Nitric oxide releasing steroids

This application is a National Stage entry of International Application No. PCT/EP2008/050938, filed Jan. 28, 2008, which claims benefit of U.S. Provisional Nos. 60/929,456 filed Jun. 28, 2007 and 60/899,376 Feb. 5, 2007. The disclosures of the prior applications are hereby incorporated in its entirety by reference.

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.

The compounds of the present invention may be used, as drugs having antiinflammatory activity at peripheral level, for the therapy of respiratory diseases such as asthma and COPD, in ocular disease therapies such as ocular hypertension, age-related macular degeneration, diabetic macular edema, diabetic retinopathy, hypertensive retinopathy and retinal vasculopathies, or in dermatological disease therapies such asdermatosis, atopic dermatitis, inflammation, eczema, erythema, papulation, scaling, erosion, oozing, crusting, pruritis, psoriasis, epidermalysis bullosa, erythema, hidradenitis suppurative, warts, diaper rash, jock itch.

In particular the compounds of the present invention are useful in ocular disease therapies.

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 —CH 2 —O—NO 2 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.

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 ONO 2 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.

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 is 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.

Object of the present invention are 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:

R 1 is OH, R 2 —CH 3 , or R 1 and R 2 are taken together to form a group of formula (III)

R 3 is Cl or F;

R 4 is H or F;

wherein R 1 , R 2 , R 3 and R 4 can be linked to the correspondent carbon atoms of the steroidal structure in position α or β; with the proviso that:

when R 1 and R 2 are the group of formula (III) then R 3 is F and R 9 is H or F;

when R 1 is OH and R 2 —CH 3 then R 4 is H and R 3 is Cl or F; preferred corticosteroid radicals are R of formula (II) wherein:

R 1 is OH in position α, R 2 —CH 3 in position β, R 3 is Cl in position α and R 4 is H; or

R 1 is OH in position α, R 2 —CH 3 in position R 3 is F in position α and R 4 is H; or

R 1 and R 2 are taken together to form a group of formula (III)

R 3 is F and R 4 is H, R 1 , R 2 and R 3 are in position α; or

R 1 and R 2 are taken together to form a group of formula (III)

R 3 and R 4 are F, R 1 , R 2 , R 3 and R 4 are in position α;

a in formula (I) is equal to 0 or 1;

Z is a group capable of binding R x and is selected from —C(O)—, or —CH(R′)—O— wherein R′ is selected from H or a straight or branched C 1 -C 4 alkyl, preferably R′ is H or —CH 3 ;

R x is a radical and is selected from the following meanings:

A)

(a1) —HN—CH(R 1 )—C(O)-(T-Y—ONO 2 )

(a2) —C(O)—CH(R 1 )—NH-(T′-Y—ONO 2 )

(a3) —HN—CH(R 1a -T″-Y—ONO 2 )—COOR 3a

(a4) —C(O)—OH(R 1a -T″-Y′—ONO 2 )

(a5) —R 1b —CH(NHR 4a )—C(O)-(T-Y—ONO 2 )

(a6) —R 1b —CH(COOR 3a )NH-(T′-Y—ONO 2 )

(a7) —HN—CH(R 1a -T″-Y′—ONO 2 )—C(O)-(T-Y—ONO 2 )

(a8) —C(O)—CH(R 1a -T″-Y′—ONO 2 )—NH-(T′-Y—ONO 2 )

(a9) —R 1b —CH(NH-T′-Y′—ONO 2 )—C(O)-(T-Y—ONO 2 )

(a10) —R 1b —CH(C(O)-T-Y—ONO 2 )—NH-(T′-Y—ONO 2 )

wherein:

R 1 is selected from:

A1) H, —CH 3 , isopropyl, isobutyl, sec-butyl, tert-butyl, methylthio-(CH 2 ) 2 —, phenyl, benzyl, C 6 H 5 —CH 2 —CH 2 —, 2-monosubstituted benzyl, or 3-monosubstituted benzyl or 4-monosubstituted benzyl wherein the substituent of the benzyl is selected from —F, —Cl, I, —NO 2 , —CF 3 , —CH 3 , CN, C 6 H 5 CO—; 2,4-dichlorobenzyl, 3,4-dichlorobenzyl, 3,4-difluorobenzyl, 2-pyrrolidyl, 3-triptophanyl-CH 2 —, 3-benzothienyl-CH 2 —, 4-imidazolyl-CH 2 —, 9-anthranyl-CH 2 —, cyclohexyl, cyclohexyl-CH 2 -cyclohexyl-(CH 2 ) 2 —, cyclopentyl-CH 2 —, (C 6 H 5 ) 2 CH—, 4-B(OH) 2 — benzyl, 4-quinolyl-CH 2 —, 3-quinolyl-CH 2 —, 2-quinolyl-CH 2 —, 2-quinoxalyl-CH 2 —, 2-furyl-CH 2 —, 1-naphtyl-CH 2 —, 2-naphtyl-CH 2 —, 2-pyridyl-CH 2 —, 3-pyridyl-CH 2 —, 4-pyridyl-CH 2 —, 2-thienyl-CH 2 —, 3-thienyl-CH 2 —, C 6 H 4 —CH═CH—CH 2 —, CH 2 ═CH—CH 2 —, CH≡CH—CH 2 —, NH 2 —CO—CH 2 —, NH 2 CH—CO—(CH 2 ) 2 —, NH 2 (═NH)NH—(CH 2 ) 3 —, P(═O)(OCH 3 ) 2 , I—CH 2 —, preferably R 1 is H, —CH 3 , isopropyl, benzyl; A2) —CH 2 —SH, —CH 2 —OH, —CH(CH 3 )—OH, —CH 2 —[(C 6 H 4 )-(4-OH)], —CH 2 —[(C 6 H 2 )-(3,5-diiodo)-(4-OH)], —CH 2 —[(C 6 H 3 )-(3-nitro)-(4-CH)], preferably R 1 is —CH 2 —OH or —CH 2 —[(C 6 H 4 )-(4-OH)]; A3) —CH 2 —NHR″, —(CH 2 ) 2 —NHR″, —(CH 2 ) 3 —NHR″, —(CH 2 ) 4 —NHR″, wherein R″ is H, —C(O)CH 3 or

wherein R 3a is H or a linear or branched C 1 -C 10 alkyl chain, preferably R 5a is H or a linear (C 1 -C 5 ) alkyl, preferably R 1 is —(CH 2 ) 4 —NHR″, wherein R″ is as above defined;

A4) —CH 2 —C(O)R″—(CH 2 ) 2 —C(O)R″—(CH 2 ) 4 —C(O)R″ wherein R″ is —OR 5a or

wherein R 5a is as above defined, preferably R 1 is —CH 2 —C(O)R′″, wherein R″ is as above defined;

R 1a is selected from,

A5) —CH 2 —S—, —CH 2 —O—, —CH(CH 3 )—O—, —CH 2 [(C 6 H 4 )—(4-O)—], —CH 2 -[(3,5-diiodo)-(C 6 H 2 )—(4-O)—], —CH 2 -[(3-nitro)-(C 6 H 3 )—(4-O)—], preferably R 1a is —CH 2 —O—; A6) —CH 2 —NH—, —(CH 2 ) 2 —NH—, —(CH 2 ) 3 —NH—, —(CH 2 ) 4 —NH—, preferably R 1a is —(CH 2 ) 4 —NH— or —CH 2 —NH—; A7) —CH 2 —C(O)—(CH 2 ) 2 —C(O)—(CH 2 ) 4 —C(O)—, preferably R 1a is —CH 2 —C(O)—;

R 3a is selected from H, —R 5a or

wherein R 5a is as above defined;

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

wherein R 5a is as above defined;

R 1b is selected from

A8) —S—CH 2 —, —O—CH(CH 3 )—, —O—CH 2 —, [-(4-O)—(C 6 H 4 )]—CH 2 —, [—(4-O)-(3,5-diiodo)-(C 6 H 2 )]—CH 2 —, [—(4-O)-(3-nitro)-(C 6 H 3 )]—CH 2 —, preferably R 1b is —O—CH 2 — or [—(4-O)—(C 6 H 4 )]—CH 2 —; A9) —HN—CH 2 —, —HN—(CH 2 ) 2 —, —HN—(CH 2 ) 3 —, —HN—(CH 2 ) 4 —, preferably R 1b is —HN—(CH 2 ) 4 — or —HN—CH 2 —; A10) —C(O)—CH 2 —, —C(O)—(CH 2 ) 2 —, —C(O)—(CH 2 ) 4 —, preferably R 1b is —C(O)—CH 2 —;

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 —O(O)—, —C(O)—X″—, —C(O)—NR′—O—, —S—, —NR′—O—CH(R′)—O—O(O)—, —O—CH(R′)—O—C(O)O—, wherein X″ and R′ are as above defined, with the proviso that T″ is —O(O)—, —O(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—O(O)—, —O—CH(R′)—O—O(O)O— when T″ is linked to —O(O)—;

Y and Y′ are as below defined;

B)

(b1) —HN—CH(R 2 )—CH 2 C(O)-(T-Y—ONO 2 )

(b2) —O(O)—CH 2 —CH(R 2 )—NH-(T′-Y—ONO 2 )

(b3) —HN—CH(R 2a -T″-Y′—NO 2 )—CH 2 COOR 3a

(b4) —C(O)—CH 2 —CH(R 1a -T″-Y′—ONO 2 )—NHR 4a

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

(b6) —R 2b —CH(CH 2 COOR 3a )NH-(T′-Y—ONO 2 )

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

(b8) —C(O)—CH 2 —CH(R 2a -T″-Y—ONO 2 )—NH-(T-Y—ONO 2 )

(b9) —R 2b —CH(NH-T′-Y′—ONO 2 )—CH 2 O(O)-(T′-Y—ONO 2 )

(b10) —R 2b —CH(CH 2 C(O)-T-Y′—ONO 2 )—NH-(T′-Y′—ONO 2 )

wherein

R 2 is selected from

B1) H, —CH 3 , CF 3 , isopropyl, isobutyl, sec-butyl, methylthio-(CH 2 ) 2 —, phenyl, benzyl, 3-triptophanyl-CH 2 —, NH 2 —C(O)—CH 2 —, NH 2 —C(O)—(CH 2 ) 2 —, NH 2 (═NH)NH—(CH 2 ) 3 —, tBuO—CH(CH 3 )—, benzyl-O—CH 2 —, 4-terbutoxy-benzyl, 4-phenylbenzyl, preferably R 2 is H, —CH 3 , isopropyl, benzyl;

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

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

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

R 2a is selected from

B5) —CH 2 —S—, —CH 2 —O—, —CH(CH 3 )—O— or —CH 2 [(C 6 H 4 )—(4-O)—], —CH 2 -[(3,5-diiodo)-(C 6 H 2 )—(4-O)—], —CH 2 -[(3-nitro)-(C 6 H 3 )—(4-O)—], preferably R 2a is —CH 2 —O—; B6) —CH 2 —NH—, —(CH 2 ) 2 —NH—, —(CH 2 ) 3 —NH—, —(CH 2 ) 4 —NH—, preferably R 2a is —(CH 2 ) 4 —NH— or —CH 2 NH—; B7) —CH 2 —C(O)—, —(CH 2 ) 2 —O(O)—(CH 2 ) 4 —O(O)—, preferably R 2a is —CH 2 —C(O)—;

R 2b is selected from

B8) —S—CH 2 —, —O—CH(CH 3 )—, —O—CH 2 —, [-(4-O)—(C 6 H 4 )]—CH 2 —, [-(4-O)-(3,5-diiodo) (C 6 H 2 )]—CH 2 —, [-(4-O)-(3-nitro)-(C 6 H 3 )]—CH 2 —, preferably R 2b is —O—CH 2 — or [-(4-O)—(C 6 H 4 )]—CH 2 —; B9) —HN—CH 2 —, —HN—(CH 2 ) 2 —, —HN—(CH 2 ) 3 —, —HN—(CH 2 ) 4 —, preferably R 2b is —HN—(CH 2 ) 4 — or —HN—CH 2 —; B10) —C(O)—CH 2 —, —C(O)—(CH 2 ) 2 —, —C(O)—(CH 2 ) 4 —, preferably R 2b is —C(O)—CH 2 —;

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

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

C)

(c1) —HN—(CH 2 ) b —C(O)-(T-Y—ONO 2 )

(c2) —C(O)—(CH 2 ) b —NH-(T′-Y—ONO 2 );

wherein b is an integer from 3 to 6,

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

D)

(d1) —HN—CH(R 12 )—CH 2 —O-(T′″-Y—ONO 2 )

(d2) —O—CH 2 —CH(R 12 )—NH-(T′-Y—ONO 2 )

(d3) —HN—CH(R 12a -T″-Y′—ONO 2 )—CH 2 OH

(d4) —O—CH 2 —CH(R 12a -T″-Y′—ONO 2 )—NHR 4a

(d5) —R 12b —CH(NHR 4a )—CH 2 —O-(T′″-Y—ONO 2 )

(d6) —R 12b —CH(CH 2 OH)—NH-(T′″-Y—ONO 2 )

(d7) —HN—CH(R 12a -T″-Y′—ONO 2 )—CH 2 —O-(T″-Y—ONO 2 )

(d8) —O—CH 2 —CH(R 12a -T″-Y′—ONO 2 )—NH-(T′-Y—ONO 2 )

(d9) —R 12b —CH(NH-T′-Y′—ONO 2 )—CH 2 —O-(T′″-Y—ONO 2 )

(d10) —R 12b —CH(CH 2 —O-T′″-Y′—ONO 2 )—NH-(T′-Y—ONO 2 )

wherein

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

T′ and T″ are as above defined;

Y and Y′ are as below defined;

R 12 is selected from:

D1) H, —CH 3 , isopropyl, isobutyl, sec-butyl, methylthio-(CH 2 ) 2 —, benzyl, 3-triptophanyl-CH 2 —, 4-imidazolyl-CH 2 —, NH 2 —CO—CH 2 —, NH 2 —CO—(CH 2 ) 2 —, NH 2 (═NH)NH—(CH 2 ) 3 —, preferably R 12 is H;

