US20100234334A1

US20100234334A1 - Nitric oxide releasing steroids

Info

Publication number: US20100234334A1
Application number: US12/525,822
Authority: US
Inventors: Francesca Benedini; Stefano Biondi; Ennio Ongini
Original assignee: Nicox SA
Current assignee: Nicox SA
Priority date: 2007-02-05
Filing date: 2008-01-28
Publication date: 2010-09-16
Also published as: CA2677441C; CA2677442A1; CA2677290A1; ES2601102T3; EP2118120B1; NZ579067A; EP2109618A1; JP5216782B2; BRPI0807078A2; IL199815A0; US20100093685A1; CA2677441A1; WO2008095808A1; RU2009132993A; AU2008213046A1; JP2010517955A; US20150105547A1; EP2118120A1; US20100041633A1; WO2008095806A1

Abstract

The invention relates to nitrooxyderivative of corticosteriods of general formula (I) and pharmaceutical acceptable salts or stereoisomers thereof wherein R is the corticosteriod residue of formulas (II): The compounds are useful in the treatment of respiratory diseases, inflammatory diseases, dermatological disease and ocular diseases.

Description

The present invention relates to steroidal compounds having an improved pharmacological activity and lower side effects, to a process for their preparation and to pharmaceutical formulation containing them.
Steroid anti-inflammatory compounds are still the most effective drugs in the treatment of inflammatory diseases and conditions such as: asthma, chronic obstructive pulmonary disease (COPD), intestinal diseases such as Crohn's disease, colitis, ulcerative colitis, dermatological inflammations such as eczema, psoriasis, allergic dermatitis, neurodermatitis, pruritus, conjunctivitis, autoimmune diseases such as rheumatoid arthritis, in substitutive hormonal therapies, preferably in the post-menopause therapy, in rheumatic disease therapies, in renal disease therapies, in ocular disease therapies such as ocular hypertension, age-related macular degeneration, diabetic macular edema, diabetic retinopathy, hypertensive retinopathy and retinal vasculopathies, in autoimmune disease. Moreover, steroids are used as adjunct chemotherapeutic agents in treating various malignancies, including leukemias, lymphomas, myelomas, and other malignancies of the hematopoietic system.
However Steroid anti-inflammatory compounds possess numerous unfavourable side-effects, e.g., on carbohydrate metabolism, calcium resorption, secretion of endogenous corticosteroids as well as on the physiological functions of the pituitary gland, adrenal cortex and thymus.
Thus there is an acute need for steroids with an improved therapeutic profile, and/or fewer or milder side effects in particular in the long-term treatments as required for the control of diseases.
The compounds of the present invention are derivatives of known steroids, containing a NO (nitric oxide)-releasing moiety and they are therapeutically useful in the treatment of illnesses wherein the known steroid, parent or precursor steroid, is generally applied, with increased benefit in terms of pharmacological profile and fewer or milder side effects than those of the known steroids.
Therefore the compounds of the present invention may be used, according to the activity of the parent drug, as drugs having antiinflammatory activity at peripheral level, immunodepressive activity, angiostatic/angiogenetic activity, antiarthritic activity, in the therapy of neurodegenerative diseases on an inflammatory and traumatic basis of the nervous system, in the therapy of respiratory diseases such as asthma and COPD, in substitutive hormonal therapies, preferably in the post-menopause therapy, in rheumatic disease therapies, in renal disease therapies, in ocular disease therapies such as ocular hypertension, age-related macular degeneration, diabetic macular edema, diabetic retinopathy, hypertensive retinopathy and retinal vasculopathies, in dermatological disease therapies, in autoimmune disease therapy in tumoral process therapies, in inflammatory pathologies affecting the gastrointestinal system.
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-hydroxy-extrane or from extr-4 en-3 one, used as vasodilators in the treatment of cardiac affections such as coronary insufficiency and angina pectoris. In the structure of said compounds a 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 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.
The present invention provides compounds of general formula (I) and pharmaceutically acceptable salts or stereoisomers thereof.
R—(Z)_a—R^x (I)
wherein R is a corticosteroid residue of formula (II):
wherein:
R₁is H, OH, —OC(O)O_mR_iwherein m is equal to 0 or 1, R₁is a branched or straight C₁-C₁₀alkyl, preferably R_iis a branched or straight C₁-C₆alkyl, preferred R_iis selected from methyl, ethyl, n-propyl, n-butyl;
R₂is H, —CH₃, ═CH₂, OH,
or R₁and R₂are taken together to form a group of formula (III)
wherein R_A1and R_A2are independently selected from H, a C₁-C₁₀linear or branched alkyl chain, preferably (C₁-C₅) alkyl, more preferably —CH₃, a C_3-C₆cycloalkyl, preferably cyclohexyl or R_A1and R_A2, taken together are a C₃-C₆cycloalkyl, preferably cyclohexyl, or R_A1and R_A2, taken together, are the group of formula (IV)
wherein R_A3is a C₁-C₁₀linear or branched alkyl chain, preferably (C₁-C₅) alkyl;
R₃is H, Cl;
R₄is H, CH₃, Cl, F, CH═O,
or R₃and R₄taken together are a double bond;
R_4Ais H;
R₅is H,
or R_4Aand R₅taken together are a double bond;
R₆is H,
or R₅and R₆taken together are a double bond;
R₇is OH, OCH₂CH₂Cl;
R_7Ais H,
or R₇and R_7Ataken together are a ═O;
R₈is H, Cl, Br,
or R₇and R₈taken together are the group of formula (V)
R_8Ais H,
or R_7Aand R_8Ataken together are a double bond;
R₉is H,
or R₈and R₉taken together are a double bond;
R₁₀is H, Cl, F;
R₁₁is H, OH,
or R₁₀and R₁₁taken together are a double bond;
R_11Ais H,
or R₁₁and R_11Ataken together are a ═O;
R₁₂is H, CH₃or ═O;
wherein R₁, R₂, R₃, R₄, R_4a, R₅, R₆, R₇, R_7A, R₈, R_8A, R₉, R₁₀, R₁₁and R_11Acan be linked to the correspondent carbon atoms of the steroidal structure in position α or β;
excluding the following corticosteroid residues R:
a in formula (I) is equal to 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^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, 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″—, —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) —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) —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) 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^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 R^12bis —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:
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;
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;
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;
wherein R₄is H, benzyl, 4-bromobenzyl, 2-bromobenzyl, T and T″ are as above defined and Y is as below defined;
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;
wherein T and T′ are as above defined and Y is as below reported;
wherein T and T″ are as above defined and Y is as below reported;
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;
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;
wherein T and T″ are as above defined and Y is as below reported;
wherein T and T′ are as above defined and Y is as below reported;
wherein T and T′ are as above defined and Y is as below reported;
wherein T and T′ are as above defined and Y is as below reported;
wherein T and T″ are as above defined and Y is as below reported;
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;
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), (ml), (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;

wherein
n⁰is an integer from 0 to 20, preferably n⁰is 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;
wherein
n⁰is an integer from 0 to 20, preferably n⁰is 0 or 1;
n1 is 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;
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;
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 Ti is —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;
wherein:
n²is an integer from 0 to 2, preferably n²is 1;
R₁₃is H or CH₃, preferably R₁₃is CH₃;
Y¹is —CH₂—CH₂— or —(CH₂)_n ^2′—CH═CH—, wherein n^2′ 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;
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;
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.
Preferred compounds of formula (I) are those wherein R is the residue of the corticosteroid selected from the group consisting of alclometasone, alclomethasone-17-propionate, betamethasone-17-benzoate, betamethasone-17-butyrate, betamethasone-17-propionate, betamethasone-17-valerate, clocortolone, cloprednol, corticosterone, cortisone, desonide, dexamethasone, dexamethasone-17-acetate, dexamethasone-17-propionate, diflorasone, diflorasone-17-acetate, difluocortolone, fludrocortisone, flucloronide, fluocortin, fluocortolone, fluperolone, fluprednidene, fluprednisolone, flurandrenolide, halomethasone, halomethasone-17-propionate, halopredone, hydrocortisone, hydrocortisone-17-butyrate, hydrocortisone-17-valerate, meprednisone, methylprednisolone, paramethasone, prednisolone, prednisolone-17-ethylcarbonate, prednisone, prednival, prednylidene, triamcinolone, triamcinolone 16-acetate, 3-(2-chloroethoxy)-9-fluoro-11β,16α,17,21-tetrahydroxy-20-oxopregna-3,5-diene-6-carboxaldehyde; 5-pregnene-3β,21-diol-20-one; (11β,16α)-16,17-[cyclopentylidenebis(oxy)]-11,21-dihydroxy-9-fluoro-pregna-1,4-diene-3,20-dione; 6,16α-dimethyl-11β,17α,21-trihydroxy-2′-phenyl[3,2-c]pyrazolo-4,6-pregnadien-20-one; (11β,16β-11,21-dihydroxy-2′-methyl-5′H-pregna-1,4-dieno[17,16-d]oxazole-3,20-dione; (11β,16β-11,21-dihydroxy-9-fluoro-2′-methyl-5/H-pregna-1,4-dieno[17,16-d]oxazole-3,2,0-dione; (6α,11β,16α)-6,9-difluoro-11,21-dihydroxy-16,17-[(1-methylethylidene)bis(oxy)]pregna-1,4-diene-3,2,0-dione; [(8R,10S,13S,14R,17R)-17-hydroxy-10,13-dimethoxy-3-oxo-2,6,7,8,12,14,15,16-octahydro-1H-cyclopenta[a]phenanthren-17-yl]-2-oxo-ethanol; (6a,11β)-6,9-difluoro-11,21-dihydroxy-17-(1-oxobutoxy)pregna-1,4-diene-3,20-dione; (11β,16β-16,17-[[(R)-cyclohexylmethylene]bis(oxy)-11,21-dihydroxy-pregna-1,4-diene-3,2,0-dione.
Preferred compounds of formula (I) for the treatment of respiratory diseases, in particular asthma and COPD, are those wherein R is the residue of the corticosteroid selected from the group consisting of dexamethasone, dexamethasone-17-acetete, dexamethasone-17-propionate, prednisolone, prednisone, (11β,16β)-16,17-[[(R)-cyclohexylmethylene]bis(oxy)-11,21-dihydroxy-pregna-1,4-diene-3,2,0-dione.
Preferred compounds of formula (I) for the treatment of ocular diseases, in particular ocular hypertension, age-related macular degeneration, diabetic macular edema, diabetic retinopathy, hypertensive retinopathy and retinal vasculopathies, are those wherein R is the residue of the corticosteroid selected from the group consisting of dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone, [(8R,10S,13S,14R,17R)-17-hydroxy-10,13-dimethyl-3-oxo-2,6,7,8,12,14,15,16-octahydro-1H-cyclopenta[a]phenanthren-17-yl]-2-oxo-ethanol; diflorasone, diflorasone-17-acetate; (11β,16β)-16,17-[[(R)-cyclohexylmethylene]bis(oxy)-11,21-dihydroxy-pregna-1,4-diene-3,2,0-dione.
Preferred compounds of formula (I) for the treatment of inflammatory diseases are those wherein R is the residue of the corticosteroid selected from the group consisting of betamethasone 17-benzoate, betamethasone 17-butyrate, betamethasone 17-propionate, betamethasone 17-valerate, cloprednol, corticosterone, cortisone, dexamethasone, fludrocortisone, flucloronide, fluocortolone, fluprednisolone, hydrocortisone, meprednisone, methylprednisolone, paramethasone, prednisolone, prednisone, prednival, prednylidene, triamcinolone, 5-pregnene-3β,21-diol-20-one, 6,16α-dimethyl-11β,17α,21-trihydroxy-2′-phenyl[3,2-c]pyrazolo-4,6-pregnadien-20-one; (11β,16β)-11,21-dihydroxy-2′-methyl-5/H-pregna-1,4-dieno[17,16-d]oxazole-3,20-dione; (11β,16β)-11,21-dihydroxy-9-fluoro-2′-methyl-5′H-pregna-1,4-dieno[17,16-d]oxazole-3,20-dione; 3-(2-chloroethoxy)-9-fluoro-11β,16α,17,21-tetrahydroxy-20-oxopregna-3,5-diene-6-carboxaldehyde.
Preferred compounds of formula (I) for the treatment of dermatological diseases, in particular corticosteroid-responsive dermatosis, atopic dermatitis, inflammation, eczema, erythema, papulation, scaling, erosion, oozing, crusting, pruritis, psoriasis, epidermalysis bullosa, erythema, hidradenitis suppurative, warts, diaper rash, jock itch, ruber lichen planus, are those wherein R is the residue of the corticosteroid selected from the group consisting of alclometasone, betamethasone-17-butyrate, betamethasone-17-propionate, betamethasone-17-benzoate, betamethasone-17-valerate, clocortolone, desonide, desoximethasone, dexamethasone, dexamethasone-17-acetate, dexamethasone-17-propionate, diflorasone, diflorasone-17-acetate, difluocortolone, flumethasone, flucloronide, fluocortolone, flurandrenolide, halomethasone, halomethasone-17-propionate, hydrocortisone, hydrocortisone-17-butyrate, hydrocortisone-17-valerate, methylprednisolone, prednisolone-17-ethylcarbonate, triamcinolone, alclomethasone 17-propionate, (11β,16α)-16,17-[cyclopentylidenebis(oxy)]-11,21-dihydroxy-9-fluoro-pregna-1,4-diene-3,20-dione; (6α,11β)-6,9-difluoro-11,21-dihydroxy-17-(1-oxobutoxy)pregna-1,4-diene-3,20-dione; (6α,11β,16α)-6,9-difluoro-11,21-dihydroxy-16,17-[(1-methylethylidene)bis(oxy)]pregna-1,4-diene-3,20-dione; fluprednidene, halopredone.
One embodiment of the present invention relates to compounds of formula (I) wherein
R is the corticosteroid residue of formula (II) as above defined;
a=0 or a=1 and Z is —CH(R′)—O— wherein R′ is selected from H or straight or branched C₁-C₄alkyl, preferably R′ is CH₃;
R_Xis selected from the following meanings

