US20100041633A1 - Nitric oxide releasing steroids - Google Patents

Nitric oxide releasing steroids Download PDF

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US20100041633A1
US20100041633A1 US12/526,005 US52600508A US2010041633A1 US 20100041633 A1 US20100041633 A1 US 20100041633A1 US 52600508 A US52600508 A US 52600508A US 2010041633 A1 US2010041633 A1 US 2010041633A1
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Francesca Benedini
Stefano Biondi
Ennio Ongini
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Nicox SA
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Nicox SA
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Assigned to NICOX S.A. reassignment NICOX S.A. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BENEDINI, FRANCESCA, BIONDI, STEFANO, ONGINI, ENNIO
Publication of US20100041633A1 publication Critical patent/US20100041633A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/005—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of only two carbon atoms, e.g. pregnane derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/12—Keratolytics, e.g. wart or anti-corn preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
    • A61P5/44—Glucocorticosteroids; Drugs increasing or potentiating the activity of glucocorticosteroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers

Definitions

  • the present invention relates to use of nitric oxide releasing steroidal compounds having an improved pharmacological activity and low side effects in the treatment of respiratory diseases, and to a process for their preparation.
  • the present invention also relates to nitric oxide releasing steroidal compounds and to pharmaceutical formulations containing them.
  • Respiratory diseases comprise asthma, COPD (chronic obstructive pulmonary diseases), ARDS (Acute Respiratory Distress Syndrome), allergic rhinitis, respiratory tract diseases associated with inflammation.
  • the most drugs used in the treatment of respiratory diseases are steroids.
  • the currently available steroids have unsatisfactory site selectivity, for example all inhaled steroids are absorbed systemically from the lungs, and thus cause serious adverse effects by long-term administration.
  • nitrooxy derivatives of steroids which are usable also as cardiovascular agents for the coronary insufficiency or angina pectoris therapy, are described.
  • German patent DE 2,222,491 describes the preparation of pregnane derivatives having in position 21 the —CH 2 —O—NO 2 group.
  • said derivatives have a cardiotropic activity. This activity represents a drawback for said compounds, since they modify the cardiac frequency.
  • U.S. Pat. No. 3,494,941 describes steroid derivatives from 3-hydroxyextrane or from extr-4 en-3 one, used as vasodilators in the treatment of cardiac affections such as coronary insufficiency and angina pectoris.
  • a ONO 2 group is at the free end of the alkylene chain which is linked by an ether bond to the steroid in position 17.
  • nitrate groups also in the positions 3 and 16 of the steroidal structure. The same drawbacks mentioned above as regards the effects on the cardiac frequency can be repeated for the compounds of this patent.
  • U.S. Pat. No. 3,183,252 describes derivatives of 16-nitrate-alkylpregnanes wherein the alkyl group is linked to the pregnane structure by a carbon-carbon bond.
  • the compounds according to said patent can be used as vasodilators.
  • the same drawbacks reported for the above prior art can be repeated.
  • WO 98/15568 and WO 03/064443 in the name of the Applicant describe nitrate esters of steroidal compounds, wherein between the steroidal structure and the nitrooxy group a bivalent linking group is inserted. Said compounds show a good efficacy and/or good tolerability with respect to the corresponding precursors.
  • Patent application WO 00/61604 in the name of the Applicant describes nitrooxy derivatives of steroidal compounds with various linking groups having at one end a nitrooxy group, and covalently linked with the other end to a steroidal compound.
  • the uses concern the compounds usable in the treatment of patients in oxidative stress.
  • Said compounds contain in the molecule also a bivalent linking group which must be capable to prevent the free radicals production and is selected on the basis of the tests reported therein.
  • the Applicant has surprisingly and unexpectedly found a class of nitric oxide releasing compounds with a better efficacy, bioavailability and/or a prolonged release of NO in comparison with the compounds known in prior art.
  • the compounds of the present invention have a better drugability in comparison to the corresponding compounds of the prior art.
  • An object of the present invention is to provide nitric oxide releasing compounds of general formula (I)
  • R is a corticosteroid residue selected from:
  • a is 0 or 1
  • Z is a group capable of binding R X and is selected from —C(O)—, or —CH(R′)—O— wherein R′ is selected from H or a straight or branched C 1 -C 4 alkyl, preferably R′ is H or —CH 3 ;
  • R x is a radical selected from the following meanings:
  • R 1 is selected from:
  • R 1a is selected from:
  • R 3a is selected from H, —R 5a or
  • R 4a is selected from H or —C(O)CH 3 or
  • R 5a is as above defined
  • R 1b is selected from
  • R 2 is selected from:
  • B1 H, —CH 3 , CF 3 , isopropyl, isobutyl, sec-butyl, methylthio-(CH 2 ) 2 —, phenyl, benzyl, 3-tryptophanyl-CH 2 —, NH 2 —C(O)—CH 2 —, NH 2 —C(O)—(CH 2 ) 2 —, NH 2 ( ⁇ NH)NH—(CH 2 ) 3 —, tBuO—CH(CH 3 )—, benzyl-O—CH 2 —, 4-terbutoxy-benzyl, 4-phenylbenzyl, preferably R 2 is H, —CH 3 , isopropyl, benzyl,
  • R 2a is selected from:
  • R 2a is —CH 2 —O—;
  • R 2a is —(CH 2 ) 4 —NH— or —CH 2 —NH—;
  • R 2a is —CH 2 —C(O)—;
  • R 2b is selected from
  • R 2b is —O—CH 2 — or [-(4-O)—(CH 4 )]—CH 2 —;
  • R 2b is —HN—(CH 2 ) 4 — or —HN—CH 2 —;
  • R 2b is —C(O)—CH 2 —;
  • R 3a and R 4a are as above defined; T, T′ and T′′ are as above defined and Y and Y′ are as below defined; or R x is selected from:
  • D1 H, —CH 3 , isopropyl, isobutyl, sec-butyl, methylthio-(CH 2 ) 2 —, benzyl, 3-triptophanyl-CH 2 —, 4-imidazolyl-CH 2 —, NH 2 —CO—CH 2 —, NH 2 —CO—(CH 2 ) 2 —, NH 2 ( ⁇ NH)NH—(CH 2 ) 3 —, preferably R 12 is H;
  • R′ is —CH 2 —[(C 6 H 3 )-(3-nitro)-(4-OH)] preferably R′ is —CH 2 —OH or —CH 2 [(C 6 H 4 )-(4-OH)]
  • R 12a is selected from
  • R 12a is CH 2 —O— or —CH 2 —[(C 6 H 4 )-(4-O)—],
  • R 12a is —(CH 2 ) 4 —NH— or —CH 2 —NH—
  • R 12b is selected from
  • R 12 is —O—CH 2 — or [-(4-O)—(C 6 H 4 )]—CH 2 —;
  • R 12b is —HN— (CH 2 ) 4 — or —HN—CH 2 —;
  • R 12b is —C(O)—CH 2 —;
  • R 4a is as above defined; or R x is selected from:
  • T and T′ are as above defined and Y is as below defined;
  • e and f are equal to 0 or 1, with the proviso that f is 0 when e is 0 and f is 0 or 1 when e is 1, T and t′ are as above defined and y is as below reported;
  • R 3 is H, CH 3 , propyl, (C 6 H 5 ) 2 CH—, 1-naphtyl-CH 2 —, benzyl, allyl, 2-bromobenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-fluorobenzyl, 4-bromobenzyl, 4-methylbenzyl, preferably R 3 is H, T and T′ are as above defined and Y is as below defined;
  • R 4 is H, benzyl, 4-bromobenzyl, 2-bromobenzyl, T and T′ are as above defined and Y is as below defined;
  • R 5 is H, R 6 is H, or R 5 and R 6 when taken together are a double bond, T and T′ are as above defined and Y is as below reported;
  • T and T′ are as above defined and Y is as below reported;
  • T and T′ are as above defined and Y is as below reported;
  • R 7 is H, R 8 is H, or R 7 and R 8 when taken together are a double bond, c is as above defined, T and T′ are as above defined and Y is as below reported;
  • T and T′ are as above defined and Y is as below reported;
  • T and T′ are as above defined and Y is as below reported;
  • T and T′ are as above defined and Y is as below reported;
  • T and T′ are as above defined and Y is as below reported;
  • T and T′ are as above defined and Y is as below reported;
  • R 9 and R 10 are H, CH 3 , R 11 is CH 3 or 4-piperidinyl with the proviso that R 9 and R 10 are H when R 11 is 4-piperidinyl and R 9 and R 10 are CH 3 when R 11 is CH 3 , T and T′ are as above defined and Y is as below reported;
  • T and T′ are as above defined and Y is as below reported; with the proviso that in the formula (I): a is 0 or a is 1 and Z is —CH(R′)—O— wherein R′ is as above defined, when R x is:
  • R 1b is selected from the group A10);
  • R 2b is selected from the group B10);
  • R 12b is selected from the group D10);
  • a 1 and Z is —C(O)—, when R x is:
  • R 1b is selected from the groups A8) and A9);
  • R 2b is selected from the groups B8) or B9);
  • R 2b is selected from the groups D8) or D9);
  • Y and Y′ are bivalent radicals each independently selected from the following meanings: a)
  • cycloalkylene with 5 to 7 carbon atoms into cycloalkylene ring, the ring being optionally substituted with one or more straight or branched C 1 -C 10 alkyl chains, preferably the ring being optionally substituted with CH 3 ;
  • n 0 is an integer from 0 to 20, preferably n C is 0 or 1; n 1 is 0 or 1, preferably n 1 is 1;
  • U is a linear or branched C 1 -C 20 alkylene optionally substituted with a ONO 2 group, preferably U is a linear C 1 -C 10 alkylene or U is a linear or branched C 1 -C 10 alkylene substituted with a —ONO 2 group;
  • n 0 is an integer from 0 to 20, preferably n C is 0 or 1; n 1 is 0 or 1, preferably n 1 is 1;
  • U is a linear or branched C 1 -C 20 alkylene optionally substituted with a —ONO 2 group, preferably U is a linear C 1 -C 10 alkylene or U is a linear or branched C 1 -C 10 alkylene substituted with a —ONO 2 group;
  • n 2 is an integer from 0 to 2
  • R 13 is H or CH 3
  • T 1 is —O—C(O)— or —C(O)O—
  • n 1 and U are as above defined; e)
  • n 2 is an integer from 0 to 2, preferably n 2 is 1;
  • R 13 is H or CH 3 , preferably R 13 is CH 3 ;
  • Y 1 is —CH 2 —CH 2 — or —CH ⁇ CH—(CH 2 ) 2 —, wherein n is 0 or 1, preferably Y 1 is —CH ⁇ CH—(CH 2 ) n 2′ — and n 2′ is 0;
  • T 1 —O—C(O)— or —C(O)O—, preferably T 1 is —C(O)O—;
  • n 1 is 0 or 1, preferably n 1 is 1;
  • U is a linear or branched C 1 -C 20 alkylene optionally substituted with a ONO 2 group, preferably U is a linear C 1 -C 10 alkylene or U is a linear or branched C 1 -C 10 alkylene substituted with a —ONO 2 group; more preferably n 2 is 1, R
  • n 2 is an integer from 0 to 2, preferably n2 is 1;
  • R 13 is H or CH 3 , preferably R 13 is CH 3 ;
  • Y 1 is —CH 2 —CH 2 — or —(CH 2 ) n 2′ —CH ⁇ CH—, wherein n is 0 or 1, preferably Y 1 is —(CH 2 ) n 2′ —CH ⁇ CH— and n 2′ is 0;
  • T 1 —O—C(O)—
  • n 1 is 0 or 1, preferably n 1 is 1;
  • U is a linear or branched C 1 -C 20 alkylene optionally substituted with a —ONO 2 group, preferably U is a linear C 1 -C 10 alkylene or U is a linear or branched C 1 -C 10 alkylene substituted with a —ONO 2 group; more preferably n 2 is 1, R 13 is CH 3 , Y 1 is —CH ⁇ CH—(CH 2 ) n 2′ — and n 2′ is 0, T 1 is —OC(O)— and U is a linear C 1 -C 10 alkylene; f)
  • T 2 is —O— or —S—, —NH—, preferably T 2 is —O—, n 3 is an integer from 1 to 6, preferably n 3 is 1; when Y and Y′ are selected from b), c), d), e), e′) or f), the —ONO 2 group of -(T-Y—ONO 2 ), -(T′-Y—ONO 2 ), -(T′′-Y′—ONO 2 ), -(T′-Y′—ONO 2 ), -(T′′′-Y—ONO 2 ) and -(T′′′-Y′—ONO 2 ) is linked to the —(CH 2 )*— group; g)
  • n 4 is an integer from 0 to 10, preferably n 4 is 0 or 1;
  • n 5 is an integer from 1 to 10, preferably n 5 is 1;
  • R 14 , R 15 , R 16 , R 17 are the same or different, and are H or straight or branched C 1 -C 4 alkyl, preferably R 14 , R 15 , R 16 and R 17 are H;
  • n 5 is as defined above;
  • Y 2 is an heterocyclic saturated, unsaturated or aromatic 5 or 6 members ring, containing one or more heteroatoms selected from nitrogen, oxygen, sulphur,
  • C 1 -C 10 alkyl refers to branched or straight alkyl groups including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl, hexyl, octyl and the like.
