Nitric oxide donor compounds

Abstract

The invention relates to nitric oxide donor compounds and their use for treating cardiovascular diseases, inflammation, pain, fever, gastrointestinal disorders, ophthalmic diseases, hepatic disorders, renal diseases, respiratory disorders, immunological diseases, bone metabolisms dysfunctions, central and peripheral nervous system diseases, sexual dysfunctions, infectious diseases, for the inhibition of platelet aggregation and platelet adhesion, for treating pathological conditions resulting from abnormal cell proliferation, vascular diseases. The invention also relates to compositions comprising at least one nitric oxide releasing compounds of the invention and composition comprising at least one nitric oxide releasing compounds according to the invention and at least one 15 therapeutic agent.

Description

The invention relates to nitric oxide donor compounds and their pharmaceutical compositions. The invention also relates to novel compositions comprising at least one nitric oxide releasing compounds and at least one therapeutic agent.

The invention also relates to the use of the nitric oxide donor compounds and their compositions for treating cardiovascular diseases, inflammation, pain, fever, gastrointestinal disorders, ophthalmic diseases, hepatic disorders, renal diseases, respiratory disorders, immunological diseases, bone metabolism dysfunctions, central and peripheral nervous system diseases, sexual dysfunctions, infectious diseases, for the inhibition of platelet aggregation and platelet adhesion, for treating pathological conditions resulting from abnormal cell proliferation, vascular diseases.

Nitric oxide (commonly referred to as NO) has been implicated in a wide range of biological functions. As a result, NO, and materials that release NO, are candidate therapeutics for a range of diverse disease states.

Nitric oxide donor compounds have been used for many years in the treatment of various clinical conditions, particularly coronary artery disease. The nitrovasodilators such as nitroglycerin (GTN) has been used for the treatment of various types of myocardial ischemia. Because of its pathogenic nature (chronicity with acute exacerbation), prophylactic and acute treatments are necessary to prevent complications with potentially fatal outcomes (>25% death for acute MI). Particularly the phenomenon of tolerance to the anti-anginal effects or GTN and to all other existing organic nitrates is of a special clinical significance. Early development of tolerance to the drug is by far the most serious drawback of nitrate therapy.

Other known methods of NO delivery include soluble, short-term NO donors, such as S-nitroso-N-acetyl-D,L-penicillamine (SNAP) and incorporation of NO donors into polymeric matrices. In general, NO-nucleophile complexes (e.g., diazeniumdiolate ions) and NO-donating groups (e.g., S-nitrosothiols) may spontaneously decompose in aqueous environments, such as physiological or bodily fluids, to release NO. This rapid, spontaneous decomposition, however, may not be a favourable property for many therapeutic applications. Generally, a slower rate of decomposition and more steady evolution of NO are more efficacious.

Many of the existing NO donors must be administered intravenously, which results in rapid onset of decreasing blood pressure accompanied by unwanted side effects. Their effect does not extend beyond the period of infusion. Another undesirable side effect of some NO donors includes an increase in heart rate. A need exists for an NO donor compound to treat diseases that does not induce undesirable side effects.

The invention is directed to compounds that are particularly useful as nitric oxide donors having an improved pharmacological profile.

The invention provides compounds of the formula (I) and pharmaceutically acceptable salts or stereoisomers thereof

wherein:

• s is 1;
• s′ and s″ are independently selected from 0 or 1, preferably s′ or s″ is 1 or s′ and s″ are both 0;
• m, m′ and m″ are each independently selected from 0 or 1 with the proviso that when m, m′ or m″ are 0, A is linked directly to the groups —(Y—ONO₂), —(Y′—ONO₂), —(Y″—ONO₂), preferably at least one of m, m′ or m″ is 1, or more preferably m, m′ and m″ are 0,
• B at each occurrence is independently selected from:

• preferably B is

• A is a radical selected from the group consisting of:

wherein:

• in formulas (IIa)-(IIm) and (IIo)-(IIu), R₁ is selected from:
• H, —C(O)O—C(CH₃)₃, —C(O)—R_1x, —C(O)O—R_1x, wherein R_1x is one of the groups —[(B)_m—(Y—ONO₂)]_s, —[(B)_m′—(Y′—ONO₂)]_s′ or —[(B)_m″—(Y″—ONO₂)]_s″ of formula (I) wherein m, m′ and m″ are 0 and Y, Y′ and Y″ are as below reported;
• in formulas (IIa)-(IIu) R₂ is selected from:
• —C(O)OH, —C(O)—OC(CH₃)₃, —C(O)OR_2x, —C(O)NHR_2xx, —C(O)N(CH₃)R_2xx where R_2x is one of the groups —[(B)_m—(Y—ONO₂)]_s, —[(B)_m′—(Y′—ONO₂)]_s′ or —[(B)_m″—(Y″—ONO₂)]_s″ of formula (I) wherein m, m′ and m″ are 0 or 1, B is as above defined and Y, Y′ and Y″ are as below reported,
• R_2xx is one of the groups —[(B)_m—(Y—ONO₂)]_s, —[(B)_m′—(Y′—ONO₂)]_s′ or —[(B)_m″—(Y″—ONO₂)]_s″ of formula (I) wherein m, m′ and m″ are 0 and Y, Y′ and Y″ are as below reported,
• or R₂ is the group R₄:

• in formula (IIa), R_a is selected from the groups consisting of:
• a) —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 with groups such as —F, —Cl, I, —NO₂, —CF₃, —CH₃, CN, C₆H₅CO—;
• or R_a is 2,4-dichlorobenzyl, 3,4-dichlorobenzyl, 3,4-difluorobenzyl, 3-triptophanyl-CH₂—, 3-benzothienyl-CH₂—, 4-imidazolyl-CH₂—, 9-anthranyl-CH₂—, cyclohexyl, cyclohexyl-CH₂—, cyclohexyl-(CH₂)₂—, cyclopentyl-CH₂—, (C₆H₅)₂CH—, 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—, or —P(═O)(OCH₃)₂;
• b) HS—CH₂—, R_bx—C(O)—S—CH₂—, R_bx—OC(O)—S—CH₂—, R_bx—NH—C(O)S—CH₂— wherein R_bx is one of the groups —[(B)_m—(Y—ONO₂)]_s, —[(B)_m′—(Y′—ONO₂)]_s′ or —[(B)_m″—(Y″—ONO₂)]_s″ of formula (I) wherein m, m′ and m″ are 0 and Y, Y′ and Y″ are as below defined;
• c) R_xO—CH₂—, R_xO—CH(CH₃)—, (R_xO)-p-C₆H₄—CH₂—, 4-(R_xO)-3,5-diiodobenzyl-, 4-(R_xO)-3-nitrobenzyl- wherein R_x is H, R_xx—C(O)—, R_xx—OC(O)—, R_xx—NHC(O)— wherein R_xx is one of the groups —[(B)_m—(Y—ONO₂)]_s, —[(B)_m′—(Y′—ONO₂)]_s′ or —[(B)_m″—(Y″—ONO₂)]_s″ of formula (I) wherein m, m′ and m″ are 0 and Y, Y′ and Y″ are as below defined;
• d) R_gC(O)CH₂—NH—, R_gC(O)CH₂—, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is OH, (CH₃)₃CO—, R_gx—O—, R_gxx—NH—, R_gxx—N(CH₃)— wherein R_gx is one of the groups —[(B)_m—(Y—ONO₂)]_s, —[(B)_m′—(Y′—ONO₂)]_s′ or —[(B)_m″—Y″—ONO₂)]_s″ of formula (I) wherein m, m′ and m″ are 0 or 1, B is as above defined and Y, Y′ and Y″ are as below reported, R_gxx is one of the groups —[(B)_m—(Y—ONO₂)]_s, —[(B)_m′—(Y′—ONO₂)]_s′ or —[(B)_m″—(Y″—ONO₂)]_s″ of formula (I) wherein m, m′ and m″ are 0 and Y, Y′ and Y″ are as below reported,
• or R_g is the group R_gg:

• e) R_hNH(CH₂)_p— or R_iNH(═NH)NH—(CH₂)₃—, wherein p is an integer from 0 to 4, R_h is H, (CH₃)₃C—OC(O)—, R_hh—C(O)— or R_hh—OC(O)—, R_i is H, R_ii—C(O)— or R_ii—OC(O)—, wherein R_hh and R_ii are each independently one of the groups —[(B)_m—(Y—ONO₂)]_s, —[(B)_m′—(Y′—ONO₂)]_s′ or —[(B)_m″—(Y″—ONO₂)]_s″ of formula (I) wherein m, m′ and m″ are 0 and Y, Y′ and Y″ are as below defined;
• in formula (IIc) R_c is selected from the following groups:
• a′) H, CH₃, isopropyl, isobutyl, sec-butyl, methylthio-(CH₂)₂—, phenyl, benzyl, biphenyl-CH₂, 3-triptophanyl-CH₂—, NH₂—CO—CH₂—, NH₂—CO—(CH₂)₂—;
• b′) HS—CH₂—, R_bx—C(O)—S—CH₂—, R_bx—OC(O)—S—CH₂—, R_bx—NH—C(O)S—CH₂— wherein R_bx is one of the groups —[(B)_m—(Y—ONO₂)]_s, —[(B)_m′—(Y′—ONO₂)]_s′ or —[(B)_m″—(Y″—ONO₂)]_s″ of formula (I) wherein m, m′ and m″ are 0 and Y, Y′ and Y″ are as below defined;
• c′) R_xO—CH₂—, R_xO—CH(CH₃)—, R_xO—C₆H₄—CH₂— wherein R_x is H, R_xx—C(O)—, R_xx—OC(O)—, R_xx—NHC(O)— wherein R_xx is one of the groups —[(B)_m—(Y—ONO₂)]_s, —[(B′)_m′—(Y′—ONO₂)]_s′ or —[(B″)_m″—(Y″—ONO₂)]_s″ of formula (I) wherein m, m′ and m″ are 0 and Y, Y′ and Y″ are as below defined;
• d′) R_gC(O)CH₂—, R_gC(O)(CH₂)₂— wherein R_g is OH, (CH₃)₃CO—, R_gx—O—, R_gxx—NH—, R_gxx—N(CH₃)— wherein R_gx is one of the groups —[(B)_m—(Y—ONO₂)]_s, —[(B)_m′—(Y′—ONO₂)]_s′ or —[(B)_m″—(Y″—ONO₂)]_s″ of formula (I) wherein m, m′ and m″ are 0 or 1, and B is as above defined and Y, Y′ and Y″ are as below reported,
• R_gxx is one of the groups —[(B)_m—(Y—ONO₂)]_s, —[(B)_m′—(Y—ONO₂)]_s′ or —[(B)_m″—(Y″—ONO₂)]_s″ of formula (I) wherein m, m′ and m″ are 0 and Y, Y′ and Y″ are as below reported;
• e′) R_hNH(CH₂)_p— or R_iNH(═NH)NH—(CH₂)₃—, wherein p is an integer from 0 to 4, R_h is H, (CH₃)₃C—OC(O)—, R_hh—C(O)— or R_hh—OC(O)—, R_i is H, R_ii—C(O)— or R_ii—OC(O)—, wherein R_hh and R_ii are each independently one of the groups —[(B)_m—(Y—ONO₂)]_s, —[(B)_m′—(Y′—ONO₂)]_s′ or —[(B)_m″—(Y″—ONO₂)]_s″ of formula (I) wherein m, m′ and m″ are 0 and Y, Y′ and Y″ are as below defined;
• in formula (IIf) Ph is phenyl, a′ is equal to 0, 1, 2, or 3, and a is equal to 0 or 1 with the proviso that a is 0 or 1 when a′ is 0 and a is 0 when a′ is 1, 2 or 3;
• in formula (IIi) the group R₂ can be attached to one of the positions 1, 2 or 3 of the cyclohexyl ring;
• in formulae (IIj) and (IIk) the symbol represents a single bond or a double bond;
• in formula (IIk) the group R₂ can be attached to one of the positions 1, 2 or 3 of the piperidyl ring;
• in formula (IIl), R_L is selected from:
• H, methyl, propyl, allyl, (C₆H₅)₂CH—, 1-naphthyl-CH₂—, benzyl, 2-bromobenzyl, 2-chlorobenzy, 3-chlorobenzyl, 4-fluorobenzyl, 4-bromobenzyl, 4-methylbenzyl;
• in formula (IIm) R_m is selected from:
• benzyl, 2-bromobenzyl, 4-bromobenzyl, 4-methylbenzyl;
• in formula (IIn) R_n is selected from:
• —H, —C(O)—R_nx, —C(O)—R_nx or —(CH₂)₂—NH—R_h wherein R_h is —H, —C(O)O—C(CH₃)₃, —C(O)—R_hh, —C(O)O—R_hh wherein R_nx and R_hh are each independently one of the groups —[(B)_m—(Y—ONO₂)]_s, —[(B)_m′—(Y′—ONO₂)]_s′ or —[(B)_m″—(Y″—ONO₂)]_s″ of formula (I) wherein m, m′ and m″ are 0 and Y, Y′ and Y″ are as below defined;
• in formula (IIp), c is 0 or 1 and R₂ can be attached to the position 1, 2 or 3 of the phenyl ring;
• in formula (IIs), R₃ is selected from:
• OH, —OC(O)—R_3x, —OC(O)O—R_3x, —OC(O)—NH—R_3x wherein R_3x is one of the groups —[(B)_m—(Y—ONO₂)]_s, —[(B)_m′—(Y′—ONO₂)]_s′ or —[(B)_m″—(Y″—ONO₂)]_s″ of formula I wherein m, m′ and m″ are 0 and Y, Y′ and Y″ are as below defined;
• in formula (IIs) R_s is selected from the following groups:
• a″) —H, —CH₃, isopropyl, isobutyl, sec-butyl, tert-butyl, methylthio-(CH₂)₂—, benzyl, 2-monosubstituted benzyl, or 3-monosubstituted benzyl, 3-triptophanyl-CH₂—, 4-imidazolyl-CH₂—, NH₂—CO—CH₂—, NH₂—CO—(CH₂)₂—;
• b″) HS—CH₂—, R_bx—C(O)—S—CH₂—, R_bx—OC(O)—S—CH₂—, R_bx—NH—C(O)S—CH₂— wherein R_bx is one of the groups —[(B)_m—(Y—ONO₂)]_s, —[(B)_m′—(Y′—ONO₂)]_s′ or —[(B)_m″—(Y″—ONO₂)]_s″ of formula (I) wherein m, m′ and m″ are 0 and Y, Y′ and Y″ are as below defined;
• c″) R_xO—CH₂—, R_xO—CH(CH₃)—, (R_xO)-p-C₆H₄—CH₂—, 4-(R_xO)-3,5-diiodobenzyl-, 4-(R_xO)-3-nitrobenzyl- wherein R_x is H, R_xx—C(O)—, R_xx—OC(O)—, R_xx—NHC(O)— wherein R_xx is one of the groups —[(B)_m—(Y—ONO₂)]_s, —[(B)_m′—(Y′—ONO₂)]_s′ or —[(B)_m″—(Y″—ONO₂)]_s″ of formula (I) wherein m, m′ and m″ are 0 and Y, Y′ and Y″ are as below defined;
• d″) R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is OH, (CH₃)₃CO—, R_gx—O—, R_gxx—NH—, R_gxx—N(CH₃)— wherein R_gx is one of the groups —[(B)_m—(Y—ONO₂)]_s—, [(B)_m′—(Y′—ONO₂)]_s′ or —[(B)_m″—(Y″—ONO₂)]_s″ of formula (I) wherein m, m′ and m″ are 0 or 1, B is as above defined and Y, Y′ and Y″ are as below reported, R_gxx is one of the groups —[(B)_m—(Y—ONO₂)]_s, —[(B)_m′—(Y′—ONO₂)]_s′ or —[(B)_m″—(Y″—ONO₂)]_s″ of formula (I) wherein m, m′ and m″ are 0 and Y, Y′ and Y″ are as below reported,
• e″) R_hNH(CH₂)_p— or R_iNH(═NH)NH—(CH₂)₃—, wherein p is an integer from 0 to 4, R_h is H, (CH₃)₃C—OC(O)—, R_hh—C(O)— or R_hh—OC(O)—, R_i is H, R_ii—C(O)— or R_ii—OC(O)—, wherein R_hh and R_ii are each independently one of the groups —[(B)_m—(Y—ONO₂)]_s, —[(B)_m′—(Y′—ONO₂)]_s′ or —[(B)_m″—(Y″—ONO₂)]_s″ of formula (I) wherein m, m′ and m″ are 0 and Y, Y′ and Y″ are as below defined;
• in formula (IIt) d is an integer from 2 to 5, d′ is 0 or 1, with the proviso that d′ is 0 when d is an integer from 3 to 5, R_t is H, —C(O)—R_tt or —C(O)O—R_tt wherein R_tt is one of the groups —[(B)_m—(Y—ONO₂)]_s, —[(B′)_m′—(Y′—ONO₂)]_s′ or —[(B″)_m″—(Y″—ONO₂)]_s″ of formula (I) wherein m, m′ and m″ are 0;
• in formula (IIu) a and b are each independently 0 or 1, R_x is H, —C(O)—R_xx, —C(O)O—R_xx—, —C(O)NH—R_xx wherein R_xx is one of the groups —[(B)_m—(Y—ONO₂)]_s, —[(B)_m′—(Y′—ONO₂)]_s′ or —[(B)_m″—(Y″—ONO₂)]_s″ of formula (I) wherein m, m′ and m″ are 0 and Y, Y′ and Y″ are as below defined;
• Y, Y′ and Y″ of the groups (Y—ONO₂), —(Y′—ONO₂) and —(Y″—ONO₂) of formula (I) are bivalent radicals and they are each independently selected from:
• A)
  • a straight or branched C₁-C₂₀ alkylene, preferably a straight or branched C₂-C₁₀ alkylene
  • a straight or branched C₁-C₂₀ alkylene substituted with one or more —ONO₂ group(s), preferably a straight or branched C₂-C₁₀ alkylene substituted with a —ONO₂ group;
  • a cycloalkylene having 5 to 7 carbon atoms, the ring being optionally substituted with a straight or branched C₁-C₁₀ alkyl;
• B)

wherein n⁰ is an integer from 0 to 20, preferably n⁰ is from 0 to 5, more preferably n⁰ is 0 or 1,

• n¹ is an integer from 1 to 20, preferably n¹ is an integer from 1 to 10, more preferably n¹ is an integer from 2 to 6;
• more preferably in formula (IB) and (IB′) n⁰ is 0 or 1 and n¹ is an integer from 1 to 10;wherein in formulas (IB) and (IB′) the —ONO₂ group is linked to —(CH₂)_n¹—;
• C)

wherein:

• n¹ is an integer from 1 to 20, preferably n¹ is an integer from 1 to 10, or more preferably n¹ is an integer from 2 to 6,
• n² is an integer from 0 to 2, preferably n² is 1,
• R² is H or CH₃, preferably R² is CH₃,
• X₁ is —OC(O)— or —C(O)O—;more preferably in formula (IC) n¹ is an integer from 1 to 10, n² is 1 and R² is CH₃, X₁ is —C(O)O—;wherein in formula (IC) the —ONO₂ group is linked to —(CH₂)_n¹—;
• D)

wherein in formula (ID):

• n¹ is an integer from 1 to 20, preferably n¹ is an integer from 1 to 10, or more preferably n¹ is an integer from 2 to 10,
• n², R² and X₁ are as defined above;
• Y¹ is —CH₂—CH₂— or —CH₂═CH—(CH₂)_n^2a— wherein n^2a is an integer from 0 to 5, preferably n^2a is 0,wherein in formula (ID) the —ONO₂ group is linked to —(CH₂)_n¹—; preferably in formula (ID), n² is 1 and R² is CH₃, Y¹ is —CH═CH—(CH₂)_n^2a— wherein n^2a is 0, X₁ is —C(O)O—, n¹ is an integer from 1 to 10;
• E)

wherein X₂ is —O—, —S—, —NH— or —N(CH₂CH₂OCH₃)—, preferably X₂ is —O— or —NH—,

• n³ is an integer from 1 to 5, preferably n³ is 1,
• n₃ is an integer from 0 to 10, preferably from 0 to 4, more preferably n₃ is 0,
• n₄ an integer from 1 to 10, preferably from 1 to 4, more preferably n₄ is 1
• preferably n₃ is 0 and n₄ is 1;
• n_3′ is an integer from 0 to 10, preferably n_3′ is from 0 to 4,
• n_4′ is an integer from 1 to 10, preferably from 1 to 4,
• more preferably n_3′ is 0 and n_4′ is 1,
• R² is H or —CH₃, preferably R² is H,
• preferably in (IE) n³ is an integer from 1 to 5, n₃ is 0 and n₄ is from 1 to 4, n_3′ is 0 and n_4′ is from 1 to 4, R² is H and X₂ is —O— or —NH—,
• more preferably in (IE) n³ is 1, n³ is 0 and n₄ is 1, n_3′ is 0 and n_4′ is 1, R² is H and X₂ is —O— or —NH—,wherein in formula (IE) the —ONO₂ group is linked to the —(CH₂)_n4′— group;
• F)

wherein:

• n⁵ is an integer from 0 to 10, preferably n⁵ is 0 or 1;
• n⁶ is an integer from 1 to 10, preferably n⁶ is 1;
• R⁴, R⁵, R⁶, R⁷ are the same or different, and are H or straight or branched C₁-C₄ alkyl, preferably R⁴, R⁵, R⁶, R⁷ are H;wherein in formula (IF) the —ONO₂ group is linked to

wherein n⁶ 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, sulfur,
• and is selected from the group consisting of:

• G)

wherein n⁰ is an integer from 0 to 10,

• n⁷ is an integer from 1 to 10, preferably n⁷ is an integer from 1 to 6, more preferably n⁷ is 1;
• n⁸ is an integer from 0 to 10, preferably n⁸ is an integer from 0 to 6, more preferably n⁸ is 0;
• R⁸ is CH₃ or CH₂ONO₂,
• more preferably in formula (IG) n⁰ is 0, n⁷ is 1, n⁸ is 0 and R⁸ is CH₃ or CH₂ONO₂,wherein in formula (IG) the —ONO₂ group is linked to the group

• preferably Y and Y′ or Y″ are equal;
• preferred (Y—ONO₂), —(Y′—ONO₂) or —(Y″—ONO₂) groups are:

• more preferably the groups (Y—ONO₂), —(Y″—ONO₂), and —(Y″—ONO₂) are each independently selected from:

• with the proviso that in formula (I) s′ and s″ cannot be both 1 when:
  • A is the radical of formulas (IIb), (IId)-(IIr), or
  • A is the radical of formula (IIt) wherein d is from 3 to 5 and d′ is 0, or
  • A is the radical of formula (IIu) wherein a is 0;
• with the proviso that s′ and s″ can be both 1 when:
  • A is the radical of formulas (IIa), (IIc) or (IIs) and R_a, R_c and R_s are selected from:
    • R_bx—C(O)—S—CH₂—, R_bx—OC(O)—S—CH₂—, R_bx—NH—C(O)S—CH₂— wherein R_bx is one of the groups —[(B)_m—(Y—ONO₂)]_s, —[(B)_m′—(Y′—ONO₂)]_s′ or —[(B)_m″—(Y″—ONO₂)]_s″ wherein m, m′ and m″, B, Y, Y′ and Y″ are as above defined;
    • R_xO—CH₂—, R_xO—CH(CH₃)—, (R_xO)-p-C₆H₄—CH₂—, 4-(R_xO)-3,5-diiodobenzyl, 4-(R_xO)-3-nitrobenzyl- wherein R_x is R_xx—C(O)—, R_xx—OC(O)— or R_xx—NHC(O)— wherein R_xx is one of the groups —[(B)_m—(Y—ONO₂)]_s, —[(B)_m′—(Y′—ONO₂)]_s′ or —[(B)_m″—(Y″—ONO₂)]_s″ wherein m, m′ and m″, B, Y, Y′ and Y″ are as above defined;
    • R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₂—, wherein R_g is OH, (CH₃)₃CO—, R_gx—O—, R_gxx—NH—, R_gxx—N(CH₃)— wherein R_gx and R_gxx are one of the groups —[(B)_m—(Y—ONO₂)]_s, —[(B)_m′—(Y′—ONO₂)]_s′ or —[(B)_m″—(Y″—ONO₂)]_s″ wherein m, m′ and m″, B, Y, Y′ and Y″ are as above defined;
    • R_hNH(CH₂)_p— or R_iNH(═NH)NH—(CH₂)₃—, wherein p is an integer from 0 to 4, R_h is R_hh—C(O)— or R_hh—OC(O)—, R_i is R_ii—C(O)— or R_ii—OC(O)—, wherein R_hh and R_ii are one of the groups —[(B)_m—(Y—ONO₂)]_s, —[(B)_m′—(Y′—ONO₂)]_s′ or —[(B)_m″—(Y″—ONO₂)]_s″ wherein m, m′ and m″, B, Y, Y′ and Y″ are as above defined;
  • A is the radical of formula (IIt) wherein d′ is 1 and d is 2 and R_t is —C(O)—R_tt or —C(O)O—R_tt wherein R_tt is one of the groups —[(B)_m—(Y—ONO₂)]_s, —[(B)_m′—(Y′—ONO₂)]_s′ or —[(B)_m″—(Y″—ONO₂)]_s″ wherein m, m′ and m″, B, Y, Y′ and Y″ are as above defined;
  • A is the radical of formula (IIu) wherein a is 1 and R_x is —C(O)—R_xx, —C(O)O—R_xx— or —C(O)NH—R_xx wherein R_xx is one of the groups —[(B)_m—(Y—ONO₂)]_s, —[(B)_m′—(Y′—ONO₂)]_s′ or —[(B)_m″—(Y″—ONO₂)]_s″ of formula (I) wherein m, m′ and m″, B, Y, Y′ and Y″ are as above definedwith the proviso that the following compounds of formula (I) are excluded:
• 3-(nitrooxy)propyl 2-(tert-butoxycarbonylamino)-4-phenyl butanoate,
• 3-(nitrooxy)propyl 2-amino-4-phenylbutanoate
• 3-(nitrooxy)propyl 2-amino-4-phenylbutanoate hydrochloride,
• 4-(nitrooxy)butyl 2-(tert-butoxycarbonylamino)-4-phenylbutanoate,
• 4-(nitrooxy)butyl 2-amino-4-phenylbutanoate,
• 4-(nitrooxy)butyl 2-amino-4-phenylbutanoate hydrochloride,
• (2-(nitrooxy)ethoxy)methyl 2-(tert-butoxycarbonylamino)-4-phenylbutanoate,
• (2-(nitrooxy)ethoxy)methyl 2-amino-4-phenylbutanoate,
• (2-(nitrooxy)ethoxy)methyl 2-amino-4-phenylbutanoate hydrochloride,
• 1-tert-butyl 2-(4-(nitrooxy)butyl)pyrrolidine-1,2-dicarboxylate,
• 4-(nitrooxy)butyl pyrrolidine-2-carboxylate hydrochloride,
• 4-(nitrooxy)butyl pyrrolidine-2-carboxylate hydrochloride,
• 1-tert-butyl 2-(3-(nitrooxy)propyl)pyrrolidine-1,2-dicarboxylate,
• 3-(nitrooxy)propyl pyrrolidine-2-carboxylate,
• 3-(nitrooxy)propyl pyrrolidine-2-carboxylate hydrochloride,

Another embodiment relates to compounds of formula (I)

wherein s is 1 and m is 0, s′ and s″ are 0,

• A is selected from:

wherein

• R₁ is H or —C(O)—OC(CH₃)₃,
• R₂ is —C(O)OR_2x, —C(O)NHR_2x, —C(O)N(CH₃)R_2x and more preferably R₂ is —C(O)OR_2x or —C(O)NHR_2x, wherein R_2x is (Y—ONO₂) of formula (I) wherein Y is below reported,
• R_a of formula (IIa) is selected from:
• a) H, CH₃, isopropyl, isobutyl, sec-butyl, methylthio-(CH₂)₂—, benzyl, C₆H₅—CH₂—CH₂—, 3-triptophanyl-CH₂—, NH₂—CO—CH₂—, NH₂—CO—(CH₂)₂—, 4-imidazolyl-CH₂—;
• b) HS—CH₂—,
• c) R_xO—CH₂—, R_xO—CH(CH₃)—, (R_xO)-p-C₆H₄—CH₂—, wherein R_x is H,
• d) R_gC(O)CH₂, R_gC(O)(CH₂)₂—, wherein R_g is OH, (CH₃)₃CO—, or the group R_gg:

• e) R_hNH(CH₂)_p— or R_iNH(═NH)NH—(CH₂)₃—, wherein p is an integer equal to 3 or 4, R_h is H or (CH₃)₃C—OC(O)—, R_i is H;
• R_c of formula (IIc) is selected from the group comprising:
• H, CH₃, isopropyl, isobutyl, sec-butyl, methylthio-(CH₂)₂—, benzyl, 3-triptophanyl-CH₂, 4-imidazolyl-CH₂—, NH₂—CO—CH₂—, NH₂—CO—(CH₂)₂—;
• R_L of formula (IIl) is H,
• Y of the group (Y—ONO₂) is selected from:
• A)
  • a straight or branched C₂-C₁₀ alkylene
  • a straight or branched C₂-C₁₀ alkylene substituted with a —ONO₂ group;
• B)

wherein in formula (IB)

• n⁰ is from 0 to 5 and n¹ is an integer from 1 to 10;
• C)

wherein in formula (IC)

• n¹ is an integer from 1 to 10,
• n² is 1 and R² is CH₃, X₁ is —C(O)O—;
• D)

wherein in formula (ID):

• n² is 1 and R² is CH₃,
• Y¹ is —CH═CH—(CH₂)_n^2a— wherein n^2a is 0,
• X₁ is —C(O)O— and n¹ is an integer from 1 to 10;
• E)

wherein in formula (IE)

• n³ is from 1 to 5,
• n₃ is 0 and n₄ is from 1 to 4,
• n_3′ is 0 and n_4′ is from 1 to 4,
• X₂ is —O— or —NH—,
• R² is H,
• preferably the group —(Y—ONO₂) is selected from:

the following are preferred compounds according to the present invention:

Another embodiment provides compounds of formula (I)

wherein s and m are 1,

• s′ and s″ are 0,
• B is selected from:

• more preferably B is

• A is a radical selected from:

wherein

• R₁ is H or —C(O)O—C(CH₃)₃,
• R₂ is —C(O)OR_2x wherein R_2x is the group —[(B)—(Y—ONO₂)] of formula (I) wherein B is as above defined and Y is below defined,
• R_a of formula (IIa) is selected from:
• a) H, CH₃, isopropyl, isobutyl, sec-butyl, methylthio-(CH₂)₂—, benzyl, C₆H₅—CH₂—CH₂—, 3-triptophanyl-CH₂—, NH₂—CO—CH₂—, NH₂—CO—(CH₂)₂—, 4-imidazolyl-CH₂—;
• b) HS—CH₂—;
• c) R_xO—CH₂—, R_xO—CH(CH₃)— or (R_xO)-p-C₆H₄—CH₂—, wherein R_x is H;
• d) R_gC(O)CH₂, R_gC(O)(CH₂)₂—, wherein R_g is OH or (CH₃)₃C—O—, or the group R_gg:

• e) R_hNH(CH₂)_p— or R_iNH(═NH)NH—(CH₂)₃— wherein p is an integer equal to 3 or 4, R_h is H or (CH₃)₃C—OC(O)—, R_i is H;
• R_L of formula (IIl) is H;
• Y of the group —(Y—ONO₂) is selected from:
• A)
  • a straight or branched C₂-C₁₀ alkylene,
  • a straight or branched C₂-C₁₀ alkylene substituted with a —ONO₂ group;
• E)

wherein in formula (IE)

• n³ is from 1 to 5
• n₃ is 0 and n₄ is from 1 to 4,
• n_3′ is 0 and n_4′ is from 1 to 4,
• X₂ is —O— or —NH—,
• R² is H;preferably —(Y—ONO₂) is selected from:

The following are preferred compounds according to the present invention:

Another embodiment relates to compounds of formula (I)

wherein s is 1 and m is 0,

• s′ and s″ are 0,
• A is a radical selected from

wherein is R₁ is —C(O)R_1x, —C(O)OR_1x wherein R_1x is the group —(Y—ONO₂) of formula (I) wherein Y is below reported,

• R₂ in formulas (IIa) (IIc) and (IIl) is —C(O)OH, —C(O)—OC(CH₃)₃ or R₂ is the group R₄:

• R₃ in formula (IIs) is OH;
• R_a of formula (IIa) is selected from:
• a) H, CH₃, isopropyl, isobutyl, sec-butyl, methylthio-(CH₂)₂—, benzyl, C₆H₅—CH₂—CH₂—, 3-triptophanyl-CH₂—, NH₂—CO—CH₂—, NH₂—CO—(CH₂)₂—, 4-imidazolyl-CH₂—;
• b) HS—CH₂—;
• c) R_xO—CH₂—, R_xO—CH(CH₃)—, (R_xO)-p-C₆H₄—CH₂— wherein R_x is H;
• d) R_gC(O)CH₂ or R_gC(O)(CH₂)₂—, wherein R_g is OH or (CH₃)₃C—O—, or R_g is the group R_gg:

• e) R_hNH(CH₂)_p— or R_iNH(═NH)NH(CH₂)₃—, wherein p is an integer equal to 3 or 4, R_h is H or (CH₃)₃C—OC(O)—, R_i is H;
• R_c of formula (IIc) is selected from:
• H, CH₃, isopropyl, isobutyl, sec-butyl, methylthio-(CH₂)₂—, benzyl, 3-triptophanyl-CH₂—, 4-imidazolyl-CH₂—, NH₂—CO—CH₂—, NH₂—CO—(CH₂)₂—;
• R_L of formula (IIl) is H;
• R_s of formula (IIs) is H, CH₃, isopropyl, isobutyl, sec-butyl, methylthio-(CH₂)₂—, benzyl, 3-triptophanyl-CH₂—, 4-imidazolyl-CH₂—, NH₂—CO—CH₂—, NH₂—CO—(CH₂)₂—;
• Y of the groups (Y—ONO₂ is selected from:
• A)
  • a straight or branched C₂-C₁₀ alkylene
  • a straight or branched C₂-C₁₀ alkylene substituted with a —ONO₂ group;
• B)

wherein in formula (IB)

• n⁰ is from 0 to 5 and n¹ is an integer from 1 to 10;
• C)

wherein in formula (IC)

• n¹ is an integer from 1 to 10,
• n² is 1 and R² is CH₃, X₁ is —C(O)O—;
• D)

wherein in formula (ID):

• n² is 1 and R² is CH₃,
• Y¹ is —CH═CH—(CH₂)_n^2a wherein n^2a is 0,
• X₁ is —C(O)O— and n¹ is an integer from 1 to 10;
• E)

wherein in formula (IE)

• n³ is from 1 to 5,
• n₃ is 0 and n₄ is from 1 to 4,
• n_3′ is 0 and n_4′ is from 1 to 4,
• X₂ is —O— or —NH—,
• R² is H,
• preferably —(Y—ONO₂) is selected from:

the following are preferred compounds according to the present invention:

Another embodiment relates to compounds of formula (I)

wherein s and s′ are 1 and m, m′ are 0,

• s″ is 0,
• A is a radical of formula (IIa)

wherein R₁ is —C(O)R_1x, or —C(O)OR_1x wherein R_1x is one of the groups —(Y—ONO₂) or —(Y′—ONO₂) of formula (I) wherein Y and Y′ are below reported,

• R₂ is —C(O)OH, —C(O)—OC(CH₃)₃ or R₂ is the group R₄:

• R_a is selected from:
• b) R_bxC(O)—S—CH₂—, R_bx—OC(O)—S—CH₂—, R_bx—NH—C(O)S—CH₂— wherein R_bx is one of the groups —(Y—ONO₂) or —(Y′—ONO₂);
• c) R_xO—CH₂—, R_xO—CH(CH₃)—, (R_xO)-p-C₆H₄—CH₂—, wherein R_x is R_xxC(O)—, R_xxOC(O)— or R_xxNHC(O)— wherein R_xx is one of the groups —(Y—ONO₂) or —(Y′—ONO₂) of formula (I) wherein Y and Y′ are below defined;
• d) R_gC(O)CH₂—, R_gC(O)(CH₂)₂—, wherein R_g is R_gx—O—, R_gxx—NH—, wherein R_gx and R_gxx are one of the groups —(Y—ONO₂) or —(Y′—ONO₂) of formula (I) wherein Y and Y′ are below defined;
• e) R_hNH(CH₂)_p— wherein p is an integer equal to 3 or 4, R_h is R_hh—C(O)— or R_hh—OC(O)— wherein R_hh is one of the groups —(Y—ONO₂) or —(Y′—ONO₂) of formula (I) wherein Y and Y′ are below defined, or R_iNH(═NH)NH—(CH₂)₃— wherein R_i is R_iiC(O)— or R_iiOC(O)— wherein R_ii is one of the groups —(Y—ONO₂) or —(Y′—ONO₂) of formula (I) wherein Y and Y′ are below defined;
• Y and Y′ of the groups —(Y—ONO₂) or —(Y′—ONO₂) are each independently selected from:
• A)
  • a straight or branched C₂-C₁₀ alkylene
  • a straight or branched C₂-C₁₀ alkylene substituted with a —ONO₂ group;
• B)

wherein in formula (IB)

• n⁰ is from 0 to 5 and n¹ is an integer from 1 to 10;
• C)

wherein in formula (IC)

• n¹ is an integer from 1 to 10,
• n² is 1 and R² is CH₃, X₁ is —C(O)O—;
• D)

wherein in formula (ID):

• n² is 1 and R² is CH₃,
• Y¹ is —CH═CH(CH₂)_n^2a— wherein n^2a is 0,
• X₁ is —C(O)O— and n¹ is an integer from 1 to 10;
• E)

wherein in formula (IE)

• n³ is from 1 to 5,
• n₃ is 0 and n₄ is from 1 to 4,
• n_3′ is 0 and n_4′ is from 1 to 4,
• X₂ is —O— or —NH—,
• R² is H,
• preferably (Y—ONO₂) and (Y′—ONO₂) are each independently selected from:

• more preferably (Y—ONO₂) and (Y′—ONO₂) are equal.The following are preferred compounds according to the present invention:

Another embodiment provides compounds of formula (I)

wherein s is 1 and m is 0,

• s′ and s″ are 0,
• A is a radical of formula (IIa) or (IIl)

wherein R₁ is —C(O)R_1x or —C(O)OR_1x wherein R_1x is the group —(Y—ONO₂) of formula (I) wherein Y is below defined,

• R₂ in formulas (IIa) and (IIl) is the group R₄

• R_a of formula (IIa) is selected from:
• a) H, CH₃, isopropyl, isobutyl, sec-butyl, methylthio-(CH₂)₂—, benzyl, C₆H₅—CH₂—CH₂—, 3-triptophanyl-CH₂—, NH₂—CO—CH₂—, NH₂—CO—(CH₂)₂—, 4-imidazolyl-CH₂—;
• b) HS—CH₂—;
• c) R_xO—CH₂—, R_xO—CH(CH₃)—, (R_xO)-p-C₆H₄—CH₂—, wherein R_x is H;
• d) R_gC(O)CH₂ or R_gC(O)(CH₂)₂—, wherein R_g is OH, (CH₃)₃O— or the group R_gg

• e) R_hNH(CH₂)_p— or R_iNH(═NH)NH—(CH₂)₃—, wherein p is an integer equal to 3 or 4, R_h is H or (CH₃)₃C—OC(O)—, R₁ is H;
• R_L of formula (IIl) is H;
• Y of the group —(Y—ONO₂) is selected from:
• A)
  • a straight or branched C₂-C₁₀ alkylene
  • a straight or branched C₂-C₁₀ alkylene substituted with a —ONO₂ group;
• B)

wherein in formula (IB)

• n⁰ is from 0 to 5 and n¹ is an integer from 1 to 10;
• C)

wherein in formula (IC)

• n¹ is an integer from 1 to 10,
• n² is 1 and R² is CH₃, X₁ is —C(O)O—;
• D)

wherein in formula (ID):

• n² is 1 and R² is CH₃,
• Y¹ is —CH═CH—(CH₂)_n^2a— wherein n^2a is 0,
• X₁ is —C(O)O— and n¹ is an integer from 1 to 10;
• E)

wherein in formula (IE)

• n³ is from 1 to 5,
• n₃ is 0 and n₄ is from 1 to 4,
• n_3′ is 0 and n_4′ is from 1 to 4,
• X₂ is —O— or —NH—,
• R² is H,
• preferably (Y—ONO₂) is selected from:

The following are preferred compounds according to the present invention:

Another embodiment relates to compounds of formula (I)

wherein s and s′ are 1 and m, m′ are 0, s″ is 0,

• A is a radical of formula (IIa) or (IIl)

wherein

• R₁ is —C(O)R_1x, —C(O)OR_1x wherein R_1x is one of the groups —(Y—ONO₂) or —(Y′—ONO₂) of formula (I) wherein Y and Y′ are below defined;
• R₂ is —C(O)OR_2x, —C(O)NHR_2x, —C(O)N)CH₃)R_2xx, wherein R_2x and R_2xx are one of the groups —(Y—ONO₂) or —(Y′—ONO₂) of formula (I) wherein Y and Y′ are below defined, more preferably R₂ is —C(O)OR_2x or —C(O)NHR_2xx;
• R_a is selected from:
• a) H, CH₃, isopropyl, isobutyl, sec-butyl, methylthio-(CH₂)₂—, benzyl, C₆H₅—CH₂—CH₂—, 3-triptophanyl-CH₂—, NH₂—CO—CH₂—, NH₂—CO—(CH₂)₂—, 4-imidazolyl-CH₂—;
• R_L in formula (IIl) is H;
• Y and Y′ of the groups (Y—ONO₂) or (Y′—ONO₂) are each independently selected from
• A)
  • a straight or branched C₂-C₁₀ alkylene
  • a straight or branched C₂-C₁₀ alkylene substituted with a —ONO₂ group;
• B)

wherein in formula (IB)

• n⁰ is from 0 to 5 and n¹ is an integer from 1 to 10;
• C)

wherein in formula (IC)

• n¹ is from 1 to 10,
• n² is 1 and R² is CH₃, X₁ is —C(O)O—;
• D)

wherein in formula (ID):

• n² is 1 and R² is CH₃,
• Y¹ is —CH═CH—(CH₂)_n^2a— n^2a is 0,
• X₁ is —C(O)O— and n₁ is an integer from 1 to 10;
• E)

wherein in formula (IE)

• n³ is from 1 to 5,
• n₃ is 0 and n₄ is from 1 to 4,
• n_3′ is 0 and n_4′ is from 1 to 4,
• X₂ is —O— or —NH—,
• R² is H,
• preferably (Y—ONO₂) and (Y′—ONO₂) are each independently selected from:

The following are preferred compounds according to the present invention:

Another embodiment relates to compounds of formula (I)

wherein s and s′ are 1, m is 1, m′ is 0, s″ is 0,

• B at each occurrence is independently selected from:

• preferably B is

• more preferably B is:

• A is a radical of formula

wherein

• R₁ is —C(O)R_1x, —C(O)OR_1x wherein R_1x is —(Y—ONO₂) of formula (I) wherein Y is below defined;
• R₂ is —C(O)OR_2x, wherein R_2x is the group —[B—(Y′—ONO₂)] of formula (I) wherein B is as above reported and Y′ is below reported,
• R_a is selected from:
• H, CH₃, isopropyl, isobutyl, sec-butyl, methylthio-(CH₂)₂—, benzyl, C₆H₅—CH₂—CH₂—, 3-triptophanyl-CH₂—, NH₂—CO—CH₂—; NH₂—CO—(CH₂)₂—, 4-imidazolyl-CH₂—;
• R_L in formula (IIl) is H,
• Y and Y′ of the groups (Y—ONO₂) and —(Y′—ONO₂) are each independently selected from:
• A)
  • a straight or branched C₂-C₁₀ alkylene
  • a straight or branched C₂-C₁₀ alkylene substituted with a —ONO₂ group;
• E)

wherein in formula (IE)

• n³ is from 1 to 5,
• n₃ is 0 and n₄ from 1 to 4,
• n_3′ is 0 and n_4′ is from 1 to 4,
• X₂ is —O— or —NH—,
• R² is H,
• preferably (Y—ONO₂) and —(Y′—ONO₂) are each independently selected from:

The following are preferred compounds according to the present invention:

Another embodiment relates to compounds of formula (I)

wherein s and s′ are 1, and s″ are 0, m and m′ are 0,

• A is a radical of formula

wherein R₁ is —C(O)R_1x or —C(O)OR_1x wherein R_1x is one of the groups —(Y—ONO₂) or (Y′—ONO₂) of formula (I) wherein Y and Y′ are below defined;

• R₂ is —C(O)OR_2x, —C(O)NHR_2xx or —C(O)N(CH₃)R_2xx, wherein R_2xx and R_2x are one of the groups —(Y—ONO₂) or —(Y′—ONO₂) of formula (I) wherein Y and Y′ are below defined, more preferably R₂ is —C(O)OR_2x, —C(O)NHR_2xx;
• R_a is selected from:
• b) HS—CH₂—;
• c) R_xO—CH₂—, R_xO—CH(CH₃)—, (R_xO)-p-C₆H₄—CH₂—, wherein R_x is H,
• d) R_gC(O)CH₂— or R_gC(O)(CH₂)₂—, wherein R_g is OH, (CH₃)₃CO—, or the group R_gg