D2) —CH 2 —OH, —CH(CH 3 )—OH, —CH 2 —[(C 6 H 4 )-(4-OH)], —CH 2 —[(C 6 H 3 )-(3,5-diiodo)-(4-OH)], —CH 2 —[(C 6 H 3 )-(3-nitro)-(4-OH)], preferably R 12 is —CH 2 —OH or —CH 2 —[(C 6 H 4 )—(4-OH)];

D3) —CH 2 —NHR″, —(CH 2 ) 2 —NHR″, —(CH 2 ) 3 —NHR″, —(CH 2 ) 4 —NHR″, wherein R″ is as above defined, preferably R 12 is —(CH 2 ) 4 —NHR″;

D4) —CH 2 —C(O)R″, —(CH 2 ) 2 —C(O)R′″, (CH 2 ) 4 —C(O)R′″ wherein R′″ is as above defined, preferably R 12 is —CH 2 —C(O)R′″;

R 12a is selected from

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

D6) —CH 2 —NH—, —(CH 2 ) 2 —NH—, —(CH 2 ) 3 —NH—, —(CH 2 ) 4 —NH—, preferably R 12a is —(CH 2 ) 4 —NH— or —CH 2 —NH—;

D7) —CH 2 —C(O)—(CH 2 ) 2 —C(O) (CH 2 ) 4 —C(O)—, preferably R 12a is —CH 2 —C(O)—;

R 12b is selected from

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

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

D10) —C(O)—CH 2 —, —C(O)—(CH 2 ) 2 —, is —C(O)—CH 2 —;

R 4a is as above defined;

E)

wherein c is equal to 0 or 1, d is an integer from 0 to 3 with the proviso that c is 0 or 1 when d is 0 and c is 0 when d is 1, 2 or 3, T and T′ are as above defined and Y is as below defined;

F)

wherein e and f are equal to 0 or 1, with the proviso that f is 0 when e is 0 and f is 0 or 1 when e is 1,

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

G)

wherein R 3 is H, CH 3 , propyl, (C 6 H 5 ) 2 CH—, 1-naphtyl-CH 2 —, benzyl, allyl, 2-bromobenzyl, 2-chlorobenzyl, 3-chlorobenzyl, fluorobenzyl, 4-bromobenzyl, 4-methylbenzyl, preferably R 3 is H, T and T′ are as above defined and Y is as below defined;

H)

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

I)

wherein R 5 is H, R 6 is H, or R 5 and R 6 when taken together are a double bond, T and T′ are as above defined and Y is as below reported;

L)

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

M)

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

N)

wherein c is as above defined, d is equal to 0 or 1, T and T′ are as above defined and Y is as below reported;

O)

wherein R 7 is H, R 8 is H, or R 7 and R 8 when taken together are a double bond, c is as above defined, T and T′ are as above defined and Y is as below reported;

P)

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

Q)

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

R)

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

S)

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

T)

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

U)

wherein R 9 and R 10 are H, CH 3 , R 11 is CH 3 or 4-piperidinyl with the proviso that R 9 and R 10 are H when R 11 is 4-piperidinyl and R 9 and R 10 are CH 3 when R 11 is CH 3 , T and T′ are as above defined and Y is as below reported;

V)

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

with the proviso that in the formula (I):

a is 0 or a is 1 and Z is —CH(R′)—O— wherein R′ is as above defined, when R x is:

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

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

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

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

(c2);

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

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

a is 1 and Z is —C(O)—, when R x is:

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

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

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

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

(c1);

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

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

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

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

a)

straight or branched C 1 -C 20 alkylene, preferably a straight or branched C 1 -C 10 alkylene,

straight or branched C 1 -C 20 alkylene substituted with one or more of the substituents selected from the group consisting of: halogen atoms, hydroxy, —ONO 2 or T 2 , wherein T 2 is —OC(O) (C 1 -C 10 alkyl)-ONO 2 or —O(C 1 -C 10 alkyl)-ONO 2 , preferably Y or Y′ is a straight or branched C 1 -C 10 alkylene substituted with a —ONO 2 group;

cycloalkylene with 5 to 7 carbon atoms into cycloalkylene ring, the ring being optionally substituted with one or more straight or branched C 1 -C 10 alkyl chains, preferably the ring being optionally substituted with CH 3 ;

wherein

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

n 1 is 0 or 1, preferably n 1 is 1;

U is a linear or branched C 1 -C 20 alkylene optionally substituted with a —ONO 2 group, preferably U is a linear C 1 -C 10 alkylene or U is a linear or branched C 1 -C 10 alkylene substituted with a —ONO 2 group;

wherein

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

n is 0 or 1, preferably n 1 is 1;

U is a linear or branched C 1 -C 20 alkylene optionally substituted with a —ONO 2 group, preferably U is a linear C 1 -C 10 alkylene or U is a linear or branched C 1 -C 10 alkylene substituted with a —ONO 2 group;

wherein:

n 2 is an integer from 0 to 2, R 13 is H or CH 3 , T 1 is —O—C(O)— or —C(O)O—;

n 1 and U are as above defined;

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

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

Y is —CH 2 —CH 2 — or —CH═CH—(CH 2 ) n 2′ —, wherein n 2′ is 0 or 1, preferably Y 1 is —CH═CH—(CH 2 ) n 2′ — and n 2′ is 0;

T 1 =—O—C(O)— or —C(O)O—, preferably T 1 is —C(O)O—;

n 1 is 0 or 1, preferably n 1 is 1;

U is a linear or branched C 1 -C 20 alkylene optionally substituted with a —ONO 2 group, preferably U is a linear C 1 -C 10 alkylene or U is a linear or branched C 1 -C 10 alkylene substituted with a —ONO 2 group;

more preferably n 2 is 1, R 13 is CH 3 , Y 1 is —CH═CH—(CH 2 ) n 2′ and n 2′ is 0, T 1 is —C(O)O— and U is a linear C 1 -C 10 alkylene;

wherein:

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

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

Y 1 is —CH 2 —CH 2 — or —(CH 2 ) n 2′ —CH═CH—, wherein n is 0 or 1,

preferably Y 1 is —(CH 2 ) n 2′ —CH═CH— and n 2′ is 0;

(T 1 )′=—O—C(O)—;

n 1 is 0 or 1, preferably n is 1;

U is a linear or branched C 1 -C 20 alkylene optionally substituted with a —ONO 2 group, preferably U is a linear C 1 -C 10 alkylene or U is a linear or branched C 1 -C 10 alkylene substituted with a —ONO 2 group;

more preferably n 2 is 1, R 13 is CH 3 , Y 1 is —CH═CH—(CH 2 ) n 2′ — and n 2′ is 0, T 1 is —OC(O)— and U is a linear C 1 -C 10 alkylene; when Y and Y′ are selected from b), c), d), e) or e′), the —ONO 2 group of -(T-Y—ONO 2 ), -(T′-Y—ONO 2 ), -(T″-Y′—ONO 2 ), -(T′Y′—ONO 2 ), -(T′″-Y—ONO 2 ) and -(T′″-Y′—ONO 2 ) is linked to the —(CH 2 )— group;

wherein T 2 is —O— or —S—, —NH—, preferably T 2 is —O—, n 3 is an integer from 1 to 6, preferably n 3 is 1;

wherein:

n 4 is an integer from 0 to 10, preferably n is 0 or 1;

n 5 is an integer from 1 to 10, preferably n 5 is 1;

R 14 , R 15 , R 16 , R 17 are the same or different, and are H or straight or branched C 1 -C 4 alkyl, preferably R 14 , R 15 , R 16 and R 17 are H;

wherein the —ONO 2 group is linked to

wherein n 5 is as defined above;

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

and is selected from the group consisting of:

The term “C 1 -C 10 alkyl” as used herein refers to branched or straight alkyl groups including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl, octyl and the like.

The term “cycloalkylene” as used herein refers to ring having from 5 to 7 carbon atoms including, but not limited to, cyclopentylene, cyclohexylene optionally substituted with side chains such as straight or branched (C 1 -C 10 )-alkyl, preferably CH 3 .

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

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 the corticosteroid residue R is selected from the group consisting of betamethasone, fluocinolone acetonide, triamcinolone acetonide.

Another embodiment of the invention relates to compounds of formula (I) wherein in the corticosteroid R of formula (II) R 1 , R 2 , R 3 and R 4 have the following meanings:

R 1 is OH in position α, R 2 —CH 3 in position β, R 3 is Cl in position α and R 4 is H; or

R 1 is OH in position α, R 2 —CH 3 in position β, R 3 is F in position α and R 4 is H; or

R 1 and R 2 are taken together to form a group of formula (III)

R 3 is F and R 4 is H, R 1 , R 2 and R 3 are in position α; or

R 1 and R 2 are taken together to form a group of formula (III)

R 3 and R 4 are F, R 1 , R 2 , R 3 and R 4 are in position α;

in formula (I)

a is 0 and

R x is selected from:

(a2) —C(O)—CH(R 1 )—NH-(T′-Y—ONO 2 )

wherein

R 1 of the group A1) is selected from H, isobutyl, benzyl, C 6 H 5 —CH 2 —CH 2 —, 2-monosubstituted benzyl, or 3-monosubstituted benzyl or 4-monosubstituted benzyl wherein the substituent of the benzyl is selected from —F, —Cl, I, —NO 2 , —CF 3 , —CH 3 , CN, C 6 H 5 CO—;

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

R 1 of the group A3) is selected from —CH 2 —NHR″, —(CH 2 ) 2 —NHR″, —(CH 2 ) 3 —NHR″, —(CH 2 ) 4 —NHR″, wherein R″ is H, or —C(O)CH 3 ;

R 1 of the group A4) is selected from —CH 2 —C(O)R″, (CH 2 ) 2 — C(O)R″, —(CH 2 ) 4 —C(O)R′″ wherein R″ is OR 5a wherein R 5a is H or a linear (C 1 -C 5 ) alkyl;

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

Y is as below defined;

or R x is

(a4) —C(O)—CH(R 1a -T″-Y′—ONO 2 )—NHR 4a

wherein R 1a of the group A5) is selected from —CH 2 —O—, —CH(CH 3 ) O— or —CH 2 [(C 6 H 4 )-(4-O)—], or

R 1a of the group A6) is selected from —CH 2 —NH—, —(CH 2 ) 2 —NH—, (CH 2 ) 3 —NH—, —(CH 2 ) 4 —NH—, or

R 1a of the group A7) is selected from —CH 2 —C(O)—(CH 2 ) 2 —C(O)—, —(CH 2 ) 4 —C(O)—;

R 4a is H or —O(O)CH 3 ;

T″ is —C(O)— or —C(O)—X″ wherein X″ is —S— or —O—, when R 1a is selected from the group A5) or A6), preferably T″ is —C(O)—;

T″ is —O—, —S—, —NR′— or —O—CH(R′)—O—C(O)— wherein R′ is H or —CH 3 , when R 1a is selected from the group A7);

Y′ is as below defined;

or R x is selected from

(a5) —R 1b —CH(NHR 4a )—C(O)-(T-Y—ONO 2 )

(a6) —R 1b —CH(COOR 3a )—NH-(T′Y—ONO 2 )

(a9) —R 1b —CH(NH-T′Y′—ONO 2 )—C(O)-(T-Y—ONO 2 ) or

(a10) —R 1b —CH(C(O)-T-Y′—ONO 2 )—NH-(T′Y—ONO 2 )

wherein

R 1b of the group A10) is selected from —C(O)—CH 2 —, —C(O)—(CH 2 ) 2 —, —C(O)—(CH 2 ) 4 —;

R 3a is H or a (C 1 -C 5 ) alkyl;

R 4a is H or —O(O)CH 3 ;

T is —O—, —S—, —NR′— or —O—CH(R′)—O—C(O)— wherein R′ is H or —CH 3 , preferably T is —O—;

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

Y and Y′ are as below defined; or R x is

(a8) —C(O)—CH(R 1a -T″-Y′—ONO 2 )—NH-(T′-Y—ONO 2 )

wherein

R 1a of the group A5) is selected from —CH 2 —O—, —CH(CH 3 )—O— or —CH 2 —[(C 6 H 4 )-(4-O—)—], or

R 1a of the group A6) is selected from —CH 2 —NH—, —(CH 2 ) 2 —NH—, (CH 2 ) 3 —NH—, —(CH 2 ) 4 —NH—, or

R 1a of the group A7) is selected from —CH 2 —C(O)—, —(CH 2 ) 2 —C(O)—, —(CH 2 ) 4 —C(O)—;

T″ is —C(O)— or —O(O)—X″ wherein X″ is —S— or —O—, when R 1a is selected from the group A5) or A6), preferably T″ is —O(O)—;

T″ is —O—, —S—, —NR′— or —O—CH(R′)—O—C(O)— wherein R′ is H or —CH 3 , when R 1a is selected from the group A7);

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

Y and Y′ are as below defined;

or R x is

(b2) —C(O)—CH 2 —CH(R 2 )—NH-(T′-Y—ONO 2 )

wherein

R 2 of the group B1) is selected from H, CH 3 , isobutyl, isopropyl, benzyl;

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

Y and Y′ are each independently selected from

a)

a straight or branched C 1 -C 10 alkylene,

a straight or branched C 1 -C 10 alkylene substituted with a —ONO 2 group;

wherein:

n 2 is an integer from 0 to 2, R 13 is H or CH 3 , T 1 is —O—C(O)— or —C(O)O—;

n 1 is 1 and U is a linear C 1 -C 10 alkylene or U is a linear or branched C 1 -C 10 alkylene substituted with a —ONO 2 group;

n 2 is 1, R 13 is CH 3 , Y 1 is —CH═CH—(CH 2 ) n 2′ — and n 2′ is 0, T 1 is —C(O)O— and U is a linear C 1 -C 10 alkylene;

wherein:

n 2 is 1, R 13 is CH 3 ;

Y 1 is —(CH 2 ) n 2′ —CH═CH— and n 2′ is 0;

