NITRIC OXIDE RELEASING STEROIDS

The present invention relates to use of nitric oxide releasing steroidal compounds having an improved pharmacological activity and low side effects in the treatment of respiratory diseases, and to a process for their preparation. The present invention also relates to nitric oxide releasing steroidal compounds and to pharmaceutical formulations containing them. Respiratory diseases comprise asthma, COPD (chronic obstructive pulmonary diseases) , ARDS (Acute Respiratory Distress Syndrome) , allergic rhinitis, respiratory tract diseases associated with inflammation.

At present, the most drugs used in the treatment of respiratory diseases are steroids. However the currently available steroids have unsatisfactory site selectivity, for example all inhaled steroids are absorbed systemically from the lungs, and thus cause serious adverse effects by long-term administration . Therefore, there is a demand for development of a new class of compounds for use in the treatment of respiratory diseases which exerts a powerful effect and low systemic effect.

BACKGROUND OF THE INVENTION

In the prior art nitrooxy derivatives of steroids, which are usable also as cardiovascular agents for the coronary insufficiency or angina pectoris therapy, are described.

For example, German patent DE 2,222,491 describes the preparation of pregnane derivatives having in position 21 the - CH2-O-NO2 group. In said patent it is stated that said derivatives have a cardiotropic activity. This activity represents a drawback for said compounds, since they modify the cardiac frequency.

USP 3,494,941 describes steroid derivatives from 3-hydroxy- extrane or from extr-4 en-3 one, used as vasodilators in the

treatment of cardiac affections such as coronary insufficiency and angina pectoris. In the structure of said compounds a ONO2 group is at the free end of the alkylene chain which is linked by an ether bond to the steroid in position 17. According to said patent it is possible to have nitrate groups also in the positions 3 and 16 of the steroidal structure. The same drawbacks mentioned above as regards the effects on the cardiac frequency can be repeated for the compounds of this patent.

USP 3,183,252 describes derivatives of 16-nitrate-alkylpre- gnanes wherein the alkyl group is linked to the pregnane structure by a carbon-carbon bond. The compounds according to said patent can be used as vasodilators. The same drawbacks reported for the above prior art can be repeated.

WO 98/15568 and WO 03/064443 in the name of the Applicant describe nitrate esters of steroidal compounds, wherein between the steroidal structure and the nitrooxy group a bivalent linking group is inserted. Said compounds show a good efficacy and/or good tolerability with respect to the corresponding precursors . Patent application WO 00/61604 in the name of the Applicant describes nitrooxy derivatives of steroidal compounds with various linking groups having at one end a nitrooxy group, and covalently linked with the other end to a steroidal compound. In said application the uses concern the compounds usable in the treatment of patients in oxidative stress. Said compounds contain in the molecule also a bivalent linking group which must be capable to prevent the free radicals production and is selected on the basis of the tests reported therein.

The Applicant has surprisingly and unexpectedly found a class of nitric oxide releasing compounds with a better efficacy, bioavailability and/or a prolonged release of NO in comparison with the compounds known in prior art. In general the compounds of the present invention have a better

drugability in comparison to the corresponding compounds of the prior art.

An object of the present invention is to provide nitric oxide releasing compounds of general formula (I)

R-(Z) ₃ -R _x

(D and pharmaceutically acceptable salts or stereoisomers thereof for use in the treatment of respiratory diseases, wherein in formula (I) R is a corticosteroid residue selected from:

a is 0 or 1,

Z is a group capable of binding R _x and is selected from -C(O)-, or -CH (R' ) -0- wherein R' is selected from H or a straight or branched C ₁ -C ₄ alkyl, preferably R' is H or -CH3; R _x is a radical selected from the following meanings: A)

(al) -HN-CH(R ¹ ) -C (0) - (T-Y-ONO ₂ )

(a2) -C (O) -CH(R ¹ ) -NH- (T' -Y-ONO ₂ )

(a3) -HN-CH (R ^la -τ"-Y' -ONO ₂ ) -C00R ^3a

(a4) -C (0) -CH (R ^la -τ"-Y' -ONO ₂ ) -NHR ^4a

(a5) -R ^lb -CH (NHR ^4a ) -C (0) - (T-Y-ONO ₂ ) (a6) -R ^lb -CH(C00R ^3a ) NH- (T' -Y-ONO ₂ )

(a7) -HN-CH (R ^la -τ"-Y' -ONO ₂ ) -C (0) - (T-Y-ONO ₂ )

(a8) -C (0) -CH (R ^la -τ"-Y' -ONO ₂ ) -NH- (T' -Y-ONO ₂ )

(a9) -R ^lb -CH (NH-T' -Y' -ONO ₂ ) -C (0) - (T-Y-ONO ₂ )

(alO) -R ^lb -CH (C (O) -T-Y' -ONO ₂ ) -NH- (T' -Y-ONO ₂ ) wherein:

R ¹ is selected from:

Al) H, -CH ₃ , isopropyl, isobutyl, sec-butyl, tert-butyl, methylthio- (CH ₂ ) ₂ -, phenyl, benzyl, C ₆ H ₅ -CH ₂ -CH ₂ -, 2-monosubstituted benzyl, or 3-monosubstituted benzyl or 4- monosubstituted benzyl wherein the substituent of the benzyl is selected from -F, -Cl, I, -NO ₂ , -CF ₃ , -CH ₃ , CN, C ₆ H ₅ CO-;

2, 4-dichlorobenzyl, 3, 4-dichlorobenzyl, 3, 4-difluorobenzyl, 2-pyrrolidyl, 3-triptophanyl-CH ₂ -, 3-benzothienyl-CH ₂ -, 4-imidazolyl-CH ₂ -, 9-anthranyl-CH ₂ -, cyclohexyl, cyclohexyl-CH ₂ -, cyclohexyl- (CH ₂ ) ₂ -, cyclopentyl-CH ₂ -, (C ₆ Hs) ₂ CH-, 4-B (0H) ₂ -benzyl, 4-quinolyl-CH ₂ -, 3-quinolyl-CH ₂ -, 2-quinolyl-CH ₂ -,

2-quinoxalyl-CH ₂ -, 2-furyl-CH ₂ -, l-naphtyl-CH ₂ -, 2-naphtyl-CH ₂ - , 2-pyridyl-CH ₂ -, 3-pyridyl-CH ₂ -, 4-pyridyl-CH ₂ -,

2-thienyl-CH ₂ -, 3-thienyl-CH ₂ -, C ₆ H ₄ -CH=CH-CH ₂ -, CH ₂ =CH-CH ₂ -, CH=CH-CH ₂ -, NH ₂ -CO-CH ₂ -, NH ₂ -CO- (CH ₂ ) ₂ -, NH ₂ (=NH) NH- (CH ₂ ) ₃ -, P (=0) (OCH ₃ ) ₂ , 1-CH ₂ -, preferably R ¹ is H, -CH ₃ , isopropyl, benzyl; A2) -CH ₂ -SH, -CH ₂ -OH, -CH (CH ₃ ) -OH, -CH ₂ [ (C ₆ H ₄ ) - (4-OH) ], -CH ₂ - [ (C ₆ H ₂ ) - (3, 5-diiodo) - (4-OH) ] ,

-CH ₂ - [ (C ₆ H ₃ ) - (3-nitro) - (4-OH) ], preferably R ¹ is -CH ₂ -OH or -CH ₂ [ (C ₆ H ₄ ) -(4-0H) ] ;

A3) -CH ₂ -NHR", - (CH ₂ ) ₂ -NHR", - (CH ₂ ) ₃ -NHR", - (CH ₂ ) ₄ -NHR", wherein R" is H, -C(O)CH ₃ or

wherein R ^5a is H or a linear or branched C1-C10 alkyl chain, preferably R ^5a is H or a linear (Ci-C ₅ ) alkyl, preferably R ¹ is - (CH ₂ ) ₄ -NHR", wherein R" is as above defined,

A4) -CH ₂ -C(O)R"', - (CH ₂ ) 2-C(O) R"' , - (CH ₂ ) ₄ -C (0) R"' wherein R"' is -OR 5a or

wherein R ^5a is as above defined, preferably R ¹ is -CH ₂ -C(O)R"', wherein R"' is as above defined, R ^la is selected from:

A5) -CH ₂ -S-, -CH ₂ -O-, -CH(CH ₃ )-O-, -CH ₂ [ (C ₆ H ₄ ) - (4-0) -], -CH ₂ - [ (3, 5-diiodo) - (C ₆ H ₂ ) - (4-0) -] , -CH ₂ - [ (3-nitro) - (C ₆ H ₃ ) - (4-0) -], preferably R ^la is -CH ₂ -O-;

A6) -CH ₂ -NH-, - (CH ₂ ) 2-NH-, - (CH ₂ ) 3-NH-, -(CH ₂ J ₄ -NH-, preferably R ^la is -(CH ₂ J ₄ -NH- or -CH ₂ -NH-,

A7) -CH ₂ -C(O)-, - (CH ₂ ) 2-C(O) -, - (CH ₂ ) ₄ -C (0) -, preferably R ^la is -CH ₂ -C(O)-; R ^3a is selected from H, -R ^5a or

wherein R ^5a is as above defined,

R ^4a is selected from H or -C(O)CH ₃ or

wherein R ^5a is as above defined, R ^lb is selected from

A8) -S-CH ₂ -, -0-CH(CH ₃ )-, -0-CH ₂ -, [-(4-O)-(C ₆ H ₄ )J-CH ₂ -, [- (4-0) - (3, 5-diiodo) - (C ₆ H ₂ ) ] -CH ₂ -,

[- (4-0) - (3-nitro) - (C ₆ H ₃ ) ] -CH ₂ -, preferably R ^lb is -0-CH ₂ - or [- (4-0)- (C ₆ H ₄ ) J-CH ₂ -;

A9) -HN-CH ₂ -, -HN- (CH ₂ ) ₂ -, -HN- (CH ₂ ) ₃ -, -HN- (CH ₂ ) ₄ -, preferably R ^lb is -HN- (CH ₂ ) ₄ - or -HN-CH ₂ -; AlO) -C(O)-CH ₂ -, -C(O) - (CH ₂ ) ₂ -, -C (0) - (CH ₂ ) ₄ -, preferably R ^lb is -C(O)-CH ₂ -;

T is selected from -0-, -S-, -NR'-, -O-CH (R' ) -0-C (0) - or -O-CH (R' ) -0-C (0) 0- wherein R' is as above defined; T' is -C(O)-, -C(O)-X"- wherein X" is -0- or -S-, or T' is -C (0) -NR' - wherein R' is as above defined;

T" is independently selected from -C(O)-, -C(O)-X"-, -C(O)-NR'-, -0-, -S-, -NR'-, -0-CH(R' ) -0-C (0) -,

-0-CH(R' ) -0-C (O)O-, wherein X" and R' are as above defined, with the proviso that T" is -C(O)-, -C(O)-X"- or -C(O)-NR'- when T" is linked to -NH-, -0-, or -S-, or

T" is -0-, -S-, -NR'-, -0-CH(R' ) -0-C (0) -, -O-CH (R' ) -0-C (0) 0- when T" is linked to -C(O)-, Y and Y' are as below defined; or R _x is selected from: B)

(bl) -HN-CH (R ² ) -CH ₂ -C (0) - (T-Y-ONO ₂ )

(b2) -C (0) -CH ₂ -CH (R ² ) -NH- (T' -Y-ONO ₂ )

(b3) -HN-CH (R ^2a -τ"-Y' -ONO ₂ ) -CH ₂ COOR ^3a

(b4) -C (0) -CH ₂ -CH (R ^2a -T"-Y' -ONO ₂ ) -NHR ^4a (b5) -R ^2b -CH(NHR ^4a ) -CH ₂ C (0) - (T-Y-ONO ₂ )

(b6) -R ^2b -CH (CH ₂ COOR ^3a ) NH- (T' -Y-ONO ₂ )

(b7 ) -HN-CH ( R ^2a - T " -Y ' -ONO ₂ ) -CH ₂ -C ( O ) - ( T -Y-ONO ₂ )

(b8) -C (0) -CH ₂ -CH (R ^2a -T"-Y' -ONO ₂ ) -NH- (T' -Y-ONO ₂ ) (b9) -R ^2b -CH (NH-T' -Y' -ONO ₂ ) -CH ₂ C (0) - (T-Y-ONO ₂ ) (blO) -R ^2b -CH (CH ₂ C (O) -T-Y' -ONO ₂ ) -NH- (T' -Y-ONO ₂ ) wherein

R ² is selected from:

Bl) H, -CH ₃ , CF ₃ , isopropyl, isobutyl, sec-butyl, methylthio- (CH ₂ ) ₂ -, phenyl, benzyl, 3-triptophanyl-CH ₂ -, NH ₂ -C(O)-CH ₂ -, NH ₂ -C(O) - (CH ₂ ) 2", NH ₂ (=NH) NH- (CH ₂ ) ₃ -, tBuO-CH (CH ₃ ) - , benzyl-O-CH ₂ -, 4-terbutoxy-benzyl, 4-phenylbenzyl, preferably R ² is H, -CH ₃ , isopropyl, benzyl,

B2) -CH ₂ -SH, -CH ₂ -OH, -CH (CH ₃ ) -OH, -CH ₂ [ (C ₆ H ₄ ) - (4-OH) ], -CH ₂ - [ (C ₆ H ₂ ) - (3, 5-diiodo) - (4-OH) ] , -CH ₂ - [ (C ₆ H ₃ ) - (3-nitro) - (4-OH) ] ; B3) -CH ₂ -NHR", - (CH ₂ ) ₂ -NHR", - (CH ₂ ) ₃ -NHR", - (CH ₂ ) ₄ -NHR", wherein R" is as above defined, preferably R ² is - (CH ₂ ) ₄ -NHR";

B4) -CH ₂ -C(O)-R"', -(CH ₂ ) ₂ -C(O)-R"', -(CH ₂ J ₄ -C(O)-R'" wherein R"' is as above defined, preferably R ² is -CH ₂ -C(O)-R"'; R ^2a is selected from: B5) -CH ₂ -S-, -CH ₂ -O-, -CH (CH ₃ ) -0- or -CH ₂ [ (C ₆ H ₄ ) - (4-0) -], -CH ₂ - [ (3, 5-diiodo) - (C ₆ H ₂ ) - (4-0) -] , -CH ₂ - [ (3-nitro) - (C ₆ H ₃ ) - (4-0) -], preferably R ^2a is -CH ₂ -O-;

B6) -CH ₂ -NH-, - (CH ₂ ) ₂ -NH-,- (CH ₂ ) ₃ -NH-, - (CH ₂ ) ₄ -NH-, preferably R ^2a is -(CH ₂ ) ₄ -NH- or -CH ₂ -NH-; B7) -CH ₂ -C(O)-, - (CH ₂ ) 2-C(O) -, - (CH ₂ ) ₄ -C (0) -, preferably R ^2a is -CH ₂ -C(O)-; R ^2b is selected from

B8) -S-CH ₂ -, -0-CH(CH ₃ )-, -0-CH ₂ -, [-(4-O)-(C ₆ H ₄ )J-CH ₂ -, [- (4-0) - (3, 5-diiodo) - (C ₆ H ₂ ) ] -CH ₂ -, [- (4-0) - (3-nitro) - (C ₆ H ₃ ) ] -CH ₂ - , preferably R ^2b is -0-CH ₂ - or [-(4-O)-(C ₆ H ₄ )J-CH ₂ -;

B9) -HN-CH ₂ -, -HN- (CH ₂ ) ₂ -, -HN- (CH ₂ ) ₃ -, -HN- (CH ₂ ) ₄ -, preferably R ^2b is -HN- (CH ₂ ) ₄ - or -HN-CH ₂ -;

BlO) -C(O)-CH ₂ -, -C(O) - (CH ₂ ) ₂ -, -C (0) - (CH ₂ ) ₄ -, preferably R ^2b is -C(O)-CH ₂ -;

R ^3a and R ^4a are as above defined;

T, T' and T" are as above defined and Y and Y' are as below defined; or R _x is selected from: C)

(cl) -HN- (CH ₂ ) _b -C (O) - (T-Y-ONO ₂ ) ; (c2) -C(O)-(CH ₂ ) _b -NH- (T' -Y-ONO ₂ ) ; wherein b is an integer from 3 to 6,

T and T' are as above defined and Y and Y' are as below defined; D)

(dl) -HN-CH (R ¹² ) -CH ₂ -O- (T"' -Y-ONO ₂ ) (d2) -0-CH ₂ -CH (R ¹² ) -NH- (T' -Y-ONO ₂ ) (d3) -HN-CH (R ^12a -τ"-Y' -ONO ₂ ) -CH ₂ OH (d4) -0-CH ₂ -CH (R ^12a -τ"-Y' -ONO ₂ ) -NHR ^4a (d5) -R ^12b -CH(NHR ^4a ) -CH ₂ -O- (T"' -Y-ONO ₂ ) (d6) -R ^12b -CH (CH ₂ OH) -NH- (T' -Y-ONO ₂ ) (d7) -HN-CH (R ^12a -T"-Y' -ONO ₂ ) -CH ₂ -O- (T"' -Y-ONO ₂ ) (d8) -0-CH ₂ -CH (R ^12a -τ"-Y' -ONO ₂ ) -NH- (T' -Y-ONO ₂ ) (d9) -R ^12b -CH (NH-T' -Y' -ONO ₂ ) -CH ₂ -O- (T"' -Y-ONO ₂ ) (dlO) -R ^12b -CH (CH ₂ -O-T"' -Y' -ONO ₂ ) -NH- (T' -Y-ONO ₂ ) wherein

T"' is independently selected from -C(O)-, -C(O)X"- wherein X" is -0- or -S-, or -C(O)-NR'- wherein R' is as above defined; T' and T" are as above defined, Y and Y' are as below defined; R ¹² is selected from:

Dl) H, -CH ₃ , isopropyl, isobutyl, sec-butyl, methylthio- (CH ₂ ) ₂ -, benzyl, 3-triptophanyl-CH ₂ -,

4-imidazolyl-CH ₂ -, NH ₂ -CO-CH ₂ -, NH ₂ -CO- (CH ₂ ) ₂ -, NH ₂ (=NH) NH- (CH ₂ ) ₃ - , preferably R ¹² is H;

D2) -CH ₂ -OH, -CH (CH ₃ ) -OH, -CH ₂ [ (C ₆ H ₄ ) - (4-OH) ], -CH ₂ - [ (C ₆ H ₃ ) - (3, 5-diiodo) - (4-OH) ] ,

-CH ₂ - [ (C ₆ H ₃ ) - (3-nitro) - (4-OH) ], preferably R ¹² is -CH ₂ -OH or - CH ₂ [ (C ₆ H ₄ ) -(4-0H) ] ;

D3) -CH ₂ -NHR", - (CH ₂ ) ₂ -NHR", - (CH ₂ ) ₃ -NHR", - (CH ₂ ) ₄ -NHR", wherein

R" is as above defined, preferably R ¹² is - (CH ₂ ) ₄ -NHR";

D4) -CH ₂ -C(O)R"', - (CH ₂ ) 2-C(O) R"' , - (CH ₂ ) ₄ -C (O) R"' wherein R"' is as above defined, preferably R ¹² is -CH ₂ -C(O)R"'; R ^12a is selected from

D5) -CH ₂ -O-, -CH (CH ₃ ) -0- or -CH ₂ [ (C ₆ H ₄ ) - (4-0) -], -CH ₂ - [3,5- diiodo- (C ₆ H ₂ ) - (4-0) -], -CH ₂ - [3-nitro- (C ₆ H ₃ ) -4-0- ] , preferably R ^12a is CH ₂ -O- or -CH ₂ [ (C ₆ H ₄ ) - (4-0) -],

D6) -CH ₂ -NH-, - (CH ₂ ) ₂ -NH-, - (CH ₂ ) ₃ -NH-, - (CH ₂ ) ₄ -NH-, preferably R ^12a is -(CH ₂ ) ₄ -NH- or -CH ₂ -NH-,

D7) -CH ₂ -C(O)-, - (CH ₂ ) ₂ -C (0) -, -(CH ₂ J ₄ -C(O)-, preferably R ^12a is -CH ₂ -C(O)-, R ^12b is selected from

D8) -0-CH ₂ -, -0-CH(CH ₃ )-, [-(4-O)-(C ₆ H ₄ )J-CH ₂ -, [- (4-0) - (3, 5-diiodo) - (C ₆ H ₂ ) ] -CH ₂ , [- (4-0) - (3-nitro) - (C ₆ H ₃ ) ] -CH ₂ -, preferably R ^12b is -0-CH ₂ - or [- (4-O)- (C ₆ H ₄ ) J-CH ₂ -;

D9) -HN-CH ₂ -, -HN- (CH ₂ ) ₂ -, -HN- (CH ₂ ) ₃ -, -HN- (CH ₂ ) ₄ -, preferably R ^12b is -HN- (CH ₂ ) ₄ - or -HN-CH ₂ -;

DlO) -C(O)-CH ₂ -, -C(O) - (CH ₂ ) ₂ -, -C (0) - (CH ₂ ) ₄ -, preferably R ^12b is -C(O)-CH ₂ -;

R ^4a is as above defined; or R _x is selected from:

E)

wherein c is equal to 0 or 1, d is an integer from 0 to 3 with the proviso that c is 0 or 1 when d is 0 and c is 0 when d is

1, 2 or 3, T and T' are as above defined and Y is as below defined;

F)

(XI) wherein e and f are equal to 0 or 1, with the proviso that f is 0 when e is 0 and f is 0 or 1 when e is 1, T and T' are as above defined and Y is as below reported; G)

wherein R is H, CH ₃ , propyl, (CeHs) ₂ CH-, l-naphtyl-CH ₂ -, benzyl, allyl, 2-bromobenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-fluorobenzyl, 4-bromobenzyl, 4-methylbenzyl, preferably R ³ is H, T and T' are as above defined and Y is as below defined; H) (hi)

wherein R ⁴ is H, benzyl, 4-bromobenzyl, 2-bromobenzyl, T and T' are as above defined and Y is as below defined; D

wherein R ⁵ is H, R is H, or R ⁵ and R when taken together are a double bond, T and T' are as above defined and Y is as below reported; L)

wherein T and T' are as above defined and Y is as below reported; M)

wherein T and T' are as above defined and Y is as below

wherein c is as above defined, d is equal to 0 or 1, T and T' are as above defined and Y is as below reported; 0) (ol)

wherein R ⁷ is H, R ⁸ is H, or R ⁷ and R ⁸ when taken together are a double bond, c is as above defined, T and T' are as above defined and Y is as below reported;

P)

wherein T and T' are as above defined and Y is as below reported; Q)

wherein T and T' are as above defined and Y is as below reported;

R)

wherein T and T' are as above defined and Y is as below reported;

S)

wherein T and T' are as above defined and Y is as below reported;

T)

wherein T and T' are as above defined and Y is as below reported; U) (ul)

wherein R ⁹ and R ¹⁰ are H, CH ₃ , R ¹¹ is CH ₃ or 4-piperidinyl with the proviso that R ⁹ and R ¹⁰ are H when R ¹¹ is 4-piperidinyl and R ⁹ and R ¹⁰ are CH ₃ when R ¹¹ is CH ₃ , T and T' are as above defined and Y is as below reported; V)

wherein T and T' are as above defined and Y is as below reported; with the proviso that in the formula (I) : a is O or a is 1 and Z is -CH (R') -O- wherein R' is as above defined, when R _x is:

- (a2), (a4) or (a8);

- (a5) , (a6) , (a9) or (alO) and R ^lb is selected from the group AlO) ;

- (b2), (b4) or (b8);

- (b5), (b6) , (b9) or (blO) and R ^2b is selected from the group BlO) ;

- ( c2 ) ;

- (d5), (d6) , (d9) or (dlO) and R ^12b is selected from the group DlO) ;

- (e2), (fl), (g2), (hi), (11), (12), (m2), (n2), (o2), ( _P 2), (q2), (r2), (s2), (tl) or (u2); a is 1 and Z is -C(O)-, when R _x is:

- (al), (a3) or (a7);

- (a5) , (a6) , (a9) or (alO) and R ^lb is selected from the groups A8) and A9) ; - (bl), (b3) or (b7);

- (b5) , (b6) , (b9) or (blO) and R ^2b is selected from the groups B8) or B9) ;

- (cl);

- (dl), (d2), (d3), (d4), (d7) or (d8) ; - (d5), (d6) , (d9) or (dlO) and R ^12b is selected from the groups D8) or D9) ;

- (el), (f2), (gl), (h2), (12), (11), (ml), (nl), (ol), (pi), (ql), (rl), (si), (t2) or (ul) .

