"New NO releasing steroids derivatives"

The present invention relates to nitrooxy derivatives of known steroids, methods for their preparation, pharmaceutical compositions containing these compounds, and methods of using these compounds and compositions for treating 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-NO2 group. In said patent it is stated that said derivatives have a cardiotropic activity. This activity represents a drawback for said compounds, since they modify the cardiac frequency.

USP 3,494,941 describes steroid derivatives from 3- hydroxy-extrane or from extr-4 en-3 one, used as vasodilators in the treatment of cardiac affections such as coronary insufficiency and angina pectoris. In the structure of said compounds a ONO2 group is at the free end of the alkylene chain which is linked by an ether bond to the steroid in position 17. According to said patent it is possible to have nitrate groups also in the positions 3 and 16 of the steroidal structure. The same drawbacks mentioned above as regards the effects on the cardiac frequency can be repeated for the compounds of this patent.

USP 3,183,252 describes derivatives of 16-nitrate- 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.

EP 1 336 602 describes new pharmacological compounds which can release nitric oxide and their use for the prevention and treatment of inflammatory, ischemic, degenerative and proliferative diseases. These compounds have a slower absorption compared to classic nitrate vasodilators. Between the compounds, steroidal nitroderivatives are disclosed.

WO 00/499993 describes nitrite, nitrate, thionitrite or thionitrate steroid derivatives optionally substituted in position 3, 11, 17 or 21 with a nitrate ester.

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.

An object of the present invention is a compound of general formula (I) and pharmaceutically acceptable salts or stereoisomers thereof

(D wherein :

Ri is -H or Ri is selected from

(A) -R^CH(NHR ² ) -C (0) -0-Y

(B) -R^CH (COOH) NH-C(O) -Y

(C) -R^CH(COOH)-O-C(O)-Y

(D) -C(O)CH(R ³ ) -NH-C(O) -Y

(E) -C (O)CH ₂ -CH(R ⁴ ) -NH-C (0) -Y

(F) -(Z)-Y (G)

(H)

:D wherein :

R ¹ is selected from R ^la )

-C(O)-S-CH ₂ -, -C(O)O-CH(CH ₃ )-, -C(O)O-CH ₂ -; preferably R ^la is

R Ib' -C(O)-CH ₂ -, -C(O) - (CH ₂ ) ₂ -; preferably R ⁱⁱ³ is -C(O)-CH ₂ -; R ² is -H or -C(O)CH ₃ ;

R ³ is -H, -CH ₃ , isopropyl, isobutyl, sec-butyl, methylthio- (CH ₂ ) ₂ -, benzyl, preferably R ³ is H or -CH ₃ ; R ⁴ is -H, -CH ₃ , isopropyl, isobutyl, sec-butyl, methylthio- (CH ₂ ) ₂ -, benzyl, preferably R ⁴ is H or -CH ₃ ;

Z is -C(O) or -C(O)-X", wherein X" is 0, S or NR ₁₁ wherein R ₁₁ is H or a C ₁ -C ₄ alkyl; preferably X" is 0;

R ₂ is a straight or branched C ₁ -C _1O alkylene; preferably R ₂ is a straight C ₁ -Ce alkylene; R ₃ is H or a straight or branched C ₁ -C ₄ alkyl, preferably R ₃ is H or -CH _3/ more preferably R ₃ is H; R ₄ is -H, -CH ₃ ; R _4A is -H, or R ₄ and R _4A taken together are =CH ₂ ; R ₅ is -H, Cl;

R ₆ is -H, Cl, F, CH ₃ ; R _6a is -H, or R ₆ and R ₅ taken together are a double bond;

R _7a is H, or R ₇ and R _7A taken together are a =0; R ₈ is H, Cl, or R ₇ and R ₈ taken together are the group of formula (V)

Rsa is H, R ₉ is -H, or R _8a and Rg taken together are a double bond Rio is -OH, RiOa is H, or Rio and Rio _a taken together are =0; Rn is -H, -Cl, -F;

Ri ₂ is -H, CH ₃ ; wherein R ₄ , R _4a , R ₅ , R ₆ , R _6a , R7, R7a, Rs, Rβa, R9, Rio, Rioa can be linked to the corresponding carbon atoms of the steroidal structure in position α or β; Y is selected from -Ri ₃ -CH(ONO ₂ )Ri ₄ -Ri ₃ -CH (ONO ₂ ) - (CRi ₅ Ri ₆ ) _t ~CH (ONO ₂ ) R _i4

- [ (CH ₂ ) o-X] p- [ (CH ₂ ) _r -X] _s - (CH ₂ ) _q - (CRi ₅ Ri ₆ ) t ^~ CH (ONO ₂ ) R _i4

- [ (CH ₂ ) _o -X] _p - [ (CH ₂ ) _r -X] _s - (CH ₂ ) _q -CH (ONO ₂ ) - (CRi ₅ Ri ₆ ) _t ^~ CH (ONO ₂ ) R ₁₄ wherein

Ri ₃ is a straight or branched C ₁ -C ₁₀ alkylene; preferably Ri ₃ is a straight Ci-C ₆ alkylene; Ri4 is H or a straight or branched Ci-C ₄ alkyl, preferably Ri ₄ is H or -CH ₃ ;

Ri ₅ and Ri ₆ are at each occurrence independently H or a straight or branched Ci-Cio alkylene, preferably Ri ₅ and Ri ₆ are H or -CH _3; o and r are integers from 1 to 6; preferably o and r are integers from 1 to 4, more preferably o is 1 and r is 2 ; p and s are integers from 1 to 6; preferably p and s are integers from 1 to 4; more preferably p and s are 1 ; q is an integer from 0 to 6; preferably q is from 0 to 4, more preferably q is 0 or 1 ; t is an integer from 0 to 6; preferably t is from 0 to 4, more preferably t is 0 or 1;

X is O, S or NRi ₇ wherein Ri ₇ is H or a C ₁ -C ₄ alkyl; preferably X is O; preferably Y is selected from -Ri ₃ -CH(ONO ₂ )Ri ₄

-Ri ₃ -CH (ONO ₂ ) - (CRi ₅ Ri ₆ ) t"CH (ONO ₂ ) R _i4

- [ (CH ₂ ) o-X] p- [ (CH ₂ ) _r -X] _s - (CH ₂ ) _q - (CRi ₅ Ri ₆ ) t~CH (ONO ₂ ) R ₁₄ wherein

Ri ₃ is a straight Ci-C ₆ alkylene; Ri ₄ is H or -CH ₃ ;

Ri ₅ and Ri ₆ at each occurrence are independently H or -CH ₃ ; o and r are integers from 1 to 4, p and s are from 1 to 4; q is from 0 to 4, t is 0 or 1, X is 0; excluding the following structures from formula (I) :

Another embodiment of the present invention relates to compounds of formula (I) wherein Ri is selected from (A) -R^CH(NHR ² ) -C (0) -0-Y (B) -R^CH (COOH) NH-C (O) -Y (C) -R^CH (COOH) -0-C (0) -Y (D) -C (0) CH (R ³ ) -NH-C (0) -Y (E) -C (0) CH ₂ -CH (R ⁴ ) -NH-C (0) -Y (F) -(Z)-Y (G)

wherein :

R ¹ is selected from R ^la )

-C(O)-S-CH ₂ -, -C(O)O-CH(CH ₃ )-, -C(O)O-CH ₂ -; preferably R ^la is

-C(O)-CH ₂ -, -C(O)-(CH ₂ ) ₂ -; preferably R ^lb is -C(O)-CH ₂ -; R ² is -H or -C(O)CH ₃ ; R ³ is -H, -CH3, isopropyl, isobutyl, sec-butyl, methylthio- (CH ₂ ) ₂ -, benzyl, preferably R ³ is H; R ⁴ is -H, -CH3, isopropyl, isobutyl, sec-butyl, methylthio- (CH ₂ ) ₂ -, benzyl, preferably R ⁴ is H;

Z is -C(O) or -C(O)-X", wherein X" is 0, S or NR ₁₁ wherein R ₁₁ is H or a C ₁ -C ₄ alkyl; preferably X" is 0;

R ₂ is a straight or branched C ₁ -C ₁ O alkylene; preferably R ₂ is a straight C ₁ -C ₅ alkylene;

R ₃ is H or a straight or branched C ₁ -C ₄ alkyl, preferably R ₃ is H or -CH _3;

R ₄ is -CH ₃ , and it is linked to the 16 position of the steroidal structure in position β; R _4A is -H; R ₅ is -H; R ₆ is -H; R _6a is —H;

R ₇ and R _7A taken together are a =0; R ₈ is H;

Rs _a and Rg taken together are a double bond;

R _1O is -OH, and it is linked to the corresponding carbon atoms of the steroidal structure in position α;

R ₁ Oa is H; R ₁₁ is -F;

R ₁₂ is -H, CH ₃ ; Y is selected from -R ₁₃ -CH(ONO ₂ )R ₁₄

-R ₁₃ -CH (ONO ₂ ) - (CR ₁₅ R ₁₆ ) t ^~ CH (ONO ₂ ) R ₁₄ -[ (CH ₂ ) _O -X _-P -. (CH ₂ ) _r -X] _s - (CH ₂ ) _q - (CR ₁₅ R ₁₆ ) t-CH (ONO ₂ ) R ₁₄

- [ (CH ₂ ) _o -X] p- [ (CH ₂ ) _r -X] _s - (CH ₂ ) _q -CH (ONO ₂ ) - (CR ₁₅ R ₁₆ ) _t -CH (ONO ₂ ) R ₁₄ wherein Ri3 is a straight or branched Ci-Cio alkylene; preferably Ri3 is a straight Ci-C ₆ alkylene;

Ri4 is H or a straight or branched Ci-C ₄ alkyl, preferably Ri ₄ is H or -CH ₃ ; Ri ₅ and Ri ₆ are at each occurrence independently H or a straight or branched Ci-Cio alkylene, preferably Ri ₅ and Ri ₆ are H or -CH _3; o and r are integers from 1 to 6; preferably o and r are integers from 1 to 4, more preferably o is 1 and r is 2 ; p and s are integers from 1 to 6; preferably p and s are integers from 1 to 4; more preferably p and s are 1 ; q is an integer from 0 to 6; preferably q is from 0 to 4, more preferably q is 0 or 1 ; t is an integer from 0 to 6; preferably t is from 0 to 4, more preferably t is 0 or 1 ;

X is O, S or NRi ₇ wherein Ri ₇ is H or a C ₁ -C ₄ alkyl; preferably X is O; preferably Y is selected from -Ri ₃ -CH(ONO ₂ )Ri ₄ -Ri ₃ -CH (ONO ₂ ) - (CRi ₅ Ri ₆ ) t"CH (ONO ₂ ) R _i4

- [ (CH ₂ ) o-X] p- [ (CH ₂ ) _r -X] _s - (CH ₂ ) _q - (CRi ₅ Ri ₆ ) t~CH (ONO ₂ ) R ₁₄ wherein

Ri ₃ is a straight Ci-C ₆ alkylene; Ri ₄ is H or -CH ₃ ; Ri ₅ and Ri ₆ at each occurrence are independently H or -CH ₃ ; o and r are integers from 1 to 4, p and s are from 1 to 4; q is from 0 to 4, t is 0 or 1, x is 0. Another embodiment of the present invention relates to compounds of formula (I) wherein Ri is selected from

