Title:
NITRIC OXIDE RELEASING STEROIDS
Kind Code:
A1


Abstract:
The invention relates to nitrooxyderivative of corticosteroids of general formula (I) and pharmaceutically acceptable salts or stereoisomers thereof


R—(Z)a—Rx (I)

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

embedded image

wherein:
R1 is OH, R2 —CH3, or R1 and R2 are taken together to form a group of formula (III)

embedded image

    • R3 is Cl or F;
    • R4 is H or F;
      wherein R1, R2, R3 and R4 can be linked to the correspondent carbon atoms of the steroidal structure in position α or β;
      with the proviso that:
      when R1 and R2 are the group of formula (III) then R3 is F and R4 is H or F;

The compounds are useful in the treatment of respiratory diseases, inflammatory diseases, dermatological diseases and ocular diseases.




Inventors:
Benedini, Francesca (San Donato Milanese (Ml), IT)
Biondi, Stefano (Pero (MI), IT)
Ongini, Ennio (Segrate (Milano), IT)
Application Number:
14/554830
Publication Date:
04/16/2015
Filing Date:
11/26/2014
Assignee:
NICOX SA
Primary Class:
Other Classes:
552/559
International Classes:
C07J41/00
View Patent Images:
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Primary Examiner:
QAZI, SABIHA NAIM
Attorney, Agent or Firm:
ARENT FOX LLP (1717 K Street, NW WASHINGTON DC 20006-5344)
Claims:
1. A compound of general formula (I) and pharmaceutically acceptable salts or stereoisomers thereof
R—(Z)a—Rx (I) wherein R is a corticosteroid residue of formula (II): embedded image wherein: R1 is OH, R2 —CH3, or R1 and R2 are taken together to form a group of formula (III) embedded image R3 is CI or F; R4 is H or F; wherein R1, R2, R3 and R4 can be linked to the correspondent carbon atoms of the steroidal structure in position α or β; with the proviso that: when R1 and R2 are the group of formula (III) then R3 is F and R4 is H or F; when R1 is OH and R2 —CH3 then R4 is H and R3 is CI or F; preferred corticosteroid radicals are R of formula (II) wherein: R1 is OH in position α, R2 —CH3 in position β, R3 is CI in position α and R4 is H; or R1 is OH in position α, R2 —CH3 in position β, R3 is F in position α and R4 is H; or R1 and R2 are taken together to form a group of formula (III) embedded image R3 is F and R4 is H, R1, R2 and R3 are in position α; or R1 and R2 are taken together to form a group of formula (III) embedded image R3 and R4 are F, R1, R2, R3 and R4 are in position α; a in formula (I) is equal to 0 or 1; Z is a group capable of binding Rx and is selected from —C(O)—, or CH(R′)—O— wherein R′ is selected from H or a straight or branched C1-C4 alkyl; Rx is a radical and is selected from the the following meanings: A)
—HN—CH(R1)—C(O)-(T-Y—ONO2) (a1)
—C(O)—CH(R1)—NH-(T′-Y—ONO2) (a2)
—HN—CH(R1a-T″-Y′—ONO2)—COOR3a (a3)
—C(O)—CH(R1a-T″-Y′—ONO2)—NHR4a (a4)
—R1b—CH(NHR4a—C(O)-(T-Y—ONO2) (a5)
—R1b—CH(COOR3a)NH-(T′-Y—ONO2) (a6)
—HN—CH(R1a-T″-Y′—ONO2)—C(O)-(T-Y—ONO2) (a7)
—C(O)—CH(R1a-T″-Y′—ONO2)—NH-(T′-Y—ONO2) (a8)
—R1b—CH(NH-T′-Y′—ONO2)—C(O)-(T-Y—ONO2) (a9) wherein: R1 is selected from: A1) H, —CH3, isopropyl, isobutyl, sec-butyl, tert-butyl, methylthio-(CH2)2—, phenyl, benzyl, C6H5—CH2—CH2—, 2-monosubstituted benzyl, or 3-monosubstituted benzyl or 4-monosubstituted benzyl wherein the substituent of the benzyl is selected from —F, —Cl, —I, —NO2, —CF3, —CH3, CN, C6H5CO—; 2,4-dichlorobenzyl, 3,4-dichlorobenzyl, 3,4-difluorobenzyl, 2-pyrrolidyl, 3-triptophanyl-CH2—, 3-benzothienyl-CH2—, 4-imidazolyl-CH2—, 9-anthranyl-CH2—, cyclohexyl, cyclohexyl-CH2—, cyclohexyl-(CH2)2—, cyclopentyl-CH2—, (C6H5)2CH—, 4-B(OH)2-benzyl, 4-quinolyl-CH2—, 3-quinolyl-CH2—, 2-quinolyl-CH2—, 2-quinoxalyl-CH2—, 2-furyl-CH2—, 1-naphtyl-CH2—, 2-naphtyl-CH2—, 2-pyridyl-CH2—, 3-pyridyl-CH2—, 4-pyridyl-CH2—, 2-thienyl-CH2—, 3-thienyl-CH2—, C6H4—CH═CH—CH2—, CH2═CH—CH2—, CH≡CH—CH2—, NH2—CO—CH2—, NH2—CO—(CH2)2—, NH2(═NH)NH—(CH2)3—, P(═O)(OCH3)2, I—CH2—; A2) —CH2—SH, —CH2—OH, —CH(CH3)—OH, —CH2[(C6H4)-(4-OH)], —CH2-[(C6H2)-(3,5-diiodo)-(4-OH)], —CH2-[(C6H3)-(3-nitro)-(4-OH)]; A3) —CH2—NHR″, —(CH2)2—NHR″, —(CH2)3—NHR″, —(CH2)4—NHR″, wherein R″ is H, —C(O)CH3 or embedded image wherein R5a is H or a linear or branched C1-C10 alkyl chain, preferably R5a is H or a linear (C1-C5) alkyl, wherein R″ is as above defined; A4) —CH2—C(O)R′″, —(CH2)2—C(O)R′″, —(CH2)4—C(O)R′″ wherein R′″ is —OR5a or embedded image wherein R5a is as above defined, wherein R′″ is as above defined; R1a is selected from, A5) —CH2—S—, —CH2—O—, —CH(CH3)—O—, —CH2[(C6H4)-(4-O)], —CH2-[(3,5-diiodo)-(C6H2)-(4-O)], —CH2-[(3-nitro)-(C6H3)-(4-O)—]; A6) —CH2—NH—, —(CH2)2—NH—, —(CH2)3—NH—, —(CH2)4—NH—; A7) —CH2—C(O)—, —(CH2)2—C(O)—, —(CH2)4—C(O)—; R3a is selected from H, —R5a or embedded image wherein R5a is as above defined; R4a is selected from H or —C(O)CH3 or embedded image wherein R5a is as above defined; R1b is selected from A8) —S—CH2—, —O—CH(CH3)—, —O—CH2—, [-(4-O)—(C6H4)]—CH2—, [-(4-O)-(3,5-diiodo)-(C6H2)]—CH2—, [-(4-O)-(3-nitro)-(C6H3)]—CH2—; A9) —HN—CH2—, —HN—(CH2)2—, —HN—(CH2)3—, —HN—(CH2)4—; A10) —C(O)—CH2—, —C(O)—(CH2)2—, —C(O)—(CH2)4—; T is selected from —O—, —S—, —NR′—, O—CH(R′)—O—C(O)— or O—CH(R′)—O—C(O)O— wherein R′ is as above defined; T′ is C(O)—, —C(O)—X″— wherein X″ is —O— or —S—, or T′ is C(O)—NR′— wherein R′ is as above defined; T″ is independently selected from C(O)—, —C(O)—X″—, —C(O)—NR′—, —O—, —S—, —NR′—, O—CH(R′)—O—C(O)—, O—CH(R′)—O—C(O)O—, wherein X″ and R′ are as above defined, with the proviso that T″ is —C(O)—, —C(O)—X″— or C(O)—NR′— when T″ is linked to —NH—, —O—, or —S—; or T″ is —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)—, —O—CH(R′)—O—C(O)O— when T″ is linked to C(O)—; Y and Y′ are as below defined; B)
—HN—CH(R2)—CH2C(O)-(T-Y—ONO2) (b1)
—C(O)—CH2—CH(R2)—NH-(T-Y—ONO2) (b2)
—HN—CH(R2a-T″-Y—ONO2)—CH2COOR3a (b3)
—C(O)—CH2—CH(R2a-T″-Y—ONO2)—NHR4a (b4)
—R2b—CH(NHR4a—CH2C(O)-(T-Y—ONO2) (b5)
—R2b—CH(CH2COOR3a)NH-(T′-Y—ONO2) (b6)
—HN—CH(R2a-T″-Y′—ONO2)—CH2—C(O)-(T-Y—ONO2) (b7)
—C(O)—CH2—CH(R2a-T″-Y′—ONO2)—NH-(T′-Y—ONO2) (b8)
—R2b—CH(NH-T′-Y′—ONO2)—CH2C(O)-(T-Y—ONO2) (b9)
—R2b—CH(CH2C(O)-T-Y′—ONO2)—NH-(T′-Y—ONO2) (b10) wherein R2 is selected from B1) H, —CH3, CF3, isopropyl, isobutyl, sec-butyl, methylthio-(CH2)2—, phenyl, benzyl, 3-triptophanyl-CH2—, NH2—C(O)—CH2—, NH2—C(O)—(CH2)2—, NH2(═NH)NH—(CH2)3—, tBuO—CH(CH3)—, benzyl-O—CH2—, 4-terbutoxy-benzyl, 4-phenylbenzyl; B2) —CH2—SH, —CH2—OH, —CH(CH3)—OH, —CH2[(C6H4)-(4-O)—], —CH2-[(C6H2)-(3,5-diiodo)-(4-OH)], —CH2-[(C6H3)-(3-nitro)-(4-OH)]; B3) —CH2—NHR″, —(CH2)2—NHR″, —(CH2)3—NHR″, —(CH2)4—NHR″, wherein R″ is as above defined; B4) —CH2—C(O)—R′″, —(CH2)2—C(O)—R′″, —(CH2)4—C(O)—R′″ wherein R′″ is as above defined; R2a is selected from B5) —CH2—S—, —CH2—O—, —CH(CH3)—O— or —CH2[(C6H4)-(4-O)], —CH2-[(3,5-diiodo)-(C6H2)-(4-O)], —CH2-[(3-nitro)-(C6H3)-(4-O)—]; B6) —CH2—NH—, —(CH2)2—NH—, —(CH2)3—NH—, —(CH2)4—NH—; B7) —CH2—C(O)—, —(CH2)2—C(O)—, —(CH2)4—C(O); R2b is selected from B8) —S—CH2—, —O—CH(CH3)—, —O—CH2—, [-(4-O)—(C6H4)]—CH2—, [-(4-O)-(3,5-diiodo)-(C6H2)]—CH2—, [-(4-O)-(3-nitro)-(C6H3)]—CH2—; B9) —HN—CH2—, —HN—(CH2)2—, —HN—(CH2)3—, —HN—(CH2)4—; B10) —C(O)—CH2—, —C(O)—(CH2)2—, —C(O)—(CH2)4—; R3a and R4a are as above defined; T, T′ and T″ are as above defined and Y and Y′ are as below defined; C)
—HN(CH2)b—C(O)-(T-Y—ONO2); (c1)
—C(O)(CH2)b—NH-(T′-Y—ONO2); (c2) wherein b is an integer from 3 to 6, T and T′ are as above defined; D)
—HN—CH(R12)—CH2—O-(T′″-Y—ONO2) (d1)
—O—CH2—CH(R12)—NH-(T′-Y—ONO2) (d2)
—HN—CH(R12a-T″-Y′—ONO2)—CH2OH (d3)
—O—CH2—CH(R12a-T″-Y′—ONO2)—NHR4a (d4)
—R12b—CH(NHR4a)—CH2—O-(T′″-Y—ONO2) (d5)
—R12b—CH(CH2OH)—NH-(T′-Y—ONO2) (d6)
—HN—CH(R12a-T″-Y′—ONO2)—CH2—O-(T′″-Y—ONO2) (d7)
—O—CH2—CH(R12a-T″-Y′—ONO2)—NH-(T′-Y—ONO2) (d8)
—R12b—CH(NH-T′-Y′—ONO2)—CH2—O-(T′″-Y—ONO2) (d9)
—R12b—CH(CH2—O-T′″-Y′—ONO2)—NH-(T′-Y—ONO2) (d10) wherein T′″ is independently selected from —C(O)—, —C(O)X″— wherein X″ is —O— or S—, or —C(O)—NR′— wherein R′ is as above defined; T′ and T″ are as above defined; Y and Y′ are as below defined; R12 is selected from: D1) H, —CH3, isopropyl, isobutyl, sec-butyl, methylthio-(CH2)2—, benzyl, 3-triptophanyl-CH2—, 4-imidazolyl-CH2—, NH2—CO—CH2—, NH2—CO—(CH2)2—, NH2(═NH)NH—(CH2)3—; D2) —CH2—OH, —CH(CH3)—OH, CH2[(C6H4)-(4-OH)], CH2-[(C6H3)-(3,5-diiodo)-(4-OH)], —CH2-[(C6H3)-(3-nitro)-(4-ON; D3) —CH2—NHR″, —(CH2)2—NHR″, —(CH2)3—NHR″, —(CH2)4—NHR″, wherein R″ is as above defined, preferably Ru is —(CH2)4—NHR″; D4) —CH2—C(O)R′″, —(CH2)2—C(O)R′″, —(CH2)4—C(O)R′″ wherein R′″ is as above defined; R12a is selected from D5) —CH2—O—, —CH(CH3)—O— or CH2[(C6H4)-(4-O)], —CH2-[3,5-diiodo-(C6H2)-(4-O)], —CH2-[3-nitro-(C6H3)-4-O-]; D6) —CH2—NH—, —(CH2)2—NH—, —(CH2)3—NH—, —(CH2)4—NH—; D7) —CH2—C(O)—, —(CH2)2—C(O)—, —(CH2)4—C(O)—; R12b is selected from D8) —O—CH2—, —O—CH(CH3)—, [-(4-O)—(C6H4)]—CH2—, [-(4-O)-(3,5-diiodo)-(C6H2)]—CH2, [-(4-O)-(3-nitro)-(C6H3)]—CH2—; D9) —HN—CH2—, —HN—(CH2)2—, —HN—(CH2)3—, —HN—(CH2)4—; D10) —C(O)—CH2—, —C(O)—(CH2)2—, —C(O)—(CH2)4—; R4a is as above defined; embedded image 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; embedded image 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; embedded image wherein R3 is H, CH3, propyl, (C6H5)2CH—, 1-naphtyl-CH2—, benzyl, allyl, 2-bromobenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-fluorobenzyl, 4-bromobenzyl, 4-methylbenzyl, T and T′ are as above defined; embedded image wherein R4 is H, benzyl, 4-bromobenzyl, 2-bromobenzyl, T and T′ are as above defined; embedded image wherein R5 is H, R6 is H, or R5 and R6 when taken together are a double bond, T and T′ are as above defined; embedded image wherein T and T′ are as above defined; embedded image wherein T and T′ are as above defined; embedded image wherein c is as above defined, d is equal to 0 or 1, T and T′ are as above defined; embedded image wherein R7 is H, R8 is H, or R7 and R8 when taken together are a double bond, c is as above defined, T and T′ are as above defined; embedded image wherein T and T′ are as above defined; embedded image wherein T and T′ are as above defined and; embedded image wherein T and T′ are as above defined; embedded image wherein T and T′ are as above defined; embedded image wherein T and T′ are as above defined; embedded image wherein R9 and R19 are H, CH3, R11 is CH3 or 4-piperidinyl with the proviso that R9 and R19 are H when R11 is 4-piperidinyl and R9 and R19 are CH3 when R11 is CH3, T and T′ are as above defined; embedded image wherein T and T′ are as above defined; with the proviso that in the formula (I): a is 0 or a is 1 and Z is CH(R)—O— wherein R′ is as above defined, when Rx is: (a2), (a4) or (a8); (a5), (a6), (a9) or (a10) and R1b is selected from the group A10); (b2), (b4) or (b8); (b5), (b6), (b9) or (b10) and R2b is selected from the group B10); (c2); (d5), (d6), (d9) or (d10) and R12b is selected from the group D10); (e2), (f1), (g2), (h1), (i1) (l2), (m2), (n2), (o2), (p2), (q2), (r2), (s2), (t1) or (u2); a is 1 and Z is —C(O)—, when Rx is: (a1), (a3) or (a7); (a5), (a6), (a9) or (a10) and R1b is selected from the groups A8) and A9); (b1), (b3) or (b7); (b5), (b6), (b9) or (b10) and R2b is selected from the groups B8) or B9); (c1); (d1), (d2), (d3), (d4), (d7) or (d8); (d5), (d6), (d9) or (d10) and R2b is selected from the groups D8) or D9); (e1), (f2), (g1), (h2), (i2), (11), (m1), (n1), (o1), (p1), (q1), (r1), (s1), (t2) or (u1). Y and Y′ are bivalent radicals each independently selected from the following meanings: a) straight or branched C1-C20 alkylene; straight or branched C1-C20 alkylene substituted with one or more of the substituents selected from the group consisting of: halogen atoms, hydroxy, —ONO2 or T2, wherein T2 is —OC(O)(C1-C10 alkyl)-ONO2 or —O(C1-C10 alkyl)-ONO2; cycloalkylene with 5 to 7 carbon atoms into cycloalkylene ring, the ring being optionally substituted with one or more straight or branched C1-C10 alkyl chains; embedded image wherein n0 is an integer from 0 to 20; n1 is 0 or 1; U is a linear or branched C1-C20 alkylene optionally substituted with a —ONO2 group; embedded image wherein n0 is an integer from 0 to 20; n1 is 0 or 1; U is a linear or branched C1-C20 alkylene optionally substituted with a —ONO2 group; embedded image wherein: n2 is an integer from 0 to 2, R13 is H or CH3, T1 is —O—C(O)— or —C(O)O—; n1 and U are as above defined; embedded image n2 is an integer from 0 to 2; R13 is H or CH3; Y1 is CH2—CH2— or —CH═CH—(CH2)n2′—, wherein n2′ is 0 or 1; T1=—O—C(O)— or C(O)O—; U is a linear or branched C1-C20 alkylene optionally substituted with a —ONO2 group; embedded image wherein: n2 is an integer from 0 to 2, preferably n2 is 1; R13 is H or CH3, preferably R13 is CH3; Y1 is —CH2—CH2— or (CH2)n2′—CH═CH—, wherein n2′ is 0 or 1; (T1)′=—O—C(O)—; n1 is 0 or 1; U is a linear or branched C1-C20 alkylene optionally substituted with a —ONO2 group; when Y and Y′ are selected from b), c), d), e) or e′), the —ONO2 group of -(T-Y—ONO2), -(T′-Y—ONO2), -(T″-Y′—ONO2), -(T′-Y′—ONO2), -(T′″-Y—ONO2) and -(T′″-Y′—ONO2) is linked to the (CH2)— group;
—(CH2—CH2-T2)n3-CH2—CH2— f) wherein T2 is —O— or —S—, —NH— and n3 is an integer from 1 to 6; embedded image wherein: n4 is an integer from 0 to 10; n5 is an integer from 1 to 10; R14, R15, R16, R17 are the same or different, and are H or straight or branched C1-C4 alkyl; wherein the —ONO2 group is linked to embedded image wherein n5 is as defined above; Y2 is an heterocyclic saturated, unsaturated or aromatic 5 or 6 members ring, containing one or more heteroatoms selected from nitrogen, oxygen, sulphur, and is selected from the group consisting of: embedded image embedded image

2. A compound of formula (I) according to claim 1 wherein R, R1, R2, R3 and R4 are as defined in claim 1; a is 0 and Rx is selected from:
—C(O)—CH(R1)—NH-(T′-Y—ONO2) (a2) wherein R1 of the group A1) is selected from H, isobutyl, benzyl, C6H5—CH2—CH2—, 2-monosubstituted benzyl, or 3-monosubstituted benzyl or 4-monosubstituted benzyl wherein the substituent of the benzyl is selected from —F, —Cl, —I, —NO2, —CF3, —CH3, CN, C6H5CO—; R1 of the group A2) is selected from —CH2—OH, —CH(CH3)OH— or —CH2[(C6H4)-(4-OH)], or R1 of the group A3) is selected from —CH2—NHR″, —(CH2)2—NHR″, —(CH2)3—NHR″, —(CH2)4—NHR″, wherein R″ is H, or —C(O)CH3; R1 of the group A4) is selected from —CH2—C(O)R′″, —(CH2)2—C(O)R′″, —(CH2)4—C(O)R′″ wherein R′″ is OR5a wherein R5a is H or a linear (C1-C5) alkyl; T′ is —C(O)—, —C(O)—X″ wherein X″ is —S— or —O—; or Rx is
—C(O)—CH(R1a-T″-Y′—ONO2)—NHR4a (a4) wherein R1a of the group A5) is selected from —CH2—O—, —CH(CH3)O— or —CH2[(C6H4)-(4-O)—], or R1a of the group A6) is selected from —CH2—NH—, —(CH2)2—NH—, —(CH2)3—NH—, —(CH2)4—NH—, or R1a of the group A7) is selected from —CH2—C(O)—, —(CH2)2—C(O)—, —(CH2)4—C(O)—; R4a is H or —C(O)CH3; T″ is C(O)— or —C(O)—X″ wherein X″ is —S— or —O—, when R1a is selected from the group A5) or A6); T″ is —O—, —S—, —NR′— or O—CH(R′)—O—C(O)— wherein R′ is H or CH3, when R1a is selected from the group A7); or Rx is selected from
—R1b—CH(NHR4a)—C(O)-(T-Y—ONO2) (a5)
—R1b—CH(COOR3a)NH-(T′-Y—ONO2) (a6)
—R1b—CH(NH-T′-Y′—ONO2)—C(O)-(T-Y—ONO2) or (a9)
—R1b—CH(C(O)-T-Y′—ONO2)—NH-(T′-Y—ONO2) (a10) wherein R1b of the group A10) is selected from —C(O)—CH2—, —C(O)—(CH2)2—, —C(O)—(CH2)4—; R3a is H or a (C1-C5) alkyl; R4a is H or —C(O)CH3; T is —O—, —S—, —NR′— or —O—CH(R′)—O—C(O)— wherein R′ is H or CH3; T′ is C(O)— or —C(O)—X″ wherein X″ is —S— or —O—; or Rx is
—C(O)—CH(R1a-T″-Y′—ONO2)—NH-(T′-Y—ONO2) (a8) wherein R1a of the group A5) is selected from CH2—O—, —CH(CH3)—O— or CH2[(C6H4)-(4-O)], or R1a of the group A6) is selected from —CH2—NH—, —(CH2)2—NH—, —(CH2)3—NH—, —(CH2)4—NH—, or R1a of the group A7) is selected from —CH2—C(O)—, —(CH2)2—C(O)—, —(CH2)4—C(O)—; T″ is C(O)— or —C(O)—X″ wherein X″ is —S— or —O—, when R1a is selected from the group A5) or A6)-; T″ is —O—, —S—, —NR′— or —O—CH(R′)—O—C(O)— wherein R′ is H or CH3, when R1a is selected from the group A7); T′ is C(O)— or —C(O)—X″ wherein X″ is —S— or —O—; or Rx is
—C(O)—CH2—CH(R2)—NH-(T′-Y—ONO2) (b2) wherein R2 of the group B1) is selected from H, CH3, isobutyl, isopropyl, benzyl; T′ is —C(O)—, —C(O)—X″ wherein X″ is —S— or —O—; Y and Y′ are each independently selected from a) a straight or branched C1-C10 alkylene, a straight or branched C1-C10 alkylene substituted with a —ONO2 group; embedded image wherein: n2 is an integer from 0 to 2, R13 is H or CH3, T1 is —O—C(O)— or —C(O)O—; n1 is 1 and U is a linear C1-C10 alkylene or U is a linear or branched C1-C10 alkylene substituted with a —ONO2 group; embedded image n2 is 1, R13 is CH3, Y1 is CH═CH—(CH2)n2′ and n7 is 0, T1 is C(O)O— and U is a linear C1-C10 alkylene; embedded image wherein: n2 is 1, R13 is CH3; Y1 is (CH2)n2′—CH═CH— and n2′ is 0; (T1)′=—O—C(O)—; n1 is 1 and U is a linear C1-C10 alkylene or U is a linear or branched C1-C10 alkylene substituted with a —ONO2 group; when Y and Y′ are selected from d), e) or e′), the —ONO2 group of -(T-Y—ONO2), -(T′-Y—ONO2), -(T″-Y′—ONO2), -(T′-Y′—ONO2), -(T′″-Y—ONO2) and -(T′″-Y′—ONO2) is linked to the (CH2)— group;
—(CH2—CH2-T2)n3—CH2—CH2— f) wherein T2 is —O— or —S—, —NH—, n3 is 1 or 2.