(T 1 )′=—O—C(O)—;

n 1 is 1 and U is a linear C 1 -C 10 alkylene or U is a linear or branched C 1 -C 10 alkylene substituted with a —ONO 2 group;

when Y and Y′ are selected from d), e) or e′), the —ONO 2 group of -(T-Y—ONO 2 ), -(T′-Y—ONO 2 ), (T″-Y′—ONO 2 ) (T′-Y′—ONO 2 ), -(T′″-Y—ONO 2 ) and -(T″-Y′—ONO 2 ) is linked to the —(CH 2 )— group;

wherein T 2 is —O— or —S—, —NH—, preferably T 2 is —O—, n 3 is 1 or 2;

Another embodiment of the invention relates to compounds of formula (I) wherein in the corticosteroid R of formula (II) R 1 , R 2 , R 3 and R 4 have the following meanings:

R 1 is OH in position α, R 2 —CH 3 in position β, R 3 is Cl in position α and R 4 is H; or

R 1 is OH in position α, R 2 —CH 3 in position β, R 3 is F in position α and R 4 is H; or

R 1 and R 2 are taken together to form a group of formula (III)

R 3 is F and R 4 is H, R 1 , R 2 and R 3 are in position α; or

R 1 and R 2 are taken together to form a group of formula (III)

R 3 and R 4 are F, R 1 , R 2 , R 3 and R 4 are in position α;

in formula (I)

a is 1 and Z is —C(O)—;

R x is

(a1) —HN—CH(R 1 )—C(O)-(T-Y—ONO 2 )

wherein

R 1 of the group A1) is selected from H, isobutyl, benzyl, C 6 H 5 —CH 2 —CH 2 —, 2-monosubstituted benzyl, or 3-monosubstituted benzyl or 4-monosubstituted benzyl wherein the substituent of the benzyl is selected from —F, —Cl, I, —NO 2 , —CF 3 , —CH 3 , CN, C 6 H 5 CO—;

or

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

R 1 of the group A3) is selected from —CH 2 —NHR″, —(CH 2 ) 2 —NHR″, —(CH 2 ) 3 —NHR″, —(CH 2 ) 4 —NHR″, wherein R″ is H, or —C(O)CH 3 ,

R 1 of the group A4) is —CH 2 —C(O)R′″, —(CH 2 ) 2 —C(O) R′″, —(CH 2 ) 4 —C(O)R′″ wherein R′″ is OR 5a wherein R 5a is H or a linear (C 1 -C 5 ) alkyl;

T is —O—, —S—, —NR′-O—CH(R′)—O—C(O)— wherein R′ is H or a straight or branched C 1 -C 4 alkyl, preferably T is —O—;

Y is as below defined;

or R x is

(a3) —HN—CH(R 1a -T″-Y′—ONO 2 )—COOR 3a wherein

R 1a of the group A5) is selected from —CH 2 —O—, —CH(CH 3 ) O— or —CH 2 [(C 6 H 4 )O p —], or

R 1a of the group A6) is selected from —CH 2 —NH—, —(CH 2 ) 2 —NH—, (CH 2 ) 3 —NH—, —(CH 2 ) 4 —NH—, or

R 1a of the group A7) is —CH 2 —C(O)—(CH 2 ) 2 —C(O)—(CH 2 ) 4 —C(O)—;

R 3a is H or a (C 1 -C 5 ) alkyl;

T″ is —C(O)— or —C(O)—X″ wherein X″ is —S— or —O—, when R 1a is selected from the group A5) or A6), preferably T″ is —O(O)—;

T″ is —O—, —S—, —NR′-O—CH(R′)—O—C(O)— wherein R′ is H or a straight or branched C 1 -C 4 alkyl, when R 1a is selected from the group A7);

Y′ is as below defined;

or R x is

(a5) —R 1b —CH(NHR 4a )—C(O)-(T-Y—ONO 2 )

(a6) —R 1b —CH(COOR 3a )NH-(T′-Y—ONO 2 )

(a9) —R 1b —CH(NH-T′-Y′—ONO 2 )—C(O)-(T-Y—ONO 2 ) or

(a10) —R 1b —CH(C(O)-T-Y′—ONO 2 )—NH-(T′-Y—ONO 2 )

wherein

R 1b of the group A8) is selected from —O—CH(CH 3 )—, —O—CH 2 —, [-4-O)—(C 6 H 4 )]—CH 2 —, or

R 1b of the group A9) is selected from —HN—CH 2 —, —HN—(CH 2 ) 2 —, —HN—(CH 2 ) 3 —, —HN—(CH 2 ) 4 —;

R 3a is H or a (C 1 -C 5 ) alkyl;

R 4a is H or —C(O)CH 3 ;

T is —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)— wherein R′ is H or a straight or branched C 1 -C 4 alkyl, preferably T is —O—;

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

Y and Y′ are as below defined;

or R x is

(a7) —HN—CH—ONO 2 )—O(O)-(T-Y—ONO 2 )

wherein

R 1a of the group A5) is selected from —OH 2 —O—, —CH(CH 3 )—O— or —CH 2 —[(C 6 H 4 )-(4-O)—], or

R 1a of the group A6) is selected from —CH 2 —NH—, —(CH 2 ) 2 —NH—, —(CH 2 ) 3 —NH—, —(CH 2 ) 4 —NH—, or

R 1a of the group A7) is —CH 2 —C(O)—, —(CH 2 ) 2 —C(O)—, —(CH 2 ) 4 —C(O)—;

T″ is —C(O)— or —C(O)—X″ wherein X″ is —S— or —O—, preferably T″ is —C(O)— when R 1a is selected from A5) or A6);

T″ is —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)— wherein R′ is H or a straight or branched C 1 -C 4 alkyl, preferably T″ is —O—, when R 1a is selected from A7);

T is —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)— wherein R′ is H or a straight or branched C 1 -C 4 alkyl, preferably T is —O—;

Y and Y′ are as below defined;

or R x is

(b1) —HN—OH(R 2 )—CH 2 C(O)-(T-Y—ONO 2 )

wherein

R 2 of the group 131) is selected from H, CH 3 , isobutyl, isopropyl, benzyl;

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

R 2 of the group B3) is selected from —CH 2 —NHR″, —(CH 2 ) 2 —NHR″, —(CH 2 ) 3 —NHR″, —(CH 2 ) 4 —NHR″, wherein R″ is H, or —C(O)CH 3 ,

R 2 of the group B4) is —CH 2 —C(O)R′″, —(CH 2 ) 2 —C(O)R′″, —(CH 2 ) 4 —C(O)R′″ wherein R′″ is OR 5a wherein R 5a is H or a linear (C 1 -C 5 ) alkyl;

T is —O—, —S—, —NR′—, —O—CH)(R′)—O—C(O)— wherein R′ is H or a straight or branched C 1 -C 4 alkyl, preferably T is —O—;

Y is as below defined;

or R x is selected from

(d1) —HN—CH(R 12 )—CH 2 —O-(T″-Y—ONO 2 )

(d2) —O—CH 2 —CH(R 12 )—NH-(T′-Y—ONO 2 )

wherein

R 12 of the group D1) is selected from H, CH 3 , isobutyl, isopropyl, benzyl, or

R 12 of the group D2) is selected from —CH 2 —OH, —CH(CH 3 ) OH— or —CH 2 [(C 6 H 4 )—(4-OH)], or

R 12 of the group D3) is selected from —CH 2 —NHR″, —(CH 2 ) 2 —NHR″, (CH 2 ) 3 —NHR″, —(CH 2 ) 4 —NHR″ wherein R″ is H, or

R 12 of the group D4) is —CH 2 —C(O)R″, —(CH 2 ) 2 —C(O)R′″, —(CH 2 ) 4 —C(O)R′″ wherein R′″ is OR 5a wherein R 5a is H or a linear (C 1 -C 5 ) alkyl;

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

Y is as below defined;

or R x is selected from

(d3) —HN—CH(R 12a -T″-Y—ONO 2 )—CH 2 OH

(d4) —O—CH 2 —CH(R 12a -T″-Y′—ONO 2 )—NHR 4a

(d7) —HN—CH(R 12a -T″-Y′—ONO 2 )—CH 2 —O-(T″-Y—ONO 2 ) or

(d8) —O—CH 2 —CH(R 12a -T″-Y′—ONO 2 )—NH-(T′-Y—ONO 2 )

wherein

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

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

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

R 4a is H or —C(O)CH 3 ;

T″ is selected from —C(O)— or —C(O)—X″ wherein X″ is —S— or —O—, preferably T′ and T″ are —C(O)—, when R 12a is selected from D5) or D6);

T″ is —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)— wherein R′ is H or a straight or branched C 1 -C 4 alkyl, preferably T is —O—, when R 12a is selected from D7);

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

Y and Y′ are as below defined;

or R x is selected from

(d5) —R 12b —CH(NHR 4a )—CH 2 —O-(T″-Y—ONO 2 )

(d6) —R 12b —CH(CH 2 OH)—NH-(T′-Y—ONO 2 )

(d9) —R 12b —CH(NH-T′-Y′—ONO 2 )—CH 2 —O-(T″-Y—ONO 2 ) or

(d10) —R 12b —CH(CH 2 —O-T″-Y′—ONO 2 )—NH-(T′-Y—ONO 2 )

wherein

R 12b of the group D8) is selected from —O—CH(CH 3 )—, —O—CH 2 —, O p (C 6 H 4 )—CH 2 —, or

R 12b of the group D9) is selected from —HN—CH 2 —, —HN—(CH 2 ) 2 —,

HN—(CH 2 ) 3 —, —HN—(CH 2 ) 4 —;

R 4a is H or —C(O)—CH 3 ,

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

Y and Y′ are each independently selected from

a)

a straight or branched C 1 -C 10 alkylene,

a straight or branched C 1 -C 10 alkylene substituted with a —ONO 2 group;

wherein:

n 2 is an integer from 0 to 2, R 13 is H or CH 3 , T 1 is —O—C(O)— or —C(O)O—;

n 1 is 1 and U is a linear C 1 -C 10 alkylene or U is a linear or branched C 1 -C 10 alkylene substituted with a —ONO 2 group;

n 2 is 1, R 13 is CH 3 , Y is —CH═CH—(CH 2 ) n 2′ — and n 2′ is 0, T 1 is —C(O)O— and U is a linear C 1 -C 10 alkylene;

wherein:

n 2 is 1, R 13 is CH 3 ;

Y 1 is —(CH 2 ) n 2′ —CH═CH— and n 2′ is 0;

(T 1 )′=—O—C(O)—;

n 1 is 1 and U is a linear C 1 -C 10 alkylene or U is a linear or branched C 1 -C 10 alkylene substituted with a —ONO 2 group;

when Y and Y′ are selected from d), e) or e′), the —ONO 2 group of -(T-Y—ONO 2 ), -(T′-Y—ONO 2 ), -(T″-Y′—ONO 2 )-(T′-Y′—ONO 2 ) (T′″-Y—ONO 2 ) and -(T″-Y′—ONO 2 ) is linked to the —(CH 2 ) — group;

wherein T 2 is —O— or —S—, —NH—, preferably T 2 is —O—, n 3 is 1 or 2;

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

R is the corticosteroid of formula (II) as above defined;

a is 0,

R x is

(a2) —C(O)—CH(R 1 )—NH-(T′-Y—ONO 2 )

wherein

R 1 of A1) is selected from H

T′ is —C(O)—;

Y is selected from

a)

a straight or branched C 1 -C 10 alkylene,

a straight or branched C 1 -C 10 alkylene substituted with a —ONO 2 group;

wherein:

n 2 is an integer from 0 to 2, R 13 is H or CH 3 , T 1 is —O—C(O)— or —C(O)O—;

n 1 is 1 and U is a linear C 1 -C 10 alkylene or U is a linear or branched C 1 -C 10 alkylene substituted with a —ONO 2 group;

n 2 is 1, R 13 is CH 3 , Y 1 is —CH═CH—(CH 2 ) n 2′ and n 2′ is 0, T 1 is —C(O)O— and U is a linear C 1 -C 10 alkylene;

wherein:

n 2 is 1, R 13 is CH 3 ;

Y 1 is —(CH 2 ) n 2′ —CH═CH— and n 2′ is 0;

(T 1 )′=—O—C(O)—;

n is 1 and U is a linear C 1 -C 10 alkylene or U is a linear or branched C 1 -C 10 alkylene substituted with a —ONO 2 group;

when Y and Y′ are selected from d), e) or e∝ 0 ), the —ONO 2 group of -(T′-Y—ONO 2 ) is linked to the —(CH 2 )— group;

wherein T 2 is —O— or —S—, —NH—, preferably T 2 is —O—, n 3 is 1 or 2;

Another embodiment relates to compounds of formula (I) wherein R is the corticosteroid of formula (II) as above defined;

a is 0, R x is

(a5) —R 1b —CH(NHR 4a )—C(O)-(T-Y—ONO 2 ) or

(a9) —R 1b —CH(NH-T′-Y′—ONO 2 )—C(O)-(T-Y—ONO 2 )

wherein

R 1b of A10) is —C(O)—CH 2 —,

R 4d is H or —C(O)CH 3 ;

T is selected from —O—, —S—, —NR′— wherein R′ is as above defined,

T′ is —C(O)— and

Y and Y′ are each independently selected from

a)

a straight or branched C 1 -C 10 alkylene,

a straight or branched C 1 -C 10 alkylene substituted with a —ONO 2 group;

wherein:

n 2 is an integer from 0 to 2, R 13 is H or CH 3 , T 1 is —O—C(O)— or —C(O)O—;

n is 1 and U is a linear C 1 -C 10 alkylene or U is a linear or branched C 1 -C 10 alkylene substituted with a —ONO 2 group;

n 2 is 1, R 13 is CH 3 , T 1 is —CH═CH—(CH 2 ) n 2′ — and n 2′ is 0, T 1 is —C(O)O— and U is a linear C 1 -C 10 alkylene;

wherein:

n 2 is 1, R 13 is CH 3 ;

Y is —(CH 2 ) n 2′ —CH═CH— and n 2′ is 0;