- (a2) wherein R₁is selected from A1), A2), A3) or A4);
- (a4) wherein R^1ais selected from A5), A6) or A7);
- (a5), (a6), (a9) or (a10) wherein R^1bis selected from A10);
- (a8) wherein R^1ais selected from A5) or A6) or A7);
- (b2) wherein R₂is selected from B1);
- (g2) wherein R₃is H;

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″—, —O— or —S—, or —C(O)—NR′, wherein X″ and R′ are as above defined;
T″ is independently selected from —C(O)—, —O—CH(R′)—O—C(O)—, —C(O)—X″—, wherein X″ is —O— or —S—, —NR′—;
Y and Y′ are bivalent radicals independently selected from a), b), c), e) or f).
Another embodiment of the present invention relates to compounds of formula (I) wherein
R is the corticosteroid residue of formula (II) as above defined;
a=0 or a=1 and Z is —CH(R′)—O— wherein R′ is selected from H or straight or branched C₁-C₄alkyl, preferably R′ is CH₃;
R_Xis

- (a2) 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, 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
  R₁of the group A4) is selected from —CH₂—C(O)R″′, —(CH₂)₂—C(O)R″′, —(CH₂)₄—C(O)R″′ wherein R″′ is OH;

or R_Xis
(a4) 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)—;
or R_Xis selected from
(a5), (a6), (a9) or (a10) wherein
R^1bof the group A10) is selected from —C(O)—CH₂—, —C(O)—(CH₂)₂—, —C(O)—(CH₂)₄—;
or R_Xis
(a8) 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)—;
or R_Xis
(b2) wherein
R₂of the group B1) is selected from H, CH₃, isobutyl, isopropyl, benzyl;
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 —S— or —O—, or —C(O)—NR′—;
T″ is independently selected from —C(O)—, —C(O)—X″, wherein X″ is —S— or —O—, —C(O)—NR′—, —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)—;
Y and Y′ are bivalent radicals independently selected from
a) C₁-C₁₀alkylene or a C₁-C₁₀alkylene substituted with —ONO₂,
b) wherein n¹is 0 or n¹is 1;
e) wherein n²is 1, R₁₃is CH₃, Y¹is —CH═CH—(CH₂)_n ^2′—, wherein n^2′ is 0 and Ti is —C(O) and n¹is 0 or 1, U is a C₁-C₁₀alkylene optionally substituted with a —ONO₂group;
f) wherein T₂is —O, R₁₃is H and n³is 1.
Another embodiment of the present invention relates to compounds of formula (I) wherein
R is the corticosteroid residue of formula (II) as above defined;
a=1 and Z is —C(O)—;
R_Xis selected from

- (a1) wherein R₁is selected from A1), A2), A3) or A4);
- (a3) wherein R^1ais selected from A5), A6) or A7);
- (a5), (a6), (a9) or (a10) wherein R^1bis selected from A8) or A9);
- (a7) wherein R^1ais selected from A5) or A6) or A7);
- (b1) wherein R₂is selected from B1);
  - (d1) or (d2) wherein R₁₂is selected from D1), D2), D3) or D4);
- (d3), (d4), (d7) or (d8) wherein R^12ais selected from D5), D6) or D7);
- (d5), (d6), (d9) or (d10) wherein R^12bis selected from D8) or D9);
- (g1) wherein R₃is H;

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 —S— or —O—, or —C(O)—NR′—;
T″ is independently selected from —C(O)—, —C(O)—X″, wherein X″ is —S— or —O—, —C(O)—NR′—, —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)—;
T″′ is independently selected from —C(O)—, —C(O)—X″, wherein X″ is —S— or —O—, or —C(O)—NR′—;
Y and Y′ are bivalent radicals independently selected from a), b), e) or f).
Another embodiment of the present invention relates to compounds of formula (I) wherein
R is the corticosteroid residue of formula (II) as above defined;
a=1 and Z is —C(O)—;
R_Xis

- (a1) 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, 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
  R₁of the group A4) is —CH₂—C(O)R″′, —(CH₂)₂—C(O)R″′, —(CH₂)₄—C(O)R″′ wherein R″′ is OH;

or R_Xis

- (a3) 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)—;

or R_Xis

(a5), (a6), (a9) or (a10) 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—;
or R_Xis

- (a7) 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)—;

or R_Xis

- (b1) wherein
  R₂of the group B1) is selected from H, CH₃, isobutyl, isopropyl, benzyl;

or R_Xis selected from

- (d1) or (d2), 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 OH;

or R_Xis selected from

- (d3), (d4), (d7) or (d8) 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)—;

or R_Xis selected from

- (d5), (d6), (d9) or (d10) wherein
  R^12bof the group D8) is selected from —O—CH(CH₃)—, —O—CH₂—, [(4-O)—(C₆H₄)]—CH₂—, or
  R^12bof the group D9) is selected from —HN—CH₂—, —HN—(CH₂)₂—, —HN—(CH₂)₃—, —HN—(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 —S— or —O—, or —C(O)—NR′—;
T″ is independently selected from —C(O)—, —C(O)—X″, wherein X″ is —S— or —O—, —C(O)—NR′—, —O—, —S—, —NR′— or —O—CH(R′)—O—C(O)—;
Y and Y′ are bivalent radicals independently selected from
a) C₁-C₁₀alkylene or a C₁-C₁₀alkylene substituted with —ONO₂,
b) wherein n¹is 0 or n¹is 1
e) wherein n²is 1, R₁₃is CH₃, Y¹is —CH═CH—(CH₂) n^2′, wherein n^2′ is 0 and Ti is —C(O) and n¹is 0 or 1, U is a C₁-C₁₀alkylene optionally substituted with a —ONO₂group;
f) wherein T₂is —O, R₁₃is H and n³is 1.
Another embodiment of the present invention relates to compounds of formula (I) wherein
R is the corticosteroid residue of formula (II) as above defined;
a=0 or a=1 and Z is —CH(R′)—O—;
R_Xis selected from
(d5), (d6), (d9) or (d10) wherein R^12bis selected from D10);
T′ is —C(O)—, —C(O)—X″, wherein X″ is —S— or —O—, or —C(O)—NR′—;
T″′ is independently selected from —C(O)—, —C(O)—X″, wherein X″ is —S— or —O—, or —C(O)—NR′—;
Y and Y′ are bivalent radicals independently selected from
a) C₁-C₁₀alkylene or a C₁-C₁₀alkylene substituted with —ONO₂,
b) wherein n¹is 0 or n¹is 1;
e) wherein n²is 1, R₁₃is CH₃, Y¹is —CH═CH—(CH₂) n^2′—, wherein
n^2′ is 0 and Ti is —C(O) and n¹is 0 or 1, U is a C₁-C₁₀alkylene optionally substituted with a —ONO₂group;
f) wherein T₂is —O, R₁₃is H and n³is 1.
Another embodiment of the present invention relates to compounds of formula (I) wherein
R is the corticosteroid residue of formula (II) as above defined;
a=1 and Z is —C(O)—;
R_Xis
(d1) wherein
R₁₂is selected from D1);
T″′ is independently selected from —C(O)—, —C(O)—X″, wherein X″ is —O—, or —C(O)—NR′—;
Y and Y′ are bivalent radicals independently selected from
a) C₁-C₁₀alkylene or a C₁-C₁₀alkylene substituted with —ONO₂,
b) wherein n¹is 0 or n¹is 1;
e) wherein n²is 1, R₁₃is CH₃, Y¹is —CH═CH—(CH₂) n^2′—, wherein _n ^2′ is 0 and T₁is —C(O) and n¹is 0 or 1, U is a C₁-C₁₀alkylene optionally substituted with a —ONO₂group;
Another embodiment of the present invention relates to compounds of formula (I) wherein
R is the corticosteroid residue of formula (II) wherein
R₁is OH and it is linked to the carbon atoms in 17 of the steroidal structure in position α;
R₂is CH₃and it is linked to the carbon atoms in 16 of the steroidal structure in position β;