3. A compound of formula (I) according to claim 1 wherein R, R1, R2, R3 and R4 are as defined in claim 1, A is 1 and Z is C(O)—, Rx is
—HN—CH(R1)—C(O)-(T-Y—ONO2) (a1) wherein R1 of the group A1) is selected from H, isobutyl, benzyl, C6H5—CH2—CH2—, 2-monosubstituted benzyl, or 3-monosubstituted benzyl or 4-monosubstituted benzyl wherein the substituent of the benzyl is selected from F, —Cl, —I, —NO2, —CF3, —CH3, CN, C6H5CO—; or R1 of A2) is selected from CH2—OH, —CH(CH3)—OH— or —CH2[(C6H4)-(4-OH)], or R1 of the group A3) is selected from —CH2—NHR″, —(CH2)2—NHR″, —(CH2)3—NHR″, —(CH2)4—NHR″, wherein R″ is H, or C(O)CH3, R1 of the group A4) is —CH2—C(O)R′″, —(CH2)2—C(O)R′″, —(CH2)4—C(O)R′″ wherein R′″ is OR5a wherein R5a is H or a linear (C1-C5) alkyl; T is —O—, —S—, —NR′—, O—CH(R′)—O—C(O)— wherein R′ is H or a straight or branched C1-C4 alkyl; Y is as below defined; or Rx is
—HN—CH(R1a-T′″-Y′—ONO2)—COOR3a (a3) wherein R1a of the group A5) is selected from CH2—O—, —CH(CH3)O— or CH2[(C6H4)Op-], or R1a of the group A6) is selected from —CH2—NH—, —(CH2)2—NH—, —(CH2)3—NH—, —(CH2)4—NH—, or R1a of the group A7) is —CH2—C(O)—, —(CH2)2—C(O)—, —(CH2)4—C(O)—; R3a is H or a (C1-C5) alkyl; T″ is C(O)— or —C(O)—X″ wherein X″ is —S— or —O—, when R1a is selected from the group A5) or A6); T″ is —O—, —S—, —NR′—, O—CH(R′)—O—C(O)— wherein R′ is H or a straight or branched C1-C4 alkyl, when R1a is selected from the group A7); Y′ is as below defined; or Rx is
—R1b—CH(NHR4a)—C(O)-(T-Y—ONO2) (a5)
—R1b—CH(COOR3a)NH-(T′-Y—ONO2) (a6)
—R1b—CH(NH-T′-Y′—ONO2)—C(O)-(T-Y—ONO2) or (a9)
—R1b—CH(C(O)-T-Y′—ONO2)—NH-(T′-Y—ONO2) (a10) wherein R1b of the group A8) is selected from —O—CH(CH3)—, —O—CH2—, [-4-O)—(C6H4)]—CH2—, or R1b of the group A9) is selected from —HN—CH2—, —HN—(CH2)2—, —HN—(CH2)3—, —HN—(CH2)4—; R3a is H or a (C1-C5) alkyl; R4a is H or C(O)CH3; T is —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)— wherein R′ is H or a straight or branched C1-C4 alkyl; T′ is C(O)— or —C(O)—X″ wherein X″ is —S— or —O—; Y and Y′ are as below defined; or Rx is
—HN—CH(R1a-T″-Y′—ONO2)—C(O)-(T-Y—ONO2) (a7) wherein R1a of the group A5) is selected from CH2—O—, —CH(CH3)—O— or CH2[(C6H4)-(4-O)—], or R1a of the group A6) is selected from —CH2—NH—, —(CH2)2—NH—, —(CH2)3—NH—, —(CH2)4—NH—, or R1a of the group A7) is —CH2—C(O)—, —(CH2)2—C(O)—, —(CH2)4—C(O)—; T″ is C(O)— or —C(O)—X″ wherein X″ is —S— or —O—; T″ is —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)— wherein R′ is H or a straight or branched C1-C4 alkyl, when R1a is selected from A7); T is —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)— wherein R′ is H or a straight or branched C1-C4 alkyl; Y and Y′ are as below defined; or Rx is
—HN—CH(R2)—CH2C(O)-(T-Y—ONO2) (b1) wherein R2 of the group B1) is selected from H, CH3, isobutyl, isopropyl, benzyl; R2 of the group B2) is selected from CH2—OH, —CH(CH3)—OH— or CH2[(C6H4)(4-OH)], or R2 of the group B3) is selected from —CH2—NHR″, —(CH2)2—NHR″, —(CH2)3—NHR″, —(CH2)4—NHR″, wherein R″ is H, or C(O)CH3, R2 of the group B4) is —CH2—C(O)R′″, —(CH2)2—C(O)R′″, —(CH2)4—C(O)R′″ wherein R′″ is OR5a wherein R5a is H or a linear (C1-C5) alkyl; T is —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)— wherein R′ is H or a straight or branched C1-C4 alkyl; Y is as below defined; or Rx is selected from
—HN—CH(R12)—CH2—O-(T′″-Y—ONO2) (d1)
—O—CH2—CH(R12)—NH-(T′-Y—ONO2) (d2) wherein R12 of the group D1) is selected from H, CH3, isobutyl, isopropyl, benzyl, or R12 of the group D2) is selected from CH2—OH, —CH(CH3)OH— or CH2[)C6H4)-(4-OH)], or R12 of the group D3) is selected from —CH2—NHR″, —(CH2)2—NHR″, —(CH2)3—NHR″, —(CH2)4—NHR″ wherein R″ is H, or R12 of the group D4) is —CH2—C(O)R′″, —(CH2)2—C(O)R′″, —(CH2)4—C(O)R′″ wherein R′″ is OR5a wherein R5a is H or a linear (C1-C5) alkyl; T′ and T′″ are each independently selected from C(O)— or —C(O)—X″ wherein X″ is —S— or —O—; Y is as below defined; or Rx is selected from
—HN—CH(R12a-T″-Y′—ONO2)—CH2OH (d3)
—O—CH2—CH(R12a-T″-Y′—ONO2)—NHR4a (d4)
—HN—CH(R12a-T″-Y′—ONO2)—CH2—O-(T′″-Y—ONO2) or (d7)
—O—CH2—CH(R12a-T″-Y′—ONO2)—NH-(T′-Y—ONO2) (d8) wherein R12a of the group D5) is selected from CH2—O—, —CH(CH3)—O— or CH2[(C6H4)-(4-O)—], or R12a of the group D6) is selected from —CH2—NH—, —(CH2)2—NH—, —(CH2)3—NH—, —(CH2)4—NH—, or R12a of the group D7) is —CH2—C(O)—, —(CH2)2—C(O)—, —(CH2)4—C(O)—; R4a is H or —C(O)CH3; T″ is selected from C(O)— or —C(O)—X″ wherein X″ is —S— or —O—; T″ is —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)— wherein R′ is H or a straight or branched C1-C4 alkyl; T′″ is selected from C(O)— or —C(O)—X″ wherein X″ is —S— or —O—; Y and Y′ are as below defined; or Rx is selected from
—R12b—CH(NHR4a)—CH2—O-(T′″-Y—ONO2) (d5)
—R12b—CH(CH2OH)—NH-(T′-Y—ONO2) (d6)
—R12b—CH(NH-T′-Y′—ONO2)—CH2—O-(T′″-Y—ONO2) or (d9)
—R12b—CH(CH2—O-T′″-Y′—ONO2)—NH-(T′-Y—ONO2) (d10) wherein R12b of the group D8) is selected from —O—CH(CH3)—, —O—CH2—, [—Op(C6H4)]—CH2—, or R12b of the group D9) is selected from —HN—CH2—, —HN—(CH2)2—, —HN—(CH2)3—, —HN—(CH2)4—; R4a is H or —C(O)—CH3, T′ and T′″ are each independently selected from —C(O)—, —C(O)—X″, wherein X″ is —S— or —O—; Y and Y′ are each independently selected from a) a straight or branched C1-C10 alkylene, a straight or branched C1-C10 alkylene substituted with a —ONO2 group; embedded image wherein: n2 is an integer from 0 to 2, R13 is H or CH3, T1 is —O—C(O)— or C(O)O—; n1 is 1 and U is a linear C1-C10 alkylene or U is a linear or branched C1-C10 alkylene substituted with a —ONO2 group; embedded image n2 is 1, R13 is CH3, Y1 is CH═CH—(CH2)n2′- and n7 is 0, T1 is C(O)O— and U is a linear C1-C10 alkylene; embedded image wherein: n2 is 1, R13 is CH3; Y1 is (CH2)n2′—CH═CH— and n2′ is 0; (T1)′=—O—C(O)—; n1 is 1 and U is a linear C1-C10 alkylene or U is a linear or branched C1-C10 alkylene substituted with a —ONO2 group; when Y and Y′ are selected from d), e) or e′), the —ONO2 group of -(T-Y—ONO2), -(T′-Y—ONO2), -(T″-Y′—ONO2), -(T′-Y′—ONO2), -(T′″-Y—ONO2) and -(T′″Y′—ONO2) is linked to the (CH2)— group;
—(CH2—CH2-T2)n3—CH2—CH2— f) wherein T2 is —O— or —S—, —NH—, n3 is 1 or 2.

4. (canceled)

5. A compound of formula (I) according to claim 1 wherein R, R1, R2, R3, and R4 are as defined in claim 1; A is 0; Rx is
—R1b—CH(NHR4a)—C(O)-(T-Y—ONO2) or (a5)
—R1b—CH(NH-T′-Y′—ONO2)—C(O)-(T-Y—ONO2) (a9) wherein R1b is C(O)—CH2—, R4a is H or C(O)CH3; T is selected from O—, —S—, —NR′— wherein R′ is as above defined, T′ is C(O)— and Y and Y′ are each independently selected from a) a straight or branched C1-C10 alkylene, a straight or branched C1-C10 alkylene substituted with a —ONO2 group; embedded image wherein: n2 is an integer from 0 to 2, R13 is H or CH3, T1 is —O—C(O)— or C(O)O—; n1 is 1 and U is a linear C1-C10 alkylene or U is a linear or branched C1-C10 alkylene substituted with a —ONO2 group; embedded image n2 is 1, R13 is CH3, Y1 is CH═CH—(CH2)n2′- and n7 is 0, T1 is C(O)O— and U is a linear C1-C10 alkylene; embedded image wherein: n2 is 1, R13 is CH3; Y1 is (CH2)n2′—CH═CH— and n2′ is 0; T1)′=—O—C(O)—; n1 is 1 and U is a linear C1-C10 alkylene or U is a linear or branched C1-C10 alkylene substituted with a —ONO2 group; when Y and Y′ are selected from d), e) or e′), the —ONO2 group of -(T-Y—ONO2), -(T′-Y—ONO2), -(T″-Y′—ONO2), -(T′-Y′—ONO2), -(T′″-Y—ONO2) and -(T′″-Y′—ONO2) is linked to the (CH2)— group;
—(CH2—CH2-T2)n3—CH2—CH2— f) wherein T2 is —O— or —S—, —NH—, n3 is 1 or 2;

6. A compound of formula (I) according to claim 1 wherein R, R1, R2, R3 and R4 are as defined in claim 1; A is 1 and Z is C(O)—, Rx is
—R1b—CH(NHR4a)—C(O)-(T-Y—ONO2) or (a5)
—R1b—CH(NH-T′-Y′—ONO2)—C(O)-(T-Y—ONO2) (a9) wherein R1b of A10) is —O—CH2— or [—Op—(C6H4)]—CH2—, R4a is H or C(O)CH3, T is selected from O—, —S—, —NR′— wherein R′ is as above defined, T′ is C(O)— and Y and Y′ are each independently selected from a) a straight or branched C1-C10 alkylene, a straight or branched C1-C10 alkylene substituted with a —ONO2 group; embedded image wherein: n2 is an integer from 0 to 2, R13 is H or CH3, T1 is —O—C(O)— or C(O)O—; n1 is 1 and U is a linear C1-C10 alkylene or U is a linear or branched C1-C10 alkylene substituted with a —ONO2 group; embedded image n2 is 1, R13 is CH3, Y1 is —CH═CH—(CH2)n2′— and n2′ is 0, T1 is C(O)O— and U is a linear C1-C10 alkylene; embedded image wherein: n2 is 1, R13 is CH3; Y1 is (CH2)n2′—CH═CH— and n2′ is 0; (T1)′=—O—C(O)—; n1 is 1 and U is a linear C1-C10 alkylene or U is a linear or branched C1-C10 alkylene substituted with a —ONO2 group; when Y and Y′ are selected from d), e) or e′), the —ONO2 group of -(T-Y—ONO2), -(T′-Y—ONO2), -(T″-Y′—ONO2), -(T′-Y′—ONO2), -(T′″-Y—ONO2) and -(T′″-Y′—ONO2) is linked to the (CH2)— group;
—(CH2—CH2-T2)n3—CH2—CH2— f) wherein T2 is —O— or —S—, —NH—, n3 is 1 or 2.

7. A compound of formula (I) according to claim 1 wherein R, R1, R2, R3 and R4 are as defined in claim 1; A is 0, Rx is
—C(O)—CH2—CH(R2)—NH-(T′-Y—ONO2) (b2) wherein R2 is H, T′ is C(O)—; Y and Y′ are each independently selected from a) a straight or branched C1-C10 alkylene, a straight or branched C1-C10 alkylene substituted with a —ONO2 group; embedded image wherein: n2 is an integer from 0 to 2, R13 is H or CH3, T1 is —O—C(O)— or C(O)O—; n1 is 1 and U is a linear C1-C10 alkylene or U is a linear or branched C1-C10 alkylene substituted with a —ONO2 group; embedded image n2 is 1, R13 is CH3, Y1 is CH═CH—(CH2)n2′- and n7 is 0, T1 is C(O)O— and U is a linear C1-C10 alkylene; embedded image wherein: n2 is 1, R13 is CH3; Y1 is (CH2)n2′—CH═CH— and n2′ is 0; (T1)′=—O—C(O)—; n1 is 1 and U is a linear C1-C10 alkylene or U is a linear or branched C1-C10 alkylene substituted with a —ONO2 group; when Y and Y′ are selected from d), e) or e′), the —ONO2 group of -(T-Y—ONO2), -(T′-Y—ONO2), -(T″-Y′—ONO2), -(T′-Y′—ONO2), -(T′″-Y—ONO2) and -(T′∝1-Y′—ONO2) is linked to the (CH2)— group;
—(CH2—CH2-T2)n3—CH2—CH2— f) wherein T2 is —O— or —S—, —NH— n3 is 1 or 2.

8. (canceled)

9. (canceled)

10. A compound of formula (I) according to claim 1 for use in the treatment of ocular diseases.

11. (canceled)

12. A compound of formula (I) according to claim 1 for use in the treatment of respiratory diseases.

13. (canceled)

14. A compound of formula (I) according to claim 1 for use in the treatment of dermatological diseases.

15. (canceled)

16. (canceled)

Description:

FIELD OF THE INVENTION

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.

BACKGROUND OF THE INVENTION

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

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

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

U.S. Pat. No. 3,183,252 describes derivatives of 16-nitrate-alkylpre-gnanes wherein the alkyl group is linked to the pregnane structure by a carbon-carbon bond. The compounds according to said patent can be used as vasodilators. The same drawbacks reported for the above prior art can be repeated.

WO 98/15568 and WO 03/064443 in the name of the Applicant describe nitrate esters of steroidal compounds, wherein between the steroidal structure and the nitrooxy group a bivalent linking group is inserted. Said compounds show a good efficacy and/or good tolerability with respect to the corresponding precursors.

Patent application WO 00/61604 in the name of the Applicant describes nitrooxy derivatives of steroidal compounds with various linking groups having at one end a nitrooxy group, and covalently linked with the other end to a steroidal compound. In said application the uses concern the compounds usable in the treatment of patients in oxidative stress. Said compounds contain in the molecule also a bivalent linking group which must be capable to prevent the free radicals production and is selected on the basis of the tests reported therein.

SUMMARY OF THE INVENTION

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.

DETAILED DESCRIPTION OF THE INVENTION

Object of the present invention are compounds of general formula (I) and pharmaceutically acceptable salts or stereoisomers thereof


R—(Z)a—Rx (I)

wherein R is a corticosteroid residue of formula (II):

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wherein:
R1 is OH, R2 —CH3, or R1 and R2 are taken together to form a group of formula (III)

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R3 is Cl or F;

R4 is H or F;

wherein R1, R2, R3 and R4 can be linked to the correspondent carbon atoms of the steroidal structure in position α or β;
with the proviso that:
when R1 and R2 are the group of formula (III) then R3 is F and R4 is H or F;
when R1 is OH and R2 —CH3 then R4 is H and R3 is Cl or F;
preferred corticosteroid radicals are R of formula (II) wherein:
R1 is OH in position α, R2 —CH3 in position β, R3 is Cl in position α and R4 is H; or
R1 is OH in position α, R2 —CH3 in position β, R3 is F in position α and R4 is H; or
R1 and R2 are taken together to form a group of formula (III)

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R3 is F and R4 is H, R1, R2 and R3 are in position α; or
R1 and R2 are taken together to form a group of formula (III)

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R3 and R4 are F, R1, R2, R3 and R4 are in position α;
a in formula (I) is equal to 0 or 1;
Z is a group capable of binding Rx and is selected from —C(O)—, or —CH(R′)—O— wherein R′ is selected from H or a straight or branched C1-C4 alkyl, preferably R′ is H or —CH3;
Rx is a radical and is selected from the the following meanings:

A)


—HN—CH(R1)—C(O)-(T-Y—ONO2) (a1)


—C(O)—CH(R1)—NH-(T′-Y—ONO2) (a2)


—HN—CH(R1a-T″-Y′—ONO2)—COOR3a (a3)


—C(O)—CH(R1a-T″-Y′—ONO2)—NHR4a (a4)


—R1b—CH(NHR4a)—C(O)-(T-Y—ONO2) (a5)


—R1b—CH(COOR3a)NH-(T′-Y—ONO2) (a6)


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


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


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


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

wherein:

R1 is selected from:

A1) H, —CH3, isopropyl, isobutyl, sec-butyl, tert-butyl, methylthio-(CH2)2—, phenyl, benzyl, C6H5—CH2—CH2-, 2-monosubstituted benzyl, or 3-monosubstituted benzyl or 4-monosubstituted benzyl wherein the substituent of the benzyl is selected from —F, —Cl, —I, —NO2, —CF3, —CH3, CN, C6H5CO—;

2,4-dichlorobenzyl, 3,4-dichlorobenzyl, 3,4-difluorobenzyl, 2-pyrrolidyl, 3-triptophanyl-CH2—, 3-benzothienyl-CH2—, 4-imidazolyl-CH2—, 9-anthranyl-CH2—, cyclohexyl, cyclohexyl-CH2—, cyclohexyl-(CH2)2—, cyclopentyl-CH2—, (C6H5)2CH—, 4-B(OH)2-benzyl, 4-quinolyl-CH2—, 3-quinolyl-CH2—, 2-quinolyl-CH2—, 2-quinoxalyl-CH2—, 2-furyl-CH2—, 1-naphtyl-CH2—, 2-naphtyl-CH2—, 2-pyridyl-CH2-, 3-Pyridyl-CH2-, 4-pyridyl-CH2—, 2-thienyl-CH2—, 3-thienyl-CH2—, C6H4—CH═CH—CH2—, CH2═CH—CH2—, CH═CH—CH2—, NH2—CO—CH2—, NH2—CO—(CH2)2—, NH2(═NH)NH—(CH2)3—, P(═O) (OCH3)2, I—CH2—, preferably R1 is H, —CH3, isopropyl, benzyl;

A2) —CH2—SH, —CH2—OH, —CH(CH3)—OH, —CH2[(C6H4)-(4-OH)], —CH2-[(C6H2)-(3,5-diiodo)-(4-OH)], —CH2-[(C6H3)-(3-nitro)-(4-0H)], preferably R1 is —CH2—OH or —CH2[(C6H4)-(4-OH)];

A3) —CH2—NHR″, —(CH2)2—NHR″, —(CH2)3—NHR″, —(CH2)4—NHR″, wherein R″ is H, —C(O)CH3 or

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wherein R5a is H or a linear or branched C1-C13 alkyl chain, preferably R5a is H or a linear (C1-C5) alkyl, preferably R1 is —(CH2)4—NHR″, wherein R″ is as above defined;

A4) —CH—C(O)R″′, —(CH2)2—C(O)R′″, —(CH2)4—C(O)R′″ wherein R′″ is —OR5a or

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wherein R5a is as above defined, preferably R1 is —CH2—C(O)R′″, wherein R′″ is as above defined;
R1a is selected from,

A5) —CH2—S—, —CH2—O—, —CH(CH3)—O—, —CH2[(C6H4)-(4-O)—], —CH2-[(3,5-diiodo)-(C6H2)-(4-O)—], —CH2-[(3-nitro)-(C6H3)-(4-O)—], preferably R1a is —CH2—O—;

A6) —CH2—NH—, —(CH2)2—NH—, —(CH2)3—NH—, —(CH2)4—NH—, preferably R1a is —(CH2)4—NH— or —CH2—NH—;

A7) —CH2—C(O)—, —(CH2)2—C(O)—, —(CH2)4—C(O)—, preferably R1a is —CH2—C(O)—;

R3a is selected from H, —R5a or

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wherein R5a is as above defined;

R4a is selected from H or —C(O)CH3 or

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wherein R5a is as above defined;

R1b is selected from

A8) —S—CH2—, —O—CH(CH3)—, —O—CH2—, [-(4-O)—(C6H4)]—CH2—, [-(4-O)-(3,5-diiodo)-(C6H2)]—CH2—, [-(4-O)-(3-nitro)-(C6H3)]-CH2—, preferably R1b is —O—CH2— or [-(4-O)—(C6H4)]—CH2—;