Y and Y' are bivalent radicals each independently selected from the following meanings: a)

- straight or branched C1-C20 alkylene, preferably a straight or branched C1-C10 alkylene,

- straight or branched C1-C20 alkylene substituted with one or more of the substituents selected from the group consisting of: halogen atoms, hydroxy, -ONO2 or T ₂ , wherein T ₂ is -OC(O) (C1-C10 alkyl)-ONO ₂ or -0(Ci-Ci ₀ alkyl)-ONO ₂ , preferably Y or Y' is a straight or branched C1-C10 alkylene substituted with a -ONO ₂ group; - cycloalkylene with 5 to 7 carbon atoms into cycloalkylene ring, the ring being optionally substituted with one or more straight or branched C1-C10 alkyl chains, preferably the ring being optionally substituted with CH ₃ ;

b)

wherein n ⁰ is an integer from 0 to 20, preferably n ⁰ is 0 or 1 ; n ¹ is 0 or 1, preferably n ¹ is 1 ;

U is a linear or branched C1-C20 alkylene optionally substituted with a -ONO2 group, preferably U is a linear C1-C10 alkylene or U is a linear or branched C1-C10 alkylene substituted with a -ONO2 group; O

wherein n is an integer from 0 to 20, preferably n is 0 or 1 ; n ¹ is 0 or 1, preferably n ¹ is 1 ;

U is a linear or branched C1-C20 alkylene optionally substituted with a -ONO2 group, preferably U is a linear C1-C10 alkylene or U is a linear or branched C1-C10 alkylene substituted with a -ONO2 group; d)

wherein : n ² is an integer from 0 to 2, R ¹³ is H or CH ₃ , Ti is -0-C(O)- or -C(O)O-;

n ¹ and U are as above defined;

n ² is an integer from 0 to 2, preferably n ² is 1 ;

R ¹³ is H or CH ₃ , preferably R ¹³ is CH ₃ ;

Y ¹ is -CH ₂ -CH ₂ - or -CH=CH- (CH ₂ ) _n ^2' -, wherein n ^2' is 0 or 1, preferably Y ¹ is -CH=CH- (CH ₂ ) _n ^2' - and n ^2' is 0;

T ₁ = -0-C(O)- or -C(O)O-, preferably T ₁ is -C(O)O-; n ¹ is 0 or 1, preferably n ¹ is 1;

U is a linear or branched C ₁ -C ₂ O alkylene optionally substituted with a -ONO ₂ group, preferably U is a linear C ₁ -C ₁ O alkylene or U is a linear or branched C ₁ -C ₁ O alkylene substituted with a -ONO ₂ group; more preferably n ² is 1, R ¹³ is CH ₃ , Y ¹ is -CH=CH- (CH ₂ ) _n ^2' - and n ^2' is 0, T ₁ is -C(O)O- and U is a linear C ₁ -C ₁ O alkylene; e')

wherein: n ² is an integer from 0 to 2, preferably n ² is 1;

R ¹³ is H or CH ₃ , preferably R ¹³ is CH ₃ ;

Y ¹ is -CH ₂ -CH ₂ - or - (CH ₂ ) _n ^2' -CH=CH-, wherein n ^2' is 0 or 1, preferably Y ¹ is - (CH ₂ ) _n ^2' -CH=CH- and n ^2' is 0; T ₁ = -O-C(O) -; n ¹ is 0 or 1, preferably n ¹ is 1;

U is a linear or branched C ₁ -C ₂ O alkylene optionally substituted with a -ONO ₂ group, preferably U is a linear C ₁ -C ₁ Q alkylene or U

is a linear or branched Ci-Cio alkylene substituted with a -ONO2 group; more preferably n ² is 1, R ¹³ is CH ₃ , Y ¹ is -CH=CH- (CH ₂ ) _n ^2' - and n ^2' is 0, Ti is -OC(O)- and U is a linear C ₁ -C ₁₀ alkylene; f)

—(CH ₂ -CH ₂ -T ₂ )- CH ₂ -(CH ₂ )*—

f) wherein T ₂ is -O- or -S-, -NH-, preferably T ₂ is -O-, n is an integer from 1 to 6, preferably n ³ is 1; when Y and Y' are selected from b) , c) , d) , e) , e' ) or f) , the -ONO ₂ group of -(T-Y-ONO ₂ ), - (T' -Y-ONO ₂ ) , - (T"-Y' -ONO ₂ ) , -(T' -Y'- ONO ₂ ), - (T"' -Y-ONO ₂ ) and - (T"' -Y' -ONO ₂ ) is linked to the -(CH ₂ )*- group; g)

wherein : n ⁴ is an integer from 0 to 10, preferably n ⁴ is 0 or 1; n ⁵ is an integer from 1 to 10, preferably n ⁵ is 1; R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ are the same or different, and are H or straight or branched Ci-C ₄ alkyl, preferably R ¹⁴ , R ¹⁵ , R ¹⁶ and R ¹⁷ are H; wherein the -ONO ₂ group is linked to

wherein n ⁵ is as defined above;

Y ² is an heterocyclic saturated, unsaturated or aromatic 5 or 6 members ring, containing one or more heteroatoms selected from nitrogen, oxygen, sulphur,

and is selected from the group consisting of:

The term "Ci-Cio alkyl" as used herein refers to branched or straight alkyl groups 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

CH ₃ .

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.

Respiratory diseases comprises asthma, COPD (chronic obstructive pulmonary diseases) , ARDS (Acute Respiratory Distress Syndrome) , allergic rhinitis, respiratory tract diseases associated with inflammation.

An embodiment of the invention relates to nitric oxide releasing compounds of general formula (I)

R-(Z) ₃ -R _x

(D and pharmaceutically acceptable salts or stereoisomers thereof for use in the treatment of respiratory diseases wherein in formula (I) the corticosteroid residue R is selected from:

a is 0 and R _x is selected from: (a2) -C (0) -CH (R ¹ ) -NH- (T' -Y-ONO ₂ ) wherein

R ¹ of the group Al) is selected from H, isobutyl, benzyl, CeH ₅ -CH ₂ -CH ₂ -, 2-monosubstituted benzyl, or 3-monosubstituted benzyl or 4- monosubstituted benzyl wherein the substituent of

the benzyl is selected from -F, -Cl, I, -NO ₂ , -CF ₃ , -CH ₃ , CN,

C ₆ H ₅ CO-;

R ¹ of the group A2) is selected from -CH ₂ -OH, -CH(CH ₃ )OH- or

-CH ₂ [ (C ₆ H ₄ ) -(4-0H) ], or R ¹ of the group A3) is selected from -CH ₂ -NHR", - (CH ₂ ) ₂ -NHR",

-(CH ₂ ) ₃ -NHR", - (CH ₂ ) ₄ -NHR", wherein R" is H, or -C(O)CH ₃ ;

R ¹ of the group A4) is selected from -CH ₂ -C(O)R"',

- (CH ₂ ) 2-C(O) R"' , - (CH ₂ ) 4-C (O)R"' wherein R"' is 0R ^5a wherein R ^5a is H or a linear (Ci-C ₅ ) alkyl; T' is -C(O)-, -C(O)-X" wherein X" is -S- or -0-, preferably T' is -C(O)-;

Y is as below defined; or R _x is

(a4) -C (0) -CH (R ^la -τ"-Y' -ONO ₂ ) -NHR ^4a wherein R ^la of the group A5) is selected from -CH ₂ -O-, -CH (CH ₃ )O- or -CH ₂ [ (C ₆ H ₄ ) - (4-0) -], or

R ^la of the group A6) is selected from -CH ₂ -NH-, - (CH ₂ ) ₂ -NH-,

-(CH ₂ ) ₃ -NH-, - (CH ₂ ) ₄ -NH-, or

R ^la of the group A7) is selected from -CH ₂ -C(O)-, - (CH ₂ ) ₂ -C (0) -, - (CH ₂ ) ₄ -C(O)-,

R ^4a is H or -C(O)CH ₃ ,

T" is -C(O)- or -C(O)-X" wherein X" is -S- or -0-, when R ^la is selected from the group A5) or A6) , preferably T" is -C(O)-;

T" is -0-, -S-, -NR'- or -O-CH (R' ) -0-C (0) - wherein R' is H or -CH ₃ , when R ^la is selected from the group Al),

Y' is as below defined; or R _x is selected from:

(a5) -R ^lb -CH (NHR ^4a ) -C (0) - (T-Y-ONO ₂ )

(a6) -R ^lb -CH (COOR ^3a ) NH- (T' -Y-ONO ₂ ) (a9) -R ^lb -CH (NH-T' -Y' -ONO ₂ ) -C (0) - (T-Y-ONO ₂ ) or

(alO) -R ^lb -CH (C (0) -T-Y' -ONO ₂ ) -NH- (T' -Y-ONO ₂ ) wherein

R ^lb of the group AlO) is selected from -C(O)-CH ₂ -, -C (0) - (CH ₂ ) ₂ -,

-C(O)- (CH ₂ J ₄ -,

R ^3a i s H or a ( Ci-C ₅ ) al kyl ,

R ^4a i s H or -C ( O) CH ₃ ,

T is -O-, -S-, -NR'- or -O-CH (R' ) -O-C (O) - wherein R' is H or -CH ₃ , preferably T is -0-, T' is -C(O)- or -C(O)-X" wherein X" is -S- or -0-, preferably T' is -C(O)-,

Y and Y' are as below defined; or R _x is

(a8) -C (0) -CH (R ^la -τ"-Y' -ONO ₂ ) -NH- (T' -Y-ONO ₂ ) wherein

R ^la of the group A5) is selected from -CH ₂ -O-, -CH (CH ₃ ) -0- or

-CH ₂ [ (C ₆ H ₄ ) -(4-0)-], or

R ^la of the group A6) is selected from -CH ₂ -NH-, - (CH ₂ ) ₂ -NH-,

- (CH ₂ ) 3-NH-, - (CH ₂ ) 4-NH-, or R ^la of the group A7) is selected from -CH ₂ -C(O)-, - (CH ₂ ) ₂ -C (0) -, -(CHz) ₄ -C(O)-,

T" is -C(O)- or -C(O)-X" wherein X" is -S- or -0-, when R ^la is selected from the group A5) or A6) , preferably T" is -C(O)-, T" is -0-, -S-, -NR'- or -O-CH (R' ) -0-C (0) - wherein R' is H or - CH ₃ , when R ^la is selected from the group A7);

T' is -C(O)- or -C(O)-X" wherein X" is -S- or -0-, preferably T' is -C(O)-,

Y and Y' are as below defined, or R _x is (b2) -C(O) -CH ₂ -CH(R ² ) -NH- (T' -Y-ONO ₂ ) wherein

R ² of the group Bl) is selected from H, CH ₃ , isobutyl, isopropyl, benzyl;

T' is -C(O)-, -C(O)-X" wherein X" is -S- or -0-, preferably T' is -C(O)-;

Y and Y' are each independently selected from a)

- a straight or branched Ci-Cio alkylene,

- a straight or branched Ci-Cio alkylene substituted with a -ONO2

wherein : n ² is an integer from 0 to 2, R ¹³ is H or CH ₃ , T ₁ is -0-C(O)- or -C(O)O-; n ¹ is 1 and U is a linear C1-C10 alkylene or U is a linear or branched C1-C10 alkylene substituted with a -ONO2 group; e)

n ² is 1, R ¹³ is CH ₃ , Y ¹ is -CH=CH- (CH ₂ ) _n ^2' - and n ^2' is 0, T ₁ is -C(O)O- and U is a linear C ₁ -C ₁ O alkylene; e' )

wherein : n ² is 1, R ¹³ is CH ₃ ;

Y ¹ is - (CH ₂ ) _n ^2' -CH=CH- and n ^2' is 0;

T ₁ = -O-C(O)-; n ¹ is 1 and U is a linear C ₁ -C ₁ O alkylene or U is a linear or branched C ₁ -C ₁ O alkylene substituted with a -ONO ₂ group; f)

—(CH ₂ -CH ₂ -T ₂ )- CH ₂ -(CH ₂ )*- f)

wherein T ₂ is -O- or -S-, -NH-, preferably T ₂ is -O-, n is 1 or

2; when Y and Y' are selected from d) , e) , e' ) or f) , the -ONO ₂ group of -(T-Y-ONO ₂ ), - (T' -Y-ONO ₂ ) , - (T"-Y' -ONO ₂ ) , - (T' -Y' -ONO ₂ ) ,

- (T"' -Y-ONO ₂ ) and - (T"' -Y' -ONO ₂ ) is linked to the -(CH ₂ )*- group .

Another embodiment of the invention relates to nitric oxide releasing compounds of general formula (I)

R-(Z) ₃ -R _x

(D and pharmaceutically acceptable salts or stereoisomers thereof for use in the treatment of respiratory diseases wherein in formula (I) the corticosteroid residue R is selected from:

a i s 1 and Z i s -C ( 0) - _;

R _x is

(al) -HN-CH(R ¹ ) -C(O) - (T-Y-ONO ₂ ) wherein

R ¹ of the group Al) is selected from H, isobutyl, benzyl, C ₆ H ₅ - CH ₂ -CH ₂ -, 2-monosubstituted benzyl, or 3-monosubstituted benzyl or 4- monosubstituted benzyl wherein the substituent of the benzyl is selected from -F, -Cl, I, -NO ₂ , -CF ₃ , -CH ₃ , CN, C ₆ H ₅ CO- or

R ¹ of of the group A2) is selected from: -CH ₂ -OH, -CH (CH ₃ ) -OH- or -CH ₂ [ (C ₆ H ₄ ) - (4-OH) ], or

R ¹ of the group A3) is selected from -CH ₂ -NHR", - (CH ₂ ) ₂ -NHR",

-(CH ₂ ) ₃ -NHR", - (CH ₂ ) ₄ -NHR", wherein R" is H, or -C(O)CH ₃ ,

R ¹ of the group A4) is -CH ₂ -C(O)R"', - (CH ₂ ) ₂ -C (0) R"' ,

- (CH ₂ ) ₄ -C (O)R"' wherein R"' is 0R ^5a wherein R ^5a is H or a linear (Ci-C ₅ ) alkyl;

T is -0-, -S-, -NR'-, -0-CH(R' ) -O-C(O) - wherein R' is H or a straight or branched Ci-C ₄ alkyl, preferably T is -0-,

Y is as below defined; or R _x i s ( a3 ) -HN-CH ( R ^la - T " -Y ' -ONO ₂ ) -COOR ^3a where in

R ^la of the group A5) is selected from -CH ₂ -O-, -CH(CH ₃ )O- or

-CH ₂ [ (C ₆ H ₄ ) -(4-0)-], or

R ^la of the group A6) is selected from -CH ₂ -NH-, - (CH ₂ ) ₂ -NH-, - (CH ₂ ) 3-NH-, - (CH ₂ ) 4-NH-, or

R ^la of the group A7) is -CH ₂ -C(O)-, - (CH ₂ ) ₂ -C (0) -, - (CH ₂ ) ₄ -C (0) -,

R ^3a is H or a (Ci-C ₅ ) alkyl,

T" is -C(O)- or -C(O)-X" wherein X" is -S- or -0-, when R ^la is selected from the group A5) or A6) , preferably T" is -C(O)-; T" is -0-, -S-, -NR'-, -0-CH(R' ) -O-C(O) - wherein R' is H or a straight or branched Ci-C ₄ alkyl, when R ^la is selected from the group A7) ;

Y' is as below defined; or R _x is selected from.

(a5) -R ^lb -CH (NHR ^4a ) -C (O) - (T-Y-ONO ₂ )

(a6) -R ^lb -CH (COOR ^3a ) NH- (T' -Y-ONO ₂ )

(a9) -R ^lb -CH (NH-T' -Y' -ONO ₂ ) -C (0) - (T-Y-ONO ₂ ) or

(alO) -R ^lb -CH (C (O) -T-Y' -ONO ₂ ) -NH- (T' -Y-ONO ₂ ) wherein

R ^lb of the group A8) is selected from -0-CH(CH ₃ )-, -0-CH ₂ -,

[-4-O)-(C ₆ H ₄ )I-CH ₂ -, or

R ^lb of the group A9) is selected from -HN-CH ₂ -, -HN- (CH ₂ ) ₂ -,

-HN-(CH ₂ ) ₃ -, -HN- (CH ₂ ) ₄ -, R ^3a is H or a (Ci-C ₅ ) alkyl,

R ^4a is H or -C(O)CH ₃ ,

T is -0-, -S-, -NR'-, -0-CH(R' ) -O-C(O) - wherein R' is H or a straight or branched Ci-C ₄ alkyl, preferably T is -0-,

T' is -C(O)- or -C(O)-X" wherein X" is -S- or -0-, preferably T' is -C(O)-,

Y and Y' are as below defined; or R _x is

(a7) -HN-CH (R ^la -τ"-Y' -ONO ₂ ) -C (0) - (T-Y-ONO ₂ ) wherein R ^la of the group A5) is selected from -CH ₂ -O-, -CH (CH ₃ ) -0- or

-CH ₂ [ (C ₆ H ₄ ) -(4-0)-], or

R ^la of the group A6) is selected from -CH ₂ -NH-, - (CH ₂ ) ₂ -NH-,

-(CH ₂ ) ₃ -NH-, - (CH ₂ ) ₄ -NH-, or

R ^la of the group A7) is -CH ₂ -C(O)-, - (CH ₂ ) ₂ -C (0) -, - (CH ₂ ) ₄ -C (0) -; T" is -C(O)- or -C(O)-X", wherein X" is -S- or -0-, when R ^la is selected from A5) or A6) , preferably T" is -C(O)-

T" is -0-, -S-, -NR'-, -0-CH(R' ) -O-C(O) -, wherein R' is H or a straight or branched Ci-C ₄ alkyl, when R ^la is selected from A7), preferably T" is -0-, T is -0-, -S-, -NR'-, -0-CH(R' ) -O-C(O) - wherein R' is H or a straight or branched Ci-C ₄ alkyl, preferably T is -0-;

Y and Y' are as below defined; or R _x is

(bl) -HN-CH (R ² ) -CH ₂ -C (0) - (T-Y-ONO ₂ )

where in

R ² of the group Bl) is selected from H, CH ₃ , isobutyl, isopropyl, benzyl;

R ² of the group B2) is selected from -CH ₂ -OH, -CH (CH ₃ ) -OH- or -CH ₂ [ (C ₆ H ₄ ) (4-OH) ] , or

R ² of the group B3) is selected from -CH ₂ -NHR", - (CH ₂ ) ₂ -NHR",

-(CH ₂ ) ₃ -NHR", - (CH ₂ ) 4-NHR", wherein R" is H, or -C(O)CH ₃ ,

R ² of the group B4) is -CH ₂ -C(O)R"', - (CH ₂ ) ₂ -C (0) R"' ,

- (CH ₂ ) ₄ -C (O)R"' wherein R"' is 0R ^5a wherein R ^5a is H or a linear (Ci-C ₅ ) alkyl;

T is -0-, -S-, -NR'-, -0-CH(R' ) -O-C(O) - wherein R' is H or a straight or branched Ci-C ₄ alkyl, preferably T is -0-,

Y is as below defined; or R _x is selected from (dl) -HN-CH(R ¹² ) -CH ₂ -O- (T"' -Y-ONO ₂ ) or

(d2) -0-CH ₂ -CH (R ¹² ) -NH- (T' -Y-ONO ₂ ) wherein

R ¹² of the group Dl) is selected from H, CH ₃ , isobutyl, isopropyl, benzyl, or R ¹² of the group D2) is selected from -CH ₂ -OH, -CH(CH ₃ )OH- or

-CH ₂ [ (C ₆ H ₄ )- (4-OH) ], or

R ¹² of the group D3) is selected from -CH ₂ -NHR", - (CH ₂ ) ₂ -NHR",

-(CH ₂ ) ₃ -NHR", -(CH ₂ ) ₄ -NHR" wherein R" is H, or

R ¹² of the group D4) is -CH ₂ -C(O)R"', - (CH ₂ ) ₂ -C (0) R"' , - (CH ₂ ) ₄ -C (O)R"' wherein R"' is 0R ^5a wherein R ^5a is H or a linear

(Ci-C ₅ ) alkyl;

T' and T"' are each independently selected from -C(O)- or

-C(O)-X" wherein X" is -S- or -0-, preferably T' and T"' are

-C(O)-, Y is as below defined; or R _x is selected from:

(d3) -HN-CH (R ^12a -τ"-Y' -ONO ₂ ) -CH ₂ OH

(d4) -0-CH ₂ -CH (R ^12a -τ"-Y' -ONO ₂ ) -NHR ^4a

(d7) -HN-CH (R ^12a -T"-Y' -ONO ₂ ) -CH ₂ -O- (T"' -Y-ONO ₂ ) or

(d8) -0-CH ₂ -CH (R ^12a -τ"-Y' -ONO ₂ ) -NH- (T' -Y-ONO ₂ ) wherein

R ^12a of the group D5) is selected from -CH ₂ -O-, -CH (CH ₃ ) -0- or -CH ₂ [ (C ₆ H ₄ ) -(4-0)-], or R ^12a of the group D6) is selected from -CH ₂ -NH-, - (CH ₂ ) ₂ -NH-,

- (CH ₂ ) 3-NH-, - (CH ₂ ) 4-NH-, or

R ^12a of the group D7) is -CH ₂ -C(O)-, - (CH ₂ ) ₂ -C (0) -, - (CH ₂ ) ₄ -C (0) -;

R ^4a is H or -C(O)CH ₃ ,

T" is selected from -C(O)- or -C(O)-X", wherein X" is -S- or - 0-, when R ^12a is selected from D5) or D6) , preferably T' and T"' are -C(O)-,

T" is -0-, -S-, -NR'-, -0-CH(R' ) -0-C (0) -, wherein R' is H or a straight or branched Ci-C ₄ alkyl, when R ^12a is selected from D7),

, preferably T is -0-, T"' is selected from -C(O)- or -C(O)-X" wherein X" is -S- or -

0-, preferably T"' is -C(O)-,

Y and Y' are as below defined; or R _x is selected from:

(d5) -R ^12b -CH (NHR ^4a ) -CH ₂ -O- (T"' -Y-ONO ₂ ) (d6) -R ^12b -CH (CH ₂ OH) -NH- (T' -Y-ONO ₂ )

(d9) -R ^12b -CH (NH-T' -Y' -ONO ₂ ) -CH ₂ -O- (T"' -Y-ONO ₂ ) or (dlO) -R ^12b -CH (CH ₂ -O-T"' -Y' -ONO ₂ ) -NH- (T' -Y-ONO ₂ ) wherein

R ^12b of the group D8) is selected from -0-CH(CH ₃ )-, -0-CH ₂ -, [-4-0-(C ₆ H ₄ )J-CH ₂ -, or

R ^12b of the group D9) is selected from -HN-CH ₂ -, -HN- (CH ₂ ) ₂ -, -HN-(CH ₂ ),-, -HN-(CH ₂ ),-; R ^4a is H or -C (0) -CH ₃ ,

T' and T"' are each independently selected from -C(O)-, -C(O)- X", wherein X" is -S- or -0-, preferably T' and T"' are -C(O)-,

Y and Y' are each independently selected from a)

- a straight or branched Ci-Cio alkylene,

- a straight or branched Ci-Cio alkylene substituted with a -ONO2

wherein : n ² is an integer from 0 to 2, R ¹³ is H or CH ₃ , T ₁ is -0-C(O)- or -C(O)O-, n ¹ is 1 and U is a linear C1-C10 alkylene or U is a linear or branched C1-C10 alkylene substituted with a -ONO2 group; e)

n ² is 1, R ¹³ is CH ₃ , Y ¹ is -CH=CH- (CH ₂ ) _n ^2' - and n ^2' is 0, Ti is -C(O)O- and U is a linear C1-C10 alkylene; e' )

wherein : n ² is 1, R ¹³ is CH ₃ ,

Y ¹ is - (CH ₂ ) _n ^2' -CH=CH- and n ^2' is 0,

T ₁ = -O-C(O)-, n ¹ is 1 and U is a linear C1-C10 alkylene or U is a linear or branched C1-C10 alkylene substituted with a -ONO ₂ group; f)

—(CH ₂ -CH ₂ -T ₂ )- CH ₂ -(CH ₂ )*- f)

wherein T ₂ is -O- or -S-, -NH-, preferably T ₂ is -O-, n is 1 or

2, when Y and Y' are selected from d) , e) , e' ) or f) , the -ONO ₂ group of -(T-Y-ONO ₂ ), - (T' -Y-ONO ₂ ) , - (T"-Y' -ONO ₂ ) , - (T' -Y' -ONO ₂ ) ,

- (T"' -Y-ONO ₂ ) and - (T"' -Y' -ONO ₂ ) is linked to the -(CH ₂ )*- group .

Another embodiment of the present invention is to provide nitric oxide releasing compounds of general formula (I)

R-(Z) ₃ -R _x

(D and pharmaceutically acceptable salts or stereoisomers thereof for use in the treatment of respiratory diseases, wherein in formula (I) the corticosteroid residue R is selected from:

a is 0,

Rx is

(a2) -C(O) -CH(R ¹ ) -NH- (T' -Y-ONO ₂ ) wherein

R ¹ of of the group Al) is H T' is -C (0) -;

Y is selected from a)

- a straight or branched Ci-Cio alkylene,

- a straight or branched Ci-Cio alkylene substituted with a -ONO ₂ group;

Another embodiment relates to nitric oxide releasing compounds of general formula (I)

R-(Z) ₃ -R _x

(D and pharmaceutically acceptable salts or stereoisomers thereof for use in the treatment of respiratory diseases, wherein in formula (I) the corticosteroid residue R is selected from:

a is 0,

R _x is selected from

R _x is selected from

(a5) -R ^lb -CH (NHR ^4a ) -C (O) - (T-Y-ONO ₂ )

(a6) -R ^lb -CH(COOR ^3a ) NH- (T' -Y-ONO ₂ ) or

(a9) -R ^lb -CH (NH-T' -Y' -ONO ₂ ) -C (0) - (T-Y-ONO ₂ ) wherein

R ^lb of the group AlO) is -C(O)-CH ₂ -,

R ^3a is H or a (Ci-C ₅ ) alkyl,

R 4a is H or -C(O)CH ₃ ,

T is selected from -0-, -S-, -NR'- wherein R' is as above defined,

T' is -C(O)- and

Y and Y' are each independently selected from a)

- a straight or branched Ci-Cio alkylene,

- a straight or branched Ci-Cio alkylene substituted with a -ONO ₂ group .

Another embodiment relates to nitric oxide releasing compounds of general formula (I)

R-(Z) ₃ -R _x

(D and pharmaceutically acceptable salts or stereoisomers thereof for use in the treatment of respiratory diseases, wherein in formula (I)

the corticosteroid residue R is selected from:

a is 1 and Z is -C (0) -, R _x is

(a5) -R ^lb -CH(NHR ^4a ) -C(O) - (T-Y-ONO ₂ ) or

Ca9) -R ₅ Ib-CH (NH-T' -Y' -ONO ₂ ) -C (0) - (T-Y-ONO ₂ ; wherein R ^ii} of AlO) is -0-CH ₂ - or [-4-0-(C ₆ H ₄ ) J-CH ₂ -,

R ^4a is H or -C(O)CH ₃ ,

T is selected from -0-, -S-, -NR'- wherein R' is as above defined,

T' is -C(O)- and Y and Y' are each independently selected from a)

- a straight or branched Ci-Cio alkylene,

- a straight or branched Ci-Cio alkylene substituted with a -ONO ₂ group .

Another embodiment of the invention relates to nitric oxide releasing compounds of general formula (I)

R-(Z) ₃ -R _x

(D and pharmaceutically acceptable salts or stereoisomers thereof for use in the treatment of respiratory diseases, wherein in formula (I) the corticosteroid residue R is selected from:

a is 0, R _x is

(b2) -C (0) -CH ₂ -CH (R ² ) -NH- (T' -Y-ONO ₂ ) wherein

R ² of the group Bl) is H, T' is -C (0) -;

Y and Y' are each independently selected from a)

- a straight or branched Ci-Cio alkylene,

- a straight or branched Ci-Cio alkylene substituted with a -ONO2 group .

