US2010099729A1PendingUtilityA1
Nitric oxide donor compounds
Est. expiryFeb 5, 2027(~0.6 yrs left)· nominal 20-yr term from priority
A61P 37/00A61P 9/10A61P 9/00A61P 29/00A61P 31/00A61P 25/02A61K 31/403A61K 31/40C07C 229/24A61K 31/225A61K 45/06C07C 229/26C07C 229/08C07C 229/36C07C 271/22C07C 291/02C07C 203/02C07C 279/14C07D 209/52A61P 19/08A61K 31/27A61K 31/223C07C 323/58C07C 229/20A61K 31/265C07D 207/16C07C 229/22C07C 237/08
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Claims
Abstract
The invention relates to nitric oxide donor compounds and their use for treating cardiovascular diseases, inflammation, pain, fever, gastrointestinal disorders, ophthalmic diseases, hepatic disorders, renal diseases, respiratory disorders, immunological diseases, bone metobolismsdysfunctions, central and peripheral nervous system diseases, sexual dysfunctions, infectious diseases, for the inhibition of platelet aggregation and platelet adhesion, for treating pathological conditions resulting from abnormal cell proliferation, vascular diseases. The invention also relates to compositions comprising at least one nitric oxide releasing compounds of the invention and composition comprising at least one nitric oxide releasing compounds according to the invention and at least one 15 therapeutic agent.
Claims
exact text as granted — not AI-modified1 . A compound of formula (I) and pharmaceutically acceptable salts or stereoisomers thereof:
wherein
s is 1,
s′ and s″ are independently selected from 0 or 1,
m, m′ and m″ are each independently selected from 0 or 1 with the proviso that when m, m′ or m″ are 0, A is linked directly to the groups —(Y—ONO 2 ), —(Y′—ONO 2 ), —(Y″—ONO 2 ),
B at each occurrence is independently selected from:
A is a radical selected from the group consisting of:
wherein
in formulas (IIa)-(IIm) and (IIo)-(IIu), R 1 is selected from:
H, —C(O)O—C(CH 3 ) 3 , —C(O)—R n , —C(O)O—R 1x , wherein R 1x is one of the groups —[(B) m —(Y—ONO 2 )] s , —[(B) m′ —(Y′—ONO 2 )] s′ or
—[(B) m″ —(Y″—ONO 2 )] s″ of formula (I) wherein m, m′ and m″ are 0 and Y, Y′ and Y″ are as below reported;
in formulas (IIa)-(IIu) R 2 is selected from:
—C(O)OH, —C(O)—OC(CH 3 ) 3 , —C(O)OR 2x , —C(O)NHR 2xx , —C(O)N(CH 3 )R 2xx wherein R 2x and R 2xx are one of the groups —[(B) m —(Y—ONO 2 )] s , —[(B) m′ —(Y′—ONO 2 )] s′ or —[(B) m″ —(Y″—ONO 2 )] s″ of formula (I) wherein m, m′ and m″ are 0 or 1, B is as above defined and Y, Y′ and Y″ are as below reported,
R 2xx is one of the groups —[(B) m —(Y—ONO 2 )] s , —[(B) m′ —(Y′—ONO 2 )] s′ or —[(B) m″ —(Y″—ONO 2 )] s″ of formula (I) wherein m, m′ and m″ are 0 and Y, Y′ and Y″ are as below reported,
or R 2 is the group R 4 :
in formula (IIa), R a is selected from the groups consisting of:
a) —H, —CH 3 , isopropyl, isobutyl, sec-butyl, tert-butyl, methylthio-(CH 2 ) 2 —, phenyl, benzyl, C 6 H 5 —CH 2 —CH 2 —,
2-monosubstituted benzyl, or 3-monosubstituted benzyl or
4-monosubstituted benzyl with groups such as —F, —Cl, I, —NO 2 ,
—CF 3 , —CH 3 , CN, C 6 H 5 CO—;
or R a is 2,4-dichlorobenzyl, 3,4-dichlorobenzyl, 3,4-difluorobenzyl, 3-triptophanyl-CH 2 —, 3-benzothienyl-CH 2 —,
4-imidazolyl-CH 2 —, 9-anthranyl-CH 2 —, cyclohexyl,
cyclohexyl-CH 2 —, cyclohexyl-(CH 2 ) 2 —, cyclopentyl-CH 2 —,
(C 6 H 5 ) 2 CH—,
4-quinolyl-CH 2 —, 3-quinolyl-CH 2 —, 2-quinolyl-CH 2 —,
2-quinoxalyl-CH 2 —, 2-furyl-CH 2 —, 1-naphtyl-CH 2 —, 2-naphtyl-CH 2 —, 2-pyridyl-CF 12 —, 3-pyridyl-CH 2 —, 4-pyridyl-CH 2 —, 2-thienyl-CH 2 —,
3-thienyl-CH 2 —, C 6 H 4 —CH═CH—CH 2 —, CH≡CH—CH 2 —,
NH 2 —CO—CH 2 —, NH 2 —CO—(CH 2 ) 2 —, or —P(═O)(OCH 3 ) 2 ;
b) HS—CH 2 —, R bx —C(O)—S—CH 2 —, R bx —OC(O)—S—CH 2 —, R bx —NH—C(O)S—CH 2 — wherein R bx is one of the groups —[(B) m —(Y—ONO 2 )] s ,
—[(B) m′ —(Y—ONO 2 )] s′ or —[(B) m″ —(Y″—ONO 2 )] s ″ of formula (I) wherein m, m′ and m″ are 0 and Y, Y′ and Y″ are as below defined;
c) R x O—CH 2 —, R x O—CH(CH 3 )—, (R x O)-p-C 6 H 4 —CH 2 —,
4-(R x O)-3,5-diiodobenzyl-, 4-(R x O)-3-nitrobenzyl- wherein R x is H, R xx —C(O)—, R xx —OC(O)—, R xx —NHC(O)— wherein R xx is one of the groups —[(B) m —(Y—ONO 2 )] s , —[(B) m′ —(Y′—ONO 2 )] s′ or —[(B) m″ —(Y″—ONO 2 )] s″ of formula (I) wherein m, m′ and m″ are 0 and Y, Y′ and Y″ are as below defined;
d) R g C(O)CH 2 —NH—, R g C(O)CH 2 —, R g C(O)(CH 2 ) 2 —, R g C(O)(CH 2 ) 4 —, wherein R g is OH, (CH 3 ) 3 CO—, R gx —O—, R g —NH—, R g —N(CH 3 )— wherein R gx is one of the groups —[(B) m —(Y—ONO 2 )] s , —[(B) m′ —(Y′—ONO 2 )] s′ or