A9) —HN—CH2—, —HN—(CH2)2—, —HN—(CH2)3—, —HN—(CH2)4— preferably R1b is —HN—(CH2)4— or —HN—CH2—;

A10) —C(O)—CH2—, —C(O)—(CH2)2—, —C(O)—(CH2)4—, preferably R1b is —C(O)—CH2—;

T is selected from —O—, —S—, —NR′—, —O—CH(R′)—O— C(O)— or —O—CH(R′)—O— C(O)O— wherein R′ is as above defined;
T′ is —C(O)—, —C(O)—X″— wherein X″ is —O— or —S—, or T′ is —C(O)—NR′— wherein R′ is as above defined;
T″ is independently selected from —C(O)—, —C(O)—X″—, —C(O)—NR′—, —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)—, —O—CH(R′)—O—C(O)O—, wherein X″ and R′ are as above defined, with the proviso that T″ is —C(O)—C(O), —C(O)—X″— or —C(O)—NR′— when T″ is linked to —NH—, —O—, or —S—; or
T″ is —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)—, —O—CH(R′)—O— C(O)O-when T″ is linked to —C(O)—;
Y and Y′ are as below defined;

B)


—HN—CH(R2)—CH2C(O)-(T-Y—ONO2) (b1)


—C(O)—CH2—CH(R2)—NH-(T′-Y—ONO2) (b2)


—HN—CH(R2a-T″-Y′—ONO2)—CH2COOR3a (b3)


—C(O)—CH2—CH(R2a-T″-Y′—ONO2)—NHR4a (b4)


—R2b—CH(NHR4a)—CH2C(O)-(T-Y—ONO2) (b5)


—R2b—CH(CH2COOR3a)NH-(T′-Y—ONO2) (b6)


—HN—CH(R2a-T″-Y′—ONO2)—CH2—C(O)-(T-Y—ONO2) (b7)


—C(O)—CH2—CH(R2a-T″-Y′—ONO2)—NH-(T′-Y—ONO2) (b8)


—R2b—CH(NH-T′-Y′—ONO2)—CH2C(O)-(T-Y—ONO2) (b9)


—R2b—CH(CH2C(O)-T-Y′—ONO2)—NH-(T′-Y—ONO2) (b10)

wherein

R2 is selected from

B1) H, —CH3, CF3, isopropyl, isobutyl, sec-butyl, methylthio-(CH2)2—, phenyl, benzyl, 3-triptophanyl-CH2—, NH2—C(O)—CH2—, NH2—C(O)—(CH2)2—, NH2 (═NH) NH—(CH2)3—, tBuO—CH(CH3)—, benzyl-O—CH2—, 4-terbutoxy-benzyl, 4-phenylbenzyl, preferably R2 is H, —CH3, isopropyl, benzyl;

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

B3) —CH2—NHR″, —(CH2)2—NHR″, —(CH2)3—NHR″, —(CH2)4—NHR″, wherein R′″ is as above defined, preferably R2 is —(CH2)4—NHR

B4) —CH—C(O)—R′″, —(CH2)2—C(O)—R′″, —(CH2)4—C(O)—R′″ wherein R′″ is as above defined, preferably R2 is —CH—C(O)—R′″;

R2a is selected from

B5) —CH2—S—, —CH2—O—, —CH(CH3)—O— or —CH2[(C6H4)-(4-O)—], —CH2-[(3,5-diiodo)-(C6H2)—(4-O)—], —CH2-[(3-nitro)-(C6H3)-(4-O)—], preferably R2a is —CH2—O—;

B6) —CH2—NH—, —(CH2)2—NH—, —(CH2)3—NH—, —(CH2)4—NH—, preferably R2a is (CH2)4—NH— or —CH2—NH—;

B7) —CH—C(O)—, —(CH2)2—C(O)—, —(CH2)4—C(O)—, preferably R2a is —CH2—C(O)—;

R2b is selected from

B8) —S—CH2—, —O—CH(CH3)—, —O—CH2—, [-(4-O)—(C6H4)]—CH2—, [-(4-O)-(3,5-diiodo)-(C6H2)]—CH2—, [-(4-O)-(3-nitro)-(C6H3)]—CH2—, preferably R2b is —O—CH2— or [-(4-O)—(C6H4)]-CH2—;

B9) —HN—CH2—, —HN—(CH2)2—, —HN—(CH2)3—, —HN—(CH2)4—, preferably R2b is —HN—(CH2)4— or —HN—CH2—;

B10) —C(O)—CH2—, —C(O)—(CH2)2—, —C(O)—(CH2)4, preferably R2b is —C(O)—CH2—;

R3a and R4a are as above defined;
T, T′ and T″ are as above defined and Y and Y′ are as below defined;

C)


—HN—(CH2)b—C(O)-(T-Y—ONO2); (c1)


—C(O)—(CH2)b—NH-(T′-Y—ONO2); (c2)

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)


—HN—CH(R12)—CH2—O-(T″-Y—ONO2) (d1)


—O—CH2—CH(R12)—NH-(T′-Y—ONO2) (d2)


—HN—CH(R12a-T″-Y′—ONO2)—CH2OH (d3)


—O—CH2—CH(R12a-T″-Y′—ONO2)—NHR4a (d4)


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


—R12b—CH(CH2OH)—NH-(T′-Y—ONO2) (d6)


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


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


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


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

wherein
T′″ is independently selected from —C(O)—, —C(O)X″— wherein X″ is —O— or —S—, or —C(O)—NR′— wherein R′ is as above defined;
T′ and T″ are as above defined;
Y and Y′ are as below defined;
R12 is selected from:

D1) H, —CH3, isopropyl, isobutyl, sec-butyl, methylthio-(CH2)2—, benzyl, 3-triptophanyl-CH2—, 4-imidazolyl-CH2—, NH2—CO—CH2—, NH2—CO—(CH2)2—, NH2 (═NH) NH—(CH2)3, preferably R12 is H;

D2) —CH2—OH, —CH(CH3)—OH, —CH2[(C6H4)-(4-OH)], —CH2-[(C6H3)-(3,5-diiodo)-(4-OH)], —CH2—[(C6H3)-(3-nitro)-(4-OH)], preferably R12 is —CH2—OH or —CH2[(C6H4)-(4-OH)];

D3) —CH2—NHR″, —(CH2)2—NHR″, —(CH2)3—NHR″, —(CH2)4—NHR″, wherein R″ is as above defined, preferably R12 is —(CH2)4—NHR″;

D4) —CH2—C(O)R′″, —(CH2)2—C(O)R′″, —(CH2)4—C(O)R′″ wherein R′″ is as above defined, preferably R12 is —CH2—C(O)R″;

R12a is selected from

D5) —CH2—O—, —CH(CH3)—O— or —CH2[(C6H4)-(4-O)—], —CH2-[3,5-diiodo-(C6H2)-(4-O)—], —CH2-[3-nitro-(C6H3)-4-O—], preferably R12a is CH2—O— or —CH2[(C6H4)-(4-O)—];

D6) —CH2—NH—, —(CH2)2—NH—, —(CH2)3—NH—, —(CH2)4—NH—, preferably R12a is —(CH2)4—NH— or —CH2—NH—;

D7) —CH2—C(O)—, —(CH2)2—C(O)—, —(CH2)4—C(O)—, preferably R12a is —CH2—C(O)—;

R12b is selected from

D8) —O—CH2—, —O—CH(CH3)—, [-(4-O)—(C6H4)]—CH2—, [-(4-O)-(3,5-diiodo)-(C6H2)]—CH2, [-(4-O)-(3-nitro)-(C6H3)]—CH2—, preferably R12b is —O—CH2— or [-(4-O)—(C6H4)]-CH2—;

D9) —HN—CH2—, —HN—(CH2)2—, —HN—(CH2)2—, —HN—(CH2)4—, preferably R12b is —HN—(CH2)4— or —HN—CH2—;

D10) —C(O)—CH2—, —C(O)—(CH2)2—, —C(O)—(CH2)4—, preferably R12b is —C(O)—CH2—;

R4a is as above defined;

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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;

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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;

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

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

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wherein R5 is H, R6 is H, or R5 and R6 when taken together are a double bond, T and T′ are as above defined and Y is as below reported;

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

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

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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;

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wherein R7 is H, R8 is H, or R7 and R8 when taken together are a double bond, c is as above defined, T and T′ are as above defined and Y is as below reported;

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

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

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

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

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

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wherein R9 and R10 are H, CH3, R11 is CH3 or 4-piperidinyl with the proviso that R9 and R10 are H when R11 is 4-piperidinyl and R9 and R10 are CH3 when R11 is CH3, T and T′ are as above defined and Y is as below reported;

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wherein T and T′ are as above defined and Y is as below reported;
with the proviso that in the formula (I):
a is 0 or a is 1 and Z is —CH(R′)—O— wherein R′ is as above defined, when Rx is:

    • (a2), (a4) or (a8);
    • (a5), (a6), (a9) or (a10) and R1b is selected from the group A10);
    • (b2), (b4) or (b8);
    • (b5), (b6), (b9) or (b10) and R1b is selected from the group B10);
    • (c2);
    • (d5), (d6), (d9) or (d10) and R12b is selected from the group D10);
    • (e2), (f1), (g2), (h1), (i1), (l2), (m2), (n2), (o2), (p2), (q2), (r2), (s2), (t1) or (u2);
      a is 1 and Z is —C(O)—, when Rx is:
    • (a1), (a3) or (a7);
    • (a5), (a6), (a9) or (a10) and R1b is selected from the groups A8) and A9);
    • (b1), (b3) or (b7);
    • (b5), (b6), (b9) or (b10) and R2b is selected from the groups B8) or B9);
    • (c1);
    • (d1), (d2), (d3), (d4), (d7) or (d8);
    • (d5), (d6), (d9) or (d10) and R12b is selected from the groups D8) or D9);
    • (e1), (f2), (g1), (h2), (i2), (11), (m1), (n1), (01), (p1), (q1), (r1), (s1), (t2) or (u1).
      Y and Y′ are bivalent radicals each independently selected from the following meanings:
      a)
    • straight or branched C1-C20 alkylene, preferably a straight or branched C1-C10 alkylene,
    • straight or branched C1-C20 alkylene substituted with one or more of the substituents selected from the group consisting of: halogen atoms, hydroxy, —ONO2 or T2, wherein T2 is —OC(O)(C1-C10 alkyl)-ONO2 or —O(C1-C10 alkyl)-ONO2, preferably Y or Y′ is a straight or branched C1-C10 alkylene substituted with a —ONO2 group;
    • cycloalkylene with 5 to 7 carbon atoms into cycloalkylene ring, the ring being optionally substituted with one or more straight or branched C1-C10 alkyl chains, preferably the ring being optionally substituted with CH3;

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wherein
n0 is an integer from 0 to 20, preferably n0 is 0 or 1;
n1 is 0 or 1, preferably n0 is 1;
U is a linear or branched C1-C20 alkylene optionally substituted with a —ONO2 group, preferably U is a linear C1-C10 alkylene or U is a linear or branched C1-C10 alkylene substituted with a —ONO2 group;

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wherein
n0 is an integer from 0 to 20, preferably n0 is 0 or 1;
n1 is 0 or 1, preferably n0 is 1;
U is a linear or branched C1-C20 alkylene optionally substituted with a —ONO2 group, preferably U is a linear C1-C10 alkylene or U is a linear or branched C1-C10 alkylene substituted with a —ONO2 group;

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wherein:
n2 is an integer from 0 to 2, R13 is H or CH3, T1 is —O—C(O)— or —C(O)O—;
n1 and U are as above defined;

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n2 is an integer from 0 to 2, preferably n2 is 1;
R13 is H or CH3, preferably R13 is CH3;
Y1 is —CH2—CH2— or —CH═CH—(CH2)n2′—, wherein n2′ is 0 or 1, preferably Y1 is —CH═CH—(CH2)n2′- and n2′ is 0;
T1=—O—C(O)— or —C(O)O—, preferably T1 is —C(O)O—;
n1 is 0 or 1, preferably n1 is 1;
U is a linear or branched C1-C20 alkylene optionally substituted with a —ONO2 group, preferably U is a linear C1-C10 alkylene or U is a linear or branched C1-C10 alkylene substituted with a —ONO2 group;
more preferably n2 is 1, R13 is CH3, Y1 is —CH═CH—(CH2)n2′- and n2′ is 0, T1 is —C(O)O— and U is a linear C1-C10 alkylene;

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wherein:
n2 is n2 is an integer from 0 to 2, preferably n0 is 1;
R13 is H or CH3, preferably R13 is CH3;
Y1 is —CH2—CH2— or —(CH2)n2′—CH═CH—, wherein n2′ is 0 or 1, preferably Y1 is —(CH2)n2′—CH═CH— and n2′ is 0;

(T1)′=—O—C(O)—;

n1 is 1 is 0 or 1, preferably n1 is 1;
U is a linear or branched C1-C20 alkylene optionally substituted with a —ONO2 group, preferably U is a linear C1-C10 alkylene or U is a linear or branched C1-C10 alkylene substituted with a —ONO2 group;
more preferably n2 is 1, R13 is CH3, Y1 is —CH═CH—(CH2)n2′- and n2′ is 0, T1 is —OC(O)— and U is a linear C1-C10 alkylene;
when Y and Y′ are selected from b), c), d), e) or e′), the —ONO2 group of -(T-Y—ONO2), -(T′-Y—ONO2), -(T″-Y′—ONO2), -(T′Y′—ONO2), -(T″-Y—ONO2) and -(T″-Y′—ONO2) is linked to the —(CH2)— group;


—(CH2—CH2-T2)n3—CH2—CH2— f)

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

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wherein:
n4 is n4 is an integer from 0 to 10, preferably n4 is 0 or 1;
n5 is an integer from 1 to 10, preferably n5 is 1;

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

wherein the —ONO2 group is linked to

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wherein n5 is as defined above;

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

and is selected from the group consisting of:

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The term “C1-C10 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 (C1-C10)-alkyl, preferably CH3.

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

Preferred compounds of formula (I) 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) R1, R2, R3 and R4 have the following meanings:
R1 is OH in position α, R2 —CH3 in position β, R3 is Cl in position α and R4 is H; or
R1 is OH in position α, R2 —CH3 in position β, R3 is F in position α and R4 is H; or
R1 and R2 are taken together to form a group of formula (III)

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R3 is F and R4 is H, R1, R2 and R3 are in position α; or
R1 and R2 are taken together to form a group of formula (III)

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R3 and R4 are F, R1, R2, R3 and R4 are in position α;
in formula (I):
a is 0 and
Rx is selected from:


—C(O)—CH(R1)—NH-(T′-Y—ONO2) (a2)

wherein
R1 of the group A1) is selected from H, isobutyl, benzyl, C6H5—CH2—CH2—, 2-monosubstituted benzyl, or 3-monosubstituted benzyl or 4-monosubstituted benzyl wherein the substituent of the benzyl is selected from —F, —Cl, —I, —NO2, —CF3, —CH3, CN, C6H5CO—;
R1 of the group A2) is selected from —CH2—OH, —CH(CH3)OH— or —CH2[(C6H4)-(4-OH)], or
R1 of the group A3) is selected from —CH2—NHR″, —(CH2)2—NHR″, —(CH2)3—NHR″, —(CH2)4—NHR″, wherein R″ is H, or —C(O)CH3;
R1 of the group A4) is selected from —CH2—C(O)R″, —(CH2)2—C(O)R′″, —(CH2)4—C(O)R′″ wherein R′″ is OR5a wherein R5a is H or a linear (C1-C5) alkyl;
T′ is —C(O)—, —C(O)—X″ wherein X″ is —S— or —O—, preferably T′ is —C(O)—;
Y is as below defined;

or Rx is


C(O)—CH(R1a-T″-Y′—ONO2)—NHR4a (a4)

wherein R1a of the group A5) is selected from —CH2—O—, —CH(CH3)O— or —CH2[(C6H4)-(4-O)—], or
R1a of the group A6) is selected from —CH2—NH—, —(CH2)2—NH—, —(CH2)3—NH—, —(CH2)4—NH—, or
R1a of the group A7) is selected from —CH2—C(O)—, —(CH2)2—C(O)—, —(CH2)4—C(O)—;

R4a is H or —C(O)CH3;

T″ is —C(O)— or —C(O)—X″ wherein X″ is —S— or —O—, when R1a is selected from the group A5) or A6), preferably T″ is —C(O)—;
T″ is —O—, —S—, —NR′— or —O—CH(R′)—O—C(O)— wherein R′ is H or —CH3, when R1a is selected from the group A7);
Y′ is as below defined;
or Rx is selected from


—R1b—CH(NHR4a)—C(O)-(T-Y—ONO2) (a5)


—R1b—CH(COOR3a)NH-(T′-Y—ONO2) (a6)


R1bCH(NH-T′-Y′—ONO2)—C(O)-(T-Y—ONO2) or (a9)


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

wherein
R1b of the group A10) is selected from —C(O)—CH2—, —C(O)—(CH2)2—, —C(O)—(CH2)4;
R1a is H or a (C1-C5) alkyl;

R4a is H or —C(O)CH3;

T is —O—, —S—, —NR′— or —O—CH(R′)—O— C(O)— wherein R′ is H or —CH3, 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 Rx is


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

wherein
R1a of the group A5) is selected from —CH2—O—, —CH(CH3)—O— or —CH2[(C6H4)-(4-O)—], or
R1a of the group A6) is selected from —CH2—NH—, —(CH2)2—NH—, —(CH2)3—NH—, —(CH2)4—NH—, or
R1a of the group A7) is selected from —CH2—C(O)—, —(CH2)2—C(O)—, (CH2)4—C(O)—;
T″ is —C(O)— or —C(O)—X″ wherein X″ is —S— or —O—, when R1a is selected from the group A5) or A6), preferably T″ is —C(O)—;
T″ is —O—, —S—, —NR′— or —O—CH(R′)—O— C(O)— wherein R′ is H or —CH3, when R1a is selected from the group A7);
T′ is —C(O)— or —C(O)—X″ wherein X″ is —S— or —O—, preferably T′ is —C(O)—;
Y and Y′ are as below defined;

or Rx is


—C(O)—CH2—CH(R2)—NH-(T′-Y—ONO2) (b2)

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

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

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wherein:
n2 is an integer from 0 to 2, R13 is H or CH3, T1 is —O—C(O)— or —C(O)O—;
n1 is 1 and U is a linear C1-C10 alkylene or U is a linear or branched C1-C10 alkylene substituted with a —ONO2 group;

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n2 is 1, R13 is CH3, Y1 is CH═CH(CH2)n2′ and n2 is 0, T1 is —C(O)O— and U is a linear C1-C10 alkylene;

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

(T1)′=—O—C(O)—;

n1 is 1 and U is a linear C1-C10 alkylene or U is a linear or branched C1-C10 alkylene substituted with a —ONO2 group; when Y and Y′ are selected from d), e) or e′), the —ONO2 group of -(T-Y—ONO2), -(T′-Y—ONO2), -(T″-Y′—ONO2), -(T′Y′—ONO2), -(T′″-Y—ONO2) and -(T′″-Y′—ONO2) is linked to the —(CH2)— group;


—(CH2—CH2-T2)n3—CH2—CH2— f)

wherein T2 is —O— or —S—, —NH—, preferably T2 is —O—, n3 is 1 or 2;
Another embodiment of the invention relates to compounds of formula (I) wherein in the corticosteroid R of formula (II) R1, R2, R3 and R4 have the following meanings:
R1 is OH in position α, R2 —CH3 in position β, R3 is Cl in position α and R4 is H; or
R1 is OH in position α, R2 —CH3 in position β, R3 is F in position α and R4 is H; or
R1 and R2 are taken together to form a group of formula (III)

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R3 is F and R4 is H, R1, R2 and R3 are in position α; or
R1 and R2 are taken together to form a group of formula (III)

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R3 and R4 are F, R1, R2, R3 and R4 are in position α;
in formula (I):

a is 1 and Z is —C(O)—;

Rx is


—HN—CH(R1)—C(O)-(T-Y—ONO2) (a1)

wherein
R1 of the group A1) is selected from H, isobutyl, benzyl, C6H5—CH2—CH2—, 2-monosubstituted benzyl, or 3-monosubstituted benzyl or 4-monosubstituted benzyl wherein the substituent of the benzyl is selected from —F, —Cl, —I, —NO2, —CF3, —CH3, CN, C6H5CO—;
or
R1 of A2) is selected from —CH2—OH, —CH(CH3)—OH— or —CH2[(C6H4)-(4-OH)], or
R1 of the group A3) is selected from —CH2—NHR″, —(CH2)2—NHR″, —(CH2)3—NHR″, —(CH2)4—NHR″, wherein R″ is H, or —C(O)CH3,
R1 of the group A4) is —CH2—C(O)R″, —(CH2)2—C(O)R′″, —(CH2)4—C(O)R′″ wherein R′″ is OR5a wherein R5a is H or a linear (C1-C5) alkyl;
T is —O—, —S—, —NR′—, —O—CH(R′)—O— C(O)— wherein R′ is H or a straight or branched C1-C4 alkyl, preferably T is —O—;
Y is as below defined;

or Rx is


—HN—CH(R1a-T″-Y′—ONO2)—COOR3a (a3)

wherein
R1a of the group A5) is selected from —CH2—O—, —CH(CH3)O— or —CH2[(C6H4)Op-], or
R1a of the group A6) is selected from —CH2—NH—, —(CH2)2—NH—, —(CH2)3—NH—, —(CH2)4—NH—, or
R1a of the group A7) is —CH2—C(O)—, —(CH2)2—C(O)—, —(CH2)4—C(O)—;
R3a is H or a (C1-C5) alkyl;
T″ is —C(O)— or —C(O)—X″ wherein X″ is —S— or —O—, when R1a is selected from the group A5) or A6), preferably T″ is —C(O)—;
T″ is —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)— wherein R′ is H or a straight or branched C1-C4 alkyl, when R1a is selected from the group A7);
Y′ is as below defined;

or Rx is


—R1b—CH(NHR4a)—C(O)-(T-Y—ONO2) (a5)


—R1b—CH(COOR3a)NH-(T′-Y—ONO2) (a6)


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


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

wherein
R1b of the group A8) is selected from —O—CH(CH3)—, —O—CH2—, [-4-O)—(C6H4)]-CH2—, or
R1b of the group A9) is selected from —HN—CH2—, —HN—(CH2)2—, —HN—(CH2)3, —HN—(CH2)4;
R3a is H or a (C1-C5) alkyl;

R4a is H or —C(O)CH3;

