U.S. patent application number 12/525988 was filed with the patent office on 2010-04-22 for nitric oxide donor compounds.
This patent application is currently assigned to NICOX S.A.. Invention is credited to Nicoletta Almirante, Stefano Biondi, Alessia Nicotra, Ennio Ongini, Laura Storoni.
Application Number | 20100099729 12/525988 |
Document ID | / |
Family ID | 39433740 |
Filed Date | 2010-04-22 |
United States Patent
Application |
20100099729 |
Kind Code |
A1 |
Almirante; Nicoletta ; et
al. |
April 22, 2010 |
NITRIC OXIDE DONOR COMPOUNDS
Abstract
The invention relates to nitric oxide donor compounds and their
use for treating cardiovascular diseases, inflammation, pain,
fever, gastrointestinal disorders, ophthalmic diseases, hepatic
disorders, renal diseases, respiratory disorders, immunological
diseases, bone 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.
Inventors: |
Almirante; Nicoletta;
(Milano, IT) ; Biondi; Stefano; (Pero (Milano),
IT) ; Ongini; Ennio; (Segrate (Milano), IT) ;
Storoni; Laura; (Cesano Maderno, IT) ; Nicotra;
Alessia; (Grandate (Como), IT) |
Correspondence
Address: |
ARENT FOX LLP
1050 CONNECTICUT AVENUE, N.W., SUITE 400
WASHINGTON
DC
20036
US
|
Assignee: |
NICOX S.A.
Sophia Antipois-Valbonne
FR
|
Family ID: |
39433740 |
Appl. No.: |
12/525988 |
Filed: |
January 30, 2008 |
PCT Filed: |
January 30, 2008 |
PCT NO: |
PCT/EP08/51092 |
371 Date: |
November 17, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60899422 |
Feb 5, 2007 |
|
|
|
Current U.S.
Class: |
514/412 ;
514/423; 514/551; 548/452; 548/536; 560/156 |
Current CPC
Class: |
A61P 9/00 20180101; C07C
229/08 20130101; A61K 31/27 20130101; C07C 229/24 20130101; A61K
31/223 20130101; C07C 237/08 20130101; A61K 31/225 20130101; C07D
209/52 20130101; A61K 31/403 20130101; A61P 29/00 20180101; A61K
31/40 20130101; C07C 229/20 20130101; C07C 323/58 20130101; C07C
279/14 20130101; A61P 25/02 20180101; C07C 271/22 20130101; A61P
19/08 20180101; A61P 31/00 20180101; C07C 203/02 20130101; A61P
9/10 20180101; A61P 37/00 20180101; C07C 229/36 20130101; A61K
31/265 20130101; C07C 229/26 20130101; A61K 45/06 20130101; C07D
207/16 20130101; C07C 229/22 20130101; C07C 291/02 20130101 |
Class at
Publication: |
514/412 ;
560/156; 548/536; 548/452; 514/551; 514/423 |
International
Class: |
A61K 31/40 20060101
A61K031/40; C07C 205/02 20060101 C07C205/02; C07D 207/08 20060101
C07D207/08; C07D 209/02 20060101 C07D209/02; A61K 31/22 20060101
A61K031/22; A61P 9/00 20060101 A61P009/00; A61P 29/00 20060101
A61P029/00; A61P 37/00 20060101 A61P037/00; A61P 31/00 20060101
A61P031/00; A61P 19/08 20060101 A61P019/08; A61P 25/02 20060101
A61P025/02 |
Claims
1. A compound of formula (I) and pharmaceutically acceptable salts
or stereoisomers thereof: ##STR00411## 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.sub.2),
--(Y'--ONO.sub.2), --(Y''--ONO.sub.2), B at each occurrence is
independently selected from: ##STR00412## A is a radical selected
from the group consisting of: ##STR00413## ##STR00414##
##STR00415## wherein in formulas (IIa)-(IIm) and (IIo)-(IIu),
R.sub.1 is selected from: H, --C(O)O--C(CH.sub.3).sub.3,
--C(O)--R.sub.n, --C(O)O--R.sub.1x, wherein R.sub.1x is one of the
groups --[(B).sub.m--(Y--ONO.sub.2)].sub.s,
--[(B).sub.m'--(Y'--ONO.sub.2)].sub.s' or
--[(B).sub.m''--(Y''--ONO.sub.2)].sub.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.sub.2 is selected from: --C(O)OH,
--C(O)--OC(CH.sub.3).sub.3, --C(O)OR.sub.2x, --C(O)NHR.sub.2xx,
--C(O)N(CH.sub.3)R.sub.2xx wherein R.sub.2x and R.sub.2xx are one
of the groups --[(B).sub.m--(Y--ONO.sub.2)].sub.s,
--[(B).sub.m'--(Y'--ONO.sub.2)].sub.s' or
--[(B).sub.m''--(Y''--ONO.sub.2)].sub.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.sub.2xx is one of the groups
--[(B).sub.m--(Y--ONO.sub.2)].sub.s,
--[(B).sub.m'--(Y'--ONO.sub.2)].sub.s' or
--[(B).sub.m''--(Y''--ONO.sub.2)].sub.s'' of formula (I) wherein m,
m' and m'' are 0 and Y, Y' and Y'' are as below reported, or
R.sub.2 is the group R.sub.4: ##STR00416## in formula (IIa),
R.sub.a is selected from the groups consisting of: a) --H,
--CH.sub.3, isopropyl, isobutyl, sec-butyl, tert-butyl,
methylthio-(CH.sub.2).sub.2--, phenyl, benzyl,
C.sub.6H.sub.5--CH.sub.2--CH.sub.2--, 2-monosubstituted benzyl, or
3-monosubstituted benzyl or 4-monosubstituted benzyl with groups
such as --F, --Cl, I, --NO.sub.2, --CF.sub.3, --CH.sub.3, CN,
C.sub.6H.sub.5CO--; or R.sub.a is 2,4-dichlorobenzyl,
3,4-dichlorobenzyl, 3,4-difluorobenzyl, 3-triptophanyl-CH.sub.2--,
3-benzothienyl-CH.sub.2--, 4-imidazolyl-CH.sub.2--,
9-anthranyl-CH.sub.2--, cyclohexyl, cyclohexyl-CH.sub.2--,
cyclohexyl-(CH.sub.2).sub.2--, cyclopentyl-CH.sub.2--,
(C.sub.6H.sub.5).sub.2CH--, 4-quinolyl-CH.sub.2--,
3-quinolyl-CH.sub.2--, 2-quinolyl-CH.sub.2--,
2-quinoxalyl-CH.sub.2--, 2-furyl-CH.sub.2--, 1-naphtyl-CH.sub.2--,
2-naphtyl-CH.sub.2--, 2-pyridyl-CF.sub.12--, 3-pyridyl-CH.sub.2--,
4-pyridyl-CH.sub.2--, 2-thienyl-CH.sub.2--, 3-thienyl-CH.sub.2--,
C.sub.6H.sub.4--CH.dbd.CH--CH.sub.2--, CH.ident.CH--CH.sub.2--,
NH.sub.2--CO--CH.sub.2--, NH.sub.2--CO--(CH.sub.2).sub.2--, or
--P(.dbd.O)(OCH.sub.3).sub.2; b) HS--CH.sub.2--,
R.sub.bx--C(O)--S--CH.sub.2--, R.sub.bx--OC(O)--S--CH.sub.2--,
R.sub.bx--NH--C(O)S--CH.sub.2-- wherein R.sup.bx is one of the
groups --[(B).sub.m--(Y--ONO.sub.2)].sub.s,
--[(B).sub.m'--(Y--ONO.sub.2)].sub.s' or
--[(B).sub.m''--(Y''--ONO.sub.2)].sub.s'' of formula (I) wherein m,
m' and m'' are 0 and Y, Y' and Y'' are as below defined; c)
R.sub.xO--CH.sub.2--, R.sub.xO--CH(CH.sub.3)--,
(R.sub.xO)-p-C.sub.6H.sub.4--CH.sub.2--,
4-(R.sub.xO)-3,5-diiodobenzyl-, 4-(R.sub.xO)-3-nitrobenzyl- wherein
R.sub.x is H, R.sub.xx--C(O)--, R.sub.xx--OC(O)--,
R.sub.xx--NHC(O)-- wherein R.sub.xx is one of the groups
--[(B).sub.m--(Y--ONO.sub.2)].sub.s,
--[(B).sub.m'--(Y'--ONO.sub.2)].sub.s' or
--[(B).sub.m''--(Y''--ONO.sub.2)].sub.s'' of formula (I) wherein m,
m' and m'' are 0 and Y, Y' and Y'' are as below defined; d)
R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2--,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is OH, (CH.sub.3).sub.3CO--, R.sub.gx--O--,
R.sub.g--NH--, R.sub.g--N(CH.sub.3)-- wherein R.sub.gx is one of
the groups --[(B).sub.m--(Y--ONO.sub.2)].sub.s,
--[(B).sub.m'--(Y'--ONO.sub.2)].sub.s' or
--[(B).sub.m''--Y''--ONO.sub.2)].sub.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.sub.gxx is one of the groups
--[(B).sub.m--(Y--ONO.sub.2)].sub.s, --[(B).sub.m',
--(Y'--ONO.sub.2)].sub.s' or
--[(B).sub.m''--(Y''--ONO.sub.2)].sub.s'' of formula (I) wherein m,
m' and m'' are 0 and Y, Y' and Y'' are as below reported, or
R.sub.g is the group R.sub.gg: ##STR00417## e)
R.sub.hNH(CH.sub.2).sub.p-- or
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--, wherein p is an integer
from 0 to 4, R.sub.h is H, (CH.sub.3).sub.3C--OC(O)--,
R.sub.hh--C(O)-- or R.sub.hh--OC(O)--, R.sub.i is H,
R.sub.ii--C(O)-- or R.sub.ii--OC(O)--, wherein R.sub.hh and
R.sub.ii are each independently one of the groups
--[(B).sub.m--(Y--ONO.sub.2)].sub.s,
--[(B).sub.m'--(Y'--ONO.sub.2)].sub.s' or
--[(B).sub.m''--(Y''--ONO.sub.2)].sub.s'' of formula (I) wherein m,
m' and m'' are 0 and Y, Y' and Y'' are as below defined; in formula
(IIc) R.sub.c is selected from the following groups: a') H,
CH.sub.3, isopropyl, isobutyl, sec-butyl,
methylthio-(CH.sub.2).sub.2, phenyl, benzyl, biphenyl-CH.sub.2,
3-triptophanyl-CH.sub.2, NH.sub.2--CO--CH.sub.2,
NH.sub.2--CO--(CH.sub.2).sub.2--; b') HS--CH.sub.2--,
R.sub.bx--C(O)--S--CH.sub.2--, R.sub.bx--OC(O)--S--CH.sub.2--,
R.sub.bx--NH--C(O)S--CH.sub.2-- wherein R.sub.bx is one of the
groups --[(B).sub.m--(Y--ONO.sub.2)].sub.s,
--[(B).sub.m'--(Y'--ONO.sub.2)].sub.s' or
--[(B).sub.m''--(Y''--ONO.sub.2)].sub.s'' of formula (I) wherein m,
m' and m'' are 0 and Y, Y' and Y'' are as below defined; c')
R.sub.xO--CH.sub.2--, R.sub.xO--CH(CH.sub.3)--,
R.sub.xO--C.sub.6H.sub.4--CH.sub.2-- wherein R.sub.x is H,
R.sub.xx--C(O)--, R.sub.xx--OC(O)--, R.sub.xx--NHC(O)-- wherein
R.sub.xx is one of the groups --[(B).sub.m--(Y--ONO.sub.2)].sub.s,
--[(B').sub.m'--(Y'--ONO.sub.2)].sub.s' or
--[(B'').sub.m''--(Y''--ONO.sub.2)].sub.s'' of formula (I) wherein
m, m' and m'' are 0 and Y, Y' and Y'' are as below defined; d')
R.sub.gC(O)CH.sub.2--, R.sub.gC(O)(CH.sub.2).sub.2-- wherein
R.sub.g is OH, (CH.sub.3).sub.3CO--, R.sub.gx--O--,
R.sub.gxx--NH--, R.sub.gxx--N(CH.sub.3)-- wherein R.sub.gx is one
of the groups --[(B).sub.m--(Y--ONO.sub.2)].sub.s,
--[(B).sub.m'--(Y'--ONO.sub.2)].sub.s' or
--[(B).sub.m''--(Y''--ONO.sub.2)].sub.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.sub.gxx is one of the groups
--[(B).sub.m'--(Y--ONO.sub.2)].sub.s',
--[(B).sub.m'--(Y'--ONO.sub.2)].sub.s' or
--[(B).sub.m''--(Y''--ONO.sub.2)].sub.s'' of formula (I) wherein m,
m' and m'' are 0 and Y, Y' and Y'' are as below reported; e')
R.sub.hNH(CH.sub.2).sub.p-- or
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--, wherein p is an integer
from 0 to 4, R.sub.h is H, --C(O)O--C(CH.sub.3).sub.3,
R.sub.hh--C(O)-- or R.sub.hh--OC(O)--, R.sub.i is H,
R.sub.ii--C(O)-- or R.sub.ii--OC(O)--, wherein R.sub.hh and
R.sub.ii are each independently one of the groups
--[(B).sub.m--(Y--ONO.sub.2)].sub.s,
--[(B).sub.m'--(Y''--ONO.sub.2)].sub.s' or
--[(B).sub.m''-(Y''--ONO.sub.2)].sub.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.sub.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.sub.2 can be attached
to one of the positions 1, 2 or 3 of the piperidyl ring; in formula
(IIl), R.sub.L is selected from: H, methyl, propyl, allyl,
(C.sub.6H.sub.5).sub.2CH--, 1-naphtyl-CH.sub.2--, benzyl,
2-bromobenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-fluorobenzyl,
4-bromobenzyl, 4-methylbenzyl; in formula (IIm) R.sub.m is selected
from: benzyl, 2-bromobenzyl, 4-bromobenzyl, 4-methylbenzyl; in
formula (IIn) R.sub.n is selected from: --H, --C(O)--R.sub.nx,
--C(O)O--R.sub.nx or --(CH.sub.2).sub.2--NH--R.sub.h wherein
R.sub.h is --H, --C(O)O--C(CH.sub.3).sub.3, --C(O)--R.sub.hh,
--C(O)O--R.sub.hh wherein R.sub.nx and R.sub.hh are each
independently one of the groups
--[(B).sub.m--(Y--ONO.sub.2)].sub.s,
--[(B).sub.m'--(Y'--ONO.sub.2)].sub.s' or
--[(B).sub.m''--(Y''--ONO.sub.2)].sub.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.sub.2 can be attached to the position 1, 2
or 3 of the phenyl ring; in formula (IIs), R.sub.3 is selected
from: OH, --OC(O)--R.sub.3x, --OC(O)O--R.sub.3x,
--OC(O)--NH--R.sub.3x wherein R.sub.3x is one of the groups
--[(B).sub.m--(Y--ONO.sub.2)].sub.s,
--[(B).sub.m'--(Y'--ONO.sub.2)].sub.s' or
--[(B).sub.m''--(Y''--ONO.sub.2)].sub.s'' of formula (I) wherein m,
m' and m'' are 0 and Y, Y' and Y'' are as below defined; in formula
(IIs) R.sub.s is selected from the following groups: a'') --H,
--CH.sub.3, isopropyl, isobutyl, sec-butyl, tert-butyl,
methylthio-(CH.sub.2).sub.2--, benzyl, 2-monosubstituted benzyl, or
3-monosubstituted benzyl, 3-triptophanyl-CH.sub.2--,
4-imidazolyl-CH.sub.2--, NH.sub.2--CO--CH.sub.2--,
NH.sub.2--CO--(CH.sub.2).sub.2--; b'') HS--CH.sub.2--,
R.sub.bx--C(O)--S--CH.sub.2--, R.sub.bx--OC(O)--S--CH.sub.2--,
R.sub.bx--NH--C(O)S--CH.sub.2-- wherein R.sub.bx is one of the
groups --[(B).sub.m--(Y--ONO.sub.2)].sub.s,
--[(B).sub.m'--(Y'--ONO.sub.2)].sub.s' or
--[(B).sub.m''--(Y''--ONO.sub.2)].sub.s'' of formula (I) wherein m,
m' and m'' are 0 and Y, Y' and Y'' are as below defined; c'')
R.sub.xO--CH.sub.2--, R.sub.xO--CH(CH.sub.3)--,
(R.sub.xO)-p-C.sub.6H.sub.4--CH.sub.2--,
4-(R.sub.xO)-3,5-diiodobenzyl-, 4-(R.sub.xO)-3-nitrobenzyl- wherein
R.sub.x is H, R.sub.xx--C(O)--, R.sub.xx--OC(O)--,
R.sub.xx--NHC(O)-- wherein R.sub.xx is one of the groups
--[(B).sub.m--(Y--ONO.sub.2)].sub.s,
--[(B).sub.m'--(Y'--ONO.sub.2)].sub.s' or
--[(B).sub.m''--(Y''--ONO.sub.2)].sub.s'' of formula (I) wherein m,
m' and m'' are 0 and Y, Y' and Y'' are as below defined; d'')
R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is OH, (CH.sub.3).sub.3CO--, R.sub.gx--O--,
R.sub.g--NH--, R.sub.g--N(CH.sub.3)-- wherein R.sub.gx is one of
the groups --[(B).sub.m--(Y--ONO.sub.2)].sub.s,
--[(B).sub.m'--(Y'--ONO.sub.2)].sub.s' or
--[(B).sub.m''--(Y''--ONO.sub.2)].sub.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.sub.gxx is one of the groups
--[(B).sub.m--(Y--ONO.sub.2)].sub.s,
--[(B).sub.m'--(Y'--ONO.sub.2)].sub.s' or
--[(B).sub.m''--(Y''--ONO.sub.2)].sub.s'' of formula (I) wherein m,
m' and m'' are 0 and Y, Y' and Y'' are as below reported, e'')
R.sub.hNH(CH.sub.2).sub.p-- or
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--, wherein p is an integer
from 0 to 4, R.sub.h is H, (CH.sub.3).sub.3C--OC(O)--,
R.sub.hh--C(O)-- or R.sub.hh--OC(O)--, R.sub.i is H,
R.sub.ii--C(O)-- or R.sub.ii--OC(O)--, wherein R.sub.hh and
R.sub.ii are each independently one of the groups
--[(B).sub.m--(Y--ONO.sub.2)].sub.s,
--[(B).sub.m'--(Y'--ONO.sub.2)].sub.s' or
--[(B).sub.m''--(Y''--ONO.sub.2)].sub.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.sub.t is H,
--C(O)--R.sub.tt or --C(O)O--R.sub.tt wherein R.sub.tt is one of
the groups --[(B).sub.m--(Y--ONO.sub.2)].sub.s,
--[(B').sub.m'--(Y'--ONO.sub.2)].sub.s' or
--[(B'').sub.m''--(Y''--ONO.sub.2)].sub.s'' of formula (I) wherein
m, m' and m'' are 0; in formula (IIu) a and b are each
independently 0 or 1, R.sub.x is H, --C(O)--R.sub.xx,
--C(O)O--R.sub.xx--, --C(O)NH--R.sub.xx wherein R.sub.xx is one of
the groups --[(B).sub.m--(Y--ONO.sub.2)].sub.s,
--[(B).sub.m'--(Y'--ONO.sub.2)].sub.s' or
--[(B).sub.m''--(Y''--ONO.sub.2)].sub.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.sub.2), --(Y'--ONO.sub.2) and
--(Y''--ONO.sub.2) of formula (I) are bivalent radicals and they
are each independently selected from: A) a straight or branched
C.sub.1-C.sub.20 alkylene, a straight or branched C.sub.1-C.sub.20
alkylene substituted with one or more --ONO.sub.2 group(s); a
cycloalkylene having 5 to 7 carbon atoms, the ring being optionally
substituted with a straight or branched C.sub.1-C.sub.10 alkyl; B)
##STR00418## wherein n.sup.0 is an integer from 0 to 20, n.sup.1 is
an integer from 1 to 20, wherein in formulas (IB) and (IB') the
--ONO.sub.2 group is linked to C) ##STR00419## wherein: n is an
integer from 1 to 20, n.sub.2 is an integer from 0 to 2, R.sup.2 is
H or CH.sub.3, X.sub.1 is --OC(O)-- or --C(O)O--; wherein in
formula (IC) the --ONO.sub.2 group is linked to
--(CH.sub.2).sub.n.sup.1--; D) ##STR00420## wherein in formula
(ID): n.sup.1 is an integer from 1 to 20, n.sup.2, R.sup.2 and
X.sub.1 are as defined above; Y.sup.1 is --CH.sub.2--CH.sub.2-- or
--CH.dbd.CH--(CH.sub.2).sub.n.sup.2a-- wherein n.sup.2a is an
integer from 0 to 5, wherein in formula (ID) the --ONO.sub.2 group
is linked to --(CH.sub.2).sub.n.sup.1--; E) ##STR00421## wherein
X.sub.2 is --O--, --S--, --NH-- or
--N(CH.sub.2CH.sub.2OCH.sub.3)--, n.sup.3 is an integer from 1 to
5, n.sub.3 is an integer from 0 to 10, n.sub.4 an integer from 1 to
10, n.sub.3' is an integer from 0 to 10, n.sub.4' an integer from 1
to 10, R.sup.2 is H or --CH.sub.3, wherein in formula (IE) the
--ONO.sub.2 group is linked to the --(CH.sub.2).sub.n4' group; F)
##STR00422## wherein: n.sup.5 is an integer from 0 to 10; n.sup.6
is an integer from 1 to 10; R.sup.4, R.sup.5, R.sup.6, R.sup.7 are
the same or different, and are H or straight or branched
C.sub.1-C.sub.4 alkyl, wherein in formula (IF) the --ONO.sub.2
group is linked to ##STR00423## wherein n.sup.6 is as defined
above; Y.sup.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: ##STR00424## G) ##STR00425## wherein n.sup.0
is an integer from 0 to 10, n.sup.7 is an integer from 1 to 10,
n.sup.8 is an integer from 0 to 10, R.sup.8 is CH.sub.3 or
CH.sub.2ONO.sub.2, wherein in formula (IG) the --ONO.sub.2 group is
linked to the group ##STR00426## 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.sub.a, R.sub.c and R.sub.s are selected from
R.sub.bx--C(O)--S--CH.sub.2--, R.sub.bx--OC(O)--S--CH.sub.2--,
R.sub.bx--NH--C(O)S--CH.sub.2-- wherein R.sub.bx is one of the
groups --[(B).sub.m--(Y--ONO.sub.2)].sub.s,
--[(B).sub.m'--(Y'--ONO.sub.2)].sub.s' or --[(B)
.sub.m''--(Y''--ONO.sub.2)].sub.s'' wherein m, m' and m'', B, Y, Y'
and Y'' are as above defined; R.sub.xO--CH.sub.2--,
R.sub.xO--CH(CH.sub.3)--,
(R.sub.xO)-p---C.sub.6H.sub.4--CH.sub.2--,
4-(R.sub.xO)-3,5-diiodobenzyl-, 4-(R.sub.xO)-3-nitrobenzyl- wherein
R.sub.x is R.sub.xx--C(O)--, R.sub.xx--OC(O)-- or
R.sub.xx--NHC(O)-- wherein R.sub.xx is one of the groups
--[(B).sub.m--(Y--ONO.sub.2)].sub.s,
--[(B).sub.m'--(Y'--ONO.sub.2)].sub.s' or
--[(B).sub.m''--(Y''--ONO.sub.2)].sub.s'' wherein m, m' and m'', B,
Y, Y' and Y'' are as above defined; R.sub.gC(O)CH.sub.2--NH--,
R.sub.gC(O)CH.sub.2, R.sub.gC(O)(CH.sub.2).sub.2--,
R.sub.gC(O)(CH.sub.2).sub.4--, wherein R.sub.g is OH,
(CH.sub.3).sub.3CO--, R.sub.gx--O--, R.sub.gxx--NH--,
R.sub.gxx--N(CH.sub.3)-- wherein R.sub.gx and R.sub.gxx are one of
the groups --[(B).sub.m--(Y--ONO.sub.2)].sub.s,
--[(B).sub.m'--(Y'--ONO.sub.2)].sub.s' or
--[(B).sub.m''--(Y''--ONO.sub.2)].sub.s'' wherein m, m' and m'', B,
Y, Y' and Y'' are as above defined; R.sub.hNH(CH.sub.2).sub.p-- or
R.sub.iNH(.dbd.NH)NH--(CF.sub.2).sub.3--, wherein p is an integer
from 0 to 4, R.sub.h is R.sub.hh--C(O)-- or R.sub.hh--OC(O)--,
R.sub.i is R.sub.ii--C(O)-- or R.sub.ii--OC(O)--, wherein R.sub.hh
and R.sub.ii are one of the groups
--[(B).sub.m--(Y--ONO.sub.2)].sub.s,
--[(B).sub.m'--(Y'--ONO.sub.2)].sub.s' or
--[(B).sub.m''--(Y''--ONO.sub.2)].sub.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.sub.t is --C(O)--R.sub.tt or
--C(O)O--R.sub.tt wherein R.sub.tt is one of the groups --[(B),
--(Y--ONO.sub.2)].sub.s, --[(B).sub.m'--(Y'--ONO.sub.2)].sub.s' or
--[(B).sub.m''--(Y''--ONO.sub.2)].sub.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.sub.x is C(O)--R.sub.xx,
--C(O)O--R.sub.xx or --C(O)NH--R.sub.xx wherein R.sub.xx is one of
the groups --[(B).sub.m--(Y--ONO.sub.2)].sub.s,
--[(B).sub.m'--(Y'--ONO.sub.2)].sub.s' or
--[(B).sub.m''--(Y''--ONO.sub.2)].sub.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.sub.2), --(Y'--ONO.sub.2) or
--(Y''--ONO.sub.2) are each independently selected from: A) a
straight or branched C.sub.2-C.sub.10 alkylene a straight or
branched C.sub.2-C.sub.10 alkylene substituted with a --ONO.sub.2
group; E) ##STR00427## wherein in formula (IE) n.sup.3 is from 1 to
5 n.sub.3 is 0 and n.sub.4 is from 1 to 4, n.sub.3' is 0 and
n.sub.4' is from 1 to 4, X.sub.2 is or --NH--, R.sup.2 is H.
3. The compounds according to claim 1 wherein in formula (I) Y, Y'
and Y'' of the groups (Y--ONO.sub.2), --(Y'--ONO.sub.2) or
--(Y''--ONO.sub.2) are each independently selected from: B)
##STR00428## wherein in formula (IB) n.sup.0 is from 0 to 5 and
n.sup.1 is an integer from 1 to 10; C) ##STR00429## wherein in
formula (IC) n.sup.1 is an integer from 1 to 10, n.sup.2 is 1 and
R.sup.2 is CH.sub.3, X.sub.1 is --C(O)O--; D) ##STR00430## wherein
in formula (ID): n.sup.2 is 1 and R.sup.2 is CH.sub.3, Y.sup.1 is
--CH.dbd.CH--(CH.sub.2).sub.n.sup.2a-- wherein n.sup.2a is 0,
X.sub.1 is --C(O)O-- and n.sup.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: ##STR00431##
wherein R.sub.1 is H or --C(O)--OC(CH.sub.3).sub.3, R.sub.2 is
--C(O)OR.sub.2x, --C(O)NHR.sub.2xx, --C(O)N(CH.sub.3)R.sub.2xx
wherein R.sub.2x and R.sub.2xx are the group --(Y--ONO.sub.2),
R.sub.a of formula (ha) is selected from: a) H, CH.sub.3,
isopropyl, isobutyl, sec-butyl, methylthio-(CH.sub.2).sub.2--,
benzyl, C.sub.6H.sub.5--CH.sub.2--CH.sub.2--,
3-triptophanyl-CH.sub.2--, NH.sub.2--CO--CH.sub.2--,
NH.sub.2--CO--(CH.sub.2).sub.2--, 4-imidazolyl-CH.sub.2--; b)
HS--CH.sub.2--, c) R.sub.xO--CH.sub.2--, R.sub.xO--CH(CH.sub.3)--,
(R.sub.xO)-p---C.sub.6H.sub.4--CH.sub.2--, wherein R.sub.x is H, d)
R.sub.gC(O)CH.sub.2, R.sub.gC(O)(CH.sub.2).sub.2--, wherein R.sub.g
is OH, (CH.sub.3).sub.3CO--, or the group R.sub.gg: ##STR00432## e)
R.sub.hNH(CH.sub.2).sub.p-- or
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--, wherein p is an integer
equal to 3 or 4, R.sub.h is H or (CH.sub.3).sub.3C--OC(O)--,
R.sub.i is H; R.sub.c of formula (IIc) is selected from the group
comprising: H, CH.sub.3, isopropyl, isobutyl, sec-butyl,
methylthio-(CH.sub.2).sub.2--, benzyl, 3-triptophanyl-CH.sub.2,
4-imidazolyl-CH.sub.2--, NH.sub.2--CO--CH.sub.2--,
NH.sub.2--CO--(CH.sub.2).sub.2--; R.sub.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
##STR00433## wherein R.sub.1 is --C(O)R.sub.1x, --C(O)OR.sub.1x
wherein R.sub.1x is the group --(Y--ONO.sub.2), R.sub.2 in formulas
(IIa) (He) and (IIl) is --C(O)OH, --C(O)--OC(CH.sub.3).sub.3 or
R.sub.2 is the group R.sub.4: ##STR00434## R.sub.3 in formula (IIs)
is OH; R.sub.a of formula (ha) is selected from: a) H, CH.sub.3,
isopropyl, isobutyl, sec-butyl, methylthio-(CH.sub.2).sub.2--,
benzyl, C.sub.6H.sub.5--CH.sub.2--CH.sub.2--,
3-triptophanyl-CH.sub.2--, NH.sub.2--CO--CH.sub.2--,
NH.sub.2--CO--(CH.sub.2).sub.2--, 4-imidazolyl-CH.sub.2--; b)
HS--CH.sub.2--; c) R.sub.xO--CH.sub.2--, R.sub.xO--CH(CH.sub.3)--,
(R.sub.xO)-p-C.sub.6H.sub.4--CH.sub.2-- wherein R.sub.x is H; d)
R.sub.gC(O)CH.sub.2 or R.sub.gC(O)(CH.sub.2).sub.2--, wherein
R.sub.g is OH or (CH.sub.3).sub.3C--O--, or R.sub.g is the group
R.sub.gg: ##STR00435## e) R.sub.hNH(CH.sub.2).sub.p-- or
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--, wherein p is an integer
equal to 3 or 4, R.sub.h is H or (CH.sub.3).sub.3C--OC(O)--,
R.sub.i is H; R.sub.c of formula (IIc) is selected from: H,
CH.sub.3, isopropyl, isobutyl, sec-butyl,
methylthio-(CH.sub.2).sub.2--, benzyl, 3-triptophanyl-CH.sub.2--,
4-imidazolyl-CH.sub.2--, NH.sub.2--CO--CH.sub.2--,
NH.sub.2--CO--(CH.sub.2).sub.2--; R.sub.L of formula (IIl) is H;
R.sub.s of formula (IIs) is H, CH.sub.3, isopropyl, isobutyl,
sec-butyl, methylthio-(CH.sub.2).sub.2, benzyl,
triptophanyl-CH.sub.2, 4-imidazolyl-CH.sub.2--,
NH.sub.2--CO--CH.sub.2--, NH.sub.2--CO--(CH.sub.2).sub.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) ##STR00436## wherein R.sub.1 is --C(O)R.sub.1x or
--C(O)OR.sub.1x wherein R.sub.1x is the group --(Y--ONO.sub.2),
R.sub.2 in formulas (IIa) and (IIl) is the group R.sub.4:
##STR00437## R.sub.a of formula (IIa) is selected from: a) H,
CH.sub.3, isopropyl, isobutyl, sec-butyl,
methylthio-(CH.sub.2).sub.2--, benzyl,
C.sub.6H.sub.5--CH.sub.2--CH.sub.2--, 3-triptophanyl-CH.sub.2--,
NH.sub.2--CO--CH.sub.2--, NH.sub.2--CO--(CH.sub.2).sub.2--,
4-imidazolyl-CH.sub.2--; b) HS--CH.sub.2--; c)
R.sub.xO--CH.sub.2--, R.sub.xO--CH(CH.sub.3)--,
(R.sub.xO)-p-C.sub.6H.sub.4--CH.sub.2--, wherein R.sub.x is H; d)
R.sub.gC(O)CH.sub.2 or R.sub.gC(O)(CH.sub.2).sub.2--, wherein
R.sub.g is OH or the group R.sub.gg: ##STR00438## e)
R.sub.hNH(CH.sub.2).sub.p-- or
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--, wherein p is an integer
equal to 3 or 4, R.sub.h is H or (CH.sub.3).sub.3C--OC(O)--,
R.sub.i is H; R.sub.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
##STR00439## wherein R.sub.1 is H or --C(O)O--C(CH.sub.3).sub.3,
R.sub.2 is --C(O)OH or R.sub.2 is equal to the group R.sub.4
##STR00440## R.sub.a is selected from: b)
R.sub.bxC(O)--S--CH.sub.2--, R.sub.bxOC(O)--S--CH.sub.2--,
R.sub.bxNH--C(O)S--CH.sub.2-- wherein R.sub.bx is the group
--(Y--ONO.sub.2), c) R.sub.xO--CH.sub.2--,
R.sub.xO--CH(CH.sub.3)--, (R.sub.xO)-p-C.sub.6H.sub.4--CH.sub.2--,
wherein R.sub.x is R.sub.xxC(O)--, R.sub.xxOC(O)-- or
R.sub.xxNHC(O)-- wherein R.sub.xx is the group --(Y--ONO.sub.2); d)
R.sub.gC(O)CH.sub.2, R.sub.gC(O)(CH.sub.2).sub.2-- wherein R.sub.g
is R.sub.gxO--, R.sub.gxx--NH--, or R.sub.gxx--N(CH.sub.3)--,
wherein R.sub.gx and R.sub.gxx are the group --(Y--ONO.sub.2); e)
R.sub.hNH(CH.sub.2).sub.p-- wherein p is 3 or 4, and R.sub.h is
R.sub.hhC(O)-- or R.sub.hhOC(O)-- wherein R.sub.hh is the group
--(Y--ONO.sub.2); or R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--
wherein R.sub.i is R.sub.iiC(O)-- or R.sub.iiOC(O)-- wherein
R.sub.ii is the group --(Y--ONO.sub.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 ##STR00441##
wherein R.sub.1 is H or --C(O)--OC(CH.sub.3).sub.3; R.sub.3 is
--OC(O)R.sub.3x, OC(O)OR.sub.3x, --OC(O)--NHR.sub.3x, wherein
R.sub.3x is the group --(Y--ONO.sub.2); R.sub.s is selected from:
a'') H, CH.sub.3, isopropyl, isobutyl, sec-butyl,
methylthio-(CH.sub.2).sub.2--, benzyl,
C.sub.6H.sub.5--CH.sub.2--CH.sub.2--, 3-triptophanyl-CH.sub.2--,
NH.sub.2--CO--CH.sub.2, NH.sub.2--CO--(CH.sub.2).sub.2--,
4-imidazolyl-CH.sub.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)
##STR00442## R.sub.1 is H, --C(O)O--C(CH.sub.3).sub.3, R.sub.2 is
--C(O)OR.sub.2x, --C(O)NHR.sub.2xx--C(O)N(CH.sub.3)R.sub.2xx
wherein R.sub.2x and R.sub.2xx are the group --(Y--ONO.sub.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)
##STR00443## wherein a is 1 and b is 0; R.sub.1 is H,
--C(O)O--C(C.sub.1-13).sub.3, R.sub.2 is --C(O)OR.sub.2x,
--C(O)NHR.sub.2xx--C(O)N(CH.sub.3)R.sub.2xx wherein R.sub.2x and
R.sub.2xx are the group --(Y--ONO.sub.2), R.sub.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:
##STR00444## wherein R.sub.1 is H or --C(O)O--C(CH.sub.3).sub.3,
R.sub.2 is --C(O)OR.sub.2x wherein R.sub.2x is the group
--[(B)--(Y--ONO.sub.2)] of formula (I) wherein B is ##STR00445##
R.sub.a of formula (IIa) is selected from: a) H, CH.sub.3,
isopropyl, isobutyl, sec-butyl, methylthio-(CH.sub.2).sub.2--,
benzyl, C.sub.6H.sub.5--CH.sub.2--CH.sub.2--,
3-triptophanyl-CH.sub.2--, NH.sub.2--CO--CH.sub.2--,
NH.sub.2--CO--(CH.sub.2).sub.2--, 4-imidazolyl-CH.sub.2--; b)
HS--CH.sub.2--; c) R.sub.xO--CH.sub.2--, R.sub.xO--CH(CH.sub.3)--
or (R.sub.xO)-p-C.sub.6H.sub.4--CH.sub.2--, wherein R.sub.x is H;
d) R.sub.gC(O)CH.sub.2, R.sub.gC(O)(CH.sub.2).sub.2--, wherein
R.sub.g is OH, (CH.sub.3).sub.3C--O--, or the group R.sub.gg:
##STR00446## e) R.sub.hNH(CH.sub.2).sub.p-- or
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3-- wherein p is an integer
equal to 3 or 4, R.sub.h is H or (CH.sub.3).sub.3C--OC(O)--,
R.sub.i is H; R.sub.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)
##STR00447## wherein R.sub.1 is --C(O)R.sub.1x, or --C(O)OR.sub.1x
wherein R.sub.1x is one of the groups --(Y--ONO.sub.2) or
--(Y'--ONO.sub.2), R.sub.2 is --C(O)OH, --C(O)--OC(CH.sub.3).sub.3;
or R.sub.2 is the group R.sub.4 ##STR00448## R.sub.a is selected
from: b) R.sub.bxC(O)--S--CH.sub.2--,
R.sub.bx--OC(O)--S--CH.sub.2--, R.sub.bx--NH--C(O)S--CH.sub.2--
wherein R.sub.bx is one of the groups --(Y--ONO.sub.2) or
--(Y'--ONO.sub.2); c) R.sub.xO--CH.sub.2--,
R.sub.xO--CH(CH.sub.3)--, (R.sub.xO)-p-C.sub.6H.sub.4--CH.sub.2--,
wherein R.sub.x is R.sub.xxC(O)--, R.sub.xxC(O)-- or
R.sub.xxNHC(O)-- wherein R.sub.xx is one of the groups
--(Y--ONO.sub.2) or --(Y'--ONO.sub.2); d) R.sub.gC(O)CH.sub.2--,
R.sub.gC(O)(CH.sub.2).sub.2--, wherein R.sub.g is R.sub.gx--O--,
R.sub.gxx--NH--, wherein R.sub.gx and R.sub.gxx are one of the
groups --(Y--ONO.sub.2) or --(Y'--ONO.sub.2) of formula (I); e)
R.sub.hNH(CH.sub.2).sub.p-- wherein p is an integer equal to 3 or
4, R.sub.h is R.sub.hh--C(O)-- or R.sub.hh--OC(O)-- wherein
R.sub.hh is one of the groups --(Y--ONO.sub.2) or
--(Y'--ONO.sub.2), or R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--
wherein R.sub.i is R.sub.iiC(O)-- or R.sub.iiOC(O)-- wherein
R.sub.ii is one of the groups --(Y--ONO.sub.2) or
--(Y'--ONO.sub.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) ##STR00449## wherein R.sub.1 is --C(O)R.sub.1x,
--C(O)OR.sub.1x wherein R.sub.1x is one of the groups
--(Y--ONO.sub.2) or --(Y'--ONO.sub.2) of formula (I); R.sub.2 is
--C(O)OR.sub.2x, --C(O)NHR.sub.2xx, --C(O)N(CH)R.sub.2xx, wherein
R.sub.2x and R.sub.2xx are one of the groups --(Y--ONO.sub.2) or
--(Y'--ONO.sub.2) of formula (I) below defined; R.sub.a is selected
from: a) H, CH.sub.3, isopropyl, isobutyl, sec-butyl,
methylthio-(CH.sub.2).sub.2--, benzyl,
C.sub.6H.sub.5--CH.sub.2--CH.sub.2--, 3-triptophanyl-CH.sub.2--,
NH.sub.2--CO--CH.sub.2--, NH.sub.2--CO--(CH.sub.2).sub.2--,
4-imidazolyl-CH.sub.2--; R.sub.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
##STR00450## wherein R.sub.1 is --C(O)R.sub.1x, --C(O)OR.sub.1x
wherein R.sub.1x is --(Y--ONO.sub.2); R.sub.2 is --C(O)OR.sub.2x,
wherein R.sub.2x is the group --[B--(Y'--ONO.sub.2)] wherein B is
##STR00451## R.sub.a is selected from: H, CH.sub.3, isopropyl,
isobutyl, sec-butyl, methylthio-(CH.sub.2).sub.2--, benzyl,
C.sub.6H.sub.5--CH.sub.2--CH.sub.2--, 3-triptophanyl-CH.sub.2--,
NH.sub.2--CO--CH.sub.2-- --NH.sub.2--CO--(CH.sub.2).sub.2--,
4-imidazolyl-CH.sub.2--; R.sub.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
##STR00452## wherein R.sub.1 is --C(O)R.sub.1x or --C(O)OR.sub.1x
wherein R.sub.1x is one of the groups --(Y--ONO.sub.2) or
(Y'--ONO.sub.2); R.sub.2 is --C(O)OR.sub.2x, --C(O)NHR.sub.2xx or
--C(O)N(CH.sub.3)R.sub.2xx, wherein R.sub.2x and R.sub.2xx are one
of the groups --(Y--ONO.sub.2) or --(Y'--ONO.sub.2); R.sub.a is
selected from: b) HS--CH.sub.2--; c) R.sub.xO--CH.sub.2--,
R.sub.xO--CH(CH.sub.3)--, (R.sub.xO)-p-C.sub.6H.sub.4--CH.sub.2--,
wherein R.sub.x is H, d) R.sub.gC(O)CH.sub.2-- or
R.sub.gC(O)(CH.sub.2).sub.2--, wherein R.sub.g is OH,
(CH.sub.3).sub.3CO--, or the group R.sub.gg: ##STR00453## e)
R.sub.hNH(CH.sub.2).sub.p-- or
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--, wherein p is an integer
equal to 3 or 4, R.sub.h is H, (CH.sub.3).sub.3C--OC(O)--, R.sub.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
##STR00454## wherein R.sub.1 is H or --C(O)O--C(CH.sub.3).sub.3,
R.sub.2 is --C(O)OR.sub.2x, --C(O)NHR.sub.2xx,
--C(O)N(CH.sub.3)R.sub.2xx wherein R.sub.2x and R.sub.2xx are one
of the groups --(Y--ONO.sub.2) or --(Y'--ONO.sub.2); R.sub.a is
selected from: b) R.sub.bxC(O)--S--CH.sub.2--,
R.sub.bxOC(O)--S--CH.sub.2--, R.sub.bxNH--C(O)S--CH.sub.2-- wherein
R.sub.bx is one of the groups --(Y--ONO.sub.2) or
--(Y'--ONO.sub.2); c) R.sub.xO--CH.sub.2--,
R.sub.xO--CH(CH.sub.3)--, (R.sub.xO)-p-C.sub.6H.sub.4--CH.sub.2--,
wherein R.sub.x is R.sub.xxC(O)--, R.sub.xxOC(O)-- or
R.sub.xxNHC(O)-- wherein R.sub.xx is one the groups
--(Y--ONO.sub.2) or --(Y'--ONO.sub.2); e)
R.sub.hNH(CH.sub.2).sub.p-- wherein p is 3 or 4, and R.sub.h is
R.sub.hhC(O)-- or R.sub.hhOC(O)-- wherein R.sub.hh is one the
groups --(Y--ONO.sub.2) or --(Y'--ONO.sub.2); or R.sub.a is
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3-- wherein R.sub.i is
R.sub.iiC(O)-- or R.sub.iiOC(O)-- wherein R.sub.ii is one the
groups --(Y--ONO.sub.2) or --(Y'--ONO.sub.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
##STR00455## wherein R.sub.i is H or --C(O)O--C(CH.sub.3).sub.3,
R.sub.2 is --C(O)OR.sub.2x, --C(O)NHR.sub.2xx,
--C(O)N(CH.sub.3)R.sub.2xx wherein R.sub.2x and R.sub.2xx are one
of the groups --(Y--ONO.sub.2) or --(Y'--ONO.sub.2); R.sub.a is
selected from: d) R.sub.gC(O)CH.sub.2--,
R.sub.gC(O)(CH.sub.2).sub.2--, wherein R.sub.9 is R.sub.g--NH--,
R.sub.gxxN(CH.sub.3)--, wherein R.sub.gx and R.sub.gxx are one of
the groups --(Y--ONO.sub.2) or --(Y'--ONO.sub.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
##STR00456## wherein R.sub.1 is --C(O)R.sub.1x, --C(O)OR.sub.1x
wherein R.sub.1x is one of the groups --(Y--ONO.sub.2) or
--(Y'--ONO.sub.2) or --(Y''--ONO.sub.2); R.sub.2 is
--C(O)OR.sub.2x, --C(O)NHR.sub.2xx, --C(O)N(CH.sub.3)R.sub.2xx
wherein R.sub.2x and R.sub.2xx are one of the groups
--(Y--ONO.sub.2) or --(Y'--ONO.sub.2) or --(Y''--ONO.sub.2);
R.sub.a is selected from: b) R.sub.bxC(O)--S--CH.sub.2--,
R.sub.bxOC(O)--S--CH.sub.2--, R.sub.bxNH--C(O)S--CH.sub.2-- wherein
R.sub.bx is one of the groups --(Y--ONO.sub.2) or --(Y'--ONO.sub.2)
or --(Y''--ONO.sub.2); c) R.sub.xO--CH.sub.2--,
R.sub.xO--CH(CH.sub.3)--, (R.sub.xO)-p-C.sub.6H.sub.4--CH.sub.2--,
wherein R.sub.x is R.sub.xxC(O)--, R.sub.xxOC(O)-- or
R.sub.xxNHC(O)-- wherein R.sub.xx is one of the groups
--(Y--ONO.sub.2) or --(Y'--ONO.sub.2) or --(Y''--ONO.sub.2); d)
R.sub.gC(O)CH.sub.2, R.sub.gC(O)(CH.sub.2).sub.2--, wherein R.sub.g
is R.sub.gxO--, R.sub.gxx--NH--, R.sub.gxx--N(CH.sub.3)--, wherein
R.sub.gx and R.sub.gxx are one of the groups --(Y--ONO.sub.2) or
--(Y'--ONO.sub.2) or --(Y''--ONO.sub.2), e)
R.sub.hNH(CH.sub.2).sub.p-- wherein p is 3 or 4, and R.sub.h is
R.sub.hhC(O)-- or R.sub.hhOC(O)-- wherein R.sub.hh is one of the
groups --(Y--ONO.sub.2) or --(Y''--ONO.sub.2) or
--(Y''--ONO.sub.2), or R.sub.a is
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3-- wherein R.sub.i is
R.sub.iiC(O)-- or R.sub.iiOC(O)-- wherein R.sub.ii is one of the
groups --(Y--ONO.sub.2) or --(Y'--ONO.sub.2) or
--(Y''--ONO.sub.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
##STR00457## wherein R.sub.1 is H or --C(O)--OC(CH.sub.3).sub.3;
R.sub.3 is --OC(O)R.sub.3x, OC(O)OR.sub.3x, --OC(O)--NHR.sub.3x,
wherein R.sub.3x is one of the groups --(Y--ONO.sub.2) or
--(Y'--ONO.sub.2); R.sub.s is selected from: b'')
R.sub.bx--C(O)--S--CH.sub.2--, R.sub.bx--OC(O)--S--CH.sub.2--,
R.sub.bx--NH--C(O)S--CH.sub.2-- wherein R.sub.bx is one of the
groups --(Y--ONO.sub.2) or --(Y'--ONO.sub.2); c'')
R.sub.xO--CH.sub.2--, R.sub.xO--CH(CH.sub.3)--,
(R.sub.xO)-p-C.sub.6H.sub.4--CH.sub.2--, wherein R.sub.x is
R.sub.xxC(O)--, R.sub.xxOC(O)--, R.sub.xxNHC(O)-- wherein R.sub.xx
is one of the groups --(Y--ONO.sub.2) or --(Y'--ONO.sub.2); d'')
R.sub.gC(O)CH.sub.2, R.sub.gC(O)(CH.sub.2).sub.2--, wherein R.sub.g
is R.sub.gxO-- or R.sub.gxxNH-- wherein R.sub.gx and R.sub.gxx are
each independently one of the groups --(Y--ONO.sub.2) or
--(Y'--ONO.sub.2); e'') R.sub.hNH(CH.sub.2).sub.p-- wherein p is 3
or 4 and R.sub.h is R.sub.hhC(O)-- or R.sub.hhOC(O)-- wherein
R.sub.hh is one of the groups --(Y--ONO.sub.2) or
--(Y'--ONO.sub.2), or R.sub.3 is
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--, wherein R.sub.i is
R.sub.iiC(O)-- or R.sub.iiOC(O)-- wherein R.sub.ii is one of the
groups --(Y--ONO.sub.2) or --(Y'--ONO.sub.2);
20. A compound according to claim 4 selected from: ##STR00458##
##STR00459## ##STR00460## ##STR00461## ##STR00462## ##STR00463##
##STR00464## ##STR00465## ##STR00466## ##STR00467## ##STR00468##
##STR00469## ##STR00470## ##STR00471## ##STR00472## ##STR00473##
##STR00474## ##STR00475## ##STR00476## ##STR00477## ##STR00478##
##STR00479## ##STR00480## ##STR00481## ##STR00482##
##STR00483##
21. A compound according to claim 5 selected from: ##STR00484##
##STR00485## ##STR00486## ##STR00487## ##STR00488## ##STR00489##
##STR00490## ##STR00491## ##STR00492## ##STR00493## ##STR00494##
##STR00495## ##STR00496## ##STR00497## ##STR00498## ##STR00499##
##STR00500## ##STR00501## ##STR00502## ##STR00503## ##STR00504##
##STR00505## ##STR00506## ##STR00507##
22. A compound according to claim 6 selected from: ##STR00508##
##STR00509## ##STR00510## ##STR00511##
23. A compounds according to claim 7 selected from: ##STR00512##
##STR00513## ##STR00514## ##STR00515## ##STR00516## ##STR00517##
##STR00518## ##STR00519## ##STR00520## ##STR00521##
##STR00522##
24. A compound according to claim 8 selected from: ##STR00523##
25. A compound according to claim 9 selected from: ##STR00524##
##STR00525##
26. A compound according to claim 10 selected from:
##STR00526##
27. A compound according to claim 11 selected from:
##STR00527##
28. A compound according to claim 12 selected from: ##STR00528##
##STR00529## ##STR00530## ##STR00531## ##STR00532## ##STR00533##
##STR00534## ##STR00535## ##STR00536## ##STR00537##
29. A compound according to claim 13 selected from: ##STR00538##
##STR00539## ##STR00540##
30. A compound according to claim 14 is selected from:
##STR00541##
31. A compound according to claim 15 selected from: ##STR00542##
##STR00543##
32. A compound according to claim 16 selected from:
##STR00544##
33. A compound according to claim 17 selected from: ##STR00545##
##STR00546## ##STR00547##
34. A compounds according to claim 18 selected from: ##STR00548##
##STR00549## ##STR00550## ##STR00551## ##STR00552##
##STR00553##
35. A compound according to claim 19 selected from:
##STR00554##
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.
Description
[0001] The invention relates to nitric oxide donor compounds and
their pharmaceutical compositions. The invention also relates to
novel compositions comprising at least one nitric oxide releasing
compounds and at least one therapeutic agent.
[0002] The invention also relates to the use of the nitric oxide
donor compounds and their compositions for treating cardiovascular
diseases, inflammation, pain, fever, gastrointestinal disorders,
ophthalmic diseases, hepatic disorders, renal diseases, respiratory
disorders, immunological diseases, bone metabolism dysfunctions,
central and peripheral nervous system diseases, sexual
dysfunctions, infectious diseases, for the inhibition of platelet
aggregation and platelet adhesion, for treating pathological
conditions resulting from abnormal cell proliferation, vascular
diseases.
[0003] Nitric oxide (commonly referred to as NO) has been
implicated in a wide range of biological functions. As a result,
NO, and materials that release NO, are candidate therapeutics for a
range of diverse disease states.
[0004] Nitric oxide donor compounds have been used for many years
in the treatment of various clinical conditions, particularly
coronary artery disease. The nitrovasodilators such as
Nitroglycerin (GTN) has been used for the treatment of various
types of myocardial ischemia. Because of its pathogenic nature
(chronicity with acute exacerbation), prophylactic and acute
treatments are necessary to prevent complications with potentially
fatal outcomes (>25% death for acute MI). Particularly the
phenomenon of tolerance to the anti-anginal effects of GTN and to
all other existing organic nitrates is of a special clinical
significance. Early development of tolerance to the drug is by far
the most serious drawback of nitrate therapy.
[0005] Other known methods of NO delivery include soluble,
short-term NO donors, such as S-nitroso-N-acetyl-D,L-penicillamine
(SNAP) and incorporation of NO donors into polymeric matrices. In
general, NO-nucleophile complexes (e.g., diazeniumdiolate ions) and
NO-donating groups (e.g., S-nitrosothiols) may spontaneously
decompose in aqueous environments, such as physiological or bodily
fluids, to release NO. This rapid, spontaneous decomposition,
however, may not be a favourable property for many therapeutic
applications. Generally, a slower rate of decomposition and more
steady evolution of NO are more efficacious.
[0006] Many of the existing NO donors must be administered
intravenously, which results in rapid onset of decreasing blood
pressure accompanied by unwanted side effects. Their effect does
not extend beyond the period of infusion. Another undesirable side
effect of some NO donors includes an increase in heart rate. A need
exists for an NO donor compound to treat diseases that does not
induce undesirable side effects.
[0007] The invention is directed to compounds that are particularly
useful as nitric oxide donors having an improved pharmacological
profile.