The most preferred nitric oxide releasing compounds of general formula (I) for the use in the treatment of respiratory diseases are:







Another object of the present invention provides nitric oxide releasing compounds of general formula (I) and pharmaceutically acceptable salts or stereoisomers thereof

R-(Z) ₃ -R _x

(D wherein R is a corticosteroid residue selected from:

a is O or 1,

Z is a group capable of binding R _x and is selected from -C(O)-, or -CH (R' ) -O- wherein R' is selected from H or a straight or branched Ci-C ₄ alkyl, preferably R' is H or -CH ₃ ;

R _x is a radical selected from the following meanings:

A)

(al) -HN-CH (R ¹ ) -C (O) - (T-Y-ONO ₂ ) (a2) -C (O) -CH (R ¹ ) -NH- (T' -Y-ONO ₂ ) (a3) -HN-CH (R ^la -T"-Y' -ONO ₂ ) -COOR ^3a (a4) -C (0) -CH (R ^la -T"-Y' -ONO ₂ ) -NHR ^4a (a5) -R ^lb -CH (NHR ^4a ) -C (0) - (T-Y-ONO ₂ ) (a6) -R -CH (COOR ^Ja ) NH- (T' -Y-ONO ₂ ; (a7) -HN-CH (R ,1 ⁱ a ^a -T"-Y' -ONO ₂ ) -C (O) - (T-Y-ONO ₂ ; (a8) -C (O) -CH (R ,1 ⁱ a ^a -T"-Y' -ONO ₂ ) -NH- (T' -Y-ONO ₂ ; (a9) -R ₅ Ib-CH (NH-T' -Y' -ONO ₂ ) -C (O) - (T-Y-ONO ₂ ; (alO) -R -CH (C (O) -T-Y' -ONO ₂ ) -NH- (T' -Y-ONO ₂ ;

wherein :

R ¹ is selected from:

Al) H, -CH ₃ , isopropyl, isobutyl, sec-butyl, tert-butyl, methylthio- (CH ₂ ) 2-, phenyl, benzyl, C ₆ H ₅ -CH ₂ -CH ₂ -, 2-monosubstituted benzyl, or 3-monosubstituted benzyl or

4- monosubstituted benzyl wherein the substituent of the benzyl is selected from -F, -Cl, I, -NO ₂ , -CF ₃ , -CH ₃ , CN, C ₆ H ₅ CO-;

2, 4-dichlorobenzyl, 3, 4-dichlorobenzyl, 3, 4-difluorobenzyl, 2-pyrrolidyl, 3-triptophanyl-CH ₂ -, 3-benzothienyl-CH ₂ -, 4-imidazolyl-CH ₂ -, 9-anthranyl-CH ₂ -, cyclohexyl, cyclohexyl-CH ₂ -, cyclohexyl- (CH ₂ ) ₂ -, cyclopentyl-CH ₂ -, (C ₆ Hs) ₂ CH-, 4-B (OH) ₂ -benzyl, 4-quinolyl-CH ₂ -, 3-quinolyl-CH ₂ -, 2-quinolyl-CH ₂ -, 2-quinoxalyl-CH ₂ -, 2-furyl-CH ₂ -, l-naphtyl-CH ₂ -, 2-naphtyl-CH ₂ - , 2-pyridyl-CH ₂ -, 3-pyridyl-CH ₂ -, 4-pyridyl-CH ₂ -, 2-thienyl-CH ₂ -, 3-thienyl-CH ₂ -, C ₆ H ₄ -CH=CH-CH ₂ -, CH ₂ =CH-CH ₂ -, CH≡CH-CH ₂ -, NH ₂ -CO-CH ₂ -, NH ₂ -CO- (CH ₂ ) ₂ -, NH ₂ (=NH) NH- (CH ₂ ) ₃ -, P (=0) (OCH ₃ ) 2, 1-CH ₂ -, preferably R ¹ is H, -CH ₃ , isopropyl, benzyl;

A2) -CH ₂ -SH, -CH ₂ -OH, -CH (CH ₃ ) -OH, -CH ₂ [ (C ₆ H ₄ ) - (4-OH) ], -CH ₂ - [ (C ₆ H ₂ ) - (3, 5-diiodo) - (4-OH) ] ,

-CH ₂ - [ (C ₆ H ₃ ) - (3-nitro) - (4-OH) ] , preferably R ¹ is -CH ₂ -OH or -CH ₂ [ (C ₆ H ₄ ) - (4-0H) ] ; A3) -CH ₂ -NHR", - (CH ₂ ) ₂ -NHR", - (CH ₂ ) ₃ -NHR", - (CH ₂ ) ₄ -NHR", wherein R" is H, -C(O)CH ₃ or

wherein R ^5a is H or a linear or branched Ci-Cio alkyl chain, pprreeffeerraabbllyy RR ^55aa iiss HH oorr aa lliinneeaarr ((CCii--CC ₅₅ )) aallkkyy!l, preferably R ¹ is - (CH ₂ ) ₄ -NHR", wherein R" is as above defined,

A4) -CH ₂ -C(O)R"', - (CH ₂ ) 2-C(O) R"' , - (CH ₂ ) ₄ -C (O) R"' wherein R"' is -OR 5a or

wherein R ^5a is as above defined, preferably R ¹ is -CH ₂ -C(O)R"', wherein R"' is as above defined, R ^la is selected from:

A5) -CH ₂ -S-, -CH ₂ -O-, -CH(CH ₃ )-O-, -CH ₂ [ (C ₆ H ₄ ) - (4-0) -], -CH ₂ - [ (3, 5-diiodo) - (C ₆ H ₂ ) - (4-0) -] ,

-CH ₂ - [ (3-nitro) - (C ₆ H ₃ ) - (4-0) -], preferably R ^la is -CH ₂ -O-; A6) -CH ₂ -NH-, - (CH ₂ ) ₂ -NH-, - (CH ₂ ) ₃ -NH-, - (CH ₂ ) ₄ -NH-, preferably R ^la is -(CH ₂ J ₄ -NH- or -CH ₂ -NH-,

A7) -CH ₂ -C(O)-, - (CH ₂ ) ₂ -C(O) -, - (CH ₂ ) ₄ -C (0) -, preferably R ^la is -CH ₂ -C(O)-;

R ^3a is selected from H, -R ^5a or

wherein R ^5a is as above defined,

R ^4a is selected from H or -C(O)CH ₃ or

wherein R ^5a is as above defined, R ^lb is selected from

A8) -S-CH ₂ -, -0-CH(CH ₃ )-, -0-CH ₂ -, [-(4-O)-(C ₆ H ₄ )J-CH ₂ -, [- (4-0) - (3, 5-diiodo) - (C ₆ H ₂ ) ] -CH ₂ -,

[- (4-0) - (3-nitro) - (C ₆ H ₃ ) ] -CH ₂ -, preferably R ^lb is -0-CH ₂ - or [-(4-O)-(C ₆ H ₄ ) J-CH ₂ -;

A9 ) -HN-CH ₂ - , -HN- ( CH ₂ ) ₂ - , -HN- ( CH ₂ ) ₃ - , -HN- ( CH ₂ ) ₄ " , pre ferabl y

R ^lb i s -HN- ( CH ₂ ) ₄ - or -HN-CH ₂ - ;

AlO) -C(O)-CH ₂ -, -C(O) - (CH ₂ ) ₂ -, -C (O) - (CH ₂ ) ₄ -, preferably R ^lb is -C(O)-CH ₂ -; T is selected from -O-, -S-, -NR'-, -O-CH (R' ) -O-C (O) - or -O-CH (R' ) -0-C (0) 0- wherein R' is as above defined; T' is -C(O)-, -C(O)-X"- wherein X" is -0- or -S-, or T' is -C (0) -NR' - wherein R' is as above defined; T" is independently selected from -C(O)-, -C(O)-X"-, -C(O)-NR'-, -0-, -S-, -NR'-, -O-CH (R' ) -0-C (0) -,

-O-CH (R' ) -0-C (0) 0-, wherein X" and R' are as above defined, with the proviso that T" is -C(O)-, -C(O)-X"- or -C(O)-NR'- when T" is linked to -NH-, -0-, or -S-, or

T" is -0-, -S-, -NR'-, -0-CH(R' ) -0-C (0) -, -O-CH (R' ) -C-C (0) 0- when T" is linked to -C(O)-, Y and Y' are as below defined; or R _x is selected from: B)

(bl) -HN-CH (R ² ) -CH ₂ -C (0) - (T-Y-ONO ₂ ) (b2) -C (0) -CH ₂ -CH(R ² ) -NH- (T' -Y-ONO ₂ ) (b3) -HN-CH (R ^2a -τ"-Y' -ONO ₂ ) -CH ₂ COOR ^3a (b4) -C (0) -CH ₂ -CH (R ^2a -T"-Y' -ONO ₂ ) -NHR ^4a (b5) -R ^2b -CH (NHR ^4a ) -CH ₂ -C (0) - (T-Y-ONO ₂ ) (b6) -R ^2b -CH (CH ₂ COOR ^3a ) NH- (T' -Y-ONO ₂ ) (b7) -HN-CH (R ^2a -T"-Y' -ONO ₂ ) -CH ₂ -C(O) - (T-Y-ONO ₂ ) (b8) -C (0) -CH ₂ -CH (R ^2a -τ"-Y' -ONO ₂ ) -NH- (T' -Y-ONO ₂ ) (b9) -R ^2b -CH (NH-T' -Y' -ONO ₂ ) -CH ₂ C (0) - (T-Y-ONO ₂ ) (blO) -R ^2b -CH (CH ₂ C (0) -T-Y' -ONO ₂ ) -NH- (T' -Y-ONO ₂ ) wherein R ² is selected from:

Bl) H, -CH ₃ , CF ₃ , isopropyl, isobutyl, sec-butyl, methylthio- (CH ₂ ) ₂ -, phenyl, benzyl, 3-triptophanyl-CH ₂ -,

NH ₂ -C ( O) -CH ₂ - , NH ₂ -C ( O) - ( CH ₂ ) 2" , NH ₂ ( =NH) NH- ( CH ₂ ) ₃ - , tBuO-CH ( CH ₃ ) -

, benzyl-O-CH ₂ -, 4-terbutoxy-benzyl, 4-phenylbenzyl, preferably R ² is H, -CH ₃ , isopropyl, benzyl,

B2) -CH ₂ -SH, -CH ₂ -OH, -CH (CH ₃ ) -OH, -CH ₂ [ (C ₆ H ₄ ) - (4-OH) ], -CH ₂ - [ (C ₆ H ₂ ) - (3, 5-diiodo) - (4-OH) ] , -CH ₂ - [ (C ₆ H ₃ ) - (3-nitro) - (4-OH) ] ;

B3) -CH ₂ -NHR", - (CH ₂ ) ₂ -NHR", - (CH ₂ ) ₃ -NHR", - (CH ₂ ) ₄ -NHR", wherein R" is as above defined, preferably R ² is - (CH ₂ ) ₄ -NHR";

B4) -CH ₂ -C(O)-R"', - (CH ₂ ) 2-C(O) -R"' , -(CH ₂ J ₄ -C(O)-R"' wherein R"' is as above defined, preferably R ² is -CH ₂ -C(O)-R"'; R ^2a is selected from:

B5) -CH ₂ -S-, -CH ₂ -O-, -CH (CH ₃ ) -0- or -CH ₂ [ (C ₆ H ₄ ) - (4-0) -], -CH ₂ - [ (3, 5-diiodo) - (C ₆ H ₂ ) - (4-0) -] ,

-CH ₂ - [ (3-nitro) - (C ₆ H ₃ ) - (4-0) -], preferably R ^2a is -CH ₂ -O-; B6) -CH ₂ -NH-, - (CH ₂ ) 2-NH-,- (CH ₂ ) 3-NH-, -(CH ₂ J ₄ -NH-, preferably R ^2a is - (CH ₂ ) ₄ -NH- or -CH ₂ -NH-;

B7) -CH ₂ -C(O)-, - (CH ₂ ) 2-C(O) -, - (CH ₂ ) ₄ -C (0) -, preferably R ^2a is -CH ₂ -C(O)-; R ^2b is selected from B8) -S-CH ₂ -, -0-CH(CH ₃ )-, -0-CH ₂ -, [-(4-O)-(C ₆ H ₄ )J-CH ₂ -,

[- (4-0) - (3, 5-diiodo) - (C ₆ H ₂ ) ] -CH ₂ -, [- (4-0) - (3-nitro) - (C ₆ H ₃ ) ] -CH ₂ - , preferably R ^2b is -0-CH ₂ - or [-(4-O)-(C ₆ H ₄ )J-CH ₂ -;

B9) -HN-CH ₂ -, -HN- (CH ₂ ) ₂ -, -HN- (CH ₂ ) ₃ -, -HN- (CH ₂ ) ₄ -, preferably R ^2b is -HN- (CH ₂ ) ₄ - or -HN-CH ₂ -; BlO) -C(O)-CH ₂ -, -C(O) - (CH ₂ ) ₂ -, -C (0) - (CH ₂ ) ₄ -, preferably R ^2b is -C(O)-CH ₂ -;

R ^3a and R ^4a are as above defined;

T, T' and T" are as above defined and Y and Y' are as below defined; or R _x is selected from: C)

(cl) -HN- (CH ₂ ) _b -C (0) - (T-Y-ONO ₂ ) ; (c2) -C (0) - (CH ₂ ) _b -NH- (T' -Y-ONO ₂ ) ; wherein b is an integer from 3 to 6,

T and T' are as above defined and Y and Y' are as below defined;

D)

(dl) -HN-CH (R ¹² ) -CH ₂ -O- (T"' -Y-ONO ₂ )

(d2) -0-CH ₂ -CH (R ¹² ) -NH- (T' -Y-ONO ₂ ) (d3) -HN-CH (R ^12a -T"-Y' -ONO ₂ ) -CH ₂ OH

(d4) -0-CH ₂ -CH (R ^12a -τ"-Y' -ONO ₂ ) -NHR ^4a

(d5) -R ^12b -CH (NHR ^4a ) -CH ₂ -O- (T"' -Y-ONO ₂ )

(d6) -R ^12b -CH (CH ₂ OH) -NH- (T' -Y-ONO ₂ )

(d7) -HN-CH (R ^12a -τ"-Y' -ONO ₂ ) -CH ₂ -O- (T"' -Y-ONO ₂ ) (d8) -0-CH ₂ -CH (R ^12a -T"-Y' -ONO ₂ ) -NH- (T' -Y-ONO ₂ )

(d9) -R ^12b -CH (NH-T' -Y' -ONO ₂ ) -CH ₂ -O- (T"' -Y-ONO ₂ )

(dlO) -R ^12b -CH (CH ₂ -O-T"' -Y' -ONO ₂ ) -NH- (T' -Y-ONO ₂ ) wherein

T"' is independently selected from -C(O)-, -C(O)X"- wherein X" is -O- or -S-, or -C(O)-NR'- wherein R' is as above defined;

T' and T" are as above defined,

Y and Y' are as below defined;

R ¹² is selected from:

Dl) H, -CH ₃ , isopropyl, isobutyl, sec-butyl, methylthio- (CH ₂ ) ₂ -, benzyl, 3-triptophanyl-CH ₂ -,

4-imidazolyl-CH ₂ -, NH ₂ -CO-CH ₂ -, NH ₂ -CO- (CH ₂ ) ₂ -, NH ₂ (=NH) NH- (CH ₂ ) ₃ -

, preferably R ¹² is H;

D2) -CH ₂ -OH, -CH(CH ₃ )-OH, -CH ₂ [ (C ₆ H ₄ ) - (4-OH) ] ,

-CH ₂ - [ (C ₆ H ₃ ) - (3, 5-diiodo) - (4-OH) ] , -CH ₂ - [ (C ₆ H ₃ ) - (3-nitro) - (4-OH) ] , preferably R ¹² is -CH ₂ -OH or -

CH ₂ [ (C ₆ H ₄ ) - (4-OH) ] ;

D3) -CH ₂ -NHR", - (CH ₂ ) ₂ -NHR", - (CH ₂ ) ₃ -NHR", - (CH ₂ ) ₄ -NHR", wherein

R" is as above defined, preferably R ¹² is - (CH ₂ ) ₄ -NHR";

D4) -CH ₂ -C(O)R"', -(CH ₂ ) ₂ -C(O)R"', - (CH ₂ ) ₄ -C (0) R"' wherein R"' is as above defined, preferably R ¹² is -CH ₂ -C(O)R"';

R ^12a is selected from

D5) -CH ₂ -O-, -CH (CH ₃ ) -0- or -CH ₂ [ (C ₆ H ₄ ) - (4-0) -], -CH ₂ - [3,5- di_iiooddoo-- ((CC ₆₆ HH ₂₂ )) -- ((44--00)) --]],, --CCHH ₂₂ -- [[33--nniitro- (C ₆ H ₃ ) -4-0- ] , preferably R 12a is CH ₂ -O- or -CH ₂ [ (C ₆ H ₄ ) - (4-0) -],

D6) -CH ₂ -NH-, - (CH ₂ ) ₂ -NH-, -(CH ₂ ) ₃ "NH-, -(CH ₂ J ₄ -NH-, preferably

R ^12a is - (CH ₂ ) ₄ -NH- or -CH ₂ -NH-,

D7) -CH ₂ -C(O)-, - (CH ₂ ) ₂ -C(O) -, - (CH ₂ ) ₄ -C (O) -, preferably R ^12a is -CH ₂ -C(O)-, R ^12b is selected from

D8) -0-CH ₂ -, -0-CH(CH ₃ )-, [-(4-O)-(C ₆ H ₄ )J-CH ₂ -,

[- (4-0) - (3, 5-diiodo) - (C ₆ H ₂ ) ] -CH ₂ , [- (4-0) - (3-nitro) - (C ₆ H ₃ ) ] -CH ₂ -, preferably R ^12b is -0-CH ₂ - or [-(4-O)-(C ₆ H ₄ )J-CH ₂ -;

D9) -HN-CH ₂ -, -HN- (CH ₂ ) ₂ -, -HN- (CH ₂ ) ₃ -, -HN- (CH ₂ ) ₄ -, preferably R ^12b is -HN- (CH ₂ ) ₄ - or -HN-CH ₂ -;

DlO) -C(O)-CH ₂ -, -C(O) - (CH ₂ ) ₂ -, -C (0) - (CH ₂ ) ₄ -, preferably R ^12b is -C(O)-CH ₂ -; R ^4a is as above defined;

wherein c is equal to 0 or 1, d is an integer from 0 to 3 with the proviso that c is 0 or 1 when d is 0 and c is 0 when d is 1, 2 or 3, T and T' are as above defined and Y is as below defined; F) (fl)

wherein e and f are equal to 0 or 1, with the proviso that f is 0 when e is 0 and f is 0 or 1 when e is 1, T and T' are as above defined and Y is as below reported; G)

wherein R ³ is H, CH ₃ , propyl, (C ₆ Hs) ₂ CH-, l-naphtyl-CH ₂ -, benzyl, allyl, 2-bromobenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-fluorobenzyl, 4-bromobenzyl, 4-methylbenzyl, preferably R ³ is H, T and T' are as above defined and Y is as below defined; H)

wherein R ⁴ is H, benzyl, 4-bromobenzyl, 2-bromobenzyl, T and T' are as above defined and Y is as below defined;

D

wherein R ⁵ is H, R is H, or R ⁵ and R when taken together are a double bond, T and T' are as above defined and Y is as below reported; L)

wherein T and T' are as above defined and Y is as below reported; M)

wherein T and T' are as above defined and Y is as below

wherein c is as above defined, d is equal to 0 or 1, T and T' are as above defined and Y is as below reported; 0)

wherein R ⁷ is H, R ⁸ is H, or R ⁷ and R ⁸ when taken together are a double bond, c is as above defined, T and T' are as above defined and Y is as below reported;

P)

wherein T and T' are as above defined and Y is as below reported; Q)

wherein T and T' are as above defined and Y is as below reported; R)

wherein T and T' are as above defined and Y is as below reported;

S)

wherein T and T' are as above defined and Y is as below reported;

T)

wherein T and T' are as above defined and Y is as below reported; U)

wherein R ⁹ and R ¹⁰ are H, CH ₃ , R ¹¹ i s CH ₃ or 4 -piperidinyl with the provi so that R ⁹ and R ¹⁰ are H when R ¹¹ i s 4 -piperidinyl and R ⁹ and R ¹⁰ are CH ₃ when R ¹¹ i s CH ₃ , T and T ' are as above def ined and Y i s as below reported; V)

wherein T and T' are as above defined and Y is as below reported; with the proviso that in the formula (I) : a is 0 or a is 1 and Z is -CH(R')~O- wherein R' is as above defined, when R _x is:

- (a2), (a4) or (a8);

- (a5) , (a6) , (a9) or (alO) and R ^lb is selected from the group AlO) ;

- (b2), (b4) or (b8); - (b5), (b6) , (b9) or (blO) and R ^2b is selected from the group BlO) ;

- (c2);

- (d5), (d6) , (d9) or (dlO) and R ^12b is selected from the group DlO) ;

- (e2), (fl), (g2), (hi), (il), (12), (m2), (n2), (o2), ( _P 2),

(q2), (r2), (s2), (tl) or (u2); a is 1 and Z is -C(O)-, when R _x is:

- (al), (a3) or (a7); - (a5) , (a6) , (a9) or (alO) and R ^lb is selected from the groups A8) and A9) ;

- (bl), (b3) or (b7);

- (b5) , (b6) , (b9) or (blO) and R ^2b is selected from the groups B8) or B9) ; - (cl) ;

- (dl), (d2), (d3), (d4), (d7) or (d8) ;

- (d5), (d6) , (d9) or (dlO) and R ^12b is selected from the groups D8) or D9) ;

- (el), (f2), (gl), (h2), (12), (11), (ml), (nl), (ol), (pi), (ql), (rl), (si), (t2) or (ul) .

Y and Y' are bivalent radicals each independently selected from the following meanings: a)

- straight or branched C1-C20 alkylene, preferably a straight or branched C1-C10 alkylene,

- straight or branched C1-C20 alkylene substituted with one or more of the substituents selected from the group consisting of: halogen atoms, hydroxy, -ONO2 or T ₂ , wherein T ₂ is -OC(O) (C1-C10 alkyl)-ONO ₂ or -0(Ci-Ci ₀ alkyl)-ONO ₂ , preferably Y or Y' is a straight or branched C1-C10 alkylene substituted with a -ONO ₂ group;

- cycloalkylene with 5 to 7 carbon atoms into cycloalkylene ring, the ring being optionally substituted with one or more straight or branched C1-C10 alkyl chains, preferably the ring being optionally substituted with CH ₃ ; b)

wherein n is an integer from 0 to 20, preferably n is 0 or 1 ; n ¹ is 0 or 1, preferably n ¹ is 1 ;

U is a linear or branched C1-C20 alkylene optionally substituted with a -ONO2 group, preferably U is a linear C1-C10 alkylene or U is a linear or branched C1-C10 alkylene substituted with a -ONO2 group; c)

wherein n ⁰ is an integer from 0 to 20, preferably n ⁰ is 0 or 1 ; n ¹ is 0 or 1, preferably n ¹ is 1 ;

U is a linear or branched C1-C20 alkylene optionally substituted with a -ONO2 group, preferably U is a linear C1-C10 alkylene or U is a linear or branched C1-C10 alkylene substituted with a -ONO2 group; d)

wherein : n ² i s an integer from 0 to 2 , R ¹³ i s H or CH ₃ , Ti i s -0-C ( O) - or

-C ( O) O- ; n ¹ and U are as above defined;

n ² is an integer from 0 to 2, preferably n ² is 1 ; R ¹³ is H or CH ₃ , preferably R ¹³ is CH ₃ ;

Y ¹ is -CH ₂ -CH ₂ - or -CH=CH- (CH ₂ ) _n ^2' -, wherein n ^2' is 0 or 1, preferably Y ¹ is -CH=CH- (CH ₂ ) _n ^2' - and n ^2' is 0 ;

T ₁ = -0-C(O)- or -C(O)O-, preferably T ₁ is -C(O)O-; n ¹ is 0 or 1, preferably n ¹ is 1; U is a linear or branched C ₁ -C ₂ O alkylene optionally substituted with a -ONO ₂ group, preferably U is a linear C ₁ -C ₁ O alkylene or U is a linear or branched C ₁ -C ₁ O alkylene substituted with a -ONO ₂ group; more preferably n ² is 1 , R ¹³ is CH ₃ , Y ¹ is -CH=CH- (CH ₂ ) _n ^{2 '} - and n ^{2 '} is 0 , T ₁ is -C (O) O- and U is a linear C ₁ -C ₁ O alkylene ; e ' )

wherein : n ² is an integer from 0 to 2, preferably n ² is 1;

R ¹³ is H or CH ₃ , preferably R ¹³ is CH ₃ ;

Y ¹ is -CH ₂ -CH ₂ - or - (CH ₂ ) _n ^2' -CH=CH-, wherein n ^2' is 0 or 1, preferably Y ¹ is - (CH ₂ ) _n ^2' -CH=CH- and n ^2' is 0;

T ₁ = -O-C(O)-; n ¹ is 0 or 1, preferably n ¹ is 1;

U is a linear or branched C ₁ -C ₂ O alkylene optionally substituted with a -ONO ₂ group, preferably U is a linear C ₁ -C ₁ Q alkylene or U

is a linear or branched Ci-Cio alkylene substituted with a -ONO2 group; more preferably n ² is 1, R ¹³ is CH ₃ , Y ¹ is -CH=CH- (CH ₂ ) _n ^2' - and n ^2' is 0, Ti is -OC(O)- and U is a linear C ₁ -C ₁ 0 alkylene; f)

—(CH ₂ -CH ₂ -T ₂ )- CH ₂ -(CH ₂ )*—

f) wherein T ₂ is -O- or -S-, -NH-, preferably T ₂ is -O-, n is an integer from 1 to 6, preferably n ³ is 1; when Y and Y' are selected from b) , c) , d) , e) , e' ) or f) , the -ONO ₂ group of -(T-Y-ONO ₂ ), - (T' -Y-ONO ₂ ) , - (T"-Y' -ONO ₂ ) , -(T' -Y'- ONO ₂ ), - (T"' -Y-ONO ₂ ) and - (T"' -Y' -ONO ₂ ) is linked to the -(CH ₂ )*- group; g)

wherein : n ⁴ is an integer from 0 to 10, preferably n ⁴ is 0 or 1; n ⁵ is an integer from 1 to 10, preferably n ⁵ is 1; R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ are the same or different, and are H or straight or branched Ci-C ₄ alkyl, preferably R ¹⁴ , R ¹⁵ , R ¹⁶ and R ¹⁷ are H; wherein the -ONO ₂ group is linked to

wherein n ⁵ is as defined above;

Y ² is an heterocyclic saturated, unsaturated or aromatic 5 or 6 members ring, containing one or more heteroatoms selected from nitrogen, oxygen, sulphur,

and is selected from the group consisting of:

Another object of the present invention provides nitric oxide releasing compounds of general formula (I) and pharmaceutically acceptable salts or stereoisomers thereof