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


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

wherein
R1a of the group A5) is selected from —CH2—O—, —CH(CH3)—O— or —CH2[(C6H4)-(4-O)—], or
R1a of the group A6) is selected from —CH2—NH—, —(CH2)2—NH—, —(CH2)3—NH—, —(CH2)4—NH—, or
R1a of the group A7) is —CH2—C(O)—, —(CH2)2—C(O)—, —(CH2)4—C(O)—;
T″ is —C(O)— or —C(O)—X″ wherein X″ is —S— or —O—, preferably T″ is —C(O)— when R1a is selected from A5) or A6);
T″ is —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)— wherein R′ is H or a straight or branched C1-C4 alkyl, preferably T″ is —O—, when R1a is selected from A7);
T is —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)— wherein R′ is H or a straight or branched C1-C4 alkyl, preferably T is —O—;
Y and Y′ are as below defined;

or Rx is


—HN—CH(R2)—CH2C(O)-(T-Y—ONO2) (b1)

wherein
R2 of the group B1) is selected from H, CH3, isobutyl, isopropyl, benzyl;
R2 of the group B2) is selected from —CH2—OH, —CH(CH3)—OH— or —CH2[(C6H4) (4-OH)], or
R2 of the group B3) is selected from —CH2—NHR″, —(CH2)2—NHR″, —(CH2)3—NHR″, —(CH2)4—NHR″, wherein R″ is H, or —C(O)CH3,
R2 of the group B4) is —CH2—C(O)R′″, —(CH2)2—C(O)R′″, —(CH2)4—C(O)R′″ wherein R′″ is OR5a wherein R5a is H or a linear (C1-C5) alkyl;
T is —O—, —S—, —NR′—, —O—CH(R′)—O— C(O)— wherein R′ is H or a straight or branched C1-C4 alkyl, preferably T is —O—;
Y is as below defined;
or Rx is selected from


—HN—CH(R12)—CH2—O-(T′″-Y—ONO2) (d1)


—O—CH2—CH(R12)—NH-(T′-Y—ONO2) (d2)

wherein
R12 of the group D1) is selected from H, CH3, isobutyl, isopropyl, benzyl, or
R12 of the group D2) is selected from —CH2—OH, —CH(CH3)OH— or —CH2[(C6H4)-(4-OH)], or
R12 of the group D3) is selected from —CH2—NHR″, —(CH2)2—NHR″, —(CH2)3—NHR″, —(CH2)4—NHR″ wherein R″ is H, or
R12 of the group D4) is —CH2—C(O)R′″, —(CH2)2—C(O)R′″, —(CH2)4—C(O)R′″ wherein R′″ is OR5a wherein R5a is H or a linear (C1-C5) alkyl;
T′ and T′″ are each independently selected from —C(O)— or —C(O)—X″ wherein X″ is —S— or —O—, preferably T′ and T′″ are —C(O)—;
Y is as below defined;
or Rx is selected from


—HN—CH(R12a-T″-Y′—ONO2)—CH2OH (d3)


—O—CH2—CH(R12a-T″-Y′—ONO2)—NHR4a (d4)


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


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

wherein
R12a of the group D5) is selected from —CH2—O—, —CH(CH3)—O— or —CH2[(C6H4)-(4-O)—], or
R12a of the group D6) is selected from —CH2—NH—, —(CH2)2—NH—, —(CH2)3—NH—, —(CH2)4—NH—, or
R12a of the group D7) is —CH2—C(O)—, —(CH2)2—C(O)—, —(CH2)4—C(O)—;

R4a is H or —C(O)CH3;

T″ is selected from —C(O)— or —C(O)—X″ wherein X″ is —S— or —O—, preferably T′ and T′″ are —C(O)—, when R12a is selected from D5) or D6);
T″ is —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)— wherein R′ is H or a straight or branched C1-C4 alkyl, preferably T is —O—, when R12a 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 Rx is selected from


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


—R12b—CH(CH2OH)—NH-(T′-Y—ONO2) (d6)


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


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

wherein
R12b of the group D8) is selected from —O—CH(CH3)—, —O—CH2—, [—Op(C6H4)]—CH2—, or
R12b of the group D9) is selected from —HN—CH2—, —HN—(CH4)2—, —HN—(CH2)3, —HN—(CH2)4—;

R4a is H or —C(O)—CH3,

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

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

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wherein:
n2 is an integer from 0 to 2, R13 is H or CH3, T1 is —O—C(O)— or —C(O)O—;
n1 is 1 and U is a linear C1-C10 alkylene or U is a linear or branched C1-C10 alkylene substituted with a —ONO2 group;

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n2 is 1, R is CH3, Y1 is CH═CH(CH2)n2′ and n2 is 0, T1 is C(O)O— and U is a linear C1-C10 alkylene;

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

(T1)′=—O—C(O)—;

n1 is 1 and U is a linear C1-C10 alkylene or U is a linear or branched C1-C10 alkylene substituted with a —ONO2 group;
when Y and Y′ are selected from d), e) or e′), the —ONO2 group of -(T-Y—ONO2), -(T′-Y—ONO2), -(T″-Y′—ONO2), -(T′-Y′—ONO2), -(T′″-Y—ONO2) and -(T′″-Y′—ONO2) is linked to the —(CH2)— group;


—(CH2—CH2-T2)n3—CH2—CH2— f)

wherein T2 is —O— or —S—, —NH—, preferably T2 is —O—, n3 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,

Rx is


—C(O)—CH(R1)—NH-(T′-Y—ONO2) (a2)

wherein
R1 of A1) is selected from H

T′ is —C(O)—;

Y is selected from
a)

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

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wherein:
n2 is an integer from 0 to 2, R13 is H or CH3, T1 is —O—C(O)— or —C(O)O—;
n1 is 1 and U is a linear C1-C10 alkylene or U is a linear or branched C1-C10 alkylene substituted with a —ONO2 group;

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n2 is 1, R13 is CH3, Y1 is —CH═CH—(CH2)n2′— and n2′ is 0, T1 is —C(O)O— and U is a linear C1-C10 alkylene;

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

(T1)′=—O—C(O)—;

n1 is 1 and U is a linear C1-C10 alkylene or U is a linear or branched C1-C10alkylene substituted with a —ONO2 group; when Y and Y′ are selected from d), e) or e′), the —ONO2 group of -(T′-Y—ONO2) is linked to the —(CH2)— group;


—(CH2—CH2-T2)n3—CH2—CH2— f)

wherein T2 is —O— or —S—, —NH—, preferably T2 is —O—, n3 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, Rx is


—R1b—CH(NHR4a)—C(O)-(T-Y—ONO2) or (a5)


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

wherein

R1b of A10) is —C(O)—CH2—,

R4a is H or —C(O)CH3;

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

T′ is —C(O)— and

Y and Y′ are each independently selected from
a)

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

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wherein:
n2 is an integer from 0 to 2, R13 is H or CH3, T1 is —O—C(O)— or —C(O)O—;
n1 is 1 and U is a linear C1-C10 alkylene or U is a linear or branched C1-C10 alkylene substituted with a —ONO2 group;

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n2 is 1, R13 is CH3, Y1 is CH═CH(CH2)n2′ and n2 is 0, T1 is C(O)O— and U is a linear C1-C10 alkylene;

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

(T1)′=—O—C(O)—;

n1 is 1 and U is a linear C1-C10 alkylene or U is a linear or branched C1-C10 alkylene substituted with a —ONO2 group;
when Y and Y′ are selected from d), e) or e′), the —ONO2 group of -(T-Y—ONO2), -(T′-Y—ONO2), -(T″-Y′—ONO2), -(T′-Y′—ONO2), -(T′″-Y—ONO2) and -(T′″-Y-f-ONO2) is linked to the —(CH2)— group;


—(CH2—CH2-T2)n3—CH2—CH2— f)

wherein T2 is —O— or —S—, —NH—, preferably T2 is —O—, n3 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)—, Rx is


—R1b—CH(NHR4a)—C(O)-(T-Y—ONO2) or (a5)


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

wherein R1b of A10) is —O—CH2— or [—Op—(C6H4)]—CH2—,

R4a is H or —C(O)CH3,

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

T′ is —C(O)— and

Y and Y′ are each independently selected from
a)

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

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wherein:
n2 is an integer from 0 to 2, R13 is H or CH3, T1 is —O—C(O)— or —C(O)O—;
n1 is 1 and U is a linear C1-C10 alkylene or U is a linear or branched C1-C10 alkylene substituted with a —ONO2 group;

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n2 is 1, R13 is CH3, Y1 is CH═CH(CH2)n2′ and n2 is 0, T1 is —C(O)O— and U is a linear C1-C10 alkylene;

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

(T1)′=—O—C(O)—;

n1 is 1 and U is a linear C1-C10 alkylene or U is a linear or branched C1-C10 alkylene substituted with a —ONO2 group;
when Y and Y′ are selected from d), e) or e′), the —ONO2 group of -(T-Y—ONO2), -(T′-Y—ONO2), -(T″-Y′—ONO2), -(T′-Y′—ONO2), -(T″-Y—ONO2) and -(T″-Y′—ONO2) is linked to the —(CH2)— group;


—(CH2—CH2-T2)n3—CH2—CH2— f)

wherein T2 is —O— or —S—, —NH—, preferably T2 is —O—, n3 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,

Rx is


—C(O)—CH2—CH(R2)—NH-(T′-Y—ONO2) (b2)

wherein

R2 of B1) is H,

T′ is —C(O)—;

Y and Y′ are each independently selected from
a)

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

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wherein:
n2 is an integer from 0 to 2, R13 is H or CH3, T1 is —O—C(O)— or —C(O)O—;
n1 is 1 and U is a linear C1-C10 alkylene or U is a linear or branched C1-C10 alkylene substituted with a —ONO2 group;

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n2 is 1, R13 is CH3, Y1 is —CH═CH—(CH2)n2′- and n2′ is 0, T1 is —C(O)O— and U is a linear C1-C10 alkylene;

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wherein:
n2 is 1, R13 is CH3;
Y1 is —(CH2)n2′—CH═CH— and n2′ is 0; (T1)′=—O—C(O)—;
n1 is 1 and U is a linear C1-C10 alkylene or U is a linear or branched C1-C10 alkylene substituted with a —ONO2 group;
when Y and Y′ are selected from d), e) or e′), the —ONO2 group of -(T-Y—ONO2), -(T′-Y—ONO2), -(T″-Y′—ONO2), -(T′-Y′—ONO2), -(T″-Y—ONO2) and -(T″-Y′—ONO2) is linked to the —(CH2)— group;


—(CH2—CH2-T2)n3—CH2—CH2— f)

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

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

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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” 15th Ed.

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

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

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 Rx is selected from (a2), (a4), (a8), (b2), (b4), (b8), (c2), (e2), (f1), (g2), (h1), (i1), (12), (m2), (n2), (o2), (p2), (q2), (r2), (s2), (t2), (u2), (v2), can be obtained:
1-i) by reacting a compound of (IIa)

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wherein R1, R2, R3, R4, are as above defined, with a compound of formula (Ia)


W—X1 (Ia)

wherein W is —OH, Cl, O—Ra wherein Ra is pentafluorophenyl, 4-nitrophenyl or —(N-succimidyl), X1 is as below defined, to obtain the compound of formula (IIa′)

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wherein R1, R2, R3, R4, are as above defined and X1 is as below defined,
X1 is a radical having the following meaning:


—C(O)—CH(R1′)—NH-(T′-Y-Q) (a2′)

wherein R1′ is selected from
A1) as defined above or
A2′) —CH2—SP1, —CH2—OP1, —CH(CH3)—OP1, —CH2[(C6H4)-4-OP1], —CH2-[(C6H3)-(3,5-diiodo)-4-OP1], —CH2-[(C6H3)-3-nitro-4-OP1] or
A3′) —CH2—NHR″″, (CH2)2—NHR″″, (CH2)3—NHR″″, —(CH2)4—NHR″″, wherein R″″ is P3 or —C(O)CH3 or

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wherein R5a is as defined above;

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

wherein R′″″ is P2, —OR5a or

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wherein R5a is as above defined;


—C(O)—CH(R1a-T″-Y′-Q)-NHR4a′ (a4′)


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

wherein R1a is as defined above;


—C(O)—CH2—CH(R2′)—NH-(T′-Y-Q) (b2′)

wherein R2′ is selected from
B1) as defined above or

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

B3′) —CH2—NHR″″, —(CH2)2—NHR″″, —(CH2)3—NHR″″, —(CH2)4—NHR″″, wherein R″″ is as above defined;
B4′) —CH2—C(O)—R′″″, —(CH2)2—C(O)—R′″″, —(CH2)4—C(O)—R′″″ wherein R′″″ is as above defined;

R4a′ is P3 or —C(O)—CH3 or

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—C(O)—CH2—CH(R2a-T″-Y′-Q)-NHR4a′ (b4′)


—C(O)—CH2—CH(R2a-T″-Y′-Q)-NH-(T′-Y-Q) (b8′)

wherein R2a and R4a are as defined above;


—C(O)—(CH2)b—NH-(T′-Y-Q); (c2′)

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wherein R3, R4, R5, R6, R7, R8, R9, R10, R11, b, c, d, e and f are as above defined;
wherein P1 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, P2 is a carboxylic protecting group such as tert-butyl ester and those described in T. W. Greene “Protective groups in organic synthesis”, Harvard University Press, 1980, P3 is a amino protecting group such as Boc, Fmoc or those described in T. W. Greene “Protective groups in organic synthesis”, Harvard University Press, 1980,
T, T′, T″, Y and Y′ are as above defined,
Q is independently —ONO2 or Z2 wherein Z2 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 Z2, by converting the compound obtained in the step 1-i) into nitro derivative by reaction with a nitrate source such as silver nitrate, lithium nitrate, sodium nitrate, potassium nitrate, magnesium nitrate, calcium nitrate, iron nitrate, zinc nitrate or tetraalkylammonium nitrate (wherein alkyl is C1-C10 alkyl) in a suitable organic solvent such as acetonitrile, tetrahydrofurane, methyl ethyl ketone, ethyl acetate, DMF, the reaction is carried out, in the dark, at a temperature from room temperature to the boiling temperature of the solvent. Preferred nitrate source is silver nitrate and 1-iii) optionally deprotecting the compounds obtained in step 1-i) or 1-ii) as described in T. W. Greene “Protective groups in organic synthesis”, Harvard University Press, 1980, 2nd 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 X1 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—Ra wherein Ra and X1 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 X1 is are as above defined, with a compound of formula (IIa) may be carried out in presence of 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 X1 is the radical selected from (a2′), (a4′), (b2′), (b4′), (c2′), (e2′), (f1′), (g2′), (h1′), (i1′), (12′), (m2′), (n2′), (o2′), (p2′), (q2′), (r2′), (s2′), (t2′), (u2′), (v2′), wherein R′ is selected from A1), A2′), A3′), A4′), R1a is selected from A5) or A6), R2a is selected from B5) or B6) and R2′ is selected from B1), B2′), B3′), B4′) and Y, Y′ and R4a′ are as above defined, can be obtained
1a-i) by reacting a compound of formula (IIIa)


P2—X2 (IIIa)

wherein P2 is as above defined, X2 is a radical having the following meaning


—C(O)—CH(R1′)—NH2 (a2″)


—C(O)—CH(R1a—H)—NHR4a′ (a4″)

wherein R1′ is selected from A1), A2′), A3′), A4′), R1a is selected from A5) or A6) and R4a′ is as defined above


—C(O)—CH2—CH(R2′)—NH2, (b2″)


—C(O)—CH2—CH(R2a—H)—NHR4a′ (b4″)

wherein R2′ is selected from B1), B2′), B3′), B4′), R2a is selected from B5) or B6) and R4a′ is as defined above,


—C(O)—(CH2)bNH2, (c2″)

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


W1—(O)C-y-Q (IVa)

wherein W1 is OH or O—Ra and Ra and Q are as above defined, y is the radical Y when X2 is selected from (a2′), (b2′), (c2′), (e2′), (f1′), (g2′), (h1′), (i1′), (12′), (m2′), (n2′), (o2′), (p2′), (q2′), (r2′), (s2′), (t2′), (u2′), (v2′), and y is the radical Y′ when X2 is selected from (a4′) or (b4′), wherein Y and Y′ are as defined above, and
1a-ii) when Q is Z2, by converting the compound obtained in the step 1a-i) into nitro derivative by reaction with a nitrate source as above described and
1a-iii) optionally deprotecting the compounds obtained in step 1a-i) or 1a-ii) as above described.

The reaction of a compound of formula (IIIa) wherein P2 and X2 are as above defined, with a compound of formula (IVa) wherein W1 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 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU).

The reaction of a compound of formula (IIIa) wherein P2 and X2 are as above defined, with a compound of formula (IVa) wherein W1 is O—Ra, 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 W1 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-Z2 (IVc) wherein Z2 is as above defined, by reaction with a nitrate source as above described. Alternatively the reaction with AgNO3 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 W1 is O—Ra, y, Q are as above defined, can be obtained from the corresponding acids of formula (IVa) wherein W1 is OH as known in the literature.

The compounds of formula (Ia) wherein W=Cl or O—Ra, X1 is selected from (a2′), (a4′), (b2′), (b4′), (c2′), (e2′), (f1′), (g2′), (h1′), (i1′), (12′), (m2′), (n2′), (o2′), (p2′), (q2′), (r2′), (s2′), (t2′), (u2′), (v2′), wherein R′ is selected from A1), A2′), A3′), A4′), R1a is selected from A5) or A6), R2a is selected from B5) or B6) and R2′ 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, X1 is the radical selected from (a2′), (a4′), (b2′), (b4′) (c2′), (e2′), (f1′), (g2′), (h1′), (i1′), (12′), (m2′), (n2′), (o2′), (p2′), (q2′), (r2′), (s2′), (t2′), (u2′), (v2′), wherein R′ is selected from A1), A2′), A3′), A4′), R1a is selected from A5) or A6), R2a is selected from B5) or B6) and R2′ 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)


P2—X2 (IIIa)

wherein P2 and X2 are as defined above, with a compound of formula (IVd)


Ra—O—C(O)—X″-y-Q (IVd)

wherein Ra, X″ and Q are as above defined, y is the radical Y when X2 is selected from (a2′), (b2′), (c2′), (e2′), (f1′), (g2′), (h1′), (i1′), (12′), (m2′), (n2′), (o2′), (p2′), (q2′), (r2′), (s2′), (t2′), (u2′), (v2′), and y is the radical Y′ when X2 is selected from (a4′) or (b4′), wherein Y and Y′ are as above defined, and
1b-ii) when Q is Z2, by converting the compound obtained in the step 1b-i) into nitro derivative by reaction with a nitrate source as above described and
1b-iii) optionally deprotecting the compounds obtained in step 1b-i) or 1b-ii) as above described.

The reaction of a compound of formula (IIIa) wherein P2 and X2 are as above defined, with a compound of formula (IVd) wherein Ra, X″, y and Q are as above defined, may be carried out as described in 1-i-2)

The compounds of formula (IVd) wherein Ra, 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—Ra, X1 is selected from (a2′), (a4′), (b2′), (b4′), (c2′), (e2′), (f1′), (g2′), (h1′), (i1′), (12′), (m2′), (n2′), (o2′), (p2′), (q2′), (r2′), (s2′), (t2′), (u2′), (v2′), wherein R1a is selected from A1), A2′), A3′), A4′), R1a is selected from A5) or A6), R2a is selected from B5) or B6) and R2′ 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 X1 is a radical selected from (a8′) or (b8′), wherein R1a is selected from A5) or A6), R2a 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),


P2—X3 (IIIb)

wherein P2 is as above defined, X3 is the radical of formula


—C(O)—CH(R1a—H)—NH2 (a8″)


—C(O)—CH2—CH(R2a—H)—NH2 (b8″)

wherein R1a is selected from A5) or A6), R2a is selected from B5) or B6), with a compound of formula (IVa)


W1—(O)C-y-Q (IVa)

wherein W1 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 Z2, by converting the compound obtained in the step 1c-i) into nitro derivative by reaction with a nitrate source as above described and
1c-iii) optionally deprotecting the compounds obtained in step 1c-i) or 1c-ii) as above described.

The reaction of a compound of formula (IIIb) wherein P2 and X3 are as above defined, with a compound of formula (IVa) wherein W1 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 P2 and X3 are as above defined, with a compound of formula (IVa) wherein W1 is ORa, 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—Ra, X1 is the radical selected from (a8′) or (b8′) wherein R1a is selected from A5) or A6), R2a is selected from B5) or B6) and wherein Y, Y′ and Q are as above defined and T′ and T″ are C(O), can be obtained from the corresponding acids (Ia) wherein W is —OH as known in the literature.

1d) The compounds of formula (Ia) wherein W is —OH, X1 is the radical selected from (a8′) or (b8′), wherein R1a is selected from A5) or A6), R2a 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)


P2—X3, (Ib)

wherein P2 is as above defined, X3, is the radical of formula


—C(O)—CH(R1a—H)—NH-(T′-Y-Q) (a8″)


—C(O)—CH2—CH(R2a—H)—NH-(T′-Y-Q) (b8′″)

wherein R1a is selected from A5) or A6), R2a is selected from B5) or B6), with a compound of formula (IVa)


W1—(O)C-y-Q (IVa)

wherein W1 and Q are as above defined, wherein y is the radical Y′, wherein Y′ is as above defined, and
1d-ii) when Q is Z2, by converting the compound obtained in the step 1d-i) into nitro derivative by reaction with a nitrate source as above described and
1d-iii) optionally deprotecting the compounds obtained in step 1d-i) or 1d-ii) as above described.

The reaction of a compound of formula (Ib) wherein P2 and X3, are as above defined, with a compound of formula (IVa) wherein W1 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 P2 and X3, are as above defined, with a compound of formula (IVa) wherein W1 is ORa, 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), P2 and X3, are as above defined, are obtained as described in 1a).

The compounds of formula (Ib) wherein T′ is C(O)—X″, P2 and X3, are as above defined, are obtained as described in 1b).

The compounds of formula (Ia) wherein W is —Cl or O—Ra′, X1 is the radical selected from (a8′) or (b8′) wherein R1a is selected from A5) or A6), R2a 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, X1 is the radical selected from (a8′) or (b8′), wherein R1a is selected from A5) or A6), R2a 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)


P2—X3 (IIIb)

wherein P2 and X3 are as above defined, with a compound of formula (IVd)


Ra—O—C(O)—X″-y-Q (IVd)

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

The reaction of a compound of formula (IIIb) wherein P2 and X3 are as above defined, with a compound of formula (IVd) wherein Ra, 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—Ra, X1 is the radical selected from (a8′) or (b8′) wherein R1a is selected from A5) or A6), R2a 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, X1 is selected from (a8′) or (b8′), wherein R1a is selected from A5) or A6), R2a 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)


P2—X3, (Ib)

wherein X3, and P2 are as above defined, with a compound of formula (IVd)


W1—O—C(O)—X″-y-Q (IVd)

wherein W1 and Q are as above defined, y is the radical Y′, wherein Y′ is as above defined, and
1f-ii) when Q is Z2, by converting the compound obtained in the step 1f-i) into nitro derivative by reaction with a nitrate source as above described and
1f-iii) optionally deprotecting the compounds obtained in step 1f-i) or 1f-ii) as above described.

The reaction of a compound of formula (Ib) wherein P2 and X3, are as above defined, with a compound of formula (IVd) wherein W1 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 P2 and X3, are as above defined, with a compound of formula (IVd) wherein W1 is ORa, 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), P2 and X3, are as above defined, are obtained as described in 1a).

The compounds of formula (Ib) wherein T′ is C(O)—X″, P2 and X3, are as above defined, are obtained as described in 1b).