• e) R_hNH(CH₂)_p— or R_iNH(═NH)NH—(CH₂)₃—, wherein p is an integer equal to 3 or 4, R_h is H, (CH₃)₃C—OC(O)—, R_i is H;
• Y and Y′ of the groups (Y—ONO₂), —(Y′—ONO₂) are each independently selected from:
• A)
  • a straight or branched C₂-C₁₀ alkylene
  • a straight or branched C₂-C₁₀ alkylene substituted with a —ONO₂ group;
• E)

wherein in formula (IE)

• n³ is from 1 to 5,
• n₃ is 0 and n₄ is from 1 to 4,
• n_3′ is 0 and n_4′ is from 1 to 4,
• X₂ is —O— or —NH—,
• R² is H,
• preferably (Y—ONO₂) and (Y′—ONO₂) are each independently selected from:

The following are preferred compounds according to the present invention:

Another embodiment provides compounds of formula (I)

wherein s is 1 and m is 0, s′ and s″ are 0,

• A is a radical of formula

wherein R₁ is H or —C(O)O—C(CH₃)₃,

• R₂ is —C(O)OH or R₂ is equal to the group R₄

• R_a is selected from:
• b) R_bxC(O)—S—CH₂—, R_bxOC(O)—S—CH₂—, R_bxNH—C(O)S—CH₂— wherein R_bx is the group —(Y—ONO₂) of formula (I) wherein Y is below defined,
• c) R_xO—CH₂—, R_xO—CH(CH₃)—, (R_xO)-p-C₆H₄—CH₂—, wherein R_x is R_xxC(O)—, R_xxOC(O)— or R_xxNHC(O)— wherein R_xx is the group —(Y—ONO₂) of formula (I) wherein Y is below defined;
• d) R_gC(O)CH₂, R_gC(O)(CH₂)₂— wherein R_g is R_gxO—, R_gxx—NH—, or Rg_xx—N(CH₃)—, wherein R_gx and R_gxx are the group —(Y—ONO₂) of formula (I) wherein Y is below defined, more preferably R_g is R_gxO—, R_gxx—NH—
• e) R_hNH(CH₂)_p— wherein p is 3 or 4, and R_h is R_hhC(O)— or R_hhOC(O)— wherein R_hh is the group —(Y—ONO₂) of formula (I) wherein Y is below defined;
• or R_iNH(═NH)NH—(CH₂)₂— wherein R_i is R_iiC(O)— or R_iiOC(O)— wherein R_ii is the group —(Y—ONO₂) of formula (I) wherein Y is below defined;
• Y of the group (Y—ONO₂) is selected from:
• A)
  • a straight or branched C₂-C₁₀ alkylene
  • a straight or branched C₂-C₁₀ alkylene substituted with a —ONO₂ group;
• E)

wherein in formula (IE)

• n³ is from 1 to 5,
• n₃ is 0 and n₄ is from 1 to 4,
• n_3′ is 0 and n_4′ is from 1 to 4,
• X₂ is —O— or —NH—,
• R² is H,
• preferably (Y—ONO₂) is selected from:

The following are preferred compounds according to the present invention:

Another embodiment provides compounds of formula (I)

wherein s and s′ are 1 and m, m′ are 0, s″ is 0,

• A is a radical of formula

wherein R₁ is H or —C(O)O—C(CH₃)₃—,

• R₂ is —C(O)OR_2x, —C(O)NHR_2xx, —C(O)N(CH₃)R_2xx wherein R_2x and R_2xx are one of the groups —(Y—ONO₂) or —(Y′—ONO₂) of formula (I) wherein Y and Y′ are below defined, more preferably R₂ is —C(O)OR_2x, —C(O)NHR_2x;
• R_a is selected from:
• b) R_bxC(O)—S—CH₂—, R_bxOC(O)—S—CH₂—, R_bxNH—C(O)S—CH₂— wherein R_bx is one of the groups —(Y—ONO₂) or —(Y′—ONO₂) wherein Y and Y′ are below defined;
• c) R_xO—CH₂—, R_xO—CH(CH₃)—, (R_xO)-p-C₆H₄—CH₂—, wherein R_x is R_xxC(O)—, R_xxOC(O)— or R_xxNHC(O)— wherein R_xx is one the groups —(Y—ONO₂) or —(Y′—ONO₂) of formula (I) wherein Y and Y′ are below reported;
• e) R_hNH(CH₂)_p— wherein p is 3 or 4, and R_h is R_hhC(O)— or R_hhOC(O)— wherein R_hh is one the groups —(Y—ONO₂) or —(Y′—ONO₂) of formula (I) wherein Y and Y′ are below reported;
• or R_a is R_iNH(═NH)NH—(CH₂)₂— wherein R_i is R_iiC(O)— or R_iiOC(O)— wherein R_ii is one the groups —(Y—ONO₂) or —(Y′—ONO₂) of formula (I) wherein Y and Y′ are below defined;
• Y and Y′ of the groups (Y—ONO₂) or —(Y′—ONO₂) are each independently selected from:
• A)
  • a straight or branched C₂-C₁₀ alkylene
  • a straight or branched C₂-C₁₀ alkylene substituted with a —ONO₂ group;
• E)

wherein in formula (IE)

• n³ is from 1 to 5,
• n₃ is 0 and n₄ is from 1 to 4,
• n_3′ is 0 and n_4′ is from 1 to 4,
• X₂ is —O— or —NH—,
• R² is H,
• preferably —(Y—ONO₂) and —(Y′—ONO₂) are each independently selected from:

The following are preferred compounds according to the present invention:

Another embodiment provides compounds of formula (I)

wherein s and s′ are 1 and m, m′ are 0, s″ is 0,

• A is a radical of formula

wherein R₁ is H or —C(O)O—C(CH₃)₃,

• R₂ is —C(O)OR_2x, —C(O)NHR_2xx, —C(O)N(CH₃)R_2xx wherein R_2x and R_2xx are one of the groups —(Y—ONO₂) or —(Y′—ONO₂) of formula (I) wherein Y and Y′ are below defined, more preferably R₂ is —C(O)OR_2x, —C(O)NHR_2xx;
• R_a is selected from:
• d) R_gC(O)CH₂—, R_gC(O)(CH₂)₂—, wherein R_g is R_gxO—, R_gxx—NH—, R_gxxN(CH₃)—, wherein R_gx and R_gxx are one of the groups —(Y—ONO₂) or —(Y′—ONO₂) of formula (I) wherein Y and Y′ are below defined, more preferably R_g is R_gxO— or R_gxx—NH—;
• Y and Y′ of the groups (Y—ONO₂) and —(Y′—ONO₂) are each independently selected from:
• A)
  • a straight or branched C₂-C₁₀ alkylene
  • a straight or branched C₂-C₁₀ alkylene substituted with a —ONO₂ group;
• E)

wherein in formula (IE)

• n³ is from 1 to 5,
• n₃ is 0 and n₄ is from 1 to 4,
• n_3′ is 0 and n_4′ is from 1 to 4,
• X₂ is —O— or —NH—,
• R² is H,
• preferably (Y—ONO₂) and (Y′—ONO₂) are each independently selected from:

The following are preferred compounds according to the present invention:

Another embodiment provides compounds of formula (I)

wherein s, s′ and s″ are 1, m, m′ and m″ are 0,

• A is a radical of formula

wherein R₁ is —C(O)R_1x, —C(O)OR_1x wherein R_1x is one of the groups —(Y—ONO₂) or —(Y′—ONO₂) or —(Y″—ONO₂) of formula (I) wherein Y, Y′ and Y″ are below defined;

• R₂ is —C(O)OR_2x, —C(O)NHR_2xx, —C(O)N(CH₃)R_2xx wherein R_2x and R_2xx are one of the groups —(Y—ONO₂) or —(Y′—ONO₂) or —(Y″—ONO₂) of formula (I) wherein Y, Y′ and Y″ are below reported, and more preferably R₂ is —C(O)OR_2x, —C(O)NHR_2x;
• R_a is selected from:
• b) R_bxC(O)—CH₂—, R_bxOC(O)—S—CH₂—, R_bxNH—C(O)S—CH₂— wherein R_bx is one of the groups —(Y—ONO₂) or —(Y′—ONO₂) or —(Y″—ONO₂) of formula (I) wherein Y, Y′ and Y″ are below reported;
• c) R_xO—CH₂—, R_xO—CH(CH₃)—, (R_xO)-p-C₆H₄—CH₂—, wherein R_x is R_xxC(O)—, R_xxOC(O)— or R_xxNHC(O)— wherein R_xx is one of the groups —(Y—ONO₂) or —(Y′—ONO₂) or —(Y″—ONO₂) of formula (I) wherein Y, Y′ and Y″ are below reported;
• d) R_gC(O)CH₂, R_gC(O)(CH₂)₂—, wherein R_g is R_gxO—, R_gxx—NH—, R_gxx—N(CH₃)—, wherein R_gx and R_gxx are one of the groups —(Y—ONO₂) or —(Y′—ONO₂) or —(Y″—ONO₂) of formula (I) wherein Y, Y′ and Y″ are below defined, more preferably R_g is R_gxO— or R_gxxNH—,
• e) R_hNH(CH₂)_p— wherein p is 3 or 4, and R_h is R_hhC(O)— or R_hhOC(O)— wherein R_hh is one of the groups —(Y—ONO₂) or —(Y′—ONO₂) or —(Y″—ONO₂) of formula (I) wherein Y, Y′ and Y″ are below defined,
• or R_a is R_iNH(═NH)NH—(CH₂)₃— wherein R_i is R_iiC(O)— or R_iiOC(O)— wherein R_ii is one of the groups —(Y—ONO₂) or —(Y′—ONO₂) or —(Y″—ONO₂) of formula (I) wherein Y, Y′ and Y″ are below reported;
• Y, Y′ and Y″ of the groups (Y—ONO₂) or —(Y′—ONO₂) or —(Y″—ONO₂) are each independently selected from:
• A)
  • a straight or branched C₂-C₁₀ alkylene
  • a straight or branched C₂-C₁₀ alkylene substituted with a —ONO₂ group;
• E)

wherein in formula (IE)

• n³ is from 1 to 5,
• n₃ is 0 and n₄ is from 1 to 4,
• n_3′ is 0 and n_4′ is from 1 to 4,
• X₂ is —O— or —NH—,
• R² is H,
• preferably —(Y—ONO₂), —(Y′—ONO₂) and —(Y″—ONO₂) are each independently selected from:

The following are preferred compounds according to the present invention:

Another embodiment provides compounds or formula (I)

wherein s and s′ are 1, m and m′ are 0, s″ is 0,

• A is a radical of formula

wherein R₁ is H or —C(O)—OC(CH₃)₃—;

• R₃ is —OC(O)R_3x, OC(O)OR_3x, —OC(O)—NHR_3x, wherein R_3x is one of the groups —(Y—ONO₂) or —(Y′—ONO₂) of formula (I) wherein Y and Y′ are below defined;
• R₃ is selected from:
• b″) R_bx—C(O)—S—CH₂—, R_bx—OC(O)—S—CH₂—, R_bx—NH—C(O)S—CH₂— wherein R_bx is one of the groups —(Y—ONO₂) or —(Y′—ONO₂) of formula (I) wherein Y and Y′ are below defined;
• c″) R_xO—CH₂—, R_xO—CH(CH₃)—, (R_xO)-p-C₆H₄—CH₂—, wherein R_x is R_xxC(O)—, R_xxOC(O)—, R_xxNHC(O)— wherein R_xx is one of the groups —(Y—ONO₂) or —(Y′—ONO₂) of formula (I) wherein Y and Y′ are below defined;
• d″) R_gC(O)CH₂, R_gC(O)(CH₂)₂—, wherein R_g is R_gxO— or R_gxxNH— wherein R_gx and R_gxx are one of the groups —(Y—ONO₂) or —(Y′—ONO₂) of formula (I) wherein Y and Y′ are below defined;
• e″) R_hNH(CH₂)_p— wherein p is 3 or 4 and R_h is R_hhC(O)— or R_hhOC(O)— wherein R_hh is one of the groups —(Y—ONO₂) or —(Y′—ONO₂) of formula (I) wherein Y and Y′ are below defined, or R_iNH(═NH)NH—(CH₂)₃—, wherein R_i is R_iiC(O)— or R_iiOC(O)— wherein R_ii is one of the groups —(Y—ONO₂) or —(Y′—ONO₂) of formula (I) wherein Y and Y′ are below defined;
• Y and Y′ of the groups (Y—ONO₂) or —(Y′—ONO₂) are each independently selected from:
• A)
  • a straight or branched C₂-C₁₀ alkylene
  • a straight or branched C₂-C₁₀ alkylene substituted with a —ONO₂ group;
• E)

wherein in formula (IE)

• n³ is from 1 to 5,
• n₃ is 0 and n₄ is from 1 to 4,
• n_3′ is 0 and n_4′ is from 1 to 4,
• X₂ is —O— or —NH—,
• R² is H,
• preferably (Y—ONO₂) and (Y′—ONO₂) are each independently selected from:

The following are preferred compounds according to the present invention:

Another embodiment provides compounds of formula (I)

wherein s is 1, m is 0, s′ and s″ are 0,

• A is a radical of formula

wherein R₁ is H or —C(O)—OC(CH₃)₃;

• R₃ is —OC(O)R_3x, OC(O)OR_3x, —OC(O)—NHR_3x, wherein R_3x is the group —(Y—ONO₂) of formula (I) wherein Y is below reported;
• R₃ is selected from:
• a″) H, CH₃, isopropyl, isobutyl, sec-butyl, methylthio-(CH₂)₂—, benzyl, C₆H₅—CH₂—CH₂—, 3-triptophanyl-CH₂—, NH₂—CO—CH₂—, NH₂—CO—(CH₂)₂—, 4-imidazolyl-CH₂—;
• Y of the group (Y—ONO₂) is selected from:
• A)
  • a straight or branched C₂-C₁₀ alkylene
  • a straight or branched C₂-C₁₀ alkylene substituted with a —ONO₂ group;
• E)

wherein in formula (IE)

• n³ is from 1 to 5,
• n₃ is 0 and n₄ is from 1 to 4,
• n_3′ is 0 and n_4′ is from 1 to 4,
• X₂ is —O— or —NH—,
• R² is H,
• preferably (Y—ONO₂) is selected from:

The following are preferred compounds according to the present invention:

Another embodiment provides compounds or formula (I)

wherein s is 1 and m is 0, s′ and s″ are 0,

• A is a radical of formula (IIq)

• R₁ is H or —C(O)O—C(CH₃)₃—,
• R₂ is —C(O)OR_2x, —C(O)NHR_2x —C(O)N(CH₃) wherein R_2x is the group —(Y—ONO₂) of formula (I) wherein Y is below reported, more preferably R₂ is —C(O)OR_2x or —C(O)NHR_2x;
• Y of the group (Y—ONO₂) is selected from:
• A)
  • a straight or branched C₂-C₁₀ alkylene
  • a straight or branched C₂-C₁₀ alkylene substituted with a —ONO₂ group;
• E)

wherein in formula (IE)

• n³ is from 1 to 5,
• n₃ is 0 and n₄ is from 1 to 4,
• n_3′ is 0 and n_4′ is from 1 to 4,
• X₂ is —O— or —NH—,
• R² is H,
• preferably (Y—ONO₂) is selected from:

The following are preferred compounds according to the present invention:

Another embodiment relates to compounds of formula (I)

wherein s is 1 and m is 0, s′ and s″ are 0,

• A is a radical of formula (IIu)

wherein a is 1 and b is 0;

• R₁ is H or —C(O)O—C(CH₃)₃,
• R₂ is —C(O)OR_2x, —C(O)NHR_2x—C(O)N(CH₃)R_2x wherein R_2x is the group —(Y—ONO₂) of formula (I) wherein Y is below reported, more preferably R₂ is —C(O)OR_2x, or —C(O)NHR_2x,
• R_x is H,
• Y of the group (Y—ONO₂) is selected from:
• A)
  • a straight or branched C₂-C₁₀ alkylene
  • a straight or branched C₂-C₁₀ alkylene substituted with a —ONO₂ group;
• E)

wherein in formula (IE)

• n³ is from 1 to 5,
• n₃ is 0 and n₄ is from 1 to 4,
• n_3′ is 0 and n_4′ is from 1 to 4,
• X₂ is —O— or —NH—,
• R² is H,
• preferably (Y—ONO₂), is selected from:

The following are preferred compounds according to the present invention:

The compound's of the present invention show significant advantages over the other known nitric oxide donor compounds, they release nitric oxide (NO) slower, they do not induce hypotension in normotensive subjects and moreover they do not induce increasing of heart rate in hypertensive patients.

The term “C₁-C₂₀ alkylene” as used herein refers to branched or straight chain C₁-C₂₀ hydrocarbon, preferably having from 1 to 10 carbon atoms such as methylene, ethylene, propylene, isopropylene, n-butylene, pentylene, n-hexylene and the like.

The term “C₁-C₁₀ alkyl” as used herein refers to branched or straight chain alkyl groups comprising one to ten carbon atoms, including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl, octyl and the like.

One 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.

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 invention also relates to the use of the compounds of formula (I) or their salts for treating cardiovascular diseases, inflammation, pain, fever, gastrointestinal disorders, ophthalmic diseases including glaucoma, hepatic disorders, renal diseases, respiratory disorders, immunological diseases, bone metabolism dysfunctions, central and peripheral nervous system diseases, sexual dysfunctions, infectious diseases, for the inhibition of platelet aggregation and platelet adhesion, for treating pathological conditions resulting from abnormal cell proliferation and vascular diseases.

Another embodiment of the present invention relates to compositions comprising at least a compound of formula (I) or its salt and at least one therapeutic agent selected from anti-inflammatory drugs, drugs used to treat cardiovascular diseases, drugs for treating ocular diseases, drugs for treating respiratory disorders.

Anti-inflammatory drugs include, but are not limited to, non steroidal anti-inflammatory drugs and steroidal anti-inflammatory drugs

Drugs used to treat cardiovascular diseases refers to any therapeutic compound, or a pharmaceutically acceptable salt thereof, used to treat any cardiovascular disease. Suitable compounds include, but are not limited to aspirin and derivatives thereof, anti-thrombotic drugs, angiotensin-converting enzyme inhibitors (ACE inhibitors), beta-adrenergic blockers, calcium, channel blockers, angiotensin II receptor antagonists, endothelin antagonists, renin inhibitors, β-adrenergic receptor agonists, cholesterol reducers such as, for example, HMG-CoA reductase inhibitors, including, but not limited to, lovastatin, simvastatin, pravastatin, fluvastatin, cerivastatin, atorvastatin.Drugs for treating ocular diseases include, but are not limited to, prostaglandins.

In another object of the invention the two components of the composition above defined are administered simultaneously or sequentially wherein the two components may be administered by the same or different administration pathways.

Another object of the invention provide the use of the composition above reported for the treatment of cardiovascular diseases, inflammation, pain, fever, gastrointestinal disorders, ophthalmic diseases including glaucoma, hepatic disorders, renal diseases, respiratory disorders, immunological diseases, bone metabolism dysfunctions, central and peripheral nervous system diseases, sexual dysfunctions, infectious diseases, for the inhibition of platelet aggregation and platelet adhesion, for treating pathological conditions resulting from abnormal cell proliferation and vascular diseases.

Generally the treatment of cardiovascular disease and/or peripheral vascular disorders is a long-term therapy, and it is directed to patients suffering from cardiovascular disease and/or peripheral vascular disorders or inflammatory diseases which suffer from hypertension or diabetes.Long term treatment ranges from about one month to over two years of chronic/maintenance administration.

Another object of the present invention relates to pharmaceutical compositions comprising the composition above reported and non toxic adjuvants and/or carriers usually employed in the pharmaceutical field.

An object of the present invention relates to pharmaceutical compositions comprising at least a compound of formula (I) together with non toxic adjuvants and/or carriers usually employed in the pharmaceutical field.

The invention also relates to the use of the following compounds

• 3-(nitrooxy)propyl 2-(tert-butoxycarbonylamino)-4-phenyl butanoate,
• 3-(nitrooxy)propyl 2-amino-4-phenylbutanoate,
• 3-(nitrooxy)propyl 2-amino-4-phenylbutanoate hydrochloride,
• 4-(nitrooxy)butyl 2-(tert-butoxycarbonylamino)-4-phenylbutanoate,
• 4-(nitrooxy)butyl 2-amino-4-phenylbutanoate,
• 4-(nitrooxy)butyl 2-amino-4-phenylbutanoate hydrochloride,
• (2-(nitrooxy)ethoxy)methyl 2-(tert-butoxycarbonylamino)-4-phenyl butanoate,
• (2-(nitrooxy)ethoxy)methyl 2-amino-4-phenylbutanoate,
• (2-(nitrooxy)ethoxy)methyl 2-amino-4-phenylbutanoate hydrochloride,
• 1-tert-butyl 2-(4-(nitrooxy)butyl)pyrrolidine-1,2-dicarboxylate
• 4-(nitrooxy)butyl pyrrolidine-2-carboxylate,
• 4-(nitrooxy)butyl pyrrolidine-2-carboxylate hydrochloride,
• 1-tert-butyl 2-(3-(nitrooxy)propyl)pyrrolidine-1,2-dicarboxylate,
• 3-(nitrooxy)propyl pyrrolidine-2-carboxylate,
• 3-(nitrooxy)propyl pyrrolidine-2-carboxylate hydrochloride,for treating cardiovascular diseases, inflammation, pain, fever, gastrointestinal disorders, ophthalmic diseases including glaucoma, hepatic disorders, renal diseases, respiratory disorders, immunological diseases, bone metabolism dysfunctions, central and peripheral nervous system diseases, sexual dysfunctions, infectious diseases, for the inhibition of platelet aggregation and platelet adhesion, for treating pathological conditions resulting from abnormal cell proliferation and vascular diseases.

Another object of the present invention relates to compositions comprising at least one of the following compounds:

• 3-(nitrooxy)propyl 2-(tert-butoxycarbonylamino)-4-phenyl butanoate,
• 3-(nitrooxy)propyl 2-amino-4-phenylbutanoate,
• 3-(nitrooxy)propyl 2-amino-4-phenylbutanoate hydrochloride,
• 4-(nitrooxy)butyl 2-(tert-butoxycarbonylamino)-4-phenyl butanoate,
• 4-(nitrooxy)butyl 2-amino-4-phenylbutanoate,
• 4-(nitrooxy)butyl 2-amino-4-phenylbutanoate hydrochloride,
• (2-(nitrooxy)ethoxy)methyl 2-(tert-butoxycarbonylamino)-4-phenyl butanoate,
• (2-(nitrooxy)ethoxy)methyl 2-amino-4-phenylbutanoate,
• (2-(nitrooxy)ethoxy)methyl 2-amino-4-phenylbutanoate hydrochloride,
• 1-tert-butyl 2-(4-(nitrooxy)butyl)pyrrolidine-1,2-dicarboxylate,
• 4-(nitrooxy)butylpyrrolidine-2-carboxylate,
• 4-(nitrooxy)butylpyrrolidine-2-carboxylate hydrochloride,
• 1-tert-butyl 2-(3-(nitrooxy)propyl)pyrrolidine-1,2-dicarboxylate,
• 3-(nitrooxy)propylpyrrolidine-2-carboxylate,
• 3-(nitrooxy)propylpyrrolidine-2-carboxylate hydrochloride,and at least one therapeutic agent selected from anti-inflammatory drugs, drugs used to treat cardiovascular diseases, drugs for treating ocular diseases, drugs for treating respiratory disorders.Anti-inflammatory drugs include, but are not limited to, non steroidal anti-inflammatory drugs and steroidal anti-inflammatory drugsDrugs used to treat cardiovascular diseases refers to any therapeutic compound, or a pharmaceutically acceptable salt thereof, used to treat any cardiovascular disease. Suitable compounds include, but are not limited to aspirin and derivatives thereof, anti-thrombotic drugs, angiotensin-converting enzyme inhibitors (ACE inhibitors), beta-adrenergic pinchers, calcium channel blockers, angiotensin II receptor antagonists, endothelin antagonists, renin inhibitors, β-adrenergic receptor agonists, cholesterol reducers such as, for example, HMG-CoA reductase inhibitors, including, but not limited to, lovastatin, simvastatin, pravastatin, fluvastatin, cerivastatin, atorvastatin.Drugs for treating ocular diseases include, but are not limited to, prostaglandins.

In another object of the invention the two components of the composition above defined are administered simultaneously or sequentially wherein the two components may be administered by the same or different administration pathways.

Another object of the invention provides the use of the composition comprising at least one of the following compounds:

• 3-(nitrooxy)propyl 2-(tert-butoxycarbonylamino)-4-phenyl Butanoate,
• 3-(nitrooxy)propyl 2-amino-4-phenylbutanoate,
• 3-(nitrooxy)propyl 2-amino-4-phenylbutanoate hydrochloride,
• 4-(nitrooxy)butyl 2-(tert-butoxycarbonylamino)-4-phenyl butanoate,
• 4-(nitrooxy)butyl 2-amino-4-phenylbutanoate,
• 4-(nitrooxy)butyl 2-amino-4-phenylbutanoate hydrochloride,
• (2-(nitrooxy)ethoxy)methyl 2-(tert-butoxycarbonylamino)-4-phenyl butanoate,
• (2-(nitrooxy)ethoxy)methyl 2-amino-4-phenylbutanoate,
• (2-(nitrooxy)ethoxy)methyl 2-amino-4-phenylbutanoate hydrochloride,
• 1-tert-butyl 2-(4-(nitrooxy)butyl)pyrrolidine-1,2-dicarboxylate,
• 4-(nitrooxy)butyl pyrrolidine-2-carboxylate,
• 4-(nitrooxy)butyl pyrrolidine-2-carboxylate hydrochloride,
• 1-tert-butyl 2-(3-(nitrooxy)propyl)pyrrolidine-1,2-dicarboxylate,
• 3-(nitrooxy)propyl pyrrolidine-2-carboxylate,
• 3-(nitrooxy)propyl pyrrolidine-2-carboxylate hydrochlorideand at least one therapeutic agent selected from anti-inflammatory drugs, drugs used to treat cardiovascular diseases, drugs for treating ocular diseases, drugs for treating respiratory disorders, for the treatment of cardiovascular diseases, inflammation, pain, fever, gastrointestinal disorders, ophthalmic diseases including glaucoma, hepatic disorders, renal disease, respiratory disorders, immunological diseases, bone metabolism dysfunctions, central and peripheral nervous system diseases, sexual dysfunctions, infectious diseases, for the inhibition of platelet aggregation and platelet adhesion, for treating pathological conditions resulting from abnormal cell proliferation and vascular diseases.

An object of the present invention relates to pharmaceutical compositions comprising the composition above reported together with non toxic adjuvants and/or carriers usually employed in the pharmaceutical field.

The daily dose of the active ingredient that should be administered can be a single dose or it can be an effective amount divided into several smaller doses that are to be administered throughout the day. The dosage regimen and administration frequency for treating the mentioned diseases with the compound of the invention and/or with the pharmaceutical compositions of the present invention will be selected in accordance with a variety of factors, including for example age, body weight, sex and medical condition of the patient as well as severity of the disease, route of administration, pharmacological considerations and eventual concomitant therapy with other drugs. In some instances, dosage levels below or above the aforesaid range and/or more frequent may be adequate, and this logically will be within the judgment of the physician and will depend on the disease state.

The compounds of the invention may be administered orally, parenterally, rectally or topically, by inhalation or aerosol, in formulations eventually containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles as desired. Topical administration may also involve the use of transdermal administration such as transdermal patches or iontophoresis devices. The term “parenteral” as used herein, includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.

Injectable preparations, for example sterile injectable aqueous or oleaginous suspensions may be formulated according to known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent. Among the acceptable vehicles and solvents are water, Ringer's solution and isotonic sodium chloride. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono or diglycerides, in addition fatty acids such as oleic acid find use in the preparation of injectables.

Suppositories for rectal administration of the drug can be prepared by mixing the active ingredient with a suitable non-irritating excipient, such as cocoa butter and polyethylene glycols.

Solid dosage forms for oral administration may include capsules, tablets, pills, powders, granules and gels. In such solid dosage forms, the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as in normal practice, additional substances other than inert diluents, e.g. lubricating agents such as magnesium stearate. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.

Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art, such as water. Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavouring and the like.

Synthesis Procedure

1. The Compounds of General Formula (I)

wherein:

• s is equal to 1;
• m, m′, m″, s′ and s″ are 0
• Y is as above defined,
• A is a radical of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein R₁ is —C(O)—R_1x and it binds the group —Y—ONO₂, R₂ is —COOH;
• in formula (IIn) R_n is —C(O)—R_nx, or is —(CH₂)₂—NH—R_h wherein R_h is —C(O)R_hh and it binds the group —Y—ONO₂
• R_a of formula (IIa) is selected in group a)
• R_c of formula (IIc) is selected in group a′)
• in formula (IIt) d is an integer from 3 to 5, d′ is 0;can be prepared as follows
• 1a) by reacting a compound of formula (I) wherein s, s′, s″, m, m′, m″, Y, Y′, Y″ are as above defined in 1., A is a radical of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein R₂ is —C(O)OC(CH₃)₃; R₁, R_a, R_c, R_h, R_n, d, and d′ are as defined in 1., with anhydrous or aqueous organic or inorganic acid to hydrolyze the t-butyl ester following procedure well known in the literature.
• 1b) by reacting a compound of formula A with a compound of formula (IIIa)A+HOOC—Y—ONO₂  (IIIa)wherein Y is as above defined and A is selected from (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein R₁, is —H and R₂ is —C(O)O(CH₃)₃;
• in formula (IIn) R_n is H, or is —(CH₂)₂—NH—R_h wherein R_h is H;
• R_a of formula (IIa) is selected in group a);
• R_c of formula (IIc) is selected in group a′);
• in formula, (IIt) d and d′ are as above defined;in the presence of a condensing agent such as dicyclohexylcarbodiimide (DCC) or N,N′-carbonyldiimidazol (CDI) or other known condensing reagents such as O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU), in the presence or not of 1-Hydroxybenzotriazole (HOBT) in solvent such as DMF, THF, chloroform at a temperature in the range from −5° C. to 80° C. in the presence or not of a base as for example DMAP.The nitric acid ester compounds of formula (IIIa) can be obtained from the corresponding alcohols of formula HOOC—Y—OH (IIIb), that are commercially available, by reaction with nitric acid and acetic anhydride in a temperature range from −51° C. to 0° C. or reacting the corresponding halogen derivatives of formula HOOC—Y-Hal (IIIc) wherein Hal is an halogen atom preferably Cl, Br, I, that are commercially available, with AgNO₃ as known in the literature. 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.Dinitrated compounds of formula (IIIa) can be also directly prepared with I₂ and AgNO₃ starting from carboxylic acids with a double bond in the chain as described in WO 2005/070868.Compounds (IIIa) can be also prepared from the corresponding Tosyl derivative (IIId) HOOC—Y—OTs by reacting with AgNO₃ or MetalNO₃ wherein Metal is Li⁺, Na⁺, K⁺, in solvents such acetonitrile or DMF at refluxing temperature or under microwave irradiation at temperatures in the range between about 100-180° C. for time range about 1-120 min.
• 1b′) alternatively compound A reported in 1b) can be reacted with a compound of formula (IIIe):A+Act-CO—Y—ONO₂  (IIIe)wherein Y is as above defined; Act is an Halogen atom or a carboxylic acid activating group used in peptide chemistry such as:

the reaction is generally carried out in 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°-80° C. or in a double phase system H₂O/Et₂O at temperatures range between 20°-40° C.; or in the presence of DMAP and a Lewis acid such as Sc(OTf)₃ or Bi(OTf)₃ in solvents such as DMF, CH₂Cl₂.The compounds of formula (IIIe) can be obtained as described in WO 2006/008196.

• 1c) compounds A reported in 1b) are commercially available or can be prepared by reacting a compound of formula A₁ wherein A₁ is a radical of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein R₂ is —COOH, R₁ and R₆ are substituted by the Fmoc protective group and R_a, R_c, d and d′ are as defined in 1., with tert-butyl alcohol and sulphuric acid or other methods to obtain a tert-butyl ester well known in the literature. Eventually removing the Fmoc protective group using methods known in the literature.Compounds A₁ are commercially available or can be prepared by the correspondent compounds A₂:A₂→A₁ wherein A₂ is a radical of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein R₂ is —COOH, and R₁ is —C(O)OC(CH₃)₃, R_n is —C(O)OC(CH₃)₃ or is —(CH₂)₂—NH—C(O)OC(CH₃)₃, R_a, R_c d and d′ are as defined in 1., by converting the —BOC protective group into the Fmoc protective group as described in the literature.
• Compounds A₂ are commercially available.
• 2. Alternatively compounds of formula (I) described in 1. can be obtained:
• 2a) by reacting a compound of formula (IVa)A-(Y—X)  (IVa)wherein X is an halogen atom or tosyl group, Y is as above defined and A is as above defined in 1b), with AgNO₃ or MetalNO₃ as above described in 1b).Compounds (IVa) can be obtained by reacting compound A as above defined in 1b), with compounds (IIIc) as above described in 1b), with a condensing reagent such as DCC or CDI as above described in 1b);
• or
• 2a′) alternatively compounds of formula (I) described in 1a) can be obtained by reacting a compound of formula (Va):A-(Y—OH)  (Va)wherein A and Y are as above defined in 1a), with triflic anhydride/tetraalkylammonium nitrate salt in an aprotic polar/non-polar solvent such as DMF, THF or CH₂Cl₂ at temperatures range between −78° to 80° C.Compounds (Va) can be obtained by reacting compound A as defined in 1b), with compounds (IIIb) with a condensing reagent as above described for (IIIa) in 1b).
• 3. The compounds of general formula (I) wherein:
• s is equal to 1;
• m, m′, m″, s′ and s″ are 0
• Y is as above defined,
• A is a radical of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein R₁ is —C(O)O—R_1x and it binds the group —Y—ONO₂,
• R₂ is —COOH;
• in formula (IIn) R_n is —C(O)O—R_nx or —(CH₂)₂—NH—R_h wherein R_h is —C(O)O—R_hh, and it binds the group —Y—ONO₂
• R_a of formula (IIa) is selected in group a)
• R_c of formula (IIc) is selected in group a′)
• in formula (IIt) d is an integer from 3 to 5, d′ is 0;can be prepared as follows
• 3a) by reacting a compound of formula (I) wherein s, s′, s″, m, m′, m″, Y, Y′, Y″ are as above defined in 3., A is a radical of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein R₂ is —C(O)OC(CH₃)₃; R₁, R_a, R_c, R_n, R_h, d and d′ are as defined in 3. with anhydrous or aqueous organic or inorganic acid to hydrolyze the t-butyl ester following procedure well known in the literature.
• 3b) by reacting a compound of formula A with a compound of formula (IIIf)A+Act-(O)C—O—Y—ONO₂  (IIIf)wherein A is as above reported in 1b), Y is as above reported and Act is as above defined in 1b′).

The reaction is generally carried out in 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°-80° C. or in a double phase system H₂O/Et₂O at temperatures range between 20°-40° C.; or in the presence of DMAP and a Lewis acid such as Sc(OTf)₃ or Bi(OTf)₃ in solvents such as DMF, CH₂Cl₂. Compounds (IIIf) are obtained as described in WO 2006/008196.

• 4. The compounds of general formula (I) wherein:
• s and m are equal to 1;
• s′, s″, m′, m″ are equal to 0;
• Y is as above defined;
• B is:

• A is a radical of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein R₁ is —H and R₂ is —C(O)OR_2x and binds the group —B—Y—ONO₂
• in formula (IIn) R_n is —H or is —(CH₂)₂—NH₂;
• R_a of formula (IIa) is selected in group a),
• R_c of formula (IIc) is selected in group a′),
• in formula (IIt) d is an integer from 3 to 5, d′ is 0;can be obtained as follows:
• 4a) reacting a compound of formula (I) wherein B, s, s′, s″, m, m′, m″, Y, Y′ and Y″ are as above defined in 4., A is a radical of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein R₂, R_a, R_c, d and d′ and of are as defined in 4., R₁ is —C(O)OC(CH₃)₃; R_n or is —C(O)OC(CH₃)₃ or is —(CH₂)₂—NH—C(O)OC(CH₃)₃;
• with anhydrous or aqueous organic or inorganic acid as well known in the literature to remove all the —BOC protective groups.
• 4b) by reacting a compound of formula A with compounds of formula (IIIg)A+Hal-W₁—OC(O)O—Y—ONO₂  (IIIg)wherein Y is as above described, Hal is an halogen atom and W₁ is —CH₂— or —CH(CH₃)—, and A is a compound of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein R₁ is —C(O)OC(CH₃)₃ and R₂ is —COOH;
• R_a of formula (IIa) is selected in group a),
• R_c of formula (IIc) is selected in group a′),
• in formula (IIt) d and d′ are as above defined;
• in formula (IIn) R_n is —C(O)OC(CH₃)₃ or is —(CH₂)₂—NH—C(O)OC(CH₃)₃;
• 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°-40° C. Compounds A as above defined are commercially available.

The compounds of formula (IIIg) are obtained by reacting the commercially available haloalkylhalocarbonate of formula (IIIh)Hal-W₁—OC(O)Hal  (IIIh)wherein Hal and W₁ are as above defined, with a compound of formula (IIIi)HO—Y—ONO₂  (IIIi)wherein Y is 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 80° C.

Dinitrated compounds of formula (IIIi) can be also prepared with I₂ and AgNO₃ or by Sharpless oxidation and then Nitration with Acetic anhydride and nitric acid starting from a double bond in the chain as described in WO 2005/070868.

The compounds of formula (IIIi) are obtained by reacting compounds of formula HO—Y-Hal (IIIj) wherein Y and Hal are as above defined or compounds of formula HO—Y—OTs (IIIk) wherein Ts is the tosyl group, with AgNO₃ on MetalNO₃ in a suitable organic solvent such as acetonitrile or tetrahydrofuran (THF) under nitrogen in the dark at temperatures range between 20°-80° C.; alternatively the reaction with AgNO₃ or MetalNO₃ 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 1-120 min as already described in 1b)

The compounds of formula (IIIj) and (IIIk) are commercially available or can be obtained from commercially available compounds HO—Y—OH (IIIl) with methods well known in the literature.

• 5. Alternatively compounds (I) described in 4a) can be obtained
• 5a) by reacting compounds of formula (VIa) wherein A, B and Y have been already defined in 4. with tetraalkylammonium nitrate and triflic anhydride as previously describedA-(B)—(Y—OH)  (VIa)
• Compounds (VIa) can be obtained by reacting compounds A as defined in 4b) with compounds (IIIm):Hal-W₁—OC(O)O—Y—OH  (IIIm)
• Using the same procedure described in 4b). Compounds (IIIm) are prepared from commercially available compounds Hal-W₁—OC(O)Hal (IIIh) by reacting with compounds HO—Y—OH (IIIl) 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°-80° C., using a ratio (IIIh)/(IIIl) 1:1.
• 6. The compounds of general formula (I) wherein:
• s and m are equal to 1
• s′, s″, m′, m″ are equal to 0;
• Y is as above defined;
• B is:

• A is a radical of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein R₁ is —H and R₂ is —C(O)OR_2x and binds the group —B—Y—ONO₂
• in formula (IIn) R_n is —H or is —(CH₂)₂—NH₂;
• R_a of formula (IIa) is selected in group a)
• R_c of formula (IIc) is selected in group a′),
• in formula (IIt) d is an integer from 3 to 5, d′ is 0;can be obtained as follows:
• 6a) reacting a compound of formula (I) wherein s, s′, s″, m, m′, m″, Y, Y′ and Y″ are as above defined in 6., A is a radical of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein R₂, R_a, and R_c, d and d′ as defined in 6., R₁ or R_n is —C(O)OC(CH₃)₃ or —(CH₂)₂—NH—C(O)OC(CH₃)₃; with anhydrous or aqueous organic or inorganic acid as well known in the literature to remove all the —BOC protective groups.
• 6b) by reacting a compound of formula A with compounds of formula (IIIn)A+Hal-W₁—OC(O)—Y—ONO₂  (IIIn)wherein Y is as above described, Hal is an halogen atom and W₁ is —CH₂— or —CH(CH₃)—, and A is a compound of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein R₁ is —C(O)OC(CH₃)₃ and R₂ is —COOH;
• R_a of formula (IIa) is selected in group a),
• R_c of formula (IIc) is selected in group a′),
• in formula (IIn) R_n is —C(O)OC(CH₃)₃ or is —(CH₂)₂—NHR_h wherein R_h is —C(O)OC(CH₃)₃;
• in formula (IIt) d is an integer from 3 to 5, d′ is 0;
• 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°-100° C. or in a double phase system H₂O/Et₂O at temperatures range between 20°-40° C.The compounds of formula (IIIn) are obtained by reacting a compound W₂—CHO, wherein W₂ is H—, CH₃— with compounds of formula (IIIe), wherein Y and Act are as above defined, and ZnCl₂ as described in the literature (Steven K. Davidsen and al., J. Med Chem., 37(26), 4423, 1994).W₂—CHO+ZnCl₂+Act-(O)C—Y—ONO₂  (IIIe)
• 7. The compounds of general formula (I) wherein:
• s is equal to 1;
• s′, s″, m, m′, m″ are equal to 0;
• Y is as above defined;
• A is a radical of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein R₁ is —H and R₂ is —C(O)NHR_2xx or —C(O)N(CH₂)R_2xx and R₂ binds the group —Y—ONO₂
• in formula (IIn) R_n is —H or is —(CH₂)₂—NH₂;
• R_a of formula (IIa) is selected in group a);
• R_c of formula (IIc) is selected in group a′);
• in formula (IIt) d is an integer from 3 to 5, d′ is 0;can be obtained as follows:
• 7a) reacting a compound of formula (I) wherein s, s′, s″, m, m′, m″, Y, Y′ and Y″ are as above defined in 7., A is a radical of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein R₂, R_a R_c, d and d′ are as defined in 7., R₁ is —C(O)OC(CH₃)₃; R_n is —C(O)OC(CH₃)₃ or is —(CH₂)₂—NHR_h wherein R_h is —C(O)OC(CH₃)₃;
• with anhydrous or aqueous organic or inorganic acid as well known in the literature to remove all the —BOC protective groups.
• 7b) by reacting a compound of formula A with compounds of formula (IIIo)W₃NH—Y—ONO₂  (IIIo)wherein Y is as above described, W₃ is H or —CH₃, A has been already defined in 4b), in the presence of a condensing agent like dicyclohexylcarbodiimide (DCC) or N,N′-carbonyldiimidazol (CDI) or other known condensing reagents such as O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) in the presence or not of 1-Hydroxybenzotriazole (HOBT) in solvent such as DMF, THF, chloroform at a temperature in the range from −5° C. to 60° C. in the presence or not of a base as for example DMAP. Compounds (IIIo) can be prepared from compounds (IIIp), wherein Y and W₃ are as above defined by hydrolysing the BOC protecting group as known in the literature:(CH₃)₃CO(O)C—NW₃—Y—ONO₂  (IIIp)
• Compounds (IIIp) can be prepared from compounds (IIIq) or (IIIr) wherein W₃, Y, Hal and Ts are as above described, by reacting with AgNO₃ as already described for analogous compounds:(CH₃)₃CO(O)C—NW₃—Y-Hal  (IIIq)(CH₃)₃CO(O)C—NW₃—Y—OTs  (IIIr)Alternatively compounds (IIIp) can be prepared from compounds (IIIs) by reacting with tetraalkylammonium nitrate as already described for analogous compounds.(CH₃)₃CO(O)C—NW₃—Y—OH  (IIIs)Compounds (IIIq) and (IIIr) can be prepared from compounds (IIIs) by halogenation or tosylation as known an the literature. Compounds (IIIs) are obtained by known methods from compounds (IIIt) that are commercially available.W₃NH—Y—OH  (IIIt)
• 8. The compounds of general formula (I) wherein:
• s is equal to 1;
• s′, s″, m, m′, m″ are equal to 0;
• Y is as above defined;
• A is a radical of formula ((IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein R₁ is —H and R₂ is —C(O)OR_2x and binds the group —Y—ONO₂
• in formula (IIn) R_n is —H or is —(CH₂)₂—NH₂;
• R_a of formula (IIa) is selected in group a);
• R_c of formula (IIc) is selected in group a′);
• in formula (IIt) d is an integer from 3 to 5, d′ is 0;can be obtained as follows:
• 8a) reacting a compound of formula (I) wherein s, s′, s″, m, m′, m″, Y, Y′ and Y″ are as above defined in 8., A is a radical of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein R₂, R_a, R_c d and d′ are as defined in 8., R₁ is —C(O)OC(CH₃)₃; R_n is —C(O)OC(CH₃)₃ or is —(CH₂)₂—NHR—C(O)OC(CH₃)₃;
• with anhydrous or aqueous organic or inorganic acid as well known in the literature to remove all the —BOC protective groups.
• 8b) by reacting a compound of formula A with compounds of formula (IIIi)HO—Y—ONO₂  (IIIi)wherein Y is as above described, A is a radical of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein R₁ is —C(O)OC(CH₃)₃; R₂ is —COOH or is equal to R_2a wherein R_2a is the group —COAct wherein Act is as above described in 1b′) and is a carboxylic acid activating group, R_a, R_c d and d′ are as defined in 8., R_n is —C(O)OC(CH₃)₃ or is —(CH₂)₂—NHR—C(O)OC(CH₃)₃;
• in the presence of a condensing agent such as dicyclohexylcarbodiimide (DCC) or N,N′-carbonyldiimidazol (CDI) or other known condensing reagents such as O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU), in the presence or not or 1-Hydroxybenzotriazole (HOBT) in solvent such as DMF, THF or chloroform at a temperature in the range from −5° C. to 60° C. in the presence or not of a base as for example DMAP when R₂ is —COOH; or in the presence of equimolar amount of DMAP
• in solvent such as DMF, THF, chloroform at a temperature in the range from −5° C. to 60° C. when R₂ is equal to R_2a.
• 9. Alternatively the compounds of formula (I) as defined in 8a) can be obtained as follow:
• 9a) reacting a compound of formula (IVb)A-Y—X  (IVb)wherein Y is as above defined and A is as above defined in 8a) and X is an halogen atom or a tosyl group, by reacting with AgNO₃ or MetalNO₃ as above described. Compounds (IVb) can be obtained by reacting compound A defined as above in 6b), with compounds (IIIj) or (IIIk)HO—Y-Hal  (IIIj)HO—Y—OTs  (IIIk)
• with a condensing reagent such as DCC or CDI or HATU as shove defined in 6b).
• 10. Alternatively the compounds of formula (I) as defined in 8a) can be obtained
• 10a) by reacting a compound of formula (Vb)A-Y—OH  (Vb)wherein Y is as above defined, and A is as already defined in 8) with triflic anhydride/tetraalkylammonium nitrate as already described. Compounds (Vb) can be obtained by reacting components A as above described in 8b) with a compound of formula HO—Y—OH (IIIl) with a condensing reagent such as DCC or CDI or HATU as above defined in 8b) using a ratio A/(IIIl) 1:1.
• 11. The compounds of general formula (I) wherein:
• s and s′ are equal to 1;
• s″, m, m′, m″, are 0
• Y, Y′ can be equal or different and are as above defined,
• A is selected from (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein:
• R₁ is —C(O)R_1x and binds the group —Y—ONO₂, R₂ is —C(O)OR_2x and binds the group —Y′—ONO₂;
• in formula (IIn) R_n is —C(O)—R_nx or —(CH₂)₂—NH—R_h wherein R_h is —C(O)—R_hh, R_n or R_h binds the group —Y—ONO₂;
• R_a of formula (IIa) is selected in group a);
• R_c of formula (IIc) is selected in group a′);
• in formula (IIt) d is an integer from 3 to 5, d′ is 0;can be prepared as follows:
• 11a) by reacting compounds of formula (I) as defined in 1., obtained with the procedure described in 1. with compounds (IIIi)