(A) -R^CH(NHR ² ) -C (O) -O-Y

(B) -R^CH (COOH) NH-C (O) -Y

(C) -R^CH (COOH) -0-C(O)-Y

(D) -C (O)CH(R ³ ) -NH-C (0) -Y

(E) -C(O)CH ₂ -CH(R ⁴ ) -NH-C(O) -Y

(F) -(Z)-Y (G)

(H)

:D wherein :

R ¹ is selected from R ^la )

-C(O)-S-CH ₂ -, -C(O)O-CH(CH ₃ )-, -C(O)O-CH ₂ -; preferably R ^la is -C(O)-CH ₂ -, -C(O)-(CH ₂ ) ₂ -; preferably R ^lb is -C(O)-CH ₂ -;

R ² is -H or -C(O)CH ₃ ; R ³ is -H, -CH ₃ , isopropyl, isobutyl, sec-butyl, methylthio- (CH ₂ ) ₂ -, benzyl, preferably R ³ is H; R ⁴ is -H, -CH ₃ , isopropyl, isobutyl, sec-butyl, methylthio- (CH ₂ ) ₂ -, benzyl, preferably R ⁴ is H;

Z is -C(O) or -C(O)-X", wherein X" is 0, S or NR ₁₁ wherein R ₁₁ is H or a C ₁ -C ₄ alkyl; preferably X" is 0;

R ₂ is a straight or branched C ₁ -C ₁ O alkylene; preferably R ₂ is a straight C ₁ -C ₅ alkylene;

R ₃ is H or a straight or branched C ₁ -C ₄ alkyl, preferably R ₃ is H or -CH _3; R ₄ is -CH ₃ , and it is linked to the corresponding carbon atoms of the steroidal structure in position β; R _4A is -H; R ₅ is -H;

Re is -F and it is linked to the corresponding carbon atoms of the steroidal structure in position β; R _6a is -H;

R ₇ and R _7A taken together are a =0; R ₈ is H;

Rs _a and Rg taken together are a double bond; R ₁ O is -OH, and it is linked to the corresponding carbon atoms of the steroidal structure in position α; R ₁ Oa is H; Rn is -F; R ₁₂ is -H, CH ₃ ; Y is selected from

-R ₁₃ -CH(ONO ₂ )R ₁₄ -Ri ₃ -CH (ONO ₂ ) - (CRi ₅ Ri ₆ ) t"CH (ONO ₂ ) Ri ₄

- [ (CH ₂ ) o-X] p- [ (CH ₂ ) _r -X] _s - (CH ₂ ) _q - (CRi ₅ Ri ₆ ) t ^~ CH (ONO ₂ ) R ₁₄

- [ (CH ₂ ) _o -X] p- [ (CH ₂ ) _r -X] _s - (CH ₂ ) _q -CH (ONO ₂ ) - (CRi ₅ Ri ₆ ) _t ~CH (ONO ₂ ) R _i4 wherein Ri3 is a straight or branched Ci-Cio alkylene; preferably Ri3 is a straight Ci-C ₆ alkylene;

Ri ₄ is H or a straight or branched Ci-C ₄ alkyl, preferably Ri ₄ is H or -CH ₃ ;

Ri ₅ and Ri ₆ are at each occurrence independently H or a straight or branched Ci-Cio alkylene, preferably Ri ₅ and Ri ₆ are H or -CH ₃ ; o and r are integers from 1 to 6; preferably o and r are integers from 1 to 4, more preferably o is 1 and r is 2 ; p and s are integers from 1 to 6; preferably p and s are integers from 1 to 4; more preferably p and s are 1 ; q is an integer from 0 to 6; preferably q is from 0 to 4, more preferably q is 0 or 1 ; t is an integer from 0 to 6; preferably t is from 0 to 4, more preferably t is 0 or 1; X is 0, S or NR _i7 wherein R _i7 is H or a C ₁ -C ₄ alkyl; preferably X is 0; preferably Y is selected from -Ri ₃ -CH(ONO ₂ )Ri ₄

-Ri ₃ -CH (ONO ₂ ) - (CRi ₅ Ri ₆ ) _t "CH (ONO ₂ ) R _i4 -[ (CH ₂ )O-X _-P -. (CH ₂ ) _r -X] _s - (CH ₂ ) _q - (CRi ₅ Ri ₆ ) t-CH (ONO ₂ ) Ri ₄ wherein

Ri ₃ is a straight Ci-C ₆ alkylene; Ri ₄ is H or -CH ₃ ;

Ri ₅ and Ri ₆ at each occurrence are independently H or -CH ₃ ; o and r are integers from 1 to 4, p and s are from 1 to 4; q is from 0 to 4, t is 0 or 1, X is 0.

Another embodiment of the present invention relates to compounds of formula (I) wherein Ri is selected from

(A) -R^CH(NHR ² ) -C (O) -O-Y

(B) -R^CH (COOH) NH-C (O) -Y

(C) -R^CH(COOH)-O-C(O)-Y

(D) -C(O)CH(R ³ ) -NH-C(O) -Y

(E) -C (O)CH ₂ -CH(R ⁴ ) -NH-C (0) -Y

(F) -(Z)-Y (G)

(H)

:D wherein :

R ¹ is selected from R ^la )

-C(O)-S-CH ₂ -, -C(O)O-CH(CH ₃ )-, -C(O)O-CH ₂ -; preferably R ^la is

R ^lb )

-C(O)-CH ₂ -, -C(O) - (CH ₂ ) 2-; preferably R ^lb is -C(O)-CH ₂ -; R ² is -H or -C(O)CH ₃ ;

R ^J is -H, -CH ₃ , isopropyl, isobutyl, sec-butyl, methylthio- (CH ₂ ) ₂ -, benzyl, preferably R is H; R ⁴ is -H, -CH ₃ , isopropyl, isobutyl, sec-butyl, methylthio- (CH ₂ ) ₂ -, benzyl, preferably R ⁴ is H;

Z is -C(O) or -C(O)-X", wherein X" is 0, S or NR ₁₁ wherein R ₁₁ is H or a C ₁ -C ₄ alkyl; preferably X" is 0;

R ₂ is a straight or branched C ₁ -C ₁ O alkylene; preferably R ₂ is a straight C ₁ -C ₅ alkylene;

R ₃ is H or a straight or branched C ₁ -C ₄ alkyl, preferably R ₃ is H or -CH ₃ ; R ₄ is -H; R _4A is -H; R ₅ is -H; R ₆ is -H; R _6a is -H,

R ₇ and R _7A taken together are a =0; R ₈ is H; R _8a is H; R ₉ is -H;

R ₁ O is -OH, and it is linked to the corresponding carbon atoms of the steroidal structure in position α; R ₁ Oa is H; Rn is H;

Ri ₂ is -H, CH ₃ ; Y is selected from -Ri ₃ -CH(ONO ₂ )Ri ₄ -Ri ₃ -CH (ONO ₂ ) - (CRi ₅ Ri ₆ ) t"CH (ONO ₂ ) R _i4

- [ (CH ₂ ) o-X] p- [ (CH ₂ ) _r -X] _s - (CH ₂ ) _q - (CRi ₅ Ri ₆ ) t ^~ CH (ONO ₂ ) R ₁₄

- [ (CH ₂ ) _o -X] p- [ (CH ₂ ) _r -X] _s - (CH ₂ ) _q -CH (ONO ₂ ) - (CRi ₅ Ri ₆ ) _t ~CH (ONO ₂ ) R ₁₄ wherein

Ri ₃ is a straight or branched Ci-Cio alkylene; preferably Ri ₃ is a straight Ci-C ₆ alkylene;

Ri ₄ is H or a straight or branched Ci-C ₄ alkyl, preferably Ri ₄ is H or -CH ₃ ;

Ri ₅ and Ri ₆ are at each occurrence independently H or a straight or branched Ci-Cio alkylene, preferably Ri ₅ and Ri ₆ are H or -CH ₃ ; o and r are integers from 1 to 6; preferably o and r are integers from 1 to 4, more preferably o is 1 and r is 2; p and s are integers from 1 to 6; preferably p and s are integers from 1 to 4; more preferably p and s are 1; q is an integer from 0 to 6; preferably q is from 0 to 4, more preferably q is 0 or 1; t is an integer from 0 to 6; preferably t is from 0 to 4, more preferably t is 0 or 1;

X is 0, S or NRi ₇ wherein R ₁₇ is H or a C ₁ -C ₄ alkyl; preferably X is 0; preferably Y is selected from

-Ri ₃ -CH(ONO ₂ )Ri ₄

-Ri ₃ -CH (ONO ₂ ) - (CRi ₅ Ri ₆ ) _t "CH (ONO ₂ ) R _i4

- [ (CH ₂ ) o-X] p- [ (CH ₂ ) _r -X] _s - (CH ₂ ) _q - (CRi ₅ Ri ₆ ) t ^~ CH (ONO ₂ ) R ₁₄ wherein

Ri ₃ is a straight Ci-C ₆ alkylene; Ri ₄ is H or -CH ₃ ; Ri5 and Ri6 at each occurrence are independently H or -CH ₃ ; o and r are integers from 1 to 4, p and s are from 1 to 4 ; q is from 0 to 4, t is 0 or 1,

X is 0.

Another embodiment of the present invention relates to compounds of formula (I) wherein Ri is selected from

(A) -R^CH(NHR ² ) -C (O) -O-Y

(B) -R^CH(COOH)NH-C(O)-Y

(C) -R^CH(COOH)-O-C(O)-Y

(D) -C(O)CH(R ³ ) -NH-C(O) -Y

(E) -C (O)CH ₂ -CH(R ⁴ ) -NH-C (0) -Y

(F) -(Z)-Y (G)

(H)

:D

OMe wherein :

R ¹ is selected from

R )l ¹ a _\

-C(O)-S-CH ₂ -, -C(O)O-CH(CH ₃ )-, -C(O)O-CH ₂ -; preferably R ^la is

-C(O)-CH ₂ -, -C(O) - (CH ₂ ) ₂ -; preferably R ⁱⁱ³ is -C(O)-CH ₂ -; R ² is -H or -C(O)CH ₃ ;

R ³ is -H, -CH ₃ , isopropyl, isobutyl, sec-butyl, methylthio- (CH ₂ ) ₂ -, benzyl, preferably R ³ is H;

R ⁴ is -H, -CH ₃ , isopropyl, isobutyl, sec-butyl, methylthio- (CH ₂ ) ₂ -, benzyl, preferably R ⁴ is H; Z is -C(O) or -C(O)-X", wherein X" is 0, S or NR ₁₁ wherein R ₁₁ is H or a C ₁ -C ₄ alkyl; preferably X" is 0;

R ₂ is a straight or branched C ₁ -C _1O alkylene; preferably R ₂ is a straight C ₁ -C ₅ alkylene;

R ₃ is H or a straight or branched C ₁ -C ₄ alkyl, preferably R ₃ is H or -CH ₃ ;

R ₄ is -H;

R _4A is -H;

R ₅ is -H;

R ₆ is -H; R _6a is -H,

R ₇ and R _7A taken together are a =0;

