NITRIC OXIDE RELEASING STEROIDS

Info

Publication number: 20100041633
Type: Application
Filed: Jan 28, 2008
Publication Date: Feb 18, 2010
Applicant: NICOX S.A. (Sophia Antipolis-Valbonne)
Inventors: Francesca Benedini (San Donato Milanese), Stefano Biondi (Pero), Ennio Ongini (Segrate (Milano))
Application Number: 12/526,005

Abstract

The invention relates to nitrooxyderivative of corticosteroids of general formula (I) and pharmaceutically acceptable salts or stereoisomers thereof wherein R is a corticosteroid residue selected from: The compounds are useful in the treatment of respiratory diseases.

Description

Description

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—NO₂group. 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.

U.S. Pat. No. 3,494,941 describes steroid derivatives from 3-hydroxyextrane 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 ONO₂group 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.

U.S. Pat. No. 3,183,252 describes derivatives of 16-nitrate-alkylpregnanes 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)_a-R_x (I)

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_Xand is selected from —C(O)—, or —CH(R′)—O— wherein R′ is selected from H or a straight or branched C₁-C₄alkyl, preferably R′ is H or —CH₃;
R_xis a radical selected from the following meanings:

A)

(a1) —HN—CH(R¹)—C(O)-(T-Y—ONO₂)

(a2) —C(O)—CH(R¹)—NH-(T′-Y—ONO₂)

(a3) —HN—CH(R^1a-T″-Y′—ONO₂)—COOR^3a

(a4) —C(O)—CH(R^1a-T″-Y′—ONO₂)—NHR^4a

(a5) —R^1b—CH(NHR^4a)—C(O)-(T-Y—ONO₂)

(a6) —R^1b—CH(COOR^1a) NH-(T′-Y′—ONO₂)

(a7) —HN—CH(R^1a-T′-Y′—ONO₂)—C(O)-(T-Y—ONO₂)

(a8) —C(O)—CH(R^1a-T″-Y′—ONO₂)—NH-(T′-Y—ONO₂)

(a9) —R^1b—CH(NH-T′-Y′—ONO₂)—C(O)-(T-Y—ONO₂)

(a10) —R^1b—CH(C(O)-T-Y′—ONO₂)—NH-(T′-Y—ONO₂)

wherein:

R¹is selected from:

- A1) H, —CH₃, isopropyl, isobutyl, sec-butyl, tert-butyl, methylthio-(CH₂)₂—, phenyl, benzyl, C₆H, —CH₂—CH₂—, 2-monosubstituted benzyl, or 3-monosubstituted benzyl or 4-monosubstituted benzyl wherein the substituent of the benzyl is selected from —F, —Cl, I, —NO₂, —CF₃, —CH₃, CN, C₆H₅CO—;
- 2,4-dichlorobenzyl, 3,4-dichlorobenzyl, 3,4-difluorobenzyl, 2-pyrrolidyl, 3-tryptophanyl-CH₂—, 3-benzothienyl-CH₂—, 4-imidazolyl-CH₂—, 9-anthranyl-CH₂—, cyclohexyl,
- cyclohexyl-CH₂—, cyclohexyl-(CH₂)₂—, cyclopentyl-CH₂—, (C₆H₅)₂CH—, 4-B(OH)₂-benzyl, 4-quinolyl-CH₂—, 3-quinolyl-CH₂—, 2-quinolyl-CH₂—,
- 2-quinoxalyl-CH₂—, 2-furyl-CH₂—, 1-naphtyl-CH₂—, 2-naphtyl-CH₂—, 2-pyridyl-CH₂—, 3-pyridyl-CH₂—, 4-pyridyl-CH₂—, 2-thienyl-CH₂—, 3-thienyl-CH₂—, C₆H₄—CH═CH—CH₂—, CH₂═CH—CH₂—, CH≡CH—CH₂—, NH₂—CO—CH₂—, NH₂—CO—(CH₂)₂—, NH₂(═NH)NH—(CH₂)₃—, P(═O)(OCH₃)₂, I—CH₂—, preferably R¹is H, —CH₃, isopropyl, benzyl;
- A2) —CH₂—SH, —CH₂—OH, —CH(CH₃)—OH, —CH₂[(C₆H₄)-(4-OH)], —CH₂—[(C₆H₂)-(3,5-diiodo)-(4-OH)]
- —CH₂—[(C₆H₃)-(3-nitro)-(4-OH)], preferably R¹is —CH₂—OH or —CH₂[(C₆H₄)-(4-OH)];
- A3) —CH₂—NHR″, —(CH₂)₂—NHR″, —(CH₂)₃—NHR″, —(CH₂)₄—NHR″, wherein R″ is H, —C(O)CH₃or

- wherein R^5ais H or a linear or branched C₁-C₁₀alkyl chain, preferably R^5ais H or a linear (C₁-C₅) alkyl, preferably R¹is —(CH₂)₄—NHR″, wherein R″ is as above defined,
- A4) —CH₂—C(O)R″′, —(CH₂)₂—C(O)R″′, —(CH₂)₄—C(O)R″′ wherein R″′ is —OR^5aor

- wherein R^5ais as above defined, preferably R¹is —CH₂—C(O)R″′, wherein R″′ is as above defined,

R^1ais selected from:

- A5) —CH₂—S—, —CH₂—O—, —CH(CH₃)—O—, —CH₂[(C₆H₄)-(4-O)—], —CH₂-[(3,5-diiodo)-(C₆H₂)-(4-O)—], —CH₂-[(3-nitro)-(C₆H₃)-(4-O)—], preferably R^1ais —CH₂—O—;
- A6) —CH₂—NH—, —(CH₂)₂—NH—, —(CH₂)₃—NH—, —(CH₂)₄—NH—, preferably R^1ais —(CH₂)₄—NH— or —CH₂—NH—,
- A7) —CH₂—C(O)—, —(CH₂)₂—C(O)—, —(CH₂)₄—C(O)—, preferably R^1ais —CH₂—C(O)—;

R^3ais selected from H, —R^5aor

- wherein R^5ais as above defined,

R^4ais selected from H or —C(O)CH₃or

wherein R^5ais as above defined,

R^1bis selected from

- A8) —S—CH₂—, —O—CH(CH₃)—, —O—CH₂—, [-(4-O)—(C₆H₄)]—CH₂—, [-(4-O)-(3,5-diiodo)-(C₆H₂)]—CH₂—, [-(4-O)-(3-nitro)-(C₆H₃)]—CH₂—, preferably R^1bis —O—CH₂— or [-(4-O)—(C₆H₄)]—CH₂—;
- A9) —HN—CH₂—, —HN—(CH₂)₂—, —HN—(CH₂)₃—, —HN—(CH₂)₄—, preferably R^1bis —HN—(CH₂)₄— or —HN—CH₂—;
- A10) —C(O)—CH₂—, —C(O)—(CH₂)₂—, —C(O)—(CH₂)₄—, preferably R^1bis —C(O)—CH₂—;
  T is selected from —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)— or —O—CH(R′)—O—C(O)O— wherein R′ is as above defined;
  T′ is —C(O)—, —C(O)—X″— wherein X″ is —O— or —S—, or T′ is —C(O)—NR′— wherein R′ is as above defined;
  T″ is independently selected from —C(O)—, —C(O)—X″—, —C(O)—NR′—, —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)—, —O—CH(R′)—O—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—, —O—, or —S—, or
  T″ is —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)—, —O—CH(R′)—O—C(O)O— when T″ is linked to —C(O)—,
  Y and Y′ are as below defined;
  or R_xis selected from:

B)

(b1) —HN—CH(R²)—CH₂—C(O)-(T-Y—ONO₂)

(b2) —C(O)—CH₂—CH(R²)—NH-(T′-Y—ONO₂)

(b3) —HN—CH(R^2a-T″-Y′—ONO₂)—CH₂COOR^3a

(b4) —C(O)—CH₂—CH(R^2a-T″-Y′—ONO₂)—NHR^4a

(b5) —R^2b—CH(NHR^4a)—CH₂C(O)-(T-Y—ONO₂)

(b6) —R²—CH(CH₂COOR^3a)NH-(T′-Y—ONO₂)

(b7) —HN—CH(R^2a-T″-Y′—ONO₂)—CH₂—C(O)-(T-Y—ONO₂)

(b8) —C(O)—CH₂—CH(R^2a-T″-Y′—ONO₂)—NH-(T′-Y—ONO₂)

(b9) —R²—CH(NH-T′-Y′—ONO₂)—CH₂C(O)-(T-Y—ONO₂)

(b10) —R²—CH(CH₂C(O)-T-Y′—ONO₂)—NH-(T′-Y—ONO₂)

wherein

R²is selected from:

B1) H, —CH₃, CF₃, isopropyl, isobutyl, sec-butyl, methylthio-(CH₂)₂—, phenyl, benzyl, 3-tryptophanyl-CH₂—, NH₂—C(O)—CH₂—, NH₂—C(O)—(CH₂)₂—, NH₂(═NH)NH—(CH₂)₃—, tBuO—CH(CH₃)—, benzyl-O—CH₂—, 4-terbutoxy-benzyl, 4-phenylbenzyl, preferably R²is H, —CH₃, isopropyl, benzyl,

B2) —CH₂—SH, —CH₂—OH, —CH(CH₃)—OH, —CH₂—[(C₆H₄)-(4-OH)], —CH₂—[(C₆H₂)-(3,5-diiodo)-(4-OH)]

—CH₂—[(C₆H₃)-(3-nitro)-(4-OH)];

B3) —CH₂—NHR″, —(CH₂)₂—NHR″, —(CH₂)₃—NHR″, —(CH₂)₄—NHR″, wherein R″ is as above defined, preferably R²is —(CH₂)₄—NHR″;

B4) —CH₂—C(O)—R″′, —(CH₂)₂—C(O)—R″′, —(CH₂)₄—C(O)—R″′ wherein R″′ is as above defined, preferably R²is —CH₂—C(O)—R″′;

R^2ais selected from:

B5) CH₂—S—, CH₂—O—, —CH(CH₃)—O— or CH₂[(C₆H₄)-(4-O)—], —CH₂-[(3,5-diiodo)-(C₆H₂)-(4-O)—], —CH₂-[(3-nitro)-(C₆H₃)-(4-O)—], preferably R^2ais —CH₂—O—;

B6) —CH₂—NH—, —(CH₂)₂—NH—, —(CH₂)₃—NH—, —(CH₂)₄—NH—, preferably R^2ais —(CH₂)₄—NH— or —CH₂—NH—;

B7) —CH₂—C(O)—, —(CH₂)₂—C(O)—, —(CH₂)₄—C(O)—, preferably R^2ais —CH₂—C(O)—;

R^2bis selected from

B8) —S—CH₂—, —O—CH(CH₃)—, —O—CH₂—, [-(4-O)—(C₆H₄)]—CH₂—, [-(4-O)-(3,5-diiodo)-(C₆H₂)]—CH₂—, [-(4-O)-(3-nitro)-(C₆H₃)]—CH₂—, preferably R^2bis —O—CH₂— or [-(4-O)—(CH₄)]—CH₂—;

B9) —HN—CH₂—, —HN—(CH₂)₂—, —HN—(CH₂)₃—, —HN—(CH₂)₄—, preferably R^2bis —HN—(CH₂)₄— or —HN—CH₂—;

B10) —C(O)—CH₂—, —C(O)—(CH₂)₂—, —C(O)—(CH₂)₄—, preferably R^2bis —C(O)—CH₂—;

R^3aand R^4aare as above defined;
T, T′ and T″ are as above defined and Y and Y′ are as below defined;
or R_xis selected from:

C)

(c1) —HN—(CH₂)_b—C(O)-(T-Y—ONO₂);
(c2) —C(O)—(CH₂)_b—NH-(T′-Y—ONO₂)
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)

(d1) —HN—CH(R¹²)—CH₂—O-(T″′-Y—ONO₂)
(d2) —O—CH₂—CH(R¹²)—NH-(T′-Y—ONO₂)
(d3) —HN—CH(R^12a-T″-Y′—ONO₂)—CH₂OH
(d4) —O—CH₂—CH(R^12a-T″-Y′—ONO₂)—NHR^4a
(d5) —R^12a—CH(NHR^4a)—CH₂—O-(T″′-Y—ONO₂)
(d6) —R^12b—CH(CH₂OH)—NH-(T′-Y—ONO₂)
(d7) —HN—CH(R^12a-T″-Y′—ONO₂)—CH₂—O-(T″′-Y—ONO₂)
(d8) —O—CH₂—CH(R^12a-T″-Y′—ONO₂)—NH-(T′-Y—ONO₂)
(d9) —R^12b—CH(NH-T′-Y′—ONO₂)—CH₂—O-(T″′-Y—ONO₂)
(d10) —R^12b—CH(CH₂—O-T″′-Y′—ONO₂)—NH-(T′-Y—ONO₂)
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;
R¹²is selected from:

D1) H, —CH₃, isopropyl, isobutyl, sec-butyl, methylthio-(CH₂)₂—, benzyl, 3-triptophanyl-CH₂—, 4-imidazolyl-CH₂—, NH₂—CO—CH₂—, NH₂—CO—(CH₂)₂—, NH₂(═NH)NH—(CH₂)₃—, preferably R¹²is H;

D2) —CH₂—OH, —CH(CH₃)—OH, —CH₂[(C₆H₄)-(4-OH)], —CH₂—[(C₆H₃)— (3,5-diiodo)-(4-OH)],

—CH₂—[(C₆H₃)-(3-nitro)-(4-OH)] preferably R′ is —CH₂—OH or —CH₂[(C₆H₄)-(4-OH)]

D3) —CH₂—NHR″, —(CH₂)₂—NHR″, —(CH₂)₃—NHR″, —(CH₂)₄—NHR″, wherein R″ is as above defined, preferably R¹²is —(CH₂)₄—NHR″;

D4) —CH₂—C(O)R″′, —(CH₂)₂—C(O)R″′, —(CH₂)₄—C(O)R″′ wherein R″′ is as above defined, preferably R¹²is —CH₂—C(O)R″′;

R^12ais selected from

D5) —CH₂—O—, —CH(CH₃)—O— or —CH₂[(C₆H₂)-(4-O)—], —CH₂-[3,5-diiodo-(C₆H₂)-(4-O)—], —CH₂-[3-nitro-(C₆H₃)-4-O—], preferably R^12ais CH₂—O— or —CH₂—[(C₆H₄)-(4-O)—],

D6) —CH₂—NH—, —(CH₂)₂—NH—, —(CH₂)₃—NH—, —(CH₂)₄—NH—, preferably R^12ais —(CH₂)₄—NH— or —CH₂—NH—,

D7) —CH₂—C(O)—, —(CH₂)₂—C(O)—, —(CH₂)₄—C(O)—, preferably R^12ais —CH₂—C(O)—,

R^12bis selected from

D8) —O—CH₂—, —O—CH(CH₃)—, [-(4-O)—(C₆H₄)]—CH₂—, [-(4-O)-(3,5-diiodo)-(C₆H₂)]—CH₂, [-(4-O)-(3-nitro)-(C₆H₃)]—CH₂—, preferably R¹²is —O—CH₂— or [-(4-O)—(C₆H₄)]—CH₂—;

D9) —HN—CH₂—, —HN— (CH₂)₂—, —HN— (CH₂)—-HN— (CH₂)₄—, preferably R^12bis —HN— (CH₂)₄— or —HN—CH₂—;

D10) —C(O)—CH₂—, —C(O)— (CH₂)₂—, —C(O)—(CH₂)₄—, preferably R^12bis —C(O)—CH₂—;

R^4ais as above defined;
or R_xis 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 R³is H, CH₃, propyl, (C₆H₅)₂CH—, 1-naphtyl-CH₂—, benzyl, allyl, 2-bromobenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-fluorobenzyl, 4-bromobenzyl, 4-methylbenzyl, preferably R³is H, T and T′ are as above defined and Y is as below defined;

H)

wherein R⁴is H, benzyl, 4-bromobenzyl, 2-bromobenzyl, T and T′ are as above defined and Y is as below defined;

I)

wherein R⁵is H, R⁶is H, or R⁵and R⁶when 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 reported;

N)

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;

O)

wherein R⁷is H, R⁸is H, or R⁷and R⁸when 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 R⁹and R¹⁰are H, CH₃, R¹¹is CH₃or 4-piperidinyl with the proviso that R⁹and R¹⁰are H when R¹¹is 4-piperidinyl and R⁹and R¹⁰are CH₃when R¹¹is CH₃, 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 0 or a is 1 and Z is —CH(R′)—O— wherein R′ is as above defined, when R_xis:

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

(a5), (a6), (a9) or (a10) and R^1bis selected from the group A10);

(b2), (b4) or (b8)

(b5), (b6), (b9) or (b10) and R^2bis selected from the group B10);

(c2);

(d5), (d6), (d9) or (d10) and R^12bis selected from the group D10);

(e2), (f1), (g2), (h1), (i1), (l2), (m2), (n2), (o2), (p2), (q2), (r2), (s2), (t1) or (u2);

a is 1 and Z is —C(O)—, when R_xis:

(a1), (a3) or (a7);

(a5), (a6), (a9) or (a10) and R^1bis selected from the groups A8) and A9);

(b1), (b3) or (b7);

(b5), (b6), (b9) or (b10) and R^2bis selected from the groups B8) or B9);

(c1);

(d1), (d2), (d3), (d4), (d7) or (d8);

(d5), (d6), (d9) or (d10) and R^2bis selected from the groups D8) or D9);

(e1), (f2), (g1), (h2), (i2), (l1), (m1), (n1), (o1), (p1), (q1), (r1), (s1), (t2) or (u1).

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

straight or branched C₁-C₂₀alkylene, preferably a straight or branched C₁-C₁₀alkylene,

straight or branched C₁-C₂₀alkylene substituted with one or more of the substituents selected from the group consisting of: halogen atoms, hydroxy, —ONO₂or T₂, wherein T₂is —OC(O)(C₁-C₁₀alkyl)-ONO₂or —O(C₁-C₁₀alkyl)-ONO₂, preferably Y or Y′ is a straight or branched C₁-C₁₀alkylene substituted with a —ONO₂group;

cycloalkylene with 5 to 7 carbon atoms into cycloalkylene ring, the ring being optionally substituted with one or more straight or branched C₁-C₁₀alkyl chains, preferably the ring being optionally substituted with CH₃;

b)

wherein
n⁰is an integer from 0 to 20, preferably n^Cis 0 or 1;
n¹is 0 or 1, preferably n¹is 1;

U is a linear or branched C₁-C₂₀alkylene optionally substituted with a ONO₂group, preferably U is a linear C₁-C₁₀alkylene or U is a linear or branched C₁-C₁₀alkylene substituted with a —ONO₂group;

c)

wherein
n⁰is an integer from 0 to 20, preferably n^Cis 0 or 1;
n¹is 0 or 1, preferably n¹is 1;

U is a linear or branched C₁-C₂₀alkylene optionally substituted with a —ONO₂group, preferably U is a linear C₁-C₁₀alkylene or U is a linear or branched C₁-C₁₀alkylene substituted with a —ONO₂group;

d)

wherein:
n²is an integer from 0 to 2, R¹³is H or CH₃, T₁is —O—C(O)— or —C(O)O—;
n¹and U are as above defined;
e)

n²is an integer from 0 to 2, preferably n²is 1;
R¹³is H or CH₃, preferably R¹³is CH₃;
Y¹is —CH₂—CH₂— or —CH═CH—(CH₂)₂—, wherein n is 0 or 1, preferably Y¹is —CH═CH—(CH₂)_n^2′— and n^2′ is 0;
T₁=—O—C(O)— or —C(O)O—, preferably T₁is —C(O)O—;
n¹is 0 or 1, preferably n¹is 1;
U is a linear or branched C₁-C₂₀alkylene optionally substituted with a ONO₂group, preferably U is a linear C₁-C₁₀alkylene or U is a linear or branched C₁-C₁₀alkylene substituted with a —ONO₂group;
more preferably n²is 1, R¹³is CH₃, Y¹is —CH═CH—(CH₂)_n^2′— and n^2′ is 0, T₁is C(O)O— and U is a linear C₁-C₁₀alkylene;
e′)

wherein:
n²is an integer from 0 to 2, preferably n2 is 1;
R¹³is H or CH₃, preferably R¹³is CH₃;
Y¹is —CH₂—CH₂— or —(CH₂)_n^2′—CH═CH—, wherein n is 0 or 1, preferably Y¹is —(CH₂)_n^2′—CH═CH— and n^2′ is 0;

T₁=—O—C(O)—;

n¹is 0 or 1, preferably n¹is 1;
U is a linear or branched C₁-C₂₀alkylene optionally substituted with a —ONO₂group, preferably U is a linear C₁-C₁₀alkylene or U is a linear or branched C₁-C₁₀alkylene substituted with a —ONO₂group;
more preferably n²is 1, R¹³is CH₃, Y¹is —CH═CH—(CH₂)_n^2′— and n^2′ is 0, T₁is —OC(O)— and U is a linear C₁-C₁₀alkylene;
f)

wherein T₂is —O— or —S—, —NH—, preferably T₂is —O—, n³is an integer from 1 to 6, preferably n³is 1;
when Y and Y′ are selected from b), c), d), e), e′) or f), the —ONO₂group of -(T-Y—ONO₂), -(T′-Y—ONO₂), -(T″-Y′—ONO₂), -(T′-Y′—ONO₂), -(T″′-Y—ONO₂) and -(T″′-Y′—ONO₂) is linked to the —(CH₂)*— group;
g)

wherein:
n⁴is an integer from 0 to 10, preferably n⁴is 0 or 1;
n⁵is an integer from 1 to 10, preferably n⁵is 1;

R¹⁴, R¹⁵, R¹⁶, R¹⁷are the same or different, and are H or straight or branched C₁-C₄alkyl, preferably R¹⁴, R¹⁵, R¹⁶and R¹⁷are H;

wherein the —ONO₂group is linked to

wherein n⁵is as defined above;

Y²is 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 “C₁-C₁₀alkyl” 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 (C₁-C₁₀)-alkyl, preferably CH₃.

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

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)_a-R_x (I)

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_Xis selected from:
(a2) —C(O)—CH(R¹)—NH-(T′-Y—ONO₂)
wherein
R¹of the group A1) is selected from H, isobutyl, benzyl, C₆H₅—CH₂—CH₂—, 2-monosubstituted benzyl, or 3-monosubstituted benzyl or 4-monosubstituted benzyl wherein the substituent of the benzyl is selected from —F, —Cl, I, —NO₂, —CF₃, —CH₃, CN, C₆H₅CO—;
R¹of the group A2) is selected from —CH₂—OH, —CH(CH₃)OH— or —CH₂[(C₆H₄)-(4-OH)], or
R¹of the group A3) is selected from —CH₂—NHR″, —(CH₂)₂—NHR″, —(CH₂)₃—NHR″, —(CH₂)₄—NHR″, wherein R″ is H, or —C(O)CH₃;
R¹of the group A4) is selected from —CH₂—C(O)R″′, —(CH₂)₂—C(O)R″′, —(CH₂)₄—C(O)R″′ wherein R″′ is OR^5awherein R^5ais H or a linear (C₁-C₅) alkyl;
T′ is —C(O)—, —C(O)—X″ wherein X″ is —S— or —O—, preferably T′ is —C(O)—;
Y is as below defined;

or R_Xis

(a4) —C(O)—CH(R^1a-T″-Y′—ONO₂)—NHR^4a
wherein R^1aof the group A5) is selected from —CH₂—O—, —CH(CH₃)O— or —CH₂—[(C₆H₄)-(4-O)—], or
R^1aof the group A6) is selected from —CH₂—NH—, —(CH₂)₂—NH—, —(CH₂)₃—NH—, —(CH₂)₄—NH—, or
R^1aof the group A7) is selected from —CH₂—C(O)—, —(CH₂)₂—C(O)—, —(CH₂)₄—C(O)—,

R^4ais H or —C(O)CH₃,

T″ is —C(O)— or —C(O)—X″ wherein X″ is —S— or —O—, when R^1ais selected from the group A5) or A6), preferably T″ is —C(O)—;
T″ is —O—, —S—, —NR′— or —O—CH(R′)—O—C(O)— wherein R′ is H or —CH₃, when R^1ais selected from the group A7),
Y′ is as below defined;
or R_Xis selected from:
(a5) —R^1b—CH(NHR^4a)—C(O)-(T-Y—ONO₂)
(a6) —R^1b—CH(COOR^3a)NH-(T′-Y—ONO₂)
(a9) —R^1b—CH(NH-T′-Y′—ONO₂)—C(O)-(T-Y—ONO₂) or
(a10) —R^1b—CH(C(O)-T-Y′—ONO₂)—NH-(T′-Y—ONO₂)
wherein
R^1bof the group A10) is selected from —C(O)—CH₂—, —C(O)—(CH₂)₂—, —C(O)—(CH₂)₄—,
R^3ais H or a (C₁-C₅) alkyl,

R^4ais H or —C(O)CH₃,

T is —O—, —S—, —NR′— or —O—CH(R′)—O—C(O)— wherein R′ is H or —CH₃, preferably T is —O—,
T′ is —C(O)— or —C(O)—X″ wherein X″ is —S— or —O—, preferably T′ is —C(O)—,
Y and Y′ are as below defined;

or R_Xis

(a8) —C(O)—CH(R^1a-T″-Y′—ONO₂)—NH-(T′-Y—ONO₂)
wherein
R^1aof the group A5) is selected from —CH₂—O—, —CH(CH₃)—O— or —CH₂—[(C₆H₄)-(4-O)—], or
R^1aof the group A6) is selected from —CH₂—NH—, —(CH₂)₂—NH—, —(CH₂)₃—NH—, —(CH₂)₄—NH—, or
R^1aof the group A7) is selected from —CH₂—C(O)—, —(CH₂)₂—C(O)—, —(CH₂)₄—C(O)—,
T″ is —C(O)— or —C(O)—X″ wherein X″ is —S— or —O—, when R^1ais selected from the group A5) or A6), preferably T″ is —C(O)—,
T″ is —O—, —S—, —NR′— or —O—CH(R′)—O—C(O)— wherein R′ is H or —CH₃, when R^1ais selected from the group A7);

T′ is —C(O)— or —C(O)—X″ wherein X″ is —S— or —O—, preferably T′ is —C(O)—,

Y and Y′ are as below defined,

or R_Xis

(b2) —C(O)—CH₂—CH(R²)—NH-(T′-Y—ONO₂)
wherein
R²of the group B1) is selected from H, CH₃, isobutyl, isopropyl, benzyl;
T′ is —C(O)—, —C(O)—X″ wherein X″ is —S— or —O—, preferably T′ is —C(O)—;
Y and Y′ are each independently selected from a)

- a straight or branched C₁-C₁₀alkylene,
- a straight or branched C₁-C₁₀alkylene substituted with a —ONO₂group;
  d)

wherein:
n²is an integer from 0 to 2, R¹³is H or CH₃, T₁is —O—C(O)— or —C(O)O—;
n′ is 1 and U is a linear C₁-C₁₀alkylene or U is a linear or branched C₁-C₁₀alkylene substituted with a —ONO₂group;
e)

n²is 1, R¹³is CH₃, Y¹is —CH═CH—(CH₂)_n^2′— and n is 0, T₁is —C(O)O— and U is a linear C₁-C₁₀alkylene;
e′)

wherein:
n²is 1, R¹³is CH₃;
Y¹is —(CH₂)_n^2′—CH═CH— and n^2′ is 0;

T₁=—O—C(O)—;

n¹is 1 and U is a linear C₀-C₁₀alkylene or U is a linear or branched C₁-C₁₀alkylene substituted with a —ONO₂group;
f)

wherein T₂is —O— or —S—, —NH—, preferably T₂is —O—, n³is 1 or 2;
when Y and Y′ are selected from d), e), e′) or f), the —ONO₂group of -(T-Y—ONO₂), -(T′-Y—ONO₂), -(T″-Y′—ONO₂), -(T′-Y′—ONO₂), -(T″′-Y—ONO₂) and -(T″′-Y′—ONO₂) is linked to the —(CH₂)*— group.