The compounds of formula (Ia) wherein W is —Cl or O—Ra′, X1 is a radical selected from (a8′) or (b8′) wherein R1a is A5) or A6), R2a 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, X1 is a radical is selected from (a8′) or (b8′), wherein R1a is selected from A5), A6), R2a 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)


P2—X3, (Ib)

wherein P2 and X3, are as above defined, with a compound of formula


Ra—O—(O)C—NR′-y-Q (IVf)

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

The reaction of a compound of formula (Ib) wherein P2 and X3, are as above defined, with a compound of formula (IVf) wherein Ra, 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 P2 and X3, 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 P2 and X3, 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 Z2 is commercially available, the compounds of formula (IVg) wherein y is as above defined and Q is —ONO2 may be obtained from the compound of formula P3—R′N-y-ONO2 (IVh) wherein P3 is as above defined by deprotection of amino group as known in literature. The compounds of formula (IVh) wherein P3, y are as above defined may be obtained from the alcohol P3—R′N-y-OH (IVi) by reacting with tetraalkylammonium nitrate as already described for analogous compounds. The compounds of formula (IVi) are commercially available or known in literature. Alternatively the compounds of formula (IVh) wherein P3, y are as above defined may be obtained from the corresponding compounds of formula P3—R′N-y-Z2 (IVl) wherein P3, y, Z2 are as above defined, by reaction with a nitrate source as above described.

The compounds of formula (Ia) wherein W is —Cl or O—Ra, X1 is a radical selected from (a8′) or (b8′) wherein R1a is selected from A5) or A6), R2a 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, X1 is a radical selected from (a8′) or (b8′), wherein R1a is selected from A7), R2a 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
1h-i) by reacting a compound of formula (Ie),


P2—X5 (Ie)

wherein P2 is defined above, X5 is the radical of formula


—C(O)—CH(R1a—OH)—NH-(T′-Y-Q) (a8′″)


—C(O)—CH2—CH(R2a—OH)—NH-(T′-Y-Q) (b8′″)

wherein R1a is selected from A7), R2a 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
1h-ii) when Q is Z2, by converting the compound obtained in the step 1h-i) into nitro derivative by reaction with a nitrate source as above described and
1h-iii) optionally deprotecting the compounds obtained in step 1h-i) or 1h-ii) as above described.

The reaction of a compound of formula (Ie) wherein P2 and X5 are as above defined, with a compound of formula (IVe) wherein y, X″ and Q are as above defined, may be carried out as described in 1-i-1).

The compounds of formula (Ie) wherein T′ is C(O), wherein P2 and X5 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 P2 and X5 are as above defined, are obtained as described in 1b-i), 1b-ii).

The compounds of formula (Ia) wherein W is —Cl or O—Ra, X1 is a radical selected from (a8′) or (b8′) wherein R1a is selected from A7), R2a 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, X1 is a radical selected from (a8′) or (b8′), wherein R1a is selected from A7), R2a 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),


P2—X5 (Ie)

wherein is P2 and X5 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 Z2, by converting the compound obtained in the step 1i-i) into nitro derivative by reaction with a nitrate source such above described and
1i-iii) optionally deprotecting the compounds obtained in step 1i-i) or 1i-ii) as above described.

The reaction of a compound of formula (Ie) wherein P2 and X5 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—Ra, X1 is the radical selected from (a8′) or (b8′) wherein R1a is selected from A7), R2a 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, X1 is a radical selected from (a8′) or (b8′), wherein R1a is selected from A7), R2a 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),


P2—X5 (Ie)

wherein is P2 and X5 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 Z2, by converting the compound obtained in the step 1l-i) into nitro derivative by reaction with a nitrate source such above described and
1l-iii) optionally deprotecting the compounds obtained in step 1l-i) or 1l-ii) as above described.

The reaction of a compound of formula (Ie) wherein P5 and X5 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 CH2Cl2 at temperatures range between 0° to 100° C. or in a double phase system H2O/Et2O at temperatures range between 20° to 40° C.

The compounds of formula (IVm) wherein y, Q, R′ are as above defined, Hal is an halogen atom may be obtained by reacting a compound R′—CH2—CHO, commercially available, with a compound of formula Hal-(O)C-y-Q (IVn), wherein y and Q are as above defined, Hal is a chlorine atom and ZnCl2 as known in literature.

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

The compounds of formula (Ia) wherein W is —Cl or O—Ra, X1 is a radical selected from (a8′) or (b8′) wherein R1a is selected from A7), R2a 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, X1 is a radical selected from (a8′) or (b8′), wherein R1a is selected from A7), R2a 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),


P2—X5 (Ie)

wherein is P2 and X5 are defined above, with a compound of formula (IVo)


Hal-CH(R′)—O—(O)C—O-y-Q (IVo)

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

The reaction of a compound of formula (Ie) wherein P2 and X5 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 CH2Cl2 at temperatures range between 0° to 65° C.

The compounds of formula (Ia) wherein W is —Cl or O—Ra, X1 is a radical selected from (a8′) or (b8′) wherein R1a selected from A7), R2a 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, X1 is a radical selected from (a4′) or (b4′), wherein R1a is selected from A7), R2a is selected from B7), Y′, Q and R4a′ are as above defined and T″ is X″ wherein X″ is as above defined, can be obtained
1n-i) by reacting a compound of formula (IIIc)


P2—X5, (IIIc)

wherein P2 is defined above, X5′ is


—C(O)—CH(R1a—OH)—NHR4a′ (a4″)


—C(O)—CH2—CH(R2a—OH)—NHR4a′ (b4″)

wherein R1a is selected from A7), R2a is selected from B7) and P3 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 Z2, by converting the compound obtained in the step 1n-i) into nitro derivative by reaction with a nitrate source as above described and
1n-iii) optionally deprotecting the compounds obtained in step 1n-i) or 1n-ii) as above described.

The reaction of a compound of formula (IIIc) wherein X5′ and P2 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 X5′ and P2 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—Ra, X1 is a radical selected from (a4′) or (b4′), wherein R1a is selected from A7), R2a 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.

1o) The compounds of formula (Ia) wherein W is —OH, X1 is a radical selected from (a4′) or (b4′), wherein R1a is selected from A7), R2a is selected from B7), Y′, Q and R4a′ are as above defined and T″ is —NR′ wherein R′ is as above defined, can be obtained
1o-i) by reacting a compound of formula (IIIc)


P2—X5, (IIIc)

wherein P2 and X5, are as above defined, with a compound of formula (IVg)


HR′N-y-Q (IVg)

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

The reaction of a compound of formula (IIIc) wherein X5, and P2 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 —ORa, X1 is a radical selected from (a4′) or (b4′), wherein R1a is selected from A7), R2a 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, X1 is a radical selected from (a4′) or (b4′), wherein R1a is selected from A7), R2a is selected from B7), Y′, Q and R4a′ are as above defined and T″ is —O—CH(R′)—O—C(O), wherein R′ is as above defined, can be obtained
1p-i) by reacting a compound of formula (IIIc)


P2—X5, (IIIc)

wherein P2 and X5, are as above defined, with a compound of formula (IVm)


Hal-CH(R′)—O—(O)C-y-Q (IVm)

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

The reaction of a compound of formula (IIIc) wherein P2 and X5, are as above defined, with a compound of formula (IVm) wherein R′, y, Q, Hal are as above defined, may be carried out as described in 1l-1).

The compounds of formula (Ia) wherein W is —Cl or ORa, X1 is a radical selected from (a4′) or (b4′), wherein R1a is selected from A7), R2a 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.

1q) The compounds of formula (Ia) wherein W is —OH, X1 is a radical selected from (a4′) or (b4′), wherein R1a is selected from A7), R2a is selected from B7), Y′, Q and R4a′ are as above defined and T″ is —O—CH(R′)—O—C(O)—O—, wherein R′ is as above defined, can be obtained
1q-i) by reacting a compound of formula (IIIc)


P2—X5, (IIIc)

wherein P2 and X5, are as above defined, with a compound of formula (IVo)


Hal-CH(R′)—O—(O)C—O-y-Q (IVo)

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

The reaction of a compound of formula (IIIc) wherein P2 and X5, 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 ORa, X1 is a radical selected from (a4′) or (b4′), wherein R1a is selected from A7), R2a 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 Rx is the radical selected from (a2), (a4), (a8), (b2), (b4), (b8), (c2), (e2), (f1), (g2), (h1), (i1), (12), (m2), (n2), (o2), (p2), (q2), (r2), (s2), (t2), (u2), (v2), Z is —CH(R′)—O— wherein R′ is selected from H or straight or branched C1-C4 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—X1 (If)

wherein Hal is an halogen atom, R′ and X1 are as above defined and
2-ii) when Q is Z2, by converting the compound obtained in the step 2-i) into nitro derivative by reaction with a nitrate source as above described and
2-iii) optionally deprotecting the compounds obtained in step 2-i) or 2-ii) as above described.

The reaction of a compound of formula (If) wherein X1 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 (If) are obtained by reacting a compound R′—CHO, wherein R′ is as above defined with compounds of formula (Ia)


W—X1 (Ia)

wherein W is a chlorine atom, X1 is as above defined, and ZnCl2 as known in literature.
3) The compound of general formula (I) as above defined wherein a is equal to 1, the radical Rx is selected from (a1), (a3), (a7), (b1), (b3), (b7), (c1), (e1), (f2), (g1), (h2), (i2), (11), (m1), (n1), (01), (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—Ra (IIb)

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


H—X2 (Ig)

wherein X2 is a radical having the following meanings:


—HN—CH(R1′)—C(O)-(T-Y-Q) (a1′)


—HN—CH(R1a-T″-Y′-Q)-COOR3a′ (a3′)


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


—HN—CH(R2′)—CH2C(O)-(T-Y-Q) (b1′)


—HN—CH(R2a-T″-Y′-Q)-CH2COOR2a′ (b3′)


—HN—CH(R2a-T″-Y′-Q)-CH2—C(O)-(T-Y-Q) (b7′)

wherein R1′, R1a, R2′, R2a are as above defined R3a′ is selected from P2, —OR5a or

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wherein R5a is as above defined;


—HN—(CH2)b—C(O)-(T-Y-Q); (c1′)

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wherein T, T″, Y and Y′ are as above defined,
3-ii) when Q is Z2, by converting the compound obtained in the step 3-i) into nitro derivative by reaction with a nitrate source such above described and
3-iii) optionally deprotecting the compounds obtained in step 3-i) or 3-ii) as above described.

The reaction of a compound of formula (IIb) wherein R and Ra are as above defined, with a compound of formula (Ig) wherein X1 is as above defined, may be carried out as described in 1-i-2).

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

3a) The compounds of formula (Ig) wherein X2 is selected from (a1′), (a3′), (b1′), (b3′), (c1′), (e1′), (f2′), (g1′), (h2′), (i2′), (11′), (m1′), (n1′), (o1′), (p1′), (q1′), (r1′), (s1′), (t1′), (u1′), (v1′), wherein R′ is selected from A1), A2′), A3′), A4′), R1a is selected from A7), R2a is selected from B7) and R2′ is selected from B1), B2′), B3′), B4′), Y and Y′ are as above defined, T and T″ are X″ wherein X″ is as above defined may be obtained
3a-i) by reacting a compound of formula (IIIe),


P3—X6 (IIIe)

wherein P3 is as above defined, X6 is a radical having the following meanings:


—HN—CH(R1′)—C(O)—OH (a1″)


—HN—CH(R1a—OH)—COOR3a′ (a3″)


—HN—CH(R2′)—CH2C(O)—OH (b1″)


—HN—CH(R2a—OH)—CH2COOR3a′ (b3″)

wherein R1′ is selected from A1), A2′), A3′), A4′), selected from A7), R2a is selected from B7) and R2′ is selected from B1), B2′), B3′), B4′), and R3a′ is defined above


—HN—(CH2)b—C(O)—OH; (c1″)

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with a compound of formula (IVe)


HX″-y-Q (IVe)

wherein Q and X″ are as above defined y is the radical Y when X6 is selected from (a1′), (b1′), (c1′), (e1′), (f2′), (g1′), (h2′), (i2′), (11′), (m1′), (n1′), (o1′), (p1′), (q1′), (r1′), (s1′), (t1′), (u1′) and (v1′), y is the radical Y′ when X6 is selected from (a3′) and (b3′), wherein Y and Y′ are as defined above, and
3a-ii) when Q is Z2, by converting the compound obtained in the step 3a-i) into nitro derivative by reaction with a nitrate source as above described and
3a-iii) optionally deprotecting the compounds obtained in step 3a-i) or 3a-ii) as above described.

The reaction of a compound of formula (IIIe) wherein P3 and X6 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 X2 is selected from (a1′), (a3′), (b1′), (b3′), (c1′), (e1′), (f2′), (g1′), (h2′), (i2′), (11′), (m1′), (n1′), (o1′), (p1′), (q1′), (r1′), (s1′), (t1′), (u1′), (v1′), wherein R′ is selected from A1), A2′), A3′), A4′), R1a is selected from A7), R2a is selected from B7) and R2′ is selected from B1), B2′), B3′), B4′), and R3a′, Y and Y′ are as above defined, T and T″ are —NR′ wherein R′ is as above defined may be obtained
3b-i) by reacting a compound of formula (IIIe),


P3—X6 (IIIe)

wherein P3 and X6 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 X6 is selected from (a1′), (b1′), (c1′), (e1′), (f2′), (g1′), (h2′), (i2′), (11′), (m1′), (n1′), (o1′), (p1′), (q1′), (r1′), (s1′), (t1′), (u1′) and (v1′), y is the radical Y′ when X6 is selected from (a3′) and (b3′), wherein Y and Y′ are as defined above, and
3b-ii) when Q is Z2, by converting the compound obtained in the step 3b-i) into nitro derivative by reaction with a nitrate source as above described and
3b-iii) optionally deprotecting the compounds obtained in step 3b-i) or 3b-ii) as above described.

The reaction of a compound of formula (IIIe) wherein P3 and X6 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 X2 is selected from (a1′), (a3′), (b1′), (b3′), (c1′), (e1′), (f2′), (g1′), (h2′), (i2′), (11′), (m1′), (n1′), (o1′), (p1′), (q1′), (r1′), (s1′), (t1′), (u1′), (v1′), wherein R1a is selected from A1), A2′), A3′), A4′), R1a is selected from A7), R2a is selected from B7) and R2′ is selected from B1), B2′), B3′), B4′), and R3a′, Y and Y′ are as above defined, T and T″ are —O—CH(R′)—O—C(O)—, wherein R′ is as above defined, may be obtained
3c-i) by reacting a compound of formula (IIIe)


P3—X6 (IIIe)

wherein P3, X6 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 X6 is selected from (a1′), (b1′), (c1′), (e1′), (f2′), (g1′), (h2′), (i2′), (11′), (m1′), (n1′), (o1′), (p1′), (q1′), (r1′), (s1′), (t1′), (u1′) and (v1′), y is the radical Y′ when X6 is selected from (a3′) and (b3′), wherein Y and Y′ are as defined above, and
3c-ii) when Q is Z2, by converting the compound obtained in the step 3c-i) into nitro derivative by reaction with a nitrate source as above described and
3c-iii) optionally deprotecting the compounds obtained in step 3c-i) or 3c-ii) as above described.

The reaction of a compound of formula (IIIe) wherein P3 and X6 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 X2 is selected from (a1′), (a3′), (b1′), (b3′), (c1′), (e1′), (f2′), (g1′), (h2′), (i2′), (11′), (m1′), (n1′), (o1′), (p1′), (q1′), (r1′), (s1′), (t1′), (u1′), (v1′), wherein R1a is selected from A1), A2′), A3′), A4′), R1a is selected from A7), R2a is selected from B7) and R2′ is selected from B1), B2′), B3′), B4′), and R3a′, Y and Y′ are as above defined, T and T″ are —O—CH(R′)—O—C(O)O— wherein R′ is as above defined may be obtained
3d-i) by reacting a compound of formula (IIIe)


P3—X6 (IIIe)

wherein P3 and X6 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 X6 is selected from (a1′), (b1′), (c1′), (e1′), (f2′), (g1′), (h2′), (i2′), (11′), (m1′), (n1′), (o1′), (p1′), (q1′), (r1′), (s1′), (t1′), (u1′) and (v1′), y is the radical Y′ when X6 is selected from (a3′) and (b3′), wherein Y and Y′ are as defined above, and
3d-ii) when Q is Z2, by converting the compound obtained in the step 3d-i) into nitro derivative by reaction with a nitrate source as above described and
3d-iii) optionally deprotecting the compounds obtained in step 3d-i) or 3d-ii) as above described.

The reaction of a compound of formula (IIIe) wherein P3 and X6 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 X2 is selected from (a7′) or (b7′) wherein R1a is selected from A5) or A6), R1b 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)


P3-X7 (Ih)

wherein P3 is as above defined and X7 is the radical having the following meaning


—HN—CH(R1a—H)—C(O)-(T-Y-Q) (a7″)


—HN—CH(R2a—H)—CH2—C(O)-(T-Y-Q) (b7″)

wherein R1a is selected from A5) or A6), R2a is selected from B5) or B6), with compounds of formula (IVa)


W1—C(O)—Y-Q (IVa)

wherein W1 and Q are as above defined, y is the radical Y′, wherein Y′ is as above defined, and
3e-ii) when Q is Z2, by converting the compound obtained in the step 3e-i) into nitro derivative by reaction with a nitrate source as above described and
3e-iii) optionally deprotecting the compounds obtained in step 3e-i) or 3e-ii) as above described.

The reaction of a compound of formula (Ih) wherein P3 and X7 are as above defined, with a compound of formula (IVa) wherein y, Q, W1 are as above defined may be carried out as described in 1-i-1), 1-i-2), 1-i-3) and 1a-i).

The compounds of formula (Ih) wherein P3 and X7 are as above defined, T is —X″ are obtained as described in 3a).

The compounds of formula (Ih) wherein P3 and X7 are as above defined, T is —NR′ are obtained as described in 3b).

The compounds of formula (Ih) wherein P3 and X7 are as above defined, T is —O—CH(R′)—O—C(O)— are obtained as described in 3c).

The compounds of formula (Ih) wherein P3 and X7 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 X2 is selected from (a7′) or (b7′) wherein R1a is selected from A5) or A6), R1b 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)


P3—X7 (Ih)

wherein P3 and X7 are as above defined with compounds of formula (IVd)


Ra—O—C(O)—X″-y-Q (IVd)

wherein Ra, X″ and Q are as above defined, y is the radical Y′, wherein Y′ is as above defined, and
3f-ii) when Q is Z2, by converting the compound obtained in the step 3f-i) into nitro derivative by reaction with a nitrate source as above described and
3f-iii) optionally deprotecting the compounds obtained in step 3e-i) or 3f-ii) as above described.

The reaction of a compound of formula (Ih) wherein P3 and X7 are as above defined, with a compound of formula (IVd) wherein y, Q, Ra are as above defined, may be carried out as described in 1-i-2).

3g) The compounds of formula (Ig) wherein X2 is selected from (a7′) or (b7′) wherein R1a is selected from A5), A6), R1b 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)


P3—X7 (Ih)

wherein P3 and X7 are as above defined, with compounds of formula (IVf)


Ra—O—C(O)—NR′-y-Q (IVf)

wherein Ra and Q are as above defined, y is the radical Y′, wherein Y′ is as above defined, and
3g-ii) when Q is Z2, by converting the compound obtained in the step 3g-i) into nitro derivative by reaction with a nitrate source as above described and
3g-iii) optionally deprotecting the compounds obtained in step 3g-i) or 3g-ii) as above described.

The reaction of a compound of formula (Ih) wherein P3 and X7 are as above defined, with a compound of formula (IVf) wherein y, Q, Ra and R′ are as above defined may be carried out as described in 1-i-2).

The compounds of formula (Ih) wherein P3 and X7 are as above defined, T is —X″ are obtained as described in 3a).

The compounds of formula (Ih) wherein P3 and X7 are as above defined, T is —NR′ are obtained as described in 3b).

The compounds of formula (Ih) wherein P3 and X7 are as above defined, T is —O—CH(R′)—O—C(O)— are obtained as described in 3c).

The compounds of formula (Ii) wherein P3 and X7 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 X2 is selected from (a7′) or (b7′) wherein R1a is selected from A7), R1b 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)


P3—X2 (Iv)

wherein P3 is as above defined and X8 is the radical having the following meaning


—HN—CH(R1a—H)—C(O)-(T-Y-Q) (a7″)


—HN—CH(R2a—H)—CH2—C(O)-(T-Y-Q) (b7″)

wherein R1a is selected from A7), R1b is selected from B7), with compounds of formula (IVe)


H—X″-y-Q (IVe)

wherein X″ and Q are as above defined, y is the radical Y′, wherein Y′ is as above defined, and
3h-ii) when Q is Z2, by converting the 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 P3 and X8 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 P3 and X8 are as above defined, T is —X″ are obtained as described in 3a).

The compounds of formula (Iv) wherein P3 and X8 are as above defined, T is —NR′ are obtained as described in 3b).

The compounds of formula (Iv) wherein P3 and X8 are as above defined, T is —O—CH(R′)—O—C(O)— are obtained as described in 3c).

The compounds of formula (Iv) wherein P3 and X8 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 X2 is selected from (a7′) or (b7′) wherein R1a is selected from A7), R1b 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)


P3—X2 (Iv)

wherein P3 and X8 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 Z2, by converting the compound obtained in the step 3i-i) into nitro derivative by reaction with a nitrate source as above described and
3i-iii) optionally deprotecting the compounds obtained in step 3i-i) or 3i-ii) as above described.

The reaction of a compound of formula (Iv) wherein P3 and X8 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 X2 is selected from (a7′) or (b7′) wherein R1a is selected from A7), R1b 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)


P3—X8 (Iv)

wherein P3 and X8 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, y is the radical Y′, wherein Y′ is as above defined, Hal is an halogen atom and 3l-ii) when Q is Z2, by converting the compound obtained in the step 3l-i) into nitro derivative by reaction with a nitrate source as above described and
3l-iii) optionally deprotecting the compounds obtained in step 3l-i) or 3l-ii) as above described.

The reaction of a compound of formula (Iv) wherein P3 and X8 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 X2 is selected from (a7′) or (b7′) wherein R1a is selected from A7), R1b 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)


P3—X2 (Iv)

m wherein P3 and X8 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 Z2, by converting the compound obtained in the step 3m-i) into nitro derivative by reaction with a nitrate source as above described and
3m-iii) optionally deprotecting the compounds obtained in step 3l-i) or 3m-ii) as above described.

The reaction of a compound of formula (Iv) wherein P3 and X8 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 X2 is selected from (a3′) or (b3′), wherein R1a is selected from A5) or A6), R2a 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),


P3—X9 (IIIf)

wherein P3 is as above defined, X9 is a radical having the following meaning


—HN—CH(R1a—H)—COOR3a′ (a3″)


—HN—CH(R2a—H)—CH2COOR3a′ (b3″)

wherein R1a is selected from A5 or A6) and R2a is selected from B5) or B6), wherein R3a′ is as above defined, with compounds of formula (IVa)


W1—C(O)—Y-Q (IVa)

wherein W1 and Q are as above defined, y is the radical Y′, wherein Y′ is as above defined, and
3n-ii) when Q is Z2, by converting the compound obtained in the step 3n-i) into nitro derivative by reaction with a nitrate source as above described and
3n-iii) optionally deprotecting the compounds obtained in step 3n-i) or 3n-ii) as above described.

The reaction of a compound of formula (IIIf) wherein P3 and X9 are as above defined, with a compound of formula (IVa) wherein W1, y, Q are as above defined, may be carried out as described in 1-i-1), 1-i-2), 1a-1).