R ₈ is H;

R _8a is H;

R ₉ is -H; Rio is -OH, and it is linked to the corresponding carbon atoms of the steroidal structure in position α;

Rioa is H;

Rn is H; Ri ₂ is -H, CH ₃ ;

Y is selected from

-Ri ₃ -CH(ONO ₂ )Ri ₄

-Ri ₃ -CH (ONO ₂ ) - (CRi ₅ Ri ₆ ) t ^~ CH (ONO ₂ ) R _i4

- [ (CH ₂ ) o-X] p- [ (CH ₂ ) _r -X] _s - (CH ₂ ) _q - (CRi ₅ Ri ₆ ) t ^~ CH (ONO ₂ ) R ₁₄ - [ (CH ₂ ) _o -X] p- [ (CH ₂ ) _r -X] _s - (CH ₂ ) _q -CH (ONO ₂ ) - (CRi ₅ Ri ₆ ) _t ~CH (ONO ₂ ) R ₁₄ wherein

Ri ₃ is a straight or branched Ci-Cio alkylene; preferably Ri ₃ is a straight Ci-C ₆ alkylene;

Ri ₄ is H or a straight or branched Ci-C ₄ alkyl, preferably Ri ₄ is H or -CH ₃ ;

Ri ₅ and R ₁₆ are at each occurrence independently H or a straight or branched Ci-Cio alkylene, preferably Ri ₅ and Ri ₆ are H or -CH ₃ ; o and r are integers from 1 to 6; preferably o and r are integers from 1 to 4, more preferably o is 1 and r is 2; p and s are integers from 1 to 6; preferably p and s are integers from 1 to 4; more preferably p and s are 1; q is an integer from 0 to 6; preferably q is from 0 to 4, more preferably q is 0 or 1; t is an integer from 0 to 6; preferably t is from 0 to 4, more preferably t is 0 or 1;

X is 0, S or NRi ₇ wherein Ri ₇ is H or a C ₁ -C ₄ alkyl; preferably X is 0; preferably Y is selected from -Ri ₃ -CH(ONO ₂ )Ri ₄

-Ri ₃ -CH (ONO ₂ ) - (CRi ₅ Ri ₆ ) _t ~CH (ONO ₂ ) R _i4

- [ (CH ₂ ) o-X] p- [ (CH ₂ ) _r -X] _s - (CH ₂ ) _q - (CRi ₅ Ri ₆ ) t ^~ CH (ONO ₂ ) R ₁₄ wherein

Ri3 is a straight Ci-C ₆ alkylene; Ri ₄ is H or -CH ₃ ;

Ri5 and Ri6 at each occurrence are independently H or -CH ₃ ; o and r are integers from 1 to 4, p and s are from 1 to 4; q is from 0 to 4, t is 0 or 1, X is 0.

Another embodiment of the present invention relates to compounds of formula (I) wherein Ri is -H;

R2 is a straight or branched C1-C10 alkylene; preferably R2 is a straight Ci-C ₅ alkylene;

R3 is H or a straight or branched Ci-C ₄ alkyl, preferably R ₃ is H or -CH ₃ ;

R ₄ is -CH3, and it is linked to the 16 position of the steroidal structure in position β;

R _4A is -H;

R ₅ is -H;

R ₆ is -H;

R _6a is -H; R ₇ and R _7A taken together are a =0;

R ₈ is H;

Rs _a and Rg taken together are a double bond;

Rio is -OH, and it is linked to the corresponding carbon atoms of the steroidal structure in position α; Rioa is H;

Rn is -F;

R12 is -H, CH ₃ . Another embodiment of the present invention relates to compounds of formula (I) wherein

Ri is -H;

R2 is a straight or branched C1-C10 alkylene; preferably R2 is a straight Ci-C ₅ alkylene;

R3 is H or a straight or branched Ci-C ₄ alkyl, preferably R ₃ is H or -CH ₃ ;

R ₄ is -CH3, and it is linked to the corresponding carbon atoms of the steroidal structure in position β; R _4A is -H; R ₅ is -H;

Re is -F and it is linked to the corresponding carbon atoms of the steroidal structure in position β;

R _6a is -H; R ₇ and R _7A taken together are a =0; R ₈ is H;

Rs _a and Rg taken together are a double bond;

Rio is -OH, and it is linked to the corresponding carbon atoms of the steroidal structure in position α; Rioa is H; Rn is -F; R12 is -H, CH ₃ .

Another embodiment of the present invention relates to compounds of formula (I) wherein

Ri is -H;

R2 is a straight or branched C1-C10 alkylene; preferably R2 is a straight Ci-C ₅ alkylene;

R ₃ is H or a straight or branched Ci-C ₄ alkyl, preferably R ₃ is H or -CH ₃ ; R ₄ is -H; R _4A is -H;

R ₅ is -H; R ₆ is -H; R _6a is -H,

R ₇ and R _7A taken together are a =0; R ₈ is H; R _8a is H; R ₉ is -H;

Rio is -OH, and it is linked to the corresponding carbon atoms of the steroidal structure in position α;

Rioa is H; Rn is H;

Ri ₂ is -H, CH ₃ .

Another embodiment of the present invention relates to compounds of formula (I) wherein Ri is -H;

R2 is a straight or branched C1-C10 alkylene; preferably R2 is a straight Ci-C ₅ alkylene;

R3 is H or a straight or branched Ci-C ₄ alkyl, preferably R ₃ is H or -CH ₃ ; R ₄ is -H;

R _4A is -H;

R ₅ is -H;

R ₆ is -H;

R _6a is -H, R ₇ and R _7A taken together are a =0;

R ₈ is H;

R _8a is H;

R ₉ is -H;

Rio is -OH, and it is linked to the corresponding carbon atoms of the steroidal structure in position α;

Rioa is H;

Rn is H;

R12 is -H, CH ₃ . Another embodiment of the invention provides a compound of general formula (I) and pharmaceutically acceptable salts or stereoisomers thereof

(D wherein Ri is

(F) -(Z)-Y wherein:

Z is -C(O) or -C(O)-X", wherein X" is 0, S or NR ₁₁ wherein R ₁₁ is H or a C ₁ -C ₄ alkyl; preferably X" is 0;

R2 is a straight or branched C ₁ -C ₁ O alkylene; preferably R2 is a straight C ₁ -Ce alkylene; R3 is H or a straight or branched C ₁ -C ₄ alkyl, preferably R3 is H or -CH ₃ , more preferably R2 is H; R ₄ is -H, -CH ₃ ; R _4A is -H, or R ₄ and R _4A taken together are =CH ₂ ; R ₅ is -H, Cl;

R ₆ is -H, Cl, F, CH ₃ ; R _6a is -H, or R ₆ and R ₅ taken together are a double bond; R _7a is H,

R ₇ and R _7A taken together are a =0; R ₈ is H, Cl, or R ₇ and R ₈ taken together are the group of formula (V)

(V)

Rsa is H, R ₉ is -H, or R _8a and Rg taken together are a double bond Rio is -OH,

Rioa is H, or Rio and Rio _a taken together are =0; Rn is -H, -Cl, -F; Ri ₂ is -H, CH ₃ ; wherein R ₄ , R _4a , R ₅ , R ₆ , R _6a , R7, R7a, Rs, Rβa, R9, Rio, Rioa can be linked to the corresponding carbon atoms of the steroidal structure in position α or β; Y is selected from -Ri ₃ -CH(ONO ₂ )Ri ₄ -Ri ₃ -CH (ONO ₂ ) - (CRi ₅ Ri ₆ ) t ^~ CH (ONO ₂ ) R _i4

- [ (CH ₂ ) o-X] p- [ (CH ₂ ) _r -X] _s - (CH ₂ ) _q - (CRi ₅ Ri ₆ ) t ^~ CH (ONO ₂ ) R _i4

- [ (CH ₂ ) _o -X] p- [ (CH ₂ ) _r -X] _s - (CH ₂ ) _q -CH (ONO ₂ ) - (CRi ₅ Ri ₆ ) _t ~CH (ONO ₂ ) R ₁₄ wherein

Ri ₃ is a straight or branched C ₁ -C ₁ 0 alkylene; preferably Ri ₃ is a straight Ci-C ₆ alkylene;

Ri ₄ is H or a straight or branched Ci-C ₄ alkyl, preferably Ri ₄ is H or -CH ₃ ; Ri ₅ and Ri ₆ are at each occurrence independently H or a straight or branched Ci-Cio alkylene, preferably Ri ₅ and Ri ₆ are H or -CH _3; o and r are integers from 1 to 6; preferably o and r are integers from 1 to 4, more preferably o is 1 and r is 2 ; p and s are integers from 1 to 6; preferably p and s are integers from 1 to 4; more preferably p and s are 1 ; q is an integer from 0 to 6; preferably q is from 0 to 4, more preferably q is 0 or 1 ; t is an integer from 0 to 6; preferably t is from 0 to 4, more preferably t is 0 or 1;

X is O, S or NRi ₇ wherein Ri ₇ is H or a C ₁ -C ₄ alkyl; preferably X is O; preferably Y is selected from -Ri ₃ -CH(ONO ₂ )Ri ₄

-Ri ₃ -CH (ONO ₂ ) - (CRi ₅ Ri ₆ ) t"CH (ONO ₂ ) R _i4

- [ (CH ₂ ) o-X] p- [ (CH ₂ ) _r -X] _s - (CH ₂ ) _q - (CRi ₅ Ri ₆ ) t~CH (ONO ₂ ) R ₁₄ wherein

Ri ₃ is a straight Ci-C ₆ alkylene; Ri ₄ is H or -CH ₃ ;

Ri ₅ and Ri ₆ at each occurrence are independently H or -CH ₃ ; o and r are integers from 1 to 4, p and s are from 1 to 4; q is from 0 to 4, t is 0 or 1, X is 0; excluding the following structures from formula (I) :

(H ₁ :

(H ₁₁ : R-,

(H ₁₁₁ ;

(H ₁ ,

Another embodiment of the invention provides a compound of general formula (I) and pharmaceutically acceptable salts or stereoisomers thereof IR ^LX 3

(i:

(H)

:D

wherein :

R2 is a straight or branched C1-C10 alkylene; preferably R2s a straight Ci-Cε alkylene; R ₃ is H or a straight or branched Ci-C ₄ alkyl, preferably R ₃ is H or -CH ₃ , more preferably R ₃ is H;

R ₄ is -H, -CH ₃ ;

R _4A is -H, or R ₄ and R _4A taken together are =CH ₂ ;

R ₅ is -H, Cl;

R ₆ is -H, Cl, F, CH ₃ ;

R _6a is -H, or R ₆ and R ₅ taken together are a double bond; R _7a is H,

R ₇ and R _7A taken together are a =0;

R ₈ is H, Cl, or R ₇ and R ₈ taken together are the group of formula (V)

(V)

R _8a is H,

R ₉ is -H, or R _8a and Rg taken together are a double bond

Rio is -OH, Ri _Oa is H, or Rio and Rio _a taken together are =0;

Rn is -H, -Cl, -F;