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

R-(Z)_a-R_x (I)

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(O)—;

R_Xis

(a1) —HN—CH(R′)—C(O)-(T-Y—ONO₂)
wherein
R¹of the group A1) is selected from H, isobutyl, benzyl, C₆H₅—CH₂—CH₂—, 2-monosubstituted benzyl, or 3-monosubstituted benzyl or 4-monosubstituted benzyl wherein the substituent of the benzyl is selected from —F, —Cl, I, —NO₂, —CF₃, —CH₃, CN, C₆H₅CO— or
R¹of the group A2) is selected from:

—CH₂—OH, —CH(CH₃)—OH— or —CH₂—[(C₆H₄)-(4-OH)], or

R¹of the group A3) is selected from —CH₂—NHR″, —(CH₂)₂—NHR″, —(CH₂)₃—NHR″, —(CH₂)₄—NHR″, wherein R″ is H, or —C(O)CH₃,
R¹of the group A4) is —CH₂—C(O)R″′, —(CH₂)₂—C(O)R″′, —(CH₂)₄—C(O)R″′ wherein R″′ is OR^5awherein R^5ais H or a linear (C₁-C₅) alkyl;
T is —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)— wherein R′ is H or a straight or branched C₁-C₄alkyl, preferably T is —O—,
Y is as below defined;

or R_Xis

(a3) —HN—CH(R^1a-T″-Y′—ONO₂)—COOR^3a
wherein
R^1aof the group A5) is selected from —CH₂—O—, —CH(CH₃)O— or —CH₂[(C₆H₄)-(4-O)—], or
R^1aof the group A6) is selected from —CH₂—NH—, —(CH₂)₂—NH—, —(CH₂)₃—NH—, —(CH₂)₄—NH—, or
R^1aof the group A7) is —CH₂—C(O)—, —(CH₂)₂—C(O)—, —(CH₂)₄—C(O)—,
R^3ais H or a (C₁-C₅) alkyl,
T″ is —C(O)— or —C(O)—X″ wherein X″ is —S— or —O—, when R^1ais selected from the group A5) or A6), preferably T′ is —C(O)—;
T″ is —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)— wherein R′ is H or a straight or branched C₁-C₄alkyl, when R^1ais selected from the group A7);
Y′ is as below defined;
or R_Xis selected from.
(a5) —R^1b—CH(NHR^4a)—C(O)-(T-Y—ONO₂)
(a6) —R^1b—CH(COOR^3a)NH-(T′-Y—ONO₂)
(a9) —R^1b—CH(NH-T′-Y′—ONO₂)—C(O)-(T-Y—ONO₂) or
(a10) —R^1b—CH(C(O)-T-Y′—ONO₂)—NH-(T′-Y—ONO₂)
wherein
R^1bof the group A8) is selected from —O—CH(CH₃)—, —O—CH₂—, [-4-O)—(C₆H₄)]—CH₂—, or

R^1bof the group A9) is selected from —HN—CH₂—, —HN—(CH₂)₂—, —HN—(CH₂)₃—, —HN—(CH₂)₄—,

R^3ais H or a (C₁-C₅) alkyl, R^4ais H or —C(O)CH₃,
T is —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)— wherein R′ is H or a straight or branched C₁-C₄alkyl, preferably T is —O—,
T′ is —C(O)— or —C(O)—X″ wherein X″ is —S— or —O—, preferably T′ is —C(O)—,
Y and Y′ are as below defined;

or R_Xis

(a7) —HN—CH(R^1a-T″-Y′—ONO₂)—C(O)-(T-Y—ONO₂)
wherein
R^1aof the group A5) is selected from CH₂—O—, —CH(CH₃)—O— or —CH₂—[(C₆H₄)-(4-O)—], or
R^1aof the group A6) is selected from —CH₂—NH—, —(CH₂)₂—NH—, —(CH₂)₃—NH—, —(CH₂)₄—NH—, or
R^1aof the group A7) is —CH₂—C(O)—, —(CH₂)₂—C(O)—, —(CH₂)₄—C(O)—;
T″ is —C(O)— or —C(O)—X″, wherein X″ is —S— or —O—, when R^1ais selected from A5) or A6), preferably T″ is —C(O)—
T″ is —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)—, wherein R′ is H or a straight or branched C₁-C₄alkyl, when R^1ais selected from A7), preferably T″ is —O—,
T is —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)— wherein R′ is H or a straight or branched C₁-C₄alkyl, preferably T is —O—;
Y and Y′ are as below defined;

or R_Xis

(b1) —HN—CH(R²)—CH₂—C(O)-(T-Y—ONO₂)
wherein
R²of the group B1) is selected from H, CH₃, isobutyl, isopropyl, benzyl;
R²of the group B2) is selected from —CH₂—OH, —CH(CH₃)—OH— or —CH₂[(C₆H₄)(4-OH)], or
R²of the group B3) is selected from —CH₂—NHR″, —(CH₂)₂—NHR″, —(CH₂)₃—NHR″, —(CH₂)₄—NHR″, wherein R″ is H, or —C(O)CH₃,
R²of the group B4) is —CH₂—C(O)R″′, —(CH₂)₂—C(O)R″′, —(CH₂)₄—C(O)R″′ wherein R″′ is OR^5awherein R^5ais H or a linear (C₁-C₅) alkyl;
T is —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)— wherein R′ is H or a straight or branched C₁-C₄alkyl, preferably T is —O—,
Y is as below defined;
or R_Xis selected from
(d1) —HN—CH(R¹²)—CH₂—O-(T″′-Y—ONO₂) or
(d2) —O—CH₂—CH(R¹²)—NH-(T′-Y—ONO₂)
wherein
R¹²of the group D1) is selected from H, CH₃, isobutyl, isopropyl, benzyl, or
R¹²of the group D2) is selected from CH₂—OH, —CH(CH₃)OH— or —CH₂[(C₆H₄)-(4-OH)], or

R¹²of the group D3) is selected from —CH₂—NHR″, —(CH₂)₂—NHR″, —(CH₂)₃—NHR″, —(CH₂)₄—NHR″ wherein R″ is H, or

R¹²of the group D4) is —CH₂—C(O)R″′, —(CH₂)₂—C(O)R″′, —(CH₂)₄—C(O)R″′ wherein R″′ is OR^5awherein R^5ais H or a linear (C₁-C₅) alkyl;
T′ and T″′ are each independently selected from —C(O)— or —C(O)—X″ wherein X″ is —S— or —O—, preferably T′ and T″′ are —C(O)—,
Y is as below defined;
or R_Xis selected from:
(d3) —HN—CH(R^12a-T″-Y′—ONO₂)—CH₂OH
(d4) —O—CH₂—CH(R^12a-T″-Y′—ONO₂)—NHR^4a

- (d7) —HN—CH(R^12a-T″-Y′—ONO₂)—CH₂—O-(T″′-Y—ONO₂) or
  (d8) —O—CH₂—CH(R^12a-T″-Y′—ONO₂)—NH-(T′-Y—ONO₂) wherein
  R^12aof the group D5) is selected from —CH₂—O—, —CH(CH₃)—O— or —CH₂—[(C₆H₄)-(4-O)—], or
  R^12aof the group D6) is selected from —CH₂—NH—, —(CH₂)₂—NH—, —(CH₂)₃—NH—, —(CH₂)₄—NH—, or
  R^12aof the group D7) is —CH₂—C(O)—, —(CH₂)₂—C(O)—, —(CH₂)₄—C(O)—;

R^4ais H or —C(O)CH₃,

T″ is selected from —C(O)— or —C(O)—X″, wherein X″ is —S— or —O—, when R^12ais selected from D5) or D6), preferably T′ and T″′ are —C(O)—,
T″ is —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)—, wherein R′ is H or a straight or branched C₁-C₄alkyl, when R^12ais selected from D7), preferably T is —O—,
T″′ is selected from —C(O)— or —C(O)—X″ wherein X″ is —S— or —O—, preferably T″′ is —C(O)—,
Y and Y′ are as below defined;
or R_Xis selected from:
(d5) —R^12b—CH(NHR^4a)—CH₂—O-(T″′-Y—ONO₂)
(d6) —R^12b—CH(CH₂OH)—NH-(T′-Y—ONO₂)
(d9) —R^12b—CH(NH-T′-Y′—ONO₂)—CH₂—O-(T″′-Y—ONO₂) or
(d10) —R^12b—CH(CH₂—O-T″′-Y′—ONO₂)—NH-(T′-Y—ONO₂)
wherein
R^12bof the group D8) is selected from —O—CH(CH₃)—, —O—CH₂—, [-4-O—(CH₄)]—CH₂—, or

R^12bof the group D9) is selected from —HN—CH₂—, —HN— (CH₂)₂—, —HN— (CH₂)₃—, —HN— (CH₂)₄—;

R^4ais H or —C(O)—CH₃.

T′ and T″′ are each independently selected from —C(O)—, —C(O)—X″, wherein X″ is —S— or —O—, preferably T′ and T″′ are —C(O)—,
Y and Y′ are each independently selected from
a)

- a straight or branched C₁-C₁₀alkylene,
- a straight or branched C₁-C₁₀alkylene substituted with a —ONO₂group;
  d)

wherein:
n²is an integer from 0 to 2, R¹³is H or CH₃, T₁is —O—C(O)— or —C(O)O—,
n¹is 1 and U is a linear C₁-C₁₀alkylene or U is a linear or branched C₁-C₁₀alkylene substituted with a —ONO₂group;
e)

n²is 1, R¹³is CH₃, Y¹is —CH═CH— (CH₂)_n^2′— and n^2′ is 0,
T₁is —C(O)O— and U is a linear C₁-C₁₀alkylene;
e′)

wherein:
n²is 1, R¹³is CH₃,
Y¹is —(CH₂)_n^2′—CH═CH— and n^2′ is 0,

T₁=—O—C(O)—,

n¹is 1 and U is a linear C₁-C₁₀alkylene or U is a linear or branched C₁-C₁₀alkylene substituted with a —ONO₂group;
f)

wherein T₂is —O— or —S—, —NH—, preferably T₂is —O—, n³is 1 or 2,
when Y and Y′ are selected from d), e), e′) or f), the —ONO₂group of -(T-Y—ONO₂), -(T″-Y—ONO₂), -(T″-Y′—ONO₂), -(T″-Y′—ONO₂), -(T″′-Y—ONO₂) and -(T″′-Y′—ONO₂) is linked to the —(CH₂)*— group.

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

R-(Z)_a-R_x (I)

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_Xis

(a2) —C(O)—CH(R¹)—NH-(T′-Y—ONO₂)
wherein
R¹of the group A1) is H

T′ is —C(O)—;

Y is selected from
a)

- a straight or branched C₁-C₁₀alkylene,
- a straight or branched C₁-C₁₀alkylene substituted with a —ONO₂group;

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

R-(Z)_a-R_x (I)

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_Xis selected from
R_Xis selected from

- (a5) —R^1b—CH(NHR^4a)—C(O)-(T-Y—ONO₂)
- (a6) —R^1b—CH(COOR^1a)NH-(T′-Y—ONO₂) or
- (a9) —R^1b—CH(NH-T′-Y′—ONO₂)—C(O)-(T-Y—ONO₂)
  wherein
  R^1bof the group A10) is C(O)—CH₂—,
  R^3ais H or a (C₁-C₅) alkyl,

R^4ais H or —C(O)CH₃,

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 C₁-C₁₀alkylene,
- a straight or branched C₁-C₁₀alkylene substituted with a —ONO₂group.

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

R-(Z)_a-R_X (I)

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(O)—, R_Xis

- (a5) —R^1b—CH(NHR^4a)—C(O)-(T-Y—ONO₂) or
- (a9) —R^1b—CH(NH-T′-Y′—ONO₂)—C(O)-(T-Y—ONO₂)
  wherein R^1bof A10) is —O—CH₂— or [-4-O—(C₆H₄)]—CH₂—,

R^4ais H or —C(O)CH₃,

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 C₁-C₁₀alkylene,
- a straight or branched C₁-C₁₀alkylene substituted with a —ONO₂group.

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

R-(Z)_a-R_x (I)

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_Xis

(b2) —C(O)—CH₂—CH(R²)—NH-(T′-Y—ONO₂)
wherein
R²of the group B1) is H,

T′ is —C(O)—;

Y and Y′ are each independently selected from
a)

- a straight or branched C₁-C₁₀alkylene,
- a straight or branched C₁-C₁₀alkylene substituted with a —ONO₂group.

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)_a-R_x (I)

wherein R is a corticosteroid residue selected from:

a is 0 or 1,
Z is a group capable of binding R_Xand is selected from —C(O)—, or —CH(R′)—O— wherein R′ is selected from H or a straight or branched C₁-C₄alkyl, preferably R′ is H or —CH₃;
R_xis a radical selected from the following meanings:

A)

- (a1) —HN—CH(R¹)—C(O)-(T-Y—ONO₂)
- (a2) —C(O)—CH(R¹)—NH-(T′-Y—ONO₂)
- (a3) —HN—CH(R^1a-T′-Y′—ONO₂)—COOR^3a
- (a4) —C(O)—CH(R^1a-T″-Y′—ONO₂)—NHR^4a
- (a5) —R^1b—CH(NHR^4a)—C(O)-(T-Y—ONO₂)
- (a6) —R^1b—CH(COOR^3a)NH-(T′-Y—ONO₂)
- (a7) —HN—CH(R^1a-T″-Y′—ONO₂)—C(O)-(T-Y—ONO₂)
- (a8) —C(O)—CH(R^1d-T″-Y′—ONO₂)—NH-(T′-Y—ONO₂)
- (a9) —R^1b—CH(NH-T′-Y′—ONO₂)—C(O)-(T-Y—ONO₂)
- (a10) —R^1b—CH(C(O)-T-Y′—ONO₂)—NH-(T′-Y—ONO₂)
- wherein:
- R¹is selected from:
  - A1) H, —CH₃, isopropyl, isobutyl, sec-butyl, tert-butyl, methylthio-(CH₂)₂—, phenyl, benzyl, C₆H₅—CH₂—CH₂—, 2-monosubstituted benzyl, or 3-monosubstituted benzyl or 4-monosubstituted benzyl wherein the substituent of the benzyl is selected from —F, —Cl, I, —NO₂, —CF₃, —CH₃, CN, C₆H₅CO—;
  - 2,4-dichlorobenzyl, 3,4-dichlorobenzyl, 3,4-difluorobenzyl, 2-pyrrolidyl, 3-triptophanyl-CH₂—, 3-benzothienyl-CH₂—, 4-imidazolyl-CH₂—, 9-anthranyl-CH₂—, cyclohexyl, cyclohexyl-CH₂—, cyclohexyl-(CH₂)₂—, cyclopentyl-CH₂—, (C₆H₅)₂CH—, 4-B(OH)₂-benzyl, 4-quinolyl-CH₂—, 3-quinolyl-CH₂—, 2-quinolyl-CH₂—, 2-quinoxalyl-CH₂—, 2-furyl-CH₂—, 1-naphtyl-CH₂—, 2-naphtyl-CH₂—, 2-pyridyl-CH₂—, 3-pyridyl-CH₂—, 4-pyridyl-CH₂—, 2-thienyl-CH₂—, 3-thienyl-CH₂—, C₆H₄—CH═CH—CH₂—, CH₂═CH—CH₂—, CH≡CH—CH₂—, NH₂—CO—CH₂—, NH₂—CO—(CH₂)₂—, NH₂(═NH)NH—(CH₂)₃—, P(═O)(OCH₃)₂, I—CH₂—, preferably R¹is H, —CH₃, isopropyl, benzyl;
  - A2) —CH₂—SH, —CH₂—OH, —CH(CH₃)—OH, —CH₂—[(C₆H₄)-(4-OH)], —CH₂—[(C₆H₂)-(3,5-diiodo)-(4-OH)], —CH₂—[(C₆H₃)-(3-nitro)-(4-OH)], preferably R¹is —CH₂—OH or —CH₂[(C₆H₄)-(4-OH)];
  - A3) —CH₂—NHR″, —(CH₂)₂—NHR″, —(CH₂)₃—NHR″, —(CH₂)₄—NHR″, wherein R″ is H, —C(O)CH₃or

- - wherein R^5ais H or a linear or branched C₁-C₁₀alkyl chain, preferably R^5ais H or a linear (C₁-C₅) alkyl, preferably R¹is —(CH₂)₄—NHR″, wherein R″ is as above defined,
  - A4) —CH₂—C(O)R″′, —(CH₂)₂—C(O)R″′, —(CH₂)₄—C(O)R″′ wherein R″′ is —OR^5aor

- - wherein R^5ais as above defined, preferably R¹is —CH₂—C(O)R″′, wherein R″′ is as above defined,
- R^1ais selected from:
  - A5) —CH₂—S—, —CH₂—O—, —CH(CH₃)—O—, —CH₂[(C₆H₄)-(4-O)—], —CH₂-[(3,5-diiodo)-(C₆H₂)-(4-O)—], —CH₂-[(3-nitro)-(C₆H₃)-(4-O)—], preferably R^1ais —CH₂—O—;
  - A6) —CH₂—NH—, —(CH₂)₂—NH—, —(CH₂)₃—NH—, —(CH₂)₄—NH—, preferably R^1ais —(CH₂)₄—NH— or —CH₂—NH—,
  - A7) —CH₂—C(O)—, —(CH₂)₂—C(O)—, —(CH₂)₄—C(O)—, preferably R^1ais —CH₂—C(O)—;
- R^3ais selected from H, —R^5aor

- - wherein R^5ais as above defined,
- R^4ais selected from H or —C(O)CH₃or

- wherein R^5ais as above defined,
- R^1bis selected from
  - A8) —S—CH₂—, —O—CH(CH₃)—, —O—CH₂—, [-(4-O)—(C₆H₄)]—CH₂—, [-(4-O)-(3,5-diiodo)-(C₆H₂)]—CH₂—, [-(4-O)-(3-nitro)-(C₆H₃)]—CH₂—, preferably R^1bis —O—CH₂— or [-(4-O)—(C₆H₄)]—CH₂—;
  - A9) —HN—CH₂—, —HN—(CH₂)₂—, —HN—(CH₂)₃—, —HN—(CH₂)₄—, preferably R^1bis —HN—(CH₂)₄— or —HN—CH₂—;
  - A10) —C(O)—CH₂—, —C(O)—(CH₂)₂—, —C(O)—(CH₂)₄—, preferably R^1bis —C(O)—CH₂—;
    T is selected from —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)— or —O—CH(R′)—O—C(O)O— wherein R′ is as above defined;
    T′ is —C(O)—, —C(O)—X″— wherein X″ is —O— or —S—, or T′ is —C(O)—NR′— wherein R′ is as above defined;
    T″ is independently selected from —C(O)—, —C(O)—X″—, —C(O)—NR′—, —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)—, —O—CH(R′)—O—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—, —O—, or —S—, or
    T″ is —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)—, —O—CH(R′)—O—C(O)O— when T″ is linked to —C(O)—,
    Y and Y′ are as below defined;
    or R_xis selected from:

B)

(b1) —HN—CH(R²)—CH₂—C(O)-(T-Y—ONO₂)

(b2) —C(O)—CH₂—CH(R²)—NH-(T′-Y—ONO₂)

(b3) —HN—CH(R^2a-T″-Y′—ONO₂)—CH₂COOR^3a

(b4) —C(O)—CH₂—CH(R^2a-T″-Y′—ONO₂)—NHR^4a

(b5) —R^2b—CH(NHR^4a)—CH₂—C(O)-(T-Y—ONO₂)

(b6) —R^2b—CH(CH₂COOR^3a)NH—-(T′-Y—ONO₂)

(b7) —HN—CH(R^2a-T″-Y′—ONO₂)—CH₂—C(O)-(T-Y—ONO₂)

(b8) —C(O)—CH₂—CH(R^2a-T″-Y′—ONO₂)—NH-(T′-Y—ONO₂)

(b9) —R^2b—CH(NH-T′-Y′—ONO₂)—CH₂C(O)-(T-Y—ONO₂)

(b10) —R^2b—CH(CH₂C(O)-T-Y′—ONO₂)—NH-(T′-Y—ONO₂)

wherein

R²is selected from:

B1) H, —CH₃, CF₃, isopropyl, isobutyl, sec-butyl, methylthio-(CH₂)₂—, phenyl, benzyl, 3-triptophanyl-CH₂—, NH₂—C(O)—CH₂—, NH₂—C(O)—(CH₂)₂—, NH₂(═NH)NH—(CH₂)₃—, tBuO—CH(CH₃)—, benzyl-O—CH₂—, 4-terbutoxy-benzyl, 4-phenylbenzyl, preferably R²is H, —CH₃, isopropyl, benzyl,

B2) —CH₂—SH, —CH₂—OH, —CH(CH₃)—OH, —CH₂—[(C₆H₄)-(4-OH)], —CH₂—[(C₆H₂)-(3,5-diiodo)-(4-OH)], —CH₂—[(C₆H₃)-(3-nitro)-(4-OH)];

B3) —CH₂—NHR″, —(CH₂)₂—NHR″, —(CH₂)₃—NHR″, —(CH₂)₄—NHR″, wherein R″ is as above defined, preferably R²is —(CH₂)₄—NHR″;

B4) —CH₂—C(O)—R″′, —(CH₂)₂—C(O)—R″′, —(CH₂)₄—C(O)—R″′ wherein R″′ is as above defined, preferably R²is —CH₂—C(O)—R″′;

R^2ais selected from:

B5) —CH₂—S—, —CH₂—O—, —CH(CH₃)—O— or —CH₂[(C₆H₄)-(4-O)—], —CH₂-[(3,5-diiodo)-(C₆H₂)-(4-O)—], —CH₂-[(3-nitro)-(C₆H₃)-(4-O)—], preferably R^2ais —CH₂—O—;

B6) —CH₂—NH—, —(CH₂)₂—NH—, —(CH₂)₃—NH—, —(CH₂)₄—NH—, preferably R^2ais —(CH₂)₄—NH— or —CH₂—NH—;

B7) —CH₂—C(O)—, —(CH₂)₂—C(O)—, —(CH₂)₄—C(O)—, preferably R^2ais —CH₂—C(O)—;

R^2bis selected from

B8) —S—CH₂—, —O—CH(CH₃)—, —O—CH₂—, [-(4-O)—(C₆H₄)]—CH₂—, [-(4-O)-(3,5-diiodo)-(C₆H₂)]—CH₂—, [-(4-O)-(3-nitro)-(C₆H₃)]—CH₂—, preferably R^2bis —O—CH₂— or [-(4-O)—(C₆H₄)]—CH₂—;

B9) —HN—CH₂—, —HN—(CH₂)₂—, —HN—(CH₂)₃—, —HN—(CH₂)₄—, preferably R^2bis —HN— (CH₂)₄— or —HN—CH₂—;

B10) —C(O)—CH₂—, —C(O)—(CH₂)₂—, —C(O)—(CH₂)₄—, preferably R^2bis —C(O)—CH₂—;

R^3aand R^4aare as above defined;
T, T′ and T″ are as above defined and Y and Y′ are as below defined;
or R_xis selected from:

C)

(c1) —HN—(CH₂)_b—C(O)-(T-Y—ONO₂);
(c2) —C(O)—(CH₂)_b—NH-(T′-Y—ONO₂)
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)

(d1) —HN—CH(R¹²)—CH₂—O-(T″′-Y—ONO₂)
(d2) —O—CH₂—CH(R¹²)—NH-(T′-Y—ONO₂)
(d3) —HN—CH(R^12a-T″-Y″—ONO₂)—CH₂OH
(d4) —O—CH₂—CH(R^12a-T″-Y′—ONO₂)—NHR^4a
(d5) —R^12b—CH(NHR^4a)—CH₂—O-(T″′-Y—ONO₂)
(d6) —R^12b—CH(CH₂OH)—NH-(T′-Y—ONO₂)
(d7) —HN—CH(R^12a-T″-Y′—ONO₂)—CH₂—O-(T″′-Y—ONO₂)
(d8) —O—CH₂—CH(R^12a-T″-Y′—ONO₂)—NH-(T′-Y—ONO₂)
(d9) —R¹²—CH(NH-T′-Y′—ONO₂)—CH₂—O-(T″′-Y—ONO₂)
(d10) —R¹²—CH(CH₂—O-T″′-Y′—ONO₂)—NH-(T′-Y—ONO₂)
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;
R¹²is selected from:

D1) H, —CH₃, isopropyl, isobutyl, sec-butyl, methylthio-(CH₂)₂—, benzyl, 3-triptophanyl-CH₂—, 4-imidazolyl-CH₂—, NH₂—CO—CH₂—, NH₂—CO—(CH₂)₂—, NH₂(═NH)NH—(CH₂)₃—, preferably R¹²is H;

D2) —CH₂—OH, —CH(CH₃)—OH, —CH₂[(C₆H₄)-(4-OH)], —CH₂—[(C₆H₃)-(3,5-diiodo)-(4-OH)], —CH₂—[(C₆H₃)-(3-nitro)-(4-OH)], preferably R¹²is —CH₂—OH or —CH₂[(C₆H₄)-(4-OH)];

D3) —CH₂—NHR″, —(CH₂)₂—NHR″, —(CH₂)₃—NHR″, —(CH₂)₄—NHR″, wherein R″ is as above defined, preferably R¹²is —(CH₂)₄—NHR″;

D4) —CH₂—C(O)R″′, —(CH₂)₂—C(O)R″′, —(CH₂)₄—C(O)R″′ wherein R″′ is as above defined, preferably R¹²is —CH₂—C(O)R″′;

R^12ais selected from

D5) —CH₂—O—, —CH(CH₃)—O— or —CH₂[(C₆H₄)-(4-O)—], —CH₂-[3,5-diiodo-(C₆H₂)-(4-O)—], —CH₂-[3-nitro-(C₆H₃)-4-O—], preferably R^12ais CH₂—O— or —CH₂—[(C₆H₄)-(4-O)—],

D6) —CH₂—NH—, —(CH₂)₂—NH—, —(CH₂)₃—NH—, —(CH₂)₄—NH—, preferably R^12ais —(CH₂)₄—NH— or —CH₂—NH—,

D7) —CH₂—C(O)—, —(CH₂)₂—C(O)—, —(CH₂)₄—C(O)—, preferably R^2ais —CH₂—C(O)—,

R^12bis selected from

D8) —O—CH₂—, —O—CH(CH₃)—, [-(4-O)—(C₆H₄)]—CH₂—, [-(4-O)-(3,5-diiodo)-(C₆H₂)]—CH₂, [-(4-O)-(3-nitro)-(C₆H₃)]—CH₂—, preferably R¹²is —O—CH₂— or [-(4-O)—(C₆H₄)]—CH₂—;

D9) —HN—CH₂—, —HN—(CH₂)₂—, —HN—(CH₂)₃—, —HN—(CH₂)₄—, preferably R^12bis —HN— (CH₂)₄— or —HN—CH₂—;

- D10) —C(O)—CH₂—, —C(O)—(CH₂)₂—, —C(O)—(CH₂)₄—, preferably R^12bis —C(O)—CH₂—;
  R^4ais as above defined;
  or R_xis selected from:

HE)

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 R³is H, CH₃, propyl, (C₆H₅)₂CH—, 1-naphtyl-CH₂—, benzyl, allyl, 2-bromobenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-fluorobenzyl, 4-bromobenzyl, 4-methylbenzyl, preferably R³is H, T and T′ are as above defined and Y is as below defined;

H)

wherein R⁴is H, benzyl, 4-bromobenzyl, 2-bromobenzyl, T and T′ are as above defined and Y is as below defined;

I)

wherein R⁵is H, R^pis H, or R⁵and 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 reported;

N)

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;

O)

wherein R⁷is H, R⁸is H, or R⁷and R⁸when 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 R⁹and R¹⁰are H, CH₃, R¹¹is CH₃or 4-piperidinyl with the proviso that R⁹and R¹⁰are H when R¹¹is 4-piperidinyl and R⁹and R¹⁰are CH₃when R¹¹is CH₃, 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 0 or a is 1 and Z is —CH(R′)—O— wherein R′ is as above defined, when R_Xis:

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

(a5), (a6), (a9) or (a10) and R^1bis selected from the group A10);

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

(b5), (b6), (b9) or (b10) and R^2bis selected from the group B10);

(c2);

(d5), (d6), (d9) or (d10) and R^12bis selected from the group D10);

(e2), (f1), (g2), (h1), (i1), (l2), (m2), (n2), (o2), (p2), (q2), (r2), (s2), (t1) or (u2);

a is 1 and Z is —C(O)—, when R_Xis:

(a1), (a3) or (a7);

(a5), (a6), (a9) or (a10) and R^1bis selected from the groups A8) and A9);

(b1), (b3) or (b7);

(b5), (b6), (b9) or (b10) and R^2bis selected from the groups B8) or B9);

(c1);

(d1), (d2), (d3), (d4), (d7) or (d8);

(d5), (d6), (d9) or (d10) and R^12bis selected from the groups D8) or D9);

(e1), (f2), (g1), (h2), (i2), (l1), (m1), (n1), (o1), (p1), (q1), (r1), (s1), (t2) or (u1).