  • cycloalkylene refers to ring having from 5 to 7 carbon atoms including, but not limited to, cyclopentylene, cyclohexylene optionally substituted with side chains such as straight or branched (C 1 -C 10 )-alkyl, preferably CH 3 .
  • heterocyclic 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.
  • Respiratory diseases comprises asthma, COPD (chronic obstructive pulmonary diseases), ARDS (Acute Respiratory Distress Syndrome), allergic rhinitis, respiratory tract diseases associated with inflammation.
  • An embodiment of the invention relates to nitric oxide releasing compounds of general formula (I)
  • corticosteroid residue R is selected from:
  • R X is selected from: (a2) —C(O)—CH(R 1 )—NH-(T′-Y—ONO 2 ) wherein R 1 of the group A1) is selected from H, isobutyl, benzyl, C 6 H 5 —CH 2 —CH 2 —, 2-monosubstituted benzyl, or 3-monosubstituted benzyl or 4-monosubstituted benzyl wherein the substituent of the benzyl is selected from —F, —Cl, I, —NO 2 , —CF 3 , —CH 3 , CN, C 6 H 5 CO—; R 1 of the group A2) is selected from —CH 2 —OH, —CH(CH 3 )OH— or —CH 2 [(C 6 H 4 )-(4-OH)], or R 1 of the group A3) is selected from —CH 2 —NHR′′, —(CH 2 ) 2 —N
  • R 1a of the group A5) is selected from —CH 2 —O—, —CH(CH 3 )O— or —CH 2 —[(C 6 H 4 )-(4-O)—], or R 1a of the group A6) is selected from —CH 2 —NH—, —(CH 2 ) 2 —NH—, —(CH 2 ) 3 —NH—, —(CH 2 ) 4 —NH—, or R 1a of the group A7) is selected from —CH 2 —C(O)—, —(CH 2 ) 2 —C(O)—, —(CH 2 ) 4 —C(O)—,
  • R 4a is H or —C(O)CH 3 ,
  • T′′ is —C(O)— or —C(O)—X′′ wherein X′′ is —S— or —O—, when R 1a is selected from the group A5) or A6), preferably T′′ is —C(O)—; T′′ is —O—, —S—, —NR′— or —O—CH(R′)—O—C(O)— wherein R′ is H or —CH 3 , when R 1a is selected from the group A7), Y′ is as below defined; or R X is selected from: (a5) —R 1b —CH(NHR 4a )—C(O)-(T-Y—ONO 2 ) (a6) —R 1b —CH(COOR 3a )NH-(T′-Y—ONO 2 ) (a9) —R 1b —CH(NH-T′-Y′—ONO 2 )—C(O)-(T-Y—ONO 2 ) or (a10) —R
  • R 4a is H or —C(O)CH 3 ,
  • T is —O—, —S—, —NR′— or —O—CH(R′)—O—C(O)— wherein R′ is H or —CH 3 , preferably T is —O—, T′ is —C(O)— or —C(O)—X′′ wherein X′′ is —S— or —O—, preferably T′ is —C(O)—, Y and Y′ are as below defined;
  • R 1a of the group A5) is selected from —CH 2 —O—, —CH(CH 3 )—O— or —CH 2 —[(C 6 H 4 )-(4-O)—], or R 1a of the group A6) is selected from —CH 2 —NH—, —(CH 2 ) 2 —NH—, —(CH 2 ) 3 —NH—, —(CH 2 ) 4 —NH—, or R 1a of the group A7) is selected from —CH 2 —C(O)—, —(CH 2 ) 2 —C(O)—, —(CH 2 ) 4 —C(O)—, T′′ is —C(O)— or —C(O)—X′′ wherein X′′ is —S— or —O—, when R 1a is
  • T′ is —C(O)— or —C(O)—X′′ wherein X′′ is —S— or —O—, preferably T′ is —C(O)—,
  • Y and Y′ are as below defined
  • n 2 is an integer from 0 to 2
  • R 13 is H or CH 3
  • T 1 is —O—C(O)— or —C(O)O—
  • n′ is 1 and U is a linear C 1 -C 10 alkylene or U is a linear or branched C 1 -C 10 alkylene substituted with a —ONO 2 group;
  • n 2 is 1, R 13 is CH 3 , Y 1 is —CH ⁇ CH—(CH 2 ) n 2′ — and n is 0, T 1 is —C(O)O— and U is a linear C 1 -C 10 alkylene; e′)
  • n 2 is 1, R 13 is CH 3 ;
  • Y 1 is —(CH 2 ) n 2′ —CH ⁇ CH— and n 2′ is 0;
  • T 1 —O—C(O)—
  • n 1 is 1 and U is a linear C 0 -C 10 alkylene or U is a linear or branched C 1 -C 10 alkylene substituted with a —ONO 2 group; f)
  • T 2 is —O— or —S—, —NH—, preferably T 2 is —O—, n 3 is 1 or 2; when Y and Y′ are selected from d), e), e′) or f), the —ONO 2 group of -(T-Y—ONO 2 ), -(T′-Y—ONO 2 ), -(T′′-Y′—ONO 2 ), -(T′-Y′—ONO 2 ), -(T′′′-Y—ONO 2 ) and -(T′′′-Y′—ONO 2 ) is linked to the —(CH 2 )*— group.
  • Another embodiment of the invention relates to nitric oxide releasing compounds of general formula (I)
  • corticosteroid residue R is selected from:
  • a is 1 and Z is —C(O)—;
  • R 1 of the group A1 is selected from H, isobutyl, benzyl, C 6 H 5 —CH 2 —CH 2 —, 2-monosubstituted benzyl, or 3-monosubstituted benzyl or 4-monosubstituted benzyl wherein the substituent of the benzyl is selected from —F, —Cl, I, —NO 2 , —CF 3 , —CH 3 , CN, C 6 H 5 CO— or R 1 of the group A2) is selected from:
  • R 1 of the group A3) is selected from —CH 2 —NHR′′, —(CH 2 ) 2 —NHR′′, —(CH 2 ) 3 —NHR′′, —(CH 2 ) 4 —NHR′′, wherein R′′ is H, or —C(O)CH 3
  • R 1 of the group A4) is —CH 2 —C(O)R′′′, —(CH 2 ) 2 —C(O)R′′′, —(CH 2 ) 4 —C(O)R′′′ wherein R′′′ is OR 5a wherein R 5a is H or a linear (C 1 -C 5 ) alkyl; T is —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)— wherein R′ is H or a straight or branched C 1 -C 4 alkyl, preferably T is —O—, Y is as below defined;
  • R 1a of the group A5) is selected from —CH 2 —O—, —CH(CH 3 )O— or —CH 2 [(C 6 H 4 )-(4-O)—], or R 1a of the group A6) is selected from —CH 2 —NH—, —(CH 2 ) 2 —NH—, —(CH 2 ) 3 —NH—, —(CH 2 ) 4 —NH—, or R 1a of the group A7) is —CH 2 —C(O)—, —(CH 2 ) 2 —C(O)—, —(CH 2 ) 4 —C(O)—, R 3a is H or a (C 1 -C 5 ) alkyl, T′′ is —C(O)— or —C(O)—X′′ wherein X′′ is —S— or —O—,
  • R 1b of the group A8) is selected from —O—CH(CH 3 )—, —O—CH 2 —, [-4-O)—(C 6 H 4 )]—CH 2 —, or
  • R 1b of the group A9) is selected from —HN—CH 2 —, —HN—(CH 2 ) 2 —, —HN—(CH 2 ) 3 —, —HN—(CH 2 ) 4 —,
  • R 3a is H or a (C 1 -C 5 ) alkyl
  • R 4a is H or —C(O)CH 3
  • T is —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)— wherein R′ is H or a straight or branched C 1 -C 4 alkyl, preferably T is —O—, T′ is —C(O)— or —C(O)—X′′ wherein X′′ is —S— or —O—, preferably T′ is —C(O)—, Y and Y′ are as below defined;
  • R 1a of the group A5) is selected from CH 2 —O—, —CH(CH 3 )—O— or —CH 2 —[(C 6 H 4 )-(4-O)—], or R 1a of the group A6) is selected from —CH 2 —NH—, —(CH 2 ) 2 —NH—, —(CH 2 ) 3 —NH—, —(CH 2 ) 4 —NH—, or R 1a of the group A7) is —CH 2 —C(O)—, —(CH 2 ) 2 —C(O)—, —(CH 2 ) 4 —C(O)—; T′′ is —C(O)— or —C(O)—X′′, wherein X′′ is —S— or —O—, when R 1a is selected from A
  • R 2 of the group B1 is selected from H, CH 3 , isobutyl, isopropyl, benzyl;
  • R 2 of the group B2) is selected from —CH 2 —OH, —CH(CH 3 )—OH— or —CH 2 [(C 6 H 4 )(4-OH)], or
  • R 2 of the group B3) is selected from —CH 2 —NHR′′, —(CH 2 ) 2 —NHR′′, —(CH 2 ) 3 —NHR′′, —(CH 2 ) 4 —NHR′′, wherein R′′ is H, or —C(O)CH 3 ,
  • R 2 of the group B4) is —CH 2 —C(O)R′′′, —(CH 2 ) 2 —C(O)R′′′, —(CH 2 ) 4 —C(O)R′′′
  • R 12 of the group D3) is selected from —CH 2 —NHR′′, —(CH 2 ) 2 —NHR′′, —(CH 2 ) 3 —NHR′′, —(CH 2 ) 4 —NHR′′ wherein R′′ is H, or
  • R 12 of the group D4) is —CH 2 —C(O)R′′′, —(CH 2 ) 2 —C(O)R′′′, —(CH 2 ) 4 —C(O)R′′′ wherein R′′′ is OR 5a wherein R 5a is H or a linear (C 1 -C 5 ) alkyl; T′ and T′′′ are each independently selected from —C(O)— or —C(O)—X′′ wherein X′′ is —S— or —O—, preferably T′ and T′′′ are —C(O)—, Y is as below defined; or R X is selected from: (d3) —HN—CH(R 12a -T′′-Y′—ONO 2 )—CH 2 OH (d4) —O—CH 2 —CH(R 12a -T′′-Y′—ONO 2 )—NHR 4a
  • R 4a is H or —C(O)CH 3 ,
  • T′′ is selected from —C(O)— or —C(O)—X′′, wherein X′′ is —S— or —O—, when R 12a is selected from D5) or D6), preferably T′ and T′′′ are —C(O)—, T′′ is —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)—, wherein R′ is H or a straight or branched C 1 -C 4 alkyl, when R 12a is selected from D7), preferably T is —O—, T′′′ is selected from —C(O)— or —C(O)—X′′ wherein X′′ is —S— or —O—, preferably T′′′ is —C(O)—, Y and Y′ are as below defined; or R X is selected from: (d5) —R 12b —CH(NHR 4a )—CH 2 —O-(T′′′-Y—ON
  • R 12b of the group D9) is selected from —HN—CH 2 —, —HN— (CH 2 ) 2 —, —HN— (CH 2 ) 3 —, —HN— (CH 2 ) 4 —;
  • R 4a is H or —C(O)—CH 3 .