Wherein Y and Y′ are equal or different and are as above defined and A has the following meanings:

• A is a radical of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein R₁ is —C(O)—R_1x and binds the group —Y—ONO₂, R₂ is —COOH;
• in formula (IIn) R_n is —C(O)—R_nx or —(CH₂)₂—NH—R_h wherein R_h is —C(O)—R_hh, R_n or R_h binds the group —Y—ONO₂;
• R_a of formula (IIa) is selected in group a);
• R_c of formula (IIc) is selected in group a′);
• in formula (IIt) d is an integer from 3 to 5, d′ is 0;using the same procedure described in 8b).
• 12. The compounds of general formula (I) wherein:
• s and a′ are equal to 1;
• s″, m, m′, m″, are 0
• Y, Y′ can be equal or different and are as above defined,
• A is a radical of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein R₁ is —C(O)O—R_1x and binds the group —Y—ONO₂; R₂ is —C(O)OR_2x and R₂ binds the group —Y—ONO₂;
• in formula (IIn) R_n is —C(O)O—R_nx or —(CH₂)₂—NH—R_h wherein R_h is —C(O)O—R_hh, R_n or R_h binds the group —Y—ONO₂;
• R_a of formula (IIa) is selected in group a),
• R_c of formula (IIc) is selected in group a′);
• in formula (IIt) d is an integer from 3 to 5, d′ is 0;can be prepared as follows:
• 12a) by reacting compounds of formula (I) obtained with the procedure described in 3. with compounds (IIIi)

Wherein Y and Y′ are equal or different and are as above defined and A has the following meanings:

• A is a radical of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein R₁ is —C(O)O—R_1x and binds the group —Y—ONO₂, R₂ is —COOH;
• in formula (IIn) R_n is —C(O)O—R_nx or —(CH₂)₂—NH—R_h wherein R_h is —C(O)O—R_hh, R_n or R_h binds the group —Y—ONO₂;
• R_a of formula (IIa) is selected in group a);
• R_c of formula (IIc) is selected in group a′);
• in formula (IIt) d is an integer from 3 to 5, d′ is 0;using the same procedure described in 8b).
• 13. The compounds of general formula (I) wherein:
• s and s′ are equal to 1;
• s″, m, m′, m″, are 0
• Y, Y′ can be equal or different and are as above defined,
• A is selected from (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein:
• R₁ is —C(O)—R_1x and binds the group —Y—ONO₂, R₂ is —C(O)NHR_2xx or —C(O)N(CH₃)R_2xx and binds the group —Y—ONO₂;
• in formula (IIn) R_n is —C(O)—R_nx or —(CH₂)₂—NH—R_h wherein R_h is —C(O)—R_hh, R_n or R_h binds the group —Y—ONO₂;
• R_a of formula (IIa) is selected in group a);
• R_c of formula (IIc) is selected in group a′);
• in formula (IIt) d is an integer from 3 to 5, d′ is 0;can be prepared as follows:
• 13a) by reacting compounds of formula (I) obtained with the procedure described in 1. with compounds (IIIo)

Wherein Y and Y′ are equal or different and are as above defined, W₃ is as above defined and A has the following meanings:

• A is a radical of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein R₁ is —C(O)—R_1x and binds the group —Y—ONO₂, R₂ is —COOH;
• in formula (IIn) R_n is —C(O)—R_nx or —(CH₂)₂—NH—R_h wherein R_h is —C(O)—R_hh, R_n or R_h binds the group —Y—ONO₂;
• R_a of formula (IIa) is selected in group a);
• R_c of formula (IIc) is selected in group a′);
• in formula (IIt) d is an integer from 3 to 5, d′ is 0;using the same procedure described in 7b).
• 14. The compounds of general formula (I) wherein:
• s and s′ are equal to 1;
• s″, m, m′, m″, are 0
• Y, Y′ can be equal or different and are as above defined,
• A is a radical of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein R₁ is —C(O)O—R_1x and R₁ binds the group —Y—ONO₂, R₂ is —C(O)NHR_2xx or —C(O)N(CH₃)R_2xx and R₂ binds the group —Y—ONO₂;
• in formula (IIn) R_n is —C(O)O—R_nx or —(CH₂)₂—NH—R_n wherein R_h is —C(O)O—R_hh, R_n or R_h binds the group —Y—ONO₂;
• R_a of formula (IIa) is selected in group a),
• R_c of formula (IIc) is selected in group a′);
• in formula (IIt) d is an integer from 3 to 5, d′ is 0;can be prepared as follows:
• 14a) by reacting compounds of formula (I) obtained with the procedure described in 3. with compounds (IIIo)

Wherein Y and Y′ are equal or different and are as above defined, W₃ is as above defined and A has the following meanings:

• A is a radical of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein R₁ is —C(O)O—R_1x and binds the group —Y—ONO₂, R₂ is —COOH;
• in formula (IIn) R_n is —C(O)O—R_nx or —(CH₂)₂—NH—R_h wherein R_h is —C(O)O—R_hh, R_n or R_h binds the group —Y—ONO₂;
• R_a of formula (IIa) is selected in group a);
• R_c of formula (IIc) is selected in group a′);
• in formula (IIt) d is an integer from 3 to 5, d′ is 0;using the same procedure described in 7b).
• 15. The compounds of general formula (I) wherein:
• s, s′ and m′ are equal to 1;
• s″, m, m″, are 0
• Y, Y′ can be equal or different and are as above defined;
• B is:

• A is selected from (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein:
• R₁ is —C(O)—R_1x and binds the group —Y—ONO₂, R₂ is —C(O)OR_2x and R₂ binds the group —B—Y′—ONO₂;
• in formula (IIn) R_n is —C(O)—R_nx or —(CH₂)₂—NH—R_h wherein R_h is —C(O)—R_hh, R_n or R_h binds the group —Y—ONO₂;
• R_a of formula (IIa) is selected in group a);
• R_c of formula (IIc) is selected in group a′);
• in formula (IIt) d is an integer from 3 to 5, d′ is 0;can be prepared as follows:
• 15a) By reacting compounds of formula (I) obtained with the procedure described in 1. with compounds (IIIg)A-Y—ONO₂+Hal-W₁—OC(O)O—Y—ONO₂  (IIIg)wherein Y is as above described, Hal is an halogen atom and W₁ is —CH₂— or —CH(CH₃)—, and A has the following meanings:
• A is a radical of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein R₁ is —C(O)—R_1x— and binds the group —Y—ONO₂, R₂ is —COOH;
• in formula (IIn) R_n is —C(O)—R_nx or —(CH₂)₂—NH—R_h wherein R_h is —C(O)—R_hh, R_n or R_h binds the group —Y—ONO₂;
• R_a of formula (IIa) is selected in group a);
• R_c of formula (IIc) is selected in group a′);
• in formula (IIt) d is an integer from 3 to 5, d′ is 0;using the same procedure described in 4b).
• 16. The compounds of general formula (I) wherein:
• s, s′ and m′ are equal to 1;
• s″, m, m″, are 0
• Y, Y′ can be equal or different and are as above defined;
• B is:

• A is selected from (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein:
• R₁ is —C(O)—R_1x and binds the group —Y—ONO₂, is R₂ is —C(O)OR_2x and binds the group —B—Y′—ONO₂;
• in formula (IIn) R_n is —C(O)—R_nx or —(CH₂)₂—NH—R_h wherein R_h is —C(O)—R_hh, R_n or R_h binds the group —Y—ONO₂,
• R_a of formula (IIa) is selected in group a),
• R_c of formula (IIc) is selected in group a′),
• in formula (IIt) d is an integer from 3 to 5, d′ is 0;can be prepared as follows
• 16a) by reacting compounds of formula (I) obtained with the procedure described in 1, with compounds (IIIn)

wherein 1 is as above described, Hal is an halogen atom and W₁ is —CH₂— or —CH(CH₃)—, and A has the following meanings:

• A is a radical of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein R₁ is —C(O)—R_1x— and binds the group —Y—ONO₂,
• R₂ is —COOH;
• in formula (IIn) R_n is —C(O)—R_nx— or —(CH₂)₂—NH—R_h wherein R_h is —C(O)—R_hh, R_n or R_h binds the group —Y—ONO₂,
• R_a of formula (IIa) is selected in group a),
• R_c of formula (IIc) is selected in group a′),
• in formula (IIt) d is an integer from 3 to 5, d′ is 0;using the same procedure described in 6b).
• 17. The compounds of general formula wherein:
• s, s′ and m′ are equal to 1;
• s″, m, m″, are 0
• Y, Y′ can be equal or different and are as above defined;
• B is:

• A is a radical of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein R₁ is —C(O)O—R_1x and R₂ is —C(O)OR_2x and R₁ binds the group —Y—ONO₂ and R₂ binds the group —B—Y′—ONO₂;
• in formula (IIn) R_n is —C(O)O—R_nx or —(CH₂)₂—NH—R_h wherein R_h is —C(O)O—R_hh, R_n or R_h binds the group —Y—ONO₂,
• R_a of formula (IIa) is selected in group a),
• R_c of formula (IIc) is selected in group a′),
• in formula (IIt) d is an integer from 3 to 5, d′ is 0;can be prepared as follows:
• 17a) by reacting compounds of formula (I) obtained with the procedure described in 3. with compounds (IIIg)

wherein Y is as above described, Hal is an halogen atom and W₁ is —CH₂— or —CH(CH₃)—, and A has the following meanings:

• A is a radical of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein R₁ is —C(O)O—R_1x— binds the group —Y—ONO₂, R₂ is —COOH;
• in formula (IIn) R_n is —C(O)O—R_nx, or is —(CH₂)₂—NH—R_h wherein R_h is —C(O)O—R_hh, R_n or R_h binds the group —Y—ONO₂;
• R_a of formula (IIa) is selected in group a),
• R_c of formula (IIc) is selected in group a′),
• in formula (IIt) d is an integer from 3 to 5, d′ is 0;using the same procedure described in 4b).
• 18. The compounds of general formula (I) wherein:
• s, s′ and m′ are equal to 1;
• s″, m, m″, are 0
• Y, Y′ can be equal or different and are as above defined;
• B is:

• A is a radical of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein R₁ is —C(O)O—R_1x and R₂ is —C(O)OR_2x and R₁ binds the group —Y—ONO₂ and R₂ binds the group —B—Y′—ONO₂;
• in formula (IIn) R_n is —C(O)O—R_nx or —(CH₂)₂—NH—R_h wherein R_h is —C(O)O—R_hh, R_n or R_h binds the group —Y—ONO₂;
• R_a of formula (IIa) is selected in group a),
• R_c of formula (IIc) is selected in group a′);
• in formula (IIt) d is an integer from 3 to 5, d′ is 0;can be prepared as follows:
• 18a) By reacting compounds of formula I obtained with the procedure described in 3. with compounds (IIIn)

wherein Y is as above described, Hal is an halogen atom and W₁ is —CH₂— or —CH(CH₃)—, and A has the following meanings:

• A is a radical of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein R₁ is —C(O)O—R_1x— and binds the group —Y—ONO₂, R₂ is —COOH;
• in formula (IIn) R_n is —C(O)O—R_nx, or is —(CH₂)₂—NH—R_h wherein R_h is —C(O)O—R_hh, R_n or R_h binds the group —Y—ONO₂;
• R_a of formula (IIa) is selected in group a),
• R_c of formula (IIc) is selected in group a′),
• in formula (IIt) d is an integer from 3 to 5, d′ is 0;using the same procedure described in 6b).
• 19. Alternatively the compounds of general formula (I) described in procedure 11. wherein:
• s and s′ are equal to 1;
• s″, m, m′, m″, are 0
• Y, Y′ can be equal or different and are as above defined,
• A is a radical of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein R₁ is —C(O)—R_1x and R₂ is —C(O)OR_2x and R₂ binds the group —Y—ONO₂ and R₂ binds the group —Y′—ONO₂;
• in formula (IIn) R_n is —C(O)—R_nx, or is —(CH₂)₂—NH—R_h wherein R_h is —C(O)—R_hh, R_n or R_h binds the group —Y′—ONO₂;
• R_a of formula (IIa) is selected in group a),
• R_c of formula (IIc) is selected in group a′),
• in formula (IIt) d is an integer from 3 to 5, d′ is 0;can be prepared as follows:
• 19a) By reacting compounds of formula (I) obtained with the procedure described in 8. with compounds (IIIa) or (IIIe)

Wherein Y and Y′ are equal or different and are as above defined, Act is as above defined and A has the following meanings:

• A is a radical of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein R₂ is —C(O)OR_2x and binds the group —Y—ONO₂, R₁ is —H;
• in formula (IIn) R_n is —H or is —(CH₂)₂—NH₂;
• R_a of formula (IIa) is selected in group a),
• R_c of formula (IIc) is selected in group a′),
• in formula (IIt) d is an integer from 3 to 5, d′ is 0;using the same procedure described in 1b) or 1b′).
• 20. Alternatively the compounds of general formula (I) described in procedure 12., wherein:
• s and s′ are equal to 1;
• s″, m, m′, m″, are 0
• Y, Y′ can be equal or different and are as above defined;
• A is selected from (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein:
• R₁ is —C(O)O—R_1x and R₂ is —C(O)OR_2x and R₂ binds the group —Y—ONO₂ and R₁ binds the group —Y′—ONO₂;
• in formula (IIn) R_n is —C(O)O—R_nx or —(CH₂)₂—NH—R_h wherein R_h is —C(O)O—R_hh, R_n or R_h binds the group —Y′—ONO₂;
• R_a of formula (IIa) is selected in group a),
• R_c of formula (IIc) is selected in group a′),
• in formula (IIt) d is an integer from 3 to 5, d′ is 0;can be prepared as follows:
• 20a) By reacting compounds of formula (I) obtained with the procedure described in 8. with compounds (IIIf)

• Wherein Y and Y′ are equal or different and are as above defined and A has the following meanings:
• A is a radical of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein R₂ is —C(O)OR_2x and binds the group —Y—ONO₂, R₁ is —H;
• in formula (IIn) R_n is —H or is —(CH₂)₂—NH₂;
• R_a of formula (IIa) is selected in group a),
• R_c of formula (IIc) is selected in group a′),
• in formula (IIt) d is an integer from 3 to 5, d′ is 0;using the same procedure described in 3b).
• 21. Alternatively the compounds of general formula (I) described in procedure 13. wherein:
• s and s′ are equal to 1;
• s″, m, m′, m″, are 0
• Y, Y′ can be equal or different and are as above defined,
• A is selected from (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein:
• R₁ is —C(O)—R_1x and R₂ is —C(O)NHR_2xx or —C(O)NCH₃—R_2xx and R₂ binds the group —Y—ONO₂ and R₁ binds the group —Y′—ONO₂;
• in formula (IIn) R_n is —C(O)—R_nx, or is —(CH₂)₂—NH—R_h wherein R_h is —C(O)—R_hh, R_n or R_h binds the group —Y′—ONO₂;
• R_a of formula (IIa) is selected in group a),
• R_c of formula (IIc) is selected in group a′),
• in formula (IIt) d is an integer from 3 to 5, d′ is 0;can be prepared as follows:
• 21a) By reacting compounds of formula (I) obtained with the procedure described in 7. with compounds (IIIa) or (IIIe)

wherein Y and Y′ are equal or different and are as above defined, Act is as above defined and A has the following meanings:

• A is a radical of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein R₂ is —C(O)NHR_2xx or —C(O)N(CH₃)R_2xx and binds the group —Y—ONO₂, R₁ is —H;
• in formula (IIn) R_n is —H or is —(CH₂)₂—NH₂;
• R_a of formula (IIa) is selected in group a),
• R_c of formula (IIc) is selected in group a′),
• in formula (IIt) d is an integer from 3 to 5, d′ is 0;using the same procedure described in 1b) or 1b′).
• 22. Alternatively the compounds of general formula (I) wherein:
• s and s′ are equal to 1;
• s″, m, m′, m″, are 0, Y, Y′ can be equal or different and are as above defined;
• A is a radical of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein R₁ is —C(O)O—R_1x and R₂ is —C(O)NHR_2xx or —C(O)N(CH₃)R_2xx and R₂ binds the group —Y—ONO₂ and R₁ binds the group —Y′—ONO₂;
• in formula (IIn) R_n is —C(O)O—R_nx or —(CH₂)₂—NH—R_h wherein R_h is —C(O)O—R_hh, R_n or R_h binds the group —Y′—ONO₂;
• R_a of formula (IIa) is selected in group a),
• R_c of formula (IIc) is selected in group a′),
• in formula (IIt) d is an integer from 3 to 5, d′ is 0;can be prepared as follows:
• 22a) By reacting compounds of formula (I) obtained with the procedure described in 7. with compounds (IIIf)

wherein Y and Y′ are equal or different and are as above defined and A has the following meanings:

• A is a radical of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein R₂ is —C(O)NHR_2xx or —C(O)N(CH₃)R_2xx and binds the group —Y—ONO₂, R₁ is —H;
• in formula (IIn) R_n is —H or is —(CH₂)₂—NH₂;
• R_a of formula (IIa) is selected in group a),
• R_c of formula (IIc) is selected in group a′),
• in formula (IIt) d is an integer from 3 to 5, d′ is 0;using the same procedure described in 3b).
• 23. Alternatively the compounds of general formula (I) wherein:
• s, s′ and m are equal to 1;
• s″, m, m″, are 0
• Y, Y′ can be equal or different and are as above defined;
• B is:

• A is selected from (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein:
• R₁ is —C(O)—R_1x and R₂ is —C(O)OR_2x and R₂ binds the group —B—Y—ONO₂ and R₁ binds the group —Y′—ONO₂;
• in formula (IIn) R_n is —C(O)—R_nx, or is —(CH₂)₂—NH—R_h wherein R_h is —C(O)—R_hh, R_n or R_h binds the group —Y′—ONO₂;
• R_a of formula (IIa) is selected in group a),
• R_c of formula (IIc) is selected in group a′),
• in formula (IIt) d is an integer from 3 to 5, d′ is 0;can be prepared as follows:
• 23a) By reacting compounds of formula (I) obtained with the procedure described in 4. or 6. with compounds (IIIa) or (IIIe)

wherein Y, and Y′ are equal or different and are as above defined, Act and B are as above described and A has the following meanings:

• A is a radical of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein R₁ is —H, R₂ is —C(O)OR_2x and R₂ binds the group —B—Y—ONO₂
• in formula (IIn) R_n is —H or is —(CH₂)₂—NH₂;
• R_a of formula (IIa) is selected in group a),
• R_c of formula (IIc) is selected in group a′),
• in formula (IIt) d is an integer from 3 to 5, d′ is 0;using the same procedure described in 1b) or 1b′).
• 24. Alternatively the compounds of general formula (I) wherein:
• s, s′ and m are equal to 1;
• s″, m, m″, are 0
• Y, Y′ can be equal or different and are as above defined;
• B is:

• A is a radical of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein R₁ is —C(O)O—R_1x and R₂ is —C(O)OR_2x and R₂ binds the group —B—Y—ONO₂ and R₁ binds the group —Y′—ONO₂;
• in formula (IIn) R_n is —C(O)O—R_nx or —(CH₂)₂—NH—R_h wherein R_h is —C(O)O—R_hh, R_n or R_h binds the group —Y′—ONO₂;
• R_a of formula (IIa) is selected in group a),
• R_c of formula (IIc) is selected in group a′),
• in formula (IIt) d is an integer from 3 to 5, d′ is 0;can be prepared as follows:
• 24a) by reacting compounds of formula (I) obtained with the procedure described in 4. or 6. depending on the meanings of B with compounds (IIIf)

wherein Y, and Y′ are equal or different and are as above defined, Act is as above described and A has the following meanings:

• A is a radical of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein R₁ is —H, R₂ is —C(O)OR_2x and binds the group —B—Y—ONO₂
• B is:

• in formula (IIn) R_n is —H or is —(CH₂)₂—NH₂;
• R_a of formula (IIa) is selected in group a),
• R_c of formula (IIc) is selected in group a′),
• in formula (IIt) d is an integer from 3 to 5, d′ is 0;using the same procedure described in 3b).
• 25. The compounds of general formula (I) wherein:
• s, is equal to 1;
• s′ s″, m, m′, m″, are 0
• Y is as above defined;
• A is a radical of formula (IIs) wherein R₁ is —C(O)—R_1x and it binds the group —Y—ONO₂, R₃ is —OH and R_s is selected in group a″), can be prepared as follows
• 25a) by reacting compounds of formula A with a compound of formula (IIIa) or (IIIe):HOOC—Y—ONO₂  (IIIa)ActOC—Y—ONO₂  (IIIe)wherein Y is as above defined, Act is as above described and A is a compound of formula (IIs) wherein R₁ is —H, R₃ is —OH and R_s is selected in group a″), using the same procedure described in 1b) or 1b′) using a ratio A/(IIIa) or A/(IIIe) 1:1.Compounds A are commercially available.
• 26. The compounds of general formula (I) wherein:
• s is equal to 1;
• s′, s″, m, m′, m″, are 0
• Y is as above defined;
• A is a radical of formula (IIs) wherein R₁ is —C(O)O—R_1x and it binds the group —Y—ONO₂, R₃ is —OH and R_s is selected in group a″), can be prepared as follows:
• 26a) by reacting compounds of formula A with a compound of formula (IIIf):Act-(O)C—O—Y—ONO₂  (IIIf)wherein Y is as above defined, Act is as above described and A is a compound of formula (IIs) described, in 25a) wherein R₁ is —H, R₃ is —OH and R_s is selected in group a″), using the same procedure described, in 3b) using a ratio A/(IIIf) 1:1.
• 27. The compounds of general formula (I) wherein:
• s is equal to 1;
• s′, s″, m, m′, m″, are 0
• Y is as above defined;
• A is a radical of formula (IIs) wherein R₃ is —OC(O)—R_3x and it binds the group —Y—ONO₂; R₁ is —H and R_s is selected in group a″), can be prepared as follows:
• 27a) by reacting compounds of formula (I) wherein s, s′, s″, m, m′, m″, Y, Y′, Y″ are as above defined in 27., A is a radical of formula (IIs) R₁ is —C(O)OC(CH₃)₃; R₃ and R_s are as defined in 27.; with anhydrous or aqueous organic or inorganic acid to hydrolyze the —BOC protective groups following procedure well known in the literature.
• 27b) by reacting a compound of formula A with a compound of formula (IIIe)Act-(O)C—Y—ONO₂  (IIIe)wherein Y and Act are as above defined; A is a compound of formula (IIs) wherein R₁ is —C(O)OC(CH₃)₃, R₃ is —OH and R_s is selected in group a″), using the same procedure described in 1b′). Compounds A are commercially available.
• 28. The compounds of general formula (I) wherein:
• s is equal to 1;
• s′, s″, m, m′, m″, are 0
• Y is as above defined;
• A is a radical of formula (IIs) wherein R₃ is —OC(O)O—R_3x and it binds the group —Y—ONO₂; R₁ is —H and R_s is selected in group a″), can be prepared as follows:
• 28a) by reacting compounds of formula (I) wherein s, s′, s″, m, m′, m″, Y, Y′, Y″ are as above defined in 28., A is a radical of formula (IIs) R₁ is —C(O)OC(CH₃)₃; R₃ and R_s are as defined in 28. with anhydrous or aqueous organic or inorganic acid to hydrolyze the —BOC protective groups following procedure well known in the literature.
• 28b) By reacting a compound of formula A with a compound of formula (IIf)Act-(O)C—O—Y—ONO₂  (IIIf)wherein Y and Act are as above defined; A is a compound of formula (IIs) described in 27a) wherein R₁ is —C(O)OC(CH₃)₃, R₃ is —OH and R_s is selected in group a″), using the same procedure described in 3b)
• 29. The compounds of general formula (I) wherein:
• s is equal to 1;
• s′, s″, m, m′, m″, are 0
• Y is as above defined;
• A is a radical of formula (IIs) wherein R₃ is —OC(O)—NH—R_3x— and it binds the group —Y—ONO₂; R₁ is —H and R_s is selected in group a″), can be prepared as follows:
• 29a) by reacting compounds of formula (I) wherein s, s′, s″, m, m′, m″, Y, Y′, Y″ are as above defined in 29., A is a radical of formula (IIs) R₁ is —C(O)OC(CH₃)₃; R₃ and R_s are as defined in 29. with anhydrous or aqueous organic or inorganic acid to hydrolyze the —BOC protective groups following procedure well known in the literature.
• 29b) by reacting a compound of formula A with a compound of formula (IIIu)Act-(O)C—NH—Y—ONO₂  (IIIu)wherein Y and Act are as above defined; A is a compound of formula (IIs) described in 27b) wherein R₁ is —C(O)OC(CH₃)₃, R₃ is —OH and R_s is selected in group a″), 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°-100° C. for time range of 1-60 hrs, or under microwave irradiation in the presence of DMAP and a Lewis acid such as Sc(OTf)₃ or Bi(OTf)₃ in solvents such as DMF, CH₂Cl₂ at temperatures range between 60°-120° C. for time range of 1-120 min;Compounds (IIIu) can be prepared from compounds Act-(O)C—NH—Y—OH (IIIv) by nitrating reactions with tetraalkylammonium nitrate as already described. Compounds (IIIv) can be prepared from commercially available Act-CO-Hal (IIIw) and compounds W₃NH—Y—OH (IIIt) with the proviso that in (IIIt) W₃ has only the meaning of —H.
• 30. The compounds of general formula (I) wherein:
• s and s′ are equal to 1;
• s″, m, m′, m″, are 0
• Y, Y′ can be equal or different and are as above defined;
• A is a radical of formula (IIs) wherein R₃ is —OC(O)—R_3x and it binds the group —Y—ONO₂ or the group —Y—ONO₂; R₁ is —C(O)—R_1x and it binds the group —Y—ONO₂ or the group —Y′—ONO₂;
• R_s is selected in group a″), can be prepared as follows:
• 30a) Y and Y′ are equalby reacting compounds of formula A described in 25a) with a compound of formula (IIIe)Act-(O)C—Y—ONO₂  (IIIe)wherein Y and Act are as above defined; A is a compound of formula (IIs) wherein R₁ is —H, R₃ is —OH and R_s is selected in group a″), using a ratio A/(IIIe) 1:2 and applying the same procedure described in 1b′).
• 30a′) Y and Y′ are equal or differentby reacting compounds of formula (I) prepared in 25. with a compound of formula (IIIe)A-Y—ONO₂+Act-(O)C—Y′—ONO₂  (IIIe)wherein Y, Y′ and Act are as above defined; A is a compound of formula (IIs) wherein R₁ is —C(O)—R_1x and binds the group —Y—ONO₂, R₃ is —OH and R_s is selected in group a″), applying the same procedure described in 1b′).
• 30a″) Y and Y′ are equal or differentby reacting compounds of formula (I) prepared in 27. with a compound of formula (IIIe)A-Y—ONO₂+Act-(O)C—Y′—ONO₂  (IIIe)wherein Y, Y′ and Act are as above defined; A is selected from (IIs) wherein R₁ is —H, R₃ is —OC(O)—R_3x and R_s is selected in group a″), applying the same procedure described in 1b′).
• 31. The compounds of general formula (I) wherein:
• s and s′ are equal to 1;
• s″, m, m′, m″, are 0
• Y and Y′ can be equal or different and are as above defined;
• A is a radical of formula (IIs) wherein R₃ is —OC(O)O—R_3x— and it binds the group —Y—ONO₂ or the group —Y′—ONO₂; R₁ is —C(O)—R_1x and it binds the group —Y—ONO₂ or the group —Y′—ONO₂, R_s is selected in group a″), can be prepared as follows:
• 31a) by reacting compounds of formula (I) obtained in procedure 25. with a compound of formula (IIIf)A-Y—ONO₂+Act-(O)C—O—Y′—ONO₂  (IIIf)wherein Y, Y′ and Act are as above defined; A is a radical of formula (IIs) wherein R₁ is —C(O)—R_1x and it binds the group —Y—ONO₂, R₃ is —OH and R_s is selected in group a″), applying the same procedure described in 28b).
• 31a′) alternatively by reacting compounds of formula (I) prepared as described in 28. with a compound of formula (IIIe)A-Y—ONO₂+Act-(O)C—Y′—ONO₂  (IIIe)wherein Y, Y′ and Act are as above defined; A is the radical of formula (IIs) wherein R₁ is —H, R₃ is —OC(O)O—R_3x and R₃ binds the group —Y—ONO₂, R_s is selected in group a″), applying the same procedure described in 25a).
• 32. The compounds of general formula (I) wherein:
• s and s′ are equal to 1;
• s″, m, m′, m″, are 0
• Y and Y′ can be equal or different and are as above defined;
• A is a radical of formula (IIs) wherein R₃ is —OC(O)—NH—R_3x and it binds the group —Y—ONO₂; R₁ is —C(O)—R_1x and it binds the group —Y′—ONO₂, R_s is selected in group a″), can be prepared as follows:
• 32a) by reacting compounds of formula (I) obtained in procedure 29. with a compound of formula (IIIe)

wherein Y, Y′ and Act are as above defined; A is a radical of formula (IIs) wherein R₁ is —H, R₃ is —OC(O)—NH—R_3x it binds the group —Y—ONO₂, R_s is selected in group a″),applying the same procedure described in 25a).

• 33. The compounds of general formula (I) wherein:
• s and s′ are equal to 1;
• s″, m, m′, m″, are 0
• Y and Y′ can be equal or different and are as above defined;
• A is a radical of formula (IIs) wherein R₃ is —OC(O)—R_3x and it binds the group —Y′—ONO₂; R₁ is —C(O)O—R_1x and it binds the group —Y—ONO₂, R_s is selected in group a″), can be prepared as follows:
• 33a) by reacting compounds of formula (I) obtained in procedure 26. with a compound of formula (IIIe)

wherein Y, Y′ and Act are as above defined; A is a radical of formula (IIs) wherein R₁ is —C(O)O—R_1x and it binds the group —Y—ONO₂, R₃ is —OH and R_s is selected in group a″),applying the same procedure described in 27b).

• 34. The compounds of general formula (I) wherein:
• s and s′ are equal to 1;
• s″, m, m′, m″, are 0
• Y and Y′ can be equal or different and are as above defined;
• A is a radical of formula (IIs) wherein R₃ is —OC(O)O—R_3x and it binds the group —Y—ONO₂ or the group —Y′—ONO₂, R₁ is —C(O)O—R_1x and it binds the group —Y—ONO₂ or the group —Y′—ONO₂, R_s is selected in group a″), can be prepared as follows:
• 34a) Y and Y′ are equal;by reacting compounds of formula A described in 25a) with a compound of formula (IIIf)A+Act-(O)C—O—Y′—ONO₂  (IIIf)wherein Y, Y′ and Act are as above defined; A is a compound of formula (IIs) wherein R₁ is —H, R₃ is —OH and R_s is selected in group a″), using a ratio A/(IIIf) 1:2 and applying the same procedure described in 3b).
• 34a′) Y and Y′ are equal or differentby reacting compounds of formula (I) prepared in 26. with a compound of formula (IIIf)

wherein Y, Y′ and Act are as above defined; A is a radical of formula (IIs) wherein R₁ is —C(O)O—R_1x and it binds the group —Y—ONO₂ and R₃ is —OH, R₃ is selected in group a″);applying the same procedure described in 3b).

• 34a″) Y and Y′ are equal or differentby reacting compounds of formula (I) prepared in 28. with a compound of formula (IIIf)

wherein Y, Y′ and Act are as above defined; A is a radical of formula (IIs) wherein R₁ is —H, R₃ is —OC(O)O—R_3x and R₃ binds the group —Y—ONO₂, R_s is selected in group a″),applying the same procedure described in 3b).

• 35. The compounds of general formula (I) wherein:
• s and s′ are equal to 1;
• s″, m, m′, m″, are 0
• Y and Y′ can be equal or different and are as above defined;
• A is a radical of formula (IIs) wherein R₃ is —OC(O)—NH—R_3x and it binds the group —Y′—ONO₂; R₁ is —C(O)O—R_1x and it binds the group —Y—ONO₂, R_s is selected in group a″),can be prepared as follows:
• 35a) by reacting compounds of formula (I) obtained in procedure 26. with a compound of formula (IIIu)

wherein Y, Y′ and Act are as above defined; A is a radical of formula (IIs) wherein R₁ is —C(O)O—R_1x and it binds the group —Y—ONO₂, R₃ is —OH and R_s is selected in group a″),using the same procedure described in 29b).

• 35a″) alternatively by reacting compound of formula (I) prepared in 29. with a compound of formula (IIIf)

wherein Y, Y′ and Act are as above defined; A is a radical of formula (IIs) wherein R₁ is —H, R₃ is —OC(O)—NH—R_3x and it binds the group —Y—ONO₂, R_s is selected in group a″),applying the same procedure described in 3b).

• 36. The compounds of general formula (I) wherein:
• s is equal to 1;
• s′ can be 0 or 1; with the proviso that s′ is 1 when A is the radical (IIs) and (IIs) is as defined in iii) below reported,
• s″, m, m′, m″, are 0
• Y and Y′ when presents are equal and are as above defined;
• A is selected among:
• i) (IIa) wherein R₁ is —H, R₂ is —COOH and R_a is selected from R_bx—C(O)—S—CH₂—, or R_xO—CH₂—, R_xO—CH(CH₃)—, (R_xO)-p-C₆H₄—CH₂—, 4-(R_xO)-3,5-diiodobenzyl-4-(R_xO)-3-nitrobenzyl- wherein R_x —C(O)— and R_a binds a group —Y—ONO₂;
• ii) (IIc) wherein R₁ is —H, R₂ is —COOH and R_c is selected from R_bx—C(O)—S—CH₂—, or R_xO—CH₂—, R_xO—CH(CH₃)—, (R_xO)-p-C₆H₄—CH₂—, 4-(R_xO)-3,5-diiodobenzyl-4-(R_xO)-3-nitrobenzyl- wherein R_x—C(O)— and R_c binds a group —Y—ONO₂;
• iii) (IIs) (s′ is 1) wherein R₁ is —H, R₃ is —OC(O) and R_s is selected from R_bx—C(O)—S—CH₂—, or R_xO—CH₂—, R_xO—CH(CH₃)—, (R_xO)-p-C₆H₄—CH₂—, 4-(R_xO)-3,5-diiodobenzyl-4-(R_xO)-3-nitrobenzyl- wherein R_x is R_xx—C(O)—; both R₃ and R_s bind a group —Y—ONO₂ or a —Y′—ONO₂;
• vi) (IIs) (s′ is 0) wherein R₁ is —H, R₃ is —OC(O) and R₃ binds a group —Y—ONO₂; R_s is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is —OH;v) (IIu) wherein R₁ is —H, R₂ is —COOH, a is 1; b is 0 or 1; and R_x is R_xx—C(O)— and R_x binds a group —Y—ONO₂;can be prepared as follows:
• 36a) by reacting a compound of formula (I) wherein s, s′, s″, m, m′, m″, Y, Y′, Y″ are as above defined in 36., A is a radical of formula (IIa), (IIc), (IIs) or (IIu) wherein; R₂, R₃, a, b, R_a, R_c, R_s, R_g and R_x, are as defined in 36.; R₁ is —C(O)OC(CH₃)₃ with anhydrous or aqueous organic or inorganic acid to hydrolyze the —BOC protective groups following procedure well known in the literature.
• 36b) by reacting a compound of formula A with a compound of formula (IIIa)A+Act(O)C—Y—ONO₂  (IIIe)wherein Act and Y are as above defined and A has the following meanings:
• i′) a radical of formula (IIa) wherein R₁ is —C(O)OC(CH₃)₃, R₂ is —COOH and R_a is selected from HS—CH₂—, or R_xO—CH₂—, R_xO—CH(CH₃)—, (R_xO)-p-C₆H₄—CH₂—, 4-(R_xO)-3,5-diiodobenzyl-4-(R_xO)-3-nitrobenzyl- wherein R_x —H;
• ii′) a radical of formula (IIc) wherein R₁ is —C(O)OC(CH₃)₃, R₂ is —COOH and R_c is selected from HS—CH₂—, or R_xO—CH₂—, R_xO—CH(CH₃)—, (R_xO)-p-C₆H₄—CH₂—, 4-(R_xO)-3,5-diiodobenzyl-4-(R_xO)-3-nitrobenzyl- wherein R_x —H;
• iii′) a radical of formula (IIs) wherein R₁ is —C(O)OC(CH₃)₃, R₃ is —OH and R_s is selected from HS—CH₂—, or R_xO—CH₂—, R_xO—CH(CH₃)—, (R_xO)-p-C₆H₄—CH₂—, 4-(R_xO)-3,5-diiodobenzyl-4-(R_xO)-3-nitrobenzyl- wherein R_x —H;
• iv′) a radical of formula (IIs) wherein R₁ is —C(O)OC(CH₃)₃, R₃ is —OH; R_s is R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is —OH;
• v′) a radical of formula (IIu) wherein R₁ is —C(O)OC(CH₃)₃, R₂ is —COOH, a is 1; b is 0 or 1 and R_x is —H;following the same procedure described in 1b′) using a ratio A/(IIIe) 1:1 or 1:2 for s′ equal to 1.
• 37. The compounds of general formula (I) wherein:
• s is equal to 1;
• s′ can be 0 or 1; with the proviso that s′ is 1 when A is the radical (IIs) and (IIs) is as defined in iii),
• s″, m, m′, m″, are 0
• Y and Y′, when present are equal and are as above defined;
• A is selected among:
• i) (IIa) wherein R₁ is —H, R₂ is —COOH and R_a is selected from R_bx—OC(O)—S—CH₂—, or R_xO—CH₂—, R_xO—CH(CH₃)—, (R_xO)-p-C₆H₄—CH₂—, 4-(R_xO)-3,5-diiodobenzyl-4-(R_xO)-3-nitrobenzyl- wherein R_x is R_xx—OC(O)— and R_a binds a group —Y—ONO₂;
• ii) (IIc) wherein R₁ is —H, R₂ is —COOH and R_c is selected from R_bx—OC(O)—S—CH₂—, or R_xO—CH₂—, R_xO—CH(CH₃)—, (R_xO)-p-C₆H₄—CH₂—, 4-(R_xO)-3,5-diiodobenzyl-4-(R_xO)-3-nitrobenzyl- wherein R_x is R_xx—OC(O)— and R_c binds a group —Y—ONO₂;
• iii) (IIs) (s′ is 1) wherein R₁ is —H, R₃ is —OC(O)O—R_3x and R_s is selected from R_bx—OC(O)—S—CH₂—, or R_xO—CH₂—, R_xO—CH(CH₃)—, (R_xO)-p-C₆H₄—CH₂—, 4-(R_xO)-3,5-diiodobenzyl-4-(R_xO)-3-nitrobenzyl- wherein R_x is R_xx—OC(O)— both R₃ and R_s bind a group —Y—ONO₂ or a group —Y′—ONO₂;
• vi) (IIs) (s′ is 0) wherein R₁ is —H, R₃ is —OC(O)O—R_3x and R₃ binds a group —Y—ONO₂; R_s is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is —OH;
• v) (IIu) wherein R₁ is —H, R₂ is —COOH, a is 1; b is 0 or 1; and R_x is R_xx—OC(O)— and R_x binds a group —Y—ONO₂;can be prepared as follows:
• 37a) by reacting a compound of formula (I) wherein s, s′, s″, m, m′, m″, Y, Y′, Y″ are as above defined in 37., A is a radical of formula (IIa), (IIc), (IIs) or (IIu) wherein; R₂, R₃, a, b, R_a, R_c, R_s, R_g and R_x, are as defined in 37.; R₁ is —C(O)OC(CH₃)₃ with anhydrous or aqueous organic or inorganic acid to hydrolyze the —BOC protective groups following procedure well known in the literature.
• 37b) by reacting a compound of formula A with a compound of formula (IIIf)A+Act(O)C—O—Y—ONO₂  (IIIf)wherein Act and Y are as above defined and A has the same meanings described in 36b);following the same procedure described in 3b) using a ratio A/(IIIf) 1:1 or 1:2 for s′ equal to 1.
• 38. The compounds of general formula (I) wherein:
• s is equal to 1;
• s′ can be 0 or 1; with the proviso that s′ is 1 when A is the radical (IIs) and (IIs) is as defined in iii),
• s″, m, m′, m″, are 0
• Y and Y′, when presents, are equal and are as above defined;
• A is selected among:
• i) (IIa) wherein R₁ is —H, R₂ is —COOH and R_a is selected from R_bx—NH(O)C—S—CH₂—, or R_xO—CH₂—, R_xO—CH(CH₃)—, (R_xO)-p-C₆H₄—CH₂—, 4-(R_xO)-3,5-diiodobenzyl-4-(R_xO)-3-nitrobenzyl- wherein R_x is R_xxNH—C(O)— and R_a binds a group —Y—ONO₂;
• ii) (IIc) wherein R₁ is —H, R₂ is —COOH and R_c is selected from R_bx—NH(O)C—S—CH₂—, or R_xO—CH₂—, R_xO—CH(CH₃)—, (R_xO)-p-C₆H₄—CH₂—, 4-(R_xO)-3,5-diiodobenzyl-4-(R_xO)-3-nitrobenzyl- wherein R_x is R_xxNH—C(O)— and R_c binds a group —Y—ONO₂;
• iii) (IIs) (s′ is 1) wherein R₁ is —H, R₃ is —OC(O)—NH—R_3x and R_s is selected from R_bx—NH(O)C—S—CH₂—, or R_xO—CH₂—, R_xO—CH(CH₃)—, (R_xO)-p-C₆H₄—CH₂—, 4-(R_xO)-3,5-diiodobenzyl-4-(R_xO)-3-nitrobenzyl- wherein R_x is R_xxNH—C(O)— both R_s and R_s bind a group —Y—ONO₂ or a group —Y′—ONO₂;
• vi) (IIs) (s′ is 0) wherein R₁ is —H, R₃ is R₃ is —OC(O)—NH—R_3x and R₃ binds a group —Y—ONO₂; R_s is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is —OH;
• v) (IIu) wherein R₁ is —H, R₂ is —COOH, a is 1; b is 0 or 1; and R_x is R_xx—NHC(O)— and R_x binds a group —Y—ONO₂;can be prepared as follows:
• 38a) by reacting a compound of formula (I) wherein s, s′, s″, m, m′, m″, Y, Y′, Y″ are as above defined in 38., A is a radical of formula (IIa), (IIc), (IIs) or (IIu) wherein; R₂, R₃, a, b, R_a, R_c, R_s, R_g and R_x, are as defined in 38.; R₁ is —C(O)OC(CH₃)₃ with anhydrous or aqueous organic or inorganic acid to hydrolyze the —BOC protective groups following procedure well known in the literature.
• 38b) by reacting a compound of formula A with a compound of formula (IIIu)A+Act(O)C—NH—Y—ONO₂  (IIIu)wherein Act and Y are as above defined and A has the same meanings described in 36b);following the same procedure described in 29. using a ratio A/(IIIu) 1:1 or 1:2 for s′ equal to 1.
• 39. The compounds of general formula (I) wherein:
• s and a′ are equal to 1;
• s″, m, m′, m″, are 0
• Y and Y′ are equal or different and are as above defined;
• A is selected among:
• i) (IIa) wherein R₁ is —H, R₂ is —C(O)OR_2x and R₂ binds a group —Y′—ONO₂; and R_a is selected from R_bx—C(O)—S—CH₂—, or R_xO—CH₂—, R_xO—CH(CH₃)—, (R_xO)-p-C₆H₄—CH₂—, 4-(R_xO)-3,5-diiodobenzyl-4-(R_xO)-3-nitrobenzyl- wherein R_x is R_xx—C(O)— and R_a binds a group —Y—ONO₂;
• ii) (IIc) wherein R₁ is —H, R₂ is —C(O)OR_2x and R₂ binds a group —Y′—ONO₂; R_c is selected from R_bx—C(O)—S—CH₂—, or R_xO—CH₂—, R_xO—CH(CH₃)—, (R_xO)-p-C₆H₄—CH₂—, 4-(R_xO)-3,5-diiodobenzyl-4-(R_xO)-3-nitrobenzyl- wherein R_x is R_xx—C(O)— and R_c binds a group —Y—ONO₂;
• iii) (IIs) wherein R₁ is —H, R₃ is —OC(O)R_3x and R₃ binds a group —Y—ONO₂; R_s is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is R_gx—O—, and R_g binds a group —Y′—ONO₂;
• v) (IIu) wherein R₁ is —H, R₂ is —C(O)O—R_2x, R₂ binds a group —Y′—ONO₂; a is 1; b is 0 or 1; and R_x is R_xx—C(O)— and R_x binds a group —Y—ONO₂;can be prepared as follows:
• 39a) by reacting a compound of formula (I) wherein s, s′, s″, m, m′, m″, Y, Y′, Y″ are as above defined in 39., A is a radical of formula (IIa), (IIc), (IIs) or (IIu) wherein; R₂, R₃, a, b, R_a, R_c, R_s, R_g and R_x, as defined in 39.; R₁ is —C(O)OC(CH₃)₃ with anhydrous or aqueous organic or inorganic acid to hydrolyze the —BOC protective groups following procedure well known in the literature.
• 39b) by reacting a compound of formula (I) obtained in 36b) with a compound of formula (IIIi)

wherein Y and Y′ are as above defined and in formula (I) A is a radical of formula (IIa), (IIc), (IIs) or (IIu) wherein R₁ is —C(O)OC(CH₃)₃, R₂ is —COOH, R₃, R_a, R_c R_x a and b are as above defined in 39.; R_s is R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is —OH;following the same procedure described in 8b).