(T 1 ) 1 =—O—C(O)—;

n is 1 and U is a linear C 1 -C 10 alkylene or U is a linear or branched C 1 -C 10 alkylene substituted with a —ONO 2 group;

when Y and Y′ are selected from d), e) or e), the —ONO 2 group of -(T-Y—ONO 2 ), -(T′-Y—ONO 2 ), -(T″-Y′—ONO 2 ), -(T″-Y′—ONO 2 ), (T″-Y—ONO 2 ) and -(T″-Y′—ONO 2 ) is linked to the —(CH 2 )— group;

wherein T 2 is —O— or —S—, —NH—, preferably T 2 is —O—, n 3 is 1 or 2;

Another embodiment relates to compounds of formula (I) wherein R is the corticosteroid of formula (II) as above defined;

a is 1 and Z is —C(O)—, R x is

(a5) —R 1b —(NHR 4a )—C(O)-(T-Y—ONO 2 ) or

(a9) —R 1b —CH(NH-T′-Y′—ONO 2 )—C(O) (T-Y—ONO 2 )

wherein R 1b of A10) is —O—CH 2 — or [—O p —(C 6 H 4 )]—CH 2 —,

R 4a is H or —C(O)CH 3 ,

T is selected from —O—, —S—, —NR′— wherein R′ is as above defined,

T′ is —C(O)— and

Y and Y′ are each independently selected from

a)

a straight or branched C 1 -C 10 alkylene,

a straight or branched C 1 -C 10 alkylene substituted with a —ONO 2 group;

wherein:

n 2 is an integer from 0 to 2, R 13 is H or CH 3 , T 1 is —O—C(O)— or —C(O)O—;

n 1 is 1 and U is a linear C 1 -C 10 alkylene or U is a linear or branched C 1 -C 10 alkylene substituted with a —ONO 2 group;

n 2 is 1, R 13 is CH 3 , Y 1 is —CH═CH—(CH 2 ) n 2′ — and n 2′ is 0, T 1 is —C(O)O— and U is a linear C 1 -C 10 alkylene;

wherein:

n 2 , is 1, R 13 is CH 3 ;

Y 1 is —(CH 2 ) n 2′ —CH═CH— and n 2′ is 0;

(T 1 )′=—O—C(O)—;

n 1 is 1 and U is a linear C 1 -C 10 alkylene or U is a linear or branched C 1 -C 10 alkylene substituted with a —ONO 2 group;

when Y and Y′ are selected from d), e) or e′), the —ONO 2 group of -(T-Y—ONO 2 ), -(T′-Y—ONO 2 ), -(T″-Y′—ONO 2 ), -(T′-Y′—ONO 2 ), -(T″-Y—ONO 2 ) and -(T″-Y′—ONO 2 ) is linked to the —(CH 2 )— group;

wherein T 2 is —O— or —S—, —NH—, preferably T 2 is —O—, n 3 is 1 or 2;

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

R is the corticosteroid of formula (II) as above defined;

a is 0,

R x is

(b2) —C(O)—CH 2 —CH(R 2 )—NH-(T′-Y—ONO 2 )

wherein

R 2 of B1) is H,

T′ is —C(O)—;

Y and Y′ are each independently selected from

a)

a straight or branched C 1 -C 10 alkylene,

a straight or branched O 1 —C 10 alkylene substituted with a —ONO 2 group;

wherein:

n 2 is an integer from 0 to 2, R 13 is H or CH 3 , T 1 is —O—C(O)— or —C(O)O—;

n 1 is 1 and U is a linear C 1 -C 10 alkylene or U is a linear or branched C 1 -C 10 alkylene substituted with a —ONO 2 group;

n 2 is 1, R 13 is CH 3 , Y 1 is —CH═CH—(CH 2 ) n 2′ and n 2′ is 0, T 1 is —C(O)O— and U is a linear C 1 -C 10 alkylene;

wherein:

n 2 is 1, R 13 is CH 3 ;

Y 1 is —(CH 2 ) n 2′ —CH═CH— and n 2′ is 0;

(T 1 )′=—O—C(O)—;

n 1 is 1 and U is a linear C 1 -C 10 alkylene or U is a linear or branched C 1 -C 10 alkylene substituted with a —ONO 2 group;

when Y and Y′ are selected from d), e) or e′), the —ONO 2 group of -(T-Y—ONO 2 )-(T′-Y—ONO 2 ), -(T″-Y′—ONO 2 ), -(T′-Y′—ONO 2 ), -(T′″-Y—ONO 2 ) and -(T″-Y′—ONO 2 ) is linked to the —(CH 2 )— group;

wherein T 2 is —O— or —S—, —NH—, preferably T 2 is —O—, n 3 is 1 or 2;

Preferred specific embodiments of the present invention are the selected compounds of formula below reported:

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

Examples of pharmaceutically acceptable salts are either those with inorganic bases, such as sodium, potassium, calcium and aluminium hydroxides, or with organic bases, such as lysine, arginine, triethylamine, dibenzylamine, piperidine and other acceptable organic amines.

The compounds according to the present invention, when they contain in the molecule one salifiable nitrogen atom, can be transformed into the corresponding salts by reaction in an organic solvent such as acetonitrile, tetrahydrofuran with the corresponding organic or inorganic acids.

Examples of organic acids are: oxalic, tartaric, maleic, succinic, citric acids. Examples of inorganic acids are: nitric, hydrochloric, sulphuric, phosphoric acids. Salts with nitric acid are preferred.

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

The compounds 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 th Ed.

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

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

The present invention compounds are used in particular for the treatment of ocular disease therapies such as ocular hypertension, age-related macular degeneration, diabetic macular edema, diabetic retinopathy, hypertensive retinopathy and retinal vasculopathies.

Synthesis Procedure

1) The compound of general formula (I) as above defined wherein a is equal to 0, the radical R x is selected from (a2), (a4), (a8), (b2), (b4), (b8), (c2), (e2), (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 R 1 , R 2 , R 3 , R 4 , are as above defined, with a compound of formula (Ia)

W—X 1   (Ia)

wherein W is —OH, Cl, O—R a , wherein R a is pentafluorophenyl, 4-nitrophenyl or —(N-succimidyl), X 1 is as below defined, to obtain the compound of formula (IIa′)

wherein R 1 , R 2 , R 3 , R 4 , are as above defined and X 1 is as below defined,

X 1 is 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′)—CH 2 —SP 1 , —CH 2 —OP 1 , —CH(CH 3 ) —OP 1 , —CH 2 [(C 6 H 4 )-4-OP 1 ]—CH 2 —[(C 6 H 3 )-(3,5-diiodo)-4-OP 1 ], —(CH 2 —[(C 6 H 3 )-3-nitro-4-OP 1 ] or

A3′) —CH 2 —NHR″″, —(CH 2 ) 2 —NHR″″, —(CH 2 ) 3 —NHR″″, —(CH 2 ) 4 —NHR″″, wherein R″″ is P 3 or —C(O)CH 3 or

wherein R 5a is as defined above;

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

wherein R′″″ is P 2 , —OR 5a or

wherein R 5a is as above defined;

(a4′) —C(O)—CH(R 1a -T″-Y′-Q)-NHR 4a′

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

wherein R 1a is as defined above;

(b2′) —C(O)—CH 2 —CH(R 2′ )—NH-(T′-Y-Q)

wherein R 2′ is selected from

B1) as defined above or

B2′) —CH(CH 3 )—OP 1 , —CH 2 —[(C 6 H 4 ) 4 —OP 1 ];

B3′) —CH 2 —NHR″″, —(CH 2 ) 2 —NHR″″—(CH 2 ) 3 —NHR″″, —(CH 2 ) 4 —NHR″″,

wherein R″″ is as above defined;

B4′) —CH 2 —C(O)—R″″, —(CH 2 ) 2 —C(O)—R′″″, —(CH 2 ) 4 —C(O)—R′″″ wherein

R′″″ is as above defined;

R 4a′ is P 3 or —C(O)—CH 3 or

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

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

wherein R 2a and R 4a′ are as defined above;

(c2′) —C(O)—(CH 2 ) b —NH-(T′-Y-Q);

wherein R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , b, c, d, e and f are as above defined;

wherein P 1 is a hydroxyl or thiol protecting group such as silyl ethers, such as trimethylsilyl, tert-butyl-dimethylsilyl or trityl and those described in T. W. Greene “Protective groups in organic synthesis”, Harvard University Press, 1980, P 2 is a carboxylic protecting group such as tert-butyl ester and those described in T. W. Greene “Protective groups in organic synthesis”, Harvard University Press, 1980, P 3 is a amino protecting group such as Boc, Fmoc or those described in T. W. Greene “Protective groups in organic synthesis”, Harvard University Press, 1980,

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

Q is independently —ONO 2 or Z 2 wherein Z 2 is selected from the group consisting of: a chlorine atom, a bromine atom, a iodine atom, a mesyl group or a tosyl group, and

1-ii) when Q is Z 2r 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 C 1 -C 10 alkyl) in a suitable organic solvent such as acetonitrile, tetrahydrofurane, methyl ethyl ketone, ethyl acetate, DMF, the reaction is carried out, in the dark, at a temperature from room temperature to the boiling temperature of the solvent. Preferred nitrate source is silver nitrate and

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

1-i-1) The reaction of a compound of formula (Ia) wherein W=—OH and X 1 is 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. and 50° C. The reaction is completed within a time range from 30 minutes to 36 hours.

1-i-2) The reaction of a compound of formula (Ia) wherein W=—O—R, wherein R a and X 1 are 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) 3 or Bi(OTf) 3 .

The reaction is carried out in an inert organic solvent such as N,N′-dimethylformamide, tetrahydrofuran, benzene, toluene, dioxane, a polyhalogenated aliphatic hydrocarbon at a temperature from −20° C. and 40° C. The reaction is completed within a time range from 30 minutes to 36 hours.

1-i-3) The reaction of a compound of formula (Ia) wherein W=—Cl, and X 1 is 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. and 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 X 1 is 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 1a is selected from A5) or A6), R 2a is 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)

P 2 —X 2   (IIIa)

wherein P 2 is as above defined, X 2 is a radical having the following meaning

(a2″) —C(O)—CH(R 1′ )—NH 2

(a4″) —C(O)—CH(R 1a —H)—NHR 4a′

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

(b2″) —C(O)—CH 2 —CH(R 2′ )—NH 2 ,

(b4″) —C(O)—CH 2 —CH(R 2a —H)—NHR 4a′

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

(c2″) —C(O)—(CH 2 ) b —NH 2 ,

wherein R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , b, c, d, e and f are as above defined;

with a compound of formula (IVa)

W 1 —(O)C- y -Q  (IVa)

wherein W 1 is OH or O—R a , and R a and Q are as above defined, y is the radical Y when X 2 is selected from (a2′), (b2′), (c2′), (e2′), (f1′), (g2′), (h1′), (i1′), (l2′), (m2′), (n2′), (o2′), (p2′), (q2′), (r2′), (s2′), (t2′), (u2′), (v2′), and y is the radical Y′ when X 2 is selected from (a4′) or (b4′), wherein Y and Y′ are as defined above, and

1a-ii) when Q is Z 2 , 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 P 2 and X 2 are as above defined, with a compound of formula (IVa) wherein W 1 is OH, y, Q are as above defined, may be carried out as described in 1-i-1) or in presence of other known condensing reagents such as O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU).

The reaction of a compound of formula (IIIa) wherein P 2 and X 2 are as above defined, with a compound of formula (IVa) wherein W 1 is O—R a , y, Q are as above defined, may be carried as described in 1-i-2).

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

The compounds of formula (IVa) wherein W 1 is OH, y and Q are as above defined, can be obtained from the corresponding alcohols of formula HOOC-y-OH (IVb) by reaction with nitric acid and acetic anhydride in a temperature range from −50° C. to 0° C. or from the corresponding derivatives of formula HOOC-y-Z 2 (IVc) wherein Z 2 is as above defined, by reaction with a nitrate source as above described. Alternatively the reaction with AgNO 3 can 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 W 1 is O—R a , y, Q are as above defined, can be obtained from the corresponding acids of formula (IVa) wherein W 1 is OH as known in the literature.

The compounds of formula (Ia) wherein W=Cl or O—R a , X 1 is 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 1a is selected from A5) or A6), R ea is 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, X 1 is 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 1a is selected from A5) or A6), R 2a is 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 —X 2   (IIIa)

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

R a —O—C(O)—X″- y -Q  (IVd)

wherein R, X″ and Q are as above defined, y is the radical Y when X 2 is 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 X 2 is selected from (a4′) or (b4′), wherein Y and Y′ are as above defined, and

1b-ii) when Q is Z 2 , 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 (IIIc) wherein P 2 and X 2 are as above defined, with a compound of formula (IVd) wherein R a , X″, y and Q are as above defined, may be carried out as described in 1-i-2)

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

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

The compounds of formula (Ia) wherein W is —Cl or O—R, X 1 is 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 1a is selected from A5) or A6), R ea is 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 X 1 is a radical selected from (a8′) or (b8′), wherein R 1a is selected from A5) or A6), R 2a is selected from B5) or B6), Q is as above defined, T′ and T″ are C(O), Y and Y′ are the same and are as above defined, can be obtained

1c-i) by reacting a compound of formula (IIIb),

P 2 —X 3   (IIIb)

wherein P 2 is as above defined, X 3 is the radical of formula

(a8″) —C(O)—CH(R 1a —H)—NH 2

(b8″) —C(O)—CH 2 —CH(R 2a —H)—NH 2

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

W 1 —(O)C- y -Q  (IVa)

wherein W 1 and 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 Z 2 , 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 P 2 and X 3 are as above defined, with a compound of formula (IVa) wherein W 1 is 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 P 2 and X 3 are as above defined, with a compound of formula (IVa) wherein W 1 is OR a , y and Q are as above defined, may be carried out as described in 1-i-2) using a ratio (IIIb)/(IVa) 1:2.

