Classifications

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  • 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
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  • 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.
• 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 - CH2-O-NO2 group.
• said derivatives have a cardiotropic activity. This activity represents a drawback for said compounds, since they modify the cardiac frequency.
• USP 3,494,941 describes steroid derivatives from 3-hydroxy- extrane or from extr-4 en-3 one, used as vasodilators in the treatment of cardiac affections such as coronary insufficiency and angina pectoris.
• a ONO2 group is at the free end of the alkylene chain which is linked by an ether bond to the steroid in position 17.
• 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.
• WO 98/15568 and WO 03/064443 in the name of the Applicant describe nitrate esters of steroidal compounds, wherein between the steroidal structure and the nitrooxy group a bivalent linking group is inserted. Said compounds show a good efficacy and/or good tolerability with respect to the corresponding precursors .
• Patent application WO 00/61604 in the name of the Applicant describes nitrooxy derivatives of steroidal compounds with various linking groups having at one end a nitrooxy group, and covalently linked with the other end to a steroidal compound. In said application the uses concern the compounds usable in the treatment of patients in oxidative stress. Said compounds contain in the molecule also a bivalent linking group which must be capable to prevent the free radicals production and is selected on the basis of the tests reported therein.
• 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 0 or 1
• Z is a group capable of binding R x and is selected from -C(O)-, or -CH (R' ) -0- wherein R' is selected from H or a straight or branched C 1 -C 4 alkyl, preferably R' is H or -CH3; R x is a radical selected from the following meanings: A)
• R 1 is selected from:
• R 1 is -CH 2 -OH or -CH 2 [ (C 6 H 4 ) -(4-0H) ] ;
• R 5a is H or a linear or branched C1-C10 alkyl chain, preferably R 5a is H or a linear (Ci-C 5 ) alkyl, preferably R 1 is - (CH 2 ) 4 -NHR", wherein R" is as above defined,
• R 5a is as above defined, preferably R 1 is -CH 2 -C(O)R"', wherein R"' is as above defined, R la is selected from:
• R la is -CH 2 -C(O)-;
• R 3a is selected from H, -R 5a or
• R 5a is as above defined
• R 4a is selected from H or -C(O)CH 3 or wherein R 5a is as above defined, R lb is selected from
• R lb is -0-CH 2 - or [- (4-0)- (C 6 H 4 ) J-CH 2 -;
• R lb is -HN- (CH 2 ) 4 - or -HN-CH 2 -; AlO) -C(O)-CH 2 -, -C(O) - (CH 2 ) 2 -, -C (0) - (CH 2 ) 4 -, preferably R lb is -C(O)-CH 2 -;
• T is selected from -0-, -S-, -NR'-, -O-CH (R' ) -0-C (0) - or -O-CH (R' ) -0-C (0) 0- wherein R' is as above defined;
• T' is -C(O)-, -C(O)-X"- wherein X" is -0- or -S-, or T' is -C (0) -NR' - wherein R' is as above defined;
• T" is independently selected from -C(O)-, -C(O)-X"-, -C(O)-NR'-, -0-, -S-, -NR'-, -0-CH(R' ) -0-C (0) -,
• T" is -C(O)-, -C(O)-X"- or -C(O)-NR'- when T" is linked to -NH-, -0-, or -S-, or
• T" is -0-, -S-, -NR'-, -0-CH(R' ) -0-C (0) -, -O-CH (R' ) -0-C (0) 0- when T" is linked to -C(O)-, Y and Y' are as below defined; or R x is selected from: B)
• R 2 is selected from:
• R 2a is selected from: B5) -CH 2 -S-, -CH 2 -O-, -CH (CH 3 ) -0- or -CH 2 [ (C 6 H 4 ) - (4-0) -], -CH 2 - [ (3, 5-diiodo) - (C 6 H 2 ) - (4-0) -] , -CH 2 - [ (3-nitro) - (C 6 H 3 ) - (4-0) -], preferably R 2a is -CH 2 -O-;
• R 2b is -0-CH 2 - or [-(4-O)-(C 6 H 4 )J-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: C)
• T and T' are as above defined and Y and Y' are as below defined; D)
• T"' is independently selected from -C(O)-, -C(O)X"- wherein X" is -0- or -S-, or -C(O)-NR'- wherein R' is as above defined; T' and T" are as above defined, Y and Y' are as below defined; R 12 is selected from:
• R 12 is H;
• R 12 is -CH 2 -OH or - CH 2 [ (C 6 H 4 ) -(4-0H) ] ; D3) -CH 2 -NHR", - (CH 2 ) 2 -NHR", - (CH 2 ) 3 -NHR", - (CH 2 ) 4 -NHR", wherein
• R" is as above defined, preferably R 12 is - (CH 2 ) 4 -NHR";
• R 12a is CH 2 -O- or -CH 2 [ (C 6 H 4 ) - (4-0) -],
• R 12a is -(CH 2 ) 4 -NH- or -CH 2 -NH-,
• R 12a is -CH 2 -C(O)-
• R 12b is selected from
• R 12b is -0-CH 2 - or [- (4-O)- (C 6 H 4 ) J-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:
• c is equal to 0 or 1
• d is an integer from 0 to 3 with the proviso that c is 0 or 1 when d is 0 and c is 0 when d is 1, 2 or 3
• T and T' are as above defined and Y is as below defined;
• R is H, CH 3 , propyl, (CeHs) 2 CH-, l-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; H) (hi)
• 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 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; L)
• T and T' are as above defined and Y is as below
• 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;
