potassium activators, diuretics, vasodilators, antithrombotics such as aspirin or nitrosated compounds thereof .