[0008] The invention provides compounds of the formula (I) and
pharmaceutically acceptable salts or stereoisomers thereof
##STR00001##
wherein: s is 1; s' and s'' are independently selected from 0 or 1,
preferably s' or s'' is 1 or s' and s'' are both 0; m, m' and m''
are each independently selected from 0 or 1 with the proviso that
when m, m' or m'' are 0, A is linked directly to the groups
--(Y--ONO.sub.2), --(Y'--ONO.sub.2), --(Y''--ONO.sub.2), preferably
at least one of m, m' or m'' is 1, or more preferably m, m' and m''
are 0, B at each occurrence is independently selected from:
##STR00002##
preferably B is
##STR00003##
A is a radical selected from the group consisting of:
##STR00004## ##STR00005## ##STR00006##
wherein: in formulas (IIa)-(IIm) and (IIo)-(IIu), R.sub.1 is
selected from: H, --C(O)O--C(CH.sub.3).sub.3, --C(O)O--R.sub.1x,
--C(O)O--R.sub.1x, wherein R.sub.1x is one of the groups
--[(B).sub.m--(Y--ONO.sub.2)].sub.s,
--[(B).sub.m'--(Y'--ONO.sub.2].sub.s', or
--[(B).sub.m''--(Y''--ONO.sub.2)].sub.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.sub.2 is selected from: --C(O)OH,
--C(O)--OC(CH.sub.3).sub.3, --C(O)OR.sub.2x, --C(O)NHR.sub.2xx,
--C(O)N(CH.sub.3)R.sub.2xx wherein R.sub.2x is one of the groups
--[(B).sub.m--(Y--ONO.sub.2)].sub.s,
--[(B).sub.m'--(Y'--ONO.sub.2)].sub.s' or
--[(B).sub.m''--(Y''--ONO.sub.2)].sub.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.sub.2xx is one of the groups
--[(B).sub.m--(Y--ONO.sub.2)].sub.s,
--[(B).sub.m'--(Y'--ONO.sub.2)].sub.s' or
--[(B).sub.m''--(Y''--ONO.sub.2)].sub.s'' of formula (I) wherein m,
m' and m'' are 0 and Y, Y' and Y'' are as below reported, or
R.sub.2 is the group R.sub.4:
##STR00007##
in formula (IIa), R.sub.a is selected from the groups consisting
of: a) --H, --CH.sub.3, isopropyl, isobutyl, sec-butyl, tert-butyl,
methylthio-(CH.sub.2).sub.2--, phenyl, benzyl,
C.sub.6H.sub.5--CH.sub.2--CH.sub.2--, 2-monosubstituted benzyl, or
3-monosubstituted benzyl or 4-monosubstituted benzyl with groups
such as --F, --Cl, I, --NO.sub.2, --CF.sub.3, --CH.sub.3, CN,
C.sub.6H.sub.5CO--; or R.sub.a is 2,4-dichlorobenzyl,
3,4-dichlorobenzyl, 3,4-difluorobenzyl, 3-triptophanyl-CH.sub.2--,
3-benzothienyl-CH.sub.2--, 4-imidazolyl-CH.sub.2--,
9-anthranyl-CH.sub.2--, cyclohexyl, cyclohexyl-CH.sub.2--,
cyclohexyl--(CH.sub.2).sub.2--, cyclopentyl-CH.sub.2--,
(C.sub.6H.sub.5).sub.2CH--, 4-quinolyl-CH.sub.2--,
3-quinolyl-CH.sub.2--, 2-quinolyl-CH.sub.2--,
2-quinoxalyl-CH.sub.2--, 2-furyl-CH.sub.2--, 1-naphtyl-CH.sub.2--,
2-naphtyl-CH.sub.2--, 2-pyridyl-CH.sub.2--, 3-Pyridyl-CH.sub.2--,
4-pyridyl-CH.sub.2--, 2-thienyl-CH.sub.2--, 3-thienyl-CH.sub.2--,
C.sub.6H.sub.4--CH.dbd.CH--CH.sub.2--, CH.sub.2.dbd.CH--CH.sub.2--,
CH.ident.CH--CH.sub.2--, NH.sub.2--CO--CH.sub.2--,
NH.sub.2--OC--(CH.sub.2).sub.2--, or --P(.dbd.O) (OCH.sub.3).sub.2;
b) HS--CH.sub.2--, R.sub.bx--C(O)--S--CH.sub.2--,
R.sub.bx--OC(O)--S--CH.sub.2--, R.sub.bx--NH--C(O)S--CH.sub.2--
wherein R.sub.bx is one of the groups
--[(B).sub.m--(Y--ONO.sub.2)].sub.s,
--[(B).sub.m'--(Y'--ONO.sub.2)].sub.s', or
--[(B).sub.m''--(Y''--ONO.sub.2)].sub.s'' of formula (I) wherein m,
m' and m'' are 0 and Y, Y' and Y'' are as below defined; c)
R.sub.xO--CH.sub.2--, R.sub.xO--CH(CH.sub.3)--,
(R.sub.xO)-p-C.sub.6H.sub.4--CH.sub.2--,
4-(R.sub.xO)-3,5-diiodobenzyl-, 4-(R.sub.xO)-3-nitrobenzyl- wherein
R.sub.x is H, R.sub.xx--C(O)--, R.sub.xx--OC(O)--,
R.sub.xx--NHC(O)-- wherein R.sub.xx is one of the groups
--[(B).sub.m--(Y--ONO.sub.2)].sub.s,
--[(B).sub.m'--(Y'--ONO.sub.2)].sub.s' or
--[(B).sub.m''--(Y''--ONO.sub.2)].sub.s'' of formula (I) wherein m,
m' and m'' are 0 and Y, Y' and Y'' are as below defined; d)
R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2--,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is OH, (CH.sub.3).sub.3CO--, R.sub.gx--O--,
R.sub.gxx--NH--, R.sub.gxx--N(CH.sub.3)-- wherein R.sub.gx is one
of the groups --[(B).sub.m--(Y--ONO.sub.2)].sub.s,
--[(B).sub.m'--(Y'--ONO.sub.2)].sub.s' or
--[(B).sub.m''--Y''--ONO.sub.2)].sub.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.sub.gxx is one of the groups
--[(B).sub.m--(Y--ONO.sub.2)].sub.s,
--[(B).sub.m'--(Y'--ONO.sub.2)].sub.s' or
--[(B).sub.m''--(Y''--ONO.sub.2)].sub.s'' of formula (I) wherein m,
m' and m'' are 0 and Y, Y' and Y'' are as below reported, or
R.sub.g is the group R.sub.gg:
##STR00008##
e) R.sub.hNH(CH.sub.2).sub.p-- or
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--, wherein p is an integer
from 0 to 4, R.sub.h is H, (CH.sub.3).sub.3C--OC(O)--,
R.sub.hh--C(O)-- or R.sub.hh--OC(O)--, R.sub.i is H,
R.sub.ii--C(O)-- or R.sub.ii--C(O)--, wherein R.sub.hh and R.sub.ii
are each independently one of the groups
--[(B).sub.m--(Y--ONO.sub.2)].sub.s,
--[(B).sub.m'--(Y'--ONO.sub.2)].sub.s' or
[(B).sub.m''--(Y''--ONO.sub.2)].sub.s'' of formula (I) wherein m,
m' and m'' are 0 and Y, Y' and Y'' are as below defined; in formula
(IIc) R.sub.c is selected from the following groups: a') H,
CH.sub.3, isopropyl, isobutyl, sec-butyl,
methylthio-(CH.sub.2).sub.2--, phenyl, benzyl, biphenyl-CH.sub.2,
3-triptophanyl-CH.sub.2--, NH.sub.2--CO--CH.sub.2--,
NH.sub.2--CO--(CH.sub.2).sub.2--; b') HS--CH.sub.2--,
R.sub.bx--C(O)--S--CH.sub.2--, R.sub.bx--OC(O)--S--CH.sub.2--,
R.sub.bx--NH--C(O)S--CH.sub.2-- wherein R.sub.bx is one of the
groups --[(B).sub.m--(Y--ONO.sub.2)].sub.s,
--[(B).sub.m'--(Y'--ONO.sub.2)].sub.s' or
--[(B).sub.m''--(Y''--ONO.sub.2)].sub.s'' of formula (I) wherein m,
m' and m'' are 0 and Y, Y' and Y'' are as below defined; c')
R.sub.xO--CH.sub.2--, R.sub.xO--CH(CH.sub.3)--,
R.sub.xO--C.sub.6H.sub.4--CH.sub.2-- wherein R.sub.x is H,
R.sub.xx--C(O)--, R.sub.xx--OC(O)--, R.sub.xx--NHC(O)-- wherein
R.sub.xx is one of the groups --[(B).sub.m--(Y--ONO.sub.2)].sub.s',
[(B').sub.m'--(Y'--ONO.sub.2)].sub.s' or
--[(B'').sub.m''--(Y''--ONO.sub.2)].sub.s'' of formula (I) wherein
m, m' and m'' are 0 and Y, Y' and Y'' are as below defined; d')
R.sub.gC(O)CH.sub.2--, R.sub.gC(O)(CH.sub.2).sub.2-- wherein
R.sub.g is OH, (CH.sub.3).sub.3CO--, R.sub.gx--O--,
R.sub.gxx--NH--, R.sub.gxx--N(CH.sub.3)-- wherein R.sub.gx is one
of the groups --[(B).sub.m--(Y--ONO.sub.2)].sub.s,
--[(B).sub.m'--(Y'--ONO.sub.2)].sub.s' or
--[(B).sub.m''--(Y''--ONO.sub.2)].sub.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.sub.gxx is one of the groups
--[(B).sub.m--(Y--ONO.sub.2)].sub.s,
--[(B).sub.m'--(Y'--ONO.sub.2)].sub.s' or
--[(B).sub.m''--(Y''--ONO.sub.2)].sub.s'' of formula (I) wherein m,
m' and m'' are 0 and Y, Y' and Y'' are as below reported; e')
R.sub.hNH(CH.sub.2).sub.p-- or
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--, wherein p is an integer
from 0 to 4, R.sub.h is H, (CH.sub.3).sub.3C--OC(O)--,
R.sub.hh--C(O)-- or R.sub.hh--OC(O)--, R.sub.i is H,
R.sub.ii--C(O)-- or R.sub.ii--OC(O)--, wherein R.sub.hh and
R.sub.ii are each independently one of the groups
--[(B).sub.m--(Y--ONO.sub.2)].sub.s,
--[(B).sub.m'--(Y'--ONO.sub.2)].sub.s' or
--[(B).sub.m''--(Y''--ONO.sub.2)].sub.s'' of formula (I) wherein m,
m' and m'' are 0 and Y, Y' and Y'' are as below defined; in formula
(IIf) Ph is phenyl, a' is equal to 0, 1, 2, or 3, and a is equal to
0 or 1 with the proviso that a is 0 or 1 when a' is 0 and a is 0
when a' is 1, 2 or 3; in formula (IIi) the group R.sub.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 (Ilk) the group R.sub.2 can be attached
to one of the positions 1, 2 or 3 of the piperidyl ring; in formula
(IIl), R.sub.L is selected from: H, methyl, propyl, allyl,
(C.sub.6H.sub.5).sub.2CH--, 1-naphtyl-CH.sub.2--, benzyl,
2-bromobenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-fluorobenzyl,
4-bromobenzyl, 4-methylbenzyl; in formula (IIm) R.sub.m is selected
from: benzyl, 2-bromobenzyl, 4-bromobenzyl, 4-methylbenzyl; in
formula (IIn) R.sub.n is selected from: --H, --C(O)--R.sub.nx,
--C(O)O--R.sub.nx or --(CH.sub.2).sub.2--NH--R.sub.h wherein
R.sub.h is --H, --C(O)O--C(CH.sub.3).sub.3, --C(O)--R.sub.hh,
--C(O)O--R.sub.hh wherein R.sub.nx and R.sub.hh are each
independently one of the groups
--[(B).sub.m--(Y--ONO.sub.2)].sub.s,
--[(B).sub.m'--(Y'--ONO.sub.2)].sub.s' or
--[(B).sub.m''--(Y''--ONO.sub.2)].sub.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.sub.2 can be attached to the position 1, 2
or 3 of the phenyl ring; in formula (IIs), R.sub.3 is selected
from: OH, --OC(O)--R.sub.3x, --OC(O)O--R.sub.3x,
--OC(O)--NH--R.sub.3x wherein R.sub.3x is one of the groups
--[(B).sub.m--(Y--ONO.sub.2)].sub.s,
--[(B).sub.m'--(Y'--ONO.sub.2)].sub.s' or
--[(B).sub.m''--(Y''--ONO.sub.2)].sub.s'' of formula (I) wherein m,
m' and m'' are 0 and Y, Y' and Y'' are as below defined; in formula
(IIs) R.sub.s is selected from the following groups: a'') --H,
--CH.sub.3, isopropyl, isobutyl, sec-butyl, tert-butyl,
methylthio--(CH.sub.2).sub.2--, benzyl, 2-monosubstituted benzyl,
or 3-monosubstituted benzyl, 3-triptophanyl-CH.sub.2--,
4-imidazolyl-CH.sub.2--, NH.sub.2--CO--CH.sub.2--,
NH.sub.2--CO--(CH.sub.2).sub.2--; b'') HS--CH.sub.2--,
R.sub.bx--C(O)--S--CH.sub.2--, R.sub.bx--OC(O)--S--CH.sub.2--,
R.sub.bx--NH--C(O)S--CH.sub.2-- wherein R.sub.bx is one of the
groups --[(B).sub.m--(Y--ONO.sub.2)].sub.s,
--[(B).sub.m'--(Y'--ONO.sub.2)].sub.s' or
--[(B).sub.m''--(Y''--ONO.sub.2)].sub.s'' of formula (I) wherein m,
m' and m'' are 0 and Y, Y' and Y'' are as below defined; c'')
R.sub.xO--CH.sub.2--, R.sub.xO--CH(CH.sub.3)--,
(R.sub.xO)-p-C.sub.6H.sub.4--CH.sub.2--,
4-(R.sub.xO)-3,5-diiodobenzyl-, 4-(R.sub.xO)-3-nitrobenzyl- wherein
R.sub.x is H, R.sub.xx--C(O)--, R.sub.xx--OC(O)--,
R.sub.xx--NHC(O)-- wherein R.sub.xx is one of the groups
--[(B).sub.m--(Y--ONO.sub.2)].sub.s,
--[(B).sub.m'--(Y'--ONO.sub.2)].sub.s' or
--[(B).sub.m''--(Y''--ONO.sub.2)].sub.s'' of formula (I) wherein m,
m' and m'' are 0 and Y, Y' and Y'' are as below defined; d'')
R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is OH, (CH.sub.3).sub.3CO--, R.sub.gx--O--,
R.sub.g--NH--, R.sub.gxx--N(CH.sub.3)-- wherein R.sub.gx is one of
the groups --[(B).sub.m--(Y--ONO.sub.2)].sub.s,
--[(B).sub.m'--(Y'--ONO.sub.2)].sub.s' or
--[(B).sub.m''--(Y''--ONO.sub.2)].sub.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.sub.gxx is one of the groups
--[(B).sub.m--(Y--ONO.sub.2)].sub.s,
--[(B).sub.m'--(Y'--ONO.sub.2)].sub.s' or
--[(B).sub.m''--(Y''--ONO.sub.2)].sub.s'' of formula (I) wherein m,
m' and m'' are 0 and Y, Y' and Y'' are as below reported, e'')
R.sub.hNH(CH.sub.2).sub.p-- or
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--, wherein p is an integer
from 0 to 4, R.sub.h is H, (CH.sub.3).sub.3C--OC(O)--,
R.sub.hh--C(O)-- or R.sub.hh--OC(O)--, R.sub.i is H,
R.sub.ii--C(O)-- or R.sub.ii--OC(O)--, wherein R.sub.hh and
R.sub.ii are each independently one of the groups
--[(B).sub.m--(Y--ONO.sub.2)].sub.s,
--[(B).sub.m'--(Y'--ONO.sub.2)].sub.s' or
--[(B).sub.m''--(Y''--ONO.sub.2)].sub.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.sub.t is H,
--C(O)--R.sub.tt or --C(O)O--R.sub.tt wherein R.sub.tt is one of
the groups --[(B).sub.m--(Y--ONO.sub.2)].sub.s,
--[(B').sub.m'--(Y'--ONO.sub.2)].sub.s' or
--[(B'').sub.m''--(Y''--ONO.sub.2)].sub.s'' of formula (I) wherein
m, m' and m'' are 0; in formula (IIu) a and b are each
independently 0 or 1, R.sub.x is H, --C(O)--R.sub.xx,
--C(O)O--R.sub.xx--, --C(O)NH--R.sub.xx wherein R.sub.xx is one of
the groups --[(B).sub.m--(Y--ONO.sub.2)].sub.s,
--[(B).sub.m'--(Y'--ONO.sub.2)].sub.s' or
--[(B).sub.m''--(Y''--ONO.sub.2)].sub.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.sub.2), --(Y'--ONO.sub.2) and
--(Y''--ONO.sub.2) of formula (I) are bivalent radicals and they
are each independently selected from:
A)
[0009] a straight or branched C.sub.1-C.sub.20 alkylene, preferably
a straight or branched C.sub.2-C.sub.10 alkylene
[0010] a straight or branched C.sub.1-C.sub.20 alkylene substituted
with one or more --ONO.sub.2 group(s), preferably a straight or
branched C.sub.2-C.sub.10 alkylene substituted with a --ONO.sub.2
group;
[0011] a cycloalkylene having 5 to 7 carbon atoms, the ring being
optionally substituted with a straight or branched C.sub.1-C.sub.10
alkyl;
B)
##STR00009##
[0012] wherein n.sup.0 is an integer from 0 to 20, preferably
n.sup.0 is from 0 to 5, more preferably n.sup.0 is 0 or 1, n.sup.1
is an integer from 1 to 20, preferably n.sup.1 is an integer from 1
to 10, more preferably n.sup.1 is an integer from 2 to 6; more
preferably in formula (IB) and (IB') n.sup.0 is 0 or 1 and n.sup.1
is an integer from 1 to 10; wherein in formulas (IB) and (IB') the
--ONO.sub.2 group is linked to --(CH.sub.2).sub.n.sup.1--;
C)
##STR00010##
[0013] wherein: n.sup.1 is an integer from 1 to 20, preferably
n.sup.1 is an integer from 1 to 10, or more preferably n.sup.1 is
an integer from 2 to 6, n.sup.2 is an integer from 0 to 2,
preferably n.sup.2 is 1, R.sup.2 is H or CH.sub.3, preferably
R.sup.2 is CH.sub.3,
X.sub.1 is --OC(O)-- or --C(O)O--;
[0014] more preferably in formula (IC) n.sup.1 is an integer from 1
to 10, n.sup.2 is 1 and R.sup.2 is CH.sub.3, X.sub.1 is --C(O)O--;
wherein in formula (IC) the --ONO.sub.2 group is linked to
--(CH.sub.2).sub.n.sup.1--;
D)
##STR00011##
[0015] wherein in formula (ID): n.sup.1 is an integer from 1 to 20,
preferably n.sup.1 is an integer from 1 to 10, or more preferably
n.sup.1 is an integer from 2 to 10, n.sup.2, R.sup.2 and X.sub.1
are as defined above; Y.sup.1 is --CH.sub.2--CH.sub.2-- or
--CH.dbd.CH--(CH.sub.2).sub.n.sup.2a-- wherein n.sup.2a is an
integer from 0 to 5, preferably n.sup.2a is 0, wherein in formula
(ID) the --ONO.sub.2 group is linked to --(CH.sub.2).sub.n.sup.1--;
preferably in formula (ID), n.sup.2 is 1 and R.sup.2 is CH.sub.3,
Y.sup.1 is --CH.dbd.CH--(CH.sub.2).sub.n.sup.2a-- wherein n.sup.2a
is 0, X.sub.1 is --C(O)O--, n.sup.1 is an integer from 1 to 10;
E)
##STR00012##
[0016] wherein X.sub.2 is --O--, --S--, --NH-- or
--N(CH.sub.2CH.sub.2OCH.sub.3)--, preferably X.sub.2 is --O-- or
--NH--, n.sup.3 is an integer from 1 to 5, preferably n.sup.3 is 1,
n.sub.3 is an integer from 0 to 10, preferably from 0 to 4, more
preferably n.sub.3 is 0, n.sub.4 an integer from 1 to 10,
preferably from 1 to 4, more preferably n.sub.4 is 1 preferably
n.sub.3 is 0 and n.sub.4 is 1; n.sub.3' is an integer from 0 to 10,
preferably n.sub.3' is from 0 to 4, n.sub.4' is an integer from 1
to 10, preferably from 1 to 4, more preferably n.sub.3' is 0 and
n.sub.4' is 1, R.sup.2 is H or --CH.sub.3, preferably R.sup.2 is H,
preferably in (IE) n.sup.3 is an integer from 1 to 5, n.sub.3 is 0
and n.sub.4 is from 1 to 4, n.sub.3' is 0 and n.sub.4' is from 1 to
4, R.sup.2 is H and X.sub.2 is --O-- or --NH--, more preferably in
(IE) n.sup.3 is 1, n.sub.3 is 0 and n.sub.4 is 1, n.sub.3' is 0 and
n.sub.4' is 1, R.sup.2 is H and X.sub.2 is --O-- or --NH--, wherein
in formula (IE) the --ONO.sub.2 group is linked to the
--(CH.sub.2).sub.n4' group;
F)
##STR00013##
[0017] wherein: n.sup.5 is an integer from 0 to 10, preferably
n.sup.5 is 0 or 1; n.sup.6 is an integer from 1 to 10, preferably
n.sup.6 is 1; R.sup.4, R.sup.5, R.sup.6, R.sup.7 are the same or
different, and are H or straight or branched C.sub.1-C.sub.4 alkyl,
preferably R.sup.4, R.sup.5, R.sup.6, R.sup.7 are H; wherein in
formula (IF) the --ONO.sub.2 group is linked to
##STR00014##
wherein n.sup.6 is as defined above; Y.sup.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:
##STR00015## ##STR00016##
G)
##STR00017##
[0018] wherein n.sup.0 is an integer from 0 to 10, n.sup.7 is an
integer from 1 to 10, preferably n.sup.7 is an integer from 1 to 6,
more preferably n.sup.7 is 1; n.sup.8 is an integer from 0 to 10,
preferably n.sup.8 is an integer from 0 to 6, more preferably
n.sup.8 is 0;
R.sup.8 is CH.sub.3 or CH.sub.2ONO.sub.2,
[0019] more preferably in formula (IG) n.sup.0 is 0, n.sup.7 is 1,
n.sup.8 is 0 and R.sup.8 is CH.sub.3 or CH.sub.2ONO.sub.2, wherein
in formula (IG) the --ONO.sub.2 group is linked to the group
##STR00018##
preferably Y and Y' or Y'' are equal; preferred (Y--ONO.sub.2),
--(Y'--ONO.sub.2) or --(Y''--ONO.sub.2) groups are:
##STR00019## ##STR00020##
more preferably the groups (Y--ONO.sub.2), --(Y'--ONO.sub.2), and
--(Y''--ONO.sub.2) are each independently selected from:
##STR00021##
with the proviso that in formula (I) s' and s'' cannot be both 1
when: [0020] A is the radical of formulas (IIb), (IId)-(IIr), or
[0021] A is the radical of formula (IIt) wherein d is from 3 to 5
and d' is 0, or [0022] A is the radical of formula (IIu) wherein a
is 0; with the proviso that s' and s'' can be both 1 when: [0023] A
is the radical of formulas (IIa), (IIc) or (IIs) and R.sub.a,
R.sub.c and R.sub.s are selected from: [0024]
R.sub.bx--C(O)--S--CH.sub.2--, R.sub.bx--OC(O)--S--CH.sub.2--,
R.sub.bx--NH--C(O)S--CH.sub.2-- wherein R.sub.bx is one of the
groups --[(B).sub.m--(Y--ONO.sub.2)].sub.s,
--[(B).sub.m'--(Y'--ONO.sub.2)].sub.s', or
[(B).sub.m''--(Y''--ONO.sub.2)].sub.s'' wherein m, m' and m'', B,
Y, Y' and Y'' are as above defined; [0025] R.sub.xO--CH.sub.2--,
R.sub.xO--CH(CH.sub.3)--, (R.sub.xO)-p-C.sub.6H.sub.4--CH.sub.2--,
4-(R.sub.xO)-3,5-diiodobenzyl-, 4-(R.sub.xO)-3-nitrobenzyl- wherein
R.sub.x is R.sub.xx--C(O)--, R.sub.xx--OC(O)-- or
R.sub.xx--NHC(O)-- wherein R.sub.xx is one of the groups
--[(B).sub.m--(Y--ONO.sub.2)].sub.s,
[(B).sub.m'--(Y'--ONO.sub.2)].sub.s' or
--[(B).sub.m''--(Y''--ONO.sub.2)].sub.s'' wherein m, m' and m'', B,
Y, Y' and Y'' are as above defined; [0026]
R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is OH, (CH.sub.3).sub.3CO--, R.sub.gx--O--,
R.sub.gxx--NH--, R.sub.gxx--N(CH.sub.3)-- wherein R.sub.gx and
R.sub.gxx are one of the groups
--[(B).sub.m--(Y--ONO.sub.2)].sub.s,
--[(B).sub.m'--(Y'--ONO.sub.2)].sub.s' or
--[(B).sub.m''--(Y''--ONO.sub.2)].sub.s'' wherein m, m' and m'', B,
Y, Y' and Y'' are as above defined; [0027]
R.sub.hNH(CH.sub.2).sub.p-- or
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--, wherein p is an integer
from 0 to 4, R.sub.h is R.sub.hh--C(O)-- or R.sub.hh--OC(O)--,
R.sub.i is R.sub.ii--C(O)-- or R.sub.ii--OC(O)--, wherein R.sub.hh
and R.sub.ii are one of the groups
--[(B).sub.m--(Y--ONO.sub.2)].sub.s,
--[(B).sub.m'--(Y'--ONO.sub.2)].sub.s' or
--[(B).sub.m''--(Y''--ONO.sub.2)].sub.s'' wherein m, m' and m'', B,
Y' and Y'' are as above defined; [0028] A is the radical of formula
(IIt) wherein d' is 1 and d is 2 and R.sub.t is --C(O)--R.sub.tt or
--C(O)O--R.sub.tt wherein R.sub.tt is one of the groups
--[(B).sub.m--(Y--ONO.sub.2)].sub.s,
--[(B).sub.m'--(Y'--ONO.sub.2)].sub.s', or
--[(B).sub.m''--(Y''--ONO.sub.2)].sub.s'' wherein m, m' and m'' Y'
and Y'' are as above defined; [0029] A is the radical of formula
(IIu) wherein a is 1 and R.sub.x is --C(O)--R.sub.xx,
--C(O)O--R.sub.xx-- or --C(O)NH--R.sub.xx wherein R.sub.xx is one
of the groups --[(B).sub.m--(Y--ONO.sub.2)].sub.s,
--[(B).sub.m'--(Y'--ONO.sub.2)].sub.s' or
--[(B).sub.m''--(Y''--ONO.sub.2)].sub.s'' of formula (I) wherein m,
m' and m'' B, Y' and Y'' are as above defined with the proviso that
the following compounds of formula (I) are excluded: [0030]
3-(nitrooxy)propyl 2-(tert-butoxycarbonylamino)-4-phenyl butanoate,
[0031] 3-(nitrooxy)propyl 2-amino-4-phenylbutanoate, [0032]
3-(nitrooxy)propyl 2-amino-4-phenylbutanoate hydrochloride, [0033]
4-(nitrooxy)butyl 2-(tert-butoxycarbonylamino)-4-phenylbutanoate,
[0034] 4-(nitrooxy)butyl 2-amino-4-phenylbutanoate, [0035]
4-(nitrooxy)butyl 2-amino-4-phenylbutanoate hydrochloride, [0036]
(2-(nitrooxy)ethoxy)methyl 2-(tert-butoxycarbonylamino)-4-phenyl
butanoate, [0037] (2-(nitrooxy)ethoxy)methyl
2-amino-4-phenylbutanoate, [0038] (2-(nitrooxy)ethoxy)methyl
2-amino-4-phenyl butanoate hydrochloride, [0039] 1-tert-butyl
2-(4-(nitrooxy)butyl)pyrrolidine-1,2-dicarboxylate, [0040]
4-(nitrooxy)butyl pyrrolidine-2-carboxylate, [0041]
4-(nitrooxy)butyl pyrrolidine-2-carboxylate hydrochloride, [0042]
1-tert-butyl 2-(3-(nitrooxy)propyl)pyrrolidine-1,2-dicarboxylate,
[0043] 3-(nitrooxy)propyl pyrrolidine-2-carboxylate, [0044]
3-(nitrooxy)propyl pyrrolidine-2-carboxylate hydrochloride.
[0045] Another embodiment relates to compounds of formula (I)
##STR00022##
wherein s is 1 and m is 0, s' and s'' are 0, A is selected
from:
##STR00023##
wherein
R.sub.1 is H or --C(O)--OC(CH.sub.3).sub.3,
[0046] R.sub.2 is --C(O)OR.sub.2x, --C(O)NHR.sub.2x,
--C(O)N(CH.sub.3)R.sub.2x and more preferably R.sub.2 is
--C(O)OR.sub.2x or --C(O)NHR.sub.2x, wherein R.sub.2x is
(Y--ONO.sub.2) of formula (I) wherein Y is below reported, R.sub.a
of formula (IIa) is selected from: a) H, CH.sub.3, isopropyl,
isobutyl, sec-butyl, methylthio-(CH.sub.2).sub.2--, benzyl,
C.sub.6H.sub.5--CH.sub.2--CH.sub.2--, 3-triptophanyl-CH.sub.2--,
NH.sub.2--CO--CH.sub.2--, NH.sub.2--CO--(CH.sub.2).sub.2--,
4-imidazolyl-CH.sub.2--;
b) HS--CH.sub.2--,
[0047] c) R.sub.xO--CH.sub.2--, R.sub.xO--CH(CH.sub.3)--,
(R.sub.xO)-p-C.sub.6H.sub.4--CH.sub.2--, wherein R.sub.x is H, d)
R.sub.gC(O)CH.sub.2, R.sub.gC(O)(CH.sub.2).sub.2--, wherein R.sub.g
is OH, (CH.sub.3).sub.3CO--, or the group R.sub.gg:
##STR00024##
e) R.sub.hNH(CH.sub.2).sub.p-- or
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--, wherein p is an integer
equal to 3 or 4, R.sub.h is H or (CH.sub.3).sub.3C--OC(O)--,
R.sub.i is H; R.sub.c of formula (IIc) is selected from the group
comprising: H, CH.sub.3, isopropyl, isobutyl, sec-butyl,
methylthio-(CH.sub.2).sub.2--, benzyl, 3-triptophanyl-CH.sub.2,
4-imidazolyl-CH.sub.2--, NH.sub.2--CO--CH.sub.2--,
NH.sub.2--CO--(CH.sub.2).sub.2--; R.sub.L of formula (IIl) is H, Y
of the group (Y--ONO.sub.2) is selected from:
A)
[0048] a straight or branched C.sub.2-C.sub.10 alkylene
[0049] a straight or branched C.sub.2-C.sub.10 alkylene substituted
with a --ONO.sub.2 group;
B)
##STR00025##
[0050] wherein in formula (IB) n.sup.0 is from 0 to 5 and n.sup.1
is an integer from 1 to 10;
C)
##STR00026##
[0051] wherein in formula (IC) n.sup.1 is an integer from 1 to 10,
n.sup.2 is 1 and R.sup.2 is CH.sub.3, X.sub.1 is --C(O)O--;
D)
##STR00027##
[0052] wherein in formula (ID): n.sup.2 and R is CH.sub.3, Y.sup.1
is --CH.dbd.CH--(CH.sub.2).sub.n.sup.2a-- wherein n.sup.2a is 0,
X.sub.1 is --C(O)O-- and n.sup.1 is an integer from 1 to 10;
E)
##STR00028##
[0053] wherein in formula (IE) n.sup.3 is from 1 to 5, n.sub.3 is 0
and n.sub.4 is from 1 to 4, n.sub.3' is 0 and n.sub.4' is from 1 to
4,
X.sub.2 is --O-- or --NH--,
R.sup.2 is H,
[0054] preferably the group --(Y--ONO.sub.2) is selected from:
##STR00029##
the following are preferred compounds according to the present
invention:
##STR00030## ##STR00031## ##STR00032## ##STR00033## ##STR00034##
##STR00035## ##STR00036## ##STR00037## ##STR00038## ##STR00039##
##STR00040## ##STR00041## ##STR00042## ##STR00043## ##STR00044##
##STR00045## ##STR00046## ##STR00047## ##STR00048## ##STR00049##
##STR00050## ##STR00051## ##STR00052## ##STR00053## ##STR00054##
##STR00055##
[0055] Another embodiment provides compounds of formula (I)
##STR00056##
wherein s and m are 1, s' and s'' are 0, B is selected from:
##STR00057##
more preferably B is
##STR00058##
A is a radical selected from:
##STR00059##
wherein
R.sub.1 is H or --C(O)O--C(CH.sub.3).sub.3,
[0056] R.sub.2 is --C(O)OR.sub.2x wherein R.sub.2x is the group
--[(B)--(Y--ONO.sub.2)] of formula (I) wherein B is as above
defined and Y is below defined, R.sub.a of formula (IIa) is
selected from: a) H, CH.sub.3, isopropyl, isobutyl, sec-butyl,
methylthio-(CH.sub.2).sub.2--, benzyl,
C.sub.6H.sub.5--CH.sub.2--CH.sub.2--, 3-triptophanyl-CH.sub.2--,
NH.sub.2--CO--CH.sub.2--, NH.sub.2--CO--(CH.sub.2).sub.2--,
4-imidazolyl-CH.sub.2--;
b) HS--CH.sub.2--;
[0057] c) R.sub.xO--CH.sub.2--, R.sub.xO--CH(CH.sub.3)-- or
(R.sub.xO)-p-C.sub.6H.sub.4--CH.sub.2--, wherein R.sub.x is H; d)
R.sub.gC(O)CH.sub.2, R.sub.gC(O)(CH.sub.2).sub.2--, wherein R.sub.g
is OH or (CH.sub.3).sub.3C--O--, or the group R.sub.gg:
##STR00060##
e) R.sub.hNH(CH.sub.2).sub.p-- or
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3-- wherein p is an integer
equal to 3 or 4, R.sub.h is H or (CH.sub.3).sub.3C--OC(O)--,
R.sub.i is H; R.sub.L of formula (IIl) is H; Y of the group
--(Y--ONO.sub.2) is selected from:
A)
[0058] a straight or branched C.sub.2-C.sub.10 alkylene,
[0059] a straight or branched C.sub.2-C.sub.10 alkylene substituted
with a --ONO.sub.2 group;
E)
##STR00061##
[0060] wherein in formula (IE) n.sup.3 is from 1 to 5 n.sub.3 is 0
and n.sub.4 is from 1 to 4, n.sub.3' is 0 and n.sub.4' is from 1 to
4,
X.sub.2 is --O-- or --NH--,
R.sup.2 is H;
[0061] preferably --(Y--ONO.sub.2) is selected from:
##STR00062##
The following are preferred compounds according to the present
invention:
##STR00063##
[0062] Another embodiment relates to compounds of formula (I)
##STR00064##
wherein s is 1 and m is 0, s' and s'' are 0, A is a radical
selected from
##STR00065##
wherein R.sub.1 is --C(O)R.sub.1x, --C(O)OR.sub.1x wherein R.sub.1x
is the group --(Y--ONO.sub.2) of formula (I) wherein Y is below
reported, R.sub.2 in formulas (IIa) (IIc) and (IIl) is --C(O)OH,
--C(O)--OC(CH.sub.3).sub.3 or R.sub.2 is the group R.sub.4:
##STR00066##
R.sub.3 in formula (IIs) is OH; R.sub.a of formula (IIa) is
selected from: a) H, CH.sub.3, isopropyl, isobutyl, sec-butyl,
methylthio-(CH.sub.2).sub.2--, benzyl,
C.sub.6H.sub.5--CH.sub.2--CH.sub.2--, 3-triptophanyl-CH.sub.2--,
NH.sub.2--CO--CH.sub.2--, NH.sub.2--CO--(CH.sub.2).sub.2--,
4-imidazolyl-CH.sub.2--;
b) HS--CH.sub.2--;
[0063] c) R.sub.xO--CH.sub.2--, R.sub.xO--CH(CH.sub.3)--,
(R.sub.xO)-p-C.sub.6H.sub.4--CH.sub.2-- wherein R.sub.x is H; d)
R.sub.gC(O)CH.sub.2 or R.sub.gC(O)(CH.sub.2).sub.2--, wherein
R.sub.g is OH or (CH.sub.3).sub.3C--O--, or R.sub.g is the group
R.sub.gg:
##STR00067##
e) R.sub.hNH(CH.sub.2).sub.p-- or
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--, wherein p is an integer
equal to 3 or 4, R.sub.h is H or (CH.sub.3).sub.3C--OC(O)--,
R.sub.i is H; R.sub.c of formula (IIc) is selected from: H,
CH.sub.3, isopropyl, isobutyl, sec-butyl,
methylthio--(CH.sub.2).sub.2--, benzyl, 3-triptophanyl-CH.sub.2--,
4-imidazolyl-CH.sub.2--, NH.sub.2--CO--CH.sub.2--,
NH.sub.2--CO--(CH.sub.2).sub.2--; R.sub.L of formula (IIl) is H;
R.sub.s of formula (IIs) is H, CH.sub.3, isopropyl, isobutyl,
sec-butyl, methylthio-(CH.sub.2).sub.2--, benzyl,
3-triptophanyl-CH.sub.2--, 4-imidazolyl-CH.sub.2--,
NH.sub.2--CO--CH.sub.2--, NH.sub.2--CO--(CH.sub.2).sub.2--; Y of
the groups (Y--ONO.sub.2 is selected from:
A)
[0064] a straight or branched C.sub.2-C.sub.10 alkylene
[0065] a straight or branched C.sub.2-C.sub.10 alkylene substituted
with a --ONO.sub.2 group;
B)
##STR00068##
[0066] wherein in formula (IB) n.sup.0 is from 0 to 5 and n.sup.1
is an integer from 1 to 10;
C)
##STR00069##
[0067] wherein in formula (IC) n.sup.1 is an integer from 1 to 10,
n.sup.2 is 1 and R.sup.2 is CH.sub.3, X.sub.1 is --C(O)O--;
D)
##STR00070##
[0068] wherein in formula (ID): n.sup.2 is 1 and R.sup.2 is
CH.sub.3, Y.sup.1 is --CH.dbd.CH--(CH.sub.2).sub.n.sup.2a-- wherein
n.sup.2a is 0, X.sub.1 is --C(O)O-- and n.sup.1 is an integer from
1 to 10;
E)
##STR00071##
[0069] wherein in formula (IE) n.sup.3 is from 1 to 5, n.sub.3 is 0
and n.sub.4 is from 1 to 4, n.sub.3' is 0 and n.sub.4' is from 1 to
4,
X.sub.2 is --O-- or --NH--,
R.sup.2 is H,
[0070] preferably --(Y--ONO.sub.2) is selected from:
##STR00072##
the following are preferred compounds according to the present
invention:
##STR00073## ##STR00074## ##STR00075## ##STR00076## ##STR00077##
##STR00078## ##STR00079## ##STR00080## ##STR00081## ##STR00082##
##STR00083## ##STR00084## ##STR00085## ##STR00086## ##STR00087##
##STR00088## ##STR00089## ##STR00090## ##STR00091## ##STR00092##
##STR00093## ##STR00094## ##STR00095## ##STR00096##
[0071] Another embodiment relates to compounds of formula (I)
##STR00097##
wherein s and s' are 1 and m, m' are 0, s'' is 0, A is a radical of
formula (IIa)
##STR00098##
wherein R.sub.1 is --C(O)R.sub.1x, or --C(O)OR.sub.1x wherein
R.sub.1x is one of the groups --(Y--ONO.sub.2) or --(Y'--ONO.sub.2)
of formula (I) wherein Y and Y' are below reported, R.sub.2 is
--C(O)OH, --C(O)--OC(CH.sub.3).sub.3 or R.sub.2 is the group
R.sub.4:
##STR00099##
R.sub.a is selected from: b) R.sub.bxC(O)--S--CH.sub.2--,
R.sub.bx--OC(O)--S--CH.sub.2--, R.sub.bx--NH--C(O)S--CH.sub.2--
wherein R.sub.bx is one of the groups --(Y--ONO.sub.2) or
--(Y'--ONO.sub.2); c) R.sub.xO--CH.sub.2--,
R.sub.xO--CH(CH.sub.3)--, (R.sub.xO)-p-C.sub.6H.sub.4--CH.sub.2--,
wherein R.sub.x is R.sub.xxC(O)--, R.sub.xxOC(O)-- or
R.sub.xxNHC(O)-- wherein R.sub.xx is one of the groups
--(Y--ONO.sub.2) or --(Y'--ONO.sub.2) of formula (I) wherein Y and
Y' are below defined; d) R.sub.gC(O)CH.sub.2--,
R.sub.gC(O)(CH.sub.2).sub.2--, wherein R.sub.g is R.sub.gx--O--,
R.sub.gxx--NH--, wherein R.sub.gx and R.sub.gxx are one of the
groups --(Y--ONO.sub.2) or --(Y'--ONO.sub.2) of formula (I) wherein
Y and Y' are below defined; e) R.sub.hNH(CH.sub.2).sub.p-- wherein
p is an integer equal to 3 or 4, R.sub.h is R.sub.hh--C(O)-- or
R.sub.hh--OC(O)-- wherein R.sub.hh is one of the groups
--(Y--ONO.sub.2) or --(Y'--ONO.sub.2) of formula (I) wherein Y and
Y' are below defined, or R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--
wherein R.sub.i is R.sub.iiC(O)-- or R.sub.iiOC(O)-- wherein
R.sub.ii is one of the groups --(Y--ONO.sub.2) or --(Y'--ONO.sub.2)
of formula (I) wherein Y and Y' are below defined; Y and Y' of the
groups (Y--ONO.sub.2) and --(Y'--ONO.sub.2) are each independently
selected from:
A)
[0072] a straight or branched C.sub.2-C.sub.10 alkylene
[0073] a straight or branched C.sub.2-C.sub.10 alkylene substituted
with a --ONO.sub.2 group;
B)
##STR00100##
[0074] wherein in formula (IB) n.sup.0 is from 0 to 5 and n.sup.1
is an integer from 1 to 10;
C)
##STR00101##
[0075] wherein in formula (IC) n.sup.1 is an integer from 1 to 10,
n.sup.2 is 1 and R.sup.2 is CH.sub.3, X.sub.1 is --C(O)O--;
D)
##STR00102##
[0076] wherein in formula (ID): n.sup.2 is 1 and R.sup.2 is
CH.sub.3, Y.sup.1 is --CH.dbd.CH--(CH.sub.2).sub.n.sup.2a-- wherein
n.sup.2a is 0, X.sub.1 is --C(O)O-- and n.sup.1 is an integer from
1 to 10;
E)
##STR00103##
[0077] wherein in formula (IE) n.sup.3 is from 1 to 5, n.sub.3 is 0
and n.sub.4 is from 1 to 4, n.sub.3' is 0 and n.sub.4' is from 1 to
4,
X.sub.2 is --O-- or --NH--,
R.sup.2 is H,
[0078] preferably (Y--ONO.sub.2) and (Y'--ONO.sub.2) are each
independently selected from:
##STR00104##
more preferably (Y--ONO.sub.2) and (Y'--ONO.sub.2) are equal. The
following are preferred compounds according to the present
invention:
##STR00105## ##STR00106## ##STR00107## ##STR00108## ##STR00109##
##STR00110## ##STR00111## ##STR00112## ##STR00113##
##STR00114##
[0079] Another embodiment provides compounds of formula (I)
##STR00115##
wherein s is 1 and m is 0, s' and s'' are 0, A is a radical of
formula (IIa) or (IIl)
##STR00116##
wherein R.sub.1 is --C(O)R.sub.1x or --C(O)OR.sub.1x wherein
R.sub.1x is the group --(Y--ONO.sub.2) of formula (I) wherein Y is
below defined, R.sub.2 in formulas (IIa) and (IIl) is the group
R.sub.4
##STR00117##
R.sub.a of formula (IIa) is selected from: a) H, CH.sub.3,
isopropyl, isobutyl, sec-butyl, methylthio-(CH.sub.2).sub.2--,
benzyl, C.sub.6H.sub.5--CH.sub.2--CH.sub.2--,
3-triptophanyl-CH.sub.2--, NH.sub.2--CO--CH.sub.2--,
NH.sub.2--CO--(CH.sub.2).sub.2--, 4-imidazolyl-CH.sub.2--;
b) HS--CH.sub.2--;
[0080] c) R.sub.xO--CH.sub.2--, R.sub.xO--CH(CH.sub.3)--,
(R.sub.xO)-p-C.sub.6H.sub.4--CH.sub.2--, wherein R.sub.x is H; d)
R.sub.gC(O)CH.sub.2 or R.sub.gC(O)(CH.sub.2).sub.2--, wherein
R.sub.g is OH, (CH.sub.3).sub.3O-- or the
##STR00118##
e) R.sub.hNH(CH.sub.2).sub.p-- or
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--, wherein p is an integer
equal to 3 or 4, R.sub.h is H or (CH.sub.3).sub.3C--OC(O)--,
R.sub.i is H; R.sub.L of formula (IIl) is H; Y of the group
(Y--ONO.sub.2) is selected from:
A)
[0081] a straight or branched C.sub.2-C.sub.10 alkylene
[0082] a straight or branched C.sub.2-C.sub.10 alkylene substituted
with a --ONO.sub.2 group;
B)
##STR00119##
[0083] wherein in formula (IB) n.sup.0 is from 0 to 5 and n.sup.1
is an integer from 1 to 10;
C)
##STR00120##
[0084] wherein in formula (IC) n.sup.1 is an integer from 1 to 10,
n.sup.2 is 1 and R.sup.2 is CH.sub.3, X.sub.1 is --C(O)O--;
D)
##STR00121##
[0085] wherein in formula (ID): n.sup.2 is 1 and R.sup.2 is
CH.sub.3, Y.sup.1 is --CH.dbd.CH--(CH.sub.2).sub.n.sup.2a-- wherein
n.sup.2a is 0, X.sub.1 is --C(O)O-- and n.sup.1 is an integer from
1 to 10;
E)
##STR00122##
[0086] wherein in formula (IE) n.sup.3 is from 1 to 5, n.sub.3 is 0
and n.sub.4 is from 1 to 4, n.sub.3' is 0 and n.sub.4' is from 1 to
4,
X.sub.2 is --O-- or --NH--,
R.sup.2 is H,
[0087] preferably (Y--ONO.sub.2) is selected from:
##STR00123##
The following are preferred compounds according to the present
invention:
##STR00124## ##STR00125## ##STR00126## ##STR00127##
[0088] Another embodiment relates to compounds of formula (I)
##STR00128##
wherein s and s' are 1 and m, m' are 0, s'' is 0, A is a radical of
formula (IIa) or (IIl)
##STR00129##
wherein R.sub.1 is --C(O)R.sub.1x, --C(O)OR.sub.1x wherein R.sub.1x
is one of the groups --(Y--ONO.sub.2) or --(Y'--ONO.sub.2) of
formula (I) wherein Y and Y' are below defined; R.sub.2 is
--C(O)OR.sub.2x, --C(O)NHR.sub.2x, --C(O)N(CH.sub.3)R.sub.2xx,
wherein R.sub.2x and R.sub.2xx are one of the groups
--(Y--ONO.sub.2) or --(Y'--ONO.sub.2) of formula (I) wherein Y and
Y' are below defined, more preferably R.sub.2 is --C(O)OR.sub.2x or
--C(O)NHR.sub.2xx; R.sub.a is selected from: a) H, CH.sub.3,
isopropyl, isobutyl, sec-butyl, methylthio--(CH.sub.2).sub.2--,
benzyl, C.sub.6H.sub.5--CH.sub.2--CH.sub.2--,
3-triptophanyl-CH.sub.2--, NH.sub.2--CO--CH.sub.2--,
NH.sub.2--CO--(CH.sub.2).sub.2--, 4-imidazolyl-CH.sub.2--; R.sub.L
in formula (IIl) is H; Y and Y' of the groups (Y--ONO.sub.2) and
--(Y'--ONO.sub.2) are each independently selected from:
A)
[0089] a straight or branched C.sub.2-C.sub.10 alkylene
[0090] a straight or branched C.sub.2-C.sub.10 alkylene substituted
with a --ONO.sub.2 group;
B)
##STR00130##
[0091] wherein in formula (IB) n.sup.0 is from 0 to 5 and n.sup.1
is an integer from 1 to 10;
C)
##STR00131##
[0092] wherein in formula (IC) n.sup.1 is an integer from 1 to 10,
n.sup.2 is 1 and R.sup.2 is CH.sub.3, X.sub.1 is --C(O)O--;
D)
##STR00132##
[0093] wherein in formula (ID): n.sup.2 is 1 and R.sup.2 is
CH.sub.3, Y.sup.1 is --CH.dbd.CH--(CH.sub.2).sub.n.sup.2a-- wherein
n.sup.2a is 0, X.sub.1 is --C(O)O-- and n.sup.1 is an integer from
1 to 10;
E)
##STR00133##
[0094] wherein in formula (IE) n.sup.3 is from 1 to 5, n.sub.3 is 0
and n.sub.4 is from 1 to 4, n.sub.3' is 0 and n.sub.4' is from 1 to
4,
X.sub.2 is --O-- or --NH--,
R.sup.2 is H,
[0095] preferably (Y--ONO.sub.2) and (Y'--ONO.sub.2) are each
independently selected from:
##STR00134##
The following are preferred compounds according to the present
invention:
##STR00135## ##STR00136## ##STR00137##
[0096] Another embodiment relates to compounds of formula (I)
##STR00138##
wherein s and s' are 1, m is 1, m' is 0, s'' is 0, B at each
occurrence is independently selected from:
##STR00139##
preferably B is
##STR00140##
more preferably B is:
##STR00141##
A is a radical of formula
##STR00142##
wherein R.sub.1 is --C(O)R.sub.1x, --C(O)OR.sub.1x wherein R.sub.1x
is --(Y--ONO.sub.2) of formula (I) wherein Y is below defined;
R.sub.2 is --C(O)OR.sub.2x, wherein R.sub.2x is the group
--[B--(Y'--ONO.sub.2)] of formula (I) wherein B is as above
reported and Y' is below reported, R.sub.a is selected from: H,
CH.sub.3, isopropyl, isobutyl, sec-butyl,
methylthio--(CH.sub.2).sub.2--, benzyl,
C.sub.6H.sub.5--CH.sub.2--CH.sub.2--, 3-triptophanyl-CH.sub.2--,
NH.sub.2--CO--CH.sub.2--; NH.sub.2--CO--(CH.sub.2).sub.2--,
4-imidazolyl-CH.sub.2--; R.sub.L in formula (IIl) is H, Y and Y' of
the groups (Y--ONO.sub.2) and --(Y'--ONO.sub.2) are each
independently selected from:
A)
[0097] a straight or branched C.sub.2-C.sub.10 alkylene
[0098] a straight or branched C.sub.2-C.sub.10 alkylene substituted
with a --ONO.sub.2 group;
E)
##STR00143##
[0099] wherein in formula (IE) n.sup.3 is from 1 to 5, n.sub.3 is 0
and n.sub.4 is from 1 to 4, n.sub.3' is 0 and n.sub.4' is from 1 to
4, X.sub.2 is --O-- or --NH--,
R.sup.2 is H,
[0100] preferably (Y--ONO.sub.2) and --(Y'--ONO.sub.2) are each
independently selected from:
##STR00144##
The following are preferred compounds according to the present
invention:
##STR00145##
[0101] Another embodiment relates to compounds of formula (I)
##STR00146##
wherein s and s' are 1, and s'' are 0, m and m' are 0, A is a
radical of formula
##STR00147##
wherein R.sub.1 is --C(O)R.sub.1x or --C(O)OR.sub.1x wherein
R.sub.1x is one of the groups --(Y--ONO.sub.2) or (Y'--ONO.sub.2)
of formula (I) wherein Y and Y' are below defined; R.sub.2 is
--C(O)OR.sub.2x, --C(O)NHR.sub.2xx or --C(O)N(CH.sub.3)R.sub.2xxr
wherein R.sub.2xx and R.sub.2x are one of the groups
--(Y--ONO.sub.2) or --(Y'--ONO.sub.2) of formula (I) wherein Y and
Y' are below defined, more preferably R.sub.2 is --C(O)OR.sub.2x,
--C(O)NHR.sub.2xx; R.sub.a is selected from:
b) HS--CH.sub.2--;
[0102] c) R.sub.xO--CH.sub.2--, R.sub.xO--CH(CH.sub.3)--,
(R.sub.xO)-p-C.sub.6H.sub.4--CH.sub.2--, wherein R.sub.x is H, d)
R.sub.gC(O)CH.sub.2-- or R.sub.gC(O)(CH.sub.2).sub.2--, wherein
R.sub.g is OH, (CH.sub.3).sub.3CO--, or the group R.sub.gg
##STR00148##
e) R.sub.hNH(CH.sub.2).sub.p-- or
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--, wherein p is an integer
equal to 3 or 4, R.sub.h is H, (CH.sub.3).sub.3C--OC(O)--, R.sub.2
is H; Y and Y' of the groups (Y--ONO.sub.2), --(Y'--ONO.sub.2) are
each independently selected from:
A)
[0103] a straight or branched C.sub.2-C.sub.10 alkylene
[0104] a straight or branched C.sub.2-C.sub.10 alkylene substituted
with a --ONO.sub.2 group;
E)
##STR00149##
[0105] wherein in formula (IE) n.sup.3 is from 1 to 5, n.sub.3 is 0
and n.sub.4 is from 1 to 4, n.sub.3' is 0 and n.sub.4' is from 1 to
4,
X.sub.2 is --O-- or --NH--,
R.sup.2 is H,
[0106] preferably (Y--ONO.sub.2) and (Y'--ONO.sub.2) are each
independently selected from:
##STR00150##
The following are preferred compounds according to the present
invention:
##STR00151## ##STR00152##
[0107] Another embodiment provides compounds of formula (I)
##STR00153##
wherein s is 1 and m is 0, s' and s'' are 0, A is a radical of
formula
##STR00154##
wherein R.sub.1 is H or --C(O)O--C(CH.sub.3).sub.3, R.sub.2 is
--C(O)OH or R.sub.2 is equal to the group R.sub.4
##STR00155##
R.sub.a is selected from: b) R.sub.bxC(O)--S--CH.sub.2--,
R.sub.bxOC(O)--S--CH.sub.2--, R.sub.bxNH--C(O)S--CH.sub.2-- wherein
R.sub.bx is the group --(Y--ONO.sub.2) of formula (I) wherein Y is
below defined, c) R.sub.xO--CH.sub.2--, R.sub.xO--CH(CH.sub.3)--,
(R.sub.xO)-p-C.sub.6H.sub.4--CH.sub.2--, wherein R.sub.x is
R.sub.xxC(O)--, R.sub.xxOC(O)-- or R.sub.xxNHC(O)-- wherein
R.sub.xx is the group --(Y--ONO.sub.2) of formula (I) wherein Y is
below defined; d) R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2-- wherein R.sub.g is R.sub.gxO--,
R.sub.gxx--NH--, or Rg.sub.xx--N(CH.sub.3)--, wherein R.sub.gx and
R.sub.gxx are the group --(Y--ONO.sub.2) of formula (I) wherein Y
is below defined, more preferably R.sub.g is R.sub.gxO--,
R.sub.gxx--NH-- e) R.sub.hNH(CH.sub.2).sub.p-- wherein p is 3 or 4,
and R.sub.h is R.sub.hhC(O)-- or R.sub.hhOC(O)-- wherein R.sub.hh
is the group --(Y--ONO.sub.2) of formula (I) wherein Y is below
defined; or R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3-- wherein
R.sub.i is R.sub.iiC(O)-- or R.sub.iiOC(O)-- wherein R.sub.ii is
the group --(Y--ONO.sub.2) of formula (I) wherein Y is below
defined; Y of the group (Y--ONO.sub.2) is selected from:
A)
[0108] a straight or branched C.sub.2-C.sub.10 alkylene
[0109] a straight or branched C.sub.2-C.sub.10 alkylene substituted
with a --ONO.sub.2 group;
E)
##STR00156##
[0110] wherein in formula (IE) n.sup.3 is from 1 to 5, n.sub.3 is 0
and n.sub.4 is from 1 to 4, n.sub.3' is 0 and n.sub.4' is from 1 to
4,
X.sub.2 is --O-- or --NH--,
R.sup.2 is H,
[0111] preferably (Y--ONO.sub.2) is selected from:
##STR00157##
The following are preferred compounds according to the present
invention:
##STR00158## ##STR00159## ##STR00160## ##STR00161## ##STR00162##
##STR00163## ##STR00164## ##STR00165## ##STR00166## ##STR00167##
##STR00168##
[0112] Another embodiment provides compounds of formula (I)
##STR00169##
wherein s and s' are 1 and m, m' are 0, s'' is 0, A is a radical of
formula
##STR00170##
wherein R.sub.1 is H or --C(O)O--C(CH.sub.3).sub.3, R.sub.2 is
--C(O)OR.sub.2x, --C(O)NHR.sub.2xx, --C(O)N(CH.sub.3)R.sub.2xx
wherein R.sub.2x and R.sub.2xx are one of the groups
--(Y--ONO.sub.2) or --(Y'--ONO.sub.2) of formula (I) wherein Y and
Y' are below defined, more preferably R.sub.2 is --C(O)OR.sub.2x,
--C(O)NHR.sub.2x; R.sub.a is selected from: b)
R.sub.bxC(O)--S--CH.sub.2--, R.sub.bxOC(O)--S--CH.sub.2--,
R.sub.bxNH--C(O)S--CH.sub.2-- wherein R.sub.bx is one of the groups
--(Y--ONO.sub.2) or --(Y'--ONO.sub.2) wherein Y and Y' are below
defined; c) R.sub.xO--CH.sub.2--, R.sub.xO--CH(CH.sub.3)--,
(R.sub.xO)-p-C.sub.6H.sub.4--CH.sub.2--, wherein R.sub.x is
R.sub.xxC(O)--, R.sub.xxOC(O)-- or R.sub.xxNHC(O)-- wherein
R.sub.xx is one the groups --(Y--ONO.sub.2) or --(Y'--ONO.sub.2) of
formula (I) wherein Y and Y' are below reported; e)
R.sub.hNH(CH.sub.2).sub.p-- wherein p is 3 or 4, and R.sub.h is
R.sub.hhC(O)-- or R.sub.hhOC(O)-- wherein R.sub.hh is one the
groups --(Y--ONO.sub.2) or --(Y'--ONO.sub.2) of formula (I) wherein
Y and Y' are below reported; or R.sub.a is
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3-- wherein R.sub.i is
R.sub.iiC(O)-- or R.sub.iiOC(O)-- wherein R.sub.ii is one the
groups --(Y--ONO.sub.2) or --(Y'--ONO.sub.2) of formula (I) wherein
Y and Y' are below defined; Y and Y' of the groups (Y--ONO.sub.2)
and --(Y'--ONO.sub.2) are each independently selected from:
A)
[0113] a straight or branched C.sub.2-C.sub.10 alkylene
[0114] a straight or branched C.sub.2-C.sub.10 alkylene substituted
with a --ONO.sub.2 group;
E)
##STR00171##
[0115] wherein in formula (IE) n.sup.3 is from 1 to 5, n.sub.3 is 0
and n.sub.4 is from 1 to 4, n.sub.3' is 0 and n.sub.4' is from 1 to
4,
X.sub.2 is --O-- or --NH--,
R.sup.2 is H,
[0116] preferably --(Y--ONO.sub.2) and --(Y'--ONO.sub.2) are each
independently selected from:
##STR00172##
The following are preferred compounds according to the present
invention:
##STR00173##
[0117] Another embodiment provides compounds of formula (I)
##STR00174##
wherein s and s' are 1 and m, m' are 0, s'' is 0, A is a radical of
formula
##STR00175##
wherein R.sub.1 is H or --C(O)O--C(CH.sub.3).sub.3, R.sub.2 is
--C(O)OR.sub.2x, --C(O)NHR.sub.2xx, --C(O)N(CH.sub.3)R.sub.2xx
wherein R.sub.2x and R.sub.2xx are one of the groups
--(Y--ONO.sub.2) or --(Y'--ONO.sub.2) of formula (I) wherein Y and
Y' are below defined, more preferably R.sub.2 is --C(O)OR.sub.2x,
--C(O)NHR.sub.2xx; R.sub.a is selected from: d)
R.sub.gC(O)CH.sub.2--, R.sub.gC(O)(CH.sub.2).sub.2--, wherein
R.sub.g is R.sub.gxO--, R.sub.gxx--NH--, R.sub.gxxN(CH.sub.3)--,
wherein R.sub.gx and R.sub.gxx are one of the groups
--(Y--ONO.sub.2) or --(Y'--ONO.sub.2) of formula (I) wherein Y and
Y' are below defined, more preferably R.sub.g is R.sub.gxO-- or
R.sub.gxx--NH--; Y and Y' of the groups (Y--ONO.sub.2) and
--(Y'--ONO.sub.2) are each independently selected from:
A)
[0118] a straight or branched C.sub.2-C.sub.10 alkylene
[0119] a straight or branched C.sub.2-C.sub.10 alkylene substituted
with a --ONO.sub.2 group;
E)
##STR00176##
[0120] wherein in formula (IE) n.sup.3 is from 1 to 5, n.sub.3 is 0
and n.sub.4 is from 1 to 4, n.sub.3' is 0 and n.sub.4' is from 1 to
4,
X.sub.2 is --O-- or --NH--,
R.sup.2 is H,
[0121] preferably (Y--ONO.sub.2) and (Y'--ONO.sub.2) are each
independently selected from:
##STR00177##
The following are preferred compounds according to the present
invention:
##STR00178## ##STR00179## ##STR00180##
[0122] Another embodiment provides compounds of formula (I)
##STR00181##
wherein s, s' and s'' are 1, m, m' and m'' are 0, A is a radical of
formula
##STR00182##
wherein R.sub.1 is --C(O)R.sub.1x, --C(O)OR.sub.1x wherein R.sub.1x
is one of the groups --(Y--ONO.sub.2) or --(Y'--ONO.sub.2) or
--(Y''--ONO.sub.2) of formula (I) wherein Y, Y' and Y'' are below
defined; R.sub.2 is --C(O)OR.sub.2x, --C(O)NHR.sub.2xx,
--C(O)N(CH.sub.3)R.sub.2xx wherein R.sub.2x and R.sub.2xx are one
of the groups --(Y--ONO.sub.2) or --(Y'--ONO.sub.2) or
--(Y''--ONO.sub.2) of formula (I) wherein Y, Y' and Y'' are below
reported, and more preferably R.sub.2 is --C(O)OR.sub.2x,
--C(O)NHR.sub.2x; R.sub.a is selected from: b)
R.sub.bxC(O)--S--CH.sub.2--, R.sub.bxOC(O)--S--CH.sub.2--,
R.sub.bxNH--C(O)S--CH.sub.2-- wherein R.sub.bx is one of the groups
--(Y--ONO.sub.2) or --(Y'--ONO.sub.2) or --(Y''--ONO.sub.2) of
formula (I) wherein Y, Y' and Y'' are below reported; c)
R.sub.xO--CH.sub.2--, R.sub.xO--CH(CH.sub.3)--,
(R.sub.xO)-p-C.sub.6H.sub.4--CH.sub.2--, wherein R.sub.x is
R.sub.xxC(O)--, R.sub.xxOC(O)-- or R.sub.xxNHC(O)-- wherein
R.sub.xx is one of the groups --(Y--ONO.sub.2) or --(Y'--ONO.sub.2)
or --(Y''--ONO.sub.2) of formula (I) wherein Y, Y' and Y'' are
below reported; d) R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, wherein R.sub.g is R.sub.gxO--,
R.sub.gxx--NH--, R.sub.gxx--N(CH.sub.3)--, wherein R.sub.gx and
R.sub.gxx are one of the groups --(Y--ONO.sub.2) or
--(Y'--ONO.sub.2) or --(Y''--ONO.sub.2) of formula (I) wherein Y,
Y' and Y'' are below defined, more preferably R.sub.g is
R.sub.gxO-- or R.sub.gxxNH--, e) R.sub.hNH(CH.sub.2).sub.p--
wherein p is 3 or 4, and R.sub.h is R.sub.hhC(O)-- or
R.sub.hhOC(O)-- wherein R.sub.hh is one of the groups
--(Y--ONO.sub.2) or --(Y'--ONO.sub.2) or --(Y''--ONO.sub.2) of
formula (I) wherein Y, Y' and Y'' are below defined, or R.sub.a is
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3-- wherein R.sub.i is
R.sub.iiC(O)-- or R.sub.iiOC(O)-- wherein R.sub.ii is one of the
groups --(Y--ONO.sub.2) or --(Y'--ONO.sub.2) or --(Y''--ONO.sub.2)
of formula (I) wherein Y, Y' and Y'' are below reported; Y, Y' and
Y'' of the groups (Y--ONO.sub.2), --(Y'--ONO.sub.2) or
--(Y''--ONO.sub.2) are each independently selected from:
A)
[0123] a straight or branched C.sub.2-C.sub.10 alkylene
[0124] a straight or branched C.sub.2-C.sub.10 alkylene substituted
with a --ONO.sub.2 group;
E)
##STR00183##
[0125] wherein in formula (IE) n.sup.3 is from 1 to 5, n.sub.3 is 0
and n.sub.4 is from 1 to 4, n.sub.3' is 0 and n.sub.4' is from 1 to
4,
X.sub.2 is --O-- or --NH--,
R.sup.2 is H,
[0126] preferably --(Y--ONO.sub.2), --(Y'--ONO.sub.2) and
--(Y''--ONO.sub.2) are each independently selected from:
##STR00184##
The following are preferred compounds according to the present
invention:
##STR00185## ##STR00186## ##STR00187## ##STR00188## ##STR00189##
##STR00190##
[0127] Another embodiment provides compounds of formula (I)
##STR00191##
wherein s and s' are 1, m and m' are 0, s'' is 0, A is a radical of
formula
##STR00192##
wherein R.sub.1 is H or --C(O)--OC(CH.sub.3).sub.3; R.sub.3 is
--OC(O)R.sub.3x, OC(O)R.sub.3x, --C(O)--NHR.sub.3x, wherein
R.sub.3x is one of the groups --(Y--ONO.sub.2) or --(Y'--ONO.sub.2)
of formula (I) wherein Y and Y' are below defined; R.sub.s is
selected from: b'') R.sub.bx--C(O)--S--CH.sub.2--,
R.sub.bx--OC(O)--S--CH.sub.2--, R.sub.bx--NH--C(O)S--CH.sub.2--
wherein R.sub.bx is one of the groups --(Y--ONO.sub.2) or
--(Y'--ONO.sub.2) of formula (I) wherein Y and Y' are below
defined; c'') R.sub.xO--CH.sub.2--, R.sub.xO--CH(CH.sub.3)--,
(R.sub.xO)-p-C.sub.6H.sub.4--CH.sub.2--, wherein R.sub.x is
R.sub.xxC(O)--, R.sub.xxOC(O)--, R.sub.xxNHC(O)-- wherein R.sub.xx
is one of the groups --(Y--ONO.sub.2) or --(Y'--ONO.sub.2) of
formula (I) wherein Y and Y' are below defined; d'')
R.sub.gC(O)CH.sub.2, R.sub.gC(O)(CH.sub.2).sub.2--, wherein R.sub.g
is R.sub.gxO-- or R.sub.gxxNH-- wherein R.sub.gx and R.sub.gxx are
one of the groups --(Y--ONO.sub.2) or --(Y'--ONO.sub.2) of formula
(I) wherein Y and Y' are below defined; e'')
R.sub.hNH(CH.sub.2).sub.p-- wherein p is 3 or 4 and R.sub.h is
R.sub.hhC(O)-- or R.sub.hhOC(O)-- wherein R.sub.hh is one of the
groups --(Y--ONO.sub.2) or --(Y'--ONO.sub.2) of formula (I) wherein
Y and Y' are below defined, or
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--, wherein R.sub.i is
R.sub.iiC(O)-- or R.sub.iiOC(O)-- wherein R.sub.ii is one of the
groups --(Y--ONO.sub.2) or --(Y'--ONO.sub.2) of formula (I) wherein
Y and Y' are below defined; Y and Y' of the groups (Y--ONO.sub.2)
and --(Y'--ONO.sub.2) are each independently selected from:
A)
[0128] a straight or branched C.sub.2-C.sub.10 alkylene
[0129] a straight or branched C.sub.2-C.sub.10 alkylene substituted
with a --ONO.sub.2 group;
E)
##STR00193##
[0130] wherein in formula (IE) n.sup.3 is from 1 to 5, n.sub.3 is 0
and n.sub.4 is from 1 to 4, n.sub.3' is 0 and n.sub.4' is from 1 to
4,
X.sub.2 is --O-- or --NH--,
R.sup.2 is H,
[0131] preferably (Y--ONO.sub.2) and (Y'--ONO.sub.2) are each
independently selected from:
##STR00194##
The following are preferred compounds according to the present
invention:
##STR00195##
[0132] Another embodiment provides compounds of formula (I)
##STR00196##
wherein s is 1, m is 0, s' and s'' are 0, A is a radical of
formula
##STR00197##
wherein R.sub.1 is H or --C(O)--OC(CH.sub.3).sub.3; R.sub.3 is
--OC(O)R.sub.3x, OC(O)OR.sub.3x, --OC(O)--NHR.sub.3x, wherein
R.sup.3x is the group --(Y--ONO.sub.2) of formula (I) wherein Y is
below reported; R.sub.s is selected from: a'') H, CH.sub.3,
isopropyl, isobutyl, sec-butyl, methylthio-(CH.sub.2).sub.2--,
benzyl, C.sub.6H.sub.5--CH.sub.2--CH.sub.2--,
3-triptophanyl-CH.sub.2--, NH.sub.2--CO--CH.sub.2--,
NH.sub.2--CO--(CH.sub.2).sub.2--, 4-imidazolyl-CH.sub.2--; Y of the
group (Y--ONO.sub.2) is selected from:
A)
[0133] a straight or branched C.sub.2-C.sub.10 alkylene
[0134] a straight or branched C.sub.2-C.sub.10 alkylene substituted
with a --ONO.sub.2 group;
E)
##STR00198##
[0135] wherein in formula (IE) n.sup.3 is from 1 to 5, n.sub.3 is 0
and n.sub.4 is from 1 to 4, n.sub.3' is 0 and n.sub.4' is from 1 to
4, X.sub.2 is --O-- or --NH--,
R.sup.2 is H,
[0136] preferably (Y--ONO.sub.2) is selected from:
##STR00199##
The following are preferred compounds according to the present
invention:
##STR00200##
[0137] Another embodiment provides compounds of formula (I)
##STR00201##
wherein s is 1 and m is 0, s' and s'' are 0, A is a radical of
formula (IIq)
##STR00202##
R.sub.1 is H or --C(O)O--C(CH.sub.3).sub.3,
[0138] R.sub.2 is --C(O)OR.sub.2x,
--C(O)NHR.sub.2x--C(O)N(CH.sub.3) wherein R.sub.2x is the group
--(Y--ONO.sub.2) of formula (I) wherein Y is below reported, more
preferably R.sub.2 is --C(O)OR.sub.2x or --C(O)NHR.sub.2x; Y of the
group (Y--ONO.sub.2) is selected from:
A)
[0139] a straight or branched C.sub.2-C.sub.10 alkylene
[0140] a straight or branched C.sub.2-C.sub.10 alkylene substituted
with a --ONO.sub.2 group;
##STR00203##
wherein in formula (IE) n.sup.3 is from 1 to 5, n.sub.3 is 0 and
n.sub.4 is from 1 to 4, n.sub.3' is 0 and n.sub.4' is from 1 to
4,
X.sub.2 is --O-- or --NH--,
R.sup.2 is H,
[0141] preferably and (Y--ONO.sub.2) is selected from:
##STR00204##
The following are preferred compounds according to the present
invention:
##STR00205## ##STR00206##
[0142] Another embodiment relates to compounds of formula (I)
##STR00207##
wherein s is 1 and m is 0, s' and s'' are 0, A is a radical of
formula (IIu)
##STR00208##
wherein a is 1 and b is 0;
R.sub.1 is H or --C(O)O--C(CH.sub.3).sub.3,
[0143] R.sub.2 is --C(O)OR.sub.2x,
--C(O)NHR.sub.2x--C(O)N(CH.sub.3)R.sub.2x wherein R.sub.2x is the
group --(Y--ONO.sub.2) of formula (I) wherein Y is below reported,
more preferably R.sub.2 is --C(O)OR.sub.2x, or
--C(O)NHR.sub.2x,
R.sub.x is H,
[0144] Y of the group (Y--ONO.sub.2) is selected from:
A)
[0145] a straight or branched C.sub.2-C.sub.10 alkylene
[0146] a straight or branched C.sub.2-C.sub.10 alkylene substituted
with a --ONO.sub.2 group;
E)
##STR00209##
[0147] wherein in formula (IE) n.sup.3 is from 1 to 5, n.sub.3 is 0
and n.sub.4 is from 1 to 4, n.sub.3' is 0 and n.sub.4' is from 1 to
4,
X.sub.2 is --O-- or --NH--,
R.sup.2 is H,
[0148] preferably (Y--ONO.sub.2), is selected from:
##STR00210##
The following are preferred compounds according to the present
invention:
##STR00211##
[0149] The compounds of the present invention show significant
advantages over the other known nitric oxide donor compounds, they
release nitric oxide (NO) slower, they do not induce hypotension in
normotensive subjects and moreover they do not induce increasing of
heart rate in hypertensive patients.