• R 9 and R 10 are H, CH 3 , R 11 is CH 3 or 4-piperidinyl with the proviso that R 9 and R 10 are H when R 11 is 4-piperidinyl and R 9 and R 10 are CH 3 when R 11 is CH 3 , T and T' are as above defined and Y is as below reported; V)
• T and T' are as above defined and Y is as below reported; with the proviso that in the formula (I) : a is O or a is 1 and Z is -CH (R') -O- wherein R' is as above defined, when R x is:
• R lb is selected from the group AlO) ;
• R 2b is selected from the group BlO) ; - ( c2 ) ;
• R 12b is selected from the group DlO) ;
• R lb is selected from the groups A8) and A9) ; - (bl), (b3) or (b7);
• 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)
• n 0 is an integer from 0 to 20, preferably n 0 is 0 or 1 ; n 1 is 0 or 1, preferably n 1 is 1 ;
• U is a linear or branched C1-C20 alkylene optionally substituted with a -ONO2 group, preferably U is a linear C1-C10 alkylene or U is a linear or branched C1-C10 alkylene substituted with a -ONO2 group;
• n is an integer from 0 to 20, preferably n is 0 or 1 ; n 1 is 0 or 1, preferably n 1 is 1 ;
• U is a linear or branched C1-C20 alkylene optionally substituted with a -ONO2 group, preferably U is a linear C1-C10 alkylene or U is a linear or branched C1-C10 alkylene substituted with a -ONO2 group; d)
• n 2 is an integer from 0 to 2
• R 13 is H or CH 3
• Ti is -0-C(O)- or -C(O)O-
• n 1 and U are as above defined;
• n 2 is an integer from 0 to 2, preferably n 2 is 1 ;
• R 13 is H or CH 3 , preferably R 13 is CH 3 ;
• T 1 -0-C(O)- or -C(O)O-, preferably T 1 is -C(O)O-; n 1 is 0 or 1, preferably n 1 is 1;
• 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 ;
• T 2 is -O- or -S-, -NH-, preferably T 2 is -O-, n 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 Ci-C 4 alkyl, preferably R 14 , R 15 , R 16 and R 17 are H; wherein the -ONO 2 group is linked to wherein n 5 is as defined above;
• Y 2 is an heterocyclic saturated, unsaturated or aromatic 5 or 6 members ring, containing one or more heteroatoms selected from nitrogen, oxygen, sulphur, and is selected from the group consisting of:
• Ci-Cio 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 (Ci-Cio) -alkyl, preferably
• 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)
• R x is selected from: (a2) -C (0) -CH (R 1 ) -NH- (T' -Y-ONO 2 ) wherein
• R 1 of the group Al is selected from H, isobutyl, benzyl, CeH 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,
• R 1 of the group A2) is selected from -CH 2 -OH, -CH(CH 3 )OH- or
• R 1 of the group A3) is selected from -CH 2 -NHR", - (CH 2 ) 2 -NHR",
• R 1 of the group A4) is selected from -CH 2 -C(O)R"',
• R x is as below defined; or R x is
• R la of the group A6) is selected from -CH 2 -NH-, - (CH 2 ) 2 -NH-,
• R la of the group A7) is selected from -CH 2 -C(O)-, - (CH 2 ) 2 -C (0) -, - (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 -0-, when R la is selected from the group A5) or A6) , preferably T" is -C(O)-;
• T" is -0-, -S-, -NR'- or -O-CH (R' ) -0-C (0) - wherein R' is H or -CH 3 , when R la is selected from the group Al),
• R x is selected from:
• R lb of the group AlO) is selected from -C(O)-CH 2 -, -C (0) - (CH 2 ) 2 -,
• T is -O-, -S-, -NR'- or -O-CH (R' ) -O-C (O) - wherein R' is H or -CH 3 , preferably T is -0-, T' is -C(O)- or -C(O)-X" wherein X" is -S- or -0-, preferably T' is -C(O)-,
• Y and Y' are as below defined; or R x is
• R la of the group A5) is selected from -CH 2 -O-, -CH (CH 3 ) -0- or
• R la of the group A6) is selected from -CH 2 -NH-, - (CH 2 ) 2 -NH-,
• R la of the group A7) is selected from -CH 2 -C(O)-, - (CH 2 ) 2 -C (0) -, -(CHz) 4 -C(O)-,
• T" is -C(O)- or -C(O)-X" wherein X" is -S- or -0-, when R la is selected from the group A5) or A6) , preferably T" is -C(O)-, T" is -0-, -S-, -NR'- or -O-CH (R' ) -0-C (0) - wherein R' is H or - CH 3 , when R la is selected from the group A7);
• T' is -C(O)- or -C(O)-X" wherein X" is -S- or -0-, preferably T' is -C(O)-,
• Y and Y' are as below defined, or R x is (b2) -C(O) -CH 2 -CH(R 2 ) -NH- (T' -Y-ONO 2 ) wherein
• R 2 of the group Bl is selected from H, CH 3 , isobutyl, isopropyl, benzyl;
• T' is -C(O)-, -C(O)-X" wherein X" is -S- or -0-, preferably T' is -C(O)-;
• Y and Y' are each independently selected from a)
• Ci-Cio alkylene - a straight or branched Ci-Cio alkylene, - a straight or branched Ci-Cio alkylene substituted with a -ONO2
• n 2 is 1, R 13 is CH 3 ;
• T 1 -O-C(O)-; n 1 is 1 and U is a linear C 1 -C 1 O alkylene or U is a linear or branched C 1 -C 1 O alkylene substituted with a -ONO 2 group; f)
• T 2 is -O- or -S-, -NH-, preferably T 2 is -O-, n is 1 or
• Another embodiment of the invention relates to nitric oxide releasing compounds of general formula (I)
• R 1 of the group Al 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 of the group A2) is selected from: -CH 2 -OH, -CH (CH 3 ) -OH- or -CH 2 [ (C 6 H 4 ) - (4-OH) ], or
• R 1 of the group A3) is selected from -CH 2 -NHR", - (CH 2 ) 2 -NHR",
• R 1 of the group A4) is -CH 2 -C(O)R"', - (CH 2 ) 2 -C (0) R"' ,
• T is -0-, -S-, -NR'-, -0-CH(R' ) -O-C(O) - wherein R' is H or a straight or branched Ci-C 4 alkyl, preferably T is -0-,