• 40. The compounds of general formula (I) wherein:
• s and s′ are equal to 1;
• s″, m, m′, m″, are 0
• Y and Y′ are equal or different and are as above defined;
• A is selected among:
• i) (IIa) wherein R₁ is —H, R₂ is —C(O)OR_2x and R₂ binds a group —Y′—ONO₂; and R_a is selected from R_bx—OC(O)—S—CH₂—, or R_xO—CH₂—, R_xO—CH(CH₃)—, (R_xO)-p-C₆H₄—CH₂—, 4-(R_xO)-3,5-diiodobenzyl-4-(R_xO)-3-nitrobenzyl- wherein R_x is R_xx—OC(O)— and R_a binds a group —Y—ONO₂;
• ii) (IIc) wherein R₁ is —H, R₂ is —C(O)OR_2x and R₂ binds a group —Y′—ONO₂; R_c is selected from R_bx—OC(O)—S—CH₂—, or R_xO—CH₂—, R_xO—CH(CH₃)—, (R_xO)-p-C₆H₄—CH₂—, 4-(R_xO)-3,5-diiodobenzyl-4-(R_xO)-3-nitrobenzyl- wherein R_x is R_xx—OC(O)— and R_c binds a group —Y—ONO₂;
• iii) (IIs) wherein R₁ is —H, R₃ is —OC(O)O—R_3x and R₃ binds a group —Y—ONO₂; R_s is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, R_g is R_gx—O—, and R_s binds a group —Y′—ONO₂;
• v) (IIu) wherein R₁ is —H, R₂ is —C(O)O—R_2x, R₂ binds a group —Y′—ONO₂; a is 1; b is 0 or 1 and R_x is R_xx—OC(O)— and R_x binds a group —Y—ONO₂;can be prepared as follows:
• 40a) by reacting a compound of formula (I) wherein s, s′, s″, m, m′, m″, Y, Y′, Y″ are as above defined, in 40., A is a radical of formula (IIa), (IIc), (IIs) or (IIu) wherein; R₂, R₃, a, b, R_a, R_c, R_s, R_g and R_x, are as defined in 40.; R₁ is —C(O)OC(CH₃)₃ with anhydrous or aqueous organic or inorganic acid to hydrolyze the —BOC protective groups following procedure well known in the literature.
• 40b) by reacting a compound of formula (I) obtained in 37b) with a compound of formula (IIIi)

wherein Y and Y′ are as above defined and in formula (I) A is a radical of formula (IIa), (IIc), (IIs) or (IIu) wherein R₁ is —C(O)OC(CH₃)₃, R₂ is —COOH, R₃, R_a, R_c R_x a and b are as above defined in 40., R_s is R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is —OH;following the same procedure described in 8b).

• 41. The compounds of general formula (I) wherein:
• s and s′ are equal to 1;
• s″, m, m′, m″, are 0
• Y and Y′ are equal or different and are as above defined;
• A is selected among:
• i) (IIa) wherein R₁ is —H, R₂ is —C(O)OR_2x and R₂ binds a group —Y′—ONO₂; and R_a is selected from R_bx—NH(O)C—S—CH₂—, or R_xO—CH₂—, R_xO—CH(CH₃)—, (R_xO)-p-C₆H₄—CH₂—, 4-(R_xO)-3,5-diiodobenzyl-4-(R_xO)-3-nitrobenzyl- wherein R_x is R_xxNH—C(O)— and R_a binds a group —Y—ONO₂;
• ii) (IIc) wherein R₁ is —H, R₂ is —C(O)OR_2x and R₂ binds a group —Y′—ONO₂; R_c is selected from R_bx—NH(O)C—S—CH₂—, or R_xO—CH₂—, R_xO—CH(CH₃)—, (R_xO)-p-C₆H₄—CH₂—, 4-(R_xO)-3,5-diiodobenzyl-4-(R_xO)-3-nitrobenzyl- wherein R_x is R_xxNH—C(O)— and R_c binds a group —Y—ONO₂;
• iii) (IIs) wherein R₁ is —H, R₃ is —OC(O)—NH—R_3x and R₃ binds a group —Y—ONO₂; R_s is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is R_gx—O—, and R_s binds a group —Y′—ONO₂;
• v) (IIu) wherein R₁ is —H, R₂ is —C(O)O—R_2x, R₂ binds a group —Y′—ONO₂; a is 1; b is 0 or 1 and R_x is R_xx—NHC(O)— and R_x binds a group —Y—ONO₂;can be prepared as follows:
• 41a) by reacting a compound of formula (I) wherein s, s′, s″, m, m′, m″, Y, Y′, Y″ are as above defined in 41., A is a radical of formula (IIa), (IIc), (IIs) or (IIu) wherein; R₂, R₃, a, b, R_a, R_c, R_s, R_g and R_x, are as defined in 41.; R₁ is —C(O)OC(CH₃)₃ with anhydrous or aqueous organic or inorganic acid to hydrolyze the —BOC protective groups following procedure well known in the literature.
• 41b) by reacting a compound of formula (I) obtained in 38b) with a compound of formula (IIIi)

wherein Y and Y′ are as above defined and in formula (I) A is a radical of formula (IIa), (IIc), (IIs) or (IIu) wherein R₁ is C(O)OC(CH₃)₃, R₂ is —COOH, R₃, R_a, R_c R_x a and b are as above defined in 41., R_s is R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is —OH;following the same procedure described in 8b).

• 42. The compounds of general formula (I) wherein:
• s and s′ are equal to 1;
• s″, m, m′, m″, are 0
• Y and Y′ are equal or different and are as above defined;
• A is selected among:
• i) (IIa) wherein R₁ is —H, R₂ is —C(O)NHR_2xx or —C(O)N(CH₃)R_2xx and R₂ binds a group —Y′—ONO₂; and R_a is selected from R_bx—C(O)—S—CH₂—, or R_xO—CH₂—, R_xO—CH(CH₃)—, (R_xO)-p-C₆H₄—CH₂—, 4-(R_xO)-3,5-diiodobenzyl-4-(R_xO)-3-nitrobenzyl- wherein R_x is R_xx—C(O)— and R_a binds a group —Y—ONO₂;
• ii) (IIc) wherein is R₁ is —H, R₂ is —C(O)NHR_2xx or —C(O)N(CH₃)R_2xx and R₂ binds a group —Y′—ONO₂; R_c is selected free R_bx—C(O)—S—CH₂—, or R_xO—CH₂—, R_xO—CH(CH₃)—, (R_xO)-p-C₆H₄—CH₂—, 4-(R_xO)-3,5-diiodobenzyl-4-(R_xO)-3-nitrobenzyl- wherein R_x is R_xx—C(O)— and R_c binds a group —Y—ONO₂;
• iii) (IIs) wherein R₁ is —H, R₃ is —OC(O)R_3x and R₃ binds a group —Y—ONO₂; R_s is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is R_gxx—NH— or R_gxx—N(CH₃)— and R_s binds a group —Y′—ONO₂;
• v) (IIu) wherein R₁ is —H, R₂ is —C(O)NHR_2xx or —C(O)N(CH₃)R_2xx and R₂ binds a group —Y′—ONO₂; a is 1; b is 0 or 1 and R_x is R_xx—C(O)— and R_x binds a group —Y—ONO₂;can be prepared as follows:
• 42a) by reacting a compound of formula (I) wherein s, s′, s″, m, m′, m″, Y, Y′, Y″ are as above defined, in 42., A is a radical of formula (IIa), (IIc), (IIs) or (IIu) wherein; R₂, R₃, a, b, R_a, R_c, R_s, R_g and R_x, are as defined in 42.; R₁ is —C(O)OC(CH₃)₃ with anhydrous or aqueous organic or inorganic acid to hydrolyze the —BOC protective groups following procedure well known in the literature.
• 42b) by reacting a compound of formula (I) obtained in 36b) with a compound of formula (IIIo)

wherein Y and Y′ are as above defined, W₃ is as above defined and in formula (I) A is a radical of formula (IIa), (IIc), (IIs) or (IIu) wherein R₁ is —C(O)OC(CH₃)₃, R₂ is —COOH, R₃, R_a, R_c R_x a and b are as above defined in 42., R_s is R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is —OH;following the same procedure described in 7b).

• 43. The compounds of general formula (I) wherein:
• s and s′ are equal to 1;
• s″, m, m′, m″, are 0
• Y and Y′ are equal or different and are as above defined;
• A is selected among:
• i) (IIa) wherein R₁ is —H, R₂ is —C(O)NHR_2xx or —C(O)N(CH₃)R_2xx and R₂ binds a group —Y′—ONO₂; and R_a is selected from R_bx—OC(O)—S—CH₂—, or R_xO—CH₂—, R_xO—CH(CH₃)—, (R_xO)-p-C₆H₄—CH₂—, 4-(R_xO)-3,5-diiodobenzyl-4-(R_xO)-3-nitrobenzyl- wherein R_x is R_xx—OC(O)— and R_a binds a group —Y—ONO₂;
• ii) (IIc) wherein R₁ is —H, R₂—C(O)NHR_2xx or —C(O)N(CH₃)R_2xx and R₂ binds a group —Y′—ONO₂; R_c is selected from R_bx—OC(O)—S—CH₂—, or R_xO—CH₂—, R_xO—CH(CH₃)—, (R_xO)-p-C₆H₄—CH₂—, 4-(R_xO)-3,5-diiodobenzyl-4-(R_xO)-3-nitrobenzyl- wherein R_x is R_xx—OC(O)— and R_c binds a group —Y—ONO₂;
• iii) (IIs) wherein R₁ is —H, R₃ is —OC(O)O—R_3x and R₃ binds a group —Y—ONO₂; R_s is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is R_gxx—NH— or R_gxx—N(CH₃)— and R_s binds a group —Y′—ONO₂;
• v) (IIu) wherein R₁ is —H, R₂ is —C(O)NHR_2xx or —C(O)NHR_2xx and R₂ binds a group —Y′—ONO₂; a is 1; b is 0 or 1 and R_x is R_xx—OC(O)— and R_x binds a group —Y—ONO₂;can be prepared as follows:
• 43a) by reacting a compound of formula (I) wherein s, s′, s″, m, m′, m″, Y, Y′, Y″ are as above defined in 43., A is a radical of formula (IIa), (IIc), (IIs) or (IIu) wherein; R₂, R₃, a, b, R_a, R_c, R_s, R_g and R_x, are as defined, an 43.; R₁ is —C(O)OC(CH₃)₃ with anhydrous or aqueous organic or inorganic acid to hydrolyze the —BOC protective groups following procedure well known in the literature.
• 43b) by reacting a compound of formula (I) obtained in 37b) with a compound of formula (IIIo)

wherein Y and Y′ are as above defined, W₃ is as above defined and in formula (I) A is a radical of formula (IIa), (IIc), (IIs) or (IIu) wherein R₁ is —C(O)OC(CH₃)₃, R₂ is —COOH, R₃, R_a, R_c R_x a and b are as above defined in 43., R_g is R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is —OH;following the same procedure described in 7b).

• 44. The compounds of general formula (I) wherein:
• s and s′ are equal to 1;
• s″, m, m′, m″, are 0
• Y and Y′ are equal or different and are as above defined;
• A is selected among:
• i) (IIa) wherein R₁ is —H, R₂ is —C(O)NHR_2xx or —C(O)N(CH₃)R_2xx and R₂ binds a group —Y′—ONO₂; R_a is selected from R_bx—NH(O)C—S—CH₂—, or R_xO—CH₂—, R_xO—CH(CH₃)—, (R_xO)-p-C₆H₄—CH₂—, 4-(R_xO)-3,5-R_xxNH—C(O)— and R_a binds a group —Y—ONO₂;
• ii) (IIc) wherein R₁ is —H, R₂ is —C(O)NHR_2xx or —C(O)N(CH₃)R_2xx and R₂ binds a group —Y′—ONO₂; R_c is selected from R_bx—NH(O)C—S—CH₂—, or R_xO—CH₂—, R_xO—CH(CH₃)—, (R_xO)-p-C₆H₄—CH₂—, 4-(R_xO)-3,5-diiodobenzyl-4-(R_xO)-3-nitrobenzyl- wherein R_x is R_xxNH—C(O)— and R_c binds a group —Y—ONO₂;
• iii) (IIs) wherein R₁ is —H, R₃ is —OC(O)—NH—R_3x and R₃ binds a group —Y—ONO₂; R_s is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is R_gxx—NH— or R_gxx—N(CH₃)— and R_s binds a group —Y′—ONO₂;
• v) (IIu) wherein R₁ is —H, R₂ is —C(O)NHR_2xx or —C(O)N(CH₃)R_2xx R₂ binds a group —Y′—ONO₂; a is 1; b is 0 or 1; and R_x is R_xx—NHC(O)— and R_x binds a group —Y—ONO₂;can be prepared as follows:
• 44a) by reacting a compound of formula (I) wherein s, s′, s″, m, m′, m″, Y, Y′, Y″ are as above defined in 44., A is a radical of formula (IIa), (IIc), (IIs) or (IIu) wherein; R₂, R₃, a, b, R_a, R_c, R_s, R_g and R_x, are as defined in 44.; R₁ is C(O)OC(CH₃)₃ with anhydrous or aqueous organic or inorganic acid to hydrolyze the —BOC protective groups following procedure well known in the literature.
• 44b) by reacting a compound of formula (I) obtained in 38b) with a compound of formula (IIIo)

wherein Y and Y′ are as above defined, W₃ is as above defined and in formula (I) A is a radical of formula (IIa), (IIc), (IIs) or (IIu) wherein R₁ is —C(O)OC(CH₃)₃, R₂ is —COOH, R₃, R_a, R_c, R_x a and b are as above defined in 44., R_s is R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is —OH;following the same procedure described in 7b).

• 45. The compounds of general formula (I) wherein:
• s is equal to 1;
• s′, s″, m, m′, m″, are 0
• Y is as above defined;
• A is selected among:
• i) (IIa) wherein R₁ is —H, R₂ is —C(O)OR_2x and R₂ binds a group —Y—ONO₂; and R_a is selected from HS—CH₂—, R_xO—CH₂—, R_xO—CH(CH₃)—, (R_xO)-p-C₆H₄—CH₂—, 4-(R_xO)-3,5-diiodobenzyl-4-(R_xO)-3-nitrobenzyl- wherein R_x —H;
• ii) (IIc) wherein R₁ is —H, R₂ is —C(O)OR_2x and R₂ binds a group —Y—ONO₂; and R_a is selected from HS—CH₂—, or R_xO—CH₂—, R_xO—CH(CH₃)—, (R_xO)-p-C₆H₄—CH₂—, 4-(R_xO)-3,5-diiodobenzyl-4-(R_xO)-3-nitrobenzyl- wherein R_x —H;
• iii) (IIs) wherein R₁ is —H, R₃ is —H; R_s is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is R_gx—O—, and R_s binds a group —Y—ONO₂;
• v) (IIu) wherein R₁ is —H, R₂ is —C(O)OR_2x, R₂ binds a group —Y—ONO₂; a is 1; b is 0 or 1 and R_x is —H;can be prepared as follows:
• 45a) by reacting a compound of formula (VIIa)A_3a-Y′—ONO₂  (VIIa)wherein Y is as above defined and A_3a is a radical of formula (IIa), (IIc), (IIs) or (IIu) wherein R₂, a, b and R_s are as defined in 45.; R₁ is —C(O)OC(CH₃)₃;
• in formula (IIs) R₃ is equal to R_3a wherein R_3a is —OTrt, wherein Trt is the trityl protecting group; in formula (IIa) and (IIc) R_a and R_c have the meanings: Trt-S—CH₂—, or R_xO—CH₂—, R_xO—CH(CH₃)—, (R_xO)-p-C₆H₄—CH₂—, 4-(R_xO)-3,5-diiodobenzyl-4-(R_xO)-3-nitrobenzyl- wherein R_xa is -Trt, the trityl protecting group or the dimethyltertbutylsilyl group;
• in formula (IIu) R_x is equal to R_xa, wherein R_xa is as above defined;
• with anhydrous or aqueous organic or inorganic acid to hydrolyze the —BOC and the other protective groups following procedure well known in the literature.
• 45b) by reacting a compound of formula A₃ with a compound of formula (IIIi)A₃+HO—Y—ONO₂  (IIIi)wherein Y is as above defined and A₃ is a radical of formula (IIa), (IIc), (IIs) or (IIu) wherein R₁ is —C(O)OC(CH₃)₃, R₂ is —COOH, a is as above defined in 45., R₃ is equal to R_3a and is —OTrt, R_a and R_c are TrtS—CH₂—, or R_xO—CH₂—, R_xO—CH(CH₃)—, (R_xO)-p-C₆H₄—CH₂—, 4-(R_xO)-3,5-diiodobenzyl-4-(R_xO)-3-nitrobenzyl- wherein R_xa is as above defined; R_x of formula (IIu) is equal to R_xa and is as above defined; R_s is R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is —OH;following the same procedure described in 8b).Compounds A₃ are commercially available or can be prepared from commercially available compounds by simple deprotection/protection steps well known in the literature.
• 46. The compounds of general formula (I) wherein:
• s is equal to 1;
• s′, s″, m, m′, m″, are 0
• Y is as above defined;
• A is selected among:
• i) (IIa) wherein R₁ is —H, R₂ is —C(O)NHR_2xx or —C(O)N(CH₃)R_2xx and R₂ binds a group —Y—ONO₂; and R_a is selected from HS—CH₂—, or R_xO—CH₂—, R_xO—CH(CH₃)—, (R_xO)-p-C₆H₄—CH₂—, 4-(R_xO)-3,5-diiodobenzyl-4-(R_xO)-3-nitrobenzyl- wherein R_x —H;
• ii) (IIc) wherein R₁ is —H, R₂ is —C(O)NHR_2xx or —C(O)N(CH₃)R_2xx and R₂ binds a group —Y—ONO₂; and R_a is selected from HS—CH₂—, or R_xO—CH₂—, R_xO—CH(CH₃)—, (R_xO)-p-C₆H₄—CH₂—, 4-(R_xO)-3,5-diiodobenzyl-4-(R_xO)-3-nitrobenzyl- wherein R_x —H;
• iii) (IIs) wherein R₁ is —H, R₃ is —H; R_s is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is R_gxx—NH— or R_gxx—N(CH₃)— and R_s binds a group —Y′—ONO₂;
• v) (IIu) wherein R₁ is —H, R₂ is —C(O)NHR_2xx or —C(O)N(CH₃)R_2xx and R₂ binds a group —Y—ONO₂; a is 1; b is 0 or 1 and R_x is —H; can be prepared as follows:
• 46a) by reacting a compound of formula (VIIb)A_3b-Y—ONO₂  (VIIb)wherein Y is as above defined and A_3b is a radical of formula (IIa), (IIc), (IIs) or (IIu) wherein R₂, a, b and R_s are as defined in 46.; R₁ is —C(O)OC(CH₃)₃;
• in formula (IIs) R₃ is equal to R_3a wherein R_3a is —OTrt, wherein Trt is the trityl protecting group; in formula (IIa) and (IIc) R_a and R_c have the meanings: Trt-S—CH₂—, or R_xO—CH₂—, R_xO—CH(CH₃)—, O-p-C₆H₄—CH₂—, 4-(R_xO)-3,5-diiodobenzyl-4-(R_xO)-3-nitrobenzyl- wherein R_xa is as above defined;
• In formula (IIu) R_x is equal to R_xa and is as above defined;
• with anhydrous or aqueous organic or inorganic acid to hydrolyze the —BOC and the other protective groups following procedure well known in the literature.
• 46b) by reacting a compound of formula A₃ defined in 45b) with a compound of formula (IIIo)A₃+W₃NH—Y′—ONO₂  (IIIo)following the same procedure described in 7b).
• 47. The compounds of general formula (I) wherein:
• s and m are equal to 1;
• s′, s″, m′, m″, are 0
• Y is as above defined;
• B is:

• A is selected among:
• i) (IIa) wherein R₁ is —H, R₂ is —C(O)OR_2x and R₂ binds a group B—Y—ONO₂; and R_a is selected from HS—CH₂—, or R_xO—CH₂—, R_xO—CH(CH₃)—, O-p-C₆H₄—CH₂—, 4-(R_xO)-3,5-diiodobenzyl-4-(R_xO)-3-nitrobenzyl- wherein R_x —H;
• ii) (IIc) wherein R₁ is —H, R₂ is —C(O)OR₂ and R₂ binds a group B—Y—ONO₂; and R_c is selected from HS—CH₂—, or R_xO—CH₂—, R_xO—CH(CH₃), (R_x)-p-C₆H₄—CH₂—, 4-(R_xO)-3,5-diiodobenzyl-4-(R_xO)-3-nitrobenzyl- wherein R_x —H;
• iii) (IIs) wherein R₁ is —H, R₃ is —H; R_s is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is R_gx—O—, and R_g binds a group B—Y—ONO₂;
• v) (IIu) wherein R₁ is —H, R₂ is —C(O)OR_2x, R₂ binds a group B—Y—ONO₂; a is 1; b is 0 or 1 and R_x is —H; can be prepared as follows:
• 47a) by reacting a compound of formula (VIIc)A_3c-Y—ONO₂  (VIIc)wherein Y is as above defined and A_3c is a radical of formula (IIa), (IIc), (IIs) or (IIu) wherein R₂, a, b and R_s are as defined in 47., R₁ is —C(O)OC(CH₃)₃;
• in formula (IIs) R₃ is equal to R_3a wherein R_3a is —OTrt, wherein Trt is the trityl protecting group; in formula (IIa) and (IIc) R_a and R_c have the meanings: Trt-S—CH₂—, or R_x3O—CH₂—, R_x3O—CH(CH₃)—, (R_xO)-p-C₆H₄—CH₂—, 4-(R_xO)-3,5-diiodobenzyl-4-(R_xO)-3-nitrobenzyl- wherein R_xa is above defined;
• In formula (IIu) R_x is equal to R_xa and is as above defined;
• with anhydrous or aqueous organic or inorganic acid to hydrolyze the —BOC and the other protective groups following procedure well known in the literature.
• 47b) compound (VIIc) can be prepared by reacting a compound of formula A₃ defined in 45b) with a compound of formula (IIIg) or (IIIn) depending on the meaning of BA₃+Hal-W₁—OC(O)O—Y—ONO₂  (IIIg)A₃+Hal-W₁—OC(O)—Y—ONO₂  (IIIn)following the same procedure described in 4b) or 6b).
• 48. The compounds of general formula (I) wherein:
• s is equal to 1;
• s′, s″, m, m′, m″, are 0
• Y is as above defined;
• A is selected among:
• i) (IIa) wherein R₁ is —C(O)R_1x, and R₁ binds a group Y—ONO₂; R₂ is —COOH; and R_a is selected from HS—CH₂—, or R_xO—CH₂—, R_xO—CH(CH₃)—, (R_xO)-p-C₆H₄—CH₂—, 4-(R_xO)-3,5-diiodobenzyl-4-(R_xO)-3-nitrobenzyl- wherein R_x —H;
• ii) (IIc) wherein R₁ is —C(O)R_1x, and R₁ binds a group Y—ONO₂; R₂ is —COOH; and R_a is selected from HS—CH₂—, or R_xO—CH₂—, R_xO—CH(CH₃)—, (R_xO)-p-C₆H₄—CH₂—, 4-(R_xO)-3,5-diiodobenzyl-4-(R_xO)-3-nitrobenzyl- wherein R_x —H;
• iii) (IIs) wherein R₁ is —C(O)—R_1x and R₁ binds a group Y—ONO₂; R₃ is —H; R_s is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is —OH;
• v) (IIu) wherein and R₁ binds a group —Y—ONO₂; R₂ is —COOH, a is 1, b is 0; R_x is —H;can be prepared as follows:
• 48a) by reacting a compound of formula (VIId)A_4a-Y—ONO₂  (VIId)wherein Y, is as above defined and A_4a is a radical of formula (IIa), (IIc), (IIs) or (IIu) wherein; R₁, R₂, a, b and R_s are as defined in 48.; in formula (IIs) R₃ is R_3a and is —OTrt; in formula (IIa) and (IIc) R_a and R_c are TrtS—CH₂—, or R_xO—CH₂—, R_xaO—CH(CH₃)—, (R_xaO)-p-C₆H₄—CH₂—, 4-(R_xaO)-3,5-diiodobenzyl-4-(R_xaO)-3-nitrobenzyl- wherein R_xa is -Trt or the group dimethyl-tert-butylsilyl; R_x of formula (IIu) is H or R_xa wherein R_xa is as above defined;
• with anhydrous or aqueous organic or inorganic acid to remove the protective groups following procedure well known in the literature.
• 48b) compound (VIId) are prepared by reacting a compound of formula A₄ with a compound of formula (IIIe)A₄+Act-C(O)—Y—ONO₂  (IIIe)Wherein Act and Y are as above defined, A₄ is a radical of formula (IIa), (IIc), (IIs) or (IIu) wherein R₁ is —H, R₂ is —COOH, a and b are as above defined in 48., R₃ is R_3a, R_a and R_c are TrtS—CH₂—, or R_xaO—CH₂—, R_xaO—CH(CH₃)—, (R_xaO)-p-C₆H₄—CH₂—, 4-(R_xaO)-3,5-diiodobenzyl-4-(R_xaO)-3-nitrobenzyl- wherein R_xa is -Trt or dimethyl-tert-butylsilyl; R_x of formula (IIu) is H or R_xa wherein R_xa is as above defined; R_s is R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is OH;following the same procedure described in 1b′).Compounds A₄ are commercially available.
• 49. The compounds of general formula (I) wherein:
• s is equal to 1;
• s′, s″, m, m′, m″, are 0
• Y is as above defined;
• A is selected among:
• i) (IIa) wherein R₁ is —C(O)O—R_1x, and R₁ binds a group —Y—ONO₂; R₂ is —COOH; and R_a is selected from HS—CH₂—, or OR_x—CH₂—, R_xO—CH(CH₃)—, (R_xO)-p-C₆H₄—CH₂—, 4-(R_xO)-3,5-diiodobenzyl-4-(R_xO)-3-nitrobenzyl- wherein R_x —H;
• ii) (IIc) wherein R₁ is —C(O)O—R_1x, and R₁ binds a group —Y—ONO₂; R₂ is —COOH; and R_a is selected from HS—CH₂—, or R_xO—CH₂—, R_xO—CH(CH₃)—, (R_xO)-p-C₆H₄—CH₂—, 4-(R_xO)-3,5-diiodobenzyl-4-(R_xO)-3-nitrobenzyl- wherein R_x —H;
• iii) (IIs) wherein R₁ is —C(O)—R_1x and R₁ binds a group Y—ONO₂; R₃ is —H; R_s is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is —OH;
• v) (IIu) wherein and R₁ binds a group —C(O)O—R_1x and R₁ binds a group —Y—ONO₂; R₂ is —COOH, a is 1, b is 0 or 1 and R_x is —H;can be prepared as follows:
• 49a) by reacting a compound of formula (VIIf)A_4b-Y—ONO₂  (VIIf)wherein Y is as above defined and A_4b is a radical of formula (IIa), (IIc), (IIs) or (IIu) wherein; R₁, R₂, a, b and R_s are as defined in 49.; R₃ is R_3a, R_a and R_c are TrtS—CH₂—, or R_xO—CH₂—, R_xO—CH(CH₃)—, (R_xaO)-p-C₆H₄—CH₂—, 4-(R_xO)-3,5-diiodobenzyl-4-(R_xaO)-3-nitrobenzyl- wherein R_xa is -Trt or dimethyltert-butyl silyl, R_x of formula (IIu) is H or R_xa wherein R_xa is as above defined;
• with anhydrous or aqueous organic or inorganic acid to remove the Trityl or dimethyltert-butyl silyl protective groups following procedure well known in the literature.
• 49b) by reacting a compound of formula A₄ with a compound of formula (IIIf) or (IIIi)A₄+Act-C(O)O—Y—ONO₂  (IIf)A₄+HO—Y—ONO₂  (IIIi)Wherein Act and Y are as above defined, A₄ is as defined in 48b), following the same procedure described in 3b).
• 50. The compounds of general formula (I) wherein:
• s and s′ are equal to 1;
• s″, m, m′, m″, are 0
• Y and Y′ are equal and are as above defined;
• A is selected among:
• (IIa) wherein R₁ is —H, R₂ is —C(O)O, and R_a is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is R_gx—O—, both R₂ and R_a bind a group —Y—ONO₂ or a group —Y′—ONO₂;
• (IIc) wherein R₁ is —H, R₂ is —C(O)O, and R_c is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is R_gx—O—, both R₂ and R_c bind a group —Y—ONO₂ or a group —Y′—ONO₂;can be prepared as follows:
• 50a) by reacting a compound of formula (I) wherein s, s′, s″, m, m′, m″, Y, Y′, Y″ are as above defined in 50., A is a radical of formula (IIa), (IIc), wherein; R₂, R_a, R_c, are as defined in 50.; R₁ is —C(O)OC(CH₃)₃ with anhydrous or aqueous organic or inorganic acid to hydrolyze the —BOC protective groups following procedure well known in the literature.
• 50b) by reacting a compound of formula A with a compound of formula (IIIi)A+HO—Y—ONO₂  (IIIi)wherein Y is as above defined and A is a radical of formula (IIa), (IIc) wherein R₁ is —C(O)OC(CH₃)₃, R₂ is —COOH, R_a and R_c are selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is —OH;following the same procedure described in 8b) using a ratio A/(IIIi) 1:2
• 51. The compounds of general formula (I) wherein:
• s and s′ are equal to 1;
• s″, m, m′, m″, are 0
• Y and Y′ are equal and as above defined;
• A is selected among:
• (IIa) wherein R₁ is —H, R₂ is —C(O)NHR_2xx or —C(O)N(CH₃)R_2xx and R_a is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is R_gxx—NH— or R_gxx—N(CH₃)— and both R₂ and R_a bind a group —Y—ONO₂ or a group —Y′—ONO₂;
• (IIc) wherein R₁ is —H, R₂ is —C(O)NHR_2xx or —C(O)N(CH₃)— and R_c is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is R_gxx—NH— or R_gxx—N(CH₃)— and both R₂ and R_c bind a group —Y—ONO₂ or a group —Y′—ONO₂;can be prepared as follows:
• 51a) by reacting a compound of formula (I) wherein s, s′, s″, m, m′, m″, Y, Y′, Y″ are as above defined in 51., A is a radical of formula (IIa), (IIc), wherein R₂, R_a, R_c, are as defined in 51., R₁ is —C(O)OC(CH₃)₃ with anhydrous or aqueous organic or inorganic acid to hydrolyze the —BOC protective groups following procedure well known in the literature.
• 51b) by reacting a compound of formula A with a compound of formula (IIIo)A+W₃NH—Y—ONO₂  (IIIo)wherein Y is as above defined, W₃ is as above defined and A is a radical of formula (IIa), (IIc) wherein R₁ is —C(O)OC(CH₃)₃, R₂ is —COOH, R_a and R_c are selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is —OH;following the same procedure described in 7b) using a ratio A/(IIIo) 1:2.
• 52. The compounds of general formula (I) wherein:
• s and s′ are equal to 1;
• m and m′ are equal to 1;
• m″ and s″ are 0
• B is:

• Y and Y′ are equal and are as above defined;
• A is selected among (IIa) and (IIc) wherein R₁ is —H and R₂ is —C(O)OR_2x and binds a group —B—Y—ONO₂ or —B′—Y′—ONO₂;
• R_a and R_c are selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is R_gx—O—, and R_a and R_c bind one of the groups —B—Y—ONO₂ or —B′—Y′—ONO₂;Can be prepared as follows:
• 52a) by reacting a compound of formula (I) wherein B, s, s′, s″, m, m′, m″, Y, Y′, Y″ are as above defined in 52., A is a radical of formula (IIa) or (IIc) wherein R₁ is —C(O)OC(CH₃)₃; R₂, R_a and R_c as defined in 52.,
• with anhydrous or aqueous organic or inorganic acid to hydrolyze the —BOC protective groups following procedure well known in the literature.
• 52b) by reacting a compound of formula A with a compound of formula (IIIg)A+Hal-W₁—OC(O)O—Y—ONO₂  (IIIg)wherein Y is as above defined and A is selected from (IIa) or (IIc) wherein R₂ is —COOH and R₁ is —C(O)O(CH₃)₃;
• R_a and R_c are selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is —OH;using a ratio A/(IIIg) 1:2 and applying the procedure described on 4b).
• 33. One compounds of general formula (I) wherein:
• s and s′ are equal to 1;
• m and m′ are equal to 1;
• m″ and s″ are 0
• B is:

• Y and Y′ are equal and are as above defined;
• A is selected among (IIa) and (IIc) wherein R₁ is —H and R₂ is —C(O)OR_2x and binds a group —B—Y—ONO₂ or —B′—Y′—ONO₂;
• R_a and R_c are selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is R_gx—O—, and R_a and R_c bind one of the groups —B—Y—ONO₂ or —B′—Y′—ONO₂;Can be prepared as follows:
• 53a) by reacting a compound of formula (I) wherein B, s, s′, s″, m, m′, m″, Y, Y′, Y″ are as above defined in 53., A is a radical of formula (IIa) or (IIc) wherein R₁ is —C(O)OC(CH₃)₃;
• R₂, R_a and R_c are as defined in 53.,
• with anhydrous or aqueous organic or inorganic acid to hydrolyze the —BOC protective groups following procedure well known in the literature.
• 53b) by reacting a compound of formula A with a compound of formula (IIIn)A+Hal-W₁—O(O)C—B—Y—ONO₂  (IIIn)wherein Y is as above defined and A is selected from (IIa) or (IIc) wherein R₂ is —COOH and R₁ is —C(O)O(CH₃)₃;
• R_a and R_c are selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is —OH;Using a ratio A/(IIIn) 1:2 and applying the procedure described in 6b).
• 54. The compounds of general formula (I) wherein:
• s, s′ and s″ are equal to 1;
• m, m′, m″, are 0
• Y, Y′ and Y″ are as above defined with the proviso that Y is equal to Y′
• A is a radical of formula (IIa) or (IIc) wherein R₁ is —C(O)—R_1x and it binds the group —Y″—ONO₂, R₂—C(O)OR_2x and it binds the group Y—ONO₂ or Y′—ONO₂;
• R_a and R_c are selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is R_gxO—, and R_a and R_c bind one of the groups —Y—ONO₂ or —Y′—ONO₂;can be prepared as follows:
• 54a) by reacting a compound of formula (I) prepared as described in 49.with a compound of formula (IIIe):

wherein in formula (I) Y and Y′ are equal and A is a radical of formula (IIa) or (IIc) wherein R₁ is —H; R₂, R_a and R_c are as defined in 54.,following the same procedure described in 1b′).

• 55. The compounds of general formula (I) wherein:
• s, s′ and s″ are equal to 1;
• m, m′, m″, are 0
• Y, Y′ and Y″ are as above defined with the proviso that Y is equal to Y′
• A is a radical of formula (IIa) or (IIc) wherein —C(O)O—R_1x and it binds the group —Y″—ONO₂, R₂ is —C(O)OR_2x and it binds the group —Y—ONO₂ or —Y′—ONO₂;
• R_a and R_c are selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is R_gxO—, and R_a and R_c bind one of the groups —Y—ONO₂ or —Y′—ONO₂;can be prepared as follows:
• 55a) by reacting a compound of formula (I) prepared as described in 49.with a compound of formula (IIIf):

wherein in formula (I) Y and Y′ are equal and A has been already defined in 54.;following the same procedure described in 3b).

• 56. The compounds of general formula (I) wherein:
• s, s′ and s″ are equal to 1;
• m, m′, m″, are 0
• Y, Y′ and Y″ are as above defined with the proviso that Y is equal to Y′
• A is a radical of formula (IIa) or (IIc) wherein R₁ is —C(O)—R_1x and it binds the group —Y″—ONO₂, R₂ is —C(O)NHR_2xx or —C(O)N(CH₂)R_2xx and it binds the group —Y—ONO₂ or —Y′—ONO₂;
• R_a and R_c are selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is R_gxNH— or R_gx—N(CH₃)— and R_a and R_c bind one of the groups —Y—ONO₂ or —Y′—ONO₂;can be prepared as follows:
• 56a) by reacting a compound of formula (I) prepared as described in 51.with a compound of formula (IIIe):

wherein in formula (I) Y and Y′ are equal and A is a radical of formula (IIa) or (IIc) wherein R₁ is —H; R₂, R_a and R_c are as defined in 56.,following the same procedure described in 1b′).

• 57. The compounds of general formula (I) wherein:
• s, s′ and s″ are equal to 1;
• m, m′, m″, are 0
• Y, Y′ and Y″ are as above defined with the proviso that Y is equal to Y′
• A is a radical of formula (IIa) or (IIc) wherein R₁ is —C(O)O—R_1x and it binds the group —Y″—ONO₂, R₂ is —C(O)NHR_2xx or —C(O)N(CH₃)R_2xx and it binds the group —Y—ONO₂ or —Y′—ONO₂;
• R_a and R_c are selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is R_gxNH— or R_gxN(CH₃)— and R_a and R_c bind one of the groups —Y—ONO₂ or —Y′—ONO₂;can be prepared as follows:
• 57a) by reacting a compound of formula (I) prepared as described in 51.with a compound of formula (IIIf):

wherein in formula (I) Y and Y′ are equal and A has been already defined in 56.,following she same procedure described in 3b).

• 58. The compounds of general formula (I) wherein:
• s, s′ and s″ are equal to 1;
• m and m′ are equal to 1
• m″ is 0;
• B is:

• Y, Y′ and Y″ are as above defined with the proviso that Y is equal to Y′
• A is a radical of formula (IIa) or (IIc) wherein R₁ is —C(O)—R_1x and it binds the group —Y″—ONO₂, R₂ is —C(O)OR_2x and it binds the group B—Y—ONO₂ or B—Y′—ONO₂ wherein B—Y—ONO₂ or B—Y′—ONO₂ are equal;
• R_a and R_c are selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is R_gxO—, and R_a and R_c bind one of the groups B—Y—ONO₂ or B—Y′—ONO₂ wherein in B—Y—ONO₂ or B—Y′—ONO₂ are equal;can be prepared as follows:
• 58a) by reacting a compound of formula (I) prepared as described in 52. if B is:

or prepared in 53. if B is:

with a compound of formula (IIIe):

wherein in formula (I) B, Y and Y′ are as defined in 58.; and A is a radical of formula (IIa) or (IIc) wherein R₁ is —H; R₂, R_a and R_c are as defined in 58.,following the same procedure described in 1b′).

• 59. The compounds of general formula (I) wherein:
• s, s′ and s″ are equal to 1;
• m and m′ are equal to 1;
• m″ is 0
• B is:

• Y, Y′ and Y″ are as above defined with the proviso that Y is equal to Y′
• A is a radical of formula (IIa) or (IIc) wherein R₁ is —C(O)O—R_1x and it binds the group —Y″—ONO₂, R₂ is —C(O)OR_2x and it binds the group B—Y—ONO₂ or B—Y′—ONO₂ wherein B—Y—ONO₂ or B—Y′—ONO₂ are equal;
• R_a and R_c are selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is R_gx—O—, and R_a and R_c bind one of the groups B—Y—ONO₂ or B—Y′—ONO₂ wherein B—Y—ONO₂ or B—Y′—ONO₂ are equal;can be prepared as follows:
• 59a) by reacting a compound of formula (I) prepared as described in 52. if B is:

• or prepared in 53. if B is:

with a compound of formula (IIIf):

wherein in formula (I) B, Y and Y′ are as defined in 59.; A is a radical of formula (IIa) or (IIc) wherein R₁ is —H; R₂, R_a and R_c are as defined in 59.,following the same procedure described in 3b).

• 60. The compounds of general formula (I) wherein:
• s, is equal to 1;
• s′, s″, m, m′ and m″ are equal to 0;
• Y is as above defined;
• A is selected from (IIa) and (IIc) wherein R₁ is —C(O)—R_1x and binds a group —Y—ONO₂, R₂ is —COOH;
• R_a and R_c are selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is —OH; can be prepared as follows:
• 60a) by reacting a compound of formula A with a compound of formula (IIIe)A+Act-(O)C—Y—ONO₂  (IIIe)wherein Y is as above defined and A is a commercially available compound of formula (IIa) or (IIc) wherein R₂ is —COOH and R₁ is —H;
• R_a and R_c are selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is —OH;applying the procedure described in 1b′).
• 61. The compounds of general formula (I) wherein:
• s, is equal to 1;
• s′, s″, m, m′ and m″ are 0;
• Y is as above defined;
• A is selected among (IIa) and (IIc) wherein R₁ is —C(O)O—R_1x and binds a group —Y—ONO₂, R₂ is —COOH;
• R_a and R_c are selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is —OH; can be prepared as follows:
• 61a) by reacting a compound of formula A with a compound of formula (IIIf)A+Act-(O)C—O—Y—ONO₂  (IIIf)wherein Y is as above defined and A is as defined in 60a) applying the procedure described in 3b).
• 62. Alternatively compounds (I) described in 54. can be prepared starting from compounds (I) prepared as described in 60. and compounds (IIIi) applying the same procedure described in 8b) using a ratio (I)/(IIIi) 1:2. In this case Y′ and Y″ are equal.

• 63. Alternatively compounds (I) described in 55. can be prepared starting from compounds (I) prepared as described in 61. and compounds (IIIi) applying the same procedure described in 8b) using a ratio (I)/(IIIi) 1:2. In this case Y′ and Y″ are equal.

• 64. Alternatively compounds (I) described in 56. can be prepared starting from compounds (I) prepared as described in 60. and compounds (IIIo) applying the same procedure described in 7b) using a ratio (I)/(IIIo) 1:2. In this case Y′ and Y′ are equal.

• 65. Alternatively compounds (I) described in 57. can be prepared starting from compounds (I) prepared as described in 61. and compounds (IIIo) applying the same procedure described in 7b) using a ratio (I)/(IIIo) 1:2. In this case Y′ and Y″ are equal.

• 66. Alternatively compounds (I) described in 58. can be prepared starting from compounds (I) prepared as described in 60. and compounds (IIIg) or (IIIn) depending on the meaning of B, and applying the same procedure described in 4b) or 6b) using a ratio (I)/(IIIg) or (I)/(IIIn) 1:2. In this case Y′ and Y″ are equal.

• 67. Alternatively compounds (I) described in 59. can be prepared starting from compounds (I) prepared as described in 61. and compounds (IIIg) or (IIIn) depending on the meaning of B, and applying the same procedure described in 4b) or 6b) using a ratio (I)/(IIIg) or (I)/(IIIn) 1:2. In this case Y′ and Y″ are equal.