The compounds of formula (IIIf) wherein P3 and X9 are as above defined, is commercially available or obtained as known in literature.

3o) The compounds of formula (Ig) wherein X2 is selected from (a3′) or (b3′), wherein R1a is selected from A5) or A6), R2a 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)


P3—X9 (IIIf)

wherein P3 and X9 are as above defined with compounds of formula (IVd)


Ra—O—C(O)—X″-y-Q (IVd)

wherein Ra, X″, Q are as above defined, y is the radical Y′, wherein Y′ is as above defined, and
3o-ii) when Q is Z2, by converting the compound obtained in the step 3o-i) into nitro derivative by reaction with a nitrate source as above described and
3o-iii) optionally deprotecting the compounds obtained in step 3o-i) or 3o-ii) as above described.

The reaction of a compound of formula (IIIf) wherein P3 and X9 are as above defined, with a compound of formula (IVd) wherein Ra, X″, y, Q are as above defined, may be carried out as described in 1-i-2).

3p) The compounds of formula (Ig) wherein X2 is selected from (a3′) or (b3′), wherein R1a is selected from A5) or A6), Rea 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),


P3—X9 (IIIf)

wherein P3 and X9 are as above defined, with compounds of formula (IVf)


Ra—O—(O)C—NR′-y-Q (IVf)

wherein Ra, R′ and Q are as above defined, y is the radical Y′, wherein Y′ is as above defined, and
3p-ii) when Q is Z2, by converting the compound obtained in the step 3p-i) into nitro derivative by reaction with a nitrate source as above described and
3p-iii) optionally deprotecting the compounds obtained in step 3p-i) or 3p-ii) as above described.

The reaction of a compound of formula (IIIf) wherein P3 and X9 are as above defined, with a compound of formula (IVf) wherein Ra, 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 Rx 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—Ra (IIb)

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


H—X12 (Im)

wherein X12 is the radical Rx having the following meaning


—HN—CH(R12′)—CH2—O-(T′″-Y-Q) (d1′)


—O—CH2—CH(R12′)—NH-(T′-Y-Q) (d2′)


—HN—CH(R12a-T″-Y′-Q)-CH2OH (d3′)


—O—CH2—CH(R12a-T′″-Y′-Q)-NHR4a (d4′)


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


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

wherein R12′ is

D1),

D2′) —CH2—OP1, —CH(CH3)—OP1, —CH2[(C6H4)-4-OP1], —CH2-[(C6H3)-(3,5-diiodo)-4-OP1], —CH2-[(C6H3)-3-nitro-4-OP1];
D3′) —CH2—NHR″″, —(CH2)2—NHR″″, —(CH2)3—NHR″″, —(CH2)4—NHR″″, wherein R″″ is as above defined;
D4′) —CH2—C(O)R′″″, —(CH2)2—C(O)R″″, —(CH2)4—C(O)R″″, wherein R′″″ is as above defined;
wherein R12a is as above defined;
and
4-ii) when Q is Z2, by converting the compound obtained in the step 4-i) into nitro derivative by reaction with a nitrate source as above described and
4-iii) optionally deprotecting the compounds obtained in step 4-i) or 4-ii) as above described.

The reaction of a compound of formula (IIb) wherein R and Ra are as above defined, with a compound of formula (Im) wherein X12 is as above defined, may be carried out as described in 1-i-2).

4a) The compound of formula (Im) wherein X12 is selected from (d1′), (d2′), (d3′) or (d4′) wherein R12′ is selected from D1), D2′), D3′) or D4′) and R12a 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),


P4—X13 (IIIi)

wherein P4 is P3 or P1 as above defined and X13 is a radical having the following meaning


—HN—CH(R12′)—CH2—OH (d1″)


—O—CH2—CH(R12′)—NH2 (d2″)


—HN—CH(R12a—H)—CH2OP1 (d3″)


—O—CH2—CH(R12a—H)—NHR4a′ (d4″)

wherein R12′ is D1), D2′), D3′) or D4′), R12a is D5) or D6), R4a′ and P1 are as above defined, with a compound of formula (IVa)


W1—(O)C-y-Q (IVa)

wherein Q and W1 are as above defined, y is the radical Y when X13 is selected from (d1′) or (d2′), y is the radical Y′ when X13 is selected from (d3′) or (d4′), wherein Y and Y′ are as above defined, and
4a-ii) when Q is Z2, by converting the compound obtained in the step 4a-i) into nitro derivative by reaction with a nitrate source as above described and
4a-iii) optionally deprotecting the compounds obtained in step 4a-i) or 4a-ii) as above described.

The reaction of a compound of formula (IIIi) wherein X13 and P4 are as above defined, with a compound of formula (IVa) wherein W1, y and Q are as above defined, may be carried out as described in 1-i-1) and 1-i-2).

The compounds of formula (IIIi) wherein X13 and P4 are as above described, are commercially available or known in literature.

4b) The compound of formula (Im) wherein X12 is selected from (d1′), (d2′), (d3′) or (d4′) wherein R12′ is selected from D1), D2′), D3′) or D4′) and R12a 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),


P4—X13 (IIIi)

wherein P4 and X13 are defined above, with a compound of formula (IVd)


Ra—O—(O)C—X″-y-Q (IVd)

wherein Q, Ra and X″ are as above defined, y is the radical Y when X13 is selected from (d1′) or (d2′), y is the radical Y's when X13 is selected from (d3′) or (d4′), wherein Y and Y′ are as above defined, and
4b-ii) when Q is Z2, by converting the compound obtained in the step 4b-i) into nitro derivative by reaction with a nitrate source as above described and
4b-iii) optionally deprotecting the compounds obtained in step 4b-i) or 4b-ii) as above described.

The reaction of a compound of formula (IIIi) wherein X13 and P4 are as above defined, with a compound of formula (IVd) wherein y, Q, Ra and X″ are as above defined, may be carried out as described in 1-i-2).

4c) The compound of formula (Im) wherein X12 is selected from (d7′) or (d8′) wherein R12a 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),


P4—X14 (IIIl)

wherein P4 is P1 or P3, X14 is the radical having the following meaning


—HN—CH(R12a—H)—CH2—OH (d7″)


—O—CH2—CH(R12a—H)—NH2 (d8″)

wherein R12a is selected from D5) or D6), with a compound of formula (IVa)


W1—(O)C-y-Q (IVa)

wherein W1 and Q are as above defined, y is the radical Y′, wherein Y′ is as above defined, and
4c-ii) when Q is Z2, by converting the compound obtained in the step 4c-i) into nitro derivative by reaction with a nitrate source as above described and
4c-iii) optionally deprotecting the compounds obtained in step 4c-i) or 4c-ii) as above described.

The reaction of a compound of formula (IIIl) wherein P4 and X14 are as above defined, with a compound of formula (IVa) wherein W1 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 P4 and X14 are as above defined, with a compound of formula (IVa) wherein W1 is ORa, 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 P4 and X14 are as above described, are commercially available or known in literature.

4d) The compound of formula (Im) wherein X12 is selected from (d7′) or (d8′) wherein R12a 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)


P4—X15 (In)

wherein P4 is defined above and X15 is the radical having the following meaning


—HN—CH(R12a—H)—CH2—O-(T′″-Y-Q) (d7′″)


—O—CH2—CH(R12a—H)—NH-(T′-Y-Q) (d8′″)

wherein R12a is selected from D5) or D6), Y, Q, T′ and T′″ are as above defined, with a compound of formula (IVa)


W1—(O)C-y-Q (IVa)

wherein W1, y and Q′ are as above defined, y is the radical Y′, wherein Y′ is as above defined, and
4d-ii) when Q is Z2, by converting the compound obtained in the step 4d-i) into nitro derivative by reaction with a nitrate source as above described and
4d-iii) optionally deprotecting the compounds obtained in step 4d-i) or 4d-ii) as above described.

The reaction of a compound of formula (In) wherein P4 and X15 are as above defined, with a compound of formula (IVa) wherein W1 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 P4 and X15 are as above defined, with a compound of formula (IVa) wherein W1 is ORa, y and Q are as above defined, may be carried out as described in 1-i-2).

The compounds of formula (In) wherein P4 and X15 are as above defined, T′ and T′″ are —C(O)— can by obtained as described in 4a).

4e) The compound of formula (Im) wherein X12 is selected from (d7′) or (d8′) wherein R12a 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)


P4X15 (In)

wherein P4 and X15 are defined above, with a compound of formula (IVa)


W1—(O)C-y-Q (IVa)

wherein W1, y and Q are as above defined, y is the radical Y′, wherein Y′ is as above defined, and
4e-ii) when Q is Z2, by converting the compound obtained in the step 1e-i) into nitro derivative by reaction with a nitrate source as above described and
4e-iii) optionally deprotecting the compounds obtained in step 4e-i) or 4e-ii) as above described.

The reaction of a compound of formula (In) wherein P4 and X15 are as above defined, with a compound of formula (IVa) wherein W1 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 P4 and X15 are as above defined, with a compound of formula (IVa) wherein W1 is ORa, y and Q are as above defined, can by carried out as described in 1-i-2).

The compounds of formula (In) wherein P4 and X15 are as above defined can by obtained as described in 4b).

4f) The compound of formula (Im) wherein X12 is selected from (d7′) or (d8′) wherein R12a 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),


P4—X14 (IIIl)

wherein P4 and X14 are as above defined, with a compound of formula (IVd)


Ra—O—C(O)—X″-y-Q (IVd)

wherein Ra, X″ and Q are as above defined, y is the radical Y′, wherein Y′ is as above defined, and
4f-ii) when Q is Z2, by converting the compound obtained in the step 4f-i) into nitro derivative by reaction with a nitrate source as above described and
4f-iii) optionally deprotecting the compounds obtained in step 4f-i) or 4f-ii) as above described.

The reaction of a compound of formula (IIIl) wherein P4 and X14 are as above defined, with a compound of formula (IVd) wherein Ra, 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 X12 is selected from (d7′) or (d8′) wherein R12a 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)


P4X15 (In)

wherein P4 and X15 are as above defined, with a compound of formula (IVd)


Ra—O—C(O)—X″-y-Q (IVd)

wherein Ra, X″ and Q are as above defined, y is the radical Y′, wherein Y′ is as above defined, and
4g-ii) when Q is Z2, by converting the compound obtained in the step 4g-i) into nitro derivative by reaction with a nitrate source as above described and
4g-iii) optionally deprotecting the compounds obtained in step 4g-i) or 4g-ii) as above described.

The reaction of a compound of formula (In) wherein P4 and X15 are as above defined, with a compound of formula (IVd) wherein Ra, 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), P4 and X15 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 P4 and X15 are as above defined are obtained as described in 4b-i), 4b-ii).

4h) The compound of formula (Im) wherein X12 is selected from (d7′) or (d8′) wherein R12′ 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)


P4—X15 (In)

wherein P4 and X15 are as above defined, with a compound of formula


Ra—O—(O)C—NR′-y-Q (IVf)

wherein Ra, R′ and Q are as above defined, y is the radical Y′, wherein Y′ is as above defined, and
4h-ii) when Q is Z2, by converting the compound obtained in the step 4h-i) into nitro derivative by reaction with a nitrate source as above described and
4h-iii) optionally deprotecting the compounds obtained in step 4h-i) or 4h-ii) as above described.

The reaction of a compound of formula (In) P4 and X15 are as above defined, with a compound of formula (IVf) wherein Ra, 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 P4 and X15 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 P4 and X15 are as above defined, are obtained as described in 4b-i), 4b-ii).

4i) The compound of formula (Im) wherein X12 is selected from (d7′) or (d8′) wherein R12a 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),


P4—X16 (Ir)


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


—O—CH2—CH(R12a—OH)—NH-(T′-Y-Q) (d8″″)

wherein P4 is as above defined, R12a 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 Z2, by converting the compound obtained in the step 4i-i) into nitro derivative by reaction with a nitrate source as above described and
4i-iii) optionally deprotecting the compounds obtained in step 4i-i) or 4i-ii) as above described.

The reaction of a compound of formula (Ir) wherein P4 and X16 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), P4 and X16 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″, P4 and X16 are as above defined, are obtained as described in 4b-i), 4b-ii).

41) The compound of formula (Im) wherein X12 is selected from (d7′) or (d8′) wherein R12a 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),


P4—X16 (Ir)

wherein P4 and X16 are as above defined and R12a 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 Z2, by converting the compound obtained in the step 4l-i) into nitro derivative by reaction with a nitrate source such above described and
4l-iii) optionally deprotecting the compounds obtained in step 4l-i) or 4l-ii) as above described.

The reaction of a compound of formula (Ir) P4 and X16 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-4m) The compound of formula (Im) wherein X12 is selected from (d7′) or (d8′) wherein R12′ 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),


P4—X16 (Ir)

wherein P4 and X16 are as above defined and R12a 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
4m-ii) when Q is Z2, by converting the compound obtained in the step 4m-i) into nitro derivative by reaction with a nitrate source such above described and
4m-iii) optionally deprotecting the compounds obtained in step 4m-i) or 1m-ii) as above described.

The reaction of a compound of formula (Ir) wherein P4 and X16 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 X12 is selected from (d7′) or (d8′) wherein R12′ 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),


P4—X16 (Ir)

wherein P4 and X16 are as above defined and R12′ 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 Z2, by converting the compound obtained in the step 4n-i) into nitro derivative by reaction with a nitrate source as above described and
4n-iii) optionally deprotecting the compounds obtained in step 4n-i) or 4n-ii) as above described.

The reaction of a compound of formula (Ir) wherein P4 and X16 are as above defined, with a compound of formula (IVo) wherein y, R′, Q, Hal are as above defined, may be carried out as described in 1l-i).

4o) The compound of formula (Im) wherein X12 is (selected from d3′) or (d4′) wherein R12a 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),


P4X17 (IIIm)

wherein P4 is defined above and X17 is the radical


—HN—CH(R12a—H)—CH2OP1 (d3″)


—O—CH2—CH(R12a—H)—NHR4a′ (d4″)

wherein R12a is selected from D7), wherein P1 and R4a′ are as above defined, with a compound of formula (IVe)


HX″-y-Q (IVe)

wherein X″ and Q are as above defined, y is the radical Y′, wherein Y′ is as above defined, and
4o-ii) when Q is Z2, by converting the compound obtained in the step 4o-i) into nitro derivative by reaction with a nitrate source as above described and
4o-iii) optionally deprotecting the compounds obtained in step 4o-i) or 4o-ii) as above described.

The reaction of a compound of formula (IIIm) wherein P4 and X17 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 P4 and X17 are as above defined, are commercially available or obtained as known in literature.

4p) The compound of formula (Im) wherein X12 is selected from (d3′) or (d4′) wherein R12a 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),


P4—X17 (IIIm)

wherein P4 and X17 are as defined above, wherein R12a 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 Z2, by converting the compound obtained in the step 4p-i) into nitro derivative by reaction with a nitrate source such above described and
4p-iii) optionally deprotecting the compounds obtained in step 4p-i) or 4p-ii) as above described.

The reaction of a compound of formula (IIIm) wherein P4 and X17 are as above defined, with a compound of formula (IVg) wherein R′, y, Q are as above defined, may be carried out as described in 1a-i).

4q) The compound of formula (Im) wherein X12 is selected from (d3′) or (d4′) wherein R12a 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),


P4—X17 (IIIm)

wherein P4 and X17 are as defined above, wherein R12a 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 Z2, by converting the compound obtained in the step 4q-i) into nitro derivative by reaction with a nitrate source such above described and
4q-iii) optionally deprotecting the compounds obtained in step 4q-i) or 4q-ii) as above described.

The reaction of a compound of formula (IIIm) wherein P4 and X17 are as above defined, with a compound of formula (IVm) wherein R′, y, Q are as above defined, may be carried out as described in 1l-i).

4r) The compound of formula (Im) wherein X12 is selected from (d3′) or (d4′) wherein R12a 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),


P4—X17 (IIIm)

wherein P4 and X17 are as defined above, wherein R12a 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 Z2, by converting the compound obtained in the step 4r-i) into nitro derivative by reaction with a nitrate source as above described and
4r-iii) optionally deprotecting the compounds obtained in step 4r-i) or 4r-ii) as above described.

The reaction of a compound of formula (IIIm) wherein P4 and X17 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, Rx is a radical selected from (d5), (d6), (d9) or (d10), wherein R12b 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—X18 (Is)

wherein W is as above defined, X18 is the radical having the following meanings


—R12b—CH(NHR4a)—CH2—O-(T′″-Y-Q) (d5′)


—R12b—CH(CH2OH)—NH-(T′-Y-Q) (d6′)


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


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

wherein R12b is selected from D10), T′, T′″, Y, Y′ and Q are as above defined and
5-ii) when Q is Z2, by converting the compound obtained in the step 5-i) into nitro derivative by reaction with a nitrate source as above described and
5-iii) optionally deprotecting the compounds obtained in step 5-i) or 5-ii) as above described.

The reaction of a compound of formula (IIa) wherein R is as above defined, with a compound of formula (Is) wherein W and X18 are as above defined may be carried out as described in 1).

5a) The compounds of formula (Is) wherein X18 is a radical of formula (d5′) or (d6′), wherein R12b is selected from D10), T′ and T′″ are C(O) can be obtained
5a-i) by reacting a compound of formula (IIIn),


P2—X19 (IIIn)

wherein P2 is as above defined, X19 is the radical having the following meanings


—R12b—CH(NHP3)—CH2—OH (d5″)


—R12b—CH(CH2OP1)—NH2 (d6″)

wherein P1 and P3 are as above defined and R12b is selected from D10), with a compound of formula (IVa)


W1—C(O)—Y-Q (IVa)

wherein W1, y, Q are as above defined, y is the radical Y, wherein Y is as above defined, and
5a-ii) when Q is Z2, by converting the compound obtained in the step 5a-i) into nitro derivative by reaction with a nitrate source as above described and
5a-iii) optionally deprotecting the compounds obtained in step 5a-i) or 5a-ii) as above described.

The reaction of a compound of formula (IIIn) wherein P2 and X19 are as above defined, with a compound of formula (IVa) W1, y, and Q are as above defined may be carried out as described in 1-i-1), 1-i-2), 1-i-3) and 1a-1).

The compounds of formula (IIIn), wherein P2 and X19 are as above defined, are commercially available or obtained as known in literature.

5b) The compounds of formula (Is) wherein X18 is a radical of formula (d5′) or (d6′), wherein R12b 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),


P2—X19 (IIIn)

wherein P2 and X19 are as above defined, with a compound of formula (IVd)


Ra—O—C(O)—X″-y-Q (IVd)

wherein Ra and Q, X″ are as above defined, y is the radical Y, wherein Y is as above defined, and
5b-ii) when Q is Z2, by converting the compound obtained in the step 5b-i) into nitro derivative by reaction with a nitrate source as above described and
5b-iii) optionally deprotecting the compounds obtained in step 5b-i) or 5b-ii) as above described.

The reaction of a compound of formula (IIIn) wherein P2 and X19 are as above defined, with a compound of formula (IVd) Ra, y, Q, X″ are as above defined may be carried out as described in 1-i-2).

5c) The compounds of formula (Is) wherein X18 is a radical of formula (d9′), wherein R12b 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),


P2—X20 (It)

wherein P2 is as above defined and X20 is the radical having the following meanings


—R12b—CH(NH2)—CH2—O-(T′″-Y-Q) (d9″)

wherein R12b is selected from D10), T′″, Y and Q are as above defined, with a compound of formula (IVa)


W1—C(O)—Y-Q (IVa)

wherein W1 and Q are as above defined, y is the radical Y′, wherein Y′ is as above defined, and
5c-ii) when Q is Z2, by converting the compound obtained in the step 5c-i) into nitro derivative by reaction with a nitrate source as above described and
5c-iii) optionally deprotecting the compounds obtained in step 5c-i) or 5c-ii) as above described.

The reaction of a compound of formula (It) wherein P2 and X20 are as above defined, with a compound of formula (IVa) wherein W1, y, Q are as above defined, may be carried out as described in 1-i-1), 1-i-2), 1-i-3) and 1a-1).

5d) The compounds of formula (Is) wherein X18 is a radical of formula (d9′), wherein R12b 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′),


P2—X20′ (It′)

wherein P2 and X20′ are as above defined, with a compound of formula (IVd)


Ra—O—C(O)—X″-y-Q (IVd)

wherein Ra and Q, X″ are as above defined, y is the radical Y′, wherein Y′ is as above defined, and
5d-ii) when Q is Z2, by converting the 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 P2 and X20′ are as above defined, with a compound of formula (IVd) Ra, y, Q, X″ are as above defined may be carried out as described in 1-i-2).

5e) The compounds of formula (Is) wherein X18 is the radical of formula (d10′), wherein R12b 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),


P2—X20 (It)

wherein P2 is as above defined and X20 is the radical having the following meaning


—R12b—CH(CH2—OH)—NH-(T′-Y-Q) (d10″)

wherein R12b is selected from D10), T′, Y and Q are as above defined, with a compound of formula (IVa)


W1—C(O)—Y-Q (IVa)

wherein W1 and Q are as above defined, y is the radical Y′, wherein Y′ is as above defined, and
5e-ii) when Q is Z2, by converting the compound obtained in the step 5e-i) into nitro derivative by reaction with a nitrate source as above described and
5e-iii) optionally deprotecting the compounds obtained in step 5e-i) or 5e-ii) as above described.

The reaction of a compound of formula (It) wherein P2 and X20 are as above defined, with a compound of formula (IVa) wherein W1, y, Q are as above defined, may be carried out as described in 1-i-1), 1-i-2), 1-i-3) and 1a-1).

5f) The compounds of formula (Is) wherein X18 is the radical of formula (d10′), wherein R12b 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′),


P2—X20 (It′)

wherein P2 and X20′ are as above defined, with a compound of formula (IVd)


Ra—O—C(O)—X″-y-Q (IVd)

wherein Ra and Q, X″ are as above defined, y is the radical Y′, wherein Y′ is as above defined, and
5f-ii) when Q is Z2, by converting the compound obtained in the step 5f-i) into nitro derivative by reaction with a nitrate source as above described and
5f-iii) optionally deprotecting the compounds obtained in step 5f-i) or 5f-ii) as above described.

The reaction of a compound of formula (It′) wherein P2 and X20′ are as above defined, with a compound of formula (IVd) Ra, 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, Rx is a radical selected from (d5), (d6), (d9) or (d10), wherein R12b 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—X21 (Iu)

wherein Hal is an halogen atom, R′ is as above defined and X21 is a radical selected from (d5′), (d6′), (d9′) or (d10′), wherein R12b is selected from D10), and
6-ii) when Q is Z2, by converting the compound obtained in the step 6-i) into nitro derivative by reaction with a nitrate source as above described and
6-iii) optionally deprotecting the compounds obtained in step 6-i) or 6-ii) as above described.

The reaction of a compound of formula (Iu) wherein Hal, X21 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—X22 (IIIo)

wherein W is a chlorine atom, X22 is the radical having the following meanings


—R12b—CH(NHP3)—CH2—O-(T′″-Y-Q) (d5′″)


—R12b—CH(CH2OP1-—H-(T′-Y-Q) (d6′″)


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


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

wherein R12b, P3, P1, T′, T″, Y′, Y and Q are as above defined, and ZnCl2 as known in literature.