• Y is as below defined; or R x i s ( a3 ) -HN-CH ( R la - T " -Y ' -ONO 2 ) -COOR 3a where in
• R la of the group A5) is selected from -CH 2 -O-, -CH(CH 3 )O- or
• R la of the group A6) is selected from -CH 2 -NH-, - (CH 2 ) 2 -NH-, - (CH 2 ) 3-NH-, - (CH 2 ) 4-NH-, or
• R la of the group A7) is -CH 2 -C(O)-, - (CH 2 ) 2 -C (0) -, - (CH 2 ) 4 -C (0) -,
• R 3a is H or a (Ci-C 5 ) alkyl
• T" is -C(O)- or -C(O)-X" wherein X" is -S- or -0-, when R la is selected from the group A5) or A6) , preferably T" is -C(O)-; T" is -0-, -S-, -NR'-, -0-CH(R' ) -O-C(O) - wherein R' is H or a straight or branched Ci-C 4 alkyl, when R la is selected from the group A7) ;
• Y' is as below defined; or R x is selected from. (a5) -R lb -CH (NHR 4a ) -C (O) - (T-Y-ONO 2 )
• R lb of the group A8) is selected from -0-CH(CH 3 )-, -0-CH 2 -,
• R lb of the group A9) is selected from -HN-CH 2 -, -HN- (CH 2 ) 2 -,
• R 3a is H or a (Ci-C 5 ) alkyl
• R 4a is H or -C(O)CH 3 ,
• T is -0-, -S-, -NR'-, -0-CH(R' ) -O-C(O) - wherein R' is H or a straight or branched Ci-C 4 alkyl, preferably T is -0-,
• T' is -C(O)- or -C(O)-X" wherein X" is -S- or -0-, preferably T' is -C(O)-,
• Y and Y' are as below defined; or R x is
• R la of the group A6) is selected from -CH 2 -NH-, - (CH 2 ) 2 -NH-,
• R la of the group A7) is -CH 2 -C(O)-, - (CH 2 ) 2 -C (0) -, - (CH 2 ) 4 -C (0) -;
• T" is -C(O)- or -C(O)-X", wherein X" is -S- or -0-, when R la is selected from A5) or A6) , preferably T" is -C(O)-
• T" is -0-, -S-, -NR'-, -0-CH(R' ) -O-C(O) -, wherein R' is H or a straight or branched Ci-C 4 alkyl, when R la is selected from A7), preferably T" is -0-, T is -0-, -S-, -NR'-, -0-CH(R' ) -O-C(O) - wherein R' is H or a straight or branched Ci-C 4 alkyl, preferably T is -0-;
• Y and Y' are as below defined; or R x is
• R 2 of the group Bl 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",
• R 2 of the group B4) is -CH 2 -C(O)R"', - (CH 2 ) 2 -C (0) R"' ,
• T is -0-, -S-, -NR'-, -0-CH(R' ) -O-C(O) - wherein R' is H or a straight or branched Ci-C 4 alkyl, preferably T is -0-,
• R x is selected from (dl) -HN-CH(R 12 ) -CH 2 -O- (T"' -Y-ONO 2 ) or
• R 12 of the group Dl is selected from H, CH 3 , isobutyl, isopropyl, benzyl, or R 12 of the group D2) is selected from -CH 2 -OH, -CH(CH 3 )OH- or
• R 12 of the group D3) is selected from -CH 2 -NHR", - (CH 2 ) 2 -NHR",
• R 12 of the group D4) is -CH 2 -C(O)R"', - (CH 2 ) 2 -C (0) R"' , - (CH 2 ) 4 -C (O)R"' wherein R"' is 0R 5a wherein R 5a is H or a linear
• T' and T"' are each independently selected from -C(O)- or
• R x is selected from:
• R 12a of the group D5) is selected from -CH 2 -O-, -CH (CH 3 ) -0- or -CH 2 [ (C 6 H 4 ) -(4-0)-], or R 12a of the group D6) is selected from -CH 2 -NH-, - (CH 2 ) 2 -NH-,
• R 12a of the group D7) is -CH 2 -C(O)-, - (CH 2 ) 2 -C (0) -, - (CH 2 ) 4 -C (0) -;
• R 4a is H or -C(O)CH 3 ,
• T" is selected from -C(O)- or -C(O)-X", wherein X" is -S- or - 0-, when R 12a is selected from D5) or D6) , preferably T' and T"' are -C(O)-,
• T" is -0-, -S-, -NR'-, -0-CH(R' ) -0-C (0) -, wherein R' is H or a straight or branched Ci-C 4 alkyl, when R 12a is selected from D7),
• T is -0-
• T"' is selected from -C(O)- or -C(O)-X" wherein X" is -S- or -
• T"' is -C(O)-
• R x is selected from:
• R 12b of the group D8) is selected from -0-CH(CH 3 )-, -0-CH 2 -, [-4-0-(C 6 H 4 )J-CH 2 -, or
• R 12b of the group D9) is selected from -HN-CH 2 -, -HN- (CH 2 ) 2 -, -HN-(CH 2 ),-, -HN-(CH 2 ),-;
• R 4a is H or -C (0) -CH 3 ,
• T' and T"' are each independently selected from -C(O)-, -C(O)- X", wherein X" is -S- or -0-, preferably T' and T"' are -C(O)-,
• Y and Y' are each independently selected from a)
• Ci-Cio alkylene - a straight or branched Ci-Cio alkylene, - a straight or branched Ci-Cio alkylene substituted with a -ONO2
• n 2 is an integer from 0 to 2
• R 13 is H or CH 3
• T 1 is -0-C(O)- or -C(O)O-
• n 1 is 1
• U is a linear C1-C10 alkylene or U is a linear or branched C1-C10 alkylene substituted with a -ONO2 group
• n 2 is 1, R 13 is CH 3 ,
• T 1 -O-C(O)-, n 1 is 1 and U is a linear C1-C10 alkylene or U is a linear or branched C1-C10 alkylene substituted with a -ONO 2 group; f)
• T 2 is -O- or -S-, -NH-, preferably T 2 is -O-, n is 1 or
• Another embodiment of the present invention is to provide nitric oxide releasing compounds of general formula (I)
• R 1 of of the group Al) is H T' is -C (0) -;
• Y is selected from a)
• Ci-Cio alkylene a straight or branched Ci-Cio alkylene
• Ci-Cio alkylene substituted with a -ONO 2 group a straight or branched Ci-Cio alkylene substituted with a -ONO 2 group
• Another embodiment relates to nitric oxide releasing compounds of general formula (I)
• R x is selected from
• R x is selected from
• R lb of the group AlO) is -C(O)-CH 2 -
• R 3a is H or a (Ci-C 5 ) alkyl
• R 4a is H or -C(O)CH 3 ,
• T is selected from -0-, -S-, -NR'- wherein R' is as above defined,
• T' is -C(O)-
• Y and Y' are each independently selected from a)
• Ci-Cio alkylene a straight or branched Ci-Cio alkylene
• Ci-Cio alkylene substituted with a -ONO 2 group .