[0150] The term "C.sub.1-C.sub.20 alkylene" as used herein refers
to branched or straight chain C.sub.1-C.sub.20 hydrocarbon,
preferably having from 1 to carbon atoms such as methylene,
ethylene, propylene, isopropylene, n-butylene, pentylene,
n-hexylene and the like.
[0151] The term "C.sub.1-C.sub.10 alkyl" as used herein refers to
branched or straight chain alkyl groups comprising one to ten
carbon atoms, including methyl, ethyl, n-propyl, isopropyl,
n-butyl, isobutyl, t-butyl, pentyl, hexyl, octyl and the like.
[0152] The term "cycloalkylene" as used herein refers to ring
having from 5 to 7 carbon atoms including, but not limited to,
cyclopentylene, cyclohexylene optionally substituted with side
chains such as straight or branched (C.sub.1-C.sub.10)-alkyl,
preferably CH.sub.3.
[0153] The term "heterocyclic" as used herein refers to saturated,
unsaturated or aromatic 5 or 6 members ring, containing one or more
heteroatoms selected from nitrogen, oxygen, sulphur, such as for
example pyridine, pyrazine, pyrimidine, pyrrolidine, morpholine,
imidazole and the like.
[0154] As stated above, the invention includes also the
pharmaceutically acceptable salts of the compounds of formula (I)
and stereoisomers thereof.
[0155] Examples of pharmaceutically acceptable salts are either
those with inorganic bases, such as sodium, potassium, calcium and
aluminium hydroxides, or with organic bases, such as lysine,
arginine, triethylamine, dibenzylamine, piperidine and other
acceptable organic amines.
[0156] 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.
[0157] Examples of organic acids are: oxalic, tartaric, maleic,
succinic, citric acids. Examples of inorganic acids are: nitric,
hydrochloric, sulphuric, phosphoric acids. Salts with nitric acid
are preferred.
[0158] 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).
[0159] The invention also relates to the use of the compounds of
formula (I) or their salts for treating cardiovascular diseases,
inflammation, pain, fever, gastrointestinal disorders, ophthalmic
diseases including glaucoma, hepatic disorders, renal diseases,
respiratory disorders, immunological diseases, bone metabolism
dysfunctions, central and peripheral nervous system diseases,
sexual dysfunctions, infectious diseases, for the inhibition of
platelet aggregation and platelet adhesion, for treating
pathological conditions resulting from abnormal cell proliferation
and vascular diseases.
[0160] Another embodiment of the present invention relates to
compositions comprising at least a compound of formula (I) or its
salt and at least one therapeutic agent selected from
anti-inflammatory drugs, drugs used to treat cardiovascular
diseases, drugs for treating ocular diseases, drugs for treating
respiratory disorders.
[0161] Anti-inflammatory drugs include, but are not limited to, non
steroidal anti-inflammatory drugs and steroidal anti-inflammatory
drugs
[0162] Drugs used to treat cardiovascular diseases refers to any
therapeutic compound, or a pharmaceutically acceptable salt
thereof, used to treat any cardiovascular disease. Suitable
compounds include, but are not limited to aspirin and derivatives
thereof, anti-thrombotic drugs, angiotensin-converting enzyme
inhibitors (ACE inhibitors), beta-adrenergic blockers, calcium
channel blockers, angiotensin II receptor antagonists, endothelin
antagonists, renin inhibitors, (.beta.-adrenergic receptor
agonists, cholesterol reducers such as, for example, HMG-CoA
reductase inhibitors, including, but not limited to, lovastatin,
simvastatin, pravastatin, fluvastatin, cerivastatin,
atorvastatin.
[0163] Drugs for treating ocular diseases include, but are not
limited to, prostaglandins.
[0164] In another object of the invention the two components of the
composition above defined are administered simultaneously or
sequentially wherein the two components may be administered by the
same or different administration pathways.
[0165] Another object of the invention provide the use of the
composition above reported for the treatment of cardiovascular
diseases, inflammation, pain, fever, gastrointestinal disorders,
ophthalmic diseases including glaucoma, hepatic disorders, renal
diseases, respiratory disorders, immunological diseases, bone
metabolism dysfunctions, central and peripheral nervous system
diseases, sexual dysfunctions, infectious diseases, for the
inhibition of platelet aggregation and platelet adhesion, for
treating pathological conditions resulting from abnormal cell
proliferation and vascular diseases.
[0166] Generally the treatment of cardiovascular disease and/or
peripheral vascular disorders is a long-term therapy, and it is
directed to patients suffering from cardiovascular disease and/or
peripheral vascular disorders or inflammatory diseases which suffer
from hypertension or diabetes.
[0167] Long term treatment ranges from about one month to over two
years of chronic/maintenance administration.
[0168] Another object of the present invention relates to
pharmaceutical compositions comprising the composition above
reported and non toxic adjuvants and/or carriers usually employed
in the pharmaceutical field.
[0169] An object of the present invention relates to pharmaceutical
compositions comprising at least a compound of formula (I) together
with non toxic adjuvants and/or carriers usually employed in the
pharmaceutical field.
[0170] The invention also relates to the use of the following
compounds [0171] 3-(nitrooxy)propyl
2-(tert-butoxycarbonylamino)-4-phenyl butanoate, [0172]
3-(nitrooxy)propyl 2-amino-4-phenylbutanoate, [0173]
3-(nitrooxy)propyl 2-amino-4-phenylbutanoate hydrochloride, [0174]
4-(nitrooxy)butyl 2-(tert-butoxycarbonylamino)-4-phenylbutanoate,
[0175] 4-(nitrooxy)butyl 2-amino-4-phenylbutanoate, [0176]
4-(nitrooxy)butyl 2-amino-4-phenylbutanoate hydrochloride, [0177]
(2-(nitrooxy)ethoxy)methyl 2-(tert-butoxycarbonylamino)-4-phenyl
butanoate, [0178] (2-(nitrooxy)ethoxy)methyl
2-amino-4-phenylbutanoate, [0179] (2-(nitrooxy)ethoxy)methyl
2-amino-4-phenyl butanoate hydrochloride, [0180] 1-tert-butyl
2-(4-(nitrooxy)butyl)pyrrolidine-1,2-dicarboxylate [0181]
4-(nitrooxy)butyl pyrrolidine-2-carboxylate, [0182]
4-(nitrooxy)butyl pyrrolidine-2-carboxylate hydrochloride, [0183]
1-tert-butyl 2-(3-(nitrooxy)propyl)pyrrolidine-1,2-dicarboxylate,
[0184] 3-(nitrooxy)propyl pyrrolidine-2-carboxylate, [0185]
3-(nitrooxy)propyl pyrrolidine-2-carboxylate hydrochloride, for
treating cardiovascular diseases, inflammation, pain, fever,
gastrointestinal disorders, ophthalmic diseases including glaucoma,
hepatic disorders, renal diseases, respiratory disorders,
immunological diseases, bone metabolism dysfunctions, central and
peripheral nervous system diseases, sexual dysfunctions, infectious
diseases, for the inhibition of platelet aggregation and platelet
adhesion, for treating pathological conditions resulting from
abnormal cell proliferation and vascular diseases.
[0186] Another object of the present invention relates to
compositions comprising at least one of the following compounds:
[0187] 3-(nitrooxy)propyl 2-(tert-butoxycarbonylamino)-4-phenyl
butanoate, [0188] 3-(nitrooxy)propyl 2-amino-4-phenylbutanoate,
[0189] 3-(nitrooxy)propyl 2-amino-4-phenylbutanoate hydrochloride,
[0190] 4-(nitrooxy)butyl 2-(tert-butoxycarbonylamino)-4-phenyl
butanoate, [0191] 4-(nitrooxy)butyl 2-amino-4-phenylbutanoate,
[0192] 4-(nitrooxy)butyl 2-amino-4-phenylbutanoate hydrochloride,
[0193] (2-(nitrooxy)ethoxy)methyl
2-(tert-butoxycarbonylamino)-4-phenyl butanoate, [0194]
(2-(nitrooxy)ethoxy)methyl 2-amino-4-phenylbutanoate, [0195]
(2-(nitrooxy)ethoxy)methyl 2-amino-4-phenyl butanoate
hydrochloride, [0196] 1-tert-butyl
2-(4-(nitrooxy)butyl)pyrrolidine-1,2-dicarboxylate, [0197]
4-(nitrooxy)butyl pyrrolidine-2-carboxylate, [0198]
4-(nitrooxy)butyl pyrrolidine-2-carboxylate hydrochloride, [0199]
1-tert-butyl 2-(3-(nitrooxy)propyl)pyrrolidine-1,2-dicarboxylate,
[0200] 3-(nitrooxy)propyl pyrrolidine-2-carboxylate, [0201]
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.
[0202] Anti-inflammatory drugs include, but are not limited to, non
steroidal anti-inflammatory drugs and steroidal anti-inflammatory
drugs
[0203] Drugs used to treat cardiovascular diseases refers to any
therapeutic compound, or a pharmaceutically acceptable salt
thereof, used to treat any cardiovascular disease. Suitable
compounds include, but are not limited to aspirin and derivatives
thereof, anti-thrombotic drugs, angiotensin-converting enzyme
inhibitors (ACE inhibitors), beta-adrenergic blockers, calcium
channel blockers, angiotensin II receptor antagonists, endothelin
antagonists, renin inhibitors, .beta.-adrenergic receptor agonists,
cholesterol reducers such as, for example, HMG-CoA reductase
inhibitors, including, but not limited to, lovastatin, simvastatin,
pravastatin, fluvastatin, cerivastatin, atorvastatin.
[0204] Drugs for treating ocular diseases include, but are not
limited to, prostaglandins.
[0205] In another object of the invention the two components of the
composition above defined are administered simultaneously or
sequentially wherein the two components may be administered by the
same or different administration pathways.
[0206] Another object of the invention provides the use of the
composition comprising at least one of the following compounds:
[0207] 3-(nitrooxy)propyl 2-(tert-butoxycarbonylamino)-4-phenyl
Butanoate, [0208] 3-(nitrooxy)propyl 2-amino-4-phenylbutanoate,
[0209] 3-(nitrooxy)propyl 2-amino-4-phenylbutanoate hydrochloride,
[0210] 4-(nitrooxy)butyl 2-(tert-butoxycarbonylamino)-4-phenyl
butanoate, [0211] 4-(nitrooxy)butyl 2-amino-4-phenylbutanoate,
[0212] 4-(nitrooxy)butyl 2-amino-4-phenylbutanoate hydrochloride,
[0213] (2-(nitrooxy)ethoxy)methyl
2-(tert-butoxycarbonylamino)-4-phenyl butanoate, [0214]
(2-(nitrooxy)ethoxy)methyl 2-amino-4-phenylbutanoate, [0215]
(2-(nitrooxy)ethoxy)methyl 2-amino-4-phenyl butanoate
hydrochloride, [0216] 1-tert-butyl
2-(4-(nitrooxy)butyl)pyrrolidine-1,2-dicarboxylate, [0217]
4-(nitrooxy)butyl pyrrolidine-2-carboxylate, [0218]
4-(nitrooxy)butyl pyrrolidine-2-carboxylate hydrochloride, [0219]
1-tert-butyl 2-(3-(nitrooxy)propyl)pyrrolidine-1,2-dicarboxylate,
[0220] 3-(nitrooxy)propyl pyrrolidine-2-carboxylate, [0221]
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, for the
treatment of cardiovascular diseases, inflammation, pain, fever,
gastrointestinal disorders, ophthalmic diseases including glaucoma,
hepatic disorders, renal diseases, respiratory disorders,
immunological diseases, bone metabolism dysfunctions, central and
peripheral nervous system diseases, sexual dysfunctions, infectious
diseases, for the inhibition of platelet aggregation and platelet
adhesion, for treating pathological conditions resulting from
abnormal cell proliferation and vascular diseases.
[0222] An object of the present invention relates to pharmaceutical
compositions comprising the composition above reported together
with non toxic adjuvants and/or carriers usually employed in the
pharmaceutical field.
[0223] The daily dose of the active ingredient that should be
administered can be a single dose or it can be an effective amount
divided into several smaller doses that are to be administered
throughout the day. The dosage regimen and administration frequency
for treating the mentioned diseases with the compound of the
invention and/or with the pharmaceutical compositions of the
present invention will be selected in accordance with a variety of
factors, including for example age, body weight, sex and medical
condition of the patient as well as severity of the disease, route
of administration, pharmacological considerations and eventual
concomitant therapy with other drugs. In some instances, dosage
levels below or above the aforesaid range and/or more frequent may
be adequate, and this logically will be within the judgment of the
physician and will depend on the disease state.
[0224] The compounds of the invention may be administered orally,
parenterally, rectally or topically, by inhalation or aerosol, in
formulations eventually containing conventional non-toxic
pharmaceutically acceptable carriers, adjuvants and vehicles as
desired. Topical administration may also involve the use of
transdermal administration such as transdermal patches or
iontophoresis devices. The term "parenteral" as used herein,
includes subcutaneous injections, intravenous, intramuscular,
intrasternal injection or infusion techniques.
[0225] Injectable preparations, for example sterile injectable
aqueous or oleaginous suspensions may be formulated according to
known art using suitable dispersing or wetting agents and
suspending agents. The sterile injectable preparation may also be a
sterile injectable solution or suspension in a non-toxic
parenterally acceptable diluent or solvent. Among the acceptable
vehicles and solvents are water, Ringer's solution and isotonic
sodium chloride. In addition, sterile, fixed oils are
conventionally employed as a solvent or suspending medium. For this
purpose any bland fixed oil may be employed including synthetic
mono or diglycerides, in addition fatty acids such as oleic acid
find use in the preparation of injectables.
[0226] Suppositories for rectal administration of the drug can be
prepared by mixing the active ingredient with a suitable
non-irritating excipient, such as cocoa butter and polyethylene
glycols.
[0227] Solid dosage forms for oral administration may include
capsules, tablets, pills, powders, granules and gels. In such solid
dosage forms, the active compound may be admixed with at least one
inert diluent such as sucrose, lactose or starch. Such dosage forms
may also comprise, as in normal practice, additional substances
other than inert diluents, e.g. lubricating agents such as
magnesium stearate. In the case of capsules, tablets and pills, the
dosage forms may also comprise buffering agents. Tablets and pills
can additionally be prepared with enteric coatings.
[0228] Liquid dosage forms for oral administration may include
pharmaceutically acceptable emulsions, solutions, suspensions,
syrups and elixirs containing inert diluents commonly used in the
art, such as water. Such compositions may also comprise adjuvants,
such as wetting agents, emulsifying and suspending agents, and
sweetening, flavouring and the like.
Synthesis Procedure
[0229] 1. The Compounds of General Formula (I)
##STR00212##
wherein: s is equal to 1; m, m', m'', s' and s'' are 0 Y is as
above defined, A is a radical of formula (IIa)-(IIm), (IIo)-(IIr),
(IIt)-(IIu) and (IIn) wherein R.sub.1 is --C(O)--R.sub.1x and it
binds the group --Y--ONO.sub.2, R.sub.2 is --COOH; in formula (IIn)
R.sub.n is --C(O)--R.sub.nx, or is --(CH.sub.2).sub.2--NH--R.sub.h
wherein R.sub.h is --C(O)--R.sub.hh and it binds the group
--Y--ONO.sub.2 R.sub.a of formula (IIa) is selected in group a)
R.sub.c of formula (IIc) is selected in group a') in formula (IIt)
d is an integer from 3 to 5, d' is 0; can be prepared as
follows
[0230] 1a) by reacting a compound of formula (I) wherein s, s',
s'', m, m', m'', Y, Y', Y'' are as above defined in 1, A is a
radical of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn)
wherein R.sub.2 is --C(O)OC(CH.sub.3).sub.3; R.sub.1, R.sub.a,
R.sub.c, R.sub.h, R.sup.n, d, and d' are as defined in 1, with
anhydrous or aqueous organic or inorganic acid to hydrolyze the
t-butyl ester following procedure well known in the literature.
[0231] 1b) by reacting a compound of formula A with a compound of
formula (IIIa)
A+HOOC--Y--ONO.sub.2 (IIIa)
wherein Y is as above defined and A is selected from (IIa)-(IIm),
(IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein R.sub.1 is --H and
R.sub.2 is --C(O)O(CH.sub.3).sub.3; in formula (IIn) R.sub.n is H,
or is --(CH.sub.2).sub.2--NH--R.sub.h wherein R.sub.h is H; R.sub.a
of formula (IIa) is selected in group a); R.sub.c of formula (IIc)
is selected in group a'); in formula (IIt) d and d' are as above
defined; in the presence of a condensing agent such as
dicyclohexylcarbodiimide (DCC) or N,N'-carbonyldiimidazol (CDI) or
other known condensing reagents such as
O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HATU), in the presence or not of
1-Hydroxybenzotriazole (HOBT) in solvent such as DMF, THF,
chloroform at a temperature in the range from -5.degree. C. to
80.degree. C. in the presence or not of a base as for example
DMAP.
[0232] The nitric acid ester compounds of formula (IIIa) can be
obtained from the corresponding alcohols of formula HOOC--Y--OH
(IIIb), that are commercially available, by reaction with nitric
acid and acetic anhydride in a temperature range from -51.degree.
C. to 0.degree. C. or reacting the corresponding halogen
derivatives of formula HOOC--Y--Hal (IIIc) wherein Hal is an
halogen atom preferably Cl, Br, I, that are commercially available,
with AgNO.sub.3 as known in the literature. Alternatively the
reaction with AgNO.sub.3 can be performed under microwave
irradiation in solvents such acetonitrile or THF at temperatures in
the range between about 100-180.degree. C. for time range about
1-60 min.
[0233] Dinitrated compounds of formula (IIIa) can be also directly
prepared with 12 and AgNO.sub.3 starting from carboxylic acids with
a double bond in the chain as described in WO 2005/070868.
[0234] Compounds (IIIa) can be also prepared from the corresponding
Tosyl derivative (IIId) HOOC--Y--OTs by reacting with AgNO.sub.3 or
MetalNO.sub.3 wherein Metal is Li.sup.+, Na.sup.+, K.sup.+, in
solvents such acetonitrile or DMF at refluxing temperature or under
microwave irradiation at temperatures in the range between about
100-180.degree. C. for time range about 1-120 min.
[0235] 1b') alternatively compound A reported in 1b) can be reacted
with a compound of formula (IIIe):
A+Act-CO--Y--ONO.sub.2 (IIIe)
wherein Y is as above defined; Act is an Halogen atom or a
carboxylic acid activating group used in peptide chemistry such
as:
##STR00213##
the reaction is generally carried out in presence of a inorganic or
organic base in an aprotic polar/non-polar solvent such as DMF, THF
or CH.sub.2Cl.sub.2 at temperatures range between
0.degree.-80.degree. C. or in a double phase system
H.sub.2O/Et.sub.2O at temperatures range between
20.degree.-40.degree. C.; or in the presence of DMAP and a Lewis
acid such as Sc(OTf).sub.3 or Bi(OTf).sub.3 in solvents such as
DMF, CH.sub.2Cl.sub.2.
[0236] The compounds of formula (IIIe) can be obtained as described
in WO 2006/008196.
[0237] 1c) compounds A reported in 1b) are commercially available
or can be prepared by reacting a compound of formula A.sub.1
wherein A.sub.1 is a radical of formula (IIa)-(IIm), (IIo)-(IIr),
(IIt)-(IIu) and (IIn) wherein R.sub.2 is --COOH, R.sub.1 and
R.sub.n are substituted by the Fmoc protective group and R.sub.a,
R.sub.c, d and d' are as defined in 1, with tert-butyl alcohol and
sulphuric acid or other methods to obtain a tert-butyl ester well
known in the literature. Eventually removing the Fmoc protective
group using methods known in the literature.
[0238] Compounds A.sub.1 are commercially available or can be
prepared by the correspondent compounds A.sub.2:
A.sub.2.fwdarw.A.sub.1
wherein A.sub.2 is a radical of formula (IIa)-(IIm), (IIo)-(IIr),
(IIt)-(IIu) and (IIn) wherein R.sub.2 is --COOH, and R.sub.1 is
--C(O)OC(CH.sub.3).sub.3, R.sub.n is --C(O)OC(CH.sub.3).sub.3 or is
--(CH.sub.2).sub.2--NH--C(O)OC(CH.sub.3).sub.3, R.sub.a, R.sub.c d
and d' are as defined in 1, by converting the --BOC protective
group into the Fmoc protective group as described in the
literature.
[0239] Compounds A.sub.2 are commercially available.
[0240] 2. Alternatively compounds of formula (I) described in 1.
can be obtained:
[0241] 2a) by reacting a compound of formula (IVa)
A-(Y--X) (IVa)
wherein X is an halogen atom or tosyl group, Y is as above defined
and A is as above defined in 1b), with AgNO.sub.2 or MetalNO.sub.2
as above described in 1b).
[0242] Compounds (IVa) can be obtained by reacting compound A as
above defined in 1b), with compounds (IIIc) as above described in
1b), with a condensing reagent such as DCC or CDI as above
described in 1b);
or
[0243] 2a') alternatively compounds of formula (I) described in 1a)
can be obtained by reacting a compound of formula (Va):
A-(Y--OH) (Va)
wherein A and Y are as above defined in 1a), with triflic
anhydride/tetraalkylammonium nitrate salt in an aprotic
polar/non-polar solvent such as DMF, THF or CH.sub.2Cl.sub.2 at
temperatures range between -78.degree. to 80.degree. C.
[0244] Compounds (Va) can be obtained by reacting compound A as
defined in 1b), with compounds (IIIb) with a condensing reagent as
above described for (IIIa) in 1b).
[0245] 3. The compounds of general formula (I) wherein:
s is equal to 1; m, m', m'', s' and s'' are 0 Y is as above
defined, A is a radical of formula (IIa)-(IIm), (IIo)-(IIr),
(IIt)-(IIu) and (IIn) wherein R.sub.1 is --C(O)O--R.sub.1x and it
binds the group --Y--ONO.sub.2, R.sub.2 is --COOH; in formula (IIn)
R.sub.n is --C(O)O--R.sub.nx or --(CH.sub.3).sub.3--NH--R.sub.h
wherein R.sub.h is --C(O)O--R.sub.hh, and it binds the group
--Y--ONO.sub.2 R.sub.a of formula (IIa) is selected in group a)
R.sub.c of formula (IIc) is selected in group a') in formula (IIt)
d is an integer from 3 to 5, d' is 0; can be prepared as
follows
[0246] 3a) by reacting a compound of formula (I) wherein s, s',
s'', m, m', m'', Y, Y', Y'' are as above defined in 3, A is a
radical of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn)
wherein R.sub.2 is --C(O)OC(CH.sub.3).sub.3; R.sub.1, R.sub.a,
R.sub.c R.sub.n, R.sub.h, d and d' are as defined in 3. with
anhydrous or aqueous organic or inorganic acid to hydrolyze the
t-butyl ester following procedure well known in the literature.
[0247] 3b) by reacting a compound of formula A with a compound of
formula (IIIf)
A+Act-(O)C--O--Y--ONO.sub.2 (IIIf)
wherein A is as above reported in 1b), Y is as above reported and
Act is as above defined in 1b').
[0248] The reaction is generally carried out in presence of a
inorganic or organic base in an aprotic polar/non-polar solvent
such as DMF, THF or CH.sub.2Cl.sub.2 at temperatures range between
0.degree.-80.degree. C. or in a double phase system
H.sub.2O/Et.sub.2O at temperatures range between
20.degree.-40.degree. C.; or in the presence of DMAP and a Lewis
acid such as Sc(OTf).sub.3 or Bi(OTf).sub.3 in solvents such as
DMF, CH.sub.2Cl.sub.2. Compounds (IIIf) are obtained as described
in WO 2006/008196.
[0249] 4. The compounds of general formula (I) wherein:
s and m are equal to 1; s', s'', m', m'' are equal to 0; Y is as
above defined;
B is:
##STR00214##
[0250] A is a radical of formula (IIa)-(IIm), (IIo)-(IIr),
(IIt)-(IIu) and (IIn) wherein R.sub.1 is --H and R.sub.2 is
--C(O)OR.sub.2x and binds the group --B--Y--ONO.sub.2 in formula
(IIn) R.sub.1 is --H or is --(CH.sub.3).sub.2--NH.sub.2; R.sub.a of
formula (IIa) is selected in group a), R.sub.c of formula (IIc) is
selected in group a'), in formula (IIt) d is an integer from 3 to
5, d' is 0; can be obtained as follows:
[0251] 4a) reacting a compound of formula (I) wherein B, s, s',
s'', m, m', m'', Y, Y' and Y'' are as above defined in 4, A is a
radical of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn)
wherein R.sub.2, R.sub.a, R.sub.c, d and d' are as defined in 4,
R.sub.1 is --C(O)OC(CH.sub.3).sub.3; R.sub.n is
--C(O)OC(CH.sub.3).sub.3 or is
--(CH.sub.3).sub.3--NH--C(O)OC(CH.sub.3).sub.3;
with anhydrous or aqueous organic or inorganic acid as well known
in the literature to remove all the --BOC protective groups.
[0252] 4b) by reacting a compound of formula A with compounds of
formula (IIIg)
A+Hal-W.sub.1--C(O)O--Y--ONO.sub.2 (IIIg)
wherein Y is as above described, Hal is an halogen atom and W.sub.1
is --CH.sub.2-- or --CH(CH.sub.3)--, and A is a compound of formula
(IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein R.sub.1 is
--C(O)OC(CH.sub.3).sub.3 and R.sub.2 is --COOH; R.sub.a of formula
(IIa) is selected in group a), R.sub.c of formula (IIc) is selected
in group a'), in formula (IIt) d and d' are as above defined; in
formula (IIn) R.sub.n is --C(O)OC(CH.sub.3).sub.3 or is
--(CH.sub.3).sub.3--NH--C(O)OC(CH.sub.3).sub.3; in the presence of
a inorganic or organic base in an aprotic polar/non-polar solvent
such as DMF, THF or CH.sub.2Cl.sub.2 at temperatures range between
0.degree. to 100.degree. C. or in a double phase system
H.sub.2O/Et.sub.2O at temperatures range between 20.degree. to
40.degree. C. Compounds A as above defined are commercially
available.
[0253] The compounds of formula (IIIg) are obtained by reacting the
commercially available haloalkylhalocarbonate of formula (IIIh)
Hal-W.sub.1--OC(O)Hal (IIIh)
wherein Hal and W.sub.1 are as above defined, with a compound of
formula (IIIi)
HO--Y--ONO.sub.2 (IIIi)
wherein Y is as above defined, in the presence of a inorganic or
organic base in an aprotic polar or in an aprotic non-polar solvent
such as DMF, THF or CH.sub.2Cl.sub.2 at temperatures range between
0.degree. to 80.degree. C.
[0254] Dinitrated compounds of formula (IIIi) can be also prepared
with I.sub.2 and AgNO.sub.3 or by Sharpless oxidation and then
Nitration with Acetic anhydride and nitric acid starting from a
double bond in the chain as described in WO 2005/070868.
[0255] The compounds of formula (IIIi) are obtained by reacting
compounds of formula HO--Y--Hal (IIIj) wherein Y and Hal are as
above defined or compounds of formula HO--Y--OTs (IIIk) wherein Ts
is the tosyl group, with AgNO.sub.3 on MetalNO.sub.3 in a suitable
organic solvent such as acetonitrile or tetrahydrofuran (THF) under
nitrogen in the dark at temperatures range between
20.degree.-80.degree. C.; alternatively the reaction with
AgNO.sub.3 or MetalNO.sub.3 can be performed under microwave
irradiation in solvents such acetonitrile or THF at temperatures in
the range between about 100-180.degree. C. for time range about
1-120 min as already described in 1b)
[0256] The compounds of formula (IIIj) and (IIIk) are commercially
available or can be obtained from commercially available compounds
HO--Y--OH (IIIl) with methods well known in the literature.
[0257] 5. Alternatively compounds (I) described in 4a) can be
obtained
[0258] 5a) by reacting compounds of formula (VIa) wherein A, B and
Y have been already defined in 4. with tetraalkylammonium nitrate
and triflic anhydride as previously described
A-(B)--(Y--OH) (VIa)
Compounds (VIa) can be obtained by reacting compounds A as defined
in 4b) with compounds (IIIm):
Hal-W.sub.1--OC(O)O--Y--OH (IIIm)
Using the same procedure described in 4b). Compounds (IIIm) are
prepared from commercially available compounds
Hal-W.sub.1--OC(O)Hal (IIIh) by reacting with compounds HO--Y--OH
(IIIl) in the presence of a inorganic or organic base in an aprotic
polar or in an aprotic non-polar solvent such as DMF, THF or
CH.sub.2Cl.sub.2 at temperatures range between 0.degree. to
80.degree. C., using a ratio (IIIh)/(IIIl) 1:1.
[0259] 6. The compounds of general formula (I) wherein:
s and m are equal to 1; s', s'', m', m'' are equal to 0; Y is as
above defined;
B is:
##STR00215##
[0260] A is a radical of formula (IIa)-(IIm), (IIo)-(IIr),
(IIt)-(IIu) and (IIn) wherein R.sub.1 is --H and R.sub.2 is
--C(O)OR.sub.2x and binds the group
--B--Y--ONO.sub.2
in formula (IIn) R.sub.n is --H or is --(CH.sub.2).sub.2--NH.sub.2;
R.sub.a of formula (IIa) is selected in group a) R.sub.c of formula
(IIc) is selected in group a'), in formula (IIt) d is an integer
from 3 to 5, d' is 0; can be obtained as follows:
[0261] 6a) reacting a compound of formula (I) wherein s, s', s'',
m, m', m'', Y, Y' and Y'' are as above defined in 6, A is a radical
of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein
R.sub.2, R.sub.a, and R.sub.c, d and d' are as defined in 6,
R.sub.1 or R.sub.n is --C(O)OC(CH.sub.3).sub.3 or
--(CH.sub.2).sub.2--NH--C(O)OC(CH.sub.3).sub.3; with anhydrous or
aqueous organic or inorganic acid as well known in the literature
to remove all the --BOC protective groups.
[0262] 6b) by reacting a compound of formula A with compounds of
formula (IIIn)
A+Hal-W.sub.1--OC(O)--Y--ONO.sub.2 (IIIn)
wherein Y is as above described, Hal is an halogen atom and W.sub.1
is --CH.sub.2-- or --CH(CH.sub.3)--, and A is a compound of formula
(IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein R.sub.1 is
--C(O)OC(CH.sub.3).sub.3 and R.sub.2 is --COOH; R.sub.a of formula
(IIa) is selected in group a), R.sub.c of formula (IIc) is selected
in group a'), in formula (IIn) R.sub.n is --C(O)OC(CH.sub.3).sub.3
or is --(CH.sub.2).sub.2--NHR.sub.h wherein R.sub.h is
--C(O)OC(CH.sub.3).sub.3; in formula (IIt) d is an integer from 3
to 5, d' is 0; in the presence of a inorganic or organic base in an
aprotic polar/non-polar solvent such as DMF, THF or
CH.sub.2Cl.sub.2 at temperatures range between 0.degree. to
100.degree. C. or in a double phase system H.sub.2O/Et.sub.2O at
temperatures range between 20.degree. to 40.degree. C.
[0263] The compounds of formula (IIIn) are obtained by reacting a
compound W.sub.2--CHO, wherein W.sub.2 is H--, CH.sub.3-- with
compounds of formula (IIIe), wherein Y and Act are as above
defined, and ZnCl.sub.2 as described in the literature (Steven K.
Davidsen and al., J. Med. Chem., 37(26), 4423, 1994).
W.sub.2--CHO+ZnCl.sub.2+Act-(O)C--Y--ONO.sub.2 (IIIe)
[0264] 7. The compounds of general formula (I) wherein:
s is equal to 1; s', s'', m, m', m'' are equal to 0; Y is as above
defined; A is a radical of formula (IIa)-(IIm), (IIo)-(IIr),
(IIt)-(IIu) and (IIn) wherein R.sub.1 is --H and R.sub.2 is
--C(O)NHR.sub.2xx or --C(O)N(CH.sub.3)R.sub.2xx and R.sub.2 binds
the group --Y--ONO.sub.2 in formula (IIn) R.sub.n is --H or is
--(CH.sub.2).sub.2--NH.sub.2; R.sub.a of formula (IIa) is selected
in group a); R.sub.c of formula (IIc) is selected in group a'); in
formula (IIt) d is an integer from 3 to 5, d' is 0; can be obtained
as follows:
[0265] 7a) reacting a compound of formula (I) wherein s, s', s'',
m, m', m'', Y, Y' and Y'' are as above defined in 7, A is a radical
of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein
R.sub.2, R.sub.a R.sub.c, d and d' are as defined in 7, R.sub.1 is
--C(O)OC(CH.sub.3).sub.3; R.sub.n is --C(O)OC(CH.sub.3).sub.3 or is
--(CH.sub.2).sub.2--NHR.sub.h wherein R.sub.h is
--C(O)OC(CH.sub.3).sub.3;
with anhydrous or aqueous organic or inorganic acid as well known
in the literature to remove all the --BOC protective groups.
[0266] 7b) by reacting a compound of formula A with compounds of
formula (IIIo)
W.sub.3NH--Y--ONO.sub.2 (IIIo)
wherein Y is as above described, W.sub.3 is H or --CH.sub.3, A has
been already defined in 4b), in the presence of a condensing agent
like dicyclohexylcarbodiimide (DCC) or N,N'-carbonyldiimidazol
(CDI) or other known condensing reagents such as
O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HATU), in the presence or not of
1-Hydroxybenzotriazole (HOBT) in solvent such as DMF, THF,
chloroform at a temperature in the range from -5.degree. C. to
60.degree. C. in the presence or not of a base as for example DMAP.
Compounds (IIIo) can be prepared from compounds (IIIA), wherein Y
and W.sub.3 are as above defined by hydrolysing the BOC protecting
group as known in the literature:
(CH.sub.3).sub.3CO(O)C--NW.sub.3--Y--ONO.sub.2 (IIIP)
[0267] Compounds (IIIA) can be prepared from compounds (IIIq) or
(IIIr) wherein W.sub.3, Y, Hal and Ts are as above described, by
reacting with AgNO.sub.2 as already described for analogous
compounds:
(CH.sub.3).sub.3CO(O)C--NW.sub.2--Y--Hal (IIIq)
(CH.sub.3).sub.3CO(O)C--NW.sub.3--Y--OTs (IIIr)
Alternatively compounds (IIIA) can be prepared from compounds
(IIIs) by reacting with tetraalkylammonium nitrate as already
described for analogous compounds.
(CH.sub.3).sub.3CO(O)C--NW.sub.2--Y--OH (IIIs)
Compounds (IIIq) and (IIIr) can be prepared from compounds (IIIs)
by halogenation or tosylation as known in the literature. Compounds
(IIIs) are obtained by known methods from compounds (IIIt) that are
commercially available.
W.sub.3NH--Y--OH (IIIt)
[0268] 8. The compounds of general formula (I) wherein:
s is equal to 1; s', s'', m, m', m'' are equal to 0; Y is as above
defined;
[0269] A is a radical of formula (IIa)-(IIm), (IIo)-(IIr),
(IIt)-(IIu) and (IIn) wherein R.sub.1 is --H and R.sub.2 is
--C(O)OR.sub.2x and binds the group --Y--ONO.sub.2
in formula (IIn) R.sub.n is --H or is --(CH.sub.2).sub.2--NH.sub.2;
R.sub.a of formula (IIa) is selected in group a); R.sub.c of
formula (IIc) is selected in group a'); in formula (IIt) d is an
integer from 3 to 5, d' is 0; can be obtained as follows:
[0270] 8a) reacting a compound of formula (I) wherein s, s', s'',
m, m', m'', Y, Y' and Y'' are as above defined in 8, A is a radical
of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein
R.sub.2, R.sub.a R.sub.c d and d' are as defined in 8, R.sub.1, is
--C(O)OC(CH.sub.3).sub.3; R.sub.n is --C(O)OC(CH.sub.3).sub.3 or is
--(CH.sub.2).sub.2--NHR--C(O)OC(CH.sub.3).sub.3;
with anhydrous or aqueous organic or inorganic acid as well known
in the literature to remove all the --BOC protective groups.
[0271] 8b) by reacting a compound of formula A with compounds of
formula (IIIi)
HO--Y--ONO.sub.2 (IIIi)
wherein Y is as above described, A is a radical of formula
(IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein R.sub.1 is
--C(O)OC(CH.sub.3).sub.3; R.sub.2 is --COOH or is equal to R.sub.2a
wherein R.sub.2a is the group --COAct wherein Act is as above
described in 1b') and is a carboxylic acid activating group,
R.sub.a R.sub.c d and d' are as defined in 8, R.sub.n is
--C(O)OC(CH.sub.3).sub.3 or is
--(CH.sub.2).sub.2--NHR--C(O)OC(CH.sub.3).sub.3; in the presence of
a condensing agent such as dicyclohexylcarbodiimide (DCC) or
N,N'-carbonyldiimidazol (CDI) or other known condensing reagents
such as O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HATU), in the presence or not of
1-Hydroxybenzotriazole (HOBT) in solvent such as DMF, THF,
chloroform at a temperature in the range from -5.degree. C. to
60.degree. C. in the presence or not of a base as for example DMAP
when R.sub.2 is --COOH; or in the presence of equimolar amount of
DMAP in solvent such as DMF, THF, chloroform at a temperature in
the range from -5.degree. C. to 60.degree. C. when R.sub.2 is equal
to R.sub.2a.
[0272] 9. Alternatively the compounds of formula (I) as defined in
8a) can be obtained as follow:
[0273] 9a) reacting a compound of formula (IVb)
A-Y--X (IVb)
wherein Y is as above defined and A is as above defined in 8a) and
X is an halogen atom or a tosyl group, by reacting with AgNO.sub.2
or MetalNO.sub.2 as above described. Compounds (IVb) can be
obtained by reacting compound A defined as above in 6b), with
compounds (IIIj) or (IIIk)
HO--Y--Hal (IIIj)
HO--Y--OTs (IIIk)
with a condensing reagent such as DCC or CDI or HATU as above
defined in 6b).
[0274] 10. Alternatively the compounds of formula (I) as defined in
8a) can be obtained
[0275] 10a) by reacting a compound of formula (Vb)
A-Y--OH (Vb)
wherein Y is as above defined, and A is as already defined in 8a)
with triflic anhydride/tetraalkylammonium nitrate as already
described. Compounds (Vb) can be obtained by reacting compounds A
as above described in 8b) with a compound of formula HO--Y--OH
(IIIl) with a condensing reagent such as DCC or CDI or HATU as
above defined in 8b) using a ratio A/(IIIl) 1:1.
[0276] 11. The compounds of general formula (I) wherein:
s and s' are equal to 1; s'', m, m', m'', are 0 Y, Y' can be equal
or different and are as above defined, A is selected from
(IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein: R.sub.1 is
--C(O)--R.sub.1x and binds the group --Y--ONO.sub.2, R.sub.2 is
--C(O)OR.sub.2x and binds the group --Y'--ONO.sub.2; in formula
(IIn) R.sub.n is --C(O)--R.sub.nx or
--(CH.sub.2).sub.2--NH--R.sub.h wherein R.sub.h is
--C(O)--R.sub.hh, R.sup.n or R.sub.h binds the group
--Y--ONO.sub.2; R.sub.a of formula (IIa) is selected in group a);
R.sub.c of formula (IIc) is selected in group a'); in formula (IIt)
d is an integer from 3 to 5, d' is 0; can be prepared as
follows:
[0277] 11a) by reacting compounds of formula (I) as defined in 1,
obtained with the procedure described in 1. with compounds
(IIIi)
##STR00216##
Wherein Y and Y' are equal or different and are as above defined
and A has the following meanings: A is a radical of formula
(IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein R.sub.1 is
--C(O)--R.sub.1x and binds the group --Y--ONO.sub.2, R.sub.2 is
--COOH; in formula (IIn) R.sub.n is --C(O)--R.sub.nx or
--(CH.sub.2).sub.2--NH--R.sub.h wherein R.sub.h is
--C(O)--R.sub.hh, R.sub.n or R.sub.h binds the group
--Y--ONO.sub.2; R.sub.a of formula (IIa) is selected in group a);
R.sub.c of formula (IIc) is selected in group a'); in formula (IIt)
d is an integer from 3 to 5, d' is 0; using the same procedure
described in 8b).
[0278] 12. The compounds of general formula (I) wherein:
s and s' are equal to 1; s'', m, m', m'', are 0 Y, Y' can be equal
or different and are as above defined, A is a radical of formula
(IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein R.sub.1 is
--C(O)O--R.sub.1x and binds the group --Y--ONO.sub.2, R.sub.2 is
--C(O)OR.sub.2x and R.sub.2 binds the group --Y'--ONO.sub.2; in
formula (IIn) R.sub.n is --C(O)O--R.sub.nx or
--(CH.sub.2).sub.2--NH--R.sub.h wherein R.sub.h is
--C(O)O--R.sub.hh, R.sub.n or R.sub.h binds the group
--Y--ONO.sub.2; R.sub.a of formula (IIa) is selected in group a),
R.sub.c of formula (IIc) is selected in group a'); in formula (IIt)
d is an integer from 3 to 5, d' is 0; can be prepared as
follows:
[0279] 12a) by reacting compounds of formula (I) obtained with the
procedure described in 3. with compounds (IIIi)
##STR00217##
Wherein Y and Y' are equal or different and are as above defined
and A has the following meanings: A is a radical of formula
(IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein R.sub.1 is
--C(O)O--R.sub.1x and binds the group --Y--ONO.sub.2, R.sub.2 is
--COOH; in formula (IIn) R.sub.n is --C(O)O--R.sub.nx or
--(CH.sub.2).sub.2--NH--R.sub.h wherein R.sub.h is
--C(O)O--R.sub.hh, R.sub.n or R.sub.h binds the group
--Y--ONO.sub.2; R.sub.a of formula (IIa) is selected in group a);
R.sub.c of formula (IIc) is selected in group a'); in formula (IIt)
d is an integer from 3 to 5, d' is 0; using the same procedure
described in 8b).
[0280] 13. The compounds of general formula (I) wherein:
s and s' are equal to 1; s'', m, m', m'', are 0 Y, Y' can be equal
or different and are as above defined, A is selected from
(IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein: R.sub.1 is
--C(O)--R.sub.1x and binds the group --Y--ONO.sub.2, R.sub.2 is
--C(O)NHR.sub.2xx or --C(O)N(CH.sub.3)R.sub.2xx and binds the group
--Y'--ONO.sub.2; in formula (IIn) R.sub.n is --C(O)--R.sub.nx or
--(CH.sub.2).sub.2--NH--R.sub.h wherein R.sub.h is
--C(O)--R.sub.hh, R.sub.n, or R.sub.h binds the group
--Y--ONO.sub.2; R.sub.a of formula (IIa) is selected in group a);
R.sub.c of formula (IIc) is selected in group a'); in formula (IIt)
d is an integer from 3 to 5, d' is 0; can be prepared as
follows:
[0281] 13a) by reacting compounds of formula (I) obtained with the
procedure described in 1. with compounds (IIIo)
##STR00218##
Wherein Y and Y' are equal or different and are as above defined,
W.sub.3 is as above defined and A has the following meanings: A is
a radical of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and
(IIn) wherein R.sub.1 is --C(O)--R.sub.1x and binds the group
--Y--ONO.sub.2, R.sub.2 is --COOH; in formula (IIn) R.sub.n is
--C(O)--R.sub.nx or --(CH.sub.2).sub.2--NH--R.sub.h wherein R.sub.h
is --C(O)--R.sub.hh, R.sub.n, or R.sub.h binds the group
--Y--ONO.sub.2; R.sub.a of formula (IIa) is selected in group a);
R.sub.c of formula (IIc) is selected in group a'); in formula (IIt)
d is an integer from 3 to 5, d' is 0; using the same procedure
described in 7b).
[0282] 14. The compounds of general formula (I) wherein:
s and s' are equal to 1; s'', m, m', m'', are 0 Y, Y' can be equal
or different and are as above defined, A is a radical of formula
(IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein R.sub.1 is
--C(O)O--R.sub.1x and R.sub.1 binds the group --Y--ONO.sub.2,
R.sub.2 is --C(O)NHR.sub.2xx or --C(O)N(CH.sub.3)R.sub.2xx and
R.sub.2 binds the group --Y'--ONO.sub.2; in formula (IIn) R.sub.n
is --C(O)O--R.sub.nx or --(CH.sub.2).sub.2--NH--R.sub.h wherein
R.sub.h is --C(O)O--R.sub.hh, R.sub.n, or R.sub.h binds the group
--Y--ONO.sub.2; R.sub.a of formula (IIa) is selected in group a),
R.sub.c of formula (IIc) is selected in group a'); in formula (IIt)
d is an integer from 3 to 5, d' is 0; can be prepared as
follows:
[0283] 14a) by reacting compounds of formula (I) obtained with the
procedure described in 3. with compounds (IIIo)
##STR00219##
Wherein Y and Y' are equal or different and are as above defined,
W.sub.3 is as above defined and A has the following meanings: A is
a radical of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and
(IIn) wherein R.sub.1 is --C(O)O--R.sub.1x and binds the group
--Y--ONO.sub.2, R.sub.2 is --COOH; in formula (IIn) R.sub.n is
--C(O)O--R.sub.nx or --(CH.sub.2).sub.2--NH--R.sub.h wherein
R.sub.h is --C(O)O--R.sub.hh, R.sub.n, or R.sub.h binds the group
--Y--ONO.sub.2; R.sub.a of formula (IIa) is selected in group a);
R.sub.c of formula (IIc) is selected in group a'); in formula (IIt)
d is an integer from 3 to 5, d' is 0; using the same procedure
described in 7b).
[0284] 15. The compounds of general formula (I) wherein:
s, s' and m' are equal to 1; s'', m, m'', are 0 Y, Y' can be equal
or different and are as above defined;
B is:
##STR00220##
[0285] A is selected from (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and
(IIn) wherein: R.sub.1 is --C(O)--R.sub.1x and binds the group
--Y--ONO.sub.2, R.sub.2 is --C(O)OR.sub.2x and R.sub.2 binds the
group --B--Y'--ONO.sub.2; in formula (IIn) R.sub.n is
--C(O)--R.sub.nx or --(CH.sub.2).sub.2--NH--R.sub.h wherein R.sub.h
is --C(O)--R.sub.hh, R.sub.n, or R.sub.h binds the group
--Y--ONO.sub.2; R.sub.a of formula (IIa) is selected in group a),
R.sub.c of formula (IIc) is selected in group a'), in formula (IIt)
d is an integer from 3 to 5, d' is 0; can be prepared as
follows:
[0286] 15a) By reacting compounds of formula (I) obtained with the
procedure described in 1. with compounds (IIIg)
A-Y--ONO.sub.2+Hal-W.sub.1--OC(O)O--Y--ONO.sub.2 (IIIg)
wherein Y is as above described, Hal is an halogen atom and W.sub.1
is --CH.sub.2-- or --CH(CH.sub.3)--, and A has the following
meanings: A is a radical of formula (IIa)-(IIm), (IIo)-(IIr),
(IIt)-(IIu) and (IIn) wherein R.sub.1 is --C(O)--R.sub.1x-- and
binds the group --Y--ONO.sub.2, R.sub.2 is --COOH; in formula (IIn)
R.sub.n is --C(O)--R.sub.nx or --(CH.sub.2).sub.2--NH--R.sub.h
wherein R.sub.h is --C(O)--R.sub.hh, R.sub.n, or R.sub.h binds the
group --Y--ONO.sub.2; R.sub.a of formula (IIa) is selected in group
a); R.sub.c of formula (IIc) is selected in group a'), in formula
(IIt) d is an integer from 3 to 5, d' is 0; using the same
procedure described in 4b).
[0287] 16. The compounds of general formula (I) wherein:
s, s' and m' are equal to 1; s'', m, m'', are 0 Y, Y' can be equal
or different and are as above defined;
B is:
##STR00221##
[0288] A is selected from (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and
(IIn) wherein: R.sub.1 is --C(O)--R.sub.1x and binds the group
--Y--ONO.sub.2, R.sub.2 is --C(O)OR.sub.2x and binds the group
--B--Y'--ONO.sub.2; in formula (IIn) R.sub.n is --C(O)--R.sub.nx or
--(CH.sub.2).sub.2--NH--R.sub.h wherein R.sub.h is
--C(O)--R.sub.hh, R.sub.n, or R.sub.h binds the group
--Y--ONO.sub.2; R.sub.a of formula (IIa) is selected in group a),
R.sub.c of formula (IIc) is selected in group a'), in formula (IIt)
d is an integer from 3 to 5, d' is 0; can be prepared as
follows:
[0289] 16a) by reacting compounds of formula (I) obtained with the
procedure described in 1. with compounds (IIIn)
##STR00222##
wherein Y is as above described, Hal is an halogen atom and W.sub.1
is --CH.sub.2-- or --CH(CH.sub.3)--, and A has the following
meanings: A is a radical of formula (IIa)-(IIm), (IIo)-(IIr),
(IIt)-(IIu) and (IIn) wherein R.sub.1 is --C(O)--R.sub.1x-- and
binds the group --Y--ONO.sub.2, R.sub.2 is --COOH; in formula (IIn)
R.sub.n is --C(O)--R.sub.nx or --(CH.sub.2).sub.2--NH--R.sub.h
wherein R.sub.h is --C(O)--R.sub.hh, R.sub.n, or R.sub.h binds the
group --Y--ONO.sub.2; R.sub.a of formula (IIa) is selected in group
a); R.sub.c of formula (IIc) is selected in group a'); in formula
(IIt) d is an integer from 3 to 5, d' is 0; using the same
procedure described in 6b).