R₃is H;

R₄is F and it is linked to the carbon atoms in 6 of the steroidal structure in position α;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R_8Ais H;

R₈and R₉form a double bond;
R₁₀is F and it is linked to the carbon atoms in 9 of the steroidal structure in position α;
R₁₁is OH and it is linked to the carbon atoms in 11 of the steroidal structure in position β;

R_11Ais H;

R₁₂is H;

or wherein R is the corticosteroid residue of formula (II) wherein
R₁is OH and it is linked to the carbon atoms in 17 of the steroidal structure in position α;

R₂is H;

R₃is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R_8Ais H;

R_11Ais H;

R₁₂is H;

or wherein R is the corticosteroid residue of formula (II) wherein
R₁and R₂are taken together to form a group of formula (III) wherein R_A1is CH₃and R_A2is H, and R₁and R₂are linked to the carbon atoms in 17 and 16 of the steroidal structure in position α,

R₃is H;

R₄is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R_8Ais H;

R_11Ais H;

R₁₂is H;

or wherein R is the corticosteroid residue of formula (II) wherein
R₁is OC(O)O_mR_iwherein m is 0 and R_iis —CH₂CH₃and it is linked to the carbon atoms in 17 of the steroidal structure in position α;
R₂is CH₃and it is linked to the carbon atoms in 16 of the steroidal structure in position β;

R₃is H;

R₄is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R_8Ais H;

R_11Ais H;

R₁₂is H;

or wherein R is the corticosteroid residue of formula (II) wherein
R₁is OH and it is linked to the carbon atoms in 17 of the steroidal structure in position α;
R₂is CH₃and it is linked to the carbon atoms in 16 of the steroidal structure in position α;

R₃is H;

R₄is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R_8Ais H;

R_11Ais H;

R₁₂is H;

R₂is H;

R₃is H;

R₄is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R₈is H;

R_8Ais H;

R₉is H;

R₁₀is H;

R₁₁is OH and it is linked to the carbon atoms in 11 of the steroidal structure in position β;

R_11Ais H;

R₁₂is H;

R₂is H;

R₃is H;

R₄is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R_8Ais H;

R₈and R₉form a double bond;

R₁₀is H;

R_11Ais H;

R₁₂is H;

or wherein R is the corticosteroid residue of formula (II) wherein
R₁is OH and it is linked to the carbon atoms in 17 of the steroidal structure in position α;
R₂is OH and it is linked to the carbon atoms in 16 of the steroidal structure in position α;

R₃is H;

R₄is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R_8Ais H;

R_11Ais H;

R₁₂is H;

and wherein
a=0 or a=1 and Z is —CH(R′)O— wherein R′ is selected from H or straight or branched C₁-C₄alkyl, preferably R′ is CH₃;
R_Xis selected from

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 —C(O)—NR′—, wherein R′ is defined above;
T″ is independently selected from —C(O)—, —C(O)—X″— wherein X″ is —O— or —S—, —NR′—, —O—CH(R′)—O—C(O)—;
Y and Y′ are bivalent radicals independently selected from a), b), d), e) or f).
Another embodiment of the present invention relates to compounds of formula (I) wherein
R is the corticosteroid residue of formula (II) wherein
R₁is OH and it is linked to the carbon atoms in 17 of the steroidal structure in position α;
R₂is CH₃and it is linked to the carbon atoms in 16 of the steroidal structure in position β;

R₃is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R_8Ais H;

R_11Ais H;

R₁₂is H;

R₂is H;

R₃is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R_8Ais H;

R₈and R₉form a double bond;
R₁₁is OH and it is linked to the carbon atoms in 11 of the steroidal structure in position β;

R_11Ais H;

R₁₂is H;

R₃is H;

R₄is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R_8Ais H;

R_11Ais H;

R₁₂is H;

or wherein R is the corticosteroid residue of formula (II) wherein
R₁is OC(O)O_mR_iwherein m is O and R_iis —CH₂CH₃and it is linked to the carbon atoms in 17 of the steroidal structure in position α;
R₂is CH₃and it is linked to the carbon atoms in 16 of the steroidal structure in position β;

R₃is H;

R₄is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R_8Ais H;

R_11Ais H;

R₁₂is H;

R₃is H;

R₄is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R_8Ais H;

R_11Ais H;

R₁₂is H;

R₂is H;

R₃is H;

R₄is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R₈is H;

R_8Ais H;

R₉is H;

R₁₀is H;

R_11Ais H;

R₁₂is H;

R₂is H;

R₃is H;

R₄is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R_8Ais H;

R₈and R₉form a double bond;

R₁₀is H;

R_11Ais H;

R₁₂is H;

R₃is H;

R₄is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R_8Ais H;

R_11Ais H;

R₁₂is H;

and wherein
a=0 or a=1 and Z is —CH(R′)—O— wherein R′ is selected from H or straight or branched C₁-C₄alkyl, preferably R′ is CH₃;
R_Xis

or R_Xis

- (a4) 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)—;

or R_Xis selected from

- (a5), (a6), (a9) or (a10) wherein
  R^1bof the group A10) is selected from —C(O)—CH₂—, —C(O)—(CH₂)₂—, —C(O)—(CH₂)₄—;

or R_Xis

- (a8) 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)—;

or R_Xis

- (b2) wherein
  R₂of the group B1) is selected from H, CH₃, isobutyl, isopropyl, benzyl;

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 —S— or —O—, or —C(O)—NR′—;
T″ is independently selected from —C(O)—, —C(O)—X″, wherein X″ is —S— or —O—, —C(O)—NR′—, —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)—;
Y and Y′ are bivalent radicals independently selected from
a) C₁-C₁₀alkylene or a C₁-C₁₀alkylene substituted with —ONO₂,
b) wherein n¹is 0 or n¹is 1;
e) wherein n²is 1, R₁₃is CH₃, Y¹is —CH═CH—(CH₂) n^2′—, wherein n^2′ is 0 and Ti is —C(O) and n¹is 0 or 1, U is a C₁-C₁₀alkylene optionally substituted with a —ONO₂group;
f) wherein T₂is —O, R₁₃is H and n³is 1.
Another embodiment of the present invention relates to compounds of formula (I) wherein
R is the corticosteroid residue of formula (II) wherein
R₁is OH and it is linked to the carbon atoms in 17 of the steroidal structure in position α;
R₂is CH₃and it is linked to the carbon atoms in 16 of the steroidal structure in position β;

R₃is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R_8Ais H;

R_11Ais H;

R₁₂is H;

R₂is H;

R₃is H;

R⁴is F and it is linked to the carbon atoms in 6 of the steroidal structure in position α;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R_8Ais H;

R_11Ais H;

R₁₂is H;

R₃is H;

R₄is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R_8Ais H;

R_11Ais H;

R₁₂is H;

R₃is H;

R₄is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R_8Ais H;

R_11Ais H;

R₁₂is H;

R₃is H;

R₄is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R_8Ais H;

R_11Ais H;

R₁₂is H;

R₂is H;

R₃is H;

R₄is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R₈is H;

R_8Ais H;

R₉is H;

R₁₀is H;

R_11Ais H;

R₁₂is H;

R₂is H;

R₃is H;

R₄is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R_8Ais H;

R₈and R₉form a double bond;

R₁₀is H;

R_11Ais H;

R₁₂is H;

R₃is H;

R₄is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R_8Ais H;

R_11Ais H;

R₁₂is H;

and wherein
a=1 and Z is —C(O)—;
R_Xis selected from

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 —S— or —O—, or —C(O)—NR′—;
T″ is independently selected from —C(O)—, —C(O)—X″, wherein X″ is —S— or —O—, —C(O)—NR′—, —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)—;
T″′ is independently selected from —C(O)—, —C(O)—X″, wherein X″ is —S— or —O—, or —C(O)—NR′—;
Y and Y′ are bivalent radicals independently selected from a), b), d), e) or f).
Another embodiment of the present invention relates to compounds of formula (I) wherein
R is the corticosteroid residue of formula (II) wherein
R₁is OH and it is linked to the carbon atoms in 17 of the steroidal structure in position α;
R₂is CH₃and it is linked to the carbon atoms in 16 of the steroidal structure in position β;

R₃is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R_8Ais H;

R_11Ais H;

R₁₂is H;

R₂is H;

R₃is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R_8Ais H;

R_11Ais H;

R₁₂is H;

R₃is H;

R₄is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R_8Ais H;

R_11Ais H;

R₁₂is H;

R₃is H;

R₄is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R_8Ais H;

R_11Ais H;

R₁₂is H;

R₃is H;

R₄is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R_8Ais H;

R_11Ais H;

R₁₂is H;

R₂is H;

R₃is H;

R₄is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R₈is H;

R_8Ais H;

R₉is H;

R₁₀is H;

R_11Ais H;

R₁₂is H;

R₂is H;

R₃is H;

R₄is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R_8Ais H;

R₈and R₉form a double bond;

R₁₀is H;

R_11Ais H;

R₁₂is H;

R₃is H;

R₄is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R_8Ais H;

R_11Ais H;