  • T′ and T′′′ are each independently selected from —C(O)—, —C(O)—X′′, wherein X′′ is —S— or —O—, preferably T′ and T′′′ are —C(O)—, Y and Y′ are each independently selected from a)
  • n 2 is an integer from 0 to 2
  • R 13 is H or CH 3
  • T 1 is —O—C(O)— or —C(O)O—
  • n 1 is 1
  • U is a linear C 1 -C 10 alkylene or U is a linear or branched C 1 -C 10 alkylene substituted with a —ONO 2 group;
  • n 2 is 1, R 13 is CH 3 , Y 1 is —CH ⁇ CH— (CH 2 ) n 2′ — and n 2′ is 0, T 1 is —C(O)O— and U is a linear C 1 -C 10 alkylene; e′)
  • n 2 is 1, R 13 is CH 3 , Y 1 is —(CH 2 ) n 2′ —CH ⁇ CH— and n 2′ is 0,
  • T 1 —O—C(O)—
  • n 1 is 1 and U is a linear C 1 -C 10 alkylene or U is a linear or branched C 1 -C 10 alkylene substituted with a —ONO 2 group; f)
  • T 2 is —O— or —S—, —NH—, preferably T 2 is —O—, n 3 is 1 or 2, when Y and Y′ are selected from d), e), e′) or f), the —ONO 2 group of -(T-Y—ONO 2 ), -(T′′-Y—ONO 2 ), -(T′′-Y′—ONO 2 ), -(T′′-Y′—ONO 2 ), -(T′′′-Y—ONO 2 ) and -(T′′′-Y′—ONO 2 ) is linked to the —(CH 2 )*— group.
  • Another embodiment of the present invention is to provide nitric oxide releasing compounds of general formula (I)
  • corticosteroid residue R is selected from:
  • T′ is —C(O)—
  • Y is selected from a)
  • Another embodiment relates to nitric oxide releasing compounds of general formula (I)
  • corticosteroid residue R is selected from:
  • R X is selected from R X is selected from
  • R 4a is H or —C(O)CH 3 ,
  • T is selected from —O—, —S—, —NR′— wherein R′ is as above defined, T′ is —C(O)— and Y and Y′ are each independently selected from a)
  • Another embodiment relates to nitric oxide releasing compounds of general formula (I)
  • corticosteroid residue R is selected from:
  • a 1 and Z is —C(O)—
  • R 4a is H or —C(O)CH 3 ,
  • T is selected from —O—, —S—, —NR′— wherein R′ is as above defined,
  • T′ is —C(O)—
  • Y and Y′ are each independently selected from a)
  • Another embodiment of the invention relates to nitric oxide releasing compounds of general formula (I)
  • corticosteroid residue R is selected from:
  • T′ is —C(O)—
  • Y and Y′ are each independently selected from a)
  • nitric oxide releasing compounds of general formula (I) for the use in the treatment of respiratory diseases are:
  • Another object of the present invention provides nitric oxide releasing compounds of general formula (I) and pharmaceutically acceptable salts or stereoisomers thereof
  • R is a corticosteroid residue selected from:
  • a is 0 or 1
  • Z is a group capable of binding R X and is selected from —C(O)—, or —CH(R′)—O— wherein R′ is selected from H or a straight or branched C 1 -C 4 alkyl, preferably R′ is H or —CH 3 ;
  • R x is a radical selected from the following meanings:
  • R 2 is selected from:
  • B1 H, —CH 3 , CF 3 , isopropyl, isobutyl, sec-butyl, methylthio-(CH 2 ) 2 —, phenyl, benzyl, 3-triptophanyl-CH 2 —, NH 2 —C(O)—CH 2 —, NH 2 —C(O)—(CH 2 ) 2 —, NH 2 ( ⁇ NH)NH—(CH 2 ) 3 —, tBuO—CH(CH 3 )—, benzyl-O—CH 2 —, 4-terbutoxy-benzyl, 4-phenylbenzyl, preferably R 2 is H, —CH 3 , isopropyl, benzyl,
  • B2 —CH 2 —SH, —CH 2 —OH, —CH(CH 3 )—OH, —CH 2 —[(C 6 H 4 )-(4-OH)], —CH 2 —[(C 6 H 2 )-(3,5-diiodo)-(4-OH)], —CH 2 —[(C 6 H 3 )-(3-nitro)-(4-OH)];
  • R 2a is selected from:
  • R 2a is —CH 2 —O—;
  • R 2a is —(CH 2 ) 4 —NH— or —CH 2 —NH—;
  • R 2a is —CH 2 —C(O)—;
  • R 2b is selected from
  • R 2b is —O—CH 2 — or [-(4-O)—(C 6 H 4 )]—CH 2 —;
  • R 2b is —HN— (CH 2 ) 4 — or —HN—CH 2 —;
  • R 2b is —C(O)—CH 2 —;
  • R 3a and R 4a are as above defined; T, T′ and T′′ are as above defined and Y and Y′ are as below defined; or R x is selected from:
  • D1 H, —CH 3 , isopropyl, isobutyl, sec-butyl, methylthio-(CH 2 ) 2 —, benzyl, 3-triptophanyl-CH 2 —, 4-imidazolyl-CH 2 —, NH 2 —CO—CH 2 —, NH 2 —CO—(CH 2 ) 2 —, NH 2 ( ⁇ NH)NH—(CH 2 ) 3 —, preferably R 12 is H;
  • R 12 is —CH 2 —OH or —CH 2 [(C 6 H 4 )-(4-OH)];
  • R 12a is selected from
  • R 12a is CH 2 —O— or —CH 2 —[(C 6 H 4 )-(4-O)—],
  • R 12a is —(CH 2 ) 4 —NH— or —CH 2 —NH—
  • R 12b is selected from
  • R 12 is —O—CH 2 — or [-(4-O)—(C 6 H 4 )]—CH 2 —;
  • R 12b is —HN— (CH 2 ) 4 — or —HN—CH 2 —;
  • T and T′ are as above defined and Y is as below defined;
  • e and f are equal to 0 or 1, with the proviso that f is 0 when e is 0 and f is 0 or 1 when e is 1, T and t′ are as above defined and y is as below reported;
  • R 3 is H, CH 3 , propyl, (C 6 H 5 ) 2 CH—, 1-naphtyl-CH 2 —, benzyl, allyl, 2-bromobenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-fluorobenzyl, 4-bromobenzyl, 4-methylbenzyl, preferably R 3 is H, T and T′ are as above defined and Y is as below defined;
  • R 4 is H, benzyl, 4-bromobenzyl, 2-bromobenzyl, T and T′ are as above defined and Y is as below defined;
  • R 5 is H, R p is H, or R 5 and R when taken together are a double bond, T and T′ are as above defined and Y is as below reported;
  • T and T′ are as above defined and Y is as below reported;
  • T and T′ are as above defined and Y is as below reported;
  • R 7 is H, R 8 is H, or R 7 and R 8 when taken together are a double bond, c is as above defined, T and T′ are as above defined and Y is as below reported;
  • T and T′ are as above defined and Y is as below reported;
  • T and T′ are as above defined and Y is as below reported;
  • T and T′ are as above defined and Y is as below reported;
  • T and T′ are as above defined and Y is as below reported;
  • T and T′ are as above defined and Y is as below reported;
  • R 9 and R 10 are H, CH 3 , R 11 is CH 3 or 4-piperidinyl with the proviso that R 9 and R 10 are H when R 11 is 4-piperidinyl and R 9 and R 10 are CH 3 when R 11 is CH 3 , T and T′ are as above defined and Y is as below reported;
  • T and T′ are as above defined and Y is as below reported; with the proviso that in the formula (I): a is 0 or a is 1 and Z is —CH(R′)—O— wherein R′ is as above defined, when R X is:
  • R 1b is selected from the group A10);
  • R 2b is selected from the group B10);
  • R 12b is selected from the group D10);