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

The compounds of formula (Ia) wherein W is —Cl or O—R a , X 1 is the radical selected from (a8′) or (b8′) wherein R 1a is selected from A5) or A6), R 2a is selected from 35) or 36) 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, X 1 is the radical selected from (a8′) or (b8′), wherein R 1a is selected from A5) or A6), R 2a is selected from B5) or B6), Q, Y and Y′ are as above defined, T′ is C(O) or C(O)—X″ wherein X″ is as above defined, T″ is C(O), can be obtained

1d-i) by reacting a compound of formula (Ib)

P 2 —X 3′   (Ib)

wherein P 2 is as above defined, X 3′ , is the radical of formula

(a8″) —C(O)—CH(R 1a —H)—NH-(T′-Y-Q))

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

wherein R 1a is selected from A5) or A6), R 2a is selected from 35) or B6), with a compound of formula (IVa)

W 1 —(O)C- y -Q  (IVa)

wherein W 1 and Q are as above defined, wherein y is the radical Y′, wherein Y′ is as above defined, and

1d-ii) when Q is Z 2 , 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 P 2 and X 3′ , are as above defined, with a compound of formula (IVa) wherein W 1 is 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 P 2 and X 3′ , are as above defined, with a compound of formula (IVa) wherein W 1 is OR a , y and Q are as above defined may be carried out as described in 1-i-2).

The compounds of formula (Ib) wherein T′ is C(O), P 2 and X 3′ , are as above defined, are obtained as described in 1a).

The compounds of formula (Ib) wherein T′ is C(O)—X″, P 2 and X 3′ , are as above defined, are obtained as described in 1b).

The compounds of formula (Ia) wherein W is —Cl or O—R a ′, X 1 is the radical selected from (a8′) or (b8′) wherein R 1a is selected from A5) or A6), R 2a is selected from B5) or B6) and wherein Q, Y and Y′ are as above defined, T′ is C(O) or C(O)—X″ wherein X″ is as above defined, T″ is C(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, X 1 is the radical selected from (a8′) or (b8′), wherein R 1a is selected from A5) or A6), R 2a is selected from B5) or B6), Q is as above defined, Y and Y′ are the same and are as above defined, T′ and T″ are C(O)—X″— wherein X″ is as above defined, can be obtained

1e-i) by reacting a compound of formula (IIIb)

P 2 —X 3   (IIIb)

wherein P 2 and X 3 are as above defined, with a compound of formula (IVd)

R a —O—C(O)—X″- y -Q  (IVd)

wherein R a and Q are as above defined, wherein y is the radical Y′, wherein Y′ is as above defined, and

1e-ii) when Q is Z 2 , 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 P 2 and X 3 are as above defined, with a compound of formula (IVd) wherein R a , y and Q are as above defined, may be carried out as described in 1-i-2) using a ratio (IIIb)/(IVd) 1:2.

The compounds of formula (Ia) wherein W is —Cl or O—R, X 1 is the radical selected from (a8′) or (b8′) wherein R 1a is selected from A5) or A6), R 2a is selected from B5) or B6) and wherein Y and Y′, Q is as above defined and T′ and T″ are C(O)—X″— wherein X″ is as above defined, can be obtained from the corresponding acids (Ia) wherein W is —OH as known in literature.

1f) The compounds of formula (Ia) wherein W is —OH, X 1 is selected from (a8′) or (b8′), wherein R 1a is selected from A5) or A6), R 2a is selected from B5) or B6), Q, Y and Y′ are as above defined, T′ is C(O) or C(O)—X″ wherein X″ is as above defined, T″ is C(O)—X″, can be obtained

1f-i) by reacting a compound of formula (Ib)

P 2 —X 3′   (Ib)

wherein X 3′ and P 2 are as above defined, with a compound of formula (IVd)

W 1 —O—C(O)—X″- y -Q  (IVd)

wherein W 1 and Q are as above defined, y is the radical Y′,

wherein Y′ is as above defined, and

1f-ii) when Q is Z 2 , 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 P 2 and X 3′ are as above defined, with a compound of formula (IVd) wherein W 1 is 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 P 2 and X 3′ are as above defined, with a compound of formula (IVd) wherein W 1 is OR a , y and Q are as above defined may be carried out as described in 1-i-2).

The compounds of formula (Ib) wherein T′ is C(O), P 2 and X 3′ are as above defined, are obtained as described in 1a).

The compounds of formula (Ib) wherein T′ is C(O)—X″, P 2 and X 3′ are as above defined, are obtained as described in 1b).

The compounds of formula (Ia) wherein W is —Cl or O—R a ′, X 1 is a radical selected from (a8′) or (b8′) wherein R 1a is A5) or A6), R 2a is B5) or B6) and wherein Q, Y and Y′ are as above defined, T′ is C(O) or C(O)—X″ and T″ is C(O)—X, wherein X″ is as above defined, can be obtained from the corresponding acids (Ia) wherein W is —OH as known in literature.

1g) The compounds of formula (Ia) wherein W is —OH, X 1 is a radical is selected from (a8′) or (b8′), wherein R 1a is selected from A5), A6), R 2a is 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)

P 2 —X 3′   (Ib)

wherein P 2 and 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 Z 2 , 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 P 2 and X 3′ are as above defined, with a compound of formula (IVf) wherein R a , R′, y, Q are as above defined, may be carried out as described in 1-i-2).

The compounds of formula (Ib) wherein T′ is C(O), wherein P 2 and 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 P 2 and 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 Z 2 is commercially available, the compounds of formula (IVg) wherein y is as above defined and Q is —ONO 2 may be obtained from the compound of formula

P 3 —R′N- y -ONO 2   (IVh)

wherein P 3 is as above defined by deprotection of amino group as known in literature. The compounds of formula (IVh) wherein P 3 , y are as above defined may be obtained from the alcohol

P 3 —R′N- y -OH  (IVi)

by reacting with tetraalkylammonium nitrate as already described for analogous compounds. The compounds of formula (IVi) are commercially available or known in literature. Alternatively the compounds of formula (IVh) wherein P 3 , y are as above defined may be obtained from the corresponding compounds of formula

P 3 —R′N- y -Z 2   (IVl)

wherein P 3 , y, Z 2 are as above defined, by reaction with a nitrate source as above described.

The compounds of formula (Ia) wherein W is —Cl or O—R a , X 1 is a radical selected from (a8′) or (b8′) wherein R selected from A5) or A6), R 2a is selected from B5) or B6) and wherein Y, Y′ and Q are as above defined and T′ is C(O) or C(O)—X″, T″ is C(O)—NR′—, wherein X″ and R′ are as above defined, can be obtained from the corresponding acids (Ia) wherein W is —OH as known in literature.

1h) The compounds of formula (Ia) wherein W is —OH, X 1 is a radical selected from (a8′) or (b8′), wherein R 1a is selected from A7), R 2a is selected from B7), Q, Y and Y′ are as above defined, T′ is C(O) or C(O)—X″, T″ is X″ wherein X″ is above defined, can be obtained

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

P 2 —X 5   (Ie)

wherein P 2 is defined above, X 5 is the radical of formula

(a8″) —C(O)—CH(R 1a —OH)—NH-(T′-Y-Q)

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

wherein R 1a is selected from A7), R 2a is selected from B7), with a compound of formula (IVe)

HX″- y -Q  (IVe)

wherein X″ and Q are as above defined, y is the radical Y′,

wherein Y′ is as above defined, and

1 h-ii) when Q is Z 2 , 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 1 h-ii) as above described.

The reaction of a compound of formula (Ie) wherein P 2 and X 5 are as above defined, with a compound of formula (IVe) wherein y, X″ and Q are as above defined, may be carried out as described in 1-i-1).

The compounds of formula (Ie) wherein T′ is C(O), wherein P 2 and X 5 are as above defined, are obtained as described in 1a-i), 1a-ii).

The compounds of formula (Ie) wherein T′ is C(O)—X″, wherein P 2 and X 5 are as above defined, are obtained as described in 1b-i), 1b-ii).

The compounds of formula (Ia) wherein W is —Cl or O—R a , X 1 is a radical selected from (a8′) or (b8′) wherein R 1a is selected from A7), R 2a is selected from B7) and wherein Y, Y′ and Q are as above defined, T′ is C(O) or C(O)—X″, and T″ is X″ wherein X″ is as above defined, can be obtained from the corresponding acids (Ia) wherein W is —OH as known in literature.

1i) The compounds of formula (Ia) wherein W is —OH, X 1 is a radical selected from (a8′) or (b8′), wherein R 1a is selected from A7), R 2a is selected from B7), Q, Y and Y′ are as above defined, T′ is C(O) or C(O)—X″ wherein X″ is as above defined, T″ is —NR′ wherein R′ is above defined, can be obtained

1i-i) by reacting a compound of formula (Ie),

P 2 —X 5   (Ie)

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

HR′N- y -Q  (IVg)

wherein R′ and Q are as above defined, y is the radical Y′,

wherein Y′ is as above defined, and

1i-ii) when Q is Z 2 , by converting the compound obtained in the step 11-i) into nitro derivative by reaction with a nitrate source such above described and

1i-iii) optionally deprotecting the compounds obtained in step 1i-i) or 1i-ii) as above described.

The reaction of a compound of formula (Ie) wherein P 2 and X 5 are as above defined, with a compound of formula (IVg) wherein R′, y and Q are as above defined, may be carried out as described in 1a-i).

The compounds of formula (Ia) wherein W is —Cl or O—R a , X 1 is the radical selected from (a8′) or (b8′) wherein R selected from A7), R 2a is selected from B7) and wherein Y, Y′ and Q are as above defined, T′ is C(O) or C(O)—X″ wherein X″ is as above defined, and T″ is —NR′ wherein R′ is as above defined can be obtained from the corresponding acids (Ia) wherein W is —OH as known in literature

1l) The compounds of formula (Ia) wherein W is —OH, X 1 is a radical selected from (a8′) or (b8′), wherein R 1a is selected from A7), R 2a is selected from B7), Q, Y and Y′ are as above defined, T′ is C(O) or C(O)—X″ wherein X″ is as above defined, T″ is —O—CH(R′)—O—C(O)—, wherein R′ is as above defined, can be obtained

1l-i) by reacting a compound of formula (Ie),

P 2 —X 5   (Ie)

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

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 Z 2 , by converting the compound obtained in the step 11-i) into nitro derivative by reaction with a nitrate source such above described and

1l-iii) optionally deprotecting the compounds obtained in step 11-i) or 11-ii) as above described.

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

Hal-(O)C- y -Q  (IVn),

wherein y and Q are as above defined, Hal is a chlorine atom and ZnCl 2 as known in literature.

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

The compounds of formula (Ia) wherein W is —Cl or O—R a , X 1 , is a radical selected from (a8′) or (b8′) wherein R 1a is selected from A7), R 2a is selected from B7) and wherein Y, Y′, and Q are as above defined, T′ is C(O) or C(O)—X″ wherein X″ is as above defined, and T″ is —O—CH(R′)—O—C(O)— wherein R′ is as above defined can be obtained from the corresponding acids (Ia) wherein W is —OH as known in literature.

1m) The compounds of formula (Ia) wherein W is —OH, X 1 is a radical selected from (a8′) or (b8′), wherein R 1a is selected from A7), R 2a is 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 —X 5   (Ie)

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

Hal-OH(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 Z 2 , by converting the compound obtained in the step 11-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 P 2 and X 5 are as above defined, with a compound of formula (IVo) wherein y, R′, Q, Hal are as above defined may be carried out as described in 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 CH 2 Cl 2 at temperatures range between 0° to 65° C.

The compounds of formula (Ia) wherein W is —Cl or O—R a , X 1 is a radical selected from (a8′) or (b8′) wherein R 1a selected from A7), R 2a selected from B7) and wherein Y, Y′ and Q are as above defined, T′ is C(O) or C(O)—X″ wherein X″ is as above defined, and T″ is —O—CH(R′)—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, X 2 is a radical selected from (a4′) or (b4′), wherein R 1a is selected from A7), R 2a is selected from B7), Y′, Q and R 4a′ are as above defined and T″ is X″ wherein X″ is as above defined, can be obtained

1n-i) by reacting a compound of formula (IIIc)

P 2 —X 5′   (IIIc)

wherein P 2 is defined above, X 5′ is

(a4″) —C(O)—CH(R 1a —OH)—NHR 4a′

(b4″) —C(O)—CH 2 —CH(R 2a —OH)—NHR 4a′

wherein R 1a is selected from A7), R 2a is selected from B7) and P 3 is 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 Z 2 , 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 y and P 2 are as above defined, with a compound of formula (IVe) wherein X″, y, Q are as above defined may be carried out as described in 1-i-1).

The compounds of formula (IIIc) wherein X 5′ and P 2 are as above defined, are commercially available or can be obtained as known in the literature.

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

The compounds of formula (Ia) wherein W is —OH, X 1 is a radical selected from (a4′) or (b4′), wherein R 1a is selected from A7), R 2a is selected from B7), Y′, Q and R 4a′ are as above defined and T″ is —NR′ wherein R′ is as above defined, can be obtained

1o-i) by reacting a compound of formula (IIIc)

P 2 —X 5′   (IIIc)

wherein P 2 and X y 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 Z 2 , 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 P 2 are as above defined, with a compound of formula (IVg) wherein R′, y and Q are as above defined may be carried out as described in 1a-i).

The compounds of formula (Ia) wherein W is —Cl or —OR a , X 1 is a radical selected from (a4′) or (b4′), wherein R 1a is selected from A7), R 2a is 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, X 1 is a radical selected from (a4′) or (b4′), wherein R 1a is selected from A7), R 2a is selected from B7), Y′, Q and R 4a′ are as above defined and T″ is —O—CH(R′)—O—C(O), wherein R′ is as above defined, can be obtained

1p-i) by reacting a compound of formula (IIIc)

P 2 —X 5′   (IIIc)

wherein P 2 and X y are as above defined, with a compound of formula (IVm)

Hal-CR(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 Z 2 , 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 P 2 and X y 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 —C 1 or OR a , X 1 is a radical selected from (a4′) or (b4′), wherein R 1a is selected from A7), R 2a is 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.