R-(Z) ₃ -R _x

(D wherein R is a corticosteroid residue selected from:

a is 0 and R _x is selected from: (a2) -C (O) -CH (R ¹ ) -NH- (T' -Y-ONO ₂ ) wherein R ¹ of the group Al) is selected from H, isobutyl, benzyl,

CeH ₅ -CH ₂ -CH ₂ -, 2-monosubstituted benzyl, or 3-monosubstituted benzyl or 4- monosubstituted benzyl wherein the substituent of the benzyl is selected from -F, -Cl, I, -NO ₂ , -CF ₃ , -CH ₃ , CN,

C ₆ H ₅ CO-;

R ¹ of the group A2) is selected from -CH ₂ -OH, -CH(CH ₃ )OH- or

-CH ₂ [ (C ₆ H ₄ ) -(4-0H) ], or R ¹ of the group A3) is selected from -CH ₂ -NHR", - (CH ₂ ) ₂ -NHR",

-(CH ₂ ) ₃ -NHR", - (CH ₂ ) ₄ -NHR", wherein R" is H, or -C(O)CH ₃ ;

R ¹ of the group A4) is selected from -CH ₂ -C(O)R"',

- (CH ₂ ) 2-C(O) R"' , - (CH ₂ ) 4-C (O)R"' wherein R"' is 0R ^5a wherein R ^5a is H or a linear (Ci-C ₅ ) alkyl; T' is -C(O)-, -C(O)-X" wherein X" is -S- or -0-, preferably T' is -C(O)-;

Y is as below defined; or R _x is

(a4) -C (0) -CH (R ^la -τ"-Y' -ONO ₂ ) -NHR ^4a wherein R ^la of the group A5) is selected from -CH ₂ -O-, -CH (CH ₃ )O- or -CH ₂ [ (C ₆ H ₄ )- (4-0)-] , or

R ^la of the group A6) is selected from -CH ₂ -NH-, - (CH ₂ ) ₂ -NH-,

- ( CH ₂ ) _S -NH- , - ( CHs ) ₄ -NH- , or

R ^la of the group A7) is selected from -CH ₂ -C(O)-, - (CH ₂ ) ₂ -C (0) -, -(CHz) ₄ -C(O)-, R ^4a is H or -C(O)CH ₃ , T" is -C(O)- or -C(O)-X" wherein X" is -S- or -0-, when R ^la is selected from the group A5) or A6) , preferably T" is -C(O)-; T" is -0-, -S-, -NR'- or -O-CH (R' ) -0-C (0) - wherein R' is H or -CH ₃ , when R ^la is selected from the group A7), Y' is as below defined; or R _x is selected from:

(a5) -R ^lb -CH (NHR ^4a ) -C (0) - (T-Y-ONO ₂ ) (a6) -R ^lb -CH (COOR ^3a ) NH- (T' -Y-ONO ₂ ) (a9) -R ^lb -CH (NH-T' -Y' -ONO ₂ ) -C (0) - (T-Y-ONO ₂ ) or (alO) -R ^lb -CH (C (0) -T-Y' -ONO ₂ ) -NH- (T' -Y-ONO ₂ ) wherein

R ^lb of the group AlO) is selected from -C(O)-CH ₂ -, -C (0) - (CH ₂ ) ₂ -,

-C ⁽ O ⁾ - ⁽ CHz ⁾ ₄ -,

R ^3a is H or a (Ci-C ₅ ) alkyl, R ^4a is H or -C(O)CH ₃ ,

T is -0-, -S-, -NR'- or -O-CH (R' ) -0-C (0) - wherein R' is H or

-CH ₃ , preferably T is -0-,

T' is -C(O)- or -C(O)-X" wherein X" is -S- or -0-, preferably T' is -C(O)-, Y and Y' are as below defined; or R _x is

(a8) -C (0) -CH (R ^la -τ"-Y' -ONO ₂ ) -NH- (T' -Y-ONO ₂ ) wherein

R ^la of the group A5) is selected from -CH ₂ -O-, -CH (CH ₃ ) -0- or -CH ₂ [ (C ₆ H ₄ ) - (4-0) -], or

R ^la of the group A6) is selected from -CH ₂ -NH-, - (CH ₂ ) ₂ -NH-,

- (CH ₂ ) 3-NH-, -(CH ₂ ) ₄ -NH-, or

R ^la of the group A7) is selected from -CH ₂ -C(O)-, - (CH ₂ ) ₂ -C (0) -,

-(CHz) ₄ -C(O)-,

T" is -C(O)- or -C(O)-X" wherein X" is -S- or -0-, when R ^la is selected from the group A5) or A6) , preferably T" is -C(O)-,

T" is -0-, -S-, -NR'- or -O-CH (R' ) -0-C (0) - wherein R' is H or -

CH ₃ , when R ^la is selected from the group A7) ; T' is -C(O)- or -C(O)-X" wherein X" is -S- or -0-, preferably T' is -C(O)-,

Y and Y' are as below defined, or R _x is

(b2) -C (0) -CH ₂ -CH (R ² ) -NH- (T' -Y-ONO ₂ ) wherein

R ² of the group Bl) is selected from H, CH ₃ , isobutyl, isopropyl, benzyl;

T' is -C(O)-, -C(O)-X" wherein X" is -S- or -0-, preferably T' is -C(O)-; Y and Y' are each independently selected from a)

- a straight or branched C1-C10 alkylene,

- a straight or branched C1-C10 alkylene substituted with a -ONO ₂ group; d)

n ² is an integer from 0 to 2, R ¹³ is H or CH ₃ , Ti is -0-C(O)- or -C(O)O-; n ¹ is 1 and U is a linear C1-C10 alkylene or U is a linear or branched C1-C10 alkylene substituted with a -ONO ₂ group; e)

n is 1, R ¹³ is CH ₃ , Y ¹ is -CH=CH- (CH ₂ ) _n ^2' - and n ^2' is 0, T ₁ is -C(O)O- and U is a linear Ci-Cio alkylene; e' )

wherein : n ² is 1, R ¹³ is CH ₃ ; Y ¹ is - (CH ₂ ) _n ^2' -CH=CH- and n ^2' is O ; T ₁ = -O-C(O) -; n ¹ is 1 and U is a linear C ₁ -C ₁ O alkylene or U is a linear or branched C ₁ -C ₁ O alkylene substituted with a -ONO ₂ group; f) — (CH ₂ -CH ₂ -T ₂ )- CH ₂ -(CH ₂ )*-

f) wherein T ₂ is -O- or -S-, -NH-, preferably T ₂ is -O-, n ³ is 1 or 2; when Y and Y' are selected from d) , e) , e' ) or f) , the -ONO ₂ group of -(T-Y-ONO ₂ ), - (T' -Y-ONO ₂ ) , - (T"-Y' -ONO ₂ ) , - (T' -Y' -ONO ₂ ) , - (T"' -Y-ONO ₂ ) and - (T"' -Y' -ONO ₂ ) is linked to the -(CH ₂ )*- group .

Another object of the present invention provides nitric oxide releasing compounds of general formula (I) and pharmaceutically acceptable salts or stereoisomers thereof R-(Z) ₃ -Rx

(D wherein R is a corticosteroid residue selected from:

a is 1 and Z is -C (O) - _; R _x is

(al) -HN-CH(R ¹ ) -C(O) - (T-Y-ONO ₂ ) wherein R ¹ of the group Al) is selected from H, isobutyl, benzyl, C ₆ H ₅ - CH ₂ -CH ₂ -, 2-monosubstituted benzyl, or 3-monosubstituted benzyl or 4- monosubstituted benzyl wherein the substituent of the benzyl is selected from -F, -Cl, I, -NO ₂ , -CF ₃ , -CH ₃ , CN, C ₆ H ₅ CO- or R ¹ of of the group A2) is selected from: -CH ₂ -OH, -CH (CH ₃ ) -OH- or -CH ₂ [ (C ₆ H ₄ ) - (4-OH) ], or

R ¹ of the group A3) is selected from -CH ₂ -NHR", - (CH ₂ ) ₂ -NHR",

-(CH ₂ ) ₃ -NHR", - (CH ₂ ) ₄ -NHR", wherein R" is H, or -C(O)CH ₃ ,

R ¹ of the group A4) is -CH ₂ -C(O)R"', - (CH ₂ ) ₂ -C (0) R"' ,

- (CH ₂ ) ₄ -C (O)R"' wherein R"' is 0R ^5a wherein R ^5a is H or a linear (Ci-C ₅ ) alkyl;

T is -O-, -S-, -NR'-, -0-CH(R' ) -O-C(O) - wherein R' is H or a straight or branched Ci-C ₄ alkyl, preferably T is -O-,

Y is as below defined; or R _x is (a3) -HN-CH (R ^la -T"-Y' -ONO ₂ ) -COOR ^3a wherein

R ^la of the group A5) is selected from -CH ₂ -O-, -CH(CH ₃ )O- or

-CH ₂ [ (C ₆ H ₄ ) -(4-0)-], or

R ^la of the group A6) is selected from -CH ₂ -NH-, - (CH ₂ ) ₂ -NH-, - (CH ₂ ) 3-NH-, - (CH ₂ ) 4-NH-, or

R ^la of the group A7) is -CH ₂ -C(O)-, - (CH ₂ ) ₂ -C (0) -, - (CH ₂ ) ₄ -C (0) -,

R ^3a is H or a (Ci-C ₅ ) alkyl,

T" is -C(O)- or -C(O)-X" wherein X" is -S- or -0-, when R ^la is selected from the group A5) or A6) , preferably T" is -C(O)-; T" is -0-, -S-, -NR'-, -0-CH(R' ) -O-C(O) - wherein R' is H or a straight or branched Ci-C ₄ alkyl, when R ^la is selected from the group A7) ;

Y' is as below defined; or R _x is selected from. (a5) -R ^lb -CH(NHR ^4a ) -C (0) - (T-Y-ONO ₂ )

(a6) -R ^lb -CH (COOR ^3a ) NH- (T' -Y-ONO ₂ )

(a9) -R ^lb -CH (NH-T' -Y' -ONO ₂ ) -C (0) - (T-Y-ONO ₂ ) or

(alO) -R ^lb -CH (C (0) -T-Y' -ONO ₂ ) -NH- (T' -Y-ONO ₂ ) wherein R ^lb of the group A8) is selected from -0-CH(CH ₃ )-, -0-CH ₂ -,

[-4-O)-(C ₆ H ₄ )J-CH ₂ -, or

R ^lb of the group A9) is selected from -HN-CH ₂ -, -HN- (CH ₂ ) ₂ -,

-HN- (CH ₂ ) ₃ -, -HN- (CH ₂ ) 4-,

R ^3a is H or a (Ci-C ₅ ) alkyl, R ^4a is H or -C(O)CH ₃ ,

T is -0-, -S-, -NR'-, -0-CH(R' ) -O-C(O) - wherein R' is H or a straight or branched Ci-C ₄ alkyl, preferably T is -0-,

T' is -C(O)- or -C(O)-X" wherein X" is -S- or -0-, preferably T' is -C(O)-,

Y and Y' are as below defined; or R _x is

(a7) -HN-CH (R ^la -τ"-Y' -ONO ₂ ) -C (0) - (T-Y-ONO ₂ ) wherein R ^la of the group A5) is selected from -CH ₂ -O-, -CH (CH ₃ ) -0- or -CH ₂ [ (C ₆ H ₄ ) -(4-0)-], or R ^la of the group A6) is selected from -CH ₂ -NH-, - (CH ₂ ) ₂ -NH-,

- (CH ₂ ) 3-NH-, - (CH ₂ ) 4-NH-, or

R ^la of the group A7) is -CH ₂ -C(O)-, - (CH ₂ ) ₂ -C (0) -, - (CH ₂ ) ₄ -C (0) -; T" is -C(O)- or -C(O)-X", wherein X" is -S- or -0-, when R ^la is selected from A5) or A6) , preferably T" is -C(O)-

T" is -0-, -S-, -NR'-, -0-CH(R' ) -O-C(O) -, wherein R' is H or a straight or branched Ci-C ₄ alkyl, when R ^la is selected from A7), preferably T" is -0-, T is -0-, -S-, -NR'-, -0-CH(R' ) -O-C(O) - wherein R' is H or a straight or branched Ci-C ₄ alkyl, preferably T is -0-;

Y and Y' are as below defined; or R _x is

(bl) -HN-CH (R ² ) -CH ₂ -C (0) - (T-Y-ONO ₂ ) wherein

R ² of the group Bl) is selected from H, CH ₃ , isobutyl, isopropyl, benzyl;

R ² of the group B2) is selected from -CH ₂ -OH, -CH (CH ₃ ) -OH- or

-CH ₂ [ (C ₆ H ₄ ) (4-OH) ] , or R ² of the group B3) is selected from -CH ₂ -NHR", - (CH ₂ ) ₂ -NHR",

-(CH ₂ ) ₃ -NHR", - (CH ₂ ) ₄ -NHR", wherein R" is H, or -C(O)CH ₃ ,

R ² of the group B4) is -CH ₂ -C(O)R"', -(CH ₂ J ₂ -C(O)R'",

- (CH ₂ ) ₄ -C (O)R"' wherein R"' is 0R ^5a wherein R ^5a is H or a linear (Ci-C ₅ ) alkyl; T is -0-, -S-, -NR'-, -0-CH(R' ) -O-C(O) - wherein R' is H or a straight or branched Ci-C ₄ alkyl, preferably T is -0-,

Y is as below defined; or R _x is selected from

(dl) -HN-CH(R ¹² ) -CH ₂ -O- (T"' -Y-ONO ₂ ) or

( d2 ) -0-CH ₂ -CH ( R ¹² ) -NH- ( T ' -Y-ONO ₂ ) where in

R ¹² of the group Dl) is selected from H, CH ₃ , isobutyl, isopropyl, benzyl, or R ¹² of the group D2) is selected from -CH ₂ -OH, -CH(CH ₃ )OH- or

-CH ₂ [ (C ₆ H ₄ ) -(4-0H) ], or

R ¹² of the group D3) is selected from -CH ₂ -NHR", - (CH ₂ ) ₂ -NHR",

-(CH ₂ ) ₃ -NHR", - (CH ₂ ) ₄ -NHR" wherein R" is H, or

R ¹² of the group D4) is -CH ₂ -C(O)R"', - (CH ₂ ) ₂ -C (0) R"' , - (CH ₂ ) ₄ -C (O)R"' wherein R"' is 0R ^5a wherein R ^5a is H or a linear

(Ci-C ₅ ) alkyl;

T' and T"' are each independently selected from -C(O)- or

-C(O)-X" wherein X" is -S- or -0-, preferably T' and T"' are

-C(O)-, Y is as below defined; or R _x is selected from:

(d3) -HN-CH (R ^12a -τ"-Y' -ONO ₂ ) -CH ₂ OH

(d4) -0-CH ₂ -CH (R ^12a -τ"-Y' -ONO ₂ ) -NHR ^4a

(d7) -HN-CH (R ^12a -T"-Y' -ONO ₂ ) -CH ₂ -O- (T"' -Y-ONO ₂ ) or (d8) -0-CH ₂ -CH (R ^12a -T"-Y' -ONO ₂ ) -NH- (T' -Y-ONO ₂ ) wherein

R ^12a of the group D5) is selected from -CH ₂ -O-, -CH (CH ₃ ) -0- or

-CH ₂ [ (C ₆ H ₄ ) -(4-0)-], or

R ^12a of the group D6) is selected from -CH ₂ -NH-, - (CH ₂ ) ₂ -NH-, - (CH ₂ ) 3-NH-, - (CH ₂ ) 4-NH-, or

R ^12a of the group D7) is -CH ₂ -C(O)-, - (CH ₂ ) ₂ -C (0) -, - (CH ₂ ) ₄ -C (0) -;

R ^4a is H or -C(O)CH ₃ ,

T" is selected from -C(O)- or -C(O)-X", wherein X" is -S- or -

0-, when R ^12a is selected from D5) or D6) , preferably T' and T"' are -C (0) -,

T" is -0-, -S-, -NR'-, -0-CH(R' ) -0-C (0) -, wherein R' is H or a straight or branched Ci-C ₄ alkyl, when R ^12a is selected from D7),

, preferably T is -0-,

T"' is selected from -C(O)- or -C(O)-X" wherein X" is -S- or -

0-, preferably T"' is -C(O)-,

Y and Y' are as below defined; or R _x is selected from: (d5) -R ^12b -CH(NHR ^4a ) -CH ₂ -O- (T"' -Y-ONO ₂ ) (d6) -R ^12b -CH (CH ₂ OH) -NH- (T' -Y-ONO ₂ )

(d9) -R ^12b -CH (NH-T' -Y' -ONO ₂ ) -CH ₂ -O- (T"' -Y-ONO ₂ ) or (dlO) -R ^12b -CH (CH ₂ -O-T"' -Y' -ONO ₂ ) -NH- (T' -Y-ONO ₂ ) wherein R ^12b of the group D8) is selected from -0-CH(CH ₃ )-, -0-CH ₂ -, [-4-0- (C ₆ H ₄ ) ] -CH ₂ -, or

R ^12b of the group D9) is selected from -HN-CH ₂ -, -HN- (CH ₂ ) ₂ -, -HN- (CH ₂ ) 3-, -HN- (CH ₂ ) 4-; R ^4a is H or -C (0) -CH ₃ , T' and T"' are each independently selected from -C(O)-, -C(O)- X", wherein X" is -S- or -0-, preferably T' and T"' are -C(O)-,

Y and Y' are each independently selected from a)

- a straight or branched Ci-Cio alkylene, - a straight or branched Ci-Cio alkylene substituted with a -ONO ₂ group; d)

wherein: n ² i s an integer from 0 to 2 , R ¹³ i s H or CH ₃ , T ₁ i s -0-C ( O ) - or

-C ( O ) O- , n ¹ is 1 and U is a linear Ci-Cio alkylene or U is a linear or branched Ci-Cio alkylene substituted with a -ONO ₂ group; e)

n ² is 1, R ¹³ is CH ₃ , Y ¹ is -CH=CH- (CH ₂ ) _n ^2' - and n ^2' is 0, Ti is -C(O)O- and U is a linear Ci-Cio alkylene; e' )

wherein : n ² is 1, R ¹³ is CH ₃ , Y ¹ is - (CH ₂ ) _n ^2' -CH=CH- and n ^2' is O, T ₁ = -O-C(O)-, n ¹ is 1 and U is a linear Ci-Cio alkylene or U is a linear or branched Ci-Cio alkylene substituted with a -ONO ₂ group; f)

wherein T ₂ is -O- or -S-, -NH-, preferably T ₂ is -O-, n ³ is 1 or 2, when Y and Y' are selected from d) , e) , e' ) or f) , the -ONO ₂ group of -(T-Y-ONO ₂ ), - (T' -Y-ONO ₂ ) , - (T"-Y' -ONO ₂ ) , - (T' -Y' -ONO ₂ ) , - (T"' -Y-ONO ₂ ) and - (T"' -Y' -ONO ₂ ) is linked to the -(CH ₂ )*- group .

Another object of the present invention provides nitric oxide releasing compounds of general formula (I) and pharmaceutically acceptable salts or stereoisomers thereof

R-(Z) ₃ -R _x

(D wherein R is a corticosteroid residue selected from:

a is O, R _x is

(a2) -C(O) -CH(R ¹ ) -NH- (T' -Y-ONO ₂ ) wherein

R ¹ of of the group Al) is H T' is -C (O) -;

Y is selected from a)

- a straight or branched Ci-Cio alkylene,

- a straight or branched Ci-Cio alkylene substituted with a -ONO ₂ group;

Another object of the present invention provides nitric oxide releasing compounds of general formula (I) and pharmaceutically acceptable salts or stereoisomers thereof

R-(Z) ₃ -R _x (I)

wherein R is a corticosteroid residue selected from:

a is 0,

R _x is selected from

R _x is selected from

(a5) -R ^lb -CH (NHR ^4a ) -C (0) - (T-Y-ONO ₂ ) (a6) -R ^lb -CH(COOR ^3a ) NH- (T' -Y-ONO ₂ ) or

(a9) -R ^lb -CH (NH-T' -Y' -ONO ₂ ) -C (0) - (T-Y-ONO ₂ ) wherein

R ^lb of the group AlO) is -C(O)-CH ₂ -,

R ^3a is H or a (Ci-C ₅ ) alkyl, R ^4a is H or -C(O)CH ₃ ,

T is selected from -0-, -S-, -NR'- wherein R' is as above defined,

T' is -C(O)- and

Y and Y' are each independently selected from a)

- a straight or branched Ci-Cio alkylene,

- a straight or branched Ci-Cio alkylene substituted with a -ONO2 group .

Another object of the present invention provides nitric oxide releasing compounds of general formula (I) and pharmaceutically acceptable salts or stereoisomers thereof

R-(Z) ₃ -R _x

(D wherein R is a corticosteroid residue selected from:

a is 1 and Z is -C (0) -, R _x is

(a5) -R ^lb -CH(NHR ^4a ) -C(O) - (T-Y-ONO ₂ ) or

Ca9) -R ₅ Ib-CH (NH-T' -Y' -ONO ₂ ) -C (0) - (T-Y-ONO ₂ ; wherein R ^lb of AlO) is -0-CH ₂ - or [-4-0-(C ₆ H ₄ ) J-CH ₂ -, R ^4a is H or -C(O)CH ₃ ,

T is selected from -O-, -S-, -NR'- wherein R' is as above defined,

T' is -C(O)- and

Y and Y' are each independently selected from a)

- a straight or branched Ci-Cio alkylene,

- a straight or branched Ci-Cio alkylene substituted with a -ONO2 group .

Another object of the present invention provides nitric oxide releasing compounds of general formula (I) and pharmaceutically acceptable salts or stereoisomers thereof

R-(Z) ₃ -R _x

(D wherein R is a corticosteroid residue selected from:

a i s 0 , R _x i s

(b2) -C (O) -CH ₂ -CH (R ^z ) -NH- (T' -Y-ONO ₂ ) wherein

R ² of the group Bl) is H, T' is -C(O) -;

Y and Y' are each independently selected from a)

- a straight or branched Ci-Cio alkylene,

- a straight or branched Ci-Cio alkylene substituted with a -ONO ₂ group .

The most preferred nitric oxide releasing compounds of general formula (I) are:







Another object of the invention is a composition comprising a compound of formula (I) above reported and at least one bronchodilator or a pharmaceutical acceptable salt or solvate thereof . Bronchodilators that can be used in the composition of the invention include: anticholinergic bronchodilators which includes tiotropium and ipratropium, β ₂ -agonists which include salbutamol, bitolterol mesylate, formoterol, isoproterenol, levalbuterol, metaproterenol, salmeterol, terbutaline and fenoterol. In addition to β2~agonists and anticholinergics, other bronchodilator that may be used in the composition of the present invention are ephedrine and xanthines. Representative xanthines include theophylline, aminophylline and oxtriphyline .

In another embodiment, the compound of formula (I) and at least one bronchodilator are administered simultaneously wherein the two components may be administered by the same or different administration pathways.

In another embodiment, the compound of formula (I) and at least one bronchodilator are administered sequentially wherein the compound of formula (I) may be administered before or after the bronchodilator and the two components may be administered by the same or different administration pathways.

In another embodiment the invention provides the use of a composition comprising a compound of formula (I) above reported and at least one bronchodilator or a pharmaceutical acceptable salt or solvate thereof in the treatment of respiratory diseases which comprise asthma, COPD (chronic obstructive pulmonary diseases) , ARDS (Acute Respiratory Distress Syndrome) , allergic rhinitis and respiratory tract diseases associated with inflammation.

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) .

The compounds of the present invention are formulated in the corresponding pharmaceutical compositions, also with belated release, for parenteral, oral and topic use, such as for example inhalatory, suppository, transdermal, according to the well known techniques in the art, together with the usual excipients; see for example the publication "Remington's Pharmaceutical Sciences" 15 ^th Ed.

The amount on a molar basis of the active principle in said compositions is generally the same, or lower than that of the corresponding precursor drug.

The daily administrable doses are those of the precursor drugs, or optionally lower. The precursor daily doses can be

found in the publications of the field, such for example in the "Physician's Desk reference".