—[(B) m″ —Y″—ONO 2 )] s″ of formula (I) wherein m, m′ and m″ are 0 or 1, B is as above defined and Y, Y′ and Y″ are as below reported, R gxx is one of the groups —[(B) m —(Y—ONO 2 )] s ,
—[(B) m′ , —(Y′—ONO 2 )] s′ or —[(B) m″ —(Y″—ONO 2 )] s″ of formula (I) wherein m, m′ and m″ are 0 and Y, Y′ and Y″ are as below reported,
or R g is the group R gg :
e) R h NH(CH 2 ) p — or R i NH(═NH)NH—(CH 2 ) 3 —, wherein p is an integer from 0 to 4, R h is H, (CH 3 ) 3 C—OC(O)—, R hh —C(O)— or R hh —OC(O)—, R i is H, R ii —C(O)— or R ii —OC(O)—, wherein R hh and R ii are each independently one of the groups —[(B) m —(Y—ONO 2 )] s ,
—[(B) m′ —(Y′—ONO 2 )] s′ or —[(B) m″ —(Y″—ONO 2 )] s″ of formula (I) wherein m, m′ and m″ are 0 and Y, Y′ and Y″ are as below defined;
in formula (IIc) R c is selected from the following groups:
a′) H, CH 3 , isopropyl, isobutyl, sec-butyl, methylthio-(CH 2 ) 2 , phenyl, benzyl, biphenyl-CH 2 , 3-triptophanyl-CH 2 , NH 2 —CO—CH 2 ,
NH 2 —CO—(CH 2 ) 2 —;
b′) HS—CH 2 —, R bx —C(O)—S—CH 2 —, R bx —OC(O)—S—CH 2 —, R bx —NH—C(O)S—CH 2 — wherein R bx is one of the groups —[(B) m —(Y—ONO 2 )] s ,
—[(B) m′ —(Y′—ONO 2 )] s′ or —[(B) m″ —(Y″—ONO 2 )] s ″ of formula (I) wherein m, m′ and m″ are 0 and Y, Y′ and Y″ are as below defined;
c′) R x O—CH 2 —, R x O—CH(CH 3 )—, R x O—C 6 H 4 —CH 2 — wherein R x is H,
R xx —C(O)—, R xx —OC(O)—, R xx —NHC(O)— wherein R xx is one of the groups —[(B) m —(Y—ONO 2 )] s , —[(B′) m′ —(Y′—ONO 2 )] s′ or
—[(B″) m″ —(Y″—ONO 2 )] s″ of formula (I) wherein m, m′ and m″ are 0 and Y, Y′ and Y″ are as below defined;
d′) R g C(O)CH 2 —, R g C(O)(CH 2 ) 2 — wherein R g is OH, (CH 3 ) 3 CO—, R gx —O—, R gxx —NH—, R gxx —N(CH 3 )— wherein R gx is one of the groups
—[(B) m —(Y—ONO 2 )] s , —[(B) m′ —(Y′—ONO 2 )] s′ or —[(B) m″ —(Y″—ONO 2 )] s″ of formula (I) wherein m, m′ and m″ are 0 or 1, B is as above defined and Y, Y′ and Y″ are as below reported, R gxx is one of the groups —[(B) m′ —(Y—ONO 2 )] s′ , —[(B) m′ —(Y′—ONO 2 )] s′ or —[(B) m″ —(Y″—ONO 2 )] s″ of formula (I) wherein m, m′ and m″ are 0 and Y, Y′ and Y″ are as below reported;
e′) R h NH(CH 2 ) p — or R i NH(═NH)NH—(CH 2 ) 3 —, wherein p is an integer from 0 to 4, R h is H, —C(O)O—C(CH 3 ) 3 , R hh —C(O)— or R hh —OC(O)—, R i is H, R ii —C(O)— or R ii —OC(O)—, wherein R hh and R ii are each independently one of the groups —[(B) m —(Y—ONO 2 )] s ,
—[(B) m′ —(Y″—ONO 2 )] s′ or —[(B) m″ -(Y″—ONO 2 )] s″ of formula (I) wherein m, m′ and m″ are 0 and Y, Y′ and Y″ are as below defined;
in formula (IIl) Ph is phenyl, a′ is equal to 0, 1, 2, or 3; and a is equal to 0 or 1 with the proviso that a is 0 or 1 when a′ is 0 and a is 0 when a′ is 1, 2 or 3;
in formula (IIi) the group R 2 can be attached to one of the positions 1, 2 or 3 of the cyclohexyl ring;
in formulae (IIj) and (IIk) the symbol represents a single bond or a double bond;
in formula (IIk) the group R 2 can be attached to one of the positions 1, 2 or 3 of the piperidyl ring;
in formula (IIl), R L is selected from:
H, methyl, propyl, allyl, (C 6 H 5 ) 2 CH—,
1-naphtyl-CH 2 —, benzyl, 2-bromobenzyl, 2-chlorobenzyl,
3-chlorobenzyl, 4-fluorobenzyl, 4-bromobenzyl, 4-methylbenzyl;
in formula (IIm) R m is selected from:
benzyl, 2-bromobenzyl, 4-bromobenzyl, 4-methylbenzyl;
in formula (IIn) R n is selected from:
—H, —C(O)—R nx , —C(O)O—R nx or —(CH 2 ) 2 —NH—R h wherein R h is —H,
—C(O)O—C(CH 3 ) 3 , —C(O)—R hh , —C(O)O—R hh wherein R nx and R hh are each independently one of the groups —[(B) m —(Y—ONO 2 )] s ,
—[(B) m′ —(Y′—ONO 2 )] s′ or —[(B) m″ —(Y″—ONO 2 )] s″ of formula (I) wherein m, m′ and m″ are 0 and Y, Y′ and Y″ are as below defined;
in formula (IIp), c is 0 or 1 and R 2 can be attached to the position 1, 2 or 3 of the phenyl ring;
in formula (IIs), R 3 is selected from:
OH, —OC(O)—R 3x , —OC(O)O—R 3x , —OC(O)—NH—R 3x wherein R 3x is one of the groups —[(B) m —(Y—ONO 2 )] s , —[(B) m′ —(Y′—ONO 2 )] s′ or
—[(B) m″ —(Y″—ONO 2 )] s″ of formula (I) wherein m, m′ and m″ are 0 and Y, Y′ and Y″ are as below defined;
in formula (IIs) R s is selected from the following groups:
a″) —H, —CH 3 , isopropyl, isobutyl, sec-butyl, tert-butyl, methylthio-(CH 2 ) 2 —, benzyl, 2-monosubstituted benzyl, or
3-monosubstituted benzyl, 3-triptophanyl-CH 2 —,
4-imidazolyl-CH 2 —, NH 2 —CO—CH 2 —, NH 2 —CO—(CH 2 ) 2 —;
b″) HS—CH 2 —, R bx —C(O)—S—CH 2 —, R bx —OC(O)—S—CH 2 —, R bx —NH—C(O)S—CH 2 — wherein R bx is one of the groups —[(B) m —(Y—ONO 2 )] s ,