• 68. The compounds of general formula (I) wherein:
• s is equal to 1;
• s′, s″, m, m′, m″, are 0
• Y is as above defined;
• A is selected among:
• (IIa) wherein R₁ is —H, R₂ is —C(O)OR_2x and R₂ binds a group —Y—ONO₂; R_a is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is —OH;
• (IIc) wherein R₁ is —H, R₂ is —C(O)OR_2x and R₂ binds a group —Y—ONO₂; R_c is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is —OH; can be prepared as follows:
• 68a) by reacting a compound of formula (I) wherein s, s′, s″, m, m′, m″, Y, Y′, Y″ are as above defined in 68., A is a radical of formula (IIa), (IIc), wherein R₂ is as above defined in 68.; R₁ is —C(O)OC(CH₃)₃; R_a and R_c are R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is —C(O)OC(CH₃)₃;
• with anhydrous or aqueous organic or inorganic acid to hydrolyze the tert-butyl esters and the —BOC protective groups following procedure well known in the literature.
• 68b) by reacting a compound of formula A with a compound of formula (IIIi)A+HO—Y—ONO₂  (IIIi)wherein Y is as above defined and A is a compound of formula (IIa) or (IIc) wherein R₁ is —C(O)OC(CH₃)₃, R₂ is —COOH, R_a and R_c are selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is —C(O)OC(CH₃)₃;
• following the same procedure described in 8b). Compounds A are commercially available.
• 69. The compounds of general formula (I) wherein:
• s is equal to 1;
• s′, s″, m, m′, m″, are 0
• Y is as above defined;
• A is a radical of formula
• (IIa) wherein R₁ is —H, R₂ is —C(O)NHR_2xx or —C(O)N(CH₃)R_2xx and R₂ binds a group —Y—ONO₂; R_a is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is —OH; or
• (IIc) wherein R₁ is —H, R₂ is —C(O)NHR_2xx or —C(O)N(CH₃)R_2xx and R₂ binds a group —Y—ONO₂; R_c is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is —OH; can be prepared as follows:
• 69a) by reacting a compound of formula (I) wherein s, s′, s″, m, m′, m″, Y, Y′, Y″ are as above defined in 69., A is a radical of formula (IIa), (IIc), wherein R₂ is as above defined in 69.; R₁ is —C(O)OC(CH₃)₃); R_a and R_c are R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is —C(O)OC(CH₃)₃;
• with anhydrous or aqueous organic or inorganic acid to hydrolyze the tert-butyl esters and the —BOC protective groups following procedure well known in the literature.
• 69b) by reacting a compound of formula A with a compound of formula (IIIo)A+W₃NH—Y—ONO₂  (IIIo)wherein Y is as above defined, W₃ is as above defined and A is as defined in 68b),following the sane procedure described in 7b).
• 70. The compounds of general formula (I) wherein:
• s and m are equal to 1;
• s′, s″, m′, m″, are 0
• Y is as above defined;
• B is:

• A is a radical selected among:
• (IIa) wherein R₁ is —H, R₂ is —C(O)OR_2x and R₂ binds a group —B—Y—ONO₂; R_a is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is —OH;
• (IIc) wherein R₁ is —H, R₂ is —C(O)OR_2x and R₂ binds a group —B—Y—ONO₂; R_c is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is —OH; can be prepared as follows:
• 70a) by reacting a compound of formula (I) wherein s, s′, s″, m, m′, m″, B, Y, Y′, Y″ are as above defined in 70., A is a radical of formula (IIa), (IIc), wherein R₂ is as above defined in 70.; R₁ is —C(O)OC(CH₃)₃); R_a and R_c are R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is —C(O)OC(CH₃)₃;
• with anhydrous or aqueous organic or inorganic acid to hydrolyze the tert-butyl esters and the —BOC protective groups following procedure well known in the literature.
• 70b) by reacting a compound of formula A with a compound of formula (IIIg) or (IIIn) depending on the meaning of BA+Hal-W₁—OC(O)O—Y—ONO₂  (IIIg)A+Hal-W₁—OC(O)—Y—ONO₂  (IIIn)wherein Y, Hal, W₁ are as above defined and A is as defined in 68b),following the same procedures described in 4b) or 6b).
• 71. The compounds of general formula (I) wherein:
• s is equal to 1;
• s′, s″, m, m′, m″, are 0
• Y is as above defined;
• A is selected among:
• (IIa) wherein R₁ is —H, R₂ is —COOH; R_a is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is R_gx—O—, and R_g binds a group —Y—ONO₂;
• (IIc) wherein R₁ is —H, R₂ is —COOH; R_c is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is R_gx—O—, and R_c binds a group —Y—ONO₂;can be prepared as follows:
• 71a) by reacting a compound of formula (I) wherein s, s′, s″, m, m′, m″, Y, Y′, Y″ are as above defined in 71., A is a radical of formula (IIa), (IIc), wherein R_a and R_c are as above defined in 71.; R₁ is —C(O)OC(CH₃)₃; R₂ is —C(O)OC(CH₃)₃;
• with anhydrous or aqueous organic or inorganic acid to hydrolyze the tert-butyl esters and the —BOC protective groups following procedure well known in the literature.
• 68b) by reacting a compound of formula A with a compound of formula (IIIi)A+HO—Y—ONO₂  (IIIi)wherein Y is as above defined and A is a radical of formula (IIa), (IIc) wherein R₁ is —C(O)OC(CH₃)₃, R₂ is —C(O)OC(CH₃)₃, R_a and R_c are selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is —OH;following the same procedure described in 8b).
• Compounds A are commercially available.
• 72. The compounds of general formula (I) wherein:
• s is equal to 1;
• s′, s″, m, m′, m″, are 0
• Y is as above defined;
• A is selected among:
• (IIa) wherein R₁ is —H, R₂ is —COOH; R_a is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is R_gxx—NH— or R_gxx—N(CH₃)— and R_a binds a group —Y—ONO₂;
• (IIc) wherein R₁ is —H, R₂ is —COOH; R_c is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is R_gxx—NH— or R_gxx—N(CH₃)— and R_c binds a group —Y—ONO₂;can be prepared as follows:
• 72a) by reacting a compound of formula (I) wherein s, s′, s″, m, m′, m″, Y, Y′, Y″ are as above defined in 72., A is a radical of formula (IIa), (IIc), wherein R_a and R_c are as above defined in 71.; R₁ is —C(O)OC(CH₃)₃; R₂ is —C(O)OC(CH₃)₃;
• with anhydrous or aqueous organic or inorganic acid to hydrolyze the tert-butyl esters and the —BOC protective groups following procedure well known in the literature.
• 72b) by reacting a compound of formula A with a compound of formula (IIIo):A+W₃NH—Y—ONO₂  (IIIo)wherein Y and W₃ are as above defined and A is as defined in 71b) following the same procedure described in 7b).
• 73. One compounds of general formula (I) wherein:
• s and m are equal to 1;
• s′, s″, m′, m″, are 0
• Y is as above defined;
• B is:

• A is selected among:
• (IIa) wherein R₁ is —H, R₂ is —COOH; R_a is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is R_gx—O—, and R_a binds a group —B—Y—ONO₂;
• (IIc) wherein R₁ is —H, R₂ is —COOH; R_c is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is R_gx—O—, and R_c binds a group B—Y—ONO₂;can be prepared as follows:
• 73a) by reacting a compound of formula (I) wherein s, s′, s″, m, m′, m″, B, Y, Y′, Y″ are as above defined in 73., A is a radical of formula (IIa), (IIc), wherein R_a and R_c are as above defined in 71.; R₁—C(O)OC(CH₃)₃); R₂ is —C(O)OC(CH₃)₃;
• with anhydrous or aqueous organic or inorganic acid to hydrolyze the tert-butyl esters and the —BOC protective groups following procedure well known in the literature.
• 73b) by reacting a compound of formula A with a compound of formula (IIIg) or (IIIn) depending on the meaning of BA+Hal-W₁—OC(O)O—Y—ONO₂  (IIIg)A+Hal-W₁—OC(O)—Y—ONO₂  (IIIn)wherein Y, Hal, W₁ are as above defined and A is as defined in 71b),following the same procedures described in 4b) or 6b).
• 74. The compounds of general formula (I) wherein:
• s and s′ are equal to 1;
• s″, m, m′, m″, are 0
• Y and Y′ can be equal or different and are as above defined;
• A is selected among:
• (IIa) wherein R₁ is —C(O)—R_1x and binds a group —Y′—ONO₂; R₂ is —C(O)OR_2x and binds a group —Y—ONO₂; R_a is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is —OH;
• (IIc) wherein R₁ is —C(O)—R_1x and binds a group —Y′—ONO₂; R₂ is —C(O)OR_2x and binds a group —Y—ONO₂; R_s is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is —OH;can be prepared as follows:
• 74a) by reacting a compound of formula (I) prepared as described in 68. with a compound of formula (IIIe):

wherein Act, Y and Y′ are as above defined and A is a radical of formula (IIa), (IIc), wherein R₁ is —H, R₂ is —C(O)OR_2x and binds a group —Y—ONO₂; R_a and R_c are selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is —OH;following the same procedures described in 1b′).

• 75. The compounds of general formula (I) wherein:
• s and s′ are equal to 1;
• s″, m, m′, m″, are 0
• Y and Y′ can be equal or different and are as above defined;
• A is selected among:
• (IIa) wherein R₁ is —C(O)—R_1x and binds a group —Y′—ONO₂; R₂ is —C(O)OR_2x and binds a group —Y—ONO₂; wherein R_g is —OH;
• (IIc) wherein R₁ is —C(O)O—R_1x and binds a group —Y′—ONO₂; R₂ is —C(O)OR_2x and binds a group —Y—ONO₂; R_c is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is —OH;can be prepared as follows:
• 75a) by reacting a compound of formula (I) prepared as described in 68. with a compound of formula (IIIf):

wherein Act, Y and Y′ are as above defined and A is as defined in 74a);following the same procedures described in 3b).

• 76. The compounds of general formula (I) wherein:
• s and s′ are equal to 1;
• s″, m, m′, m″, are 0
• Y and Y′ can be equal or different and are as above defined;
• A is selected among:
• (IIa) wherein R₁ is —C(O)—R₁ and binds a group —Y′—ONO₂; R₂ is —C(O)NHR_2xx or —C(O)N(CH₃)R_2xx and binds a group —Y—ONO₂; R_a is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is —OH;
• (IIc) wherein R₁ is —C(O)—R_1x and binds a group —Y′—ONO₂; R₂ is —C(O)NHR_2xx or —C(O)N(CH₂)R_2xx and binds a group —Y—ONO₂; R_c is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is —OH; can be prepared as follows:
• 76a) by reacting a compound of formula (I) prepared as described in 69. with a compound of formula (IIIe):

wherein Act, Y and Y′ are as above defined and A is a radical of formula (IIa), (IIc), wherein R₁ is —H, R₂ is —C(O)NHR_2xx or —C(O)N(CH₃)R_2xx and binds a group —Y—ONO₂; R_a and R_c are selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is —OH;following the same procedures described in 1b′).

• 77. The compounds of general formula (I) wherein:
• s and s′ are equal to 1;
• s″, m, m′, m″, are 0
• Y and Y′ can be equal or different and are as above defined;
• A is selected among:
• (IIa) wherein R₁ is —C(O)—R_1x and binds a group —Y′—ONO₂; R₂ is —C(O)NHR_2xx or —C(O)N(CH₃)R_2xx and binds a group —Y—ONO₂; R_a is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is —OH;
• (IIc) wherein R₁ is —C(O)O—R_1x and binds a group —Y′—ONO₂; R₂ is —C(O)NHR_2xx or —C(O)N(CH₂)R_2xx and binds a group —Y—ONO₂; R_c is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—,
• 77a) by reacting a compound of formula (I) prepared as described in 69. with a compound of formula (IIIf):

wherein Act, Y and Y′ are as above defined and A is as above defined in 76., following the same procedures described in 3b).

• 78. The compounds of general formula (I) wherein:
• s, s′ and m are equal to 1;
• s″, m′, m″, are 0
• Y and Y′ can be equal or different and are as above defined;
• B is:

• A is selected among:
• (IIa) wherein R₁ is —C(O)—R_1x and binds a group —Y′—ONO₂; R₂ is —C(O)OR_2x and binds a group —B—Y—ONO₂; R_a is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is —OH; can be prepared as follows:
• 78a) by reacting a compound of formula (I) prepared as described in 70. with a compound of formula (IIIe):

wherein Act, B, Y and Y′ are as above defined and A is a radical of formula (IIa), (IIc), wherein R₁ is —H, R₂ is —C(O)OR_2x and binds a group B—Y—ONO₂; R_a and R_c are selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is —OH;

• 79. The compounds of general formula (I) wherein:
• s, s′ and m are equal to 1;
• s″, m′, m″, are 0
• Y and Y′ can be equal or different and are as above defined;
• B is:

• A is selected among:
• (IIa) wherein R₁ is —C(O)O—R_1x and binds a group —Y′—ONO₂; R₂ is —C(O)OR_2x and binds a group —B—Y—ONO₂; R_a is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is —OH;
• (IIc) wherein R₁ is —C(O)O—R_1x and binds a group —Y′—ONO₂; R₂ is —C(O)OR_2x and binds a group —B—Y—ONO₂; R_c is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is —OH; can be prepared as follows:
• 79a) by reacting a compound of formula (I) prepared as described in 70. with a compound of formula (IIIf):

wherein Act, B, Y and Y′ are as above defined and A is as defined in 78a), following the same procedures described in 3b).

• 80. The compounds of general formula (I) wherein:
• s and s′ are equal to 1;
• s″, m, m′, m″, are 0
• Y and Y′ can be equal or different and are as above defined;
• A is selected among:
• (IIa) wherein R₁ is —C(O)—R_1x and binds a group —Y′—ONO₂; R₂ is —COOH; R_a is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is R_gx—O—, and R_a binds a group —Y—ONO₂
• (IIc) wherein R₁ is —C(O)—R_1x and binds a group —Y′—ONO₂; R₂ is —COOH; R_c is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_gx is R_gx—O—, and R_c binds a group —Y—ONO₂;can be prepared as follows:
• 80a) by reacting a compound, of formula (I) prepared as described in 71. with a compound of formula (IIIe):

wherein Act, Y and Y′ are as above defined and A is a radical of formula (IIa), (IIc), wherein R₁ is —H, R₂ is —COOH; R_a and R_c are selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is R_gx—O—, and R_a and R_c bind a group —Y—ONO₂ following the same procedures described in 1b′).

• 81. The compounds of general formula (I) wherein:
• s and s′ are equal to 1;
• s″, m, m′, m″, are 0
• Y and Y′ can be equal or different and are as above defined;
• A is selected among:
• (IIa) wherein R₁ is —C(O)O—R_1x and it binds a group —Y′—ONO₂; R₂ is —COOH; R_a is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is R_gx—O—, and R_a binds a group —Y—ONO₂
• (IIc) wherein R₁ is —C(O)O—R_1x and binds a group —Y′—ONO₂; R₂ is —COOH; R_c is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is R_gx—O—, and R_c binds a group —Y—ONO₂;can be prepared as follows:
• 81a) by reacting a compound of formula (I) prepared as described in 71. with a compound of formula (IIIf):

wherein Act, Y and Y′ are as above defined and A is a radical of formula (IIa), (IIc), wherein R₁ is —H, R₂ is —COOH; R_a and R_c are selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is R_gxO— and R_a and R_c bind a group —Y—ONO₂, following the same procedures described in 3b).

• 82. The compounds of general formula (I) wherein:
• s and s′ are equal to 1;
• s″, m, m′, m″, are 0
• Y and Y′ can be equal or different and are as above defined;
• A is selected among:
• (IIa) wherein R₁ is —C(O)—R_1x and it binds a group —Y′—ONO₂; R₂ is —COOH; R_a is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is R_gxx—NH— or R_gxx—N(CH₃)— and R_a binds a group —Y′—ONO₂
• (IIc) wherein R₁ is —C(O)—R_1x and it binds a group —Y′—ONO₂; R₂ is —COOH; R_c is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is R_gxx—NH— or R_gxx—N(CH₃)— and R_c binds a group —Y—ONO₂;can be prepared as follows:
• 82a) by reacting a compound of formula (I) prepared as described in 72. with a compound of formula (IIIe):

wherein Act, Y and Y′ are as above defined and A is a radical of formula (IIa), (IIc), wherein R₁ is —H, R₂ is —COOH; R_a and R_c are selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is R_gxx—NH— or R_gxx—N(CH₃)—

• and R_a and R_c bind a group —Y—ONO₂
• following the same procedures described in 1b′).
• 83. The compounds of general formula (I) wherein:
• s and s′ are equal to 1;
• s″, m, m′, m″, are 0
• Y and Y′ can be equal or different and are as above defined;
• A is selected among:
• (IIa) wherein R₁ is —C(O)O—R_1x and binds a group —Y′—ONO₂; R₂ is —COOH; R_a is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is R_gxx—NH— or R_gxx—N(CH₃)— and R_a binds a group —Y—ONO₂;
• (IIc) wherein R₁ is —C(O)O—R_1x and binds a group —Y′—ONO₂; R₂ is —COOH; R_c is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is R_gxx—NH— or R_gxx—N(CH₃)— and R_c binds a group —Y—ONO₂;can be prepared as follows:
• 83a) by reacting a compound of formula (I) prepared as described in 72. with a compound of formula (IIIf):

wherein Act, Y and Y′ are as above defined and A is as defined in 82a), following the same procedures described in 3b).

• 84. The compounds of general formula (I) wherein:
• s, s′ and m are equal to 1;
• s″, m′, m″, are 0
• Y and Y′ can be equal or different and are as above defined;
• B is:

• A is selected among:
• (IIa) wherein R₁ is —C(O)O—R_1x and binds a group —Y′—ONO₂; R₂ is —COOH; R_a is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is R_gx—O—, and R_a binds a group —B—ONO₂;
• (IIc) wherein R₁ is —C(O)—R_1x and binds a group —Y′—ONO₂; R₂ is —COOH; R_c is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is R_gx—O—, and R_c binds a group —B—Y—ONO₂;can be prepared as follows:
• 84a) by reacting a compound of formula (I) prepared as described in 73. with a compound of formula (IIIe):

wherein Act, B, Y and Y′ are as above defined and A is a radical of formula, (IIa), (IIc), wherein R₁ is —H, R₂ is —COOH; R_a and R_c are selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is R_gxO— and R_a and R_c bind a group B—Y—ONO₂,following the same procedures described in 1b′).

• 85. The compounds of general formula (I) wherein:
• s, s′ and m are equal to 1;
• s″, m′, m″, are 0
• Y and Y′ can be equal or different and are as above defined;
• B is:

• A is selected among:
• (IIa) wherein R₁ is —C(O)O—R_1x and binds a group —Y′—ONO₂; R₂ is —COOH; R_a is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is R_gx—O—, and R_a binds a group —B—Y—ONO₂;
• (IIc) wherein R₁ is —C(O)—R_1x and it binds a group —Y′—ONO₂; R₂ is —COOH; R_c is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is R_gx—O— and R_c binds a group —B—Y—ONO₂;can be prepared as follows:
• 85a) by reacting a compound of formula (I) prepared as described in 73. with a compound of formula (IIIf):

wherein Act, B, Y and Y′ are as above defined and A is as defined in 84a), following the same procedures described in 3b).

• 86. The compound of general formula (I) wherein:
• s and s′ are equal to 1;
• s″, m, m′, m″ are equal to 0;
• Y and Y′ are equal and are as above defined;
• A is selected from (IIa), (IIc) or (IIt) wherein R₁ is —C(O)—R_1x and it binds a group —Y—ONO₂ or a group —Y′—ONO₂, R₂ is —COOH; R_a of formula (IIa) and R_c of formula (IIc) are R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, or R_iNH(═NH)NH—(CH₂)₃—, and R_h and R_i are R_hh—C(O)— or R_ii—C(O)— and R_a and R_c bind a group —Y—ONO₂ or a group —Y′—ONO₂;
• in formula (IIt) R₁ is —C(O)—R_1x and it binds a group —Y—ONO₂ or a group —Y′—ONO₂, R₂ is —COOH; d is 2 d′ is 1, R_t is —C(O)—R_tt and it binds a group —Y—ONO₂ or a group —Y′—ONO₂;can be prepared as follows:
• 86a) by reacting a compound of formula A with a compound of formula (IIIe)A+Act-(O)C—Y—ONO₂  (IIIe)wherein Act and Y are as above defined and A is a compound of formula (IIa), (IIc) or (IIt) wherein R₁ is —H and R₂ is —COOH; R_a of formula (IIa) and R_c of formula (IIc) are R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, R_iNH(═NH)NH—(CH₂)₃—, and R_h and R_i are —H;

in formula (IIt) R₁ is —H, R₂ is —COOH, d is 2 d′ is 1, R_t is —H; using a ratio A/(IIIe) 1:2 and applying the same procedure described in 1b′). Compounds A are commercially available.

• 87. The compounds of general formula (I) wherein:
• s and s′ are equal to 1;
• s″, m, m′, m″, are 0
• Y and Y′ are equal and are as above defined;
• A is a radical selected from (IIa), (IIc) or (IIt) wherein R₁ is —C(O)—R_1x and binds a group —Y—ONO₂ or a group —Y′—ONO₂, R₂ is —COOH;
• R_a of formula (IIa) and R_c of formula (IIc) are R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, or R_iNH(═NH)NH—(CH₂)₃—, and R_h and R_i are R_hh—C(O)— or R_ii—C(O)— and R_a and R_c bind a group —Y—ONO₂ or a group —Y′—ONO₂;
• in formula (IIt) R₁ is —C(O)—R_1x and binds a group —Y—ONO₂ or a group —Y′—ONO₂, R₂ is —COOH;
• d is 2 d′ is 1, R_t is —C(O)—R_tt and binds a group —Y—ONO₂ or a group —Y′—ONO₂;can be prepared as follows.
• 87a) by reacting a compound of formula A with a compound of formula (IIIf)A+Act-(O)C—O—Y—ONO₂  (IIIf)wherein Act and Y are as above defined and A is as defined in 86a) using a ratio A/(IIIf) 1:2 and applying the same procedure described in 3b).
• 88. The compounds of general formula (I) wherein:
• s is equal to 1;
• s′, s″, m, m′, m″, are equal to 0;
• Y is as above defined;
• A is a radical of formula (IIa), (IIc) or (IIt) wherein R₁ is —H,
• R₂ is —C(O)OR_2x and it binds a group —Y—ONO₂;
• R_a of formula (IIa) and R_c of formula (IIc) are the groups R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, R_iNH(═NH)NH—(CH₂)₃—, R_h and R_i are —H;
• in formula (IIt) R₁ is —H, and R₂ is —C(O)OR_2x and it binds a group —Y—ONO₂; d is 2 d′ is 1, R_t is —H;can be obtained as follows:
• 88a) R_a=R_c selected from R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, R_h is —H;by reacting a compound of formula (I) wherein s, s′, s″, m, m′, m″, Y, Y′, Y″ are as above defined in 88. A is a radical of (IIa), (IIc) or (IIt) wherein R₁ is —C(O)OC(CH₃)₃; R₂ is —CO(O)R_2x and bind; R_a of formula (IIa) and R_c of formula (IIc) are selected from R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, or R_h is —C(O)OC(CH₃)₃;
• in formula (IIt) R₁ and R₂ are as above defined d is 2 d′ is 1, R_t is —C(O)OC(CH₃)₃;
• with anhydrous or aqueous organic or inorganic acid to hydrolyze the —BOC protective groups following procedure well known in the literature.
• 88a′) R_a=R_c selected from R_iNH(═NH)—(CH₂)₃—, R_i is —H:by reacting a compound of formula (VIIa)A_5a-Y—ONO₂  (VIIIa)wherein Y, is as above defined; A_5a is a radical of formula (IIa), (IIc) wherein R₁ is —C(O)OC(CH₃)₃; R₂ is —CO(O)R_2x; R_a of formula (IIa) and R_c of formula (IIc) are R_ia—NH(═NH)NH—(CH₂)₃— wherein R_ia is the known protective group —Pbf (2,2,4,6,7-pentamethyl-dihydrobenzofuran-5-sulfonyl)-;
• with anhydrous or aqueous organic or inorganic acid to hydrolyze the —HOC and the —Pbf protective groups following procedure well known in the literature.
• 88b) compounds described in 88a) and 88a′) can be respectively obtained by reacting a compound of formula A or A₅ with a compound of formula (IIIi)A+HO—Y—ONO₂→(I)  (IIIi)A₅+HO—Y—ONO₂→(VIIIa)  (IIIi)wherein Y is as above defined, and:
• A is a radical of formula (IIa), (IIc) or (IIt) wherein R₁ is —C(O)OC(CH₃)₃; R₂ is —COOH; R_a and R_c are R_hNH(CH₂)_p— wherein p as above defined and R_h is —C(O)OC(CH₃)₃; d and d′ are as above defined, and R_t is —C(O)OC(CH₃)₃;
• A₅ is a radical of formula (IIa) or (IIc) wherein R₁ is —C(O)OC(CH₃)₃; R₂ is —COOH; R_a and R_c are R_iaNH(═NH)NH—(CH₂)₃— wherein R_ia is as above defined using the same procedure described in 8b).Compounds A and A₅ as above defined are commercially available or can be easily obtained from commercially available compounds by simple deprotection/protection steps as known in the literature.
• 89. The compounds of general formula (I) wherein:
• s is equal to 1;
• s′, s″, m, m′, m″ are equal to 0;
• Y is as above defined;
• A is a radical of formula (IIa), (IIc) or (IIt) wherein R₁ is —H,
• R₂ is —C(O)NHR_2xx or —C(O)N(CH₃)R_2xx and it binds a group —Y—ONO₂;
• R_a of formula (IIa) and R_c of formula (IIc) are R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, or R_iNH(═NH)NH—(CH₂)₃—, and R_h and R_i are —H;
• in formula (IIt) R₁ is —H, R₂ is —C(O)NHR_2xx or —C(O)N(CH₃)R_2xx and it binds a group —Y—ONO₂; d is 2 d′ is 1, R_t is —H;can be obtained as follows:
• 89a) R_a=R_c are selected from R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, R_h is —H:by reacting a compound of formula (I) wherein s, s′, s″, m, m′, m″, Y, Y′, Y″ are as above defined in 89. A is a radical of formula (IIa), (IIc) or (IIt) wherein R₁ is —C(O)OC(CH₃)₃; R₂ is —C(O)NHR_2xx or —C(O)N(CH₃)R_2xx; R_a, R_c, p, d, d′, R_h and R_t are as defined in 88a) with anhydrous or aqueous organic or inorganic acid to hydrolyze the —BOC protective groups.
• 89a′) R_a=R_c selected from R_iNH(═NH)NH—(CH₂)₃—, R_i is —H:by reacting a compound of formula (VIIIb):A₆-Y—ONO₂  (VIIIb)wherein Y, is as above defined; A₆ is a radical of formula (IIa), (IIc) wherein R₁ is —C(O)OC(CH₃)₃; R₂ is —C(O)NHR_2xx or —C(O)N(CH₃)_2xx; R_a of formula (IIa) and R_c of formula (IIc) are R_ia—NH(═NH)NH—(CH₂)₃ wherein R_ia is the —Pbf group as above defined;
• with anhydrous or aqueous organic or inorganic acid to hydrolyze the —BOC and the —Pbf protective groups following procedure well known in the literature.
• 89b) compounds described in 89a) and 89a′) can be respectively obtained by reacting a compound of formula A or a compound of formula A₅ already defined in 88b) with a compound of formula (IIIo)A+W₃NH—Y—ONO₂→(I)  (IIIo)A₅+W₃NH—Y—ONO₂→(VIIIb)  (IIIo)using the same procedure described in 7b).
• 90. The compounds of general formula (I) wherein:
• s and m are equal to 1;
• s′, s″, m′, m″ are equal to 0;
• Y is as above defined;
• B is:

• A is a radical of formula (IIa), (IIc) or (IIt) wherein R₁ is —H,
• R₂ is —C(O)OR_2x and binds a group —B—Y—ONO₂;
• R_a of formula (IIa) and R_c of formula (IIc) are R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, or R_iNH(═NH)NH—(CH₂)₃—, and R_h and R_i are —H;
• in formula (IIt) R₁ is —H, R₂ is —C(O)OR_2x and it binds a group —B—Y—ONO₂; d is 2 d′ is 1, R_t is —H;can be obtained as follows:
• 90a) R_a=R_c selected from R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, R_h is —H:by reacting a compound of formula (I) wherein B, s, s′, s″, m, m′, m″, Y, Y′, Y″ are as above defined in 90. A is a radical of formula (IIa), (IIc) or (IIt) wherein R₁ is —C(O)OC(CH₃)₃; R₂ is —C(O)OR_2x; B, R_a, R_c, p, d, d′, R_h and R_t are as defined in 90. with anhydrous or aqueous organic or inorganic acid to hydrolyze the —BOC protective groups.
• 90a′) R_a=R_c selected from R_iNH(═NH)NH—(CH₂)₃—, R_i is —H:by reacting a compound of formula (VIIIc):A_5a-B—Y—ONO₂  (VIIIc)wherein B, and Y, are as above defined in 90. and A_5a is as defined in 88a′) with anhydrous or aqueous organic or inorganic acid to hydrolyze the —BOC and the —Pbf protective groups following procedure well known in the literature.
• 90b) compounds described in 90a) and 90a′) can be respectively obtained by reacting a compound of formula A or a compound of formula A₅ already defined in 88b) with compounds (IIIg) or (IIIn) depending on the meaning of B, and applying the same procedure described in 4b) or 6b):A or A₅+Hal-W₁—OC(O)—Y—ONO₂→(I) or (VIIIc)  (IIIg)A or A₅+Hal-W₁—OC(O)—O—Y—ONO₂→(I) or (VIIIc)  (IIIn)
• 91. The compounds of general formula (I) wherein:
• s and s′ are equal to 1;
• s″, m, m′, m″ are equal to 0;
• Y and Y′ can be equal or different and are as above defined;
• A is selected from (IIa), (IIc) and (IIt) wherein R₁ is —C(O)—R_1x and binds a group —Y′—ONO₂, R₂ is —C(O)OR_2x and binds a group —Y—ONO₂;
• R_a of formula (IIa) and R_c of formula (IIc) are R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, or R_iNH(═NH)NH—(CH₂)₃—, and R_h and R_i are —H;
• in formula (IIt) R₁ is —C(O)—R_1x and it binds a group —Y′—ONO₂, R₂ is —C(O)OR_2x and R₂ binds a group —Y—ONO₂; d is 2 d′ is 1, R_t is —H;can be obtained as follows:
• 91a) R_a=R_c selected from R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, R_h is —H:by reacting a compound of formula (I) wherein s, s′, s″, m, m′, m″, Y, Y′, Y″ are as above defined in 91. A is a radical of (IIa), (IIc) or (IIt) wherein R₁ is —C(O)—R_1x; R₂ is —C(O)OR_2x; R_a of formula (IIa) and R_c of formula (IIc) are selected from R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, R_h is —C(O)OC(CH₃)₃;
• in formula (IIt) R₁ and R₂ are as above defined d is 2 d′ is 1, R_t is —C(O)OC(CH₃)₃;
• with anhydrous or aqueous organic or inorganic acid to hydrolyze the —BOC protective groups following procedure well known in the literature.
• 91a′) R_a=R_c selected from R_iNH(═NH)NH—(CH₂)₃—, R_i is —H:
• by reacting a compound of formula (VIIId)

wherein Y and Y′ are as above defined; A_7a is a radical of formula (IIa), (IIc) wherein R₁ is —C(O)—R_1x; R₂ is —CO(O); R_a of formula (IIa) and R_c of formula (IIc) are R_iaNH(═NH)NH—(CH₂)₃— wherein R_ia is group —Pbf as already defined;

• with anhydrous or aqueous organic or inorganic acid to hydrolyze the —Pbf protective groups following procedure well known in the literature.
• 91b) R_a and R_c are selected from R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, R_h is —H:by reacting a compound of formula (I) with a compound of formula (IIIe)

wherein Y and Y′ are as above defined and A is a radical of formula (IIa), (IIc) or (IIt) wherein R₁ is —H, R₂ is —C(O)OR_2x and binds the group —Y—ONO₂; R_a and R_c are R_hNH(CH₂)_p— wherein p as above defined and R_h is —C(O)OC(CH₃)₃; d and d′ are as above defined, and R_t is —C(O)OC(CH₃)₃; using the same procedure described in 1b′).

• 91b′) R_a=R_c selected from R_iNH(═NH)NH—(CH₂)₃—, R_i is —H:by reacting a compound of formula (VIIIe) with a compound of formula (IIIe):

wherein Y and Y′ are as above defined and A₇ is a radical of formula (IIa), (IIc) wherein R₁ is —H, R₂ is —C(O)OR_2x and binds the group —Y—ONO₂; R_a and R_c are R_iaNH(═NH)NH—(CH₂)₃— wherein R_ia is group —Pbf as above defined;using the same procedure described in 1b′).

• 91c) compounds described in 91b) and 91b′) can be respectively prepared by deprotecting the Fmoc group of a compound of formula (VIIIf₁) or (VIIIf₂)A_8a-Y—ONO₂→(I)  (VIIIf₁)A_8b-Y—ONO₂→(VIIIe)  (VIIIf₂)wherein Y is as above defined and:
• A_8a is a radical of formula (IIa), (IIc) or (IIt) wherein R₁ is the Fmoc protective group; R₂ is —C(O)OR_2x and binds the group —Y—ONO₂; R_a and R_c are R_hNH(CH₂)_p— wherein p is as above defined and R_h is —C(O)OC(CH₃)₃,
• A_8b is a radical of formula (IIa) or (IIc) wherein R₁ is the Fmoc protective group; R₂ is —C(O)OR_2x and binds the group —Y—ONO₂; R_a and R_c are R_iaNH(═NH)NH—(CH₂)₃—, wherein R_ia is the —Pbf group as above defined;
• 91d) compound of formula (VIIIf₁) or (VIIIf₂) are prepared by reacting a compound of formula A_9a or A_9b with composed (IIIi) using the same procedure described in 8b)A_ga+HO—Y—ONO₂→(VIIIf₁)  (IIIi)A_gb+HO—Y—ONO₂→(VIIIf₂)  (IIIi)wherein Y is as above defined and:
• A_9a is a radical of formula (IIa), (IIc) or (IIt) wherein R₁ is the Fmoc protective group; R₂ is —COOH; R_a and R_c are R_hNH(CH₂)_p— wherein p as above defined and R_h is —C(O)OC(CH₃)₃;
• A_9b is a radical of formula (IIa) or (IIc) wherein R₁ is the Fmoc protective group; R₂ is —COOH; R_a and R_c are R_iaNH(═NH)NH—(CH₂)₃— wherein R_ia is the —Pbf group as previously defined.Compounds A_9a and A_9b are commercially available.
• 92. The compounds of general formula (I) wherein:
• s and s′ are equal to 1;
• s″, m, m′, m″ are equal to 0;
• Y and Y′ can be equal or different and are as above defined;
• A is a radical of formula (IIa), (IIc) or (IIt) wherein R₁ is —C(O)—R_1x and it binds a group —Y′—ONO₂, R₂ is —C(O)NHR_2xx or —C(O)N(CH₃R_2xx and it binds a group —Y—ONO₂;
• R_a of formula (IIa) and R_c of formula (IIc) are —R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, or R_iNH(═NH)NH—(CH₂)₃—, and R_h and R_i are —H;
• in formula (IIt) R₁ is —C(O)—R_1x and binds a group —Y′—ONO₂; R₂ is —C(O)NHR_2xx or —C(O)N(CH₃)R_2xx and it binds a group —Y—ONO₂; d is 2 d′ is 1, R_t is —H;can be obtained as follows:
• 92a) R_a=R_c selected from R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, R_h is —H:by reacting a compound of formula (I) wherein s, s′, s″, m, m′, m″, Y, Y′, Y″ are as above defined in 92. A is a radical of (IIa), (IIc) or (IIt) wherein R₁ is —C(O)—R_1x; R₂ is —C(O)NHR_2xx or —C(O)N(CH₃)R_2xx;
• R_a of formula (IIa) and R_c of formula (IIc) are R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, R_h is —C(O)OC(CH₃)₃;
• in formula (IIt) R₁ and R₂ are as above defined d is 2 d′ is 1, R_t is —C(O)OC(CH₃)₃;
• with anhydrous or aqueous organic or inorganic acid to hydrolyze the —BOC protective groups following procedure well known in the literature.
• 92a′) R_a=R_c selected from R_iNH(═NH)NH—(CH₂)₃—, R_i is —H:by reacting a compound of formula (VIIIg)

wherein Y and Y′ are as above defined; A_10a is a radical of formula (IIa), (IIc) wherein R₁ R₁ is —C(O)—R_1x; R₂ is —C(O)NHR_2xx or —C(O)N(CH₃)R_2xx;

• R_a of formula (IIa) and R_c of formula (IIc) are R_ia—NH(═NH)NH—(CH₂)₃— wherein R_ia is the —Pbf group
• with anhydrous or aqueous organic or inorganic acid to hydrolyze the —Pbf protective groups following procedure well known in the literature.
• 92b) R_a=R_c are selected from R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, R_h is —H:by reacting a compound of formula (I) with a compound of formula (IIIe)

wherein Y and Y′ are as above defined and A is a radical of formula (IIa), (IIc) or (IIt) wherein R₁ is R₁ is —H, R₂ is —C(O)NHR_2xx or —C(O)N(CH₃)R_2xx and binds the group —Y—ONO₂; R_a and R_c are R_hNH(CH₂)_p— wherein p as above defined and R_h is —C(O)OC(CH₃)₃; d and d′ are as above defined, and R_t is —C(O)OC(CH₃)₃; using the same procedure described in 1b′).

• 92b′) R_a=R_c selected from R_iNH(═NH)NH—(CH₂)₃—, R_i is —H:compound (VIIIg) is prepared by reacting a compound of formula (VIIIh) with a compound of formula (IIIe)

wherein Y and Y′ are as above defined and A_10a is a radical of formula (IIa), (IIc) wherein R₁ is —H, R₂ is —C(O)NHR_2xx or —C(O)N(CH₃)R_2xx and binds the group —Y—ONO₂; R_a and R_c are R_1a—NH(═NH)NH—(CH₂)₃— wherein R_ia is as above defined using the same procedure described in 1b′).

• 92c) compounds described in 92b) and 92b′) can be prepared by deprotecting the Fmoc group of a compound, of formula (VIIIi₁) or (VIIIi₂)A_11a-Y—ONO₂→(I)  (VIIIi₁)A_11b-Y—ONO₂→(VIIIh)  (VIIIi₂)wherein Y is as above defined and:
• A_11a is a radical of formula (IIa), (IIc) or (IIt) wherein R₁ is the Fmoc protective group; R₂ is —C(O)NHR_2xx or —C(O)N(CH₃)R_2xx and binds the group —Y—ONO₂; R_a and R_c are R_hNH(CH₂)_p— wherein p is as above defined and R_h is —C(O)OC(CH₃)₃,
• A_11b is a radical of formula (IIa) or (IIc) wherein R₁ is the Fmoc protective group; R₂ is —C(O)NHR_2xx or —C(O)N(CH₃)R_2xx and binds the group —Y—ONO₂; R_a and R_c are R_iaNH(═NH)NH—(CH₂)₃, wherein R_ia is as above defined;
• 92d) compounds described on 92c) can be prepared by reacting a compound of formula A_9a or a compound of formula A_9b defined in 91d) with compound (IIIo) using the same procedure described in 7b)A_9a+W₃NH—Y—ONO₂→(VIIIi₁)  (IIIo)A_9b+W₃NH—Y—ONO₂→(VIIIi₂)  (IIIo)wherein Y and W₃ are as above defined.
• 93. The compounds of general formula (I) wherein:
• s and s′ are equal to 1;
• s″, m, m′ and m″ are equal to 0;
• Y and Y′ can be equal or different and are as above defined;
• A is a radical of formula (IIa), (IIc) and (IIt) wherein R₁ is —C(O)O—R_1x and binds a group —Y′—ONO₂, R₂ is —C(O)OR_2x and binds a group —Y—ONO₂;
• R_a of formula (IIa) and R_c of formula (IIc) are R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, or R_iNH(═NH)NH—(CH₂)₃, and R_h and R_i are —H;
• in formula (IIt) R₁ is —C(O)O—R_1x and binds a group —Y′—ONO₂, and R₂ is —C(O)OR_2x and binds a group —Y—ONO₂; d is 2 d′ is 1, R_t is —H;can be obtained as follows:
• 93a) R_a=R_c selected from R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, R_h is —H:by reacting a compound of formula (I) wherein s, s′, s″, m, m′, m″, Y, Y′, Y″ are as above defined in 93. A is a radical of formula (IIa), (IIc) or (IIt) wherein R₁ is —C(O)O—R_1x; R₂ is —C(O)OR_2x;
• R_a of formula (IIa) and R_c of formula (IIc) are selected from R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, R_h is —C(O)OC(CH₃)₃;
• in formula (IIt) R₁ and R₂ are as above defined d is 2 d′ is 1, R_t is —C(O)OC(CH₃)₃;
• with anhydrous or aqueous organic or inorganic acid to hydrolyze the —BOC protective groups following procedure well known in the literature.
• 93a′) R_a=R_c selected from R_iNH(═NH)NH—(CH₂)₃—, R_i is —H:by reacting a compound of formula (VIIIj)

wherein Y and Y′ are as above defined; A_11a is a radical of formula (IIa), (IIc) wherein R₁ is —C(O)O—R_1x; R₂ is —C(O)OR_2x R_a of formula (IIa) and R_c of formula (IIc) are R_iaNH(═NH)NH—(CH₂)₃— wherein R_ia is as already defined;

• with anhydrous or aqueous organic or inorganic acid to hydrolyze the —Pbf protective groups following procedure well known in the literature.
• 93b) R_a=R_c are selected from R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, R_h is —H:by reacting a compound of formula (I) with a compound of formula (IIIf)

wherein Y and Y′ are as above defined and A is a radical of formula (IIa), (IIc) or (IIt) already defined in 91b) and obtained as described in 91c), using the same procedure described in 3b).

• 93b′) R_a=R_c selected from R_iNH(═NH)NH—(CH₂)₃—, R_i—H:Compound of formula (VIIIj) are prepared by reacting a compound of formula (VIIIe) already defined in 91b′) and obtained as described in 91c) with a compound of formula (IIIf)

wherein A₈, Y and Y′ are as above defined, using the same procedure described in 3b).

• 94. The compounds of general formula (I) wherein:
• s and s′ are equal to 1;
• s″, m, m′ and m″ are equal to 0;
• Y and Y′ can be equal or different and are as above defined;
• A is selected from (IIa), (IIc) and (IIt) wherein R₁ is —C(O)O—R_1x and binds a group —Y′—ONO₂, R₂ is —C(O)NHR_2xx or —C(O)N(CH₃)R_2xx and binds a group —Y—ONO₂;
• R_a of formula (IIa) and R_c of formula (IIc) are R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, or R_iNH(═NH)NH—(CH₂)₃—, and R_h and R_i are —H;
• in formula (IIt) R₁ is —C(O)O—R_1x and binds a group —Y′—ONO₂, and R₂ is —C(O)NHR_2xx or —C(O)N(CH₃)R_2xx and binds a group —Y—ONO₂; d is 2 d′ is 1 R_t is —H;can be obtained as follows:
• 94a) R_a=R_c selected from R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, R_h is —H;by reacting a compound of formula (I) wherein s, s′, s″, m, m′, m″, Y, Y′, Y″ are as above defined in 94. A is a radical of (IIa), (IIc) or (IIt) wherein R₁ is —C(O)O—R_1x; R₂ is —C(O)NHR_2xx or —C(O)N(CH₃)R_2xx;
• R_a of formula (IIa) and R_c of formula (IIc) are selected from R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, R_h is —C(O)OC(CH₃)₃;
• in formula (IIt) R₁ and R₂ are as above defined d is 2 d′ is 1, R_t as —C(O)OC(CH₃)₃;
• with anhydrous or aqueous organic or inorganic acid to hydrolyze the —BOC protective groups following procedure well known in the literature.
• 94a′) R_a=R_c selected from R_iNH(═NH)NH—(CH₂)₃—, R_i is —H:by reacting a compound of formula (VIIIk)

wherein Y and Y′ are as above defined; A_12a is a radical of formula (IIa), (IIc) wherein R₁ is —C(O)O—R_1x, R₂ is —C(O)NHR_2xx or —C(O)N(CH₃)R_2xx;

• R_a of formula (IIa) and R_c of formula (IIc) are R_iaNH(═NH)NH—(CH₂)₃— wherein R_ia is group —Pbf
• with anhydrous or aqueous organic or inorganic acid to hydrolyze the —Pbf protective groups following procedure well known in the literature.
• 94b) R_a=R_c are selected from R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, R_h is —H:
• by reacting a compound of formula (I) with a compound of formula (IIIf)

wherein Y and Y′ are as above defined and A is a radical of formula (IIa), (IIc) or (IIt) already defined in 92b) and obtained as described in 92c), using the same procedure described in 3b).

• 94b′) R_a=R_c selected from R_iNH(═NH)NH—(CH₂)₃—, R_i is —H:Compound (VIIIk) are prepared by reacting a compound of formula (VIIIh) already defined in 92b′) and obtained as described in 92c) with a compound of formula (IIIf)

wherein Y and Y′ are as above defined using the same procedure described in 3b).