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

straight or branched C₁-C₂₀alkylene, preferably a straight or branched C₁-C₁₀alkylene,

straight or branched C₁-C₂₀alkylene substituted with one or more of the substituents selected from the group consisting of: halogen atoms, hydroxy, —ONO₂or T₂, wherein T₂is —OC(O)(C₁-C₁₀alkyl)-ONO₂or O(C₁-C₁₀alkyl)-ONO₂, preferably Y or Y′ is a straight or branched C₁-C₁₀alkylene substituted with a —ONO₂group;

cycloalkylene with 5 to 7 carbon atoms into cycloalkylene ring, the ring being optionally substituted with one or more straight or branched C₁-C₁₀alkyl chains, preferably the ring being optionally substituted with CH₃;

b)

wherein
n⁰is an integer from 0 to 20, preferably n^Cis 0 or 1;
n¹is 0 or 1, preferably n′ is 1;
U is a linear or branched C₁-C₂₀alkylene optionally substituted with a —ONO₂group, preferably U is a linear C₁-C₁₀alkylene or U is a linear or branched C₁-C₁₀alkylene substituted with a ONO₂group;
c)

wherein
n⁰is an integer from 0 to 20, preferably n^Cis 0 or 1;
n¹is 0 or 1, preferably n′ is 1;

U is a linear or branched C₁-C₂₀alkylene optionally substituted with a —ONO₂group, preferably U is a linear C₁-C₁₀alkylene or U is a linear or branched C₁-C₁₀alkylene substituted with a —ONO₂group;

d)

wherein:
n²is an integer from 0 to 2, R¹³is H or CH₃, T₁is —O—C(O)— or —C(O)O—;
n¹and U are as above defined;
e)

n²is an integer from 0 to 2, preferably n²is 1;
R¹³is H or CH₃, preferably R¹³is CH₃;
Y¹is —CH₂—CH₂— or —CH═CH—(CH₂)_n^2′—, wherein n^2′ is 0 or 1, preferably Y¹is —CH═CH—(CH₂)_n^2′— and n^2′ is 0;
T₁=—O—C(O)— or —C(O)O—, preferably T₁is —C(O)O—;
n¹is 0 or 1, preferably n¹is 1;
U is a linear or branched C₁-C₂₀alkylene optionally substituted with a —ONO₂group, preferably U is a linear C₁-C₁₀alkylene or U is a linear or branched C₁-C₁₀alkylene substituted with a ONO₂group;
more preferably n²is 1, R¹³is CH₃, Y¹is —CH═CH—(CH₂)_n^2′— and n^2′ is 0, T₁is —C(O)O— and U is a linear C₁-C₁₀alkylene;
e′)

wherein:
n²is an integer from 0 to 2, preferably n²is 1;
R¹³is H or CH₃, preferably R¹³is CH₃;
Y¹is —CH₂—CH₂— or —(CH₂)₂—CH═CH—, wherein n is 0 or 1, preferably Y¹is —(CH₂)_n^2′—CH═CH— and n^2′ is 0;

T₁=—O—C(O)—;

n¹is 0 or 1, preferably n¹is 1;
U is a linear or branched C₁-C₂₀alkylene optionally substituted with a —ONO₂group, preferably U is a linear C₁-C₁₀alkylene or U is a linear or branched C₁-C₁₀alkylene substituted with a —ONO₂group;
more preferably n²is 1, R¹³is CH₃, Y¹is —CH═CH—(CH₂)_n^2′— and n^2′ is 0, T₁is —OC(O)— and U is a linear C₁-C₁₀alkylene;
f)

wherein T₂is —O— or —S—, —NH—, preferably T₂is —O—, n³is an integer from 1 to 6, preferably n³is 1;
when Y and Y′ are selected from b), c), d), e), e′) or f), the —ONO₂group of -(T-Y—ONO₂), -(T′-Y—ONO₂), -(T″-Y′—ONO₂), -(T′-Y′—ONO₂), -(T″′-Y—ONO₂) and -(T″′-Y′—ONO₂) is linked to the —(CH₂)*— group;
g)

wherein:
n⁴is an integer from 0 to 10, preferably n⁴is 0 or 1;
n⁵is an integer from 1 to 10, preferably n⁵is 1;

R¹⁴, R¹⁵, R¹⁶, R¹⁷are the same or different, and are H or straight or branched C₁-C₄alkyl, preferably R¹⁴, R¹⁵, R¹⁶and R¹⁷are H;

wherein the —ONO₂group is linked to

wherein n⁵is as defined above;

Y²is 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)_a-R_x (I)

wherein R is a corticosteroid residue selected from:

a is 0 and
R_Xis selected from:
(a2) —C(O)—CH(R¹)—NH-(T′-Y—ONO₂)
wherein
R¹of the group A1) is selected from H, isobutyl, benzyl, C₆H₅—CH₂—CH₂—, 2-monosubstituted benzyl, or 3-monosubstituted benzyl or 4-monosubstituted benzyl wherein the substituent of the benzyl is selected from —F, —Cl, I, —NO₂, —CF₃, —CH₃, CN, C₆H₅CO—;
R¹of the group A2) is selected from —CH₂—OH, —CH(CH₃)OH— or —CH₂[(C₆H₄)-(4-OH)], or
R¹of the group A3) is selected from —CH₂—NHR″, —(CH₂)₂—NHR″, —(CH₂)₃—NHR″, —(CH₂)₄—NHR″, wherein R″ is H, or —C(O)CH₃;
R¹of the group A4) is selected from —CH₂—C(O)R″′, —(CH₂)₂—C(O)R″′, —(CH₂)₄—C(O)R″′ wherein R″′ is OR^5awherein R^5ais H or a linear (C₁-C₅) alkyl;
T′ is —C(O)—, —C(O)—X″ wherein X″ is —S— or —O—, preferably T′ is —C(O)—;
Y is as below defined;

or R_Xis

(a4) —C(O)—CH(R^1a-T″-Y′—ONO₂)—NHR^4a
wherein R^1aof the group A5) is selected from —CH₂—O—, —CH(CH₃)O— or —CH₂—[(C₆H₄)-(4-O)—], or
R^1aof the group A6) is selected from —CH₂—NH—, —(CH₂)₂—NH—, (CH₂)₃—NH—, —(CH₂)₄—NH—, or
R^1aof the group A7) is selected from —CH₂—C(O)—, —(CH₂)₂—C(O)—, —(CH₂)₄—C(O)—,

R^4ais H or —C(O)CH₃,

T″ is —C(O)— or —C(O)—X″ wherein X″ is —S— or —O—, when R^1ais selected from the group A5) or A6), preferably T″ is —C(O)—;
T″ is —O—, —S—, —NR′— or —O—CH(R′)—O—C(O)— wherein R′ is H or —CH₃, when R^1ais selected from the group A7),
Y′ is as below defined;
or R_Xis selected from:
(a5) —R^1b—CH(NHR^4a)—C(O)-(T-Y—ONO₂)
(a6) —R^1b—CH(COOR^3a)NH-(T′—Y—ONO₂)
(a9) —R^1b—CH(NH-T′-Y′—ONO₂)—C(O)-(T-Y—ONO₂) or
(a10) —R^1b—CH(C(O)-T-Y′—ONO₂)—NH-(T′-Y—ONO₂)
wherein
R^1bof the group A10) is selected from —C(O)—CH₂—, —C(O)—(CH₂)₂—, —C(O)—(CH₂)₄—,
R^3ais H or a (C₁-C₅) alkyl,

R^4ais H or C(O)CH₃,

T is —O—, —S—, —NR′— or —O—CH(R′)—O—C(O)— wherein R′ is H or —CH₃, preferably T is —O—,
T′ is —C(O)— or —C(O)—X″ wherein X″ is —S— or —O—, preferably T′ is —C(O)—,
Y and Y′ are as below defined;

or R_Xis

(a8) —C(O)—CH(R^1a-T″-Y′—ONO₂)—NH-(T′-Y—ONO₂)
wherein
R^1aof the group A5) is selected from —CH₂—O—, —CH(CH₃)—O— or —CH₂[(C₆H₄)-(4-O)—], or
R^1aof the group A6) is selected from —CH₂—NH—, —(CH₂)₂—NH—, —(CH₂)₃—NH—, —(CH₂)₄—NH—, or
R^1aof the group A7) is selected from —CH₂—C(O)—, —(CH₂)₂—C(O)—, —(CH₂)₄—C(O)—,
T″ is —C(O)— or —C(O)—X″ wherein X″ is —S— or —O—, when R^1ais selected from the group A5) or A6), preferably T″ is —C(O)—, T″ is —O—, —S—, —NR′— or —O—CH(R′)—O—C(O)— wherein R′ is H or —CH₃, when R^1ais selected from the group A7);
T′ is —C(O)— or —C(O)—X″ wherein X″ is —S— or —O—, preferably T′ is —C(O)—,
Y and Y′ are as below defined,

or R_Xis

(b2) —C(O)—CH₂—CH(R²)—NH-(T′-Y—ONO₂)
wherein
R²of the group B1) is selected from H, CH₃, isobutyl, isopropyl, benzyl;
T′ is —C(O)—, —C(O)—X″ wherein X″ is —S— or —O—, preferably T′ is —C(O)—;
Y and Y′ are each independently selected from
a)

a straight or branched C₁-C₁₀alkylene,

a straight or branched C₁-C₁₀alkylene substituted with a —ONO₂group;

d)

wherein:
n²is an integer from 0 to 2, R¹³is H or CH₃, T₁is —O—C(O)— or —C(O)O—;
n¹is 1 and U is a linear C₁-C₁₀alkylene or U is a linear or branched C₁-C₁₀alkylene substituted with a —ONO₂group;
e)

n²is 1, R¹³is CH₃, Y¹is —CH═CH—(CH₂)_n^2′— and n^2′ is 0, T₁is —C(O)O— and U is a linear C₁-C₁₀alkylene;
e′)

wherein:
n²is 1, R¹³is CH₃;
Y¹is —(CH₂)_n^2′—CH═CH— and n^2′ is 0;

T₁=—O—C(O)—;

n¹is 1 and U is a linear C₁-C₁₀alkylene or U is a linear or branched C₁-C₁₀alkylene substituted with a —ONO₂group;
f)

wherein T₂is —O— or —S—, —NH—, preferably T₂is —O—, n³is 1 or 2;
when Y and Y′ are selected from d), e), e′) or f), the —ONO₂group of -(T-Y—ONO₂), -(T′-Y—ONO₂), -(T″-Y′—ONO₂), -(T′-Y′—ONO₂), -(T″′-Y—ONO₂) and -(T″′-Y′—ONO₂) is linked to the —(CH₂)*— 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)_a-R_x (I)

wherein R is a corticosteroid residue selected from:

a is 1 and Z is —C(O)—; R_Xis

(a1) —HN—CH(R¹)—C(O)-(T-Y—ONO₂)
wherein
R¹of the group A1) is selected from H, isobutyl, benzyl, C₆H₅—CH₂—CH₂—, 2-monosubstituted benzyl, or 3-monosubstituted benzyl or 4-monosubstituted benzyl wherein the substituent of the benzyl is selected from —F, —Cl, I, —NO₂, —CF₃, —CH₃, CN, C₆H₅CO— or
R¹of the group A2) is selected from:

—CH₂—OH, —CH(CH₃)—OH— or —CH₂[(C₆H₄)-(4-OH)], or

R¹of the group A3) is selected from —CH₂—NHR″, —(CH₂)₂—NHR″, —(CH₂)₃—NHR″, —(CH₂)₄—NHR″, wherein R″ is H, or —C(O)CH₃,
R¹of the group A4) is —CH₂—C(O)R″′, —(CH₂)₂—C(O)R″′, —(CH₂)₄—C(O)R″′ wherein R″′ is OR^5awherein R^5ais H or a linear (C₃-C₅) alkyl;
T is —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)— wherein R′ is H or a straight or branched C₁-C₄alkyl, preferably T is —O—,
Y is as below defined;

or R_Xis

(a3) —HN—CH(R^1a-T″-Y′—ONO₂)—COOR^3a
wherein
R^1aof the group A5) is selected from —CH₂—O—, —CH(CH₃)O— or —CH₂—[(C₆H₄)-(4-O)—], or
R^1aof the group A6) is selected from —CH₂—NH—, —(CH₂)₂—NH—, —(CH₂)₃—NH—, —(CH₂)₄—NH—, or
R^1aof the group A7) is —CH₂—C(O)—, —(CH₂)₂—C(O)—, —(CH₂)₄—C(O)—,
R^3ais H or a (C₁-C₅) alkyl,
T″ is —C(O)— or —C(O)—X″ wherein X″ is —S— or —O—, when R^1ais selected from the group A5) or A6), preferably T″ is —C(O)—;
T″ is —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)— wherein R′ is H or a straight or branched C₁-C₄alkyl, when R^1ais selected from the group A7);
Y¹is as below defined;
or R_Xis selected from.
(a5) —R^1b—OCH(NHR^4a)—C(O)-(T-Y—ONO₂)
(a6) —R^1b—CH(COOR^3a)NH-(T′-Y—ONO₂)
(a9) —R^1b—OCH(NH-T′-Y′—ONO₂)—C(O)-(T-Y—ONO₂) or
(a10) —R^1b—CH(C(O)-T-Y′—ONO₂)—NH-(T′-Y—ONO₂)
wherein
R^1bof the group AB) is selected from —O—CH(CH₃)—, —O—CH₂—, [-4-O)—(C₆H₄)]—CH₂—, or
R^1bof the group A9) is selected from —HN—CH₂—, —HN—(CH₂)₂—, —HN— (CH₂)₃—, —HN— (CH₂)₄—,
R^3ais H or a (C₁-C₅) alkyl,

R^4ais H or —C(O)CH₃,

T is —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)— wherein R′ is H or a straight or branched C₁-C₄alkyl, preferably T is —O—,
T′ is —C(O)— or —C(O)—X″ wherein X″ is —S— or —O—, preferably T′ is —C(O)—,
Y and Y′ are as below defined;

or R_Xis

(a7) —HN—CH(R^1a-T′-Y′—ONO₂)—C(O)-(T-Y—ONO₂)
wherein
R^1aof the group A5) is selected from —CH₂—O—, —CH(CH₃)—O— or —CH₂[(C₆H₄)-(4-O)—], or
R^1aof the group A6) is selected from —CH₂—NH—, —(CH₂)₂—NH—, —(CH₂)₃—NH—, —(CH₂)₄—NH—, or
R^1aof the group A7) is —CH₂—C(O)—, —(CH₂)₂—C(O)—, —(CH₂)₄—C(O)—;
T″ is —C(O)— or —C(O)—X″, wherein X″ is —S— or —O—, when R″ is selected from A5) or A6), preferably T″ is —C(O)—;
T″ is —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)—, wherein R′ is H or a straight or branched C₁-C₄alkyl, when R^1ais selected from A7), preferably T″ is —O—,
T is —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)— wherein R′ is H or a straight or branched C₁-C₄alkyl, preferably T is —O—;
Y and Y′ are as below defined;

or R_Xis

(b1) —HN—CH(R²)—CH₂—C(O)-(T-Y—ONO₂)
wherein
R²of the group B1) is selected from H, CH₃, isobutyl, isopropyl, benzyl;
R²of the group B2) is selected from —CH₂—OH, —CH(CH₃)—OH— or —CH₂—[(C₆H₄)(4-OH)], or
R²of the group B3) is selected from —CH₂—NHR″, —(CH₂)₂—NHR″, —(CH₂)₃—NHR″, —(CH₂)₄—NHR″, wherein R″ is H, or —C(O)CH₃,
R²of the group B4) is —CH₂—C(O)R″′, —(CH₂)₂—C(O)R″′, —(CH₂)₄—C(O)R″′ wherein R″′ is OR^5awherein R^5ais H or a linear (C₁-C₅) alkyl;
T is —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)— wherein R′ is H or a straight or branched C₁-C₄alkyl, preferably T is —O—,
Y is as below defined;
or R_Xis selected from
(d1) —HN—CH(R¹²)—CH₂—O-(T″′-Y—ONO₂) or
(d2) —O—CH₂—CH(R¹²)—NH-(T′-Y—ONO₂)
wherein
R¹²of the group D1) is selected from H, CH₃, isobutyl, isopropyl, benzyl, or
R¹²of the group D2) is selected from —CH₂—OH, —CH(CH₃)OH— or —CH₂[(C₆H₄)-(4-OH)], or
R¹²of the group D3) is selected from —CH₂—NHR″, —(CH₂)₂—NHR″, —(CH₂)₃—NHR″, —(CH₂)₄—NHR″ wherein R″ is H, or
R¹²of the group D4) is —CH₂—C(O)R″′, —(CH₂)₂—C(O)R″′, —(CH₂)₄—C(O)R″′ wherein R″′ is OR^5awherein R^5ais H or a linear (C₁-C₅) alkyl;
T′ and T″′ are each independently selected from —C(O)— or —C(O)—X″ wherein X″ is —S— or —O—, preferably T′ and T″′ are —C(O)—,
Y is as below defined;
or R_Xis selected from:
(d3) —HN—CH(R^12a-T″-Y′—ONO₂)—CH₂OH
(d4) —O—CH₂—CH(R^12a-T″-Y′—ONO₂)—NHR^4a
(d7) —HN—CH(R^12a-T″-Y′—ONO₂)—CH₂—O-(T″′-Y—ONO₂) or
(d8) —O—CH₂—CH(R^12a-T″-Y′—ONO₂)—NH-(T′-Y—ONO₂)
wherein
R^12aof the group D5) is selected from —CH₂—O—, —CH(CH₃)—O— or —CH₂[(C₆H₄)-(4-O)—], or
R^12aof the group D6) is selected from —CH₂—NH—, —(CH₂)₂—NH—, —(CH₂)₃—NH—, —(CH₂)₄—NH—, or
R^12aof the group D7) is —CH₂—C(O)—, —(CH₂)₂—C(O)—, —(CH₂)₄—C(O)—;

R^4ais H or —C(O)CH,

T″ is selected from —C(O)— or —C(O)—X″, wherein X″ is —S— or —O—, when R^12ais selected from D5) or D6), preferably T′ and T″′ are —C(O)—,
T″ is —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)—, wherein R′ is H or a straight or branched C₁-C₄alkyl, when R^12ais selected from D7), preferably T is —O—,
T″′ is selected from —C(O)— or —C(O)—X″ wherein X″ is —S— or —O—, preferably T″′ is —C(O)—,
Y and Y′ are as below defined;
or R_Xis selected from:
(d5) —R^12b—CH(NHR^4a)—CH₂—O-(T″′-Y—ONO₂)
(d6) —R^12b—CH(CH₂OH)—NH-(T′-Y—ONO₂)
(d9) —R^12b—CH(NH-T′-Y′—ONO₂)—CH₂—O-(T″′-Y—ONO₂) or
(d10) —R^12b—CH(CH₂—O-T″′-Y′—ONO₂)—NH-(T′-Y—ONO₂)
wherein
R^12bof the group D8) is selected from —O—CH(CH₃)—, —O—CH₂—, [-4-O—(C₈H₄)]-CH₂—, or
R^12bof the group D9) is selected from —HN—CH₂—, —HN—(CH₂)₂—, —HN— (CH₂)₃—, —HN—(CH₂)₄—;

R^4ais H or —C(O)—CH₃,

T′ and T″′ are each independently selected from —C(O)—, —C(O)—X″, wherein X″ is —S— or —O—, preferably T′ and T″′ are —C(O)—,
Y and Y′ are each independently selected from
a)

a straight or branched C₁-C₁₀alkylene,

a straight or branched C₁-C₁₀alkylene substituted with a ONO₂group;

d)

wherein:
n²is an integer from 0 to 2, R¹³is H or CH₃, T₁is —O—C(O)— or —C(O)O—,
n¹is 1 and U is a linear C₁-C₁₀alkylene or U is a linear or branched C₁-C₁₀alkylene substituted with a —ONO₂group;
e)

n²is 1, R¹³is CH₃, Y¹is —CH═CH—(CH₂)_n^2′— and n^2′ is 0, T₁is —C(O)O— and U is a linear C₁-C₁₀alkylene;
e′)

wherein:
n²is 1, R¹³is CH₃,
Y¹is —(CH₂)_n^2′—CH═CH— and n^2′ is 0,

T₁=—O—C(O)—,

n¹is 1 and U is a linear C₁-C₁₀alkylene or U is a linear or branched C₁-C₁₀alkylene substituted with a —ONO₂group;
f)

wherein T₂is —O— or —S—, —NH—, preferably T₂is —O—, n³is 1 or 2,
when Y and Y′ are selected from d), e), e′) or f), the —ONO₂group of -(T-Y—ONO₂), -(T′-Y—ONO₂), -(T″-Y′—ONO₂), -(T′-Y′—ONO₂), -(T″′-Y—ONO₂) and -(T″′-Y′—ONO₂) is linked to the —(CH₂)*— 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)_a-R_x (I)

wherein R is a corticosteroid residue selected from:

a is 0,

R_Xis

(a2) —C(O)—CH(R¹)—NH-(T′-Y—ONO₂)
wherein
R¹of the group A1) is H

T′ is —C(O)—;

Y is selected from
a)

a straight or branched C₁-C₁₀alkylene,

a straight or branched C₁-C₁₀alkylene substituted with a —ONO₂group;

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

R-(Z)_a-R_x (I)

wherein R is a corticosteroid residue selected from:

a is 0,
R_Xis selected from
R_Xis selected from

(a5) —R^1b—CH(NHR^4a)—C(O)-(T-Y—ONO₂)

(a6) —R^1b—CH(COOR^3a)NH-(T′-Y—ONO₂) or

(a9) —R^1b—CH(NH-T′-Y′—ONO₂)—C(O)-(T-Y—ONO₂)

wherein
R^1bof the group A10) is —C(O)—CH₂—,
R^3ais H or a (C₁-C₅) alkyl,

R^4ais H or —C(O)CH₃,

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 C₁-C₁₀alkylene,

a straight or branched C₁-C₁₀alkylene substituted with a —ONO₂group.

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

R-(Z)_a-R_x (I)

wherein R is a corticosteroid residue selected from:

a is 1 and Z is —C(O)—, R_Xis

(a5) —R^1b—CH(NHR^4a)—C(O)-(T-Y—ONO₂) or

(a9) —R^1b—CH(NH-T′-Y′—ONO₂)—C(O)-(T-Y—ONO₂)

wherein R^1bof A10) is —O—CH₂— or [-4-O—(C₆H₄)]—CH₂—,

R^4ais H or —C(O)CH₃,

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 C₁-C₁₀alkylene,

a straight or branched C₁-C₁₀alkylene substituted with a —ONO₂group.

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

R-(Z)_a-R_x (I)

wherein R is a corticosteroid residue selected from:

a is 0,

R_Xis

(b2) —C(O)—CH₂—CH(R²)—NH-(T′-Y—ONO₂)
wherein
R²of the group B1) is H,

T′ is —C(O)—;

Y and Y′ are each independently selected from
a)

a straight or branched C₁-C₁₀alkylene,

a straight or branched C₁-C₁₀alkylene substituted with a —ONO₂group.

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, β₂-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^thEd.