R12 is -H, CH ₃ ; wherein R ₄ , R _4a , R ₅ , R ₆ , R _6a , R ₇ , R _7a , R ₈ , R _8a , R ₉ , Ri ₀ , Rio _a can be linked to the corresponding carbon atoms of the steroidal structure in position α or β; Y is selected from -Ri ₃ -CH(ONO ₂ )Ri ₄ -Ri ₃ -CH (ONO ₂ ) - (CRi ₅ Ri ₆ ) t"CH (ONO ₂ ) Ri ₄

- [ (CH ₂ ) o-X] p- [ (CH ₂ ) _r -X] _s - (CH ₂ ) _q - (CRi ₅ Ri ₆ ) t ^~ CH (ONO ₂ ) R ₁₄

- [ (CH ₂ ) _o -X] p- [ (CH ₂ ) _r -X] _s - (CH ₂ ) _q -CH (ONO ₂ ) - (CRi ₅ Ri ₆ ) _t ~CH (ONO ₂ ) R _i4 wherein Ri3 is a straight or branched Ci-Cio alkylene; preferably Ri3 is a straight Ci-C ₆ alkylene;

Ri4 is H or a straight or branched Ci-C ₄ alkyl, preferably Ri ₄ is H or -CH _3;

Ri ₅ and R _i6 are ^at each occurrence independently H or a straight or branched Ci-Cio alkylene, preferably Ri ₅ and Ri ₆ are H or -CH _3; o and r are integers from 1 to 6; preferably o and r are integers from 1 to 4, more preferably o is 1 and r is 2 ; p and s are integers from 1 to 6; preferably p and s are integers from 1 to 4; more preferably p and s are 1 ; q is an integer from 0 to 6; preferably q is from 0 to 4, more preferably q is 0 or 1 ; t is an integer from 0 to 6; preferably t is from 0 to 4, more preferably t is 0 or 1; X is 0, S or NR _i7 wherein R _i7 is H or a C ₁ -C ₄ alkyl; preferably X is 0;

preferably Y is selected from -Ri ₃ -CH(ONO ₂ )Ri ₄ -Ri ₃ -CH (ONO ₂ ) - (CRi ₅ Ri ₆ ) _t ~CH (ONO ₂ ) R _i4

- [ (CH ₂ ) o-X] p- [ (CH ₂ ) _r -X] _s - (CH ₂ ) _q - (CRi ₅ Ri ₆ ) t~CH (ONO ₂ ) R _i4 wherein

Ri ₃ is a straight Ci-C ₆ alkylene; Ri ₄ is H or -CH ₃ ; Ri ₅ and Ri ₆ at each occurrence are independently H or -CH ₃ ; o and r are integers from 1 to 4, p and s are from 1 to 4; q is from 0 to 4, t is 0 or 1, X is O; excluding the following structures from formula (I ^'

Another embodiment of the invention provides a compound of general formula (I) and pharmaceutically acceptable salts or stereoisomers thereof

(D wherein Ri is (A) -R^CH (NHR ² ) -C (0) -0-Y (B) -R^CH (COOH) NH-C (0) -Y

(C) -R^CH (COOH) -0-C(O)-Y

(D) -C (O)CH(R ³ ) -NH-C (0) -Y

(E) -C(O)CH ₂ -CH(R ⁴ ) -NH-C(O) -Y wherein :

R ¹ is selected from: R ^la )

-C(O)-S-CH ₂ -, -C(O)O-CH(CH ₃ )-, -C(O)O-CH ₂ -; preferably R ^la is

-C(O)-CH ₂ -, -C(O) - (CH ₂ ) 2-; preferably R ^lb is -C(O)-CH ₂ -; R ² is -H or -C(O)CH ₃ ;

R ³ is -H, -CH ₃ , isopropyl, isobutyl, sec-butyl, methylthio- (CH ₂ ) ₂ -, benzyl; preferably R ³ is H or -CH ₃ ; R ⁴ is -H, -CH ₃ , isopropyl, isobutyl, sec-butyl, methylthio- (CH ₂ ) 2-, benzyl; preferably R ⁴ is H or -CH ₃ ;

R ₂ is a straight or branched Ci-Cio alkylene; preferably R ₂ is a straight Ci-C ₆ alkylene;

R ₃ is H or a straight or branched Ci-C ₄ alkyl, preferably R ₃ is H or -CH _3/ more preferably R ₆ is H; R ₄ is -H, -CH ₃ ;

R _4A is -H, or R ₄ and R _4A taken together are =CH ₂ ;

R ₅ is -H, Cl;

R ₆ is -H, Cl, F, CH ₃ ; R _6a is -H, or R ₆ and R ₅ taken together are a double bond;

R _7a is H,

R ₇ and R _7A taken together are a =0;

R ₈ is H, Cl, or R ₇ and R ₈ taken together are the group of formula (V)

(V)

Rsa is H, R ₉ is -H, or R _8a and Rg taken together are a double bond Rio is -OH, Rioa is H, or Rio and Rio _a taken together are =0; Rn is -H, -Cl, -F;

Ri ₂ is -H, CH ₃ ; wherein R ₄ , R _4a , R ₅ , R ₆ , R _6a , R7, R7a, Rs, Rβa, R9, Rio, Rioa can be linked to the corresponding carbon atoms of the steroidal structure in position α or β; Y is selected from -Ri ₃ -CH(ONO ₂ )Ri ₄ -Ri ₃ -CH (ONO ₂ ) - (CRi ₅ Ri ₆ ) t ^~ CH (ONO ₂ ) R _i4

- [ (CH ₂ ) o-X] p- [ (CH ₂ ) _r -X] _s - (CH ₂ ) _q - (CRi ₅ Ri ₆ ) t ^~ CH (ONO ₂ ) R ₁₄ - [ (CH ₂ ) _o -X] p- [ (CH ₂ ) _r -X] _s - (CH ₂ ) _q -CH (ONO ₂ ) - (CRi ₅ Ri ₆ ) _t ~CH (ONO ₂ ) R ₁₄ wherein

Ri ₃ is a straight or branched C ₁ -C ₁ 0 alkylene; preferably Ri ₃ is a straight Ci-C ₆ alkylene;

Ri ₄ is H or a straight or branched Ci-C ₄ alkyl, preferably Ri ₄ is H or -CH ₃ ;

Ri ₅ and R ₁₆ are ^at each occurrence independently H or a straight or branched C ₁ -C ₁ 0 alkylene, preferably Ri ₅ and Ri ₆ are H or -CH ₃ ; o and r are integers from 1 to 6; preferably o and r are integers from 1 to 4, more preferably o is 1 and r is 2; p and s are integers from 1 to 6; preferably p and s are integers from 1 to 4; more preferably p and s are 1; q is an integer from 0 to 6; preferably q is from 0 to 4, more preferably q is 0 or 1; t is an integer from 0 to 6; preferably t is from 0 to 4, more preferably t is 0 or 1;

X is 0, S or NR ₁₇ wherein Ri ₇ is H or a C ₁ -C ₄ alkyl; preferably X is 0; preferably Y is selected from -Ri ₃ -CH(ONO ₂ )Ri ₄

-Ri ₃ -CH (ONO ₂ ) - (CRi ₅ Ri ₆ ) _t ~CH (ONO ₂ ) R _i4

- [ (CH ₂ ) o-X] p- [ (CH ₂ ) _r -X] _s - (CH ₂ ) _q - (CRi ₅ Ri ₆ ) t ^~ CH (ONO ₂ ) R ₁₄ wherein

Ri3 is a straight Ci-Cε alkylene;

Ri ₄ is H or -CH ₃ ;

Ri5 and Ri6 at each occurrence are independently H or -CH ₃ ; o and r are integers from 1 to 4, p and s are from 1 to 4; q is from 0 to 4, t is 0 or 1,

X is O; excluding the following structures from formula (I) :

Another embodiment of the invention provides a compound selected from the group:

⁽ i: (2:

o:

:i2)

:i3)

:i4)

:4i)

:42)

:43)

In another aspect of the invention, there is provided a compound of formula (I) for the use in the treatment of rheumatic diseases, renal and bronchial pathologies, ocular and dermatological diseases, autoimmune diseases, tumoral processes, also in combination with chemotherapeutic and/or radiotherapeutic treatments, in neurodegenerative diseases, for example in spinal lesions from trauma and in the post- transplant therapy. Furthermore inflammatory pathologies affecting the gatrointestinal system (Crohn disease, ulcerous colitis and IBD (inflammatory bowel diseases) can be mentioned.

In yet another aspect of the invention, there is provided a pharmaceutical composition comprising an acceptable carrier and a pharmaceutically effective amount of a compound of formula (I) and/or a salt or stereoisomer thereof, or such a pharmaceutical composition in a suitable form 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" 15th Ed.

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

The daily administrable doses are those of the precursor drugs, or optionally lower. The precursor daily doses can be found in the publications of the field, such for example in the "Physician's Desk reference".

As used herein, the terms "treat," "treating" or "treatment" includes preventative (e.g., prophylactic) and palliative treatment.

As used herein, the term "pharmaceutically acceptable" means the carrier, diluent, excipients and/or salt must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. As used herein, the term "alkyl" means a straight or branched chain saturated hydrocarbon. Exemplary alkyl groups include but are not limited to methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2- methylbutyl, 3-methylbutyl, hexyl, isohexyl, heptyl, octyl and the like.

The term "Ci-Cio alkylene" as used herein refers to branched or straight alkylene groups including methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene, t-butylene, pentylene, hexylene, octylene and the like.

Synthesis procedure In general the term "amino protecting group" as used herein refers to Boc, Fmoc or those described in T. W. Greene "Protective groups in organic synthesis", Wiley- Interscience, 2007, 4th edition. The term " carboxylic protecting group" as used herein refers to tert-butyl ester and those described in T. W. Greene "Protective groups in organic synthesis", Wiley- Interscience, 2007, 4th edition.

The term "diol protecting group" as used herein refers to acetal, such as p-methoxybenzylidene, butylidene, and those described in T. W. Greene "Protective groups in organic synthesis", Wiley-Interscience, 2007, 4nd edition; The term "hydroxyl protecting group" as used herein refers to silyl ethers, such as trimethylsilyl, tert-butyl- dimethylsilyl or trityl and those described in T. W. Greene "Protective groups in organic synthesis", Wiley- Interscience, 2007, 4th edition. 1) The compound of general formula (I) as above defined wherein R ₁ is H, R ₂ , R ₃ , R ₄ , FUa, Rs, Re, Re _a , R7, R7a, Rs, Rs _a , R ₉ , Rio, Rioa are as above defined, can be obtained: 1.1) by reacting a compound of formula (Ha), i.e. the precursor corticosteroid,

O—H

(Ha) wherein R ₄ , R _4a , R ₅ , R ₆ , R _6a , R ₇ , R _7a , R ₈ , R _8a , R ₉ , R _i0 , Rio _a are as above defined with a compound of formula (HIa)

(RAO) ₃ C-R ₂ -CH(Q)R ₃

(HIa) wherein : R _A is straight alkyl C1-C10, R2 and R ₃ are as above defined and Q is ONO ₂ or Qi, wherein Qi is selected from the group consisting of: a chlorine atom, a bromine atom, a iodine atom, a mesyl group or a tosyl group; the reaction is carried out in presence of an organic acid such as p- toluensulfonic acid. The reaction is carried out in an inert organic solvent such as tetrahydrofuran, dioxane, at a temperature from -20 ⁰ C and 40 ⁰ C. The reaction is completed within a time range from 30 minutes to 36 hours and 1.2) hydrolyze the ortho ester of formula (lib) obtained in 1.1)

(lib) wherein R4, R4 _a , R5/ Rβ/ Rβa/ R7/ R7a/ Rs / Rsa^ R9/ Rio/ Rioa/ RA and Q are as above defined, by reacting the compound (lib) with an organic acid such as AICI3, acetic acid, ossalic acid in an organic aqueous solvent such as methanol, ethanol, propanol, isopropanol at a temperature from -20 ⁰ C and 40 ⁰ C. The reaction is completed within a time range from 30 minutes to 36 hours and 1.3) when Q is Qi, by reacting the compound obtained in the step 1.2) 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 Ci- Cio alkyl) in a suitable organic solvent such as acetonitrile, tetrahydrofurane, methyl ethyl ketone, ethyl acetate, DMF; the reaction is carried out, in the dark, at a temperature from room temperature to the boiling temperature of the solvent. Alternatively, the reaction with AgNO ₃ can be performed under microwave irradiation in solvents such acetonitrile or THF at temperatures in the range between about 100-180 ⁰ C for time range about 1-60 min. Preferred nitrate source is silver nitrate.