• Another embodiment relates to nitric oxide releasing compounds of general formula (I)
• a 1 and Z is -C (0) -, R x is
• R 4a is H or -C(O)CH 3 ,
• T is selected from -0-, -S-, -NR'- wherein R' is as above defined,
• T' is -C(O)- and Y and Y' are each independently selected from a)
• Ci-Cio alkylene a straight or branched Ci-Cio alkylene
• Ci-Cio alkylene substituted with a -ONO 2 group Another embodiment of the invention relates to nitric oxide releasing compounds of general formula (I)
• R 2 of the group Bl) is H, T' is -C (0) -;
• Y and Y' are each independently selected from a) - a straight or branched Ci-Cio alkylene,
• Ci-Cio alkylene substituted with a -ONO2 group .
• 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 O 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 Ci-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 1 is -CH 2 -OH or -CH 2 [ (C 6 H 4 ) - (4-0H) ] ;
• R 5a is H or a linear or branched Ci-Cio alkyl chain, pprreeffeerraabbllyy RR 55aa iiss HH oorr aa lliinneeaarr ((CCii--CC 55 )) aallkkyy!l, preferably R 1 is - (CH 2 ) 4 -NHR", wherein R" is as above defined, A4) -CH 2 -C(O)R"', - (CH 2 ) 2-C(O) R"' , - (CH 2 ) 4 -C (O) R"' wherein R"' is -OR 5a or
• R 5a is as above defined, preferably R 1 is -CH 2 -C(O)R"', wherein R"' is as above defined, R la is selected from:
• R la is -CH 2 -O-; A6) -CH 2 -NH-, - (CH 2 ) 2 -NH-, - (CH 2 ) 3 -NH-, - (CH 2 ) 4 -NH-, preferably R la is -(CH 2 J 4 -NH- or -CH 2 -NH-,
• R 3a is selected from H, -R 5a or
• R 5a is as above defined
• R 4a is selected from H or -C(O)CH 3 or
• R 5a is as above defined, R lb is selected from
• R lb is -0-CH 2 - or [-(4-O)-(C 6 H 4 ) J-CH 2 -; A9 ) -HN-CH 2 - , -HN- ( CH 2 ) 2 - , -HN- ( CH 2 ) 3 - , -HN- ( CH 2 ) 4 " , pre ferabl y
• R lb is -C(O)-CH 2 -;
• T is selected from -O-, -S-, -NR'-, -O-CH (R' ) -O-C (O) - or -O-CH (R' ) -0-C (0) 0- wherein R' is as above defined;
• T' is -C(O)-, -C(O)-X"- wherein X" is -0- or -S-, or T' is -C (0) -NR' - wherein R' is as above defined;
• T" is independently selected from -C(O)-, -C(O)-X"-, -C(O)-NR'-, -0-, -S-, -NR'-, -O-CH (R''
• T" is -0-, -S-, -NR'-, -0-CH(R' ) -0-C (0) -, -O-CH (R' ) -C-C (0) 0- when T" is linked to -C(O)-, Y and Y' are as below defined; or R x is selected from: B)
• R 2 is H, -CH 3 , isopropyl, benzyl,
• R 2a is selected from:
• R 2a is -CH 2 -O-;
• B6 -CH 2 -NH-, - (CH 2 ) 2-NH-,- (CH 2 ) 3-NH-, -(CH 2 J 4 -NH-, preferably R 2a is - (CH 2 ) 4 -NH- or -CH 2 -NH-;
• R 2a is -CH 2 -C(O)-;
• R 2b is selected from B8) -S-CH 2 -, -0-CH(CH 3 )-, -0-CH 2 -, [-(4-O)-(C 6 H 4 )J-CH 2 -,
• R 2b is -0-CH 2 - or [-(4-O)-(C 6 H 4 )J-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: C)
• T"' is independently selected from -C(O)-, -C(O)X"- wherein X" is -O- or -S-, or -C(O)-NR'- wherein R' is as above defined;
• T' and T" are as above defined
• Y and Y' are as below defined;
• R 12 is selected from:
• R 12 is H
• R 12 is -CH 2 -OH or -
• R" is as above defined, preferably R 12 is - (CH 2 ) 4 -NHR";
• R 12a is selected from
• R 12a is - (CH 2 ) 4 -NH- or -CH 2 -NH-,
• R 12a is -CH 2 -C(O)-
• R 12b is selected from
• R 12b is -0-CH 2 - or [-(4-O)-(C 6 H 4 )J-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;
• c is equal to 0 or 1
• d is an integer from 0 to 3 with the proviso that c is 0 or 1 when d is 0 and c is 0 when d is 1, 2 or 3
• T and T' are as above defined and Y is as below defined;
• R 3 is H, CH 3 , propyl, (C 6 Hs) 2 CH-, l-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; H)
• 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 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; L)
• T and T' are as above defined and Y is as below
• 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;
• R 9 and R 10 are H, CH 3 , R 11 i s CH 3 or 4 -piperidinyl with the provi so that R 9 and R 10 are H when R 11 i s 4 -piperidinyl and R 9 and R 10 are CH 3 when R 11 i s CH 3 , T and T ' are as above def ined and Y i s as below reported; V)
• 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 lb is selected from the group AlO) ;
• R 2b is selected from the group BlO) ;
• R 12b is selected from the group DlO) ; - (e2), (fl), (g2), (hi), (il), (12), (m2), (n2), (o2), ( P 2),
• R lb is selected from the groups A8) and A9) ;
• R 2b is selected from the groups B8) or B9) ; - (cl) ;
• R 12b is selected from the groups D8) or D9) ;
• Y and Y' are bivalent radicals each independently selected from the following meanings: a)
• n is an integer from 0 to 20, preferably n is 0 or 1 ; n 1 is 0 or 1, preferably n 1 is 1 ;