R₁₂is H;

and wherein
a=1 and Z is —C(O)—;
R_Xis

- (a1) wherein
  R₁of the group A1) is H, isobutyl, benzyl, C₆H₅—CH₂—CH₂—, 2-monosubstituted benzyl, or 3-monosubstituted benzyl or 4-monosubstituted benzyl or
  R₁of the group A2) is —CH₂—OH, —CH(CH₃)OH— or —CH₂[(C₆H₄)-(4-OH)] or
  R₁of the group A3) is —CH₂—NHR″, —(CH₂)₂—NHR″, —(CH₂)₃—NHR″, —(CH₂)₄—NHR″, wherein R″ is H or
  R₁of the group A4) is —CH₂—C(O)R″′, —(CH₂)₂—C(O)R″′, —(CH₂)₄—C(O)R″′ wherein R″′ is OH;

or R_Xis

- (a3) 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)—;

or R_Xis selected from

- (a5), (a6), (a9) or (a10) 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—;

or R_Xis

- (a7) wherein
  R^1aof the group A5) is selected from —CH₂—O—, —CH(CH₃)—O— or —CH₂[(C₆H₄)-(4-O)—], or
  R^1aof 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)—;

or R_Xis

- (b1) wherein
  R of the group B1) is selected from H, CH₃, isobutyl, isopropyl, benzyl;

or R_Xis selected from

- (d1) or (d2) 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 selected from —CH₂—C(O)R″′, —(CH₂)₂—C(O)R″′, —(CH₂)₄—C(O)R″′ wherein R″′ is OH;

or R_Xis selected from

or R_Xis selected from

- (d5), (d6), (d9) or (d10) wherein
  R^12bof the group D8) is selected from —O—CH(CH₃)—, —O—CH₂—, [(4-O)—(C₆H₄)]—CH₂—, or
  R^12bof the group D9) is selected from —HN—CH₂—, —HN—(CH₂)₂—, —HN—(CH₂)₃—, —HN—(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 —S— or —O—, or —C(O)—NR′—;
  T″ is independently selected from —C(O)—, —C(O)—X″, wherein X″ is —S— or —O—, —C(O)—NR′—, —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)—;
  Y and Y′ are bivalent radicals independently selected from
  a) C₁-C₁₀alkylene or a C₁-C₁₀alkylene substituted with —ONO₂;
  b) wherein n¹is 0 or n¹is 1;
  e) wherein n²is 1, R is CH₃, Y¹is —CH═CH—(CH₂) n wherein n^2′ is 0 and Ti is —C(O) and n¹is 0 or 1, U is a C₁-C₁₀alkylene optionally substituted with a —ONO₂group;
  f) wherein T₂is —O, R₁₃is H and n³is 1.

Another embodiment of the present invention relates to compounds of formula (I) wherein
R is the corticosteroid residue of formula (II) wherein
R₁is OH and it is linked to the carbon atoms in 17 of the steroidal structure in position α;
R₂is CH₃and it is linked to the carbon atoms in 16 of the steroidal structure in position β;

R₃is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R_8Ais H;

R_11Ais H;

R₁₂is H;

R₂is H;

R₃is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R_8Ais H;

R_11Ais H;

R₁₂is H;

R₃is H;

R₄is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R_8Ais H;

R_11Ais H;

R₁₂is H;

R₃is H;

R₄is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R_8Ais H;

R_11Ais H;

R₁₂is H;

R₃is H;

R₄is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R_8Ais H;

R_11Ais H;

R₁₂is H;

R₂is H;

R₃is H;

R₄is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R₈is H;

R_8Ais H;

R₉is H;

R₁₀is H;

R_11Ais H;

R₁₂is H;

R₂is H;

R₃is H;

R₄is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R_8Ais H;

R₈and R₉form a double bond;

R₁₀is H;

R_11Ais H;

R₁₂is H;

R₃is H;

R₄is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R_8Ais H;

R_11Ais H;

R₁₂is H;

and wherein
a=0 or a=1 and Z is —CH(R′)—O—
R_Xis selected from

- (d5), (d6), (d9) or (d10) wherein R^12bis selected from D10);

T′ is —C(O)—, —C(O)—X″, wherein X″ is —S— or —O—, or —C(O)—NR′—;
T″′ is independently selected from —C(O)—, —C(O)—X″, wherein X″ is —S— or —O—, or —C(O)—NR′—;
Y and Y′ are bivalent radicals independently selected from
a) C₁-C₁₀alkylene or a C₁-C₁₀alkylene substituted with —ONO₂;
b) wherein n¹is 0 or n¹is 1;
e) wherein n²is 1, R₁₃is CH₃, Y¹is —CH═CH—(CH₂) n^2′—, wherein n^2′ is 0 and Ti is —C(O) and n¹is 0 or 1, U is a C₁-C₁₀alkylene optionally substituted with a —ONO₂group;
f) wherein T₂is —O, R₁₃is H and n³is 1.
Another embodiment of the present invention relates to compounds of formula (I) wherein
R is the corticosteroid residue of formula (II) wherein the corticosteroid is selected from the group consisting of dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone, [(8R,10S,13S,14R,17R)-17-hydroxy-10,13-dimethyl-3-oxo-2,6,7,8,12,14,15,16-octahydro-1H-cyclopenta[a]phenanthren-17-yl]-2-oxo-ethanol; diflorasone, diflorasone-17-acetate, (11β,16β)-16,17-[[(R)-cyclohexylmethylene]bis(oxy)-11,21-dihydroxy-pregna-1,4-diene-3,20-dione;
a=0 or a=1 and Z is —CH(R′)—O— wherein R′ is selected from H or straight or branched C₁-C₄alkyl, preferably R′ is CH₃;
R_Xis

- (a2) wherein
  R₁of the group A1) is H;
  R₁of the group A2) is selected from —CH₂—OH or —CH₂[(C₆H₄)-(4-OH)];
  R₁of the group A3) is —(CH₂)₄—NHR″, wherein R″ is H;
  R₁of the group A4) is —CH₂—C(O)R″′, wherein R″′ is OH;

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 —S— or —O—, or —C(O)—NR′—;
T″ is independently selected from —C(O)—, —C(O)—X″, wherein X″ is —S— or —O—, —C(O)—NR′—, —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)—;
Y and Y′ are bivalent radicals independently selected from
a) C₁-C₁₀alkylene or a C₁-C₁₀alkylene substituted with —ONO₂;
b) wherein n¹is 0 or n¹is 1;
e) wherein n²is 1, R₁₃is CH₃, Y¹is —CH═CH—(CH₂) n^2′—, wherein n2′ is 0 and Ti is —C(O) and n¹is 0 or 1, U is a C₁-C₁₀alkylene optionally substituted with a —ONO₂group;
f) wherein T₂is —O, R₁₃is H and n³is 1.
Another embodiment of the present invention relates to compounds of formula (I) wherein
R is the corticosteroid residue of formula (II) wherein the corticosteroid is selected from the group consisting of dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone, triamcinolone, [(8R,10S,13S,14R,17R)-17-hydroxy-10,13-dimethyl-3-oxo-2,6,7,8,12,14,15,16-octahydro-1H-cyclopenta[a]phenanthren-17-yl]-2-oxo-ethanol; diflorasone, diflorasone-17-acetate, (11β,16β)-16,17-[[(R)-cyclohexylmethylene]bis(oxy)-11,21-dihydroxy-pregna-1,4-diene-3,20-dione;
a=1 and Z is —C(O)—;
R_Xis

- (a1) wherein
  R₁of the group A1) is H;
  R₁of the group A2) is selected from —CH₂—OH or —CH₂[(C₆H₄)-(4-OH)];
  R₁of the group A3) is —(CH₂)₄—NHR″, wherein R″ is H or R₁of A4) is —CH₂—C(O)R″′, wherein R″′ is OH;

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 —S— or —O—, or —C(O)—NR′—;
T″ is independently selected from —C(O)—, —C(O)—X″, wherein X″ is —S— or —O—, —C(O)—NR′—, —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)—;
Y and Y′ are bivalent radicals independently selected from
a) C₁-C₁₀alkylene or a C₁-C₁₀alkylene substituted with —ONO₂;
b) wherein n¹is 0 or n¹is 1;
e) wherein n²is 1, R₁₃is CH₃, Y¹is —CH═CH—(CH₂) n^2′—, wherein _n ^2′ is 0 and T₁is —C(O) and n¹is 0 or 1, U is a C₁-C₁₀alkylene optionally substituted with a —ONO₂group;
f) wherein T₂is —O, R₁₃is H and n³is 1.
Preferred specific embodiments of the present invention are the selected compounds reported below:
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).
Another object of the present invention provides the use of the compounds of formula (I) above reported in the treatment of inflammatory diseases and conditions such as asthma, chronic obstructive pulmonary disease (COPD), intestinal diseases such as Crohn's disease, colitis, ulcerative colitis, dermatological inflammations such as eczema, psoriasis, allergic dermatitis, neurodermatitis, pruritus, conjunctivitis, autoimmune diseases such as rheumatoid arthritis, in substitutive hormonal therapies, preferably in the post-menopause therapy, in rheumatic disease therapies, in renal disease therapies, in ocular disease therapies such as ocular hypertension, age-related macular degeneration, diabetic macular edema, diabetic retinopathy, hypertensive retinopathy and retinal vasculopathies, in autoimmune disease.
The compounds object 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 sublingual, inhalatory, suppository, transdermal, enema, 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 compound 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 (IIa)
wherein R₁, R₂, R₃, R₄, are as above defined, with a compound of formula (Ia)
W—X₁ (Ia)
wherein W is —OH, C_1-10—R_awherein R_ais pentafluorophenyl, 4-nitrophenyl or —(N-succimidyl), X₁is as below defined, to obtain the compound of formula (IIa′)
wherein R₁, R₂, R₃, R₄, are as above defined and X₁is as below defined,
X₁is a radical having the following meaning:

- (a2′) —C(O)—CH(R^1′)—NH-(T′-Y-Q)
  wherein R^1′ is selected from
  A1) as defined above or
  A2′) —CH₂—OP¹, —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)₄—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;
- (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)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;