—[(B) m′ —(Y′—ONO 2 )] s′ or —[(B) m″ —(Y″—ONO 2 )] s″ of formula (I) wherein m, m′ and m″ are 0 and Y, Y′ and Y″ are as below defined;
c″) R x O—CH 2 —, R x O—CH(CH 3 )—, (R x O)-p-C 6 H 4 —CH 2 —,
4-(R x O)-3,5-diiodobenzyl-, 4-(R x O)-3-nitrobenzyl- wherein R x is H, R xx —C(O)—, R xx —OC(O)—, R xx —NHC(O)— wherein R xx is one of the groups —[(B) m —(Y—ONO 2 )] s , —[(B) m′ —(Y′—ONO 2 )] s′ or —[(B) m″ —(Y″—ONO 2 )] s″ of formula (I) wherein m, m′ and m″ are 0 and Y, Y′ and Y″ are as below defined;
d″) R g C(O)CH 2 —NH—, R g C(O)CH 2 , R g C(O)(CH 2 ) 2 —, R g C(O)(CH 2 ) 4 —, wherein R g is OH, (CH 3 ) 3 CO—, R gx —O—, R g —NH—, R g —N(CH 3 )— wherein R gx is one of the groups —[(B) m —(Y—ONO 2 )] s , —[(B) m′ —(Y′—ONO 2 )] s′ or
—[(B) m″ —(Y″—ONO 2 )] s″ of formula (I) wherein m, m′ and m″ are 0 or 1, B is as above defined and Y, Y′ and Y″ are as below reported, R gxx is one of the groups —[(B) m —(Y—ONO 2 )] s , —[(B) m′ —(Y′—ONO 2 )] s′ or —[(B) m″ —(Y″—ONO 2 )] s″ of formula (I) wherein m, m′ and m″ are 0 and Y, Y′ and Y″ are as below reported,
e″) R h NH(CH 2 ) p — or R i NH(═NH)NH—(CH 2 ) 3 —, wherein p is an integer from 0 to 4, R h is H, (CH 3 ) 3 C—OC(O)—, R hh —C(O)— or R hh —OC(O)—, R i is H, R ii —C(O)— or R ii —OC(O)—, wherein R hh and R ii are each independently one of the groups —[(B) m —(Y—ONO 2 )] s , —[(B) m′ —(Y′—ONO 2 )] s′ or —[(B) m″ —(Y″—ONO 2 )] s″ of formula (I) wherein m, m′ and m″ are 0 and Y, Y′ and Y″ are as below defined;
in formula (IIt) d is an integer from 2 to 5, d′ is 0 or 1, with the proviso that d′ is 0 when d is an integer from 3 to 5, R t is H, —C(O)—R tt or —C(O)O—R tt wherein R tt is one of the groups —[(B) m —(Y—ONO 2 )] s , —[(B′) m′ —(Y′—ONO 2 )] s′ or
—[(B″) m″ —(Y″—ONO 2 )] s″ of formula (I) wherein m, m′ and m″ are 0;
in formula (IIu) a and b are each independently 0 or 1, R x is H, —C(O)—R xx , —C(O)O—R xx —, —C(O)NH—R xx wherein R xx is one of the groups —[(B) m —(Y—ONO 2 )] s , —[(B) m′ —(Y′—ONO 2 )] s′ or —[(B) m″ —(Y″—ONO 2 )] s″ of formula (I) wherein m, m′ and m″ are 0 and Y, Y′ and Y″ are as below defined;
Y, Y′ and Y″ of the groups (Y—ONO 2 ), —(Y′—ONO 2 ) and —(Y″—ONO 2 ) of formula (I) are bivalent radicals and they are each independently selected from:
A)
a straight or branched C 1 -C 20 alkylene,
a straight or branched C 1 -C 20 alkylene substituted with one or more —ONO 2 group(s);
a cycloalkylene having 5 to 7 carbon atoms, the ring being optionally substituted with a straight or branched C 1 -C 10 alkyl;
B)
wherein n 0 is an integer from 0 to 20,
n 1 is an integer from 1 to 20,
wherein in formulas (IB) and (IB′) the —ONO 2 group is linked to
C)
wherein:
n is an integer from 1 to 20,
n 2 is an integer from 0 to 2,
R 2 is H or CH 3 ,
X 1 is —OC(O)— or —C(O)O—;
wherein in formula (IC) the —ONO 2 group is linked to —(CH 2 ) n 1 —;
D)
wherein in formula (ID):
n 1 is an integer from 1 to 20,
n 2 , R 2 and X 1 are as defined above;
Y 1 is —CH 2 —CH 2 — or —CH═CH—(CH 2 ) n 2a — wherein n 2a is an integer from 0 to 5,
wherein in formula (ID) the —ONO 2 group is linked to —(CH 2 ) n 1 —;
E)
wherein X 2 is —O—, —S—, —NH— or —N(CH 2 CH 2 OCH 3 )—,
n 3 is an integer from 1 to 5,
n 3 is an integer from 0 to 10,
n 4 an integer from 1 to 10,
n 3′ is an integer from 0 to 10,
n 4′ an integer from 1 to 10,
R 2 is H or —CH 3 ,
wherein in formula (IE) the —ONO 2 group is linked to the —(CH 2 ) n4′ group;
F)
wherein:
n 5 is an integer from 0 to 10;
n 6 is an integer from 1 to 10;
R 4 , R 5 , R 6 , R 7 are the same or different, and are H or straight or branched C 1 -C 4 alkyl,
wherein in formula (IF) the —ONO 2 group is linked to
wherein n 6 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, sulfur,
and is selected from the group consisting of:
G)
wherein n 0 is an integer from 0 to 10,
n 7 is an integer from 1 to 10,
n 8 is an integer from 0 to 10,
R 8 is CH 3 or CH 2 ONO 2 ,
wherein in formula (IG) the —ONO 2 group is linked to the group
with the proviso that in formula (I) s′ and s″ cannot be both 1 when:
A is the radical of formulas (IIb), (IId)-(IIr), or
A is the radical of formula (IIt) wherein d is from 3 to 5 and d′ is 0, or
A is the radical of formula (IIu) wherein a is 0;
with the proviso that s′ and s″ can be both 1 when:
A is the radical of formulas (IIa), (IIc) or (IIs) and R a , R c and R s are selected from
R bx —C(O)—S—CH 2 —, R bx —OC(O)—S—CH 2 —, R bx —NH—C(O)S—CH 2 — wherein R bx is one of the groups —[(B) m —(Y—ONO 2 )] s , —[(B) m′ —(Y′—ONO 2 )] s′ or —[(B) m″ —(Y″—ONO 2 )] s″ wherein m, m′ and m″, B, Y, Y′ and Y″ are as above defined;