• U is a linear or branched C1-C20 alkylene optionally substituted with a -ONO2 group, preferably U is a linear C1-C10 alkylene or U is a linear or branched C1-C10 alkylene substituted with a -ONO2 group; c)
• n 0 is an integer from 0 to 20, preferably n 0 is 0 or 1 ; n 1 is 0 or 1, preferably n 1 is 1 ;
• U is a linear or branched C1-C20 alkylene optionally substituted with a -ONO2 group, preferably U is a linear C1-C10 alkylene or U is a linear or branched C1-C10 alkylene substituted with a -ONO2 group; d)
• n 2 i s an integer from 0 to 2 , R 13 i s H or CH 3 , Ti i s -0-C ( O) - or
• n 1 and U are as above defined; n 2 is an integer from 0 to 2, preferably n 2 is 1 ; R 13 is H or CH 3 , preferably R 13 is CH 3 ;
• 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 ;
• T 1 -O-C(O)-; n 1 is 0 or 1, preferably n 1 is 1;
• T 2 is -O- or -S-, -NH-, preferably T 2 is -O-, n 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 Ci-C 4 alkyl, preferably R 14 , R 15 , R 16 and R 17 are H; wherein the -ONO 2 group is linked to wherein n 5 is as defined above;
• Y 2 is an heterocyclic saturated, unsaturated or aromatic 5 or 6 members ring, containing one or more heteroatoms selected from nitrogen, oxygen, sulphur, and is selected from the group consisting of:
• 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 Al) is selected from H, isobutyl, benzyl,
• R 1 of the group A2) is selected from -CH 2 -OH, -CH(CH 3 )OH- or
• R 1 of the group A3) is selected from -CH 2 -NHR", - (CH 2 ) 2 -NHR",
• R 1 of the group A4) is selected from -CH 2 -C(O)R"',
• R x is as below defined; or R x is
• R la of the group A6) is selected from -CH 2 -NH-, - (CH 2 ) 2 -NH-, - ( CH 2 ) S -NH- , - ( CHs ) 4 -NH- , or
• R la of the group A7) is selected from -CH 2 -C(O)-, - (CH 2 ) 2 -C (0) -, -(CHz) 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 -0-, when R la is selected from the group A5) or A6) , preferably T" is -C(O)-; T" is -0-, -S-, -NR'- or -O-CH (R' ) -0-C (0) - wherein R' is H or -CH 3 , when R la is selected from the group A7), Y' is as below defined; or R x is selected from:
• R lb of the group AlO) is selected from -C(O)-CH 2 -, -C (0) - (CH 2 ) 2 -,
• R 3a is H or a (Ci-C 5 ) alkyl
• R 4a is H or -C(O)CH 3
• T is -0-, -S-, -NR'- or -O-CH (R' ) -0-C (0) - wherein R' is H or
• T is -0-
• T' is -C(O)- or -C(O)-X" wherein X" is -S- or -0-, preferably T' is -C(O)-, Y and Y' are as below defined; or R x is
• R la of the group A5) is selected from -CH 2 -O-, -CH (CH 3 ) -0- or -CH 2 [ (C 6 H 4 ) - (4-0) -], or
• R la of the group A6) is selected from -CH 2 -NH-, - (CH 2 ) 2 -NH-,
• R la of the group A7) is selected from -CH 2 -C(O)-, - (CH 2 ) 2 -C (0) -,
• T" is -C(O)- or -C(O)-X" wherein X" is -S- or -0-, when R la is selected from the group A5) or A6) , preferably T" is -C(O)-,
• T" is -0-, -S-, -NR'- or -O-CH (R' ) -0-C (0) - wherein R' is H or -
• T' is -C(O)- or -C(O)-X" wherein X" is -S- or -0-, preferably T' is -C(O)-,
• Y and Y' are as below defined, or R x is
• R 2 of the group Bl is selected from H, CH 3 , isobutyl, isopropyl, benzyl;
• T' is -C(O)-, -C(O)-X" wherein X" is -S- or -0-, preferably T' is -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
• Ti is -0-C(O)- or -C(O)O-
• n 1 is 1 and U is a linear C1-C10 alkylene or U is a linear or branched C1-C10 alkylene substituted with a -ONO 2 group; e)
• n 1
• R 13 is CH 3
• T 1 is -C(O)O- and
• U is a linear Ci-Cio alkylene; e' )
• 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-(Z) 3 -Rx
• R is a corticosteroid residue selected from: a is 1 and Z is -C (O) - ; R x is
• R 1 of the group Al 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 of the group A2) is selected from: -CH 2 -OH, -CH (CH 3 ) -OH- or -CH 2 [ (C 6 H 4 ) - (4-OH) ], or
• R 1 of the group A3) is selected from -CH 2 -NHR", - (CH 2 ) 2 -NHR",
• R 1 of the group A4) is -CH 2 -C(O)R"', - (CH 2 ) 2 -C (0) R"' ,
• T is -O-, -S-, -NR'-, -0-CH(R' ) -O-C(O) - wherein R' is H or a straight or branched Ci-C 4 alkyl, preferably T is -O-,
• R x is (a3) -HN-CH (R la -T"-Y' -ONO 2 ) -COOR 3a wherein
• R la of the group A5) is selected from -CH 2 -O-, -CH(CH 3 )O- or
• R la of the group A6) is selected from -CH 2 -NH-, - (CH 2 ) 2 -NH-, - (CH 2 ) 3-NH-, - (CH 2 ) 4-NH-, or
• R la of the group A7) is -CH 2 -C(O)-, - (CH 2 ) 2 -C (0) -, - (CH 2 ) 4 -C (0) -,
• R 3a is H or a (Ci-C 5 ) alkyl
• T" is -C(O)- or -C(O)-X" wherein X" is -S- or -0-, when R la is selected from the group A5) or A6) , preferably T" is -C(O)-; T" is -0-, -S-, -NR'-, -0-CH(R' ) -O-C(O) - wherein R' is H or a straight or branched Ci-C 4 alkyl, when R la is selected from the group A7) ;