• 95. The compounds of general formula (I) wherein:
• s, s′ and s″ are equal to 1;
• m, m′ and m″ are equal to 0;
• Y, Y′ and Y″ are as above defined, with the proviso that Y and Y′ are equal;
• A is selected from (IIa), (IIc) and (IIt) wherein R₁—C(O)—R_1x and it binds a group —Y—ONO₂ or a group —Y′—ONO₂, R₂ is —C(O)OR_2x and it binds a group —Y″—ONO₂;
• R_a of formula (IIa) and R_c of formula (IIc) are R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, or R_iNH(═NH)NH—(CH₂)₃—, wherein R_h and R_i are R_hh—C(O)— or R_ii—C(O)— and R_a and R_c bind a group —Y—ONO₂ or a group —Y′—ONO₂;
• in formula (IIt) R₁ and R₂ are as above defined, d is 2 d′ is 1, R_t is —C(O)—R_tt and it binds a group —Y—ONO₂ or a group —Y′—ONO₂;can be prepared as follows:
• 95a) by reacting a compound of formula (I) with a compound of formula (IIIi)

wherein in compounds (I), obtained as described in 86. Y and Y′ are equal and are as above defined and A is selected from (IIa), (IIc) and (IIt) wherein R₁ is —C(O)—R_1x and binds a group —Y—ONO₂ or a group —Y′—ONO₂ and R₂ is —COOH;

• R_a of formula (IIa) and R_c of formula (IIc) are R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, or R_iNH(═NH)NH—(CH₂)₃—, and R_h and R_i are R_hh—C(O)— or R_ii—C(O)— and bind a group —Y—ONO₂ or a group —Y′—ONO₂;
• in formula (IIt) R₁ and R₂ are as above defined, d is 2 d′ is 1, R_t is —C(O)—R_tt and it binds a group —Y—ONO₂ or a group —Y′—ONO₂;using the same procedure described in 8b).
• 96. The compounds of general formula (I) wherein:
• s, s′ and s″ are equal to 1;
• m, m′ and m″ are equal to 0;
• Y, Y′ and Y″ are as above defined, with the proviso that Y and Y′ are equal;
• A is a radical of formula (IIa), (IIc) and (IIt) wherein R₁ is —C(O)O—R_1x and it binds a group —Y—ONO₂ or a group —Y′—ONO₂, R₂ is —C(O)OR_2x and it binds a group —Y″—ONO₂;
• R_a of formula (IIa) and R_c of formula (IIc) are R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, or R_iNH(═NH)NH—(CH₂)₃—, wherein R_h and R_i are R_hh—OC(O)— or R_ii—OC(O)— and R_a and R_c bind a group —Y—ONO₂ or a group —Y′—ONO₂;
• in formula (IIt) R₁ and R₂ are as above defined, d is 2 d′ is 1, R_t is —C(O)O—R_tt and binds a group —Y—ONO₂ or a group —Y′—ONO₂;can be prepared as follows:
• 96a) by reacting a compound of formula (I) with a compound of formula (IIIi)

wherein in compounds (I), obtained as described in 87. Y and Y′ are equal and are as above defined and A is selected from (IIa), (IIc) and (IIt) wherein R₁ is —C(O)O—R_1x and binds a group —Y—ONO₂ or a group —Y′—ONO₂ and R₂ is —COOH;

• R_a of formula (IIa) and R_c of formula (IIc) are R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, or R_iNH(═NH)NH—(CH₂)₃—, and R_h and R_i are R_hh—OC(O)— or R_ii—OC(O)— and bind a group —Y—ONO₂ or a group —Y′—ONO₂;
• in formula (IIt) R₁ and R₂ are as above defined, d is 2 d′ is 1, R_t is —C(O)O—R_tt; and binds a group —Y—ONO₂ or a group —Y′—ONO₂; using the same procedure described in 8b).
• 97. The compounds of general formula (I) wherein:
• s, s′ and s″ are equal to 1;
• m, m′ and m″ are equal to 0;
• Y, Y′ and Y″ are as above defined, and Y and Y′ are equal;
• A is a radical of formula from (IIa), (IIc) or (IIt) wherein R₁ is —C(O)—R_1x and it binds a group —Y—ONO₂ or a group —Y′—ONO₂, R₂ is —C(O)NHR_2xx or —C(O)N(CH₃)R_2xx and it binds a group —Y″—ONO₂;
• R_a of formula (IIa) and R_c of formula (IIc) are R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, or R_iNH(═NH)NH—(CH₂)₃—, wherein R_h and R_i are R_hh—C(O)— or R_ii—C(O)— and R_a and R_c bind a group —Y—ONO₂ or a group —Y′—ONO₂;
• in formula (IIt) R₁ and R₂ are as above defined, d is 2 d′ is 1, R_t is —C(O)—R_tt and binds a group —Y—ONO₂ or a group —Y′—ONO₂;can be prepared as follows:
• 97a) by reacting a compound of formula (I) with a compound of formula (IIIo)

wherein in compounds (I), obtained as described in 86. Y and Y′ are equal and are as above defined and A is selected from (IIa), (IIc) and (IIt) wherein R₁ is —C(O)—R_1x and binds a group —Y—ONO₂ or a group —Y′—ONO₂ and R₂ is —COOH;

• R_a of formula (IIa) and R_c of formula (IIc) are R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, or R_iNH(═NH)NH—(CH₂)₃—, and R_h and R_i are R_hh—C(O)— or R_ii—C(O)— and bind a group —Y—ONO₂ or a group —Y′—ONO₂;
• in formula (IIt) R₁ and R₂ are as above defined, d is 2 d′ is 1, R_t is —C(O)—R_tt and binds a group —Y—ONO₂ or a group —Y′—ONO₂;using the same procedure described in 7b).
• 98. The compounds of general formula (I) wherein:
• s, s′ and s″ are equal to 1;
• m, m′ and m″ are equal to 0;
• Y, Y′ and Y″ are as above defined and Y and Y′ are equal;
• A is selected from (IIa), (IIc) and (IIt) wherein R₁ is —C(O)O—R_1x and binds a group —Y—ONO₂ or a group —Y′—ONO₂, R₂ is —C(O)NHR_2xx or —C(O)N(CH₃)R_2xx and binds a group —Y″—ONO₂;
• R_a of formula (IIa) and R_c of formula (IIc) are R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, or R_iNH(═NH)NH—(CH₂)₃—, wherein R_h and R_i are R_hh—OC(O)— or R_ii—OC(O)— and R_a and R_c bind a group —Y—ONO₂ or a group —Y′—ONO₂;
• in formula (IIt) R₁ and R₂ are as above defined, d is 2 d′ is 1, R_t is —C(O)O—R_tt and binds a group —Y—ONO₂ or a group —Y′—ONO₂;can be prepared as follows:
• 98a) by reacting a compound of formula (I) with a compound of formula (IIIo)

wherein in compounds (I), obtained as described in 87. Y and Y′ are equal and are as above defined, W₃ is as above defined and A is selected from (IIa), (IIc) and (IIt) wherein R₁ is —C(O)O—R_1x and binds a group —Y—ONO₂ or a group —Y′—ONO₂ and R₂ is —COOH;

• R_a of formula (IIa) and R_c of formula (IIc) are R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, or R_iNH(═NH)NH—(CH₂)₃—, and R_h and R_i are R_hh—OC(O)— or R_ii—OC(O)— and bind a group —Y—ONO₂ or a group —Y′—ONO₂;
• in formula (IIt) R₁ and R₂ are as above defined, d is 2 d′ is 1, R_t is —C(O)O—R_tt and binds a group —Y—ONO₂ or a group —Y′—ONO₂;using the same procedure described in 7b).
• 99. The compounds of general formula (I) wherein:
• s, s′, s″ and m″ are equal to 1;
• m, m′ are equal to 0;
• Y, Y′ and Y″ are as above defined, with the proviso that Y and Y′ are equal;
• B is:

• A is a radical of formula (IIa), (IIc) and (IIt) wherein R₁ is —C(O) and binds a group —Y—ONO₂ or a group —Y′—ONO₂, R₂ is —C(O)OR_2x and binds a group —B—Y″—ONO₂;
• R_a of formula (IIa) and R_c of formula (IIc) are R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, or R_iNH(═NH)NH—(CH₂)₃—, wherein R_h and R_i are R_hh—C(O)— or R_ii—OC(O)— and R_a and R_c bind a group —Y—ONO₂ or a group —Y′—ONO₂;
• in formula (IIt) R₁ and R₂ are as above defined d is 2 d′ is 1, R_t is —C(O)—R_tt and binds a group —Y—ONO₂ or a group —Y′—ONO₂;can be prepared as follows:
• 99a) by reacting a compound of formula (I) obtained as described in 86.

with compounds (IIIg) or (IIIn) depending on the meaning of B:(I)+Hal-W₁—OC(O)O—Y′—ONO₂  (IIIg)(I)+Hal-W₁—OC(O)—Y′—ONO₂  (IIIn)wherein in compounds (I), obtained as described in 86. Y and Y′ are equal and are as above defined and A is selected from (IIa), (IIc) and (IIt) wherein R₁ is —C(O)R_1x and binds a group —Y—ONO₂ or a group —Y′—ONO₂ and R₂ is —COOH;

• R_a of formula (IIa) and R_c of formula (IIc) are R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, or R_iNH(═NH)NH—(CH₂)₃—, and R_h and R_i are R_hh—C(O)— and bind a group —Y—ONO₂ or a group —Y′—ONO₂;
• in formula (IIt) R₁ and R₂ are as above defined, d is 2 d′ is 1, R_t is —C(O)—R_tt and binds a group —Y—ONO₂ or a group —Y′—ONO₂;and applying the same procedure described in 4b) or 6b).
• 100. The compounds of general formula (I) wherein:
• s, s′, s″ and m″ are equal to 1;
• m, m′ are equal to 0;
• Y, Y′ and Y″ are as above defined, with the proviso that Y and Y′ are equal;
• B is:

• A is a radical of formula (IIa), (IIc) and (IIt) wherein R₁ is —C(O)O—R_1x and it binds a group —Y—ONO₂ or a group —Y′—ONO₂, R₂ is —C(O)OR_2x and it binds a group —B—Y″—ONO₂;
• R_a of formula (IIa) and R_c of formula (IIc) are R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, or R_iNH(═NH)NH—(CH₂)₃—, wherein R_h and R_i are R_hh—OC(O)— or R_ii—OC(O)— and R_a and R_c bind a group —Y—ONO₂ or a group —Y′—ONO₂;
• in formula (IIt) R₁ and R₂ are as above defined, d is 2 d′ is 1, R_t is —C(O)O—R_tt and it binds a group —Y—ONO₂ or a group —Y′—ONO₂;can be prepared as follows:
• 100a) by reacting a compound of formula (I) obtained as described in 87.

with compounds (IIIg) or (IIIn) depending on the meaning of B:(I)+Hal-W₁—OC(O)O—Y′—ONO₂  (IIIg)(I)+Hal-W₁—OC(O)—Y′—ONO₂  (IIIn)wherein is compounds (I) Y and Y′ are equal and are as above defined and A is selected from (IIa), (IIc) and (IIt) wherein R₁ is —C(O)O—R_1x and binds a group —Y—ONO₂ or a group —Y′—ONO₂ and R₂ is —COOH;

• R_a of formula (IIa) and R_c of formula (IIc) are R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, or R_iNH(═NH)NH—(CH₂)₃—, and R_h and R_i are R_hh—OC(O)— or R_ii—C(O)— and bind a group —Y—ONO₂ or a group —Y′—ONO₂;
• in formula (IIt) R₁ and R₂ are as above defined, d is 2 d′ is 1, R_t is —C(O)O—R_tt and binds a group —Y—ONO₂ or a group —Y′—ONO₂;and applying the same procedure described in 4b) or 6b).
• 101. The compounds of general formula (I) wherein:
• s and s′ are equal to 1;
• s″, m, m′ and m″ are equal to 0;
• Y and Y′ can be equal or different and are as above defined;
• A is a radical of formula (IIa), (IIc) or (IIt) wherein R₁ is —H,
• R₂ is —C(O)OR_2x and it binds a group —Y—ONO₂;
• R_a of formula (IIa) and R_c of formula (IIc) are R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, or R_iNH(═NH)NH—(CH₂)₃—, wherein R_h and R_i are R_hh—C(O)— or R_ii—C(O)— and R_a and R_c bind a group —Y′—ONO₂
• in formula (IIt) R₁ is —H, and R₂ is —C(O)OR_2x and binds a group —Y—ONO₂; d is 2 d′ is 1, R_t is —C(O)—R_tt, and binds a group —Y′—ONO₂ can be obtained as follows:
• 101a) R_a=R_c selected from R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, R_h is R_hh—C(O)—:by reacting a compound of formula (I) wherein s, s′, s″, m, m′, m″, Y, Y′, Y″ are as above defined in 101., A is a radical of (IIa), (IIc) or (IIt) wherein R₂, d, d′, R_t are as defined in 101., R_a and R_c are selected from R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, R_h is R_hh—C(O)—; R_i is —C(O)OC(CH₃)₃;
• with anhydrous or aqueous organic or inorganic acid to hydrolyze the —BOC protective groups following procedure well known in the literature.
• 101a′) R_a=R_c selected from R_iNH(═NH)NH—(CH₂)₃—, R_i is R_ii—OC(O)—;by reacting a compound of formula (VIIIL)

wherein Y and Y′ are as above defined; A_13a is a radical of formula (IIa), (IIc) wherein R₁ is the —Fmoc protective group;

• R₂ is —C(O)OR_2x and binds a group —Y—ONO₂; R_a of formula (IIa) and R_c of formula (IIc) are R_iNH(═NH)NH—(CH₂)₃— wherein R_i is R_ii—C(O)— and binds a group —Y′—ONO₂ known procedure to remove the —Fmoc protective groups;
• 101b) R_a=R_c are selected from R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, R_h is —H:by reacting a compound of formula (I) with a compound of formula (IIIe)

wherein Y and Y′ are as above defined and A is a radical of formula (IIa), (IIc) or (IIt) wherein R₁ is —C(O)OC(CH₃)₃; —R₂ is —C(O)OR_2x and binds the group —Y—ONO₂; R_a and R_c are selected from R_hNH(CH₂)_p— wherein p as above defined and R_h is —H; in formula (IIt) d and d′ are as above defined, and R_t is —H;using the same procedure described in 1b′).

• 101b′) R_a=R_c selected from R_iNH(═NH)NH—(CH₂)₃—, R_i is —H:Compound (VIIIL) are prepared by reacting a compound of formula (VIIIm) with a compound of formula (IIIe)

wherein Y and Y′ are as above defined, and A₁₃ is a radical of formula (IIa), (IIc) wherein R₁ is the Fmoc protective group, R₂ is —C(O)OR_2x and binds the group —Y—ONO₂; R_a and R_c are R_iNH(═NH)NH—(CH₂)₃— wherein R_i is —H using the same procedure described in 1b′).

• 101c) R_a=R_c are selected from R_haNH(CH₂)_p— wherein p is an integer from 0 to 4, R_ha is —Fmoc:by deprotecting the Fmoc group of a compound of formula (VIIIn)

wherein Y is as above defined and A₁₄ as a radical of formula (IIa), (IIc) or (IIt) wherein R₁ is —C(O)OC(CH₃)₃; R₂ is —C(O)OR_2x and binds the group —Y—ONO₂; R_a and R_c are R_haNH(CH₂)_p— wherein p as above defined, and R_ha is the Fmoc protective group; d and d′ are as above defined, and R_t is equal to R_ta and is the Fmoc protective group

• 101′c) R_a=R_c selected from R_iaNH(═NH)NH—(CH₂)₃—, R_ia=—PbfCompound (VIIIm) are prepared by deprotecting the —Pbf group of a compound of formula (VIIIo)

wherein Y is as above defined, and A_15a is a radical of formula (IIa), (IIc) wherein R₁ is —Fmoc; R₂ is —C(O)OR_2x and binds the group —Y—ONO₂; R_a and R_c are R_iaNH(═NH)NH—(CH₂)₃— R_ia is —Pbf protective group;

• 101d) compound described in 101c) and 101c′) can be prepared by reacting a compound of formula A₁₄ or A₁₅ with compound (IIIi) using the same procedure described in 8b)A₁₄+HO—Y—ONO₂→(VIIIn)  (IIIi)A₁₅+HO—Y—ONO₂→(VIIIm)  (IIIi)wherein Y is as above defined and:
• A₁₄ is a radical of formula (IIa), (IIc) or (IIt) wherein R₁ is —C(O)OC(CH₃)₃; R₂ is —COOH; R_a and R_c are R_haNH(CH₂)_p— wherein p as above defined and by R_ha is Fmoc protective group; d and d′ are as above defined, and R_t is R_ta and is the Fmoc protective group.
• A₁₅ is a radical of formula (IIa), (IIc) wherein R₁ is —Fmoc; R₂ is —COOH; R_a and R_c are selected from R_iaNH(═NH)NH—(CH₂)₃—, wherein R_ia is —Pbf.Compounds A₁₄ and A₁₅ are commercially available.
• 102. The compounds of general formula (I) wherein:
• s and s′ are equal to 1;
• s″, m, m′ and m″ are equal to 0;
• Y and Y′ can be equal or different and are as above defined;
• A is selected from (IIa), (IIc) and (IIt) wherein R₁ is —H, R₂ is —C(O)OR_2x and binds a group —Y—ONO₂;
• R_a of formula (IIa) and R_c of formula (IIc) are R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, or R_iNH(═NH)NH—(CH₂)₃—, wherein R_h and R_i are R_hh—OC(O)— or R_ii—OC(O)—, and binds a group —Y′—ONO₂
• in formula (IIt) R₁ is —H, and R₂ is —C(O)OR_2x and binds a group —Y—ONO₂; d is 2 d′ is 1, R_t is —C(O)O—R_tt, and binds a group —Y′—ONO₂ can be obtained as follows:
• 102a) R_a=R_c selected from R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, R_h is R_hh—OC(O)—:by reacting a compound of formula (I) wherein s, s′, s″, m, m′, m″, Y, Y′, Y″ are as above defined in 102., A is a radical of (IIa), (IIc) or (IIt) wherein R₂, d, d′, R_t are as defined in
• 102., R_a and R_c are selected from R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, R_h is R_hh—OC(O)—; R₁ is —C(O)OC(CH₃)₃;
• with anhydrous or aqueous organic or inorganic acid to hydrolyze the —BOC protective groups following procedure well known in the literature.
• 102a′) R_a=R_c selected from R_iNH(═NH)NH—(CH₂)₃—, R_i is R_ii—OC(O)—;by reacting a compound of formula (VIIIp)

wherein Y and Y′ are as above defined; A₁₆ is a radical of formula (IIa), (IIc) wherein R₁ is the —Fmoc protective group;

• R₂ is —C(O)OR_2x and binds a group —Y′—ONO₂; R_a of formula (IIa) and R_c of formula (IIc) are R_iNH(═NH)NH—(CH₂)₃— wherein R_i is R_ii—OC(O)— and binds a group —Y′—ONO₂ by known procedure to remove the —Fmoc protective groups;
• 102b) R_a=R_c are selected from R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, R_h is —H:by reacting a compound of formula (I) with a compound of formula (IIIf)

wherein Y and Y′ are as above defined and A is as above defined in 101b), using the same procedure described in 3b).

• 102b′) R_a=R_c selected from R_iNH(═NH)NH—(CH₂)₃—, R_i is —H:by reacting a compound of formula (VIIIm) already described in 101b′) and obtained as described in 101c′) with a compound of formula (IIIf)

wherein Y and Y′ are as above defined and A_13′ is as defined in 101b′) using the same procedure described in 3b).

• 103. The compounds of general formula (I) wherein:
• s and s′ are equal to 1;
• s″, m, m′ and m″ are equal to 0;
• Y and Y′ can be equal or different and are as above defined;
• A is selected from (IIa), (IIc) and (IIt) wherein R₁ is —H, R₂ is —C(O)NHR_2xx or —C(O)N(CH₃)R_2xx and binds a group —Y—ONO₂;
• R_a of formula (IIa) and R_c of formula (IIc) are R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, or R_iNH(═NH)NH—(CH₂)₃—, wherein R_h and R_i are R_hh—OC(O)— or R_ii—OC(O)—, and binds a group —Y′—ONO₂
• in formula (IIt) R₁ is —H, and R₂ is —C(O)NHR_2xx or —C(O)N(CH₃)R_2xx and binds a group —Y—ONO₂; d is 2 d′ is 1, R_t is —C(O)—R_tt, and binds a group —Y′—ONO₂ can be obtained as follows:
• 103a) R_a=R_c selected from R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, R_h is R_hh—C(O):by reacting a compound of formula (I) wherein s, s′, a″, m, m′, m″, Y, Y′, Y″ are as above defined in 103., A is a radical of (IIa), (IIc) or (IIt) wherein R₂, d, d′, R_t are as defined in 103., R_a and R_c are selected from R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, R_h is R_hh—C(O)—; R₁ is —C(O)OC(CH₃)₃;
• with anhydrous or aqueous organic or inorganic acid to hydrolyze the —BOC protective groups following procedure well known in the literature.
• 103a′) R_a=R_c selected from R_iNH(═NH)NH—(CH₂)₃—, R_i is R_ii—C(O)—;by reacting a compound of formula (VIIIq)

wherein Y and Y′ are as above defined; A_17a is a radical of formula (IIa), (IIc) wherein R₁ is the —Fmoc protective group; R₂ is —C(O)NHR_2xx or —C(O)N(CH₃)R_2xx and binds a group —Y—ONO₂; R_a of formula (IIa) and R_c of formula (IIc) are R_iNH(═NH)NH—(CH₂)₃— wherein R_i is R_ii—C(O)— and binds a group —Y′—ONO₂ by known procedure to remove the —Fmoc protective groups;

• 103b) R_a=R_c are selected from R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, R_h is —Hby reacting a compound of formula (I) with a compound of formula (IIIe)

wherein Y and Y′ are as above defined and A is a radical of formula (IIa), (IIc) or (IIt) wherein R₁ is —C(O)OC(CH₃)₃; —R₂ is —C(O)NHR_2xx or —C(O)N(CH₃)R_2xx and binds the group —Y—ONO₂; R_a and R_c are R_hNH(CH₂)_p— wherein p as above defined and R_h is —H; in formula (IIt) d and d′ are as above defined, and R_t is —H;using the same procedure described in 1b′).

• 103b′) R_a=R_c selected from R_iNH(═NH)NH—(CH₂)₃—, R_i is —H:by reacting a compound of formula (VIIIr) with a compound of formula (IIIe)

wherein Y and Y′ are as above defined and A₁₇ is a radical of formula (IIa), (IIc) wherein R₁ is the Fmoc protective group, R₂ is —C(O)NHR_2xx or —C(O)N(CH₃)R_2xx and binds the group —Y—ONO₂; R_a and R_c are R_iNH(═NH)NH—(CH₂)₃— wherein R_i is —H using the same procedure described in 1b′).

• 103c) R_a=R_c are selected from R_haNH(CH₂)_p— wherein p is an integer from 0 to 4, R_ha is —Fmoc

Compound (I) described in 103b) can be prepared by deprotecting the Fmoc group of a compound of formula (VIIIs)

wherein Y is as above defined and A₁₈ is a radical of formula (IIa), (IIc) or (IIt) wherein R₁ is —C(O)OC(CH₃)₃; —R₂ is —C(O)NHR_2xx or —C(O)N(CH₃)R_2xx and binds the group —Y—ONO₂; R_a and R_c are R_haNH(CH₂)_p— wherein p as above defined and R_ha is the Fmoc protective group; d and d′ are as above defined, and R_t is R_ta and is the Fmoc group.

• 103c′) R_a=R_c selected from R_iaNH(═NH)NH—(CH₂)₃—, R_ia=—PbfCompound (VIIIr) described in 103b′) by deprotecting the —Pbf group of a compound of formula (IIIt)

wherein Y is as above defined and A₁₉ is a radical of formula (IIa), (IIc) wherein R₁ is —Fmoc; —R₂ is —C(O)NHR_2xx or —C(O)N(CH₃)R_2xx and binds the group —Y—ONO₂; R_a and R_c are R_iaNH(═NH)NH—(CH₂)₃— R_ia is the —Pbf protective group;

• 103d) compounds described in 103c) and 103c′) can be prepared by reacting a compound of formula A₁₄ or A₁₅ described in 101d) with compound (IIIo) using the same procedure described in 7b)A₁₄+W₃NH—Y—ONO₂→(VIIIs)  (IIIo)A₁₅+W₃NH—Y—ONO₂→(VIIIt)  (IIIo)wherein Y is as above defined and W₃ is H or —CH₃.
• 104. The compounds of general formula (I) wherein:
• s and s′ are equal to 1;
• s″, m, m′ and m″ are equal to 0;Y and Y′ can be equal or different and are as above defined;
• A is selected from (IIa), (IIc) and (IIt) wherein R₁ is —H, R₂ is —C(O)NHR_2xx or —C(O)N(CH₃)R_2xx and binds the group —Y—ONO₂;
• R_a of formula (IIa) and R_c of formula (IIc) are R_hNH(CH₂)_p— wherein p is as integer from 0 to 4, or R_iNH(═NH)NH—(CH₂)₃—, wherein R_h and R_i are R_hh—OC(O)— or R_ii—OC(O)—, and binds a group —Y′—ONO₂;
• in formula (IIt) R₁ is —H; and R₂ is —C(O)NHR_2xx or —C(O)N(CH₃)R_2xx and binds the group —Y—ONO₂; d is 2 d′ is 1, R_t is —C(O)O—R_tt, and binds a group —Y′—ONO₂ can be obtained as follows:
• 104a) R_a=R_c are selected from R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, R_h is R_hh—O—C(O)—:by reacting a compound of formula (I) wherein s, s′, s″, m, m′, m″, Y, Y′, Y″ are as above defined in 104., A is a radical of (IIa), (IIc) or (IIt) wherein R₂, d, d′, R_t are as defined in 104., R_a and R_c are selected from R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, R_h is R_hh—O—C(O)—; R₁ is —C(O)OC(CH₃)₃;
• with anhydrous or aqueous organic or inorganic acid to hydrolyze the —BOC protective groups following procedure well known in the literature.
• 104a′) R_a=R_c are selected from R_iNH(═NH)NH—(CH₂)₃—, R_i is R_ii—OC(O)—;by reacting a compound of formula (VIIIu)

wherein Y and Y′ are as above defined and A₂₀ is a radical of formula (IIa), (IIc) wherein R₁ is the —Fmoc protective group;

• R₂ is —C(O)NHR_2xx or —C(O)N(CH₃)R_2xx and binds a group —Y—ONO₂; R_a of formula (IIa) and R_c of formula (IIc) are R_iNH(═NH)NH—(CH₂)₃— wherein R_i is R_ii—OC(O)— and binds a group —Y′—ONO₂ by known procedure to remove the —Fmoc protective groups;
• 104b) R_a=R_c are selected from R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, R_h is —Hby reacting a compound of formula (I) with a compound of formula (IIIf)

wherein Y and Y′ are as above defined and A is as defined in 103b), using the same procedure described in 3b).

• 104b′) R_a=R_c selected from R_iNH(═NH)NH—(CH₂)₃—, R_i is —H:Compound (VIIIu) can be prepared by reacting a compound of formula (VIIIr) with a compound of formula (IIIf)

wherein Y and Y′ are as above defined and A₁₇ is as defined in 103b′) using the same procedure described in 3b).

• 105. The compounds of general formula (I) wherein:
• s, s′ and m are equal to 1;
• s″, m′ and m″ are equal to 0;
• Y and Y′ are as above defined;
• B is:

• A is selected from (IIa), (IIc) and (IIt) wherein R₁ is —H, —R₂ is —C(O)OR_2x and binds a group —B—Y—ONO₂;
• R_a of formula (IIa) and R_c of formula (IIc) are R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, or R_iNH(═NH)NH—(CH₂)₃—, wherein R_h and R_i are R_hh—C(O)— or R_ii—C(O)—, and bind a group —Y′—ONO₂
• in formula (IIt) R₁ is —H, and R₂ is —C(O)OR_2x and binds a group —B—Y—ONO₂, d is 2 d′ is 1, R_t is —C(O)—R_tt and binds a group —Y′—ONO₂;can be obtained as follows:
• 105a) R_a=R_c are selected from R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, R_h is R_hh—C(O)—:by reacting a compound of formula (I) wherein s, s′, a″, m, m′, m″, B, Y, Y′, Y″ are an above defined in 105., A is a radical of (IIa), (IIc) or (IIt) wherein R₂, d, d′, R_t are as defined in 105., R_a and R_c are selected from R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, R_h is —R_hh—C(O)—; R₁ is —C(O)OC(CH₃)₃;
• with anhydrous or aqueous organic or inorganic acid to hydrolyze the —BOC protective groups following procedure well known in the literature.
• 105a′) R_a=R_c are selected from R_iNH(═NH)NH—(CH₂)₃—, R_i is R_ii—OC(O)—; by reacting a compound of formula (VIIIv)

wherein B, Y and Y′ are as above defined and A_21a is a radical of formula (IIa), (IIc) wherein R₁ is the —Fmoc protective group;

• R₂ is —C(O)OR_2x and binds the group —B—Y—ONO₂; R_a of formula (IIa) and R_c of formula (IIc) are R_iNH(═NH)NH—(CH₂)₃ wherein R_i is R_ii—C(O)— and binds a group —Y′—ONO₂ by known procedure to remove the —Fmoc protective groups;
• 105b) R_a=R_c are selected from R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, R_h is —Hby reacting a compound of formula (I) with a compound of formula (IIIe)

wherein Y and Y′ are as above defined and A is a radical of formula (IIa), (IIc) or (IIt) wherein R₁ is —C(O)OC(CH₃)₃; —R₂ is —C(O)OR_2x and binds the group —B—Y—ONO₂; R_a and R_c are R_hNH(CH₂)_p— wherein p as above defined and R_h is —H; in formula (IIt) d and d′ are as above defined, and R_t is —H;using the same procedure described in 1b′);

• 105b′) R_a=R_c selected from R_iNH(═NH)NH—(CH₂)₃—, R_i is —H:Compound of formula (VIIIv) can be prepared by reacting a compound of formula (VIIIw) with a compound of formula (IIIe)

wherein Y and Y′ are as above defined and A₂₁ is a radical of formula (IIa), (IIc) wherein R₁ is the Fmoc protective group, R₂ is —C(O)OR_2x and binds the group —B—Y—ONO₂; R_a and R_c are R_iNH(═NH)NH—(CH₂)₃— wherein R₁ is —H using the same procedure described in 1b′).

• 105c) R_a=R_c are selected from R_haNH(CH₂)_p— wherein p is an integer from 0 to 4, R_ha is —FmocCompound (I) described in 105b) by deprotecting the Fmoc group of a compound of formula (VIIIx)

wherein Y and B are as above defined and A₂₂ is a radical of formula (IIa), (IIc) or (IIt) wherein R₁ is —C(O)OC(CH₃)₃; R₂ is —C(O)OR_2x and binds the group —B—Y—ONO₂; R_a and R_c are R_haNH(CH₂)_p— wherein p as above defined and R_ha is the Fmoc protective group; d and d′ are as above defined, and R_t is R_ta and is the Fmoc protecting group.

• 105c′) R_a=R_c selected from R_iaNH(═NH)NH—(CH₂)₃—, R_ia=—PbfCompound described in 105b′) are prepared by deprotecting the —Pbf group of a compound of formula (VIIIy)

wherein Y is as above defined and A₂₃ is a radical of formula (IIa), (IIc) wherein R₁ is —Fmoc; R₂ is —C(O)OR_2x and binds the group —B—Y—ONO₂; R_a and R_c R_iaNH(═NH)NH—(CH₂)₃— R_ia is the —Pbf protective group;

• 105d) compounds (VIIIx) and (VIIIy) are prepared by reacting respectively a compound of formula A₁₄ or A₁₅ described in 101d) with compound (IIIg) or (IIIn) depending on the meaning of B, and applying the same procedure described in 4b) or 6b):A₁₄ or A₁₅+Hal-W₁—OC(O)O—Y—ONO₂  (IIIg)A₁₄ or A₁₅+Hal-W₁—OC(O)—Y—ONO₂  (IIIn)wherein Hal, W₁ and Y are as above.
• 106. The compounds of general formula (I) wherein:
• s s′ and m are equal to 1;
• s″, m′ and m″ are equal to 0;
• Y and Y′ can be equal or different and are as above defined;
• B is:

• A is a radical of formula (IIa), (IIc) or (IIt) wherein R₁ is —H,
• R₂ is —C(O)OR_2x and binds a group —B—Y—ONO₂;
• R_a of formula (IIa) and R_c of formula (IIc) are R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, or R_iNH(═NH)NH—(CH₂)₃—, wherein R_h and R_i are R_hh—OC(O)— or R_ii—OC(O)—, and bind a group —Y′—ONO₂
• in formula (IIt) R₁ is —H, and R₂ is —C(O)OR_2x and binds a group —B—Y—ONO₂, d is 2 d′ is 1, R_t is —C(O)O—R_tt and binds a group —Y′—ONO₂;can be obtained as follows:
• 106a) R_a=R_c selected from R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, R_h is R_hh—OC(O)—:by reacting a compound of formula (I) wherein s, s′, s″, m, m′, m″, B, Y, Y′, Y″ are as above defined in 106., A is a radical of (IIa), (IIc) or (IIt) wherein R₂, d, d′, R_t are as defined in 106., R_a and R_c are selected from R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, R_h is —R_hh—OC(O)—; R₁ is —C(O)OC(CH₃)₃;
• with anhydrous or aqueous organic or inorganic acid to hydrolyze the —BOC protective groups following procedure well known in the literature.
• 106a′) R_a=R_c selected from R_iNH(═NH)NH—(CH₂)₃—, R_i is R_ii—OC(O)—;by reacting a compound of formula (VIIIz)

wherein B, Y and Y′ are as above defined and A₂₄ is a radical of formula (IIa), (IIc) wherein R₁ is the —Fmoc protective group; R₂ is —C(O)OR_2x and binds a group —B—Y—ONO₂; R_a of formula (IIa) and R_c of formula (IIc) are R_iNH(═NH)NH—(CH₂)₃— wherein R_i is R_ii—OC(O)— and binds a group —Y′—ONO₂ by known procedure to remove the —Fmoc protective groups;

• 106b) R_a=R_c are selected from R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, R_h is —Hby reacting a compound of formula (I) obtained as described in 105c) with a compound of formula (IIIf)

wherein Act, B, Y and Y′ are as above defined and A is as defined in 105b), using the same procedure described in 3b).

• 106b′) R_a=R_c selected from R_iNH(═NH)NH—(CH₂)₃—, R_i is —H:by reacting a compound of formula (VIIIw) obtained as described in 105c′) with a compound of formula (IIIf)

wherein B, Y and Y′ are as above defined and A₂₁ is as defined in 105b′), using the same procedure described in 3b).

• 107. The compounds of general formula (I) wherein:
• s is equal to 1;
• s′, s″, m, m′ and m″ are equal to 0;
• Y is as above defined;
• A is a radical of formula (IIa), (IIc) or (IIt) wherein R₁ is —C(O)—R_1x and binds a group —Y′—ONO₂; R₂ is —COOH
• R_a of formula (IIa) and R_c of formula (IIc) are R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, or R_iNH(═NH)NH—(CH₂)₃—, wherein R_h and R_i are —H;an formula (IIt) d is 2 d′ is 1, R_t is —H;can be obtained as follows:
• 107a) R_a=R_c selected from R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, R_h is —Hby reacting a compound of formula (I) wherein s, s′, s″, m, m′, m″, Y, Y′, Y″ are as above defined in 107., A is a radical of (IIa), (IIc) or (IIt) wherein R₁, R₂, d, d′, are as defined in 107., R_a of formula (IIa) and R_c of formula (IIc) are selected from R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, R_h is —C(O)OC(CH₃)₃;
• in formula (IIt) R₁ is —C(O)OC(CH₃)₃;
• with anhydrous or aqueous organic or inorganic acid to hydrolyze the —BOC protective groups following procedure well known in the literature.
• 107a′) R_a=R_c selected from R_iNH(═NH)NH—(CH₂)₃—, R_i is —H;reacting a compound of formula (VIIIaa)A₂₅-Y—ONO₂  (VIIIaa)wherein Y is as above defined and A₂₅ is a radical of formula (IIa), (IIc) wherein R₁, R₂ are as defined in 107., R_a of formula (IIa) and R_c of formula (IIc) are selected from R_iaNH(═NH)NH—(CH₂)₃—, wherein R_ia is the —Pbf protective group as already defined;
• with anhydrous or aqueous organic or inorganic acid to hydrolyze the —Pbf protective groups following procedure well known in the literature.
• 107b) compounds described in 107a) and 107a′) can be prepared by reacting a compound of formula A or a compound of formula A₂₆ with a compound of formula (IIIe)A+Act(O)C—Y—ONO₂→(I)  (IIIe)A₂₆+Act(O)C—Y—ONO₂→(VIIIaa)  (IIIe)wherein Act and Y are as above defined and:
• A is a compound of formula (IIa), (IIc) or (IIt) wherein R₁ is —H, R₂ is —COOH; R_a of formula (IIa) and R_c of formula (IIc) are R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, R_h is —C(O)OC(CH₃)₃; in formula (IIt) d and d′ are as defined on 107., R_t is —C(O)OC(CH₃)₃;
• A₂₆ is a compound of formula (IIa) or (IIc) wherein R₁ is —H, R₂ is —COOH; R_a of formula (IIa) and R_c of formula (IIc) are R_iaNH(═NH)NH—(CH₂)₃—, wherein R_ia is the —Pbf protective group as already defined;using the same procedure described in 1b′),Compounds A and A₂₆ are commercially available.
• 108. The compounds of general formula (I) wherein:
• s is equal to 1;
• s′, s″, m, m′ and m″ are equal to 0;
• Y is as above defined;
• A is selected from (IIa), (IIc) and (IIt) wherein R₁ is —C(O)O—R_1x and binds a group —Y—ONO₂; R₂ is —COOH
• R_a of formula (IIa) and R_c of formula (IIc) are R_hNH(CH₂)_p— wherein p is an integer front 0 to 4, or R_iNH(═NH)NH—(CH₂)₃—, wherein R_h and R_i are —H;
• in formula (IIt) d is 2 d′ is 1, R_t is —H;can be obtained as follows:
• 108a) R_a=R_c selected from R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, R_h is —Hby reacting a compound of formula (I) wherein s, s′, s″, m, m′, m″, Y, Y′, Y″ are as above defined in 108., A is a radical of (IIa), (IIc) or (IIt) wherein R₁, R₂, d, d′, are as defined in 108., R_a of formula (IIa) and R_c of formula (IIc) are selected from R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, R_h is —C(O)OC(CH₃)₃;
• in formula (IIt) R_t is —C(O)OC(CH₃)₃;
• with anhydrous or aqueous organic or inorganic acid to hydrolyze the —BOC protective groups following procedure well known in the literature.
• 108a′) R_a=R_c selected from R_iNH(═NH)NH—(CH₂)₃—, R_i is —H;reacting a compound of formula (VIIIab)A₂₇-Y—ONO₂  (VIIIab)wherein Y is as above defined and A₂₇ is a radical of (IIa), (IIc) wherein R₁, R₂, are as defined in 108., R_a of formula (IIa) and R_c of formula (IIc) are selected from R_iaNH(═NH)NH—(CH₂)₃—, wherein R_ia is the —Pbf protective group as already defined;
• with anhydrous or aqueous organic or inorganic acid to hydrolyze the —Pbf protective groups following procedure well known in the literature.108b) compounds described in 108a) and 108a′) can be prepared by reacting a compound of formula A or a compound of formula A₂₆ both already defined in 107b) with a compound of formula (IIIf)A+Act(O)C—O—Y—ONO₂→(I)  (IIIf)A₂₆+Act(O)C—O—Y—ONO₂→(VIIIab)  (IIIf)wherein Act and Y are as above defined, using the same procedure described, in 3b).
• 109. The compounds of general formula (I) wherein:
• s is equal to 1;
• s′, s″, m, m′ and m″ are equal to 0;
• Y is as above defined;
• A is selected from (IIa), (IIc) and (IIt) wherein R₁ is —H; R₂ is —COOH;
• R_a of formula (IIa) and R_c of formula (IIc) are R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, or R_iNH(═NH)NH—(CH₂)₃—, wherein R_h and R_i are R_hh—C(O)— or R_ii—C(O)—, and bind a group —Y—ONO₂;
• in formula (IIt) d is 2 d′ is 1, R_t is —C(O)—R_tt, and binds a group —Y—ONO₂;can be obtained as follows:
• 109a) by reacting a compound of formula (I) wherein s, s′, s″, m, m′, m″, Y, Y′, Y″ are as above defined in 109., A is a radical of (IIa), (IIc) or (IIt) wherein R₂, R_a, R_c, d, d′ and R_t are as defined in 109., R₁ is —C(O)OC(CH₃)₃;
• with anhydrous or aqueous organic or inorganic acid to hydrolyze the —BOC protective groups following procedure well known in the literature.
• 109b) by reacting a compound of formula A with a compound of formula (IIIe)A+Act(O)C—Y—ONO₂  (IIIe)wherein Act and Y are as above defined and A is a radical of (IIa), (IIc) or (IIt) wherein R₁ is —C(O)OC(CH₃)₃; R₂ is —COOH;
• R_a of formula (IIa) and R_c of formula (IIc) are R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, or R_iNH(═NH)NH—(CH₂)₃—, wherein R_h and R_i are —H;
• in formula (IIt) d and d′ are as defined in 109., R_t is —H;using the same procedure described in 1b′).Compounds A are commercially available.
• 110. The compounds of general formula (I) wherein:
• s is equal to 1;
• s′, s″, m, m′ and m″ are equal to 0;
• Y is as above defined;
• A is selected from (IIa), (IIc) and (IIt) wherein R₁ is —H, R₂ is —COOH;
• R_a of formula (IIa) and R_c of formula (IIc) are R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, or R_iNH(═NH)NH—(CH₂)₃—, wherein R_h and R_i are R_hh—OC(O)— or R_ii—OC(O)—, and bind a group —Y—ONO₂;
• in formula (IIt) d is 2 d′ is 1, R_t is —C(O)O—R_tt, and it binds a group —Y—ONO₂;can be obtained as follows:
• 110a) by reacting a compound of formula (I) wherein s, s′, s″, m, m′, m″, Y, Y′, Y″ are as above defined in 110., A is a radical of (IIa), (IIc) or (IIt) wherein R₂, R_a, R_c, d, d′ and R_t are as defined in 110., R₁ is —C(O)OC(CH₃)₃;
• with anhydrous or aqueous organic or inorganic acid to hydrolyze the —BOC protective groups following procedure well known in the literature.
• 110b) by reacting a compound of formula A with a compound of formula (IIIf)A+Act(O)C—O—Y—ONO₂  (IIIf)wherein Act and Y are as above defined and A is as defined in 109b), using the same procedure described in 3b).
• 111. The compounds of general formula (I) wherein:
• s, s′ and m′ are equal to 1;
• s″, m, m″, are equal to 0;
• Y and Y′ are equal or different and are as above defined;
• B is:

• A is selected among:
• i) (IIa) wherein R₁ is —H, R₂ is —C(O)OR_2x and R₂ binds a group B—Y—ONO₂; R₁ is selected from R_bx—C(O)—S—CH₂—, or R_xO—CH₂—, R_xO—CH(CH₃)—, (R_xO)-p-C₆H₄—CH₂—, 4-(R_xO)-3,5-diiodobenzyl-4-(R_xO)-3-nitrobenzyl- wherein R_x is R_xx—C(O)— and R_a binds a group —Y—ONO₂;
• ii) (IIc) wherein R₁ is —H, R₂ is —C(O)OR_2x and R₂ binds a group B—Y′—ONO₂; R_c is selected from R_bx—C(O)—S—CH₂—, or R_xO—CH₂—, R_xO—CH(CH₃)—, (R_xO)-p-C₆H₄—CH₂—, 4-(R_xO)-3,5-diiodobenzyl-4-(R_xO)-3-nitrobenzyl- wherein R_x is R_xx—C(O)— and R_c binds a group —Y—ONO₂;iii) (IIs) wherein R₁ is —H, R₃ is —OC(O)R_3x and R₃ binds a group —Y—ONO₂; R_s is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is R_gx—O—, and R_s binds a group B—Y′—ONO₂;
• v) (IIn), wherein R₁ is —H, R₂ is —C(O)OR_2x, R₂ binds a group B—Y′—ONO₂; a is 1, b is 0 or 1; R_x is R_xx—C(O)— and R_x binds a group —Y—ONO₂;can be prepared as follows:
• 111a) by reacting a compound of formula (I) wherein B, s, s′, s″, m, m′, m″, Y, Y′, Y″ are as above defined in 111., A is a radical, of formula (IIa), (IIc), (IIs) or (IIu) wherein; R₂, R₃, a, b, R_a, R_c, R_g and R_x, are as defined in 111.; R₁ is —C(O)OC(CH₃)₃, with anhydrous or aqueous organic or inorganic acid to hydrolyze the —BOC protective groups following procedure well known in the literature.
• 111b) by reacting a compound of formula (I) obtained in 36b) with a compound of formula (IIIg) or (IIIn) depending on the meaning of B

wherein Y and Y′, Hal, W₁ are as above defined and in formula (I) A is selected among:

• i) (IIa) wherein R₁ is —C(O)OC(CH₃)₃, R₂ is —COOH, R_a is selected from R_bx—C(O)—S—CH₂—, or R_xO—CH₂—, R_xO—CH(CH₃)—, (R_xO)-p-C₆H₄—CH₂—, 4-(R_xO)-3,5-diiodobenzyl-4-(R_xO)-3-nitrobenzyl- wherein R_x is R_xx—C(O)— and R_a binds a group —Y—ONO₂;
• ii) (IIc) wherein R₁ is —C(O)OC(CH₃)₃, R₂ is —COOH, R_c is selected from R_bx—C(O)—S—CH₂, or R_xO—CH₂—, R_xO—CH(CH₃)—, (R_xO)-p-C₆H₄—CH₂—, 4-(R_xO)-3,5-diiodobenzyl-4-(R_xO)-3-nitrobenzyl- wherein R_x is R_xx—C(O)— and R_c binds a group —Y—ONO₂;
• iii) (IIs) wherein R₁ is —C(O)OC(CH₃)₃, R₃ is —OC(O)R_3x and R₃ binds a group —Y—ONO₂; R_s is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is —OH,
• v) (IIu) wherein R₁ is —C(O)OC(CH₃)₃, R₂ is —COOH, a is 1, b is 0 or 1; and R_x is R_xx—C(O)— and R_x binds a group —Y′—ONO₂;following the same procedures described in 4b) or 6b).
• 112. The compounds of general formula (I) wherein:
• s, s′ and m′ are equal to 1;
• s″, m, m″, are 0
• Y and Y′ are equal or different and are as above defined;
• B is

• A is selected among:
• i) (IIa) wherein R₁ is —H, R₂ is —C(O)OR_2x and R₂ binds a group B—Y′—ONO₂; and R_a is selected from R_bx—OC(O)—S—CH₂, or R_xO—CH₂—, R_xO—CH(CH₃)—, (R_xO)-p-C₆H₄—CH₂—, 4-(R_xO)-3,5-diiodobenzyl-4-(R_xO)-3-nitrobenzyl- wherein R_x is R_xx—OC(O)— and R_a binds a group —Y—ONO₂;
• ii) (IIc) wherein R₁ is —H, R₂ is —C(O)OR_2x and R₂ binds a group B—Y′—ONO₂; R_c is selected from R_bx—OC(O)—S—CH₂, or R_xO—CH₂—, R_xO—CH(CH₃)—, (R_xO)-p-C₆H₄—CH₂—, 4-(R_xO)-3,5-diiodobenzyl-4-(R_xO)-3-nitrobenzyl- wherein R_x is R_xx—OC(O)— and R_c binds a group —Y—ONO₂;
• iii) (IIs) wherein R₁ is —H, R₃ is —OC(O)O—R_3x and R₃ binds a group —Y—ONO₂; R_s is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is R_gx—O—, and R_s binds a group B—Y′—ONO₂;
• v) wherein R₁ is —H, R₂ is —C(O)OR_2x, R₂ binds a group —B—Y′—ONO₂; a is 1; b is 0 or 1; R_x is R_xx—OC(O)— and R_x binds a group —Y—ONO₂;can be prepared as follows:
• 112a) by reacting a compound of formula (I) wherein B, s, s′, s″, m, m′, m″, Y, Y′, Y″ are as above defined in 112., A is a radical of formula (IIa), (IIc), (IIs) or (IIu) wherein; R₂, R₃, a, b, R_a, R_c, R_g and R_x, are as defined in 112.; R₁ is —C(O)OC(CH₃)₃ with anhydrous or aqueous organic or inorganic acid to hydrolyze the —BOC protective groups following procedure well known in the literature.
• 112b) by reacting a compound of formula (I) obtained in 37b) with a compound of formula (IIIg) or (IIIn) depending on the meaning of B

wherein Y and Y′, Hal, W₁ are as above defined and in formula (I) A is as above defined in 111b);following the same procedures described in 4b) or 6b).