R x O—CH 2 —, R x O—CH(CH 3 )—, (R x O)-p-—C 6 H 4 —CH 2 —,
4-(R x O)-3,5-diiodobenzyl-, 4-(R x O)-3-nitrobenzyl- wherein R x is R xx —C(O)—, R xx —OC(O)— or R xx —NHC(O)— wherein R xx is one of the groups —[(B) m —(Y—ONO 2 )] s , —[(B) m′ —(Y′—ONO 2 )] s′ or
—[(B) m″ —(Y″—ONO 2 )] s″ wherein m, m′ and m″, B, Y, Y′ and Y″ are as above defined;
R g C(O)CH 2 —NH—, R g C(O)CH 2 , R g C(O)(CH 2 ) 2 —, R g C(O)(CH 2 ) 4 —, wherein R g is OH, (CH 3 ) 3 CO—, R gx —O—, R gxx —NH—, R gxx —N(CH 3 )— wherein R gx and R gxx are one of the groups —[(B) m —(Y—ONO 2 )] s ,
—[(B) m′ —(Y′—ONO 2 )] s′ or —[(B) m″ —(Y″—ONO 2 )] s″ wherein m, m′ and m″, B, Y, Y′ and Y″ are as above defined;
R h NH(CH 2 ) p — or R i NH(═NH)NH—(CF 2 ) 3 —, wherein p is an integer from 0 to 4, R h is R hh —C(O)— or R hh —OC(O)—, R i is R ii —C(O)— or R ii —OC(O)—, wherein R hh and R ii are one of the groups
—[(B) m —(Y—ONO 2 )] s , —[(B) m′ —(Y′—ONO 2 )] s′ or
—[(B) m″ —(Y″—ONO 2 )] s″ wherein m, m′ and m″, B, Y, Y′ and Y″ are as above defined;
A is the radical of formula (IIt) wherein d′ is 1 and d is 2 and R t is —C(O)—R tt or —C(O)O—R tt wherein R tt is one of the groups —[(B), —(Y—ONO 2 )] s , —[(B) m′ —(Y′—ONO 2 )] s′ or
—[(B) m″ —(Y″—ONO 2 )] s″ wherein m, m′ and m″, B, Y, Y′ and Y″ are as above defined;
A is the radical of formula (IIu) wherein a is 1 and R x is
C(O)—R xx , —C(O)O—R xx or —C(O)NH—R xx wherein R xx is one of the groups —[(B) m —(Y—ONO 2 )] s , —[(B) m′ —(Y′—ONO 2 )] s′ or
—[(B) m″ —(Y″—ONO 2 )] s″ of formula (I) wherein m, m′ and m″ B, Y, Y′ and Y″ are as above defined
with the proviso that the following compounds of formula (I) are excluded:
3-(nitrooxy)propyl 2-(tert-butoxycarbonylamino)-4-phenyl butanoate,
3-(nitrooxy)propyl 2-amino-4-phenylbutanoate,
3-(nitrooxy)propyl 2-amino-4-phenylbutanoate hydrochloride,
4-(nitrooxy)butyl 2-(tert-butoxycarbonylamino)-4-phenylbutanoate,
4-(nitrooxy)butyl 2-amino-4-phenylbutanoate,
4-(nitrooxy)butyl 2-amino-4-phenylbutanoate hydrochloride,
(2-(nitrooxy)ethoxy)methyl 2-(tert-butoxycarbonylamino)-4-phenyl butanoate,
(2-(nitrooxy)ethoxy)methyl 2-amino-4-phenylbutanoate,
(2-(nitrooxy)ethoxy)methyl 2-amino-4-phenylbutanoate hydrochloride,
1-tert-butyl 2-(4-(nitrooxy)butyl)pyrrolidine-1,2-dicarboxylate,
4-(nitrooxy)butyl pyrrolidine-2-carboxylate,
4-(nitrooxy)butyl pyrrolidine-2-carboxylate hydrochloride,
1-tert-butyl 2-(3-(nitrooxy)propyl)pyrrolidine-1,2-dicarboxylate,
3-(nitrooxy)propyl pyrrolidine-2-carboxylate
3-(nitrooxy)propyl pyrrolidine-2-carboxylate Hydrochloride.
2 . The compounds according to claim 1 wherein in formula (I) Y, Y′ and Y″ of the groups (Y—ONO 2 ), —(Y′—ONO 2 ) or —(Y″—ONO 2 ) are each independently selected from:
A)
a straight or branched C 2 -C 10 alkylene
a straight or branched C 2 -C 10 alkylene substituted with a —ONO 2 group;
E)
wherein in formula (IE)
n 3 is from 1 to 5
n 3 is 0 and n 4 is from 1 to 4,
n 3′ is 0 and n 4′ is from 1 to 4,
X 2 is or —NH—,
R 2 is H.
3 . The compounds according to claim 1 wherein in formula (I) Y, Y′ and Y″ of the groups (Y—ONO 2 ), —(Y′—ONO 2 ) or —(Y″—ONO 2 ) are each independently selected from:
B)
wherein in formula (IB)
n 0 is from 0 to 5 and n 1 is an integer from 1 to 10;
C)
wherein in formula (IC)
n 1 is an integer from 1 to 10,
n 2 is 1 and R 2 is CH 3 , X 1 is —C(O)O—;
D)
wherein in formula (ID):
n 2 is 1 and R 2 is CH 3 ,
Y 1 is —CH═CH—(CH 2 ) n 2a — wherein n 2a is 0,
X 1 is —C(O)O— and n 1 is an integer from 1 to 10;
4 . The compounds according to claim wherein in formula (I) s is 1 and m is 0, s′ and s″ are 0,
A is selected from:
wherein
R 1 is H or —C(O)—OC(CH 3 ) 3 ,
R 2 is —C(O)OR 2x , —C(O)NHR 2xx , —C(O)N(CH 3 )R 2xx wherein R 2x and R 2xx are the group —(Y—ONO 2 ),
R a of formula (ha) is selected from:
a) H, CH 3 , isopropyl, isobutyl, sec-butyl, methylthio-(CH 2 ) 2 —, benzyl, C 6 H 5 —CH 2 —CH 2 —, 3-triptophanyl-CH 2 —, NH 2 —CO—CH 2 —,
NH 2 —CO—(CH 2 ) 2 —, 4-imidazolyl-CH 2 —;
b) HS—CH 2 —,
c) R x O—CH 2 —, R x O—CH(CH 3 )—, (R x O)-p-—C 6 H 4 —CH 2 —, wherein R x is H,
d) R g C(O)CH 2 , R g C(O)(CH 2 ) 2 —, wherein R g is OH, (CH 3 ) 3 CO—, or the group R gg :
e) R h NH(CH 2 ) p — or R i NH(═NH)NH—(CH 2 ) 3 —, wherein p is an integer equal to 3 or 4, R h is H or (CH 3 ) 3 C—OC(O)—, R i is H;
R c of formula (IIc) is selected from the group comprising:
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 —;
R L of formula (IIl) is H.