• Y' is as below defined; or R x is selected from. (a5) -R lb -CH(NHR 4a ) -C (0) - (T-Y-ONO 2 )
• R lb of the group A8 is selected from -0-CH(CH 3 )-, -0-CH 2 -,
• R lb of the group A9) is selected from -HN-CH 2 -, -HN- (CH 2 ) 2 -,
• R 3a is H or a (Ci-C 5 ) alkyl
• R 4a is H or -C(O)CH 3
• T is -0-, -S-, -NR'-, -0-CH(R' ) -O-C(O) - wherein R' is H or a straight or branched Ci-C 4 alkyl, preferably T is -0-,
• T' is -C(O)- or -C(O)-X" wherein X" is -S- or -0-, preferably T' is -C(O)-, Y and Y' are as below defined; or R x is
• R la of the group A5 is selected from -CH 2 -O-, -CH (CH 3 ) -0- or -CH 2 [ (C 6 H 4 ) -(4-0)-], or R la of the group A6) is selected from -CH 2 -NH-, - (CH 2 ) 2 -NH-,
• R la of the group A7) is -CH 2 -C(O)-, - (CH 2 ) 2 -C (0) -, - (CH 2 ) 4 -C (0) -;
• T" is -C(O)- or -C(O)-X", wherein X" is -S- or -0-, when R la is selected from A5) or A6) , preferably T" is -C(O)-
• T" is -0-, -S-, -NR'-, -0-CH(R' ) -O-C(O) -, wherein R' is H or a straight or branched Ci-C 4 alkyl, when R la is selected from A7), preferably T" is -0-, T is -0-, -S-, -NR'-, -0-CH(R' ) -O-C(O) - wherein R' is H or a straight or branched Ci-C 4 alkyl, preferably T is -0-;
• Y and Y' are as below defined; or R x is
• R 2 of the group Bl 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
• R 2 of the group B3 is selected from -CH 2 -NHR", - (CH 2 ) 2 -NHR",
• R 2 of the group B4) is -CH 2 -C(O)R"', -(CH 2 J 2 -C(O)R'",
• T is -0-, -S-, -NR'-, -0-CH(R' ) -O-C(O) - wherein R' is H or a straight or branched Ci-C 4 alkyl, preferably T is -0-,
• R x is selected from
• R 12 of the group Dl is selected from H, CH 3 , isobutyl, isopropyl, benzyl, or R 12 of the group D2) is selected from -CH 2 -OH, -CH(CH 3 )OH- or
• R 12 of the group D3) is selected from -CH 2 -NHR", - (CH 2 ) 2 -NHR",
• R 12 of the group D4) is -CH 2 -C(O)R"', - (CH 2 ) 2 -C (0) R"' , - (CH 2 ) 4 -C (O)R"' wherein R"' is 0R 5a wherein R 5a is H or a linear
• T' and T"' are each independently selected from -C(O)- or
• R x is selected from:
• R 12a of the group D5) is selected from -CH 2 -O-, -CH (CH 3 ) -0- or
• R 12a of the group D6) is selected from -CH 2 -NH-, - (CH 2 ) 2 -NH-, - (CH 2 ) 3-NH-, - (CH 2 ) 4-NH-, or
• R 12a of the group D7) is -CH 2 -C(O)-, - (CH 2 ) 2 -C (0) -, - (CH 2 ) 4 -C (0) -;
• R 4a is H or -C(O)CH 3 ,
• T" is selected from -C(O)- or -C(O)-X", wherein X" is -S- or -
• T' and T"' are -C (0) -
• T" is -0-, -S-, -NR'-, -0-CH(R' ) -0-C (0) -, wherein R' is H or a straight or branched Ci-C 4 alkyl, when R 12a is selected from D7),
• T is -0-
• T"' is selected from -C(O)- or -C(O)-X" wherein X" is -S- or -
• T"' is -C(O)-
• R x is selected from: (d5) -R 12b -CH(NHR 4a ) -CH 2 -O- (T"' -Y-ONO 2 ) (d6) -R 12b -CH (CH 2 OH) -NH- (T' -Y-ONO 2 )
• 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 (0) -CH 3
• T' and T"' are each independently selected from -C(O)-, -C(O)- X", wherein X" is -S- or -0-, preferably T' and T"' are -C(O)-,
• Y and Y' are each independently selected from a)
• Ci-Cio alkylene - a straight or branched Ci-Cio alkylene substituted with a -ONO 2 group; d)
• n 2 i s an integer from 0 to 2 , R 13 i s H or CH 3 , T 1 i s -0-C ( O ) - or
• 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 O, R x is
• R 1 of of the group Al) is H T' is -C (O) -;
• Y is selected from a)
• Ci-Cio alkylene a straight or branched Ci-Cio alkylene
• Ci-Cio alkylene substituted with a -ONO 2 group a straight or branched Ci-Cio alkylene substituted with a -ONO 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 x is selected from
• R x is selected from
• R lb of the group AlO) is -C(O)-CH 2 -
• R 3a is H or a (Ci-C 5 ) alkyl
• R 4a is H or -C(O)CH 3
• T is selected from -0-, -S-, -NR'- wherein R' is as above defined,
• T' is -C(O)-
• Y and Y' are each independently selected from a) - a straight or branched Ci-Cio alkylene,
• Ci-Cio alkylene substituted with a -ONO2 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 1 and Z is -C (0) -, R x is
• T' is -C(O)-
• Y and Y' are each independently selected from a)
• Ci-Cio alkylene a straight or branched Ci-Cio alkylene
• Ci-Cio alkylene substituted with a -ONO2 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:
• R 2 of the group Bl) is H, T' is -C(O) -;
• Y and Y' are each independently selected from a)
• Ci-Cio alkylene a straight or branched Ci-Cio alkylene
• Ci-Cio alkylene substituted with a -ONO 2 group .