  • a 1 and Z is —C(O)—, when R X is:
  • R 1b is selected from the groups A8) and A9);
  • R 2b is selected from the groups B8) or B9);
  • R 12b is selected from the groups D8) or D9);
  • Y and Y′ are bivalent radicals each independently selected from the following meanings: a)
  • cycloalkylene with 5 to 7 carbon atoms into cycloalkylene ring, the ring being optionally substituted with one or more straight or branched C 1 -C 10 alkyl chains, preferably the ring being optionally substituted with CH 3 ;
  • n 0 is an integer from 0 to 20, preferably n C is 0 or 1; n 1 is 0 or 1, preferably n′ is 1; U is a linear or branched C 1 -C 20 alkylene optionally substituted with a —ONO 2 group, preferably U is a linear C 1 -C 10 alkylene or U is a linear or branched C 1 -C 10 alkylene substituted with a ONO 2 group; c)
  • n 0 is an integer from 0 to 20, preferably n C is 0 or 1; n 1 is 0 or 1, preferably n′ is 1;
  • U is a linear or branched C 1 -C 20 alkylene optionally substituted with a —ONO 2 group, preferably U is a linear C 1 -C 10 alkylene or U is a linear or branched C 1 -C 10 alkylene substituted with a —ONO 2 group;
  • n 2 is an integer from 0 to 2
  • R 13 is H or CH 3
  • T 1 is —O—C(O)— or —C(O)O—
  • n 1 and U are as above defined; e)
  • n 2 is an integer from 0 to 2, preferably n 2 is 1;
  • R 13 is H or CH 3 , preferably R 13 is CH 3 ;
  • Y 1 is —CH 2 —CH 2 — or —CH ⁇ CH—(CH 2 ) n 2′ —, wherein n 2′ is 0 or 1, preferably Y 1 is —CH ⁇ CH—(CH 2 ) n 2′ — and n 2′ is 0;
  • T 1 —O—C(O)— or —C(O)O—, preferably T 1 is —C(O)O—;
  • n 1 is 0 or 1, preferably n 1 is 1;
  • U is a linear or branched C 1 -C 20 alkylene optionally substituted with a —ONO 2 group, preferably U is a linear C 1 -C 10 alkylene or U is a linear or branched C 1 -C 10 alkylene substituted with a ONO 2 group; more preferably
  • n 2 is an integer from 0 to 2, preferably n 2 is 1;
  • R 13 is H or CH 3 , preferably R 13 is CH 3 ;
  • Y 1 is —CH 2 —CH 2 — or —(CH 2 ) 2 —CH ⁇ CH—, wherein n is 0 or 1, preferably Y 1 is —(CH 2 ) n 2′ —CH ⁇ CH— and n 2′ is 0;
  • T 1 —O—C(O)—
  • n 1 is 0 or 1, preferably n 1 is 1;
  • U is a linear or branched C 1 -C 20 alkylene optionally substituted with a —ONO 2 group, preferably U is a linear C 1 -C 10 alkylene or U is a linear or branched C 1 -C 10 alkylene substituted with a —ONO 2 group; more preferably n 2 is 1, R 13 is CH 3 , Y 1 is —CH ⁇ CH—(CH 2 ) n 2′ — and n 2′ is 0, T 1 is —OC(O)— and U is a linear C 1 -C 10 alkylene; f)
  • T 2 is —O— or —S—, —NH—, preferably T 2 is —O—, n 3 is an integer from 1 to 6, preferably n 3 is 1; when Y and Y′ are selected from b), c), d), e), e′) or f), the —ONO 2 group of -(T-Y—ONO 2 ), -(T′-Y—ONO 2 ), -(T′′-Y′—ONO 2 ), -(T′-Y′—ONO 2 ), -(T′′′-Y—ONO 2 ) and -(T′′′-Y′—ONO 2 ) is linked to the —(CH 2 )*— group; g)
  • n 4 is an integer from 0 to 10, preferably n 4 is 0 or 1;
  • n 5 is an integer from 1 to 10, preferably n 5 is 1;
  • R 14 , R 15 , R 16 , R 17 are the same or different, and are H or straight or branched C 1 -C 4 alkyl, preferably R 14 , R 15 , R 16 and R 17 are H;
  • n 5 is as defined above;
  • Y 2 is an heterocyclic saturated, unsaturated or aromatic 5 or 6 members ring, containing one or more heteroatoms selected from nitrogen, oxygen, sulphur, and is selected from the group consisting of:
  • Another object of the present invention provides nitric oxide releasing compounds of general formula (I) and pharmaceutically acceptable salts or stereoisomers thereof
  • R is a corticosteroid residue selected from:
  • R X is selected from: (a2) —C(O)—CH(R 1 )—NH-(T′-Y—ONO 2 ) wherein R 1 of the group A1) is selected from H, isobutyl, benzyl, C 6 H 5 —CH 2 —CH 2 —, 2-monosubstituted benzyl, or 3-monosubstituted benzyl or 4-monosubstituted benzyl wherein the substituent of the benzyl is selected from —F, —Cl, I, —NO 2 , —CF 3 , —CH 3 , CN, C 6 H 5 CO—; R 1 of the group A2) is selected from —CH 2 —OH, —CH(CH 3 )OH— or —CH 2 [(C 6 H 4 )-(4-OH)], or R 1 of the group A3) is selected from —CH 2 —NHR′′, —(CH 2 ) 2 —N
  • R 1a of the group A5) is selected from —CH 2 —O—, —CH(CH 3 )O— or —CH 2 —[(C 6 H 4 )-(4-O)—], or R 1a of the group A6) is selected from —CH 2 —NH—, —(CH 2 ) 2 —NH—, (CH 2 ) 3 —NH—, —(CH 2 ) 4 —NH—, or R 1a of the group A7) is selected from —CH 2 —C(O)—, —(CH 2 ) 2 —C(O)—, —(CH 2 ) 4 —C(O)—,
  • R 4a is H or —C(O)CH 3 ,
  • T′′ is —C(O)— or —C(O)—X′′ wherein X′′ is —S— or —O—, when R 1a is selected from the group A5) or A6), preferably T′′ is —C(O)—; T′′ is —O—, —S—, —NR′— or —O—CH(R′)—O—C(O)— wherein R′ is H or —CH 3 , when R 1a is selected from the group A7), Y′ is as below defined; or R X is selected from: (a5) —R 1b —CH(NHR 4a )—C(O)-(T-Y—ONO 2 ) (a6) —R 1b —CH(COOR 3a )NH-(T′—Y—ONO 2 ) (a9) —R 1b —CH(NH-T′-Y′—ONO 2 )—C(O)-(T-Y—ONO 2 ) or (a10) —R
  • R 4a is H or C(O)CH 3 ,
  • T is —O—, —S—, —NR′— or —O—CH(R′)—O—C(O)— wherein R′ is H or —CH 3 , preferably T is —O—, T′ is —C(O)— or —C(O)—X′′ wherein X′′ is —S— or —O—, preferably T′ is —C(O)—, Y and Y′ are as below defined;
  • R 1a of the group A5) is selected from —CH 2 —O—, —CH(CH 3 )—O— or —CH 2 [(C 6 H 4 )-(4-O)—], or R 1a of the group A6) is selected from —CH 2 —NH—, —(CH 2 ) 2 —NH—, —(CH 2 ) 3 —NH—, —(CH 2 ) 4 —NH—, or R 1a of the group A7) is selected from —CH 2 —C(O)—, —(CH 2 ) 2 —C(O)—, —(CH 2 ) 4 —C(O)—, T′′ is —C(O)— or —C(O)—X′′ wherein X′′ is —S— or —O—, when R 1a is selected from
  • n 2 is 1, R 13 is CH 3 , Y 1 is —CH ⁇ CH—(CH 2 ) n 2′ — and n 2′ is 0, T 1 is —C(O)O— and U is a linear C 1 -C 10 alkylene; e′)
  • n 2 is 1, R 13 is CH 3 ;
  • Y 1 is —(CH 2 ) n 2′ —CH ⁇ CH— and n 2′ is 0;
  • T 1 —O—C(O)—
  • n 1 is 1 and U is a linear C 1 -C 10 alkylene or U is a linear or branched C 1 -C 10 alkylene substituted with a —ONO 2 group; f)
  • T 2 is —O— or —S—, —NH—, preferably T 2 is —O—, n 3 is 1 or 2; when Y and Y′ are selected from d), e), e′) or f), the —ONO 2 group of -(T-Y—ONO 2 ), -(T′-Y—ONO 2 ), -(T′′-Y′—ONO 2 ), -(T′-Y′—ONO 2 ), -(T′′′-Y—ONO 2 ) and -(T′′′-Y′—ONO 2 ) is linked to the —(CH 2 )*— group.