[0290] 17. The compounds of general formula wherein:
s, s' and m' are equal to 1; s'', m, m'', are 0 Y, Y' can be equal
or different and are as above defined;
B is:
##STR00223##
[0291] A is a radical of formula (IIa)-(IIm), (IIo)-(IIr),
(IIt)-(IIu) and (IIn) wherein R.sub.1 is --C(O)O--R.sub.1x and
R.sub.2 is --C(O)OR.sub.2x and R.sub.1 binds the group
--Y--ONO.sub.2 and R.sub.2 binds the group --B--Y'--ONO.sub.2; in
formula (IIn) R.sub.n is --C(O)O--R.sub.nx or
--(CH.sub.2).sub.2--NH--R.sub.h wherein R.sub.h is
--C(O)O--R.sub.hh, R.sub.n, or R.sub.h binds the group
--Y--ONO.sub.2; R.sub.a of formula (IIa) is selected in group a),
R.sub.c of formula (IIc) is selected in group a') in formula (IIt)
d is an integer from 3 to 5, d' is 0; can be prepared as
follows:
[0292] 17a) by reacting compounds of formula (I) obtained with the
procedure described in 3. with compounds (IIIg)
##STR00224##
wherein Y is as above described, Hal is an halogen atom and W.sub.1
is --CH.sub.2-- or --CH(CH.sub.3)--, and A has the following
meanings: A is a radical of formula (IIa)-(IIm), (IIo)-(IIr),
(IIt)-(IIu) and (IIn) wherein R.sub.1 is --C(O)O--R.sub.1x-- and
binds the group --Y--ONO.sub.2,
R.sub.2 is --COOH;
[0293] in formula (IIn) R.sub.n is --C(O)O--R.sub.nx, or is
--(CH.sub.2).sub.2--NH--R.sub.h wherein R.sub.h is
--C(O)O--R.sub.hh, R.sub.n, or R.sub.h binds the group
--Y--ONO.sub.2; R.sub.a of formula (IIa) is selected in group a);
R.sub.c of formula (IIc) is selected in group a'), in formula (IIt)
d is an integer from 3 to 5, d' is 0; using the same procedure
described in 4b).
[0294] 18. The compounds of general formula (I) wherein:
s, s' and m' are equal to 1; s'', m, m'', are 0 Y, Y' can be equal
or different and are as above defined;
B is:
##STR00225##
[0295] A is a radical of formula (IIa)-(IIm), (IIo)-(IIr),
(IIt)-(IIu) and (IIn) wherein R.sub.1 is --C(O)O--R.sub.1x and
R.sub.2 is --C(O)OR.sub.2x and R.sub.1 binds the group
--Y--ONO.sub.2 and R.sub.2 binds the group --B--Y'--ONO.sub.2; in
formula (IIn) R.sub.n is --C(O)O--R.sub.nx or
--(CH.sub.2).sub.2--NH--R.sub.h wherein R.sub.h is
--C(O)O--R.sub.hh, R.sub.n, or R.sub.h binds the group
--Y--ONO.sub.2; R.sub.a of formula (IIa) is selected in group a),
R.sub.c of formula (IIc) is selected in group a'); in formula (IIt)
d is an integer from 3 to 5, d' is 0; can be prepared as
follows:
[0296] 18a) By reacting compounds of formula (I) obtained with the
procedure described in 3. with compounds (IIIn)
##STR00226##
wherein Y is as above described, Hal is an halogen atom and W.sub.1
is --CH.sub.2-- or --CH(CH.sub.3)--, and A has the following
meanings: A is a radical of formula (IIa)-(IIm), (IIo)-(IIr),
(IIt)-(IIu) and (IIn) wherein R.sub.1 is --C(O)O--R.sub.1x-- and
binds the group --Y--ONO.sub.2, R.sub.2 is --COOH; in formula (IIn)
R.sub.n is --C(O)O--R.sub.nx, or is --(CH.sub.2).sub.2--NH--R.sub.h
wherein R.sub.h is --C(O)O--R.sub.hh, R.sub.n, or R.sub.h binds the
group --Y--ONO.sub.2; R.sub.a of formula (IIa) is selected in group
a); R.sub.c of formula (IIc) is selected in group a'); in formula
(IIt) d is an integer from 3 to 5, d' is 0; using the same
procedure described in 6b).
[0297] 19. Alternatively the compounds of general formula (I)
described in procedure 11. wherein:
s and s' are equal to 1; s'', m, m', m'', are 0 Y, Y' can be equal
or different and are as above defined, A is a radical of formula
(IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein R.sub.1 is
--C(O)--R.sub.1x and R.sub.2 is --C(O)OR.sub.2x and R.sub.2 binds
the group --Y--ONO.sub.2 and R.sub.1 binds the group
--Y'--ONO.sub.2; in formula (IIn) R.sub.n is --C(O)--R.sub.nx, or
is --(CH.sub.2).sub.2--NH--R.sub.h, wherein R.sub.h is
--C(O)--R.sub.hh, R.sub.n, or R.sub.h binds the group
--Y'--ONO.sub.2; R.sub.a of formula (IIa) is selected in group a),
R.sub.c of formula (IIc) is selected in group a'); in formula (IIt)
d is an integer from 3 to 5, d' is 0; can be prepared as
follows:
[0298] 19a) By reacting compounds of formula (I) obtained with the
procedure described in 8. with compounds (IIIa) or (IIIe)
##STR00227##
Wherein Y and Y' are equal or different and are as above defined,
Act is as above defined and A has the following meanings: A is a
radical of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn)
wherein R.sub.2 is --C(O)OR.sub.2x and binds the group
--Y--ONO.sub.2, R.sub.1 is --H; in formula (IIn) R.sub.n is --H or
is --(CH.sub.2).sub.2--NH.sub.2; R.sub.a of formula (IIa) is
selected in group a); R.sub.c of formula (IIc) is selected in group
a'); in formula (IIt) d is an integer from 3 to 5, d' is 0; using
the same procedure described in 1b) or 1b').
[0299] 20. Alternatively the compounds of general formula (I)
described in procedure 12, wherein:
s and s' are equal to 1; s'', m, m', m'', are 0 Y, Y' can be equal
or different and are as above defined, A is selected from
(IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein: R.sub.1 is
--C(O)O--R.sub.1x and R.sub.2 is --C(O)OR.sub.2x and R.sub.2 binds
the group --Y--ONO.sub.2 and R.sub.1 binds the group
--Y'--ONO.sub.2; in formula (IIn) R.sub.n is --C(O)O--R.sub.nx or
--(CH.sub.2).sub.2--NH--R.sub.h wherein R.sub.h is
--C(O)O--R.sub.hh, R.sub.n, or R.sub.h binds the group
--Y'--ONO.sub.2; R.sub.a of formula (IIa) is selected in group a),
R.sub.c of formula (IIc) is selected in group a'); in formula (IIt)
d is an integer from 3 to 5, d' is 0; can be prepared as
follows:
[0300] 20a) By reacting compounds of formula (I) obtained with the
procedure described in 8. with compounds (IIIf)
##STR00228##
Wherein Y and Y' are equal or different and are as above defined
and A has the following meanings: A is a radical of formula
(IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein R.sub.2 is
--C(O)OR.sub.2x and binds the group --Y--ONO.sub.2, R.sub.1 is --H;
in formula (IIn) R.sub.n is --H or is --(CH.sub.2).sub.2--NH.sub.2;
R.sub.a of formula (IIa) is selected in group a); R.sub.c of
formula (IIc) is selected in group a'), in formula (IIt) d is an
integer from 3 to 5, d' is 0; using the same procedure described in
3b).
[0301] 21. Alternatively the compounds of general formula (I)
described in procedure 13. wherein:
s and s' are equal to 1; s'', m, m', m'', are 0 Y, Y' can be equal
or different and are as above defined, A is selected from
(IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein: R.sub.1 is
--C(O)--R.sub.1x and R.sub.2 is --C(O)NHR.sub.2xx or
--C(O)NCH.sub.3--R.sub.2xx and R.sub.2 binds the group
--Y--ONO.sub.2 and R.sub.1 binds the group --Y'--ONO.sub.2; in
formula (IIn) R.sub.n is --C(O)--R.sub.nx, or is
--(CH.sub.2).sub.2--NH--R.sub.h wherein R.sub.h is
--C(O)--R.sub.hh, R.sub.n, or R.sub.h binds the group
--Y'--ONO.sub.2; R.sub.a of formula (IIa) is selected in group a),
R.sub.c of formula (IIc) is selected in group a'); in formula (IIt)
d is an integer from 3 to 5, d' is 0; can be prepared as
follows:
[0302] 21a) By reacting compounds of formula (I) obtained with the
procedure described in 7. with compounds (IIIa) or (IIIe)
##STR00229##
wherein Y and Y' are equal or different and are as above defined,
Act is as above defined and A has the following meanings: A is a
radical of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn)
wherein R.sub.2 is --C(O)NHR.sub.2xx or --C(O)N(CH.sub.3)R.sub.2xx
and binds the group --Y--ONO.sub.2, R.sub.1 is --H; in formula
(IIn) R.sub.n is --H or is --(CH.sub.2).sub.2--NH.sub.2; R.sub.a of
formula (IIa) is selected in group a); R.sub.c of formula (IIc) is
selected in group a'); in formula (IIt) d is an integer from 3 to
5, d' is 0; using the same procedure described in 1b) or 1b').
[0303] 22. Alternatively the compounds of general formula (I)
wherein:
s and s' are equal to 1; s'', m, m', m'', are 0, Y, Y' can be equal
or different and are as above defined, A is a radical of formula
(IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein R.sub.1 is
--C(O)O--R.sub.1x and R.sub.2 is --C(O)NHR.sub.2xx or
--C(O)N(CH.sub.3)R.sub.2xx and R.sub.2 binds the group
--Y--ONO.sub.2 and R.sub.1 binds the group --Y'--ONO.sub.2; in
formula (IIn) R.sub.n is --C(O)O--R.sub.n, or
--(CH.sub.2).sub.2--NH--R.sub.h wherein R.sub.h is
--C(O)O--R.sub.hh, R.sub.n, or R.sub.h binds the group
--Y'--ONO.sub.2; R.sub.a of formula (IIa) is selected in group a),
R.sub.c of formula (IIc) is selected in group a') in formula (IIt)
d is an integer from 3 to 5, d' is 0; can be prepared as
follows:
[0304] 22a) By reacting compounds of formula (I) obtained with the
procedure described in 7. with compounds (IIIf)
##STR00230##
wherein Y and Y' are equal or different and are as above defined
and A has the following meanings: A is a radical of formula
(IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein R.sub.2 is
--C(O)NHR.sub.2xx or --C(O)N(CH.sub.3)R.sub.2xx and binds the group
--Y--ONO.sub.2, R.sub.1 is --H; in formula (IIn) R.sub.n is --H or
is --(CH.sub.2).sub.2--NH.sub.2; R.sub.a of formula (IIa) is
selected in group a); R.sub.c of formula (IIc) is selected in group
a'), in formula (IIt) d is an integer from 3 to 5, d' is 0; using
the same procedure described in 3b).
[0305] 23. Alternatively the compounds of general formula (I)
wherein:
s, s' and m are equal to 1; s'', m', m'', are 0 Y, Y' can be equal
or different and are as above defined;
B is:
##STR00231##
[0306] A is selected from (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and
(IIn) wherein: R.sub.1 is --C(O)--R.sub.1x and R.sub.2 is
--C(O)OR.sub.2x and R.sub.2 binds the group --B--Y--ONO.sub.2 and
R.sub.1 binds the group --Y'--ONO.sub.2; in formula (IIn) R.sub.n
is --C(O)--R.sub.nx, or is --(CH.sub.2).sub.2--NH--R.sub.h wherein
R.sub.h is --C(O)--R.sub.hh, R.sub.n, or R.sub.h binds the group
--Y'--ONO.sub.2; R.sub.a of formula (IIa) is selected in group a),
R.sub.c of formula (IIc) is selected in group a'), in formula (IIt)
d is an integer from 3 to 5, d' is 0; can be prepared as
follows:
[0307] 23a) By reacting compounds of formula (I) obtained with the
procedure described in 4. or 6. with compounds (IIIa) or (IIIe)
##STR00232##
wherein Y, and Y' are equal or different and are as above defined,
Act and B are as above described and A has the following meanings:
A is a radical of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and
(IIn) wherein R.sub.1 is --H, R.sub.2 is --C(O)OR.sub.2x and
R.sub.2 binds the group --B--Y--ONO.sub.2 in formula (IIn) R.sub.n
is --H or is --(CH.sub.2).sub.2--NH.sub.2; R.sub.a of formula (IIa)
is selected in group a); R.sub.c of formula (IIc) is selected in
group a'), in formula (IIt) d is an integer from 3 to 5, d' is 0;
using the same procedure described in 1b) or 1b').
[0308] 24. Alternatively the compounds of general formula (I)
wherein:
s, s' and m are equal to 1; s'', m', m'', are 0 Y, Y' can be equal
or different and are as above defined;
B is:
##STR00233##
[0309] A is a radical of formula (IIa)-(IIm), (IIo)-(IIr),
(IIt)-(IIu) and (IIn) wherein R.sub.1 is --C(O)O--R.sub.1x and
R.sub.2 is --C(O)OR.sub.2x and R.sub.2 binds the group
--B--Y--ONO.sub.2 and R.sub.1 binds the group --Y'--ONO.sub.2; in
formula (IIn) R.sub.n is --C(O)O--R.sub.nx or
--(CH.sub.2).sub.2--NH--R.sub.h wherein R.sub.h is
--C(O)O--R.sub.hh, R.sub.n, or R.sub.h binds the group
--Y'--ONO.sub.2; R.sub.a of formula (IIa) is selected in group a),
R.sub.c of formula (IIc) is selected in group a'); in formula (IIt)
d is an integer from 3 to 5, d' is 0; can be prepared as
follows:
[0310] 24a) by reacting compounds of formula (I) obtained with the
procedure described in 4. or 6. depending on the meanings of B with
compounds (IIIf)
##STR00234##
wherein Y, and Y' are equal or different and are as above defined,
Act is as above described and A has the following meanings: A is a
radical of formula (IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn)
wherein R.sub.1 is --H, R.sub.2 is --C(O)OR.sub.2x and binds the
group --B--Y--ONO.sub.2
B is:
##STR00235##
[0311] in formula (IIn) R.sub.n is --H or is
--(CH.sub.2).sub.2--NH.sub.2; R.sub.a of formula (IIa) is selected
in group a); R.sub.c of formula (IIc) is selected in group a'), in
formula (IIt) d is an integer from 3 to 5, d' is 0; using the same
procedure described in 3b).
[0312] 25. The compounds of general formula (I) wherein:
s, is equal to 1; s' s'', m, m', m'', are 0 Y is as above defined;
A is a radical of formula (IIs) wherein R.sub.1 is --C(O)--R.sub.1x
and it binds the group --Y--ONO.sub.2, R.sub.3 is --OH and R.sub.s
is selected in group a''), can be prepared as follows
[0313] 25a) by reacting compounds of formula A with a compound of
formula (IIIa) or (IIIe):
HOOC--Y--ONO.sub.2 (IIIa)
ActOC--Y--ONO.sub.2 (IIIe)
wherein Y is as above defined, Act is as above described and A is a
compound of formula (IIs) wherein R.sub.1 is --H, R.sub.3 is --OH
and R.sub.s is selected in group a''), using the same procedure
described in 1b) or 1b') using a ratio A/(IIIa) or A/(IIIe)
1:1.
[0314] Compounds A are commercially available.
[0315] 26. The compounds of general formula (I) wherein:
s is equal to 1; s', s'', m, m', m'', are 0 Y is as above defined;
A is a radical of formula (IIs) wherein R.sub.1 is
--C(O)O--R.sub.1x and it binds the group --Y--ONO.sub.2, R.sub.3 is
--OH and R.sub.s is selected in group a''), can be prepared as
follows:
[0316] 26a) by reacting compounds of formula A with a compound of
formula (IIIf):
Act-(O)C--O--Y--ONO.sub.2 (IIIf)
wherein Y is as above defined, Act is as above described and A is a
compound of formula (IIs) described in 25a) wherein R.sub.1 is --H,
R.sub.3 is --OH and R.sub.s is selected in group a''), using the
same procedure described in 3b) using a ratio A/(IIIf) 1:1.
[0317] 27. The compounds of general formula (I) wherein:
s is equal to 1; s', s'', m, m', m'', are 0 Y is as above defined;
A is a radical of formula (IIs) wherein R.sub.3 is
--OC(O)--R.sub.3x and it binds the group --Y--ONO.sub.2; R.sub.1 is
--H and R.sub.s is selected in group a''), can be prepared as
follows:
[0318] 27a) by reacting compounds of formula (I) wherein s, s',
s'', m, m', m'', Y, Y', Y'' are as above defined in 27, A is a
radical of formula (IIs) R.sub.1 is --C(O)OC(CH.sub.3).sub.3;
R.sub.3, and R.sub.s are as defined in 27; with anhydrous or
aqueous organic or inorganic acid to hydrolyze the --BOC protective
groups following procedure well known in the literature.
[0319] 27b) by reacting a compound of formula A with a compound of
formula (IIIe)
Act-(O)C--Y--ONO.sub.2 (IIIe)
wherein Y and Act are as above defined; A is a compound of formula
(IIs) wherein R.sub.1 is --C(O)OC(CH.sub.3).sub.3, R.sub.3 is --OH
and R.sub.s is selected in group a''), using the same procedure
described in 1b'). Compounds A are commercially available.
[0320] 28. The compounds of general formula (I) wherein:
s is equal to 1; s', s'', m, m', m'', are 0 Y is as above defined;
A is a radical of formula (IIs) wherein R.sub.3 is
--OC(O)O--R.sub.3x and it binds the group --Y--ONO.sub.2; R.sub.1
is --H and R.sub.1 is selected in group a''), can be prepared as
follows:
[0321] 28a) by reacting compounds of formula (I) wherein s, s',
s'', m, m', m'', Y, Y', Y'' are as above defined in 28, A is a
radical of formula (IIs) R.sub.1 is --C(O)OC(CH.sub.3).sub.3;
R.sub.3 and R.sub.s are as defined in 28. with anhydrous or aqueous
organic or inorganic acid to hydrolyze the --BOC protective groups
following procedure well known in the literature.
[0322] 28b) By reacting a compound of formula A with a compound of
formula (IIIf)
Act-(O)C--O--Y--ONO.sub.2 (IIIf)
wherein Y and Act are as above defined; A is a compound of formula
(IIs) described in 27a) wherein R.sub.1 is
--C(O)OC(CH.sub.3).sub.3, R.sub.3 is --OH and R.sub.s is selected
in group a''), using the same procedure described in 3b)
[0323] 29. The compounds of general formula (I) wherein:
s is equal to 1; s', s'', m, m', m'', are 0 Y is as above defined;
A is a radical of formula (IIs) wherein R.sub.3 is
--OC(O)--NH--R.sub.3x-- and it binds the group --Y--ONO.sub.2;
R.sub.1 is --H and R.sub.s is selected in group a''), can be
prepared as follows:
[0324] 29a) by reacting compounds of formula (I) wherein s, s',
s'', m, m', m'', Y, Y', Y'' are as above defined in 29, A is a
radical of formula (IIs) R.sub.1 is --C(O)OC(CH.sub.3).sub.3;
R.sub.3 and R.sub.s are as defined in 29. with anhydrous or aqueous
organic or inorganic acid to hydrolyze the --BOC protective groups
following procedure well known in the literature.
[0325] 29b) by reacting a compound of formula A with a compound of
formula (IIIu)
Act-(O)C--NH--Y--ONO.sub.2 (IIIu)
wherein Y and Act are as above defined; A is a compound of formula
(IIs) described in 27b) wherein R.sub.1 is
--C(O)OC(CH.sub.3).sub.3, R.sub.3 is --OH and R.sub.1 is selected
in group a''), in the presence of a inorganic or organic base in an
aprotic polar/non-polar solvent such as DMF, THF or
CH.sub.2Cl.sub.2 at temperatures range between
0.degree.-100.degree. C. for time range of 1-60 hrs, or under
microwave irradiation in the presence of DMAP and a Lewis acid such
as Sc(OTf).sub.3 or Bi(OTf).sub.3 in solvents such as DMF,
CH.sub.2Cl.sub.2 at temperatures range between
60.degree.-120.degree. C. for time range of 1-120 min;
[0326] Compounds (IIIu) can be prepared from compounds
Act-(O)C--NH--Y--OH (IIIu) by nitrating reactions with
tetraalkylammonium nitrate as already described. Compounds (IIIu)
can be prepared from commercially available Act-CO-Hal (IIIw) and
compounds W.sub.3NH--Y--OH (IIIt) with the proviso that in (IIIt)
W.sub.3 has only the meaning of --H.
[0327] 30. The compounds of general formula (I) wherein:
s and s' are equal to 1; s'', m, m', m'', are 0 Y and Y' are equal
or different and are as above defined; A is a radical of formula
(IIs) wherein R.sub.3 is --C(O)--R.sub.3x and it binds the group
--Y--ONO.sub.2 or the group --Y'--ONO.sub.2; R.sub.1 is
--C(O)--R.sub.1x and it binds the group --Y--ONO.sub.2 or the group
--Y'--ONO.sub.2; R.sub.s is selected in group a''), can be prepared
as follows:
[0328] 30a) Y and Y' are equal
by reacting compounds of formula A described in 25a) with a
compound of formula (IIIe)
Act-(O)C--Y--ONO.sub.2 (IIIe)
wherein Y and Act are as above defined; A is a compound of formula
(IIs) wherein R.sub.1 is --H, R.sub.3 is --OH and R.sub.s is
selected in group a''), using a ratio A/(IIIe) 1:2 and applying the
same procedure described in 1b').
[0329] 30a') Y and Y' are equal or different
by reacting compounds of formula (I) prepared in 25. with a
compound of formula (IIIe)
A-Y--ONO.sub.2+Act-(O)C--Y'--ONO.sub.2 (IIIe)
wherein Y, Y' and Act are as above defined; A is a compound of
formula (IIs) wherein R.sub.1 is --C(O)--R.sub.1x and binds the
group --Y--ONO.sub.2, R.sub.3 is --OH and R.sub.s is selected in
group a''), applying the same procedure described in 1b').
[0330] 30a'') Y and Y' are equal or different
by reacting compounds of formula (I) prepared in 27. with a
compound of formula (IIIe)
A-Y--ONO.sub.2+Act-(O)C--Y'--ONO.sub.2 (IIIe)
wherein Y, Y' and Act are as above defined; A is selected from
(IIs) wherein R.sub.1 is --H, and R.sub.3 is --C(O)--R.sub.3x and
R.sub.s is selected in group a''), applying the same procedure
described in 1b').
[0331] 31. The compounds of general formula (I) wherein:
s and s' are equal to 1; s'', m, m', m'', are 0 Y and Y' are equal
or different and are as above defined; A is a radical of formula
(IIs) wherein R.sub.3 is --C(O)O--R.sub.3x-- and it binds the group
--Y--ONO.sub.2 or the group --Y'--ONO.sub.2; R.sub.1 is
--C(O)--R.sub.1x and it binds the group --Y--ONO.sub.2 or the group
--Y'--ONO.sub.2, R.sub.s is selected in group a''), can be prepared
as follows:
[0332] 31a) by reacting compounds of formula (I) obtained in
procedure 25. with a compound of formula (IIIf)
A-Y--ONO.sub.2+Act-(O)C--O--Y'--ONO.sub.2 (IIIf)
wherein Y, Y' and Act are as above defined; A is a radical of
formula (IIs) wherein R.sub.1 is --C(O)--R.sub.1x and it binds the
group --Y--ONO.sub.2, R.sub.3 is --OH and R.sub.s is selected in
group a''), applying the same procedure described in 28b).
[0333] 31a') alternatively by reacting compounds of formula (I)
prepared as described in 28. with a compound of formula (IIIe)
A-Y--ONO.sub.2+Act-(O)C--Y'--ONO.sub.2 (IIIe)
wherein Y, Y' and Act are as above defined; A is the radical of
formula (IIs) wherein R.sub.1 is --H, R.sub.3 is --C(O)O--R.sub.3x
and R.sub.3 binds the group --Y--ONO.sub.2, R.sub.s is selected in
group a''), applying the same procedure described in 25a).
[0334] 32. The compounds of general formula (I) wherein:
s and s' are equal to 1; s'', m, m', m'', are 0 Y and Y' are equal
or different and are as above defined; A is a radical of formula
(IIs) wherein R.sub.3 is --C(O)--NH--R.sub.3x and it binds the
group --Y--ONO.sub.2; R.sub.1 is --C(O)--R.sub.1x and it binds the
group --Y'--ONO.sub.2, R.sub.1 is selected in group a''), can be
prepared as follows:
[0335] 32a) by reacting compounds of formula (I) obtained in
procedure 29. with a compound of formula (IIIe)
##STR00236##
wherein Y, Y' and Act are as above defined; A is a radical of
formula (IIs) wherein R.sub.1 is --H, R.sub.3 is
--C(O)--NH--R.sub.3x and it binds the group --Y--ONO.sub.2, R.sub.s
is selected in group a''), applying the same procedure described in
25a).
[0336] 33. The compounds of general formula (I) wherein:
s and s' are equal to 1; s'', m, m', m'', are 0 Y and Y' are equal
or different and are as above defined; A is a radical of formula
(IIs) wherein R.sub.3 is --OC(O)--R.sub.3x and it binds the group
--Y'--ONO.sub.2; R.sub.1 is --C(O)O--R.sub.1x and it binds the
group --Y--ONO.sub.2, R.sub.s is selected in group a''), can be
prepared as follows:
[0337] 33a) by reacting compounds of formula (I) obtained in
procedure 26. with a compound of formula (IIIe)
##STR00237##
wherein Y, Y' and Act are as above defined; A is a radical of
formula (IIs) wherein R.sub.1 is --C(O)O--R.sub.1x and it binds the
group --Y--ONO.sub.2, R.sub.3 is --OH and R.sub.s is selected in
group a''), applying the same procedure described in 27b).
[0338] 34. The compounds of general formula (I) wherein:
s and s' are equal to 1; s'', m, m', m'', are 0 Y and Y' are equal
or different and are as above defined; A is a radical of formula
(IIs) wherein R.sub.3 is --C(O)O--R.sub.3x and it binds the group
--Y--ONO.sub.2 or the group --Y'--ONO.sub.2; R.sub.1 is
--C(O)O--R.sub.1x and it binds the group --Y--ONO.sub.2 or the
group --Y'--ONO.sub.2, R.sub.s is selected in group a''), can be
prepared as follows:
[0339] 34a) Y and Y' are equal;
by reacting compounds of formula A described in 25a) with a
compound of formula (IIIf)
A+Act-(O)C--O--Y'--ONO.sub.2 (IIIf)
wherein Y, Y' and Act are as above defined; A is a compound of
formula (IIs) wherein R.sub.1 is --H, R.sub.3 is --OH and R.sub.s
is selected in group a''), using a ratio A/(IIIf) 1:2 and applying
the same procedure described in 3b).
[0340] 34a') Y and Y' are equal or different
by reacting compounds of formula (I) prepared in 26. with a
compound of formula (IIIf)
##STR00238##
wherein Y, Y' and Act are as above defined; A is a radical of
formula (IIs) wherein R.sub.1 is --C(O)O--R.sub.1x and it binds the
group --Y--ONO.sub.2 and R.sub.3 is --OH, R.sub.s is selected in
group a''); applying the same procedure described in 3b).
[0341] 34a'') Y and Y' are equal or different
by reacting compounds of formula (I) prepared in 28. with a
compound of formula (IIIf)
##STR00239##
wherein Y, Y' and Act are as above defined; A is a radical of
formula (IIs) wherein R.sub.1 is --H, R.sub.3 is --C(O)O--R.sub.3x
and R.sub.3 binds the group --Y--ONO.sub.2, R.sub.s is selected in
group a''), applying the same procedure described in 3b).
[0342] 35. The compounds of general formula (I) wherein:
s and s' are equal to 1; s'', m, m', m'', are 0 Y and Y' are equal
or different and are as above defined; A is a radical of formula
(IIs) wherein R.sub.3 is --C(O)--NH--R.sub.3x and it binds the
group --Y'--ONO.sub.2; R.sub.1 is --C(O)O--R.sub.1x and it binds
the group --Y--ONO.sub.2, R.sub.s is selected in group a''), can be
prepared as follows:
[0343] 35a) by reacting compounds of formula (I) obtained in
procedure 26. with a compound of formula (IIIu)
##STR00240##
wherein Y, Y' and Act are as above defined; A is a radical of
formula (IIs) wherein R.sub.1 is --C(O)O--R.sub.1x and it binds the
group --Y--ONO.sub.2, R.sub.3 is --OH and R.sub.s is selected in
group a''), using the same procedure described in 29b).
[0344] 35a') alternatively by reacting compound of formula (I)
prepared in 29. with a compound of formula (IIIf)
##STR00241##
wherein Y, Y' and Act are as above defined; A is a radical of
formula (IIs) wherein R.sub.1 is --H, R.sub.3 is
--C(O)--NH--R.sub.3x and it binds the group --Y--ONO.sub.2, R.sub.s
is selected in group a''), applying the same procedure described in
3b).
[0345] 36. The compounds of general formula (I) wherein:
s is equal to 1;
[0346] s' can be 0 or 1; with the proviso that s' is 1 when A is
the radical (IIs) and (IIs) is as defined in iii) below
reported,
s'', m, m', m'', are 0 Y and Y' when presents are equal and are as
above defined; A is selected among: i) (IIa) wherein R.sub.1 is
--H, R.sub.2 is --COOH and R.sub.a is selected from
R.sub.bx--C(O)--S--CH.sub.2--, or R.sub.xO--CH.sub.2--,
R.sub.xO--CH(CH.sub.3)--, (R.sub.xO)-p-C.sub.6H.sub.4--CH.sub.2--,
4-(R.sub.xO)-3,5-diiodobenzyl-4-(R.sub.xO)-3-nitrobenzyl- wherein
R.sub.x--C(O)-- and R.sub.a binds a group --Y--ONO.sub.2; ii) (IIc)
wherein R.sub.1 is --H, R.sub.2 is --COOH and R.sub.x is selected
from R.sub.bx--C(O)--S--CH.sub.2--, or R.sub.xO--CH.sub.2--,
R.sub.xO--CH(CH.sub.3)--, (R.sub.xO)-p-C.sub.6H.sub.4--CH.sub.2--,
4-(R.sub.xO)-3,5-diiodobenzyl-4-(R.sub.xO)-3-nitrobenzyl- wherein
R.sub.x--C(O)-- and R.sub.c binds a group --Y--ONO.sub.2; iii)
(IIs) (s' is 1) wherein R.sub.1 is --H, R.sub.3 is --OC(O) and
R.sub.s is selected from R.sub.bx--C(O)--S--CH.sub.2--, or
R.sub.xO--CH.sub.2--, R.sub.xO--CH(CH.sub.3)--,
(R.sub.xO)-p-C.sub.6H.sub.4--CH.sub.2--,
4-(R.sub.xO)-3,5-diiodobenzyl-4-(R.sub.xO)-3-nitrobenzyl- wherein
R.sub.x is R.sub.xx--C(O)--; both R.sub.3 and R.sub.s bind a group
--Y--ONO.sub.2 or a group --Y'--ONO.sub.2; vi) (IIs) (s' is 0)
wherein R.sub.1 is --H, R.sub.3 is --OC(O) and R.sub.3 binds a
group --Y--ONO.sub.2; R.sub.s is selected from
R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is --OH; v) (IIu) wherein R.sub.1 is --H, R.sub.2
is --COOH, a is 1: b is 0 or 1; and R.sub.x is R.sub.xx--C(O)-- and
R.sub.x binds a group --Y--ONO.sub.2; can be prepared as
follows:
[0347] 36a) by reacting a compound of formula (I) wherein s, s',
s'', m, m', m'', Y, Y', Y'' are as above defined in 36, A is a
radical of formula (IIa), (IIc), (IIs) or (IIu) wherein; R.sub.2,
R.sub.3, a, b, R.sub.a, R.sub.c, R.sub.s, R.sub.g and R.sub.x are
as defined in 36; R.sub.1 is --C(O)OC(CH.sub.3).sub.3 with
anhydrous or aqueous organic or inorganic acid to hydrolyze the
--BOC protective groups following procedure well known in the
literature.
[0348] 36b) by reacting a compound of formula A with a compound of
formula (IIIa)
A+Act(O)C--Y--ONO.sub.2 (IIIe)
wherein Act and Y are as above defined and A has the following
meanings: i') a radical of formula (IIa) wherein R.sub.1 is
--C(O)OC(CH.sub.3).sub.3, R.sub.2 is --COOH and R.sub.a is selected
from HS--CH.sub.2--, or R.sub.xO--CH.sub.2--,
R.sub.xO--CH(CH.sub.3)--, (R.sub.xO)-p-C.sub.6H.sub.4--CH.sub.2--,
4-(R.sub.xO)-3,5-diiodobenzyl-4-(R.sub.xO)-3-nitrobenzyl- wherein
R.sub.x--H; ii') a radical of formula (IIc) wherein R.sub.1 is
--C(O)OC(CH.sub.3).sub.3, R.sub.2 is --COOH and R.sub.c is selected
from HS--CH.sub.2--, or R.sub.xO--CH.sub.2--,
R.sub.xO--CH(CH.sub.3)--, (R.sub.xO)-p-C.sub.6H.sub.4--CH.sub.2--,
4-(R.sub.xO)-3,5-diiodobenzyl-4-(R.sub.xO)-3-nitrobenzyl- wherein
R.sub.x--H; iii') a radical of formula (IIs) wherein R.sub.1 is
--C(O)OC(CH.sub.3).sub.3, R.sub.3 is --OH and R.sub.s is selected
from HS--CH.sub.2--, or R.sub.xO--CH.sub.2--,
R.sub.xO--CH(CH.sub.3)--, (R.sub.xO)-p-C.sub.6H.sub.4--CH.sub.2--,
4-(R.sub.xO)-3,5-diiodobenzyl-4-(R.sub.xO)-3-nitrobenzyl- wherein
R.sub.x--H; iv') a radical of formula (IIs) wherein R.sub.1 is
--C(O)OC(CH.sub.3).sub.3, R.sub.3 is --OH; R.sub.s is
R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is --OH; v') a radical of formula (IIu) wherein
R.sub.1 is --C(O)OC(CH.sub.3).sub.3, R.sub.2 is --COOH, a is 1; b
is 0 or 1 and R.sub.x is --H; following the same procedure
described in 1b') using a ratio A/(IIIe) 1:1 or 1:2 for s' equal to
1.
[0349] 37. The compounds of general formula (I) wherein:
s is equal to 1; s' can be 0 or 1; with the proviso that s' is 1
when A is the radical (IIs) and (IIs) is as defined in iii), S'',
m, m', m'', are 0 Y and Y', when present are equal and are as above
defined; A is selected among: i) (IIa) wherein R.sub.1 is --H,
R.sub.2 is --COOH and R.sub.a is selected from
R.sub.bx--OC(O)--S--CH.sub.2--, or R.sub.xO--CH.sub.2--,
R.sub.xO--CH(CH.sub.3)--, (R.sub.xO)-p-C.sub.6H.sub.4--CH.sub.2--,
4-(R.sub.xO)-3,5-diiodobenzyl-4-(R.sub.xO)-3-nitrobenzyl- wherein
R.sub.x is R.sub.xx--OC(O)-- and R.sub.a binds a group
--Y--ONO.sub.2; ii) (IIc) wherein R.sub.1 is --H, R.sub.2 is --COOH
and R.sub.b is selected from R.sub.bx--OC(O)--S--CH.sub.2--, or
R.sub.xO--CH.sub.2--, R.sub.xO--CH(CH.sub.3)--,
(R.sub.xO)-p-C.sub.6H.sub.4--CH.sub.2--,
4-(R.sub.xO)-3,5-diiodobenzyl-4-(R.sub.xO)-3-nitrobenzyl- wherein
R.sub.x is R.sub.xx--CC(O)-- and R.sub.b binds a group
--Y--ONO.sub.2; iii) (IIs) (s' is 1) wherein R.sub.1 is --H,
R.sub.3 is --C(O)O--R.sub.3x and R.sub.s is selected from
R.sub.bx--OC(O)--S--CH.sub.2--, or R.sub.xO--CH.sub.2--,
R.sub.xO--CH(CH.sub.3)--, (R.sub.xO)-p-C.sub.6H.sub.4--CH.sub.2--,
4-(R.sub.xO)-3,5-diiodobenzyl-4-(R.sub.xO)-3-nitrobenzyl- wherein
R.sub.x is R.sub.xx--OC(O)-- both R.sub.3 and R.sub.s bind a group
--Y--ONO.sub.2 or a group --Y'--ONO.sub.2; vi) (IIs) (s' is 0)
wherein R.sub.1 is --H, R.sub.3 is --OC(O)O--R.sub.3x and R.sub.3
binds a group --Y--ONO.sub.2; R.sub.s is selected from
R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is --OH; v) (IIu) wherein R.sub.1 is --H, R.sub.2
is --COOH, a is 1; b is 0 or 1; and R.sub.x is R.sub.xx--OC(O)--
and R.sub.x binds a group --Y--ONO.sub.2; can be prepared as
follows:
[0350] 37a) by reacting a compound of formula (I) wherein s, s',
s'', m, m', m'', Y, Y', Y'' are as above defined in 37, A is a
radical of formula (IIa), (IIc), (IIs) or (IIu) wherein; R.sub.2,
R.sub.3, a, b, R.sub.a, R.sub.c, R.sub.s, R.sub.g and R.sub.x are
as defined in 37; R.sub.1 is --C(O)OC(CH.sub.3).sub.3 with
anhydrous or aqueous organic or inorganic acid to hydrolyze the
--BOC protective groups following procedure well known in the
literature.
[0351] 37b) by reacting a compound of formula A with a compound of
formula (IIIf)
A+Act(O)C--O--Y--ONO.sub.2 (IIIf)
wherein Act and Y are as above defined and A has the same meanings
described in 36b); following the same procedure described in 3b)
using a ratio A/(IIIf) 1:1 or 1:2 for s' equal to 1.
[0352] 38. The compounds of general formula (I) wherein:
s is equal to 1; s' can be 0 or 1; with the proviso that s' is 1
when A is the radical (IIs) and (IIs) is as defined in iii), s'',
m, m', m'', are 0 Y and Y', when presents, are equal and are as
above defined; A is selected among: i) (IIa) wherein R.sub.1 is
--H, R.sub.2 is --COOH and R.sub.a is selected from
R.sub.bx--NH(O)C--S--CH.sub.2--, or R.sub.xO--CH.sub.2--,
R.sub.xO--CH(CH.sub.3)--, (R.sub.xO)-p-C.sub.6H.sub.4--CH.sub.2--,
4-(R.sub.xO)-3,5-diiodobenzyl-4-(R.sub.xO)-3-nitrobenzyl- wherein
R.sub.x is R.sub.xxNH--C(O)-- and R.sub.a binds a group
--Y--ONO.sub.2; ii) (IIc) wherein R.sub.1 is --H, R.sub.2 is --COOH
and R.sub.c is selected from R.sub.bx--NH(O)C--S--CH.sub.2--, or
R.sub.xO--CH.sub.2--, R.sub.xO--CH(CH.sub.3)--,
(R.sub.xO)-p-C.sub.6H.sub.4--CH.sub.2--,
4-(R.sub.xO)-3,5-diiodobenzyl-4-(R.sub.xO)-3-nitrobenzyl- wherein
R.sub.x is R.sub.xxNH--C(O)-- and R.sub.c binds a group
--Y--ONO.sub.2; iii) (IIs) (s' is 1) wherein R.sub.1 is --H,
R.sub.3 is --C(O)--NH--R.sub.3x and R.sub.s is selected from
R.sub.bx--NH(O)C--S--CH.sub.2--, or R.sub.xO--CH.sub.2--,
R.sub.xO--CH(CH.sub.3)--, (R.sub.xO)-p-C.sub.6H.sub.4--CH.sub.2--,
4-(R.sub.xO)-3,5-diiodobenzyl-4-(R.sub.xO)-3-nitrobenzyl- wherein
R.sub.x is R.sub.xxNH--C(O)-- both R.sub.3 and R.sub.s bind a group
--Y--ONO.sub.2 or a group --Y'--ONO.sub.2; vi) (IIs) (s' is 0)
wherein R.sub.1 is --H, R.sub.3 is --C(O)--NH--R.sub.3x and R.sub.3
binds a group --Y--ONO.sub.2; R.sub.s is selected from
R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is --OH; v) (IIu) wherein R.sub.1 is --H, R.sub.2
is --COOH, a is 1; b is 0 or 1; and R.sub.x is R.sub.xx--NHC(O)--
and R.sub.x binds a group --Y--ONO.sub.2; can be prepared as
follows:
[0353] 38a) by reacting a compound of formula (I) wherein s, s',
s'', m, m', m'', Y, Y', Y'' are as above defined in 38, A is a
radical of formula (IIa), (IIc), (IIs) or (IIu) wherein; R.sub.2,
R.sub.3, a, b, R.sub.a, R.sub.c, R.sub.s, R.sub.g and R.sub.x are
as defined in 38; R.sub.1 is --C(O)OC(CH.sub.3).sub.3 with
anhydrous or aqueous organic or inorganic acid to hydrolyze the
--BOC protective groups following procedure well known in the
literature.
[0354] 38b) by reacting a compound of formula A with a compound of
formula (IIIu)
A+Act(O)C--NH--Y--ONO.sub.2 (IIIu)
wherein Act and Y are as above defined and A has the same meanings
described in 36b); following the same procedure described in 29.
using a ratio A/(IIIu) 1:1 or 1:2 for s' equal to 1.
[0355] 39. The compounds of general formula (I) wherein:
s and s' are equal to 1; s'', m, m', m'', are 0 Y and Y' are equal
or different and are as above defined; A is selected among: i)
(IIa) wherein R.sub.1 is --H, R.sub.2 is --C(O)OR.sub.2x and
R.sub.2 binds a group --Y'--ONO.sub.2; and R.sub.a is selected from
R.sub.bx--C(O)--S--CH.sub.2--, or R.sub.xO--CH.sub.2--,
R.sub.xO--CH(CH.sub.3)--, (R.sub.xO)-p-C.sub.6H.sub.4--CH.sub.2--,
4-(R.sub.xO)-3,5-diiodobenzyl-4-(R.sub.xO)-3-nitrobenzyl- wherein
R.sub.x is R.sub.xx--C(O)-- and R.sub.a binds a group
--Y--ONO.sub.2; ii) (IIc) wherein R.sub.1 is --H, R.sub.2 is
--C(O)OR.sub.2x and R.sub.2 binds a group --Y'--ONO.sub.2; R.sub.c
is selected from R.sub.bx--C(O)--S--CH.sub.2--, or
R.sub.xO--CH.sub.2--, R.sub.xO--CH(CH.sub.3)--,
(R.sub.xO)-p-C.sub.6H.sub.4--CH.sub.2--,
4-(R.sub.xO)-3,5-diiodobenzyl-4-(R.sub.xO)-3-nitrobenzyl- wherein
R.sub.x is R.sub.xx--C(O)-- and R.sub.c binds a group
--Y--ONO.sub.2; iii) (IIs) wherein R.sub.1 is --H, R.sub.3 is
--OC(O)R.sub.3x and R.sub.3 binds a group --Y--ONO.sub.2; R.sub.s
is selected from R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is R.sub.gx--O--, and R.sub.s binds a group
--Y'--ONO.sub.2; v) (IIu) wherein R.sub.1 is --H, R.sub.2 is
--C(O)O--R.sub.2x, R.sub.2 binds a group --Y'--ONO.sub.2; a is 1; b
is 0 or 1; and R.sub.x is R.sub.xx--C(O)-- and R.sub.x binds a
group --Y--ONO.sub.2; can be prepared as follows:
[0356] 39a) by reacting a compound of formula (I) wherein s, s',
s'', m, m', m'', Y, Y', Y'' are as above defined in 39, A is a
radical of formula (IIa), (IIc), (IIs) or (IIu) wherein; R.sub.2,
R.sub.3, a, b, R.sub.a, R.sub.c, R.sub.s, R.sub.g and R.sub.x are
as defined in 39; R.sub.1 is --C(O)OC(CH.sub.3).sub.3 with
anhydrous or aqueous organic or inorganic acid to hydrolyze the
--BOC protective groups following procedure well known in the
literature.
[0357] 39b) by reacting a compound of formula (I) obtained in 36b)
with a compound of formula (IIIi)
##STR00242##
wherein Y and Y' are as above defined and in formula (I) A is a
radical of formula (IIa), (IIc), (IIs) or (IIu) wherein R.sub.1 is
--C(O)OC(CH.sub.3).sub.3, R.sub.2 is --COOH, R.sub.3, R.sub.a,
R.sub.c R.sub.x a and b are as above defined in 39; R.sub.s is
R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is --OH; following the same procedure described in
8b).
[0358] 40. The compounds of general formula (I) wherein:
s and s' are equal to 1; s'', m, m', m'', are 0 Y and Y' are equal
or different and are as above defined; A is selected among: i)
(IIa) wherein R.sub.1 is --H, R.sub.2 is --C(O)OR.sub.2x and
R.sub.2 binds a group --Y'--ONO.sub.2; and R.sub.a is selected from
R.sub.bx--OC(O)--S--CH.sub.2--, or R.sub.xO--CH.sub.2--,
R.sub.xO--CH(CH.sub.3)--, (R.sub.xO)-p-C.sub.6H.sub.4--CH.sub.2--,
4-(R.sub.xO)-3,5-diiodobenzyl-4-(R.sub.xO)-3-nitrobenzyl- wherein
R.sub.x is R.sub.xx--OC(O)-- and R.sub.a binds a group
--Y--ONO.sub.2; ii) (IIc) wherein R.sub.1 is --H, R.sub.2 is
--C(O)OR.sub.2x and R.sub.2 binds a group --Y'--ONO.sub.2; R.sub.c
is selected from R.sub.bx--OC(O)--S--CH.sub.2--, or
R.sub.xO--CH.sub.2--, R.sub.xO--CH(CH.sub.3)--,
(R.sub.xO)-p-C.sub.6H.sub.4--CH.sub.2--,
4-(R.sub.xO)-3,5-diiodobenzyl-4-(R.sub.xO)-3-nitrobenzyl- wherein
R.sub.x is R.sub.xx--OC(O)-- and R.sub.c binds a group
--Y--ONO.sub.2; iii) (IIs) wherein R.sub.1 is --H, R.sub.3 is
--OC(O)O--R.sub.3x and R.sub.3 binds a group --Y--ONO.sub.2;
R.sub.s is selected from R.sub.gC(O)CH.sub.2--NH--,
R.sub.gC(O)CH.sub.2. R.sub.gC(O)(CH.sub.2).sub.2--,
R.sub.gC(O)(CH.sub.2).sub.4--, wherein R.sub.g is R.sub.gx--O--,
and R.sub.s binds a group --Y'--ONO.sub.2; v) (IIu) wherein R.sub.1
is --H, R.sub.2 is --C(O)O--R.sub.2x, R.sub.2 binds a group
--Y'--ONO.sub.2; a is 1; b is 0 or 1 and R.sub.x is
R.sub.xx--OC(O)-- and R.sub.x binds a group --Y--ONO.sub.2; can be
prepared as follows:
[0359] 40a) by reacting a compound of formula (I) wherein s, s',
s'', m, m', m'', Y, Y', Y'' are as above defined in 40, A is a
radical of formula (IIa), (IIc), (IIs) or (IIu) wherein; R.sub.2,
R.sub.3, a, b, R.sub.a, R.sub.c, R.sub.s, R.sub.g and R.sub.x are
as defined in 40; R.sub.1 is --C(O)OC(CH.sub.3).sub.3 with
anhydrous or aqueous organic or inorganic acid to hydrolyze the
--BOC protective groups following procedure well known in the
literature.
[0360] 40b) by reacting a compound of formula (I) obtained in 37b)
with a compound of formula (IIIi)
##STR00243##
wherein Y and Y' are as above defined and in formula (I) A is a
radical of formula (IIa), (IIc), (IIs) or (IIu) wherein R.sub.1 is
--C(O)OC(CH.sub.3).sub.3, R.sub.2 is --COOH, R.sub.3, R.sub.a,
R.sub.c R.sub.x a and b are as above defined in 40, R.sub.s is
R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is --OH; following the same procedure described in
8b).
[0361] 41. The compounds of general formula (I) wherein:
s and s' are equal to 1; s'', m, m', m'', are 0 Y and Y' are equal
or different and are as above defined; A is selected among: i)
(IIa) wherein R.sub.1 is --H, R.sub.2 is --C(O)OR.sub.2x and
R.sub.2 binds a group --Y'--ONO.sub.2; and R.sub.a is selected from
R.sub.bx--NH(O)C--S--CH.sub.2--, or R.sub.xO--CH.sub.2--,
R.sub.xO--CH(CH.sub.3)--, (R.sub.xO)-p-C.sub.6H.sub.4--CH.sub.2--,
4-(R.sub.xO)-3,5-diiodobenzyl-4-(R.sub.xO)-3-nitrobenzyl- wherein
R.sub.x is R.sub.xxNH--C(O)-- and R.sub.a binds a group
--Y--ONO.sub.2; ii) (IIc) wherein R.sub.1 is --H, R.sub.2 is
--C(O)OR.sub.2x and R.sub.2 binds a group --Y'--ONO.sub.2; R.sub.c
is selected from R.sub.bx--NH(O)C--S--CH.sub.2--, or
R.sub.xO--CH.sub.2--, R.sub.xO--CH(CH.sub.3)--,
(R.sub.xO)-p-C.sub.6H.sub.4--CH.sub.2--,
4-(R.sub.xO)-3,5-diiodobenzyl-4-(R.sub.xO)-3-nitrobenzyl- wherein
R.sub.x is R.sub.xxNH--C(O)-- and R.sub.c binds a group
--Y--ONO.sub.2; iii) (IIs) wherein R.sub.1 is --H, R.sub.3 is
--OC(O)--NH--R.sub.3x and R.sub.3 binds a group --Y--ONO.sub.2;
R.sub.s is selected from R.sub.gC(O)CH.sub.2--NH--,
R.sub.gC(O)CH.sub.2, R.sub.gC(O)(CH.sub.2).sub.2--,
R.sub.gC(O)(CH.sub.2).sub.4--, wherein R.sub.g is R.sub.gx--O--,
and R.sub.s binds a group --Y'--ONO.sub.2; v) (IIu) wherein R.sub.1
is --H, R.sub.2 is --C(O)O--R.sub.2x, R.sub.2 binds a group
--Y'--ONO.sub.2; a is 1; b is 0 or 1 and R.sub.x is
R.sub.xx--NHC(O)-- and R.sub.x binds a group --Y--ONO.sub.2; can be
prepared as follows:
[0362] 41a) by reacting a compound of formula (I) wherein s, s',
s'', m, m', m'', Y, Y', Y'' are as above defined in 41, A is a
radical of formula (IIa), (IIc), (IIs) or (IIu) wherein; R.sub.2,
R.sub.3, a, b, R.sub.a, R.sub.c, R.sub.s, R.sub.g and R.sub.x are
as defined in 41; R.sub.1 is --C(O)OC(CH.sub.3).sub.3 with
anhydrous or aqueous organic or inorganic acid to hydrolyze the
--BOC protective groups following procedure well known in the
literature.
[0363] 41b) by reacting a compound of formula (I) obtained in 38b)
with a compound of formula (IIIi)
##STR00244##
wherein Y and Y' are as above defined and in formula (I) A is a
radical of formula (IIa), (IIc), (IIs) or (IIu) wherein R.sub.1 is
--C(O)OC(CH.sub.3).sub.3, R.sub.2 is --COOH, R.sub.3, R.sub.a,
R.sub.c R.sub.x a and b are as above defined in 41, R.sub.s is
R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is --OH; following the same procedure described in
8b).
[0364] 42. The compounds of general formula (I) wherein:
s and s' are equal to 1; s'', m, m', m'', are 0 Y and Y' are equal
or different and are as above defined; A is selected among: i)
(IIa) wherein R.sub.1 is --H, R.sub.2 is --C(O)NHR.sub.2xx or
--C(O)N(CH.sub.3)R.sub.2xx and R.sub.2 binds a group
--Y'--ONO.sub.2; and R.sub.a is selected from
R.sub.bx--C(O)--S--CH.sub.2--, or R.sub.xO--CH.sub.2--,
R.sub.xO--CH(CH.sub.3)--, (R.sub.xO)-p-C.sub.6H.sub.4--CH.sub.2--,
4-(R.sub.xO)-3,5-diiodobenzyl-4-(R.sub.xO)-3-nitrobenzyl- wherein
R.sub.x is R.sub.xx--C(O)-- and R.sub.a binds a group
--Y--ONO.sub.2; ii) (IIc) wherein R.sub.1 is --H, R.sub.2 is
--C(O)NHR.sub.2xx or --C(O)N(CH.sub.3)R.sub.2xx and R.sub.2 binds a
group --Y'--ONO.sub.2; R.sub.x is selected from
R.sub.bx--C(O)--S--CH.sub.2-- or R.sub.xO--CH.sub.2--,
R.sub.xO--CH(CH.sub.3)--, (R.sub.xO)-p-C.sub.6H.sub.4--CH.sub.2--,
4-(R.sub.xO)-3,5-diiodobenzyl-4-(R.sub.xO)-3-nitrobenzyl- wherein
R.sub.x is R.sub.xx--C(O)-- and R.sub.c binds a group
--Y--ONO.sub.2; iii) (IIs) wherein R.sub.1 is --H, R.sub.3 is
--OC(O)R.sub.3x and R.sub.3 binds a group --Y--ONO.sub.2; R.sub.s
is selected from R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is R.sub.gxx--NH-- or R.sub.gxx--N(CH.sub.3)-- and
R.sub.s binds a group --Y'--ONO.sub.2; v) (IIu) wherein R.sub.1 is
--H, R.sub.2 is --C(O)NHR.sub.2xx or --C(O)N(CH.sub.3)R.sub.2xx and
R.sub.2 binds a group --Y'--ONO.sub.2; a is 1; b is 0 or 1 and
R.sub.x is R.sub.xx--C(O)-- and R.sub.x binds a group
--Y--ONO.sub.2; can be prepared as follows:
[0365] 42a) by reacting a compound of formula (I) wherein s, s',
s'', m, m', m'', Y, Y', Y'' are as above defined in 42, A is a
radical of formula (IIa), (IIc), (IIs) or (IIu) wherein; R.sub.2,
R.sub.3, a, b, R.sub.a, R.sub.c, R.sub.s, R.sub.g and R.sub.x are
as defined in 42; R.sub.1 is --C(O)OC(CH.sub.3).sub.3 with
anhydrous or aqueous organic or inorganic acid to hydrolyze the
--BOC protective groups following procedure well known in the
literature.
[0366] 42b) by reacting a compound of formula (I) obtained in 36b)
with a compound of formula (IIIo)
##STR00245##
wherein Y and Y' are as above defined, W.sub.3 is as above defined
and in formula (I) A is a radical of formula (IIa), (IIc), (IIs) or
(IIu) wherein R.sub.1 is --C(O)OC(CH.sub.3).sub.3, R.sub.2 is
--COOH, R.sub.3, R.sub.a, R.sub.c R.sub.x a and b are as above
defined in 42, R.sub.s is R.sub.gC(O)CH.sub.2--NH--,
R.sub.gC(O)CH.sub.2, R.sub.gC(O)(CH.sub.2).sub.2--,
R.sub.gC(O)(CH.sub.2).sub.4--, wherein R.sub.g is --OH; following
the same procedure described in 7b).
[0367] 43. The compounds of general formula (I) wherein:
s and s' are equal to 1; s'', m, m', m'', are 0 Y and Y' are equal
or different and are as above defined; A is selected among: i)
(IIa) wherein R.sub.1 is --H, R.sub.2 is --C(O)NHR.sub.2xx or
--C(O)N(CH.sub.3)R.sub.2xx and R.sub.2 binds a group
--Y'--ONO.sub.2; and R.sub.a is selected from
R.sub.bx--OC(O)--S--CH.sub.2--, or R.sub.xO--CH.sub.2--,
R.sub.xO--CH(CH.sub.3)--, (R.sub.xO)-p-C.sub.6H.sub.4--CH.sub.2--,
4-(R.sub.xO)-3,5-diiodobenzyl-4-(R.sub.xO)-3-nitrobenzyl- wherein
R.sub.x is R.sub.xx--OC(O)-- and R.sub.a binds a group
--Y--ONO.sub.2; ii) (IIc) wherein R.sub.1 is --H, R.sub.2 is
--C(O)NHR.sub.2xx or --C(O)N(CH.sub.3)R.sub.2xx and R.sub.2 binds a
group --Y'--ONO.sub.2; R.sub.c is selected from
R.sub.bx--OC(O)--S--CH.sub.2--, or R.sub.xO--CH.sub.2--,
R.sub.xO--CH(CH.sub.3)--, (R.sub.xO)-p-C.sub.6H.sub.4--CH.sub.2--,
4-(R.sub.xO)-3,5-diiodobenzyl-4-(R.sub.xO)-3-nitrobenzyl- wherein
R.sub.x is R.sub.xx--OC(O)-- and R.sub.c binds a group
--Y--ONO.sub.2; iii) (IIs) wherein R.sub.1 is --H, R.sub.3 is
--C(O)O--R.sub.3x and R.sub.3 binds a group --Y--ONO.sub.2; R.sub.s
is selected from R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is R.sub.gxx--NH-- or R.sub.2xx--N(CH.sub.3)-- and
R.sub.s binds a group --Y'--ONO.sub.2; v) (IIu) wherein R.sub.1 is
--H, R.sub.2 is --C(O)NHR.sub.2xx or --C(O)NHR.sub.2xx and R.sub.2
binds a group --Y'--ONO.sub.2; a is 1; b is 0 or 1 and R.sub.x is
R.sub.xx--OC(O)-- and R.sub.x binds a group --Y--ONO.sub.2; can be
prepared as follows:
[0368] 43a) by reacting a compound of formula (I) wherein s, s',
s'', m, m', m'', Y, Y', Y'' are as above defined in 43, A is a
radical of formula (IIa), (IIc), (IIs) or (IIu) wherein; R.sub.2,
R.sub.3, a, b, R.sub.a, R.sub.c, R.sub.s, R.sub.g and R.sub.x are
as defined in 43; R.sub.1 is --C(O)OC(CH.sub.3).sub.3 with
anhydrous or aqueous organic or inorganic acid to hydrolyze the
--BOC protective groups following procedure well known in the
literature.
[0369] 43b) by reacting a compound of formula (I) obtained in 37b)
with a compound of formula (IIIo)
##STR00246##
wherein Y and Y' are as above defined, W.sub.3 is as above defined
and in formula (I) A is a radical of formula (IIa), (IIc), (IIs) or
(IIu) wherein R.sub.1 is --C(O)OC(CH.sub.3).sub.3, R.sub.2 is
--COOH, R.sub.3, R.sub.a, R.sub.c R.sub.x a and b are as above
defined in 43, R.sub.s is R.sub.gC(O)CH.sub.2--NH--,
R.sub.gC(O)CH.sub.2. R.sub.gC(O)(CH.sub.2).sub.2--,
R.sub.gC(O)(CH.sub.2).sub.4--, wherein R.sub.g is --OH; following
the same procedure described in 7b).