R^4a′ is P³or —C(O)—CH₃or

- (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, P²is 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-i1) The reaction of a compound of formula (Ia) wherein W=—OH and X₁is as above defined, with a compound of formula (IIa) 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-i2) The reaction of a compound of formula (Ia) wherein W=—O—R_awherein R_aand X₁are as above defined, with a compound of formula (IIa) 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-i3) The reaction of a compound of formula (Ia) wherein W═—Cl, and X₁is are as above defined, with a compound of formula (IIa) 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 (IIa) are commercially available.
1a) The compounds of formula (Ia) wherein W is —OH, T″ and T″ are C(O), 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′), 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′) 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(R^2′)—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-i1) 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-i2).
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 about 100-180° C. for time range about 1-60 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′), (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′), 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′), (f1l′), (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 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)
P^2-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-i2)
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 compound of formula (IVe) are commercially available or are known in literature.
The compounds of formula (Ia) wherein W is —Cl or O—R_{a, X} ₁is 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),
P^2-X₃ (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)—NH₂
  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 or Y′, wherein Y and Y′ are as above defined, and
1c-ii) when Q is Z₂, by converting the compound 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-i2) 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 compound 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-i2).
The compounds of formula (Ib) wherein T″ is C(O), P²and X₃′ are as above defined, are obtained as described in 1a).
The compounds of formula (Ib) wherein T″ is C(O)—X″, P²and X₃′ 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)
P^2-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 compound 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-i2) 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 compound 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 X₃′ 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 X₃′ 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-i2).
The compounds of formula (Ib) wherein T″ is C(O), P²and X₃′ are as above defined, are obtained as described in 1a).
The compounds of formula (Ib) wherein T″ is C(O)—X″, P²and X₃′ 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), A6), R^2ais selected from B5), 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′ (Ib)
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 compound 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-i2).
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 Z₂is commercially available, the compounds of formula (IVg) wherein y is as above defined and Q is —ONO₂may be obtained from the compound 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 P³, 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 P³, y are as above defined may be obtained from the corresponding compounds of formula P³—R′N-y-Z₂(IVl) wherein P³, y, 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),
P^2-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 compound 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-i1).
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, X} ₁is 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),
P^2-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 compound obtained in the step 1i-i) into nitro derivative by reaction with a nitrate source such above described and
1n-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
11) 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),
P^2-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 compound 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 temperatures range between 0° to 100° C. or in a double phase system H₂O/Et₂O at temperatures range between 20° to 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 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),
P^2-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
1l-ii) when Q is Z₂, by converting the compound 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 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 1l-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 R^4a′ 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, X₅′ is

- (a4″) —C(O)—CH(R^1a—OH)—NHR^4a′
- (b4″) —C(O)—CH₂—CH(R^2a—OH)—NHR^4a′
  wherein R^1ais selected from A7), R^2ais selected from B7) and P³is 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
1n-ii) when Q is Z₂, by converting the compound 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 1n-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-i1).
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^4a′ are 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 X₅′ 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 compound 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′, Q are as above defined and T″ is —NR′ wherein R′ is as above defined, can be obtained may 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—X_5′ (IIIe)
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 compound obtained in the step 1p-i) into nitro derivative by reaction with a nitrate 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, 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)—O—, wherein R′ is as above defined, can be obtained
1q-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 (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 compound 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, 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 may be obtained from the corresponding acids (Ia) wherein W═—OH as known in literature.
2) The compound of general formula (I) as above defined wherein a is equal to 1, the radical R_Xis the radical selected from (a2), (a4), (a8), (b2), (b4), (b8), (c2), (e2), (f1), (g2), (hi), (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 (IIa)
R—OH (IIa)
wherein R is 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 compound 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 (IIa) wherein R is as above defined, 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 compound of general formula (I) as above defined wherein a is equal to 1, the radical R_Xis selected from (al), (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
R—C(O)—O—R_a (IIb)
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)-CH₂COOR_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 compound 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 (IIb) 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-i2).
The compounds of formula R—C(O)—O—R_a(IIb) wherein R and R_aare as above defined, are obtained from the compounds R—H (IIa) 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′), (i2′), (l1′), (m1′), (n1′), (o1′), (p1′), (q1′), (r1′), (s1′), (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′), 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′)—CH₂C(O)—OH
- (b3″) —HN—CH(R^2a—OH)—CH₂COOR^3a′
  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′ 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′), (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
3a-ii) when Q is Z₂, by converting the compound 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-i1).
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′), (f2′), (g1′), (h2′), (i2′), (l1′), (m1′), (n1′), (o1′), (p1′), (q1′), (r1′), (s1′), (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 —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′), (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
3b-ii) when Q is Z₂, by converting the compound 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′), (f2′), (g1′), (h2′), (i2′), (l1′), (m1′), (n1′), (o1′), (p1′), (q1′), (r1′), (s1′), (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)
P^3-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 compound 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′), (f2′), (g1′), (h2′), (i2′), (l1′), (m1′), (n1′), (o1′), (p1′), (q1′), (r1′), (s1′), (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)O— wherein R′ is as above defined may be obtained
3d-i) by reacting a compound of formula (IIIe)
P^3-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 compound 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^1bis 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)
P^3-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 compound 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-i1), 1-i2), 1-i3) 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 compound 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-i2).
3g) The compounds of formula (Ig) wherein X₂is selected from (a7′) or (b7′) wherein R^1ais selected from A5), A6), R^1bis selected from B5), 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 compound 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-i2).
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 (II) 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^1ais 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 (Iv)
P³—X₈ (Iv)
wherein P³is as above defined and X₈is 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 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 compound 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 (Iv) wherein P³and X₈are 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-i1), 1-i2) and 1a-1).
The compounds of formula (Iv) wherein P³and X₈are as above defined, T is —X″ are obtained as described in 3a).
The compounds of formula (Iv) wherein P³and X₈are as above defined, T is —NR′ are obtained as described in 3b).
The compounds of formula (Iv) wherein P³and X₈are as above defined, T is —O—CH(R′)—O—C(O)— are obtained as described in 3c).
The compounds of formula (Iv) wherein P³and X₈are 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 (Iv)
P³—X₈ (Iv)
wherein P³and X₈are 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 (Iv) wherein P³and X₈are 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 (Iv)
P³—X₈ (Iv)
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 compound 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 (Iv) wherein P³and X₈are 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 (Iv)
P³—X₈ (Iv)
wherein P³and X₈are 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, 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 compound 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 (Iv) wherein P³and X₈are 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, X₈is a radical having the following meaning

- (a3″) —HN—CH(R^1a—H)—COOR^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 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
3n-ii) when Q is Z₂, by converting the compound 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-i1), 1-i2), 1a-1).
The compounds of formula (IIIf) wherein P³and X₉are as above defined, is 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 compounds 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 compound 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 l-1-2).
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 compounds 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 compound 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-i2).
4) The compound of general formula (I) as above defined wherein a is equal to 1, the radical R_Xis selected from (d1), (d2), (d3), (d4), (d7), (d8), Z is C(O), can be obtained
4-i) by reacting a compound of formula (IIb)
R—C(O)—O—R_a (IIb)
wherein R and R_aare as above defined, with a compound of formula (Im)
H—X₁₂ (Im)
wherein X₁₂is the radical R_Xhaving the following meaning

- (d1′) —HN—CH(R₁₂′)—CH₂—O-(T″′-Y-Q)
- (d2′) —O—CH₂—CH(R₁₂′)—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 R₁₂′ 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 compound 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 (IIb) 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-i2).
4a) The compound of formula (Im) wherein X₁₂is selected from (d1′), (d2′), (d3′) or (d4′) wherein R₁₂′ 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(R₁₂′)—CH₂—OH
- (d2″)—O—CH₂—CH(R₁₂′)—NH₂
- (d3″)—HN—CH(R^12a—H)—CH₂OP¹
- (d4″)—O—CH₂—CH(R^12a—H)—NHR^4a′
  wherein R₁₂′ 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 compound 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-i1) and 1-i2).
The compounds of formula (IIIi) wherein X₁₃and P⁴are as above described, are commercially available or known in literature.
4b) The compound of formula (Im) wherein X₁₂is selected from (d1′), (d2′), (d3′) or (d4′) wherein R₁₂′ 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)—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 compound 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_aand X″ are as above defined, may be carried out as described in 1-i2).
4c) The compound of formula (Im) wherein X₁₂is selected from (d7′) or (d8′) wherein 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
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^12a—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 compound 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-i1) 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-i2) 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 compound 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

- (d1″′) —HN—CH(R^12a—H)—CH₂—O-(T″′-Y-Q)
- (d8″′) —O—CH₂—CH(R^12a—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 compound 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-i1).
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-i2).
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 compound 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″ wherein X″ is as above defined, T″ and T″′ are C(O), can be obtained
4e-i) by reacting a compound of formula (In)
P⁴—X₁₅ (In)
wherein P⁴and X₁₅are defined above, 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
4e-ii) when Q is Z₂, by converting the compound obtained in the step 1e-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 (In) wherein P⁴and X₁₅are as above defined, with a compound of formula (IVa) wherein W₁is OH, y and Q are as above defined, can by carried out as described in 1-i1).
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, can by carried out as described in 1-i2).
The compounds of formula (In) wherein P⁴and X₁₅are as above defined can by obtained as described in 4b).
4f) The compound 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
4f-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
4f-ii) when Q is Z₂, by converting the compound 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 (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-i2) using a ratio (IIIl)/(IVd) 1:2.
4g) The compound 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
4g-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
4g-ii) when Q is Z₂, by converting the compound 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) 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-i2).
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).
4h) The compound 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)—NR′—, 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 (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
4h-ii) when Q is Z₂, by converting the compound 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 (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-i2).
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).
4i) The compound 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
4i-i) by reacting a compound of formula (Ir),
P⁴—X₁₆ (Ir)

- (d7″″)—HN—CH(R^12a—OH)—CH₂—O-(T″′-Y-Q)
- (d8″″)—O—CH₂—CH(R^12a—OH)—NH-(T′-Y-Q)
  wherein P4 is as above defined, 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
4i-ii) when Q is Z₂, by converting the compound obtained in the step 4i-i) into nitro derivative by reaction with a nitrate source as above described and
4i-iii) optionally deprotecting the compounds obtained in step 4i-i) or 4i-ii) as above described.
The reaction of a compound of formula (Ir) wherein P4 and 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-i1).
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).
4l) The compound 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
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
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
4l-ii) when Q is Z₂, by converting the compound 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) 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-i1).
4m) The compound 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
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 (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
4m-ii) when Q is Z₂, by converting the compound obtained in the step 4m-i) into nitro derivative by reaction with a nitrate source such above described and
4m-iii) optionally deprotecting the compounds obtained in step 4m-i) or l1-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).
4n) The compound 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
4n-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 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′, wherein Y′ is as above defined, and 4n-ii) when Q is Z₂, by converting the compound 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 (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).
4o) The compound of formula (Im) wherein X₁₂is (selected from d3′) or (d4′) wherein R^12ais selected from D7), Y′ is as above defined, T″ is X″, wherein X″ is defined above, can be obtained
4o-i) by reacting a compound of formula (IIIm),
P⁴—X₁₇ (IIIm)
wherein P⁴is defined above and X₁₇is the radical