5 . The compounds according to claim 1 wherein in formula (I) s is 1 and m is 0,
s′ and s″ are 0, A is a radical selected from
wherein R 1 is —C(O)R 1x , —C(O)OR 1x wherein R 1x is the group
—(Y—ONO 2 ),
R 2 in formulas (IIa) (He) and (IIl) is —C(O)OH, —C(O)—OC(CH 3 ) 3 or R 2 is the group R 4 :
R 3 in formula (IIs) is OH;
R a of formula (ha) is selected from:
a) H, CH 3 , isopropyl, isobutyl, sec-butyl, methylthio-(CH 2 ) 2 —, benzyl, C 6 H 5 —CH 2 —CH 2 —, 3-triptophanyl-CH 2 —, NH 2 —CO—CH 2 —,
NH 2 —CO—(CH 2 ) 2 —, 4-imidazolyl-CH 2 —;
b) HS—CH 2 —;
c) R x O—CH 2 —, R x O—CH(CH 3 )—, (R x O)-p-C 6 H 4 —CH 2 — wherein R x is H;
d) R g C(O)CH 2 or R g C(O)(CH 2 ) 2 —, wherein R g is OH or (CH 3 ) 3 C—O—, or R g is the group R gg :
e) R h NH(CH 2 ) p — or R i NH(═NH)NH—(CH 2 ) 3 —, wherein p is an integer equal to 3 or 4, R h is H or (CH 3 ) 3 C—OC(O)—, R i is H;
R c of formula (IIc) is selected from:
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 —;
R L of formula (IIl) is H;
R s of formula (IIs) is H, CH 3 , isopropyl, isobutyl, sec-butyl, methylthio-(CH 2 ) 2 , benzyl, triptophanyl-CH 2 , 4-imidazolyl-CH 2 —, NH 2 —CO—CH 2 —, NH 2 —CO—(CH 2 ) 2 —;
6 . The compounds according to claim 1 wherein in formula (I) s is 1 and m is 0, s′ and s″ are 0,
A is a radical of formula (IIa) or (IIl)
wherein R 1 is —C(O)R 1x or —C(O)OR 1x wherein R 1x is the group
—(Y—ONO 2 ),
R 2 in formulas (IIa) and (IIl) is the group R 4 :
R a of formula (IIa) is selected from:
a) H, CH 3 , isopropyl, isobutyl, sec-butyl, methylthio-(CH 2 ) 2 —, benzyl, C 6 H 5 —CH 2 —CH 2 —, 3-triptophanyl-CH 2 —, NH 2 —CO—CH 2 —,
NH 2 —CO—(CH 2 ) 2 —, 4-imidazolyl-CH 2 —;
b) HS—CH 2 —;
c) R x O—CH 2 —, R x O—CH(CH 3 )—, (R x O)-p-C 6 H 4 —CH 2 —, wherein R x is H;
d) R g C(O)CH 2 or R g C(O)(CH 2 ) 2 —, wherein R g is OH or the group R gg :
e) R h NH(CH 2 ) p — or R i NH(═NH)NH—(CH 2 ) 3 —, wherein p is an integer equal to 3 or 4, R h is H or (CH 3 ) 3 C—OC(O)—, R i is H;
R L of formula (IIl) is H.
7 . The compounds according to claim 1 wherein in formula (I) s is 1 and m is 0, s′ and s″ are 0,
A is a radical of formula
wherein R 1 is H or —C(O)O—C(CH 3 ) 3 ,
R 2 is —C(O)OH or R 2 is equal to the group R 4
R a is selected from:
b) R bx C(O)—S—CH 2 —, R bx OC(O)—S—CH 2 —, R bx NH—C(O)S—CH 2 — wherein R bx is the group —(Y—ONO 2 ),
c) R x O—CH 2 —, R x O—CH(CH 3 )—, (R x O)-p-C 6 H 4 —CH 2 —, wherein R x is R xx C(O)—, R xx OC(O)— or R xx NHC(O)— wherein R xx is the group —(Y—ONO 2 );
d) R g C(O)CH 2 , R g C(O)(CH 2 ) 2 — wherein R g is R gx O—, R gxx —NH—, or
R gxx —N(CH 3 )—, wherein R gx and R gxx are the group —(Y—ONO 2 );
e) R h NH(CH 2 ) p — wherein p is 3 or 4, and R h is R hh C(O)— or R hh OC(O)— wherein R hh is the group —(Y—ONO 2 );
or R i NH(═NH)NH—(CH 2 ) 3 — wherein R i is R ii C(O)— or R ii OC(O)— wherein R ii is the group —(Y—ONO 2 ).
8 . The compounds according to claim 1 wherein in formula (I) s is 1, m is 0, s′ and s″ are 0,
A is a radical of formula
wherein R 1 is H or —C(O)—OC(CH 3 ) 3 ;
R 3 is —OC(O)R 3x , OC(O)OR 3x , —OC(O)—NHR 3x , wherein R 3x is the group —(Y—ONO 2 );
R s is selected from:
a″) H, CH 3 , isopropyl, isobutyl, sec-butyl, methylthio-(CH 2 ) 2 —, benzyl, C 6 H 5 —CH 2 —CH 2 —, 3-triptophanyl-CH 2 —, NH 2 —CO—CH 2 ,
NH 2 —CO—(CH 2 ) 2 —, 4-imidazolyl-CH 2 —.
9 . The compounds according to claim 1 wherein in formula (I) s is 1 and m is 0, s′ and s″ are 0,
A is a radical of formula (IIq)
R 1 is H, —C(O)O—C(CH 3 ) 3 ,
R 2 is —C(O)OR 2x , —C(O)NHR 2xx —C(O)N(CH 3 )R 2xx wherein R 2x and R 2xx are the group —(Y—ONO 2 ).
10 . The compounds according to claim 1 wherein in formula (I) s is 1 and m is 0, s′ and s″ are 0,
A is a radical of formula (IIu)
wherein a is 1 and b is 0;
R 1 is H, —C(O)O—C(C 1-13 ) 3 ,
R 2 is —C(O)OR 2x , —C(O)NHR 2xx —C(O)N(CH 3 )R 2xx wherein R 2x and R 2xx are the group —(Y—ONO 2 ),
R K is H.