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_Xis selected from (a2), (a4), (a8), (b2), (b4), (b8), (c2), (e2), (f1), (g2), (h1), (i1), (l2), (m2), (n2), (o2), (p2), (q2), (r2), (s2), (t2), (u2), (v2), can be obtained:
1-i) by reacting a compound of formula (II₁)

R—H (II₁)

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

W—X₁ (Ia)

wherein W is —OH, Cl, O—R_awherein R_ais pentafluorophenyl, 4-nitrophenyl or —(N-succimidyl), X₁is as below defined, to obtain the compounds of formula (II₂)

R—X₁ (II₂)

wherein X₁is as below defined,
X₁is a radical having the following meaning:

(a2′) —C(O)—CH(R^1′)—NH-(T′-Y-Q)

wherein R″ is selected from
A1) as defined above or
A2′) —CH₂—SP¹, —CH₂—OP¹, —CH(CH₃)—OP¹, —CH₂—[(C₆H₄)-4-OP¹], —CH₂—[(C₆H₃)-(3,5-diiodo)-4-OP¹], —CH₂—[(C₆H₃)-3-nitro-4-OP¹] or

A3′) —CH₂—NHR″″, —(CH₂)₂—NHR″″, —(CH₂)₃—NHR″″, —(CH₂), —NHR″″,

wherein R″″ is P³or —C(O)CH₃or

wherein R^5ais as defined above;

A4′) —CH₂—C(O)R″″′, —(CH₂)₂—C(O)R″″′, —(CH₂)₄—C(O)R″″′

wherein R″″′ is P², —OR^5aor

wherein R^5ais as above defined;

(a4′) —C(O)—CH(R^1a-T″-Y′-Q)-NHR^4a′

(a8′) —C(O)—CH(R^1a-T″-Y′-Q)-NH-(T′-Y-Q)

wherein R^1ais as defined above and R^4ais P³or —C(O)—CH₃or

(b2′) —C(O)—CH₂—CH(R^2′)—NH-(T′-Y-Q)

wherein R^2′ is selected from B1) as defined above or

B2′) —CH(CH₃)—OP¹, —CH₂—[(C₆H₄)-4-OP¹]; B3′) —CH₂—NHR″″, —(CH₂)₂—NHR″″, —(CH₂), —NHR″″, —(CH₂)₄—NHR″″,

wherein R″″ is as above defined;
B4′) —CH₂—C(O)—R″″′, —(CH₂)₂—C(O)—R″″′, —(CH₂)₄—C(O)—R″″′ wherein R″″′ is as above defined;

(b4′) —C(O)—CH₂—CH(R^2a-T″-Y′-Q)-NHR^4a′

(b8′) —C(O)—CH₂—CH(R^2a-T″-Y′-Q)-NH-(T′-Y-Q) wherein R^2aand R^4a′ are as defined above;

(c2′) —C(O)—(CH₂)_b—NH-(T′-Y-Q);

wherein R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, b, c, d, e and f are as above defined;
wherein P¹is 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, P2 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, P³is 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 —ONO₂or Z₂wherein Z₂is 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 Z₂, 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-C₁₀alkyl) 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^ndedition. 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-1) The reaction of a compound of formula (Ia) wherein W=—OH and X₁is as above defined, with a compound of formula (II₁) 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° C. to 50° C. The reaction is completed within a time range from 30 minutes to 36 hours.

1-i-2) The reaction of a compound of formula (Ia) wherein W=—O—R_awherein R_aand X₁are as above defined, with a compound of formula (II₁) 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)₃or 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° C. to 40° C. The reaction is completed within a time range from 30 minutes to 36 hours.

1-i-3) The reaction of a compound of formula (Ia) wherein W=—Cl, and X₁is are as above defined, with a compound of formula (II₁) 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° C. to 40° C. The reaction is completed within a time range from 30 minutes to 36 hours.

The compounds of formula (II₁) are commercially available.

1a) The compounds of formula (Ia) wherein W is —OH, and X₁is the radical selected from (a2′), (a4′), (b2′), (b4′), (c2′), (e2′), (f1′), (g2′), (h1′), (i1′), (l2′), (m2′), (n2′), (o2′), (p2′), (q2′), (r2′), (s2′), (t2′), (u2′), (v2′), wherein R^1′ is selected from A1), A2′), A3′) or A4′), R^1ais selected from A5) or A6), R^2ais selected from B5) or B6) and R^2′ is selected from B1), B2′), B3′) or B4′), wherein T′ and T″ are C(O) and Y, Y′ and R^4a′ are as above defined, can be obtained
1a-i) by reacting a compound of formula (IIIa)

P²—X₂ (IIIa)

wherein P²is as above defined, X₂is a radical having the following meaning

(a2″) —C(O)—CH(R^1′)—NH₂

(a4″) —C(O)—CH(R^1a—H)—NHR^4a′

wherein R^1′ is selected from A1), A2′), A3′), A4′), R^1ais selected from A5) or A6) and R^4a′ is as defined above

(b2″) —C(O)—CH₂—CH(R²)—NH₂,

(b4″) —C(O)—CH₂—CH(R^2a—H)—NHR^4a′

wherein R^2′ is selected from B1), B2′), B3′), B4′), R^2ais selected from B5) or B6) and R^4a′ is as defined above,

(c2″) —C(O)—(CH₂)_b—NH₂,

wherein R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, b, c, d, e and f are as above defined;
with a compound of formula (IVa)

W₁—(O)C-y-Q (IVa)

wherein W₁is OH or O—R_aand R_aand Q are as above defined, y is the radical Y when X₂is selected from (a2′), (b2′), (c2′), (e2′), (f1′), (g2′), (h1′), (i1′), (l2′), (m2′), (n2′), (o2′), (p2′), (q2′), (r2′), (s2′), (t2′), (u2′), (v2′), and y is the radical Y′ when X₂is selected from (a4′) or (b4′), wherein Y and Y′ are as defined above, and
1a-ii) when Q is Z₂, by converting the compound obtained in the step 1a-i) into nitro derivative by reaction with a nitrate source as above described and
1a-iii) optionally deprotecting the compounds obtained in step 1a-i) or 1a-ii) as above described.

The reaction of a compound of formula (IIIa) wherein P²and X₂are as above defined, with a compound of formula (IVa) wherein W₁is OH, y, Q are as above defined, may be carried out as described in 1-i-1) or in presence of other known condensing reagents such as O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU).

The reaction of a compound of formula (IIIa) wherein P²and X₂are as above defined, with a compound of formula (IVa) wherein W₁is O—R_a, y, Q are as above defined, may be carried as described in 1-i-2).

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

The compounds of formula (IVa) wherein W₁is 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° C. to 0° C. or from the corresponding derivatives of formula HOOC-y-Z₂(IVc) wherein Z₂is as above defined, by reaction with a nitrate source as above described. Alternatively the reaction with AgNO₃can be performed under microwave irradiation in solvents such acetonitrile or THF at temperatures in the range between 100 and 180° 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 W₁is O—R_a, y, Q are as above defined, can be obtained from the corresponding acids of formula (IVa) wherein W₁is OH as known in the literature.

The compounds of formula (Ia) wherein W═Cl or O—R_a, X₁is selected from (a2′), (a4′), (b2′), (b4′), (c2′), (e2′), (f1′), (g2′), (h1′), (i1′), (l2′), (m2′), (n2′), (o2′), (p2′), (q2′), (r2′), (s2′), (t2′), (u21), (v2′), wherein R″ is selected from A1), A2′), A3′) or A4′), R^1ais selected from A5) or A6), R^2ais selected from B5) or B6) and R^2′ is selected from B1), 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.

1b) The compounds of formula (Ia) wherein W is —OH, X₁is the radical selected from (a2′), (a4′), (b2′), (b4′) (c2′), (e2′), (f1′), (g2′), (h1′), (i1′), (l2′), (m2′), (n2′), (o2′), (p2′), (q2′), (r2′), (s2′), (t2′), (u2′), (v2′), wherein R^1′ is selected from A1), A2′), A3′) or A4′), R^1ais selected from A5) or A6), R^2ais selected from B5) or B6) and R^2′ is selected from B1), B2′), B3′) or B4′), Y and Y′ are as above defined, T′ and T″ are C(O)—X″, wherein X″ is —O— or —S— can be obtained
1b-i) by reacting a compound of formula (IIIa)

P²—X₂ (IIIa)

wherein P²and X₂are as defined above, with a compound of formula (IVd)

R_a—O—C(O)—X″-y-Q (IVd)

wherein R_a, X″ and Q are as above defined, y is the radical Y when X₂is selected from (a2′), (b2′), (c2′), (e2′), (f1′), (g2′), (h1′), (i1′), (l2′), (m2′), (n2′), (o2′), (p2′), (q2′), (r2′), (s2′), (t2′), (u2′), (v2′), and y is the radical Y′ when X₂is selected from (a4′) or (b4′), wherein Y and Y′ are as above defined, and

1b-ii) when Q is Z₂, by converting the compound obtained in the step 1b-i) into nitro derivative by reaction with a nitrate source as above described and
1b-iii) optionally deprotecting the compounds obtained in step 1b-i) or 1b-ii) as above described.

The reaction of a compound of formula (IIIa) wherein P²and X₂are 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 1-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, X₁is selected from (a2′), (a4′), (b2′), (b4′), (c2′), (e2′), (f1′), (g2′), (h1′), (i1′), (l2′), (m2′), (n2′), (o2′), (p2′), (q2′), (r2′), (s2′), (t2′), (u2′), (v2′), wherein R^1′ is selected from A1), A2′), A3′), A4′), R^1ais selected from A5) or A6), R^2ais selected from B5) or B6) and R^2′ is selected from B1), 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.

1c) The compounds of formula (Ia) wherein W is —OH and X₁is a radical selected from (a8′) or (b8′), wherein R^1ais selected from A5) or A6), R^2ais 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
1c-i) by reacting a compound of formula (IIIb),

P²—X_{3 (IIIb)}

wherein P²is as above defined, X₃is the radical of formula

(a8″) —C(O)—CH(R^1a—H)—NH₂

(b8″) —C(O)—CH₂—CH(R^2a—H)—NH₂wherein R^1ais selected from A5) or A6), R^2ais selected from B5) or B6), with a compound of formula (IVa)

W₁—(O)C-y-Q (IVa)

wherein W₁and Q are as above defined, wherein y is the radical Y or Y′, wherein Y and Y′ are as above defined, and
1c-ii) when Q is Z₂, by converting the compounds obtained in the step 1c-i) into nitro derivative by reaction with a nitrate source as above described and
1c-iii) optionally deprotecting the compounds obtained in step 1c-i) or 1c-ii) as above described.

The reaction of a compound of formula (IIIb) wherein P²and X₃are as above defined, with a compound of formula (IVa) wherein W₁is OH, y and Q are as above defined, may be carried out as described in 1a-i) using a ratio (IIIb)/(IVa) 1:2.

The reaction of a compound of formula (IIIb) wherein P²and X₃are as above defined, with a compound of formula (IVa) wherein W₁is OR_a, y and Q are as above defined, may be carried out as described in 1-i-2) using a ratio (IIIb)/(IVa) 1:2.

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

The compounds of formula (Ia) wherein W is —Cl or O—R_a, X₁is the radical selected from (a8′) or (b8′) wherein R^1ais selected from A5) or A6), R^2ais 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.

1d) The compounds of formula (Ia) wherein W is —OH, X₁is the radical selected from (a8′) or (b8′), wherein R^1ais selected from A5) or A6), R^2ais 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), can be obtained
1d-i) by reacting a compound of formula (Ib)

P²—X_3′ (Ib)

wherein P²is as above defined, X_3′ is the radical of formula

(a8″′) —C(O)—CH(R^1a—H)—NH-(T′-Y-Q)

(b8″′) —C(O)—CH₂—CH(R^2a—H)—NH-(T′-Y-Q)

wherein R^1ais selected from A5) or A6), R^2ais selected from B5) or B6), with a compound of formula (IVa)

W₁—(O)C-y-Q (IVa)

wherein W₁and Q are as above defined, wherein y is the radical Y′, wherein Y′ is as above defined, and
1d-ii) when Q is Z₂, by converting the compounds obtained in the step 1d-i) into nitro derivative by reaction with a nitrate source as above described and
1d-iii) optionally deprotecting the compounds obtained in step 1d-i) or 1d-ii) as above described.

The reaction of a compound of formula (Ib) wherein P²and X_3′ are as above defined, with a compound of formula (IVa) wherein W₁is OH, y and Q are as above defined, may be carried out as described in 1a-i).

The reaction of a compound of formula (Ib) wherein P²and X_3′ are as above defined, with a compound of formula (IVa) wherein W₁is OR_a, y and Q are as above defined may be carried out as described in 1-i-2).

The compounds of formula (Ib) wherein T′ is C(O), P²and X_3′ are as above defined, are obtained as described in 1a).

The compounds of formula (Ib) wherein T′ is C(O)—X″, P²and X_3′ are as above defined, are obtained as described in 1b).

The compounds of formula (Ia) wherein W is —Cl or O—R_a, X₁is the radical selected from (a8′) or (b8′) wherein R^1ais selected from A5) or A6), R^2ais 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(O), can be obtained from the corresponding acids (Ia) wherein W is —OH as known in literature.

1e) The compounds of formula (Ia) wherein W is —OH, X₁is the radical selected from (a8′) or (b8′), wherein R^1ais selected from A5) or A6), R^2ais 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(O)—X″— wherein X″ is as above defined, can be obtained 1e-i) by reacting a compound of formula (IIIb)

P²—X₃ (IIIb)

wherein P²and X₃are as above defined, with a compound of formula (IVd)

R_a—O—C(O)—X″-y-Q (IVd)

wherein R_aand Q are as above defined, wherein y is the radical Y′, wherein Y′ is as above defined, and
1e-ii) when Q is Z₂, by converting the compounds obtained in the step 1e-i) into nitro derivative by reaction with a nitrate source as above described and
1e-iii) optionally deprotecting the compounds obtained in step 1e-i) or 1e-ii) as above described.

The reaction of a compound of formula (IIIb) wherein P²and X₃are 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 1-i-2) using a ratio (IIIb)/(IVd) 1:2.

The compounds of formula (Ia) wherein W is —Cl or O—R_a, X₁is the radical selected from (a8′) or (b8′) wherein R^1ais selected from A5) or A6), R^2ais 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.

1f) The compounds of formula (Ia) wherein W is —OH, X₁is selected from (a8′) or (b8′), wherein R^1ais selected from A5) or A6), R^2ais 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
1f-i) by reacting a compound of formula (Ib)

P²—X_3′ (Ib)

wherein X_3′ and P²are as above defined, with a compound of formula (IVd)

W₁—O—C(O)—X″-y-Q (IVd)

wherein W₁and Q are as above defined, y is the radical Y′,
wherein Y′ is as above defined, and
1f-ii) when Q is Z₂, by converting the compounds obtained in the step 1f-i) into nitro derivative by reaction with a nitrate source as above described and
1f-iii) optionally deprotecting the compounds obtained in step 1f-i) or 1f-ii) as above described.

The reaction of a compound of formula (Ib) wherein P²and X_3′ are as above defined, with a compound of formula (IVd) wherein W₁is OH, y and Q are as above defined, may be carried out as described in 1a-i).

The reaction of a compound of formula (Ib) wherein P²and X_3′ are as above defined, with a compound of formula (IVd) wherein W₁is OR_a, y and Q are as above defined may be carried out as described in 1-i-2).

The compounds of formula (Ib) wherein T′ is C(O), P²and X_3′ are as above defined, are obtained as described in 1a).

The compounds of formula (Ib) wherein T′ is C(O)—X″, P²and X_3′ are as above defined, are obtained as described in 1b).

The compounds of formula (Ia) wherein W is —Cl or O—R_a, X₁is a radical selected from (a8′) or (b8′) wherein R^1ais A5) or A6), R^2ais 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.

1g) The compounds of formula (Ia) wherein W is —OH, X₁is a radical is selected from (a8′) or (b8′), wherein R^1ais selected from A5) or A6), R^2ais 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)—NR′ wherein R′ is above defined, can be obtained
1g-i) by reacting a compound of formula (Ib)

P²—X_3′ (1b)

wherein P²and X_3′ 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
1g-ii) when Q is Z₂, by converting the compounds obtained in the step 1g-i) into nitro derivative by reaction with a nitrate source as above described and
1g-iii) optionally deprotecting the compounds obtained in step 1g-i) or 1g-ii) as above described.

The reaction of a compound of formula (Ib) wherein P²and X_3′ 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 1-i-2).

The compounds of formula (Ib) wherein T′ is C(O), wherein P²and X_3′ are as above defined, are obtained as described in 1a-i), 1a-ii).

The compounds of formula (Ib) wherein T′ is C(O)—X″, wherein P²and X_3′ are as above defined, are obtained as described in 1b-i), 1b-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 Z₂are commercially available, the compounds of formula (IVg) wherein y is as above defined and Q is —ONO₂may be obtained from the compounds of formula P³—R′N-y-ONO₂(IVh) wherein P³is as above defined by deprotection of amino group as known in literature. The compounds of formula (IVh) wherein P³and y are as above defined may be obtained from the alcohol P³—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 P³and y are as above defined may be obtained from the corresponding compounds of formula P³—R′N-y-Z₂(IVl) wherein P³, y and Z₂are 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, X₁is a radical selected from (a8′) or (b8′) wherein R^1ais selected from A5) or A6), R^2ais 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.

1h) The compounds of formula (Ia) wherein W is —OH, X₁is a radical selected from (a8′) or (b8′), wherein R^1ais selected from A7), R^2ais 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
1h-i) by reacting a compound of formula (Ie),

P²—X₅ (Ie)

wherein P²is defined above, X₅is the radical of formula

(a8″′) —C(O)—CH(R^1a—OH)—NH-(T′-Y-Q)

(b8″′) —C(O)—CH₂—CH(R^2a—OH)—NH-(T′-Y-Q)

wherein R^1ais selected from A7), R^2ais 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
1h-ii) when Q is Z₂, by converting the compounds obtained in the step 1h-i) into nitro derivative by reaction with a nitrate source as above described and
1h-iii) optionally deprotecting the compounds obtained in step 1h-i) or 1h-ii) as above described.

The reaction of a compound of formula (Ie) wherein P²and X₅are 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-1).

The compounds of formula (Ie) wherein T′ is C(O), wherein P²and X₅are as above defined, are obtained as described in 1a-i), 1a-ii).

The compounds of formula (Ie) wherein T′ is C(O)—X″, wherein P²and X₅are as above defined, are obtained as described in 1b-i), 1b-ii).

The compounds of formula (Ia) wherein W is —Cl or O—R_a, X₁is a radical selected from (a8′) or (b8′) wherein R^1ais selected from A7), R^2ais 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.

1i) The compounds of formula (Ia) wherein W is —OH, X₁is a radical selected from (a8′) or (b8′), wherein R^1ais selected from A7), R^2ais 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 1i-i) by reacting a compound of formula (Ie),

P²—X₅ (Ie)

wherein is P²and X₅are 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
1i-ii) when Q is Z₂, by converting the compounds obtained in the step 1i-i) into nitro derivative by reaction with a nitrate source such above described and
1i-iii) optionally deprotecting the compounds obtained in step 1i-i) or 1i-ii) as above described.

The reaction of a compound of formula (Ie) wherein P²and X₅are 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 1a-i).

The compounds of formula (Ia) wherein W is —Cl or O—R_a, X₁is the radical selected from (a8′) or (b8′) wherein R^1ais selected from A7), R^2ais 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

1l) The compounds of formula (Ia) wherein W is —OH, X₁is a radical selected from (a8′) or (b8′), wherein R^1ais selected from A7), R^2ais 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)—O—C(O)—, wherein R′ is as above defined, can be obtained
1l-i) by reacting a compound of formula (Ie),

P²—X₅ (Ie)

wherein is P²and X₅are defined above, with a compound of formula (IVm)

Hal-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′, wherein Y′ is as above defined, and
1l-ii) when Q is Z₂, by converting the compounds obtained in the step 1l-i) into nitro derivative by reaction with a nitrate source such above described and
1l-iii) optionally deprotecting the compounds obtained in step 1l-i) or 1l-ii) as above described.

The reaction of a compound of formula (Ie) wherein P⁵and X₅are 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 CH₂Cl₂at temperature in the range between 0° and 100° C. or in a double phase system H₂O/Et₂O temperature in the range between 20° and 40° 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′—CH₂—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 ZnCl₂as 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, X₁is a radical selected from (a8′) or (b8′) wherein R^1ais selected from A7), R^2ais 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.

1m) The compounds of formula (Ia) wherein W is —OH, X₁is a radical selected from (a8′) or (b8′), wherein R^1ais selected from A7), R^2ais 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′)—O—C(O)O—, wherein R′ is as above defined, can be obtained
1m-i) by reacting a compound of formula (Ie),

P²—X₅ (Ie)

wherein is P²and X₅are defined above, with a compound of formula (IVo)

Hal-CH(R′)—O—(O)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
1m-ii) when Q is Z₂, by converting the compounds obtained in the step 1m-i) into nitro derivative by reaction with a nitrate source such above described and
1m-iii) optionally deprotecting the compounds obtained in step 1m-i) or 1m-ii) as above described.

The reaction of a compound of formula (Ie) wherein P²and X₅are 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 1m-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(O)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 CH₂Cl₂at temperatures range between 0° to 65° C.

The compounds of formula (Ia) wherein W is —Cl or O—R_a, X₁is a radical selected from (a8′) or (b8′) wherein R^1aselected from A7), R^2aselected 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)O—, may be obtained from the corresponding acids (Ia) wherein W is —OH as known in literature.

1n) The compounds of formula (Ia) wherein W is —OH, X₁is a radical selected from (a4′) or (b4′), wherein R^1ais selected from A7), R^2ais selected from B7), Y′, Q and R⁴, are as above defined and T″ is X″ wherein X″ is as above defined, can be obtained
1n-i) by reacting a compound of formula (IIIc)

P²—X_5′ (IIIc)

wherein P²is defined above, X_5′ is

(a4″) —C(O)—CH(R_1a—OH)—NH^4a′

(b4″) —C(O)—CH₂—CH(R_2a—OH)—NHR^4a′

wherein R_ais selected from A7), R^2ais 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
1n-ii) when Q is Z₂, by converting the compounds obtained in the step 1n-i) into nitro derivative by reaction with a nitrate source as above described and
1n-iii) optionally deprotecting the compounds obtained in step 1n-i) or 1-ii) as above described.

The reaction of a compound of formula (IIIc) wherein X_5′ and P²are 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-1).

The compounds of formula (IIIc) wherein X_5′and P²are 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 O—R_a, X₁is a radical selected from (a4′) or (b4′), wherein R^1ais selected from A7), R^2ais 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.

1o) The compounds of formula (Ia) wherein W is —OH, X₁is a radical selected from (a4′) or (b4′), wherein R^1ais selected from A7), R^2ais selected from B7), Y′, Q and R^4aare as above defined and T″ is —NR′ wherein R′ is as above defined, can be obtained
1o-i) by reacting a compound of formula (IIIc)

P²—X_5′ (IIIc)

wherein P²and 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 1o-ii) when Q is Z₂, by converting the compounds obtained in the step 1o-i) into nitro derivative by reaction with a nitrate source as above described and
1o-iii) optionally deprotecting the compounds obtained in step 1o-i) or 1o-ii) as above described.

The reaction of a compound of formula (IIIc) wherein X_5′ and P²are 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 1a-i).

The compounds of formula (Ia) wherein W is —Cl or —OR_a, X₁is a radical selected from (a4′) or (b4′), wherein R^1ais selected from A7), R^2ais 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.

1p) The compounds of formula (Ia) wherein W is —OH, X₁is a radical selected from (a4′) or (b4′), wherein R^1ais selected from A7), R^2ais 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
1p-i) by reacting a compound of formula (IIIc)

P²—X₅ (IIIc)

wherein P²and X_5′are as above defined, with a compound of formula (IVm)

Hal-CH(R′)—O—(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
1p-ii) when Q is Z₂, by converting the compounds obtained in the step 1p-i) into nitro derivative by reaction with a nitrate is source as above described and
1p-iii) optionally deprotecting the compounds obtained in step 1p-i) or 1p-ii) as above described.

The reaction of a compound of formula (IIIc) wherein P²and X_5′ 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 1l-1).

The compounds of formula (Ia) wherein W is —Cl or OR_a, X₁is a radical selected from (a4′) or (b4′), wherein R^1ais selected from A7), R^2ais selected from B7) and wherein Y and Q are as above defined and T″ is the group —O—CH(R′)—O—C(O), wherein R′ is as above defined, can be obtained from the corresponding acids (Ia) wherein W=—OH as known in literature.

1q) The compounds of formula (Ia) wherein W is —OH, X, is a radical selected from (a4′) or (b4′), wherein R^1ais selected from A7), R^2ais 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
1q-i) by reacting a compound of formula (IIIc)

P²—X₅ (IIIc)

wherein P²and X_5′ are as above defined, with a compound of formula (IVo)

Hal-CH(R′)—O—(O)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
1q-ii) when Q is Z₂, by converting the compounds obtained in the step 1q-i) into nitro derivative by reaction with a nitrate source as above described and
1q-iii) optionally deprotecting the compounds obtained in step 1q-i) or 1q-ii) as above described.

The reaction of a compound of formula (IIIc) wherein P²and 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 1l-1).

The compounds of formula (Ia) wherein W is —Cl or OR_a, X₁is a radical selected from (a4′) or (b4′), wherein R^1ais selected from A7), R^2ais selected from B7) and wherein Y and Q, are as above defined and T″ is the group —O—CH(R′)—O—C(O)—O—, 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_Xis selected from (a2), (a4), (a8), (b2), (b4), (b8), (c2), (e2), (f1), (g2), (h1), (i1), (l2), (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 C₁-C₄alkyl, can be obtained:
2-i) by reacting a compound of formula (II₁) as above defined with a compound of formula (If)

Hal-CH(R′)—O—X₁ (If)

wherein Hal is an halogen atom, R′ and X₁are as above defined and
2-ii) when Q is Z₂, 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 X₁and R′ are as above defined, with a compound of formula (II₁) may be carried out as described in 1l-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—X₁ (Ia)

wherein W is a chlorine atom, X₁is as above defined, and ZnCl₂as known in literature.
3) The compounds of general formula (I) as above defined wherein a is equal to 1, the radical R_Xis selected from (a1), (a3), (a7), (b1), (b3), (b7), (c1), (e1), (f2), (g1), (h2), (i2), (l1), (m1), (n1), (o1), (p1), (q1), (r1), (s1), (t1), (u1), (v1), Z is C(O), can be obtained
3-i) by reacting a compound of formula (II₃)

R—C(O)—O—R_a (II₃)

wherein R and R_aare as above defined, with a compound of formula (Ig)

H—X₂ (Ig)

wherein X₂is a radical having the following meanings:

(a1′) —HN—CH(R^1′)—C(O)-(T-Y-Q)

(a3′) —HN—CH(R^1a-T″-Y′-Q)-COOR^3a′

(a7′) —HN—CH(R^1a-T″-Y∝-Q)-C(O)-(T-Y-Q)

(b1′) —HN—CH(R^2′)—CH₂C(O)-(T-Y-Q)

(b3′) —HN—CH(R^2a-T″-Y′-Q)-CH₂COR^3a′

(b7′) —HN—CH(R^2a-T″-Y′-Q)-CH₂—C(O)-(T-Y-Q)

wherein R^1′, R_1a, R^2′, R^2aare as above defined
R^3a′ is selected from P², —OR^5aor

wherein R_5ais as above defined;

(c1′) —HN—(CH₂)_b—C(O)-(T-Y-Q);

wherein T, T″, Y and Y′ are as above defined,
3-ii) when Q is Z₂, 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_aare as above defined, with a compound of formula (Ig) wherein X₁is as above defined, may be carried out as described in 1-i-2).