Synthesis procedure 1) The compounds of general formula (I) as above defined wherein a is equal to 0, the radical R _x is selected from (a2), (a4), (a8), (b2), (b4), (b8), (c2), (e2), (fl), (g2), (hi), (il), (12), (m2), (n2), (o2), (p2), (q2), (r2), (s2), (t2), (u2), (v2), can be obtained: 1-i) by reacting a compound of formula (Hi)

R-H (Hi)

wherein R is as defined above, with a compound of formula (Ia) W-Xi

(Ia) wherein W is -OH, Cl, O-R _a wherein R _a is pentafluorophenyl, 4- nitrophenyl or - (N-succimidyl) , Xi is as below defined, to obtain the compounds of formula (II2) R-Xi

(H ₂ ) wherein Xi is as below defined, Xi is a radical having the following meaning: -(a2') -C(O) -CH(R ^1' ) -NH- (T'-Y-Q)

wherein R ¹ is selected from Al) as defined above or

KZ') -CH ₂ -SP ¹ , -CH ₂ -OP ¹ , -CH(CHs)-OP ¹ , -CH ₂ [ (C ₆ H ₄ ) -4-OP ¹ ] , -CH ₂ - [ (C ₆ H ₃ ) - (3, 5-diiodo) -4-OP ¹ ] , -CH ₂ - [ (C ₆ H ₃ ) -3-nitro-4-OP ¹ ] or A3') -CH ₂ -NHR"", - (CH ₂ ) ₂ -NHR"", - (CH ₂ ) ₃ -NHR"", - (CH ₂ ) ₄ -NHR"", where in R" " i s P ³ or -C ( O ) CH ₃ or

wherein R ^5a is as defined above;

A4') -CH ₂ -C(O)R""', -(CHs) ₂ -C(O)R""', -(CHz) ₄ -C(O)R""' wherein R""' is P ² , -0R ^5a or

wherein R ^5a is as above defined;

- (a4' ) -C (0) -CH (R ^la -τ"-Y' -Q) -NHR ^4a'

- (a8' ) -C (0) -CH (R ^la -τ"-Y' -Q) -NH- (T' -Y-Q) wherein R ^la i s as def ined above and R ^4a' i s P ³ or -C ( O) -CH ₃ or

- (b2' ) -C (0) -CH ₂ -CH(R ^2' ) -NH- (T' -Y-Q) wherein R ² is selected from

Bl) as defined above or B2') -CH(CH ₃ ) -OP ¹ , -CH ₂ - [ (C ₆ H ₄ ) -4-0P ¹ ] ; B3') -CH ₂ -NHR"", - (CH ₂ ) ₂ -NHR"", - (CH ₂ ) ₃ -NHR"", - (CH ₂ ) ₄ -NHR"", wherein R"" is as above defined;

B4') -CH ₂ -C(O)-R""', -(CH ₂ ) ₂ -C(O)-R""', - (CH ₂ ) ₄ -C (0) -R""' wherein R""' is as above defined;

- (b4' ) -C (0) -CH ₂ -CH (R ^2a -T"-Y' -Q) -NHR ^4a' -(b8') -C (0) -CH ₂ -CH (R ^2a -T"-Y' -Q) -NH- (T' -Y-Q) wherein R ^2a and R ^4a' are as defined above;

- (c2' ) -C(O)-(CH ₂ ) _b -NH- (T' -Y-Q) ; -(e2')

wherein R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , b, c, d, e and f are as above defined; wherein P ¹ is a hydroxyl or thiol protecting group such as silyl ethers, such as trimethylsilyl, tert-butyl-dimethylsilyl or trityl and those described in T. W. Greene "Protective groups in organic synthesis", Harvard University Press, 1980, P ² is a carboxylic protecting group such as tert-butyl ester and those described in T. W. Greene "Protective groups in organic synthesis", Harvard University Press, 1980, P ³ is a amino protecting group such as Boc, Fmoc or those described in T. W. Greene "Protective groups in organic synthesis", Harvard University Press, 1980, T, T', T", Y and Y' are as above defined,

Q is independently -ONO2 or Z ₂ wherein Z ₂ is selected from the group consisting of: a chlorine atom, a bromine atom, a iodine atom, a mesyl group or a tosyl group, and 1-ii) when Q is Z ₂ , by converting the compound obtained in the step 1-i) into nitro derivative by reaction with a nitrate source such as silver nitrate, lithium nitrate, sodium nitrate, potassium nitrate, magnesium nitrate, calcium nitrate, iron nitrate, zinc nitrate or tetraalkylammonium nitrate (wherein alkyl is C1-C10 alkyl) in a suitable organic solvent such as acetonitrile, tetrahydrofurane, methyl ethyl ketone, ethyl acetate, DMF, the reaction is carried out, in the dark, at a temperature from room temperature to the boiling temperature of the solvent. Preferred nitrate source is silver nitrate and

1-iii) optionally deprotecting the compounds obtained in step 1-i) or 1-ii) as described in T. W. Greene "Protective groups in organic synthesis", Harvard University Press, 1980, 2 ^nd edition. Fluoride ion is the preferred method for removing silyl ether protecting group. Trifluoroacetic acid or anhydrous inorganic acid are the preferred method for removing Boc protecting group, anhydrous organic or inorganic acid is the preferred method for removing trityl protecting group. Organic base such as piperidine is the preferred method for removing Fmoc protecting group. Aqueous or anhydrous organic or inorganic acid is the preferred method for removing t-butyl ester protecting group.

1-i-l) The reaction of a compound of formula (Ia) wherein W = - OH and Xi is as above defined, with a compound of formula (Hi) may be carried out in presence of a condensing agent as dicyclohexylcarbodiimide (DCC), N' - (3-dimethylaminopropyl) -N- ethylcarbodiimide hydrochloride (EDAC) N, N' -carbonyldiimidazole (CDI), in the presence or not of a base as for example as N, N- dimethylamino pyridine (DMAP) . The reaction is carried out in an inert organic dry solvent such as N, N' -dimethylformamide, tetrahydrofuran, benzene, toluene, dioxane, a polyhalogenated aliphatic hydrocarbon at a temperature from -20 ⁰ C to 50 ⁰ C. The reaction is completed within a time range from 30 minutes to 36 hours. l-i-2) The reaction of a compound of formula (Ia) wherein W = - O-R _a wherein R _a and Xi are as above defined, with a compound of formula (Hi) may be carried out in presence of a catalyst, such as N, N-dimethylamino pyridine (DMAP) or in the presence of DMAP and a Lewis acid such as Sc(OTf) ₃ or Bi(OTf) ₃ . The reaction is carried out in an inert organic solvent such as N, N' -dimethylformamide, tetrahydrofuran, benzene, toluene, dioxane, a polyhalogenated aliphatic hydrocarbon at a

temperature from -20 ⁰ C to 40 ⁰ C. The reaction is completed within a time range from 30 minutes to 36 hours. l-i-3) The reaction of a compound of formula (Ia) wherein W = - Cl, and Xi is are as above defined, with a compound of formula (Hi) may be carried out in presence of an organic base such as N, N-dimethylamino pyridine (DMAP), triethylamine, pyridine. The reaction is carried out in an inert organic solvent such as N, N' -dimethylformamide, tetrahydrofuran, benzene, toluene, dioxane, a polyhalogenated aliphatic hydrocarbon at a temperature from -20 ⁰ C to 40 ⁰ C. The reaction is completed within a time range from 30 minutes to 36 hours.

The compounds of formula (Hi) are commercially available.

Ia) The compounds of formula (Ia) wherein W is -OH, and Xi is the radical selected from (a2'), (a4'), (b2'), (b4'), (c2'),

(e2'), (fl'), (g2'), (hi'), (H'), (12'), (m2'), (n2'), (o2'),

(p2'), (q2'), (r2'), (s2'), (t2'), (u2'), (v2'), wherein R ^1' is selected from Al), A2'), A3') or A4'), R ^la is selected from A5) or A6) , R ^2a is selected from B5) or B6) and R ² is selected from

Bl), B2'), B3') or B4'), wherein T' and T" are C(O) and Y, Y' and R ^4a' are as above defined, can be obtained la-i) by reacting a compound of formula (HIa)

P ² -X ₂ (HIa) wherein P ² is as above defined, X ₂ is a radical having the following meaning

-(a2") -C(O) -CH(R ^1' ) -NH ₂

-(a4") -C(O) -CH(R ^la -H) -NHR ^4a' wherein R ^1' is selected from Al), A2'), A3'), A4'), R ^la is selected from A5) or A6) and R ^4a is as defined above

-(b2") -C(O) -CH ₂ -CH(R ^2' ) -NH ₂ ,

-(b4") -C(O) -CH ₂ -CH (R 2 ^z a ^a -H) -NHR , 4a' wherein R ^2' is selected from Bl), B2'), B3' ) , B4'), R ^2a is selected from B5) or B6) and R ^4a' is as defined above, -(c2") -C(O)-(CH ₂ ) _b -NH ₂ ,

R ¹⁰ , R ¹¹ , b, c, d, e and f are as above defined; with a compound of formula (IVa)

W ₁ -(O)C-Y-Q

(IVa) wherein Wi is OH or 0-R _a and R _a and Q are as above defined, y is the radical Y when X ₂ is selected from (a2'), (b2'), (c2'),

(e2'), (fl'), (g2'), (hi'), (H'), (12'), (m2'), (n2'), (o2'), ( _P 2'), (q2'), (r2'), (s2'), (t2'), (u2'), (v2'), and y is the radical Y' when X ₂ is selected from (a4') or (b4'), wherein Y and Y' are as defined above, and la-ii) when Q is Z ₂ , by converting the compound obtained in the step la-i) into nitro derivative by reaction with a nitrate source as above described and la-iii) optionally deprotecting the compounds obtained in step la-i) or la-ii) as above described. The reaction of a compound of formula (Ilia) wherein P ² and X ₂ are as above defined, with a compound of formula (IVa) wherein Wi is OH, y, Q are as above defined, may be carried out as described in 1-i-l) or in presence of other known condensing reagents such as 0- (7-azabenzotriazol-l-yl) -N, N, N ' , N ' - tetramethyluronium hexafluorophosphate (HATU) .

The reaction of a compound of formula (Ilia) wherein P ² and X ₂ are as above defined, with a compound of formula (IVa) wherein

Wi is O-R _a , y, Q are as above defined, may be carried as described in l-i-2).

The compounds of formula (Ilia) are commercially available or can be obtained as known in the literature.

The compounds of formula (IVa) wherein Wi is OH, y and Q are as above defined, can be obtained from the corresponding alcohols of formula HOOC-y-OH (IVb) by reaction with nitric acid and acetic anhydride in a temperature range from -50 ⁰ C to 0 ⁰ C or from the corresponding derivatives of formula HOOC-y-Z ₂ (IVc) wherein Z ₂ is as above defined, by reaction with a nitrate source as above described. Alternatively the reaction with AgNθ3 can be performed under microwave irradiation in solvents such acetonitrile or THF at temperatures in the range between 100 and 180 ⁰ C for time range from 1 to 60 min.

The compounds of formula (IVb) are commercially available.

The compounds of formula (IVc) are commercially available or can be obtained as known in the literature.

The compounds of formula (IVa) wherein Wi is O-R _a , y, Q are as above defined, can be obtained from the corresponding acids of formula (IVa) wherein Wi is OH as known in the literature.

The compounds of formula (Ia) wherein W= Cl or O-R _a , Xi is selected from (a2'), (a4'), (b2'), (b4'), (c2'), (e2'), (fl'), (g2'), (hi'), (H'), (12'), (m2'), (n2'), (o2'), (p2'), (q2'), (r2'), (s2'), (t2'), (u2'), (v2'), wherein R ^1' is selected from Al), A2'), A3') or A4 ' ) , R ^la is selected from A5) or A6) , R ^2a is selected from B5) or B6) and R ^2' is selected from Bl), B2'),

B3') or B4'), and wherein Y, Y' and Q are as above defined and T' and T" are C(O), can be obtained from the corresponding acids (Ia) wherein W is -OH as known in the literature.

Ib) The compounds of formula (Ia) wherein W is -OH, Xi is the radical selected from (a2'), (a4'), (b2'), (b4') (c2'), (e2'), (fl'), (g2'), (hi'), (H'), (12'), (m2'), (n2'), (o2'), ( _P 2'), (q2'), (r2'), (s2'), (t2'), (u2'), (v2'), wherein R ^1' is selected from Al), A2'), A3') or A4'), R ^la is selected from A5) or A6) , R ^2a is selected from B5) or B6) and R ^2' is selected from Bl), B2'), B3') or B4'), Y and Y' are as above defined, T' and T" are C(O)-X", wherein X" is -0- or -S-can be obtained lb-i) by reacting a compound of formula (Ilia)

P ² -X ₂ (Ilia) wherein P ² and X ₂ are as defined above, with a compound of formula (IVd)

Ra-O-C (O)-X"-y-Q (IVd) wherein R _a , X" and Q are as above defined, y is the radical Y when X ₂ is selected from (a2'), (b2'), (c2'), (e2'), (fl'), (g2'), (hi'), (H'), (12'), (m2'), (n2'), (o2'), (p2'), (q2'), (r2'), (s2'), (t2'), (u2'), (v2'), and y is the radical Y' when X ₂ is selected from (a4') or (b4'), wherein Y and Y' are as above defined, and lb-ii) when Q is Z ₂ , by converting the compound obtained in the step lb-i) into nitro derivative by reaction with a nitrate source as above described and lb-iii) optionally deprotecting the compounds obtained in step lb-i) or lb-ii) as above described.

The reaction of a compound of formula (Ilia) wherein P ² and X ₂ are as above defined, with a compound of formula (IVd) wherein

R _a , X", y and Q are as above defined, may be carried out as described in l-i-2)

The compounds of formula (IVd) wherein R _a , X", y, Q are as above defined, can be obtained from the compounds of formula HX"-y-Q (IVe) wherein X", y, Q are as above defined, as known in literature .

The compounds of formula (IVe) are commercially available or are known in literature.

The compounds of formula (Ia) wherein W is -Cl or O-R _a , Xi is selected from (a2'), (a4'), (b2'), (b4'), (c2'), (e2'), (fl'), (g2'), (hi'), (H'), (12'), (m2'), (n2'), (o2'), (p2'), (q2'), (r2'), (s2'), (t2'), (u2'), (v2'), wherein R ^1' is selected from Al), A2'), A3'), A4'), R ^la is selected from A5) or A6) , R ^2a is selected from B5) or B6) and R ^2' is selected from Bl), B2'), B3'), B4'), Y, Y' and Q are as above defined, T' and T" are C(O)-X" wherein X" is O or S, can be obtained from the corresponding acids (Ia) wherein W is -OH as known in the literature .

Ic) The compounds of formula (Ia) wherein W is -OH and Xi is a radical selected from (a8') or (b8'), wherein R ^la is selected from A5) or A6) , R ^2a is selected from B5) or B6) , Q is as above defined, T' and T" are C(O), Y and Y' are the same and are as above defined, can be obtained lc-i) by reacting a compound of formula (HIb),

P ² -X ₃ (HIb) wherein P ² is as above defined, X3 is the radical of formula

-(a8") -C(O) -CH(R ^la -H) -NH ₂

- (b8 " ) -C ( O) -CH ₂ -CH (R ^2a -H) -NH ₂ wherein R ^la is selected from A5) or A6) , R ^2a is selected from B5) or B6) , with a compound of formula (IVa)

W ₁ -(O)C-Y-Q (IVa) wherein Wi and Q are as above defined, wherein y is the radical Y or Y' , wherein Y and Y' are as above defined, and lc-ii) when Q is Z ₂ , by converting the compounds obtained in the step lc-i) into nitro derivative by reaction with a nitrate source as above described and lc-iii) optionally deprotecting the compounds obtained in step lc-i) or lc-ii) as above described.

The reaction of a compound of formula (HIb) wherein P ² and X3 are as above defined, with a compound of formula (IVa) wherein Wi is OH, y and Q are as above defined, may be carried out as described in la-i) using a ratio (HIb)/ (IVa) 1:2. The reaction of a compound of formula (HIb) wherein P ² and X3 are as above defined, with a compound of formula (IVa) wherein Wi is 0R _a , y and Q are as above defined, may be carried out as described in l-i-2) using a ratio (HIb) /(IVa) 1:2.

The compounds of formula (HIb) are commercially available or can be obtained as known in the literature.

The compounds of formula (Ia) wherein W is -Cl or 0-R _a , Xi is the radical selected from (a8') or (b8') wherein R ^la is selected from A5) or A6) , R ^2a is selected from B5) or B6) and wherein Y, Y' and Q are as above defined and T' and T" are C(O), can be obtained from the corresponding acids (Ia) wherein W is -OH as known in the literature.

Id) The compounds of formula (Ia) wherein W is -OH, Xi is the radical selected from (a8') or (b8'), wherein R ^la is selected from A5) or A6) , R ^2a is selected from B5) or B6) , Q, Y and Y' are as above defined, T' is C(O) or C(O)-X" wherein X" is as above defined, T" is C (0) , can be obtained ld-i) by reacting a compound of formula (Ib)

P ² -X _3' (Ib) wherein P ² is as above defined, X3 _' is the radical of formula -(a8"') -C (0) -CH(R ^la -H) -NH- (T' -Y-Q)

- (b8"' ) -C (0) -CH ₂ -CH (R ^2a -H) -NH- (T' -Y-Q) wherein R ^la is selected from A5) or A6) , R ^2a is selected from B5) or B6) , with a compound of formula (IVa)

W ₁ -(O)C-Y-Q (IVa) wherein Wi and Q are as above defined, wherein y is the radical Y' , wherein Y' is as above defined, and ld-ii) when Q is Z ₂ , by converting the compounds obtained in the step ld-i) into nitro derivative by reaction with a nitrate source as above described and ld-iii) optionally deprotecting the compounds obtained in step ld-i) or ld-ii) as above described.

The reaction of a compound of formula (Ib) wherein P ² and X3 _' are as above defined, with a compound of formula (IVa) wherein Wi is OH, y and Q are as above defined, may be carried out as described in la-i) .

The reaction of a compound of formula (Ib) wherein P ² and X3 _' are as above defined, with a compound of formula (IVa) wherein Wi is 0R _a , y and Q are as above defined may be carried out as described in l-i-2) .

The compounds of formula (Ib) wherein T' is C(O), P ² and X3 _' are as above defined, are obtained as described in Ia) .

The compounds of formula (Ib) wherein T' is C(O)-X", P ² and X _3' are as above defined, are obtained as described in Ib) .

The compounds of formula (Ia) wherein W is -Cl or 0-R _a , Xi is the radical selected from (a8') or (b8') wherein R ^la is selected from A5) or A6) , R ^2a is selected from B5) or B6) and wherein Q, Y and Y' are as above defined, T' is C(O) or C(O)-X" wherein X" is as above defined, T" is C (0) , can be obtained from the corresponding acids (Ia) wherein W is -OH as known in literature .

Ie) The compounds of formula (Ia) wherein W is -OH, Xi is the radical selected from (a8') or (b8'), wherein R ^la is selected from A5) or A6) , R ^2a is selected from B5) or B6) , Q is as above defined, Y and Y' are the same and are as above defined, T' and T" are C (0) -X"- wherein X" is as above defined, can be obtained le-i) by reacting a compound of formula (HIb)

P ² -X ₃ (HIb) wherein P ² and X ₃ are as above defined, with a compound of formula (IVd) Ra-O-C (O)-X"-y-Q

(IVd) wherein R _a and Q are as above defined, wherein y is the radical Y' , wherein Y' is as above defined, and le-ii) when Q is Z ₂ , by converting the compounds obtained in the step le-i) into nitro derivative by reaction with a nitrate source as above described and

le-iii) optionally deprotecting the compounds obtained in step le-i) or le-ii) as above described.

The reaction of a compound of formula (HIb) wherein P ² and X3 are as above defined, with a compound of formula (IVd) wherein R _a , y and Q are as above defined, may be carried out as described in l-i-2) using a ratio (HIb)/ (IVd) 1:2.

The compounds of formula (Ia) wherein W is -Cl or O-R _a , Xi is the radical selected from (a8') or (b8') wherein R ^la is selected from A5) or A6) , R ^2a is selected from B5) or B6) and wherein Y and Y', Q is as above defined and T' and T" are C(O)-X"- wherein X" is as above defined, can be obtained from the corresponding acids (Ia) wherein W is -OH as known in literature .

If) The compounds of formula (Ia) wherein W is -OH, Xi is selected from (a8') or (b8'), wherein R ^la is selected from A5) or A6) , R ^2a is selected from B5) or B6) , Q, Y and Y' are as above defined, T' is C(O) or C(O)-X" wherein X" is as above defined, T" is C(O)-X", can be obtained lf-i) by reacting a compound of formula (Ib)

P ² -X _3' (Ib) wherein X3 _' and P ² are as above defined, with a compound of formula (IVd)

Wi-O-C(O) -X"-y-Q

(IVd) wherein Wi and Q are as above defined, y is the radical Y' , wherein Y' is as above defined, and lf-ii) when Q is Z2, by converting the compounds obtained in the step lf-i) into nitro derivative by reaction with a nitrate source as above described and

lf-iii) optionally deprotecting the compounds obtained in step lf-i) or lf-ii) as above described.

The reaction of a compound of formula (Ib) wherein P ² and X3 _' are as above defined, with a compound of formula (IVd) wherein Wi is OH, y and Q are as above defined, may be carried out as described in la-i) .

The reaction of a compound of formula (Ib) wherein P ² and X3 _' are as above defined, with a compound of formula (IVd) wherein Wi is 0R _a , y and Q are as above defined may be carried out as described in l-i-2) .

The compounds of formula (Ib) wherein T' is C(O), P ² and X3 _' are as above defined, are obtained as described in Ia) .

The compounds of formula (Ib) wherein T' is C(O)-X", P ² and X _3' are as above defined, are obtained as described in Ib) .

The compounds of formula (Ia) wherein W is -Cl or 0-R _a , Xi is a radical selected from (a8') or (b8') wherein R ^la is A5) or A6) , R ^2a is B5) or B6) and wherein Q, Y and Y' are as above defined, T' is C(O) or C(O)-X" and T" is C(O)-X, wherein X" is as above defined, can be obtained from the corresponding acids (Ia) wherein W is -OH as known in literature.

Ig) The compounds of formula (Ia) wherein W is -OH, Xi is a radical is selected from (a8') or (b8'), wherein R ^la is selected from A5) or A6) , R ^2a is selected from B5) or B6) , Q, Y and Y' are as above defined, T' is C(O) or C(O)-X" wherein X" is as above defined, T" is C (0) -NR' wherein R' is above defined, can be obtained lg-i) by reacting a compound of formula (Ib)

P ² -Xs'

( Ib ) wherein P ² and X3 _' are as above defined, with a compound of formula

R _a -O- (O)C-NR' -y-Q (IVf) wherein R _a , R' and Q are as above defined, y is the radical Y' , wherein Y' is as above defined, and lg-ii) when Q is Z2, by converting the compounds obtained in the step lg-i) into nitro derivative by reaction with a nitrate source as above described and lg-iii) optionally deprotecting the compounds obtained in step lg-i) or lg-ii) as above described.

The reaction of a compound of formula (Ib) wherein P ² and X3 _' are as above defined, with a compound of formula (IVf) wherein R _a , R' , y, Q are as above defined, may be carried out as described in l-i-2) .

The compounds of formula (Ib) wherein T' is C(O), wherein P ² and X3 _' are as above defined, are obtained as described in la-i) , la-ii) .

The compounds of formula (Ib) wherein T' is C(O)-X", wherein P ² and X3 _' are as above defined, are obtained as described in Ib- i) , lb-ii) .

The compounds of formula (IVf) wherein R', y and Q are as above defined, can be obtained from the compounds of formula HR'N-y-Q (IVg) by reaction with a chloroformate as known in the literature . The compounds of formula (IVg) wherein y is as above defined and Q is Z2 are commercially available, the compounds of formula (IVg) wherein y is as above defined and Q is -ONO2 may be

obtained from the compounds of formula P ³ -R' N-y-ONO ₂ (IVh) wherein P ³ is as above defined by deprotection of amino group as known in literature. The compounds of formula (IVh) wherein P ³ and y are as above defined may be obtained from the alcohol P ³ - R'N-y-OH (IVi) by reacting with tetraalkylammonium nitrate as already described for analogous compounds. The compounds of formula (IVi) are commercially available or known in literature. Alternatively the compounds of formula (IVh) wherein P ³ and y are as above defined may be obtained from the corresponding compounds of formula P ³ -R'N-y-Z ₂ (IVl) wherein P ³ , y and Z ₂ are as above defined, by reaction with a nitrate source as above described.

The compounds of formula (Ia) wherein W is -Cl or O-R _a , Xi is a radical selected from (a8') or (b8') wherein R ^la is selected from A5) or A6) , R ^2a is selected from B5) or B6) and wherein Y , Y' and Q are as above defined and T' is C(O) or C(O)-X", T" is C(O)-NR'-, wherein X" and R' are as above defined, can be obtained from the corresponding acids (Ia) wherein W is -OH as known in literature.

Ih) The compounds of formula (Ia) wherein W is -OH, Xi is a radical selected from (a8') or (b8'), wherein R ^la is selected from A7), R ^2a is selected from B7), Q, Y and Y' are as above defined, T' is C(O) or C(O)-X", T" is X" wherein X" is above defined, can be obtained lh-i) by reacting a compound of formula (Ie),

P ² -X ₅ (Ie) wherein P ² is defined above, X ₅ is the radical of formula

- (a8"' ) -C (0) -CH (R ^la -OH) -NH- (T' -Y-Q)

- (b8"' ) -C (0) -CH ₂ -CH (R ^2a -OH) -NH- (T' -Y-Q)

wherein R ^la is selected from Al), R ^2a is selected from B7), with a compound of formula (IVe)

HX"-y-Q

(IVe) wherein X" and Q are as above defined, y is the radical Y' , wherein Y' is as above defined, and lh-ii) when Q is Z ₂ , by converting the compounds obtained in the step lh-i) into nitro derivative by reaction with a nitrate source as above described and lh-iii) optionally deprotecting the compounds obtained in step lh-i) or lh-ii) as above described.

The reaction of a compound of formula (Ie) wherein P ² and X5 are as above defined, with a compound of formula (IVe) wherein y,

X" and Q are as above defined, may be carried out as described in 1-i-l) .

The compounds of formula (Ie) wherein T' is C(O), wherein P ² and X ₅ are as above defined, are obtained as described in la-i) , Ia- ϋ) •

The compounds of formula (Ie) wherein T' is C(O)-X", wherein P ² and X ₅ are as above defined, are obtained as described in lb-i) , lb-ii) .

The compounds of formula (Ia) wherein W is -Cl or O-R _a , Xi is a radical selected from (a8') or (b8') wherein R ^la is selected from A7), R ^2a is selected from B7) and wherein Y, Y' and Q are as above defined, T' is C(O) or C(O)-X", and T" is X" wherein X" is as above defined, can be obtained from the corresponding acids (Ia) wherein W is -OH as known in literature.

Ii) The compounds of formula (Ia) wherein W is -OH, Xi is a radical selected from (a8') or (b8'), wherein R ^la is selected from A7), R ^2a is selected from B7), Q, Y and Y' are as above defined, T' is C(O) or C(O)-X" wherein X" is as above defined, T" is -NR' wherein R' is above defined, can be obtained li-i) by reacting a compound of formula (Ie),

P ² -X ₅ (Ie) wherein is P ² and X ₅ are defined above, with a compound of formula (IVg)

HR'N-y-Q

(IVg) wherein R' and Q are as above defined, y is the radical Y' , wherein Y' is as above defined, and li-ii) when Q is Z ₂ , by converting the compounds obtained in the step li-i) into nitro derivative by reaction with a nitrate source such above described and li-iii) optionally deprotecting the compounds obtained in step li-i) or li-ii) as above described. The reaction of a compound of formula (Ie) wherein P ² and X ₅ are as above defined, with a compound of formula (IVg) wherein R', y and Q are as above defined, may be carried out as described in la-i) .

The compounds of formula (Ia) wherein W is -Cl or O-R _a , Xi is the radical selected from (a8') or (b8') wherein R ^la is selected from A7), R ^2a is selected from B7) and wherein Y, Y' and Q are as above defined, T' is C(O) or C(O)-X" wherein X" is as above defined, and T" is -NR' wherein R' is as above defined can be obtained from the corresponding acids (Ia) wherein W is -OH as known in literature

11) The compounds of formula (Ia) wherein W is -OH, Xi is a radical selected from (a8') or (b8'), wherein R ^la is selected from A7), R ^2a is selected from B7), Q, Y and Y' are as above defined, T' is C(O) or C(O)-X" wherein X" is as above defined, T" is -O-CH (R' ) -0-C (0) -, wherein R' is as above defined, can be obtained

11-i) by reacting a compound of formula (Ie),

P ² -X ₅ (Ie) wherein is P ² and X ₅ are defined above, with a compound of formula (IVm)

HaI-CH (R' ) -0- (0) C-y-Q

(IVm) wherein R' and Q are as above defined, Hal is an halogen atom, y is the radical Y' , wherein Y' is as above defined, and

11-ii) when Q is Z ₂ , by converting the compounds obtained in the step 11-i) into nitro derivative by reaction with a nitrate source such above described and 11-iii) optionally deprotecting the compounds obtained in step 11-i) or 11-ii) as above described.