[0370] 44. The compounds of general formula (I) wherein:
s and s' are equal to 1; s'', m, m', m'', are 0 Y and Y' are equal
or different and are as above defined; A is selected among: i)
(IIa) wherein R.sub.1 is --H, R.sub.2 is --C(O)NHR.sub.2xx or
--C(O)N(CH.sub.3)R.sub.2xx and R.sub.2 binds a group
--Y'--ONO.sub.2; and R.sub.a is selected from
R.sub.bx--NH(O)C--S--CH.sub.2--, or R.sub.xO--CH.sub.2--,
R.sub.xO--CH(CH.sub.3)--, (R.sub.xO)-p-C.sub.6H.sub.4--CH.sub.2--,
4-(R.sub.xO)-3,5-R.sub.xxNH--C(O)-- and R.sub.a binds a group
--Y--ONO.sub.2; ii) (IIc) wherein R.sub.1 is --H, R.sub.2 is
--C(O)NHR.sub.2xx or --C(O)N(CH.sub.3)R.sub.2xx and R.sub.2 binds a
group --Y'--ONO.sub.2; R.sub.c is selected from
R.sub.bx--NH(O)C--S--CH.sub.2--, or R.sub.xO--CH.sub.2--,
R.sub.xO--CH(CH.sub.3)--, (R.sub.xO)-p-C.sub.6H.sub.4--CH.sub.2--,
4-(R.sub.xO)-3,5-diiodobenzyl-4-(R.sub.xO)-3-nitrobenzyl- wherein
R.sub.x is R.sub.xxNH--C(O)-- and R.sub.c binds a group
--Y--ONO.sub.2; iii) (IIs) wherein R.sub.1 is --H, R.sub.3 is
--C(O)--NH--R.sub.3x and R.sub.3 binds a group --Y--ONO.sub.2;
R.sub.s is selected from R.sub.gC(O)CH.sub.2--NH--,
R.sub.gC(O)CH.sub.2. R.sub.gC(O)(CH.sub.2).sub.2--,
R.sub.gC(O)(CH.sub.2).sub.4--, wherein R.sub.g is R.sub.gxx--NH--
or R.sub.2xx--N(CH.sub.3)-- and R.sub.s binds a group
--Y'--ONO.sub.2; v) (IIu) wherein R.sub.1 is --H, R.sub.2 is
--C(O)NHR.sub.2xx or --C(O)N(CH.sub.3)R.sub.2xx R.sub.2 binds a
group --Y'--ONO.sub.2; a is 1; b is 0 or 1; and R.sub.x is
R.sub.xx--NHC(O)-- and R.sub.x binds a group --Y--ONO.sub.2; can be
prepared as follows:
[0371] 44a) by reacting a compound of formula (I) wherein s, s',
s'', m, m', m'', Y, Y', Y'' are as above defined in 44, A is a
radical of formula (IIa), (IIc), (IIs) or (IIu) wherein; R.sub.2,
R.sub.3, a, b, R.sub.a, R.sub.c, R.sub.s, R.sub.g and R.sub.x are
as defined in 44; R.sub.1 is --C(O)OC(CH.sub.3).sub.3 with
anhydrous or aqueous organic or inorganic acid to hydrolyze the
--BOC protective groups following procedure well known in the
literature.
[0372] 44b) by reacting a compound of formula (I) obtained in 38b)
with a compound of formula (IIIo)
##STR00247##
wherein Y and Y' are as above defined, W.sub.3 is as above defined
and in formula (I) A is a radical of formula (IIa), (IIc), (IIs) or
(IIu) wherein R.sub.1 is --C(O)OC(CH.sub.3).sub.3, R.sub.2 is
--COOH, R.sub.3, R.sub.a, R.sub.c R.sub.x a and b are as above
defined in 44, R.sub.s is R.sub.gC(O)CH.sub.2--NH--,
R.sub.gC(O)CH.sub.2, R.sub.gC(O)(CH.sub.2).sub.2--,
R.sub.gC(O)(CH.sub.2).sub.4--, wherein R.sub.g is --OH; following
the same procedure described in 7b).
[0373] 45. The compounds of general formula (I) wherein:
s is equal to 1; s', s'', m, m', m'', are 0 Y is as above defined;
A is selected among: i) (IIa) wherein R.sub.1 is --H, R.sub.2 is
--C(O)OR.sub.2x and R.sub.2 binds a group --Y--ONO.sub.2; and
R.sub.a is selected from HS--CH.sub.2--, or R.sub.xO--CH.sub.2--,
R.sub.xO--CH(CH.sub.3)--, (R.sub.xO)-p-C.sub.6H.sub.4--CH.sub.2--,
4-(R.sub.xO)-3,5-diiodobenzyl-4-(R.sub.xO)-3-nitrobenzyl- wherein
R.sub.x--H; ii) (IIc) wherein R.sub.1 is --H, R.sub.2 is
--C(O)OR.sub.2x and R.sub.2 binds a group --Y--ONO.sub.2; and
R.sub.a is selected from HS--CH.sub.2--, or R.sub.xO--CH.sub.2--,
R.sub.xO--CH(CH.sub.3)--, (R.sub.xO)-p-C.sub.6H.sub.4--CH.sub.2--,
4-(R.sub.xO)-3,5-diiodobenzyl-4-(R.sub.xO)-3-nitrobenzyl- wherein
R.sub.x--H; iii) (IIs) wherein R.sub.1 is --H, R.sub.3 is --H;
R.sub.s is selected from R.sub.gC(O)CH.sub.2--NH--,
R.sub.gC(O)CH.sub.2, R.sub.gC(O)(CH.sub.2).sub.2--,
R.sub.gC(O)(CH.sub.2).sub.4--, wherein R.sub.g is R.sub.gx--O--,
and R.sub.s binds a group --Y--ONO.sub.2; v) (IIu) wherein R.sub.1
is --H, R.sub.2 is --C(O)OR.sub.2x, R.sub.2 binds a group
--Y--ONO.sub.2; a is 1; b is 0 or 1 and R.sub.x is --H; can be
prepared as follows:
[0374] 45a) by reacting a compound of formula (VIIa)
A.sub.3a-Y--ONO.sub.2 (VIIa)
wherein Y is as above defined and A.sub.3a is a radical of formula
(IIa), (IIc), (IIs) or (IIu) wherein R.sub.2, a, b and R.sub.s are
as defined in 45; R.sub.1 is --C(O)OC(CH.sub.3).sub.3; in formula
(IIs) R.sub.3 is equal to R.sub.3a wherein R.sub.3a is --OTrt,
wherein Trt is the trityl protecting group; in formula (IIa) and
(IIc) R.sub.a and R.sub.c have the meanings: Trt-S--CH.sub.2--, or
R.sub.xaO--CH.sub.2--, R.sub.xaO--CH(CH.sub.3)--,
(R.sub.xaO)-p-C.sub.6H.sub.4--CH.sub.2--,
4-(R.sub.xaO)-3,5-diiodobenzyl-4-(R.sub.xaO)-3-nitrobenzyl- wherein
R.sub.xa is -Trt, the trityl protecting group or the
dimethyltertbutylsilyl group; in formula (IIu) R.sub.x is equal to
R.sub.xa, wherein R.sub.xa is as above defined; with anhydrous or
aqueous organic or inorganic acid to hydrolyze the --BOC and the
other protective groups following procedure well known in the
literature.
[0375] 45b) by reacting a compound of formula A.sub.3 with a
compound of formula (IIIi)
A.sub.3+HO--Y--ONO.sub.2 (IIIi)
wherein Y is as above defined and A.sub.3 is a radical of formula
(IIa), (IIc), (IIs) or (IIu) wherein R.sub.1 is
--C(O)OC(CH.sub.3).sub.3, R.sub.2 is --COOH, a is as above defined
in 45, R.sub.3 is equal to R.sub.3a and is --OTrt, R.sub.a and
R.sub.c are TrtS--CH.sub.2--, or R.sub.xaO--CH.sub.2--,
R.sub.xaO--CH(CH.sub.3)--,
(R.sub.xaO)-p-C.sub.6H.sub.4--CH.sub.2--,
4-(R.sub.xaO)-3,5-diiodobenzyl-4-(R.sub.xaO)-3-nitrobenzyl- wherein
R.sub.xa is as above defined; R.sub.x of formula (IIu) is equal to
R.sub.xa and is as above defined; R.sub.s is
R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is --OH; following the same procedure described in
8b).
[0376] Compounds A.sub.3 are commercially available or can be
prepared from commercially available compounds by simple
de-protection/protection steps well known in the literature.
[0377] 46. The compounds of general formula (I) wherein:
s is equal to 1; s', s'', m, m', m'', are 0 Y is as above defined;
A is selected among: i) (IIa) wherein R.sub.1 is --H, R.sub.2 is
--C(O)NHR.sub.2xx or --C(O)N(CH.sub.3)R.sub.2xx and R.sub.2 binds a
group --Y--ONO.sub.2; and R.sub.a is selected from HS--CH.sub.2--,
or R.sub.xO--CH.sub.2--, R.sub.xO--CH(CH.sub.3)--,
(R.sub.xO)-p-C.sub.6H.sub.4--CH.sub.2--,
4-(R.sub.xO)-3,5-diiodobenzyl-4-(R.sub.xO)-3-nitrobenzyl- wherein
R.sub.x--H; ii) (IIc) wherein R.sub.1 is --H, R.sub.2 is
--C(O)NHR.sub.2xx or --C(O)N(CH.sub.3)R.sub.2xx and R.sub.2 binds a
group --Y--ONO.sub.2; and R.sub.a is selected from HS--CH.sub.2--,
or R.sub.xO--CH.sub.2--, R.sub.xO--CH(CH.sub.3)--,
(R.sub.xO)-p-C.sub.6H.sub.4--CH.sub.2--,
4-(R.sub.xO)-3,5-diiodobenzyl-4-(R.sub.xO)-3-nitrobenzyl- wherein
R.sub.x--H; iii) (IIs) wherein R.sub.1 is --H, R.sub.3 is --H;
R.sub.s is selected from R.sub.gC(O)CH.sub.2--NH--,
R.sub.gC(O)CH.sub.2, R.sub.gC(O)(CH.sub.2).sub.2--,
R.sub.gC(O)(CH.sub.2).sub.4--, wherein R.sub.g is R.sub.gxx--NH--
or R.sub.gxx--N(CH.sub.3)-- and R.sub.s binds a group
--Y--ONO.sub.2; v) (IIu) wherein R.sub.1 is --H, R.sub.2 is
--C(O)NHR.sub.2xx or --C(O)N(CH.sub.3)R.sub.2xx and R.sub.2 binds a
group --Y--ONO.sub.2; a is 1; b is 0 or 1 and R.sub.x is --H; can
be prepared as follows:
[0378] 46a) by reacting a compound of formula (VIIb)
A.sub.3c-Y--ONO.sub.2 (VIIb)
wherein Y is as above defined and A.sub.3b is a radical of formula
(IIa), (IIc), (IIs) or (IIu) wherein R.sub.2, a, b and R.sub.s are
as defined in 46; R.sub.1 is --C(O)OC(CH.sub.3).sub.3; in formula
(IIs) R.sub.3 is equal to R.sub.3a wherein R.sub.3a is --OTrt,
wherein Trt is the trityl protecting group; in formula (IIa) and
(IIc) R.sub.a and R.sub.c have the meanings: Trt-S--CH.sub.2--, or
R.sub.xaO--CH.sub.2--, R.sub.xaO--CH(CH.sub.3)--,
(R.sub.xaO)-p-C.sub.6H.sub.4--CH.sub.2--,
4-(R.sub.xaO)-3,5-diiodobenzyl-4-(R.sub.xaO)-3-nitrobenzyl- wherein
R.sub.xa is as above defined; In formula (IIu) R.sub.x is equal to
R.sub.xa and is as above defined; with anhydrous or aqueous organic
or inorganic acid to hydrolyze the --BOC and the other protective
groups following procedure well known in the literature.
[0379] 46b) by reacting a compound of formula A.sub.3 defined in
45b) with a compound of formula (IIIo)
A.sub.3+W.sub.3NH--Y.sup.f--ONO.sub.2 (IIIo)
following the same procedure described in 7b).
[0380] 47. The compounds of general formula (I) wherein:
s and m are equal to 1; s', s'', m', m'', are 0 Y is as above
defined;
B is:
##STR00248##
[0381] A is selected among: i) (IIa) wherein R.sub.1 is --H,
R.sub.2 is --C(O)OR.sub.2x and R.sub.2 binds a group
B--Y--ONO.sub.2; and R.sub.a is selected from HS--CH.sub.2--, or
R.sub.xO--CH.sub.2--, R.sub.xO--CH(CH.sub.3)--,
(R.sub.xO)-p-C.sub.6H.sub.4--CH.sub.2--,
4-(R.sub.xO)-3,5-diiodobenzyl-4-(R.sub.xO)-3-nitrobenzyl- wherein
R.sub.x--H; ii) (IIc) wherein R.sub.1 is --H, R.sub.2 is
--C(O)OR.sub.2x and R.sub.2 binds a group B--Y--ONO.sub.2; and
R.sub.a is selected from HS--CH.sub.2--, or R.sub.xO--CH.sub.2--,
R.sub.xO--CH(CH.sub.3)--, (R.sub.xO)-p-C.sub.6H.sub.4--CH.sub.2--,
4-(R.sub.xO)-3,5-diiodobenzyl-4-(R.sub.xO)-3-nitrobenzyl- wherein
R.sub.x--H; iii) (IIs) wherein R.sub.1 is --H, R.sub.3 is --H;
R.sub.s is selected from R.sub.gC(O)CH.sub.2--NH--,
R.sub.gC(O)CH.sub.2, R.sub.gC(O)(CH.sub.2).sub.2--,
R.sub.gC(O)(CH.sub.2).sub.4--, wherein R.sub.g is R.sub.gx--O--,
and R.sub.g binds a group B--Y--ONO.sub.2; v) (IIu) wherein R.sub.1
is --H, R.sub.2 is --C(O)OR.sub.2x, R.sub.2 binds a group
--B--Y--ONO.sub.2; a is 1; b is 0 or 1 and R.sub.x is --H; can be
prepared as follows:
[0382] 47a) by reacting a compound of formula (VIIc)
A.sub.3c-Y--ONO.sub.2 (VIIc)
wherein Y is as above defined and A.sub.3c is a radical of formula
(IIa), (IIc), (IIs) or (IIu) wherein R.sub.2, a, b and R.sub.s are
as defined in 47; R.sub.1 is --C(O)OC(CH.sub.3).sub.3; in formula
(IIs) R.sub.3 is equal to R.sub.3a wherein R.sub.3a is --OTrt,
wherein Trt is the trityl protecting group; in formula (IIa) and
(IIc) R.sub.a and R.sub.c have the meanings: Trt-S--CH.sub.2--, or
R.sub.xaO--CH.sub.2--, R.sub.xaO--CH(CH.sub.3)--,
(R.sub.xaO)-p-C.sub.6H.sub.4--CH.sub.2--,
4-(R.sub.xaO)-3,5-diiodobenzyl-4-(R.sub.xaO)-3-nitrobenzyl- wherein
R.sub.xa is as above defined; In formula (IIu) R.sub.x is equal to
R.sub.xa and is as above defined; with anhydrous or aqueous organic
or inorganic acid to hydrolyze the --BOC and the other protective
groups following procedure well known in the literature.
[0383] 47b) compound (VIIc) can be prepared by reacting a compound
of formula A.sub.3 defined in 45b) with a compound of formula
(IIIg) or (IIIn) depending on the meaning of B
A.sub.3+Hal-W.sub.1--OC(O)O--Y--ONO.sub.2 (IIIg)
A.sub.3+Hal-W.sub.1--OC(O)--Y--ONO.sub.2 (IIIn)
following the same procedure described in 4b) or 6b).
[0384] 48. The compounds of general formula (I) wherein:
s is equal to 1; s', s'', m, m', m'', are 0 Y is as above defined;
A is selected among: i) (IIa) wherein R.sub.1 is --C(O)R.sub.1x,
and R.sub.1 binds a group Y--ONO.sub.2; R.sub.2 is --COOH; and
R.sub.a is selected from HS--CH.sub.2--, or R.sub.xO--CH.sub.2--,
R.sub.xO--CH(CH.sub.3)--, (R.sub.xO)-p-C.sub.6H.sub.4--CH.sub.2--,
4-(R.sub.xO)-3,5-diiodobenzyl-4-(R.sub.xO)-3-nitrobenzyl- wherein
R.sub.x--H; ii) (IIc) wherein R.sub.1 is --C(O)R.sub.1x, and
R.sub.1 binds a group Y--ONO.sub.2; R.sub.2 is --COOH; and R.sub.a
is selected from HS--CH.sub.2--, or R.sub.xO--CH.sub.2--,
R.sub.xO--CH(CH.sub.3)--, (R.sub.xO)-p-C.sub.6H.sub.4--CH.sub.2--,
4-(R.sub.xO)-3,5-diiodobenzyl-4-(R.sub.xO)-3-nitrobenzyl- wherein
R.sub.x--H; iii) (IIs) wherein R.sub.1 is --C(O)--R.sub.1x and
R.sub.1 binds a group Y--ONO.sub.2; R.sub.3 is --H; R.sub.s is
selected from R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is --OH; v) (IIu) wherein and R.sub.1 binds a group
--Y--ONO.sub.2; R.sub.2 is --COOH, a is 1, b is 0 or 1; R.sub.x is
--H; can be prepared as follows:
[0385] 48a) by reacting a compound of formula (VIId)
A.sub.4a-Y--ONO.sub.2 (VIId)
wherein Y, is as above defined and A.sub.4a is a radical of formula
(IIa), (IIc), (IIs) or (IIu) wherein; R.sub.1, R.sub.2, a, b and
R.sub.s are as defined in 48; in formula (IIs) R.sub.3 is R.sub.3a
and is --OTrt; in formula (IIa) and (IIc) R.sub.a and R.sub.c are
TrtS--CH.sub.2--, or R.sub.xaO--CH.sub.2--,
R.sub.xaO--CH(CH.sub.3)--,
(R.sub.xaO)-p-C.sub.6H.sub.4--CH.sub.2--,
4-(R.sub.xaO)-3,5-diiodobenzyl-4-(R.sub.xaO)-3-nitrobenzyl- wherein
R.sub.xa is -Trt or the group dimethyl-tert-butylsilyl; R.sub.x of
formula (IIu) is H or R.sub.xa wherein R.sub.xa is as above
defined; with anhydrous or aqueous organic or inorganic acid to
remove the protective groups following procedure well known in the
literature.
[0386] 48b) compound (VIId) are prepared by reacting a compound of
formula A.sub.4 with a compound of formula (IIIe)
A.sub.4+Act-C(O)--Y--ONO.sub.2 (IIIe)
Wherein Act and Y are as above defined, A.sub.4 is a radical of
formula (IIa), (IIc), (IIs) or (IIu) wherein R.sub.1 is --H,
R.sub.2 is --COOH, a and b are as above defined in 48, R.sub.3 is
R.sub.3a, R.sub.a and R.sub.c are TrtS--CH.sub.2--, or
R.sub.xaO--CH.sub.2--, R.sub.xaO--CH(CH.sub.3)--,
(R.sub.xaO)-p-C.sub.6H.sub.4--CH.sub.2--,
4-(R.sub.xaO)-3,5-diiodobenzyl-4-(R.sub.xaO)-3-nitrobenzyl- wherein
R.sub.xa is -Trt or dimethyl-tert-butylsilyl; R.sub.x of formula
(IIu) is H or R.sub.xa wherein R.sub.xa is as above defined;
R.sub.s is R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is --OH; following the same procedure described in
1b').
[0387] Compounds A.sub.4 are commercially available.
[0388] 49. The compounds of general formula (I) wherein:
s is equal to 1; s', s'', m, m', m'', are 0 Y is as above defined;
A is selected among: i) (IIa) wherein R.sub.1 is --C(O)O--R.sub.1x,
and R.sub.1 binds a group Y--ONO.sub.2; R.sub.2 is --COOH; and
R.sub.a is selected from HS--CH.sub.2--, or R.sub.xO--CH.sub.2--,
R.sub.xO--CH(CH.sub.3)--, (R.sub.xO)-p-C.sub.6H.sub.4--CH.sub.2--,
4-(R.sub.xO)-3,5-diiodobenzyl-4-(R.sub.xO)-3-nitrobenzyl- wherein
R.sub.x--H; ii) (IIc) wherein R.sub.1 is --C(O)O--R.sub.1x, and
R.sub.1 binds a group Y--ONO.sub.2; R.sub.2 is --COOH; and R.sub.a
is selected from HS--CH.sub.2--, or R.sub.xO--CH.sub.2--,
R.sub.xO--CH(CH.sub.3)--, (R.sub.xO)-p-C.sub.6H.sub.4--CH.sub.2--,
4-(R.sub.xO)-3,5-diiodobenzyl-4-(R.sub.xO)-3-nitrobenzyl- wherein
R.sub.x--H; iii) (IIs) wherein R.sub.1 is --C(O)O--R.sub.1x and
R.sub.1 binds a group Y--ONO.sub.2; R.sub.3 is --H; R.sub.s is
selected from R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is --OH; v) (IIu) wherein R.sub.1 is
--C(O)O--R.sub.1x and R.sub.1 binds a group --Y--ONO.sub.2; R.sub.2
is --COOH, a is 1, b is 0 or 1 and R.sub.x is --H; can be prepared
as follows:
[0389] 49a) by reacting a compound of formula (VIIf)
A.sub.4b-Y--ONO.sub.2 (VIIf)
wherein Y is as above defined and A.sub.4b is a radical of formula
(IIa), (IIc), (IIs) or (IIu) wherein; R.sub.1, R.sub.2, a, b and
R.sub.s are as defined in 49; R.sub.3 is R.sub.3a, R.sub.a and
R.sub.c are TrtS--CH.sub.2--, or R.sub.xaO--CH.sub.2--,
R.sub.xaO--CH(CH.sub.3)--,
(R.sub.xaO)-p-C.sub.6H.sub.4--CH.sub.2--,
4-(R.sub.xaO)-3,5-diiodobenzyl-4-(R.sub.xaO)-3-nitrobenzyl- wherein
R.sub.xa is -Trt or dimethyltert-butyl silyl; R.sub.x of formula
(IIu) is H or R.sub.xa wherein R.sub.xa is as above defined; with
anhydrous or aqueous organic or inorganic acid to remove the Trityl
or dimethyltert-butyl silyl protective groups following procedure
well known in the literature.
[0390] 49b) by reacting a compound of formula A.sub.4 with a
compound of formula (IIIf) or (IIIi)
A.sub.4+Act-C(O)O--Y--ONO.sub.2 (IIIf)
A.sub.4+HO--Y--ONO.sub.2
Wherein Act and Y are as above defined, A.sub.4 is as defined in
48b), following the same procedure described in 3b).
[0391] 50. The compounds of general formula (I) wherein:
s and s' are equal to 1; s'', m, m', m'', are 0 Y and Y' are equal
and are as above defined; A is selected among: (IIa) wherein
R.sub.1 is --H, R.sub.2 is --C(O)O, and R.sub.a is selected from
R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is R.sub.gx--O--, both R.sub.2 and R.sub.a bind a
group --Y--ONO.sub.2 or a group --Y'--ONO.sub.2; (IIc) wherein
R.sub.1 is --H, R.sub.2 is --C(O)O, and R.sub.c is selected from
R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is R.sub.gx--O--, both R.sub.2 and R.sub.c bind a
group --Y--ONO.sub.2 or a group --Y'--ONO.sub.2; can be prepared as
follows:
[0392] 50a) by reacting a compound of formula (I) wherein s, s',
s'', m, m', m'', Y, Y', Y'' are as above defined in 50, A is a
radical of formula (IIa), (IIc), wherein; R.sub.2, R.sub.a, R.sub.c
are as defined in 50; R.sub.1 is --C(O)OC(CH.sub.2).sub.2 with
anhydrous or aqueous organic or inorganic acid to hydrolyze the
--BOC protective groups following procedure well known in the
literature.
[0393] 50b) by reacting a compound of formula A with a compound of
formula (IIIi)
A+HO--Y--ONO.sub.2 (IIIi)
wherein Y is as above defined and A is a radical of formula (IIa),
(IIc) wherein R.sub.1 is --C(O)OC(CH.sub.3).sub.3, R.sub.2 is
--COOH, R.sub.a and R.sub.c are selected from
R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is --OH; following the same procedure described in
8b) using a ratio A/(IIIi) 1:2
[0394] 51. The compounds of general formula (I) wherein:
s and s' are equal to 1; s'', m, m', m'', are 0 Y and Y' are equal
and are as above defined; A is selected among: (IIa) wherein
R.sub.1 is --H, R.sub.2 is --C(O)NHR.sub.2xx or
--C(O)N(CH.sub.3)R.sub.2xx and R.sub.a is selected from
R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is R.sub.gxx--NH-- or R.sub.gxx--N(CH.sub.3)-- and
both R.sub.2 and R.sub.a bind a group --Y--ONO.sub.2 or a group
--Y'--ONO.sub.2; (IIc) wherein R.sub.1 is --H, R.sub.2 is
--C(O)NHR.sub.2xx or --C(O)N(CH.sub.3)-- and R.sub.c is selected
from R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is R.sub.gxx--NH-- or R.sub.gxx--N(CH.sub.3)-- and
both R.sub.2 and R.sub.c bind a group --Y--ONO.sub.2 or a group
--Y'--ONO.sub.2; can be prepared as follows:
[0395] 51a) by reacting a compound of formula (I) wherein s, s',
s'', m, m', m'', Y, Y', Y'' are as above defined in 51, A is a
radical of formula (IIa), (IIc), wherein R.sub.2, R.sub.a, R.sub.c
are as defined in 51; R.sub.1 is --C(O)OC(CH.sub.3).sub.3 with
anhydrous or aqueous organic or inorganic acid to hydrolyze the
--BOC protective groups following procedure well known in the
literature.
[0396] 51b) by reacting a compound of formula A with a compound of
formula (IIIo)
A+W.sub.3NH--Y--ONO.sub.2 (IIIo)
wherein Y is as above defined, W.sub.3 is as above defined and A is
a radical of formula (IIa), (IIc) wherein R.sub.1 is
--C(O)OC(CH.sub.3).sub.3, R.sub.2 is --COOH, R.sub.a and R.sub.c
are selected from R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is --OH; following the same procedure described in
7b) using a ratio A/(IIIo) 1:2.
[0397] 52. The compounds of general formula (I) wherein:
s and s' are equal to 1; m and m' are equal to 1; m'' and s'' are
0
B is:
##STR00249##
[0398] Y and Y' are equal and are as above defined; A is selected
among (IIa) and (IIc) wherein R.sub.1 is --H and R.sub.2 is
--C(O)OR.sub.2x and binds a group --B--Y--ONO.sub.2 or
--B'--Y'--ONO.sub.2; R.sub.a and R.sub.c are selected from
R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is R.sub.gx--O--, and R.sub.a and R.sub.c bind one
of the groups --B--Y--ONO.sub.2 or --B'--Y'--ONO.sub.2; Can be
prepared as follows:
[0399] 52a) by reacting a compound of formula (I) wherein B, s, s',
s'', m, m', m'', Y, Y', Y'' are as above defined in 52, A is a
radical of formula (IIa) or (IIc) wherein R.sub.1 is
--C(O)OC(CH.sub.3).sub.3; R.sub.2, R.sub.a and R.sub.c are as
defined in 52;
with anhydrous or aqueous organic or inorganic acid to hydrolyze
the --BOC protective groups following procedure well known in the
literature.
[0400] 52b) by reacting a compound of formula A with a compound of
formula (IIIg)
A+Hal-W.sub.1--OC(O)O--Y--ONO.sub.2 (IIIg)
wherein Y is as above defined and A is selected from (IIa) or (IIc)
wherein R.sub.2 is --COOH and R.sub.1 is --C(O)O(CH.sub.3).sub.3;
R.sub.a and R.sub.c are selected from R.sub.gC(O)CH.sub.2--NH--,
R.sub.gC(O)CH.sub.2, R.sub.gC(O)(CH.sub.2).sub.2--,
R.sub.gC(O)(CH.sub.2).sub.4--, wherein R.sub.g is --OH; using a
ratio A/(IIIg) 1:2 and applying the procedure described in 4b).
[0401] 53. The compounds of general formula (I) wherein:
s and s' are equal to 1; m and m' are equal to 1; m'' and s'' are
0
B is:
##STR00250##
[0402] Y and Y' are equal and are as above defined; A is selected
among (IIa) and (IIc) wherein R.sub.1 is --H and R.sub.2 is
--C(O)OR.sub.2x and binds a group --B--Y--ONO.sub.2 or
--B'--Y'--ONO.sub.2; R.sub.a and R.sub.c are selected from
R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is R.sub.gx--O--, and R.sub.a and R.sub.c bind one
of the groups --B--Y--ONO.sub.2 or --B'--Y'--ONO.sub.2; Can be
prepared as follows:
[0403] 53a) by reacting a compound of formula (I) wherein B, s, s',
s'', m, m', m'', Y, Y', Y'' are as above defined in 53, A is a
radical of formula (IIa) or (IIc) wherein R.sub.1 is
--C(O)OC(CH.sub.3).sub.3; R.sub.2, R.sub.a and R.sub.c are as
defined in 53;
with anhydrous or aqueous organic or inorganic acid to hydrolyze
the --BOC protective groups following procedure well known in the
literature.
[0404] 53b) by reacting a compound of formula A with a compound of
formula (IIIn)
A+Hal-W.sub.1--O(O)C--Y--ONO.sub.2 (IIIn)
wherein Y is as above defined and A is selected from (IIa) or (IIc)
wherein R.sub.2 is --COOH and R.sub.1 is --C(O)O(CH.sub.3).sub.3;
R.sub.a and R.sub.c are selected from R.sub.gC(O)CH.sub.2--NH--,
R.sub.gC(O)CH.sub.2, R.sub.gC(O)(CH.sub.2).sub.2--,
R.sub.gC(O)(CH.sub.2).sub.4--, wherein R.sub.g is --OH; Using a
ratio A/(IIIn) 1:2 and applying the procedure described in 6b).
[0405] 54. The compounds of general formula (I) wherein:
s, s' and s'' are equal to 1; m, m', m'', are 0 Y, Y' and Y'' are
as above defined with the proviso that Y is equal to Y' A is a
radical of formula (IIa) or (IIc) wherein R.sub.1 is
--C(O)--R.sub.1x and it binds the group --Y''--ONO.sub.2, R.sub.2
is --C(O)OR.sub.2x and it binds the group --Y--ONO.sub.2 or
--Y'--ONO.sub.2; R.sub.a and R.sub.c are selected from
R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is R.sub.gxO--, and R.sub.a and R.sub.c bind one of
the groups --Y--ONO.sub.2 or --Y'--ONO.sub.2; can be prepared as
follows:
[0406] 54a) by reacting a compound of formula (I) prepared as
described in 49.
with a compound of formula (IIIe):
##STR00251##
wherein in formula (I) Y and Y' are equal and A is a radical of
formula (IIa) or (IIc) wherein R.sub.1 is --H; R.sub.2, R.sub.a and
R.sub.c are as defined in 54; following the same procedure
described in 1b').
[0407] 55. The compounds of general formula (I) wherein:
s, s' and s'' are equal to 1; m, m', m'', are 0 Y, Y' and Y'' are
as above defined with the proviso that Y is equal to Y' A is a
radical of formula (IIa) or (IIc) wherein R.sub.1 is
--C(O)O--R.sub.1x and it binds the group --Y''--ONO.sub.2, R.sub.2
is --C(O)OR.sub.2x and it binds the group --Y--ONO.sub.2 or
--Y'--ONO.sub.2; R.sub.a and R.sub.c are selected from
R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is R.sub.gxO--, and R.sub.a and R.sub.c bind one of
the groups --Y--ONO.sub.2 or --Y'--ONO.sub.2; can be prepared as
follows:
[0408] 55a) by reacting a compound of formula (I) prepared as
described in 49.
with a compound of formula (IIIf):
##STR00252##
wherein in formula (I) Y and Y' are equal and A has been already
defined in 54; following the same procedure described in 3b).
[0409] 56. The compounds of general formula (I) wherein:
s, s' and s'' are equal to 1; m, m', m'', are 0 Y, Y' and Y'' are
as above defined with the proviso that Y is equal to Y' A is a
radical of formula (IIa) or (IIc) wherein R.sub.1 is
--C(O)--R.sub.1x and it binds the group --Y''--ONO.sub.2, R.sub.2
is --C(O)NHR.sub.2xx or --C(O)N(CH.sub.3)R.sub.2xx and it binds the
group --Y--ONO.sub.2 or --Y'--ONO.sub.2; R.sub.a and R.sub.c are
selected from R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is R.sub.gxNH-- or R.sub.gx--N(CH.sub.3)-- and
R.sub.a and R.sub.c bind one of the groups --Y--ONO.sub.2 or
--Y'--ONO.sub.2; can be prepared as follows:
[0410] 56a) by reacting a compound of formula (I) prepared as
described in 51.
with a compound of formula (IIIe):
##STR00253##
wherein in formula (I) Y and Y' are equal and A is a radical of
formula (IIa) or (IIc) wherein R.sub.1 is --H; R.sub.2, R.sub.a and
R.sub.c are as defined in 56; following the same procedure
described in 1b').
[0411] 57. The compounds of general formula (I) wherein:
s, s' and s'' are equal to 1; m, m', m'', are 0 Y, Y' and Y'' are
as above defined with the proviso that Y is equal to Y' A is a
radical of formula (IIa) or (IIc) wherein R.sub.1 is
--C(O)O--R.sub.1x and it binds the group --Y''--ONO.sub.2, R.sub.2
is --C(O)NHR.sub.2xx or --C(O)N(CH.sub.3)R.sub.2xx and it binds the
group --Y--ONO.sub.2 or --Y'--ONO.sub.2; R.sub.a and R.sub.c are
selected from R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is R.sub.gxNH-- or R.sub.gxN(CH.sub.3)-- and
R.sub.a and R.sub.c bind one of the groups --Y--ONO.sub.2 or
--Y'--ONO.sub.2; can be prepared as follows: 57a) by reacting a
compound of formula (I) prepared as described in 51. with a
compound of formula (IIIf):
##STR00254##
wherein in formula (I) Y and Y' are equal and A has been already
defined in 56; following the same procedure described in 3b).
[0412] 58. The compounds of general formula (I) wherein:
s, s' and s'' are equal to 1; m and m' are equal to 1; m'' is
0;
B is:
##STR00255##
[0413] Y, Y' and Y'' are as above defined with the proviso that Y
is equal to Y' A is a radical of formula (IIa) or (IIc) wherein
R.sub.1 is --C(O)--R.sub.1x and it binds the group
--Y''--ONO.sub.2, R.sub.2 is --C(O)OR.sub.2x and it binds the group
B--Y--ONO.sub.2 or B--Y'--ONO.sub.2 wherein B--Y--ONO.sub.2 or
B--Y'--ONO.sub.2 are equal; R.sub.a and R.sub.c are selected from
R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is R.sub.gxO--, and R.sub.a and R.sub.c bind one of
the groups a group B--Y--ONO.sub.2 or B--Y'--ONO.sub.2 wherein
B--Y--ONO.sub.2 or B--Y'--ONO.sub.2 are equal; can be prepared as
follows:
[0414] 58a) by reacting a compound of formula (I) prepared as
described in 52. if B is:
##STR00256##
or prepared in 53. if B is:
##STR00257##
with a compound of formula (IIIe):
##STR00258##
wherein in formula (I) B, Y and Y' are as defined in 58; and A is a
radical of formula (IIa) or (IIc) wherein R.sub.1 is --H; R.sub.2,
R.sub.a and R.sub.c are as defined in 58; following the same
procedure described in 1b').
[0415] 59. The compounds of general formula (I) wherein:
s, s' and s'' are equal to 1; m and m' are equal to 1; m'' is
0;
B is:
##STR00259##
[0416] Y, Y' and Y'' are as above defined with the proviso that Y
is equal to Y' A is a radical of formula (IIa) or (IIc) wherein
R.sub.1 is --C(O)O--R.sub.1x and it binds the group
--Y''--ONO.sub.2, R.sub.2 is --C(O)OR.sub.2x and it binds the group
B--Y--ONO.sub.2 or B--Y'--ONO.sub.2 wherein B--Y--ONO.sub.2 or
B--Y'--ONO.sub.2 are equal; R.sub.a and R.sub.c are selected from
R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is R.sub.gx--O--, and R.sub.a and R.sub.c bind one
of the groups a group B--Y--ONO.sub.2 or B--Y'--ONO.sub.2 wherein
B--Y--ONO.sub.2 or B--Y'--ONO.sub.2 are equal; can be prepared as
follows:
[0417] 59a) by reacting a compound of formula (I) prepared as
described in 52. if B is:
##STR00260##
or prepared in 53. if B is:
##STR00261##
with a compound of formula (IIIf):
##STR00262##
wherein in formula (I) B, Y and Y' are as defined in 59; A is a
radical of formula (IIa) or (IIc) wherein R.sub.1 is --H; R.sub.2,
R.sub.a and R.sub.c are as defined in 59; following the same
procedure described in 3b).
[0418] 60. The compounds of general formula (I) wherein:
s, is equal to 1; s', s'', m, m' and m'' are equal to 0; Y is as
above defined; A is selected from (IIa) and (IIc) wherein R.sub.1
is --C(O)--R.sub.1x and binds a group --Y--ONO.sub.2, R.sub.2 is
--COOH; R.sub.a and R.sub.c are selected from
R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is --OH; can be prepared as follows:
[0419] 60a) by reacting a compound of formula A with a compound of
formula (IIIe)
A+Act-(O)C--Y--ONO.sub.2 (IIIe)
wherein Y is as above defined and A is a commercially available
compound of formula (IIa) or (IIc) wherein R.sub.2 is --COOH and
R.sub.1 is --H; R.sub.a and R.sub.c are selected from
R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is --OH; applying the procedure described in
1b').
[0420] 61. The compounds of general formula (I) wherein:
s, is equal to 1; s', s'', m, m' and m'' are equal to 0; Y is as
above defined; A is selected from (IIa) and (IIc) wherein R.sub.1
is --C(O)O--R.sub.1x and binds a group --Y--ONO.sub.2, R.sub.2 is
--COOH; R.sub.a and R.sub.c are selected from
R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is --OH; can be prepared as follows:
[0421] 61a) by reacting a compound of formula A with a compound of
formula (IIIf)
A+Act-(O)C--O--Y--ONO.sub.2 (IIIf)
wherein Y is as above defined and A is as defined in 60a) applying
the procedure described in 3b).
[0422] 62. Alternatively compounds (I) described in 54. can be
prepared starting from compounds (I) prepared as described in 60.
and compounds (IIIf) applying the same procedure described in 8b)
using a ratio (I)/(IIIi) 1:2. In this case Y' and Y'' are
equal.
##STR00263##
[0423] 63. Alternatively compounds (I) described in 55. can be
prepared starting from compounds (I) prepared as described in 61.
and compounds (IIIi) applying the same procedure described in 8b)
using a ratio (I)/(IIIi) 1:2. In this case Y' and Y'' are
equal.
##STR00264##
[0424] 64. Alternatively compounds (I) described in 56. can be
prepared starting from compounds (I) prepared as described in 60.
and compounds (IIIo) applying the same procedure described in 7b)
using a ratio (I)/(IIIo) 1:2. In this case Y' and Y'' are
equal.
##STR00265##
[0425] 65. Alternatively compounds (I) described in 57. can be
prepared starting from compounds (I) prepared as described in 61.
and compounds (IIIo) applying the same procedure described in 7b)
using a ratio (I)/(IIIo) 1:2. In this case Y' and Y'' are
equal.
##STR00266##
[0426] 66. Alternatively compounds (I) described in 58. can be
prepared starting from compounds (I) prepared as described in 60.
and compounds (IIIg) or (IIIn) depending on the meaning of B, and
applying the same procedure described in 4b) or 6b) using a ratio
(I)/(IIIg) or (I)/(IIIn) 1:2. In this case Y' and Y'' are
equal.
##STR00267##
[0427] 67. Alternatively compounds (I) described in 59. can be
prepared starting from compounds (I) prepared as described in 61.
and compounds (IIIg) or (IIIn) depending on the meaning of B, and
applying the same procedure described in 4b) or 6b) using a ratio
(I)/(IIIg) or (I)/(IIIn) 1:2. In this case Y' and Y'' are
equal.
##STR00268##
[0428] 68. The compounds of general formula (I) wherein:
s is equal to 1; s', s'', m, m', m'', are 0 Y is as above defined;
A is selected among: (IIa) wherein R.sub.1 is --H, R.sub.2 is
--C(O)OR.sub.2x and R.sub.2 binds a group --Y--ONO.sub.2; R.sub.a
is selected from R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is --OH; (IIc) wherein R.sub.1 is --H, R.sub.2 is
--C(O)OR.sub.2x and R.sub.2 binds a group --Y--ONO.sub.2; R.sub.a
is selected from R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is --OH; can be prepared as follows:
[0429] 68a) by reacting a compound of formula (I) wherein s, s',
s'', m, m', m'', Y, Y', Y'' are as above defined in 68, A is a
radical of formula (IIa), (IIc), wherein R.sub.2 is as above
defined in 68; R.sub.1 is --C(O)OC(CH.sub.3).sub.3; R.sub.a and
R.sub.c are R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is --C(O)OC(CH.sub.3).sub.3;
with anhydrous or aqueous organic or inorganic acid to hydrolyze
the tert-butyl esters and the --BOC protective groups following
procedure well known in the literature.
[0430] 68b) by reacting a compound of formula A with a compound of
formula (IIIi)
A+HO--Y--ONO.sub.2 (IIIi)
wherein Y is as above defined and A is a compound of formula (IIa)
or (IIc) wherein R.sub.1 is --C(O)OC(CH.sub.3).sub.3, R.sub.2 is
--COOH, R.sub.a and R.sub.c are selected from
R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is --C(O)OC(CH.sub.3).sub.3; following the same
procedure described in 8b). Compounds A are commercially
available.
[0431] 69. The compounds of general formula (I) wherein:
s is equal to 1; s', s'', m, m', m'', are 0 Y is as above defined;
A is a radical of formula (IIa) wherein R.sub.1 is --H, R.sub.2 is
--C(O)NHR.sub.2xx or --C(O)N(CH.sub.3)R.sub.2xx and R.sub.2 binds a
group --Y--ONO.sub.2; R.sub.a is selected from
R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is --OH; or (IIc) wherein R.sub.1 is --H, R.sub.2
is --C(O)NHR.sub.2xx or --C(O)N(CH.sub.3)R.sub.2xx and R.sub.2
binds a group --Y--ONO.sub.2; R.sub.c is selected from
R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is --OH; can be prepared as follows:
[0432] 69a) by reacting a compound of formula (I) wherein s, s',
s'', m, m', m'', Y, Y', Y'' are as above defined in 69, A is a
radical of formula (IIa), (IIc), wherein R.sub.2 is as above
defined in 69; R.sub.1 is --C(O)OC(CH.sub.3).sub.3; R.sub.a and
R.sub.c are R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is --C(O)OC(CH.sub.3).sub.3;
with anhydrous or aqueous organic or inorganic acid to hydrolyze
the tert-butyl esters and the --BOC protective groups following
procedure well known in the literature.
[0433] 69b) by reacting a compound of formula A with a compound of
formula (IIIo)
A+W.sub.3NH--Y--ONO.sub.2 (IIIo)
wherein Y is as above defined, W.sub.3 is as above defined and A is
as defined in 68b), following the same procedure described in
7b).
[0434] 70. The compounds of general formula (I) wherein:
s and m are equal to 1; s', s'', m', m'', are 0 Y is as above
defined;
B is:
##STR00269##
[0435] A is a radical selected among: (IIa) wherein R.sub.1 is --H,
R.sub.2 is --C(O)OR.sub.2x and R.sub.2 binds a group
--B--Y--ONO.sub.2; R.sub.a is selected from
R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is --OH; (IIc) wherein R.sub.1 is --H, R.sub.2 is
--C(O)OR.sub.2x and R.sub.2 binds a group --B--Y--ONO.sub.2;
R.sub.c is selected from R.sub.gC(O)CH.sub.2--NH--,
R.sub.gC(O)CH.sub.2, R.sub.gC(O)(CH.sub.2).sub.2--,
R.sub.gC(O)(CH.sub.2).sub.4--, wherein R.sub.g is --OH; can be
prepared as follows:
[0436] 70a) by reacting a compound of formula (I) wherein s, s',
s'', m, m', m'', B, Y, Y', Y'' are as above defined in 70, A is a
radical of formula (IIa), (IIc), wherein R.sub.2 is as above
defined in 70; R.sub.1 is --C(O)OC(CH.sub.3).sub.3; R.sub.a and
R.sub.c are R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is --C(O)OC(CH.sub.3).sub.3;
with anhydrous or aqueous organic or inorganic acid to hydrolyze
the tert-butyl esters and the --BOC protective groups following
procedure well known in the literature.
[0437] 70b) by reacting a compound of formula A with a compound of
formula (IIIg) or (IIIn) depending on the meaning of B
A+Hal-W.sub.1--OC(O)O--Y--ONO.sub.2 (IIIg)
A+Hal-W.sub.1--OC(O)--Y--ONO.sub.2 (IIIn)
wherein Y, Hal, W.sub.1 are as above defined and A is as defined in
68b), following the same procedures described in 4b) or 6b).
[0438] 71. The compounds of general formula (I) wherein:
s is equal to 1; s', s'', m, m', m'', are 0 Y is as above defined;
A is selected among: (IIa) wherein R.sub.1 is --H, R.sub.2 is
--COOH; R.sub.a is selected from R.sub.gC(O)CH.sub.2--NH--,
R.sub.gC(O)CH.sub.2, R.sub.gC(O)(CH.sub.2).sub.2--,
R.sub.gC(O)(CH.sub.2).sub.4--, wherein R.sub.g is R.sub.gx--O--,
and R.sub.a binds a group --Y--ONO.sub.2; (IIc) wherein R.sub.1 is
--H, R.sub.2 is --COOH; R.sub.a is selected from
R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is R.sub.gx--O--, and R.sub.a binds a group
--Y--ONO.sub.2, can be prepared as follows:
[0439] 71a) by reacting a compound of formula (I) wherein s, s',
s'', m, m', m'', Y, Y', Y'' are as above defined in 71, A is a
radical of formula (IIa), (IIc), R.sub.a and R.sub.c are as above
defined in 71; R.sub.1 is --C(O)OC(CH.sub.3).sub.3; R.sub.2 is
--C(O)OC(CH.sub.3).sub.3;
with anhydrous or aqueous organic or inorganic acid to hydrolyze
the tert-butyl esters and the --BOC protective groups following
procedure well known in the literature.
[0440] 68b) by reacting a compound of formula A with a compound of
formula (IIIi)
A+HO--Y--ONO.sub.2 (IIIi)
wherein Y is as above defined and A is a radical of formula (IIa),
(IIc) wherein R.sub.1 is --C(O)OC(CH.sub.3).sub.3, R.sub.2 is
--C(O)OC(CH.sub.3).sub.3, R.sub.a and R.sub.c are selected from
R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is --OH; following the same procedure described in
8b).
[0441] Compounds A are commercially available.
[0442] 72. The compounds of general formula (I) wherein:
s is equal to 1; s', s'', m, m', m'', are 0 Y is as above defined;
A is selected among: (IIa) wherein R.sub.1 is --H, R.sub.2 is
--COOH; R.sub.a is selected from R.sub.gC(O)CH.sub.2--NH--,
R.sub.gC(O)CH.sub.2, R.sub.gC(O)(CH.sub.2).sub.2--,
R.sub.gC(O)(CH.sub.2).sub.4--, wherein R.sub.g is R.sub.gxx--NH--
or R.sub.gxx--N(CH.sub.3)-- and R.sub.a binds a group
--Y--ONO.sub.2; (IIc) wherein R.sub.1 is --H, R.sub.2 is --COOH;
R.sub.a is selected from R.sub.gC(O)CH.sub.2--NH--,
R.sub.gC(O)CH.sub.2, R.sub.gC(O)(CH.sub.2).sub.2--,
R.sub.gC(O)(CH.sub.2).sub.4--, wherein R.sub.g is R.sub.gxx--NH--
or R.sub.gxx--N(CH.sub.3)-- and R.sub.c binds a group
--Y--ONO.sub.2; can be prepared as follows:
[0443] 72a) by reacting a compound of formula (I) wherein s, s',
s'', m, m', m'', Y, Y', Y'' are as above defined in 72, A is a
radical of formula (IIa), (IIc), wherein R.sub.a and R.sub.c are as
above defined in 71; R.sub.1 is --C(O)OC(CH.sub.3).sub.3; R.sub.2
is --C(O)OC(CH.sub.3).sub.3;
with anhydrous or aqueous organic or inorganic acid to hydrolyze
the tert-butyl esters and the --BOC protective groups following
procedure well known in the literature.
[0444] 72b) by reacting a compound of formula A with a compound of
formula (IIIo):
A+W.sub.3NH--Y--ONO.sub.2 (IIIo)
wherein Y and W.sub.3 are as above defined and A is as defined in
71b) following the same procedure described in 7b).
[0445] 73. The compounds of general formula (I) wherein:
s and m are equal to 1; s', s'', m', m'', are 0 Y is as above
defined;
B is:
##STR00270##
[0446] A is selected among: (IIa) wherein R.sub.1 is --H, R.sub.2
is --COOH; R.sub.a is selected from R.sub.gC(O)CH.sub.2--NH--,
R.sub.gC(O)CH.sub.2, R.sub.gC(O)(CH.sub.2).sub.2--,
R.sub.gC(O)(CH.sub.2).sub.4--, wherein R.sub.g is R.sub.gx--O--,
and R.sub.a binds a group --B--Y--ONO.sub.2; (IIc) wherein R.sub.1
is --H, R.sub.2 is --COOH; R.sub.a is selected from
R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is R.sub.gx--O--, and R.sub.c binds a group
B--Y--ONO.sub.2; can be prepared as follows:
[0447] 73a) by reacting a compound of formula (I) wherein s, s',
s'', m, m', m'', B, Y, Y', Y'' are as above defined in 73, A is a
radical of formula (IIa), (IIc), wherein R.sub.a and R.sub.c are as
above defined in 71; R.sub.1 is --C(O)OC(CH.sub.3).sub.3; R.sub.2
is --C(O)OC(CH.sub.3).sub.3;
with anhydrous or aqueous organic or inorganic acid to hydrolyze
the tert-butyl esters and the --BOC protective groups following
procedure well known in the literature.
[0448] 73b) by reacting a compound of formula A with a compound of
formula (IIIg) or (IIIn) depending on the meaning of B
A+Hal-W.sub.1--OC(O)O--Y--ONO.sub.2 (IIIg)
A+Hal-W.sub.1--OC(O)--Y--ONO.sub.2 (IIIn)
wherein Y, Hal, W.sub.1 are as above defined and A is as defined in
71b), following the same procedures described in 4b) or 6b).
[0449] 74. The compounds of general formula (I) wherein:
s and s' are equal to 1; s'', m, m', m'', are 0 Y and Y' can be
equal or different and are as above defined; A is selected among:
(IIa) wherein R.sub.1 is --C(O)--R.sub.1x and binds a group
--Y'--ONO.sub.2; R.sub.2 is --C(O)OR.sub.2x and binds a group
--Y--ONO.sub.2; R.sub.a is selected from R.sub.gC(O)CH.sub.2--NH--,
R.sub.gC(O)CH.sub.2, R.sub.gC(O)(CH.sub.2).sub.2--,
R.sub.gC(O)(CH.sub.2).sub.4--, wherein R.sub.g is --OH; (IIc)
wherein R.sub.1 is --C(O)--R.sub.1x and binds a group
--Y'--ONO.sub.2; R.sub.2 is --C(O)OR.sub.2x and binds a group
--Y--ONO.sub.2; R.sub.a is selected from R.sub.gC(O)CH.sub.2--NH--,
R.sub.gC(O)CH.sub.2, R.sub.gC(O)(CH.sub.2).sub.2--,
R.sub.gC(O)(CH.sub.2).sub.4--, wherein R.sub.g is --OH; can be
prepared as follows:
[0450] 74a) by reacting a compound of formula (I) prepared as
described in 68. with a compound of formula (IIIe):
##STR00271##
wherein Act, Y and Y' are as above defined and A is a radical of
formula (IIa), (IIc), wherein R.sub.1 is --H, R.sub.2 is
--C(O)OR.sub.2x and binds a group --Y--ONO.sub.2; R.sub.a and
R.sub.c are selected from R.sub.gC(O)CH.sub.2--NH--,
R.sub.gC(O)CH.sub.2, R.sub.gC(O)(CH.sub.2).sub.2--,
R.sub.gC(O)(CH.sub.2).sub.4--, wherein R.sub.g is --OH; following
the same procedures described in 1b').
[0451] 75. The compounds of general formula (I) wherein:
s and s' are equal to 1; s'', m, m', m'', are 0 Y and Y' can be
equal or different and are as above defined; A is selected among:
(IIa) wherein R.sub.1 is --C(O)O--R.sub.1x and binds a group
--Y'--ONO.sub.2; R.sub.2 is --C(O)OR.sub.2x and binds a group
--Y--ONO.sub.2; R.sub.a is selected from R.sub.gC(O)CH.sub.2--NH--,
R.sub.gC(O)CH.sub.2, R.sub.gC(O)(CH.sub.2).sub.2--,
R.sub.gC(O)(CH.sub.2).sub.4--, wherein R.sub.g is --OH; (IIc)
wherein R.sub.1 is --C(O)O--R.sub.1x and binds a group
--Y'--ONO.sub.2; R.sub.2 is --C(O)OR.sub.2x and binds a group
--Y--ONO.sub.2; R.sub.a is selected from R.sub.gC(O)CH.sub.2--NH--,
R.sub.gC(O)CH.sub.2, R.sub.gC(O)(CH.sub.2).sub.2--,
R.sub.gC(O)(CH.sub.2).sub.4--, wherein R.sub.g is --OH; can be
prepared as follows:
[0452] 75a) by reacting a compound of formula (I) prepared as
described in 68. with a compound of formula (IIIf):
##STR00272##
wherein Act, Y and Y' are as above defined and A is as defined in
74a); following the same procedures described in 3b).
[0453] 76. The compounds of general formula (I) wherein:
s and s' are equal to 1; s'', m, m', m'', are 0 Y and Y' can be
equal or different and are as above defined; A is selected among:
(IIa) wherein R.sub.1 is --C(O)--R.sub.1x and binds a group
--Y'--ONO.sub.2; R.sub.2 is --C(O)NHR.sub.2xx or
--C(O)N(CH.sub.3)R.sub.2xx and binds a group --Y--ONO.sub.2;
R.sub.a is selected from R.sub.gC(O)CH.sub.2--NH--,
R.sub.gC(O)CH.sub.2, R.sub.gC(O)(CH.sub.2).sub.2--,
R.sub.gC(O)(CH.sub.2).sub.4--, wherein R.sub.g is --OH; (IIc)
wherein R.sub.1 is --C(O)--R.sub.1x and binds a group
--Y'--ONO.sub.2; R.sub.2 is --C(O)NHR.sub.2xx or
--C(O)N(CH.sub.3)R.sub.2xx and binds a group --Y--ONO.sub.2;
R.sub.a is selected from R.sub.gC(O)CH.sub.2--NH--,
R.sub.gC(O)CH.sub.2, R.sub.gC(O)(CH.sub.2).sub.2--,
R.sub.gC(O)(CH.sub.2).sub.4--, wherein R.sub.g is --OH; can be
prepared as follows:
[0454] 76a) by reacting a compound of formula (I) prepared as
described in 69. with a compound of formula (IIIe):
##STR00273##
wherein Act, Y and Y' are as above defined and A is a radical of
formula (IIa), (IIc), wherein R.sub.1 is --H, R.sub.2 is
--C(O)NHR.sub.2xx or --C(O)N(CH.sub.3)R.sub.2xx and binds a group
--Y--ONO.sub.2; R.sub.a and R.sub.c are selected from
R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is --OH; following the same procedures described in
1b').
[0455] 77. The compounds of general formula (I) wherein:
s and s' are equal to 1; s'', m, m', m'', are 0 Y and Y' can be
equal or different and are as above defined; A is selected among:
(IIa) wherein R.sub.1 is --C(O)O--R.sub.1x and binds a group
--Y'--ONO.sub.2; R.sub.2 is --C(O)NHR.sub.2xx or
--C(O)N(CH.sub.3)R.sub.2xx and binds a group --Y--ONO.sub.2;
R.sub.a is selected from R.sub.gC(O)CH.sub.2--NH--,
R.sub.gC(O)CH.sub.2, R.sub.gC(O)(CH.sub.2).sub.2--,
R.sub.gC(O)(CH.sub.2).sub.4--, wherein R.sub.g is --OH; (IIc)
wherein R.sub.1 is --C(O)O--R.sub.1x and binds a group
--Y'--ONO.sub.2; R.sub.2 is --C(O)NHR.sub.2xx or
--C(O)N(CH.sub.3)R.sub.2xx and binds a group --Y--ONO.sub.2;
R.sub.a is selected from R.sub.gC(O)CH.sub.2--NH--,
R.sub.gC(O)CH.sub.2, R.sub.gC(O)(CH.sub.2).sub.2--,
R.sub.gC(O)(CH.sub.2).sub.4--, wherein R.sub.g is --OH; can be
prepared as follows:
[0456] 77a) by reacting a compound of formula (I) prepared as
described in 69. with a compound of formula (IIIf):
##STR00274##
wherein Act, Y and Y' are as above defined and A is as above
defined in 76, following the same procedures described in 3b).
[0457] 78. The compounds of general formula (I) wherein:
s, s' and m are equal to 1; s'', m', m'', are 0 Y and Y' can be
equal or different and are as above defined;
B is:
##STR00275##
[0458] A is selected among: (IIa) wherein R.sub.1 is
--C(O)--R.sub.1x and binds a group --Y'--ONO.sub.2; R.sub.2 is
--C(O)OR.sub.2x and binds a group --B--Y--ONO.sub.2; R.sub.a is
selected from R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is --OH; (IIc) wherein R.sub.1 is --C(O)--R.sub.1x
and binds a group --Y'--ONO.sub.2; R.sub.2 is --C(O)OR.sub.2x and
binds a group --B--Y--ONO.sub.2; R.sub.x is selected from
R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is --OH; can be prepared as follows:
[0459] 78a) by reacting a compound of formula (I) prepared as
described in 70. with a compound of formula (IIIe):
##STR00276##
wherein Act, B, Y and Y' are as above defined and A is a radical of
formula (IIa), (IIc), wherein R.sub.1 is --H, R.sub.2 is
--C(O)OR.sub.2x and binds a group B--Y--ONO.sub.2; R.sub.a and
R.sub.c are selected from R.sub.gC(O)CH.sub.2--NH--,
R.sub.gC(O)CH.sub.2, R.sub.gC(O)(CH.sub.2).sub.2--,
R.sub.gC(O)(CH.sub.2).sub.4--, wherein R.sub.g is --OH; following
the same procedures described in 1b').