• 113. The compounds of general formula (I) wherein:
• s, s′ and m′ are equal to 1;
• s″, m, m″, are 0
• Y and Y′ are equal or different and are as above defined;
• B is:

• A is selected among:
• i) (IIa) wherein R₁ is —H, R₂ is —C(O)OR_2x and R₂ binds a group B—Y′—ONO₂; and R_a is selected from R_bx—NH(O)C—S—CH₂, or R_xO—CH₂—, R_xO—CH(CH₃)—, (R_xO)-p-C₆H₄—CH₂—, 4-(R_xO)-3,5-diiodobenzyl-4-(R_xO)-3-nitrobenzyl- wherein R_x is R_xxNH(O)C— and R_c binds a group —Y—ONO₂;
• ii) (IIc) wherein R₁ is —H, R₂ is —C(O)OR_2x and R₂ binds a group B—Y′—ONO₂; R_c is selected from R_bx—NH(O)C—S—CH₂, or R_xO—CH₂—, R_xO—CH(CH₃)—, (R_xO)-p-C₆H₄—CH₂—, 4-(R_xO)-3,5-diiodobenzyl-4-(R_xO)-3-nitrobenzyl- wherein R_x is R_xxNH(O)C— and R_c binds a group —Y—ONO₂;
• iii) (IIs) wherein R₁ is —H, R₃ is —OC(O)—NH—R_3x and R₃ binds a group —Y—ONO₂; R₃ is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is R_gx—O—, and R_g binds a group B—Y′—ONO₂;
• v) (IIu) wherein R₁ is —H, R₂ is —C(O)OR_2x, and R₂ binds a group B—Y′—ONO₂; a is 1; b is 0 or 1; R_x is R_xxNHC(O)— and R_x binds a group —Y—ONO₂;can be prepared as follows:
• 113a) by reacting a compound of formula (I) wherein B, s, s′, s″, m, m′, m″, Y, Y′, Y″ are as above defined in 113., A is a radical of formula (IIa), (IIc), (IIs) or (IIu) wherein; R₂, R₃, a, b, R_a, R_c, R_g and R_x, are as defined in 113.; R₁ is —C(O)OC(CH₃)₃ with anhydrous or aqueous organic or inorganic acid to hydrolyze the —BOC protective groups following procedure well known in the literature.
• 113b) by reacting a compound of formula (I) obtained in 38b) with a compound of formula (IIIg) or (IIIn) depending on the meaning of B

wherein Y and Y′, Hal, W₁ are as above defined and in formula (I)

• A is as above defined in 111b);following the same procedures described in 4b) or 6b).
• 114. The compounds of general formula (I) wherein:
• s is equal to 1;
• m, m′, m″, s′ and s″ are 0
• Y is as above defined;
• A is a radical of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein R₁ is —C(O)—R_1x and it binds the group —Y—ONO₂, R₂ is equal to the group R₄

• in formula (IIn) R_n is —C(O)—R_nx, or is —(CH₂)₂—NH—R_h wherein R_h is —C(O)R_hh and it binds the group —Y—ONO₂
• R_a of formula (IIa) is selected in group a)
• R_c of formula (IIc) is selected in group a′)
• in formula (IIt) d is an integer from 3 to 5, d′ is 0;
• can be prepared as follows
• 114a) by reacting a compound of formula A with a compound of formula (IIIa) or a compound of formula (IIIe)A+HOOC—Y—ONO₂  (IIIa)A+Act-CO—Y—ONO₂  (IIIe)wherein Y is as above defined and A is selected from (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein R₁ is —H and R₂ is as above defined in 114.;
• in formula (IIn) R_n is H, or is —(CH₂)₂—NH—R_h wherein R_h is H;
• R_a of formula (IIa) is selected in group a);
• R_c of formula (IIc) is selected in group a′);
• in formula (IIt) d and d′ are as above defined;following the same procedure described in 1b) or 1b′).
• 114b) compounds A as above defined can be prepared by reacting commercially available compounds of formula A₂ described in 1c) wherein A₂ is a radical of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein R₂—COOH or R_2a wherein R_2a is the group —COAct as already described in 8., R₁ is —C(O)OC(CH₃)₃, R_n is —C(O)OC(CH₃)₃ or is —(CH₂)₂—NH—C(O)OC(CH₃)₃, R_a, R_c, d and d′ are as defined in 114., with compounds (IIIx) or (IIIy):

• In case of (IIIx): 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 100° C.;
• In case of (IIIy) following the same procedure described in 8b) for R₂ equal to —COOH or equal to R_2a wherein R_2a is the group —COAct. Compound (IIIx) is commercially available. Compound (IIIy) can be obtained from (IIIx) by first reacting with formic acid and TEA in acetonitrile and then hydrolyzing the formyl ester with hydrochloric acid in methanol/water at room temperature, as described for analogous compounds by Alexander in J. Med. Chem. 1996, 39, 480-486.
• 115. The compounds of general formula (I) wherein:
• s is equal to 1;
• m, m′, m″, s′ and s″ are 0
• Y is as above defined,
• A is a radical of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein R₁ is —C(O)O—R_1x and it binds the group —Y—ONO₂, R₂ is equal to R₄, wherein R₄ is as defined in 114.;
• in formula (IIn) R_n is —C(O)O—R_nx or —(CH₂)₂—NH—R_h wherein R_h is —C(O)O—R_hh, and it binds the group —Y—ONO₂
• R_a of formula (IIa) is selected in group a)
• R_c of formula (IIc) is selected in group a′)
• in formula (IIt) d is an integer from 3 to 5, d′ is 0;can be prepared as follows
• 115a) by reacting a compound of formula A with a compound of formula (IIIf)A+Act-(O)C—O—Y—ONO₂  (IIIf)wherein A is as above reported in 114a), Act and Y are as already defined, following the same procedure described in 3b).
• 116. The compounds of general formula (I) wherein:
• s is equal to 1;
• s′, s″, m, m′, m″, are 0
• Y is as above defined;
• A is selected among:
• (IIa) wherein R₁ is —H, R₂ is —C(O)OR_2x and R₂ binds a group —Y—ONO₂; R_a is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is equal to R_gg and is equal to:

• (IIc) wherein R₁ is —H, R₂ is equal to —C(O)OR_2x and R₂ binds a group —Y—ONO₂; R_c is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is equal to R_gg and is as above defined can be prepared as follows:
• 116a) by reacting a compound of formula (VIIIa)A_28a-Y—ONO₂  (IXa)wherein Y is as above defined and A_28a is a radical of formula (IIa), (IIc), wherein R₂ is as above defined in 116.; R₁ is R_1a and is the Fmoc group; R_a and R_c are R_ggC(O)CH₂—NH—, R_ggC(O)CH₂, R_ggC(O)(CH₂)₂—, R_ggC(O)(CH₂)₄—, wherein R_gg is as above defined by known procedure to remove the —Fmoc protective groups;
• 116b) by reacting a compound of formula A₂₈ with a compound of formula (IIIi)A₂₈+HO—Y—ONO₂  (IIIi)wherein Y is as above defined and R₂₈ is a compound of formula (IIa) or (IIc) wherein R₁ is R_1a and is the Fmoc group; R₂ is —COOH, R_a and R_c are selected from R_ggC(O)CH₂—NH—, R_ggC(O)CH₂, R_ggC(O)(CH₂)₂—, R_ggC(O)(CH₂)₄—, wherein R_gg is as above defined in 116.;following the same procedure described in 8b).
• 116c) by reacting a compound A₂₉ A₂₉→A₂₈ wherein R₁ is R_1a is the Fmoc group; R₂ is —C(O)OC(CH₃)₃; R_a and R_c are selected from R_ggC(O)CH₂—NH—, R_ggC(O)CH₂, R_ggC(O)(CH₂)₂—, R_ggC(O)(CH₂)₄—, wherein R_gg is as above defined in 116 with anhydrous or aqueous organic or inorganic acid, as well known in the literature to remove the t-butyl ester.
• 116d) by reacting a compound A₃₀ A₃₀→A₂₉ wherein R₁ is R_1a and is the Fmoc group; R₂ is —C(O)OC(CH₃)₃; R_a and R_c are selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is —OH with compounds (IIIx) or (IIIy) as described in 114b). Compounds A₃₀ are commercially available.
• 117. The compounds of general formula (I) wherein:
• s is equal to 1;
• s′, s″, m, m′, m″, are 0
• Y is as above defined;
• R is a radical of formula
• (IIa) wherein R₁ is —H, R₂ is —C(O)NHR_2xx or —C(O)N(CH₃)R_2xx and R₂ binds a group —Y—ONO₂; R_a is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is R_gg and is as defined in 116.; or
• (IIc) wherein R₁ is —H, R₂ is —C(O)NHR_2xx or —C(O)N(CH₃)R_2xx and R₂ binds a group —Y—ONO₂; R_c is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is R_gg and is as defined in 116.; can be prepared as follows:
• 117a) by reacting a compound of formula (IXb)A₃₁-Y—ONO₂  (IXb)wherein Y is as above defined and A₃₁ is a radical of formula (IIa), (IIc), wherein R₂ is as above defined in 117.; R₁ is R_1a and is the Fmoc group; R_a and R_c are R_ggC(O)CH₂—NH—, R_ggC(O)CH₂, R_ggC(O)(CH₂)₂—, R_ggC(O)(CH₂)₄—, wherein R_gg is as above defined by known procedure to remove the —Fmoc protective groups;
• 117b) by reacting a compound of formula A₂₈ with a compound of formula (IIIo)A₂₈+W₃NH—Y—ONO₂→(IXb)  (IIIo)wherein Y is as above defined, W₃ is as above defined and A₂₈ is as defined in 116b),following the same procedure described in 7b).
• 118. The compounds, of general formula (I) wherein:
• s and m are equal to 1;
• s′, s″, m′, m″, are 0
• Y is as above defined;
• B is:

• A is a radical selected among:
• (IIa) wherein R₁ is —H, R₂ is —C(O)OR_2x and R₂ binds a group —B—Y—ONO₂; R_a is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is R_gg and is as defined in 116.,
• (IIc) wherein R₁ is —H, R₂ is —C(O)OR_2x and R₂ binds a group —B—Y—ONO₂; R_c is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is R_gg and is as defined in 116.; can be prepared as follows:
• 118a) by reacting a compound of formula (VIIIc)A_28a-B—Y—ONO₂  (IXc)wherein B and Y are as above defined and A_28a is as defined in 116a) a radical of formula (IIa), (IIc), wherein R₂ is as above defined in 118.; R₁ is R_1a the Fmoc group; R_a and R_c are R_ggC(O)CH₂—NH—, R_ggC(O)CH₂, R_ggC(O)(CH₂)₂—, R_ggC(O)(CH₂)₄—, wherein R_gg is as above defined by known procedure to remove the —Fmoc protective groups;
• 118b) compound (IXc) are prepared by reacting a compound of formula A₂₈ with a compound of formula (IIIg) or (IIIn) depending on the meaning of BA₂₈+Hal-W₁—OC(O)O—Y—ONO₂  (IIIg)A₂₈+Hal-W₁—OC(O)—Y—ONO₂  (IIIn)wherein Y, Hal, W₁ are as above defined and A₂₈ is as defined in 116b),following the same procedures described in 4b) or 6b).
• 119. The compounds of general formula (I) wherein:
• s is equal to 1;
• s′, s″, m, m′, m″, are 0
• Y is as above defined;
• A is selected among:
• (IIa) wherein R₁ is —H, R₂ is equal to R₄ and is as defined in 114.; R_a is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is R_gx—O—, and R_g binds a group —Y—ONO₂;
• (IIc) wherein R₁ is —H, R₂ is equal to R₄ and is as defined in 114.; R_a is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is R_gx—O—, and R_g binds a group —Y—ONO₂, can be prepared as follows:
• 119a) by reacting a compound of formula (Xa)A₃₂-Y—ONO₂  (Xa)wherein Y is as above defined and A₃₂ is a radical of formula (IIa), (IIc), wherein R_a and R_c are as above defined in 119.; R₁ is —R_1a and is the Fmoc group; R₂ is R₄ and is as defined in 114.;following procedure well known in the literature to remove the Fmoc group.
• 119b) by reacting a compound of formula A₃₃ with a compound of formula (IIIi)A₃₃+HO—Y—ONO₂→(Xa)  (IIIi)wherein Y is as above defined and A₃₃ is a radical of formula (IIa), (IIc) wherein R₁ is —R_1a and is the Fmoc group; R₂ is R₄ and is as defined in 114.; R_a and R_c are selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_c is —OH;following the same procedure described in 8b).
• 119c) by reacting a compound A₃₄ A₃₄→A₃₃ wherein R₁ is R_1a and is the Fmoc group; R₂ is R₄; R_a and R_c are selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is —C(O)OC(CH₃)₃ with anhydrous or aqueous organic or inorganic acid as well known in the literature to remove the t-butyl ester.
• 119d) by reacting a compound A₃₅ A₃₅→A₃₄ wherein R₁ is R_1a and is the Fmoc group; R₂ is —COOH; R_a and R_c are selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is —C(O)OC(CH₃)₃ with compounds (IIIx) or (IIIy) as described in 114b). Compounds A₃₅ are commercially available.
• 120. The compounds of general formula (I) wherein:
• s is equal to 1;
• s′, s″, m, m′, m″, are 0
• Y is as above defined;
• A is selected among:
• (IIa) wherein R₁ is —H, R₂ is R₄ and is as defined in 114.; R_a is selected R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is R_gxx—NH— or R_gxx—N(CH₃)— and R_g binds a group —Y—ONO₂;
• (IIc) wherein R₁ is —H, R₂ is R₄ and is as defined in 114.; R_c is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is R_gxx—NH— or R_gxx—N(CH₃)— and R_g binds a group —Y—ONO₂;can be prepared as follows:
• 120a) by reacting a compound of formula (Xb)A₃₆-Y—ONO₂  (Xb)wherein Y is as above defined and A₃₆ is a radical of formula (IIa), (IIc), wherein R_a and R_c are as above defined in 120.; R₁ is R_1a and is the Fmoc group; R₂ is R₄ and is as defined in 114.; following procedure well known in the literature to remove the Fmoc group.
• 120b) by reacting a compound of formula A₃₃ with a compound of formula (IIIo):A₃₃+W₃NH—Y—ONO₂→(Xb)  (IIIo)wherein Y and W₃ are as above defined and A₃₃ is as defined in 119b) following the same procedure described in 7b).
• 121. The compounds of general formula (I) wherein:
• s and m are equal to 1;
• s′, s″, m′, m″, are 0
• Y is as above defined;
• B is:

• A is selected among:
• (IIa) wherein R₁ is —H, R₂ is R₄ and is as defined in 114.; R_a is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is R_gx—O— and R_g binds a group —B—Y—ONO₂;
• (IIc) wherein R₁ is —H, and R₂ is R₄ as defined in 114.; R_c is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is R_gx—O—, and R_g binds a group —B—Y—ONO₂;can be prepared as follows:
• 121a) by reacting a compound of formula (Xc)A₃₇-B—Y ONO₂  (Xc)wherein B and Y are as above defined and A₃₇ is a radical of formula (IIa), (IIc), wherein R_a and R_c are as above defined in 121.; R₁ is R_1a and is the Fmoc group; R₂ is R₄ and is as defined in 114.,following procedure well known in the literature to remove the Fmoc group.
• 121b) compounds (Xc) are prepared by reacting a compound of formula A₃₃ with a compound of formula of formula (IIIg) or (IIIn) depending on the meaning of BA₃₃+Hal-W₁—OC(O)O—Y—ONO₂  (IIIg)A₃₃+Hal-W₁—OC(O)—Y—ONO₂  (IIIn)wherein Y, Hal, W₁ are as above defined and A₃ is as defined in 119b),following the same procedures described in 4b) or 6b).
• 122. The compounds of general formula (I) wherein:
• s and s′ are equal to 1;
• s″, m, m′, m″, are 0
• Y and Y′ can be equal or different and are as above defined;
• A is selected among:
• (IIa) wherein R₁ is —C(O)—R_1x and binds a group —Y′—ONO₂; R₂ is —C(O)OR_2x and binds a group —Y—ONO₂; R_a is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is equal to R_gg and is as defined in 116.,
• (IIc) wherein R₁ is —C(O)—R_1x and binds a group —Y′—ONO₂; R₂ is —C(O)OR_2x and binds a group —Y—ONO₂; R_c is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is equal to R_gg and is as defined in 116.; can be prepared as follows:
• 122a) by reacting a compound of formula (I) prepared as described in 116. with a compound of formula (IIIe):

wherein Act, Y and Y′ are as above defined and A is a radical of formula (IIa), (IIc), wherein R₁ is —H, R₂ is —C(O)OR_2x and binds a group —Y—ONO₂; R_a and R_c are selected from R_ggC(O)CH₂—NH—, R_ggC(O)CH₂, R_ggC(O)(CH₂)₂—, R_ggC(O)(CH₂)₄—, wherein R_gg is as above defined;following the same procedures described in 1b′).

• 123. The compounds of general formula (I) wherein:
• s and s′ are equal to 1;
• s″, m, m′, m″, are 0
• Y and Y′ can be equal or different and are as above defined;
• A is selected among:
• (IIa) wherein R₁ is —C(O)O—R_1x and binds a group —Y′—ONO₂; R₂ is —C(O)OR_2x and binds a group —Y—ONO₂; R_a is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is equal to R_gg and is as defined in 116.,
• (IIc) wherein R₁ is —C(O)O—R_1x and binds a group —Y′—ONO₂; R₂ is —C(O)OR_2x and binds a group —Y—ONO₂; R_c is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is equal to R_gg and is as defined in 116.; can be prepared as follows:
• 123a) by reacting a compound of formula (I) prepared as described in 116. with a compound of formula (IIIf):

wherein Act, Y and Y′ are as above defined and A is as defined in 122a);

• following the same procedures described in 3b).
• 124. The compounds of general formula (I) wherein:
• s and s′ are equal to 1;
• s″, m, m′, m″, are 0
• Y and Y′ can be equal or different and are as above defined;
• A is selected among:
• (IIa) wherein R₁ is —C(O)—R_1x and binds a group —Y′—ONO₂; R₂ is —C(O)NHR_2xx or —C(O)N(CH₃)R_2xx and binds a group —Y—ONO₂; R_a is selected R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is equal to R_gg and is as defined in 116.,
• (IIc) wherein R₁ is —C(O)—R_1x and binds a group —Y′—ONO₂; R₂ is —C(O)NHR_2xx or —C(O)N(CH₃)R_2xx and binds a group —Y—ONO₂; R_c is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is equal to R_gg and is as defined in 116.; can be prepared as follows:
• 124a) by reacting a compound of formula (I) prepared as described in 117. with a compound of formula (IIIe):

wherein Act, Y and Y′ are as above defined and A is a radical of formula (IIa), (IIc), wherein R₁ is —H, R₂ is —C(O)NHR_2xx or —C(O)NCH₃R_2xx binds a group —Y—ONO₂; R_a and R_c are selected from R_ggC(O)CH₂—NH—, R_ggC(O)CH₂, R_ggC(O)(CH₂)₂—, R_ggC(O)(CH₂)₄—, wherein R_gg is as above defined;following the same procedures described in 1b′).

• 125. The compounds of general formula (I) wherein:
• s and s′ are equal to 1;
• s″, m, m′, m″, are 0
• Y and Y′ can be equal or different and are as above defined;
• A is selected among:
• (IIa) wherein R_a is —C(O)O—R_1x and binds a group —Y′—ONO₂; R₂ is —C(O)NHR_2xx or —C(O)N(CH₃)R_2xx and binds a group —Y—ONO₂; R_a is selected R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is equal to R_gg and is as defined in 116.,
• (IIc) wherein R₁ is —C(O)O—R_1x and binds a group —Y′—ONO₂; R₂ is —C(O)NHR_2xx or —C(O)N(CH₃)R_2xx and binds a group —Y—ONO₂; R_c is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is equal to R_gg and is as defined in 116.; can be prepared as follows:
• 125a) by reacting a compound of formula (I) prepared as described in 117. with a compound of formula (IIIf):

wherein Act, Y and Y′ are as above defined and A is as above defined in 124a), following the same procedures described in 3b).

• 126. The compounds of general formula (I) wherein:
• s, s′ and m are equal to 1;
• s″, m′, m″, are 0
• Y and Y′ can be equal or different and are as above defined;
• B is:

• A is selected among:
• (IIa) wherein R₁ is —C(O)—R_1x and binds a group —Y′—ONO₂; R₂ is —C(O)OR_2x and binds a group —B—Y—ONO₂; R_a is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is equal to R_gg and is as defined in 116.;
• (IIc) wherein R₁ is —C(O)—R_1x and binds a group —Y′—ONO₂; R₂ is —C(O)OR_2x and binds a group —B—Y—ONO₂; R_c is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is equal to R_gg and is as defined in 116.;can be prepared as follows.
• 126a) by reacting a compound of formula (I) prepared as described in 118. with a compound of formula (IIIe):

wherein Act, B, Y and Y′ are as above defined and A is a radical of formula (IIa), (IIc), wherein R₁ is —H, R₂ is —C(O)OR_2x and binds a group B—Y—ONO₂; R_a and R_c are selected from R_ggC(O)CH₂—NH—, R_ggC(O)CH₂, R_ggC(O)(CH₂)₂—, R_ggC(O)(CH₂)₄—, wherein R_gg is as above defined;following the same procedures described in 1b′).

• 127. The compounds of general formula (I) wherein:
• s, s′ and m are equal to 1;
• s″, m′, m″, are 0
• Y and Y′ can be equal or different and are as above defined;
• B is:

• A is selected among:
• (IIa) wherein R₁ is —C(O)O—R_1x and binds a group —Y′—ONO₂; R₂ is —C(O)OR_2x and binds a group —B—Y—ONO₂; R_a is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is equal to R_gg and is as defined in 116.;
• (IIc) wherein R₁ is —C(O)O—R_1x and binds a group —Y′—ONO₂; R₂ is —C(O)OR_2x and binds a group —B—Y—ONO₂; R_c is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is equal to R_gg and is as defined in 116.; can be prepared as follows:
• 127a) by reacting a compound of formula (I) prepared as described in 118. with a compound of formula (IIIf):

wherein Act, B, Y and Y′ are as above defined and A is as defined in 126a), following the same procedures described in 3b).

• 128. The compounds of general formula (I) wherein:
• s and s′ are equal to 1;
• s″, m, m′, m″, are 0
• Y and Y′ can be equal or different and are as above defined;
• A is selected among:
• (IIa) wherein R₁ is —C(O)—R_1x and it binds a group —Y′—ONO₂; R₂ is equal to R₄ and is as defined in 114.; R_a is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is R_gx—O—, and binds a group —Y—ONO₂
• (IIc) wherein R₁ is —C(O)—R_1x and binds a group —Y′—ONO₂; R₂ is equal to R₄ and is as defined in 114.; R_c is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is R_gx—O— and binds a group —Y′—ONO₂;can be prepared as follows:
• 128a) by reacting a compound of formula (I) prepared as described in 119. with a compound of formula (IIIe):

wherein Act, Y and Y′ are as above defined and A is a radical of formula (IIa), (IIc), wherein R₁ is —H, R₂ is equal to R₄; R_a and R_c are selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is R_gx—O—, and binds a group —Y′—ONO₂ following the same procedures described in 1b′).

• 129. The compounds of general formula (I) wherein:
• s and s′ are equal to 1;
• s″, m, m′, m″, are 0
• Y and Y′ can be equal or different and are as above defined;
• A is selected among:
• (IIa) wherein R₁ is —C(O)O—R_1x and it binds a group —Y′—ONO₂; R₂ is equal to R₄ and is as defined in 114.; R_a is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is R_gx—O—, and binds a group —Y—ONO₂;
• (IIc) wherein R₁ is —C(O)O—R_1x and binds a group —Y′—ONO₂; R₂ is equal to R₄ and is as defined in 114.; R_c is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is R_gx—O—, and binds a group —Y—ONO₂;can be prepared as follows:
• 129a) by reacting a compound of formula (I) prepared as described in 119. with a compound of formula (IIIf):

wherein Act, Y and Y′ are as above defined and A is a radical of formula (IIa), (IIc), wherein R₁ is —H, R₂ is equal to R₄; R_a and R_c are selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is R_gxO— and binds a group —Y—ONO₂, following the same procedures described in 3b).

• 130. The compounds of general formula (I) wherein:
• s and s′ are equal to 1;
• s″, m, m′, m″, are 0
• Y and Y′ can be equal or different and are as above defined;
• A is selected among:
• (IIa) wherein R₁ is —C(O)—R_1x and it binds a group —Y′—ONO₂; R₂ is equal to R₄ and is as defined in 114.; R_a is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is R_gxx—NH— or R_gxx—N(CH₃)— binds R_a binds a group —Y—ONO₂
• (IIc) wherein R₁ is —C(O)—R_1x and it binds a group —Y′—ONO₂; R₂ is equal to R₄ and is as defined in 114.; R_c is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is R_gxx—NH— or R_gxx—N(CH₃)— and R_c binds a group —Y—ONO₂;can be prepared as follows:
• 130a) be reacting a compound of formula (I) prepared as described in 120. with a compound of formula (IIIe):

wherein Act, Y and Y′ are as above defined and A is a radical of formula (IIa), (IIc), wherein R₁ is —H, R₂ is -equal to R₄; R_a and R_c are selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is R_gxx—NH— or R_gxx—N(CH₃)— and binds a group —Y—ONO₂ following the same procedures described in 1b′).

• 131. The compounds of general formula (I) wherein:
• s and s′ are equal to 1;
• s″, m, m′, m″, are 0
• Y and Y′ can be equal or different and are as above defined;
• A is selected among:
• (IIa) wherein R₁ is —C(O)O—R_1x and binds a group —Y′—ONO₂; R₂ is equal to R₄ and is as defined in 114.; R_a is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is R_gxx—NH— or R_gxx—N(CH₃)— and binds a group —Y—ONO₂
• (IIc) wherein R₁ is —C(O)O—R_1x binds a group —Y′—ONO₂; R₂ is is -equal to R₄ and is as defined in 114.; R_c is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is R_gxx—NH— or R_gxx—N(CH₃)— and binds a group —Y—ONO₂;can be prepared as follows:
• 131a) by reacting a compound of formula (I) prepared as described in 120. with a compound of formula (IIIf):

wherein Act, Y and Y′ are as above defined and A is as defined in 130a), following the same procedures described in 3b).

• 132. The compounds of general formula (I) wherein:
• s, s′ and m are equal to 1;
• s″, m′, m″, are 0
• Y and Y′ can be equal or different and are as above defined;
• B is:

• A is selected among:
• (IIa) wherein R₁ is —C(O)—R_1x and binds a group —Y′—ONO₂; R₂ is equal to R₄ and is as defined in 114.; R_a is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is R_gxO—, and binds a group —B—Y—ONO₂;
• (IIc) wherein R₁ is —C(O)—R_1x and binds a group —Y′—ONO₂; R₂ is -equal to R₄ and is as defined in 114.; R_c is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is R_gxO—, and binds a group —B—Y—ONO₂;can be prepared as follows:
• 132a) by reacting a compound of formula (I) prepared as described in 121. with a compound of formula (IIIe):

wherein Act, B, Y and Y′ are as above defined and A is a radical of formula (IIa), (IIc), wherein R₁ is —H, R₂ is equal R₄; R_a and R_c are selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is R_gxO— and binds a group B—Y—ONO₂;following the same procedures described in 1b′).

• 133. The compounds of general formula (I), wherein:
• s, s′ and m are equal to 1;
• s″, m′, m″, are 0
• Y and Y′ can be equal or different and are as above defined;
• B is:

• A is selected among:
• (IIa) wherein R₁ is —C(O)O—R_1x and binds a group —Y′—ONO₂; R₂ is equal to R₄ and is as defined in 114.; R_a is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is R_gxO—, and binds a group —B—Y—ONO₂;
• (IIc) wherein R₁ is —C(O)O—R_1x and it binds a group —Y′—ONO₂; R₂ is equal to R₄ and is as defined in 114.; R_c is selected from R_gC(O)CH₂—NH—, R_gC(O)CH₂, R_gC(O)(CH₂)₂—, R_gC(O)(CH₂)₄—, wherein R_g is R_gxO— and R_g binds a group —B—Y—ONO₂;can be prepared as follows:
• 133a) by reacting a compound of formula (I) prepared as described in 121. with a compound of formula (IIIf):

wherein Act, B, Y and Y′ are as above defined and A is as defined in 132a), following the same procedures described in 3b).

• 134. The compounds of general formula (I) wherein:
• s and s′ are equal to 1;
• s″, m, m′, m″ are equal to 0;
• Y and Y′ are equal and are as above defined;
• A is selected from (IIa), (IIc) or (IIt) wherein R₁ is —C(O)—R_1x and it binds a group —Y—ONO₂ or a group —Y′—ONO₂, R₂ is equal to R₄ and is as defined in 114.; R_a of formula (IIa) and R_c of formula (IIc) are R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, or R_iNH(═NH)NH—(CH₂)₃—, and R_h and R_i are R_hh—C(O)— or R_ii—C(O)— and R_a and R_c bind a group —Y—ONO₂ or a group —Y′—ONO₂;
• in formula (IIt) R₁ is —C(O)—R_1x and it binds a group —Y—ONO₂ or a group —Y′—ONO₂; R₂ is equal to R₄ and is as defined in 114.; d is 2 d′ is 1, R_t is —C(O)—R_tt and it binds a group —Y—ONO₂ or a group —Y′—ONO₂;can be prepared as follows:
• 134a) by reacting a compound of formula A with a compound of formula (IIIe)A+Act-(O)C—Y—ONO₂  (IIIe)wherein Act and Y are as above defined and A is a compound of formula (IIa), (IIc) or (IIt) wherein R₁ is —H and R₂ is equal to R₄;
• R₄ of formula (IIa) and R_c of formula (IIc) are R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, or R_iNH(═NH)NH—(CH₂)₃—, and R_h and R_i are —H;
• in formula (IIt) R₁ is —H, R₂ is R₄; d is 2 d′ is 1, R_t is —H; using a ratio A/(IIIe) 1:2 and applying the same procedure described in 1b′).
• 134b) by reacting a compound of formula A₃₈ A₃₈→Awherein A₃₈ is a compound of formula (IIa), (IIc) or (IIt) wherein R₁ is —C(O)OC(CH₃)₃ and R₂ is equal to R₄;
• R_a of formula (IIa) and R_c of formula (IIc) are R_hNH(CH₂)_p— wherein p is an integer from 0 to 4 and R_h is —C(O)OC(CH₃)₃; or R_iaNH(═NH)NH—(CH₂)₃—, wherein R_ia is the —Pbf group as already described;
• in formula (IIt) R₁ is —C(O)OC(CH₃)₃, is R₂ is R₄; d is 2 d′ is 1, R_t is —C(O)OC(CH₃)₃;with organic or inorganic acid as already described to hydrolize the —BOC protecting groups;
• 134c) by reacting commercially available compounds of formula A₃₉ with compounds (IIIx) or (IIIy) using the procedures described in 114b)A₃₉+(IIIx)→A₃₈ A₃₉+(IIIy)→A₃₈ wherein A₃₉ is a radical of formula (IIa), (IIc) or (IIt) wherein R₁ is —C(O)OC(CH₃)₃ and R₂ is equal to —COOH or R_2a wherein R_2a is as described in 8b); d is 2 d′ is 1, R_t is —C(O)OC(CH₃)₃; R_a of formula (IIa) and R_c of formula (IIc) are:
• R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, R_h is —C(O)OC(CH₃)₃;
• or R_iaNH(═NH)NH—(CH₂)₃— wherein R_ia is as previously defined.
• 135. The compounds of general formula (I) wherein:
• s and s′ are equal to 1;
• s″, m, m′, m″, are equal to 0;
• Y and Y′ are equal and are as above defined;
• A is a radical selected from (IIa), (IIc) and (IIt) wherein R₁ is —C(O)O—R_1x and binds a group —Y—ONO₂ or a group —Y′—ONO₂; R₂ is equal to R₄ and is as defined in 114.,
• R_a of formula (IIa) and R_c of formula (IIc) are R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, or R_iNH(═NH)NH—(CH₂)₃—, and R_h and R_i are R_hh—OC(O)— or R_ii—OC(O)— and R_a and R_c bind a group —Y—ONO₂ or a group —Y′—ONO₂;
• in formula (IIt) R₁ is —C(O)O—R_1x and binds a group —Y—ONO₂ or a group —Y′—ONO₂, R₂ is equal to R₄ and is as defined in 114.; d is 2 d′ is 1, R_t is —C(O)O—R_tt and binds a group —Y—ONO₂ or a group —Y′—ONO₂;can be prepared as follows:
• 135a) by reacting a compound of formula A with a compound of formula (IIIf)A+Act-(O)C—O—Y—ONO₂  (IIIf)wherein Act and Y are as above defined and A is as defined in 134a) using a ratio A/(IIIf) 1:2 and applying the same procedure described in 3b).
• 136. The compounds of general formula (I) wherein:
• s is equal to 1;
• s′, s″, m, m′, m″ are equal to 0;
• Y is as above defined;
• A is a radical of formula (IIa), (IIc) or (IIt) wherein R₁ is —C(O)—R_1x and binds a group —Y—ONO₂; R₂ is equal to R₄ and is as defined in 114.; R_a of formula (IIa) and R_c of formula (IIc) are R_hNH(CH₂)_p— wherein p is on integer from 0 to 4, or R_iNH(═NH)NH—(CH₂)₃—, wherein R_h and R_i are —H;
• in formula (IIt) d is 2 d′ is 1, R_t is —H;can be obtained as follows:
• 136a) R_a=R_c selected from R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, R_h is —Hby reacting a compound of formula (I) wherein s, s′, s″, m, m′, m″, Y, Y′, Y″ are as above defined in 136., A is a radical of (IIa), (IIc) or (IIt) wherein R₁, R₂, d, d′, are as defined in 136., R_a of formula (IIa) and R_c of formula (IIc) are selected from R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, R_h is —C(O)OC(CH₃)₃;
• in formula (IIt) R_t is —C(O)OC(CH₃)₃;
• with anhydrous or aqueous organic or inorganic acid to hydrolyze the —BOC protective groups following procedure well known in the literature.
• 136a′) R_a=R_c selected from R_iNH(═NH)NH—(CH₂)₃—, R_i is —H;reacting a compound of formula (Xd)A₄₀-Y—ONO₂  (Xd)wherein Y is as above defined and A₄₀ is a radical of formula (IIa), (IIc) wherein R₁ and R₂ are as defined in 136., R_a of formula (IIa) and R_c of formula (IIc) are selected from R_iaNH(═NH)NH—(CH₂)₃—, wherein R_ia is the —Pbf protective group as already defined;
• with anhydrous or aqueous organic or inorganic acid to hydrolyze the —Pbf protective groups following procedure well known in the literature.
• 136b) compounds described in 136a) and 136a′) are respectively obtained by reacting a compound of formula A₄₁ or a compound of formula A₄₂ with a compound of formula (IIIe)A₄₁+Act(O)C—Y′—ONO₂→(I)  (IIIe)A₄₂+Act(O)C—Y′—ONO₂→(Xd)  (IIIe)wherein Act and Y are as above defined and:
• A₄₁ is a compound of formula (IIa), (IIc) or (IIt) wherein R₁ is —H, R₂ is equal to R₄; R_a of formula (IIa) and R_c of formula (IIc) are R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, R_h is —C(O)OC(CH₃)₃; in formula (IIt) d and d′ are as defined, in 136.,
• R_t is —C(O)OC(CH₃)₃;
• A₄₂ is a compound of formula (IIa) or (IIc) wherein R₁ is —H, R₂ is equal to R₄; R_a of formula (IIa) and R_c of formula (IIc) are R_iaNH(═NH)NH—(CH₂)₃—, wherein R_ia is the —Pbf protective group as already defined;using the same procedure described 1b′).
• 136c) compounds A₄₁ and A₄₂ are respectively obtained by reacting a compound of formula A or a compound of formula A₂₆, both described in 107b) with a compound of formula (IIIx) or (IIIy) as already described in 114b).
• 137. The compounds of general formula (I) wherein:
• s is equal to 1;
• s′, s″, m, m′ and m″ are equal to 0;
• Y is as above defined;
• A is selected from (IIa), (IIc) and (IIt) wherein R₁ is —C(O)O—R_1x and binds a group —Y—ONO₂; R₂ is equal to R₄ and is as defined in 114.; R_a of formula (IIa) and R_c of formula (IIc) are R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, or R_iNH(═NH)NH—(CH₂)₃, wherein R_h and R_i are —H;
• in formula (IIt) d is 2 d′ is 1, R_t is —H;can be obtained as follows:
• 137a) R_a=R_c selected from R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, R_h is —Hby reacting a compound of formula (I) wherein s, s′, s″, m, m′, m″, Y, Y′, Y″ are as above defined in 137., A is a radical of (IIa), (IIc) or (IIt) wherein R₁, R₂, d, d′, are as defined in 137., R_a of formula (IIa) and R_c of formula (IIc) are selected from R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, R_h is —C(O)OC(CH₃)₃;
• in formula (IIt) R_t is —C(O)OC(CH₃)₃;
• with anhydrous or aqueous organic or inorganic acid to hydrolyze the —BOC protective groups following procedure well known in the literature.
• 137a′) R_a=R_c selected from R_iNH(═NH)NH—(CH₂)₃—, R_i is —H;reacting a compound of formula (Xe)A₄₃-Y—ONO₂  (Xe)wherein Y is as above defined and A₄₃ is a radical of (IIa), (IIc) wherein R₁ and R₂ are as defined in 137., R_a of formula (IIa) and R_c of formula (IIc) are selected from R_iaNH(═NH)NH—(CH₂)₃—, wherein R_ia is the Pbf protective group as already defined;
• with anhydrous or aqueous organic or inorganic acid to hydrolyze the —Pbf protective groups following procedure well known in the literature.
• 137b) compounds described in 137a) and 137a′) are respectively obtained by reacting a compound of formula A₄₁ or a compound of formula A₄₂ both already defined in 136b) with a compound of formula (IIIf)A₄₁+Act(O)C—O—Y—ONO₂→(I)  (IIIf)A₄₂+Act(O)C—O—Y—ONO₂→(Xe)  (IIIf)wherein Act and Y are as above defined, using the same procedure described in 3b).
• 138. The compounds of general formula (I) wherein:
• s is equal to 1;
• s′, s″, m, m′ and m″ are equal to 0;
• Y is as above defined;
• A is selected from (IIa), (IIc) and (IIt) wherein R₁ is —H; R₂ is equal to R₄ and is as defined in 114.; R_a of formula (IIa) and R_c of formula (IIc) are R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, or R_iNH(═NH)NH—(CH₂)₃—, wherein R_h and R_i are R_hh—C(O)— or R_ii—C(O)—, and bind a group —Y—ONO₂;
• in formula (IIt) d is 2 d′ is 1, R_t is —C(O)—R_tt, and binds a group —Y—ONO₂;can be obtained as follows:
• 138a) by reacting a compound of formula (I) wherein s, s′, s″, m, m′, m″, Y, Y′, Y″ are as above defined in 138., A is a radical of (IIa), (IIc) or (IIt) wherein R₂, R_a, R_c, d, d′ and R_t are as defined in 138., R₁ is —C(O)OC(CH₃)₃;
• with anhydrous or aqueous organic or inorganic acid to hydrolyze the —BOC protective groups following procedure well known in the literature.
• 138b) by reacting a compound of formula A with a compound of formula (IIIe)A+Act(O)C—Y—ONO₂  (IIIe)wherein Act and Y are as above defined and A is a radical of (IIa), (IIc) or (IIt) wherein R₁ is —C(O)OC(CH₃)₃; R₂ is equal to R₄; R_a of formula (IIa) and R_c of formula (IIc) are R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, or R_iNH(═NH)NH—(CH₂)₃—, wherein R_h and R_i are —H;
• in formula (IIt) d and d′ are as defined in 138., R_t is —H;using the same procedure described in 1b′).
• 138c) by reacting a compound of formula A with a compound of formula (IIIx) or (IIIy)A+(IIIx)A+(IIIy)wherein A is a radical of formula (IIa), (IIc) or (IIt) wherein R₁ is —C(O)OC(CH₃)₃; R₂ is —COOH or R_2a wherein R_2a is the group —COAct as already described in 8; R_a of formula (IIa) and R_c of formula (IIc) are R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, or R_iNH(═NH)NH—(CH₂)₃—, wherein R_h and R_i are —H;
• in formula (IIt) d and d′ are as defined in 138., R_t is —H;using the same procedures described in 114b).
• 130. The compounds of general formula (I) wherein:
• s is equal to 1;
• s′, s″, m, m′ and m″ are equal to 0;
• Y is as above defined;
• A is selected from (IIa), (IIc) and (IIt) wherein R₁ is —H; R₂ is equal to R₄ and is as defined in 114.,
• R_a of formula (IIa) and R_c of formula (IIc) are R_hNH(CH₂)_p— wherein p is an integer from 0 to 4, or R_iNH(═NH)NH—(CH₂)₃—,wherein R_h and R_i are R_hh—OC(O)— or R_ii—OC(O)—; and bind a group —Y—ONO₂;
• in formula (IIt) d is 2 d′ is 1, R_t is —C(O)O—R_tt, and it binds a group —Y—ONO₂;can be obtained as follows:
• 139a) by reacting a compound of formula (I) wherein s, s′, s″, m, m′, m″, Y, Y′, Y″ are as above defined in 139., A is a radical of (IIa), (IIc) or (IIt) wherein R₂, R_a, R_c, d, d′ and R_t are as defined in 139., R₁ is —C(O)OC(CH₃)₃;
• with anhydrous or aqueous organic or inorganic acid to hydrolyze the —BOC protective groups following procedure well known in the literature.
• 139b) by reacting a compound of formula A described in 138b) with a compound of formula (IIIf)A+Act(O)C—O—Y—ONO₂  (IIIf)wherein Act and Y are as above defined using the same procedure described in 3b).