11 . The compounds according to claim 1 wherein in formula (I) s and m are 1, s′ and s″ are 0,
A is a radical selected from:
wherein
R 1 is H or —C(O)O—C(CH 3 ) 3 ,
R 2 is —C(O)OR 2x wherein R 2x is the group —[(B)—(Y—ONO 2 )] of formula (I) wherein B is
R a of formula (IIa) is selected from:
a) H, CH 3 , isopropyl, isobutyl, sec-butyl, methylthio-(CH 2 ) 2 —, benzyl, C 6 H 5 —CH 2 —CH 2 —, 3-triptophanyl-CH 2 —, NH 2 —CO—CH 2 —,
NH 2 —CO—(CH 2 ) 2 —, 4-imidazolyl-CH 2 —;
b) HS—CH 2 —;
c) R x O—CH 2 —, R x O—CH(CH 3 )— or (R x O)-p-C 6 H 4 —CH 2 —, wherein R x is H;
d) R g C(O)CH 2 , R g C(O)(CH 2 ) 2 —, wherein R g is OH, (CH 3 ) 3 C—O—, or the group R gg :
e) R h NH(CH 2 ) p — or R i NH(═NH)NH—(CH 2 ) 3 — wherein p is an integer equal to 3 or 4, R h is H or (CH 3 ) 3 C—OC(O)—, R i is H;
R L of formula (IIl) is H.
12 . The compounds according to claim 1 wherein in formula (I) s and s′ are 1 and m, m′ are 0, s″ is 0,
A is a radical of formula (IIa)
wherein R 1 is —C(O)R 1x , or —C(O)OR 1x wherein R 1x is one of the groups —(Y—ONO 2 ) or —(Y′—ONO 2 ),
R 2 is —C(O)OH, —C(O)—OC(CH 3 ) 3 ; or R 2 is the group R 4
R a is selected from:
b) R bx C(O)—S—CH 2 —, R bx —OC(O)—S—CH 2 —, R bx —NH—C(O)S—CH 2 — wherein R bx is one of the groups —(Y—ONO 2 ) or —(Y′—ONO 2 );
c) R x O—CH 2 —, R x O—CH(CH 3 )—, (R x O)-p-C 6 H 4 —CH 2 —, wherein R x is R xx C(O)—, R xx C(O)— or R xx NHC(O)— wherein R xx is one of the groups —(Y—ONO 2 ) or —(Y′—ONO 2 );
d) R g C(O)CH 2 —, R g C(O)(CH 2 ) 2 —, wherein R g is R gx —O—, R gxx —NH—, wherein R gx and R gxx are one of the groups —(Y—ONO 2 ) or —(Y′—ONO 2 ) of formula (I);
e) R h NH(CH 2 ) p — wherein p is an integer equal to 3 or 4, R h is R hh —C(O)— or R hh —OC(O)— wherein R hh is one of the groups —(Y—ONO 2 ) or —(Y′—ONO 2 ), or R i NH(═NH)NH—(CH 2 ) 3 — wherein R i is R ii C(O)— or R ii OC(O)— wherein R ii is one of the groups —(Y—ONO 2 ) or —(Y′—ONO 2 ).
13 . The compounds according to claim 1 wherein in formula (I) s and s′ are 1 and m, m′ are 0, s″ is 0,
A is a radical of formula (IIa) or (IIl)
wherein
R 1 is —C(O)R 1x , —C(O)OR 1x wherein R 1x is one of the groups
—(Y—ONO 2 ) or —(Y′—ONO 2 ) of formula (I);
R 2 is —C(O)OR 2x , —C(O)NHR 2xx , —C(O)N(CH)R 2xx , wherein R 2x and R 2xx are one of the groups —(Y—ONO 2 ) or —(Y′—ONO 2 ) of formula (I) below defined;
R a is selected from:
a) H, CH 3 , isopropyl, isobutyl, sec-butyl, methylthio-(CH 2 ) 2 —, benzyl, C 6 H 5 —CH 2 —CH 2 —, 3-triptophanyl-CH 2 —, NH 2 —CO—CH 2 —,
NH 2 —CO—(CH 2 ) 2 —, 4-imidazolyl-CH 2 —;
R L in formula MD is H.
14 . The compounds according to claim 1 wherein in formula (I) s and s′ are 1, m is 1, m′ is 0, s″ is 0,
A is a radical of formula
wherein
R 1 is —C(O)R 1x , —C(O)OR 1x wherein R 1x is —(Y—ONO 2 );
R 2 is —C(O)OR 2x , wherein R 2x is the group —[B—(Y′—ONO 2 )] wherein B
is
R a is selected from:
H, CH 3 , isopropyl, isobutyl, sec-butyl, methylthio-(CH 2 ) 2 —, benzyl, C 6 H 5 —CH 2 —CH 2 —, 3-triptophanyl-CH 2 —, NH 2 —CO—CH 2 —
—NH 2 —CO—(CH 2 ) 2 —, 4-imidazolyl-CH 2 —;
R L in formula (IIl) is H.
15 . The compounds according to claim 1 wherein in formula (I) s and s′ are 1, and s″ are 0, m and m′ are 0,
A is a radical of formula
wherein R 1 is —C(O)R 1x or —C(O)OR 1x wherein R 1x is one of the groups —(Y—ONO 2 ) or (Y′—ONO 2 );
R 2 is —C(O)OR 2x , —C(O)NHR 2xx or —C(O)N(CH 3 )R 2xx , wherein R 2x and R 2xx are one of the groups —(Y—ONO 2 ) or —(Y′—ONO 2 );
R a is selected from:
b) HS—CH 2 —;
c) R x O—CH 2 —, R x O—CH(CH 3 )—, (R x O)-p-C 6 H 4 —CH 2 —, wherein R x is H,
d) R g C(O)CH 2 — or R g C(O)(CH 2 ) 2 —, wherein R g is OH, (CH 3 ) 3 CO—, or the group R gg :
e) R h NH(CH 2 ) p — or R i NH(═NH)NH—(CH 2 ) 3 —, wherein p is an integer equal to 3 or 4, R h is H, (CH 3 ) 3 C—OC(O)—, R i is H;
16 . The compounds according to claim 1 wherein in formula (I) s and s′ are 1 and m, m′ are 0, s″ is 0,
A is a radical of formula
wherein R 1 is H or —C(O)O—C(CH 3 ) 3 ,
R 2 is —C(O)OR 2x , —C(O)NHR 2xx , —C(O)N(CH 3 )R 2xx wherein R 2x and R 2xx are one of the groups —(Y—ONO 2 ) or —(Y′—ONO 2 );
R a is selected from:
b) R bx C(O)—S—CH 2 —, R bx OC(O)—S—CH 2 —, R bx NH—C(O)S—CH 2 — wherein R bx is one of the groups —(Y—ONO 2 ) or —(Y′—ONO 2 );
c) R x O—CH 2 —, R x O—CH(CH 3 )—, (R x O)-p-C 6 H 4 —CH 2 —, wherein R x is R xx C(O)—, R xx OC(O)— or R xx NHC(O)— wherein R xx is one the groups —(Y—ONO 2 ) or —(Y′—ONO 2 );
e) R h NH(CH 2 ) p — wherein p is 3 or 4, and R h is R hh C(O)— or R hh OC(O)— wherein R hh is one the groups —(Y—ONO 2 ) or —(Y′—ONO 2 );
or R a is R i NH(═NH)NH—(CH 2 ) 3 — wherein R i is R ii C(O)— or R ii OC(O)— wherein R ii is one the groups —(Y—ONO 2 ) or —(Y′—ONO 2 ).