The compounds of formula (IIIo), wherein W and X22 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, Rx is a radical selected from (d5), (d6), (d9) or (d10), wherein R12b 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—Ra (IIb)

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


H—X23 (Iv)

wherein X23 is a radical selected from (d5′), (d6′), (d9′) or (d10′), wherein R12b is selected from D8) or D9), and
7-ii) when Q is Z2, by converting the compound obtained in the step 7-i) into nitro derivative by reaction with a nitrate source as above described and
7-iii) optionally deprotecting the compounds obtained in step 7-i) or 7-ii) as above described.

The reaction of a compound of formula (Iv) wherein X23 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, Rx is a radical selected from (a5), (a6), (a9) or (a10), (b5), (b6), (b9) or (b10) wherein R1b is selected from A10) and R2b 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—X24 (Iz)

wherein W is as above defined, X24 is the radical Rx having the following meanings


—R1b—CH(NHR4a)—C(O)-(T-Y-Q) (a5′)


—R1b—CH(COOR2a)NH-(T′-Y-Q) (a6′)


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


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


—R2b—CH(NHR4a)—CH2C(O)-(T-Y-Q) (b5′)


—R2b—CH(CH2COOR3a)NH-(T′-Y-Q) (b6′)


—R2b—CH(NH-T′-Y′-Q)-CH2C(O)-(T-Y-Q) (b9′)


—R2b—CH(CH2C(O)-T′-Y′-Q)-NH-(T-Y-Q) (b10′)

wherein R1b is selected from A10), R2b is selected from B10), T, T′, Y and Q are as above defined and
8-ii) when Q is Z2, by converting the compound obtained in the step 8-i) into nitro derivative by reaction with a nitrate source as above described and
8-iii) optionally deprotecting the compounds obtained in step 8-i) or 8-ii) as above described.

The reaction of a compound of formula (IIa) wherein R is as above defined, with a compound of formula (Iv) wherein W and X24 are as above defined may be carried out as described in 1).

8a) The compounds of formula (Iz) wherein X24 is a radical of formula (a5′), (a6′), (b5′) or (b6′), wherein R1b is selected from A10) and R2b is selected from B10), T and T′ are C(O) can be obtained
8a-i) by reacting a compound of formula (IIIq),


P2—X25 (IIIq)

wherein P2 is as above defined, X25 is the radical having the following meanings


—R1b—CH(NHP3-C(O)—OH (a5″)


—R1b—CH(COOP2—NH2 (a6″)


—R2b—CH(NHP3)—CH2C(O)—OH (b5″)


—R2b—CH(CH2COOP2)NH2 (b6″)

wherein P2 and P3 are as above defined and R1b is selected from A10), R2b is selected from B10), with a compound of formula (IVa)


W1—C(O)—Y-Q (IVa)

wherein W1 and Q are as above defined, y is the radical Y, wherein Y is as above defined, and
8a-ii) when Q is Z2, by converting the compound obtained in the step 8a-i) into nitro derivative by reaction with a nitrate source as above described and
8a-iii) optionally deprotecting the compounds obtained in step 8a-i) or 8a-ii) as above described.

The reaction of a compound of formula (IIIq) wherein P2 and X25 are as above defined, with a compound of formula (IVa) W1, Y, and Q are as above defined may be carried out as described in 1-i-1), 1-i-2), 1-i-3) and 1a-1).

The compounds of formula (IIIq), wherein P2 and X25 are as above defined, are commercially available or obtained as known in literature.

8b) The compounds of formula (Iz) wherein X24 is the radical of formula (a5′), (a6′), (b5′) or (b6′), wherein R1b is selected from A10) and R2b 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),


P2—X25 (IIIq)

wherein P2 and X25 are as above defined, with a compound of formula (IVd)


Ra—O—C(O)—X″-y-Q (IVd)

wherein Ra, Q and X″ are as above defined, y is the radical Y, wherein Y is as above defined, and
8b-ii) when Q is Z2, by converting the compound obtained in the step 8b-i) into nitro derivative by reaction with a nitrate source as above described and
8b-iii) optionally deprotecting the compounds obtained in step 8b-i) or 8b-ii) as above described.

The reaction of a compound of formula (IIIq) wherein P2 and X25 are as above defined, with a compound of formula (IVd) Ra, y, Q, X″ are as above defined may be carried out as described in 1-i-2).

8c) The compounds of formula (Iz) wherein X24 is the radical of formula (a9′) or (b9′) wherein R1b is selected from A10), and R2b 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),


P2—X26 (Iy)

wherein P2 is as above defined and X26 is the radical having the following meanings


—R1b—CH(NH2—C(O)-(T-Y-Q) (a9″)


—R2b—CH(NH2—CH2C(O)-(T-Y-Q) (b9″)

wherein R1b is selected from A10) and R2b is selected from B10), with a compound of formula (IVa)


W1—C(O)—Y-Q (IVa)

wherein W1 and Q are as above defined, y is the radical Y′, wherein Y′ is as above defined, and
8c-ii) when Q is Z2, by converting the compound obtained in the step 8c-i) into nitro derivative by reaction with a nitrate source as above described and
8c-iii) optionally deprotecting the compounds obtained in step 8c-i) or 8c-ii) as above described.

The reaction of a compound of formula (Iy) wherein P2 and X26 are as above defined, with a compound of formula (IVa) wherein W1, y, Q are as above defined, may be carried out as described in 1-i-1), 1-i-2), 1-i-3) and 1a-1).

8d) The compounds of formula (Iz) wherein X24 is the radical of formula (a9′) or (b9′) wherein R1b is selected from A10), R2b 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),


P2—X26 (Iy)

wherein P2 and X26 are as above defined, with a compound of formula (IVd)


Ra—O—C(O)—X″-y-Q (IVd)

wherein Ra and X″ are as above defined, y is the radical Y′, wherein Y′ is as above defined, and
8d-ii) when Q is Z2, by converting the compound obtained in the step 8d-i) into nitro derivative by reaction with a nitrate source as above described and
8d-iii) optionally deprotecting the compounds obtained in step 8d-i) or 8d-ii) as above described.

The reaction of a compound of formula (Iy) wherein P2 and X20 are as above defined, with a compound of formula (IVd) Ra, y, Q, X″ are as above defined may be carried out as described in 1-i-2).

8e) The compounds of formula (Iz) wherein X24 is the radical of formula (a10′) or (b10′) wherein R1b is selected from A10), and R2b 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′),


P2—X26 (Iy′)

wherein P2 is as above defined and X26′ is the radical having the following meanings


—R1b—CH(C(O)—OH)—NH-(T-Y-Q) (a10″)


—R2b—CH(CH2C(O)—OH)—NH-(T-Y-Q) (b10″)

wherein R1b is selected from selected from A10) and R2b is B10), with a compound of formula (IVa)


W1—C(O)—Y-Q (IVa)

wherein W1 and Q are as above defined, y is the radical Y′, wherein Y′ is as above defined, and
8e-ii) when Q is Z2, by converting the compound obtained in the step 8e-i) into nitro derivative by reaction with a nitrate source as above described and
8e-iii) optionally deprotecting the compounds obtained in step 8e-i) or 8e-ii) as above described.

The reaction of a compound of formula (Iy′) wherein P2 and X26, are as above defined, with a compound of formula (IVa) wherein W1, y, Q are as above defined, may be carried out as described in 1-i-1), 1-i-2), 1-i-3) and 1a-1).

8f) The compounds of formula (Iz) wherein X24 is the radical of formula (a10′) or (b10′) wherein R1b is selected from A10), and R2b 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′),


P2—X26′ (Iy′)

wherein P2 and X26′ are as above defined, with a compound of formula (IVd)


Ra—O—C(O)—X″-y-Q (IVd)

wherein Ra and X″ are as above defined, y is the radical Y′, wherein Y′ is as above defined, and
8f-ii) when Q is Z2, by converting the compound obtained in the step 8f-i) into nitro derivative by reaction with a nitrate source as above described and
8f-iii) optionally deprotecting the compounds obtained in step 8f-i) or 8f-ii) as above described.

The reaction of a compound of formula (Iy′) wherein P2 and X26′ are as above defined, with a compound of formula (IVd) Ra, 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, Rx is a radical selected from (a5), (a6), (a9) or (a10), (b5), (b6), (b9) or (b10) wherein R1b is selected from A8) or A9), R2b 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—Ra (IIb)

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


H—X27 (Ix)

wherein X2-7 is the radical selected from (a5′), (a6′), (a9′), (a10′), (b5′), (b6′), (b9′) or (b10′), wherein R1b is selected from A8) or A9), R2b is selected from B8) or B9), and 9-ii) when Q is Z2, by converting the compound obtained in the step 9-i) into nitro derivative by reaction with a nitrate source as above described and
9-iii) optionally deprotecting the compounds obtained in step 9-i) or 9-ii) as above described.

The reaction of a compound of formula (Ix) wherein X27 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).

Example 1

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

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(11β,16β)-9-Chloro-11,17-dihydroxy-16-methyl-21-[1-oxo-2-((tert-butylcarbonylamino)acetyl)]-pregna-1,4-diene-3,20-dione

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To a solution of beclomethasone (0.6 g, 1.46 mmol) in acetone (35 ml), N-Boc-glycine (0.334 g, 1.90 mmol) and DMAP (cat. amount) were added. The reaction was cooled at 0° C. and EDAC (0.365 g, 1.90 mmol) was added. The reaction was stirred at room temperature for 2 hours. The solvent was evaporated under vacuum. The residue was treated with water (50 ml) and methylene chloride (50×3 ml), the organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography, eluent n-hexane/ethyl acetate 6/4. The product (0.8 g) was obtained.

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

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A solution of compound A (0.8 g, 0.41 mmol) in methylene chloride (70 ml) was stirred at room temperature. HCl gas was buddle in the solution for 1 hour. The solvent was evaporated under reduced pressure. The product was used in the next step without any purification.

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

To a solution of B) (0.75 g, 1.46 mmol) in methylene chloride (40 ml), 4-nitrooxybutyrric acid pentafluorophenyl ester (0.41 g, 1.46 mmol), DMAP (cat. amount) and triethylamine (0.3 ml, 2.19 mmol) were added. The reaction was stirred at room temperature for 24 hours. The solution was treated with a 5% solution of H3PO4 (50 ml). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography, (Biotage System, column FLASH 40+M® KP-Sil) eluent:gradient n-hexane/ethyl acetate 1/1 (130 ml), to ethyl acetate 100% during 130 ml, ethyl acetate 100% (130 ml). The product (0.62 g) was obtained as white powder.

1H-NMR: (DMSO), δ 8.42 (1H, t); 7.30 (1H, d); 6.22 (1H, dd); 5.98 (1H, s); 5.46 (1H, d); 5.42 (2H, s); 5.05 (1H, d); 4.84 (1H, d); 4.5 (2H, t); 4.34 (1H, sb); 3.97 (2H, d); 2.71-2.57 (2H, m); 2.5-2.2 (6H, m); 2.0-1.7 (5H, m); 1.65-1.35 (5H, m); 1.25-0.97 (4H, m); 0.8 (3H, s).

Example 2

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

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The compound was synthesized using the procedure described in example 1 starting from betamethasone, Boc-glycine and 4-nitrooxybutyric acid pentafluorophenol ester.

1H-NMR: (DMSO), δ: 8.4 (1H, t); 7.28 (1H, d); 6.22 (1H, dd); 6.0 (1H, s); 5.30 (1H, d); 5.08 (1H, d); 4.83 (1H, d); 4.53 (2H, t); 4.15 (1H, bp); 3.95 (2H, d); 2.71-2.52 (1H, m); 2.51-2.4 (6H, m); 2.38-2.07 (2H, m); 2.03-1.75 (6H, m); 1.58-1.45 (4H, m), 1.11-0.8 (6H, m).

Example 3

Synthesis of (11β,16β)-9-Fluoro-11-hydroxy-16,17-(1-methylethylidenebis(oxy))-21-[1-oxo-(2-(4-(nitrooxy)butyoxy-carbonylamino)acetyl)]-pregna-1,4-diene-3 ,20-dione

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The compound was synthesized using the procedure described in example 1 starting from triamcinolone acetonide, Boc-glycine and 4-nitrooxybutyric acid pentafluorophenol ester.

1H-NMR: (DMSO), δ□: 8.43 (1H, t); 7.27 (1H, d); 6.21 (1H, dd); 6.0 (1H, s); 5.46 (1H, d); 5.18 (1H, d); 4.87-4.83 (1H, m); 4.74 (1H, d); 4.50 (1H, t); 4.18 (1H, sb); 3.98-3.96 (2H, m); 2.71-2.31 (5H, m); 2.30-2.2 (3H, m); 2.10-1.77 (6H, m); 1.75-1.42 (7H, m); 1.4-1.32 (4H, m); 1.12 (3H, s); 0.85 (3H, s).

Example 4

Synthesis of (6α,11β,16α)-6,9-difluoro-11-hydroxy-16,17-((1-methylethylidene)bis(oxy))-21-[1-oxo-(2-((4-(nitrooxy)butyoxy-carbonylamino)acetyl)]-pregna-1 ,4-diene-3,20-dione

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The compound was synthesized using the procedure described in example I starting from fluocinolone acetonide, Boc-glycine and 4-nitrooxybutyric acid pentafluorophenol ester.

1H-NMR: (DMSO), δ□:: 8.43 (1H, t); 7.25 (1H, d); 6.28 (1H, dd); 6.09 (1H, s); 5.75-5.48 (2H, m); 5.18 (1H, d); 4.83 (1H, d); 4.78 (1H, d); 4.50 (2H, t); 4.18 (1H, sb); 3.9-3.8 (2H, m); 2.72-2.48 (4H, m); 2.25 (2H, t); 2.10-1.8 (3H, m); 1.78-1.65 (1H, m); 1.62-1.51 (2H, m); 1.48 (3H, s); 1.32 (3H, s); 1.10 (3H, s); 0.8 (3H, s).

Example 5

Synthesis of 4-(nitrooxy)butyl 2-acetamido-3-(4-((2-((9R,10S,11S,13S,16R,17S)-9-fluoro-11-hydroxy-16,17-((1-methylethylidene)bis(oxy))10,13-dimethyl-3-oxo-6,7,8,9,10,11,12 ,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl)-2-oxoethoxy) carbonyloxy)phenyl)propanoate

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D) 4-(nitrooxy)butyl 2-(tert-butoxycarbonylamino)-3-(4-hydroxyphenyl)propanoate

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To a solution of Boc-(L)-tyrosine (5.0 g, 17.77 mmol) in N, N-dimethylformamide (40 ml) cesium carbonate (5.79 g, 17.77 mmol) was added. The reaction was cooled at 0° C. and a solution of 4-bromobutyl nitrate (17.77 mmol) in dichloromethane (20% w/w, 17.06 g) was added drop wise. The reaction was stirred at 0° C. for 20 minutes and then at room temperature for 22 hours. The mixture was poured into a 5% aqueous NaH2PO4 solution and extracted with diethyl ether (40×4 ml), the organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography, (Biotage System, column FLASH 65+M™ KP-Sil, eluent: gradient n-hexane/ethyl acetate 9/1 (500 ml), to n-hexane/ethyl acetate 1/1 during 4000 ml, n-hexane/ethyl acetate 1/1 (1000 ml)). The product (3.91 g) was obtained.

E) 4-(nitrooxy)butyl 2-amino-3-(4-hydroxyphenyl)propanoate

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A solution of compound D (0.96 g, 2.41 mmol) in dichloromethane (20 ml) was stirred at room temperature. HCl gas was buddle in the solution for 3 hours. The mixture was diluted with dichloromethane (25 ml), washed with saturated aqueous sodium carbonate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The product (0.71 g) was used in the next step without any purification.

F) 4-(nitrooxy)butyl 2-acetamido-3-(4-hydroxyphenyl)propanoate

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To a solution of compound E (0.63 g, 2.25 mmol) in dichloromethane (15 ml) triethylamine (0.31 ml, 2.25 mmol) was added. The reaction was cooled at 0° C. and acetyl chloride (0.17 ml, 2.48 mmol) was added drop wise. The reaction was stirred at 0° C. for 10 minutes and then at room temperature for 16 hours. The mixture was diluted with dichloromethane (25 ml), washed with water. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography, (Biotage System, column FLASH 25+M™ KP-Sil, eluent:gradient n-hexane/ethyl acetate 9/1 (100 ml), to n-hexane/ethyl acetate 2/8 during 1200 ml). The product (0.54 g) was obtained.

G) 4-(nitroooxy)butyl 2-acetamido-3-(4-((4-nitrophenoxy)carbonyloxy)phenyl)propanoate

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To a solution of compound F (0.54 g, 1.58 mmol) in dichloromethane (8 ml) pyridine (0.15 ml, 1.58 mmol) was added. The reaction was cooled at 0° C. and p-nitrophenylchloroformate (320 mg, 1.58 mmol) was added. The reaction was stirred at 0° C. for 15 minutes and then at room temperature for 48 hours. The mixture was diluted with dichloromethane (25 ml), washed with 1M aqueous HCl solution and then with saturated aqueous sodium carbonate. The organic layers was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography, (Biotage System, column FLASH 25+M™ KP-Sil, eluent:gradient n-hexane/ethyl acetate 9/1 (150 ml), to n-hexane/ethyl acetate 3/7 during 1200 ml, n-hexane/ethyl acetate 3/7 (600 ml)). The product (0.59 g) was obtained.

H) 4-(nitrooxy)butyl 2-acetamido-3-(4-((2-((9R,10S,11S,13S,16R,17S)-9-fluoro-11-hydroxy-16,17-((1-methylethylidene)bis(oxy))10,13-dimethyl-3-oxo-6,7,8,9,10,11,12 ,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl)-2-oxoethoxy) carbonyloxy)phenyl)propanoate

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To a solution of compound G (0.55 g, 1.09 mmol) in dichloromethane (12 ml), scandium triflate (0.05 g, 0.11 mmol) and DMAP (0.26 g, 2.19 mmol) were added. The reaction was cooled at 0° C. and triamcinolone acetonide (0.47 g, 1.09 mmol) was added. The reaction was stirred at room temperature for 18 hours. The mixture was diluted with dichloromethane (24 ml), washed with 5% NaH2PO4 and then with saturated aqueous sodium carbonate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography, (Biotage System, column FLASH 25+M™ KP-Sil, eluent:gradient n-hexane/ethyl acetate 9/1 (150 ml), to n-hexane/ethyl acetate 2/8 during 1200 ml, n-hexane/ethyl acetate 2/8 (800 ml)). The product (0.29 g) was obtained.

1H-NMR: (DMSO), δ: 8.36 (1H, d); 7.37-7.32 (3H, m); 7.21-7.12 (2H, m); 6.23 (1H, dd); 6.02 (1H, s); 5.47 (1H, d); 5.31 (1H, d); 4.97-4.87 (2H, m); 4.59-4.48 (3H, m); 4.27-4.17 (1H, sb); 4.11-3.97 (2H, m); 3.10-2.90 (1H, m); 2.71-2.29 (4H, m); 2.10-1.75 (5H, m); 1.60-1.40 (7H, m); 1.38 (3H, s); 1.12 (3H, s); 0.80 (3H, s).

Example 6

Synthesis of (2S)-4-(nitrooxy)butyl 2-acetamido-3-(4-((2-((6S,9R,10S,11S,13S,16R,17S)-6,9-difluoro-11-hydroxy-16,17-((1-methylethylidene)bis(oxy))-10,13-dimethyl-3-oxo-6,7,8,9, 10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl)-2-oxoethoxy)carbonyloxy)phenyl)propanoate

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The compound was synthesized using the procedure described in example 5 starting from fluocinolone acetonide and compound G.

1H-NMR: (DMSO), δ: 8.36 (1H, d); 7.28 (3H, m); 7.09 (2H, m); 6.30 (1H, dd); 6.11 (1H, d); 5.56 (1H, d); 5.31 (1H, d); 4.91 (2H, m); 4.50 (2H, t); 4.93 (1H, m); 4.25 (1H, m); 4.02 (3H, t); 2.96 (2H, m); 2.27 (1H, m); 2.01 (3H, m); 1.90-1.25 (17H, m); 1.15 (3H, s); 0.80 (3H, s).

Example 7

Synthesis of (2S)-4-(nitrooxy)butyl 2-amino-3-(4-((2-((9R,10S,11S,13S,16R,17S)-9-fluoro-11-hydroxy-16,17-((1-methylethylidene)bis(oxy))-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13 ,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl)-2-oxoethoxy)carbonyloxy)phenyl)propanoate hydrochloride

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I) 4-hydroxybutyl 2-(tert-butoxycarbonylamino)-3-(4-((4-nitrophenoxy)carbonyloxy)phenyl) propanoate

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To a solution of compound D (1.97 g, 4.86 mmol) in dichloromethane (24 ml) pyridine (0.48 ml, 4.86 mmol) was added. The reaction was cooled at 0° C. and p-nitrophenylchloroformate (980 mg, 4.86 mmol) was added. The reaction was stirred at 0° C. for 10 minutes and then at room temperature for 21 hours. The mixture was diluted with dichloromethane (25 ml), washed with 1M aqueous HCl solution and then with saturated aqueous sodium carbonate. The organic layers was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography, (Biotage System, column FLASH 40+M™ KP-Sil, eluent:gradient n-hexane/ethyl acetate 98/2 (200 ml), to n-hexane/ethyl acetate 6/4 during 1600 ml, n-hexane/ethyl acetate 6/4 (300 ml)). The product (2.19 g) was obtained.

J) (2S)-4-(nitrooxy)butyl 2-(tert-butoxycarbonylamino)-3-(4-((2-((9R,10S,11S,13S,16R,17S)-9-fluoro-11-hydroxy-16,17-((1-methylethylidene)bis(oxy))-10,13-dimethyl-3-ox o-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl)-2-oxoethoxy)carbonyloxy)phenyl)propanoate

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To a solution of compound I (1.35 g, 2.4 mmol) in dichloromethane (40 ml), scandium triflate (0.11 g, 0.24 mmol) and DMAP (0.57 g, 4.8 mmol) were added. The reaction was cooled at 0° C. and triamcinolone acetonide (1.25 g, 2.88 mmol) was added. The reaction was stirred at room temperature for 70 hours. The solvent was evaporated under reduced pressure. The residue was purified by flash chromatography, (Biotage System, column FLASH 40+M™ KP-Sil, eluent:gradient n-hexane/ethyl acetate 9/1 (200 ml), to n-hexane/ethyl acetate 3/7 during 1600 ml, n-hexane/ethyl acetate 3/7 (500 ml)). The product (0.98 g) was obtained.

K) (2S)-4-(nitrooxy)butyl-2-amino-3-(4-((2-((9R,10S,11S,13S,16R,17S)-9-fluoro-11-hydroxy-16,17-((1-methylethylidene)bis(oxy))-10,13-dimethyl-3- oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl)-2-oxoethoxy) carbonyloxy)phenyl)propanoate hydrochloride

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A solution of compound J (1.42 g, 1.65 mmol) in dichloromethane (28 ml) was stirred at room temperature. HCl gas was buddle in the solution for 15 minutes. The mixture was diluted with dichloromethane (35 ml), washed with saturated aqueous sodium carbonate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography, (Biotage System, column FLASH 40+M™ KP-Sil, eluent:gradient water/acetonitrile 9/1 (150 ml), to water/acetonitrile 2/8 during 1400 ml, water/acetonitrile 2/8 (200 ml)). The free base of product M (0.67 g) was treated with a solution of HCl in diethyl ether. The hydrochloride salt of compound M was filtered and dried under vacuum. The product (0.57 g) was obtained.