EXAMPLE 1

(S)-4-(nitrooxy)butyl 2-amino-6-(tert-butoxycarbonylamino)hexanoate (Corresponding to Compound 18)

Step A: (S)-4-(nitrooxy)butyl 1-(9H-fluoren-9-yl)-13,13-dimethyl-3,11-dioxo-2,12-dioxa-4,10-diazatetradecane-5-carboxylate

Commercial N(α)-Fmoc-N(ε)-Boc-L-lysine pentafluorophenyl ester (6.51 mmol) and 4-(nitrooxy)-1-butanol (6.55 mmol) were dissolved in DMF (12 ml) and the mixture was cooled to 0° C. N,N-dimethylaminopyridine (DMAP) (6.55 mmol) were added and the reaction was slowly warmed to room temperature and stirred for 4 hours. Then the mixture was concentrate under reduced pressure and diluted with EtOAc, washed with 5% aqueous Na₂HPO₄ and brine.

The organic layer was dried over sodium sulphate and concentrated under reduced pressure.

The residue was purified by flash chromatography (n-hexan/EtOAc 70:30 as eluent) yielding the title compound (2.52 g, 66%).

Step B: (S)-4-(nitrooxy)butyl 2-amino-6-(tert-butoxycarbonylamino)hexanoate

To a solution of S)-4-(nitrooxy)butyl 1-(9H-fluoren-9-yl)-13,13-dimethyl-3,11-dioxo-2,12-dioxa-4,10-diazatetradecane-5-carboxylate (2.52 g, 4.30 mmol) in CH₃CN (30 ml), piperidine (2.12 ml, 21.5 mmol) was added in the dark, the reaction was stirred at rt for 25 min. Then the mixture was concentrated to a small volume and diluted with EtOAc (150 ml) and washed with 5% aqueous NaHPO₄ (2×70 ml). The organic layer was dried over sodium sulphate and concentrated under reduced pressure.

The residue was purified by flash chromatography (CH₂Cl₂/MeOH 98:2 as eluent), yielding the title compound (0.960 g, 61%).

¹H-NMR (DMSO-d₆): 6.78 (1H, t), 4.55 (2H, t), 4.07 (2H, m), 3.26 (2H, t), 2.87 (1H, m), 1.73-1.65 (4H, m), 1.64-1.40 (2H, m), 1.37 (9H, s), 1.36-1.22 (4H, s).

EXAMPLE 2

2-Amino-3-tert-butoxy-3-oxopropyl 4-(nitrooxy)butanoate (Corresponding to Compound 405)

Step A: tert-butyl 2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-hydroxypropanoate

To a solution of commercial N-Fmoc-L-serine (1.5 g, 4.58 mmol) in EtOAc (40 ml), a solution of t-butyl 2,2,2-trichloroacetimidate (4.00 g, 18.32 mmol) in cyclohexane (18 ml) was added dropwise. After stirring at room temperature for 24 hrs, the solution was evaporated and the residue was purified by flash chromatography (n-Hexane/EtOAc 70:3), yielding the title compound (1.20 g, 68%).

Step B: 2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-tert-butoxy-3-oxopropyl 4-(nitrooxy)butanoate

To a solution of 2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-tert-butoxy-3-oxopropyl 4-(nitrooxy)butanoate (1.20 g, 3.13 mmol), 4-(nitrooxy)butyric acid pentafluorophenyl ester (1.18 g, 3.76 mmol) and scandium trifluoromethanesulfonate (0.308 g, 0.626 mmol) in CH₂Cl₂ (25 ml) cooled to 0° C., was added N,N-dimethylaminopyridine (DMAP) (0.459 g, 3.76 mmol). The resulting mixture was stirred at room temperature for 18 hours. Then it was diluted with CH₂Cl₂ and washed with 5% aqueous Na₂HPO₄ and brine. The organic layer was dried over sodium sulphate and concentrated under reduced pressure.

The residue was purified by flash chromatography (n-hexane/EtOAc 70:30 as eluent) affording the title compound (1.26 g, 78%).

Step C: 2-Amino-3-tert-butoxy-3-oxopropyl 4-(nitrooxy)butanoate

To a solution of 2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-tert-butoxy-3-oxopropyl 4-(nitrooxy)butanoate 1.26 g, 2.45 mmol) in CH₃CN (15 ml), piperidine (1.21 ml, 12.2 mmol) was added in the dark, the reaction was stirred at room temperature for 25 min. Then the mixture was concentrated to a small volume and diluted with EtOAc (80 ml) and washed with 5% aqueous NaHPO₄. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by flash chromatography (CH₂Cl₂/MeOH 98:2 as eluent) yielding the title compound (0.500 g, 70%).

¹H-NMR (CDCl₃): 6.49, 4.61-4.50 (3H, m), 3.95 (2H, d), 2.43 (2H, t), 2.22-2.08 (2H, m), 1.05 (9H, s).

EXAMPLE 3

1-tert-Butyl 2-(4-(nitrooxymethyl)benzyl)pyrrolidine-1,2-dicarboxylate (Corresponding to Compound 7)

Step A: 1-tert-butyl 2-(4-(chloromethyl)benzyl)pyrrolidine-1,2-dicarboxylate

N-Boc-L-prolin (2.47 g, 11.5 mmol) and 4-(chloromethyl)benzyl alcohol (1.50 g, 9.58 mmol) were dissolved in CH₂Cl₂ (50 ml) and the mixture was cooled to 0° C. N-Ethyl-N′-(3-dimethylaminopropyl)carbodiimide (EDC) (2.75 g, 14.4 mmol) and N,N-dimethylaminopyridine (DMAP) (0.235 g, 1.92 mmol) were added and the reaction was slowly warmed to room temperature and stirred for 4 hours. Then the mixture was diluted with CH₂Cl₂ (200 ml) and washed with 5% aqueous NaHCO₃, 5% aqueous Na₂HPO₄ and brine. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by flash chromatography (n-hexane/EtOAc 80:20 as eluent) affording the title compound. (2.98 g, 88%).

Step B: 1-tert-Butyl 2-(4-(nitrooxymethyl)benzyl)pyrrolidine-1,2-dicarboxylate

To a solution of 1-tert-butyl 2-(4-(chloromethyl)benzyl)pyrrolidine-1,2-dicarboxylate (0.630 g, 1.78 mmol) in CH₃CN (13 ml), AgNO₃ (0.756 g, 4.45 mmol) was added and the reaction was heated in a microwave apparatus (150° C., 20 min). The formed salts were filtered off and the solvent was concentrated, then the residue was diluted with EtOAc (100 ml) and washed with brine. The organic layer was dried over sodium sulphate and concentrated under reduced pressure yielding the title compound (0.655 g, 96%).

¹H-NMR (CDCl₃): 7.41 (4H, d), 5.44 (2H, s), 5.30-5.10 (2H, m), 4.42-4.27 (2H, m), 3.57-3.42 (2H, m), 2.30-2.15 (1H, m), 2.00-1.85 (3H, m), 1.48-1.35 (9H, m).

EXAMPLE 4

4-[(nitrooxy)methyl]benzylpyrrolidine-2-carboxylate hydrochloride (Corresponding to Compound 3)

To a solution of 1-tert-Butyl 2-(4-(nitrooxymethyl)benzyl)pyrrolidine-1,2-dicarboxylate, obtained in Example 3, (0.543 g, 1.43 mmol) in CH₂Cl₂ (14 ml) cooled to 0° C., HCl_gas was bubbled for 2 hours. The solvent was concentrated and the residue was treated with diethyl ether, affording the title compound (0.446 g, 99%.

¹H-NMR (CDCl₃): 9.16 (bs), 7.40 (4H, d), 5.43 (2H, s) 5.31-5.17 (2H, m), 4.52 (1H, m), 3.52 (2H, m), 2.49-2.38 (1H, m), 2.20-2.00 (3H, m).

EXAMPLE 5

4-(nitrooxy)butyl 2-(tert-butoxycarbonylamino)acetate (Corresponding to Compound 16)

Applying the same procedure described in Example 1, starting from commercially available N-Boc-L-glycine, N-hydroxysuccinimido ester (2.33 g, 8.56 mmol), the title compound was obtained. (3.00 g, 80%).

¹H-NMR (CDCl₃) 5.04 (1H, bt), 4.49 (2H, t), 4.20 (2H, t), 3.91 (2H, d), 1.81 (4H, m), 1.46 (9H, s).

EXAMPLE 6

4-(nitrooxy)butyl 2-aminoacetate hydrochloride (Corresponding to Compound 21)

The title compound was obtained as a white solid starting from 4-(nitrooxy)butyl 2-(tert-butoxycarbonylamino)acetate, prepared as described in Example 5 following the procedure described in Example 4 (2.34 g, quantitative yield).

¹H-NMR (CDCl₃): 4.53 (2H, t), 4.29 (2H, t), 4.04 (2H, d), 3.74 (2H, d), 1.84 (4H, m).

EXAMPLE 7

4-(Nitrooxy)butyl 2-(tert-butoxycarbonylamino)-3-methylbutanoate (Corresponding to Compound 149)

Step A: 4-chloro 2-(tert-butoxycarbonylamino)-3-methylbutanoate

N-Boc-L-valine (3.48 g, 16.0 mmol), 4-chloro-1-butanol (3.47 g, 32.0 mmol) and N-hydroxybenzotriazole (HOBT) (3.24 g, 24.0 mmol) were dissolved in CH₂Cl₂ (80 ml) and the mixture was cooled to 0° C. N-Methylmorpholine (NMM) (3.24 g, 32.0 mmol) and N,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU) (6.67 g, 17.6 mmol) were added and the reaction was slowly warmed to room temperature and stirred for 24 hours. Then the mixture was diluted with CH₂Cl₂ (200 ml) and washed with 5% aqueous NaHCO₃, HCl 1N and brine. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by flash chromatography (n-hexane/EtOAc 90:10) affording the title compound (2.98 g, 64%).

Step B: 4-(Nitrooxy)butyl 2-(tert-butoxycarbonylamino)-3-methylbutanoate methylbutanoate

To a solution of 4-chlorobutyl 2-tert-butoxycarbonylamino)-3-methylbutanoate (0.630 g, 1.78 mmol) in CH₃CN (13 ml), AgNO₃ (0.756 g, 4.45 mmol) was added and the reaction was heated in a microwave apparatus (150° C., 20 min). The formed salts were filtered off and the solvent was concentrated. Then the residue was diluted with EtOAc (100 ml) and washed with brine, dried over sodium sulphate and concentrated under reduced pressure yielding the title compound (0.655 g).

¹H-NMR (CDCl₃): 5.00 (1H, d), 4.50 (2H, t), 4.24-4.16 (3H, m), 2.20-2.09 (1H, m), 1.90-1.74 (4H, m), 1.46 (9H, s), 0.99 (3H, d), 0.92 (3H, d).

EXAMPLE 8

tert-butyl 2-(4-(nitrooxy)butylamino)-2-oxoethylcarbamate (Corresponding to Compound (12))

Step A: tert-butyl 2-(4-hydroxybutylamino)-2-oxoethylcarbamate

4-Amino-1-butanol (0.686 g, 7.70 mmol) and triethylamine (0.779 g, 7.70 mmol) were dissolved in CH₂Cl₂ (40 ml) and the mixture was cooled to 0° C. A suspension of commercial N-Boc-glycine N-hydroxysuccinimido ester (2.10 g; 7.70 mmol) in CH₂Cl₂ (40 ml) was added and the reaction was slowly warmed to room temperature and stirred for 24 hours. Then, the mixture was diluted with CH₂Cl₂ (150 ml) and washed with 5% aqueous Na₂HPO₄ and brine. The aqueous layer was extracted twice with CH₂Cl₂ and twice with a mixture of EtOAc/MeOH 98:2. The organic layers were dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by flash chromatography (n-hexane/i-prOH 80:20 affording the title compound (2.16 g).

Step B: 2-(4-(nitrooxy)butylamino)-2-oxoethylcarbamate

To a solution of tert-butyl 2-(4-hydroxybutylamino)-2-oxoethylcarbamate (2.16 g, 8.77 mmol), tetraethylammonium nitrate (3.37 g, 17.54 mmol) and 2,6-di-tert-butyl-4-methylpyridine (2.71 g, 13.16 mmol) in CH₂Cl₂ (60 ml) cooled to −70° C. and under nitrogen, a solution of trifluoromethansulfonic anhydride (2.72 g, 9.65 mmol) in CH₂Cl₂ (40 ml) was added drop wise. The resulting mixture was stirred for 3 hours at −65° C. Then the mixture was slowly warmed to room temperature, diluted with CH₂Cl₂ and washed with 5% aqueous Na₂HPO₄. The organic layer was dried over sodium sulphate and concentrated under reduced pressure.

The residue was purified by flash chromatography CH₂Cl₂/CH₃CN 70:30 as eluent) affording the title compound. (2.04 g, 80%).

¹H-NMR (CDCl₃) 6.30 (1H, s), 5.15 (1H, s), 4.48 (2H, t), 3.79 (2H, d), 3.37-3.31 (2H, m), 1.80-1.74 (2H, m), 1.67-1.62 (2H, m), 1.63 (9H, s).

EXAMPLE 9

4-(2-Aminoacetamido)butyl nitrate hydrochloride (Corresponding to Compound 23)

The title compound was obtained as a white solid from tert-butyl 2-(4-(nitrooxy)butylamino)-2-oxoethylcarbamate (Example 8) following the procedure described in Example 4. (1.58 g, quantitative yield).

¹H-NMR (CDCl₃) 8.55 (1H, s), 8.17 (2H, s), 4.54 (2H, t), 3.55-3.48 (2H, m), 3.18-3.12 (2H, m), 1.72-1.65 (2H, m), 1.53-1.48 (2H, m).

EXAMPLE 10

(2S,3aS,6aS)-4-(Nitrooxy)butyl octahydrocyclopenta[b]pyrrole-2-carboxylate (Corresponding to Compound 512

Step A: (2S,3aS,6aS)-1-(9H-fluoren-9-yl)methyl 2-benzylhexahydrocyclopenta[b]pyrrole-1,2(2H)-dicarboxylate

To a solution of commercial (2S,3aS,6aS)-benzyl octahydrocyclopenta[b]pyrrole-2-carboxylatehydrochloride (1.00 g, 3.60 mmol) and TEA (1.15 ml, 7.92 mmol) in CH₃CN (15 ml) cooled in an ice bath 9-fluorenylmethoxycarbonyl chloride (1.01 g, 4.25 mmol) was added. The resulting mixture was stirred at room temperature overnight. Then the mixture was concentrated and diluted with CH₂Cl₂ (50 ml), washed with a solution of Na₂HPO₄ 5% (2×30 ml) and brine (1×30 ml). The organic phase was dried over sodium sulphate and concentrated under reduced pressure to give an oil that slowly crystallized on storage affording the title compound (1.68 g, 100%).

Step B: (2S,3aS,6aS)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)octahydrocyclopenta[b]pyrrole-2-carboxylic acid

To a solution of (2S,3aS,6aS)-1-(9H-fluoren-9-yl)methyl 2-benzylhexahydrocyclopenta[b]pyrrole-1,2(2H)-dicarboxylate (1.68 g, 3.6 mmol) in EtOH 95% (15 ml) was added Palladium on carbon 10% (0.2 g, 0.18 mmol) and cyclohexene (3.5 ml, 36 mmol). The resulting mixture was refluxed for 7 h. The solvent was evaporated and the crude was diluted with CH₂Cl₂ (20 ml). The suspension was filtered on celite the organic phase was evaporated under vacuum. The residue was purified by flash chromatography (CH₂Cl₂/CH₃CN 50:50) to give the title compound as a white foam (0.5 g, 37%)

Step C: (2S,3aS,6aS)-(9H-fluoren-9-yl)methyl 2-(4-chlorobutyl) hexahydrocyclopenta[b]pyrrole-1,2(2H)-dicarboxylate

(2S,3aS,6aS)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)octahydrocyclopenta[b]pyrrole-2-carboxylic acid (0.250 g, 0.66 mmol) and 4-chloro-1-butanol (0.1 ml, 0.99 mmol) were dissolved under nitrogen in CH₂Cl₂ (5 ml) and the mixture was cooled to 0° C. N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) (0.190 g, 0.99 mmol) and N,N-dimethylaminopyridine (DMAP) (0.016 g, 0.13 mmol) were added and the reaction was slowly warmed to room temperature and stirred for 4 h. Then the mixture was diluted with CH₂Cl₂ (10 ml) and washed with 5% aqueous NaHCO₃, 5% aqueous Na₂HPO₄ and brine. The organic layer was dried over sodium sulphate, concentrated under reduced pressure and purified by flash chromatography (n-hexane/EtOAc 80:20 as eluent) affording the title compound as an oil (0.14 g, 45%)

Step D: (2S,3aS,6aS)-1-(9H-fluoren-9-yl)methyl 2-(4-(nitrooxy)butyl)hexahydrocyclopenta[b]pyrrole-1,2(2H)-dicarboxylate

To a solution of (2S,3aS,6aS)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)octahydrocyclopenta[b]pyrrole-2-carboxylic acid (0.13 g, 0.27 mmol) in CH₃CN (1.7 ml), AgNO₃ (0.118 g, 0.69 mmol) was added and the reaction was heated to 150° C. for 20 min in a microwave apparatus. The formed salts were filtered off and the solvent was concentrated affording the title compound as a yellow solid (0.133 g, 100%).

To a solution of (2S,3aS,6aS)-1-(9H-fluoren-9-yl)methyl 2-(4-(nitrooxy)butyl)hexahydrocyclopenta[b]pyrrole-1,2(2H)-dicarboxylate (0.133 g, 0.27 mmol) in CH₃CN (2 ml), piperidine (133 μl, 1.35 mmol) was added in the dark; the reaction was stirred at room temperature for 25 min. Then the solution was evaporated, diluted with pH 3 aqueous buffer and the aqueous phase was extracted with hexane. The solution was basified to pH 9 and finally extracted with diethyl ether. The organic layer was dried over sodium sulphate and concentrated under reduced pressure affording the title compound as an oil (0.04 g, 50%).

¹H-NMR (DMSO-d₆) 4.55 (2H, t); 4.13-3.96 (3H, m); 3.81 (1H, m); 3.68 (1H, bs); 2.66-2.51 (1H, m); 2.34-2.19 (1H, m); 1.81-1.31 (11H, m).

EXAMPLE 11

(2S,3aS,6aS)-4-(nitrooxymethyl)benzyl octahydrocyclopenta[b]pyrrole-2-carboxylate (Corresponding to Compound 520)

The title compound was prepared following the procedure described in Example 10 using 4-(chloromethyl)benzyl alcohol instead of 4-chloro-1-butanol in Step C.

¹H-NMR (DMSO-d₆): 7.51-7.21 (4H, m); 5.47 (2H, s); 5.09 (2H, s) 4.10 (1H, m); 3.82 (1H, m); 3.68 (1H, m); 2.62 (1H, m); 2.38 (1H, m); 1.92-1.05 (9H, m)

EXAMPLE 12

4-[(nitrooxy)methyl]benzyl 2-amino-6-(tert-butoxycarbonylamino)hexanoate (Corresponding to Compound 24)

The title compound was prepared following procedure already described in Examples 1 and 11 (0.010 g, 10%).

¹H-NMR (DMSO-d₆): 7.48-7.61 (8H, m); 6.78 (1H, t); 5.54 (2H, s); 5.15 (2H, s); 4.07 (1H, m); 2.87 (1H, m); 1.73-1.65 (2H, m); 1.36-1.22 (13H, m).

EXAMPLE 13

4-(nitrooxy)butyl 2-(tert-butoxycarbonylamino)-3-hydroxypropanoate (Corresponding to Compound (45))

Starting from Boc-L-serine and following the procedure described in Example 3 the title was obtained as an oil (0.350 g, 48%).

¹H-NMR (CDCl₃): 5.44 (1H, bs); 4.50 (2H, t); 4.38 (1H, m); 4.25 (2H, m); 3.97 (2H, m); 1.84 (4H, m); 1.47 (9H, s).

EXAMPLE 14

1-tert-butyl 2-(4-(nitrooxy)butyl)pyrrolidine-1,2-dicarboxylate

Starting from Boc-L-Proline and 4-chloro-1-butanol and following the procedure described in Example 3 the title compound was obtained as an oil.

¹H-NMR (CDCl₃): 4.50 (2H, t), 4.10-4.40 (3H, m), 3.65-3.33 (2H, m), 2.34-1.70 (8H, m), 1.45 (9H, d).

EXAMPLE 15

1-tert-butyl 2-(3-(nitrooxy)propyl)pyrrolidine-1,2-dicarboxylate

Starting from Boc-L-Proline and 3-bromo-1-propanol and following the procedure described in Example 3 the title compound was obtained as an oil.

¹H-NMR (CDCl₃): 4.56-4.52 (2H, m); 4.31-4.19 (3H, m); 3.57-3.35 (2H, m); 2.28-1.80 (6H, m); 1.43 (9H, d).

EXAMPLE 16

2,2-dimethyl-15-(nitrooxy)-4,9-dioxo-3,8,10,13-tetraoxa-5-azapentadecane-6-carboxylic acid (Corresponding to Compound 400)

Into a solution or N-Boc-L-Serine (1.66 g, 8.12 mmol), diisopropylethyl amine (DIPEA) (1.41 ml, 8.12 mmol), N,N-dimethylaminopyridine (DMAP) (1.19 g, 9.74 mmol) and scandium triflate (1.20 g, 2.43 mmol) in CH₂Cl₂ (40 ml), cooled to −10° C., a solution of 2-[2-(nitrooxy)ethoxy]ethyl 4-nitrophenyl carbonate in CH₂Cl₂ (40 ml) was added drop-wise. The reaction was slowly warmed to room temperature and stirred for 24 h. Then the organic phase was washed with pH 3 aqueous buffer and concentrated under reduced pressure. The crude was partitioned between aqueous 5% aqueous Na₂HPO₄ and diethyl ether and extracted twice with diethyl ether. The aqueous phase was acidified to pH 3 and extracted with CH₂Cl₂. The organic phase was finally dried over sodium sulphate and concentrated under reduced pressure to give the title compound as an oil. (2.4 g, 80%)

¹H-NMR (CDCl₃): 5.54 (1H, bs); 4.63 (2H, m); 4.52 (3H, m); 4.29 (2H, m); 3.86-3.69 (4H, m); 1.46 (9H, s).

EXAMPLE 17

2-(tert-butoxycarbonylamino)-4-methylpentyl 4-hydroxybutanoate (Corresponding to Compound (510))

Step A: 2-(tert-butoxycarbonylamino)-4-methylpentyl 4-bromobutanoate

tert-Butyl 1-hydroxy-4-methylpentan-2-ylcarbamate (2.00 g, 9.20 mmol) and 4-bromo-butyric acid (2.57 g, 15.38 mmol) were dissolved in CH₂Cl₂ (40 ml) and the mixture was cooled to 0° C. EDC (4.20 g, 21.90 mmol) and DMAP (0.27 g, 2.21 mmol) were added and the reaction was slowly warmed to room temperature and stirred overnight. Then the reaction was treated with a solution of 5% aqueous NaH₂PO₄ (100 ml). The organic layer was washed with a solution of 10% aqueous Na₂CO₃ (100 ml) and brine, dried over Na₂SO₄, filtered and concentrated. The obtained crude clear oil corresponding to the title compound (3.30 g) was used without any further purification.

Step B: 2-(tert-Butoxycarbonylamino)-4-methylpentyl 4-(nitrooxy)butanoate

To a solution of crude 2-(tert-butoxycarbonylamino)-4-methylpentyl 4-bromobutanoate (3.30 g) in CH₃CN (60 ml), AgNO₃ (4.20 g, 24.52 mmol) was added. The resulting solution (divided into 5 vials) was heated in a microwave apparatus (120° C., 3 minutes). Then the formed salts were filtered off, the solvent was concentrated and the residue purified by flash chromatography (n-hexane/EtOAc 80:20 as eluent) affording the title compound (1.05 g, yield: 33.5%) as a clear oil.

¹H-NMR (CDCl₃): 4.54 (2H, t); 4.48-4.34 (1H, m); 2.49 (2H, t); 2.18-1.99 (2H, m); 1.79-1.57 (1H, m); 1.39-1.22 (2H, m); 1.00-0.86 (6H, m).

EXAMPLE 18

2-Amino-4-methylpentyl 4-(nitrooxy)butanoate hydrochloride (Corresponding to Compound 507)

The title compound was prepared from 2-(tert-butoxycarbonylamino)-4-methylpentyl 4-(nitrooxy)butanoate (described in Example 17) following the procedure described in Example 4 (0.71 g, 90%).

¹H-NMR (DMSO-d₆): 4.56 (2H, t); 4.27-4.22 (1H, m); 4.11-4.06 (1H, m); 3.39-3.32 (2H, m); 2.51 (2H, t); 2.01-1.92 (2H, m); 1.75-1.68 (1H, m); 1.51-1.38 (2H, m); 0.90 (6H, d).

EXAMPLE 19

4-[(Nitrooxy)methyl]benzyl 2-(tert-butoxycarbonylamino)-4-phenylbutanoate (Corresponding to Compound 13)

The title compound was prepared as a clear oil from 2-(tert-butoxycarbonylamino)-4-phenylbutanoic acid following procedure described in Example 3.

¹H-NMR (CDCl₃): 7.34 (4H, m); 5.07-5.04 (1H, m); 4.49 (2H, t); 4.36-4.34 (1H, m); 4.23-4.11 (2H, m); 2.70 (2H, t); 2.19-2.11 (1H, m); 2.02-1.94 (1H, m); 1.92-1.76 (4H, m); 1.61 (9H, s).

EXAMPLE 20

3-[(Nitrooxy)methyl]phenyl 2-(tert-butoxycarbonylamino)-4-phenylbutanoate (Corresponding to Compound 86)

Starting from 2-(tert-butoxycarbonylamino)-4-phenylbutanoic acid and 3-(bromomethyl)phenyl alcohol and following the procedure reported in Example 3 the title compound was obtained as an oil.

¹H-NMR (CDCl₃): 7.50-7.16 (7H, m); 7.15-7.05 (2H, m); 5.42 (2H, s); 5.07 (1H, d); 4.65-4.47 (1H, m); 2.80 (2H, t); 2.44-2.23 (1H, m); 2.23-1.99 (1H, m); 1.48 (9H, s).

EXAMPLE 21

2-(2-(Nitrooxy)ethoxy)ethyl 2-(tert-butoxycarbonylamino)-4-phenylbutanoate

Starting from 2-(tert-butoxycarbonylamino)-4-phenylbutanoic acid and 2-chloroethoxyethyl alcohol and following the procedure reported in Example 3 the title compound was obtained as an oil.

¹H-NMR (CDCl₃): 7.19-7.03 (5H, m); 5.08 (1H, d); 4.50-4.45 (2H, m); 4.22-4.06 (3H, m); 3.65-3.55 (4H, m); 2.56 (2H, t); 2.08-1.80 (2H, m); 1.32 (9H, s).

EXAMPLE 22

2,2-Dimethyl-14-(nitrooxy)-4,9-dioxo-3,8,10-trioxa-5-azatetradecane-6-carboxylic acid (Corresponding to Compound (401))

The title compound was prepared from N-Boc-L-serine and 4-chlorobutyl chloroformate following procedure described in Example 16.

¹H-NMR (CDCl₃): 5.50 (1H, d); 4.52-4.40 (5H, m); 4.19 (2H, t); 1.88-1.75 (4H, m); 1.46 (9H, s).

EXAMPLE 23

2-amino-3-((4-(nitrooxy)butoxy)carbonyloxy)propanoic acid hydrochloride (Corresponding to Compound (407))

The title compound was obtained as a white solid from 2,2-dimethyl-14-(nitrooxy)-4,9-dioxo-3,8,10-trioxa-5-azatetradecane-6-carboxylic acid (described in Example 22) following procedure described in Example 4.

¹H-NMR (DMSO-d₆): 4.60-4.41 (4H, m); 4.18-4.13 (3H, m); 1.78-1.65 (4H, m).

EXAMPLE 24

4-(nitrooxy)butyl 2-(tert-butoxycarbonylamino)-3-(4-hydroxyphenyl)propanoate (Corresponding to Compound 67)

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 or 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 (n-hexane/EtOAc from 9:1 to 1:1 as eluent affording the title compound.

¹H-NMR (CDCl₃): 7.00 (2H, d, J=8 Hz); 6.76 (2H, d, J=8 Hz); 5.01 (1H, bd, J=8 Hz); 4.51 (1H, m); 4.42 (2H, t, J=6 Hz); 4.12 (2H, m); 3.00 (2H, d, J=6 Hz); 1.69 (4H, m); 1.44 (9H, s).

EXAMPLE 25

4-(nitrooxy)butyl 2-amino-3-(4-hydroxyphenyl)propanoate (Corresponding to Compound (58)

The title compound was obtained from 4-(nitrooxy)butyl 2-(tert-butoxycarbonylamino)-3-(4-hydroxyphenyl)propanoate (described in Example 24) following procedure described in Example 4.

¹H-NMR (CDCl₃): 7.05 (2H, dd, J=9 and 3 Hz); 6.74 (2H, dd, J=9 and 3 Hz); 4.45 (2H, t, J=6 Hz); 4.15 (2H, t, J=6 Hz); 3.73 (1H, m); 2.93 (2H, m); 1.73 (4H, m).

EXAMPLE 26

2-(R)-5,6-bis(nitrooxy)hexyl 1-tert-butyl pyrrolidine-1,2-dicarboyxlate (Corresponding to Compound 4, 5-(R)-isomer)

To a solution of N-Boc-L-Proline (288 mg, 1.34 mmol) and (2R)-6-hydroxypentane-1,2-diyl dinitrate (obtained as described in WO2005070868(A1)) (300 mg, 1.34 mmol) in CH₂Cl₂ (6 ml) was added at 0° C. EDAC (257 mg, 1.34 mmol), and then DMAP (catalytic). The reaction was stirred overnight at rt. The organic layer was washed successively with H₂O, HCl 0.1M, H₂O and brine, dried over Na₂SO₄, filtered and evaporated. The residue was purified by column chromatography on silica (15% to 25% AcOEt in n-Hexane in 20 CV then 25% to 35% in 5 CV) to give the title compound (413 mg, 73%).

¹H-NMR (300 MHz, CDCl₃) δ 5.30 (m, 1H), 4.77 (m, 1H), 4.50 (m, 1H), 4.31 (d, J=11.5 Hz, 1H), 4.19 (m, 2H), 3.47 (m, 2H), 1.94 (m, 3H), 1.76 (m, 4H), 1.56 (m, 3H), 1.45 (d, J=12.67 Hz, 9H).

EXAMPLE 27

(R)-5,6-bis(nitrooxy)hexylpyrrolidine-2-carboxylate (Corresponding to Compound 1; 5(R)-isomer)

To a solution of [(5R)-5,6-dinitroxyloxane-1-yl]N-tButoxy-L-proline ester (410 mg, 0.97 mmol) in CH₂Cl₂ (3 mL) was added TFA (223 μL, 2.91 mmol, 3 eq). The reaction was stirred at RT for 3 hrs. The organic layer was washed with H₂O, K₂CO₃ diluted, H₂O and brine, dried over Na₂SO₄, filtered and evaporated yielding the title compound (215 mg, 69%).

¹H-NMR (300 MHz, CDCl₃) δ 5.31 (ddd, J=13.23, 6.51, 3.09 Hz, 1H), 4.77 (dd, J=12.88, 3.07 Hz, 1H), 4.50 (dd, J=12.87, 6.46 Hz, 1H), 4.17 (t, J=6.30 Hz, 2H), 3.82 (dd, J=8.46, 5.25 Hz, 1H), 3.13 (dd, J=16.88, 6.54 Hz, 1H), 2.42 (s, 2H), 2.17 (m, 1H), 1.78 (m, 6H), 1.52 (m, 3H).

EXAMPLE 28

2-(tert-butoxycarbonylamino)ethyl 4-(nitrooxy)butanoate (Corresponding to Compound (508))

Step A: 2-(tert-butoxycarbonylamino)ethyl 4-bromobutanoate

N-Boc-ethanolamine (2.10 g; 13.0 mmol), 4-Bromobutyric acid (2.18 g; 13.0 mmol) and N,N-dimethylaminopyridine (0.318 g; 2.60 mmol) were dissolved in CH₂Cl₂ (35 mL) and the mixture was cooled to 0° C.; EDAC (3.75 g; 13.6 mmol) was added and the reaction was slowly warmed to room temperature and stirred for 18 hours. Then the mixture was diluted with CH₂Cl₂, washed with aqueous Na₂HPO₄ (5%, 2×50 ml) aqueous NaH₂PO₄, (5%, 2×50 ml) and brine (1×40 ml). The organic layer was dried over sodium sulfate and concentrated under reduced pressure.

The residue was purified by flash chromatography (hexane/EtOAc=75/25; R_f=40), yielding the title compound (3.03 g, 75%).

Step B: 2-(tert-butoxycarbonylamino)ethyl 4-(nitrooxy)butanoate

To a solution of 2-(tert-butoxycarbonylamino)ethyl 4-bromobutanoate (3.03 g; 9.77 mmol) in CH₃CN (80 mL), AgNO₃ (4.15 g; 24.4 mmol) was added and the reaction was performed at the microwave (120° C., 7 min). The formed salts were filtered off and the solvent was concentrated; then the residue was diluted with EtOAc and washed with water (40 ml); the organic layer was dried over sodium sulfate and concentrated under reduced pressure.

The residue was purified by flash chromatography (hexane/EtOAc=7/3; R_f=0.40), yielding the title compound (1.48 g, 52%).

¹H-NMR (300 MHz, CDCl₃): 4.77 (1H, s); 4.54 (2H, t); 4.17 (2H, t); 3.44-3.38 (2H, m); 2.49 (2H, t); 2.13-2.04 (2H, m); 1.46 (9H, s).

EXAMPLE 29

2-aminoethyl 4-(nitrooxy)butanoate hydrochloride (Corresponding to Compound (509))

The title compound was obtained as a white solid starting from 2-(tert-butoxycarbonylamino)ethyl 4-(nitrooxy) butanoate, prepared, as described in Example 28 following the procedure described in Example 4 (1.16 g; quantitative yield).

¹H-NMR (DMSO-d₆): 8.25 (2H, s); 4.56 (2H, t); 4.23 (2H, t); 3.06 (2H, t); 2.51 (2H, t); 2.01-1.91 (2H, m).

EXAMPLE 30

(S)-2-(tert-butoxycarbonylamino)-3-phenylpropyl 4-(nitrooxy)butanoate (Corresponding to Compound (511))

The title compound was prepared from (S)-tert-butyl 1-hydroxy-3-phenylpropan-2-ylcarbamate and 4-Bromobutyric acid following the procedure described in Example 29.

¹H-NMR (300 MHz, CDCl₃): 7.35-7.25 (5H, m); 4.56-4.54 (1H, m); 4.52 (2H, t); 4.15-4.04 (3H, m); 2.84-2.81 (2H, m); 2.50 (2H, t); 2.13-2.04 (2H, m); 1.32 (9H, s).

EXAMPLE 31

(S)-4-(nitrooxy)butyl 2-(tert-butoxycarbonylamino)-3-phenylpropanoate (Corresponding to Compound (15))

The title compound was prepared from (S)-2-(tert-butoxycarbonylamino)-5-phenylpropanoic acid and 4-chloro-1-butanol following the procedure described in Example 3.

¹H-NMR (300 MHz, CDCl₃): 7.31 (3H, m), 7.16 (2H, d), 4.98 (1H, bd), 4.56 (1H, bm), 4.41 (2H, t), 4.12 (2H, m), 3.08 (2H, d), 1.69 (4H, m), 1.93 (9H, s).

EXAMPLE 32

(S)-4-hydroxybutyl pyrrolidine-2-carboxylate

The title compound was prepared from Boc-Proline and 4-chloro-1-butanol following the procedure described in Example 3, eventually hydrolyzing the Boc protective group as described in Example 4.

¹H-NMR (CDCl₃): 4.5 (3H, m), 4.3 (2H, bt), 3.57 (2H, m), 2.45 (1H, m) 2.13 (3H, m), 1.87 (4H, m).

EXAMPLE 33

((S)-bis(4-nitrooxy)butyl) 2-(tert-butoxycarbonylamino)succinate (Corresponding to Compound (468))

The title compound was prepared from L-Boc-Aspartic acid and 4-chloro-1-butanol following the procedure described in Example 3.

¹H-NMR (CDCl₃): 5.48 (1H, bd), 4.58 (1H, bd), 4.51 (4H, t), 4.23 (2H, t), 2.93 (2H, m), 1.81 (8H, m), 1.47 (9H, s).

EXAMPLE 34

(S)—((R)-5,6-bis(nitrooxy)hexyl) 2-(tert)-butoxycarbonylamino)-3-phenylpropanoate (Corresponding to Compound (123, 5(R)-isomer))

The title compound was prepared from Boc-L-Phenylalanine and (2R)-6-hydroxypentane-1,2-diyl dinitrate (obtained as described in WO2005070868(A1)) following the procedure described in Example 26.

EXAMPLE 35

(S)—((R)-5,6-bis(nitrooxy)hexyl) 2-amino-3-phenylpropanoate (Corresponding to Compound 14 5(R)-isomer)

The title compound was prepared from (S)—((R)-5,6-bis)nitrooxy)hexyl) 2-(tert-butoxycarbonylamino)-3-phenylpropanoate (prepared as described in Example 34) following procedure described in Example 4.

¹H-NMR (CDCl₃): 9.04-8.65 (2H, m), 7.47-7.14 (5H, m), 5.31-5.15 (1H, m), 4.80-4.65 (1H, m), 4.55-4.31 (1H, m), 4.23-3.96 (2H, m); 3.60-3.42 (1H, m); 3.42-3.23 (1H, m); 1.74-1.46 (4H, m); 1.45-1.15 (2H, m).

EXAMPLE 35

4-[(nitrooxy)methyl]benzyl 2-(tert-butoxycarbonylamino)acetate (Corresponding to Compound (87))

The title compound was prepared from N-Boc-Glycine N-hydroxysuccinimido ester and 4-(chloromethyl)benzyl alcohol following procedures reported in Example 3.

¹H-NMR (CDCl₃): 7.41 (4H, s), 5.44 (2H, s), 5.19 (2H, s), 5.02 (1H, bs), 3.97 (2H, d), 1.47 (9H, s).

EXAMPLE 36

4-[(nitrooxy)methyl]benzyl 2-aminoacetate (Corresponding to Compound (33))

The title compound was prepared from 4-[(nitrooxy)methyl]benzyl 2-(tert-butoxycarbonylamino)acetate (prepared in Example 35) following procedures reported in Example 4.

¹H-NMR (CDCl₃): 8.66-8.34 (2H, m), 7.59-7.40 (4H, m), 5.59 (2H, s), 5.26 (2H, s), 3.87 (2H, s).

EXAMPLE 37

(S)-bis(4-nitrooxy)butyl) 2-(tert-butoxycarbonylamino)pentanedioate (Corresponding to Compound (87)) (472))

The title compound was prepared from L-Boc-Glutamic acid and 4-chloro-1-butanol following procedure described in Example 3, eventually hydrolyzing the Boc protective group as described in Example 4.

¹H-NMR (CDCl₃): 5.28 (1H, bd), 4.48 (1H, bd), 4.19 (2H, t), 4.07 (2H, t), 2.40 (3H, m), 2.03 (1H, m), 1.72 (8H, m), 1.45 (9H, s).

EXAMPLE 38

(S)-4-(nitrooxy)butyl 2-amino-3-phenylpropanoate (Corresponding to Compound (40))

The title compound was prepared from (S)-4-(nitrooxy)butyl 2-(tert-butoxycarbonylamino)-3-phenylpropanoate (prepared as described in Example 31) following procedure described in Example 4.

¹H-NMR (DMSO): 8.7 (3H, bs), 7.30 (5H, m), 4.47 (2H, d), 4.25 (1H, t), 4.08 (2H, t), 3.15 (2H, m), 1.54 (4H, m).

PHARMACOLOGICAL EXAMPLE

The ability of the compounds of the present invention to release nitric oxide was assessed testing their vasorelaxant activity in isolated rabbit thoracic aorta preparations (Wanstall J. C. et al., Br. J. Pharmacol., 134:463-472, 2001).

The compounds of the invention that were tested are the compounds of the following formulas: 7, 8, 9, 12, 13, 15, 86, 87, 123, 407, 508, 511;

and compounds reported in Examples 14, 15, and 21.

Method

Male New Zealand rabbits were anaesthetized with thiopental-Na (50 mg/kg, iv), sacrificed by exsanguinations and then the thorax was opened and the aorta dissected. Single ring preparations (4 mm in length) of thoracic aorta were set up in physiological salt solution (PSS) at 37° C. in small organ chambers (5 ml). The composition of PSS was (mM): NaCl 130, NaHCO₃ 14.9, KH₂PO₄ 1.2, MgSO₄ 1.2, HEPES 10, CaCl₂, ascorbic acid 170 and glucose 1.1 (95%)₂/5% CO₂; pH 7.4). Each ring was mounted under 2 g passive tension in 5 ml organ bath. Isometric tension was recorded with a Grass transducer (Grass FT03) attached to a BIOPAC MP150 System. Preparations were allowed to equilibrate for 1 h, then contracted submaximally with noradrenaline (NA, 1 μM) and, when the contraction was stable, acetylcholine (ACh, 10 μM) was added. A relaxant response to ACh indicated the presence of a functional endothelium. When a stable precontraction was reached, a cumulative concentration-response curve to either of the vasorelaxant agents was obtained in the presence of a functional endothelium. Time intervals between different concentrations were based on the time needed to reach a full response.

Moreover, the nitric oxide-dependent vascular relaxation elicited by the tested compounds was examined preincubating the aortic rings with the soluble guanylyl cyclase inhibitor ODQ (1H-(1,2,4)-oxadiazol(4,3-a)quinoxalin-1-one) at 10 μM for 20 min. Responses to vasorelaxing agents were measured from the plateau of NA contraction. The IC₅₀ (concentration giving 50% reversal of NA contraction) was interpolated from the plots of relaxant-response vs log molar concentration of tested compound.

During the experimental period, the plateau obtained with NA was stable without significant spontaneous loss of contraction in the aortic rings.

As shown in the following Table 1, the compounds of the invention were able to induce relaxation in a concentration-dependent manner. Furthermore, in experiments performed in the presence of ODQ (10 μM), the vascular relaxation of the tested compounds was inhibited.

TABLE 1
Compound     IC50 (μM) ± sem
Example 15   1.2 ± 0.33
Example 14   1.9 ± 0.4
Compound 8   2.6 ± 0.6
Compound 7   2.4 ± 0.5
Compound 9   4.5 ± 1.4
Compound 86  5.2 ± 0.9
Compound 13  10.2 ± 0.5
Example 21   8.0 ± 1.8
Compound 87  2.1 ± 0.4
Compound 12  10.2 ± 4.2
Compound 508 4.4 ± 0.7
Compound 15  12.6 ± 6.4
Compound 511 9.5 ± 3.6
Compound 123 0.64 ± 0.14
Compound 407 16 ± 6.4
IC50 is the concentration which inhibits 50% of the response.

Claims

1. A compound and pharmaceutically acceptable salts or stereoisomers thereof selected from the group consisting of:

2. A medicament comprising a compound according to claim 1 and one or more pharmaceutically acceptable excipients.

3. A pharmaceutical composition comprising a compound according to claim 1 and one or more pharmaceutically acceptable excipients.

4. A composition comprising at least a compound of formula (I) according to claim 1 and at least one therapeutic agent selected from the group consisting of: anti-inflammatory drugs, drugs used to treat cardiovascular diseases, drugs for treating ocular diseases, and drugs for treating respiratory disorders.

5. A medicament comprising the composition according to claim 4 and one or more pharmaceutically acceptable excipients.

6. The composition according to claim 4 wherein the compound and the at least one therapeutic agent are administered simultaneously or sequentially.

7. A pharmaceutical composition comprising the composition according to claim 4 and one or more pharmaceutically acceptable excipients.

8. A method for treating a condition comprising administering a compound according to claim 1, wherein the condition is selected from the group consisting of cardiovascular diseases, inflammation, pain, fever, gastrointestinal disorders, ophthalmic diseases including glaucoma, hepatic disorders, renal diseases, respiratory disorders, immunological diseases, bone metabolism dysfunctions, central and peripheral nervous system diseases, sexual dysfunctions, infectious diseases, inhibition of platelet aggregation and platelet adhesion, pathological conditions resulting from abnormal cell proliferation and vascular diseases.

9. A method for treating a condition comprising administering the composition according to claim 4, wherein the condition is selected from the group consisting of cardiovascular diseases, inflammation, pain, fever, gastrointestinal disorders, ophthalmic diseases including glaucoma, hepatic disorders, renal diseases, respiratory disorders, immunological diseases, bone metabolism dysfunctions, central and peripheral nervous system diseases, sexual dysfunctions, infectious diseases, inhibition of platelet aggregation and platelet adhesion, pathological conditions resulting from abnormal cell proliferation and vascular diseases.