The compounds of formula (Ha) are commercially available

2) The compound of general formula (I) as above defined wherein R ₂ , R ₃ , R ₄ , FUa, Rs, Re, Re _a , R7, R7a, Rs, Rs _a , Rg, Rio, Rioa are as above defined, and Ri is selected from:

(A) -R^CH(NHR ² ) -C (O) -O-Y

(B) -R^CH(COOH)NH-C(O)-Y

(C) -R^CH(COOH)-O-C(O)-Y (F) -(Z)-Y

(G)

(H)

(I!

wherein

R ¹ is selected from the group R ^la ) as above defined, R ² is as above defined, Z is -C(O)O- and

Y is as above defined, can be synthesized:

2.1) by reacting a compound of formula (1Ic]

wherein R ₂ , R ₃ , R ₄ , R4a, R ₅ , R ₆ , R _6a , R ₇ , R _7a , R ₈ , R ₉ , R ₁₀ , R _10a are as above defined and W is -H or -COC1 with a compound of the following formulae (A ₁ ; W ₁ -R ^la' -CH(NHR ^2a ) -C(O) -0-Y'

(B ₁ ) W ₁ -R , ¹ 1^a'-CH(COOP)NH-C(O)-Y' (C ₁ ) W ₁ -R ¹ ^-CH(COOP)-O-C(O)-Y' (F ₁ ) W ₁ -O-Y' (G ₁ )

OMe wherein

Wi is -H or R _B OC(O)- wherein R _B is pentafluorophenyl, 4- nitrophenyl, R ^la' ) is selected from

'CH ₉ —o

-S-CH ₂ -, -0-CH(CH ₃ )-, -0-CH ₂ -;

R ^2a is -H or -C(O)CH ₃ or P ₂ wherein P ₂ is a amino protecting group, P is a carboxylic protecting group, Pi is a diol protective group,

Y' is

-Ri ₃ -CH(Q)Ri ₄

-Ri ₃ -CH (Q) - (CRi ₅ Ri ₆ ) t~CH (Q) R ₁₄ -[ (CH ₂ )O-X _-P -. (CH ₂ ) _r -X] _s - (CH ₂ ) _q - (CRi ₅ Ri ₆ ) t-CH (Q) Ri ₄

-[ (CH ₂ ) ₀ -X]p-[ (CH ₂ ) _r -X] _s - (CH ₂ ) _q -CH (ONO ₂ )- (CRi ₅ Ri ₆ Jt-CH(Q)Ri ₄ wherein

X, Ri ₃ , Ri ₄ , Ri ₅ , Ri ₆ , o, p, q, r, s and t are as above defined, Q is ONO ₂ or Qi, wherein Qi is selected from Cl, Br, I, a mesyl group or a tosyl group;

2.1. a) The reaction of a compound of formula (lie) wherein

W is H with a compound of formula (Ai) , (Bi) , (Ci) , (Fi) ,

(Gi), (Hi) or (Ii) wherein Wi is R _B OC (0) - is carried out in presence of a catalyst, such as DMAP or in the presence of DMAP and a Lewis acid such as Sc(OTf) ₃ or Bi(OTf) ₃ in an inert organic solvent such as N, N' -dimethylformamide, tetrahydrofuran, benzene, toluene, dioxane, a polyhalogenated aliphatic hydrocarbon at a temperature from -20°C and 40 ⁰ C. The reaction is completed within a time range from 30 minutes to 36 hours.

2.1.b) The reaction of a compound of formula (lie) wherein W is COCl with a compound of formula with a compound of formula (A ₁ ), (B ₁ ), (C ₁ ), (F ₁ ), (G ₁ ), (H ₁ ) or (I ₁ ) wherein W ₁ is H may be carried out in presence of an organic base such as N, N-dimethylamino pyridine (DMAP), triethylamine, pyridine. The reaction is carried out in an inert organic solvent such as N, N' -dimethylformamide, tetrahydrofuran, benzene, toluene, dioxane, a polyhalogenated aliphatic hydrocarbon at a temperature from -20 ⁰ C and 40 ⁰ C. The reaction is completed within a time range from 30 minutes to 36 hours.

2.2) when Q is Q ₁ , by converting the compound obtained in the step 2.1) into nitro derivative by reaction with a nitrate source according to the method described in 1.3) and

2.3) optionally deprotecting the compounds obtained in step 2.1) or 2.2) as described in T. W. Greene "Protective groups in organic synthesis", Wiley-Interscience, 2007, 4 ^nd edition. Trifluoroacetic acid or anhydrous inorganic acid are the preferred method for removing Boc 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. Hydrochloric acid in tetrahydrofurane is the preferred method for removing acetal protecting group. Alternatively the compound of general formula (I) as defined in 2) wherein R ₁ is selected from (A), (B), (C), (F), (G), (H), (I), can be synthesized 3.1) by reacting a compound of formula (lie) wherein R2,

R ₃ , R ₄ , R _4a , R ₅ , R ₆ , R _6a , R ₇ , R _7a , R ₈ , R _8a , R ₉ , R ₁₀ , R _10a and W are as above defined with a compound of formula (A ₂ ) Wi-R ^la' -CH(NHR ^2a ) -C (O) -O-P (B ₂ ) W ₁ -R ^13' -CH (COOP) -NH-R ^2a

(C ₂ ;

wherein

Wi is -H or R _B OC(O)- wherein R _B is pentafluorophenyl, 4- nitrophenyl,

R ^la' , R ^2a , R ³ , R ⁴ , P, P ₁ are as above defined and P ₃ is a alpha hydroxyl acid protecting group such as 4-oxo-l,3- dioxolane; 3.1. a) The reaction of a compound of formula (lie) wherein W is H with a compound of formula (A ₂ ) , (B ₂ ) , (C ₂ ) , (G ₂ ) ,

(H ₂ ), (I ₂ ) wherein Wi is R _B OC (O) - is carried out according to the method described in 2.1. a) .

3.1.b) The reaction of a compound of formula (lie) wherein The reaction of a compound of formula (lie) wherein W is COCl with a compound of formula (A ₂ ) , (B ₂ ) , (C ₂ ) , (G ₂ ) ,

(H ₂ ), (I ₂ ) wherein Wi is H is carried out according to the method described in 2.1.b), and

3.2) deprotecting the compounds obtained in step 3.1) as described in T. W. Greene "Protective groups in organic synthesis", Wiley-Interscience, 2007, 4 ^nd edition, hydrochloric acid or anhydrous inorganic acid are the preferred method for removing alpha hydroxy acid protecting group, and

3.3) by reacting a compound of formula (Hd) obtained in the step 3.2)

) R ₃

(Hd) wherein R ₂ , R3, R4, R ₄₃ , Rs^ Rβ/ Rβa/ R7/ R7a/ Rs / Rsa^ R9/ Rio and Rioa are as above defined and R _4c is a radical selected from the following meaning

(A ₃ ) -R ^la -CH(NHR ^2a ) -C (O) -OH (B ₃ ) -R ,1a-CH(COOP) -NH ₂ (C ₃ ) -R ,1a-CH (COOH) -OH (G ₃ )

wherein R ¹ is selected from the group R ^la ) as above defined, R ^2a is as above defined, with a compound of formula

(Via) W ₂ -Ri ₃ -CH(Q)R ₁₄

(VIb) W ₂ -R ₁₃ -CH (Q) - (CR ₁₅ R ₁₆ ) t ^~ CH (Q) R ₁₄ (VIc) W ₂ - [ (CH ₂ ) ₀ -X]p- [ (CH ₂ ) r-X] s- (CH ₂ ) _q - (CR ₁₅ R ₁₆ ) _t ^~ CH (Q) R ₁₄

(VId) W ₂ - [ (CH ₂ ) _o -X] p- [ (CH ₂ ) _r -X] _s - (CH ₂ ) _q -CH (Q) - (CR ₁₅ R ₁₆ ) _t -CH (Q) R ₁₄ wherein W ₂ is selected from HO-, Cl, Br, I, -COOH, -COCl,

-C(O)ORB wherein R _B is as above defined;

W ₂ is -OH, Cl, Br, I when R _4c is selected from (A ₃ ) , (G ₃ ) , (H ₃ ), (I ₃ ) or W ₂ is -COOH, -C(O)OR _B , -CO-Cl when R _4c is selected from (B ₃ ) , (C ₃ ) ;

3.3. a) the reaction of the compound of formula (Hd) wherein R _4c is selected from (A ₃ ), (G ₃ ), (H ₃ ), (I ₃ ), with a compound of formula (Via) , (VIb) , (VIc) or (VId) wherein W ₂ is Cl, Br, I is carried out in the presence of a organic base such as 1, 8-diazabiciclo [5.4.0 ] undec-7-ene (DBU), N, N- diisopropylethyl amine, diisopropylamine or an inorganic base such as alkaline-earth metal carbonate or hydroxide, potassium carbonate, cesium carbonate, in an inert organic solvent such as N, N' -dimethylformamide, tetrahydrofuran, acetone, methyl ethyl ketone, acetonitrile, a polyhalogenated aliphatic hydrocarbon at a temperature from -20 ⁰ C and 40 ⁰ C, preferably from 5°C to 25°C. The reaction is completed within a time range from 1 to 8 hours. When W ₃ is chosen among chlorine or bromine the reaction is carried out in presence iodine salts such as KI . 3.3.b) the reaction of a compound of formula (lid) wherein R _4c is a radical selected (A ₃ ), (G ₃ ), (H ₃ ), (I ₃ ), with a compound of formula (Via) , (VIb) , (VIc) or (VId) wherein W ₂ is -OH is carried out in the presence of a condensing agent such as dicyclohexylcarbodiimide (DCC), N' - (3-dimethyl aminopropyl) -N-ethylcarbodiimide hydrochloride (EDAC), N, N' -carbonyldiimidazole (CDI), optionally in the presence of a base, for example DMAP, in an inert organic solvent dry such as N, N' -dimethylformamide, tetrahydrofuran, benzene, toluene, dioxane, a polyhalogenated aliphatic hydrocarbon at a temperature from -20 ⁰ C and 50 ⁰ C. The reaction is completed within a time range from 30 minutes to 36 hours;