- (d3″) —HN—CH(R^12a—H)—CH₂OP¹
- (d4″) —O—CH₂—CH(R^12a—H)—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
4o-ii) when Q is Z₂, by converting the compound obtained in the step 4o-i) into nitro derivative by reaction with a nitrate source as 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 (IVe) wherein y, X″ and Q are as above defined, may be carried out as described in 1-i1).
The compounds of formula (IIIm), wherein P⁴and X₁₇are as above defined, are commercially available or obtained as known in literature.
4p) The compound 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
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
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
4p-ii) when Q is Z₂, by converting the compound 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 (IVg) wherein R′, y, Q are as above defined, may be carried out as described in 1a-i).
4q) The compound 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
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 (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
4q-ii) when Q is Z₂, by converting the compound obtained in the step 4q-i) into nitro derivative by reaction with a nitrate source such 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 (IVm) wherein R′, y, Q are as above defined, may be carried out as described in 1-i).
4r) The compound 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
4r-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
4r-ii) when Q is Z₂, by converting the compound obtained in the step 4r-i) into nitro derivative by reaction with a nitrate source as above described and
4r-iii) optionally deprotecting the compounds obtained in step 4r-i) or 4r-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 compound 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 (IIa)
R—H (IIa)
wherein R is as above defined, with a compound of formula (Is)
W—X₁₈ (Is)
wherein W is as above defined, X is 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 compound 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 (IIa) wherein R is as above defined, with a compound of formula (Is) wherein W and X is are 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 compound 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-i1), 1-i2), 1-i3) 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 R^12bis 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 compound 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-i2).
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″) —R^12b—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 compound 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-i1), 1-i2), 1-i3) 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—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
5d-ii) when Q is Z₂, by converting the compound 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 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-i2).
5e) The compounds of formula (Is) wherein X is 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 X₂₀is 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 compound 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 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-i1), 1-i2), 1-i3) and 1a-1).
5f) The compounds of formula (Is) wherein X is 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 compound 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-i2).
6) 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 D10), Z is —CH(R′)—O—, wherein R′ is defined above, can be obtained
6-i) by reacting a compound of formula (IIa)
R—OH (IIa)
wherein R is 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 compound 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 (IIa) wherein R is 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 (IIb)
R—C(O)—O—R_a (IIb)
wherein R and R_aare 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 compound 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 (IIb) wherein R is as above defined, may be carried out as described in 1l-i).
8) The compound 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 (IIa)
R—H (IIa)
wherein R is 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 compound 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 (IIa) 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 P2 and P3 are 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 compound 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-i1), 1-i2), 1-i3) 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 compound 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-i2).
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 compound 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-i1), 1-i2), 1-i3) 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 compound 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 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-i2).
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 in 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—X_26′ (Iy′)
wherein P²is as above defined and X_26′ is 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 compound 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-i1), 1-i2), 1-i3) 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 compound 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 X_26′ 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-i2).
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 (IIb)
R—C(O)—O—R_a (IIb)
wherein R and R_aare 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 compound 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 (IIb) wherein R is as above defined, may be carried out as described in 1l-i).

Claims

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

R—(Z)_a—R_x (I)

and pharmaceutically acceptable salts or stereoisomers thereof wherein in formula (I) R is a corticosteroid residue of formula (II):

wherein:

R₁is H, OH, —OC(O)O_mR_iwherein m is equal to 0 or 1, R_iis a branched or straight C₁-C₁₀alkyl;

R₂is H, —CH₃, ═CH₂, OH,

or R₁and R₂are taken together to form a group of formula (III)

wherein R_A1and R_A2are independently selected from H, a C₁-C₁₀linear or branched alkyl chain, a C₃-C₆cycloalkyl or R_A1and R_A2, taken together, are a C₃-C₆cycloalkyl or R_A1and R_A2, taken together, are the group of formula (IV)

wherein R_A3is a C₁-C₁₀linear or branched alkyl chain;

R₃is H, Cl;

R₄is H, CH₃, Cl, F, CH═O,

or R₃and R₄taken together are a double bond; R_4Ais H;

R₅is H,

or R_4Aand R₅taken together are a double bond;

R₆is H,

or R₅and R₆taken together are a double bond;

R₇is OH, OCH₂CH₂C₁;

R_7Ais H,

or R₇and R_7Ataken together are a ═O;

R₈is H, Cl, Br,

or R₇and R₈taken together are the group of formula (V)

R_8Ais H,

or R_7Aand R_8Ataken together are a double bond;

R₉is H,

or R₈and R₉taken together are a double bond;

R₁₀is H, Cl, F;

R₁₁is H, OH,

or R₁₀and R₁₁taken together are a double bond;

R_11Ais H,

or R₁₁and R_11Ataken together are a ═O;

R₁₂is H, CH₃or ═O;

wherein R₁, R₂, R₃, R₄, R_4A, R₅, R₆, R₇, R_7A, R_8A, R₉, R₁₀, R₁₁and R_11Acan be linked to the correspondent carbon atoms of the steroidal structure in position α or β;

excluding the following corticosteroid residues R:

a in formula (I) is equal to 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;

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^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, 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-CH_2-9-anthranyl-CH₂—, cyclohexyl, cyclohexyl-CH₂—, cyclohexyl-(CH₂)₂—, cyclopentyl-CH₂—, (C₆H₅)₂CH—, 4-B(OH)-2-benzyl, 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-CH_2-3-thienyl-CH₂—, C₆H₄—CH═CH—CH₂—, CH₂═CH—CH₂—, CH═CH—CH₂—, CH₂═CH—CH₂—NH₂—CO—(CH₂)₂—NH₂(═NH)NH—(CH₂)₃—P(═O) (OCH₃)₂, I—CH₂;

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)CH₃or

wherein R^5ais H or a linear or branched C₁-C₁₀alkyl chain;

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,

R^1ais selected from:

A5) —CH₂—S—, —CH₂—O—, —CH(CH₃)—O—, —CH₂[(O₆H₄)—(4-O)—]—CH₂-[(3,5-diiodo)-(C₆H₂)-(4-O)—], —CH₂-[(3-nitro)-(C₆H₃)-(4-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)

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)—(O₆H₄)]—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)— 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) —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,

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

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)—],

B6) —CH₂—NH—, —(CH₂)₂—NH—(CH₂)—(CH₂)₄—NH—,

B7) —CH₂—C(O)—(CH₂)₂—C(O)—(CH₂)₄—C(O)—, R^2bis selected from

B8) —S—CH₂—, —O—CH(CH₂)— —O—CH₂-[-(4-O)—(C₆H₄)—CH₂—. (4-O)-(3,5-diiodo)-(C₆H₂)[-(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—,

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_cis selected from:

C)

(d) —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) —R^12b—CH(NH—R—Y′—ONO₂)(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—

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,

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

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—],

D6) —CH₂—NH—, —(CH₂)₂—NH—, —(CH₂)₃—NH—, —(CH₂)₄—NH—,

D7) —CH₂—C(O)—, —(CH₂)₂—C(O)—(CH₂)₄—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—,

D9) —HN—CH₂—, —HN—(CH₂)₂—, —HN—(CH₂)₃—HN—(CH₂)₄—,

D10) —C(O)—CH₂—C(O)—(CH₂)₂—C(O)—(CH₂)₄

R^4ais as above defined;

or R_xis selected from:

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;

(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;

wherein R₃is 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;

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

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;

wherein T and T′ are as above defined and Y is as below reported;

wherein T and T′ are as above defined and Y is as below reported;

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;

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;

wherein T and T″ are as above defined and Y is as below reported;

wherein T and T′ are as above defined and Y is as below reported;

wherein T and T are as above defined and Y is as below reported;

wherein T and T′ are as above defined and Y is as below reported;

wherein T and T′ are as above defined and Y is as below reported;

wherein R₉and R₁₀are H, CH₃, R₁₁is CH₃or 4-piperidinyl with the proviso that R₉and R₁₀are H when R₁₁is 4-piperidinyl and R₉and are CH₃when R₁₁is CH₃, T and T are as above defined and Y is as below reported;

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), (hi), (i1), (12), (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), (ml), (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;

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;

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;

wherein

n⁰is an integer from 0 to 20;

n¹is 0 or 1;

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

wherein

n⁰is an integer from 0 to 20;

n¹is 0 or 1;

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;

n²is an integer from 0 to 2;

R₁₃is H or CH₃;

Y¹is —CH₂—CH₂— or —CH═CH—(CH₂)_n ^2′—, wherein n^2′ is 0 or 1;

T1=—O—C(O)— or —C(O)O—;

n¹is 0 or 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;

wherein:

n²is an integer from 0 to 2;

R₁₃is H or CH₃;

Y¹is —CH₂—CH₂— or —(CH₂)_n ^2′—CH═CH— wherein n^2′, 0 or 1;

(T₁)′=—O—C(O)—;

n¹is 0 or 1;

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

wherein T₂is —O— or —S—, —NH;

n³is an integer from 1 to 6;

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) and -(T″′-Y′—ONO₂) is linked to the —(CH₂)*— group;

wherein:

n⁴is an integer from 0 to 10; n⁵•

n⁵is an integer from 1 to 10;

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

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:

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

a is 0 or a is 1 and Z is —CH(R′)—O— wherein R′ is selected from H or straight or branched C₁-C₄alkyl;

R_xis selected from the following meanings

(a2) wherein R₁is selected from A1), A2), A3) or A4);

(a4) wherein R^1ais selected from A5), A6) or A7);

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

(a8) wherein R^1ais selected from A5) or A6) or A7);

(b2) wherein R₂is selected from B1);

(g2) wherein R₃is H;

T′ is —C(O)—, —C(O)—X″—, —O— or —S—, or —C(O)—NR′, wherein X″ and R′ are as above defined;

T″ is independently selected from —C(O)—, —O—CH(R′)—O—C(O)—, —C(O)—X″—, wherein X″ is —O— or —S—, —NR′—;

Y and Y′ are bivalent radicals independently selected from

a)

straight or branched C₁-C₂₀alkylene;

straight or branched d-do alkylene substituted with one or more of the substituents selected from the group consisting of: halogen atoms, hydroxy, —ONO₂or 12, wherein T₂is —OC(O)(C₁-C₁₀alkyl) ONO₂or —O(C₁-C₁₀alkyl)-ONO₂;

b)

wherein

n° is an integer from 0 to 20;

n¹is 0 or 1;

n is an integer from 0 to 2;

R₁₃is H or CH₃;

Y¹is —CH₂—CH₂— or —CH═CH(CH₂)_n ^2′—, wherein n^2′ is 0 or 1; T₁=—O—C(O)— or —C(O)O—;

n¹is 0 or 1;

R₁₃is CH₃, Y¹is —CH═CH—(CH₂)_n ^2′— and e is 0, T₁is —C(O)O— and

U is a linear C₁-C₁₀alkylene;

wherein T₂is —O— or —S—, —NH;

n³is an integer from 1 to 6;

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.