17 . The compounds according to claim 1 wherein in formula (I) s and s′ are 1 and m, m′ are 0, s″ is 0,
A is a radical of formula
wherein R i is H or —C(O)O—C(CH 3 ) 3 ,
R 2 is —C(O)OR 2x , —C(O)NHR 2xx , —C(O)N(CH 3 )R 2xx wherein R 2x and R 2xx are one of the groups —(Y—ONO 2 ) or —(Y′—ONO 2 );
R a is selected from:
d) R g C(O)CH 2 —, R g C(O)(CH 2 ) 2 —, wherein R 9 is R g —NH—, R gxx N(CH 3 )—, wherein R gx and R gxx are one of the groups —(Y—ONO 2 ) or —(Y′—ONO 2 ).
18 . The compounds according to claim 1 wherein in formula (I) s, s′ and s″ are 1, in, m′ and m″ are 0,
A is a radical of formula
wherein R 1 is —C(O)R 1x , —C(O)OR 1x wherein R 1x is one of the groups —(Y—ONO 2 ) or —(Y′—ONO 2 ) or —(Y″—ONO 2 );
R 2 is —C(O)OR 2x , —C(O)NHR 2xx , —C(O)N(CH 3 )R 2xx wherein R 2x and R 2xx are one of the groups —(Y—ONO 2 ) or —(Y′—ONO 2 ) or —(Y″—ONO 2 );
R a is selected from:
b) R bx C(O)—S—CH 2 —, R bx OC(O)—S—CH 2 —, R bx NH—C(O)S—CH 2 — wherein R bx is one of the groups —(Y—ONO 2 ) or —(Y′—ONO 2 ) or —(Y″—ONO 2 );
c) R x O—CH 2 —, R x O—CH(CH 3 )—, (R x O)-p-C 6 H 4 —CH 2 —, wherein R x is R xx C(O)—, R xx OC(O)— or R xx NHC(O)— wherein R xx is one of the groups
—(Y—ONO 2 ) or —(Y′—ONO 2 ) or —(Y″—ONO 2 );
d) R g C(O)CH 2 , R g C(O)(CH 2 ) 2 —, wherein R g is R gx O—, R gxx —NH—, R gxx —N(CH 3 )—, wherein R gx and R gxx are one of the groups —(Y—ONO 2 ) or —(Y′—ONO 2 ) or —(Y″—ONO 2 ),
e) R h NH(CH 2 ) p — wherein p is 3 or 4, and R h is R hh C(O)— or R hh OC(O)— wherein R hh is one of the groups —(Y—ONO 2 ) or —(Y″—ONO 2 ) or
—(Y″—ONO 2 ),
or R a is R i NH(═NH)NH—(CH 2 ) 3 — wherein R i is R ii C(O)— or R ii OC(O)— wherein R ii is one of the groups —(Y—ONO 2 ) or —(Y′—ONO 2 ) or —(Y″—ONO 2 ).
19 . The compounds according to claim 1 wherein in formula (I) s and s′ are 1, m and m′ are 0, s″is 0,
A is a radical of formula
wherein R 1 is H or —C(O)—OC(CH 3 ) 3 ;
R 3 is —OC(O)R 3x , OC(O)OR 3x , —OC(O)—NHR 3x , wherein R 3x is one of the groups —(Y—ONO 2 ) or —(Y′—ONO 2 );
R s is selected from:
b″) R bx —C(O)—S—CH 2 —, R bx —OC(O)—S—CH 2 —, R bx —NH—C(O)S—CH 2 — wherein R bx is one of the groups —(Y—ONO 2 ) or —(Y′—ONO 2 );
c″) R x O—CH 2 —, R x O—CH(CH 3 )—, (R x O)-p-C 6 H 4 —CH 2 —, wherein R x is R xx C(O)—, R xx OC(O)—,
R xx NHC(O)— wherein R xx is one of the groups
—(Y—ONO 2 ) or —(Y′—ONO 2 );
d″) R g C(O)CH 2 , R g C(O)(CH 2 ) 2 —, wherein R g is R gx O— or R gxx NH— wherein R gx and R gxx are each independently one of the groups —(Y—ONO 2 ) or —(Y′—ONO 2 );
e″) R h NH(CH 2 ) p — wherein p is 3 or 4 and R h is R hh C(O)— or R hh OC(O)— wherein R hh is one of the groups —(Y—ONO 2 ) or —(Y′—ONO 2 ),
or R 3 is R i NH(═NH)NH—(CH 2 ) 3 —, wherein R i is R ii C(O)— or R ii OC(O)— wherein R ii is one of the groups —(Y—ONO 2 ) or —(Y′—ONO 2 );
20 . A compound according to claim 4 selected from:
21 . A compound according to claim 5 selected from:
22 . A compound according to claim 6 selected from:
23 . A compounds according to claim 7 selected from:
24 . A compound according to claim 8 selected from:
25 . A compound according to claim 9 selected from:
26 . A compound according to claim 10 selected from:
27 . A compound according to claim 11 selected from:
28 . A compound according to claim 12 selected from:
29 . A compound according to claim 13 selected from:
30 . A compound according to claim 14 is selected from:
31 . A compound according to claim 15 selected from:
32 . A compound according to claim 16 selected from:
33 . A compound according to claim 17 selected from:
34 . A compounds according to claim 18 selected from:
35 . A compound according to claim 19 selected from:
36 . Compounds according to claim 1 for use as medicaments.
37 . Compounds according to claim 1 for use in the treatment of cardiovascular diseases, inflammation, pain, fever, gastrointestinal disorders, ophthalmic diseases including glaucoma, hepatic disorders, renal diseases, respiratory disorders, immunological diseases, bone metabolism dysfunctions, central and peripheral nervous system diseases, sexual dysfunctions, infectious diseases, for the inhibition of platelet aggregation and platelet adhesion, for treating pathological conditions resulting from abnormal cell proliferation and vascular diseases.
38 . Pharmaceutical compositions comprising a compound according to claim 1 and a pharmaceutical acceptable eccipient.