The compounds of formula (Ia) wherein W is —OH, X 1 is a radical selected from (a4′) or (b4′), wherein R 1a is selected from A7), R 2a is selected from B7), Y′, Q and R 4a′ are as above defined and T″ is —O—CH(R 1 )—O—C(O)—O—, wherein R′ is as above defined, can be obtained

1q-i) by reacting a compound of formula (IIIc)

P 2 —X 5′   (IIIc)

wherein P 2 and X y are as above defined, with a compound of formula (IVo)

Hal-CR(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 Z 2 , 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 P 2 and X y 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 , X 1 is a radical selected from (a4′) or (b4′), wherein R 1a is selected from A7), R 2a is 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 x is the radical selected from (a2), (a4), (a8), (b2), (b4), (b8), (c2), (e2), (f1), (g2), (h1), (i1), (l2), (m2), (n2), (o2), (p2), (q2), (r2), (s2), (t2), (u2), (v2), Z is —CH(R′)—O— wherein R′ is selected from H or straight or branched C 1 -C 4 alkyl, 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—X 1   (If)

wherein Hal is an halogen atom, R′ and X 1 are as above defined and

2-ii) when Q is Z 2 , 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) X 1 and R′ are as above defined, with a compound of formula (IIa) wherein R is as above defined, may be carried out as described in 11-i).

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

W—X 1   (Ia)

wherein W is a chlorine atom, X 1 is as above defined, and ZnCl 2 as known in literature.

3) The compound of general formula (I) as above defined wherein a is equal to 1, the radical R x is selected from (a1), (a3), (a7), (b1), (b3), (b7), (c1), (e1), (f2), (g1), (h2), (i2), (l1), (m1), (n1), (o1), (p1), (q1), (r1), (s1), (t1), (u1), (v1), Z is C(O), can be obtained

3-i) by reacting a compound of formula

R—C(O)—O—R a   (IIb)

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

H—X 2   (Ig)

wherein X 2 is a radical having the following meanings:

(a1′) —HN—CH(R 1′ )—C(O)-(T-Y-Q)

(a3′) —HN—CH(R 1a -T″-Y′-Q)-COOR 3a′

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

(b1′) —HN—CH(R 2′ )—CH 2 C(O)-(T-Y-Q)

(b3′)—HN—CH(R 2a -T″-Y′-Q)-CH 2 COOR 3a′

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

wherein R 1′ , R 1a , R 2′ , R 2a are as above defined

R 3a′ is selected from P 2 , —OR 5a or

wherein R 5a is as above defined;

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

3-ii) when Q is Z 2 , 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 a are as above defined, with a compound of formula (Ig) wherein X, is as above defined, may be carried out as described in 1-i-2).

The compounds of formula R—C(O)—O—R a (IIb) wherein R and R a are as above defined, are obtained from the compounds R—H (IIa) by reaction with the compounds of formula Cl—C(O)—O—R a wherein R a is as above defined, as known in literature.

3a) The compounds of formula (Ig) wherein X 2 is selected from (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 1a is selected from A7), R 2a is 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),

P 3 —X 6   (IIIe)

wherein P 3 is as above defined, X 6 is a radical having the following meanings:

(a1″) —HN—CH(R 1′ )—C(O)—OH

(a3″) —HN—CH(R 1a —OH)—COOR 1a′

(b1″) —HN—CH(R 2′ )—OH 2 O(O)—OH

(b3″) —HN—OH(R 2a —OH)—CH 2 COOR 3a′

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

(c1″) —HN—(CH 2 ) b —C(O)—OH;

with a compound of formula (IVe)

HX″- y -Q  (IVe)

wherein Q and X″ are as above defined y is the radical Y when X 6 is selected from (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 X 6 is selected from (a3′) and (b3′), wherein Y and Y′ are as defined above, and

3a-ii) when Q is Z 2 , by converting the 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 P 3 and X 6 are as above defined, with a compound of formula (IVe), wherein y, Q and X″ are as above defined, may be carried out as described in 1-i-1).

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

3b) The compounds of formula (Ig) wherein X 2 is selected from (a1′), (a3′), (b1′), (b3′), (c1′), (e1′), (f2′), (g1′), (h2′), (i2′), (l1′), (m1′), (n1′), (o1′), (p1′), (q1′), (r1′), (S1′), (t1′), (u1′), (v1′), wherein is selected from A1), A2′), A3′), A4′), R 1a is selected from A7), R 2a is 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),

P 3 —X 6   (IIIe)

wherein P 3 and X 6 are as above defined, with a compound of formula

HR′N- y -Q  (IVg)

wherein R′ and Q are as above defined, y is the radical Y when X 6 is selected from (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 X 6 is selected from (a3′) and (b3′), wherein Y and Y′ are as defined above, and

3b-ii) when Q is Z 2 , by converting the 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 P 3 and X 6 are 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 X 2 is 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 1a is selected from A7), R 2a is 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 —X 6   (IIIe)

wherein P 3 , X 6 are 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 X 6 is 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 X 6 is selected from (a3′) and (b3′), wherein Y and Y′ are as defined above, and

3c-ii) when Q is Z 2 , by converting the 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 P 3 and X 6 are as above defined, with a compound of formula (IVm) wherein y, Q, R′ are as above defined, may be carried out as described in 1l-i)

3d) The compounds of formula (Ig) wherein X 2 is selected from (a1′), (a3′), (b1′), (b3′), (c1′), (e1′), (f2′), (g1′), (h2′), (i2′), (l1′), (m1′), (n1′), (o1′), (p1′), (q1′), (r1″), (s1′), (t1′), (u1′), (v1′), wherein is selected from A1), A2′), A3′), A4′), R 1a is selected from A7), R ea is 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 —X 6   (IIIe)

wherein P 3 and X 6 are 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 X 6 is 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 X 6 is selected from (a3′) and (b3′), wherein Y and Y′ are as defined above, and

3d-ii) when Q is Z 2 , by converting the 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 P 3 and X 6 are as above defined, with a compound of formula (IVo) wherein y, Q, R′ are as above defined, may be carried out as described in 1l-i).

3e) The compounds of formula (Ig) wherein X 2 is selected from (a7′) or (b7′) wherein R 1a is selected from A5) or A6), R 1b is 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 —X 7   (Ih)

wherein P 3 is as above defined and X 7 is the radical having the following meaning

(a7″) —HN—CH(R 1a —H)—C(O)-(T-Y-Q)

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

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

W 1 —C(O)- y -Q  (IVa)

wherein W 1 and Q are as above defined, y is the radical Y′, wherein Y′ is as above defined, and

3e-ii) when Q is Z 2f 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 P 3 and X 7 are as above defined, with a compound of formula (IVa) wherein y, Q, W 1 are as above defined may be carried out as described in 1-1-i), 1-i-2), 1-i-3) and 1a-i).

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

The compounds of formula (Ih) wherein P 3 and X 7 are as above defined, T is —NR′ are obtained as described in 3b).

The compounds of formula (Ih) wherein P 3 and X 7 are as above defined, T is —O—CH(R′)—O—C(O)— are obtained as described in 3c).

The compounds of formula (Ih) wherein P 3 and X 7 are as above defined, T is —O—CH(R′)—O—C(O)O— are obtained as described in 3d).

3f) The compounds of formula (Ig) wherein X 2 is selected from (a7′) or (b7′) wherein R 1a is selected from A5) or A6), R 1b is 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)

P 3 —X 7   (Ih)

wherein P 3 and X 7 are 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 Z 2f 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 P 3 and X 7 are as above defined, with a compound of formula (IVd) wherein y, Q, R a are as above defined, may be carried out as described in 1-i-2).

3g) The compounds of formula (Ig) wherein X 2 is selected from (a7′) or (b7′) wherein R 1a is selected from A5), A6), R 1b is 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)

P 3 —X 7   (Ih)

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

R a —O—C(O)—NR′- y -Q  (IVf)

wherein R a and Q are as above defined, y is the radical Y′, wherein Y′ is as above defined, and

3g-ii) when Q is Z 2f 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 P 3 and X 7 are as above defined, with a compound of formula (IVf) wherein y, Q, R a and R′ are as above defined may be carried out as described in 1-i-2).

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

The compounds of formula (Ih) wherein P 3 and X 7 are as above defined, T is —NR′ are obtained as described in 3b).

The compounds of formula (Ih) wherein P 3 and X 7 are as above defined, T is —O—CH(R′)—O—C(O)— are obtained as described in 3c).

The compounds of formula (II) wherein P 3 and X 7 are 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 X 2 is selected from (a7′) or (b7′) wherein R 1a is selected from A7), R 1b is 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)

P 3 —X 8   (IV)

wherein P 3 is as above defined and X 8 is the radical having the following meaning

(a7″) —HN—CH(R u —H)—C(O)-(T-Y-Q)

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

wherein R 1a is selected from A7), R 1b is selected from B7), with compounds of formula (IVe)

H—X″- y -Q (IVe)

wherein X″ and Q are as above defined, y is the radical Y′, wherein Y′ is as above defined, and

3h-ii) when Q is Z 2 , 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 P 3 and X 8 are as above defined, with a compound of formula (IVe) wherein y, Q, X″ are as above defined, may be carried out as described in 1-i-1), 1-i-2) and 1a-1).

The compounds of formula (Iv) wherein P 3 and X 8 are as above defined, T is —X″ are obtained as described in 3a).

The compounds of formula (Iv) wherein P 3 and X 8 are as above defined, T is —NR′ are obtained as described in 3b).

The compounds of formula (Iv) wherein P 3 and X 8 are as above defined, T is —O—CH(R′)—O—C(O)— are obtained as described in 3c).

The compounds of formula (Iv) wherein P 3 and X 8 are 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 X 2 is selected from (a7′) or (b7′) wherein R 1a is selected from A7), R 1b is 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)

P 3 —X 8   (Iv)

wherein P 3 and X 8 are as above defined, with compounds of formula (IVg)

H—NR′- y -Q  (IVg)

wherein R′ and Q are as above defined, y is the radical Y′, wherein Y′ is as above defined, and

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

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

The reaction of a compound of formula (Iv) wherein P 3 and X 8 are as above defined, with a compound of formula (IVg) wherein y, Q, R′ are as above defined, may be carried out as described in 1a-i).

3l) The compounds of formula (Ig) wherein X 2 is selected from (a7′) or (b7′) wherein R selected from A7), R 1b is 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)

P 3 —X 8   (Iv)

wherein P 3 and X 8 are as above defined with compounds of formula (IVm)

Hal-OH(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 Z 2 , by converting the compound obtained in the step 3i-i) into nitro derivative by reaction with a nitrate source as above described and

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 P 3 and X 8 are as above defined, with a compound of formula (IVm) wherein y, Q, R′ are as above defined, may be carried out as described in 1l-i).

3m) The compounds of formula (Ig) wherein X 2 is selected from (a7′) or (b7′) wherein R 1a is selected from A7), R 1b is 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)

P 3 —X 8   (Iv)

wherein P 3 and X 8 are 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 Z 2 , 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 3i-i) or 3m-ii) as above described.

The reaction of a compound of formula (Iv) wherein P 3 and X 8 are as above defined, with a compound of formula (IVo) wherein y, Q, R′ are as above defined, may be carried out as described in 1l-i).

3n) The compounds of formula (Ig) wherein X 2 is selected from (a3′) or (b3′), wherein R 1a is selected from A5) or A6), R 2a is selected from B5) or B6), Y′ is as above defined, T″ is C(O) may be obtained

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

P 3 —X 9   (IIIf)

wherein P 3 is as above defined, X 9 is a radical having the following meaning

(a3″) —HN—CH(R 1a —H)—COOR 3a′

(b3″) —HN—CH(R 2a —H)—CH 2 COOR 3a′

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

W 1 —C(O)- y -Q  (IVa)

wherein W 1 and Q are as above defined, y is the radical Y′, wherein Y′ is as above defined, and

3n-ii) when Q is Z 2 , by converting the 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 P 3 and X 9 are as above defined, with a compound of formula (IVa) wherein W 1 , y, Q are as above defined, may be carried out as described in 1-i-1), 1-i-2), 1a-1).

The compounds of formula (IIIf) wherein P 3 and X 9 are as above defined, is commercially available or obtained as known in literature.

3o) The compounds of formula (Ig) wherein X 2 is selected from (a3′) or (b3′), wherein R 1a is selected from A5) or A6), R 2a is selected from B5) or B6), Y′ is as above defined, T″ is C(O)—X″ wherein X″ is as above defined, can be obtained

3o-i) by reacting a compound of formula (IIIf)

P 3 —X 9   (IIIf)

wherein P 3 and X 9 are 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 Z 2 , 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 P 3 and X 9 are as above defined, with a compound of formula (IVd) wherein R a , X″, y, Q are as above defined, may be carried out as described in 1-i-2).

3p) The compounds of formula (Ig) wherein X 2 is selected from (a3′) or (b3′), wherein R 1a is selected from A5) or A6), R 2a is selected from B5) or B6), Y′ is as above defined, T″ is C(O)—NR′ wherein R′ is as above defined, can be obtained

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

P 3 —X 9   (IIIf)

wherein P 3 and X 9 are 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 Z 2 , 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 P 3 and X 9 are as above defined, with a compound of formula (IVf) wherein R a , R′, y, Q are as above defined, may be carried out as described in 1-i-2).

4) The compound of general formula (I) as above defined wherein a is equal to 1, the radical R x is 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 a are as above defined, with a compound of formula (Im)

H—X 12   (Im)

wherein X 12 is the radical R x having the following meaning

(d1′) —HN—CH(R 12′ )—CH 2 —O-(T″-Y-Q)

(d2′) —O—OH 2 —CH(R 12′ )—NH-(T′-Y-Q)

(d3′) —HN—CH(R 12a -T″-Y′-Q)-CH 2 OH

(d4′) —O—CH 2 —CH(R 12a -T″-Y′-Q)-NHR 4a

(d7′) —HN—CH(R 12a -T″-Y′-Q)-CH 2 —O-(T″-Y-Q)

(d8′) —O—OH 2 —CH(R 12a -T″-Y′-Q)-NH-(T′-Y-Q) wherein R 12′ is

D1),

D2′) —CH 2 —OP 1 , —CH(CH 3 )—OP 1 , —CH 2 —[(C 6 H 4 )-4-OP 1 ], —CH 2 —[(C 6 H 3 )-(3,5-diiodo)-4-OP 1 ], —CH 2 —[(C 6 H 3 )-3-nitro-4-OP 1 ];

D3′) —CH 2 —NHR″″, —(CH 2 —NHR″″, —(CH 2 ) 3 —NHR″″, —(CH 2 ) 4 —NHR″″, wherein R″″ is as above defined;

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

wherein R 12a is as above defined; and

4-i) when Q is Z 2 , 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 a are as above defined, with a compound of formula (Im) wherein X 12 is as above defined, may be carried out as described in 1-i-2).