The reaction of a compound of formula (Ie) wherein P ⁵ and X ₅ are as above defined, with a compound of formula (IVm) wherein y, Q, R' are as above defined may be carried out in the presence of a inorganic or organic base in an aprotic polar/non-polar solvent such as DMF, THF or CH ₂ Cl ₂ at temperature in the range between 0° and 100 ⁰ C or in a double phase system H ₂ 0/Et ₂ 0 temperature in the range between 20° and 40 ⁰ C.

The compounds of formula (IVm) wherein y, Q, R' are as above defined, Hal is an halogen atom may be obtained by reacting a compound R' -CH ₂ -CHO, commercially available, with a compound of formula Hal- (O) C-y-Q (IVn), wherein y and Q are as above

defined, Hal is a chlorine atom and ZnCl2 as known in literature .

The compounds of formula (IVn) may be obtained as known in literature .

The compounds of formula (Ia) wherein W is -Cl or O-R _a , , Xi is a radical selected from (a8') or (b8') wherein R ^la is selected from A7 ) , R ^2a is selected from B7) and wherein Y, Y', and Q are as above defined, T' is C(O) or C(O)-X" wherein X" is as above defined, and T" is -O-CH (R' ) -O-C (O) - wherein R' is as above defined can be obtained from the corresponding acids (Ia) wherein W is -OH as known in literature.

Im) The compounds of formula (Ia) wherein W is -OH, Xi is a radical selected from (a8') or (b8'), wherein R ^la is selected from A7), R ^2a is selected from B7), Q, Y and Y' are as above defined, T' is C(O) or C(O)-X" wherein X" is as above defined, T" is -O-CH (R' ) -0-C (0) 0-, wherein R' is as above defined, can be obtained lm-i) by reacting a compound of formula (Ie),

P ² -X ₅ (Ie) wherein is P ² and X5 are defined above, with a compound of formula (IVo)

HaI-CH (R' ) -0- (0) C-O-y-Q

(IVo) wherein R' and Q are as above defined, y is the radical Y' , wherein Y' is as above defined, Hal is an halogen atom, and lm-ii) when Q is Z2, by converting the compounds obtained in the step lm-i) into nitro derivative by reaction with a nitrate source such above described and

lm-iii) optionally deprotecting the compounds obtained in step lm-i) or lm-ii) as above described.

The reaction of a compound of formula (Ie) wherein P ² and X ₅ are as above defined, with a compound of formula (IVo) wherein y, R' , Q, Hal are as above defined may be carried out as described in lm-i) .

The compounds of formula (IVo) wherein y, R', Q are as above defined, may be obtained by reacting the compounds of formula Hal- (R' ) CH-OC (0) Hal, wherein Hal is as above defined, commercially available, with a compound of formula HO-y-Q (IVe) wherein y, Q are as above defined, in the presence of a inorganic or organic base in an aprotic polar or in an aprotic non-polar solvent such as DMF, THF or CH2CI2 at temperatures range between 0° to 65°C.

The compounds of formula (Ia) wherein W is -Cl or 0-R _a , Xi is a radical selected from (a8') or (b8') wherein R ^la selected from A7 ) , R ^2a selected from B7) and wherein Y, Y' and Q are as above defined, T' is C(O) or C(O)-X" wherein X" is as above defined, and T" is -O-CH (R' ) -0-C (0) 0-, may be obtained from the corresponding acids (Ia) wherein W is -OH as known in literature .

In) The compounds of formula (Ia) wherein W is -OH, Xi is a radical selected from (a4') or (b4'), wherein R ^la is selected from A7), R ^2a is selected from B7), Y', Q and R ^4a' are as above defined and T" is X" wherein X" is as above defined, can be obtained

ln-i) by reacting a compound of formula (IIIc)

P ² -X ₅ '

( H I c ) wherein P ² is defined above, X5 _' is

-(a4") -C (O) -CH(R ^la -OH) -NHR ^4a'

- (b4") -C (O) -CH ₂ -CH (R ^2a -OH) -NHR ^4a' wherein R ^la is selected from A7), R ^2a is selected from B7), with a compound of formula (IVe)

HX"-y-Q (IVe) wherein X" and Q are as above defined, y is the radical Y' , wherein Y' is as above defined, and ln-ii) when Q is Z ₂ , by converting the compounds obtained in the step ln-i) into nitro derivative by reaction with a nitrate source as above described and ln-iii) optionally deprotecting the compounds obtained in step ln-i) or ln-ii) as above described.

The reaction of a compound of formula (IIIc) wherein X _5' and P ² are as above defined, with a compound of formula (IVe) wherein

X", y, Q are as above defined may be carried out as described in 1-i-l) .

The compounds of formula (IIIc) wherein X _5' and P ² are as above defined, are commercially available or can be obtained as known in the literature.

The compounds of formula (Ia) wherein W is -Cl or 0-R _a , Xi is a radical selected from (a4') or (b4'), wherein R ^la is selected from A7), R ^2a is selected from B7), Y' and Q are as above defined, T" is X", wherein X" is as above defined, can be obtained from the corresponding acids (Ia) wherein W is -OH as known in literature.

lo) The compounds of formula (Ia) wherein W is -OH, Xi is a radical selected from (a4') or (b4'), wherein R ^la is selected from A7), R ^2a is selected from B7), Y', Q and R ^4a' are as above defined and T" is -NR' wherein R' is as above defined, can be obtained lo-i) by reacting a compound of formula (IIIc)

P ² -X ₅ ' (IIIc) wherein P ² and X _5' are as above defined, with a compound of formula (IVg)

HR'N-y-Q

(IVg) wherein R' and Q are as above defined, y is the radical Y' , and lo-ii) when Q is Z ₂ , by converting the compounds obtained in the step lo-i) into nitro derivative by reaction with a nitrate source as above described and lo-iii) optionally deprotecting the compounds obtained in step lo-i) or lo-ii) as above described.

The reaction of a compound of formula (IIIc) wherein X _5' and P ² are as above defined, with a compound of formula (IVg) wherein R' , y and Q are as above defined may be carried out as described in la-i) .

The compounds of formula (Ia) wherein W is -Cl or -OR _a , Xi is a radical selected from (a4') or (b4'), wherein R ^la is selected from A7 ) , R ^2a is selected from B7) and wherein Y' and Q are as above defined and T" is -NR' wherein R' is as above defined, can be obtained from the corresponding acids (Ia) wherein W= - OH as known in literature.

Ip) The compounds of formula (Ia) wherein W is -OH, Xi is a radical selected from (a4') or (b4'), wherein R ^la is selected

from A7), R ^2a is selected from B7), Y', Q and R ^4a' are as above defined and T" is -O-CH (R' ) -O-C (O) , wherein R' is as above defined, can be obtained lp-i) by reacting a compound of formula (IIIc) P ² -X ₅ '

(IIIc) wherein P ² and X5 _' are as above defined, with a compound of formula (IVm)

HaI-CH (R' ) -O- (0) C-y-Q (IVm) wherein R' and Q are as above defined, y is the radical Y' , wherein Y' is as above defined, Hal is an halogen atom and lp-ii) when Q is Z2, by converting the compounds obtained in the step lp-i) into nitro derivative by reaction with a nitrate source as above described and lp-iii) optionally deprotecting the compounds obtained in step lp-i) or lp-ii) as above described.

The reaction of a compound of formula (IIIc) wherein P ² and X5 _' are as above defined, with a compound of formula (IVm) wherein R' , y, Q, Hal are as above defined, may be carried out as described in 11-1) .

The compounds of formula (Ia) wherein W is -Cl or 0R _a , Xi is a radical selected from (a4') or (b4'), wherein R ^la is selected from Al), R ^2a is selected from B7) and wherein Y and Q are as above defined and T" is the group -O-CH (R' ) -0-C (0) , wherein R' is as above defined, can be obtained from the corresponding acids (Ia) wherein W = -OH as known in literature.

Iq) The compounds of formula (Ia) wherein W is -OH, Xi is a radical selected from (a4') or (b4'), wherein R ^la is selected from A7), R ^2a is selected from B7), Y', Q and R ^4a' are as above

defined and T" is -O-CH (R' ) -O-C (O) -O-, wherein R' is as above defined, can be obtained lq-i) by reacting a compound of formula (IIIc)

P ² -X _5' (IIIc) wherein P ² and X5 _' are as above defined, with a compound of formula (IVo)

HaI-CH (R' ) -0- (0) C-O-y-Q

(IVo) wherein R' and Q are as above defined, y is the radical Y' , wherein Y' is as above defined, Hal is an halogen atom and lq-ii) when Q is Z2, by converting the compounds obtained in the step lq-i) into nitro derivative by reaction with a nitrate source as above described and lq-iii) optionally deprotecting the compounds obtained in step lq-i) or lq-ii) as above described.

The reaction of a compound of formula (IIIc) wherein P ² and X _5' are as above defined, with a compound of formula (IVo) wherein

R' , y, Q, Hal are as above defined, may be carried out as described in 11-1) .

The compounds of formula (Ia) wherein W is -Cl or 0R _a , Xi is a radical selected from (a4') or (b4'), wherein R ^la is selected from Al), R ^2a is selected from B7) and wherein Y and Q, are as above defined and T" is the group -O-CH (R' ) -0-C (0) -0-, wherein R' is as above defined, can be obtained from the corresponding acids (Ia) wherein W = -OH as known in literature.

2) The compounds of general formula (I) as above defined wherein a is equal to 1, the radical R _x is selected from (a2), (a4), (a8), (b2), (b4), (b8), (c2), (e2), (fl), (g2), (hi), (il), (12), (m2), (n2), (o2), (p2), (q2), (r2), (s2), (t2),

(u2), (v2), Z is -CH (R') -O- wherein R' is selected from H or straight or branched Ci-C ₄ alkyl, can be obtained:

2-i) by reacting a compound of formula (Hi) as above defined with a compound of formula (If) HaI-CH(R' ) -O-Xi

(If) wherein Hal is an halogen atom, R' and Xi are as above defined and

2-ii) when Q is Z ₂ , by converting the compounds obtained in the step 2-i) into nitro derivative by reaction with a nitrate source as above described and

2-iii) optionally deprotecting the compounds obtained in step

2-i) or 2-ii) as above described.

The reaction of a compound of formula (If) wherein Xi and R' are as above defined, with a compound of formula (Hi) may be carried out as described in 11-i) .

The compounds of formula (If) are obtained by reacting a compound R' -CHO, wherein R' is as above defined with compounds of formula (Ia)

W-Xi (Ia) wherein W is a chlorine atom, Xi is as above defined, and ZnCl ₂ as known in literature.

3) The compounds of general formula (I) as above defined wherein a is equal to 1, the radical R _x is selected from (al), (a3), (al) , (bl), (b3) , (b7), (cl), (el), (f2), (gl), (h2), (12), (11), (ml), (nl), (ol), (pi), (ql), (rl), (si), (tl), (ul), (vl), Z is C(O), can be obtained

3-i) by reacting a compound of formula (II3)

R-C(O) -O-Ra

( H ₃ ) wherein R and R _a are as above defined, with a compound of formula (Ig)

H-X ₂

(ig) wherein X ₂ is a radical having the following meanings: -(al') -HN-CH(R^)-C(O)-(T-Y-Q)

- (a3' ) -HN-CH (R ^la -τ"-Y' -Q) -COOR ^3a'

- (al' ) -HN-CH (R ^la -τ"-Y' -Q) -C (O) - (T-Y-Q)

- (bl' ) -HN-CH(R ^2' ) -CH ₂ C (0) - (T-Y-Q)

- (b3' ) -HN-CH (R ^2a -T"-Y' -Q) -CH ₂ COOR ^3a'

- (bl' ) -HN-CH (R ^2a -τ"-Y' -Q) -CH ₂ -C (0) - (T-Y-Q) wherein R ^1' , R ^la , R ^2' , R ^2a are as above defined

R 3a' is selected from P ² , -0R ^5a or

wherein R ^5a is as above defined; -(Cl') -HN- (CH ₂ ) _b -C (O)- (T-Y-Q);

wherein T, T", Y and Y' are as above defined,

3-ii) when Q is Z ₂ , by converting the compounds obtained in the step 3-i) into nitro derivative by reaction with a nitrate source such above described and

3-iii) optionally deprotecting the compounds obtained in step 3-i) or 3-ii) as above described.

The reaction of a compound of formula (II3), wherein R and R _a are as above defined, with a compound of formula (Ig) wherein Xi is as above defined, may be carried out as described in l-i-2) .

The compounds of formula (II3) wherein R and R _a are as above defined, are obtained from the compounds of formula (Hi) by reaction with the compounds of formula Cl-C (O) -0-R _a wherein R _a is as above defined, as known in literature.

3a) The compounds of formula (Ig) wherein X ₂ is selected from (al'), (a3'), (bl'), (b3' ) , (cl'), (el'), (f2'), (gl'), (h2'), (12'), (H'), (ml'), (nl'), (ol'), (pi'), (ql'), (rl'), (si'), (tl'), (ul'), (vl'), wherein R ^1' is selected from Al), A2'), A3') or A4'), R ^la is selected from A7), R ^2a is selected from B7) and R ^2' is selected from Bl), B2'), B3' ) or B4'), Y and Y' are as above defined, T and T" are X" wherein X" is as above defined may be obtained

3a-i) by reacting a compound of formula (HIe),

P ³ -X ₆ (HIe) wherein P ³ is as above defined, Xe is a radical having the following meanings:

-(al") -HN-CH(R^)-C(O)-OH

-(a3") -HN-CH (R ^la -OH) -COOR ^3a' - (bl " ) -HN-CH (R ^{2 '} ) -CH ₂ C ( 0) -OH - (b3 " ) -HN-CH (R ^2a -OH) -CH ₂ COOR ^3a'

wherein R ^1' is selected from Al), A2'), A3') or A4'), R ^la is selected from Al), R ^2a is selected from B7) and R ² is selected from Bl), B2'), B3') or B4'), and R ^3a' is defined above -(Cl") -HN- (CH ₂ ) _b -C (O) -OH;

with a compound of formula (IVe)

HX"-y-Q (IVe) wherein Q and X" are as above defined y is the radical Y when X ₆ is selected from (al'), (bl'), (cl'), (el'), (f2'), (gl'), (h2'), (i2'), (H'), (ml'), (nl'), (ol'), (pi'), (ql'), (rl'), (si'), (tl'), (ul') and (vl'), y is the radical Y' when X ₆ is selected from (a3' ) and (b3' ) , wherein Y and Y' are as defined above, and

3a-ii) when Q is Z ₂ , by converting the compounds obtained in the step 3a-i) into nitro derivative by reaction with a nitrate source as above described and 3a-iii) optionally deprotecting the compounds obtained in step 3a-i) or 3a-ii) as above described.

The reaction of a compound of formula (HIe) wherein P ³ and X ₆ are as above defined, with a compound of formula (IVe), wherein

y, Q and X" are as above defined, may be carried out as described in 1-i-l).

The compounds of formula (HIe) are commercially available or can be obtained as known in the literature.

3b) The compounds of formula (Ig) wherein X ₂ is selected from (al'), (a3'), (bl'), (b3' ) , (cl'), (el'), (f2'), (gl'), (h2'), (12'), (H'), (ml'), (nl'), (ol'), (pi'), (ql'), (rl'), (si'), (tl'), (ul'), (vl'), wherein R ^1' is selected from Al), A2'),

A3') or A4'), R ^la is selected from A7), R ^2a is selected from B7) and R ^2' is selected from Bl), B2'), B3' ) or B4'), and R ^3a' , Y and Y' are as above defined, T and T" are -NR' wherein R' is as above defined may be obtained 3b-i) by reacting a compound of formula (HIe),

P ³ -X ₆ (HIe) wherein P ³ and X ₆ are as above defined, with a compound of formula HR'N-y-Q

(IVg) wherein R' and Q are as above defined, y is the radical Y when X ₆ is selected from (al'), (bl'), (cl'), (el'), (f2'), (gl'), (h2'), (12'), (H'), (ml'), (nl'), (ol'), (pi'), (ql'), (H'), (si'), (tl'), (ul') and (vl'), y is the radical Y' when X ₆ is selected from (a3' ) and (b3' ) , wherein Y and Y' are as defined above, and

3b-ii) when Q is Z ₂ , by converting the compounds obtained in the step 3b-i) into nitro derivative by reaction with a nitrate source as above described and

3b-iii) optionally deprotecting the compounds obtained in step 3b-i) or 3b-ii) as above described.

The reaction of a compound of formula (HIe) wherein P ³ and Xe are as above defined, with a compound of formula (IVg) wherein R' , y, Q are as above defined, may be carried out la-i) .

3c) The compounds of formula (Ig) wherein X ₂ is selected from (al'), (a3'), (bl'), (b3' ) , (cl'), (el'), (f2'), (gl'), (h2'), (12'), (H'), (ml'), (nl'), (ol'), (pi'), (ql'), (rl'), (si'), (tl'), (ul'), (vl'), wherein R ^1' is selected from Al), A2'), A3'), A4'), R ^la is selected from A7), R ^2a is selected from B7) and R ^2' is selected from Bl), B2'), B3' ) , B4'), and R ^3a' , Y and Y' are as above defined, T and T" are -O-CH (R' ) -O-C (O) -, wherein R' is as above defined, may be obtained 3c-i) by reacting a compound of formula (HIe)

P ³ -X ₆ (HIe) wherein P ³ , Xe are as above defined with compounds of formula (IVm) HaI-CH(R' ) -O- (O) C-y-Q

(IVm) wherein R' and Q are as above defined, Hal is an halogen atom, y is the radical Y when X ₆ is selected from (al'), (bl'), (cl'), (el'), (f2'), (gl'), (h2'), (12'), (H'), (ml'), (nl'), (ol'), (pi'), (ql'), (H'), (Sl'), (tl'), (ul') and (vl'), y is the radical Y' when X ₆ is selected from (a3' ) and (b3' ) , wherein Y and Y' are as defined above, and

3c-ii) when Q is Z ₂ , by converting the compounds obtained in the step 3c-i) into nitro derivative by reaction with a nitrate source as above described and

3c-iii) optionally deprotecting the compounds obtained in step 3c-i) or 3c-ii) as above described.

The reaction of a compound of formula (HIe) wherein P ³ and Xe are as above defined, with a compound of formula (IVm) wherein y, Q, R' are as above defined, may be carried out as described in 11-i)

3d) The compounds of formula (Ig) wherein X ₂ is selected from (al'), (a3'), (bl'), (b3' ) , (cl'), (el'), (f2'), (gl'), (h2'), (12'), (H'), (ml'), (nl'), (ol'), (pi'), (ql'), (rl'), (si'), (tl'), (ul'), (vl'), wherein R ^1' is selected from Al), A2'), A3') or A4'), R ^la is selected from A7), R ^2a is selected from B7) and R ^2' is selected from Bl), B2'), B3' ) or B4'), and R ^3a' , Y and

Y' are as above defined, T and T" are -O-CH (R' ) -O-C (O) O- wherein R' is as above defined may be obtained

3d-i) by reacting a compound of formula (HIe)

P ³ -X ₆ (HIe) wherein P ³ and Xe are as above defined, with compounds of formula (IVo) HaI-CH(R' ) -0- (O)C-O-y-Q

(IVo) wherein R' and Q are as above defined, Hal is an halogen atom y is the radical Y when X ₆ is selected from (al'), (bl'), (cl'),

(el'), (f2'), (gl'), (h2'), (12'), (H'), (ml'), (nl'), (ol'), (pi'), (ql'), (H'), (Sl'), (tl'), (ul') and (vl'), y is the radical Y' when Xe is selected from (a3' ) and (b3' ) , wherein Y and Y' are as defined above, and

3d-ii) when Q is Z ₂ , by converting the compounds obtained in the step 3d-i) into nitro derivative by reaction with a nitrate source as above described and

3d-iii) optionally deprotecting the compounds obtained in step

3d-i) or 3d-ii) as above described.

The reaction of a compound of formula (HIe) wherein P ³ and Xe are as above defined, with a compound of formula (IVo) wherein y, Q, R' are as above defined, may be carried out as described in 11-i) .

3e) The compounds of formula (Ig) wherein X ₂ is selected from (aV) or (bV) wherein R ^la is selected from A5) or A6) , R ^lb is selected from B5) or B6) T" is -C(O)-, T is -X", -NR', -0- CH(R' ) -O-C(O) - or -O-CH (R' ) -0-C (0) 0- wherein X" and R', Y and Y' are as above defined, may be obtained

3e-i) by reacting a compound of formula (Ih)

P ³ -X ₇ (Ih) wherein P ³ is as above defined and X7 is the radical having the following meaning

- (a7") -HN-CH (R ^la -H) -C (0) - (T-Y-Q)

- (hi") -HN-CH (R ^2a -H) -CH ₂ -C (0) - (T-Y-Q) wherein R ^la is selected from A5) or A6) , R ^2a is selected from B5) or B6) , with compounds of formula (IVa) Wi-C(O)-y-Q

(IVa) wherein Wi and Q are as above defined, y is the radical Y' , wherein Y' is as above defined, and

3e-ii) when Q is Z ₂ , by converting the compounds obtained in the step 3e-i) into nitro derivative by reaction with a nitrate source as above described and

3e-iii) optionally deprotecting the compounds obtained in step

3e-i) or 3e-ii) as above described.

The reaction of a compound of formula (Ih) wherein P ³ and X ₇ are as above defined, with a compound of formula (IVa) wherein y,

Q, Wi are as above defined may be carried out as described in 1- i-1), l-i-2), l-i-3) and la-i) .

The compounds of formula (Ih) wherein P ³ and X7 are as above defined, T is -X" are obtained as described in 3a) .

The compounds of formula (Ih) wherein P ³ and X ₇ are as above defined, T is -NR' are obtained as described in 3b) .

The compounds of formula (Ih) wherein P ³ and X7 are as above defined, T is -O-CH (R' ) -O-C (O) - are obtained as described in 3c) .

The compounds of formula (Ih) wherein P ³ and X7 are as above defined, T is -O-CH (R' ) -0-C (0) 0- are obtained as described in 3d) .

3f) The compounds of formula (Ig) wherein X2 is selected from (aV) or (bV) wherein R ^la is selected from A5) or A6) , R ^lb is selected from B5) or B6) T" is -C(O)-X", T is -X", -NR', -0- CH(R' ) -0-C (0) - or -O-CH (R' ) -0-C (0) 0- wherein X" and R', Y and Y' are as above defined, may be obtained

3f-i) by reacting a compound of formula (Ih)

P ³ -X ₇ (Ih) wherein P ³ and X7 are as above defined with compounds of formula (IVd)

Ra-O-C (O)-X"-y-Q

(IVd) wherein R _a , X" and Q are as above defined, y is the radical Y' , wherein Y' is as above defined, and 3f-ii) when Q is Z2, by converting the compounds obtained in the step 3f-i) into nitro derivative by reaction with a nitrate source as above described and

3f-iii) optionally deprotecting the compounds obtained in step 3e-i) or 3f-ii) as above described.

The reaction of a compound of formula (Ih) wherein P ³ and X ₇ are as above defined, with a compound of formula (IVd) wherein y, Q, R _a are as above defined, may be carried out as described in l-i-2) .

3g) The compounds of formula (Ig) wherein X ₂ is selected from

(aV) or (bV) wherein R ^la is selected from A5) or A6) , R ^lb is selected from B5) or B6) , T" is -C(O)-NR', T is X", NR', -0-

CH(R' ) -O-C(O) - or -O-CH (R' ) -0-C (0) 0- wherein X" and R', Y and

Y' are as above defined, may be obtained

3g-i) by reacting a compound of formula (Ih)

P ³ -X ₇ (Ih) wherein P ³ and X ₇ are as above defined, with compounds of formula (IVf)

R _a -O-C(O) -NR'-y-Q

(IVf) wherein R _a and Q are as above defined, y is the radical Y' , wherein Y' is as above defined, and

3g-ii) when Q is Z ₂ , by converting the compounds obtained in the step 3g-i) into nitro derivative by reaction with a nitrate source as above described and 3g-iii) optionally deprotecting the compounds obtained in step

3g-i) or 3g-ii) as above described.

The reaction of a compound of formula (Ih) wherein P ³ and X ₇ are as above defined, with a compound of formula (IVf) wherein y,

Q, R _a and R' are as above defined may be carried out as described in l-i-2) .

The compounds of formula (Ih) wherein P ³ and X7 are as above defined, T is -X" are obtained as described in 3a) .

The compounds of formula (Ih) wherein P ³ and X ₇ are as above defined, T is -NR' are obtained as described in 3b) .

The compounds of formula (Ih) wherein P ³ and X7 are as above defined, T is -O-CH (R' ) -O-C (O) - are obtained as described in 3c) .

The compounds of formula (Ih) wherein P ³ and X ₇ are as above defined, T is -O-CH (R' ) -0-C (0) 0- are obtained as described in 3d) .

3h) The compounds of formula (Ig) wherein X2 is selected from

(aV) or (bV) wherein R ^la is selected from A7), R ^lb is selected from B7), T" is -X", T is -X", -NR', -O-CH (R' ) -0-C (0) - or -0- CH(R' ) -0-C (0)0- wherein X" and R', Y and Y' are as above defined, may be obtained 3h-i) by reacting a compound of formula (Ih)

P ³ -X ₇ (Ih) wherein P ³ is as above defined and X ₇ is as above defined wherein R ^la is selected from Al), R ^lb is selected from B7), with compounds of formula (IVe)

H-X"-y-Q

(IVe) wherein X" and Q are as above defined, y is the radical Y' , wherein Y' is as above defined, and 3h-ii) when Q is Z2, by converting the compounds obtained in the step 3h-i) into nitro derivative by reaction with a nitrate source as above described and

3h-iii) optionally deprotecting the compounds obtained in step 3h-i) or 3h-ii) as above described.

The reaction of a compound of formula (Ih) wherein P ³ and X ₇ are as above defined, with a compound of formula (IVe) wherein y, Q, X" are as above defined, may be carried out as described in 1-i-l) , l-i-2) and Ia-I) .

The compounds of formula (Ih) wherein P ³ and X ₇ are as above defined, T is -X" are obtained as described in 3a) .

The compounds of formula (Ih) wherein P ³ and X ₇ are as above defined, T is -NR' are obtained as described in 3b) .

The compounds of formula (Ih) wherein P ³ and X ₇ are as above defined, T is -O-CH (R' ) -O-C (O) - are obtained as described in 3c) .