The compounds of formula (II₃) wherein R and R_aare as above defined, are obtained from the compounds of formula (II₁) by reaction with the compounds of formula Cl—C(O)—O—R_awherein R_ais as above defined, as known in literature.

3a) The compounds of formula (Ig) wherein X₂is selected from (a1′), (a3′), (b1′), (b3′), (c1′), (e1′), (f2′), (g1′), (h2′), (t1′), (u1′), (v1′), wherein R^1′ is selected from A1), A2′), A3′) or A4′), R^1ais selected from A7), R^2ais selected from B7) and R^2′ is selected from B1), 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 (IIIe),

P³—X₆ (IIIe)

wherein P³is as above defined, X₆is a radical having the following meanings:

(a1″) —HN—CH(R^1′)—C(O)—OH

(a3″) —HN—CH(R^1a—OH)—COOR^3a′

(b1″) —HN—CH(R^2′)₂—CH₂C(O)—OH

(b3″) —HN—CH(R^2a—OH)—CH₂COOR^3a′

wherein R^1′ is selected from A1), A2′), A3′) or A4′), R^1ais selected from A7), R^2ais selected from B7) and R^2′ is selected from B1), B2′), B3′) or B4′), and R^3a′ is defined above

(c1″) —HN—(CH₂)_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 X₆is selected from (a1′), (b1′), (c1′), (e1′), (r2′), (g1′), (h2′), (i2′), (l1′), (m1′), (n1′), (o1′), (p1′), (q1′), (r1′), (s1′), (t1′), (u1′) and (v1′), y is the radical Y′ when X₆is selected from (a3′) and (b3′), wherein Y and Y′ are as defined above, and
3a-ii) when Q is Z₂, 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 (IIIe) wherein P³and X₆are 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-1).

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

3b) The compounds of formula (Ig) wherein X₂is selected from (a1′), (a3′), (b1′), (b3′), (c1′), (e1′), (r2′), (g1′), (h2′), (t1′), (u1′), (v1′), wherein R^1′ is selected from A1), A2′), A3′) or A4′), R^1ais selected from A7), R^2ais selected from B7) and R^2′ is selected from B1), 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 (IIIe),

P³—X₆ (IIIe)

wherein P³and X₆are 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 X₆is selected from (a1′), (b1′), (c1′), (e1′), (r2′), (g1′), (h2′), (i2′), (l1′), (m1′), (n1′), (o1′), (p1′), (q1′), (r1′), (s1′), (t1′), (u1′) and (v1′), y is the radical Y′ when X₆is selected from (a3′) and (b3′), wherein Y and Y′ are as defined above, and
3b-ii) when Q is Z₂, 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 (IIIe) wherein P³and X₆are as above defined, with a compound of formula (IVg) wherein R′, y, Q are as above defined, may be carried out 1a-i).

3c) The compounds of formula (Ig) wherein X₂is selected from (a1′), (a3′), (b1′), (b3′), (c1′), (e1′), (r2′), (g1′), (h2′), (t1′), (u1′), (v1′), wherein R^1′ is selected from A1), A2′), A3′), A4′), R^1ais selected from A7), R^2ais selected from B7) and R^2′ is selected from B1), 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 (IIIe)

P³—X₆ (IIIe)

wherein P³, X₆are as above defined with compounds of formula (IVm)

Hal-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 X₆is selected from (a1′), (b1′), (c1′), (e1′), (f2′), (g1′), (h2′), (i2′), (l1′), (m1′), (n1′), (o1′), (p1′), (q1′), (r1′), (s1′), (t1′), (u1′) and (v1′), y is the radical Y′ when X₆is selected from (a3′) and (b3′), wherein Y and Y′ are as defined above, and
3c-ii) when Q is Z₂, 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 (IIIe) wherein P³and X₆are as above defined, with a compound of formula (IVm) wherein y, Q, R′ are as above defined, may be carried out as described in 1l-i)

3d) The compounds of formula (Ig) wherein X₂is selected from (a1′), (a3′), (b1′), (b3′), (c1′), (e1′), (r2′), (g1′), (h2′), (i2′), (l1′), (m1′), (n1′), (o1′), (p1′), (q1′), (r1′), (s1′), (t1′), (u1′), (v1′), wherein R1′ is selected from A1), A2′), A3′) or A4′), R^1ais selected from A7), R^2ais selected from B7) and R^2′ is selected from B1), 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 (IIIe)

P³—X₆ (IIIe)

wherein P³and X₆are as above defined, with compounds of formula (IVo)

Hal-CH(R′)—O—(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 X₆is selected from (a1′), (b1′), (c1′), (e1′), (f2′), (g1′), (h2′), (i2′), (l1′), (m1′), (n1′), (o1′), (p1′), (q1′), (r1′), (s1′), (t1′), (u1′) and (v1′), y is the radical Y′ when X₆is selected from (a3′) and (b3′), wherein Y and Y′ are as defined above, and
3d-ii) when Q is Z₂, 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 (IIIe) wherein P³and X₆are as above defined, with a compound of formula (IVo) wherein y, Q, R′ are as above defined, may be carried out as described in 1l-i).

3e) The compounds of formula (Ig) wherein X₂is selected from (a7′) or (b7′) wherein R^1ais selected from A5) or A6), R^bis selected from B5) or B6) T″ is —C(O)—, T is —X″, —NR′, —O—CH(R′)—O—C(O)— or —O—CH(R′)—O—C(O)O— wherein X″ and R′, Y and Y′ are as above defined, may be obtained
3e-i) by reacting a compound of formula (Ih)

P³—X₇ (Ih)

wherein P³is as above defined and X₇is the radical having the following meaning

(a7″) —HN—CH(R^1a—H)—C(O)-(T-Y-Q)

(b7″) —HN—CH(R^2a—H)—CH₂—C(O)-(T-Y-Q)

wherein R^1ais selected from A5) or A6), R^2ais selected from B5) or B6), with compounds of formula (IVa)

W₁—C(O)-y-Q (IVa)

wherein W₁and Q are as above defined, y is the radical Y′,
wherein Y′ is as above defined, and
3e-ii) when Q is Z₂, 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 P³and X₇are as above defined, with a compound of formula (IVa) wherein y, Q, W₁are as above defined may be carried out as described in 1-i-1), 1-i-2), 1-i-3) and 1a-i).

The compounds of formula (Ih) wherein P³and X₇are as above defined, T is —X″ are obtained as described in 3a).

The compounds of formula (Ih) wherein P³and X₇are as above defined, T is —NR′ are obtained as described in 3b).

The compounds of formula (Ih) wherein P³and X₇are as above defined, T is —O—CH(R′)—O—C(O)— are obtained as described in 3c).

The compounds of formula (Ih) wherein P³and X₇are as above defined, T is —O—CH(R′)—O—C(O)O— are obtained as described in 3d).

3f) The compounds of formula (Ig) wherein X₂is selected from (a7′) or (b7′) wherein R^1ais selected from A5) or A6), R^1bis selected from B5) or B6) T″ is —C(O)—X″, T is —X″, —NR′, —O—CH(R′)—O—C(O)— or —O—CH(R′)—O—C(O)O— wherein X″ and R, Y and Y′ are as above defined, may be obtained
3f-i) by reacting a compound of formula (Ih)

P³—X₇ (Ih)

wherein P³and X₇are as above defined with compounds of formula (IVd)

R_a—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 P³and X₇are as above defined, with a compound of formula (IVd) wherein y, Q, R_aare as above defined, may be carried out as described in 1-i-2).
3g) The compounds of formula (Ig) wherein X₂is selected from (a7′) or (b7′) wherein R^1ais selected from A5) or A6), R^1bis selected from B5) or B6), T″ is —C(O)—NR′, T is X″, NR′, —O—CH(R′)—O—C(O)— or —O—CH(R′)—O—C(O)O— wherein X″ and R′, Y and Y′ are as above defined, may be obtained
3g-i) by reacting a compound of formula (Ih)

P³—X₇ (Ih)

wherein P³and X₇are as above defined, with compounds of formula (IVf)

R_a—O—C(O)—NR′-y-Q (IVf)

wherein R_aand Q are as above defined, y is the radical Y′,
wherein Y′ is as above defined, and
3g-ii) when Q is Z₂, 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 P³and X₇are as above defined, with a compound of formula (IVf) wherein y, Q, R_aand R′ are as above defined may be carried out as described in 1-i-2).

The compounds of formula (Ih) wherein P³and X₇are as above defined, T is —X″ are obtained as described in 3a).

The compounds of formula (Ih) wherein P³and X₇are as above defined, T is —NR′ are obtained as described in 3b).

The compounds of formula (Ih) wherein P³and X₇are as above defined, T is —O—CH(R′)—O—C(O)— are obtained as described in 3c).

The compounds of formula (Ih) wherein P³and X₇are as above defined, T is —O—CH(R′)—O—C(O)O— are obtained as described in 3d).

3h) The compounds of formula (Ig) wherein X₂is selected from (a7′) or (b7′) wherein R_ais selected from A7), R^1bis selected from B7), T″ is —X″, T is —X″, —NR′, —O—CH(R′)—O—C(O)— or —O—CH(R′)—O—C(O)O— wherein X″ and R′, Y and Y′ are as above defined, may be obtained
3h-i) by reacting a compound of formula (Ih)

P³—X₇ (Ih)

wherein P³is as above defined and X₇is as above defined wherein R^1ais selected from A7), R^1bis 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 P³and X₇are 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-1), 1-i-2) and 1a-1).

The compounds of formula (Ih) wherein P³and X₇are as above defined, T is —X″ are obtained as described in 3a).

The compounds of formula (Ih) wherein P³and X₇are as above defined, T is —NR′ are obtained as described in 3b).

The compounds of formula (Ih) wherein P³and X₇are as above defined, T is —O—CH(R′)—O—C(O)— are obtained as described in 3c).

The compounds of formula (Ih) wherein P³and X₇are as above defined, T is —O—CH(R′)—O—C(O)O— are obtained as described in 3d).

3i) The compounds of formula (Ig) wherein X₂is selected from (a7′) or (b7′) wherein R^1ais selected from A7), R^1bis selected from B7), T″ is NR′, T is —X″, —NR′, —O—CH(R′)—O—C(O)— or —O—CH(R′)—O—C(O)O— wherein X″ and R′, Y and Y′ are as above defined, may be obtained
3i-i) by reacting a compound of formula (Ih)

P³—X₇ (Ih)

wherein P³and X₇are 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 Z₂, 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 P³and X₈₇are as above defined, with a compound of formula (IVg) wherein y, Q, R′ are as above defined, may be carried out as described in 1a-i).

3l) The compounds of formula (Ig) wherein X₂is selected from (a7′) or (b7′) wherein R_1ais selected from A7), R^1bis selected from B7), T″ is —O—CH(R′)—O—C(O)—, T is X″, NR′, —O—CH(R′)—O—C(O)— or —O—CH(R′)—O—C(O)O— wherein X″ and R′, Y and Y′ are as above defined, may be obtained
3l-i) by reacting a compound of formula (Ih)

P³—X₇ (Ih)

wherein P³and X₈are as above defined with compounds of formula (IVm)

Hal-CH(R′)—O—(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 3l-ii) when Q is Z₂, by converting the compounds obtained in the step 3l-i) into nitro derivative by reaction with a nitrate source as above described and
3l-iii) optionally deprotecting the compounds obtained in step 3l-i) or 3l-ii) as above described.

The reaction of a compound of formula (Ih) wherein P³and X₇are as above defined, with a compound of formula (IVm) wherein y, Q, R′ are as above defined, may be carried out as described in 1l-i).

3m) The compounds of formula (Ig) wherein X₂is selected from (a7′) or (b7′) wherein R_1ais selected from A7), R^1bis selected from B7), T″ is —O—CH(R′)—O—C(O)O—, T is X″, NR′, —O—CH(R′)—O—C(O)— or —O—CH(R′)—O—C(O)O— wherein X″ and R′, Y and Y′ are as above defined, may be obtained
3m-i) by reacting a compound of formula (Ih)

P³—X_{7 (Ih)}

wherein P¹and X₈are as above defined with a compound of formula (IVo)

Hal-CH(R′)—O—(O)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 Z₂, 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 3l-i) or 3m-ii) as above described.

The reaction of a compound of formula (Ih) wherein P³and X₇are as above defined, with a compound of formula (IVo) wherein y, Q, R′ are as above defined, may be carried out as described in 1l-i).

3n) The compounds of formula (Ig) wherein X₂is selected from (a3′) or (b3′), wherein R^1ais selected from A5) or A6), R^2ais 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 (IIIf),

P³—X₉ (IIIf)

wherein P³is as above defined, X₉is a radical having the following meaning

(a3″) —HN—CH(R^1a—H)—COR^3a′

(b3″) —HN—CH(R^2a—H)—CH₂COOR^3a′

wherein R^1ais selected from A5 or A6) and R^2ais selected from B5) or B6), wherein R^3a′ is as above defined, with a compound of formula (IVa)

W₁—C(O)-y-Q (IVa)

wherein W₁and Q are as above defined, y is the radical Y′,
wherein Y′ is as above defined, and
3n-ii) when Q is Z₂, 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 (IIIf) wherein P³and X₉are as above defined, with a compound of formula (IVa) wherein W₁, y, Q are as above defined, may be carried out as described in 1-i-1), 1-i-2), 1a-1).

The compounds of formula (IIIf) wherein P³and X₉are as above defined, are commercially available or obtained as known in literature.

3o) The compounds of formula (Ig) wherein X₂is selected from (a3′) or (b3′), wherein R^1ais selected from A5) or A6), R^2ais 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 (IIIf)

P³—X₉ (IIIf)

wherein P³and X₉are 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 Z₂, 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 (IIIf) wherein P³and X₉are 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 1-i-2).

3p) The compounds of formula (Ig) wherein X₂is selected from (a3′) or (b3′), wherein R^1ais selected from A5) or A6), R^2ais 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 (IIIg),

P³—X₉ (IIIf)

wherein P³and X₉are 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 Z₂, 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 (IIIf) wherein P³and X₉are 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 1-i-2).

4) The compounds of general formula (I) as above defined wherein a is equal to 1, the radical R_Xis selected from (d1), (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_ais as above defined, with a compound of formula (Im)

H—X₁₂ (Im)

wherein X₁₂is the radical R_Xhaving the following meaning

(d1′) —HN—CH(R^12′)—CH₂—O-(T″′-Y-Q)

(d2′) —O—CH₂—CH(R^12′)—NH-(T′-Y-Q)

(d3′) —HN—CH(R^12a-T″-Y′-Q)-CH₂OH

(d4′) —O—CH₂—CH(R^12a-T″-Y′-Q)-NHR^4a

(d7′) —HN—CH(R^12a-T″-Y′-Q)-CH₂—O-(T″′-Y-Q)

(d8′) —O—CH₂—CH(R^12a-T″-Y′-Q)-NH-(T′-Y-Q)

wherein R^12′ is

D1),

D2′) —CH₂—OP¹, —CH(CH₃)—OP¹, —CH₂—[(C₆H₄)-4-OP¹], —CH₂—[(C₆H₃)-(3,5-diiodo)-4-OP¹], —CH₂—[(C₆H₃)-3-nitro-4-OP¹];
D3′) —CH₂—NHR″″, —(CH₂)₂—NHR″″, —(CH₂)₃—NHR″″, —(CH₂)₄—NHR″″, wherein R″″ is as above defined;
D4′) —CH₂—C(O)R″″, —(CH₂)₂—C(O)R″″′, —(CH₂)₄—C(O)R″″′, wherein R″″′ is as above defined;
wherein R^12ais as above defined; and
4-ii) when Q is Z₂, 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_aare as above defined, with a compound of formula (Im) wherein X₁₂is as above defined, may be carried out as described in 1-i-2).

4a) The compounds of formula (Im) wherein X₁₂is selected from (d1′), (d2′), (d3′) or (d4′) wherein R^12′ is selected from D1), D2′), D3′) or D4′) and R^12ais 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 (IIIi),

P⁴—X₁₃ (IIIi)

wherein P⁴is P³or P¹as above defined and X₁₃is a radical having the following meaning

(d1″) —HN—CH(R^12′)—CH₂—OH

(d2″) —O—CH₂—CH(R^12′)—NH₂

(d3″) —HN—CH(R^2a—H)—CH₂OP¹

(d4″) —O—CH₂—CH(R^12a—H)—NHR^4a′

wherein R^12′ is D1), D2′), D3′) or D4′), R^12ais D5) or D6), R^4a′ and P¹are as above defined, with a compound of formula (IVa)

W₁—(O)C-y-Q (IVa)

wherein Q and W₁are as above defined, y is the radical Y when X₁₃is selected from (d1′) or (d2′), y is the radical Y′ when X₁₃is selected from (d3′) or (d4′), wherein Y and Y′ are as above defined, and
4a-ii) when Q is Z₂, 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 (IIIi) wherein X₁₃and P⁴are as above defined, with a compound of formula (IVa) wherein W₁, y and Q are as above defined, may be carried out as described in 1-i-1) and 1-i-2).

The compounds of formula (IIIi) wherein X₁₃and P⁴are as above described, are commercially available or known in literature.

4b) The compounds of formula (Im) wherein X₁₂is selected from (d1′), (d2′), (d3′) or (d4′) wherein R^12′ is selected from D1), D2′), D3′) or D4′) and R^2ais 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 (IIIi),

P⁴—X₁₃ (IIIi)

wherein P⁴and X₁₃are defined above, with a compound of formula (IVd)

R_a—O—(O)C—X″-y-Q (IVd)

wherein Q, R_aand X″ are as above defined, y is the radical Y when X₁₃is selected from (d1′) or (d2′), y is the radical Y′ when X₁₃is selected from (d3′) or (d4′), wherein Y and Y′ are as above defined, and
4b-ii) when Q is Z₂, 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 (IIIi) wherein X₁₃and P⁴are 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 1-i-2).

4c) The compounds of formula (Im) wherein X₁₂is selected from (d7′) or (d8′) wherein R^12ais selected from D5) or D6), Y′ and Y is are as above defined, T′ and T″ and T″′ are C(O), can be obtained
4c-i) by reacting a compound of formula (IIIl),

P⁴—X₁₄ (IIIl)

wherein P⁴is P¹or P³, X₁₄is the radical having the following meaning

(d7″) —HN—CH(R^2a—H)—CH₂—OH

(d8″) —O—CH₂—CH(R^12a—H)—NH₂

wherein R^12ais selected from D5) or D6), with a compound of formula (IVa)

W₁—(O)C-y-Q (IVa)

wherein W₁and Q are as above defined, y is the radical Y′,
wherein Y′ is as above defined, and
4c-ii) when Q is Z₂, 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 (IIIl) wherein P⁴and X₁₄are as above defined, with a compound of formula (IVa) wherein W₁is OH, y and Q are as above defined, may be carried out as described in 1-i-1) using a ratio (IIIl)/(IVa) 1:2.

The reaction of a compound of formula (IIIl) wherein P⁴and X₁₄are as above defined, with a compound of formula (IVa) wherein W₁is OR_a, y and Q are as above defined, may be carried out as described in 1-i-2) using a ratio (IIIl)/(IVa) 1:2.

The compounds of formula (IIIl) wherein P⁴and X₁₄are as above described, are commercially available or known in literature.

4d) The compounds of formula (Im) wherein X₁₂is selected from (d7′) or (d8′) wherein R^12ais 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)

P⁴—X₁₅ (In)

wherein P⁴is defined above and X₁₅is the radical having the following meaning

(d7″′) —HN—CH(R^2a—H)—CH₂—O-(T″-Y-Q)

(d8″′) —O—CH₂—CH(R^2a—H)—NH-(T′-Y-Q)

wherein R^12ais selected from D5) or D6), Y, Q, T′ and T″′ are as above defined, with a compound of formula (IVa)

W₁—(O)C-y-Q (IVa)

wherein W₁, 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 P⁴and X₁₅are as above defined, with a compound of formula (IVa) wherein W₁is OH, y and Q are as above defined, may be carried out as described in 1-i-1).

The reaction of a compound of formula (In) wherein P⁴and X₁₅are as above defined, with a compound of formula (IVa) wherein W₁is OR_a, y and Q are as above defined, may be carried out as described in 1-i-2).

The compounds of formula (In) wherein P⁴and X₁₅are as above defined, T′ and T″′ are —C(O)— can by obtained as described in 4a).

4e) The compounds of formula (Im) wherein X₁₂is selected from (d7′) or (d8′) wherein R^12ais 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 (IIIl),

P⁴—X₁₄ (IIIl)

wherein P⁴and X₁₄are as above defined, with a compound of formula (IVd)

R_a—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 (IIIl) wherein P⁴and X₁₄are 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 1-i-2) using a ratio (IIIl)/(IVd) 1:2.

4f) The compounds of formula (Im) wherein X₁₂is selected from (d7′) or (d8′) wherein R^12ais 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)

P⁴—X₁₅ (In)

wherein P⁴and X₁₅are as above defined, with a compound of formula (IVd)

R_a—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 P⁴and X₁₅are 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 1-i-2).

The compounds of formula (In) wherein T′ or T″′ are C(O), P⁴and X₁₅are 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 P⁴and X₁₅are as above defined are obtained as described in 4b-i), 4b-ii).

4g) The compounds of formula (Im) wherein X₁₂is selected from (d7′) or (d8′) wherein R^2ais 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)

P⁴—X₁₅ (In)

wherein P⁴and X₁₅are 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
4g-ii) when Q is Z₂, 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) P⁴and X₁₅are 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 1-i-2).

The compounds of formula (In) wherein T′ or T″′ are C(O), wherein P⁴and X₁₅are 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 P⁴and X₁₅are as above defined, are obtained as described in 4b-i), 4b-ii).

4h) The compounds of formula (Im) wherein X₁₂is selected from (d7′) or (d8′) wherein R^12ais 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 reacting a compound of formula (Ir),

P⁴—X_{16 (Ir)}

wherein P⁴is defined above and X₁₆is the radical having the following meaning

(d7″″)—HN—CH(R^12a—OH)—CH₂—O-(T′-Y-Q)

(d8″″)—O—CH₂—CH(R^2a—OH)—NH-(T′-Y-Q)

wherein R^12ais 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 Z₂, 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 P⁴and X₁₆are 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-1).

The compounds of formula (Ir) wherein T′ or T″′ are C(O), P⁴and X₁₆are as above defined are obtained as described in 4a-i), 4a-ii).

The compounds of formula (Ir) wherein T′ or T″′ are C(O)—X″, P⁴and X₁₆are as above defined, are obtained as described in 4b-i), 4b-ii).

4i) The compounds of formula (Im) wherein X₁₂is selected from (d7′) or (d8′) wherein R^12ais 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),

P⁴—X₁₆ (Ir)

wherein P⁴and X₁₆are as above defined and R^12ais 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 Z₂, 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 4l-ii) as above described.

The reaction of a compound of formula (Ir) P⁴and X₁₆are 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-1).

4l) The compounds of formula (Im) wherein X₁₂is selected from (d7′) or (d8′) wherein R^12ais 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
4l-i) by reacting a compound of formula (Ir),

P⁴—X₁₆ (Ir)

wherein P⁴and X₁₆are as above defined and R^12ais selected from D7), with a compound of formula (IVm)

Hal-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′, wherein Y′ is as above defined, and 4l-ii) when Q is Z₂, by converting the compounds obtained in the step 4l-i) into nitro derivative by reaction with a nitrate source such above described and 4l-iii) optionally deprotecting the compounds obtained in step 4l-i) or 4l-ii) as above described.

The reaction of a compound of formula (Ir) wherein P⁴and X₁₆are as above defined, with a compound of formula (IVm) wherein y, Q, R′ are as above defined, may be carried out as described in 1l-i).

4m) The compounds of formula (Im) wherein X₁₂is selected from (d7′) or (d8′) wherein R^12ais selected from D7), Q, Y and Y′ are as above defined, T″ is —O—CH(R′)—O—C(O)—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
4m-i) by reacting a compound of formula (Ir),

P⁴—X₁₆ (Ir)

wherein P⁴and X₁₆are as above defined and R^12ais selected from D7), with a compound of formula (IVo)

Hal-CH(R′)—O—(O)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 Z₂, 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 P⁴and X₁₆are 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 1l-i).

4n) The compounds of formula (Im) wherein X₁₂is selected from (d3′) or (d4′) wherein R^2ais 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 (IIIm),

P⁴—X₁₇ (IIIm)

wherein P⁴is defined above and X₁₇is the radical

(d3″′) —HN—CH(R¹²—OH)—CH₂OP¹

(d4″′) —O—CH₂—CH(R^2a—OH)—NHR^4a′

wherein R^12ais selected from D7), wherein P¹and 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 Z₂, 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 (IIIm) wherein P⁴and X₁₇are 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-1).

The compounds of formula (IIIm), wherein P⁴and X₁₇are as above defined, are commercially available or obtained as known in literature.

4o) The compounds of formula (Im) wherein X₁₂is selected from (d3′) or (d4′) wherein R^12ais 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 (IIIm),

P⁴—X₁₇ (IIIm)

wherein P⁴and X₁₇are as defined above, wherein R^12ais 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 (IIIm) wherein P⁴and X₁₇are as above defined, with a compound of formula (IVg) wherein R′, y, Q are as above defined, may be carried out as described in 1a-i).

4p) The compounds of formula (Im) wherein X₁₂is selected from (d3′) or (d4′) wherein R^12ais 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 (IIIm),

P⁴—X₁₇ (IIIm)

wherein P⁴and X₁₇are as defined above, wherein R^12ais selected from D7), with a compound of formula (IVm)

Hal-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′, 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 (IIIm) wherein P⁴and X₁₇are as above defined, with a compound of formula (IVm) wherein R′, y, Q are as above defined, may be carried out as described in 1l-i).