3.3.c) the reaction of a compound of formula (lid) wherein

R _4c is (B ₃ ) or (C ₃ ) with a compound of formula (Via) , (VIb) ,

(VIc) or (VId) wherein W ₂ is -COOH is carried out according to the method described in 3.3.b) or in presence of other condensing reagents such as O- (7-azabenzotriazol-l-yl) - N, N, N ' , N ' -tetramethyluronium hexafluorophosphate (HATU); 3.3. d) The reaction of a compound of formula (Hd) wherein R _4c is (B ₃ ) or (C3) with a compound of formula (Via) , (VIb) , (VIc) or (VId) wherein W ₂ is -COCl may be carried out according to the method described in 2.1.b); 3.3.e) the reaction of a compound of formula (Hd) wherein R _4c is (B ₃ ) or (C ₃ ) with a compound of formula (Via) , (VIb) , (VIc) or (VId) wherein W ₂ is R _B OC (0) - is carried out according to the method described in 2.1. a), and 3.4) when Q is Qi, by converting the compound obtained in the step 3.3) into nitro derivative according to the method described in 1.3) and 3.5) deprotecting the compounds obtained in step 3.3) or 3.4) as described in T. W. Greene "Protective groups in organic synthesis", Wiley-Interscience, 2007, 4 ^nd edition. 4) The compound of general formula (I) as above defined wherein R ₂ , R ₃ , R ₄ , R _4a , R ₅ , R ₆ , R _6a , R ₇ , R _7a , R ₈ , R _8a , R ₉ , R ₁₀ , Rio _a are as above defined and rl is selected from: (A) -R^CH(NHR ² ) -C (O) -O-Y

(B) -R^CH(COOH)NH-C(O)-Y

(C) -R^CH (COOH) -0-C(O)-Y

(D) -C (O)CH(R ³ ) -NH-C (0) -Y

(E) -C (O)CH ₂ -CH(R ⁴ ) -NH-C (0) -Y (F) -(Z)-Y wherein

R ¹ is selected from the group R ^lb ) as above defined, R ² , R ³ R ⁴ and Y are as above defined, Z is -C(O)-, can be synthesized:

4.1) by reacting a compound of formula (Hc) as above defined wherein R ₂ , R ₃ , R ₄ , R _4a , R ₅ , R ₆ , R _6a , R ₇ , R _7a , R ₈ , Rs _a , R ₉ , Rio, RiOa are as above defined and W is H, with a compound of formula:

(A ₄ ) W ₃ -R ¹ -CH(NHR ^2a ) -C (O) -O-Y'

(B ₄ ) Ws-R^CH (COOP)NH-C (O) -Y' (C ₄ ) W ₃ -R ¹ -CH(COOP) -0-C (0) -Y'

(Di) W ₃ -C(O)CH(R ³ ) -NH-C(O) -Y'

(Ei) W ₃ -C (0) CH ₂ -CH (R ⁴ ) -NH-C (0) -Y'

(F ₂ ) W ₃ -(Z)-Y' wherein W ₃ is HO- or R _B 0- wherein R _B is as above defined, R ¹ , R ^2a , R ³ , R ⁴ , P and Y' are as above defined;

4.1. a) The reaction of a compound of formula (lie) wherein

W is H with a compound of formula (A ₄ ) , (B ₄ ) , (C ₄ ) , (Di) ,

(Ei) or (F ₂ ) wherein W ₃ is R _B 0- is carried out as reported in 2.1. a) ; 4.1.b) the reaction of a compound of formula (lie) wherein

W is H with a compound of formula (A ₄ ) , (B ₄ ) , (C ₄ ) , (Di) ,

(Ei) or (F ₂ ) wherein W ₃ is HO-, is carried out as reported in 3.3.b) ; and 4.2) when Q is Qi, by reacting the compound obtained in the step 4.1) with a nitrate source according to the method described in 1.3) and

4.3) optionally deprotecting the compounds obtained in step 4.1) or 4.2) as described in T. W. Greene "Protective groups in organic synthesis", Wiley-Interscience, 2007, 4 ^nd edition .

Alternatively the compound of general formula (I) as defined in 4), wherein Ri is selected from (A), (B), (C), (F), (G), (H), (I), can be synthesized

4.4) by reacting a compound of formula (lie) as above defined with a compound of formula

(A ₅ ) W ₃ -R^CH(NHR ²³ ) -C (0) -Q-P (B ₅ ) Ws-R^CH (COOH) -NH-R ^2a (C ₅ )

(D ₂ ) W ₃ -C (0) -CH(R ³ ) -NH-R ^2a (E ₂ ) W ₃ -C (0) -CH ₂ -CH(R ⁴ ) -NH-R ^2a wherein :

W ₃ , R ¹ , R ^2a , R ³ , R ⁴ , P and P ₃ are as above defined;

4.4. a) the reaction of a compound of formula (lie) with a compound of formula (A ₅ ) , (B ₅ ) , (C ₅ ) , (D ₂ ) or (E ₂ ) wherein W ₃ is HO-, is carried out according to the method described in

4.1.b) ,

4.4.b) the reaction of a compound of formula (lie) wherein

W is H with a compound of formula (A ₅ ) , (B ₅ ) , (C ₅ ) , (D ₂ ) or

(E ₂ ) wherein W ₃ is R _B 0- is carried out according to the method described in 4.1. a), and

4.5) deprotecting the compounds obtained in step 4.4. a) or 4.4.b) as described in T. W. Greene "Protective groups in organic synthesis", Wiley-Interscience, 2007, 4 ^nd edition, and

4.6) by reacting a compound of formula (He) obtained in the step 4.5)

(He) wherein R ₂ , R3, R4, R4a/ R5/ Rβ/ Rβa/ R7/ R7a/ Rs / Rsa/ R9/ Rio/ Rio _a are as above defined and R _4f is a radical selected from: (A ₆ ) -R^CH(NHR ²³ ) -C (O)OH (B ₆ ) -R^CH(COOP)-NH ₂ (C ₆ ) -R^CH(COOH)-OH (D ₃ ) -C (O) -CH(R ³ ) -NH ₂ (E ₃ ) -C(O) -CH ₂ -CH(R ⁴ ) -NH ₂ wherein R ¹ is selected from the group R ^lb ) as above defined,

R ^' 2a R , R ⁴ and P are as above defined, with a compound of formula

(Via) W ₂ -R ₁₃ -CH(Q)R ₁₄

(VIb) W ₂ -R ₁₃ -CH (Q) - (CR ₁₅ R ₁₆ ) _t ~CH (Q) R ₁₄

(VIc) W ₂ - [ (CH ₂ )O-X _-P -. (CH ₂ ) _r -X] _s - (CH ₂ ) _q - (CR ₁₅ R ₁₆ ) t-CH (Q) R ₁₄

(VId) W ₂ - [ (CH ₂ ) _o -X] p- [ (CH ₂ ) _r -X] _s - (CH ₂ ) _q -CH (Q) - (CR ₁₅ R ₁₆ ) _t -CH (Q) R ₁₄ wherein

W ₂ is HO-, Cl, Br, I when R _4f is (A ₆ ), or W ₂ is -COOH, - C(O)OR _B or -COCl when R _4f is (B ₆ ), (C ₆ ), (D ₃ ) or (E ₃ ); 4.6. a) the reaction of the compound of formula (He) wherein R _4f is (A ₆ ) , with a compound of formula (Via) ,

(VIb), (VIc), (VId) wherein W ₂ is Cl, Br, I, is carried out according to the method described in 3.3.a); 4.6.b) the reaction of the compound of formula (He) wherein R _4f is (B ₆ ) , (C ₆ ) , (D ₃ ) or (E ₃ ) with a compound of formula (Via) , (VIb) , (VIc) , (VId) wherein W ₂ is OH, is carried out according to the method described in 2.1.c) . 4.6.c) the reaction of the compound of formula (He) wherein R _4f is (B ₆ ) , (C ₆ ) , (D ₃ ) or (E ₃ ) with a compound of formula (Via) , (VIb) , (VIc) , (VId) wherein W ₂ is COOH is carried out according to the method described in 3.3.c); 4.6.d) The reaction of the compound of formula (He) wherein R _4f is (B ₆ ) , (C ₆ ) , (D ₃ ) or (E ₃ ) with a compound of formula (Via) , (VIb) , (VIc) , (VId) wherein W ₂ is COCl may be carried out according to the method described in 2.1.b); 4.6.e) the reaction of the compound of formula (He) wherein R _4f is (B ₆ ) , (C ₆ ) , (D ₃ ) or (E ₃ ) with a compound of formula (Via), (VIb), (VIc), (VId) wherein W ₂ is -C(O)OR _B is carried out according to the method described in 2.1. a), and

4.7) when Q is Qi, by reacting the compound obtained in steps 4.6. a) -4.6. e) according to the method described in 1.3) and

4.8) deprotecting the compounds obtained in step 4.6) or 4.7) as described in T. W. Greene "Protective groups in organic synthesis", Wiley-Interscience, 2007, 4 ^nd edition. 5) Preparation of compound (lie)

The compounds of formula (Hc) wherein R ₂ , R ₃ , R ₄ , R _4a , R ₅ , R ₆ , R _6a , R ₇ , R _7a , Rs, Rβa/ R9, Rio, Rioa are as above defined and W is -COCl are prepared starting from the compounds obtained in 1.3), according to methods known in the literature.

6) Preparation of compound (Ilia) The compounds of formula (Ilia) wherein R _A , R ₂ , R3 are as above defined and Q is Qi are commercially available or can be obtained according to methods known in the literature. The compounds of formula (Ilia) wherein R _A , R ₂ , R3 are as above defined and Q is ONO2 can be obtained by reacting the compound (Ilia) wherein Q is Qi with a nitrate source as above described. 7) Preparation of the following compounds

(Ai: Wi-R ^la' -CH(NHR ^2a ) -C (0) -Q-Y' (Bi) Wi-R ^la' -CH (COOP)NH-C (0) -Y'

(Ci) Wi-R ^la' -CH(COOP) -0-C (0) -Y'

(A ₄ ) W ₃ -R ¹ -CH(NHR ^2a ) -C (0) -0-Y' (B ₄ ) W ₃ -R^CH(COOP)NH-C(O)-Y' (C ₄ ) W ₃ -R^CH(COOP)-O-C(O)-Y' (Di) W ₃ -C (O)CH(R ³ ) -NH-C (0) -Y'

(Ei) W ₃ -C (0) CH ₂ -CH (R ⁴ ) -NH-C (0) -Y'

wherein

Wi is H, W ₃ is -OH,

Rla' R 2a R ³ , R ⁴ , P and Y' are as above defined and

R ¹ is selected from the group R ^lb ) as above defined, can be synthesized

7.1) by reacting a compound of formula (A ₇ ) P ₄ -R ^la' -CH(NHR ^2a ) -C (0) -OH (A ₈ ) PO-R^CH (NHR ^2a ) -C (0) -OH

P, Pi, R ^±d , R ^2a are as above defined, R ¹ is selected from the group R ^lb ) as above defined,

P ₄ is a hydroxyl protecting group, with a compound of formula

(Via) W ₂ -Ri ₃ -CH(Q)R ₁₄

(VIb) W ₂ -Ri ₃ -CH (Q) - (CRi ₅ Ri ₆ ) t ^~ CH (Q) R ₁₄ (VIc) W ₂ - [ (CH ₂ ) ₀ -X]p-[ (CH ₂ ) r-X] s- (CH ₂ ) _q - (CRi ₅ Ri ₆ ) t ^~ CH (Q) R _i4

(VId) W ₂ - [ (CH ₂ ) ₀ -X] _p -[ (CH ₂ ) _r -X] _s - (CH ₂ ) _q -CH (Q) -(CRi ₅ Ri ₆ ) t-

CH(Q)Ri ₄ wherein

Q, X, o, p, r, s, t, Ri ₃ , Ri ₄ , Ri ₅ , Ri ₆ are as above defined, W ₂ is HO-, Cl, Br, I,

7.1. a) the reaction of a compound of formula (A ₇ ), (A ₈ )

(G ₄ ), (H ₄ ), (I ₄ ) with a compound of formula (Via) (VIb),

(VIc) , (VId) wherein W ₂ is Cl, Br, I is carried out according to the method described in 3.3. a) 7.1.b) The reaction of a compound of formula (A ₇ ), (A ₈ )

(G ₄ ), (H ₄ ), (I ₄ ) with a compound of formula (Via) (VIb),

(VIc) , (VId) wherein W ₂ is OH is carried out according to the method described in 2.1.c) .