4a) The compound of formula (Im) wherein X 12 is selected from (d1′), (d2′), (d3′) or (d4′) wherein R 12′ is selected from D1), D2′), D3′) or D4′) and R 12a is selected from D5) or D6), Y and Y′ are as above defined, T′ and T″ and T′″ are C(O) can be obtained

4a-i) by reacting a compound of formula (IIIi),

P 4 X 13   (IIIi)

wherein P 4 is P 3 or P 1 as above defined and X 13 is a radical having the following meaning

(d1″) —HN—CH(R 12′ )—CH 2 —OH

(d2″) —O—CH 2 —CH(R 12′ )—NH 2

(d3″) —HN—CH(R 12a —H)—CH 2 OP 1

(d4″) —O—CH 2 —CH(R 12a —H)—NHR 4a′

wherein R 12′ is D1), D2′), D3′) or D4′), R 12a is D5) or D6), R 4a′ and P 1 are as above defined, with a compound of formula (IVa)

W 1 —(O)C- y -Q  (IVa)

wherein Q and W 1 are as above defined, y is the radical Y when X 13 is selected from (d1′) or (d2′), y is the radical Y′ when X 13 is selected from (d3′) or (d4′), wherein Y and Y′ are as above defined, and

4a-ii) when Q is Z 2 , by converting the 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 X 13 and P 4 are as above defined, with a compound of formula (IVa) wherein W 1 , y and Q are as above defined, may be carried out as described in 1-i-1) and 1-i-2).

The compounds of formula (IIIi) wherein X 23 and P 4 are as above described, are commercially available or known in literature.

4b) The compound of formula (Im) wherein X 12 is selected from (d1′), (d2′), (d3′) or (d4′) wherein R 12′ is selected from D1), D2′), D3′) or D4′) and R 12a is selected from D5) or D6), Y and Y′ are as above defined, T′ and T″ and T′″ are C(O)—X″, wherein X″ is as above defined, can be obtained

4b-i) by reacting a compound of formula (IIIi),

P 4 —X 13   (IIIi)

wherein P 4 and X 13 are defined above, with a compound of formula (IVd)

R a —O—(O)C—X″- y -Q  (IVd)

wherein Q, R a and X″ are as above defined, y is the radical Y when X 13 is selected from (d1′) or (d2′), y is the radical Y′ when X 13 is selected from (d3′) or (d4′), wherein Y and Y′ are as above defined, and

4b-ii) when Q is Z 2 , by converting the 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 X 13 and P 4 are as above defined, with a compound of formula (IVd) wherein y, Q, R a and X″ are as above defined, may be carried out as described in 1-i-2).

4c) The compound of formula (Im) wherein X 12 is selected from (d7′) or (d8′) wherein R 12a is selected from D5) or D6), Y′ and Y are as above defined, T′ and T″ and T″ are C(O), can be obtained

4c-i) by reacting a compound of formula (IIIl),

P 4 —X 14   (IIIl)

wherein P 4 is P 1 or P 3 , X 14 is the radical having the following meaning

(d7″) —HN—CH(R 12a —H)—CH 2 —OH

(d8″) —O—CH 2 —CH(R 12a —H)—NH 2

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

W 1 —(O)C- y -Q  (IVa)

wherein W 1 and Q are as above defined, y is the radical Y′, wherein Y′ is as above defined, and

4c-ii) when Q is Z 2 , by converting the 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 P 4 and X 14 are as above defined, with a compound of formula (IVa) wherein W 1 is OH, y and Q are as above defined, may be carried out as described in 1-i-1) using a ratio (IIIl)/(IVa) 1:2.

The reaction of a compound of formula (IIIl) wherein P 4 and X 14 are as above defined, with a compound of formula (IVa) wherein W 1 is OR a , y and Q are as above defined, may be carried out as described in 1-i-2) using a ratio (IIIl)/(IVa) 1:2.

The compounds of formula (IIIl) wherein P 4 and X 14 are as above described, are commercially available or known in literature.

4d) The compound of formula (Im) wherein X 12 is selected from (d7′) or (d8′) wherein R 12a is selected from D5) or D6), Q, Y and Y′ are as above defined, T′, T″ and T″ are C(O), can be obtained

4d-i) by reacting a compound of formula (In)

P 4 —X 15   (In)

wherein P 4 is defined above and X L5 is the radical having the following meaning

(d7″) —HN—CH(R 12a —H)—CH 2 —O-(T″-Y-Q)

(d8″) —O—OH 2 —CH(R 12a —H)—NH-(T′-Y-4)

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

W 1 —(O)C- y -Q  (IVa)

wherein W 1 , y and Q′ are as above defined, y is the radical Y′, wherein Y′ is as above defined, and

4d-ii) when Q is Z 2 , 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 P 4 and X 15 it) are as above defined, with a compound of formula (IVa) wherein W 1 is OH, y and Q are as above defined, may be carried out as described in 1-i-1).

The reaction of a compound of formula (In) wherein P 4 and X 15 are as above defined, with a compound of formula (IVa) wherein W 1 is OR a , y and Q are as above defined, may be carried out as described in 1-i-2).

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

4e) The compound of formula (Im) wherein X 12 is selected from (d7′) or (d8′) wherein R 12a is 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)

P 4 —X 15   (In)

wherein P 4 and X 15 are defined above, with a compound of formula (IVa)

W 1 —(O)C- y -Q  (IVa)

wherein W 1 , y and Q are as above defined, y is the radical Y′, wherein Y′ is as above defined, and

4e-ii) when Q is Z 2 , 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 P 4 and X 15 are as above defined, with a compound of formula (IVa) wherein W 1 is OH, y and Q are as above defined, can by carried out as described in 1-i-1).

The reaction of a compound of formula (In) wherein P 4 and X 15 are as above defined, with a compound of formula (IVa) wherein W 1 is OR a , y and Q are as above defined, can by carried out as described in 1-i-2).

The compounds of formula (In) wherein P 4 and X 15 are as above defined can by obtained as described in 4b).

4f) The compound of formula (Im) wherein X 12 is selected from (d7′) or (d8′) wherein R 12a is selected from D5) or D6), Y and Y′ are the same and are as above defined, T′, T″ and T′″ are C(O)—X″ wherein X″ is as above defined, can be obtained

4f-i) by reacting a compound of formula (IIIl),

P 4 —X 14   (IIIl)

wherein P 4 and X 19 are 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 Z 2r 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 P 4 and X 14 are as above defined, with a compound of formula (IVd) wherein R a , X″, y and Q are as above defined, may be carried out as described in 1-i-2) using a ratio (IIIl)/(IVd) 1:2.

4g) The compound of formula (Im) wherein X 12 is selected from (d7′) or (d8′) wherein R 12a is selected from D5) or D6), Q, Y and Y′ are as above defined, T″ is C(O)—X″, T′ and T″ are C(O) or C(O)—X″, wherein X″ is as above defined, can be obtained

4g-i) by reacting a compound of formula (In)

P 4 —X 15   (In)

wherein P 4 and X 15 are 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 Z 2 , 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 P 4 and X 15 are as above defined, with a compound of formula (IVd) wherein R a , X″, y and Q are as above defined, may be carried out as described in 1-i-2).

The compounds of formula (In) wherein T′ or T″ are C(O), P 4 and X 15 are as above defined are obtained as described in 4a-i), 4a-ii).

The compounds of formula (In) wherein T′ or T″ are C(O)—X″, wherein P 4 and X 15 are as above defined are obtained as described in 4b-i), 4b-ii).

4h) The compound of formula (Im) wherein X 12 is selected from (d7′) or (d8′) wherein R 12a is selected from D5) or D6), Q, Y and Y′ are as above defined, T″ is C(O)—NR′—, T′ and T″ are C(O) or C(O)—X″, wherein X″ is as above defined, can be obtained

4h-i) by reacting a compound of formula (In)

P 4 —X 15   (In)

wherein P 4 and X 15 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

4h-ii) when Q is Z 2 , 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) P 4 and X 15 are as above defined, with a compound of formula (IVf) wherein R a , R′, y, Q are as above defined, may be carried out as described in 1-i-2).

The compounds of formula (In) wherein T′ or T″ are C(O), wherein P 4 and X 15 are as above defined, are obtained as described in 4a-i), 4a-ii).

The compounds of formula (In) wherein T′ or T″ are C(O)—X″, wherein P 4 and X 15 are as above defined, are obtained as described in 4b-i), 4b-ii).

4i) The compound of formula (Im) wherein X 12 is selected from (d7′) or (d8′) wherein R 12a is selected from D7), Q, Y and Y′ are as above defined, T″ is X″, wherein X″ is as above defined, T′ and T″ are C(O) or C(O)—X″, wherein X″ is as above defined, can be obtained

4i-i) by reacting a compound of formula (Ir),

P 4 X 16   (Ir)

(d7″) —HN—CH(R 12a —OH)—CH 2 —O-(T′″-Y-Q)

(d8″) —O—CH 2 —CH(R 12a —OH)—NH-(T′-Y-Q)

wherein P 4 is as above defined, R 12a is selected from D7), with a compound of formula (IVe)

HX″- y -Q  (IVe)

wherein Y′, X″ and Q are as above defined, y is the radical Y′, wherein Y′ is as above defined, and

4i-ii) when Q is Z 2 , 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 P 4 and X 16 are as above defined with a compound of formula (IVe) wherein y, X″ and Q are as above defined, may be carried out as described in 1-i-1).

The compounds of formula (Ir) wherein T′ or T″ are C(O), and X 16 are 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″, P 4 and X 16 are as above defined, are obtained as described in 4b-i), 4b-ii).

4l) The compound of formula (Im) wherein X 12 is selected from (d7′) or (d8′) wherein R 12a is selected from D7), Q, Y and Y′ are as above defined, T″ is —NR′ wherein R′ is as above defined, T′ and T″ are C(O) or C(O)—X″, wherein X″ is as above defined, can be obtained

4l-i) by reacting a compound of formula (Ir),

P 4 —X 16   (Ir)

wherein P 4 and X 16 are as above defined and R 12a is selected from D7), with a compound of formula

HR′N- y -Q  (IVg)

wherein R′ and Q are as above defined, y is the radical Y′, wherein Y′ is as above defined, and

4l-ii) when Q is Z 2f 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) P 4 and X 16 are as above defined, with a compound of formula (IVg) wherein R′, y, Q are as above defined, may be carried out as described in 1-i-1).

4m) The compound of formula (Im) wherein X 12 is selected from (d7′) or (d8′) wherein R 12′ is selected from D7), Q, Y and Y′ are as above defined, T″ is —O—CH(R′)—O—C(O)—, wherein R′ is as above defined, T′ and T″ are C(O) or C(O)—X″, wherein X″ is as above defined, can be obtained

4m-i) by reacting a compound of formula (Ir),

P 4 —X 16   (Ir)

wherein P 4 and X 16 are as above defined and R 12′ is selected from D7), with a compound of formula (IVm)

Hal-OH(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 Z 2 , 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 1m-ii) as above described.

The reaction of a compound of formula (Ir) wherein P 4 and X 16 are as above defined, with a compound of formula (IVm) wherein y, Q, R′ are as above defined, may be carried out as described in 1l-i).

4n) The compound of formula (Im) wherein X 12 is selected from (d7′) or (d8′) wherein R 12a is selected from D7), Q, Y and Y′ are as above defined, T″ is —O—CH(R′)—O—C(O)—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),

P 4 —X 16   (Ir)

wherein P 4 and X 16 are as above defined and R 12a is 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 Z 2 , 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 P 4 and X 16 are as above defined, with a compound of formula (IVo) wherein y, R′, Q, Hal are as above defined, may be carried out as described in 1l-i).

4o) The compound of formula (Im) wherein X 12 is (selected from d3′) or (d4′) wherein R 12a is selected from D7), Y′ is as above defined, T″ is X″, wherein X″ is defined above, can be obtained

4o-i) by reacting a compound of formula (IIIm),

P 4 —X 17   (IIIm)

wherein P 4 is defined above and X 17 is the radical

(d3″) —HN—CH(R 12a —H)—CH 2 OP 1

(d4″) —O—CH 2 —CH(R 12a —H)—NHR 4a′

wherein R 12a is selected from D7), wherein P 1 and R 4a′ are as above defined, with a compound of formula (IVe)

HX″- y -Q  (IVe)

wherein X″ and Q are as above defined, y is the radical Y′, wherein Y′ is as above defined, and

4o-ii) when Q is Z 2f 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 P 4 and X 17 are as above defined with a compound of formula (IVe) wherein y, X″ and Q are as above defined, may be carried out as described in 1-i-1).

The compounds of formula (IIIm), wherein P 4 and X 17 are as above defined, are commercially available or obtained as known in literature.

4p) The compound of formula (Im) wherein X 12 is selected from (d3′) or (d4′) wherein R 12a is selected from D7), Y′ is as above defined, T″ is —NR′ wherein R′ is as above defined, can be obtained

4p-i) by reacting a compound of formula (IIIm),

P 4 —X 17   (IIIm)

wherein P 4 and X 17 are as defined above, wherein R 12a is selected from D7), with a compound of formula

HR′N- y -Q  (IVg)

wherein R′ and Q are as above defined, y is the radical Y′, wherein Y′ is as above defined, and

4p-ii) when Q is Z 2 , 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 P 4 and X 17 are as above defined, with a compound of formula (IVg) wherein R′, y, Q are as above defined, may be carried out as described in 1a-i).