[0460] 79. The compounds of general formula (I) wherein:
s, s' and m are equal to 1; s'', m', m'', are 0 Y and Y' can be
equal or different and are as above defined;
B is:
##STR00277##
[0461] A is selected among: (IIa) wherein R.sub.1 is
--C(O)O--R.sub.1x and binds a group --Y'--ONO.sub.2; R.sub.2 is
--C(O)OR.sub.2x and binds a group --B--Y--ONO.sub.2; R.sub.a is
selected from R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is --OH; (IIc) wherein R.sub.1 is --C(O)O--R.sub.1x
and binds a group --Y'--ONO.sub.2; R.sub.2 is --C(O)OR.sub.2x and
binds a group --B--Y--ONO.sub.2; R.sub.a is selected from
R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is --OH; can be prepared as follows:
[0462] 79a) by reacting a compound of formula (I) prepared as
described in 70. with a compound of formula (IIIf):
##STR00278##
wherein Act, B, Y and Y' are as above defined and A is as defined
in 78a), following the same procedures described in 3b).
[0463] 80. The compounds of general formula (I) wherein:
s and s' are equal to 1; s'', m, m', m'', are 0 Y and Y' can be
equal or different and are as above defined; A is selected among:
(IIa) wherein R.sub.1 is --C(O)--R.sub.1x and it binds a group
--Y'--ONO.sub.2; R.sub.2 is --COOH; R.sub.a is selected from
R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is R.sub.gx--O--, and R.sub.a binds a group
--Y--ONO.sub.2 (IIc) wherein R.sub.1 is --C(O)--R.sub.1x and binds
a group --Y'--ONO.sub.2; R.sub.2 is --COOH; R.sub.c is selected
from R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is R.sub.gx--O--, and R.sub.c binds a group
--Y--ONO.sub.2; can be prepared as follows:
[0464] 80a) by reacting a compound of formula (I) prepared as
described in 71. with a compound of formula (IIIe):
##STR00279##
wherein Act, Y and Y' are as above defined and A is a radical of
formula (IIa), (IIc), wherein R.sub.1 is --H, R.sub.2 is --COOH;
R.sub.a and R.sub.c are selected from R.sub.gC(O)CH.sub.2--NH--,
R.sub.gC(O)CH.sub.2, R.sub.gC(O)(CH.sub.2).sub.2--,
R.sub.gC(O)(CH.sub.2).sub.4--, wherein R.sub.g is R.sub.gx--O--,
and R.sub.a and R.sub.c bind a group --Y--ONO.sub.2 following the
same procedures described in 1b').
[0465] 81. The compounds of general formula (I) wherein:
s and s' are equal to 1; s'', m, m', m'', are 0 Y and Y' can be
equal or different and are as above defined; A is selected among:
(IIa) wherein R.sub.1 is --C(O)O--R.sub.1x and it binds a group
--Y'--ONO.sub.2; R.sub.2 is --COOH; R.sub.a is selected from
R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2f
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is R.sub.gx--O--, and R.sub.a binds a group
--Y--ONO.sub.2 (IIc) wherein R.sub.1 is --C(O)O--R.sub.1x and binds
a group --Y'--ONO.sub.2; R.sub.2 is --COOH; R.sub.a is selected
from R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is R.sub.gx--O--, and R.sub.c binds a group
--Y--ONO.sub.2; can be prepared as follows:
[0466] 81a) by reacting a compound of formula (I) prepared as
described in 71. with a compound of formula (IIIf):
##STR00280##
wherein Act, Y and Y' are as above defined and A is a radical of
formula (IIa), (IIc), wherein R.sub.1 is --H, R.sub.2 is --COOH;
R.sub.a and R.sub.c are selected from R.sub.gC(O)CH.sub.2--NH--,
R.sub.gC(O)CH.sub.2, R.sub.gC(O)(CH.sub.2).sub.2--,
R.sub.gC(O)(CH.sub.2).sub.4--, wherein R.sub.g is R.sub.gxO-- and
R.sub.a and R.sub.c bind a group --Y--ONO.sub.2, following the same
procedures described in 3b).
[0467] 82. The compounds of general formula (I) wherein:
s and s' are equal to 1; s'', m, m', m'', are 0 Y and Y' can be
equal or different and are as above defined; A is selected among:
(IIa) wherein R.sub.1 is --C(O)--R.sub.1x and it binds a group
--Y'--ONO.sub.2; R.sub.2 is --COOH; R.sub.a is selected from
R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is R.sub.gxx--NH-- or R.sub.gxx--N(CH.sub.3)-- and
R.sub.a binds a group --Y--ONO.sub.2 (IIc) wherein R.sub.1 is
--C(O)--R.sub.1x and it binds a group --Y'--ONO.sub.2; R.sub.2 is
--COOH; R.sub.a is selected from R.sub.gC(O)CH.sub.2--NH--,
R.sub.gC(O)CH.sub.2, R.sub.gC(O)(CH.sub.2).sub.2--,
R.sub.gC(O)(CH.sub.2).sub.4--, wherein R.sub.g is R.sub.gxx--NH--
or R.sub.gxx--N(CH.sub.3)-- and R.sub.c binds a group
--Y--ONO.sub.2; can be prepared as follows:
[0468] 82a) by reacting a compound of formula (I) prepared as
described in 72. with a compound of formula (IIIe):
##STR00281##
wherein Act, Y and Y' are as above defined and A is a radical of
formula (IIa), (IIc), wherein R.sub.1 is --H, R.sub.2 is --COOH;
R.sub.a and R.sub.c are selected from R.sub.gC(O)CH.sub.2--NH--,
R.sub.gC(O)CH.sub.2, R.sub.gC(O)(CH.sub.2).sub.2--,
R.sub.gC(O)(CH.sub.2).sub.4--, wherein R.sub.g is R.sub.gxx--NH--
or R.sub.gxx--N(CH.sub.3)-- and R.sub.a and R.sub.c bind a group
--Y--ONO.sub.2 following the same procedures described in 1b').
[0469] 83. The compounds of general formula (I) wherein:
s and s' are equal to 1; s'', m, m', m'', are 0 Y and Y' can be
equal or different and are as above defined; A is selected among:
(IIa) wherein R.sub.1 is --C(O)O--R.sub.1x and binds a group
--Y'--ONO.sub.2; R.sub.2 is --COOH; R.sub.a is selected from
R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is R.sub.gxx--NH-- or R.sub.gxx--N(CH.sub.3)-- and
R.sub.a binds a group --Y--ONO.sub.2 (IIc) wherein R.sub.1 is
--C(O)O--R.sub.1x and binds a group --Y'--ONO.sub.2; R.sub.2 is
--COOH; R.sub.c is selected from R.sub.gC(O)CH.sub.2--NH--,
R.sub.gC(O)CH.sub.2, R.sub.gC(O)(CH.sub.2).sub.2--,
R.sub.gC(O)(CH.sub.2).sub.4--, wherein R.sub.g is R.sub.gxx--NH--
or R.sub.gxx--N(CH.sub.3)-- and R.sub.c binds a group
--Y--ONO.sub.2; can be prepared as follows:
[0470] 83a) by reacting a compound of formula (I) prepared as
described in 72. with a compound of formula (IIIf):
##STR00282##
wherein Act, Y and Y' are as above defined and A is as defined in
82a), following the same procedures described in 3b).
[0471] 84. The compounds of general formula (I) wherein:
s, s'and m are equal to 1; s'', m', m'', are 0 Y and Y' can be
equal or different and are as above defined;
B is:
##STR00283##
[0472] A is selected among: (IIa) wherein R.sub.1 is
--C(O)--R.sub.1x and binds a group --Y'--ONO.sub.2; R.sub.2 is
--COOH; R.sub.a is selected from R.sub.gC(O)CH.sub.2--NH--,
R.sub.gC(O)CH.sub.2, R.sub.gC(O)(CH.sub.2).sub.2--,
R.sub.gC(O)(CH.sub.2).sub.4--, wherein R.sub.g is R.sub.gx--O--,
and R.sub.a binds a group --B--Y--ONO.sub.2; (IIc) wherein R.sub.1
is --C(O)--R.sub.1x and binds a group --Y'--ONO.sub.2; R.sub.2 is
--COOH; R.sub.c is selected from R.sub.gC(O)CH.sub.2--NH--,
R.sub.gC(O)CH.sub.2, R.sub.gC(O)(CH.sub.2).sub.2--,
R.sub.gC(O)(CH.sub.2).sub.4--, wherein R.sub.g is R.sub.gx--O--,
and R.sub.c binds a group --B--Y--ONO.sub.2; can be prepared as
follows:
[0473] 84a) by reacting a compound of formula (I) prepared as
described in 73. with a compound of formula (IIIe):
##STR00284##
wherein Act, B, Y and Y' are as above defined and A is a radical of
formula (IIa), (IIc), wherein R.sub.1 is --H, R.sub.2 is --COOH;
R.sub.a and R.sub.c are selected from R.sub.gC(O)CH.sub.2--NH--,
R.sub.gC(O)CH.sub.2, R.sub.gC(O)(CH.sub.2).sub.2--,
R.sub.gC(O)(CH.sub.2).sub.4--, wherein R.sub.g is R.sub.gxO-- and
R.sub.a and R.sub.c bind a group B--Y--ONO.sub.2; following the
same procedures described in 1b').
[0474] 85. The compounds of general formula (I) wherein:
s, s'and m are equal to 1; s'', m', m'', are 0 Y and Y' can be
equal or different and are as above defined;
B is:
##STR00285##
[0475] A is selected among: (IIa) wherein R.sub.1 is
--C(O)O--R.sub.1x and binds a group --Y'--ONO.sub.2; R.sub.2 is
--COOH; R.sub.a is selected from R.sub.gC(O)CH.sub.2--NH--,
R.sub.gC(O)CH.sub.2, R.sub.gC(O)(CH.sub.2).sub.2--,
R.sub.gC(O)(CH.sub.2).sub.4--, wherein R.sub.g is R.sub.gx--O--,
and R.sub.a binds a group --B--Y--ONO.sub.2; (IIc) wherein R.sub.1
is --C(O)O--R.sub.1x and it binds a group --Y'--ONO.sub.2; R.sub.2
is --COOH; R.sub.c is selected from R.sub.gC(O)CH.sub.2--NH--,
R.sub.gC(O)CH.sub.2, R.sub.gC(O)(CH.sub.2).sub.2--,
R.sub.gC(O)(CH.sub.2).sub.4--, wherein R.sub.g is R.sub.gO-- and
R.sub.c binds a group --B--Y--ONO.sub.2; can be prepared as
follows:
[0476] 85a) by reacting a compound of formula (I) prepared as
described in 73. with a compound of formula (IIIf):
##STR00286##
wherein Act, B, Y and Y' are as above defined and A is as defined
in 84a), following the same procedures described in 3b).
[0477] 86. The compounds of general formula (I) wherein:
s and s' are equal to 1; s'', m, m' and m'' are equal to 0; Y and
Y' are equal and are as above defined; A is selected from (IIa),
(IIc) or (IIt) wherein R.sub.1 is --C(O)--R.sub.1x and it binds a
group --Y--ONO.sub.2 or a group --Y'--ONO.sub.2, R.sub.2 is --COOH;
R.sub.a of formula (IIa) and R.sub.c of formula (IIc) are
R.sub.hNH(CH.sub.2).sub.p-- wherein p is an integer from 0 to 4, or
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--, and R.sub.h and R.sub.i
are R.sub.hh--C(O)-- or R.sub.ii--C(O) and R.sub.a and R.sub.c bind
a group --Y--ONO.sub.2 or a group --Y'--ONO.sub.2; in formula (IIt)
R.sub.1 is --C(O)--R.sub.1x and it binds a group --Y--ONO.sub.2 or
a group --Y'--ONO.sub.2, R.sub.2 is --COOH; d is 2 d' is 1, R.sub.t
is --C(O)--R.sub.tt and it binds a group --Y--ONO.sub.2 or a group
--Y'--ONO.sub.2; can be prepared as follows:
[0478] 86a) by reacting a compound of formula A with a compound of
formula (IIIe)
A+Act-(O)C--Y--ONO.sub.2 (IIIe)
wherein Act and Y are as above defined and A is a compound of
formula (IIa), (IIc) or (IIt) wherein R.sub.1 is --H and R.sub.2 is
--COOH; R.sub.a of formula (IIa) and R.sub.c of formula (IIc) are
R.sub.hNH(CH.sub.2).sub.p-- wherein p is an integer from 0 to 4, or
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--, and R.sub.h and R.sub.i
are --H; in formula (IIt) R.sub.1 is --H, R.sub.2 is --COOH, d is 2
d' is 1, R.sub.t is --H; using a ratio A/(IIIe) 1:2 and applying
the same procedure described in 1b'). Compounds A are commercially
available.
[0479] 87. The compounds of general formula (I) wherein:
s and s' are equal to 1; s'', m, m' and m'' are equal to 0; Y and
Y' are equal and are as above defined; A is a radical selected from
(IIa), (IIc) and (IIt) wherein R.sub.1 is --C(O)O--R.sub.1x and
binds a group --Y--ONO.sub.2 or a group --Y'--ONO.sub.2, R.sub.2 is
--COOH; R.sub.a of formula (IIa) and R.sub.c of formula (IIc) are
R.sub.hNH(CH.sub.2).sub.p-- wherein p is an integer from 0 to 4, or
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--, and R.sub.h and R.sub.i
are R.sub.hh--OC(O) or R.sub.ii--OC(O)-- and R.sub.a and R.sub.c
bind a group --Y--ONO.sub.2 or a group --Y'--ONO.sub.2; in formula
(IIt) R.sub.1 is --C(O)O--R.sub.1x and binds a group --Y--ONO.sub.2
or a group --Y'--ONO.sub.2, R.sub.2 is --COOH; d is 2 d' is 1,
R.sub.t is --C(O)O--R.sub.tt and binds a group --Y--ONO.sub.2 or a
group --Y'--ONO.sub.2; can be prepared as follows:
[0480] 87a) by reacting a compound of formula A with a compound of
formula (IIIf)
A+Act-(O)C--O--Y--ONO.sub.2 (IIIf)
wherein Act and Y are as above defined and A is as defined in 86a)
using a ratio A/(IIIf) 1:2 and applying the same procedure
described in 3b).
[0481] 88. The compounds of general formula (I) wherein:
s is equal to 1; s', s'', m, m' and m'' are equal to 0; Y is as
above defined; A is a radical of formula (IIa), (IIc) or (IIt)
wherein R.sub.1 is --H, R.sub.2 is --C(O)OR.sub.2x and it binds a
group --Y--ONO.sub.2 R.sub.a of formula (IIa) and R.sub.c of
formula (IIc) are the groups R.sub.hNH(CH.sub.2).sub.p-- wherein p
is an integer from 0 to 4,
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--, R.sub.h and R.sub.i are
--H; in formula (IIt) R.sub.1 is --H, and R.sub.2 is
--C(O)OR.sub.2x and it binds a group --Y--ONO.sub.2; d is 2 d' is
1, R.sub.t is --H; can be obtained as follows:
[0482] 88a) R.sub.a=R.sub.c selected from
R.sub.hNH(CH.sub.2).sub.p-- wherein p is an integer from 0 to 4,
R.sub.h is --H:
by reacting a compound of formula (I) wherein s, s', s'', m, m',
m'', Y, Y', Y'' are as above defined in 88. A is a radical of
(IIa), (IIc) or (IIt) wherein R.sub.1 is --C(O)OC(CH.sub.3).sub.3;
R.sub.2 is --CO(O)R.sub.2x and bind; R.sub.a of formula (IIa) and
R.sub.c of formula (IIc) are selected from
R.sub.hNH(CH.sub.2).sub.p-- wherein p is an integer from 0 to 4,
R.sub.h is --C(O)OC(CH.sub.3).sub.3; in formula (IIt) R.sub.1 and
R.sub.2 are as above defined d is 2 d' is 1, R.sub.t is
--C(O)OC(CH.sub.3).sub.3; with anhydrous or aqueous organic or
inorganic acid to hydrolyze the --BOC protective groups following
procedure well known in the literature.
[0483] 88a') R.sub.a=R.sub.c selected from
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--, R.sub.i is --H:
by reacting a compound of formula (VIIa)
A.sub.5a-Y--ONO.sub.2 (VIIIa)
wherein Y, is as above defined; A.sub.5a is a radical of formula
(IIa), (IIc) wherein R.sub.1 is --C(O)OC(CH.sub.3).sub.3; R.sub.2
is --CO(O)R.sub.2x; R.sub.a of formula (IIa) and R.sub.c of formula
(IIc) are R.sub.ia--NH(.dbd.NH)NH--(CH.sub.2).sub.3-- wherein
R.sub.ia is the known protective group --Pbf
(2,2,4,6,7-pentamethyl-dihydrobenzofuran-5-sulfonyl)-; with
anhydrous or aqueous organic or inorganic acid to hydrolyze the
--BOC and the --Pbf protective groups following procedure well
known in the literature.
[0484] 88b) compounds described in 88a) and 88a') can be
respectively obtained by reacting a compound of formula A or
A.sub.5 with a compound of formula (IIIi)
##STR00287##
wherein Y is as above defined and: A is a radical of formula (IIa),
(IIc) or (IIt) wherein R.sub.1 is --C(O)OC(CH.sub.3).sub.3; R.sub.2
is --COOH; R.sub.a and R.sub.c are R.sub.hNH(CH.sub.2).sub.p--
wherein p as above defined and R.sub.h is --C(O)OC(CH.sub.3).sub.3;
d and d' are as above defined, and R.sub.t is
--C(O)OC(CH.sub.3).sub.3; A.sub.5 is a radical of formula (IIa) or
(IIc) wherein R.sub.1 is --C(O)OC(CH.sub.3).sub.3; R.sub.2 is
--COOH; R.sub.a and R.sub.c are
R.sub.iaNH(.dbd.NH)NH--(CH.sub.2).sub.3-- wherein R.sub.ia is as
above defined using the same procedure described in 8b).
[0485] Compounds A and A.sub.5 as above defined are commercially
available or can be easily obtained from commercially available
compounds by simple deprotection/protection steps as known in the
literature.
[0486] 89. The compounds of general formula (I) wherein:
s is equal to 1; s', s'', m, m' and m'' are equal to 0; Y is as
above defined; A is a radical of formula (IIa), (IIc) or (IIt)
wherein R.sub.1 is --H, R.sub.2 is --C(O)NHR.sub.2xx or
--C(O)N(CH.sub.3)R.sub.2xx and it binds a group --Y--ONO.sub.2;
R.sub.a of formula (IIa) and R.sub.c of formula (IIc) are
R.sub.hNH(CH.sub.2).sub.p-- wherein p is an integer from 0 to 4, or
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--, and R.sub.h and R.sub.i
are --H; in formula (IIt) R.sub.1 is --H, R.sub.2 is
--C(O)NHR.sub.2xx or --C(O)N(CH.sub.3)R.sub.2xx and it binds a
group --Y--ONO.sub.2; d is 2 d' is 1, R.sub.t is --H; can be
obtained as follows:
[0487] 89a) R.sub.a=R.sub.c are selected from
R.sub.hNH(CH.sub.2).sub.p-- wherein p is an integer from 0 to 4,
R.sub.h is --H:
by reacting a compound of formula (I) wherein s, s', s'', m, m',
m'', Y, Y', Y'' are as above defined in 89. A is a radical of
formula (IIa), (IIc) or (IIt) wherein R.sub.1 is
--C(O)OC(CH.sub.3).sub.3; R.sub.2 is --C(O)NHR.sub.2xx or
--C(O)N(CH.sub.3)R.sub.2xx; R.sub.a, R.sup.c, p, d, d', R.sub.h and
R.sub.t are as defined in 88a) with anhydrous or aqueous organic or
inorganic acid to hydrolyze the --BOC protective groups.
[0488] 89a') R.sub.a=R.sub.c selected from
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--, R.sub.i is --H:
by reacting a compound of formula (VIIIb):
A.sub.6-Y--ONO.sub.2 (VIIIb)
wherein Y, is as above defined; A.sub.6 is a radical of formula
(IIa), (IIc) wherein R.sub.1 is --C(O)OC(CH.sub.3).sub.3; R.sub.2
is --C(O)NHR.sub.2xx or --C(O)N(CH.sub.3)R.sub.2xx; R.sub.a of
formula (IIa) and R.sub.c of formula (IIc) are
R.sub.ia--NH(.dbd.NH)NH--(CH.sub.2).sub.3-- wherein R.sub.ia is the
--Pbf group as above defined; with anhydrous or aqueous organic or
inorganic acid to hydrolyze the --BOC and the --Pbf protective
groups following procedure well known in the literature.
[0489] 89b) compounds described in 89a) and 89a') can be
respectively obtained by reacting a compound of formula A or a
compound of formula A.sub.5 already defined in 88b) with a compound
of formula (IIIo)
##STR00288##
using the same procedure described in 7b).
[0490] 90. The compounds of general formula (I) wherein:
s and m are equal to 1; s', s'', m' and m'' are equal to 0; Y is as
above defined;
B is:
##STR00289##
[0491] A is a radical of formula (IIa), (IIc) or (IIt) wherein
R.sub.1 is --H, R.sub.2 is --C(O)OR.sub.2x and binds a group
--B--Y--ONO.sub.2; R.sub.a of formula (IIa) and R.sub.c of formula
(IIc) are R.sub.hNH(CH.sub.2).sub.p-- wherein p is an integer from
0 to 4, or R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--, and R.sub.h
and R.sub.i are --H; in formula (IIt) R.sub.1 is --H, and R.sub.2
is --C(O)OR.sub.2x and binds a group --B--Y--ONO.sub.2, d is 2 d'
is 1, R.sub.t is --H; can be obtained as follows:
[0492] 90a) R.sub.a=R.sub.c selected from
R.sub.hNH(CH.sub.2).sub.p-- wherein p is an integer from 0 to 4,
R.sub.h is --H:
by reacting a compound of formula (I) wherein B, s, s', s'', m, m',
m'', Y, Y', Y'' are as above defined in 90. A is a radical of
formula (IIa), (IIc) or (IIt) wherein R.sub.1 is
--C(O)OC(CH.sub.3).sub.3; R.sub.2 is --C(O)OR.sub.2x; B, R.sub.a,
R.sub.c, p, d, R.sub.h and R.sub.t are as defined in 90. with
anhydrous or aqueous organic or inorganic acid to hydrolyze the
--BOC protective groups.
[0493] 90a') R.sub.a=R.sub.c selected from
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--, R.sub.i is --H:
by reacting a compound of formula (VIIIc):
A.sub.5a-B--Y--ONO.sub.2 (VIIIc)
wherein B, and Y, are as above defined in 90. and A.sub.5a is as
defined in 88a') with anhydrous or aqueous organic or inorganic
acid to hydrolyze the --BOC and the --Pbf protective groups
following procedure well known in the literature.
[0494] 90b) compounds described in 90a) and 90a') can be
respectively obtained by reacting a compound of formula A or a
compound of formula A.sub.5 already defined in 88b) with compounds
(IIIg) or (IIIn) depending on the meaning of B, and applying the
same procedure described in 4b) or 6b):
##STR00290##
[0495] 91. The compounds of general formula (I) wherein:
s and s' are equal to 1; s'', m, m' and m'' are equal to 0; Y and
Y' can be equal or different and are as above defined; A is
selected from (IIa), (IIc) and (IIt) wherein R.sub.1 is
--C(O)--R.sub.1x and binds a group --Y'--ONO.sub.2, R.sub.2 is
--C(O)OR.sub.2x and binds a group --Y--ONO.sub.2; R.sub.a of
formula (IIa) and R.sub.c of formula (IIc) are
R.sub.hNH(CH.sub.2).sub.p-- wherein p is an integer from 0 to 4, or
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--, and R.sub.h and R.sub.i
are --H; in formula (IIt) R.sub.1 is --C(O)--R.sub.1x and it binds
a group --Y.sup.f-ONO.sub.2, R.sub.2 is --C(O)OR.sub.2x and R.sub.2
binds a group --Y--ONO.sub.2; d is 2 d' is 1, R.sub.t is --H; can
be obtained as follows:
[0496] 91a) R.sub.a=R.sub.c selected from
R.sub.hNH(CH.sub.2).sub.p-- wherein p is an integer from 0 to 4,
R.sub.h is --H:
by reacting a compound of formula (I) wherein s, s', s'', m, m',
m'', Y, Y', Y'' are as above defined in 91. A is a radical of
(IIa), (IIc) or (IIt) wherein R.sub.1 is --C(O)--R.sub.1x; R.sub.2
is --C(O)OR.sub.2x; R.sub.a of formula (IIa) and R.sub.c of formula
(IIc) are selected from R.sub.hNH(CH.sub.2).sub.p-- wherein p is an
integer from 0 to 4, R.sub.h is --C(O)OC(CH.sub.3).sub.3; in
formula (IIt) R.sub.1 and R.sub.2 are as above defined d is 2 d' is
1, R.sub.t is --C(O)OC(CH.sub.3).sub.3; with anhydrous or aqueous
organic or inorganic acid to hydrolyze the --BOC protective groups
following procedure well known in the literature.
[0497] 91a') R.sub.a=R.sub.c selected from
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--, R.sub.i is --H:
by reacting a compound of formula (VIIId)
##STR00291##
wherein Y and Y' are as above defined; A.sub.7a is a radical of
formula (IIa), (IIc) wherein R.sub.1 is --C(O)--R.sub.1x; R.sub.2
is CO(O); R.sub.a of formula (IIa) and R.sub.c of formula (IIc) are
R.sub.iaNH(.dbd.NH)NH--(CH.sub.2).sub.3-- wherein R.sub.ia is group
--Pbf as already defined; with anhydrous or aqueous organic or
inorganic acid to hydrolyze the --Pbf protective groups following
procedure well known in the literature.
[0498] 91b) R.sub.a=R.sub.c are selected from
R.sub.hNH(CH.sub.2).sub.p-- wherein p is an integer from 0 to 4,
R.sub.h is --H:
by reacting a compound of formula (I) with a compound of formula
(IIIe)
##STR00292##
wherein Y and Y' are as above defined and A is a radical of formula
(IIa), (IIc) or (IIt) wherein R.sub.1 is --H, R.sub.2 is
--C(O)OR.sub.2x and binds the group --Y--ONO.sub.2; R.sub.a and
R.sub.c are R.sub.hNH(CH.sub.2).sub.p-- wherein p as above defined
and R.sub.h is --C(O)OC(CH.sub.3).sub.3; d and d' are as above
defined, and R.sub.t is --C(O)OC(CH.sub.3).sub.3; using the same
procedure described in 1b').
[0499] 91b') R.sub.a=R.sub.c selected from
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--, R.sub.i is --H:
by reacting a compound of formula (VIIIe) with a compound of
formula (IIIe):
##STR00293##
wherein Y and Y' are as above defined and A.sub.7 is a radical of
formula (IIa), (IIc) wherein R.sub.1 is --H, R.sub.2 is
--C(O)OR.sub.2x and binds the group --Y--ONO.sub.2; R.sub.a and
R.sub.c are R.sub.iaNH(.dbd.NH)NH--(CH.sub.2).sub.3-- wherein
R.sub.ia is group --Pbf as above defined; using the same procedure
described in 1b').
[0500] 91c) compounds described in 91b) and 91b') can be
respectively prepared by deprotecting the Fmoc group of a compound
of formula (VIIIf.sub.1) or (VIIIf.sub.2)
##STR00294##
wherein Y is as above defined and: A.sub.8a is a radical of formula
(IIa), (IIc) or (IIt) wherein R.sub.1 is the Fmoc protective group;
R.sub.2 is --C(O)OR.sub.2x and binds the group --Y--ONO.sub.2;
R.sub.a and R.sub.c are R.sub.hNH(CH.sub.2).sub.p-- wherein p is as
above defined and R.sub.h is --C(O)OC(CH.sub.3).sub.3, A.sub.8b is
a radical of formula (IIa) or (IIc) wherein R.sub.1 is the Fmoc
protective group; R.sub.2 is --C(O)OR.sub.2x and binds the group
--Y--ONO.sub.2; R.sub.a and R.sub.c are
R.sub.iaNH(.dbd.NH)NH--(CH.sub.2).sub.3--, wherein R.sub.ia is the
--Pbf group as above defined;
[0501] 91d) compound of formula (VIIIf.sub.1) or (VIIIf.sub.2) are
prepared by reacting a compound of formula A.sub.9a or A.sub.9b
with compound (IIIi) using the same procedure described in 8b)
##STR00295##
wherein Y is as above defined and: A.sub.9a is a radical of formula
(IIa), (IIc) or (IIt) wherein R.sub.1 is the Fmoc protective group;
R.sub.2 is --COOH; R.sub.a and R.sub.c are
R.sub.hNH(CH.sub.2).sub.p-- wherein p as above defined and R.sub.h
is --C(O)OC(CH.sub.3).sub.3; A.sub.9b is a radical of formula (IIa)
or (IIc) wherein R.sub.1 is the Fmoc protective group; R.sub.2 is
--COOH; R.sub.a and R.sub.c are
R.sub.iaNH(.dbd.NH)NH--(CH.sub.2).sub.3-- wherein R.sub.ia is the
--Pbf group as previously defined.
[0502] Compounds A.sub.9a and A.sub.9b are commercially
available.
[0503] 92. The compounds of general formula (I) wherein:
s and s' are equal to 1; s'', m, m' and m'' are equal to 0; Y and
Y' can be equal or different and are as above defined; A is a
radical of formula (IIa), (IIc) or (IIt) wherein R.sub.1 is
--C(O)--R.sub.1x and it binds a group --Y.sup.f-ONO.sub.2, R.sub.2
is --C(O)NHR.sub.2xx or --C(O)N(CH.sub.3)R.sub.2xx and it binds a
group --Y--ONO.sub.2; R.sub.a of formula (IIa) and R.sub.c of
formula (IIc) are R.sub.hNH(CH.sub.2).sub.p-- wherein p is an
integer from 0 to 4, or R.sub.2NH(.dbd.NH)NH--(CH.sub.2).sub.3--,
and R.sub.h and R.sub.i are --H; in formula (IIt) R.sub.1 is
--C(O)--R.sub.1x and binds a group --Y'--ONO.sub.2, R.sub.2 is
C(O)NHR.sub.2xx or --C(O)N(CH.sub.3)R.sub.2xx and it binds a group
--Y--ONO.sub.2; d is 2 d' is 1, R.sub.t is --H; can be obtained as
follows:
[0504] 92a) R.sub.a=R.sub.c selected from
R.sub.hNH(CH.sub.2).sub.p-- wherein p is an integer from 0 to 4,
R.sub.h is --H:
by reacting a compound of formula (I) wherein s, s', s'', m, m',
m'', Y, Y', Y'' are as above defined in 92. A is a radical of
(IIa), (IIc) or (IIt) wherein R.sub.1 is --C(O)--R.sub.1x; R.sub.2
is --C(O)NHR.sub.2xx or --C(O)N(CH.sub.3)R.sub.2xx; R.sub.a of
formula (IIa) and R.sub.c of formula (IIc) are
R.sub.hNH(CH.sub.2).sub.p-- wherein p is an integer from 0 to 4,
R.sub.h is --C(O)OC(CH.sub.3).sub.3; in formula (IIt) R.sub.1 and
R.sub.2 are as above defined d is 2 d' is 1, R.sub.t is
--C(O)OC(CH.sub.3).sub.3; with anhydrous or aqueous organic or
inorganic acid to hydrolyze the --BOC protective groups following
procedure well known in the literature.
[0505] 92a') R.sub.a=R.sub.c selected from
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--, R.sub.i is --H:
by reacting a compound of formula (VIIIg)
##STR00296##
wherein Y and Y' are as above defined; A.sub.10a is a radical of
formula (IIa), (IIc) wherein R.sub.1 R.sub.1 is --C(O)--R.sub.1x;
R.sub.2 is --C(O)NHR.sub.2xx or --C(O)N(CH.sub.3)R.sub.2xx; R.sub.a
of formula (IIa) and R.sub.c of formula (IIc) are
R.sub.ia--NH(.dbd.NH)NH--(CH.sub.2).sub.3-- wherein R.sub.1a is the
--Pbf group with anhydrous or aqueous organic or inorganic acid to
hydrolyze the --Pbf protective groups following procedure well
known in the literature.
[0506] 92b) R.sub.a=R.sub.c are selected from
R.sub.hNH(CH.sub.2).sub.p-- wherein p is an integer from 0 to 4,
R.sub.h is --H:
by reacting a compound of formula (I) with a compound of
formula
##STR00297##
wherein Y and Y' are as above defined and A is a radical of formula
(IIa), (IIc) or (IIt) wherein R.sub.1 is --H, R.sub.2 is
--C(O)NHR.sub.2xx or --C(O)N(CH.sub.3)R.sub.2xx and binds the group
--Y--ONO.sub.2; R.sub.a and R.sub.c are R.sub.hNH(CH.sub.2).sub.p--
wherein p as above defined and R.sub.h is --C(O)OC(CH.sub.3).sub.3;
d and d' are as above defined, and R.sub.t is
--C(O)OC(CH.sub.3).sub.3; using the same procedure described in
1b').
[0507] 92b') R.sub.a=R.sub.c selected from
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--, R.sub.i is --H:
[0508] compound (VIIIg) is prepared by reacting a compound of
formula (VIIIh) with a compound of formula (IIIe)
##STR00298##
wherein Y and Y' are as above defined and A is a radical of formula
(IIa), (IIc) wherein R.sub.1 is --H, R.sub.2 is --C(O)NHR.sub.2xx
or --C(O)N(CH.sub.3)R.sub.2xx and binds the group --Y--ONO.sub.2;
R.sub.a and R.sub.c are R.sub.ia--NH(.dbd.NH)NH--(CH.sub.2).sub.3--
wherein R.sub.ia is as above defined using the same procedure
described in 1b').
[0509] 92c) compounds described in 92b) and 92b') can be prepared
by deprotecting the Fmoc group of a compound of formula
(VIIIi.sub.1) or
##STR00299##
wherein Y is as above defined and: A.sub.11a is a radical of
formula (IIa), (IIc) or (IIt) wherein R.sub.1 is the Fmoc
protective group; R.sub.2 is --C(O)NHR.sub.2xx or
--C(O)N(CH.sub.3)R.sub.2xx and binds the group --Y--ONO.sub.2;
R.sub.a and R.sub.c are R.sub.hNH(CH.sub.2).sub.p-- wherein p is as
above defined and R.sub.h is --C(O)OC(CH.sub.3).sub.3, A.sub.11b is
a radical of formula (IIa) or (IIc) wherein R.sub.1 is the Fmoc
protective group; R.sub.2 is --C(O)NHR.sub.2xx or
--C(O)N(CH.sub.3)R.sub.2xx and binds the group --Y--ONO.sub.2;
R.sub.a and R.sub.c are R.sub.iaNH(.dbd.NH)NH--(CH.sub.2).sub.3--,
wherein R.sub.ia is as above defined;
[0510] 92d) compounds described in 92c) can be prepared by reacting
a compound of formula A.sub.9a or a compound of formula A.sub.m
defined in 91d) with compound (IIIo) using the same procedure
described in 7b)
##STR00300##
wherein Y and W.sub.3 are as above defined.
[0511] 93. The compounds of general formula (I) wherein:
s and s' are equal to 1; s'', m, m' and m'' are equal to 0; Y and
Y' can be equal or different and are as above defined; A is a
radical of formula (IIa), (IIc) and (IIt) wherein R.sub.1 is
--C(O)O--R.sub.1x and binds a group --Y'--ONO.sub.2, R.sub.2 is
--C(O)OR.sub.2x and binds a group --Y--ONO.sub.2; R.sub.a of
formula (IIa) and R.sub.c of formula (IIc) are
R.sub.hNH(CH.sub.2).sub.p-- wherein p is an integer from 0 to 4, or
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--, and R.sub.h and R.sub.i
are --H; in formula (IIt) R.sub.1 is --C(O)O--R.sub.1x and binds a
group --Y'--ONO.sub.2, and R.sub.2 is --C(O)OR.sub.2x and binds a
group --Y--ONO.sub.2; d is 2 d' is 1, R.sub.t is --H; can be
obtained as follows:
[0512] 93a) R.sub.a=R.sub.c selected from
R.sub.hNH(CH.sub.2).sub.p-- wherein p is an integer from 0 to 4,
R.sub.h is --H:
by reacting a compound of formula (I) wherein s, s', s'', m, m',
m'', Y, Y', Y'' are as above defined in 93. A is a radical of
formula (IIa), (IIc) or (IIt) wherein R.sub.1 is --C(O)O--R.sub.1x;
R.sub.2 is --C(O)OR.sub.2x; R.sub.a of formula (IIa) and R.sub.c of
formula (IIc) are selected from R.sub.hNH(CH.sub.2).sub.p-- wherein
p is an integer from 0 to 4, R.sub.h is --C(O)OC(CH.sub.3).sub.3;
in formula (IIt) R.sub.1 and R.sub.2 are as above defined d is 2 d'
is 1, R.sub.t is --C(O)OC(CH.sub.3).sub.3; with anhydrous or
aqueous organic or inorganic acid to hydrolyze the --BOC protective
groups following procedure well known in the literature.
[0513] 93a') R.sub.a=R.sub.c selected from
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--, R.sub.i is --H:
by reacting a compound of formula (VIIIj)
##STR00301##
wherein Y and Y' are as above defined; A.sub.11a is a radical of
formula (IIa), (IIc) wherein R.sub.1 is --C(O)O--R.sub.1x; R.sub.2
is --C(O)OR.sub.2x R.sub.a of formula (IIa) and R.sub.c of formula
(IIc) are R.sub.iaNH(.dbd.NH)NH--(CH.sub.2).sub.3-- wherein
R.sub.ia is as already defined; with anhydrous or aqueous organic
or inorganic acid to hydrolyze the --Pbf protective groups
following procedure well known in the literature.
[0514] 93b) R.sub.a=R.sub.c are selected from
R.sub.hNH(CH.sub.2).sub.p-- wherein p is an integer from 0 to 4,
R.sub.h is --H:
by reacting a compound of formula (I) with a compound of formula
(IIIf)
##STR00302##
wherein Y and Y' are as above defined and A is a radical of formula
(IIa), (IIc) or (IIt) already defined in 91b) and obtained as
described in 91c), using the same procedure described in 3b).
[0515] 93b') R.sub.a=R.sub.c selected from
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--, R.sub.i is --H:
[0516] Compound of formula (VIIIj) are prepared by reacting a
compound of formula (VIIIe) already defined in 91b') and obtained
as described in 91c), with a compound of formula (IIIf)
##STR00303##
wherein A.sub.8, Y and Y' are as above defined, using the same
procedure described in 3b).
[0517] 94. The compounds of general formula (I) wherein:
s and s' are equal to 1; s'', m, m' and m'' are equal to 0; Y and
Y' can be equal or different and are as above defined; A is
selected from (IIa), (IIc) and (IIt) wherein R.sub.1 is
--C(O)O--R.sub.1x and binds a group --Y'--ONO.sub.2, R.sub.2 is
--C(O)NHR.sub.2xx or --C(O)N(CH.sub.3)R.sub.2xx and binds a group
--Y--ONO.sub.2; R.sub.a of formula (IIa) and R.sub.c of formula
(IIc) are R.sub.hNH(CH.sub.2).sub.p-- wherein p is an integer from
0 to 4, or R.sub.2NH(.dbd.NH)NH--(CH.sub.2).sub.3--, and R.sub.h
and R.sub.i are --H; in formula (IIt) R.sub.1 is --C(O)O--R.sub.1x
and binds a group --Y'--ONO.sub.2, and R.sub.2 is --C(O)NHR.sub.2xx
or --C(O)N(CH.sub.3)R.sub.2xx and binds a group --Y--ONO.sub.2; d
is 2 d' is 1, R.sub.t is --H; can be obtained as follows:
[0518] 94a) R.sub.a=R.sub.c selected from
R.sub.hNH(CH.sub.2).sub.p-- wherein p is an integer from 0 to 4,
R.sub.h is --H;
by reacting a compound of formula (I) wherein s, s', s'', m, m',
m'', Y, Y', Y'' are as above defined in 94. A is a radical of
(IIa), (IIc) or (IIt) wherein R.sub.8 is --C(O)O--R.sub.1x; R.sub.2
is --C(O)NHR.sub.2xx or --C(O)N(CH.sub.3)R.sub.2xx; R.sub.a of
formula (IIa) and R.sub.c of formula (IIc) are selected from
R.sub.hNH(CH.sub.2).sub.p-- wherein p is an integer from 0 to 4,
R.sub.h is --C(O)OC(CH.sub.3).sub.3; in formula (IIt) R.sub.1 and
R.sub.2 are as above defined d is 2 d' is 1, R.sub.t is
--C(O)OC(CH.sub.3).sub.3; with anhydrous or aqueous organic or
inorganic acid to hydrolyze the --BOC protective groups following
procedure well known in the literature.
[0519] 94a') R.sub.a=R.sub.c selected from
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--, R.sub.i is --H:
by reacting a compound of formula (VIIIk)
##STR00304##
wherein Y and Y' are as above defined; A.sub.12a is a radical of
formula (IIa), (IIc) wherein R.sub.1 is --C(O)O--R.sub.1x; R.sub.2
is --C(O)NHR.sub.2xx or --C(O)N(CH.sub.3)R.sub.2xx; R.sub.a of
formula (IIa) and R.sub.c of formula (IIc) are
R.sub.iaNH(.dbd.NH)NH (CH.sub.2).sub.3-- wherein R.sub.ia is group
--Pbf with anhydrous or aqueous organic or inorganic acid to
hydrolyze the --Pbf protective groups following procedure well
known in the literature.
[0520] 94b) R.sub.a=R.sub.c are selected from
R.sub.hNH(CH.sub.2).sub.p-- wherein p is an integer from 0 to 4,
R.sub.h is --H:
by reacting a compound of formula (I) with a compound of formula
(IIIf)
##STR00305##
wherein Y and Y' are as above defined and A is a radical of formula
(IIa), (IIc) or (IIt) already defined in 92b) and obtained as
described in 92c), using the same procedure described in 3b).
[0521] 94b') R.sub.a=R.sub.c selected from
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--, R.sub.i is --H:
[0522] Compound (VIIIk) are prepared by reacting a compound of
formula (VIIIk) already defined in 92b') and obtained as described
in 92c), with a compound of formula (IIIf)
##STR00306##
wherein Y and Y' are as above defined using the same procedure
described in 3b).
[0523] 95. The compounds of general formula (I) wherein:
s, s' and s'' are equal to 1; m, m' and m'' are equal to 0; Y, Y'
and Y'' are as above defined, with the proviso that Y and Y' are
equal; A is selected from (IIa), (IIc) and (IIt) wherein R.sub.1 is
--C(O)--R.sub.1x and it binds a group --Y--ONO.sub.2 or a group
--Y'--ONO.sub.2, R.sub.2 is --C(O)OR.sub.2x and it binds a group
--Y''--ONO.sub.2; R.sub.a of formula (IIa) and R.sub.c of formula
(IIc) are R.sub.hNH(CH.sub.2).sub.p-- wherein p is an integer from
0 to 4, or R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--, wherein
R.sub.h and R.sub.i are R.sub.hh--C(O)-- or R.sub.ii--C(O) and
R.sub.a and R.sub.c bind a group --Y--ONO.sub.2 or a group
--Y'--ONO.sub.2; in formula (IIt) R.sub.1 and R.sub.2 are as above
defined, d is 2 d' is 1, R.sub.t is --C(O)--R.sub.tt and it binds a
group --Y--ONO.sub.2 or a group --Y'--ONO.sub.2; can be prepared as
follows:
[0524] 95a) by reacting a compound of formula (I) with a compound
of formula (IIIi)
##STR00307##
wherein in compounds (I), obtained as described in 86. Y and Y' are
equal and are as above defined and A is selected from (IIa), (IIc)
and (IIt) wherein R.sub.1 is --C(O)--R.sub.1x and binds a group
--Y--ONO.sub.2 or a group --Y'--ONO.sub.2 and R.sub.2 is --COOH;
R.sub.a of formula (IIa) and R.sub.c of formula (IIc) are
R.sub.hNH(CH.sub.2).sub.p-- wherein p is an integer from 0 to 4, or
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--, and R.sub.h and R.sub.i
are R.sub.hh--C(O)-- or R.sub.aa--C(O)-- and bind a group
--Y--ONO.sub.2 or a group --Y'--ONO.sub.2; in formula (IIt) R.sub.1
and R.sub.2 are as above defined, d is 2 d' is 1, R.sub.t is
--C(O)--R.sub.tt and it binds a group --Y--ONO.sub.2 or a group
--Y'--ONO.sub.2; using the same procedure described in 8b).
[0525] 96. The compounds of general formula (I) wherein:
s, s' and s'' are equal to 1; m, m' and m'' are equal to 0; Y, Y'
and Y'' are as above defined, with the proviso that Y and Y' are
equal; A is a radical of formula (IIa), (IIc) and (IIt) wherein
R.sub.1 is --C(O)O--R.sub.1x and it binds a group --Y--ONO.sub.2 or
a group --Y'--ONO.sub.2, R.sub.2 is --C(O)OR.sub.2x and it binds a
group --Y''--ONO.sub.2; R.sub.a of formula (IIa) and R.sub.c of
formula (IIc) are R.sub.hNH(CH.sub.2).sub.p-- wherein p is an
integer from 0 to 4, or R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--,
wherein R.sub.h and R.sub.i are R.sub.hh--OC(O) or
R.sub.ii--OC(O)-- and R.sub.a and R.sub.c bind a group
--Y--ONO.sub.2 or a group --Y'--ONO.sub.2; in formula (IIt) R.sub.1
and R.sub.2 are as above defined, d is 2 d' is 1, R.sub.t is
--C(O)O--R.sub.tt and binds a group --Y--ONO.sub.2 or a group
--Y'--ONO.sub.2; can be prepared as follows:
[0526] 96a) by reacting a compound of formula (I) with a compound
of formula (IIIi)
##STR00308##
wherein in compounds (I), obtained as described in 87. Y and Y' are
equal and are as above defined and A is selected from (IIa), (IIc)
and (IIt) wherein R.sub.1 is --C(O)O--R.sub.1x and binds a group
--Y--ONO.sub.2 or a group --Y'--ONO.sub.2 and R.sub.2 is --COOH;
R.sub.a of formula (IIa) and R.sub.c of formula (IIc) are
R.sub.hNH(CH.sub.2).sub.p-- wherein p is an integer from 0 to 4, or
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--, and R.sub.h and R.sub.i
are R.sub.hh--OC(O)-- or R.sub.ii--OC(O) and bind a group
--Y--ONO.sub.2 or a group --Y'--ONO.sub.2; in formula (IIt) R.sub.1
and R.sub.2 are as above defined, d is 2 d' is 1, R.sub.t is
--C(O)O--R.sub.tt and binds a group --Y--ONO.sub.2 or a group
--Y'--ONO.sub.2; using the same procedure described in 8b).
[0527] 97. The compounds of general formula (I) wherein:
s, s' and s'' are equal to 1; m, m' and m'' are equal to 0; Y, Y'
and Y'' are as above defined, and Y and Y' are equal;
[0528] A is a radical of formula from (IIa), (IIc) or (IIt) wherein
R.sub.1 is --C(O)--R.sub.1x and it binds a group --Y--ONO.sub.2 or
a group --Y'--ONO.sub.2, R.sub.2 is --C(O)NHR.sub.2xx or
--C(O)N(CH.sub.3)R.sub.2xx and it binds a group
--Y''--ONO.sub.2;
R.sub.a of formula (IIa) and R.sub.c of formula (IIc) are
R.sub.hNH(CH.sub.2).sub.p-- wherein p is an integer from 0 to 4, or
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--, wherein R.sub.h and
R.sub.i are R.sub.hh--C(O)-- or R.sub.ii--C(O)-- and R.sub.a and
R.sub.c bind a group --Y--ONO.sub.2 or a group --Y'--ONO.sub.2; in
formula (IIt) R.sub.1 and R.sub.2 are as above defined, d is 2 d'
is 1, R.sub.t is --C(O)--R.sub.tt and binds a group --Y--ONO.sub.2
or a group --Y'--ONO.sub.2; can be prepared as follows:
[0529] 97a) by reacting a compound of formula (I) with a compound
of formula (IIIo)
##STR00309##
wherein in compounds (I), obtained as described in 86. Y and Y' are
equal and are as above defined and A is selected from (IIa), (IIc)
and (IIt) wherein R.sub.1 is --C(O)--R.sub.1x and binds a group
--Y--ONO.sub.2 or a group --Y'--ONO.sub.2 and R.sub.2 is --COOH;
R.sub.a of formula (IIa) and R.sub.c of formula (IIc) are
R.sub.hNH(CH.sub.2).sub.p-- wherein p is an integer from 0 to 4, or
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--, and R.sub.h and R.sub.i
are R.sub.hh--C(O)-- or R.sub.ii--C(O)-- and bind a group
--Y--ONO.sub.2 or a group --Y'--ONO.sub.2; in formula (IIt) R.sub.1
and R.sub.2 are as above defined, d is 2 d' is 1, R.sub.t is
--C(O)--R.sub.tt and binds a group --Y--ONO.sub.2 or a group
--Y'--ONO.sub.2; using the same procedure described in 7b).
[0530] 98. The compounds of general formula (I) wherein:
s, s' and s'' are equal to 1; m, m' and m'' are equal to 0; Y, Y'
and Y'' are as above defined and Y and Y' are equal; A is selected
from (IIa), (IIc) and (IIt) wherein R.sub.1 is --C(O)O --R.sub.1x
and binds a group --Y--ONO.sub.2 or a group --Y'--ONO.sub.2,
R.sub.2 is --C(O)NHR.sub.2xx or --C(O)N(CH.sub.3)R.sub.2xx and
binds a group --Y''--ONO.sub.2; R.sub.a of formula (IIa) and
R.sub.c of formula (IIc) are R.sub.hNH(CH.sub.2).sub.p-- wherein p
is an integer from 0 to 4, or
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--, wherein R.sub.h and
R.sub.i are R.sub.hh--OC(O)-- or R.sub.ii--OC(O)-- and R.sub.a and
R.sub.c bind a group --Y--ONO.sub.2 or a group --Y'--ONO.sub.2; in
formula (IIt) R.sub.1 and R.sub.2 are as above defined, d is 2 d'
is 1, R.sub.t is --C(O)O--R.sub.tt and binds a group --Y--ONO.sub.2
or a group --Y'--ONO.sub.2; can be prepared as follows:
[0531] 98a) by reacting a compound of formula (I) with a compound
of formula (IIIo)
##STR00310##
wherein in compounds (I), obtained as described in 87. Y and Y' are
equal and are as above defined, W.sub.3 is as above defined and A
is selected from (IIa), (IIc) and (IIt) wherein R.sub.1 is
--C(O)O--R.sub.1x and binds a group --Y--ONO.sub.2 or a group
--Y'--ONO.sub.2 and R.sub.2 is --COOH; R.sub.a of formula (IIa) and
R.sub.c of formula (IIc) are R.sub.hNH(CH.sub.2).sub.p-- wherein p
is an integer from 0 to 4, or
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--, and R.sub.h and R.sub.i
are R.sub.hh--OC(O)-- or R.sub.ii--OC(O)-- and bind a group
--Y--ONO.sub.2 or a group --Y'--ONO.sub.2; in formula (IIt) R.sub.1
and R.sub.2 are as above defined, d is 2 d' is 1, R.sub.t is
--C(O)O--R.sub.tt and binds a group --Y--ONO.sub.2 or a group
--Y'--ONO.sub.2; using the same procedure described in 7b).
[0532] 99. The compounds of general formula (I) wherein:
s, s', s'' and m'' are equal to 1; m, m' are equal to 0; Y, Y' and
Y'' are as above defined, with the proviso that Y and Y' are
equal;
B is:
##STR00311##
[0533] A is a radical of formula (IIa), (IIc) or (IIt) wherein
R.sub.1 is --C(O) and binds a group --Y--ONO.sub.2 or a group
--Y'--ONO.sub.2, R.sub.2 is --C(O)OR.sub.2x and binds a group
--B--Y''--ONO.sub.2; R.sub.a of formula (IIa) and R.sub.c of
formula (IIc) are R.sub.hNH(CH.sub.2).sub.p-- wherein p is an
integer from 0 to 4, or R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--,
wherein R.sub.h and R.sub.i are R.sub.hh--C(O)-- or
R.sub.ii--C(O)-- and R.sub.a and R.sub.c bind a group
--Y--ONO.sub.2 or a group --Y'--ONO.sub.2; in formula (IIt) R.sub.1
and R.sub.2 are as above defined, d is 2 d' is 1, R.sub.t is
--C(O)--R.sub.tt and binds a group --Y--ONO.sub.2 or a group
--Y'--ONO.sub.2; can be prepared as follows:
[0534] 99a) by reacting a compound of formula (I) obtained as
described in 86.
##STR00312##
with compounds (IIIg) or (IIIn) depending on the meaning of B:
(I)+Hal-W.sub.1--OC(O)O--Y'--ONO.sub.2 (IIIg)
(I)+Hal-W.sub.1--OC(O)--Y'--ONO.sub.2 (IIIn)
wherein in compounds (I), obtained as described in 86. Y and Y' are
equal and are as above defined and A is selected from (IIa), (IIc)
and (IIt) wherein R.sub.1 is --C(O)R.sub.1x and binds a group
--Y--ONO.sub.2 or a group --Y'--ONO.sub.2 and R.sub.2 is --COOH;
R.sub.a of formula (IIa) and R.sub.c of formula (IIc) are
R.sub.hNH(CH.sub.2).sub.p-- wherein p is an integer from 0 to 4, or
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--, and R.sub.h and R.sub.i
are R.sub.hh--C(O)-- or R.sub.ii--C(O) and bind a group
--Y--ONO.sub.2 or a group --Y'--ONO.sub.2; in formula (IIt) R.sub.1
and R.sub.2 are as above defined, d is 2 d' is 1, R.sub.t is
--C(O)--R.sub.tt and binds a group --Y--ONO.sub.2 or a group
--Y'--ONO.sub.2; and applying the same procedure described in 4b)
or 6b).
[0535] 100. The compounds of general formula (I) wherein:
s, s', s'' and m'' are equal to 1; m, m' are equal to 0; Y, Y' and
Y'' are as above defined, with the proviso that Y and Y' are
equal;
B is:
##STR00313##
[0536] A is a radical of formula (IIa), (IIc) and (IIt) wherein
R.sub.1 is --C(O)O--R.sub.1x and it binds a group --Y--ONO.sub.2 or
a group --Y'--ONO.sub.2, R.sub.2 is --C(O)OR.sub.2x and it binds a
group --B--Y''--ONO.sub.2; R.sub.a of formula (IIa) and R.sub.c of
formula (IIc) are R.sub.hNH(CH.sub.2).sub.p-- wherein p is an
integer from 0 to 4, or R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--,
wherein R.sub.h and R.sub.i are R.sub.hh--OC(O) or
R.sub.ii--OC(O)-- and R.sub.a and R.sub.c bind a group
--Y--ONO.sub.2 or a group --Y'--ONO.sub.2; in formula (IIt) R.sub.1
and R.sub.2 are as above defined, d is 2 d' is 1, R.sub.t is
--C(O)O--R.sub.tt and it binds a group --Y--ONO.sub.2 or a group
--Y'--ONO.sub.2; can be prepared as follows:
[0537] 100a) by reacting a compound of formula (I) obtained as
described in 87.
##STR00314##
with compounds (IIIg) or (IIIn) depending on the meaning of B:
(I)+Hal-W.sub.1--OC(O)O--Y'--ONO.sub.2 (IIIg)
(I)+Hal-W.sub.1--OC(O)--Y'--ONO.sub.2
wherein in compounds (I) Y and Y' are equal and are as above
defined and A is selected from (IIa), (IIc) and (IIt) wherein
R.sub.1 is --C(O)O--R.sub.1x and binds a group --Y--ONO.sub.2 or a
group --Y'--ONO.sub.2 and R.sub.2 is --COOH; R.sub.a of formula
(IIa) and R.sub.c of formula (IIc) are R.sub.hNH(CH.sub.2).sub.p--
wherein p is an integer from 0 to 4, or
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--, and R.sub.h and R.sub.i
are R.sub.hh--C(O)-- or R.sub.ii--C(O)-- and bind a group
--Y--ONO.sub.2 or a group --Y'--ONO.sub.2; in formula (IIt) R.sub.1
and R.sub.2 are as above defined, d is 2 d' is 1, R.sub.t is
--C(O)O--R.sub.tt and binds a group --Y--ONO.sub.2 or a group
--Y'--ONO.sub.2; and applying the same procedure described in 4b)
or 6b).
[0538] 101. The compounds of general formula (I) wherein:
s and s' are equal to 1; s'', m, m' and m'' are equal to 0; Y and
Y' can be equal or different and are as above defined; A is a
radical of formula (IIa), (IIc) or (IIt) wherein R.sub.1 is --H,
R.sub.2 is --C(O)OR.sub.2x and it binds a group --Y--ONO.sub.2;
R.sub.a of formula (IIa) and R.sub.c of formula (IIc) are
R.sub.hNH(CH.sub.2).sub.p-- wherein p is an integer from 0 to 4, or
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--, wherein R.sub.h and
R.sub.i are R.sub.hh--C(O)-- or R.sub.ii--C(O)-- and R.sub.a and
R.sub.c bind a group --Y'--ONO.sub.2 in formula (IIt) R.sub.1 is
--H, and R.sub.2 is --C(O)OR.sub.2x and binds a group
--Y--ONO.sub.2; d is 2 d' is 1, R.sub.t is --C(O)--R.sub.tt, and
binds a group --Y'--ONO.sub.2 can be obtained as follows:
[0539] 101a) R.sub.a=R.sub.c selected from
R.sub.hNH(CH.sub.2).sub.p-- wherein p is an integer from 0 to 4,
R.sub.h is R.sub.hh--C(O)--;
by reacting a compound of formula (I) wherein s, s', s'', m, m',
m'', Y, Y', Y'' are as above defined in 101, A is a radical of
(IIa), (IIc) or (IIt) wherein R.sub.2, d, d', R.sub.t are as
defined in 101, R.sub.a and R.sub.c are selected from
R.sub.hNH(CH.sub.2).sub.p-- wherein p is an integer from 0 to 4,
R.sub.h is R.sub.hh--C(O)--; R.sub.1 is --C(O)OC(CH.sub.3).sub.3;
with anhydrous or aqueous organic or inorganic acid to hydrolyze
the --BOC protective groups following procedure well known in the
literature.
[0540] 101a') R.sub.a=R.sub.c selected from
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--, R.sub.i is
R.sub.ii--C(O)--;
by reacting a compound of formula (VIIIL)
##STR00315##
wherein Y and Y' are as above defined; A.sub.13a is a radical of
formula (IIa), (IIc) wherein R.sub.1 is the -Fmoc protective group;
R.sub.2 is --C(O)OR.sub.2x and binds a group --Y--ONO.sub.2;
R.sub.a of formula (IIa) and R.sub.c of formula (IIc) are
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3-- wherein R.sub.i is
R.sub.ii--C(O)-- and binds a group --Y'--ONO.sub.2 by known
procedure to remove the -Fmoc protective groups;
[0541] 101b) R.sub.a=R.sub.c are selected from
R.sub.hNH(CH.sub.2).sub.p-- wherein p is an integer from 0 to 4,
R.sub.h is --H:
by reacting a compound of formula (I) with a compound of formula
(IIIe)
##STR00316##
wherein Y and Y' are as above defined and A is a radical of formula
(IIa), (IIc) or (IIt) wherein R.sub.1 is --C(O)OC(CH.sub.3).sub.3;
--R.sub.2 is --C(O)OR.sub.2x and binds the group --Y--ONO.sub.2;
R.sub.a and R.sub.c are selected from R.sub.hNH(CH.sub.2).sub.p--
wherein p as above defined and R.sub.h is --H; in formula (IIt) d
and d' are as above defined, and R.sub.t is --H; using the same
procedure described in 1b').