  • Another object of the present invention provides nitric oxide releasing compounds of general formula (I) and pharmaceutically acceptable salts or stereoisomers thereof
  • R is a corticosteroid residue selected from:
  • a is 1 and Z is —C(O)—;
  • R 1 of the group A1 is selected from H, isobutyl, benzyl, C 6 H 5 —CH 2 —CH 2 —, 2-monosubstituted benzyl, or 3-monosubstituted benzyl or 4-monosubstituted benzyl wherein the substituent of the benzyl is selected from —F, —Cl, I, —NO 2 , —CF 3 , —CH 3 , CN, C 6 H 5 CO— or R 1 of the group A2) is selected from:
  • R 1 of the group A3) is selected from —CH 2 —NHR′′, —(CH 2 ) 2 —NHR′′, —(CH 2 ) 3 —NHR′′, —(CH 2 ) 4 —NHR′′, wherein R′′ is H, or —C(O)CH 3
  • R 1 of the group A4) is —CH 2 —C(O)R′′′, —(CH 2 ) 2 —C(O)R′′′, —(CH 2 ) 4 —C(O)R′′′ wherein R′′′ is OR 5a wherein R 5a is H or a linear (C 3 -C 5 ) alkyl; T is —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)— wherein R′ is H or a straight or branched C 1 -C 4 alkyl, preferably T is —O—, Y is as below defined;
  • R 1a of the group A5) is selected from —CH 2 —O—, —CH(CH 3 )O— or —CH 2 —[(C 6 H 4 )-(4-O)—], or R 1a of the group A6) is selected from —CH 2 —NH—, —(CH 2 ) 2 —NH—, —(CH 2 ) 3 —NH—, —(CH 2 ) 4 —NH—, or R 1a of the group A7) is —CH 2 —C(O)—, —(CH 2 ) 2 —C(O)—, —(CH 2 ) 4 —C(O)—, R 3a is H or a (C 1 -C 5 ) alkyl, T′′ is —C(O)— or —C(O)—X′′ wherein X′′ is —S— or —O
  • R 1b of the group AB) is selected from —O—CH(CH 3 )—, —O—CH 2 —, [-4-O)—(C 6 H 4 )]—CH 2 —, or R 1b of the group A9) is selected from —HN—CH 2 —, —HN—(CH 2 ) 2 —, —HN— (CH 2 ) 3 —,
  • R 4a is H or —C(O)CH 3 ,
  • T is —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)— wherein R′ is H or a straight or branched C 1 -C 4 alkyl, preferably T is —O—, T′ is —C(O)— or —C(O)—X′′ wherein X′′ is —S— or —O—, preferably T′ is —C(O)—, Y and Y′ are as below defined;
  • R 1a of the group A5) is selected from —CH 2 —O—, —CH(CH 3 )—O— or —CH 2 [(C 6 H 4 )-(4-O)—], or R 1a of the group A6) is selected from —CH 2 —NH—, —(CH 2 ) 2 —NH—, —(CH 2 ) 3 —NH—, —(CH 2 ) 4 —NH—, or R 1a of the group A7) is —CH 2 —C(O)—, —(CH 2 ) 2 —C(O)—, —(CH 2 ) 4 —C(O)—; T′′ is —C(O)— or —C(O)—X′′, wherein X′′ is —S— or —O—, when R′′ is selected from A5)
  • R 2 of the group B1 is selected from H, CH 3 , isobutyl, isopropyl, benzyl;
  • R 2 of the group B2) is selected from —CH 2 —OH, —CH(CH 3 )—OH— or —CH 2 —[(C 6 H 4 )(4-OH)], or
  • R 2 of the group B3) is selected from —CH 2 —NHR′′, —(CH 2 ) 2 —NHR′′, —(CH 2 ) 3 —NHR′′, —(CH 2 ) 4 —NHR′′, wherein R′′ is H, or —C(O)CH 3 ,
  • R 2 of the group B4) is —CH 2 —C(O)R′′′, —(CH 2 ) 2 —C(O)R′′′, —(CH 2 ) 4 —C(O)R
  • R 4a is H or —C(O)CH
  • T′′ is selected from —C(O)— or —C(O)—X′′, wherein X′′ is —S— or —O—, when R 12a is selected from D5) or D6), preferably T′ and T′′′ are —C(O)—, T′′ is —O—, —S—, —NR′—, —O—CH(R′)—O—C(O)—, wherein R′ is H or a straight or branched C 1 -C 4 alkyl, when R 12a is selected from D7), preferably T is —O—, T′′′ is selected from —C(O)— or —C(O)—X′′ wherein X′′ is —S— or —O—, preferably T′′′ is —C(O)—, Y and Y′ are as below defined; or R X is selected from: (d5) —R 12b —CH(NHR 4a )—CH 2 —O-(T′′′-Y—ON
  • R 4a is H or —C(O)—CH 3 ,
  • T′ and T′′′ are each independently selected from —C(O)—, —C(O)—X′′, wherein X′′ is —S— or —O—, preferably T′ and T′′′ are —C(O)—, Y and Y′ are each independently selected from a)
  • n 2 is an integer from 0 to 2
  • R 13 is H or CH 3
  • T 1 is —O—C(O)— or —C(O)O—
  • n 1 is 1
  • U is a linear C 1 -C 10 alkylene or U is a linear or branched C 1 -C 10 alkylene substituted with a —ONO 2 group;
  • n 2 is 1, R 13 is CH 3 , Y 1 is —CH ⁇ CH—(CH 2 ) n 2′ — and n 2′ is 0, T 1 is —C(O)O— and U is a linear C 1 -C 10 alkylene; e′)
  • n 2 is 1, R 13 is CH 3 , Y 1 is —(CH 2 ) n 2′ —CH ⁇ CH— and n 2′ is 0,
  • T 1 —O—C(O)—
  • n 1 is 1 and U is a linear C 1 -C 10 alkylene or U is a linear or branched C 1 -C 10 alkylene substituted with a —ONO 2 group; f)
  • T 2 is —O— or —S—, —NH—, preferably T 2 is —O—, n 3 is 1 or 2, when Y and Y′ are selected from d), e), e′) or f), the —ONO 2 group of -(T-Y—ONO 2 ), -(T′-Y—ONO 2 ), -(T′′-Y′—ONO 2 ), -(T′-Y′—ONO 2 ), -(T′′′-Y—ONO 2 ) and -(T′′′-Y′—ONO 2 ) is linked to the —(CH 2 )*— group.
  • Another object of the present invention provides nitric oxide releasing compounds of general formula (I) and pharmaceutically acceptable salts or stereoisomers thereof
  • R is a corticosteroid residue selected from:
  • T′ is —C(O)—
  • Y is selected from a)
  • Another object of the present invention provides nitric oxide releasing compounds of general formula (I) and pharmaceutically acceptable salts or stereoisomers thereof
  • R is a corticosteroid residue selected from:
  • R X is selected from R X is selected from
  • R 1b of the group A10) is —C(O)—CH 2 —
  • R 3a is H or a (C 1 -C 5 ) alkyl
  • R 4a is H or —C(O)CH 3 ,
  • T is selected from —O—, —S—, —NR′— wherein R′ is as above defined,
  • T′ is —C(O)—
  • Y and Y′ are each independently selected from a)
  • Another object of the present invention provides nitric oxide releasing compounds of general formula (I) and pharmaceutically acceptable salts or stereoisomers thereof
  • R is a corticosteroid residue selected from:
  • a 1 and Z is —C(O)—
  • R 1b of A10) is —O—CH 2 — or [-4-O—(C 6 H 4 )]—CH 2 —,
  • R 4a is H or —C(O)CH 3 ,
  • T is selected from —O—, —S—, —NR′— wherein R′ is as above defined,
  • T′ is —C(O)—
  • Y and Y′ are each independently selected from a)
  • Another object of the present invention provides nitric oxide releasing compounds of general formula (I) and pharmaceutically acceptable salts or stereoisomers thereof
  • R is a corticosteroid residue selected from:
  • T′ is —C(O)—
  • Y and Y′ are each independently selected from a)
  • nitric oxide releasing compounds of general formula (I) are:
  • Another object of the invention is a composition comprising a compound of formula (I) above reported and at least one bronchodilator or a pharmaceutical acceptable salt or solvate thereof.
  • Bronchodilators that can be used in the composition of the invention include: anticholinergic bronchodilators which includes tiotropium and ipratropium, ⁇ 2 -agonists which include salbutamol, bitolterol mesylate, formoterol, isoproterenol, levalbuterol, metaproterenol, salmeterol, terbutaline and fenoterol.
  • ⁇ 2 -agonists and anticholinergics include ephedrine and xanthines.
  • Representative xanthines include theophylline, aminophylline and oxtriphyline.
  • the compound of formula (I) and at least one bronchodilator are administered simultaneously wherein the two components may be administered by the same or different administration pathways.
  • the compound of formula (I) and at least one bronchodilator are administered sequentially wherein the compound of formula (I) may be administered before or after the bronchodilator and the two components may be administered by the same or different administration pathways.
  • the invention provides the use of a composition comprising a compound of formula (I) above reported and at least one bronchodilator or a pharmaceutical acceptable salt or solvate thereof in the treatment of respiratory diseases which comprise asthma, COPD (chronic obstructive pulmonary diseases), ARDS (Acute Respiratory Distress Syndrome), allergic rhinitis and respiratory tract diseases associated with inflammation.
  • respiratory diseases which comprise asthma, COPD (chronic obstructive pulmonary diseases), ARDS (Acute Respiratory Distress Syndrome), allergic rhinitis and respiratory tract diseases associated with inflammation.
  • 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.
  • inorganic bases such as sodium, potassium, calcium and aluminium hydroxides
  • 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.
  • organic acids examples include oxalic, tartaric, maleic, succinic, citric acids.
  • 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.
  • optically pure enantiomers pure diastereomers, enantiomers mixtures, diastereomers mixtures, enantiomer racemic mixtures, racemates or racemate mixtures.
  • the compounds of the present invention are formulated in the corresponding pharmaceutical compositions, also with belated release, for parenteral, oral and topic use, such as for example inhalatory, suppository, transdermal, according to the well known techniques in the art, together with the usual excipients; see for example the publication “Remington's Pharmaceutical Sciences” 15 th Ed.
  • the amount on a molar basis of the active principle in said compositions is generally the same, or lower than that of the corresponding precursor drug.
  • the daily administrable doses are those of the precursor drugs, or optionally lower.
  • the precursor daily doses can be found in the publications of the field, such for example in the “Physician's Desk reference”.
  • X 1 is as below defined, X 1 is a radical having the following meaning:
  • R′′ is selected from A1) as defined above or A2′) —CH 2 —SP 1 , —CH 2 —OP 1 , —CH(CH 3 )—OP 1 , —CH 2 —[(C 6 H 4 )-4-OP 1 ], —CH 2 —[(C 6 H 3 )-(3,5-diiodo)-4-OP 1 ], —CH 2 —[(C 6 H 3 )-3-nitro-4-OP 1 ] or
  • R′′′′ is P 3 or —C(O)CH 3 or
  • R 5a is as defined above;
  • R′′′′′ is P 2 , —OR 5a or
  • R 5a is as above defined
  • R 1a is as defined above and R 4a is P 3 or —C(O)—CH 3 or
  • R 2′ is selected from B1) as defined above or
  • R′′′′ is as above defined;
  • B4′ —CH 2 —C(O)—R′′′′′, —(CH 2 ) 2 —C(O)—R′′′′′, —(CH 2 ) 4 —C(O)—R′′′′′ wherein R′′′′′ is as above defined;
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , b, c, d, e and f are as above defined;
  • P 1 is a hydroxyl or thiol protecting group such as silyl ethers, such as trimethylsilyl, tert-butyl-dimethylsilyl or trityl and those described in T. W. Greene “Protective groups in organic synthesis”, Harvard University Press, 1980, P2 is a carboxylic protecting group such as tert-butyl ester and those described in T. W.
  • Q is independently —ONO 2 or Z 2 wherein Z 2 is selected from the group consisting of: a chlorine atom, a bromine atom, a iodine atom, a mesyl group or a tosyl group, and 1-ii) when Q is Z 2 , by converting the compound obtained in the step 1-i) into nitro derivative by reaction with a nitrate source such as silver nitrate, lithium nitrate, sodium nitrate, potassium nitrate, magnesium nitrate, calcium nitrate, iron nitrate, zinc nitrate or tetraalkylammonium nitrate (wherein alkyl is C 1 -
  • Preferred nitrate source is silver nitrate and 1-iii) optionally deprotecting the compounds obtained in step 1-i) or 1-ii) as described in T. W. Greene “Protective groups in organic synthesis”, Harvard University Press, 1980, 2 nd edition. Fluoride ion is the preferred method for removing silyl ether protecting group. Trifluoroacetic acid or anhydrous inorganic acid are the preferred method for removing Boc protecting group, anhydrous organic or inorganic acid is the preferred method for removing trityl protecting group. Organic base such as piperidine is the preferred method for removing Fmoc protecting group. Aqueous or anhydrous organic or inorganic acid is the preferred method for removing t-butyl ester protecting group.