The compounds of formula (Ih) wherein P ³ and X ₇ are as above defined, T is -O-CH (R' ) -0-C (0) 0- are obtained as described in 3d) .

3i) The compounds of formula (Ig) wherein X2 is selected from (aV) or (bV) wherein R ^la is selected from A7), R ^lb is selected from B7), T" is NR', T is -X", -NR', -O-CH (R' ) -0-C (0) - or -0- CH(R' ) -0-C (0)0- wherein X" and R', Y and Y' are as above defined, may be obtained

3i-i) by reacting a compound of formula (Ih)

P ³ -X ₇ (Ih) wherein P ³ and X ₇ are as above defined, with compounds of formula (IVg)

H-NR' -y-Q

( IVg) wherein R' and Q are as above defined, y is the radical Y' , wherein Y' is as above defined, and

3i-ii) when Q is Z ₂ , by converting the compound obtained in the step 3i-i) into nitro derivative by reaction with a nitrate source as above described and

3i-iii) optionally deprotecting the compounds obtained in step 3i-i) or 3i-ii) as above described. The reaction of a compound of formula (Ih) wherein P ³ and Xs7 are as above defined, with a compound of formula (IVg) wherein y, Q, R' are as above defined, may be carried out as described in la-i) .

31) The compounds of formula (Ig) wherein X ₂ is selected from

(a7') or (b7') wherein R ^la is selected from A7), R ^lb is selected from B7), T" is -O-CH (R' ) -O-C (O) -, T is X", NR', -O-CH (R' ) -O- C(O)- or -0-CH(R' ) -0-C (0)0- wherein X" and R', Y and Y' are as above defined, may be obtained 31-i) by reacting a compound of formula (Ih)

P ³ -X ₇ (Ih) wherein P ³ and Xs are as above defined with compounds of formula (IVm) HaI-CH(R' ) -0- (O)C-y-Q

(IVm) wherein R' and Q are as above defined, y is the radical Y' , wherein Y' is as above defined, Hal is an halogen atom and 31-ii) when Q is Z ₂ , by converting the compounds obtained in the step 31-i) into nitro derivative by reaction with a nitrate source as above described and

31-iii) optionally deprotecting the compounds obtained in step 31-i) or 31-ii) as above described.

The reaction of a compound of formula (Ih) wherein P ³ and X ₇ are as above defined, with a compound of formula (IVm) wherein y, Q, R' are as above defined, may be carried out as described in 11-i) .

3m) The compounds of formula (Ig) wherein X ₂ is selected from

(a7') or (b7') wherein R ^la is selected from A7), R ^lb is selected from B7), T" is -O-CH (R' ) -O-C (O) O-, T is X", NR', -O-CH (R' ) -O-

C(O)- or -0-CH(R' ) -0-C (0)0- wherein X" and R', Y and Y' are as above defined, may be obtained

3m-i) by reacting a compound of formula (Ih)

P ³ -X ₇ (Ih) wherein P ³ and Xs are as above defined with a compound of formula

(IVo)

HaI-CH (R' ) -0- (0) C-O-y-Q

(IVo) wherein R' and Q are as above defined, y is the radical Y' , wherein Y' is as above defined, Hal is an halogen atom and

3m-ii) when Q is Z ₂ , by converting the compounds obtained in the step 3m-i) into nitro derivative by reaction with a nitrate source as above described and 3m-iii) optionally deprotecting the compounds obtained in step

31-i) or 3m-ii) as above described.

The reaction of a compound of formula (Ih) wherein P ³ and X ₇ are as above defined, with a compound of formula (IVo) wherein y,

Q, R' are as above defined, may be carried out as described in 11-i) .

3n) The compounds of formula (Ig) wherein X ₂ is selected from

(a3') or (b3'), wherein R ^la is selected from A5) or A6) , R ^2a is selected from B5) or B6) , Y' is as above defined, T" is C(O) may be obtained 3n-i) by reacting a compound of formula (HIf),

P ³ -X ₉ (HIf) wherein P ³ is as above defined, X9 is a radical having the following meaning ~(a3") -HN-CH (R ^la -H) -COOR ^3a'

-(b3") -HN-CH (R ^2a -H) -CH ₂ COOR ^3a' wherein R ^la is selected from A5 or A6) and R ^2a is selected from

B5) or B6) , wherein R ^3a is as above defined, with a compound of formula (IVa) Wi-C(O)-y-Q

(IVa) wherein Wi and Q are as above defined, y is the radical Y' , wherein Y' is as above defined, and

3n-ii) when Q is Z ₂ , by converting the compounds obtained in the step 3n-i) into nitro derivative by reaction with a nitrate source as above described and

3n-iii) optionally deprotecting the compounds obtained in step

3n-i) or 3n-ii) as above described.

The reaction of a compound of formula (HIf) wherein P ³ and X9 are as above defined, with a compound of formula (IVa) wherein

Wi, y, Q are as above defined, may be carried out as described in 1-i-l) , l-i-2) , Ia-I) .

The compounds of formula (HIf) wherein P ³ and Xg are as above defined, are commercially available or obtained as known in literature .

3o) The compounds of formula (Ig) wherein X ₂ is selected from (a3') or (b3'), wherein R ^la is selected from A5) or A6) , R ^2a is selected from B5) or B6) , Y' is as above defined, T" is C(O)-X" wherein X" is as above defined, can be obtained 3o-i) by reacting a compound of formula (HIf)

P ³ -X ₉ (HIf) wherein P ³ and X9 are as above defined with a compound of formula (IVd) R _a -O-C(O) -X"-y-Q

(IVd) wherein R _a , X", Q are as above defined, y is the radical Y' , wherein Y' is as above defined, and

3o-ii) when Q is Z ₂ , by converting the compounds obtained in the step 3o-i) into nitro derivative by reaction with a nitrate source as above described and

3o-iii) optionally deprotecting the compounds obtained in step 3o-i) or 3o-ii) as above described.

The reaction of a compound of formula (HIf) wherein P ³ and X9 are as above defined, with a compound of formula (IVd) wherein R _a , X", y, Q are as above defined, may be carried out as described in l-i-2).

3p) The compounds of formula (Ig) wherein X ₂ is selected from (a3') or (b3'), wherein R ^la is selected from A5) or A6) , R ^2a is selected from B5) or B6) , Y' is as above defined, T" is C(O)-

NR' wherein R' is as above defined, can be obtained

3p-i) by reacting a compound of formula (HIg),

P ³ -X ₉ (HIf) wherein P ³ and X9 are as above defined, with a compound of formula (IVf)

R _a -O- ( O) C-NR' -y-Q

( IVf ) wherein R _a , R' and Q are as above defined, y is the radical Y' , wherein Y' is as above defined, and 3p-ii) when Q is Z ₂ , by converting the compounds obtained in the step 3p-i) into nitro derivative by reaction with a nitrate source as above described and

3p-iii) optionally deprotecting the compounds obtained in step 3p-i) or 3p-ii) as above described. The reaction of a compound of formula (HIf) wherein P ³ and Xg are as above defined, with a compound of formula (IVf) wherein R _a , R' , y, Q are as above defined, may be carried out as described in l-i-2).

4) The compounds of general formula (I) as above defined wherein a is equal to 1, the radical R _x is selected from (dl), (d2), (d3), (d4), (d7) or (d8), Z is C(O), can be obtained 4-i) by reacting a compound of formula (II3) as above defined wherein R _a is as above defined, with a compound of formula (Im) H-X ₁₂

(Im) wherein X ₁₂ is the radical R _x having the following meaning

- (dl' ) -HN-CH(R ^12' ) -CH ₂ -O- (T"' -Y-Q)

- (d2' ) -0-CH ₂ -CH(R ^12' ) -NH- (T' -Y-Q) ~(d3') -HN-CH (R ^12a -T"-Y' -Q) -CH ₂ OH

- (d4' ) -0-CH ₂ -CH (R ^12a -τ"-Y' -Q) -NHR ^4a

- (dV ) -HN-CH (R ^12a -τ"-Y' -Q) -CH ₂ -O- (T"' -Y-Q)

- (d8' ) -0-CH ₂ -CH (R ^12a -τ"-Y' -Q) -NH- (T' -Y-Q) wherein R ^12' is Dl),

D2') -CH ₂ -OP ¹ , -CH(CH ₃ ) -OP ¹ , -CH ₂ [ (C ₆ H ₄ ) -4-OP ¹ ] , -CH ₂ - [ (C ₆ H ₃ ) - (3, 5- diiodo) -4-OP ¹ ] , -CH ₂ - [ (C ₆ H ₃ ) -3-nitro-4-OP ¹ ] ;

D3') -CH ₂ -NHR"", - (CH ₂ ) ₂ -NHR"", - (CH ₂ ) ₃ -NHR"", - (CH ₂ ) ₄ -NHR"", wherein R"" is as above defined;

D4') -CH ₂ -C(O)R""', -(CH ₂ ) ₂ -C(O)R""', - (CH ₂ ) ₄ -C (0) R""' , wherein R""' is as above defined; wherein R ^12a is as above defined; and

4-ii) when Q is Z ₂ , by converting the compounds obtained in the step 4-i) into nitro derivative by reaction with a nitrate source as above described and 4-iii) optionally deprotecting the compounds obtained in step 4-i) or 4-ii) as above described.

The reaction of a compound of formula (II3) wherein R and R _a are as above defined, with a compound of formula (Im) wherein Xi ₂ is as above defined, may be carried out as described in l-i-2) .

4a) The compounds of formula (Im) wherein Xi ₂ is selected from (dl'), (d2'), (d3') or (d4') wherein R ^12' is selected from Dl), D2'), D3') or D4') and R ^12a is selected from D5) or D6) , Y and Y' are as above defined, T' and T" and T"' are C(O) can be obtained

4a-i) by reacting a compound of formula (HIi),

P ⁴ -Xl3

(nil) wherein P ⁴ is P ³ or P ¹ as above defined and X13 is a radical having the following meaning

-(dl") -HN-CH(R ^12' ) -CH ₂ -OH

-(d2") -0-CH ₂ -CH(R ^12' ) -NH ₂

-(d3") -HN-CH (R ^12a -H) -CH ₂ OP ¹

-(d4") -0-CH ₂ -CH (R ^12a -H) -NHR ^4a' wherein R ^12' is Dl), D2'), D3' ) or D4'), R ^12a is D5) or D6) , R ^4a' and P ¹ are as above defined, with a compound of formula (IVa)

Wi-(O)C-y-Q

( IVa ) wherein Q and Wi are as above defined, y is the radical Y when Xi3 is selected from (dl') or (d2'), y is the radical Y' when X _i3 is selected from (d3' ) or (d4'), wherein Y and Y' are as above defined, and

4a-ii) when Q is Z ₂ , by converting the compounds obtained in the step 4a-i) into nitro derivative by reaction with a nitrate source as above described and

4a-iii) optionally deprotecting the compounds obtained in step 4a-i) or 4a-ii) as above described.

The reaction of a compound of formula (HIi) wherein X _i3 and P ⁴ are as above defined, with a compound of formula (IVa) wherein Wi, y and Q are as above defined, may be carried out as described in 1-i-l) and l-i-2).

The compounds of formula (HIi) wherein X _i3 and P ⁴ are as above described, are commercially available or known in literature.

4b) The compounds of formula (Im) wherein X ₁₂ is selected from (dl'), (d2'), (d3') or (d4') wherein R ^12' is selected from Dl), D2'), D3') or D4') and R ^12a is selected from D5) or D6) , Y and Y' are as above defined, T' and T" and T"' are C(O)-X", wherein X" is as above defined, can be obtained 4b-i) by reacting a compound of formula (HIi), P ⁴ -Xl3

(iiii) wherein P ⁴ and X _i3 are defined above, with a compound of formula (IVd)

Ra-O- (O) C-X"-y-Q (IVd) wherein Q, R _a and X" are as above defined, y is the radical Y when Xi ₃ is selected from (dl') or (d2'), y is the radical Y'

when Xi3 is selected from (d3' ) or (d4'), wherein Y and Y' are as above defined, and

4b-ii) when Q is Z ₂ , by converting the compounds obtained in the step 4b-i) into nitro derivative by reaction with a nitrate source as above described and

4b-iii) optionally deprotecting the compounds obtained in step 4b-i) or 4b-ii) as above described.

The reaction of a compound of formula (HIi) wherein X13 and P ⁴ are as above defined, with a compound of formula (IVd) wherein y, Q, R _a and X" are as above defined, may be carried out as described in l-i-2).

4c) The compounds of formula (Im) wherein X ₁₂ is selected from (dV) or (d8') wherein R ^12a is selected from D5) or D6) , Y' and Y are as above defined, T' and T" and T"' are C(O), can be obtained 4c-i) by reacting a compound of formula (III1),

P ⁴ -Xl4

(HIl) wherein P ⁴ is P ¹ or P ³ , Xi ₄ is the radical having the following meaning

-(d7") -HN-CH (R ^12a -H) -CH ₂ -OH -(d8") -0-CH ₂ -CH (R ^12a -H) -NH ₂ wherein R ^12a is selected from D5) or D6) , with a compound of formula (IVa)

Wi-(O)C-y-Q

(IVa) wherein Wi and Q are as above defined, y is the radical Y' , wherein Y' is as above defined, and 4c-ii) when Q is Z ₂ , by converting the compounds obtained in the step 4c-i) into nitro derivative by reaction with a nitrate source as above described and

4c-iii) optionally deprotecting the compounds obtained in step 4c-i) or 4c-ii) as above described.

The reaction of a compound of formula (III1) wherein P ⁴ and Xi ₄ are as above defined, with a compound of formula (IVa) wherein Wi is OH, y and Q are as above defined, may be carried out as described in 1-i-l) using a ratio (HIl)/ (IVa) 1:2. The reaction of a compound of formula (HIl) wherein P ⁴ and X14 are as above defined, with a compound of formula (IVa) wherein Wi is 0R _a , y and Q are as above defined, may be carried out as described in l-i-2) using a ratio (HIl) /(IVa) 1:2.

The compounds of formula (HIl) wherein P ⁴ and X14 are as above described, are commercially available or known in literature.

4d) The compounds of formula (Im) wherein X12 is selected from

(dV) or (d8') wherein R ^12a is selected from D5) or D6) , Q, Y and

Y' are as above defined, T', T"' and T" are C(O), can be obtained

4d-i) by reacting a compound of formula ( In ) P ⁴ -Xi5

( In ) wherein P ⁴ is defined above and Xi ₅ is the radical having the following meaning

- (d7"' ) -HN-CH (R ^12a -H) -CH ₂ -O- (T"' -Y-Q) -(d8"') -0-CH ₂ -CH (R ^12a -H) -NH- (T' -Y-Q) wherein R ^12a is selected from D5) or D6) , Y, Q, T' and T"' are as above defined, with a compound of formula (IVa)

Wi-(O)C-y-Q

(IVa) wherein Wi, y and Q' are as above defined, y is the radical Y' , wherein Y' is as above defined, and

4d-ii) when Q is Z2, by converting the compounds obtained in the step 4d-i) into nitro derivative by reaction with a nitrate source as above described and

4d-iii) optionally deprotecting the compounds obtained in step 4d-i) or 4d-ii) as above described.

The reaction of a compound of formula (In) wherein P ⁴ and X15 are as above defined, with a compound of formula (IVa) wherein Wi is OH, y and Q are as above defined, may be carried out as described in 1-i-l). The reaction of a compound of formula (In) wherein P ⁴ and Xi ₅ are as above defined, with a compound of formula (IVa) wherein Wi is 0R _a , y and Q are as above defined, may be carried out as described in l-i-2).

The compounds of formula (In) wherein P ⁴ and Xi ₅ are as above defined, T' and T"' are -C(O)- can by obtained as described in 4a) .

4e) The compounds of formula (Im) wherein X ₁₂ is selected from (dV) or (d8') wherein R ^12a is selected from D5) or D6) , Y and Y' are the same and are as above defined, T', T" and T"' are C(O)- X" wherein X" is as above defined, can be obtained 4e-i) by reacting a compound of formula (III1),

P ⁴ -Xl4 (HIl) wherein P ⁴ and X14 are as above defined, with a compound of formula (IVd)

Ra-O-C (O)-X"-y-Q

(IVd) wherein R _a , X" and Q are as above defined, y is the radical Y' , wherein Y' is as above defined, and

4e-ii) when Q is Z2, by converting the compounds obtained in the step 4e-i) into nitro derivative by reaction with a nitrate source as above described and

4e-iii) optionally deprotecting the compounds obtained in step 4e-i) or 4e-ii) as above described.

The reaction of a compound of formula (III1) wherein P ⁴ and X14 are as above defined, with a compound of formula (IVd) wherein R _a , X", y and Q are as above defined, may be carried out as described in l-i-2) using a ratio (HIl)/ (IVd) 1:2.

4f) The compounds of formula (Im) wherein X12 is selected from (dV) or (d8') wherein R ^12a is selected from D5) or D6) , Q, Y and Y' are as above defined, T" is C(O)-X", T' and T"' are C(O) or C(O)-X", wherein X" is as above defined, can be obtained 4f-i) by reacting a compound of formula (In)

P ⁴ -Xl5

(In) wherein P ⁴ and X15 are as above defined, with a compound of formula (IVd) Ra-O-C (O)-X"-y-Q

(IVd) wherein R _a , X" and Q are as above defined, y is the radical Y' , wherein Y' is as above defined, and

4f-ii) when Q is Z2, by converting the compounds obtained in the step 4f-i) into nitro derivative by reaction with a nitrate source as above described and

4f-iii) optionally deprotecting the compounds obtained in step

4f-i) or 4f-ii) as above described.

The reaction of a compound of formula (In) wherein P ⁴ and Xi ₅ are as above defined, with a compound of formula (IVd) wherein

R _a , X", y and Q are as above defined, may be carried out as described in l-i-2).

The compounds of formula (In) wherein T' or T"' are C(O), P and Xi5 are as above defined are obtained as described in 4a-i) , 4a- ϋ) •

The compounds of formula (In) wherein T' or T"' are C(O)-X", wherein P ⁴ and Xi ₅ are as above defined are obtained as described in 4b-i) , 4b-ii) .

4g) The compounds of formula (Im) wherein X12 is selected from

(dV) or (d8') wherein R ^12a is selected from D5) or D6) , Q, Y and Y' are as above defined, T" is C(O)-NR'-, T' and T"' are C(O) or C(O)-X", wherein X" is as above defined, can be obtained 4g-i) by reacting a compound of formula (In) P ⁴ -Xi5

(In) wherein P ⁴ and Xi ₅ are as above defined, with a compound of formula

R _a -0- (O)C-NR'-y-Q (IVf) wherein R _a , R' and Q are as above defined, y is the radical Y' , wherein Y' is as above defined, and

4g-ii) when Q is Z ₂ , by converting the compounds obtained in the step 4g-i) into nitro derivative by reaction with a nitrate source as above described and

4g-iii) optionally deprotecting the compounds obtained in step 4g-i) or 4g-ii) as above described.

The reaction of a compound of formula (In) P ⁴ and Xi ₅ are as above defined, with a compound of formula (IVf) wherein R _a , R', y, Q are as above defined, may be carried out as described in l-i-2) .

The compounds of formula (In) wherein T' or T"' are C(O), wherein P ⁴ and Xi ₅ are as above defined, are obtained as described in 4a-i) , 4a-ii) .

The compounds of formula (In) wherein T' or T"' are C(O)-X", wherein P ⁴ and Xi ₅ are as above defined, are obtained as described in 4b-i) , 4b-ii) .

4h) The compounds of formula (Im) wherein X12 is selected from (dV) or (d8') wherein R ^12a is selected from D7), Q, Y and Y' are as above defined, T" is X", wherein X" is as above defined, T' and T"' are C(O) or C(O)-X", wherein X" is as above defined, can be obtained

4h-i ) by react ing a compound o f formul a ( I r ) , P ⁴ -Xi 6

( I r ) wherein P ⁴ is defined above and X16 is the radical having the following meaning

-{άl"") -HN-CH (R ^12a -OH) -CH ₂ -O- (T"' -Y-Q)

- (d8"") -0-CH ₂ -CH (R ^12a -OH) -NH- (T' -Y-Q) wherein R ^12a is selected from D7), with a compound of formula

(IVe)

HX"-y-Q (IVe) wherein Y' , X" and Q are as above defined, y is the radical Y' , wherein Y' is as above defined, and

4h-ii) when Q is Z ₂ , by converting the compounds obtained in the step 4h-i) into nitro derivative by reaction with a nitrate source as above described and

4h-iii) optionally deprotecting the compounds obtained in step

4h-i) or 4h-ii) as above described.

The reaction of a compound of formula (Ir) wherein P ⁴ and X ₁ ^ are as above defined with a compound of formula (IVe) wherein y, X" and Q are as above defined, may be carried out as described in 1-i-l) .

The compounds of formula (Ir) wherein T' or T"' are C(O), P ⁴ and Xi6 are as above defined are obtained as described in 4a-i) , 4a- ϋ) •

The compounds of formula (Ir) wherein T' or T"' are C(O)-X", P ⁴ and Xi6 are as above defined, are obtained as described in 4b- i) , 4b-ii) .

4i) The compounds of formula (Im) wherein X ₁₂ is selected from (dV) or (d8') wherein R ^12a is selected from D7), Q, Y and Y' are as above defined, T" is -NR' wherein R' is as above defined, T' and T"' are C(O) or C(O)-X", wherein X" is as above defined, can be obtained 4i-i) by reacting a compound of formula (Ir), P ⁴ -Xl6

(Ir) wherein P ⁴ and X ₁ β are as above defined and R ^12a is selected from

D7), with a compound of formula

HR'N-y-Q (IVg) wherein R' and Q are as above defined, y is the radical Y' , wherein Y' is as above defined, and

4i-ii) when Q is Z ₂ , by converting the compounds obtained in the step 4i-i) into nitro derivative by reaction with a nitrate source such above described and

4i-iii) optionally deprotecting the compounds obtained in step

4i-i) or 4i-ii) as above described.

The reaction of a compound of formula (Ir) P ⁴ and X ₁ ^ are as above defined, with a compound of formula (IVg) wherein R', y, Q are as above defined, may be carried out as described in 1-i- D •

41) The compounds of formula (Im) wherein X ₁₂ is selected from (dV) or (d8') wherein R ^12a is selected from D7), Q, Y and Y' are as above defined, T" is -O-CH (R' ) -O-C (O) -, wherein R' is as above defined, T' and T"' are C(O) or C(O)-X", wherein X" is as above defined, can be obtained

41-i) by reacting a compound of formula (Ir),

P ⁴ -Xl6

(Ir) wherein P ⁴ and X ₁ ^ are as above defined and R ^12a is selected from D7), with a compound of formula (IVm)

HaI-CH (R' ) -0- (0) C-y-Q (IVm) wherein R' and Q are as above defined, Hal is an halogen atom, y is the radical Y' , wherein Y' is as above defined, and 41-ii) when Q is Z ₂ , by converting the compounds obtained in the step 41-i) into nitro derivative by reaction with a nitrate source such above described and

41-iii) optionally deprotecting the compounds obtained in step

41-i) or 41-ii) as above described. The reaction of a compound of formula (Ir) wherein P ⁴ and X ₁ ^ are as above defined, with a compound of formula (IVm) wherein y,

Q, R' are as above defined, may be carried out as described in

11-i) .

4m) The compounds of formula (Im) wherein X ₁₂ is selected from

(dV) or (d8') wherein R ^12a is selected from D7), Q, Y and Y' are as above defined, T" is -O-CH (R' ) -0-C (0) -0-, wherein R' is as

above defined, T' and T"' are C(O) or C(O)-X", wherein X" is as above defined, can be obtained

4m-i) by reacting a compound of formula (Ir),

P ⁴ -Xl6 (Ir) wherein P ⁴ and Xi6 are as above defined and R ^12a is selected from D7), with a compound of formula (IVo)

HaI-CH (R' ) -0- (0) C-O-y-Q (IVo) wherein R and Q' are as above defined, Hal is an halogen atom, y is the radical Y' , wherein Y' is as above defined, and 4m-ii) when Q is Z ₂ , by converting the compounds obtained in the step 4m-i) into nitro derivative by reaction with a nitrate source as above described and 4m-iii) optionally deprotecting the compounds obtained in step 4m-i) or 4m-ii) as above described.

The reaction of a compound of formula (Ir) wherein P ⁴ and X16 are as above defined, with a compound of formula (IVo) wherein y, R' , Q, Hal are as above defined, may be carried out as described in 11-i) .

4n) The compounds of formula (Im) wherein X12 is selected from (d3' ) or (d4') wherein R ^12a is selected from D7), Y' is as above defined, T" is X", wherein X" is defined above, can be obtained 4n-i) by reacting a compound of formula (Him),

P ⁴ -Xl7

(Him) wherein P ⁴ is defined above and Xi ₇ is the radical - (d3"' ) -HN-CH(R ¹ ^-OH)-CH ₂ OP ¹ -(d4"') -0-CH ₂ -CH (R ^12a -0H) -NHR ^4a' wherein R ^12a is selected from D7), wherein P ¹ and R ^4a are as above defined, with a compound of formula (IVe)

HX"-y-Q

( IVe ) wherein X" and Q are as above defined, y is the radical Y' , wherein Y' is as above defined, and 4n-ii) when Q is Z ₂ , by converting the compounds obtained in the step 4n-i) into nitro derivative by reaction with a nitrate source as above described and

4n-iii) optionally deprotecting the compounds obtained in step 4n-i) or 4n-ii) as above described. The reaction of a compound of formula (Him) wherein P ⁴ and Xi ₇ are as above defined with a compound of formula (IVe) wherein y, X" and Q are as above defined, may be carried out as described in 1-i-l).

The compounds of formula (Him), wherein P ⁴ and Xi ₇ are as above defined, are commercially available or obtained as known in literature .

4o) The compounds of formula (Im) wherein X ₁₂ is selected from (d3') or (d4') wherein R ^12a is selected from D7), Y' is as above defined, T" is -NR' wherein R' is as above defined, can be obtained 4o-i) by reacting a compound of formula (Him),

P ⁴ -Xl7 (Him) wherein P ⁴ and Xi ₇ are as defined above, wherein R ^12a is selected from D7), with a compound of formula

HR'N-y-Q

(IVg) wherein R' and Q are as above defined, y is the radical Y' , wherein Y' is as above defined, and

4o-ii) when Q is Z2, by converting the compounds obtained in the step 4o-i) into nitro derivative by reaction with a nitrate source such above described and

4o-iii) optionally deprotecting the compounds obtained in step 4o-i) or 4o-ii) as above described.