4q) The compound of formula (Im) wherein X 12 is selected from (d3′) or (d4′) wherein R 12a is selected from D7), Y′ is as above defined, T″ is —O—CH(R′)—O—C(O)— wherein R′ is as above defined, can be obtained

4q-i) by reacting a compound of formula (IIIm),

P 4 —X 17   (IIIm)

wherein P 4 and X 17 are as defined above, wherein R 12a is 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 Z 2 , 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 P 4 and X 17 are as above defined, with a compound of formula (IVm) wherein R′, y, Q are as above defined, may be carried out as described in 1l-i).

4r) The compound of formula (Im) wherein X 12 is selected from (d3′) or (d4′) wherein R 12a is selected from D7), Y′ is as above defined, T″ is —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),

P 4 —X 17   (IIIm)

wherein P 4 and X 17 are as defined above, wherein R 12a is 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 Z 2 , 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 P 4 and X 17 are as above defined, with a compound of formula (IVo) wherein y, R′, Q, Hal are as above defined, may be carried out as described in 1l-i).

5) The compound of general formula (I) as above defined wherein a is equal to 0, R x is a radical selected from (d5), (d6), (d9) or (d10), wherein R 12b is 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—X 18   (Is)

wherein W is as above defined, X 18 is the radical having the following meanings

(d5′) —R 12b —CH(NHR 4a )—CH 2 —O-(T′″-Y-Q)

(d6′) —R 12b —CH(CH 2 OH)—NH-(T′-Y-Q)

(d9′) —R 12b —CH(NH-T′″-Y′-Q)-CH 2 —O-(T′-Y-Q)

(d10′) —R 12b —CH(CH 2 —O-T″-Q)-NH-(T′-Y-Q)

wherein R 12b is selected from D10), T′, T′″, Y, Y′ and Q are as above defined and

5-ii) when Q is Z 2 , 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 18 are as above defined may be carried out as described in 1).

5a) The compounds of formula (Is) wherein X 18 is a radical of formula (d5′) or (d6′), wherein R 12b is selected from D10), T′ and T″ are C(O) can be obtained

5a-i) by reacting a compound of formula (IIIn),

P 2 —X 19   (IIIn)

wherein P 2 is as above defined, X 19 is the radical having the following meanings

(d5″) —R 12b —CH(NHP 3 )—CH 2 —OH

(d6″) —R 12b —CH(CH 2 OP 1 )—NH 2

wherein P 1 and P 3 are as above defined and R 12b is selected from D10), with a compound of formula (IVa)

W 1 —C(O)- y -Q  (IVa)

wherein W 1 , y, Q are as above defined, y is the radical Y, wherein Y is as above defined, and

5a-ii) when Q is Z 2 , by converting the compound obtained in the step 5a-i) into nitro derivative by reaction with a nitrate source as above described and

5a-i) optionally deprotecting the compounds obtained in step 5a-i) or 5a-ii) as above described.

The reaction of a compound of formula (IIIn) wherein P 2 and X 19 are as above defined, with a compound of formula (IVa) W 1 , y, and Q are as above defined may be carried out as described in 1-i-1), 1-i-2), 1-i-3) and 1a-1).

The compounds of formula (IIIn), wherein P 2 and X 19 are as above defined, are commercially available or obtained as known in literature.

5b) The compounds of formula (Is) wherein X 18 is a radical of formula (d5′) or (d6′), wherein R 12b is 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),

P 2 —X 19   (IIIn)

wherein P 2 and X 19 are as above defined, with a compound of formula (IVd)

R a —O—C(O)—X″- y -Q  (IVd)

wherein R a and Q, X″ are as above defined, y is the radical Y, wherein Y is as above defined, and

5b-ii) when Q is Z 2f 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 P 2 and X 19 are as above defined, with a compound of formula (IVd) R a , y, Q, X″ are as above defined may be carried out as described in 1-i-2).

5c) The compounds of formula (Is) wherein X 18 is a radical of formula (d9′), wherein R 12b is 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),

P 2 —X 20   (It)

wherein P 2 is as above defined and X 20 is the radical having the following meanings

(d9″) —R 12b —CH(NH 2 )—CH 2 —O-(T″-Y-Q)

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

W 1 —C(O)- y -Q  (IVa)

wherein W 1 and Q are as above defined, y is the radical Y′, wherein Y′ is as above defined, and

5c-ii) when Q is Z 2 , by converting the 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 P 2 and X 20 are as above defined, with a compound of formula (IVa) wherein W 1 , y, 4 are as above defined, may be carried out as described in 1-i-1), 1-i-2), 1-i-3) and 1a-1).

5d) The compounds of formula (Is) wherein X 18 is a radical of formula (d9′), wherein R 12b is 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′),

P 2 —X 20′   (It′)

wherein P 2 and X 20′ are as above defined, with a compound of formula (IVd)

R a —O—C(O)—X″- y -Q  (IVd)

wherein R a and Q, X″ are as above defined, y is the radical Y′, wherein Y′ is as above defined, and

5d-ii) when Q is Z 2 , 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 P 2 and X 20′ are as above defined, with a compound of formula (IVd) R a , y, X″ are as above defined may be carried out as described in 1-i-2).

5e) The compounds of formula (Is) wherein X 18 is the radical of formula (d10′), wherein R 12b is 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),

P 2 —X 20   (It)

wherein P 2 is as above defined and X 20 is the radical having the following meaning

(d10″) —R 12b —CH(CH 2 —OH)—NH-(T′-Y-Q) wherein R 12b is selected from D10), T′, Y and Q are as above defined, with a compound of formula (IVa)

W 1 —C(O)- y -Q  (IVa)

wherein W 1 and Q are as above defined, y is the radical Y′, wherein Y′ is as above defined, and

5e-ii) when Q is Z 2 , by converting the 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 P 2 and X 20 are as above defined, with a compound of formula (IVa) wherein W 1 , y, Q are as above defined, may be carried out as described in 1-i-1), 1-i-2), 1-i-3) and 1a-1).

5f) The compounds of formula (Is) wherein X 18 is the radical of formula (d10′), wherein R 12b is 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′),

P 2 —X 20′   (It′)

wherein P 2 and X 20′ are as above defined, with a compound of formula (IVd)

R a —O—C(O)—X″- y -Q  (IVd)

wherein R a and Q, X″ are as above defined, y is the radical Y′, wherein Y′ is as above defined, and

5f-ii) when Q is Z 2 , by converting the 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 P 2 and X 20′ are as above defined, with a compound of formula (IVd) R a , y, Q, X″ are as above defined may be carried out as described in 1-i-2).

6) The compounds of general formula (I) as above defined wherein a is equal to 1, R x is a radical selected from (d5), (d6), (d9) or (d10), wherein R 12b is 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—X 21   (Iu)

wherein Hal is an halogen atom, R′ is as above defined and X 21 is a radical selected from (d5′), (d6′), (d9′) or (d10′),

wherein R 12b is selected from D10), and

6-ii) when Q is Z 2f 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, X n and 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—X 22   (IIIo)

wherein W is a chlorine atom, X 22 is the radical having the following meanings

(d5′″) —R 12b —CH(NHP 3 )—CH 2 —O-(T′″-Y-Q)

(d6″) —R 12b —CH(CH 2 OP 1 )—NH-(T′-Y-Q)

(d9′″) —R 12b —CH(NH-T′-Y′-Q)-CH 2 —O-(T′″-Y-Q)

(d10″) —R 12b —CH(CH 2 —O-T″-Y′-Q)-NH-(T′-Y-Q)

wherein R 12b , P 3 , P 1 , T′, T″, Y′, Y and Q are as above defined, and ZnCl 2 as known in literature.

The compounds of formula (IIIo), wherein W and X 22 are as above defined, may be carried out as described in 5).

7) The compounds of general formula (I) as above defined wherein a is equal to 1, R x is a radical selected from (d5), (d6), (d9) or (d10), wherein R 12b is 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 a are as above defined with a compound of formula (Iv)

H—X 23   (Iv)

wherein X 23 is a radical selected from (d5′), (d6′), (d9′) or (d10′), wherein R 12b is selected from D8) or D9), and

7-ii) when Q is Z 2 , 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 X 23 and 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 x is a radical selected from (a5), (a6), (a9) or (a10), (b5), (b6), (b9) or (MO) wherein R 1b is selected from A10) and R 2b is 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—X 24   (Iz)

wherein W is as above defined, X 24 is the radical R x having 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′-Q)-NH-(T-Y-Q)

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

(b6′) —R 2b —CH(CH 2 COOR 3a )NH-(T′-Y-Q)

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

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

wherein R 1b is selected from A10), R 2b is selected from B10), T,

T′, Y and Q are as above defined and

8-ii) when Q is Z 2 , 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 X 24 are as above defined may be carried out as described in 1).

8a) The compounds of formula (Iz) wherein X 24 is a radical of formula (a5′), (a6′), (b5′) or (b6′), wherein R 1b is selected from A10) and R 2b is selected from B10), T and T′ are C(O) can be obtained

8a-i) by reacting a compound of formula (IIIq),

P 2 —X 25   (IIIq)

wherein P 2 is as above defined, X 25 is the radical having the following meanings

(a5″) —R 1b —CH(NHP 3 )—C(O)—OH

(a6″) —R 1b —CH(COOP 2 )—NH 2

(b5″) —R 2b —CH(NHP 3 )—CH 2 C(O)—OH

(b6″) —R 2b —CH(CH 2 COOP 2 )NH 2

wherein P 2 and P 3 are as above defined and R 1b is selected from A10), R 2b is selected from B10), with a compound of formula III (IVa)

W 1 —C(O)- y -Q  (IVa)

wherein W 1 , and Q are as above defined, y is the radical Y, wherein Y is as above defined, and

8a-ii) when Q is Z 2 , by converting the 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 P 2 and X 25 are as above defined, with a compound of formula (IVa) W 1 , Y, and Q are as above defined may be carried out as described in 1-i-1), 1-i-2), 1-i-3) and 1a-1).

The compounds of formula (IIIq), wherein P 2 and X 25 are as above defined, are commercially available or obtained as known in literature.

8b) The compounds of formula (Iz) wherein X 24 is the radical of formula (a5′), (a6′), (b5′) or (b6′), wherein R 1b is selected from A10) and R 2b is 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),

P 2 —X 25   (IIIq)

wherein P 2 and X 25 are 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 Z 2 , 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 P 2 and X 25 are as above defined, with a compound of formula (IVd) R a , y, Q, X″ are as above defined may be carried out as described in 1-i-2).

8c) The compounds of formula (Iz) wherein X 24 is the radical of formula (a9′) or (b9′) wherein R 1b is selected from A10), and R 2b is 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),

P 2 —X 26   (Iy)

wherein P 2 is as above defined and X 26 is the radical having the following meanings

(a9″) —R 1b —CH(NH 2 ) —C(O)-(T-Y-Q)

(b9″) —R 2b —CH(NH 2 ) —CH 2 C(O)-(T-Y-Q)

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

W 1 —C(O)- y -Q  (IVa)

wherein W 1 and Q are as above defined, y is the radical Y′, wherein Y′ is as above defined, and

8c-ii) when Q is Z 2 , by converting the 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 P 2 and X 26 are as above defined, with a compound of formula (IVa) wherein W 1 , y, Q are as above defined, may be carried out as described in 1-i-1), 1-i-2), 1-i-3) and 1a-1).

8d) The compounds of formula (Iz) wherein X 24 is the radical of formula (a9′) or (b9′) wherein R 1b is selected from A10), R 2b is 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),

P 2 —X 26   (Iy)

wherein P 2 and X 26 are as above defined, with a compound of formula (IVd)

R a —O—C(O)—X″- y -Q  (IVd)

wherein R a and X″ are as above defined, y is the radical Y′, wherein Y′ is as above defined, and

8d-ii) when Q is Z 2 , by converting the 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 P 2 and X 20 are as above defined, with a compound of formula (IVd) R a , y, Q, X″ are as above defined may be carried out as described in 1-i-2).

8e) The compounds of formula (Iz) wherein X 24 is the radical of formula (a10′) or (b10′) wherein R 1b is selected from A10), and R 2b is 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′),

P 2 —X 26′   (Iy′)

wherein P 2 is 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(CH 2 C(O)—OH)—NH-(T-Y-Q)

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

W 1 —C(O)- y -Q  (IVa)

wherein W 1 and Q are as above defined, y is the radical Y′, wherein Y′ is as above defined, and

8e-ii) when Q is Z 2 , by converting the 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 P 2 and X 26′ are as above defined, with a compound of formula (IVa) wherein W 1 , y, Q are as above defined, may be carried out as described in 1-i-1), 1-i-2), 1-i-3) and 1a-1).

8f) The compounds of formula (Iz) wherein X 24 is the radical of formula (a10′) or (b10′) wherein R 1b is selected from A10), and R 2b is 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′),

P 2 —X 26′   (Iy′)

wherein P 2 and X 26′ are as above defined, with a compound of formula (IVd)

R a —O—C(O)—X″- y -Q  (IVd)

wherein R a and X″ are as above defined, y is the radical Y′, wherein Y′ is as above defined, and

8f-ii) when Q is Z 2f 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 P 2 and 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-i-2).

9) The compounds of general formula (I) as above defined wherein a is equal to 1, R x is a radical selected from (a5), (a6), (a9) or (a10), (b5), (b6), (b9) or (b10) wherein R 1b is selected from A8) or A9), R 2b is selected from B8) or B9), Z is —C(O)—, can be obtained

9-i) by reacting a compound of formula (IIb)

R—C(O)—O—R a   (IIb)

wherein R and R a are as above defined with a compound of formula (Ix)

H—X 27   (Ix)

wherein X 27 is the radical selected from (a5′), (a6′), (a9′), (a10′), (b5′), (b6′), (b9′) or (b10′), wherein R 2b is selected from A8) or A9), R 2b is selected from B8) or B9), and

9-ii) when Q is Z 2 , by converting the 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 X 27 and 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).