  • the reaction is carried out in an inert organic dry solvent such as N,N′-dimethylformamide, tetrahydrofuran, benzene, toluene, dioxane, a polyhalogenated aliphatic hydrocarbon at a temperature from ⁇ 20° C. to 50° C.
  • an inert organic dry solvent such as N,N′-dimethylformamide, tetrahydrofuran, benzene, toluene, dioxane, a polyhalogenated aliphatic hydrocarbon
  • the reaction is carried out in an inert organic solvent such as N,N′-dimethylformamide, tetrahydrofuran, benzene, toluene, dioxane, a polyhalogenated aliphatic hydrocarbon at a temperature from ⁇ 20° C. to 40° C.
  • an inert organic solvent such as N,N′-dimethylformamide, tetrahydrofuran, benzene, toluene, dioxane, a polyhalogenated aliphatic hydrocarbon at a temperature from ⁇ 20° C. to 40° C.
  • the reaction is completed within a time range from 30 minutes to 36 hours.
  • organic base such as N,N-dimethylamino pyridine (DMAP), triethylamine, pyridine.
  • DMAP N,N-dimethylamino pyridine
  • the reaction is carried out in an inert organic solvent such as N,N′-dimethylformamide, tetrahydrofuran, benzene, toluene, dioxane, a polyhalogenated aliphatic hydrocarbon at a temperature from ⁇ 20° C. to 40° C.
  • the reaction is completed within a time range from 30 minutes to 36 hours.
  • R 1′ is selected from A1), A2′), A3′), A4′), R 1a is selected from A5) or A6) and R 4a′ is as defined above
  • R 2′ is selected from B1), B2′), B3′), B4′
  • R 2a is selected from B5) or B6) and R 4a′ is as defined above
  • y is the radical Y when X 2 is selected from (a2′), (b2′), (c2′), (e2′), (f1′), (g2′), (h1′), (i1′), (l2′), (m2′), (n2′), (o2′), (p2′), (q2′), (r2′), (s2′), (t2′), (u2′), (v2′), and y is the radical Y′ when X 2 is selected from (a4′) or (b4′), wherein Y and Y′ are as defined above, and 1a-ii) when Q is Z 2 , by converting the compound obtained in the step 1a-i) into nitro derivative by reaction with a nitrate source as above described and 1a-iii) optionally deprotecting the compounds obtained in step 1a-i) or 1a-ii) as above described.
  • reaction of a compound of formula (IIIa) wherein P 2 and X 2 are as above defined, with a compound of formula (IVa) wherein W 1 is OH, y, Q are as above defined, may be carried out as described in 1-i-1) or in presence of other known condensing reagents such as O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU).
  • HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate
  • the compounds of formula (IVa) wherein W 1 is OH, y and Q are as above defined can be obtained from the corresponding alcohols of formula HOOC-y-OH (IVb) by reaction with nitric acid and acetic anhydride in a temperature range from ⁇ 50° C. to 0° C. or from the corresponding derivatives of formula HOOC-y-Z 2 (IVc) wherein Z 2 is as above defined, by reaction with a nitrate source as above described.
  • the reaction with AgNO 3 can be performed under microwave irradiation in solvents such acetonitrile or THF at temperatures in the range between 100 and 180° C. for time range from 1 to 60 min.
  • X 1 is selected from (a2′), (a4′), (b2′), (b4′), (c2′), (e2′), (f1′), (g2′), (h1′), (i1′), (l2′), (m2′), (n2′), (o2′), (p2′), (q2′), (r2′), (s2′), (t2′), (u21), (v2′), wherein R′′ is selected from A1), A2′), A3′) or A4′), R 1a is selected from A5) or A6), R 2a is selected from B5) or B6) and R 2′ is selected from B1), B2′), B3′) or B4′), and wherein Y, Y′ and Q are as above defined and T′ and T′′ are C(O), can be obtained from the corresponding acids (Ia) wherein W is —OH as known in the literature.
  • y is the radical Y when X 2 is selected from (a2′), (b2′), (c2′), (e2′), (f1′), (g2′), (h1′), (i1′), (l2′), (m2′), (n2′), (o2′), (p2′), (q2′), (r2′), (s2′), (t2′), (u2′), (v2′), and y is the radical Y′ when X 2 is selected from (a4′) or (b4′), wherein Y and Y′ are as above defined, and
  • X 1 is selected from (a2′), (a4′), (b2′), (b4′), (c2′), (e2′), (f1′), (g2′), (h1′), (i1′), (l2′), (m2′), (n2′), (o2′), (p2′), (q2′), (r2′), (s2′), (t2′), (u2′), (v2′), wherein R 1′ is selected from A1), A2′), A3′), A4′), R 1a is selected from A5) or A6), R 2a is selected from B5) or B6) and R 2′ is selected from B1), B2′), B3′), B4′), Y, Y′ and Q are as above defined, T′ and T′′ are C(O)—X′′ wherein X′′ is O or S, can be obtained from the corresponding acids (Ia) wherein W is —Cl or O—R a , X 1 is selected from (a2′),
  • W 1 and Q are as above defined, wherein y is the radical Y or Y′, wherein Y and Y′ are as above defined, and 1c-ii) when Q is Z 2 , by converting the compounds obtained in the step 1c-i) into nitro derivative by reaction with a nitrate source as above described and 1c-iii) optionally deprotecting the compounds obtained in step 1c-i) or 1c-ii) as above described.
  • reaction of a compound of formula (IIIb) wherein P 2 and X 3 are as above defined, with a compound of formula (IVa) wherein W 1 is OH, y and Q are as above defined, may be carried out as described in 1a-i) using a ratio (IIIb)/(IVa) 1:2.
  • reaction of a compound of formula (IIIb) wherein P 2 and X 3 are as above defined, with a compound of formula (IVa) wherein W 1 is OR a , y and Q are as above defined, may be carried out as described in 1-i-2) using a ratio (IIIb)/(IVa) 1:2.
  • R 1a is selected from A5) or A6)
  • R 2a is selected from B5) or B6), with a compound of formula (IVa)
  • W 1 and Q are as above defined, wherein y is the radical Y′, wherein Y′ is as above defined, and 1d-ii) when Q is Z 2 , by converting the compounds obtained in the step 1d-i) into nitro derivative by reaction with a nitrate source as above described and 1d-iii) optionally deprotecting the compounds obtained in step 1d-i) or 1d-ii) as above described.
  • R a and Q are as above defined, wherein y is the radical Y′, wherein Y′ is as above defined, and 1e-ii) when Q is Z 2 , by converting the compounds obtained in the step 1e-i) into nitro derivative by reaction with a nitrate source as above described and 1e-iii) optionally deprotecting the compounds obtained in step 1e-i) or 1e-ii) as above described.
  • reaction of a compound of formula (IIIb) wherein P 2 and X 3 are as above defined, with a compound of formula (IVd) wherein R a , y and Q are as above defined, may be carried out as described in 1-i-2) using a ratio (IIIb)/(IVd) 1:2.
  • W 1 and Q are as above defined
  • y is the radical Y′, wherein Y′ is as above defined
  • 1f-ii) when Q is Z 2 by converting the compounds obtained in the step 1f-i) into nitro derivative by reaction with a nitrate source as above described and 1f-iii) optionally deprotecting the compounds obtained in step 1f-i) or 1f-ii) as above described.
  • R a , R′ and Q are as above defined
  • y is the radical Y′, wherein Y′ is as above defined
  • 1g-ii) when Q is Z 2 by converting the compounds obtained in the step 1g-i) into nitro derivative by reaction with a nitrate source as above described and 1g-iii) optionally deprotecting the compounds obtained in step 1g-i) or 1g-ii) as above described.
  • the compounds of formula (IVg) wherein y is as above defined and Q is Z 2 are commercially available, the compounds of formula (IVg) wherein y is as above defined and Q is —ONO 2 may be obtained from the compounds of formula P 3 —R′N-y-ONO 2 (IVh) wherein P 3 is as above defined by deprotection of amino group as known in literature.
  • the compounds of formula (IVh) wherein P 3 and y are as above defined may be obtained from the alcohol P 3 —R′N-y-OH (IVi) by reacting with tetraalkylammonium nitrate as already described for analogous compounds.
  • the compounds of formula (IVi) are commercially available or known in literature.
  • the compounds of formula (IVh) wherein P 3 and y are as above defined may be obtained from the corresponding compounds of formula P 3 —R′N-y-Z 2 (IVl) wherein P 3 , y and Z 2 are as above defined, by reaction with a nitrate source as above described.
  • R 1a is selected from A7)
  • R 2a is selected from B7)
  • X′′ and Q are as above defined
  • y is the radical Y′, wherein Y′ is as above defined
  • 1h-ii) when Q is Z 2 by converting the compounds obtained in the step 1h-i) into nitro derivative by reaction with a nitrate source as above described and 1h-iii) optionally deprotecting the compounds obtained in step 1h-i) or 1h-ii) as above described.
  • R′ and Q are as above defined
  • y is the radical Y′, wherein Y′ is as above defined
  • 1i-ii) when Q is Z 2 by converting the compounds obtained in the step 1i-i) into nitro derivative by reaction with a nitrate source such above described and 1i-iii) optionally deprotecting the compounds obtained in step 1i-i) or 1i-ii) as above described.
  • R′ and Q are as above defined, Hal is an halogen atom, y is the radical Y′, wherein Y′ is as above defined, and 1l-ii) when Q is Z 2 , by converting the compounds obtained in the step 1l-i) into nitro derivative by reaction with a nitrate source such above described and 1l-iii) optionally deprotecting the compounds obtained in step 1l-i) or 1l-ii) as above described.
  • reaction of a compound of formula (Ie) wherein P 5 and X 5 are as above defined, with a compound of formula (IVm) wherein y, Q, R′ are as above defined may be carried out in the presence of a inorganic or organic base in an aprotic polar/non-polar solvent such as DMF, THF or CH 2 Cl 2 at temperature in the range between 0° and 100° C. or in a double phase system H 2 O/Et 2 O temperature in the range between 20° and 40° C.
  • an aprotic polar/non-polar solvent such as DMF, THF or CH 2 Cl 2
  • the compounds of formula (IVm) wherein y, Q, R′ are as above defined, Hal is an halogen atom may be obtained by reacting a compound R′—CH 2 —CHO, commercially available, with a compound of formula Hal-(O)C-y-Q (IVn), wherein y and Q are as above defined, Hal is a chlorine atom and ZnCl 2 as known in literature.
  • the compounds of formula (IVn) may be obtained as known in literature.
  • R′ and Q are as above defined
  • y is the radical Y′, wherein Y′ is as above defined
  • Hal is an halogen atom
  • 1m-ii) when Q is Z 2 by converting the compounds obtained in the step 1m-i) into nitro derivative by reaction with a nitrate source such above described and 1m-iii) optionally deprotecting the compounds obtained in step 1m-i) or 1m-ii) as above described.