7.2) or by reaction a compound of formula (B ₇ ) P ₄ -R ^la' -CH(COOP) -NH ₂

(C ₇ ) P ₄ -R ^la' -CH (COOH) -OH

(D ₄ ) POC (0) -CH(R ³ ) -NH ₂

(E ₄ ) POC(O) -CH ₂ -CH(R ⁴ ) -NH ₂

(B ₈ ) PO-R^CH (COOP) -NH ₂ (C ₈ ) PO-R^CH (COOH) -OH wherein

P, R ^la' , R ³ , R ⁴ and Pare as above defined and

P ₄ is a hydroxyl protecting group, R ¹ is selected from the group R ^lb ) as above defined, with a compound of formula

(Via) W ₂ -Ri ₃ -CH(Q)R ₁₄

(VIb) W ₂ -Ri ₃ -CH (Q) - (CRi ₅ Ri ₆ ) t~CH (Q) R ₁₄

(VIc) W ₂ - [ (CH ₂ )O-X _-P -. (CH ₂ ) _r -X] _s - (CH ₂ ) _q - (CRi ₅ Ri ₆ ) t-CH (Q) Ri ₄ (VId) W ₂ - [ (CH ₂ ) ₀ -X] _p -[ (CH ₂ ) _r -X] _s - (CH ₂ ) _q -CH (Q) -(CRi ₅ Ri ₆ ) _t -

CH(Q)Ri ₄ wherein

Q, X, o, p, r, s, t, Ri ₃ , Ri ₄ , Ri ₅ , Ri ₆ are as above defined,

W ₂ is -COOH, -COCl or R _B OC (0) - wherein R _B is as above defined;

7.2. a) the reaction of a compound of formula (B ₇ ), (B ₈ ),

(C ₇ ) , (C ₈ ) , (D ₄ ) , (E ₄ ) with a compound of formula (Via) ,

(VIb) , (VIc) , (VId) wherein W ₂ is COOH is carried out according to the method described in 3.3.c), 7.2.b) the reaction of a compound of formula B ₇ ), (B ₈ ),

(C ₇ ) , (C ₈ ) , (D ₄ ) , (E ₄ ) with a compound of formula (Via) ,

(VIb) , (VIc) , (VId) wherein W ₂ is -COCl is carried out according to the method described in 2.1.b) .

7.2.c) the reaction of a compound of formula B ₇ ), (B ₈ ), (C ₇ ) , (C ₈ ) , (D ₄ ) , (E ₄ ) ) with a compound of formula (Via) ,

(VIb), (VIc), (VId) wherein W ₂ is R _B OC (0) - is carried out according to the method described in 2.1. a), and

7.3) when Q is Qi, by reacting the compound obtained in the steps 7.1. a), 7.1.b), 7.2. a) -7.2. c) with a nitrate source according to the method described in 1.3) and 7.4) deprotecting the compounds obtained in steps 6.1) and 6.2) or 6.3) as described in T. W. Greene "Protective groups in organic synthesis", Wiley-Interscience, 2007, 4 ^nd edition. Fluoride ion is the preferred method for removing the silyl ether group.

The compounds of formula (A ₇ ), (A ₈ ), (B ₇ ), (B ₈ ), (C ₇ ), (C ₈ ), (D ₄ ), (E ₄ ), (G ₄ ), (H ₄ ), (I ₄ ) are commercially available or can be obtained according to methods known in the literature 8) The compounds of formula (A ₄ ) W ₃ -R ¹ -CH(NHR ^2a ) -C (O) -O-Y' (B ₄ ) W ₃ -R ¹ -CH (COOP)NH-C (O) -Y' (C ₄ ) W ₃ -R ¹ -CH(COOP) -O-C (O) -Y' (D ₁ ) W ₃ -C(O)CH(R ³ ) -NH-C(O) -Y' (E ₁ ) W ₃ -C (O)CH ₂ -CH(R ⁴ ) -NH-C (0) -Y' wherein W ₃ is R _B O-, R ¹ is selected from the group R ^lb ),R ^2a , R ³ , R ⁴ P and Y' are as above defined can be synthesized according to methods known in the literature from the correspondend compounds of formula (A ₄ ) , (B ₄ ) , (C ₄ ) , (D ₁ ) , (E ₁ ) wherein W ₃ is -OH.

9) The compounds of formula (Via) , (VIb) , (VIc) , (VId) are commercially available or can be obtained according to methods as known in the literature.

Example 1

Synthesis of (8S, 9S, 1OR, US, 13S, 14S, 17R) -11 -hydroxy- 17- (2- hydroxyacetyl) -10, 13-dimethyl-3-oxo-6, 7,8,9,10,11,12,13, 14, 15, 16, 17-dodecahydro-3H-cyclopenta [a] phenanthren-17-yl 4-nitroxybutanoate (Compound (58))

(58)

A) (4' R, 8S, 9S, 1OR, US, 13S, 14S) -2'- (3-bromopropyl) -11- hydroxy-2 ' -methoxy-10, 13-dimethyl-7, 8, 9, 10, 11, 12, 13, 14, 15, 16-decahydrospiro [cyclopenta [a] phenanthrene-17, 4 ' - [ 1, 3] dioxane] -3, 5 ' (6H)-dione

(A) To a solution of prednisolone (1.5 g, 4.16 mmol) in toluene (28 ml) and N, N-dimethylformamide (4 ml), p- toluenesulfonic acid (cat) and trimethyl-4-bromo- orthobutyrate (1.44 ml, 8.3 mmol) were added. The reaction was stirred at room temperature for 17 hours. The mixture was poured in water (55 ml) and extracted with ethyl acetate (55x4 ml) ; the organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography, (Biotage System, SNAP Cartridge silica 100 g, eluent: gradient n- hexane/ethyl acetate 8/2 (145 ml), to n-hexane/ethyl acetate 3/7 during 1015 ml, n-hexane/ethyl acetate 3/7 (725 ml)) . The product (A) (1.83 g) was obtained.

B) !8S, 9S, 1OR, US, 13S, 14S, 17R) -ll-hydroxy-17- (2-hydroxy acetyl) -10, 13-dimethyl-3-oxo-6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-dodecahydro-3H-cyclopenta [a] phenanthren-17-yl 4- bromobutanoate

(B) To a solution of compound (A) (1.73 g, 3.31 mmol) in methanol (59 ml), a 5% aqueous AcOH solution (11.8 ml) was added. The reaction was stirred at reflux for 5 hours. The mixture was concentrated under reduced pressure. The mixture was diluted with dichloromethane (50 ml), washed with saturated aqueous sodium carbonate (2x50 ml) and water (2X50 ml); the organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography, (Biotage System, SNAP Cartridge silica 100 g, eluent: gradient acetone/dichlorometane 9/1 (145 ml), to acetone/dichlorometane 25/75 during 1015 ml, acetone/dichlorometane 25/75 (435 ml) ) . The product (B) (1.25g) was obtained.

C) (8S, 9S, 1OR, US, 13S, 14S, 17R) -ll-hydroxy-17- (2-hydroxy acetyl) -10, 13-dimethyl-3-oxo-6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-dodecahydro-3H-cyclopenta [a] phenanthren-17-yl 4-nitroxy butanoate (Compound (58))

To a solution of compound (B) (1.24 g, 2.44 mmol) in acetonitrile (39 ml), silver nitrate (1.24g, 7.32 mmol) was added. The reaction was heated to 130 ⁰ C for 15 minutes under microwave irradiation. The resulting mixture was cooled, filtered and the solvent was removed under reduced pressure. The residue was diluted with dichloromethane (50 ml) and washed with water (2X50 ml) ; the organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude was purified by flash chromatography (Biotage System, SNAP Cartridge silica 50 g, eluent: gradient acetone/dichlorometane 9/1 (75 ml) , to acetone/dichlorometane 25/75 during 375 ml, acetone/dichlorometane 25/75 (375 ml)) . The product (0.95 g) was obtained. 1H-NMR: (DMSO), δ: 7.31 (IH, ά, J = 10.1 Hz), 6.17 (IH, d,

J = 10.1 Hz), 5.92 (IH, s), 5.00 (IH, t, J = 6.0 Hz), 4.76

(IH, d, J = 3.0 Hz), 4.50 (2H, t, J = 6.3 Hz), 4.30 (IH, bs), 4.16 (IH, dd, J = 18.3, 6.0 Hz), 4.05 (IH, dd, J =

18.3, 6.0 Hz), 2.74 (IH, t, J = 11.8 Hz), 2.56 (IH, m) , 2.43 (2H, t, J = 7.3 Hz), 2.30 (IH, dd, J = 13.0, 2.5 Hz), 2.06 (2H, m) , 1.89 (3H, m) , 1.68 (3H, m) , 1.54 (IH, m) , 1.38 (3H, s), 1.37 (IH, m) , 1.11 - 0.93 (2H, m) , 0.84 (3H, s) .