1H-NMR: (DMSO), δ: 8.57 (2H, m); 7.38-7.29 (3H, m); 7.22-7.19 (2H, m); 6.22 (1H, dd); 6.00 (1H, s); 5.54 (1H, d); 5.31 (1H, d); 4.88-4.84 (2H, m); 4.52-4.40 (2H, m); 4.25-4.20 (1H, sb); 4.16-4.09 (3H, m); 3.22-3-04 (1H, m); 2.71-2.29 (4H, m); 2.10-1.75 (5H, m); 1.60-1.34 (7H, m); 1.13 (3H, s); 0.82 (3H, s).

Example 8

Synthesis of (2S)-4-(nitrooxy)butyl 2-amino-3-(4-((2-((6S,9R,10S,11S,13S,16R,17S)-6,9-difluoro-11-hydroxy-16,17-((1-methylethylidene)bis(oxy))-10,13-dimethyl-3-oxo-6,7,8,9,10,1 1,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl)-2-oxoethoxy)carbonyloxy)phenyl)propanoate hydrochloride

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The compound was synthesized using the procedure described in example 7 starting from fluocinolone acetonide and compound I.

1H-NMR: (DMSO), δ: 8.64 (2H, s); 7.41-7.35 (3H, m); 7.23 (2H, d); 6.30 (1H, dd); 6.11 (1H, s); 5.80-5.50 (2H, m); 5.40-5.27 (1H, m); 5.00-4.75 (2H, m); 4.53-4.45 (2H, m); 4.48-4.05 (4H, m); 3.31-3.03 (2H, m); 2.75-2.60 (1H, m); 2.27 (1H, sb); 2.11-1.98 (3H, m); 1.82-1.52 (5H, m); 1.50 (3H, s); 1.38 (3H, s); 1.10 (3H, s); 0.81 (3H, s).

Example 9

Synthesis of 2-((8S,9R,10S,11S,13S,14S,16R,17S)-9-fluoro-11-hydroxy-16,17-(1-methyl ethylidenebis(oxy))-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl-2-(5-(nit rooxy)pentanamido) acetate

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The compound was synthesized using the procedure described in example I starting from triamcinolone acetonide, Boc-glycine and 4-nitrooxybutyric acid pentafluorophenol ester.

1H-NMR: (DMSO), δ: 7.29 (1H, d); 6.23 (1H, dd); 6.02 (1H, s); 5.48 (1H, d); 5.20 (1H, d); 4.86 (1H, m); 4.78 (1H, d); 4.50 (2H, t); 4.18 (1H, sb); 3.98-3.96 (2H, m); 2.71-2.25 (2H, m); 2.30 (5H, m); 1.75-1.42 (14H, m); 1.4-1.32 (4H, m); 1.12 (3H, s); 0.83 (3H, s).

Example 10

Synthesis of 2-((8S,9R,10S,11S,13S,14S,16S,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopen ta[a]phenanthren-17-yl)-2-oxoethyl 2-(5-(nitrooxy)hexanamidoamido) acetate

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The compound was synthesized using the procedure described in example I starting from betamethasone, Boc-glycine and 6-nitrooxyhexanoic acid pentafluorophenol ester.

1H-NMR: (DMSO), δ: 8.28 (1H, t); 7.27 (1H, d); 6.15 (1H, dd); 5.99 (1H, s); 5.35 (1H, s); 5.27 (1H, d); 4.99 (1H, d), 4.79 (1H, d); 4.48 (2H, t), 4.11 (1H, m); 3.91 (2H, d); 2.60 (1H, m); 2.50-2.30 (2H, m); 2.10 (4H, m); 2.00-1.80 (3H, m); 1.70-1.30 (11H, m); 1.00 (4H, d); 0.99 (3H, s).

Example 11

Synthesis of 2-((6S,8S,9R,10S,11S,13S,14S,16R,17S)-6,9-difluoro-11-hydroxy-16,17-dimethoxy-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahyd ro-3H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl2-(6-nitrooxy hexanamido) acetate

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The compound was synthesized using the procedure described in example I starting from fluocinolone acetonide, Boc-glycine and 6-nitrooxyhexanoic acid pentafluorophenol ester.

1H-NMR: (DMSO), δ: 8.32 (1H, t); 7.25 (1H, d); 6.28 (1H, dd); 6.09 (1H, s); 5.74-5.50 (2H, m); 5.18 (1H, d); 4.85 (1H, d); 4.78 (1H, d); 4.48 (2H, t); 4.19 (1H, sb); 3.94 (2H, m); 2.63-2.48 (1H, m); 2.25 (1H, t); 2.13 (2H, t); 2.10-1.93 (2H, m); 1.73-1.40 (11H, m); 1.30 (5H, m); 1.10 (3H, s); 0.8 (3H, s).

Example 12

Synthesis of 1-(2-((8S,9R,10S,11S,13S,14S,16R,17S)-9-fluoro-11-hydroxy-16,17-((1-methylethylidene)bis(oxy))-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,1 5,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1-(4-(nitrooxy)butyl) 2-acetamido pentanedioate

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L) 2-acetamido-4-(2-((8S,9R,10S,11S,13S,14S,16R,17S)-9-fluoro-11-hydroxy-16,17-((1-methylethylidene)bis(oxy))-10,13-dimethyl-3-oxo-6,7,8,9,10,1 1,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl)-2-oxoethoxy)-4-oxobutanoic acid

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To a solution of triamcinolone acetonide (3.1 g, 7.13 mmol) in acetone (100 ml), N-acetyl aspartic acid (2.0 g, 11.42 mmol) and DMAP (cat. amount) were added. The reaction was cooled at 0° C. and EDAC(2.18 g, 11.42 mmol) was added. The reaction was stirred at room temperature for 24 hours. The solvent was evaporated under vacuum. The residue was purified by flash chromatography (Biotage System, column FLASH 65+M™ KP-Sil, eluent:gradient dichloromethane/methanol 95/5 (675 ml), to dichloromethane/methanol 9/1 during 3600 ml, dichloromethane/methanol 9/1 (900 ml)). The product (2.67 g) was obtained.

M) 1-(4-chlorobutyl) 4-(2-((8S,9R,10S,11S,13S,14S,16R,17S)-9-fluoro-11-hydroxy-16,17-((1-methylethylidene)bis(oxy))-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,1 5,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)2-acetamido succinate

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To a solution of compound L (0.6 g, 1.31 mmol) in dichloromethane (30 ml), 4-chlorobutanol (0.13 ml, 1.31 mmol) and DMAP (cat. amount) were added. The reaction was cooled at 0° C. and EDAC(0.25 g, 1.31 mmol) was added. The reaction was stirred at room temperature for 24 hours. The solvent was evaporated under vacuum. The residue was purified by flash chromatography (Biotage System, column FLASH 25+M™ KP-Sil, eluent:gradient n-hexane/ethyl acetate 6/4 (60 ml), to n-hexane/ethyl acetate 2/8 during 600 ml, to ethyl acetate during 60 ml, ethyl acetate (180 ml)). The product (0.65 g) was obtained.

N) 1-(4-iodobutyl) 4-(2-((8S,9R,10S,11S,13S,14S,16R,17S)-9-fluoro-11-hydroxy-16,17-((1-methylethylidene)bis(oxy))-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,1 5,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)2-acetamido succinate

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To a solution of compound M (0.55 g, 0.76 mmol) in acetonitrile (18 ml), sodium iodide (0.45 g, 3.06 mmol) was added. The reaction was heated to 120° C. for 60 minutes under microwave irradiation. The resulting mixture was cooled, filtered and the solvent was removed under reduced pressure to give a solid product which was used without further purification.

O) 1-(2-((8S,9R,10S,11S,13S,14S,16R,17S)-9-fluoro-11-hydroxy-16,17-((1-methylethylidene)bis(oxy))-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,1 5,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1-(4-(nitrooxy)butyl)2-acetamido pentanedioate

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To a solution of compound N (0.60 g, 0.76 mmol) in acetonitrile (20 ml), silver nitrate (0.51 g, 3.06 mmol) was added. The reaction was heated to 120° C. for 5 minutes under microwave irradiation. The resulting mixture was cooled, filtered and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (Biotage System, column FLASH 25+M™ KP-Sil, eluent:gradient n-hexane/ethyl acetate 4/6 (60 ml), to ethyl acetate 100% during 480 ml, ethyl acetate (120 ml)). The product (0.40 g) was obtained.

1H-NMR: (DMSO): 8.45 (1H, d); 7.26 (1H, d); 6.22 (1H, dd); 6.00 (1H, s); 5.48 (1H, m); 5.12 (1H, dd), 4.84-4.76 (3H, m); 4.52 (2H, t); 4.20 (1H, m), 4.06 (2H, m); 2.87 (1H, dm); 2.75-2.48 (3H, m); 2.10-1.75 (4H, m); 1.82 (3H, s); 1.50-1-70 (7H, m); 1.47 (3H, s); 1.33 (4H, m); 1.15 (3H, s); 0.83 (3H, s).

Example 13

Synthesis of 2-((8S,9R,10S,11S,3S,14S,16S,17R)-9-fluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopent a[a]phenanthren-17-yl)-2-oxoethyl 3-(6-(nitrooxy)hexanamido) propanoate

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The compound was synthesized using the procedure described in example I starting from betamethasone, Boc-beta-alanine and 6-nitrooxyhexanoic acid pentafluorophenol ester.

1H-NMR: (DMSO), δ: 7.88 (1H, t); 7.29 (1H, d); 6.22 (1H, dd); 6.01 (1H, s); 5.36 (1H, s); 5.31 (1H, d); 5.01 (1H, d); 4.84 (1H, d); 4.50 (2H, t); 4.15 (1H, sb); 3.48-3.25 (2H, m); 2.75-2.25 (7H, m); 2.20-2.00 (4H, m); 1.99-1.75 (4H, m); 1.71-1.61 (2H, m); 1.57-1.48 (5H, m); 1.42-1.27 (2H, m); 1.01 (3H, d); 0.90 (3H, s).

Example 14

Synthesis of 2-((8S,9R,10S,11S,13S,14S,16R,17S)-9-fluoro-11-hydroxy-16,17-dimethoxy-10,13-((1-methyl ethylidene)bis(oxy))-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl-3-(6-(nitrooxy)hexanami do) propanoate

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The compound was synthesized using the procedure described in example I starting from triamcinolone acetonide, Boc-beta-alanine and 6-nitrooxyhexanoic acid pentafluorophenol ester.

1H-NMR: (DMSO), δ: 8.31 (1H, t); 7.30 (1H, d); 6.24 (1H, dd); 6.01 (1H, s); 5.49 (1H, d); 5.25 (1H, d); 4.86 (1H, d); 4.75 (1H, d); 4.50 (2H, t); 4.19 (1H, sb); 3.93 (2H, m); 2.75-2.25 (2H, m); 2.15 (2H, t); 2.10-1.75 (3H, m); 1.75-1.45 (7H, m); 1.47 (3H, s); 1.40-1.20 (6H, m); 1.17 (5H, m); 0.80 (3H, s).

Example 15

Synthesis of 2-((6S,8S,9R,10S,11S,13S,14S,16R,17S)-6,9-difluoro-11-hydroxy-16,17-((1-methylethylidene)bis(oxy))-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13, 14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl-3-(6-(nitrooxy) hexanamido) propanoate

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The compound was synthesized using the procedure described in example I starting from fluocinolone acetonide, Boc-beta-alanine and 6-nitrooxyhexanoic acid pentafluorophenol ester.

1H-NMR: (DMSO), δ: 7.91 (1H, t); 7.27 (1H, d); 6.30 (1H, dd); 6.11 (1H, s); 5.75-5.50 (2H, m); 5.16 (1H, d); 4.85-4.90 (1H, m); 4.76 (1H, d); 4.61-4.48 (2H, t); 4.22 (1H, sb); 3.40-3.25 (3H, m); 2.70-2.50 (4H, m); 2.40-2.30 (1H, m); 2.15-1.93 (2H, m); 1.80-1.45 (10H, m); 1.41-1.28 (5H, m); 1.21 (3H, s); 0.82 (3H, s).

Example 16

Synthesis of 4-(2-((8S,9R,10S,11S,13S,14S,16R,17S)-9-fluoro-11-hydroxy-16,17-((1-methylethylidene)bis(oxy))-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,1 5,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1-(4-(nitrooxy)butyl) 2-(6-(nitrooxy)hexanamido)succinate

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P) 1-allyl 4-(2-((8S,9R,10S,11S,13S,14S,16R,17S)-9-fluoro-11-hydroxy-16,17-((1-methylethylidene)bis(oxy))-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,1 5,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)2-(tert-butoxycarbonyl amino) succinate

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To a solution of triamcinolone acetonide (3.0 g, 6.9 mmol) in dichloromethane (100 ml), 4-(allyloxy)-3-(tert-butoxycarbonylamino)-4-oxobutanoic acid (1.88 g, 6.9 mmol) and DMAP (cat. amount) were added. The reaction was cooled at 0° C. and EDAC(1.7 g, 8.97 mmol) was added. The reaction was stirred at room temperature for 12 hours. The solvent was evaporated under vacuum. The residue was purified by flash chromatography (Biotage System, column FLASH 40+M™ KP-Sil, eluent: gradient n-hexane/ethyl acetate 8/2 (300 ml), to n-hexane/ethyl acetate 4/6 during 900 ml, n-hexane/ethyl acetate 4/6 (300 ml)). The product (4.16 g) was obtained.

Q) 1-allyl 4-(2-((8S,9R,10S,11S,13S,14S,16R,17S)-9-fluoro-11-hydroxy-16,17-((1-methylethylidene)bis(oxy))-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,1 5,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)2-(amino)succinate hydrochloride

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A solution of compound P (1.0 g, 1.45 mmol) in dichloromethane (28 ml) was stirred at room temperature. HCl gas was buddle in the solution for 15 minutes. The solvent evaporated under vacuum to give a solid product which was used without further purification.

R) 1-allyl 4-(2-((8S,9R,10S,11S,13S,14S,16R,17S)-9-fluoro-11-hydroxy-16,17-((1-methylethylidene)bis(oxy))-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,1 5,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-2-(6-(nitrooxy)hexanamido) succinate

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To a solution of compound Q (0.91 g, 1.45 mmol) in dichloromethane (100 ml), DMAP (0.26 g, 2.17 mmol) and 6-nitrooxyhexanoic acid pentafluorophenol ester (0.49 g, 1.45 mmol) were added. The reaction was stirred at room temperature for 12 hours. The solvent was evaporated under reduced pressure. The residue was purified by flash chromatography, (Biotage System, column FLASH 40+M™ KP-Sil, eluent: gradient n-hexane/ethyl acetate 1/1 (150 ml), to ethyl acetate during 900 ml, ethyl acetate (450 ml)). The product (0.64 g) was obtained.

S) 4-(2-((8S,9R,10S,11S,13S,14S,16R,17S)-9-fluoro-11-hydroxy-16,17-((1-methylethyl idene)bis(oxy))-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-2-(6-(nitroo xy)hexanamido)-4-oxobutanoic acid

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To a solution of compound R (0.58 g, 0.77 mmol) in dichloromethane (20 ml), 5,5-cimethyl-1,3-cyclohexanedione (0.13 g, 0.97 mmol), triphenylphosphine (0.30 g, 1.16 mmol) and tetrakis(triphenylphosphine)palladium (0.045 g, 0.039 mmol) were added. The reaction was stirred at room temperature for 12 hours. The solvent was evaporated under reduced pressure. The residue was purified by flash chromatography, (Biotage System, column FLASH 40+M™ KP-Sil, eluent: n-hexane/acetone/acetic acid 4/6/0.1%) The product (0.31 g) was obtained.

T) 4-(2-((8S,9R,10S,11S,13S,14S,16R,17S)-9-fluoro-11-hydroxy-16,17-((1-methylethylidene)bis(oxy))-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,1 5,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1-(4-(chloro)butyl) 2-(6-(nitrooxy)hexanamido)succinate

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To a solution of compound S (0.33 g, 0.47 mmol) in dichloromethane (20 ml), 4-chlorobutanol (0.06 ml, 0.61 mmol) and DMAP (cat. amount) were added. The reaction was cooled at 0° C. and EDAC(0.12 g, 0.62 mmol) was added. The reaction was stirred at room temperature for 24 hours. The solvent was evaporated under vacuum. The residue was purified by flash chromatography (Biotage System, column FLASH 25+M™ KP-Sil, eluent:gradient n-hexane/ethyl acetate 6/4 (60 ml), to n-hexane/ethyl acetate 2/8 during 360 ml, n-hexane/ethyl acetate 2/8 (240 ml)). The product (0.25 g) was obtained.

U) 4-(2-((8S,9R,10S,11S,13S,14S,16R,17S)-9-fluoro-11-hydroxy-16,17-((1-methylethylidene)bis(oxy))-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,1 5,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl) 1-(4-(iodo)butyl) 2-(6-(nitrooxy)hexanamido)succinate

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To a solution of compound T (0.25 g, 0.31 mmol) in acetonitrile (10 ml), sodium iodide (0.18 g, 1.25 mmol) was added. The reaction was heated to 120° C. for 60 minutes under microwave irradiation. The resulting mixture was cooled, filtered and the solvent was removed under reduced pressure to give a solid product which was used without further purification.

V) 4-(2-((8S,9R,10S,11S,13S,14S,16R,17S)-9-fluoro-11-hydroxy-16,17-((1-methylethylidene)bis(oxy))-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,1 5,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1-(4-(nitrooxy)butyl) 2-(6-(nitrooxy)hexanamido)succinate

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To a solution of compound U (0.27 g, 0.31 mmol) in acetonitrile (10 ml), silver nitrate (0.21 g, 1.24 mmol) was added. The reaction was heated to 120° C. for 5 minutes under microwave irradiation. The resulting mixture was cooled, filtered and the solvent was removed under reduced pressure. The residue was purified by flash chromatography (Biotage System, column FLASH 25+M™ KP-Sil, eluent:gradient n-hexane/acetone 8/2 (120 ml), to n-hexane/acetone 55/45 during 480 ml, n-hexane/acetone 55/45 (120 ml)). The product (0.13 g) was obtained.

1H-NMR: (DMSO), δ: 7.18 (1H, d); 6.59 (1H, d); 6.32 (1H, dd); 6.13 (1H, s); 5.02-4.88 (4H, m); 4.51-4.40 (5H, m); 4.27-4.11 (2H, m); 3.05 (1H, dd); 2.90 (1H, dd); 2.68-2.30 (4H, m); 2.27 (2H, t); 2.27-2.00 (2H, m); 1.90-1.40 (18H, m); 1.21 (3H, s); 0.88 (3H, s).

Example 17

Synthesis of 1-(2,3-bis(nitrooxy) propyl) 4-(2-((9R,10S,11S,13S,16R,17S)-9-fluoro-11-hydroxy-16,17-((1-methylethylidene)bis(oxy))-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17 -dodecahydro-3H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-2-aminosuccinate hydrochloride

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W) 1-allyl-4-(4-nitrophenyl)-2-(tert-butoxycarbonylamino) succinate

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To a solution of 4-(allyloxy)-3-(tert-butoxycarbonylamino)-4-oxobutanoic acid (3.0 g, 11.0 mmol) in dichloromethane (50 ml), 4-nitrophenol (1.4 g, 11.0 mmol) and DMAP (cat. amount) were added. The reaction was cooled at 0° C. and EDAC(2.85 g, 15.0 mmol) was added. The reaction was stirred at room temperature for 12 hours. The solvent was evaporated under vacuum. The residue was purified by flash chromatography (Biotage System, column FLASH 65+M™ KP-Sil, eluent:gradient n-hexane/ethyl acetate 95/5 (450 ml), to n-hexane/ethyl acetate 6/4 during 4500 ml, n-hexane/ethyl acetate 6/4 (900 ml)). The product (1.5 g) was obtained.

X) 1-(2,3-bis(nitrooxy)propyl) 4-(4-nitrophenyl) 2-(tert-butoxycarbonylamino)succinate

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To a solution of compound W (1.5 g, 3.8 mmol) in acetonitrile (60 ml), silver nitrate (0.63 g, 3.8 mmol) was added. The reaction was cooled at −15° C. and iodine (0.96 g, 3.8 mmol) was added. The reaction was stirred at 0° C. for 1 hour. Silver nitrate (1.27 g, 7.6 mmol) was added and the mixture was stirred at 70° C. for 7 days adding silver nitrate (0.96 g, 3.8 mmol) every day. The solvent was evaporated under vacuum. The residue was purified by flash chromatography (Biotage System, column FLASH 65+M™ KP-Sil, eluent:gradient n-hexane/ethyl acetate 95/5 (450 ml), to n-hexane/ethyl acetate 6/4 during 4500 ml, n-hexane/ethyl acetate 6/4 (900 ml)). The product (0.54 g) was obtained.

Y) 1-(2,3-bis(nitrooxy)propyl) 4-(2-((9R,10S,11S,13S,16R,17S)-9-fluoro-11-hydroxy-16,17-((1-methylethylidene)bis(oxy))-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17 -dodecahydro-3H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-2-(tert-butoxy carbonylamino)succinate

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To a solution of triamcinolone acetonide (0.21 g, 0.5 mmol) in dichloromethane (13 ml), compound X (0.26 g, 0.5 mmol) and DMAP (0.06 g, 0.5 mmol)) were added. The reaction was stirred at room temperature for 12 hours. The solvent was evaporated under vacuum. The residue was purified by flash chromatography (Biotage System, SNAP Cartridge silica 100 g, eluent: gradient n-hexane/ethyl acetate 88/12 (150 ml), to ethyl acetate during 1500 ml, ethyl acetate (300 ml)). The product (0.4 g) was obtained.

Z) 1-(2,3-bis(nitrooxy)propyl) 4-(2-((9R,10S,11S,13S,16R,17S)-9-fluoro-11-hydroxy-16,17-((1-methylethylidene)bis(oxy))-10,13-dimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17 -dodecahydro-3H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl) 2-aminosuccinate hydrochloride

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A solution of compound Y (0.4 g, 0.49 mmol) in dichloromethane (8 ml) was stirred at room temperature. HCl gas was buddle in the solution for 15 minutes. The solvent evaporated under vacuum. The residue was purified by reverse phase flash chromatography (Biotage column FLASH 25+M™, eluent: water/acetonitrile 1/1. The product (0.13 g) was obtained

1H-NMR: (DMSO), δ: 7.30 (1H, d); 6.23 (1H, dd); 6.02 (1H, s); 5.66 (1H, m); 5.49 (1H, m); 5.17 (1H, dd), 4.97 (1H, dd); 4.89-4.79 (3H, m); 4.48 (1H, dm); 4.38 (1H, dd), 4.20 (1H, m); 3.82 (1H, m); 2.78 (1H, dm); 2.68-2.49 (7H, m); 2.10-1.75 (3H, m); 1.54 (1H, m); 1.49 (5H, m); 1.35 (4H, m); 1.15 (3H, s); 0.83 (3H, s).