39 . A composition comprising at least a compound of formula (I) according to claim 1 and at least one therapeutic agent selected from anti-inflammatory drugs, drugs used to treat cardiovascular diseases, drugs for treating ocular diseases, drugs for treating respiratory disorders.
40 . The composition according to claim 39 for use as medicament.
41 . The composition according to claim 39 for use in the treatment of cardiovascular diseases, inflammation, pain, fever, gastrointestinal disorders, ophthalmic diseases including glaucoma, hepatic disorders, renal diseases, respiratory disorders, immunological diseases, bone metabolism dysfunctions, central and peripheral nervous system diseases, sexual dysfunctions, infectious diseases, for the inhibition of platelet aggregation and platelet adhesion, for treating pathological conditions resulting from abnormal cell proliferation and vascular diseases.
42 . The composition according to claim 39 wherein the two components are administered simultaneously or sequentially.
43 . Pharmaceutical composition comprising the composition according to claim 39 and a pharmaceutical acceptable eccipient.
44 . A compound selected from:
3-(nitrooxy)propyl 2-(tert-butoxycarbonylamino)-4-phenyl butanoate, 3-(nitrooxy)propyl 2-amino-4-phenylbutanoate, 3-(nitrooxy)propyl 2-amino-4-phenylbutanoate hydrochloride, 4-(nitrooxy)butyl 2-(tert-butoxycarbonylamino)-4-phenylbutanoate, 4-(nitrooxy)butyl 2-amino-4-phenylbutanoate, 4-(nitrooxy)butyl 2-amino-4-phenylbutanoate hydrochloride, (2-(nitrooxy)ethoxy)methyl 2-(tert-butoxycarbonylamino)-4-phenyl butanoate, (2-(nitrooxy)ethoxy)methyl 2-amino-4-phenylbutanoate, (2-(nitrooxy)ethoxy)methyl 2-amino-4-phenylbutanoate hydrochloride, 1-tert-butyl 2-(4-(nitrooxy)butyl)pyrrolidine-1,2-dicarboxylate, 4-(nitrooxy)butyl pyrrolidine-2-carboxylate, 4-(nitrooxy)butyl pyrrolidine-2-carboxylate hydrochloride, 1-tert-butyl 2-(3-(nitrooxy)propyl)pyrrolidine-1,2-dicarboxylate, 3-(nitrooxy)propyl pyrrolidine-2-carboxylate, 3-(nitrooxy)propyl pyrrolidine-2-carboxylate hydrochloride,
for use as medicament.
45 . A compound selected from:
3-(nitrooxy)propyl 2-(tert-butoxycarbonylamino)-4-phenyl butanoate, 3-(nitrooxy)propyl 2-amino-4-phenylbutanoate, 3-(nitrooxy)propyl 2-amino-4-phenylbutanoate hydrochloride, 4-(nitrooxy)butyl 2-(tert-butoxycarbonylamino)-4-phenylbutanoate, 4-(nitrooxy)butyl 2-amino-4-phenylbutanoate, 4-(nitrooxy)butyl 2-amino-4-phenylbutanoate hydrochloride, (2-(nitrooxy)ethoxy)methyl 2-(tert-butoxycarbonylamino)-4-phenyl butanoate, (2-(nitrooxy)ethoxy)methyl 2-amino-4-phenylbutanoate, (2-(nitrooxy)ethoxy)methyl 2-amino-4-phenyl butanoate hydrochloride, 1-tert-butyl 2-(4-(nitrooxy)butyl)pyrrolidine-1,2-dicarboxylate, 4-(nitrooxy)butyl pyrrolidine-2-carboxylate, 4-(nitrooxy)butyl pyrrolidine-2-carboxylate hydrochloride, 1-tert-butyl 2-(3-(nitrooxy)propyl)pyrrolidine-1,2-dicarboxylate, 3-(nitrooxy)propyl pyrrolidine-2-carboxylate, 3-(nitrooxy)propyl pyrrolidine-2-carboxylate hydrochloride
for use in the treatment of cardiovascular diseases, inflammation, pain, fever, gastrointestinal disorders, ophthalmic diseases including glaucoma, hepatic disorders, renal diseases, respiratory disorders, immunological diseases, bone metabolism dysfunctions, central and peripheral nervous system diseases, sexual dysfunctions, infectious diseases, for the inhibition of platelet aggregation and platelet adhesion, for treating pathological conditions resulting from abnormal cell proliferation and vascular diseases.
46 . A composition comprising a compound selected from:
3-(nitrooxy)propyl 2-(tert-butoxycarbonylamino)-4-phenyl butanoate, 3-(nitrooxy)propyl 2-amino-4-phenylbutanoate, 3-(nitrooxy)propyl 2-amino-4-phenylbutanoate hydrochloride, 4-(nitrooxy)butyl 2-(tert-butoxycarbonylamino)-4-phenylbutanoate, 4-(nitrooxy)butyl 2-amino-4-phenylbutanoate, 4-(nitrooxy)butyl 2-amino-4-phenylbutanoate hydrochloride, (2-(nitrooxy)ethoxy)methyl 2-(tert-butoxycarbonylamino)-4-phenyl butanoate, (2-(nitrooxy)ethoxy)methyl 2-amino-4-phenylbutanoate, (2-(nitrooxy)ethoxy)methyl 2-amino-4-phenyl butanoate hydrochloride, 1-tert-butyl 2-(4-(nitrooxy)butyl)pyrrolidine-1,2-dicarboxylate, 4-(nitrooxy)butyl pyrrolidine-2-carboxylate, 4-(nitrooxy)butyl pyrrolidine-2-carboxylate hydrochloride, 1-tert-butyl 2-(3-(nitrooxy)propyl)pyrrolidine-1,2-dicarboxylate, 3-(nitrooxy)propyl pyrrolidine-2-carboxylate, 3-(nitrooxy)propyl pyrrolidine-2-carboxylate hydrochloride
and at least one therapeutic agent selected from anti-inflammatory drugs, drugs used to treat cardiovascular diseases, drugs for treating ocular diseases, drugs for treating respiratory disorders.
47 . The composition according to claim 46 for use in the treatment of cardiovascular diseases, inflammation, pain, fever, gastrointestinal disorders, ophthalmic diseases including glaucoma, hepatic disorders, renal diseases, respiratory disorders, immunological diseases, bone metabolism dysfunctions, central and peripheral nervous system diseases, sexual dysfunctions, infectious diseases, for the inhibition of platelet aggregation and platelet adhesion, for treating pathological conditions resulting from abnormal cell proliferation and vascular diseases.
48 . The composition according to claim 46 wherein the two components are administered simultaneously or sequentially.
49 . Pharmaceutical composition comprising the composition according to claim 46 and a pharmaceutical acceptable excipient.Cited by (0)
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