Example 2

Synthesis of 4- (nitrooxy) butyl 4- ( (2- ( (8S, 9S, 1OR, US, 13S, 14S, 17R) -ll-hydroxy-17- (4-nitroxy butanoyloxy) -10, 13-dimethyl-3-oxo-6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-dodecahydro-3H-cyclopenta [a] phenanthren-17-yl) -2- oxoethoxy) carbonyloxy) -3-methoxybenzoate (Compound (60))

(60)

D) (8S, 9S, 1OR, US, 13S, 14S, 17R) -17- (2- (chlorocarbonyloxy) acetyl) -ll-hydroxy-10, 13-dimethyl-3-oxo-6, 7,8,9,10,11,12, 13, 14, 15, 16, 17-dodecahydro-3H-cyclopenta [a] phenanthren-17- yl 4-nitroxybutanoate

(D) To a solution of compound (58) (0.5 g, 1.01 mmol) in tetrahydrofurane (4.8 ml), cooled at 0 ⁰ C and under N ₂ , a 20% toluene solution of phosgene (3.2 ml, 6.1 mmol) was added. The reaction was stirred at 0 ⁰ C for 1 hour, than at room temperature for 16 hours. The excess of phosgene was removed by heating at 40 ⁰ C for 45 minutes. The solvent was evaporated under vacuum. The crude product (D) (0.61 g) was used in the next step without any purification. E) 4- (nitrooxy) butyl 4- ( (2- ( ( 9R, 1OS, US, 13S, 16S, 17R) -9- fluoro-ll-hydroxy-10 , 13, 16-trimethyl-17- (4- (nitrooxy) butanoyloxy) -3-oxo-6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17- dodecahydro-3H-cyclopenta [a] phenanthren-17-yl) -2- oxoethoxy) carbonyloxy) -3-methoxybenzoate (Compound (60))

To a solution of compound (D) (0.6 g, 1.19 mmol) in dichloromethane (12 ml), diisopropylethylamine (0.21 ml, 1.19 mmol) was added. The reaction was cooled at 0 ⁰ C and vanillic acid 4- (nitrooxy) butyl ester (0,34 g, 1.19 mmol) was added. The reaction was stirred at room temperature for 19 hours. The solvent was evaporated under vacuum. The residue was purified by flash chromatography (Biotage System, SNAP Cartridge silica 50 g, eluent: gradient n- hexane/ethyl acetate 8/2 (75 ml) , to n-hexane/ethyl acetate 2/8 during 525 ml, n-hexane/ethyl acetate 2/8 (225 ml) ) . The product (0.34 g) was obtained.

¹ H-NMR: (DMSO), δ: 7.65 (IH, s), 7.64 (IH, ά, J = 7.9 Hz), 7.39 (IH, d, J = 7.9 Hz), 7.31 (IH, d, J = 10.1 Hz), 6.17 (IH, d, J = 10.1 Hz), 5.93 (IH, s), 5.07 (IH, d, J = 17.2 Hz), 4.91 (IH, d, J = 17.2 Hz), 4.80 (IH, d, J = 3.4 Hz), 4.60 (2H, t, J = 5.5 Hz), 4.51 (2H, t, J = 6.2 Hz), 4.32 (2H, t, J = 5.0 Hz), 3.89 (3H, s), 2.75 (IH, t, J = 12.2 Hz), 2.62 - 2.39 (3H, m) , 2.30 (IH, dd, J = 11.8, 3.7 Hz), 2.15 - 1.49 (15H, m) , 1.38 (3H, s), 1.36 (IH, m) , 1.03 (IH, m) , 0.91 (3H, s) .

Example 3

Synthesis of ( 6S, 9R, 10S, US, 13S, 16R, 17R) -6, 9-difluoro-11- hydroxy-17- (2-hydroxyacetyl) -10, 13, 16-trimethyl-3-oxo- 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-dodecahydro-3H- cyclopenta [a] phenanthren-17-yl 4-nitroxybutanoate (compound (20) )

(20)

F) (4'R, 6S,9R, 10S,llS,13S,16R)-2'- (3-bromopropyl) -6, 9- difluoro-ll-hydroxy-2 ' -methoxy-10, 13, 16-trimethyl- 7,8,9,10,11,12, 13, 14, 15, 16-decahydrospiro [cyclopenta [a] phenanthrene-17, 4 ' - [ 1, 3] dioxane] -3,5' (6H)-dione

(F) To a solution of flumethasone (0.9 g, 2.19 mmol) in toluene (15 ml) and N, N-dimethylformamide (2.1 ml), p- toluenesulfonic acid (cat) and trimethyl-4-bromo- orthobutyrate (0.76 ml, 4.38 mmol) were added. The reaction was stirred at room temperature for 72 hours. The mixture was poured in water (40 ml) and extracted with ethyl acetate (40x4 ml) , the organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography, (Biotage System, SNAP Cartridge silica 100 g, eluent: gradient n- hexane/ethyl acetate 8/2 (145 ml), to n-hexane/ethyl acetate 3/7 during 870 ml, n-hexane/ethyl acetate 3/7 (725 ml)) . The product (F) (0.89 g) was obtained. G) (8S,9S,10R, 11S,13S,14S,17R) _ ₁₁ _ _hydroxy _ ₁₇ _ ₍₂ - hydroxyacetyl) -10, 13-dimethyl-3-oxo-6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-dodecahydro-3H-cyclopenta [a] phenanthren-17-yl 4- bromobutanoate

(G)

To a solution of compound (F) (0.88 g, 1.53 mmol) in methanol (27 ml), a 5% aqueous AcOH solution (5.5 ml) was added. The reaction was stirred a reflux for 7 hours. The mixture was concentrated under reduced pressure. The mixture was diluted with dichloromethane (30 ml) , washed with saturated aqueous sodium carbonate (2x30 ml) , water

(2X30 ml) , the organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography, (Biotage System, SNAP Cartridge silica 50 g, eluent: gradient acetone/dichlorometane 9/1 (75 ml) , to acetone/dichlorometane 25/75 during 375 ml, acetone/dichlorometane 25/75 (375 ml) ) . The product (G) (0.74 g) was obtained.

H) (6S, 9R, 1OS, US, 13S, 16R, 17R) -6, 9-difluoro-ll-hydroxy-17- (2-hydroxyacetyl) -10, 13, 16-trimethyl-3-oxo-6, 7,8,9,10, 11, 12, 13, 14, 15, 16, 17-dodecahydro-3H-cyclopenta [a] phenanthren-17-yl 4-nitroxybutanoate (compound (20))

To a solution of compound (G) (0.73 g, 1.31 mmol) in acetonitrile (32 ml), silver nitrate (0.67 g, 3.95 mmol) was added. The reaction was heated to 130 ⁰ C for 15 minutes under microwave irradiation. The resulting mixture was cooled, filtered and the solvent was removed under reduced pressure. The residue was diluted with dichloromethane (40 ml) , washed with water (2X40 ml) , the organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude was purified by flash chromatography,

(Biotage System, SNAP Cartridge silica 50 g, eluent: gradient acetone/dichlorometane 9/1 (75 ml) , to acetone/dichlorometane 25/75 during 375 ml, acetone/dichlorometane 25/75 (375 ml)) . The product (0.57 g) was obtained.

¹ H-NMR: (DMSO), δ: 7.25 (IH, d, J = 10.1 Hz), 6.29 (IH, d, J = 10.1 Hz), 6.11 (IH, s), 5.63 (IH, dq, J _H - _F = 48.8, J _H - _H = 10.8, 6.5 Hz), 5.48 (IH, d, J = 3.6 Hz), 5.07 (IH, t, J = 5.9 Hz), 4.51 (2H, t, J = 6.4 Hz), 4.17 (IH, dd, J = 17.2, 5.9 Hz), 4.16 (IH, bs), 4.05 (dd, J = 17.2, 5.9, IH), 3.28 - 3.16 (IH, m) , 2.64 - 2.38 (3H, m) , 2.25 (IH, m) , 2.17 - 2.01 (2H, m) , 1.99 - 1.72 (3H, m) , 1.66 (IH, d, J = 13.8 Hz), 1.49 (IH, m) , 1.48 (3H, s), 1.23 (IH, m) , 0.93 (3H, s) , 0.84 (3H, d, J = 6.9 Hz) .

Example 4

Synthesis of 4- (nitrooxy) butyl 4- ( (2- ( (6S, 9R, 10S, US, 13S, 16R, 17R) -6, 9-difluoro-ll-hydroxy-17- (4- nitroxybutanoyloxy) -10, 13, 16-trimethyl-3-oxo-6, 7,8,9, 10, 11, 12, 13, 14, 15, 16, 17-dodecahydro-3H-cyclopenta [a] phenanthren-17-yl) -2-oxoethoxy) carbonyloxy) -3- methoxybenzoate (Compound (22))

(22)

I) (6S, 9R, 1OS, US, 13S, 16R, 17R) -17- (2- (chlorocarbonyloxy) acetyl) -6, 9-difluoro-ll-hydroxy-10, 13, 16-trimethyl-3-oxo- 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-dodecahydro-3H- cyclopenta [a] phenanthren-17-yl 4-nitroxybutanoate

(D

To a solution of compound (20) (0.35 g, 0.64 mmol) in tetrahydrofurane (3.1 ml), cooled at 0 ⁰ C and under N ₂ , a

20% toluene solution of phosgene (2.03 ml, 3.87 mmol) was added. The reaction was stirred at 0 ⁰ C for 1 hour and at room temperature for 22 hours. The excess of phosgene was removed by heating at 40 ⁰ C for 45 minutes. The solvent was evaporated under vacuum. The crude product (I) (0.38 g) was used in the next step without any purification. L) 4- (nitrooxy) butyl 4- ( (2- ( ( 6S, 9R, 1OS, US, 13S, 16R, 17R) - 6, 9-difluoro-ll-hydroxy-17- (4-nitroxybutanoyloxy) -10, 13, 16- trimethyl-3-oxo-6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17- dodecahydro-3H-cyclopenta [a] phenanthren-17-yl) -2- oxoethoxy) carbonyloxy) -3-methoxybenzoate Compound (22)

To a solution of compound (I) (0.38 g, 0.63 mmol) in dichloromethane (7 ml), diisopropylethylamine (0.12 ml, 0.69 mmol) was added. The reaction was cooled at 0 ⁰ C and vanillic acid 4- (nitrooxy) butyl ester (0,19 g, 0.69 mmol) was added. The reaction was stirred at room temperature for 18 hours. The solvent was evaporated under vacuum. The residue was purified by flash chromatography (Biotage System, SNAP Cartridge silica 50 g, eluent: gradient n- hexane/ethyl acetate 9/1 (75 ml) , to n-hexane/ethyl acetate 2/8 during 675 ml, n-hexane/ethyl acetate 2/8 (375 ml)) . The product (0.38 g) was obtained.

¹ H-NMR: (DMSO), δ 7.65 (IH, s), 7.64 (IH, d, J = 8.1 Hz), 7.39 (IH, d, J = 7.1 Hz), 7.25 (IH, d, J = 10.2 Hz), 6.29 (IH, d, J = 10.2 Hz), 6.11 (IH, s), 5.64 (IH, dq, J _H - _F = 49.0, J _H - _H = 10.6, 6.6 Hz), 5.49 (IH, d, J = 3.1 Hz), 5.16 (IH, d, J = 16.5 Hz), 4.92 (IH, ά, J = 16.5 Hz), 4.60 (2H, t, J = 5.5 Hz), 4.52 (2H, t, J = 6.1 Hz), 4.34 (2H, t, J = 5.1 Hz), 4.19 (IH, m) , 3.89 (3H, s), 2.55 (2H, t, J = 7.4 Hz), 2.51 (IH, m) , 2.25 (IH, m) , 2.19 - 2.02 (2H, m) , 1.98 - 1.74 (8H, m) , 1.66 (IH, d, J = 13.8 Hz), 1.50 (IH, m) , 1.48 (3H, s), 1.23 (IH, m) , 0.99 (3H, s), 0.89 (3H, d, J = 6.7 Hz) .