• 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.
• 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.
• 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.
• inorganic acids are: nitric, hydrochloric, sulphuric, phosphoric acids. Salts with nitric acid are preferred.
• the compounds of the invention which have one or more asymmetric carbon atoms can exist as optically pure enantiomers, pure diastereomers, enantiomers mixtures, diastereomers mixtures, enantiomer racemic mixtures, racemates or racemate mixtures. Within the object of the invention are also all the possible isomers, stereoisomers and their mixtures of the compounds of formula (I) .
• the compounds 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".
• R 1 is selected from Al) as defined above or
• R 5a 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; wherein P 1 is a hydroxyl or thiol protecting group such as silyl ethers, such as trimethylsilyl, tert-butyl-dimethylsilyl or trityl and those described in T. W. Greene "Protective groups in organic synthesis", Harvard University Press, 1980, P 2 is a carboxylic protecting group such as tert-butyl ester and those described in T. W.
• Q is independently -ONO2 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 C1-C10 alkyl) in a suitable organic solvent such as acetonitrile, tetrahydrofurane, methyl ethyl ketone, ethyl acetate, DMF, the reaction is carried out, in the dark, at a temperature from room temperature to the boiling temperature of the solvent.
• Preferred nitrate source is silver nitrate and 1-iii) optionally deprotecting the compounds obtained in step 1-i) or 1-ii) as described in T. W. Greene "Protective groups in organic synthesis", Harvard University Press, 1980, 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 0 C to 50 0 C.
• an inert organic dry solvent such as N, N' -dimethylformamide, tetrahydrofuran, benzene, toluene, dioxane, a polyhalogenated aliphatic hydrocarbon at a temperature from -20 0 C to 50 0 C.
• the reaction is completed within a time range from 30 minutes to 36 hours.
• a catalyst such as N, N-dimethylamino pyridine (DMAP) or in the presence of DMAP and a Lewis acid such as Sc(OTf) 3 or Bi(OTf) 3 .
• the reaction is carried out in an inert organic solvent such as N, N' -dimethylformamide, tetrahydrofuran, benzene, toluene, dioxane, a polyhalogenated aliphatic hydrocarbon at a temperature from -20 0 C to 40 0 C.
• the reaction is completed within a time range from 30 minutes to 36 hours.
• 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 0 C to 40 0 C.
• the reaction is completed within a time range from 30 minutes to 36 hours.
• R 1' is selected from Al), A2'), A3') or A4'
• R la is selected from A5) or A6)
• R 2a is selected from B5) or B6) and R 2 is selected from
• T' and T" are C(O) and Y, Y' and R 4a' are as above defined, can be obtained la-i) by reacting a compound of formula (HIa)
• R 1' is selected from Al
• A2' is selected from A3'
• A4' is selected from A5
• R 4a is as defined above
• R 2' is selected from Bl), B2'), B3' ) , B4'), R 2a is selected from B5) or B6) and R 4a' is as defined above, -(c2") -C(O)-(CH 2 ) b -NH 2 ,
• R 10 , R 11 , b, c, d, e and f are as above defined; with a compound of formula (IVa)
• y is the radical Y' when X 2 is selected from (a4') or (b4'), wherein Y and Y' are as defined above, and la-ii) when Q is Z 2 , by converting the compound obtained in the step la-i) into nitro derivative by reaction with a nitrate source as above described and la-iii) optionally deprotecting the compounds obtained in step la-i) or la-ii) as above described.
• reaction of a compound of formula (Ilia) wherein P 2 and X 2 are as above defined, with a compound of formula (IVa) wherein Wi is OH, y, Q are as above defined, may be carried out as described in 1-i-l) or in presence of other known condensing reagents such as 0- (7-azabenzotriazol-l-yl) -N, N, N ' , N ' - tetramethyluronium hexafluorophosphate (HATU) .
• HATU 7-azabenzotriazol-l-yl
• the compounds of formula (IVa) wherein Wi 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 0 C to 0 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 AgN ⁇ 3 can be performed under microwave irradiation in solvents such acetonitrile or THF at temperatures in the range between 100 and 180 0 C for time range from 1 to 60 min.
• Ra-O-C (O)-X"-y-Q wherein R a , X" and Q are as above defined
• y is the radical Y when X 2 is selected from (a2'), (b2'), (c2'), (e2'), (fl'), (g2'), (hi'), (H'), (12'), (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 lb-ii) when Q is Z 2 , by converting the compound obtained in the step lb-i) into nitro derivative by reaction with a nitrate source as above described and lb-iii) optionally deprotecting the compounds obtained in step lb-i) or
• reaction of a compound of formula (HIb) wherein P 2 and X3 are as above defined, with a compound of formula (IVa) wherein Wi is OH, y and Q are as above defined may be carried out as described in la-i) using a ratio (HIb)/ (IVa) 1:2.
• reaction of a compound of formula (HIb) wherein P 2 and X3 are as above defined, with a compound of formula (IVa) wherein Wi is 0R a , y and Q are as above defined may be carried out as described in l-i-2) using a ratio (HIb) /(IVa) 1:2.
• R a and Q are as above defined, wherein y is the radical Y' , wherein Y' is as above defined, and le-ii) when Q is Z 2 , by converting the compounds obtained in the step le-i) into nitro derivative by reaction with a nitrate source as above described and le-iii) optionally deprotecting the compounds obtained in step le-i) or le-ii) as above described.
• reaction of a compound of formula (HIb) wherein P 2 and X3 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 l-i-2) using a ratio (HIb)/ (IVd) 1:2.
• reaction of a compound of formula (Ib) wherein P 2 and X3 ' are as above defined, with a compound of formula (IVf) wherein R a , R' , y, Q are as above defined, may be carried out as described in l-i-2) .