[0542] 101b') R.sub.a=R.sub.c selected from
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--, R.sub.i is --H:
[0543] Compound (VIIIL) are prepared by reacting a compound of
formula (VIIIm) with a compound of formula (IIIe)
##STR00317##
wherein Y and Y' are as above defined and A.sub.13 is a radical of
formula (IIa), (IIc) wherein R.sub.1 is the Fmoc protective group,
R.sub.2 is --C(O)OR.sub.2x and binds the group --Y--ONO.sub.2;
R.sub.a and R.sub.c are R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--
wherein R.sub.i is --H using the same procedure described in
1b').
[0544] 101c) R.sub.a=R.sub.c are selected from
R.sub.haNH(CH.sub.2).sub.p-- wherein p is an integer from 0 to 4,
R.sub.ha is -Fmoc:
by deprotecting the Fmoc group of a compound of formula (VIIIn)
##STR00318##
wherein Y is as above defined and A.sub.14 is a radical of formula
(IIa), (IIc) or (IIt) wherein R.sub.1 is --C(O)OC(CH.sub.3).sub.3;
R.sub.2 is --C(O)OR.sub.2x and binds the group --Y--ONO.sub.2;
R.sub.a and R.sub.c are R.sub.haNH(CH.sub.2).sub.p-- wherein p as
above defined and R.sub.ha is the Fmoc protective group; d and d'
are as above defined, and R.sub.t is equal to R.sub.ta and is the
Fmoc protective group
[0545] 101'c) R.sub.a=R.sub.c selected from
R.sub.iaNH(.dbd.NH)NH--(CH.sub.2).sub.3--, R.sub.ia=--Pbf
[0546] Compound (VIIIm) are prepared by deprotecting the --Pbf
group of a compound of formula (VIIIo)
##STR00319##
wherein Y is as above defined and A.sub.15a is a radical of formula
(IIa), (IIc) wherein R.sub.1 is -Fmoc; R.sub.2 is --C(O)OR.sub.2x
and binds the group --Y--ONO.sub.2; R.sub.a and R.sub.c are
R.sub.iaNH(.dbd.NH)NH--(CH.sub.2).sub.3--R.sub.ia is the --Pbf
protective group;
[0547] 101d) compound described in 101c) and 101c') can be prepared
by reacting a compound of formula A.sub.14 or A.sub.15 with
compound (IIIi) using the same procedure described in 8b)
##STR00320##
wherein Y is as above defined and: A.sub.14 is a radical of formula
(IIa), (IIc) or (IIt) wherein R.sub.1 is --C(O)OC(CH.sub.3).sub.3;
R.sub.2 is --COOH; R.sub.a and R.sub.c are
R.sub.haNH(CH.sub.2).sub.p-- wherein p as above defined and
R.sub.ha is the Fmoc protective group; d and d' are as above
defined, and R.sub.t is R.sub.ta and is the Fmoc protective group.
A.sub.15 is a radical of formula (IIa), (IIc) wherein R.sub.1 is
-Fmoc; R.sub.2 is --COOH; R.sub.a and R.sub.c are selected from
R.sub.iaNH(.dbd.NH)NH--(CH.sub.2).sub.3--, wherein R.sub.ia is
--Pbf.
[0548] Compounds A.sub.14 and A.sub.15 are commercially
available.
[0549] 102. The compounds of general formula (I) wherein:
s and s' are equal to 1; s'', m, m' and m'' are equal to 0; Y and
Y' can be equal or different and are as above defined; A is
selected from (IIa), (IIc) and (IIt) wherein R.sub.1 is --H,
R.sub.2 is --C(O)OR.sub.2x and binds a group --Y--ONO.sub.2;
R.sub.a of formula (IIa) and R.sub.c of formula (IIc) are
R.sub.hNH(CH.sub.2).sub.p-- wherein p is an integer from 0 to 4, or
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--, wherein R.sub.h and
R.sub.i are R.sub.hh--OC(O)-- or R.sub.ii--OC(O) and binds a group
--Y'--ONO.sub.2 in formula (IIt) R.sub.1 is --H, and R.sub.2 is
--C(O)OR.sub.2x and binds a group --Y--ONO.sub.2; d is 2 d' is 1,
R.sub.t is --C(O)O--R.sub.tt, and binds a group --Y'--ONO.sub.2 can
be obtained as follows:
[0550] 102a) R.sub.a=R.sub.c selected from
R.sub.hNH(CH.sub.2).sub.p-- wherein p is an integer from 0 to 4,
R.sub.h is R.sub.hh--OC(O)--:
by reacting a compound of formula (I) wherein s, s', s'', m, m',
m'', Y, Y', Y'' are as above defined in 102, A is a radical of
(IIa), (IIc) or (IIt) wherein R.sub.2, d, d', R.sub.t are as
defined in 102, R.sub.a and R.sub.c are selected from
R.sub.hNH(CH.sub.2).sub.p-- wherein p is an integer from 0 to 4,
R.sub.h is R.sub.hh--OC(O)--; R.sub.1 is --C(O)OC(CH.sub.3).sub.3;
with anhydrous or aqueous organic or inorganic acid to hydrolyze
the --BOC protective groups following procedure well known in the
literature.
[0551] 102a') R.sub.a=R.sub.c selected from
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--, R.sub.i is
R.sub.ii--OC(O)--;
by reacting a compound of formula (VIIIA)
##STR00321##
wherein Y and Y' are as above defined; A.sub.16 is a radical of
formula (IIa), (IIc) wherein R.sub.1 is the -Fmoc protective group;
R.sub.2 is --C(O)OR.sub.2x and binds a group --Y--ONO.sub.2;
R.sub.a of formula (IIa) and R.sub.c of formula (IIc) are
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3-- wherein R.sub.i is
R.sub.ii--OC(O)-- and binds a group --Y'--ONO.sub.2 by known
procedure to remove the -Fmoc protective groups;
[0552] 102b) R.sub.a=R.sub.c are selected from
R.sub.hNH(CH.sub.2).sub.p-- wherein p is an integer from 0 to 4,
R.sub.h is --H:
by reacting a compound of formula (I) with a compound of formula
(IIIf)
##STR00322##
wherein Y and Y' are as above defined and A is as above defined in
101b), using the same procedure described in 3b).
[0553] 102b') R.sub.a=R.sub.c selected from
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--, R.sub.i is --H:
by reacting a compound of formula (VIIIm) already described in
101b') and obtained as described in 101c') with a compound of
formula (IIIf)
##STR00323##
wherein Y and Y' are as above defined and A.sub.13' is as defined
in 101b') using the same procedure described in 3b).
[0554] 103. The compounds of general formula (I) wherein:
s and s' are equal to 1; s'', m, m' and m'' are equal to 0; Y and
Y' can be equal or different and are as above defined; A is
selected from (IIa), (IIc) and (IIt) wherein R.sub.1 is --H,
R.sub.2 is --C(O)NHR.sub.2xx or --C(O)N(CH.sub.3)R.sub.2xx and
binds a group --Y--ONO.sub.2; R.sub.a of formula (IIa) and R.sub.c
of formula (IIc) are R.sub.hNH(CH.sub.2).sub.p-- wherein p is an
integer from 0 to 4, or R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--,
wherein R.sub.h and R.sub.i are R.sub.hh--C(O)-- or
R.sub.ii--C(O)--, and binds a group --Y'--ONO.sub.2 in formula
(IIt) R.sub.1 is --H, and R.sub.2 is --C(O)NHR.sub.2xx or
--C(O)N(CH.sub.3)R.sub.2xx and binds a group --Y--ONO.sub.2; d is 2
d' is 1, R.sub.t is --C(O)--R.sub.tt, and binds a group
--Y'--ONO.sub.2 can be obtained as follows:
[0555] 103a) R.sub.a=R.sub.c selected from
R.sub.hNH(CH.sub.2).sub.p-- wherein p is an integer from 0 to 4,
R.sub.h is R.sub.hh--C(O):
by reacting a compound of formula (I) wherein s, s', s'', m, m',
m'', Y, Y', Y'' are as above defined in 103, A is a radical of
(IIa), (IIc) or (IIt) wherein R.sub.2, d, d', R.sub.t are as
defined in 103, R.sub.a and R.sub.c are selected from
R.sub.hNH(CH.sub.2).sub.p-- wherein p is an integer from 0 to 4,
R.sub.h is R.sub.hh--C(O)--; R.sub.1 is --C(O)OC(CH.sub.3).sub.3;
with anhydrous or aqueous organic or inorganic acid to hydrolyze
the --BOC protective groups following procedure well known in the
literature.
[0556] 103a) R.sub.a=R.sub.c selected from
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--, R.sub.i is
R.sub.ii--C(O)--;
by reacting a compound of formula (VIIIq)
##STR00324##
wherein Y and Y' are as above defined; A.sub.17a is a radical of
formula (IIa), (IIc) wherein R.sub.1 is the -Fmoc protective group;
R.sub.2 is --C(O)NHR.sub.2xx or --C(O)N(CH.sub.3)R.sub.2xx and
binds a group --Y--ONO.sub.2; R.sub.a of formula (IIa) and R.sub.c
of formula (IIc) are R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--
wherein R.sub.i is R.sub.ii--C(O)-- and binds a group
--Y'--ONO.sub.2 by known procedure to remove the -Fmoc protective
groups;
[0557] 103b) R.sub.a=R.sub.c are selected from
R.sub.hNH(CH.sub.2).sub.p-- wherein p is an integer from 0 to 4,
R.sub.h is --H
by reacting a compound of formula (I) with a compound of formula
(IIIe)
##STR00325##
wherein Y and Y' are as above defined and A is a radical of formula
(IIa), (IIc) or (IIt) wherein R.sub.1 is --C(O)OC(CH.sub.3).sub.3;
--R.sub.2 is --C(O)NHR.sub.2xx or --C(O)N(CH.sub.3)R.sub.2xx and
binds the group --Y--ONO.sub.2; R.sub.a and R.sub.c are
R.sub.hNH(CH.sub.2).sub.p-- wherein p as above defined and R.sub.h
is --H; in formula (IIt) d and d' are as above defined, and R.sub.t
is --H; using the same procedure described in 1b').
[0558] 103b') R.sub.a=R.sub.c selected from
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--, R.sub.i is --H:
by reacting a compound of formula (VIIIr) with a compound of
formula (IIIe)
##STR00326##
wherein Y and Y' are as above defined and A.sub.17 is a radical of
formula (IIa), (IIc) wherein R.sub.1 is the Fmoc protective group,
R.sub.2 is --C(O)NHR.sub.2xx or --C(O)N(CH.sub.3)R.sub.2xx and
binds the group --Y--ONO.sub.2; R.sub.a and R.sub.c are
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3-- wherein R.sub.i is --H
using the same procedure described in 1b').
[0559] 103c) R.sub.a=R.sub.c are selected from
R.sub.haNH(CH.sub.2).sub.p-- wherein p is an integer from 0 to 4,
R.sub.ha is -Fmoc
[0560] Compound (I) described in 103b) can be prepared by
deprotecting the Fmoc group of a compound of formula (VIIIs)
##STR00327##
wherein Y is as above defined and A.sub.18 is a radical of formula
(IIa), (IIc) or (IIt) wherein R.sub.1 is --C(O)OC(CH.sub.3).sub.3;
R.sub.2 is --C(O)NHR.sub.2xx or --C(O)N(CH.sub.3)R.sub.2xx and
binds the group --Y--ONO.sub.2; R.sub.a and R.sub.c are
R.sub.haNH(CH.sub.2).sub.p-- wherein p as above defined and
R.sub.ha is the Fmoc protective group; d and d' are as above
defined, and R.sub.t is R.sub.ta and is the Fmoc group.
[0561] 103c') R.sub.a=R.sub.c selected from
R.sub.iaNH(.dbd.NH)NH--(CH.sub.2).sub.3--, R.sub.ia=--Pbf
[0562] Compound (VIIIr) described in 103b') by deprotecting the
--Pbf group of a compound of formula (VIIIt)
##STR00328##
wherein Y is as above defined and A.sub.19 is a radical of formula
(IIa), (IIc) wherein R.sub.1 is -Fmoc; R.sub.2 is --C(O)NHR.sub.2xx
or --C(O)N(CH.sub.3)R.sub.2xx and binds the group --Y--ONO.sub.2;
R.sub.a and R.sub.c are
R.sub.iaNH(.dbd.NH)NH--(CH.sub.2).sub.3--R.sub.ia is the --Pbf
protective group;
[0563] 103d) compounds described in 103c) and 103c') can be
prepared by reacting a compound of formula A.sub.14 or A.sub.15
described in 101d) with compound (IIIo) using the same procedure
described in 7b)
##STR00329##
wherein Y is as above defined and W.sub.3 is H or --CH.sub.3.
[0564] 104. The compounds of general formula (I) wherein:
s and s' are equal to 1; s'', m, m' and m'' are equal to 0; Y and
Y' can be equal or different and are as above defined; A is
selected from (IIa), (IIc) and (IIt) wherein R.sub.1 is --H,
R.sub.2 is --C(O)NHR.sub.2xx or --C(O)N(CH.sub.3)R.sub.2xx and
binds a group --Y--ONO.sub.2; R.sub.a of formula (IIa) and R.sub.c
of formula (IIc) are R.sub.hNH(CH.sub.2).sub.p-- wherein p is an
integer from 0 to 4, or R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--,
wherein R.sub.h and R.sub.i are R.sub.hh--OC(O)-- or
R.sub.ii--OC(O)--, and binds a group --Y'--ONO.sub.2; in formula
(IIt) R.sub.1 is --H, and R.sub.2 is --C(O)NHR.sub.2xx or
--C(O)N(CH.sub.3)R.sub.2xx and binds a group --Y--ONO.sub.2; d is 2
d' is 1, R.sub.t is --C(O)O--R.sub.xx, and binds a group
--Y'--ONO.sub.2 can be obtained as follows:
[0565] 104a) R.sub.a=R.sub.c selected from
R.sub.hNH(CH.sub.2).sub.p-- wherein p is an integer from 0 to 4,
R.sub.h is
by reacting a compound of formula (I) wherein s, s', s'', m, m',
m'', Y, Y', Y'' are as above defined in 104, A is a radical of
(IIa), (IIc) or (IIt) wherein R.sub.2, d, d', R.sub.t are as
defined in 104, R.sub.a and R.sub.c are selected from
R.sub.hNH(CH.sub.2).sub.p-- wherein p is an integer from 0 to 4,
R.sub.h is R.sub.hh--O--C(O)--; R.sub.1 is
--C(O)OC(CH.sub.3).sub.3; with anhydrous or aqueous organic or
inorganic acid to hydrolyze the --BOC protective groups following
procedure well known in the literature.
[0566] 104a') R.sub.a=R.sub.c selected from
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--, R.sub.i is
R.sub.ii--OC(O)--;
by reacting a compound of formula (VIIIu)
##STR00330##
wherein Y and Y' are as above defined and A.sub.20 is a radical of
formula (IIa), (IIc) wherein R.sub.1 is the -Fmoc protective group;
R.sub.2 is --C(O)NHR.sub.2xx or --C(O)N(CH.sub.3)R.sub.2xx and
binds a group --Y--ONO.sub.2; R.sub.a of formula (IIa) and R.sub.c
of formula (IIc) are R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--
wherein R.sub.i is R.sub.ii--OC(O)-- and binds a group
--Y'--ONO.sub.2 by known procedure to remove the -Fmoc protective
groups;
[0567] 104b) R.sub.a=R.sub.c are selected from
R.sub.hNH(CH.sub.2).sub.p-- wherein p is an integer from 0 to 4,
R.sub.h is --H
by reacting a compound of formula (I) with a compound of formula
(IIIf)
##STR00331##
wherein Y and Y' are as above defined and A is as defined in 103b),
using the same procedure described in 3b).
[0568] 104b') R.sub.a=R.sub.c selected from
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--, R.sub.i is --H:
[0569] Compound (VIIIu) can be prepared by reacting a compound of
formula (VIIIr) with a compound of formula (IIIf)
##STR00332##
wherein Y and Y' are as above defined and A.sub.17 is as defined in
103b') using the same procedure described in 3b).
[0570] 105. The compounds of general formula (I) wherein:
s, s' and m are equal to 1; s'', m' and m'' are equal to 0; Y and
Y' are as above defined;
B is:
##STR00333##
[0571] A is selected from (IIa), (IIc) and (IIt) wherein R.sub.1 is
--H, R.sub.2 is --C(O)OR.sub.2x and binds a group
--B--Y--ONO.sub.2; R.sub.a of formula (IIa) and R.sub.c of formula
(IIc) are R.sub.hNH(CH.sub.2).sub.p-- wherein p is an integer from
0 to 4, or R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--, wherein
R.sub.h and R.sub.i are R.sub.hh--C(O)-- or R.sub.ii--C(O)--, and
bind a group --Y'--ONO.sub.2 in formula (IIt) R.sub.1 is --H, and
R.sub.2 is --C(O)OR.sub.2x and binds a group --B--Y--ONO.sub.2, d
is 2 d' is 1, R.sub.t is --C(O)--R.sub.tt and binds a group
--Y'--ONO.sub.2; can be obtained as follows:
[0572] 105a) R.sub.a=R.sub.c selected from
R.sub.hNH(CH.sub.2).sub.p-- wherein p is an integer from 0 to 4,
R.sub.h is R.sub.hh--C(O)--:
by reacting a compound of formula (I) wherein s, s', s'', m, m',
m'', B, Y, Y', Y'' are as above defined in 105, A is a radical of
(IIa), (IIc) or (IIt) wherein R.sub.2, d, d', R.sub.t are as
defined in 105, R.sub.a and R.sub.c are selected from
R.sub.hNH(CH.sub.2).sub.p-- wherein p is an integer from 0 to 4,
R.sub.h is R.sub.hh--C(O)--; R.sub.1 is --C(O)OC(CH.sub.3).sub.3;
with anhydrous or aqueous organic or inorganic acid to hydrolyze
the --BOC protective groups following procedure well known in the
literature.
[0573] 105a') R.sub.a=R.sub.c selected from
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--, R.sub.i is
R.sub.ii--C(O)--;
by reacting a compound of formula (VIIIv)
##STR00334##
wherein B, Y and Y' are as above defined and A.sub.21a is a radical
of formula (IIa), (IIc) wherein R.sub.1 is the -Fmoc protective
group; R.sub.2 is --C(O)OR.sub.2x and binds a group
--B--Y--ONO.sub.2; R.sub.a of formula (IIa) and R.sub.c of formula
(IIc) are R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3-- wherein R.sub.i
is R.sub.ii--C(O)-- and binds a group --Y'--ONO.sub.2 by known
procedure to remove the -Fmoc protective groups;
[0574] 105b) R.sub.a=R.sub.c are selected from
R.sub.hNH(CH.sub.2).sub.p-- wherein p is an integer from 0 to 4,
R.sub.h is --H
by reacting a compound of formula (I) with a compound of formula
(IIIe)
##STR00335##
wherein Y and Y' are as above defined and A is a radical of formula
(IIa), (IIc) or (IIt) wherein R.sub.1 is --C(O)OC(CH.sub.3).sub.3;
--R.sub.2 is --C(O)OR.sub.2x and binds the group --B--Y--ONO.sub.2;
R.sub.a and R.sub.c are R.sub.hNH(CH.sub.2).sub.p-- wherein p as
above defined and R.sub.h is --H; in formula (IIt) d and d' are as
above defined, and R.sub.t is --H; using the same procedure
described in 1b');
[0575] 105b') R.sub.a=R.sub.c selected from
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--, R.sub.i is --H:
[0576] Compound of formula (VIIIv) can be prepared by reacting a
compound of formula (VIIIw) with a compound of formula (IIIe)
##STR00336##
wherein Y and Y' are as above defined and A.sub.21 is a radical of
formula (IIa), (IIc) wherein R.sub.1 is the Fmoc protective group,
R.sub.2 is --C(O)OR.sub.2x and binds the group --B--Y--ONO.sub.2;
R.sub.a and R.sub.c are R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--
wherein R.sub.i is --H using the same procedure described in
1b').
[0577] 105c) R.sub.a=R.sub.c are selected from
R.sub.haNH(CH.sub.2).sub.p-- wherein p is an integer from 0 to 4,
R.sub.ha is -Fmoc
[0578] Compound (I) described in 105b) by deprotecting the Fmoc
group of a compound of formula (VIIIx)
##STR00337##
wherein Y and B are as above defined and A.sub.22 is a radical of
formula (IIa), (IIc) or (IIt) wherein R.sub.1 is
--C(O)OC(CH.sub.3).sub.3; R.sub.2 is --C(O)OR.sub.2x and binds the
group --B--Y--ONO.sub.2; R.sub.a and R.sub.c are
R.sub.haNH(CH.sub.2).sub.p-- wherein p as above defined and
R.sub.ha is the Fmoc protective group; d and d' are as above
defined, and R.sub.t is R.sub.ta and is the Fmoc protecting
group.
[0579] 105c') R.sub.a=R.sub.c selected from
R.sub.iaNH(.dbd.NH)NH--(CH.sub.2).sub.3, R.sub.ia=--Pbf Compound
described in 105b') are prepared by deprotecting the --Pbf group of
a compound of formula (VIIIy)
##STR00338##
wherein Y is as above defined and A.sub.23 is a radical of formula
(IIa), (IIc) wherein R.sub.1 is -Fmoc; R.sub.2 is --C(O)OR.sub.2x
and binds the group --B--Y--ONO.sub.2; R.sub.a and R.sub.c are
R.sub.iaNH(.dbd.NH)NH--(CH.sub.2).sub.3--R.sub.ia is the --Pbf
protective group;
[0580] 105d) compounds (VIIIx) and (VIIIy) are prepared by reacting
respectively a compound of formula A.sub.14 or A.sub.15 described
in 101d) with compound (IIIg) or (IIIn) depending on the meaning of
B, and applying the same procedure described in 4b) or 6b):
A.sub.14 or A.sub.15 Hal-W.sub.1--OC(O)O--Y--ONO.sub.2 (IIIg)
A.sub.14 or A.sub.15 Hal-W.sub.1--OC(O)--Y--ONO.sub.2 (IIIn)
wherein Hal, W.sub.1 and Y are as above.
[0581] 106. The compounds of general formula (I) wherein:
s' and m are equal to 1; s'', m' and m'' are equal to 0; Y and Y'
are as above defined;
B is:
##STR00339##
[0582] A is a radical of formula (IIa), (IIc) or (IIt) wherein
R.sub.1 is --H, R.sub.2 is --C(O)OR.sub.2x and binds a group
--B--Y--ONO.sub.2; R.sub.a of formula (IIa) and R.sub.c of formula
(IIc) are R.sub.hNH(CH.sub.2).sub.p-- wherein p is an integer from
0 to 4, or R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--, wherein
R.sub.h and R.sub.i are R.sub.hh--OC(O)-- or R.sub.ii--OC(O) and
bind a group --Y'--ONO.sub.2 in formula (IIt) R.sub.1 is --H, and
R.sub.2 is --C(O)OR.sub.2x and binds a group --B--Y--ONO.sub.2, d
is 2 d' is 1, R.sub.t is --C(O)O--R.sub.tt and binds a group
--Y'--ONO.sub.2; can be obtained as follows:
[0583] 106a) R.sub.a=R.sub.c selected from
R.sub.hNH(CH.sub.2).sub.p-- wherein p is an integer from 0 to 4,
R.sub.h is R.sub.hh--OC(O)--:
by reacting a compound of formula (I) wherein s, s', s'', m, m',
m'', B, Y, Y', Y'' are as above defined in 106, A is a radical of
(IIa), (IIc) or (IIt) wherein R.sub.2, d, d', R.sub.t are as
defined in 106, R.sub.a and R.sub.c are selected from
R.sub.hNH(CH.sub.2).sub.p-- wherein p is an integer from 0 to 4,
R.sub.h is R.sub.hh--OC(O)--; R.sub.1 is --C(O)OC(CH.sub.3).sub.3;
with anhydrous or aqueous organic or inorganic acid to hydrolyze
the --BOC protective groups following procedure well known in the
literature.
[0584] 106a') R.sub.a=R.sub.c selected from
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--, R.sub.i is
R.sub.ii--OC(O)--;
by reacting a compound of formula (VIIIz)
##STR00340##
wherein B, Y and Y' are as above defined and A.sub.24 is a radical
of formula (IIa), (IIc) wherein R.sub.1 is the -Fmoc protective
group; R.sub.2 is --C(O)OR.sub.2x and binds a group
--B--Y--ONO.sub.2; R.sub.a of formula (IIa) and R.sub.c of formula
(IIc) are R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3-- wherein R.sub.i
is R.sub.ii--OC(O)-- and binds a group --Y'--ONO.sub.2 by known
procedure to remove the -Fmoc protective groups;
[0585] 106b) R.sub.a=R.sub.c are selected from
R.sub.hNH(CH.sub.2).sub.p-- wherein p is an integer from 0 to 4,
R.sub.h is --H
by reacting a compound of formula (I) obtained as described in
105c) with a compound of formula (IIIf)
##STR00341##
wherein Act, B, Y and Y' are as above defined and A is as defined
in 105b), using the same procedure described in 3b).
[0586] 106b') R.sub.a=R.sub.c selected from
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--, R.sub.i is --H:
by reacting a compound of formula (VIIIw) obtained as described in
105c') with a compound of formula (IIIf)
##STR00342##
wherein B, Y and Y' are as above defined and A.sub.21 is as defined
in 105b'), using the same procedure described in 3b).
[0587] 107. The compounds of general formula (I) wherein:
s is equal to 1; s', s'', m, m' and m'' are equal to 0; Y is as
above defined; A is a radical of formula (IIa), (IIc) or (IIt)
wherein R.sub.1 is --C(O)--R.sub.1x and binds a group
--Y--ONO.sub.2; R.sub.2 is --COOH R.sub.a of formula (IIa) and
R.sub.c of formula (IIc) are R.sub.hNH(CH.sub.2).sub.p-- wherein p
is an integer from 0 to 4, or
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--, wherein R.sub.h and
R.sub.i are --H; in formula (IIt) d is 2 d' is 1, R.sub.t is --H;
can be obtained as follows:
[0588] 107a) R.sub.a=R.sub.c selected from
R.sub.hNH(CH.sub.2).sub.p-- wherein p is an integer from 0 to 4,
R.sub.h is --H
by reacting a compound of formula (I) wherein s, s', s'', m, m',
m'', Y, Y', Y'' are as above defined in 107, A is a radical of
(IIa), (IIc) or (IIt) wherein R.sub.1, R.sub.2, d, d', are as
defined in 107, R.sub.a of formula (IIa) and R.sub.c of formula
(IIc) are selected from R.sub.hNH(CH.sub.2).sub.p-- wherein p is an
integer from 0 to 4, R.sub.h is --C(O)OC(CH.sub.3).sub.3; in
formula (IIt) R.sub.t is --C(O)OC(CH.sub.2).sub.3; with anhydrous
or aqueous organic or inorganic acid to hydrolyze the --BOC
protective groups following procedure well known in the
literature.
[0589] 107a') R.sub.a=R.sub.c selected from
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--, R.sub.i is --H;
reacting a compound of formula (VIIIaa)
A.sub.25-Y--ONO.sub.2 (VIIIaa)
wherein Y is as above defined and A.sub.25 is a radical of formula
(IIa), (IIc) wherein R.sub.1, R.sub.2 are as defined in 107,
R.sub.a of formula (IIa) and R.sub.c of formula (IIc) are selected
from R.sub.iaNH(.dbd.NH)NH--(CH.sub.2).sub.3--, wherein R.sub.ia is
the --Pbf protective group as already defined; with anhydrous or
aqueous organic or inorganic acid to hydrolyze the --Pbf protective
groups following procedure well known in the literature.
[0590] 107b) compounds described in 107a) and 107a') can be
prepared by reacting a compound of formula A or a compound of
formula A.sub.26 with a compound of formula (IIIe)
##STR00343##
wherein Act and Y are as above defined and: A is a compound of
formula (IIa), (IIc) or (IIt) wherein R.sub.1 is --H, R.sub.2 is
--COOH; R.sub.a of formula (IIa) and R.sub.c of formula (IIc) are
R.sub.hNH(CH.sub.2).sub.p-- wherein p is an integer from 0 to 4,
R.sub.h is C(O)OC(CH.sub.3).sub.3; in formula (IIt) d and d' are as
defined in 107, R.sub.t is --C(O)OC(CH.sub.3).sub.3; A.sub.26 is a
compound of formula (IIa) or (IIc) wherein R.sub.1 is --H, R.sub.2
is --COOH; R.sub.a of formula (IIa) and R.sub.c of formula (IIc)
are R.sub.iaNH(.dbd.NH)NH--(CH.sub.2).sub.3--, wherein R.sub.ia is
the --Pbf protective group as already defined; using the same
procedure described in 1b').
[0591] Compounds A and A.sub.26 are commercially available.
[0592] 108. The compounds of general formula (I) wherein:
s is equal to 1; s', s'', m, m' and m'' are equal to 0; Y is as
above defined; A is selected from (IIa), (IIc) and (IIt) wherein
R.sub.1 is --C(O)O--R.sub.1x and binds a group --Y--ONO.sub.2;
R.sub.2 is --COOH R.sub.a of formula (IIa) and R.sub.c of formula
(IIc) are R.sub.hNH(CH.sub.2).sub.p-- wherein p is an integer from
0 to 4, or R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--, wherein
R.sub.h and R.sub.i are --H; in formula (IIt) d is 2 d' is 1,
R.sub.t is --H; can be obtained as follows:
[0593] 108a) R.sub.a=R.sub.c selected from
R.sub.hNH(CH.sub.2).sub.p-- wherein p is an integer from 0 to 4,
R.sub.h is --H
by reacting a compound of formula (I) wherein s, s', s'', m, m',
m'', Y, Y', Y'' are as above defined in 108, A is a radical of
(IIa), (IIc) or (IIt) wherein R.sub.1, R.sub.2, d, d', are as
defined in 108, R.sub.a of formula (IIa) and R.sub.c of formula
(IIc) are selected from R.sub.hNH(CH.sub.2).sub.p-- wherein p is an
integer from 0 to 4, R.sub.h is --C(O)OC(CH.sub.3).sub.3; in
formula (IIt) R.sub.t is --C(O)OC(CH.sub.3).sub.3; with anhydrous
or aqueous organic or inorganic acid to hydrolyze the --BOC
protective groups following procedure well known in the
literature.
[0594] 108a') R.sub.a=R.sub.c selected from
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--, R.sub.i is --H;
reacting a compound of formula (VIIIab)
A.sub.27-Y--ONO.sub.2 (VIIIab)
wherein Y is as above defined and A.sub.27 is a radical of (IIa),
(IIc) wherein R.sub.1, R.sub.2 are as defined in 108, R.sub.a of
formula (IIa) and R.sub.c of formula (IIc) are selected from
R.sub.iaNH(.dbd.NH)NH--(CH.sub.2).sub.3--, wherein R.sub.ia is the
--Pbf protective group as already defined; with anhydrous or
aqueous organic or inorganic acid to hydrolyze the --Pbf protective
groups following procedure well known in the literature.
[0595] 108b) compounds described in 108a) and 108a') can be
prepared
by reacting a compound of formula A or a compound of formula
A.sub.26 both already defined in 107b) with a compound of formula
(IIIf)
##STR00344##
wherein Act and Y are as above defined, using the same procedure
described in 3b).
[0596] 109. The compounds of general formula (I) wherein:
s is equal to 1; s', s'', m, m' and m'' are equal to 0; Y is as
above defined; A is selected from (IIa), (IIc) and (IIt) wherein
R.sub.1 is --H; R.sub.2 is --COOH; R.sub.a of formula (IIa) and
R.sub.c of formula (IIc) are R.sub.hNH(CH.sub.2).sub.p-- wherein p
is an integer from 0 to 4, or
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--, wherein R.sub.h and
R.sub.i are R.sub.hh--C(O) or R.sub.ii--C(O) and bind a group
--Y--ONO.sub.2; in formula (IIt) d is 2 d' is 1, R.sub.t is
--C(O)--R.sub.tt, and binds a group --Y--ONO.sub.2; can be obtained
as follows:
[0597] 109a) by reacting a compound of formula (I) wherein s, s',
s'', m, m', m'', Y, Y', Y'' are as above defined in 109, A is a
radical of (IIa), (IIc) or (IIt) wherein R.sub.2, R.sub.a, R.sub.c,
d, d' and R.sub.t are as defined in 109, R.sub.1 is
--C(O)OC(CH.sub.3).sub.3;
with anhydrous or aqueous organic or inorganic acid to hydrolyze
the --BOC protective groups following procedure well known in the
literature.
[0598] 109b) by reacting a compound of formula A with a compound of
formula (IIIe)
A+Act(O)C--Y--ONO.sub.2 (IIIe)
wherein Act and Y are as above defined and A is a radical of (IIa),
(IIc) or (IIt) wherein R.sub.1 is --C(O)OC(CH.sub.3).sub.3; R.sub.2
is --COOH; R.sub.a of formula (IIa) and R.sub.c of formula (IIc)
are R.sub.hNH(CH.sub.2).sub.p-- wherein p is an integer from 0 to
4, or R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--, wherein R.sub.h and
R.sub.i are --H; in formula (IIt) d and d' are as defined in 109,
R.sub.t is --H; using the same procedure described in 1b').
[0599] Compounds A are commercially available.
[0600] 110. The compounds of general formula (I) wherein:
s is equal to 1; s', s'', m, m' and m'' are equal to 0; Y is as
above defined; A is selected from (IIa), (IIc) and (IIt) wherein
R.sub.1 is --H; R.sub.2 is --COOH; R.sub.a of formula (IIa) and
R.sub.c of formula (IIc) are R.sub.hNH(CH.sub.2).sub.p-- wherein p
is an integer from 0 to 4, or
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--, wherein R.sub.h and
R.sub.i are R.sub.hh--OC(O)-- or R.sub.ii--OC(O) and bind a group
--Y--ONO.sub.2; in formula (IIt) d is 2 d' is 1, R.sub.t is
--C(O)O--R.sub.tt, and it binds a group --Y--ONO.sub.2; can be
obtained as follows:
[0601] 110a) by reacting a compound of formula (I) wherein s, s',
s'', m, m', m'', Y, Y', Y'' are as above defined in 110, A is a
radical of (IIa), (IIc) or (IIt) wherein R.sub.2, R.sub.a, R.sub.c,
d, d' and R.sub.t are as defined in 110, R.sub.1 is
--C(O)OC(CH.sub.3).sub.3;
with anhydrous or aqueous organic or inorganic acid to hydrolyze
the --BOC protective groups following procedure well known in the
literature.
[0602] 110b) by reacting a compound of formula A with a compound of
formula (IIIf)
A+Act(O)C--O--Y--ONO.sub.2 (IIIf)
wherein Act and Y are as above defined and A is as defined in
109b), using the same procedure described in 3b).
[0603] 111. The compounds of general formula (I) wherein:
s, s' and m' are equal to 1; s'', m, m'', are 0 Y and Y' are equal
or different and are as above defined;
B is:
##STR00345##
[0604] A is selected among: i) (IIa) wherein R.sub.1 is --H,
R.sub.2 is --C(O)OR.sub.2x and R.sub.2 binds a group
B--Y'--ONO.sub.2; R.sub.a is selected from
R.sub.bx--C(O)--S--CH.sub.2--, or R.sub.xO--CH.sub.2--,
R.sub.xO--CH(CH.sub.3)--, (R.sub.xO)-p-C.sub.6H.sub.4--CH.sub.2--,
4-(R.sub.xO)-3,5-diiodobenzyl-4-(R.sub.xO)-3-nitrobenzyl- wherein
R.sub.x is R.sub.xx--C(O)-- and R.sub.a binds a group
--Y--ONO.sub.2; ii) (IIc) wherein R.sub.1 is --H, R.sub.2 is
--C(O)OR.sub.2x and R.sub.2 binds a group B--Y'--ONO.sub.2; R.sub.c
is selected from R.sub.bx--C(O)--S--CH.sub.2--, or
R.sub.xO--CH.sub.2--, R.sub.xO--CH(CH.sub.3)--,
(R.sub.xO)-p-C.sub.6H.sub.4--CH.sub.2--,
4-(R.sub.xO)-3,5-diiodobenzyl-4-(R.sub.xO)-3-nitrobenzyl- wherein
R.sub.x is R.sub.xx--C(O)-- and R.sub.c binds a group
--Y--ONO.sub.2; iii) (IIs) wherein R.sub.1 is --H, R.sub.3 is
--OC(O)R.sub.3x and R.sub.3 binds a group --Y--ONO.sub.2; R.sub.s
is selected from R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is R.sub.gx--O--, and R.sub.s binds a group
B--Y'--ONO.sub.2; v) (IIn), wherein R.sub.1 is --H, R.sub.2 is
--C(O)OR.sub.2x, R.sub.2 binds a group B--Y'--ONO.sub.2; a is 1, b
is 0 or 1; R.sub.x is R.sub.xx--C(O)-- and R.sub.x binds a group
--Y--ONO.sub.2; can be prepared as follows:
[0605] 111a) by reacting a compound of formula (I) wherein B, s,
s', s'', m, m', m'', Y, Y', Y'' are as above defined in 111, A is a
radical of formula (IIa), (IIc), (IIs) or (IIu) wherein; R.sub.2,
R.sub.3, a, b, R.sub.a, R.sub.c, R.sub.g and R.sub.x are as defined
in 111; R.sub.1 is --C(O)OC(CH.sub.3).sub.3, with anhydrous or
aqueous organic or inorganic acid to hydrolyze the --BOC protective
groups following procedure well known in the literature.
[0606] 111b) by reacting a compound of formula (I) obtained in 36b)
with a compound of formula (IIIg) or (IIIn) depending on the
meaning of B
##STR00346##
wherein Y and Y', Hal, W.sub.1 are as above defined and in formula
(I) A is selected among: i) (IIa) wherein R.sub.1 is
--C(O)OC(CH.sub.3).sub.3, R.sub.2 is --COOH, R.sub.a is selected
from R.sub.bx--C(O)--S--CH.sub.2--, or R.sub.xO--CH.sub.2--,
R.sub.xO--CH(CH.sub.2)--, (R.sub.xO)-p-C.sub.6H.sub.4--CH.sub.2--,
4-(R.sub.xO)-3,5-diiodobenzyl-4-(R.sub.xO)-3-nitrobenzyl- wherein
R.sub.x is R.sub.xx--C(O)-- and R.sub.a binds a group
--Y--ONO.sub.2; ii) (IIc) wherein R.sub.1 is
--C(O)OC(CH.sub.3).sub.3, R.sub.2 is --COOH, R.sub.c is selected
from R.sub.bx--C(O)--S--CH.sub.2--, or R.sub.xO--CH.sub.2--,
R.sub.xO--CH(CH.sub.2)--, (R.sub.xO)-p-C.sub.6H.sub.4--CH.sub.2--,
4-(R.sub.xO)-3,5-diiodobenzyl-4-(R.sub.xO)-3-nitrobenzyl- wherein
R.sub.x is R.sub.xx--C(O)-- and R.sub.c binds a group
--Y--ONO.sub.2; iii) (IIs) wherein R.sub.1 is
--C(O)OC(CH.sub.3).sub.3, R.sub.3 is --OC(O)R.sub.3x and R.sub.3
binds a group --Y--ONO.sub.2; R.sub.s is selected from
R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is --OH, v) (IIu) wherein R.sub.1 is
--C(O)OC(CH.sub.3).sub.3, R.sub.2 is --COOH, a is 1, b is 0 or 1;
and R.sub.x is R.sub.xx--C(O)-- and R.sub.x binds a group
--Y--ONO.sub.2; following the same procedures described in 4b) or
6b).
[0607] 112. The compounds of general formula (I) wherein:
s, s'and m' are equal to 1; s'', m, m'', are 0 Y and Y' are equal
or different and are as above defined;
B is:
##STR00347##
[0608] A is selected among: i) (IIa) wherein R.sub.1 is --H,
R.sub.2 is --C(O)OR.sub.2x and R.sub.2 binds a group
B--Y'--ONO.sub.2; and R.sub.a is selected from
R.sub.bx--OC(O)--S--CH.sub.2--, or R.sub.xO--CH.sub.2--,
R.sub.xO--CH(CH.sub.3)--, (R.sub.xO)-p-C.sub.6H.sub.4--CH.sub.2--,
4-(R.sub.xO)-3,5-diiodobenzyl-4-(R.sub.xO)-3-nitrobenzyl- wherein
R.sub.x is R.sub.xx--OC(O)-- and R.sub.a binds a group
--Y--ONO.sub.2; ii) (IIc) wherein R.sub.1 is --H, R.sub.2 is
--C(O)OR.sub.2x and R.sub.2 binds a group B--Y'--ONO.sub.2; R.sub.c
is selected from R.sub.bx--OC(O)--S--CH.sub.2--, or
R.sub.xO--CH.sub.2--, R.sub.xO--CH(CH.sub.3)--,
(R.sub.xO)-p-C.sub.6H.sub.4--CH.sub.2--,
4-(R.sub.xO)-3,5-diiodobenzyl-4-(R.sub.xO)-3-nitrobenzyl- wherein
R.sub.x is R.sub.xx--OC(O)-- and R.sub.c binds a group
--Y--ONO.sub.2; iii) (IIs) wherein R.sub.1 is --H, R.sub.3 is
--OC(O)O--R.sub.3x and R.sub.3 binds a group --Y--ONO.sub.2;
R.sub.s is selected from R.sub.gC(O)CH.sub.2--NH--,
R.sub.gC(O)CH.sub.2, R.sub.gC(O)(CH.sub.2).sub.2--,
R.sub.gC(O)(CH.sub.2).sub.4--, wherein R.sub.g is R.sub.gx--O--,
and R.sub.s binds a group B--Y'--ONO.sub.2; v) wherein R.sub.1 is
--H, R.sub.2 is --C(O)OR.sub.2x, R.sub.2 binds a group
--B--Y'--ONO.sub.2; a is 1; b is 0 or 1; R.sub.x is
R.sub.xx--OC(O)-- and R.sub.x binds a group --Y--ONO.sub.2; can be
prepared as follows:
[0609] 112a) by reacting a compound of formula (I) wherein B, s,
s', s'', m, m', m'', Y, Y', Y'' are as above defined in 112, A is a
radical of formula (IIa), (IIc), (IIs) or (IIu) wherein; R.sub.2,
R.sub.3, a, b, R.sub.a, R.sub.c, R.sub.g and R.sub.x are as defined
in 112; R.sub.1 is --C(O)OC(CH.sub.3).sub.3 with anhydrous or
aqueous organic or inorganic acid to hydrolyze the --BOC protective
groups following procedure well known in the literature.
[0610] 112b) by reacting a compound of formula (I) obtained in 37b)
with a compound of formula (IIIg) or (IIIn) depending on the
meaning of B
##STR00348##
wherein Y and Y', Hal, W.sub.1 are as above defined and in formula
(I) A is as above defined in 111b); following the same procedures
described in 4b) or 6b).
[0611] 113. The compounds of general formula (I) wherein:
s, s'and m' are equal to 1; s'', m, m'', are 0 Y and Y' are equal
or different and are as above defined;
B is:
##STR00349##
[0612] A is selected among: i) (IIa) wherein R.sub.1 is --H,
R.sub.2 is --C(O)OR.sub.2x and R.sub.2 binds a group
B--Y'--ONO.sub.2; and R.sub.a is selected from
R.sub.bx--NH(O)C--S--CH.sub.2--, or R.sub.xO--CH.sub.2--,
R.sub.xO--CH(CH.sub.3)--, (R.sub.xO)-p-C.sub.6H.sub.4--CH.sub.2--,
4-(R.sub.xO)-3,5-diiodobenzyl-4-(R.sub.xO)-3-nitrobenzyl- wherein
R.sub.x is R.sub.xxNH(O)C-- and R.sub.a binds a group
--Y--ONO.sub.2; ii) (IIc) wherein R.sub.1 is --H, R.sub.2 is
--C(O)OR.sub.2x and R.sub.2 binds a group B--Y'--ONO.sub.2; R.sub.c
is selected from R.sub.bx--NH(O)C--S--CH.sub.2--, or
R.sub.xO--CH.sub.2--, R.sub.xO--CH(CH.sub.3)--,
(R.sub.xO)-p-C.sub.6H.sub.4--CH.sub.2--,
4-(R.sub.xO)-3,5-diiodobenzyl-4-(R.sub.xO)-3-nitrobenzyl- wherein
R.sub.x is R.sub.xxNH(O)C-- and R.sub.c binds a group
--Y--ONO.sub.2; iii) (IIs) wherein R.sub.1 is --H, R.sub.3 is
--OC(O)--NH--R.sub.3x and R.sub.3 binds a group --Y--ONO.sub.2;
R.sub.s is selected from R.sub.gC(O)CH.sub.2--NH--,
R.sub.gC(O)CH.sub.2f R.sub.gC(O)(CH.sub.2).sub.2--,
R.sub.gC(O)(CH.sub.2).sub.4--, wherein R.sub.g is R.sub.gx--O--,
and R.sub.g binds a group B--Y'--ONO.sub.2; v) (IIu) wherein
R.sub.1 is --H, R.sub.2 is --C(O)OR.sub.2x, and R.sub.2 binds a
group B--Y'--ONO.sub.2; a is 1; b is 0 or 1; R.sub.x is
R.sub.xx--NHC(O)-- and R.sub.x binds a group --Y--ONO.sub.2; can be
prepared as follows:
[0613] 113a) by reacting a compound of formula (I) wherein B, s,
s', s'', m, m', m'', Y, Y', Y'' are as above defined in 113, A is a
radical of formula (IIa), (IIc), (IIs) or (IIu) wherein; R.sub.2,
R.sub.3, a, b, R.sub.a, R.sub.c, R.sub.g and R.sub.x are as defined
in 113; R.sub.1 is --C(O)OC(CH.sub.3).sub.3 with anhydrous or
aqueous organic or inorganic acid to hydrolyze the --BOC protective
groups following procedure well known in the literature.
[0614] 113b) by reacting a compound of formula (I) obtained in 38b)
with a compound of formula (IIIg) or (IIIn) depending on the
meaning of B
##STR00350##
wherein Y and Y', Hal, W.sub.1 are as above defined and in formula
(I) A is as above defined in 111b); following the same procedures
described in 4b) or 6b).
[0615] 114. The compounds of general formula (I) wherein:
s is equal to 1; m, m', m'', s' and s'' are 0 Y is as above
defined, A is a radical of formula (IIa)-(IIm), (IIo)-(IIr),
(IIt)-(IIu) and (IIn) wherein R.sub.1 is --C(O)--R.sub.1x and it
binds the group --Y--ONO.sub.2, R.sub.2 is equal to the group
R.sub.4
##STR00351##
in formula (IIn) R.sub.n is --C(O)--R.sub.nx, or is
--(CH.sub.2).sub.2--NH--R.sub.h wherein R.sub.h is --C(O)R.sub.hh
and it binds the group --Y--ONO.sub.2 R.sub.a of formula (IIa) is
selected in group a) R.sub.c of formula (IIc) is selected in group
a') in formula (IIt) d is an integer from 3 to 5, d' is 0; can be
prepared as follows
[0616] 114a) by reacting a compound of formula A with a compound of
formula (IIIa) or a compound of formula (IIIe)
A+HOOC--Y--ONO.sub.2 (IIIa)
A+Act-CO--Y--ONO.sub.2 (IIIe)
wherein Y is as above defined and A is selected from (IIa)-(IIm),
(IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein R.sub.1 is --H and
R.sub.2 is as above defined in 114; in formula (IIn) R.sub.n is H,
or is --(CH.sub.2).sub.2--NH--R.sub.h wherein R.sub.h is H; R.sub.a
of formula (IIa) is selected in group a); R.sub.c of formula (IIc)
is selected in group a'); in formula (IIt) d and d' are as above
defined; following the same procedure described in 1b) or 1b').
[0617] 114b) compounds A as above defined can be prepared by
reacting commercially available compounds of formula A.sub.2
described in 1c) wherein A.sub.2 is a radical of formula
(IIa)-(IIm), (IIo)-(IIr), (IIt)-(IIu) and (IIn) wherein R.sub.2 is
--COOH or R.sub.2a wherein R.sub.2a is the group --COAct as already
described in 8, R.sub.1 is --C(O)OC(CH.sub.3).sub.3, R.sub.n is
--C(O)OC(CH.sub.3).sub.3 or is
--(CH.sub.2).sub.2--NH--C(O)OC(CH.sub.3).sub.3, R.sub.a, R.sub.c, d
and d' are as defined in 114, with compounds (IIIx) or (IIIy):
##STR00352##
In case of (IIIx): in the presence of a inorganic or organic base
in an aprotic polar or in an aprotic non-polar solvent such as DMF,
THF or CH.sub.2Cl.sub.2 at temperatures range between 0.degree. to
100.degree. C.; In case of (IIIy) following the same procedure
described in 8b) for R.sub.2 equal to --COOH or equal to R.sub.2a
wherein R.sub.2a is the group --COAct. Compound (IIIx) is
commercially available. Compound (IIIy) can be obtained from (IIIx)
by first reacting with formic acid and TEA in acetonitrile and then
hydrolyzing the formyl ester with hydrochloric acid in
methanol/water at room temperature, as described for analogous
compounds by Alexander in J. Med. Chem. 1996, 39, 480-486.
[0618] 115. The compounds of general formula (I) wherein:
s is equal to 1; m, m', m'', s' and s'' are 0 Y is as above
defined, A is a radical of formula (IIa)-(IIm), (IIo)-(IIr),
(IIt)-(IIu) and (IIn) wherein R.sub.1 is --C(O)O--R.sub.1x and it
binds the group --Y--ONO.sub.2, R.sub.2 is equal to R.sub.4,
wherein R.sub.4 is as defined in 114; in formula (IIn) R.sub.n is
--C(O)O--R.sub.nx or --(CH.sub.2).sub.2--NH--R.sub.h wherein
R.sub.h is --C(O)O--R.sub.hh, and it binds the group --Y--ONO.sub.2
R.sub.a of formula (IIa) is selected in group a) R.sub.c of formula
(IIc) is selected in group a') in formula (IIt) d is an integer
from 3 to 5, d' is 0; can be prepared as follows
[0619] 115a) by reacting a compound of formula A with a compound of
formula (IIIf)
A+Act-(O)C--O--Y--ONO.sub.2 (IIIf)
wherein A is as above reported in 114a), Act and Y are as already
defined, following the same procedure described in 3b).
[0620] 116. The compounds of general formula (I) wherein:
s is equal to 1; s', s'', m, m', m'', are 0 Y is as above defined;
A is selected among: (IIa) wherein R.sub.1 is --H, R.sub.2 is
--C(O)OR.sub.2x and R.sub.2 binds a group --Y--ONO.sub.2; R.sub.a
is selected from R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is equal to R.sub.gg and is equal to:
##STR00353##
(IIc) wherein R.sub.1 is --H, R.sub.2 is --C(O)OR.sub.2x and
R.sub.2 binds a group --Y--ONO.sub.2; R.sub.c is selected from
R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is equal to R.sub.gg and is as above defined can be
prepared as follows:
[0621] 116a) by reacting a compound of formula (VIIIa)
A.sub.28a Y ONO.sub.2 (IXa)
wherein Y is as above defined and A.sub.28a is a radical of formula
(IIa), (IIc), wherein R.sub.2 is as above defined in 116; R.sub.1
is R.sub.1a and is the Fmoc group; R.sub.a and R.sub.c are
R.sub.ggC(O)CH.sub.2--NH--, R.sub.ggC(O)CH.sub.2,
R.sub.ggC(O)(CH.sub.2).sub.2--, R.sub.ggC(O)(CH.sub.2).sub.4--,
wherein R.sub.gg is as above defined by known procedure to remove
the -Fmoc protective groups;
[0622] 116b) by reacting a compound of formula A.sub.28 with a
compound of formula (IIIi)
A.sub.28+HO--Y--ONO.sub.2 (IIIi)
wherein Y is as above defined and A.sub.28 is a compound of formula
(IIa) or (IIc) wherein R.sub.1 is R.sub.1a and is the Fmoc group;
R.sub.2 is --COOH, R.sub.a and R.sub.c are selected from
R.sub.ggC(O)CH.sub.2--NH--, R.sub.ggC(O)CH.sub.2,
R.sub.ggC(O)(CH.sub.2).sub.2--, R.sub.ggC(O)(CH.sub.2).sub.4--,
wherein R.sub.gg is as above defined in 116; following the same
procedure described in 8b).
[0623] 116c) by reacting a compound A.sub.29
A.sub.29.fwdarw.A.sub.28
wherein R.sub.1 is R.sub.1a and is the Fmoc group; R.sub.2 is
--C(O)OC(CH.sub.3).sub.3; R.sub.a and R.sub.c are selected from
R.sub.ggC(O)CH.sub.2--NH--, R.sub.ggC(O)CH.sub.2,
R.sub.ggC(O)(CH.sub.2).sub.2--, R.sub.ggC(O)(CH.sub.2).sub.4--,
wherein R.sub.gg is as above defined in 116 with anhydrous or
aqueous organic or inorganic acid as well known in the literature
to remove the t-butyl ester.
[0624] 116d) by reacting a compound A.sub.30
A.sub.30.fwdarw.A.sub.29
wherein R.sub.1 is R.sub.1a and is the Fmoc group; R.sub.2 is
--C(O)OC(CH.sub.3).sub.3; R.sub.a and R.sub.c are selected from
R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.3).sub.3--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is --OH with compounds (IIIx) or (IIIy) as
described in 114b). Compounds A.sub.30 are commercially
available.
[0625] 117. The compounds of general formula (I) wherein:
s is equal to 1; s', s'', m, m', m'', are 0 Y is as above defined;
A is a radical of formula (IIa) wherein R.sub.1 is --H, R.sub.2 is
--C(O)NHR.sub.2xx or --C(O)N(CH.sub.3)R.sub.2xx and R.sub.2 binds a
group --Y--ONO.sub.2; R.sub.a is selected from
R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.4--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is R.sub.gg and is as defined in 116; or (IIc)
wherein R.sub.1 is --H, R.sub.2 is --C(O)NHR.sub.2xx or
--C(O)N(CH.sub.3)R.sub.2xx and R.sub.2 binds a group
--Y--ONO.sub.2; R.sub.c is selected from R.sub.gC(O)CH.sub.2--NH--,
R.sub.gC(O)CH.sub.2, R.sub.gC(O)(CH.sub.2).sub.2--,
R.sub.gC(O)(CH.sub.2).sub.4--, wherein R.sub.g is R.sub.gg and is
as defined in 116; can be prepared as follows:
[0626] 117a) by reacting a compound of formula (IXb)
A.sub.31-Y--ONO.sub.2 (IXb)
wherein Y is as above defined and A.sub.31 is a radical of formula
(IIa), (IIc), wherein R.sub.2 is as above defined in 117; R.sub.1
is R.sub.1a and is the Fmoc group; R.sub.a and R.sub.c are
R.sub.ggC(O)CH.sub.2--NH--, R.sub.ggC(O)CH.sub.2,
R.sub.ggC(O)(CH.sub.2).sub.2--, R.sub.ggC(O)(CH.sub.2).sub.4--,
wherein R.sub.gg is as above defined by known procedure to remove
the -Fmoc protective groups; 117b) by reacting a compound of
formula A.sub.28 with a compound of formula (IIIo)
A.sub.28+W.sub.3NH--Y--ONO.sub.2.fwdarw. (IXb)
wherein Y is as above defined, W.sub.3 is as above defined and
A.sub.28 is as defined in 116b), following the same procedure
described in 7b).
[0627] 118. The compounds of general formula (I) wherein:
s and m are equal to 1; s', s'', m', m'', are 0 Y is as above
defined;
B is:
##STR00354##
[0629] A is a radical selected among:
(IIa) wherein R.sub.8 is --H, R.sub.2 is --C(O)OR.sub.2x and
R.sub.2 binds a group --B--Y--ONO.sub.2; R.sub.a is selected from
R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is R.sub.gg and is as defined in 116; (IIc) wherein
R.sub.8 is --H, R.sub.2 is --C(O)OR.sub.2x and R.sub.2 binds a
group --B--Y--ONO.sub.2; R.sub.c is selected from
R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is R.sub.gg and is as defined in 116; can be
prepared as follows:
[0630] 118a) by reacting a compound of formula (VIIIc)
A.sub.28a-B--Y--ONO.sub.2 (IXc)
wherein B and Y are as above defined and A.sub.28a is as defined in
116a) a radical of formula (IIa), (IIc), wherein R.sub.2 is as
above defined in 118; R.sub.1 is R.sub.1a and is the Fmoc group;
R.sub.a and R.sub.c are R.sub.ggC(O)CH.sub.2--NH--,
R.sub.ggC(O)CH.sub.2, R.sub.ggC(O)(CH.sub.2).sub.2--,
R.sub.ggC(O)(CH.sub.2).sub.4--, wherein R.sub.gg is as above
defined by known procedure to remove the -Fmoc protective
groups;
[0631] 118b) compound (IXc) are prepared by reacting a compound of
formula A.sub.28 with a compound of formula (IIIg) or (IIIn)
depending on the meaning of B
A.sub.28+Hal-W.sub.1--OC(O)O--Y--ONO.sub.2 (IIIg)
A.sub.28+Hal-W.sub.1--OC(O)--Y--ONO.sub.2 (IIIn)
wherein Y, Hal, W.sub.8 are as above defined and A.sub.28 is as
defined in 116b), following the same procedures described in 4b) or
6b).
[0632] 119. The compounds of general formula (I) wherein:
s is equal to 1; s', s'', m, m', m'', are 0 Y is as above defined;
A is selected among: (IIa) wherein R.sub.8 is --H, R.sub.2 is equal
to R.sub.4 and is as defined in 114; R.sub.a is selected from
R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is R.sub.gx--O--, and R.sub.g binds a group
--Y--ONO.sub.2; (IIc) wherein R.sub.1 is --H, R.sub.2 is equal to
R.sub.4 and is as defined in 114; R.sub.c is selected from
R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is R.sub.gx--O--, and R.sub.g binds a group
--Y--ONO.sub.2, can be prepared as follows:
[0633] 119a) by reacting a compound of formula (Xa)
A.sub.32-Y--ONO.sub.2 (Xa)
wherein Y is as above defined and A.sub.32 is a radical of formula
(IIa), (IIc), wherein R.sub.a and R.sub.c are as above defined in
119; R.sub.1 is --R.sub.1a and is the Fmoc group; R.sub.2 is
R.sub.4 and is as defined in 114; following procedure well known in
the literature to remove the Fmoc group.