4q) The compounds of formula (Im) wherein X₁₂is selected from (d3′) or (d4′) wherein R^12ais selected from D7), Y′ is as above defined, T″ is —O—CH(R′)—O—C(O)—O— wherein R′ is as above defined, can be obtained
4q-i) by reacting a compound of formula (IIIm),

P⁴—X₁₇ (IIIm)

wherein P⁴and X₁₇are as defined above, wherein R^12ais selected from D7), with a compound of formula (IVo)

Hal-CH(R′)—O—(O)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 Z₂, 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 (IIIm) wherein P⁴and X₁₇are 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 1l-i).

5) The compounds of general formula (I) as above defined wherein a is equal to 0, R_Xis a radical selected from (d5), (d6), (d9) or (d10), wherein R^12bis selected from D10) can be obtained
5-i) by reacting a compound of formula (II₁) as above defined with a compound of formula (Is)

W—X₁₈ (Is)

wherein W is as above defined, X₁₈is the radical having the following meanings

(d5′) —R^12b—CH(NHR^4a)—CH₂—O-(T″′-Y-Q)

(d6′) —R^12b—CH(CH₂OH)—NH-(T′-Y-Q)

(d9′) —R^12b—CH(NH-T″′-Y′-Q)-CH₂—O-(T′-Y-Q)

(d10′) —R^12b—CH(CH₂—O-T″′-Y′-Q)-NH-(T′-Y-Q)

wherein R^12bis selected from D10), T′, T″′, Y, Y′ and Q are as above defined and
5-ii) when Q is Z₂, 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 X₁₁are as above defined may be carried out as described in 1).

5a) The compounds of formula (Is) wherein X₁₈is a radical of formula (d5′) or (d6′), wherein R^12bis selected from D10), T′ and T″′ are C(O) can be obtained
5a-i) by reacting a compound of formula (IIIn),

P²—X₁₉ (IIIn)

wherein P²is as above defined, X₁₉is the radical having the following meanings

(d5″) —R^12b—CH(NHP³)—CH₂—OH

(d6″) —R^12b—CH(CH₂OP¹)—NH₂

wherein P¹and P³are as above defined and R^12bis selected from D10), with a compound of formula (IVa)

W₁—C(O)-y-Q (IVa)

wherein W₁, y, Q are as above defined, y is the radical Y,
wherein Y is as above defined, and
5a-ii) when Q is Z₂, 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 (IIIn) wherein P²and X₁₉are as above defined, with a compound of formula (IVa) W₁, y, and Q are as above defined may be carried out as described in 1-i-1), 1-i-2), 1-i-3) and 1a-1).

The compounds of formula (IIIn), wherein P²and X₁₉are as above defined, are commercially available or obtained as known in literature.

5b) The compounds of formula (Is) wherein X₁₈is a radical of formula (d5′) or (d6′), wherein R¹²is selected from D10), T′ and T″′ are C(O)—X″, wherein X″ is defined above, can be obtained
5b-i) by reacting a compound of formula (IIIn),

P²—X₁₉ (IIIn)

wherein P²and X₁₉are as above defined, with a compound of formula (IVd)

R_a—O—C(O)—X″-y-Q (IVd)

wherein R_aand Q, X″ are as above defined, y is the radical Y,
wherein Y is as above defined, and
5b-ii) when Q is Z₂, 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 (IIIn) wherein P²and X₁₉are 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 X₁₈is a radical of formula (d9′), wherein R^12bis selected from D10), 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),

P²—X₂₀ (It)

wherein P²is as above defined and X₂₀is the radical having the following meanings

(d9″) —R¹²—CH(NH₂)—CH₂—O-(T″′-Y-Q)

wherein R^12bis selected from D10), T″′, Y and Q are as above defined, with a compound of formula (IVa)

W₁—C(O)-y-Q (IVa)

wherein W₁and Q are as above defined, y is the radical Y′,
wherein Y′ is as above defined, and
5c-ii) when Q is Z₂, 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 P²and X₂₀are as above defined, with a compound of formula (IVa) wherein W₁, y, Q are as above defined, may be carried out as described in 1-i-1), 1-i-2), 1-i-3) and 1a-1).

5d) The compounds of formula (Is) wherein X₁₈is a radical of formula (d9′), wherein R^12bis selected from D10), 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 (It),

P²—X₂₀ (It)

wherein P²and X₂₀are as above defined, with a compound of formula (IVd)

R_a—O—C(O)—X″-y-Q (IVd)

wherein R_aand 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 P²and X₂₀are 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 X₁₈is the radical of formula (d10′), wherein R^12bis selected from D10), 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),

P²—X₂₀ (It′)

wherein P²is as above defined and X_20′ is the radical having the following meaning

(d10″) —R^12b—CH(CH₂—OH)—NH-(T′-Y-Q)

wherein R^12bis selected from D10), T′, Y and Q are as above defined, with a compound of formula (IVa)

W₁—C(O)-y-Q (IVa)

wherein W₁and Q are as above defined, y is the radical Y′,
wherein Y′ is as above defined, and
5e-ii) when Q is Z₂, 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 P²and X_20′ are as above defined, with a compound of formula (IVa) wherein W₁, y, Q are as above defined, may be carried out as described in 1-i-1), 1-i-2), 1-i-3) and 1a-1).

5f) The compounds of formula (Is) wherein X₁₈is the radical of formula (d10′), wherein R^12bis selected from D10), 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′),

P²—X_20′ (It′)

wherein P²and X_20′ are as above defined, with a compound of formula (IVd)

R_a—O—C(O)—X″-y-Q (IVd)

wherein R_aand Q, X″ are as above defined, y is the radical Y′,
wherein Y′ is as above defined, and
5f-ii) when Q is Z₂, 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 P²and X_20′ 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_Xis a radical selected from (d5), is (d6), (d9) or (d10), wherein R^12bis selected from D10), Z is —CH(R′)—O—, wherein R′ is defined above, can be obtained
6-i) by reacting a compound of formula (II₁) as above defined with a compound of formula (Iu)

Hal-CH(R′)—O—X₂₁ (Iu)

wherein Hal is an halogen atom, R′ is as above defined and X₂₁is a radical selected from (d5′), (d6′), (d9′) or (d10′),
wherein R^12bis selected from D10), and
6-ii) when Q is Z₂, 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, X₂₁and R′ are as above defined, with a compound of formula (II₁) as above defined may be carried out as described in 1l-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—X₂₂ (IIIo)

wherein W is a chlorine atom, X₂₂is the radical having the following meanings

(d5″′) —R^12b—CH(NHP³)—CH₂—O-(T″′-Y-Q)

(d6″′) —R^12b—CH(CH₂OP¹)—NH-(T′-Y-Q)

(d9″′) —R^12b—CH(NH-T′-Y′-Q)-CH₂—O-(T″′-Y-Q)

(d10″′) —R^12b—CH(CH₂—O-T″′-Y′-Q)-NH-(T′-Y-Q)

wherein R^12b, P³, P¹, T′, T″′, Y′, Y and Q are as above defined, and ZnCl₂as known in literature.

The compounds of formula (IIIo), wherein W and X₂₂are 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_Xis a radical selected from (d5), (d6), (d9) or (d10), wherein R^12bis 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_ais as above defined with a compound of formula (Iv)

H—X₂₃ (Iv)

wherein X₂₃is a radical selected from (d5′), (d6′), (d9′) or (d10′), wherein R^12bis selected from D8) or D9), and
7-ii) when Q is Z₂, 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 X₂₃and is as above defined, with a compound of formula (II₃) as above defined may be carried out as described in 1l-i).

8) The compounds of general formula (I) as above defined wherein a is equal to 0, R_xis a radical selected from (a5), (a6), (a9) or (a10), (b5), (b6), (b9) or (b10) wherein R^1bis selected from A10) and R^2bis selected from B10), can be obtained
8-i) by reacting a compound of formula (II₁) as above defined with a compound of formula (Iz)

W—X₂₄ (Iz)

wherein W is as above defined, X₂₄is the radical R_Xhaving the following meanings

(a5′) —R^1b—CH(NHR^4a)—C(O)-(T-Y-Q)

(a6′) —R^1b—CH(COOR^3a)NH-(T′-Y-Q)

(a9′) —R^1b—CH(NH-T′-Y′-Q)-C(O)-(T-Y-Q)

(a10′) —R^1b—CH(C(O)-T′-Y′-Q)-NH-(T-Y-Q)

(b5′) —R^2b—CH(NHR^4a)—CH₂C(O)-(T-Y-Q)

(b6′) —R^2b—CH(CH₂COOR^3a)NH-(T′-Y-Q)

(b9′) —R^2b—CH(NH-T′-Y′-Q)-CH₂C(O)-(T-Y-Q)

(b10′) —R^2b—CH(CH₂C(O)-T′-Y′-Q)-NH-(T-Y-Q)

wherein R^1bis selected from A10), R^2bis selected from B10), T, T′, Y and Q are as above defined and
8-ii) when Q is Z₂, 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 (II₁) as above defined wherein R is as above defined, with a compound of formula (Iv) wherein W and X₂₄are as above defined may be carried out as described in 1).

8a) The compounds of formula (Iz) wherein X₂₄is a radical of formula (a5′), (a6′), (b5′) or (b6′), wherein R^1bis selected from A10) and R^2bis selected from B10), T and T′ are C(O) can be obtained
8a-i) by reacting a compound of formula (IIIq),

P²—X₂₅ (IIIq)

wherein P²is as above defined, X₂₅is the radical having the following meanings

(a5″) —R^1b—CH(NHP³)—C(O)—OH

(a6″) —R^1b—CH(COOP²)—NH₂

(b5″) —R^2b—CH(NHP³)—CH₂C(O)—OH

(b6″) —R^2b—CH(CH₂COOP²)NH₂

wherein P²and P³are as above defined and R^1bis selected from A10), R^2bis selected from B10), with a compound of formula (IVa)

W₁—C(O)-y-Q (IVa)

wherein W₁and Q are as above defined, y is the radical Y,
wherein Y is as above defined, and
8a-ii) when Q is Z₂, 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 (IIIq) wherein P²and X₂₅are as above defined, with a compound of formula (IVa) W₁, Y, and Q are as above defined may be carried out as described in 1-i-1), 1-i-2), 1-i-3) and 1a-1).

The compounds of formula (IIIq), wherein P²and X₂₅are as above defined, are commercially available or obtained as known in literature.

8b) The compounds of formula (Iz) wherein X₂₄is the radical of formula (a5′), (a6′), (b5′) or (b6′), wherein R^1bis selected from A10) and R^2bis selected from B10), T and T′ are C(O)—X″, wherein X″ is defined above, can be obtained
8b-i) by reacting a compound of formula (IIIq),

P²—X₂₅ (IIIq)

wherein P²and X₂₅are as above defined, with a compound of formula (IVd)

R_a—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 Z₂, 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 (IIIq) wherein P²and X₂₅are 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 X₂₄is the radical of formula (a9′) or (b9′) wherein R^1bis selected from A10), and R^2bis selected from B10) 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),

P²—X₂₆ (Iy)

wherein P²is as above defined and X₂₆is the radical having the following meanings

(a9″) —R^1b—CH(NH₂)—C(O)-(T-Y-Q)

(b9″) —R^2b—CH(NH₂)—CH₂C(O)-(T-Y-Q)

wherein R^1bis selected from A10) and R^2bis selected from B10), with a compound of formula (IVa)

W₁—C(O)-y-Q (IVa)

wherein W₁and Q are as above defined, y is the radical Y′,
wherein Y′ is as above defined, and
8c-ii) when Q is Z₂, 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 P²and X₂₆are as above defined, with a compound of formula (IVa) wherein W₁, y, Q are as above defined, may be carried out as described in 1-i-1), 1-i-2), 1-i-3) and 1a-1).

8d) The compounds of formula (Iz) wherein X₂₄is the radical of formula (a9′) or (b9′) wherein R^1bis selected from A10), R^2bis selected from B10), 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),

P²—X₂₆ (Iy)

wherein P²and X₂₆are as above defined, with a compound of formula (IVd)

R_a—O—C(O)—X″-y-Q (IVd)

wherein R_aand X″ are as above defined, y is the radical Y′,
wherein Y′ is as above defined, and
8d-ii) when Q is Z₂, 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 P²and X₂₀is 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 X₂₄is the radical of formula (a10′) or (b10′) wherein R^1bis selected from A10), and R^2bis selected from B10) 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′),

P²—X₂₆ (Iy′)

wherein P²is as above defined and X₂₆is the radical having the following meanings

(a10″) —R^1b—CH(C(O)—OH)—NH-(T-Y-Q)

(b10″) —R^2b—CH(CH₂C(O)—OH)—NH-(T-Y-Q)

wherein R^1bis selected from selected from A10) and R^2bis B10), with a compound of formula (IVa)

W₁—C(O)-y-Q (IVa)

wherein W₁and Q are as above defined, y is the radical Y′,
wherein Y′ is as above defined, and
8e-ii) when Q is Z₂, 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 P²and X_26′ are as above defined, with a compound of formula (IVa) wherein W₁, y, Q are as above defined, may be carried out as described in 1-i-1), 1-i-2), 1-i-3) and 1a-1).

8f) The compounds of formula (Iz) wherein X₂₄is the radical of formula (a10′) or (b10′) wherein R^1bis selected from A10), and R^2bis selected from B10), 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′),

P²—X_26′ (Iy′)

wherein P²and X_26′ are as above defined, with a compound of formula (IVd)

R_a—O—C(O)—X″-y-Q (IVd)

wherein R_aand X″ are as above defined, y is the radical Y′,
wherein Y′ is as above defined, and
8f-ii) when Q is Z₂, 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 P²and X₂₆are 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_Xis a radical selected from (a5), (a6), (a9) or (a10), (b5), (b6), (b9) or (b10) wherein R^1bis selected from A8) or A9), R^2bis 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—X₂₇ (Ix)

wherein X₂₇is the radical selected from (a5′), (a6′), (a9′), (a10′), (b5′), (b6′), (b9′) or (b10′), wherein R^1bis selected from A8) or A9), R^2bis selected from B8) or B9), and
9-ii) when Q is Z₂, 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 X₂₇and is as above defined, with a compound of formula (II₃) may be carried out as described in 1l-i).

EXAMPLE 1 Synthesis of (11β,16β)-9-Chloro-11,17-dihydroxy-16-methyl-21-[1-oxo-((2-(4-(nitrooxy)butyloxy-carbonylamino)acetyl)]-pregna-1,4-diene-3,20-dione

(11β,16β)-9-Chloro-11,17-dihydroxy-16-methyl-21-[1-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° 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 (50×3 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.

(11β,16β)-9-Chloro-11,17-dihydroxy-16-methyl-21-[1-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.

(11β,16β)-9-Chloro-11,17-dihydroxy-16-methyl-21-[1-oxo-(2-((4-(nitrooxy)butoxy-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-nitrooxybutyric 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 H₃PO₄(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™ KP-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.

¹H-NMR: (DMSO), δ: 8.42 (1H, t); 7.30 (1H, d); 6.22 (1H, dd); 5.98 (1H, s); 5.46 (1H, d); 5.42 (2H, s); 5.05 (1H, d); 4.84 (1H, d); 4.5 (2H, t); 4.34 (1H, 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).

Claims

1. Nitric oxide releasing compounds of general formula (I) 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:

R-(Z)a-RX (I)

a is 0 or 1,

Z is a group capable of binding RX and is selected from —C(O)—, or —CH(R′)—O— wherein

R′ is selected from H or a straight or branched C1-C4 alkyl, preferably R′ is H or —CH3;

Rx is a radical selected from the following meanings:

A) (a1) —HN—CH(R1)—C(O)-(T-Y—ONO2) (a2) —C(O)—CH(R1)—NH-(T′-Y—ONO2) (a3) —HN—CH(R1a-T″-Y′—ONO2)COOR3a (a4) —C(O)—CH(R1a-T″-Y—ONO2)—NHR4a (a5) —R1b—CH(NHR4a)—C(O)-(T-Y—ONO2) (a6) —R1b—CH(COOR3a)NH-(T′-Y—ONO2) (a7) —HN—CH(R1a-T″-Y′—ONO2)—C(O)-(T-Y—ONO2) (a8) —C(O)—CH(R1a-T″-Y′—ONO2)—NH-(T′-Y—ONO2) (a9) —R1b—CH(NH-T′-Y′—ONO2)—(O)-(T-Y—ONO2) (a10) —R1b—CH(C(O)-T-Y′—ONO2)—NH-(T′-Y—ONO2) wherein: R1 is selected from: A1) H, —CH3, isopropyl, isobutyl, sec-butyl, tert-butyl, methylthio-(CH2)2—, phenyl, benzyl, C6H5—CH2—CH2—, 2-monosubstituted benzyl, or 3-monosubstituted benzyl or 4-monosubstituted benzyl wherein the substituent of the benzyl is selected from —F, —Cl, I, —NO2, —CF3, —CH3, CN, C6H5CO—, 2,4-dichlorobenzyl, 3,4-dichlorobenzyl, 3,4-difluorobenzyl, 2-pyrrolidyl, 3-triptophanyl-CH2—, 3-benzothienyl-CH2—, 4-imidazolyl-CH2—, 9-anthranyl-CH2—, cyclohexyl, cyclohexyl-CH2—, cyclohexyl-(CH2)2—, cyclopentyl-CH2—, (C6H5)2CH—, 4-B(OH)2-benzyl, 4-quinolyl-CH2—, 3-quinolyl-CH2—, 2-quinolyl-CH2—, 2-quinoxalyl-CH2—, 2-furyl-CH2—, 1-naphtyl-CH2—, 2-naphtyl-CH2—, 2-pyridyl-CH2—, 3-pyridyl-CH2—, 4-pyridyl-CH2—, 2-thienyl-CH2—, 3-thienyl-ClF2—, C6H4—CH═CH—CH2—, CH2═CH—CH2—, CH═CH—CH2—, NH2—CO—CH2—, NH2—CO—(CH2)2—, NH2(═NH)NH—(CH2)3—, P(═O)(OCH3)2; A2) —CH2—SH, —CH2—OH, —CH(CH3)—OH, —OCH2—[(C6H4)-(4-OH)], —CH2—[(C6H2)-(3,5-diiodo)-(4-OH)], —CH2—[(C6H3)-(3-nitro)-(4-OH)], A3) —CH2—NHR″, —(CH2)2—NHR″, —(CH2)3—NHR″, —(CH2)4—NHR″, wherein R″ is H, —C(O)CH3 or

wherein R5a is H or a linear or branched C1-C10 alkyl chain, A4) —CH2—C(O)R″′, —(CH2)2—C(O)R″′, —(CH2)4—C(O)R″′ wherein R″′ is —OR5a or

wherein R5a is as above defined; R1a is selected from, A5) —CH2—S—, —CH2—O—, —CH(CH3)—O—, —CH2[(C6H4)-(4-O)—], —CH2-[(3,5-diiodo)-(C6H2)-(4-O)—], —CH2-[(3-nitro)-(C6H3)-(4-O)—], A6) —CH2—NH—, —(CH2)2—NH—, —(CF12)3—NH—, —(CH2)4—NH—, A7) —CH2—C(O)—, —(CH2)2—C(O), —(CH2)4—C(O)—; R3a is selected from H, —R5a or

wherein R5a is as above defined, R4a is selected from H or —C(O)CH3 or

wherein R5a is as above defined, R1b is selected from A8) —S—CH2—, —O—CH(CH3)—, —O—CH2—, [-(4-O)—(C6H4)]—CH2—, [-(4-O)-(3,5-diiodo)-(C6H2)]—CH2—, [-(4-O)-(3-nitro)-(C6H3)]—CH2—, A9) —HN—CH2—, —HN—(CH2)2—, —HN—(CH2)3—, —HN—(CH2)4—, A10) —C(O)—CH2—, —C(O)—(CH2)2—, —C(O)—(CH2)4—,

T is selected from —O—, —S—, NR′—, —O—CH(R′)—O—C(O)— or

—O—CH(R′)—O—C(O)O— wherein R′ is as above defined,

T′ is —C(O)—, —C(O)—X″— wherein X″ is —O— or —S—, or T′ is

—C(O)—NR′— wherein R′ is as above defined,

T″ is independently selected from —C(O)—, —C(O)—X″—,

—C(O)—NR′—, —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)—,

—O—CH(R′)—O—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—, —O—, or —S—, or

T″ is —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)—, —O—CH(R′)—O—C(O)O— when T″ is linked to —C(O)—,

Y and Y′ are as below defined;

or Rx is selected from:

B) (b1) —HN—CH(R2)—CH2—C(O)-(T-Y—ONO2) (b2) —C(O)—CH2—CH(R2)—NH-(T′-Y—ONO2) (b3) —HN—CH(R2a-T″-Y′—ONO2)—CH2COOR3a (b4) —C(O)—CH2—CH(R2a-T″-Y′—ONO2)—NHR4a (b5) —R2b—CH(NHR4a)—CH2—C(O)-(T-Y—ONO2) (b6) —R2b—CH(CH2COOR3a)NH-(T-Y—ONO2) (b7) —HN—CH(R2a-T″-Y′—ONO2)—CH2—C(O)-(T-Y—ONO2) (b8) —C(O)CH2—CH(R2a-T″Y′—ONO2)—NH-(T′-Y—ONO2) (b9) —R2b—CH(NH-T′-Y′—ONO2)—CH2C(O)-(T′-Y—ONO2) (b10) —R2b—CH(CH2C(O)-T-Y′—ONO2)—NH-(T′-Y—ONO2) wherein

R2 is selected from B1) H, —CH3, CF3, isopropyl, isobutyl, sec-butyl, methylthio-(CH2)2—, phenyl, benzyl, 3-triptophanyl-CH2—, NH2—C(O)—CH2—, NH2—C(O)—(CH2)2—, NH2(═NH)NH—(CH2)3—, tBuO—CH(CH3)—, benzyl-O—CH2—, 4-terbutoxy-benzyl, 4-phenylbenzyl, B2) —CH2—SH, —CH2—OH, —CH(CH3)—OH, —CH2—[(C6H4)-(4-OH)], —CH2—[(C6H2)-(3,5-diiodo)-(4-OH)], —CH2—[(C6H3)-(3-nitro)-(4-OH)], B3) —CH2—NHR″, —(CH2)2—NHR″, —(CH2)3—NHR″, —(CH2)4—NHR″, wherein R″ is as above defined, B4) —CH2—C(O)—R″′, —(CH2)2—C(O)R″′, —(CH2)4—C(O)—R″′ wherein R″′ is as above defined, preferably R2 is —CH2—C(O)—R″′;

R2a is selected from: B5) —CH2—S—, —CH2—O—, —CH(CH3)O— or —CH2—[(C6H4)-(4-O)—], —CH2-[(3,5-diiodo)-(C6H12)-(4-O)—], —CH2-[(3-nitro)-(C6H3)-(4-O)—], B6) —CH2—NH—, —(CH2)2—NH—, —(CH2)3—NH—, —(CH2)4—NH—, B7) —CH2—C(O)—, —(CH2)2—C(O)—, —(CH2)4—C(O)—,

R2b is selected from. B8) —S—CH2—, —O—CH(CH3)—, —O—CH2—, [-(4-O)—(C6H4)]—CH2—, [-(4-O)-(3,5-diiodo)-(C6H2)]—CH2—, [-(4-O)-(3-nitro)-(C6H3)]—CH2, B9) —HN—CH2—, —HN—(CH2)2—, —HN—(CH2)3—, —HN—(CH2)4—, B10) —C(O)—CH2—, —C(O)—(CH2)2—, C(O)—(CH2)4—,

R3a and R4a are as above defined,

T, T′ and T″ are as above defined and Y and Y′ are as below defined;

or Rx is selected from:

C)

(c1) —HN—(CH2)b—C(O)-(T′-Y—ONO2) or

(c2) —C(O)—(CH2)b—NH-(T′-Y—ONO2)

wherein b is an integer from 3 to 6,

T and T′ are as above defined and Y and Y′ are as below defined;

or Rx is selected from:

D)

(d1) —HN—CH(R12)—CH2—O-(T″′-Y—ONO2)

(d2) —O—CH2—CH(R12)—NH-(T′-Y—ONO2)

(d3) —HN—CH(R12a-T″-Y′—ONO2)—CH2OH

(d4) —O—CH2—CH(R12a-T″-Y′—ONO2)—NHR4a

(d5) —R12b—CH(NHR4a)—CH2—O-(T″′-Y—ONO2)

(d6) —R12b—CH(CH2OH)—NH-(T′-Y—ONO2)

(d7) —HN—CH(R12a-T″-Y′—ONO2)—CH2—O-(T″′-Y—ONO2)

(d8) —O—CH2—CH(R12a-T″-Y′—ONO2)—NH-(T′-Y—ONO2)

(d9) —R12b—CH(NH-T′-Y′—ONO2)—CH2—O-(T″′-Y—ONO2) or

(d10) —R12b—CH(CH2—O-T″′-Y′—ONO2)—NH-(T′-Y—ONO2)

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,

R12 is selected from: D1) H, —CH3, isopropyl, isobutyl, sec-butyl, methylthio-(CH2)2—, benzyl, 3-triptophanyl-CH2—, 4-imidazolyl-CH2—, NH2—CO—CH2—, NH2—CO—(CH2)2—, NH2(═NH)NH—(CH2)3—; D2) —CH2—OH, —CH(CH3)—OH, —CH2—[(C6H4)-(4-OH)], —CH2—[(C6H3)-(3,5-diiodo)-(4-OH)], —CH2—[(C6H3)-(3-nitro)-(4-OH)], D3) —CH2—NHR″, —(CH2)2—NHR″, —(CH2)3—NHR″, —(CH2)4—NHR″, wherein R″ is as above defined, preferably R12 is —(CH2)4—NHR″; D4) —CH2—C(O)R″′, —(CH2)2—C(O)R″′, (CH2)4—C(O)R″′ wherein R″′ is as above defined,

R12a is selected from: D5) —CH2—O—, —CH(CH3)—O— or —CH2—[(C6H4)-(4-O)—], —CH2-[3,5-diiodo-(C6H2)-(4-O)—], —CH2-[3-nitro-(C6H3)-4-O—], D6) —CH2—NH—, —(CH2)2—NH—, —(CH2)3—NH—, —(CH2)4—NH—, D7) —CH2—C(O)—, —(CH2)2—C(O)—, —(CH2)4—O(O)—,

R12b is selected from: D8) —O—CH2—, —O—CH(CH3)—, [-(4-O) (C6H4)]—CH2—, [-(4-O)-(3,5-diiodo)-(C6H2)]—CH2, [-(4-O)-(3-nitro)-(C6H3)]—CH2—, D9) —HN—CH2—, —HN—(CH2)2—, —HN—(CH2)3—, —HN—(CH2)4—, D10) —C(O)—CH2—, —C(O)—(CH2)2—, —C(O)—(CH2)4—,

R4a is as above defined;

or RX 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 R3 is H, CH3, propyl, (C6H5)2CH—, 1-naphtyl-CH2—, benzyl, allyl, 2-bromobenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-fluorobenzyl, 4-bromobenzyl, 4-methylbenzyl, T and T′ are as above defined and Y is as below defined;

H)

wherein R4 is H, benzyl, 4-bromobenzyl, 2-bromobenzyl, T and T′ are as above defined and Y is as below defined;

I)

wherein R5 is H, R6 is H, or R5 and R6 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 reported;

N)

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;

O)

wherein R7 is H, R8 is H, or R7 and R8 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 R9 and R10 are H, CH3, R11 is CH3 or 4-piperidinyl with the proviso that R9 and R10 are H when R11 is 4-piperidinyl and R9 and R10 are CH3 when R11 is CH3, 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 0 or a is 1 and Z is CH(R′)—O— wherein R′ is as above defined, when Rx is: (a2), (a4) or (a8); (a5), (a6), (a9) or (a10) and R1b is selected from the group A10); (b2), (b4) or (b8); (b5), (b6), (b9) or (b10) and R2b is selected from the group B10); (c2); (d5), (d6), (d9) or (d10) and R12b is selected from the group D10); (e2), (f1), (g2), (h1), (i1), (l2), (m2), (n2), (o2), (p2), (q2), (r2), (s2), (t1) or (u2);

a is 1 and Z is —C(O)—, when Rx is: (a1), (a3) or (a7); (a5), (a6), (a9) or (a10) and R1b is selected from the groups A8) and A9); (b1), (b3) or (b7); (b5), (b6), (b9) or (b10) and R2b is selected from the groups B8) or B9); (c1); (d1), (d2), (d3), (d4), (d7) or (d8); (d5), (d6), (d9) or (d10) and R12b is selected from the groups D8) or D9); (e1), (f2), (g1), (h2), (i2), (l1), (m1), (n1), (o1), (p1), (q1), (r1), (s1), (t2) or (u1).