  • the compounds of formula (IVo) wherein y, R′, Q are as above defined may be obtained by reacting the compounds of formula Hal-(R′)CH—OC(O)Hal, wherein Hal is as above defined, commercially available, with a compound of formula HO-y-Q (IVe) wherein y, Q are as above defined, in the presence of a inorganic or organic base in an aprotic polar or in an aprotic non-polar solvent such as DMF, THF or CH 2 Cl 2 at temperatures range between 0° to 65° C.
  • R a is selected from A7)
  • R 2a is selected from B7)
  • X′′ and Q are as above defined
  • y is the radical Y′, wherein Y′ is as above defined
  • 1n-ii) when Q is Z 2 by converting the compounds obtained in the step 1n-i) into nitro derivative by reaction with a nitrate source as above described and 1n-iii) optionally deprotecting the compounds obtained in step 1n-i) or 1-ii) as above described.
  • R′ and Q are as above defined, y is the radical Y′, and 1o-ii) when Q is Z 2 , by converting the compounds obtained in the step 1o-i) into nitro derivative by reaction with a nitrate source as above described and 1o-iii) optionally deprotecting the compounds obtained in step 1o-i) or 1o-ii) as above described.
  • R′ and Q are as above defined
  • y is the radical Y′, wherein Y′ is as above defined
  • Hal is an halogen atom and 1p-ii) when Q is Z 2 , by converting the compounds obtained in the step 1p-i) into nitro derivative by reaction with a nitrate is source as above described and 1p-iii) optionally deprotecting the compounds obtained in step 1p-i) or 1p-ii) as above described.
  • R′ and Q are as above defined
  • y is the radical Y′, wherein Y′ is as above defined
  • Hal is an halogen atom and 1q-ii) when Q is Z 2 , by converting the compounds obtained in the step 1q-i) into nitro derivative by reaction with a nitrate source as above described and 1q-iii) optionally deprotecting the compounds obtained in step 1q-i) or 1q-ii) as above described.
  • R X is selected from (a2), (a4), (a8), (b2), (b4), (b8), (c2), (e2), (f1), (g2), (h1), (i1), (l2), (m2), (n2), (o2), (p2), (q2), (r2), (s2), (t2), (u2), (v2), Z is —CH(R′)—O— wherein R′ is selected from H or straight or branched C 1 -C 4 alkyl, can be obtained: 2-i) by reacting a compound of formula (II 1 ) as above defined with a compound of formula (If)
  • Hal is an halogen atom
  • R′ and X 1 are as above defined and 2-ii) when Q is Z 2 , by converting the compounds obtained in the step 2-i) into nitro derivative by reaction with a nitrate source as above described and 2-iii) optionally deprotecting the compounds obtained in step 2-i) or 2-ii) as above described.
  • reaction of a compound of formula (If) wherein X 1 and R′ are as above defined, with a compound of formula (II 1 ) may be carried out as described in 1l-i).
  • X 2 is a radical having the following meanings:
  • R 1′ , R 1a , R 2′ , R 2a are as above defined R 3a′ is selected from P 2 , —OR 5a or
  • R 5a is as above defined
  • T, T′′, Y and Y′ are as above defined, 3-ii) when Q is Z 2 , by converting the compounds obtained in the step 3-i) into nitro derivative by reaction with a nitrate source such above described and 3-iii) optionally deprotecting the compounds obtained in step 3-i) or 3-ii) as above described.
  • reaction of a compound of formula (II3), wherein R and R a are as above defined, with a compound of formula (Ig) wherein X 1 is as above defined, may be carried out as described in 1-i-2).
  • X 6 is a radical having the following meanings:
  • R 1′ is selected from A1), A2′), A3′) or A4′
  • R 1a is selected from A7)
  • R 2a is selected from B7)
  • R 2′ is selected from B1), B2′), B3′) or B4′
  • R 3a′ is defined above
  • y is the radical Y when X 6 is selected from (a1′), (b1′), (c1′), (e1′), (r2′), (g1′), (h2′), (i2′), (l1′), (m1′), (n1′), (o1′), (p1′), (q1′), (r1′), (s1′), (t1′), (u1′) and (v1′), y is the radical Y′ when X 6 is selected from (a3′) and (b3′), wherein Y and Y′ are as defined above, and 3a-ii) when Q is Z 2 , by converting the compounds obtained in the step 3a-i) into nitro derivative by reaction with a nitrate source as above described and 3a-iii) optionally deprotecting the compounds obtained in step 3a-i) or 3a-ii) as above described.
  • y is the radical Y when X 6 is selected from (a1′), (b1′), (c1′), (e1′), (r2′), (g1′), (h2′), (i2′), (l1′), (m1′), (n1′), (o1′), (p1′), (q1′), (r1′), (s1′), (t1′), (u1′) and (v1′), y is the radical Y′ when X 6 is selected from (a3′) and (b3′), wherein Y and Y′ are as defined above, and 3b-ii) when Q is Z 2 , by converting the compounds obtained in the step 3b-i) into nitro derivative by reaction with a nitrate source as above described and 3b-iii) optionally deprotecting the compounds obtained in step 3b-i) or 3b-ii) as above described.
  • y is the radical Y when X 6 is selected from (a1′), (b1′), (c1′), (e1′), (f2′), (g1′), (h2′), (i2′), (l1′), (m1′), (n1′), (o1′), (p1′), (q1′), (r1′), (s1′), (t1′), (u1′) and (v1′), y is the radical Y′ when X 6 is selected from (a3′) and (b3′), wherein Y and Y′ are as defined above, and 3c-ii) when Q is Z 2 , by converting the compounds obtained in the step 3c-i) into nitro derivative by reaction with a nitrate source as above described and 3c-iii) optionally deprotecting the compounds obtained in step 3c-i) or 3c-ii) as above described.
  • Hal is an halogen atom
  • y is the radical Y when X 6 is selected from (a1′), (b1′), (c1′), (e1′), (f2′), (g1′), (h2′), (i2′), (l1′), (m1′), (n1′), (o1′), (p1′), (q1′), (r1′), (s1′), (t1′), (u1′) and (v1′), y is the radical Y′ when X 6 is selected from (a3′) and (b3′), wherein Y and Y′ are as defined above, and 3d-ii) when Q is Z 2 , by converting the compounds obtained in the step 3d-i) into nitro derivative by reaction with a nitrate source as above described and 3d-iii) optionally deprotecting the compounds obtained in step 3d-i) or 3d-ii) as above described.
  • R 1a is selected from A5) or A6)
  • R 2a is selected from B5) or B6), with compounds of formula (IVa)
  • W 1 and Q are as above defined
  • y is the radical Y′, wherein Y′ is as above defined
  • 3e-ii) when Q is Z 2 by converting the compounds obtained in the step 3e-i) into nitro derivative by reaction with a nitrate source as above described and 3e-iii) optionally deprotecting the compounds obtained in step 3e-i) or 3e-ii) as above described.
  • T is —O—CH(R′)—O—C(O)— are obtained as described in 3c).
  • T is —O—CH(R′)—O—C(O)O— are obtained as described in 3d).
  • R a and Q are as above defined
  • y is the radical Y′, wherein Y′ is as above defined
  • 3g-ii) when Q is Z 2 by converting the compounds obtained in the step 3g-i) into nitro derivative by reaction with a nitrate source as above described and 3g-iii) optionally deprotecting the compounds obtained in step 3g-i) or 3g-ii) as above described.
  • T is —O—CH(R′)—O—C(O)— are obtained as described in 3c).
  • T is —O—CH(R′)—O—C(O)O— are obtained as described in 3d).
  • X′′ and Q are as above defined
  • y is the radical Y′, wherein Y′ is as above defined
  • 3h-ii) when Q is Z 2 by converting the compounds obtained in the step 3h-i) into nitro derivative by reaction with a nitrate source as above described and 3h-iii) optionally deprotecting the compounds obtained in step 3h-i) or 3h-ii) as above described.
  • reaction of a compound of formula (Ih) wherein P 3 and X 7 are as above defined, with a compound of formula (IVe) wherein y, Q, X′′ are as above defined, may be carried out as described in 1-i-1), 1-i-2) and 1a-1).
  • T is —O—CH(R′)—O—C(O)— are obtained as described in 3c).
  • T is —O—CH(R′)—O—C(O)O— are obtained as described in 3d).
  • R′ and Q are as above defined
  • y is the radical Y′, wherein Y′ is as above defined
  • 3i-ii) when Q is Z 2 by converting the compound obtained in the step 3i-i) into nitro derivative by reaction with a nitrate source as above described and 3i-iii) optionally deprotecting the compounds obtained in step 3i-i) or 3i-ii) as above described.
  • R′ and Q are as above defined
  • y is the radical Y′, wherein Y′ is as above defined
  • Hal is an halogen atom and 3l-ii) when Q is Z 2 , by converting the compounds obtained in the step 3l-i) into nitro derivative by reaction with a nitrate source as above described and 3l-iii) optionally deprotecting the compounds obtained in step 3l-i) or 3l-ii) as above described.
  • R′ and Q are as above defined
  • y is the radical Y′, wherein Y′ is as above defined
  • Hal is an halogen atom and 3m-ii) when Q is Z 2 , by converting the compounds obtained in the step 3m-i) into nitro derivative by reaction with a nitrate source as above described and 3m-iii) optionally deprotecting the compounds obtained in step 3l-i) or 3m-ii) as above described.
  • R 1a is selected from A5 or A6) and R 2a is selected from B5) or B6), wherein R 3a′ is as above defined, with a compound of formula (IVa)
  • W 1 and Q are as above defined
  • y is the radical Y′, wherein Y′ is as above defined
  • 3n-ii) when Q is Z 2 by converting the compounds obtained in the step 3n-i) into nitro derivative by reaction with a nitrate source as above described and 3n-iii) optionally deprotecting the compounds obtained in step 3n-i) or 3n-ii) as above described.
  • R a , X′′, Q are as above defined
  • y is the radical Y′, wherein Y′ is as above defined
  • 3o-ii) when Q is Z 2 by converting the compounds obtained in the step 3o-i) into nitro derivative by reaction with a nitrate source as above described and 3o-iii) optionally deprotecting the compounds obtained in step 3o-i) or 3o-ii) as above described.
  • R a , R′ and Q are as above defined
  • y is the radical Y′, wherein Y′ is as above defined
  • 3p-ii) when Q is Z 2 by converting the compounds obtained in the step 3p-i) into nitro derivative by reaction with a nitrate source as above described and 3p-iii) optionally deprotecting the compounds obtained in step 3p-i) or 3p-ii) as above described.