• the compounds of formula (IVf) wherein R', y and Q are as above defined can be obtained from the compounds of formula HR'N-y-Q (IVg) by reaction with a chloroformate as known in the literature .
• the compounds of formula (IVg) wherein y is as above defined and Q is Z2 are commercially available, the compounds of formula (IVg) wherein y is as above defined and Q is -ONO2 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.
• X" and Q are as above defined, may be carried out as described in 1-i-l) .
• 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 0 C or in a double phase system H 2 0/Et 2 0 temperature in the range between 20° and 40 0 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 ZnCl2 as known in literature .
• the compounds of formula (IVn) may be obtained as known in literature .
• 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 (0) 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 CH2CI2 at temperatures range between 0° to 65°C.
• X", y, Q are as above defined may be carried out as described in 1-i-l) .
• R' , y, Q, Hal are as above defined, may be carried out as described in 11-1) .
• R x is selected from (a2), (a4), (a8), (b2), (b4), (b8), (c2), (e2), (fl), (g2), (hi), (il), (12), (m2), (n2), (o2), (p2), (q2), (r2), (s2), (t2), (u2), (v2), Z is -CH (R') -O- wherein R' is selected from H or straight or branched Ci-C 4 alkyl, can be obtained:
• W-Xi (Ia) wherein W is a chlorine atom, Xi is as above defined, and ZnCl 2 as known in literature.
• X 2 is a radical having the following meanings: -(al') -HN-CH(R ⁇ )-C(O)-(T-Y-Q)
• R 3a' is selected from P 2 , -0R 5a or
• R 5a is as above defined; -(Cl') -HN- (CH 2 ) b -C (O)- (T-Y-Q);
• 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
• reaction of a compound of formula (II3), wherein R and R a are as above defined, with a compound of formula (Ig) wherein Xi is as above defined, may be carried out as described in l-i-2) .
• y is the radical Y when X 6 is selected from (al'), (bl'), (cl'), (el'), (f2'), (gl'), (h2'), (i2'), (H'), (ml'), (nl'), (ol'), (pi'), (ql'), (rl'), (si'), (tl'), (ul') and (vl'), y is the radical Y' when X 6 is selected from (a3' ) and (b3' ) , wherein Y and Y' are as defined above, and
• R la is selected from A7)
• R 2a is selected from B7)
• R 2' is selected from Bl
• B2' B3'
• B4' B4'
• R 3a' , Y and Y' are as above defined
• T and T" are -NR' wherein R' is as above defined may be obtained 3b-i) by reacting a compound of formula (HIe),
• y is the radical Y when X 6 is selected from (al'), (bl'), (cl'), (el'), (f2'), (gl'), (h2'), (12'), (H'), (ml'), (nl'), (ol'), (pi'), (ql'), (H'), (si'), (tl'), (ul') and (vl'), y is the radical Y' when X 6 is selected from (a3' ) and (b3' ) , wherein Y and Y' are as defined above, and
• reaction of a compound of formula (HIe) wherein P 3 and Xe are as above defined, with a compound of formula (IVg) wherein R' , y, Q are as above defined, may be carried out la-i) .
• y is the radical Y when X 6 is selected from (al'), (bl'), (cl'), (el'), (f2'), (gl'), (h2'), (12'), (H'), (ml'), (nl'), (ol'), (pi'), (ql'), (H'), (Sl'), (tl'), (ul') and (vl'), y is the radical Y' when X 6 is selected from (a3' ) and (b3' ) , wherein Y and Y' are as defined above, and
• T and T" are -O-CH (R' ) -O-C (O) O- wherein R' is as above defined may be obtained
• Hal is an halogen atom y is the radical Y when X 6 is selected from (al'), (bl'), (cl'),
• y is the radical Y' when Xe is selected from (a3' ) and (b3' ) , wherein Y and Y' are as defined above, and
• T is -O-CH (R' ) -O-C (O) - are obtained as described in 3c) .
• T is -O-CH (R' ) -0-C (0) 0- are obtained as described in 3d) .
• T is -O-CH (R' ) -O-C (O) - are obtained as described in 3c) .
• T is -O-CH (R' ) -0-C (0) 0- are obtained as described in 3d) .
• 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-l) , l-i-2) and Ia-I) .
• T is -O-CH (R' ) -O-C (O) - are obtained as described in 3c) .
• T is -O-CH (R' ) -0-C (0) 0- are obtained as described in 3d) .
• R la is selected from A5 or A6) and R 2a is selected from
• Wi, y, Q are as above defined, may be carried out as described in 1-i-l) , l-i-2) , Ia-I) .
• reaction of a compound of formula (II3) wherein R and R a are as above defined, with a compound of formula (Im) wherein Xi 2 is as above defined, may be carried out as described in l-i-2) .
• R 4a' and P 1 are as above defined, with a compound of formula (IVa)
• Wi-(O)C-y-Q IVa
• Q and Wi are as above defined
• y is the radical Y when Xi3 is selected from (dl') or (d2')
• y is the radical Y' when X i3 is selected from (d3' ) or (d4')
• Y and Y' are as above defined
• reaction of a compound of formula (III1) wherein P 4 and Xi 4 are as above defined, with a compound of formula (IVa) wherein Wi is OH, y and Q are as above defined, may be carried out as described in 1-i-l) using a ratio (HIl)/ (IVa) 1:2.
• reaction of a compound of formula (HIl) wherein P 4 and X14 are as above defined, with a compound of formula (IVa) wherein Wi is 0R a , y and Q are as above defined may be carried out as described in l-i-2) using a ratio (HIl) /(IVa) 1:2.
• T', T"' and T" are C(O), can be obtained
• T' and T"' are -C(O)- can by obtained as described in 4a) .
• reaction of a compound of formula (III1) wherein P 4 and X14 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 l-i-2) using a ratio (HIl)/ (IVd) 1:2.
• R a , X", y and Q are as above defined, may be carried out as described in l-i-2).
• the compounds of formula (In) wherein T' or T"' are C(O), P and Xi5 are as above defined are obtained as described in 4a-i) , 4a- ⁇ ) •

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