Y and Y′ are bivalent radicals each independently selected from the following meanings:

a) straight or branched C1-C20 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 T2, wherein T2 is —OC(O)(C1-C10 alkyl)-ONO2 or —O(C1-C10 alkyl)-ONO2; 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;

b)

wherein

n0 is an integer from 0 to 20;

n1 is 0 or 1;

U is a linear or branched C1-C20 alkylene optionally substituted with a —ONO2 group;

c)

wherein

n0 is an integer from 0 to 20;

n1 is 0 or 1;

U is a linear or branched C1-C20 alkylene optionally substituted with a —ONO2 group;

d)

wherein:

n2 is an integer from 0 to 2, R13 is H or CH3, T1 is —O—C(O)— or —C(O)O—;

n1 and U are as above defined;

e)

n2 is an integer from 0 to 2,

R13 is H or CH3,

Y1 is —CH2—CH2— or —CH═CH—(CH2)n2′—, wherein n2′ is 0 or 1,

T1=—O—C(O)— or —C(O)O—,

n1 is 0 or 1, preferably n1 is 1,

U is a linear or branched C1-C20 alkylene optionally substituted with a —ONO2 group;

e′)

wherein:

n2 is an integer from 0 to 2,

R13 is H or CH3,

Y1 is —CH2—CH2— or (CH2)n2′—CH═CH—, wherein n2′ is 0 or 1,

(T1)′=—O—C(O)—;

n1 is 0 or 1,

U is a linear or branched C1-C20 alkylene optionally substituted with a —ONO2 group;

f)

wherein T2 is —O— or —S—, —NH—, preferably T2 is —O—, n3 is an integer from 1 to 6;

when Y and Y′ are selected from b), c), d), e), e′) or f), the —ONO2 group of -(T-Y—ONO2), -(T′-Y—ONO2), -(T″-Y′—ONO2), -(T′-Y′—ONO2), -(T″′-Y—ONO2) and -(T″′-Y′—ONO2) is linked to the —(CH2)*— group;

g)

wherein:

n4 is an integer from 0 to 10,

n5 is an integer from 1 to 10,

R14, R15, R16, R17 are the same or different, and are H or straight or branched C1-C4 alkyl,

wherein the —ONO2 group is linked to

wherein n5 is as defined above;

Y2 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:

2. The nitric oxide releasing compounds according to claim 1 wherein

a is 1 and Z is —C(O)—;

RX is

(a1) —HN—CH(R1)—C(O)-(T-Y—ONO2)

wherein

R1 of the group A1) is selected from H, isobutyl, benzyl,

C6H5—CH2—CH2—, 2-monosubstituted benzyl, or 3-monosubstituted benzyl or 4-monosubstituted benzyl wherein the substituent of the benzyl is selected from —F, —Cl, I, —NO2, —CF3, —CH3, CN, C6H5CO— or

R1 of the group A2) is selected from —CH2—OH, —CH(CH3)—OH— or —CH2—[(C6H4)-(4-OH)], or

R1 of the group A3) is selected from —CH2—NHR″, —(CH2)2—NHR″,

—(CH2)3—NHR″, —(CH2)4—NHR″, wherein R″ is H, or —C(O)CH3,

R1 of the group A4) is —CH2—C(O)R″′, —(CH2)2—C(O)R″′,

—(CH2)4—C(O)R″′ wherein R″′ is OR5a wherein R5a is H or a linear (C1-C5) alkyl,

T is —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)— wherein R′ is H or a straight or branched C1-C4 alkyl,

Y is as below defined;

or RX is

(a3) —HN—CH(R1a-T″-Y′—ONO2)—COOR3a

wherein

R1a of the group A5) is selected from —CH2—O—, —CH(CH3)O— or

—CH2—[(C6H4)-(4-O)—], or

R1a of the group A6) is selected from —CH2—NH—, —(CH2)2—NH—,

—(CH2)3—NH—, —(CH2)4—NH—, or

R1a of the group A7) is —CH2—C(O)—, —(CH2)2—C(O)—, —(CH2)4—C(O)—,

R3a is H or a (C1-C5) alkyl,

T″ is —C(O)— or —C(O)—X″ wherein X″ is S— or —O—, when R1a is selected from the group A5) or A6),

T″ is —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)— wherein R′ is H or a straight or branched C1-C4 alkyl, when R1a is selected from the group A7),

Y′ is as below defined;

or RX is selected from:

(a5) —R1b—CH(NHR4a)—C(O)-(T-Y—ONO2)

(a6) —R1b—CH(COOR3a)NH-(T′-Y—ONO2)

(a9) —R1b—CH(NH-T′-Y′—ONO2)—C(O)-(T-Y—ONO2) or

(a10) —R1b—CH(C(O)-T-Y′—ONO2)—NH-(T′-Y—ONO2)

wherein

R1b of the group A8) is selected from —O—CH(CH3)—, —O—CH2—,

[-4-O)—(C6H4)]—CH2—, or

R1b of the group A9) is selected from —HN—CH2—, —HN—(CH2)2—,

—HN—(CH2)3—, —HN—(CH2)4,

R1b of the group A10) is —O—CH2 or [-4-O—(C6H4)]—CH2—,

R3a is H or a (C1-C5) alkyl,

R4a is H or —C(O)CH3,

T is —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)— wherein R′ is H or a straight or branched C1-C4 alkyl,

T′ is —C(O)— or —C(O)—X″ wherein X″ is —S— or —O—,

Y and Y′ are as below defined;

or RX is

(a7) —HN—CH(R1a-T″-Y′—ONO2)—C(O)-(T-Y—ONO2)

wherein

R1a of the group A5) is selected from —CH2—O—, —CH(CH3)—O— or

—CH2—[(C6H4)-(4-O)—], or

R1a of the group A6) is selected from —CH2—NH—, —(CH2)2—NH—,

—(CH2)3—NH—, —(CH2)4—NH—, or

R1a of the group A7) is —CH2—C(O)—, —(CH2)2—C(O)—, —(CH2)4—C(O)—,

T″ is —C(O)— or —C(O)—X″ wherein X″ is —S— or —O—, when R1a is selected from A5) or A6);

T″ is —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)— wherein R′ is H or a straight or branched C1-C4 alkyl, when R1a is selected from A7),

T is —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)— wherein R′ is H or a straight or branched C1-C4 alkyl,

Y and Y′ are as below defined;

or RX is

(b1) —HN—CH(R2)—CH2C(O)-(T-Y—ONO2)

wherein

R2 of the group B1) is selected from H, CH3, isobutyl, isopropyl, benzyl,

R2 of the group B2) is selected from —CH2—OH, —CH(CH3)—OH— or

—CH2—[(C6H4)(4-OH)], or

R2 of the group B3) is selected from —CH2—NHR″, —(CH2)2—NHR″,

—(CH2)3—NHR″, —(CH2)4—NHR″, wherein R″ is H, or —C(O)CH3,

R2 of the group B4) is —CH2—C(O)R″′, —(CH2)2—C(O)R″′,

—(CH2)4—C(O)R″′ wherein R″′ is OR5a wherein R5a is H or a linear (C1-C5) alkyl,

T is —O—, —S—, —NR′—, —O—CH(R′)O—C(O)— wherein R′ is H or a straight or branched C1-C4 alkyl,

Y is as below defined;

or RX is selected from

(d1) —HN—CH(R2)—CH2O-(T″′-Y—ONO2) or

(d2) —O—CH2—CH(R12)—NH-(T′-Y—ONO2)

wherein

R12 of the group D1) is selected from H, CH3, isobutyl, isopropyl, benzyl, or

R12 of the group D2) is selected from —CH2—OH, —CH(CH3)OH— or

—CH2—[(C6H4)-(4-OH)], or

R12 of the group D3) is selected from —CH2—NHR″, —(CH2)2—NHR″,

—(CH2)3—NHR″, —(CH2)4—NHR″ wherein R″ is H, or

R12 of the group D4) is CH2—C(O)R″′, —(CH2)2—C(O)R″′,

—(CH2)4—C(O)R″′ wherein R″′ is OR5a wherein R5a is H or a linear (C1-C5) alkyl,

T′ and T″′ are each independently selected from —C(O)— or

—C(O)—X″ wherein X″ is —S— or —O—,

Y is as below defined;

or RX is selected from:

(d3) —HN—CH(R12a-T″-Y′—ONO2)—CH2OH

(d4) —O—CH2—CH(R12a-T″-Y—ONO2)—NHR4a

(d7) —HN—CH(R12a-T″-Y′—ONO2)—CH2—O-(T″′-Y—ONO2) or

(d8) —O—CH2—CH(R12a-T″-Y′—ONO2)—NH-(T′-Y—ONO2)

wherein

R12a of the group D5) is selected from —CH2—O—, —CH(CH3)—O— or

—CH2—[(C6H4)-(4-O)—], or

R12a of the group D6) is selected from —CH2—NH—, —(CH2)2—NH—,

—(CH2)3—NH—, —(CH2)4—NH—, or

R12a of the group D7) is —CH2—C(O)—, —(CH2)2—C(O)—, —(CH2)4—C(O)—,

R4a is H or —C(O)CH3,

T″ is selected from C(O)— or —C(O)—X″ wherein X″ is —S— or —O— when R12a is selected from D5) or D6),

T″ is —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)— wherein R′ is H or a straight or branched C1-C4 alkyl when R12a is selected from D7),

T″′ is selected from —C(O) or —C(O)—X″ wherein X″ is —S— or —O—,

Y and Y′ are as below defined;

or RX is selected from:

(d5) —R12b—CH(NHR4a)—CH2—O-(T″-Y—ON)2)

(d6) —R12b—CH(CH2O)—NH-(T′-Y—ONO2)

(d9) —R12b—CH(NH-T′-Y′—ONO2)—CH2—O-(T″-Y—ONO2) or

(d10) —R12b—CH(CH2—O-T″′-Y′—ONO2)—NH-(T′-Y—ONO2)

wherein

R12b of the group D8) is selected from —O—CH(CH3)—, —O—CH2—,

[-4-O—(C6H4)]—CH2—, or

R12b of the group D9) is selected from —HN—CH2—, —HN—(CH2)2—,

—HN—(CH2)3—, —HN—(CH2)4—,

R4, is H or —C(O)—CH3,

T′ and T″′ are each independently selected from —C(O)—,

—C(O)—X″, wherein X″ is —S— or —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 —ONO2 group;

d)

wherein:

n is an integer from 0 to 2, R13 is H or CH3, T1 is —O—C(O)— or —C(O)O—,

n1 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)

n2 is 1, R13 is CH3, Y1 is —CH═CH—(CH2)n2′— and n2′ is 0,

T1 is —C(O)O— and U is a linear C1-C10 alkylene;

e′)

wherein:

n2 is 1, R13 is CH3,

Y′ is —(CH2)n2′—CH═CH— and n2′ is 0,

(T1)′=—C(O)—,

n1 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;

f)

wherein T2 is —O— or —S—, —NH— and n3 is 1 or 2,

when Y and Y′ are selected from d), e), e′) or f), the —ONO2 group of -(T-Y—ONO2), -(T′-Y—ONO2), -(T″-Y′—ONO2), -(T′-Y′—ONO2), -(T″′-Y—ONO2) and -(T″′-Y′—ONO2) is linked to the —(CH2)*— group.

3. The nitric oxide releasing compounds according to claim 2 wherein RX is

(a5) —R1b—CH(NHR4a)—C(O)(T-Y—ONO2) or

(a9) —R1b—CH(NH-T′-Y′—ONO2)—C(O)-(T-Y—ONO2)

R1b of the group A10) is —O—CH2— or [-(4-O)—(C6H4)]—CH2—,

R4a is H or —C(O)CH3,

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 C1-C10 alkylene,

a straight or branched C1-C10 alkylene substituted with a —ONO2 group.

4. The nitric oxide releasing compounds according to claim 1 wherein a is 0 and

RX is

(a2) —C(O)—CH(R1)—NH-(T′-Y—ONO2)

wherein

R1 of the group A1) is selected from H, isobutyl, benzyl,

C6H5—CH2—CH2—, 2-monosubstituted benzyl, or 3-monosubstituted benzyl or 4-monosubstituted benzyl wherein the substituent of the benzyl is selected from —F, —Cl, I, —NO2, —CF3, —CH3, CN, C6H5CO—,

R1 of the group A2) is selected from —CH2—OH, —CH(CH3)OH— or

—CH2—[(C6H4)-(4-OH)], or

R1 of the group A3) is selected from CH2—NHR″, —(CH2)2—NHR″,

—(CH2)3—NHR″, —(CH2)4—NHR″, wherein R″ is H, or —C(O)CH3,

R1 of the group A4) is selected from —CH2—C(O)R″′,

—(CH2)2—C(O)R″′, —(CH2)4—C(O)R″′ wherein R″′ is OR5a wherein R5a is H or a linear (C1-C5) alkyl,

T′ is —C(O)—, —C(O)—X1 wherein X″ is —S— or —O—,

Y is as below defined;

or RX is

(a4) —C(O)—CH(R1a-T″-Y′—ONO2)—NHR4a

wherein R1a of the group A5) is selected from —CH2—O—, —CH(CH3)O— or —CH2—[(C6H4)-(4-O)—], or

R1a of the group A6) is selected from —CH2—NH—, —(CH2)2—NH—, —(CH2)3—NH—, —(CH2)4—NH—, or

R1a of the group A7) is selected from CH2—C(O)—, —(CH2)2—C(O)—, —(CH2)4—C(O)—;

R4a is H or —C(O)CH3,

T″ is —C(O)— or —C(O)—X″ wherein X″ is —S— or —O— when R1a is selected from the group A5) or A6),

T″ is —O—, —S—, —NR′— or —O—CH(R′)—O—C(O)— wherein R′ is H or —CH3 when R1a is selected from the group A7),

Y′ is as below defined;

or RX is selected from:

(a5) —R1b—CH(NHR4a)—C(O)-(T-Y—ONO2)

(a6) —R1b—CH(COOR3a)NH-(T′-Y—ONO2)

(a9) —R1b—CH(NH-T′-Y′—ONO2)—C(O)-(T-Y—ONO2) or

(a10) —R1b—CH(C(O)-T-Y′—ONO2)—NH-(T′-Y—ONO2)

wherein

R1b of the group A10) is selected from —C(O)—CH2—, —C(O)—(CH2)2—, —C(O)—(CH2)4—,

R3a is H or a (C1-C5) alkyl,

R4a is H or —C(O)CH3,

T is —O—, —S—, —NR′— or —O—CH(R′)OC(O)— wherein R′ is H or

—CH3,

T′ is —C(O)— or —C(O)—X″ wherein X″ is —S— or —O—,

Y and Y′ are as below defined;

or RX is

(a8) —C(O)—CH(R1a-T″-Y′—ONO2)—NH-(T′-Y—ONO2)

wherein

R1a of the group A5) is selected from −CH2—O—, —CH(CH3)—O— or

—CH2—[(C6H4)-(4-O)—], or

R1a of the group A6) is selected from —CH2—NH—, —(CH2)2—NH—,

—(CH2)3—NH—, —(CH2)4—NH—, or

R1a of the group A7) is selected from —CH2—C(O)—, —(CH2)2—C(O)—, —(CH2)4—C(O)—,

T″ is —C(O)— or —C(O)—X″ wherein X″ is —S— or —O—, when R1a is selected from the group A5) or A6),

T″ is —O—, —S—, —NR′— or —O—CH(R′)O—C(O) wherein R′ is H or

—CH3, when R1a is selected from the group A7),

T′ is —C(O)— or —C(O)—X″ wherein X″ is —S— or —O—,

Y and Y′ are as below defined;

or RX is

(b2) —C(O)—CH2—CH(R2)—N-(T′-Y—ONO2)

wherein

R2 of the group B1) is selected from H, CH3, isobutyl, isopropyl, benzyl,

T′ is —C(O)—, —C(O)—X″ wherein X″ is —S— or —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 —ONO2 group;

d)

wherein:

n2 is an integer from 0 to 2, R13 is H or CH3, T1 is —O—C(O)— or —C(O)O—,

n1 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)

n2 is 1, R13 is CH3, Y1 is —CH═CH—(CH2)n2′— and n2′ is 0,

T1 is —C(O)O— and U is a linear C1-C10 alkylene;

e′)

wherein:

n2 is 1, R13 is CH3,

Y1 is —(CH2)n2′—CH═CH and n2′ is 0,

(T1)′=—O—C(O)—,

n1 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;

f)

wherein T2 is —O— or —S—, —NH— and n3 is 1 or 2,

when Y and Y′ are selected from d), e), e′) or f), the —ONO2 group of -(T-Y—ONO2), -(T′-Y—ONO2), -(T″-Y′—ONO2), -(T′-Y′—ONO2), -(T″′-Y—ONO2) and -(T″′-Y′—ONO2) is linked to the —(CH2)*— group.

5. The nitric oxide releasing compounds according to claim 4 wherein

RX is

(a2) —C(O)—CH(R1)—NH-(T′-Y—ONO2)

wherein

R1 of the group A1) is H,

T′ is —C(O)—,

Y is selected from

a)

a straight or branched C1-C10 alkylene,

a straight or branched C1-C10 alkylene substituted with a —ONO2 group;

6. The nitric oxide releasing compounds of claim 4 wherein

RX is selected from (a5) —R1b—CH(NHR4a)—C(O)-(T-Y—ONO2) (a6) —R1b—CH(COOR3a)NH-(T′-Y—ONO2) or (a9) —R1b—CH(NH-T′-Y′—ONO2)—C(O)-(T-Y—ONO2)

wherein

R1b of the group A10) is —C(O)—CH2—,

R3a is H or a (C1-C5) alkyl,

R4a is H or —C(O)CH3,

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 C1-C10 alkylene, a straight or branched C1-C10 alkylene substituted with a —ONO2 group.

7. The nitric oxide releasing compounds according to claim 4 wherein

RX is

(b2) —C(O)—CH2—CH(R2)—NH-(T′-Y—ONO2)

R2 of the group B1) is H,

T′ is —C(O)—,

Y is selected from

a) a straight or branched C1-C10 alkylene, a straight or branched C1-C10 alkylene substituted with a —ONO2 group;

8. Nitric oxide releasing compounds according to claim 3

9. Nitric oxide releasing compounds according to claim 5

10. Nitric oxide releasing compounds according to claim 6

11. Nitric oxide releasing compounds according to claim 7

12. Nitric oxide releasing compounds according to claim 1 wherein the respiratory diseases comprise asthma, chronic obstructive pulmonary diseases, Acute Respiratory distress syndrome, allergic rhinitis and respiratory tract diseases associated with inflammation.

13. Nitric oxide releasing compounds of general formula (I) and pharmaceutically acceptable salts or stereoisomers thereof wherein R is a corticosteroid residue selected from: and is selected from the group consisting of:

R-(Z)a-Rx (I)

a is 0 or 1,

Z is a group capable of binding RX and is selected from —C(O)—, or —CH(R′)—O— wherein R′ is selected from H or a straight or branched C1-C4 alkyl, preferably R′ is H or —CH3;

RX is a radical selected from the Following meanings:

A) (a1) —HN—CH(R1)—C(O)-(T-Y—ONO2) (a2) —C(O)—CH(R1)—NH-(T′-Y—ONO2) (a3) —HN—CH(R1a-T″-Y′—ONO2)—COOR3a (a4) —C(O)—CH(R1a-T″-Y′—ONO2)—NHR4a (a5) —R1b—CH(NHR4a)—C(O)-(T-Y—ONO2) (a6) —R1b—CH(COOR3a)NH-(T′-Y—ONO2) (a7) —HN—CH(R1a-T″-Y′—ONO2)—C(O)-(T-Y—ONO2) (a8) —C(O)—CH(R1a—-T″-Y′—ONO2)—NH-(T′-Y—ONO2) (a9) —R1b—CH(NH-T′-Y′—ONO2)—C(O)-(T-Y—ONO2) (a10) —R1b—CH(C(O)-T-Y′—ONO2)—NH-(T-Y—ONO2) wherein: R1 is selected from: A1) H, —CH3, isopropyl, isobutyl, sec-butyl, tert-butyl, methylthio-(CH2)2—, phenyl, benzyl, C6H5—CH2—CH2—, 2-monosubstituted benzyl, or 3-monosubstituted benzyl or 4-monosubstituted benzyl wherein the substituent of the benzyl is selected from —F, —Cl, I, —NO2, —CF3, —CH3, CN, C6H5CO—, 2,4-dichlorobenzyl, 3,4-dichlorobenzyl, 3,4-difluorobenzyl, 2-pyrrolidyl, 3-triptophanyl-CH2—, 3-benzothienyl-C1H2—, 4-imidazolyl-CH2—, 9-anthranyl-CH2—, cyclohexyl, cyclohexyl-CH2—, cyclohexyl-(CH2)2—, cyclopentyl-CH2—, (C6H5)2CH—, 4-B(OH)2-benzyl, 4-quinolyl-CH2—, 3-quinolyl-CH2—, 2-quinolyl-CH2—, 2-quinoxalyl-CH2—, 2-furyl-CH2—, 1-naphtyl-CH2—, 2-naphtyl-CH2—, 2-pyridyl-CH2—, 3-pyridyl-CH2—, 4-pyridyl-CH2—, 2-thienyl-CH2—, 3-thienyl-CH2—, C6H4—CH═CH—CH2—, CH2═CH—CH2—, CH≡CH—CH2—, NH2—CO—CH2—, NH2—CO—(CH2)2—, NH2(═NH)NH—(CH2)3—, P(═O)(OCH3)2, A2) —CH2—SH, —CH2—OH, —CH(CH3)—OH, —CH2[(C6H4)-(4-OH)], —CH2—[(C6H2)-(3,5-diiodo)-(4-OH)], —CH2— [(C6H3)-(3-nitro)-(4-OH)], A3) —CH2—NHR″, —(CH2)2—NHR″, —(CH2)3—NHR″, —(CH2)4—NHR″, wherein R″ is H, —C(O)CH3 or

wherein R5a is H or a linear or branched C1-C10 alkyl chain, A4) —CH2—C(O)R″′, —(CH2)2—C(O)R″′, —(CH2)4—C(O)R″′ wherein R″′ is —OR5a or

wherein R5a is as above defined, R1a is selected from, A5) —CH2—S—, —CH2—O—, —CH(CH3)—O—, —CH2[(C6H4)-(4-O)—], —CH2-[(3,5-diiodo)-(C6H2)-(4-O)—], —CH2-[(3-nitro)-(C6H3)-(4-O)—], preferably R1a is —CH2—O—, A6) —CH2—NH—, —(CH2)2—NH—, —(CH2)3—NH—, —(CH2)4—NH—, A7) —CH2—C(O)—, —(CH2)2—C(O)—, —(CH2)4—C(O)—; R3a is selected from H, —R5a or

wherein R5a is as above defined, R4a is selected from H or C(O)CH3 or

wherein R5a is as above defined, R1b is selected from A8) —S—CH2—, —O—CH(CH3)—, —O—CH2—, [-(4-O)—(C6H4)]—CH2—, [-(4-O)-(3,5-diiodo)-(C6H2)]—CH2—, [-(4-O)-(3-nitro)-(C6H3)]—H2—, A9) —HN—CH2—, —HN—(CH2)2—, —HN—(CH2)3—, —HN—(CH2)4—, A10) —C(O)—CH2—, —C(O)—(CH2)2—, —C(O)—(CH2)4—;

T is selected from —C—, —S—, —NR′—, —O—CH(R′)—O—C(O)— or

—O—CH(R′)—O—C(O)O— wherein R′ is as above defined;

T′ is —C(O)—, —C(O)—X″— wherein X″ is —O— or —S—, or T′ is

—C(O)—NR′— wherein R′ is as above defined,

T″ is independently selected from —C(O)—, —C(O)—X″—,

—C(O)—NR′—, —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)—,

—O—CH(R′)—O—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—, —O—, or —S—, or

T″ is —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)—, —O—CH(R′)—O—C(O)O— when T″ is linked to —C(O)—,

Y and Y′ are as below defined,

B) (b1) —HN—CH(R2)—CH2C(O)-(T-Y—ONO2) (b2) —C(O)—CH2—CH(R2)—NH-(T′-Y—ONO2) (b3) —HN—CH(Ra-T″-Y—ONO2)—C—H2COOR3a (b4) —C(O)—CH2—CH(R2a-T″-Y′—ONO2)—NHR4a (b5) —R2b—CH(NHR4a)—CH2C(O)-(T-Y—ONO2) (b6) —R2b—CH(CH2COOR3a)NH-(T′-Y—ONO2) (b7) —HN—CH(R2a-T″-Y′—ONO2)—CH2—C(O)-(T-Y—ONO2) (b8) —C(O)—CH2—CH(R2a-T″-Y′—ONO2)—NH-(T″-Y—ONO2) (b9) —R2b—CH(NH-T′-Y′—ONO2)—CH2C(O)-(T-Y—ONO2) (b10) —R2b—CH(CH2C(O)-T-Y′—ONO2)—NH-(T′-Y—ONO2) wherein