  • X 12 is the radical R X having the following meaning
  • reaction of a compound of formula (II 3 ) wherein R and R a are as above defined, with a compound of formula (Im) wherein X 12 is as above defined, may be carried out as described in 1-i-2).
  • R 12′ is D1), D2′), D3′) or D4′
  • R 12a is D5) or D6)
  • R 4a′ and P 1 are as above defined, with a compound of formula (IVa)
  • y is the radical Y when X 13 is selected from (d1′) or (d2′), y is the radical Y′ when X 13 is selected from (d3′) or (d4′), wherein Y and Y′ are as above defined, and 4a-ii) when Q is Z 2 , by converting the compounds obtained in the step 4a-i) into nitro derivative by reaction with a nitrate source as above described and 4a-iii) optionally deprotecting the compounds obtained in step 4a-i) or 4a-ii) as above described.
  • y is the radical Y when X 13 is selected from (d1′) or (d2′), y is the radical Y′ when X 13 is selected from (d3′) or (d4′), wherein Y and Y′ are as above defined, and 4b-ii) when Q is Z 2 , by converting the compounds obtained in the step 4b-i) into nitro derivative by reaction with a nitrate source as above described and 4b-iii) optionally deprotecting the compounds obtained in step 4b-i) or 4b-ii) as above described.
  • R 12a is selected from D5) or D6), with a compound of formula (IVa)
  • W 1 and Q are as above defined
  • y is the radical Y′, wherein Y′ is as above defined
  • 4c-ii) when Q is Z 2 by converting the compounds obtained in the step 4c-i) into nitro derivative by reaction with a nitrate source as above described and 4c-iii) optionally deprotecting the compounds obtained in step 4c-i) or 4c-ii) as above described.
  • reaction of a compound of formula (IIIl) wherein P 4 and X 14 are as above defined, with a compound of formula (IVa) wherein W 1 is OH, y and Q are as above defined, may be carried out as described in 1-i-1) using a ratio (IIIl)/(IVa) 1:2.
  • reaction of a compound of formula (IIIl) wherein P 4 and X 14 are as above defined, with a compound of formula (IVa) wherein W 1 is OR a , y and Q are as above defined, may be carried out as described in 1-i-2) using a ratio (IIIl)/(IVa) 1:2.
  • R 12a is selected from D5) or D6), Y, Q, T′ and T′′′ are as above defined, with a compound of formula (IVa)
  • W 1 , y and Q′ are as above defined
  • y is the radical Y′, wherein Y′ is as above defined
  • 4d-ii) when Q is Z 2 by converting the compounds obtained in the step 4d-i) into nitro derivative by reaction with a nitrate source as above described and 4d-iii) optionally deprotecting the compounds obtained in step 4d-i) or 4d-ii) as above described.
  • T′ and T′′′ are —C(O)— can by obtained as described in 4a).
  • R a , X′′ and Q are as above defined
  • y is the radical Y′, wherein Y′ is as above defined
  • 4e-ii) when Q is Z 2 by converting the compounds obtained in the step 4e-i) into nitro derivative by reaction with a nitrate source as above described and 4e-iii) optionally deprotecting the compounds obtained in step 4e-i) or 4e-ii) as above described.
  • reaction of a compound of formula (IIIl) wherein P 4 and X 14 are as above defined, with a compound of formula (IVd) wherein R a , X′′, y and Q are as above defined, may be carried out as described in 1-i-2) using a ratio (IIIl)/(IVd) 1:2.
  • R a , X′′ and Q are as above defined
  • y is the radical Y′, wherein Y′ is as above defined
  • 4f-ii) when Q is Z 2 by converting the compounds obtained in the step 4f-i) into nitro derivative by reaction with a nitrate source as above described and 4f-iii) optionally deprotecting the compounds obtained in step 4f-i) or 4f-ii) as above described.
  • R a , R′ and Q are as above defined
  • y is the radical Y′, wherein Y′ is as above defined
  • 4g-ii) when Q is Z 2 by converting the compounds obtained in the step 4g-i) into nitro derivative by reaction with a nitrate source as above described and 4g-iii) optionally deprotecting the compounds obtained in step 4g-i) or 4g-ii) as above described.
  • R 12a is selected from D7), with a compound of formula (IVe)
  • Y′, X′′ and Q are as above defined
  • y is the radical Y′, wherein Y′ is as above defined
  • 4h-ii) when Q is Z 2 by converting the compounds obtained in the step 4h-i) into nitro derivative by reaction with a nitrate source as above described and 4h-iii) optionally deprotecting the compounds obtained in step 4h-i) or 4h-ii) as above described.
  • R′ and Q are as above defined
  • y is the radical Y′, wherein Y′ is as above defined
  • 4i-ii) when Q is Z 2 by converting the compounds obtained in the step 4i-i) into nitro derivative by reaction with a nitrate source such above described and 4i-iii) optionally deprotecting the compounds obtained in step 4i-i) or 4l-ii) as above described.
  • R′ and Q are as above defined, Hal is an halogen atom, y is the radical Y′, wherein Y′ is as above defined, and 4l-ii) when Q is Z 2 , by converting the compounds obtained in the step 4l-i) into nitro derivative by reaction with a nitrate source such above described and 4l-iii) optionally deprotecting the compounds obtained in step 4l-i) or 4l-ii) as above described.
  • R and Q′ are as above defined, Hal is an halogen atom, y is the radical Y′, wherein Y′ is as above defined, and 4m-ii) when Q is Z 2 , by converting the compounds obtained in the step 4m-i) into nitro derivative by reaction with a nitrate source as above described and 4m-iii) optionally deprotecting the compounds obtained in step 4m-i) or 4m-ii) as above described.
  • R 12a is selected from D7), wherein P 1 and R 4a′ are as above defined, with a compound of formula (IVe)
  • X′′ and Q are as above defined
  • y is the radical Y′, wherein Y′ is as above defined
  • 4n-ii) when Q is Z 2 by converting the compounds obtained in the step 4n-i) into nitro derivative by reaction with a nitrate source as above described and 4n-iii) optionally deprotecting the compounds obtained in step 4n-i) or 4n-ii) as above described.
  • R′ and Q are as above defined
  • y is the radical Y′, wherein Y′ is as above defined
  • 4o-ii) when Q is Z 2 by converting the compounds obtained in the step 4o-i) into nitro derivative by reaction with a nitrate source such above described and 4o-iii) optionally deprotecting the compounds obtained in step 4o-i) or 4o-ii) as above described.
  • R′ and Q are as above defined, Hal is an halogen atom, y is the radical Y′, wherein Y′ is as above defined, and 4p-ii) when Q is Z 2 , by converting the compounds obtained in the step 4p-i) into nitro derivative by reaction with a nitrate source such above described and 4p-iii) optionally deprotecting the compounds obtained in step 4p-i) or 4p-ii) as above described.
  • R′ and Q are as above defined, Hal is an halogen atom, y is the radical Y′, wherein Y′ is as above defined, and 4q-ii) when Q is Z 2 , by converting the compounds obtained in the step 4q-i) into nitro derivative by reaction with a nitrate source as above described and 4q-iii) optionally deprotecting the compounds obtained in step 4q-i) or 4q-ii) as above described.
  • X 18 is the radical having the following meanings

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US10711032B2 (en) 2016-11-08 2020-07-14 Regeneron Pharmaceuticals, Inc. Steroids and protein-conjugates thereof
US11377502B2 (en) 2018-05-09 2022-07-05 Regeneron Pharmaceuticals, Inc. Anti-MSR1 antibodies and methods of use thereof
US11491237B2 (en) 2017-05-18 2022-11-08 Regeneron Pharmaceuticals, Inc. Cyclodextrin protein drug conjugates
US12070506B2 (en) 2018-01-08 2024-08-27 Regeneron Pharmaceuticals, Inc. Steroids and antibody-conjugates thereof
US12134631B2 (en) 2017-11-07 2024-11-05 Regeneron Pharmaceuticals, Inc. Hydrophilic linkers for antibody drug conjugates

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EP2560634A1 (en) 2010-04-23 2013-02-27 Piramal Enterprises Limited Nitric oxide releasing prodrugs of therapeutic agents
US8846723B2 (en) 2010-07-29 2014-09-30 Eastman Chemical Company Esters of O-substituted hydroxy carboxylic acids and preparations thereof
WO2013053856A1 (en) 2011-10-12 2013-04-18 Ascendis Pharma A/S Prevention and treatment of ocular conditions
MX390974B (es) * 2011-12-20 2025-03-13 Oriflame Cosmetics Ag Uso cosmético o dermatológico de naringenina para combatir efectos de envejecimiento de la piel.
US10980860B2 (en) 2012-10-11 2021-04-20 Ascendis Pharma A/S Diagnosis, prevention and treatment of diseases of the joint
US9844599B2 (en) 2013-01-21 2017-12-19 Apparao Satyam Nitric oxide releasing produgs of therapeutic agents
RU2545416C1 (ru) * 2014-02-18 2015-03-27 Ксения Юрьевна Еременко Способ лечения возрастной макулярной дистрофии
CN103880907A (zh) * 2014-03-11 2014-06-25 天津金耀集团有限公司 丁酸氢化可的松半水合物
MX2021002380A (es) * 2018-08-31 2021-07-15 Aerie Pharmaceuticals Inc Conjugados de isoquinolina-esteroide y usos de los mismos.
WO2022135332A1 (zh) * 2020-12-21 2022-06-30 映恩生物制药（苏州）有限公司 一种甾体偶联物
JP7687973B2 (ja) * 2022-01-24 2025-06-03 芳弘 二村 フィブロネクチン活性化作用を介した表皮細胞増殖作用を呈するジテルペン誘導体

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US10711032B2 (en) 2016-11-08 2020-07-14 Regeneron Pharmaceuticals, Inc. Steroids and protein-conjugates thereof
US11760775B2 (en) 2016-11-08 2023-09-19 Regeneron Pharmaceuticals, Inc. Steroids and protein-conjugates thereof
US12377159B2 (en) 2016-11-08 2025-08-05 Regeneron Pharmaceuticals, Inc. Steroids and protein-conjugates thereof
US11491237B2 (en) 2017-05-18 2022-11-08 Regeneron Pharmaceuticals, Inc. Cyclodextrin protein drug conjugates
US12134631B2 (en) 2017-11-07 2024-11-05 Regeneron Pharmaceuticals, Inc. Hydrophilic linkers for antibody drug conjugates
US12070506B2 (en) 2018-01-08 2024-08-27 Regeneron Pharmaceuticals, Inc. Steroids and antibody-conjugates thereof
US11377502B2 (en) 2018-05-09 2022-07-05 Regeneron Pharmaceuticals, Inc. Anti-MSR1 antibodies and methods of use thereof
US12497460B2 (en) 2018-05-09 2025-12-16 Regeneron Pharmaceuticals, Inc. Anti-MSR1 antibodies and methods of use thereof

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