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

a is 0 or a is 1 and Z is —CH(R)—O— wherein R′ is selected from H or straight or branched C₁-C₄alkyl;

R_xis

(a2) wherein

R₁of the group AI) is selected from H, isobutyl, benzyl, C₆H₅—CH₂—CH₂—, 2-monosubstituted benzyl, or 3-monosubstituted benzyl or 4-monosubstituted benzyl, 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

R₁of the group A4) is selected from —CH₂—C(O)R″′, —(CH₂)₂—C(O)R″′, —(CH₂)₄—C(O)R″′ wherein R″′ is OH;

or R_xis

(a4) 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)—;

or R_xis selected from

(a5), (a6), (a9) or (a10) wherein

R^1bof the group A10) is selected from —C(O) CH₂—C(O)—(CH₂)₂—, —C(O)—(CH₂)₄—;

or R_xis

(a8) 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)—;

or R_xis

(b2) 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—, or —C(O)—NR′—;

T″ is independently selected from C(O)—, —C(O)—X″, wherein X″ is —S— or —O—, —C(O)—NR′—, —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)—;

Y and Y′ are bivalent radicals independently selected from

a) C₁-C₁₀alkylene or a C₁-C₁₀alkylene substituted with —ONO₂,

b) wherein n¹is 0 or n¹is 1;

e) wherein n²is 1, R₁₃is CH₃, Y¹is —CH═CH—(CH₂)_n ^2′—, wherein n^2′ is 0 and T₁is —C(O) and n¹is 0 or 1, U is a C₁-C₁₀alkylene optionally substituted with a —ONO₂group;

f) wherein T₂is —O, R₁₃is H and n3 is 1.

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

a is 1 and Z is —C(O)—;

R_xis selected from

(a1) wherein R₁is selected from A1), A2), A3) or A4);

(a3) wherein R^1ais selected from A5), A6) or A7);

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

(a7) wherein R^1ais selected from A5) or A6) or A7);

(b1) wherein R₂is selected from B1);

(d1) or (d2) wherein R₁₂is selected from D1), D2), D3) or D4);

(d3), (d4), (d7) or (d8) wherein R^12ais selected from D5), D6) or D7);

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

(g1) wherein R₃is H;

T″ is independently selected from —C(O)—, —C(O)—X″, wherein X″ is —S— or —O—, —C(O)—NR′—, —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)—;

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

Y and Y′ are bivalent radicals independently selected from

a)

straight or branched C₁-C₂₀alkylene;

wherein

n⁰is an integer from 0 to 20;

n¹is 0 or 1;

U is a linear or branched 01-C₂₀alkylene optionally substituted with a —ONO₂group;

n²is an integer from 0 to 2;

R¹³is H or CH₃;

T₁=—O—C(O)— or —C(O)O—;

n¹is 0 or 1;

wherein T₂is —O— or —S—, —NH;

n³is an integer from 1 to 6;

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.

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

a is 1 and Z is —C(O)—;

R_xis

(a1) 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, or

R₁of the group A2) is selected from —CH₂OH, —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

R₁of the group A4) is —CH₂—C(O)R″′, —(CH₂)₂—C(O)R″′, —(CH₂)₄—C(O)R″′ wherein R″′ is OH;

or R_xis

(a3) 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)—;

or R_xis

(a5), (a6), (a9) or (a10) wherein

R^1bof the group A8) is selected from —O—CH(CH₃)—, —O—CH₂-[(4-O)-(06H₄)]—CH₂—, or

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

or R_xis

(a7) wherein

R^1aof the group A6) is selected from —CH₂—NH—, —(CH₂)₂—NH—(CH₂)₃—NH—, —(CH₂)₄—NH— or

or R_xis

(b1) wherein

R₂of the group B1) is selected from H, CH₃, isobutyl, isopropyl, benzyl;

or R_xis selected from

(d1) or (d2), wherein

R₁₂of the group Di) 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 CH₂C(O)R″, —(CH₂)₂—C(O)R″′, —(CH₂)₄—C(O)R″′ wherein R″′ is OH;

or R_xis selected from

(d3), (d4), (d7) or (d8) 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)—;

or R_xis selected from

(d5), (d6), (d9) or (d10) wherein

R^12bof the group D8) is selected from —O—CH(CH₃)—, —O—CH₂—, [(4-O)—(C₆H₄)]-CH₂— or

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

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

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

Y and Y′ are bivalent radicals independently selected from

a) C₁-C₁₀alkylene or a C₁-C₁₀alkylene substituted with —ONO₂,

b) wherein n¹is 0 or n¹is 1

e) wherein n²is 1, R₁₃is CH₃, Y¹is —CH═CH(CH₂)_n ^2′—, wherein n^2′ is 0 and T₁is —C(O) and n¹is 0 or 1, U is a C₁-C₁₀alkylene optionally substituted with a —ONO₂group;

f) wherein T₂is —O, R₁₃is H and n³is 1.

6. The nitric oxide releasing compounds according to claim 1 wherein a is 0or a is 1 and Z is —CH(R′)—O—;

R_xis selected from

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

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

Y and Y′ are bivalent radicals independently selected from

a) C₁-C₁₀alkylene or a C₁-C₁₀alkylene substituted with —ONO₂,

b) wherein n¹is 0 or n¹is 1;

f) wherein T₂is —O, R₁₃is H and n³is 1.

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

A is 1 and Z is —C(O)—;

R_xis

(d1) wherein

R₁₂is selected from D1);

T″ is independently selected from —C(G), —C(O)—X″, wherein X″ is —O—, or —C(O)—NR′—;

Y and Y′ are bivalent radicals independently selected from

a) C₁-C₁₀alkylene or a C₁-C₁₀alkylene substituted with —ONO₂,

b) wherein n¹is 0 or n¹is 1;

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

R is the corticosteroid residue of formula (II) wherein

R₁is OH and it is linked to the carbon atoms in 17 of the steroidal structure in position α;

R₂is CH₃and it is linked to the carbon atoms in 16 of the steroidal structure in position β;

R₃is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R_8Ais H;

R₈and R₉form a double bond;

R₁₀is F and it is linked to the carbon atoms in 9 of the steroidal structure in position α;

R_11Ais H;

R₁₂is H;

or wherein R is the corticosteroid residue of formula (II) wherein

R₂is H;

R₃is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R_8Ais H;

R₈and R₉form a double bond;

R_11Ais H;

R₁₂is H;

or wherein R is the corticosteroid residue of formula (II) wherein

R₁and R₂are taken together to form a group of formula (III) wherein RAL is CH₃and R_A2is H, and R₁and R₂are linked to the carbon atoms in 17 and 16 of the steroidal structure in position α,

R₃is H;

R₄is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R_8Ais H;

R₈and R₉form a double bond;

R_11Ais H;

R₁₂is H;

or wherein R is the corticosteroid residue of formula (II) wherein

R₁is OC(O)O_mR_iwherein m is 0 and R_jis —CH₂CH₃and it is linked to the carbon atoms in 17 of the steroidal structure in position α;

R₃is H;

R₄is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R_8Ais H;

R₈and R₉form a double bond;

R_11Ais H;

R₁₂is H;

or wherein R is the corticosteroid residue of formula (II) wherein

R₂is CH₃and it is linked to the carbon atoms in 16 of the steroidal structure in position α;

R₃is H;

R₄is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R_8Ais H;

R₈and R₉form a double bond;

R_11Ais H;

R₁₂is H;

or wherein R is the corticosteroid residue of formula (II) wherein

R₂is H;

R₃is H;

R₄is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R₈is H;

R_8Ais H;

R₉is H;

R₁₀is H;

R_11Ais H;

R₁₂is H;

or wherein R is the corticosteroid residue of formula (II) wherein

R₂is H;

R₃is H;

R₄is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R_8Ais H;

R₈and R₉form a double bond;

R₁₀is H;

R_11Ais H;

R₁₂is H;

or wherein R is the corticosteroid residue of formula (II) wherein

R₂is OH and it is linked to the carbon atoms in 16 of the steroidal structure in position α;

R₃is H;

R₄is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R_8Ais H;

R₈and R₉form a double bond;

R_11Ais H;

R₁₂is H;

9. The nitric oxide releasing compounds according to claim 3 wherein

R is the corticosteroid residue of formula (II) wherein

R₃is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R_8Ais H;

R₈and R₉form a double bond;

R₁₁is OH and it is linked to the carbon atoms in 11 of the steroidal structure in position [3;

R_11Ais H;

R₁₂is H;

or wherein R is the corticosteroid residue of formula (II) wherein

R₂is H;

R₃is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R_8Ais H;

R₈and R₉form a double bond;

R_11Ais H;

R₁₂is H;

or wherein R is the corticosteroid residue of formula (II) wherein

R₁and R₂are taken together to form a group of formula (III) wherein R_A1is CH₃and R_A2is H, and R₁and R₂are linked to the carbon atoms in 17 and 16 of the steroidal structure in position α,

R₃is H;

R₄is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R_8Ais H;

R₈and R₉form a double bond;

R_11Ais H;

R₁₂is H;

or wherein R is the corticosteroid residue of formula (II) wherein

R₁is OC(O)O_mR_jwherein m is 0 and R_iis —CH₂CH₃and it is linked to the carbon atoms in 17 of the steroidal structure in position α;

R₃is H;

R₄is H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R_8Ais H;

R₈and R₉form a double bond;

R_11Ais H;

R₁₂is H;

or wherein R is the corticosteroid residue of formula (II) wherein

R₃is H;

R₄is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R_8Ais H;

R₈and R₉form a double bond;

R_11Ais H;

R₁₂is H;

or wherein R is the corticosteroid residue of formula (II) wherein

R₂is H;

R₃is H;

R₄is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R₈is H;

R_8Ais H;

R₉is H;

R₁₀is H;

R_11Ais H;

R₁₂is H;

or wherein R is the corticosteroid residue of formula (II) wherein

R₂is H;

R₃is H;

R₄is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R_8Ais H;

R₈and R₉form a double bond;

R₁₀is H;

R_11Ais H;

R₁₂is H;

or wherein R is the corticosteroid residue of formula (II) wherein

R₃is H;

R₄is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R_8Ais H;

R₈and R₉form a double bond;

R_11Ais H;

R₁₂is H;

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

R is the corticosteroid residue of formula (II) wherein

R₃is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R_8Ais H;

R₈and R₉form a double bond;

R_11Ais H;

R₁₂is H;

or wherein R is the corticosteroid residue of formula (II) wherein

R₂is H;

R₃is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R_8Ais H;

R₈and R₉form a double bond;

R_11Ais H;

R₁₂is H;

or wherein R is the corticosteroid residue of formula (II) wherein

R₃is H;

R₄is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R_8A, is H;

R₈and R₉form a double bond;

R_11Ais H;