R2 is selected from B1) H, —CH3, CF3, isopropyl, isobutyl, sec-butyl, methylthio-(CH2)2—, phenyl, benzyl, 3-triptophanyl-CH2—, NH2—C(O)—CH2—, NH2—C(O)—(CH2)2—, NH2(═NH)NH—(CH2)3—, tBuO—CH(CH3)—, benzyl-O—CH2—, 4-terbutoxy-benzyl, 4-phenylbenzyl, B2) —CH2—SH, —CH2—OH, —CH(CH3)—OH, —CH2—[(C6H4)-(4-OH)], CH2—[(C6H2)-(3,5-diiodo)-(4-OH)], —CH2—[(C6H3)-(3-nitro)-(4-OH)], B3) —CH2—NHR″, —(CH2)2—NHR″, —(CH2)3—NHR″, —(CH2)4—NHR″, wherein R″ is as above defined, B4) —CH2—C(O)—R″′, —(CH2)2—C(O)—R″′, —(CH2)4—C(O)—R″′ wherein R″′ is as above defined, preferably R2 is —CH2—C(O)—R″′,

R2a is selected from: B5) —CH2—S—, —CH2—O—, —CH(CH3)—O— or —CH2—[(C6H4)-(4-O)—], —CH2-[(3,5-diiodo)-(C6H2)-(4-O)—], —CH2-[(3-nitro)-(C6H3)-(4-O)—]; B6) —CH2—NH—, —(CH2)2—NH—, —(CH2)3—NH, —(CH2)4—NH—, B7) —CH2—C(O)—, —(CH2)2—C(O), —(CH2)4—C(O)—,

R2b is selected from: B8) —S—CH2—, —O—CH(CH3)—, —O—CH2—, [-(4-O)—(C6H4)]—CH2—, [-(4-O)-(3,5-diiodo)-(C6H2)]—CH2—, [-(4-O)-(3-nitro)-(C6H3)]—CH2, B9) —HN—CH2—, —HN—(CH2)2—, —HN—(CH2)3—, —HN—(CH2)4—, B10) —C(O)—CH2—, —C(O)—(CH2)2—, —C(O)—(CH2)4—,

R3a and R4a are as above defined,

T, T′ and T″ are as above defined and Y and Y′ are as below defined,

C)

(c1) —HN—(CH2)b—C(O)-(T-Y—ONO2);

(c2) —C(O)—(CH2)b—NH-(T′-Y—ONO2);

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)

(d1) —HN—CH(R12)—CH2—O-(T″′-Y—ONO2)

(d2) —O—CH2—CH(R12)—NH-(T′-Y—ONO2)

(d3) —HN—CH(R12a-T″-Y′—ONO2)—CH2OH

(d4) —O—CH2—CH(R12a-T″-Y′—ONO2)—NHR4a

(d5) —R12′—CH(NHR4a)—CH2—O-(T″′-Y—ONO2)

(d6) —R12b—CH(CH2OH)—NH-(T′-Y—ONO2)

(d7) —HN—CH(R12a-T″-Y′—ONO2), —CH2—O-(T″′-Y—ONO2)

(d8) —O—CH2—CH(R12a-T″-Y—ONO2)—NH-(T″-Y—ONO2)

(d9) —R12b—CH(NH-T′-Y′—ONO2)—CH2O-(T″′-Y—ONO2)

(d10) —R12b—CH(CH2—O-T″′-Y′—ONO2)—NH-(T′-Y—ONO2)

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,

R12 is selected from: D1) H, —CH3, isopropyl, isobutyl, sec-butyl, methylthio-(CH2)2—, benzyl, 3-triptophanyl-CH2—, 4-imidazolyl-CH2—, NH2—CO—CH2—, NH2—CO—(CH2)2—, NH2(═NH)NH—(CH2)3—, D2) —CH2—OH, —CH(CH3)—OH, —CH2—[(C6H4)-(4-OH)], —CH2—[(C6H3)-(3,5-diiodo)-(4-OH)], —CH2—[(C6H3)-(3-nitro)-(4-OH)], D3) —CH2—NHR″, —(CH2)2—NHR″, —(CH2)3—NHR″, —(CH2)4—NHR″, wherein R″ is as above defined, preferably R12 is —(CH2)4—NHR″, D4) —CH2—C(O)R″′, —(CH2)2—C(O)R″′, (CH2)4—C(O)R″′ wherein R″′ is as above defined,

R12a is selected from: D5) —CH2—O—, —CH(CH3)—O— or —CH2—[(C6H4)-(4-O)—], —CH2-[3,5-diiodo-(C61H2)-(4-O)—], —CH2-[3-nitro-(C6H3)-4-O—], D6) —CH2—NH—, —(CH2)2—NH—, —(CH2)3—NH—, —(CH2)4—NH—, D7) —CH2—C(O)—, —(CH2)2—C(O)—, —(CH2)4—C(O)—,

R12b is selected from: D8) —O—CH2—, —O—CH(CH3)X—, [(4-O)—(C6H4)]—CH2—, [-(4-O)-(3,5-diiodo)-(C6H2)]—CH2, [-(4-O)-(3-nitro)-(C6H3)]—CH2—, D9) —HN—CH2—, —HN—(CH2)2— —HN—(CH2)3—, —HN—(CH2)4—, D10) —C(O)—CH2—, —C(O)—(CH2)2, —C(O)—(CH2)4—,

R4a is as above defined,

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 R3 is H, CH3, propyl, (C6H5)2CH—, 1-naphtyl-CH2—, benzyl, allyl, 2-bromobenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-fluorobenzyl, 4-bromobenzyl, 4-methylbenzyl,

T and T′ are as above defined and Y is as below defined,

H)

wherein R4 is H, benzyl, 4-bromobenzyl, 2-bromobenzyl, T and T′ are as above defined and Y is as below defined;

I)

wherein R5 is H, R6 is H, or R5 and R6 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 reported;

N)

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;

O)

wherein R7 is H, R8 is H, or R7 and R8 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 R9 and R10 are H, CH3, R11 is CH3 or 4-piperidinyl with the proviso that R9 and R10 are H when R11 is 4-piperidinyl and R9 and R10 are CH3 when R11 is CH3, 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 0 or a is 1 and Z is —CH(R′)—O— wherein R′ is as above defined, when Rx is: (a2), (a4) or (a8); (a5), (a6), (a9) or (a10) and R1b is selected from the group A10); (b2), (b4) or (b8); (b5), (b6), (b9) or (b10) and R2b is selected from the group B10); (c2); (d5), (d6), (d9) or (d10) and R12b is selected from the group D10); (e2), (f1), (g2), (h1), (i1), (l2), (m2), (n2), (o2), (p2), (q2), (r2), (s2), (t1) or (u2);

a is 1 and Z is —C(O)—, when RX is: (a1), (a3) or (a7); (a5), (a6), (a9) or (a10) and R1b is selected from the groups A8) and A9); (b1), (b3) or (b7); (b5), (b6), (b9) or (b10) and R2b is selected from the groups B8) or B9); (c1); (d1), (d2), (d3), (d4), (d7) or (d8); (d5), (d6), (d9) or (d10) and R12b is selected from the groups D8) or D9); (e1), (f2), (g1), (h2), (i2), (l1), (m1), (n1), (o1), (p1), (q1), (r1), (s1), (t2) or (u1).

Y and Y′ are bivalent radicals each independently selected from the following meanings:

a) straight or branched C1-C20 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 T2, wherein T2 is —OC(O)(C1-C10 alkyl)-ONO2 or —O(C1-C10 alkyl)-ONO2;

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;

b)

wherein

n0 is an integer from 0 to 20;

n1 is 0 or 1;

U is a linear or branched C1-C20 alkylene optionally substituted with a —ONO2 group;

c)

wherein

n0 is an integer from 0 to 20;

n1 is 0 or 1;

U is a linear or branched C1-C20 alkylene optionally substituted with a —ONO2 group;

d)

wherein:

n is an integer from 0 to 2, R13 is H or CH3, T1 is —O—C(O)— or —C(O)O—;

n1 and U are as above defined;

e)

n2 is an integer from 0 to 2,

R13 is H or CH3,

Y1 is —CH2—CH2— or —CH═CH—(CH2)n2′—, wherein n2′ is 0 or 1, preferably Y1 is —CH═CH—(CH2)n2′ and n2′ is 0,

T1=—O—C(O)— or —C(O)O—,

n1 is 0 or 1, preferably n1 is 1;

U is a linear or branched C1-C20 alkylene optionally substituted with a —ONO2 group;

e′)

wherein:

n2 is an integer from 0 to 2,

R13 is H or CH3,

Y1 is —CH2—CH2— or —(CH2)n2′—CH═CH—, wherein n2′ is 0 or 1,

(T1)′=—O—C(O)—;

n1 is 0 or 1,

U is a linear or branched C1-C20 alkylene optionally substituted with a —ONO2 group;

f)

wherein T2 is —O— or —S—, —NH—,

when Y and Y′ are selected from b), c), d), e), e′) or f), the —ONO2 group of -(T-Y—ONO2), -(T′-Y—ONO2), -(T″-Y′—ONO2), -(T′-Y′—ONO2), -(T″′-Y—ONO2) and -(T″′-Y′—ONO2) is linked to the —(CH2)*— group;

g)

wherein:

n4 is an integer from 0 to 10,

n5 is an integer from 1 to 10,

R14, R15, R16, R17 are the same or different, and are H or straight or branched C1-C4 alkyl,

wherein the —ONO2 group is linked to

wherein n5 is as defined above;

Y2 is an heterocyclic saturated, unsaturated or aromatic 5 or 6 members ring, containing one or more heteroatoms selected from nitrogen, oxygen, sulphur,

14. The nitric oxide releasing compounds according to claim 13 wherein

a is 1 and Z is —C(O)—;

RX is

(a1) —HN—CH(R1)—C(O)-(T-Y—ONO2)

wherein

R1 of the group A1) is selected from H, isobutyl, benzyl, C6H5—CH2—CH2—, 2-monosubstituted benzyl, or 3-monosubstituted benzyl or 4-monosubstituted benzyl wherein the substituent of the benzyl is selected from —F, —Cl, I, —NO2, —CF3, —CH3, CN, C6H5CO— or

R1 of the group A2) is selected from —CH2—OH, —CH(CH3)—OH— or

—CH2—[(C6H4)-(4-OH)], or

R1 of the group A3) is selected from —CH2—NHR″, —(CH2)2—NHR″,

—(CH2)3—NHR″, —(CH2)4—NHR″, wherein R″ is H, or —C(O)CH3,

R1 of the group A4) is —CH2—C(O)R″′, —(CH2)2—C(O)R″′, —(CH2)4—C(O)R″′ wherein R″′ is OR5a wherein R5a is H or a linear (C1-C5) alkyl,

T is —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)— wherein R′ is H or a straight or branched C1-C4 alkyl,

Y is as below defined;

or RX is

(a3) —HN—CH(R1a-T″-Y′—ONO2)—COOR3a

wherein

R1a of the group A5) is selected from —CH2—O—, —CH(CH3)O— or

—CH2—[(C6H4)-(4-O)—], or

R1a of the group A6) is selected from —(H2—NH, —(CH2)2—NH—,

—(CH2)3—NH—, —(CH2)4—NH—, or

R1a of the group A7) is —CH2—C(O)—, —(CH2)2—C(O)—, —(CH2)4—C(O)—,

R3a is H or a (C1-C5) alkyl,

T″ is —C(O)— or —C(O)—X″ wherein X″ is —S— or —O—, when R1a is selected from the group A5) or A6),

T″ is —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)— wherein R′ is H or a straight or branched C1-C4 alkyl, when R1a is selected from the group A7),

Y′ is as below defined;

or RX is selected from:

(a5) —R1b—CH(NHR4a)—C(O)-(T-Y—ONO2)

(a6) —R1b—CH(COOR3a)NH-(T′-Y—ONO2)

(a9) —R1b—CH(NH-T′-Y′—ONO2)—C(O)-(T-Y—ONO2) or

(a10) —R1b—CH(C(O)-T-Y′—ONO2)—NH-(T′-Y—ONO2)

wherein

R1b of the group A8) is selected from —O—CH(CH3)—, —O—CH2—,

[-4-O)—(C6H4)]—CH2—, or

R1b of the group A9) is selected from —HN—CH2—, —HN—(CH2)2—,

—HN—(CH2)3—, —HN—(CH2)4—,

R1b of the group A10) is —O—CH2— or [-4-O(C6H4)]—CH2—,

R3a is H or a (C1-C5) alkyl;

R4a is H or —C(O)CH3,

T is —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)— wherein R′ is H or a straight or branched C1-C4 alkyl,

T′ is —C(O)— or —C(O)—X″ wherein X″ is —S— or —O—,

Y and Y′ are as below defined;

or RX is selected from:

(a7) —HN—CH(R1a-T″-Y′—ONO2)—C(O)(—Y—ONO2)

wherein

R1a of the group A5) is selected from —CH2O—, —CH(CH3)—O— or

—CH2—[(C6H4)-(4-O)—], or

R1a of the group A6) is selected from —CH2—NH—, —(CH2)2—NH—,

—(CH2)3—NH—, —(CH2)4—NH—, or

R1a of the group A7) is —CH2—C(O)—, —(CH2)2—C(O)—, —(CH2)4—C(O)—;

T″ is —C(O)— or —C(O)—X″ wherein X″ is —S— or —O—, when R1a is selected from A5) or A6),

T″ is —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)— wherein R′ is H or a straight or branched C1-C4 alkyl, when R1a is selected from A7),

T is —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)— wherein R′ is H or a straight or branched C1-C4 alkyl,

Y and Y′ are as below defined;

or RX is selected from:

(b1) —HN—CH(R2)—CH2C(O)-(T-Y—ONO2)

wherein

R2 of the group B1) is selected from H, CH3, isobutyl, isopropyl, benzyl;

R2 of the group B2) is selected from —CH2—OH, —CH(CH3)—OH— or

—CH2—[(C6H4)(4-OH)], or

R2 of the group B3) is selected from —CH2—NHR″, —(CH2)2—NHR″,

—(CH2)3—NHR″, —(CH2)4—NHR″, wherein R″ is H, or —C(O)CH3,

R2 of the group B4) is —(H2—C(O)R″′, —(CH2)2—C(O)R″′,

—(CH2)4—C(O)R″′ wherein R″′ is OR5a wherein R5a is H or a linear (C1-C5) alkyl,

T is —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)— wherein R′ is H or a straight or branched C1-C4 alkyl,

Y is as below defined;

or RX is selected from:

(d1) —HN—CH(R12)—CH2—O-(T″-Y—ONO2)

(d2) —O—CH2—CH(R12)—NH-(T′-Y—ONO2)

wherein

R12 of the group D1) is selected from H, CH3, isobutyl, isopropyl, benzyl, or

R12 of the group D2) is selected from —CH2—OH, —CH(CH3)OH— or

—CH2—[(C6H4)-(4-OH)], or

R12 of the group D3) is selected from —CH2—NHR″, —(CH2)2—NHR″,

—(CH2)3—NHR″, —(CH2)4—NHR″ wherein R″ is H, or

R12 of the group D4) is —CH2—C(O)R″′, —(CH2)2—C(O)R″′,

—(CH2)4—C(O)R″′ wherein R″′ is OR5a wherein R5a is H or a linear (C1-C5) alkyl,

T′ and T″′ are each independently selected from —C(O)— or

—C(O)—X″ wherein X″ is —S— or —O—,

Y is as below defined;

or RX is selected from:

(d3) —HN—CH(R12a-T″-Y′—ONO2)—CH2OH

(d4) —O—CH2—CH(R12a-T″-Y′—ONO2)—NHR4a

(d7) —HN—CH(R12a-T″-Y′—ONO2)—CH2—O-(T″′-Y—ONO2) or

(d8) —O—CH2—CH(R12a-T″-Y′—ONO2)—NH-(T′-Y—ONO2)

wherein

R12a of the group D5) is selected from —CH2—O—, —CH(CH3)—O— or

—CH2—[(C6H4)-(4-O)—], or

R12a of the group D6) is selected from —CH2—NH—, —(CH2)2—NH—,

—(CH2)3—NH—, —(CH2)4—NH—, or

R12a of the group D7) is —CH2—C(O)—, —(C112)2—C(O)—, —(C H2)4—C(O)—,

R4a is H or —C(O)CH3,

T″ is selected from —C(O)— or —C(O)—X″ wherein X″ is —S— or —O— when R12a is selected from D5) or D6),

T″ is —O—, —S—, —NR′—, —O—CH(R′)O—C(O)— wherein R′ is H or a straight or branched C1-C4 alkyl when R12a is selected from D7),

T″′ is selected from —C(O)— or —C(O)X″ wherein X″ is —S— or —O—,

Y and Y′ are as below defined;

or RX is selected from:

(d5) —R12b—CH(NHR4a)—CH2—O-(T″′-Y—ONO2)

(d6) —R12b—CH(CH2OH)—NH-(T′-Y—ONO2)

(d9) —R12b—CH(NH-T′-Y′—ONO2)—CH2—O-(T″′-Y—ONO2) or

(d10) —R12b—CH(CH2—O-T″-Y′—ONO2)—NH-(T′-Y—ONO2)

wherein

R12b of the group D8) is selected from —O—CH(CH3)—, —O—CH2—,

[-4-O—(C6H4)]—CH2—, or

R12b of the group D9) is selected from —HN—CH2—, —HN—(CH2)2—,

—HN—(CH2)3—, —HN—(CH2)4—,

R4a is H or —C(O)—CH3,

T′ and T″′ are each independently selected from —C(O)—,

—C(O)—X″, wherein X″ is —S— or —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 —ONO2 group;

d)

wherein:

n2 is an integer from 0 to 2 R13 is H or CH3, T1 is —O—C(O)— or —C(O)O—,

n1 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)

n2 is 1, R13 is CH3, Y1 is —CH═CH—(CH2)n2′— and n2′ is 0,

T1 is —C(O)O— and U is a linear C1-C10 alkylene;

wherein:

n2 is 1, R13 is CH3,

Y1 is —(CH2)n2′—CH═CH— and n2′ is 0,

(T1)′=—O—C(O)—,

n1 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;

f)

wherein T2 is —O— or —S—, —NH—,

n3 is 1 or 2,

when Y and Y′ are selected from d), e), e′) or f), the —ONO2 group of -(T-Y—ONO2), -(T′-Y—ONO2), -(T″-Y′—ONO2), (T′-Y′—ONO2), -(T″′-Y—ONO2) and -(T″′-Y′—ONO2) is linked to the —(CH2)*— group.

15. The nitric oxide releasing compounds according to claim 14 wherein

RX is (a5) —R1b—CH(NHR4a)—C(O)-(T-Y—ONO2) or (a9) —R1b—CH(NH-T′-Y′—ONO2)—C(O)-(T-Y—ONO2)

R1b of the group A10) is —O—CH2— or [-4-O—(C6H4)]—CH2—,

R4a is H or —C(O)CH3,

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 C1-C10 alkylene, a straight or branched C1-C10 alkylene substituted with a —ONO2 group.

16. The nitric oxide releasing compounds according to claim 13 wherein a is 0 and

RX is

(a2) —C(O)—CH(R1)—NH-(T′Y—ONO2)

wherein

R1 of the group A1) is selected from H, isobutyl, benzyl,

C6H5—CH2—CH2—, 2-monosubstituted benzyl, or 3-monosubstituted benzyl or 4-monosubstituted benzyl wherein the substituent of the benzyl is selected from —F, —Cl, I, —NO2, —CF3, —CH3, CN, C6H5CO—,

R1 of the group A2) is selected from —CH2—OH, —CH(CH3)OH— or

—CH2—[(C6H4)-(4-OH)], or

R1 of the group A3) is selected from —CH2—NHR″, —(CH2)2—NHR″,

—(CH2)3—NHR″, —(CH2)4—NHR″, wherein R″ is H or —C(O)CH3,

R1 of the group A4) is selected from —CH2—C(O)R″′,

—(CH2)2—C(O)R″′, —(CH2)4—C(O)R″′ wherein R″′ is OR5a wherein R5a is H or a linear (C1-C5) alkyl,

T′ is —C(O)—, —C(O)—X″ wherein X″ is —S— or —O—,

Y is as below defined;

or RX is

(a4) —C(O)—CH(R1a-T″-Y′—ONO2)—NHR4a

wherein R1a of the group A5) is selected from —CH2—O—, —CH(CH3)O— or —CH2—[(C6H4)-(4-O)—], or

R1a of the group A6) is selected from —CH2—NH—, —(CH2)2—NH—,

—(CH2)3—NH—, —(CH2)4—NH, or

R1a of the group A7) is selected from —CH2—C(O)—, —(CH2)2—C(O)—, —(CH2)4—C(O)—;

R4a is H or —C(O)CH3,

T″ is —C(O)— or —C(O)—X″ wherein X″ is —S— or —O— when R1a is selected from the group A5) or A6),

T″ is —O—, —S—, —NR′— or —O—CH(R′)—O—C(O)— wherein R′ is H or

—CH3 when R1a is selected from the group A7)5

Y′ is as below defined;

or RX is selected from:

(a5) —R1b—CH(NHR4a)—C(O)-(T-Y—ONO2)

(a6) R1b—CH(COOR3a)NH-(T′-Y—ONO2)

(a9) —R1b—CH(NH-T′-Y′—ONO2)—C(O)-(T-Y—ONO2) or

(a10) —R1b—CH(C(O)-T-Y′—ONO2)—NH-(T′-Y—ONO2)

wherein

R1b of the group A10) is selected from —C(O)—CH2—, —C(O)—(CH2)2—, —C(O)—(CH2)4—,

R3a is H or a (C1-C5) alkyl,

R4a is H or —C(O)CH3,

T is —O—, —S—, —NR′— or —O—CH(R′)—O—C(O)— wherein R′ is H or —CH3,

T′ is —C(O)— or —C(O)—X″ wherein X″ is —S— or —O—,

Y and Y′ are as below defined;

or RX is

(a8) —C(O)—CH(Ra-T″-Y′—ONO2)—NH-(T′-Y—ONO2)

wherein

R1a of the group A5) is selected from —CH2—O—, —CH(CH3)—O— or

—CH2—[(C6H4)-(4-O)—], or

R1a of the group A6) is selected from —CH2—NH—, —(CH2)2—NH—,

—(CH2)3—NH—, —(CH2)4—NH—, or

R1a of the group A7) is selected from —CH2—C(O)—, —(CH2)2—C(O)—, —(CH2)4—C(O)—,

T″ is —C(O)— or —C(O)—X″ wherein X″ is —S— or —O—, when R1a is selected from the group A5) or A6),

T″ is —O—, —S—, —NR′— or —O—CH(R′)—OC(O)— wherein R′ is H or —CH3, when R1a is selected from the group A7);

T′ is —C(O)— or —C(O)—X″ wherein X″ is —S— or —O—,

Y and Y′ are as below defined;

or RX is

(b2) —C(O)—CH2—CH(R2)—NH-(T′-Y—ONO2)

wherein

R2 of the group B1) is selected from H, CH3, isobutyl, isopropyl, benzyl;

T′ is —C(O)—, —C(O)—X″ wherein X″ is —S— or —O—,

Y and Y′ are each independently selected from

a) a straight or branched C1-C10 alkylene, a straight or branched C1-10 alkylene substituted with a —ONO2 group;

d)

wherein:

n2 is an integer from 0 to 2, R13 is H or CH3, T1 is —O—C(O)— or —C(O)O—,

n1 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)

n2 is 1, R13 is CH3, Y1 is —CH═CH—(CH2)n2— and n2 is 0,

T1 is —C(O)O— and U is a linear C1-C10 alkylene;

e′)

wherein:

n2 is 1, R13 is CH3,

Y1 is —(CH2)n2′—CH═CH— and n2′ is 0,

(T1)′=—O—C(O)—,

n′ 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;

f)

wherein T2 is —O— or —S—, —NH—,

n3 is 1 or 2,

when Y and Y′ are selected from d), e), e′) or f), the —ONO2 group of -(T-Y—ONO2), -(T′-Y—ONO2), -(T″-Y′—ONO2), -(T′-Y′—ONO2), -(T″′-Y—ONO2) and -(T″′-Y′—ONO2) is linked to the —(CH2)*— group.

17. The nitric oxide releasing compounds according to claim 16 wherein

RX is

(a2) —C(O)—CH(R1)—NH-(T′-Y—ONO2)

wherein

R1 of the group A1) is H,

T′ is —C(O)—,

Y is selected from

a) a straight or branched C1-C10 alkylene, a straight or branched C1-C10 alkylene substituted with a —ONO2 group.

18. The nitric oxide releasing compounds of claim 16 wherein

RX is selected from (a5) —R1b—CH(NHR4a)—C(O)-(T′-Y—ONO2) (a6) —R1b—CH(COOR3NH-(T′-Y—ONO2) or (a9) —R1b—CH(NH-T′-Y′—ONO2)—C(O)-(T′-Y—ONO2)

wherein

R1b of the group A10) is —C(O)—CH2—,

R3a is H or a (C1-C5) alkyl,

R4a is H or —C(O)CH3,

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 C1-C10 alkylene, a straight or branched C1-C10 alkylene substituted with a —ONO2 group.

19. The nitric oxide releasing compounds according to claim 16 wherein

RX is

(b2) —C(O)—CH2—CH(R2)—NH-(T′-Y—ONO2)

R2 of the group B1) is H,

T′ is —C(O)—,

Y is selected from

a) a straight or branched C1-C10 alkylene, a straight or branched C1-C10 alkylene substituted with a —ONO2 group;

20. Nitric oxide releasing compounds according to claim 13

21. Nitric oxide releasing compounds according to claim 17

22. Nitric oxide releasing compounds according to claim 18

23. Nitric oxide releasing compounds according to claim 19

24. Nitric oxide releasing compounds according to claim 13 for use as medicament.

25. Pharmaceutical composition comprising a nitric oxide releasing compound of formula (I) according to claim 13 and a pharmaceutical acceptable excipient.

26. A composition comprising a nitric oxide releasing compound of formula (I) according to claim 13 and at least one bronchodilator or a pharmaceutical acceptable salt or solvate thereof.

27. The composition according to claim 26 wherein the bronchodilator is selected from anticholinergic bronchodilators, β2-agonists, ephedrine or xanthines.

28. The composition according to claim 25 wherein the nitric oxide releasing compound and the bronchodilator are administered simultaneously.

29. The composition according to claim 25 wherein the nitric oxide releasing compound and the bronchodilator are administered sequentially.

30. The composition according to claim 29 wherein the nitric oxide releasing compound is administered before or after the bronchodilator.

31. The composition according to claim 25 for use in the treatment of respiratory diseases.

32. The composition according to claim 31 wherein respiratory diseases comprise asthma, chronic obstructive pulmonary diseases, acute respiratory distress syndrome, allergic rhinitis and respiratory tract diseases associated with inflammation.

33. The composition according to claim 25 pharmaceutical acceptable excipient.