The reaction of a compound of formula (Him) wherein P ⁴ and X17 are as above defined, with a compound of formula (IVg) wherein R' , y, Q are as above defined, may be carried out as described in la-i) .

4p) The compounds of formula (Im) wherein X12 is selected from (d3' ) or (d4') wherein R ^12a is selected from D7), Y' is as above defined, T" is -O-CH (R' ) -O-C (O) - wherein R' is as above defined, can be obtained

4p-i) by reacting a compound of formula ( H im) ,

P ⁴ -Xl 7

( H im) wherein P ⁴ and X17 are as defined above, wherein R ^12a is selected from D7), with a compound of formula (IVm)

HaI-CH (R' ) -0- (0) C-y-Q

(IVm) wherein R' and Q are as above defined, Hal is an halogen atom, y is the radical Y' , wherein Y' is as above defined, and 4p-ii) when Q is Z2, by converting the compounds obtained in the step 4p-i) into nitro derivative by reaction with a nitrate source such above described and

4p-iii) optionally deprotecting the compounds obtained in step 4p-i) or 4p-ii) as above described. The reaction of a compound of formula (Him) wherein P ⁴ and X17 are as above defined, with a compound of formula (IVm) wherein

R' , y, Q are as above defined, may be carried out as described in 11-i) .

4q) The compounds of formula (Im) wherein X12 is selected from (d3' ) or (d4') wherein R ^12a is selected from D7), Y' is as above defined, T" is -O-CH (R' ) -O-C (O) -0- wherein R' is as above defined, can be obtained 4q-i) by reacting a compound of formula (Him),

P ⁴ -Xl7 (Him) wherein P ⁴ and Xi ₇ are as defined above, wherein R ^12a is selected from D7), with a compound of formula (IVo) HaI-CH (R' ) -0- (0) C-O-y-Q (IVo) wherein R' and Q are as above defined, Hal is an halogen atom, y is the radical Y' , wherein Y' is as above defined, and 4q-ii) when Q is Z ₂ , by converting the compounds obtained in the step 4q-i) into nitro derivative by reaction with a nitrate source as above described and 4q-iii) optionally deprotecting the compounds obtained in step 4q-i) or 4q-ii) as above described.

The reaction of a compound of formula (Him) wherein P ⁴ and Xi ₇ are as above defined, with a compound of formula (IVo) wherein y, R' , Q, Hal are as above defined, may be carried out as described in 11-i) .

5) The compounds of general formula (I) as above defined wherein a is equal to 0, R _x is a radical selected from (d5) , (d6) , (d9) or (dlO), wherein R ^12b is selected from DlO) can be obtained

5-i) by reacting a compound of formula (Hi) as above defined with a compound of formula (Is)

W-Xi ₈ ( I s ) wherein W is as above defined, Xig is the radical having the following meanings -(d5') -R ^12b -CH(NHR ^4a ) -CH ₂ -O- (T"' -Y-Q)

- (d6' ) -R ^12b -CH (CH ₂ OH) -NH- (T' -Y-Q)

- (d9' ) -R ^12b -CH (NH-T"' -Y' -Q) -CH ₂ -O- (T' -Y-Q)

- (dlO' ) -R ^12b -CH (CH ₂ -O-T"' -Y' -Q) -NH- (T' -Y-Q) wherein R ^12b is selected from DlO), T', T"', Y, Y' and Q are as above defined and

5-ii) when Q is Z ₂ , by converting the compounds obtained in the step 5-i) into nitro derivative by reaction with a nitrate source as above described and

5-iii) optionally deprotecting the compounds obtained in step 5-i) or 5-ii) as above described.

The reaction of a compound of formula (II3) as above defined, with a compound of formula (Is) wherein W and Xig are as above defined may be carried out as described in 1) .

5a) The compounds of formula (Is) wherein X _i8 is a radical of formula (d5' ) or (d6' ) , wherein R ^12b is selected from DlO), T' and T"' are C(O) can be obtained

5a-i) by reacting a compound of formula (HIn),

P ² -X ₁₉ (HIn) wherein P ² is as above defined, X19 is the radical having the following meanings

-(d5") -R ^12b -CH (NHP ³ ) -CH ₂ -OH

-(d6") -R ^12b -CH (CH ₂ OP ¹ ) -NH ₂ wherein P ¹ and P ³ are as above defined and R ^12b is selected from

DlO), with a compound of formula (IVa)

Wi-C(O)-y-Q

( IVa ) wherein Wi, y, Q are as above defined, y is the radical Y, wherein Y is as above defined, and

5a-ii) when Q is Z ₂ , by converting the compounds obtained in the step 5a-i) into nitro derivative by reaction with a nitrate source as above described and

5a-iii) optionally deprotecting the compounds obtained in step 5a-i) or 5a-ii) as above described.

The reaction of a compound of formula (HIn) wherein P ² and X19 are as above defined, with a compound of formula (IVa) Wi, y, and Q are as above defined may be carried out as described in 1-i-l), l-i-2), l-i-3) and Ia-I).

The compounds of formula (HIn), wherein P ² and X19 are as above defined, are commercially available or obtained as known in literature .

5b) The compounds of formula (Is) wherein Xi ₈ is a radical of formula (d5' ) or (d6' ) , wherein R ^12b is selected from DlO), T' and T"' are C(O)-X", wherein X" is defined above, can be obtained 5b-i) by reacting a compound of formula (HIn),

P ² -Xi9 (HIn) wherein P ² and X19 are as above defined, with a compound of formula (IVd) Ra-O-C (O) -X"-y-Q (IVd) wherein R _a and Q, X" are as above defined, y is the radical Y, wherein Y is as above defined, and

5b-ii) when Q is Z ₂ , by converting the compounds obtained in the step 5b-i) into nitro derivative by reaction with a nitrate source as above described and

5b-iii) optionally deprotecting the compounds obtained in step 5b-i) or 5b-ii) as above described.

The reaction of a compound of formula (HIn) wherein P ² and X19 are as above defined, with a compound of formula (IVd) R _a , y, Q, X" are as above defined may be carried out as described in 1-i- 2) .

5c) The compounds of formula (Is) wherein Xig is a radical of formula (d9' ) , wherein R ^12b is selected from DlO), Y and Y' are as defined above, T' is C(O)- and T"' is C(O) or C(O)-X", wherein X" is defined above, can be obtained 5c-i) by reacting a compound of formula (It),

P ² -X ₂ o

(It) wherein P ² is as above defined and X20 is the radical having the following meanings -(d9") -R ^12b -CH (NH ₂ ) -CH ₂ -O- (T"' -Y-Q) wherein R ^12b is selected from DlO), T"', Y and Q are as above defined, with a compound of formula (IVa)

Wi-C(O)-y-Q

(IVa) wherein Wi and Q are as above defined, y is the radical Y' , wherein Y' is as above defined, and

5c-ii) when Q is Z ₂ , by converting the compounds obtained in the step 5c-i) into nitro derivative by reaction with a nitrate source as above described and 5c-iii) optionally deprotecting the compounds obtained in step 5c-i) or 5c-ii) as above described. The reaction of a compound of formula (It) wherein P ² and X ₂ o

are as above defined, with a compound of formula (IVa) wherein Wi, y, Q are as above defined, may be carried out as described in 1-i-l), l-i-2), l-i-3) and Ia-I).

5d) The compounds of formula (Is) wherein Xig is a radical of formula (d9' ) , wherein R ^12b is selected from DlO), T' is C(O)-X" and T"' is C(O)- or C(O)-X", wherein X" is defined above, can be obtained

5d-i) by reacting a compound of formula ( I t ) , P ² -X ₂ o

( I t ) wherein P ² and X20 are as above defined, with a compound of formula (IVd)

Ra-O-C (O)-X"-y-Q (IVd) wherein R _a and Q, X" are as above defined, y is the radical Y' , wherein Y' is as above defined, and

5d-ii) when Q is Z2, by converting the compounds obtained in the step 5d-i) into nitro derivative by reaction with a nitrate source as above described and

5d-iii) optionally deprotecting the compounds obtained in step

5d-i) or 5d-ii) as above described.

The reaction of a compound of formula (It) wherein P ² and X20 are as above defined, with a compound of formula (IVd) R _a , y, Q, X" are as above defined may be carried out as described in 1-i-

2) .

5e) The compounds of formula (Is) wherein Xig is the radical of formula (dlO'), wherein R ^12b is selected from DlO), Y and Y' are as defined above, T"' is C(O)- and T' is C(O) or C(O)-X", wherein X" is defined above, can be obtained 5e-i) by reacting a compound of formula (It),

P ² -X ₂ o' (It') wherein P ² is as above defined and X ₂ 0 _' is the radical having the following meaning -(dlO") -R ^12b -CH (CH ₂ -OH) -NH- (T' -Y-Q) wherein R ^12b is selected from DlO), T', Y and Q are as above defined, with a compound of formula (IVa)

W ₁ -C(O)-Y-Q

(IVa) wherein Wi and Q are as above defined, y is the radical Y' , wherein Y' is as above defined, and

5e-ii) when Q is Z ₂ , by converting the compounds obtained in the step 5e-i) into nitro derivative by reaction with a nitrate source as above described and 5e-iii) optionally deprotecting the compounds obtained in step 5e-i) or 5e-ii) as above described.

The reaction of a compound of formula (It') wherein P ² and X ₂ O _' are as above defined, with a compound of formula (IVa) wherein Wi, y, Q are as above defined, may be carried out as described in 1-i-l), l-i-2), l-i-3) and Ia-I).

5f) The compounds of formula (Is) wherein Xig is the radical of formula (dlO'), wherein R ^12b is selected from DlO), T"' is C(O)- X" and T' is C(O)- or C(O)-X", wherein X" is defined above, can be obtained

5f-i) by reacting a compound of formula (It'),

P ² -X ₂ o' (It') wherein P ² and X ₂ O _' are as above defined, with a compound of formula (IVd)

Ra-O-C (O) -X"-y-Q (IVd)

wherein R _a and Q, X" are as above defined, y is the radical Y' , wherein Y' is as above defined, and

5f-ii) when Q is Z ₂ , by converting the compounds obtained in the step 5f-i) into nitro derivative by reaction with a nitrate source as above described and

5f-iii) optionally deprotecting the compounds obtained in step 5f-i) or 5f-ii) as above described.

The reaction of a compound of formula (It') wherein P ² and X20 _' are as above defined, with a compound of formula (IVd) R _a , y, Q, X" are as above defined may be carried out as described in 1-i- 2) .

6) The compounds of general formula (I) as above defined wherein a is equal to 1, R _x is a radical selected from (d5) , (d6) , (d9) or (dlO), wherein R ^12b is selected from DlO), Z is -

CH(R')-O-, wherein R' is defined above, can be obtained

6-i) by reacting a compound of formula (Hi) as above defined with a compound of formula (Iu)

HaI-CH(R' ) -O-X21 (Iu) wherein Hal is an halogen atom, R' is as above defined and X21 is a radical selected from (d5' ) , (d6' ) , (d9' ) or (dlO'), wherein R ^12b is selected from DlO), and

6-ii) when Q is Z ₂ , by converting the compounds obtained in the step 6-i) into nitro derivative by reaction with a nitrate source as above described and

6-iii) optionally deprotecting the compounds obtained in step

6-i) or 6-ii) as above described.

The reaction of a compound of formula (Iu) wherein Hal, X21 and R' are as above defined, with a compound of formula (Hi) as above defined may be carried out as described in 11-i) .

The compounds of formula (Iu) are obtained by reacting a compound R' -CHO, wherein R' is as above defined with compounds of formula (IIIo)

W-X ₂₂ (HIo) wherein W is a chlorine atom, X ₂₂ is the radical having the following meanings

_ (d5"' ) -R ^12b -CH (NHP ³ ) -CH ₂ -O- (T"' -Y-Q)

- (d6"' ) -R ^12b -CH (CH ₂ OP ¹ ) -NH- (T' -Y-Q) -(d9"') -R ^12b -CH (NH-T' -Y' -Q) -CH ₂ -O- (T"' -Y-Q)

- (dlO"' ) -R ^12b -CH (CH ₂ -O-T"' -Y' -Q) -NH- (T' -Y-Q) wherein R ^12b , P ³ , P ¹ , T' , T"' , Y' , Y and Q are as above defined, and ZnCl ₂ as known in literature.

The compounds of formula (IIIo), wherein W and X ₂₂ are as above defined, may be carried out as described in 5) .

7) The compounds of general formula (I) as above defined wherein a is equal to 1, R _x is a radical selected from (d5) , (d6) , (d9) or (dlO), wherein R ^12b is selected from D8) or D9) , Z is -C(O)-, can be obtained

7-i) by reacting a compound of formula (II3) as above defined wherein R _a is as above defined with a compound of formula (Iv)

H-X ₂ 3 (Iv) wherein X ₂₃ is a radical selected from (d5' ) , (d6' ) , (d9' ) or (dlO'), wherein R ^12b is selected from D8) or D9) , and 7-ii) when Q is Z ₂ , by converting the compounds obtained in the step 7-i) into nitro derivative by reaction with a nitrate source as above described and 7-iii) optionally deprotecting the compounds obtained in step 7-i) or 7-ii) as above described.

The reaction of a compound of formula (Iv) wherein X23 and is as above defined, with a compound of formula (II3) as above defined may be carried out as described in 11-i) .

8) The compounds of general formula (I) as above defined wherein a is equal to 0, R _x is a radical selected from (a5) , (a6), (a9) or (alO), (b5) , (b6) , (b9) or (blO) wherein R ^lb is selected from AlO) and R ^2b is selected from BlO), can be obtained 8-i) by reacting a compound of formula (Hi) as above defined with a compound of formula (Iz)

W-X ₂₄ (Iz) wherein W is as above defined, X24 is the radical R _x having the following meanings

- (a5' ) -R ^lb -CH (NHR ^4a ) -C (O) - (T-Y-Q)

- (a6' ) -R ^lb -CH (COOR ^3a )NH- (T' -Y-Q)

- (a9' ) -R ^lb -CH (NH-T' -Y' -Q) -C (O) - (T-Y-Q)

- (alO' ) -R ^lb -CH (C (O) -T' -Y' -Q) -NH- (T-Y-Q) ~(b5') -R ^2b -CH(NHR ^4a ) -CH ₂ C (O) - (T-Y-Q)

- (b6' ) -R ^2b -CH (CH ₂ COOR ^3a ) NH- (T' -Y-Q)

- (b9' ) -R ^2b -CH (NH-T' -Y' -Q) -CH ₂ C (O) - (T-Y-Q)

- (blO' ) -R ^2b -CH (CH ₂ C (O) -T' -Y' -Q) -NH- (T-Y-Q) wherein R ^lb is selected from AlO), R ^2b is selected from BlO), T, T' , Y and Q are as above defined and

8-ii) when Q is Z ₂ , by converting the compounds obtained in the step 8-i) into nitro derivative by reaction with a nitrate source as above described and

8-iii) optionally deprotecting the compounds obtained in step 8-i) or 8-ii) as above described.

The reaction of a compound of formula (Hi) as above defined

wherein R is as above defined, with a compound of formula (Iv) wherein W and X ₂₄ are as above defined may be carried out as described in 1) .

8a) The compounds of formula (Iz) wherein X ₂₄ is a radical of formula (a5' ) , (a6' ) , (b5' ) or (b6' ) , wherein R ^lb is selected from AlO) and R ^2b is selected from BlO), T and T' are C(O) can be obtained

8a-i) by reacting a compound of formula ( H Iq) , P ² -X ₂ 5

( H Iq) wherein P ² is as above defined, X25 is the radical having the following meanings

-(a5") -R ^lb -CH(NHP ³ ) -C (O) -OH ~(a6") -R ^lb -CH (COOP ² ) -NH ₂

-(b5") -R ^2b -CH(NH P ³ ) -CH ₂ C (0) -OH

-(b6") -R ^2b -CH (CH ₂ COO P ² ) NH ₂ wherein P ² and P ³ are as above defined and R ^lb is selected from

AlO), R ^2b is selected from BlO), with a compound of formula (IVa)

Wi-C(O)-y-Q (IVa) wherein Wi and Q are as above defined, y is the radical Y, wherein Y is as above defined, and 8a-ii) when Q is Z ₂ , by converting the compounds obtained in the step 8a-i) into nitro derivative by reaction with a nitrate source as above described and

8a-iii) optionally deprotecting the compounds obtained in step

8a-i) or 8a-ii) as above described. The reaction of a compound of formula (HIq) wherein P ² and X ₂ s are as above defined, with a compound of formula (IVa) Wi, Y,

and Q are as above defined may be carried out as described in 1-i-l), l-i-2), l-i-3) and Ia-I).

The compounds of formula (HIq), wherein P ² and X25 are as above defined, are commercially available or obtained as known in literature .

8b) The compounds of formula (Iz) wherein X ₂₄ is the radical of formula (a5' ) , (a6' ) , (b5' ) or (b6' ) , wherein R ^lb is selected from AlO) and R ^2b is selected from BlO), T and T' are C(O)-X", wherein X" is defined above, can be obtained

8b-i) by reacting a compound of formula (HIq),

P ² -X ₂₅ ( H I q) where in P ² and X ₂₅ are as above de f ined, wi th a compound o f formul a ( IVd)

Ra-O-C ( O ) -X" - y-Q ( IVd) wherein R _a , Q and X" are as above defined, y is the radical Y, wherein Y is as above defined, and

8b-ii) when Q is Z ₂ , by converting the compounds obtained in the step 8b-i) into nitro derivative by reaction with a nitrate source as above described and

8b-iii) optionally deprotecting the compounds obtained in step 8b-i) or 8b-ii) as above described.

The reaction of a compound of formula (HIq) wherein P ² and X25 are as above defined, with a compound of formula (IVd) R _a , y, Q,

X" are as above defined may be carried out as described in 1-i-

2) .

8c) The compounds of formula (Iz) wherein X ₂₄ is the radical of formula (a9' ) or (b9' ) wherein R ^lb is selected from AlO), and R ^2b

is selected from BlO) Y and Y' are as defined above, T is C(O)- or C(O)-X", wherein X" is defined above and T' is C(O) can be obtained

8c-i) by reacting a compound of formula (Iy), P ² -X26

(Iy) wherein P ² is as above defined and X26 is the radical having the following meanings

- (a9") -R ^lb -CH (NH ₂ ) -C (0) - (T-Y-Q) -(b9") -R ^2b -CH (NH ₂ ) -CH ₂ C (0) - (T-Y-Q) wherein R ^lb is selected from AlO) and R ^2b is selected from BlO), with a compound of formula (IVa)

Wi-C(O)-y-Q

(IVa) wherein Wi and Q are as above defined, y is the radical Y' , wherein Y' is as above defined, and

8c-ii) when Q is Z ₂ , by converting the compounds obtained in the step 8c-i) into nitro derivative by reaction with a nitrate source as above described and 8c-iii) optionally deprotecting the compounds obtained in step

8c-i) or 8c-ii) as above described.

The reaction of a compound of formula (Iy) wherein P ² and X ₂ 6 are as above defined, with a compound of formula (IVa) wherein

Wi, y, Q are as above defined, may be carried out as described in 1-i-l), l-i-2), l-i-3) and Ia-I).

8d) The compounds of formula (Iz) wherein X ₂₄ is the radical of formula (a9' ) or (b9' ) wherein R ^lb is selected from AlO), R ^2b is selected from BlO), Y and Y' are as defined above, T is C(O)- or C(O)-X", wherein X" is defined above and T' is C(O)-X" can be obtained 8d-i) by reacting a compound of formula (Iy),

P ² -X ₂₆ ( I y) wherein P ² and X ₂ 6 are as above defined, with a compound of formula (IVd) R _a -O-C(O) -X"-y-Q

(IVd) wherein R _a and X" are as above defined, y is the radical Y' , wherein Y' is as above defined, and

8d-ii) when Q is Z ₂ , by converting the compounds obtained in the step 8d-i) into nitro derivative by reaction with a nitrate source as above described and

8d-iii) optionally deprotecting the compounds obtained in step

8d-i) or 8d-ii) as above described.

The reaction of a compound of formula (Iy) wherein P ² and X20 are as above defined, with a compound of formula (IVd) R _a , y, Q,

X" are as above defined may be carried out as described in 1-i-

2) .

8e) The compounds of formula (Iz) wherein X ₂₄ is the radical of formula (alO') or (blO') wherein R ^lb is selected from AlO), and R ^2b is selected from BlO) Y and Y' are as defined above, T is C(O)- or C(O)-X", wherein X" is defined above and T' is C(O) can be obtained 8e-i) by reacting a compound of formula (Iy'), P ² -X26'

(Iy') wherein P ² is as above defined and X26 _' is the radical having the following meanings

- (alO") -R ^lb -CH (C (O) -OH) -NH- (T-Y-Q) -(blO") -R ^2b -CH (CH ₂ C (O) -OH) -NH- (T-Y-Q) wherein R ^lb is selected from selected from AlO) and R ^2b is BlO), with a compound of formula (IVa)

W ₁ -C ( O ) - Y-Q

( IVa ) wherein Wi and Q are as above defined, y is the radical Y' , wherein Y' is as above defined, and 8e-ii) when Q is Z ₂ , by converting the compounds obtained in the step 8e-i) into nitro derivative by reaction with a nitrate source as above described and

8e-iii) optionally deprotecting the compounds obtained in step 8e-i) or 8e-ii) as above described. The reaction of a compound of formula (Iy') wherein P ² and X26 _' are as above defined, with a compound of formula (IVa) wherein Wi, y, Q are as above defined, may be carried out as described in 1-i-l), l-i-2), l-i-3) and Ia-I).

8f) The compounds of formula (Iz) wherein X24 is the radical of formula (alO') or (blO') wherein R ^lb is selected from AlO), and R ^2b is selected from BlO), Y and Y' are as defined above, T is C(O)- or C(O)-X", wherein X" is defined above and T' is C(O)-X" can be obtained 8f-i) by reacting a compound of formula (Iy'),

P ² -X26'

(Iy') wherein P ² and X26 _' are as above defined, with a compound of formula (IVd) Ra-O-C (O) -X"-y-Q

(IVd) wherein R _a and X" are as above defined, y is the radical Y' , wherein Y' is as above defined, and

8f-ii) when Q is Z ₂ , by converting the compounds obtained in the step 8f-i) into nitro derivative by reaction with a nitrate source as above described and

8f-iii) optionally deprotecting the compounds obtained in step 8f-i) or 8f-ii) as above described.

The reaction of a compound of formula (Iy') wherein P ² and X ₂ 6 _' are as above defined, with a compound of formula (IVd) R _a , y, Q, X" are as above defined may be carried out as described in 1-i- 2) .

9) The compounds of general formula (I) as above defined wherein a is equal to 1, R _x is a radical selected from (a5) , (a6), (a9) or (alO), (b5) , (b6) , (b9) or (blO) wherein R ^lb is selected from A8) or A9) , R ^2b is selected from B8) or B9) , Z is

-C(O)-, can be obtained

9-i) by reacting a compound of formula (II3) as above defined with a compound of formula (Ix) H-X ₂₇

(Ix) wherein X ₂₇ is the radical selected from (a5' ) , (a6' ) , (a9' ) ,

(alO'), (b5'), (b6'), (b9' ) or (blO'), wherein R ^lb is selected from A8) or A9) , R ^2b is selected from B8) or B9) , and 9-ii) when Q is Z ₂ , by converting the compounds obtained in the step 9-i) into nitro derivative by reaction with a nitrate source as above described and

9-iii) optionally deprotecting the compounds obtained in step

9-i) or 9-ii) as above described. The reaction of a compound of formula (Ix) wherein X ₂₇ and is as above defined, with a compound of formula (II3) may be carried out as described in 11-i) .

Example 1 Synthesis of (llβ,16β)-9-Chloro-ll, 17-dihydroxy-16-methyl-21- [1- 0x0- ( (2- (4- (nitrooxy) butyloxy-carbonylamino) acetyl) ] -pregna- 1, 4-diene-3, 20-dione .

(llβ,16β)-9-Chloro-ll, 17-dihydroxy-16-methyl-21- [l-oxo-2- ( (tert- butylcarbonylamino) acetyl) ] -pregna-1, 4-diene-3, 20-dione

To a solution of beclomethasone (0.6 g, 1.46 mmol) in acetone (35 ml), N-Boc-glycine (0.334 g, 1.90 mmol) and DMAP (cat. amount) were added. The reaction was cooled at 0 ⁰ C and EDAC (0.365 g, 1.90 mmol) was added. The reaction was stirred at room temperature for 2 hours. The solvent was evaporated under vacuum. The residue was treated with water (50 ml) and methylene chloride (50x3 ml), the organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography, eluent n- hexane/ethyl acetate 6/4. The product (0.8 g) was obtained.

(llβ,16β)-9-Chloro-ll, 17-dihydroxy-16-methyl-21- [l-oxo-2- ( (carbonylamino) acetyl) ] -pregna-1, 4-diene-3, 20-dione hydrochloride

A solution of compound A (0.8 g, 0.41 mmol) in methylene chloride (70 ml) was stirred at room temperature. HCl gas was buddle in the solution for 1 hour. The solvent was evaporated under reduced pressure. The product was used in the next step without any purification.

(llβ,16β)-9-Chloro-ll, 17-dihydroxy-16-methyl-21- [1-oxo- (2- ( (4- (nitrooxy) butyoxy-carbonylamino) acetyl) ] -pregna-1, 4-diene-3, 20- dione

To a solution of B) (0.75 g, 1.46 mmol) in methylene chloride (40 ml), 4-nitrooxybutyrric acid pentafluorophenyl ester (0.41 g, 1.46 mmol), DMAP (cat. amount) and triethylamine (0.3 ml, 2.19 mmol) were added. The reaction was stirred at room temperature for 24 hours. The solution was treated with a 5% solution of H ₃ PO ₄ (50 ml) . The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography, (Biotage System, column FLASH 40+M™ κp-sil ) eluent : gradient n-hexane/ethyl acetate 1/1 (130 ml), to ethyl acetate 100% during 130 ml, ethyl acetate 100% (130 ml). The product (0.62 g) was obtained as white powder.

¹ H-NMR: (DMSO), δ: 8.42 (IH, t) ; 7.30 (IH, d) ; 6.22 (IH, dd) ; 5.98 (IH, s); 5.46 (IH, d) ; 5.42 (2H, s) ; 5.05 (IH, d) ; 4.84 (IH, d) ; 4.5 (2H, t) ; 4.34 (IH, sb) ; 3.97 (2H, d) ; 2.71-2.57

(2H, m) ; 2.5-2.2 (6H, m) ; 2.0-1.7 (5H, m) ; 1.65-1.35 (5H, m) ; 1.25-0.97 (4H, m) ; 0.8 (3H, s).