R₁₂is H;

or wherein R is the corticosteroid residue of formula (II) wherein

R₁is OC(O)O_mR_iwherein m is 0 and R_iis —CH₂CH₃and it is linked to the carbon atoms in 17 of the steroidal structure in position α;

R₃is H;

R₄is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R_8Ais H;

R₈and R₉form a double bond;

R_11Ais H;

R₁₂is H;

or wherein R is the corticosteroid residue of formula (II) wherein

R₃is H;

R₄is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R_8Ais H;

R₈and R₉form a double bond;

R_11Ais H;

R₁₂is H;

or wherein R is the corticosteroid residue of formula (II) wherein

R₂is H;

R₃is H;

R₄is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R₈is H;

R_8Ais H;

R₉is H;

R₁₀is H;

R_11Ais H;

R₁₂is H;

or wherein R is the corticosteroid residue of formula (II) wherein

R₂is H;

R₃is H;

R₄is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R_8Ais H;

R₈and R₉form a double bond;

R₁₀is H;

R_11Ais H;

R₁₂is H;

or wherein R is the corticosteroid residue of formula (II) wherein

R₃is H;

R₄is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R_8Ais H;

R₈and R₉form a double bond;

R_{11A is H;}

R₁₂is H;

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

R is the corticosteroid residue of formula (II) wherein

R₃is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R_8Ais H;

R₈and R₉form a double bond;

R_11Ais H;

R₁₂is H;

or wherein R is the corticosteroid residue of formula (II) wherein

R₂is H;

R₃is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R_8Ais H;

R₈and R₉form a double bond;

R_11Ais H;

R₁₂is H;

or wherein R is the corticosteroid residue of formula (II) wherein

R₃is H;

R₄is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R_8Ais H;

R₈and R₉form a double bond;

R_11Ais H;

R₁₂is H;

or wherein R is the corticosteroid residue of formula (II) wherein

R₁is OC(O)O_mRⁱwherein m is 0 and R_iis —CH₂CH₃and it is linked to the carbon atoms in 17 of the steroidal structure in position α;

R₃is H;

R₄is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R_8Ais H;

R₈and R₉form a double bond;

R_11Ais H;

R₁₂is H;

or wherein R is the corticosteroid residue of formula (II) wherein

R₃is H;

R₄is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R_8Ais H;

R₈and R₉form a double bond;

R_11Ais H;

R₁₂is H;

or wherein R is the corticosteroid residue of formula (II) wherein

R₂is H;

R₃is H;

R₄is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R₈is H;

R_8Ais H;

R₉is H;

R₁₀is H;

R_11Ais H;

R₁₂is H;

or wherein R is the corticosteroid residue of formula (II) wherein

R₂is H;

R₃is H;

R₄is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R_8Ais H;

R₈and R₉form a double bond;

R₁₀is H;

R_11Ais H;

R₁₂is H;

or wherein R is the corticosteroid residue of formula (II) wherein

R₃is H;

R₄is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R_8Ais H;

R₈and R₉form a double bond;

R_11Ais H;

R₁₂is H;

12. The nitric oxide releasing compounds according to claim 6 wherein

R is the corticosteroid residue of formula (II) wherein

R₁₁is OH and it is linked to the carbon atoms in 17 of the steroidal structure in position α;

R₃is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R_8Ais H;

R₈and R₉form a double bond;

R_11Ais H;

R₁₂is H;

or wherein R is the corticosteroid residue of formula (II) wherein

R₂is H;

R₃is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R_8Ais H;

R₈and R₉form a double bond;

R_11Ais H;

R₁₂is H;

or wherein R is the corticosteroid residue of formula (II) wherein

R₃is H;

R₄is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R_8Ais H;

R₈and R₉form a double bond;

R_11Ais H;

R₁₂is H;

or wherein R is the corticosteroid residue of formula (II) wherein

R₃is H;

R₄is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R_8Ais H;

R₈and R₉form a double bond;

R₁₁is OH and it is linked to the carbon atoms in 11 of the steroidal structure in position f3;

R_11Ais H;

R₁₂is H;

or wherein R is the corticosteroid residue of formula (II) wherein

R₃is H;

R₄is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R_8Ais H;

R₈and R₉form a double bond;

R_11Ais H;

R₁₂is H;

or wherein R is the corticosteroid residue of formula (II) wherein

R₂is H;

R₃is H;

R₄is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R₈is H;

R_8Ais H;

R₉is H;

R₁₀is H;

R_11Ais H;

R₁₂is H;

or wherein R is the corticosteroid residue of formula (II) wherein

R₂is H;

R₃is H;

R₄is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R_8Ais H;

R₈and R₉form a double bond;

R₁₀is H;

R_11Ais H;

R₁₂is H;

or wherein R is the corticosteroid residue of formula (II) wherein

R₃is H;

R₄is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R_8Ais H;

R₈and R₉form a double bond;

R_11Ais H;

R₁₂is H;

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

R is the corticosteroid residue of formula (II) wherein

R₃is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R_8Ais H;

R₈and R₉form a double bond;

R_11Ais H;

R₁₂is H;

or wherein R is the corticosteroid residue of formula (II) wherein

R₂is H;

R₃is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R_8Ais H;

R₈and R₉form a double bond:

R_11Ais H;

R₁₂is H;

or wherein R is the corticosteroid residue of formula (II) wherein

R₃is H;

R₄is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R_8Ais H;

R₈and R₉form a double bond;

R_11Ais H;

R₁₂is H;

or wherein R is the corticosteroid residue of formula (II) wherein

R₃is H;

R₄is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R_8Ais H;

R₈and R₉form a double bond;

R_11Ais H;

R₁₂is H;

or wherein R is the corticosteroid residue of formula (II) wherein

R₃is H;

R₄is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R_{8A is H;}

R₈and R₉form a double bond;

R_11Ais H;

R₁₂is H;

or wherein R is the corticosteroid residue of formula (II) wherein

R₂is H;

R₃is H;

R₄is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R₈is H;

R_8Ais H;

R₉is H;

R₁₀is H;

R_11Ais H;

R₁₂is H;

or wherein R is the corticosteroid residue of formula (II) wherein

R₂is H;

R₃is H;

R₄is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R_8Ais H;

R₈and R₉form a double bond;

R₁₀is H;

R_11Ais H;

R₁₂is H;

or wherein R is the corticosteroid residue of formula (II) wherein

R₃is H;

R₄is H;

R_4Ais H;

R₅and R₆form a double bond;

R₇and R_7Aare ═O;

R_8Ais H;

R₈and R₉form a double bond;

R_11Ais H;

R₁₂is H;

14. (canceled)

15. (canceled)

16. Nitric oxide releasing compounds according to claim 9

17. Nitric oxide releasing compounds according to claim 11

18. Nitric oxide releasing compounds according to claim 13

19. Compounds according to claim 1 for use as a medicament.

20. Use of compounds according to claim 1 wherein R is the corticosteroid residue of formula (II) is selected from the group consisting of dexamethasone, dexamethasone-17-acetate, dexamethasone-17-propionate, prednisolone, prednisone, or (11β,16β)-16,17-[[(R)-cyclohexylmethylene]bis(oxy)-11,21-dihydroxy-pregna-1,4-diene-3,20-dione, for the preparation of medicaments for the treatment of respiratory diseases.

21. Use of compounds according to claim 1 wherein R is the corticosteroid residue of formula (II) is selected from the group consisting of dexamethasone, hydrocortisone, methylprednisoione, prednisolone, prednisone, triamcinolone, [(8R,10S,13S,14R,17R)-hydroxy-10,13-dimethyl-3-oxo-2,6,7,8,12,14,15,16-octahydro-1H-cyclopenta[a]phenanthren-17-yl]-2-oxo-ethanol; diflorasone, diflorasone-17-acetate or (11β,16β)-16,17-[[(R)-cyclohexylmethylene]bis(oxy)-11,21-dihydroxyl-pregna-1,4-diene-3,20-dione, for the preparation of medicaments for the treatment of ocular diseases.

22. Use of compounds according to claim 1 wherein R is the corticosteroid residue of formula (II) is selected from the group consisting of betamethasone 17-benzoate, betamethasone 17-butyrate, betamethasone 17-valerate, cloprednol, corticosterone, cortisone, dexamethasone, fludrocortisone, flucloronide, fluocortolone, fluprednisolone, hydrocortisone, meprednisone, methylprednisoione, paramethasone, prednisolone, prednisone, prednival, prednylidene, triamcinolone, 5-pregnene-36,21-diol-20-one, 6,16α-dimethyl-11β, 17a,21-trihydroxy-2′-phenyl[3,2-c]pyrazolo-4,6-pregnadien-20-one; (11β,16β)-11,21-dihydroxy-2′-methyl-5′H-pregna-1,4-dieno [17,16-o]oxazole-3,20-dione, (11β,16β)-11,21-dihydroxy-9-fluoro-2′-methyl-5′H-pregna-1,4-dieno[17,16-d]oxazole-3,20-dione or 3-(2-chloroethoxy)-9-fluoro-11β,16α,17,21-tetrahydroxy-20-oxopregna-3,5-diene-6-carboxaldehyde, for the preparation of medicaments for the treatment of inflammatory diseases.

23. Use of compounds according to claim 1 wherein R is the corticosteroid residue of formula (II) is selected from the group consisting of alclometasone, betamethasone-17-butyrate, betamethasone-17-propionate, betamethasone-17-benzoate, betamethasone-17-valerate, clocortolone, desonide, desoximethasone, dexamethasone, dexamethasone-17-acetate, dexamethasone-17-propionate, diflorasone, diflorasone-17-acetate, difluocortolone, flumethasone, flucloronide, fluocortolone, flurandrenolide, halomethasone, halomethasone-17-propionate, hydrocortisone, hydrocortisone-17-butyrate, hydrocortisone-17-valerate, methylprednisolone, prednisolone-17-ethylcarbonate, triamcinolone, alclomethasone 17-propionate, (11β,16α)-16,17-[cyclopentylidenebis(oxy)]-11,21-dihydroxy-9-fluoro-pregna-1,4-diene-3,20-dione; (6α,11β)-6,9-difluoro-11,21-dihydroxy-17-(1-oxobutoxy)pregna-1,4-diene-3,20-dione; (6α,11β,16α)-6,9-difluoro-11,21-dihydroxy-16,17-[(1-methylethylidene)bis(oxy)]pregna-1,4-diene-3,20-dione; fluprednidene or halopredone, for the preparation of medicaments for the treatment of dermatological diseases.

24. A pharmaceutical formulation comprising a compound of formula (I) according to claim 1 and a pharmaceutically acceptable vehicle and/or carrier.