[0634] 119b) by reacting a compound of formula A.sub.33 with a
compound of formula (IIIi)
(IIIi)
[0635] A.sub.33+HO--Y--ONO.sub.2.fwdarw. (Xa)
wherein Y is as above defined and A.sub.33 is a radical of formula
(IIa), (IIc) wherein R.sub.1 is --R.sub.1a and is the Fmoc group;
R.sub.2 is R.sub.4 and is as defined in 114; R.sub.a and R.sub.c
are selected from R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is --OH; following the same procedure described in
8b).
[0636] 119c) by reacting a compound A.sub.34
A.sub.34.fwdarw.A.sub.33
wherein R.sub.1 is R.sub.1a and is the Fmoc group; R.sub.2 is
R.sub.4; R.sub.a and R.sub.c are selected from
R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is --C(O)OC(CH.sub.3).sub.3 with anhydrous or
aqueous organic or inorganic acid as well known in the literature
to remove the t-butyl ester.
[0637] 119d) by reacting a compound A.sub.35
A.sub.35.fwdarw.A.sub.34
wherein R.sub.1 is R.sub.1a and is the Fmoc group; R.sub.2 is
--COOH; R.sub.a and R.sub.c are selected from
R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is --C(O)OC(CH.sub.3).sub.3 with compounds (IIIx)
or (IIIy) as described in 114b). Compounds A.sub.35 are
commercially available.
[0638] 120. The compounds of general formula (I) wherein:
s is equal to 1; s', s'', m, m', m'', are 0 Y is as above defined;
A is selected among: (IIa) wherein R.sub.1 is --H, R.sub.2 is
R.sub.4 and is as defined in 114; R.sub.a is selected from
R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is R.sub.gxx--NH-- or R.sub.gxx--N(CH.sub.3)-- and
R.sub.g binds a group --Y--ONO.sub.2; (IIc) wherein R.sub.1 is --H,
R.sub.2 is R.sub.4 and is as defined in 114; R.sub.c is selected
from R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is R.sub.gxx--NH-- or R.sub.gxx--N(CH.sub.3)-- and
R.sub.g binds a group --Y--ONO.sub.2; can be prepared as
follows:
[0639] 120a) by reacting a compound of formula (Xb)
A.sub.36-Y--ONO.sub.2 (Xb)
wherein Y is as above defined and A.sub.36 is a radical of formula
(IIa), (IIc), wherein R.sub.a and R.sub.c are as above defined in
120; R.sub.1 is R.sub.1a and is the Fmoc group; R.sub.2 is R.sub.4
and is as defined in 114; following procedure well known in the
literature to remove the Fmoc group.
[0640] 120b) by reacting a compound of formula A.sub.33 with a
compound of formula (IIIo):
(IIIo)
[0641] A.sub.33+W.sub.3NH--Y--ONO.sub.2.fwdarw. (Xb)
wherein Y and W.sub.3 are as above defined and A.sub.33 is as
defined in 119b) following the same procedure described in 7b).
[0642] 121. The compounds of general formula (I) wherein:
s and m are equal to 1; s', s'', m', m'', are 0 Y is as above
defined;
B is:
##STR00355##
[0643] A is selected among: (IIa) wherein R.sub.1 is --H, R.sub.2
is R.sub.4 and is as defined in 114; R.sub.a is selected from
R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is R.sub.gx--O--, and R.sub.g binds a group
--B--Y--ONO.sub.2; (IIc) wherein R.sub.1 is --H, R.sub.2 is R.sub.4
and is as defined in 114; R.sub.c is selected from
R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is R.sub.gx--O--, and R.sub.g binds a group
B--Y--ONO.sub.2; can be prepared as follows:
[0644] 121a) by reacting a compound of formula (Xc)
A.sub.37-B--YONO.sub.2 (Xc)
wherein B and Y are as above defined and A.sub.27 is a radical of
formula (IIa), (IIc), wherein R.sub.a and R.sub.c are as above
defined in 121; R.sub.1 is R.sub.1a and is the Fmoc group; R.sub.2
is R.sub.4 and is as defined in 114; following procedure well known
in the literature to remove the Fmoc group.
[0645] 121b) compounds (Xc) are prepared by reacting a compound of
formula A.sub.33 with a compound of formula of formula (IIIg) or
(IIIn) depending on the meaning of B
A.sub.33+Hal-W.sub.1--OC(O)O--Y--ONO.sub.2 (IIIg)
A.sub.33+Hal-W.sub.1--OC(O)--Y--ONO.sub.2 (IIIn)
wherein Y, Hal, W.sub.1 are as above defined and A.sub.33 is as
defined in 119b), following the same procedures described in 4b) or
6b).
[0646] 122. The compounds of general formula (I) wherein:
s and s' are equal to 1; s'', m, m', m'', are 0 Y and Y' can be
equal or different and are as above defined; A is selected among:
(IIa) wherein R.sub.1 is --C(O)--R.sub.1x and binds a group
--Y'--ONO.sub.2; R.sub.2 is --C(O)OR.sub.2x and binds a group
--Y--ONO.sub.2; R.sub.a is selected from R.sub.gC(O)CH.sub.2--NH--,
R.sub.gC(O)CH.sub.2, R.sub.gC(O)(CH.sub.2).sub.2--,
R.sub.gC(O)(CH.sub.2).sub.4--, wherein R.sub.g is equal to R.sub.gg
and is as defined in 116; (IIc) wherein R.sub.1 is --C(O)--R.sub.1x
and binds a group --Y'--ONO.sub.2; R.sub.2 is --C(O)OR.sub.2x and
binds a group --Y--ONO.sub.2; R.sub.c is selected from
R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is equal to R.sub.gg and is as defined in 116; can
be prepared as follows:
[0647] 122a) by reacting a compound of formula (I) prepared as
described in 116. with a compound of formula (IIIe):
##STR00356##
wherein Act, Y and Y' are as above defined and A is a radical of
formula (IIa), (IIc), wherein R.sub.1 is --H, R.sub.2 is
--C(O)OR.sub.2x and binds a group --Y--ONO.sub.2; R.sub.a and
R.sub.c are selected from R.sub.ggC(O)CH.sub.2--NH--,
R.sub.ggC(O)CH.sub.2, R.sub.ggC(O)(CH.sub.2).sub.2--,
R.sub.ggC(O)(CH.sub.2).sub.4--, wherein R.sub.gg is as above
defined; following the same procedures described in 1b').
[0648] 123. The compounds of general formula (I) wherein:
s and s' are equal to 1; s'', m, m', m'', are 0 Y and Y' can be
equal or different and are as above defined; A is selected among:
(IIa) wherein R.sub.1 is --C(O)O--R.sub.1x and binds a group
--Y'--ONO.sub.2; R.sub.2 is --C(O)OR.sub.2x and binds a group
--Y--ONO.sub.2; R.sub.a is selected from R.sub.gC(O)CH.sub.2--NH,
R.sub.gC(O)CH.sub.2, R.sub.gC(O)(CH.sub.2).sub.2--,
R.sub.gC(O)(CH.sub.2).sub.4--, wherein R.sub.g is equal to R.sub.gg
and is as defined in 116; (IIc) wherein R.sub.1 is
--C(O)O--R.sub.1x and binds a group --Y'--ONO.sub.2; R.sub.2 is
--C(O)OR.sub.2x and binds a group --Y--ONO.sub.2; R.sub.c is
selected from R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is equal to R.sub.gg and is as defined in 116; can
be prepared as follows:
[0649] 123a) by reacting a compound of formula (I) prepared as
described in 116. with a compound of formula (IIIf):
##STR00357##
wherein Act, Y and Y' are as above defined and A is as defined in
122a); following the same procedures described in 3b).
[0650] 124. The compounds of general formula (I) wherein:
s and s' are equal to 1; s'', m, m', m'', are 0 Y and Y' can be
equal or different and are as above defined; A is selected among:
(IIa) wherein R.sub.1 is --C(O)--R.sub.1x and binds a group
--Y'--ONO.sub.2; R.sub.2 is --C(O)NHR.sub.2xx or
--C(O)N(CH.sub.3)R.sub.2xx and binds a group --Y--ONO.sub.2;
R.sub.a is selected from R.sub.gC(O)CH.sub.2--NH--,
R.sub.gC(O)CH.sub.2, R.sub.gC(O)(CH.sub.2).sub.2--,
R.sub.gC(O)(CH.sub.2).sub.4--, wherein R.sub.g is equal to R.sub.gg
and is as defined in 116; (IIc) wherein R.sub.1 is --C(O)--R.sub.1x
and binds a group --Y'--ONO.sub.2; R.sub.2 is --C(O)NHR.sub.2xx or
--C(O)N(CH.sub.3)R.sub.2xx and binds a group --Y--ONO.sub.2;
R.sub.c is selected from R.sub.gC(O)CH.sub.2--NH--,
R.sub.gC(O)CH.sub.2, R.sub.gC(O)(CH.sub.2).sub.2--,
R.sub.gC(O)(CH.sub.2).sub.4--, wherein R.sub.g is equal to R.sub.gg
and is as defined in 116; can be prepared as follows:
[0651] 124a) by reacting a compound of formula (I) prepared as
described in 117. with a compound of formula (IIIe):
##STR00358##
wherein Act, Y and Y' are as above defined and A is a radical of
formula (IIa), (IIc), wherein R.sub.1 is --H, R.sub.2 is
--C(O)NHR.sub.2xx or --C(O)NCH.sub.3R.sub.2xx and binds a group
--Y--ONO.sub.2; R.sub.a and R.sub.c are selected from
R.sub.ggC(O)CH.sub.2--NH--, R.sub.ggC(O)CH.sub.2,
R.sub.ggC(O)(CH.sub.2).sub.2--, R.sub.ggC(O)(CH.sub.2).sub.4--,
wherein R.sub.gg is as above defined; following the same procedures
described in 1b').
[0652] 125. The compounds of general formula (I) wherein:
s and s' are equal to 1; s'', m, m', m'', are 0 Y and Y' can be
equal or different and are as above defined; A is selected among:
(IIa) wherein R.sub.1 is --C(O)O--R.sub.1x and binds a group
--Y'--ONO.sub.2; R.sub.2 is --C(O)NHR.sub.2xx or
--C(O)N(CH.sub.3)R.sub.2xx and binds a group --Y--ONO.sub.2;
R.sub.a is selected from R.sub.gC(O)CH.sub.2--NH--,
R.sub.gC(O)CH.sub.2, R.sub.gC(O)(CH.sub.2).sub.2--,
R.sub.gC(O)(CH.sub.2).sub.4--, wherein R.sub.g is equal to R.sub.gg
and is as defined in 116; (IIc) wherein R.sub.1 is
--C(O)O--R.sub.1x and binds a group --Y'--ONO.sub.2; R.sub.2 is
--C(O)NHR.sub.2xx or --C(O)N(CH.sub.3)R.sub.2xx and binds a group
--Y--ONO.sub.2; R.sub.c is selected from R.sub.gC(O)CH.sub.2--NH--,
R.sub.gC(O)CH.sub.2, R.sub.gC(O)(CH.sub.2).sub.2--,
R.sub.gC(O)(CH.sub.2).sub.4--, wherein R.sub.g is equal to R.sub.gg
and is as defined in 116; can be prepared as follows:
[0653] 125a) by reacting a compound of formula (I) prepared as
described in 117. with a compound of formula (IIIf):
##STR00359##
wherein Act, Y and Y' are as above defined and A is as above
defined in 124a), following the same procedures described in
3b).
[0654] 126. The compounds of general formula (I) wherein:
s, s' and m are equal to 1; s'', m', m'', are 0 Y and Y' can be
equal or different and are as above defined;
B is:
##STR00360##
[0655] A is selected among: (IIa) wherein R.sub.1 is
--C(O)--R.sub.1x and binds a group --Y'--ONO.sub.2; R.sub.2 is
--C(O)OR.sub.2x and binds a group --B--Y--ONO.sub.2; R.sub.a is
selected from R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is equal to R.sub.gg and is as defined in 116;
(IIc) wherein R.sub.1 is --C(O)--R.sub.1x and binds a group
--Y'--ONO.sub.2; R.sub.2 is C(O)OR.sub.2x and binds a group
--B--Y--ONO.sub.2; R.sub.a is selected from
R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is equal to R.sub.gg and is as defined in 116; can
be prepared as follows:
[0656] 126a) by reacting a compound of formula (I) prepared as
described in 118. with a compound of formula (IIIe):
##STR00361##
wherein Act, B, Y and Y' are as above defined and A is a radical of
formula (IIa), (IIc), wherein R.sub.1 is --H, R.sub.2 is
--C(O)OR.sub.2x and binds a group B--Y--ONO.sub.2; R.sub.a and
R.sub.c are selected from R.sub.ggC(O)CH.sub.2--NH--,
R.sub.ggC(O)CH.sub.2, R.sub.ggC(O)(CH.sub.2).sub.2--,
R.sub.ggC(O)(CH.sub.2).sub.4--, wherein R.sub.gg is as above
defined; following the same procedures described in 1b').
[0657] 127. The compounds of general formula (I) wherein:
s, s' and m are equal to 1; s'', m', m'', are 0 Y and Y' can be
equal or different and are as above defined;
B is:
##STR00362##
[0658] A is selected among: (IIa) wherein R.sub.1 is
--C(O)O--R.sub.1x and binds a group --Y'--ONO.sub.2; R.sub.2 is
--C(O)OR.sub.2x and binds a group --B--Y--ONO.sub.2; R.sub.a is
selected from R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is equal to R.sub.gg and is as defined in 116;
(IIc) wherein R.sub.1 is --C(O)O--R.sub.1x and binds a group
--Y'--ONO.sub.2; R.sub.2 is --C(O)OR.sub.2x and binds a group
--B--Y--ONO.sub.2; R.sub.c is selected from
R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is equal to R.sub.gg and is as defined in 116; can
be prepared as follows:
[0659] 127a) by reacting a compound of formula (I) prepared as
described in 118. with a compound of formula (IIIf):
##STR00363##
wherein Act, B, Y and Y' are as above defined and A is as defined
in 126a), following the same procedures described in 3b).
[0660] 128. The compounds of general formula (I) wherein:
s and s' are equal to 1; s'', m, m', m'', are 0 Y and Y' can be
equal or different and are as above defined; A is selected among:
(IIa) wherein R.sub.1 is --C(O)--R.sub.1x and it binds a group
--Y'--ONO.sub.2; R.sub.2 is equal to R.sub.4 and is as defined in
114; R.sub.a is selected from R.sub.gC(O)CH.sub.2--NH--,
R.sub.gC(O)CH.sub.2, R.sub.gC(O)(CH.sub.2).sub.2--,
R.sub.gC(O)(CH.sub.2).sub.4--, wherein R.sub.g is R.sub.gx--O--,
and binds a group --Y--ONO.sub.2 (IIc) wherein R.sub.1 is
--C(O)--R.sub.1x and binds a group --Y'--ONO.sub.2; R.sub.2 is
equal to R.sub.4 and is as defined in 114; R.sub.c is selected from
R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is R.sub.gx--O--, and binds a group --Y--ONO.sub.2;
can be prepared as follows:
[0661] 128a) by reacting a compound of formula (I) prepared as
described in 119. with a compound of formula (IIIe):
##STR00364##
wherein Act, Y and Y' are as above defined and A is a radical of
formula (IIa), (IIc), wherein R.sub.1 is --H, R.sub.2 is equal to
R.sub.4; R.sub.a and R.sub.c are selected from
R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is R.sub.gx--O--, and binds a group --Y--ONO.sub.2
following the same procedures described in 1b').
[0662] 129. The compounds of general formula (I) wherein:
s and s' are equal to 1; s'', m, m', m'', are 0 Y and Y' can be
equal or different and are as above defined; A is selected among:
(IIa) wherein R.sub.1 is --C(O)O--R.sub.1x and it binds a group
--Y'--ONO.sub.2; R.sub.2 is equal to R.sub.4 and is as defined in
114; R.sub.a is selected from R.sub.gC(O)CH.sub.2--NH--,
R.sub.gC(O)CH.sub.2, R.sub.gC(O)(CH.sub.2).sub.2--,
R.sub.gC(O)(CH.sub.2).sub.4--, wherein R.sub.g is R.sub.gx--O--,
and binds a group --Y--ONO.sub.2 (IIc) wherein R.sub.1 is
--C(O)O--R.sub.1x and binds a group --Y'--ONO.sub.2; R.sub.2 is
equal to R.sub.4 and is as defined in 114; R.sub.c is selected from
R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is R.sub.gx--O--, and binds a group --Y--ONO.sub.2;
can be prepared as follows:
[0663] 129a) by reacting a compound of formula (I) prepared as
described in 119. with a compound of formula (IIIf):
##STR00365##
wherein Act, Y and Y' are as above defined and A is a radical of
formula (IIa), (IIc), wherein R.sub.1 is --H, R.sub.2 is equal to
R.sub.4; R.sub.a and R.sub.c are selected from
R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is R.sub.gxO-- and R.sub.g binds a group
--Y--ONO.sub.2, following the same procedures described in 3b).
[0664] 130. The compounds of general formula (I) wherein:
s and s' are equal to 1; s'', m, m', m'', are 0 Y and Y' can be
equal or different and are as above defined; A is selected among:
(IIa) wherein R.sub.1 is --C(O)--R.sub.1x and it binds a group
--Y'--ONO.sub.2; R.sub.2 is equal to R.sub.4 and is as defined in
114; R.sub.a is selected from R.sub.gC(O)CH.sub.2--NH--,
R.sub.gC(O)CH.sub.2, R.sub.gC(O)(CH.sub.2).sub.2--,
R.sub.gC(O)(CH.sub.2).sub.4--, wherein R.sub.g is R.sub.gxx--NH--
or R.sub.gxx--N(CH.sub.3)-- and R.sub.a binds a group
--Y--ONO.sub.2 (IIc) wherein R.sub.1 is --C(O)--R.sub.1x and it
binds a group --Y'--ONO.sub.2; R.sub.2 is equal to R.sub.4 and is
as defined in 114; R.sub.c is selected from
R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is R.sub.gxx--NH-- or R.sub.gxx--N(CH.sub.3)-- and
R.sub.c binds a group --Y--ONO.sub.2; can be prepared as
follows:
[0665] 130a) by reacting a compound of formula (I) prepared as
described in 120. with a compound of formula (IIIe):
##STR00366##
wherein Act, Y and Y' are as above defined and A is a radical of
formula (IIa), (IIc), wherein R.sub.1 is --H, R.sub.2 is--equal to
R.sub.4; R.sub.a and R.sub.c are selected from
R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is R.sub.gxx--NH-- or R.sub.gxx--N(CH.sub.3)-- and
binds a group --Y--ONO.sub.2 following the same procedures
described in 1b').
[0666] 131. The compounds of general formula (I) wherein:
s and s' are equal to 1; s'', m, m', m'', are 0 Y and Y' can be
equal or different and are as above defined; A is selected among:
(IIa) wherein R.sub.1 is --C(O)O--R.sub.1x and binds a group
--Y'--ONO.sub.2; R.sub.2 is is--equal to R.sub.4 and is as defined
in 114; R.sub.a is selected from R.sub.gC(O)CH.sub.2--NH--,
R.sub.gC(O)CH.sub.2, R.sub.gC(O)(CH.sub.2).sub.2--,
R.sub.gC(O)(CH.sub.2).sub.4--, wherein R.sub.g is R.sub.gxx--NH--
or R.sub.gxx--N(CH.sub.3)-- and binds a group --Y--ONO.sub.2 (IIc)
wherein R.sub.1 is --C(O)O--R.sub.1x and binds a group
--Y'--ONO.sub.2; R.sub.2 is is--equal to R.sub.4 and is as defined
in 114; R.sub.c is selected from R.sub.gC(O)CH.sub.2--NH--,
R.sub.gC(O)CH.sub.2, R.sub.gC(O)(CH.sub.2).sub.2--,
R.sub.gC(O)(CH.sub.2).sub.4--, wherein R.sub.g is R.sub.g--NH-- or
R.sub.gxx--N(CH.sub.3)-- and binds a group --Y--ONO.sub.2; can be
prepared as follows:
[0667] 131a) by reacting a compound of formula (I) prepared as
described in 120. with a compound of formula (IIIf):
##STR00367##
wherein Act, Y and Y' are as above defined and A is as defined in
130a), following the same procedures described in 3b).
[0668] 132. The compounds of general formula (I) wherein:
s, s' and m are equal to 1; s'', m', m'', are 0 Y and Y' can be
equal or different and are as above defined;
B is:
##STR00368##
[0669] A is selected among: (IIa) wherein R.sub.1 is
--C(O)--R.sub.1x and binds a group --Y'--ONO.sub.2; R.sub.2 is
equal to R.sub.4 and is as defined in 114; R.sub.a is selected from
R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is R.sub.gxO--, and binds a group
--B--Y--ONO.sub.2; (IIc) wherein R.sub.1 is --C(O)--R.sub.1x and
binds a group --Y'--ONO.sub.2; R.sub.2 is--equal to R.sub.4 and is
as defined in 114; R.sub.c is selected from
R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is R.sub.gxO--, and binds a group
--B--Y--ONO.sub.2; can be prepared as follows:
[0670] 132a) by reacting a compound of formula (I) prepared as
described in 121. with a compound of formula (IIIe):
##STR00369##
wherein Act, B, Y and Y' are as above defined and A is a radical of
formula (IIa), (IIc), wherein R.sub.1 is --H, R.sub.2 is equal to
R.sub.4; R.sub.a and R.sub.c are selected from
R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is R.sub.gxO-- and binds a group B--Y--ONO.sub.2;
following the same procedures described in 1b').
[0671] 133. The compounds of general formula (I) wherein:
s, s' and m are equal to 1; s'', m', m'', are 0 Y and Y' can be
equal or different and are as above defined;
B is:
##STR00370##
[0672] A is selected among: (IIa) wherein R.sub.1 is
--C(O)O--R.sub.1x and binds a group --Y'--ONO.sub.2; R.sub.2 is
equal to R.sub.4 and is as defined in 114; R.sub.a is selected from
R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is R.sub.gxO--, and binds a group
--B--Y--ONO.sub.2; (IIc) wherein R.sub.1 is --C(O)O--R.sub.1x and
it binds a group --Y'--ONO.sub.2; R.sub.2 is equal to R.sub.4 and
is as defined in 114; R.sub.c is selected from
R.sub.gC(O)CH.sub.2--NH--, R.sub.gC(O)CH.sub.2,
R.sub.gC(O)(CH.sub.2).sub.2--, R.sub.gC(O)(CH.sub.2).sub.4--,
wherein R.sub.g is R.sub.gxO-- and R.sub.g binds a group
--B--Y--ONO.sub.2; can be prepared as follows:
[0673] 133a) by reacting a compound of formula (I) prepared as
described in 121. with a compound of formula (IIIf):
##STR00371##
wherein Act, B, Y and Y' are as above defined and A is as defined
in 132a), following the same procedures described in 3b).
[0674] 134. The compounds of general formula (I) wherein:
s and s' are equal to 1; s'', m, m' and m'' are equal to 0; Y and
Y' are equal and are as above defined; A is selected from (IIa),
(IIc) or (IIt) wherein R.sub.1 is --C(O)--R.sub.1x and it binds a
group --Y--ONO.sub.2 or a group --Y'--ONO.sub.2, R.sub.2 is equal
to R.sub.4 and is as defined in 114; R.sub.a of formula (IIa) and
R.sub.c of formula (IIc) are R.sub.hNH(CH.sub.2).sub.p-- wherein p
is an integer from 0 to 4, or
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--, and R.sub.h and R.sub.i
are R.sub.hh--C(O) or R.sub.ii--C(O)-- and R.sub.a and R.sub.c bind
a group --Y--ONO.sub.2 or a group --Y'--ONO.sub.2; in formula (IIt)
R.sub.1 is --C(O)--R.sub.1x and it binds a group --Y--ONO.sub.2 or
a group --Y'--ONO.sub.2, R.sub.2 is equal to R.sub.4 and is as
defined in 114; d is 2 d' is 1, R.sub.t is --C(O)--R.sub.tt and it
binds a group --Y--ONO.sub.2 or a group --Y'--ONO.sub.2; can be
prepared as follows:
[0675] 134a) by reacting a compound of formula A with a compound of
formula (IIIe)
A+Act-(O)C--Y--ONO.sub.2 (IIIe)
wherein Act and Y are as above defined and A is a compound of
formula (IIa), (IIc) or (IIt) wherein R.sub.1 is --H and R.sub.2 is
equal to R.sub.4; R.sub.a of formula (IIa) and R.sub.c of formula
(IIc) are R.sub.hNH(CH.sub.2).sub.p-- wherein p is an integer from
0 to 4, or R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--, and R.sub.h
and R.sub.i are --H; in formula (IIt) R.sub.1 is --H, R.sub.2 is
R.sub.4; d is 2 d' is 1, R.sub.t is --H; using a ratio A/(IIIe) 1:2
and applying the same procedure described in 1b').
[0676] 134b) by reacting a compound of formula A.sub.38
A.sub.38.fwdarw.A
wherein A.sub.38 is a compound of formula (IIa), (IIc) or (IIt)
wherein R.sub.1 is --C(O)OC(CH.sub.3).sub.3 and R.sub.2 is equal to
R.sub.4; R.sub.a of formula (IIa) and R.sub.c of formula (IIc) are
R.sub.hNH(CH.sub.2).sub.p-- wherein p is an integer from 0 to 4 and
R.sub.h is --C(O)OC(CH.sub.3).sub.3; or
R.sub.iaNH(.dbd.NH)NH--(CH.sub.2).sub.3--, wherein R.sub.ia is the
--Pbf group as already described; in formula (IIt) R.sub.1 is
--C(O)OC(CH.sub.3).sub.3, R.sub.2 is R.sub.4; d is 2 d' is 1,
R.sub.t is --C(O)OC(CH.sub.3).sub.3; with organic or inorganic acid
as already described to hydrolyze the --BOC protecting groups;
[0677] 134c) by reacting commercially available compounds of
formula A.sub.39 with compounds (IIIx) or (IIIy) using the
procedures described in 114b)
A.sub.39+(IIIx).fwdarw.A.sub.38
A.sub.39+(IIIy).fwdarw.A.sub.38
wherein A.sub.39 is a radical of formula (IIa), (IIc) or (IIt)
wherein R.sub.1 is --C(O)OC(CH.sub.3).sub.3 and R.sub.2 is equal to
--COOH or R.sub.2a wherein R.sub.2a is as described in 8b); d is 2
d' is 1, R.sub.t is --C(O)OC(CH.sub.3).sub.3; R.sub.a of formula
(IIa) and R.sub.c of formula (IIc) are: R.sub.hNH(CH.sub.2).sub.p--
wherein p is an integer from 0 to 4, R.sub.h is
--C(O)OC(CH.sub.3).sub.3; or
R.sub.iaNH(.dbd.NH)NH--(CH.sub.2).sub.3-- wherein R.sub.ia is as
previously defined.
[0678] 135. The compounds of general formula (I) wherein:
s and s' are equal to 1; s'', m, m' and m'' are equal to 0; Y and
Y' are equal and are as above defined; A is a radical selected from
(IIa), (IIc) and (IIt) wherein R.sub.1 is --C(O)O--R.sub.1x and
binds a group --Y--ONO.sub.2 or a group --Y'--ONO.sub.2, R.sub.2 is
equal to R.sub.4 and is as defined in 114; R.sub.a of formula (IIa)
and R.sub.c of formula (IIc) are R.sub.hNH(CH.sub.2).sub.p--
wherein p is an integer from 0 to 4, or
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--, and R.sub.h and R.sub.i
are R.sub.hh--OC(O)-- or R.sub.ii--OC(O)-- and R.sub.a and R.sub.c
bind a group --Y--ONO.sub.2 or a group --Y'--ONO.sub.2; in formula
(IIt) R.sub.1 is --C(O)O--R.sub.1x and binds a group --Y--ONO.sub.2
or a group --Y'--ONO.sub.2, R.sub.2 is equal to R.sub.4 and is as
defined in 114; d is 2 d' is 1, R.sub.t is --C(O)O--R.sub.tt and
binds a group --Y--ONO.sub.2 or a group --Y'--ONO.sub.2; can be
prepared as follows:
[0679] 135a) by reacting a compound of formula A with a compound of
formula (IIIf)
A+Act-(O)C--O--Y--ONO.sub.2 (IIIf)
wherein Act and Y are as above defined and A is as defined in 134a)
using a ratio A/(IIIf) 1:2 and applying the same procedure
described in 3b).
[0680] 136. The compounds of general formula (I) wherein:
s is equal to 1; s', s'', m, m' and m'' are equal to 0; Y is as
above defined; A is a radical of formula (IIa), (IIc) or (IIt)
wherein R.sub.1 is --C(O)--R.sub.1x and binds a group
--Y--ONO.sub.2; R.sub.2 is equal to R.sub.4 and is as defined in
114; R.sub.a of formula (IIa) and R.sub.c of formula (IIc) are
R.sub.hNH(CH.sub.2).sub.p-- wherein p is an integer from 0 to 4, or
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--, wherein R.sub.h and
R.sub.i are --H; in formula (IIt) d is 2 d' is 1, R.sub.t is --H;
can be obtained as follows:
[0681] 136a) R.sub.a=R.sub.c selected from
R.sub.hNH(CH.sub.2).sub.p-- wherein p is an integer from 0 to 4,
R.sub.h is --H
by reacting a compound of formula (I) wherein s, s', s'', m, m',
m'', Y, Y', Y'' are as above defined in 136, A is a radical of
(IIa), (IIc) or (IIt) wherein R.sub.1, R.sub.2, d, d', are as
defined in 136, R.sub.a of formula (IIa) and R.sub.c of formula
(IIc) are selected from R.sub.hNH(CH.sub.2).sub.p-- wherein p is an
integer from 0 to 4, R.sub.h is --C(O)OC(CH.sub.3).sub.3; in
formula (IIt) R.sub.t is --C(O)OC(CH.sub.3).sub.3; with anhydrous
or aqueous organic or inorganic acid to hydrolyze the --BOC
protective groups following procedure well known in the
literature.
[0682] 136a') R.sub.a=R.sub.c selected from
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--, R.sub.i is --H; reacting
a compound of formula (Xd)
A.sub.40-Y--ONO.sub.2 (Xd)
wherein Y is as above defined and A.sub.40 is a radical of formula
(IIa), (IIc) wherein R.sub.1 and R.sub.2 are as defined in 136,
R.sub.a of formula (IIa) and R.sub.c of formula (IIc) are selected
from R.sub.iaNH(.dbd.NH)NH--(CH.sub.2).sub.3--, wherein R.sub.ia is
the --Pbf protective group as already defined; with anhydrous or
aqueous organic or inorganic acid to hydrolyze the --Pbf protective
groups following procedure well known in the literature.
[0683] 136b) compounds described in 136a) and 136a') are
respectively obtained by reacting a compound of formula A.sub.41 or
a compound of formula A.sub.42 with a compound of formula
(IIIe)
(IIIe)
[0684] A.sub.41+Act(O)C--Y'--ONO.sub.2.fwdarw. (I)
(IIIe)
[0685] A.sub.42+Act(O)C--Y'--ONO.sub.2.fwdarw. (Xd)
wherein Act and Y are as above defined and: A.sub.41 is a compound
of formula (IIa), (IIc) or (IIt) wherein R.sub.1 is --H, R.sub.2 is
equal to R.sub.4; R.sub.a of formula (IIa) and R.sub.c of formula
(IIc) are R.sub.hNH(CH.sub.2).sub.p-- wherein p is an integer from
0 to 4, R.sub.h is --C(O)OC(CH.sub.3).sub.3; in formula (IIt) d and
d' are as defined in 136, R.sub.t is --C(O)OC(CH.sub.3).sub.3;
A.sub.42 is a compound of formula (IIa) or (IIc) wherein R.sub.1 is
--H, R.sub.2 is equal to R.sub.4; R.sub.a of formula (IIa) and
R.sub.c of formula (IIc) are
R.sub.iaNH(.dbd.NH)NH--(CH.sub.2).sub.3--, wherein R.sub.ia is the
--Pbf protective group as already defined; using the same procedure
described in 1b').
[0686] 136c) compounds A.sub.41 and A.sub.42 are respectively
obtained by reacting a compound of formula A or a compound of
formula A.sub.26, both described in 107b) with a compound of
formula (IIIx) or (IIIy) as already described in 114b).
[0687] 137. The compounds of general formula (I) wherein:
s is equal to 1; s', s'', m, m' and m'' are equal to 0; Y is as
above defined; A is selected from (IIa), (IIc) and (IIt) wherein
R.sub.1 is --C(O)O--R.sub.1x and binds a group --Y--ONO.sub.2;
R.sub.2 is equal to R.sub.4 and is as defined in 114; R.sub.a of
formula (IIa) and R.sub.c of formula (IIc) are
R.sub.hNH(CH.sub.2).sub.p-- wherein p is an integer from 0 to 4, or
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--, wherein R.sub.h and
R.sub.i are --H; in formula (IIt) d is 2 d' is 1, R.sub.t is --H;
can be obtained as follows:
[0688] 137a) R.sub.a=R.sub.c selected from
R.sub.hNH(CH.sub.2).sub.p-- wherein p is an integer from 0 to 4,
R.sub.h is --H
by reacting a compound of formula (I) wherein s, s', s'', m, m',
m'', Y, Y', Y'' are as above defined in 137, A is a radical of
(IIa), (IIc) or (IIt) wherein R.sub.1, R.sub.2, d, d', are as
defined in 137, R.sub.a of formula (IIa) and R.sub.c of formula
(IIc) are selected from R.sub.hNH(CH.sub.2).sub.p-- wherein p is an
integer from 0 to 4, R.sub.h is --C(O)OC(CH.sub.3).sub.3; in
formula (IIt) R.sub.t is --C(O)OC(CH.sub.3).sub.3; with anhydrous
or aqueous organic or inorganic acid to hydrolyze the --BOC
protective groups following procedure well known in the
literature.
[0689] 137a') R.sub.a=R.sub.c selected from
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--, R.sub.i is --H;
reacting a compound of formula (Xe)
A.sub.43-Y--ONO.sub.2 (Xe)
wherein Y is as above defined and A.sub.43 is a radical of (IIa),
(IIc) wherein R.sub.1 and R.sub.2 are as defined in 137, R.sub.a of
formula (IIa) and R.sub.c of formula (IIc) are selected from
R.sub.iaNH(.dbd.NH)NH--(CH.sub.2).sub.3--, wherein R.sub.ia is the
Pbf protective group as already defined; with anhydrous or aqueous
organic or inorganic acid to hydrolyze the --Pbf protective groups
following procedure well known in the literature.
[0690] 137b) compounds described in 137a) and 137a') are
respectively obtained by reacting a compound of formula A.sub.41 or
a compound of formula A.sub.42 both already defined in 136b) with a
compound of formula (IIIf)
(IIIf)
[0691] A.sub.41+Act(O)C--O--Y--ONO.sub.2.fwdarw. (I)
(IIIf)
[0692] A.sub.42+Act(O)C--O--Y--ONO.sub.2.fwdarw. (Xe)
wherein Act and Y are as above defined, using the same procedure
described in 3b).
[0693] 138. The compounds of general formula (I) wherein:
s is equal to 1; s', s'', m, m' and m'' are equal to 0; Y is as
above defined; A is selected from (IIa), (IIc) and (IIt) wherein
R.sub.1 is --H; R.sub.2 is equal to R.sub.4 and is as defined in
114; R.sub.a of formula (IIa) and R.sub.c of formula (IIc) are
R.sub.hNH(CH.sub.2).sub.p-- wherein p is an integer from 0 to 4, or
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--, wherein R.sub.h and
R.sub.i are R.sub.hh--C(O)-- or R.sub.ii--C(O)--, and bind a group
--Y--ONO.sub.2; in formula (IIt) d is 2 d' is 1, R.sub.t is
--C(O)--R.sub.tt, and binds a group --Y--ONO.sub.2; can be obtained
as follows:
[0694] 138a) by reacting a compound of formula (I) wherein s, s',
s'', m, m', m'', Y, Y', Y'' are as above defined in 138, A is a
radical of (IIa), (IIc) or (IIt) wherein R.sub.2, R.sub.a, R.sub.c,
d, d' and R.sub.t are as defined in 138, R.sub.1 is
--C(O)OC(CH.sub.3).sub.3;
with anhydrous or aqueous organic or inorganic acid to hydrolyze
the --BOC protective groups following procedure well known in the
literature.
[0695] 138b) by reacting a compound of formula A with a compound of
formula (IIIe)
A+Act(O)C--Y--ONO.sub.2 (IIIe)
wherein Act and Y are as above defined and A is a radical of (IIa),
(IIc) or (IIt) wherein R.sub.1 is --C(O)OC(CH.sub.3).sub.3; R.sub.2
is equal to R.sub.4; R.sub.a of formula (IIa) and R.sub.c of
formula (IIc) are R.sub.hNH(CH.sub.2).sub.p-- wherein p is an
integer from 0 to 4, or R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--,
wherein R.sub.h and R.sub.i are --H; in formula (IIt) d and d' are
as defined in 138, R.sub.t is --H; using the same procedure
described in 1b').
[0696] 138c) by reacting a compound of formula A with a compound of
formula (IIIx) or (IIIy)
A+(IIIx)
A+(IIIy)
Wherein A is a radical of formula (IIa), (IIc) or (IIt) wherein
R.sub.1 is --C(O)OC(CH.sub.3).sub.3; R.sub.2 is --COOH or R.sub.2a
wherein R.sub.2a is the group --COAct as already described in 8;
R.sub.a of formula (IIa) and R.sub.c of formula (IIc) are
R.sub.hNH(CH.sub.2).sub.p-- wherein p is an integer from 0 to 4, or
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--, wherein R.sub.h and
R.sub.i are --H; in formula (IIt) d and d' are as defined in 138,
R.sub.t is --H; using the same procedures described in 114b).
[0697] 139. The compounds of general formula (I) wherein:
s is equal to 1; s', s'', m, m' and m'' are equal to 0; Y is as
above defined; A is selected from (IIa), (IIc) and (IIt) wherein
R.sub.1 is --H; R.sub.2 is equal to R.sub.4 and is as defined in
114; R.sub.a of formula (IIa) and R.sub.c of formula (IIc) are
R.sub.hNH(CH.sub.2).sub.p-- wherein p is an integer from 0 to 4, or
R.sub.iNH(.dbd.NH)NH--(CH.sub.2).sub.3--, wherein R.sub.h and
R.sub.i are R.sub.hh--OC(O)-- or R.sub.ii--OC(O)--, and bind a
group --Y--ONO.sub.2; in formula (IIt) d is 2 d' is 1, R.sub.t is
--C(O)O--R.sub.tt, and it binds a group --Y--ONO.sub.2; can be
obtained as follows:
[0698] 139a) by reacting a compound of formula (I) wherein s, s',
s'', m, m', m'', Y, Y', Y'' are as above defined in 139, A is a
radical of (IIa), (IIc) or (IIt) wherein R.sub.2, R.sub.a, R.sub.c,
d, d' and R.sub.t are as defined in 139, R.sub.1 is
--C(O)OC(CH.sub.3).sub.3;
with anhydrous or aqueous organic or inorganic acid to hydrolyze
the --BOC protective groups following procedure well known in the
literature.
[0699] 139b) by reacting a compound of formula A described in 138b)
with a compound of formula (IIIf)
A+Act(O)C--O--Y--ONO.sub.2 (IIIf)
wherein Act and Y are as above defined using the same procedure
described in 3b).
EXAMPLE 1
##STR00372##
[0700] (S)-4-(nitrooxy)butyl
2-amino-6-(tert-butoxycarbonylamino)hexanoate (corresponding to
compound 18)
Step A: (S)-4-(nitrooxy)butyl
1-(9H-fluoren-9-yl)-13,13-dimethyl-3,11-dioxo-2,12-dioxa-4,10-diazatetrad-
ecane-5-carboxylate
[0701] Commercial N(.alpha.)-Fmoc-N(.epsilon.)-Boc-L-lysine
pentafluorophenyl ester (6.51 mmol) and 4-(nitrooxy)-1-butanol
(6.55 mmol) were dissolved in DMF (12 ml) and the mixture was
cooled to 0.degree. C. N,N-dimethylaminopyridine (DMAP) (6.55 mmol)
were added and the reaction was slowly warmed to room temperature
and stirred for 4 hours. Then the mixture was concentrate under
reduced pressure and diluted with EtOAc, washed with 5% aqueous
Na.sub.2HPO.sub.4 and brine. The organic layer was dried over
sodium sulphate and concentrated under reduced pressure.
[0702] The residue was purified by flash chromatography
(n-hexan/EtOAc 70:30 as eluent) yielding the title compound (2.52
g, 66%).
Step B: (S)-4-(nitrooxy)butyl
2-amino-6-(tert-butoxycarbonylamino)hexanoate
[0703] To a solution of S)-4-(nitrooxy)butyl
1-(9H-fluoren-9-yl)-13,13-dimethyl-3,11-dioxo-2,12-dioxa-4,10-diazatetrad-
ecane-5-carboxylate (2.52 g, 4.30 mmol) in CH.sub.3CN (30 ml),
piperidine (2.12 ml, 21.5 mmol) was added in the dark, the reaction
was stirred at rt for 25 min. Then the mixture was concentrated to
a small volume and diluted with EtOAc (150 ml) and washed with 5%
aqueous NaHPO.sub.4 (2.times.70 ml). The organic layer was dried
over sodium sulphate and concentrated under reduced pressure.
[0704] The residue was purified by flash chromatography
(CH.sub.2Cl.sub.2/MeOH 98:2 as eluent), yielding the title compound
(0.960 g, 61%).
[0705] .sup.1H-NMR (DMSO-d.sub.6): 6.78 (1H, t), 4.55 (2H, t), 4.07
(2H, m), 3.26 (2H, t), 2.87 (1H, m), 1.73-1.65 (4H, m), 1.64-1.40
(2H, m), 1.37 (9H, s), 1.36-1.22 (4H, s).
EXAMPLE 2
##STR00373##
[0706] 2-Amino-3-tert-butoxy-3-oxopropyl 4-(nitrooxy)butanoate
(corresponding to compound 405)
Step A: tert-butyl
2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-hydroxypropanoate
[0707] To a solution of commercial N-Fmoc-L-serine (1.5 g, 4.58
mmol) in EtOAc (40 ml), a solution of t-butyl
2,2,2-trichloroacetimidate (4.00 g, 18.32 mmol) in cyclohexane (18
ml) was added dropwise. After stirring at room temperature for 24
hrs, the solution was evaporated and the residue was purified by
flash chromatography (n-Hexane/EtOAc 70:3), yielding the title
compound (1.20 g, 68%).
Step B:
2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-tert-butoxy-3-oxopro-
pyl 4-(nitrooxy)butanoate
[0708] To a solution of
2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-tert-butoxy-3-oxopropyl
4-(nitrooxy)butanoate (1.20 g, 3.13 mmol), 4-(nitrooxy)butyric acid
pentafluorophenyl ester (1.18 g, 3.76 mmol) and scandium
trifluoromethanesulfonate (0.308 g, 0.626 mmol) in CH.sub.2Cl.sub.2
(25 ml) cooled to 0.degree. C., was added N,N-dimethylaminopyridine
(DMAP) (0.459 g, 3.76 mmol). The resulting mixture was stirred at
room temperature for 18 hours. Then it was diluted with
CH.sub.2Cl.sub.2 and washed with 5% aqueous Na.sub.2HPO.sub.4 and
brine. The organic layer was dried over sodium sulphate and
concentrated under reduced pressure.
[0709] The residue was purified by flash chromatography
(n-hexane/EtOAc 70:30 as eluent) affording the title compound (1.26
g, 78%).
Step C: 2-Amino-3-tert-butoxy-3-oxopropyl 4-(nitrooxy)butanoate
[0710] To a solution of
2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-tert-butoxy-3-oxopropyl
4-(nitrooxy)butanoate (1.26 g, 2.45 mmol) in CH.sub.3CN (15 ml),
piperidine (1.21 ml, 12.2 mmol) was added in the dark, the reaction
was stirred at room temperature for 25 min. Then the mixture was
concentrated to a small volume and diluted with EtOAc (80 ml) and
washed with 5% aqueous NaHPO.sub.4. The organic layer was dried
over sodium sulphate and concentrated under reduced pressure. The
residue was purified by flash chromatography (CH.sub.2Cl.sub.2/MeOH
98:2 as eluent) yielding the title compound (0.500 g, 70%).
[0711] .sup.1H-NMR (CDCl.sub.3): 6.49, 4.61-4.50 (3H, m), 3.95 (2H,
d), 2.43 (2H, t), 2.22-2.08 (2H, m), 1.05 (9H, s).
##STR00374##
EXAMPLE 3
1-tert-Butyl
2-(4-(nitrooxymethyl)benzyl)pyrrolidine-1,2-dicarboxylate
(corresponding to compound 7)
Step A: 1-tert-butyl
2-(4-(chloromethyl)benzyl)pyrrolidine-1,2-dicarboxylate
[0712] N-Boc-L-proline (2.47 g, 11.5 mmol) and
4-(chloromethyl)benzyl alcohol (1.50 g, 9.58 mmol) were dissolved
in CH.sub.2Cl.sub.2 (50 ml) and the mixture was cooled to 0.degree.
C. N-Ethyl-N'-(3-dimethylaminopropyl)carbodiimide (EDC) (2.75 g,
14.4 mmol) and N,N-dimethylaminopyridine (DMAP) (0.235 g, 1.92
mmol) were added and the reaction was slowly warmed to room
temperature and stirred for 4 hours. Then the mixture was diluted
with CH.sub.2Cl.sub.2 (200 ml) and washed with 5% aqueous
NaHCO.sub.3, 5% aqueous Na.sub.2HPO.sub.4 and brine. The organic
layer was dried over sodium sulphate and concentrated under reduced
pressure. The residue was purified by flash chromatography
(n-hexane/EtOAc 80:20 as eluent) affording the title compound.
(2.98 g, 88%).
Step B: 1-tert-Butyl
2-(4-(nitrooxymethyl)benzyl)pyrrolidine-1,2-dicarboxylate
[0713] To a solution of 1-tert-butyl
2-(4-(chloromethyl)benzyl)pyrrolidine-1,2-dicarboxylate (0.630 g,
1.78 mmol) in CH.sub.3CN (13 ml), AgNO.sub.3 (0.756 g, 4.45 mmol)
was added and the reaction was heated in a microwave apparatus
(150.degree. C., 20 min). The formed salts were filtered off and
the solvent was concentrated, then the residue was diluted with
EtOAc (100 ml) and washed with brine. The organic layer was dried
over sodium sulphate and concentrated under reduced pressure
yielding the title compound (0.655 g, 96%).
[0714] .sup.1H-NMR (CDCl.sub.3): 7.41 (4H, d), 5.44 (2H, s),
5.30-5.10 (2H, m), 4.42-4.27 (2H, m), 3.57-3.42 (2H, m), 2.30-2.15
(1H, m), 2.00-1.85 (3H, m), 1.48-1.35 (9H, m).
EXAMPLE 4
##STR00375##
[0715] 4-[(nitrooxy)methyl]benzyl pyrrolidine-2-carboxylate
hydrochloride (corresponding to compound 3)
[0716] To a solution of 1-tert-Butyl
2-(4-(nitrooxymethyl)benzyl)pyrrolidine-1,2-dicarboxylate, obtained
in Example 3, (0.543 g, 1.43 mmol) in CH.sub.2Cl.sub.2 (14 ml)
cooled to 0.degree. C., HCl.sub.gas was bubbled for 2 hours. The
solvent was concentrated and the residue was treated with diethyl
ether, affording the title compound (0.446 g, 99%.
[0717] .sup.1H-NMR (CDCl.sub.3): 9.16 (bs), 7.40 (4H, d), 5.43 (2H,
s), 5.31-5.17 (2H, m), 4.52 (1H, m), 3.52 (2H, m), 2.49-2.38 (1H,
m), 2.20-2.00 (3H, m).
EXAMPLE 5
##STR00376##
[0718] 4-(nitrooxy)butyl 2-(tert-butoxycarbonylamino)acetate
(corresponding to compound 16)
[0719] Applying the same procedure described in Example 1, starting
from commercially available N-Boc-L-glycine, N-hydroxysuccinimido
ester (2.33 g, 8.56 mmol), the title compound was obtained. (3.00
g, 80%).
[0720] .sup.1H-NMR (CDCl.sub.3): 5.04 (1H, bt), 4.49 (2H, t), 4.20
(2H, t), 3.91 (2H, d), 1.81 (4H, m), 1.46 (9H, s).
EXAMPLE 6
##STR00377##
[0721] 4-(nitrooxy)butyl 2-aminoacetate hydrochloride
(corresponding to compound 21)
[0722] The title compound was obtained as a white solid starting
from 4-(nitrooxy)butyl 2-(tert-butoxycarbonylamino)acetate,
prepared as described in Example 5 following the procedure
described in Example 4 (2.34 g, quantitative yield).
[0723] .sup.1H-NMR (CDCl.sub.3): 4.53 (2H, t), 4.29 (2H, t), 4.04
(2H, d), 3.74 (2H, d), 1.84 (4H, m).
##STR00378##
EXAMPLE 7
4-(Nitrooxy)butyl 2-(tert-butoxycarbonylamino)-3-methylbutanoate
(corresponding to compound 149)
Step A: 4-chlorobutyl
2-(tert-butoxycarbonylamino)-3-methylbutanoate
[0724] N-Boc-L-valine (3.48 g, 16.0 mmol), 4-chloro-1-butanol (3.47
g, 32.0 mmol) and N-hydroxybenzotriazole (HOBT) (3.24 g, 24.0 mmol)
were dissolved in CH.sub.2Cl.sub.2 (80 ml) and the mixture was
cooled to 0.degree. C. N-Methylmorpholine (NMM) (3.24 g, 32.0 mmol)
and N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium
hexafluorophosphate (HBTU) (6.67 g, 17.6 mmol) were added and the
reaction was slowly warmed to room temperature and stirred for 24
hours. Then the mixture was diluted with CH.sub.2Cl.sub.2 (200 ml)
and washed with 5% aqueous NaHCO.sub.3, HCl 1N and brine. The
organic layer was dried over sodium sulphate and concentrated under
reduced pressure. The residue was purified by flash chromatography
(n-hexane/EtOAc 90:10) affording the title compound (2.98 g,
64%).
Step B: 4-(Nitrooxy)butyl
2-(tert-butoxycarbonylamino)-3-methylbutanoate
[0725] To a solution of 4-chlorobutyl
2-(tert-butoxycarbonylamino)-3-methylbutanoate (0.630 g, 1.78 mmol)
in CH.sub.3CN (13 ml), AgNO.sub.3 (0.756 g, 4.45 mmol) was added
and the reaction was heated in a microwave apparatus (150.degree.
C., 20 min). The formed salts were filtered off and the solvent was
concentrated. Then the residue was diluted with EtOAc (100 ml) and
washed with brine, dried over sodium sulphate and concentrated
under reduced pressure yielding the title compound (0.655 g).
[0726] .sup.1H-NMR (CDCl.sub.3): 5.00 (1H, d), 4.50 (2H, t),
4.24-4.16 (3H, m), 2.20-2.09 (1H, m), 1.90-1.74 (4H, m), 1.46 (9H,
s), 0.99 (3H, d), 0.92 (3H, d).
EXAMPLE 8
##STR00379##
[0727] tert-butyl 2-(4-(nitrooxy)butylamino)-2-oxoethylcarbamate
(corresponding to compound (12))
Step A: tert-butyl 2-(4-hydroxybutylamino)-2-oxoethylcarbamate
[0728] 4-Amino-1-butanol (0.686 g, 7.70 mmol) and triethylamine
(0.779 g, 7.70 mmol) were dissolved in CH.sub.2Cl.sub.2 (40 ml) and
the mixture was cooled to 0.degree. C. A suspension of commercial
N-Boc-glycine N-hydroxysuccinimido estere (2.10 g; 7.70 mmol) in
CH.sub.2Cl.sub.2 (40 ml) was added and the reaction was slowly
warmed to room temperature and stirred for 24 hours. Then the
mixture was diluted with CH.sub.2Cl.sub.2 (150 ml) and washed with
5% aqueous Na.sub.2HPO.sub.4 and brine. The aqueous layer was
extracted twice with CH.sub.2Cl.sub.2 and twice with a mixture of
EtOAc/MeOH 98:2. The organic layers were dried over sodium sulphate
and concentrated under reduced pressure. The residue was purified
by flash chromatography (n-hexane/i-prOH 80:20) affording the title
compound (2.16 g).
Step B: 2-(4-(nitrooxy)butylamino)-2-oxoethylcarbamate
[0729] To a solution of tert-butyl
2-(4-hydroxybutylamino)-2-oxoethylcarbamate (2.16 g, 8.77 mmol),
tetraethylammonium nitrate (3.37 g, 17.54 mmol) and
2,6-di-tert-butyl-4-methylpyridine (2.71 g, 13.16 mmol) in
CH.sub.2Cl.sub.2 (60 ml) cooled to -70.degree. C. and under
nitrogen, a solution of trifluoromethansulfonic anhydride (2.72 g,
9.65 mmol) in CH.sub.2Cl.sub.2 (40 ml) was added drop wise. The
resulting mixture was stirred for 3 hours at -65.degree. C. Then
the mixture was slowly warmed to room temperature, diluted with
CH.sub.2Cl.sub.2 and washed with 5% aqueous Na.sub.2HPO.sub.4. The
organic layer was dried over sodium sulphate and concentrated under
reduced pressure.
[0730] The residue was purified by flash chromatography
CH.sub.2Cl.sub.2/CH.sub.3CN 70:30 as eluent) affording the title
compound (2.04 g, 80%).
[0731] .sup.1H-NMR (CDCl.sub.3): 6.30 (1H, s), 5.15 (1H, s), 4.48
(2H, t), 3.79 (2H, d), 3.37-3.31 (2H, m), 1.80-1.74 (2H, m),
1.67-1.62 (2H, m), 1.63 (9H, s).
##STR00380##
EXAMPLE 9
4-(2-Aminoacetamido)butyl nitrate hydrochloride (corresponding to
compound 23)
[0732] The title compound was obtained as a white solid from
tert-butyl
[0733] 2-(4-(nitrooxy)butylamino)-2-oxoethylcarbamate (Example 8)
following the procedure described in Example 4. (1.58 g,
quantitative yield).
[0734] .sup.1H-NMR (CDCl.sub.3): 8.55 (1H, s), 8.17 (2H, s), 4.54
(2H, t), 3.55-3.48 (2H, m), 3.18-3.12 (2H, m), 1.72-1.65 (2H, m),
1.53-1.48 (2H, m).
EXAMPLE 10
##STR00381##
[0735] (2S,3aS,6aS)-4-(Nitrooxy)butyl
octahydrocyclopenta[b]pyrrole-2-carboxylate (corresponding to
compound 512)
Step A: (2S,3aS,6aS)-1-(9H-fluoren-9-yl)methyl 2-benzyl
hexahydrocyclopenta[b]pyrrole-1,2(2H)-dicarboxylate
[0736] To a solution of commercial (2S,3aS,6aS)-benzyl
octahydrocyclopenta[b]pyrrole-2-carboxylatehydrochloride (1.00 g,
3.60 mmol) and TEA (1.15 ml, 7.92 mmol) in CH.sub.3CN (15 ml)
cooled in an ice bath 9-fluorenylmethoxycarbonyl chloride (1.01 g,
4.25 mmol) was added. The resulting mixture was stirred at room
temperature overnight. Then the mixture was concentrated and
diluted with CH.sub.2Cl.sub.2 (50 ml), washed with a solution of
NaH.sub.2PO.sub.4 5% (2.times.30 ml) and brine (1.times.30 ml). The
organic phase was dried over sodium sulphate and concentrated under
reduced pressure to give an oil that slowly crystallized on storage
affording the title compound (1.68 g, 100%).
Step B:
(2S,3aS,6aS)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)octahydrocyclop-
enta[b]pyrrole-2-carboxylic acid
[0737] To a solution of (2S,3aS,6aS)-1-(9H-fluoren-9-yl)methyl
2-benzyl hexahydrocyclopenta[b]pyrrole-1,2(2H)-dicarboxylate (1.68
g, 3.6 mmol) in EtOH 95% (15 ml) was added Palladium on carbon 10%
(0.2 g, 0.18 mmol) and cyclohexene (3.5 ml, 36 mmol). The resulting
mixture was refluxed for 7 h. The solvent was evaporated and the
crude was diluted with CH.sub.2Cl.sub.2 (20 ml). The suspension was
filtered on celite and the organic phase was evaporated under
vacuum. The residue was purified by flash chromatography
(CH.sub.2Cl.sub.2/CH.sub.3CN 50:50) to give the title compound as a
white foam (0.5 g, 37%)
Step C: (2S,3aS,6aS)-1-(9H-fluoren-9-yl)methyl 2-(4-chlorobutyl)
hexahydrocyclopenta[b]pyrrole-1,2(2H)-dicarboxylate
[0738] (2S,3aS,6aS)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)
octahydrocyclopenta[b]pyrrole-2-carboxylic acid (0.250 g, 0.66
mmol) and 4-chloro-1-butanol (0.1 ml, 0.99 mmol) were dissolved
under nitrogen in CH.sub.2Cl.sub.2 (5 ml) and the mixture was
cooled to 0.degree. C.
N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC)
(0.190 g, 0.99 mmol) and N,N-dimethylaminopyridine (DMAP) (0.016 g,
0.13 mmol) were added and the reaction was slowly warmed to room
temperature and stirred for 4 h. Then the mixture was diluted with
CH.sub.2Cl.sub.2 (10 ml) and washed with 5% aqueous NaHCO.sub.3, 5%
aqueous Na.sub.2HPO.sub.4 and brine. The organic layer was dried
over sodium sulphate, concentrated under reduced pressure and
purified by flash chromatography (n-hexane/EtOAc 80:20 as eluent)
affording the title compound as an oil (0.14 g, 45%)
Step D: (2S,3aS,6aS)-1-(9H-fluoren-9-yl)methyl
2-(4-(nitrooxy)butyl)
hexahydrocyclopenta[b]pyrrole-1,2(2H)-dicarboxylate
[0739] To a solution of
(2S,3aS,6aS)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)
octahydrocyclopenta[b]pyrrole-2-carboxylic acid (0.13 g, 0.27 mmol)
in CH.sub.3CN (1.7 ml), AgNO.sub.3 (0.118 g, 0.69 mmol) was added
and the reaction was heated to 150.degree. C. for 20 min in a
microwave apparatus. The formed salts were filtered off and the
solvent was concentrated affording the title compound as a yellow
solid (0.133 g, 100%).
[0740] To a solution of (2S,3aS,6aS)-1-(9H-fluoren-9-yl)methyl
2-(4-(nitrooxy)butyl)
hexahydrocyclopenta[b]pyrrole-1,2(2H)-dicarboxylate (0.133 g, 0.27
mmol) in CH.sub.3CN (2 ml), piperidine (133 .mu.l, 1.35 mmol) was
added in the dark; the reaction was stirred at room temperature for
25 min. Then the solution was evaporated, diluted with pH 3 aqueous
buffer and the aqueous phase was extracted with hexane. The
solution was basified to pH 9 and finally extracted with diethyl
ether. The organic layer was dried over sodium sulphate and
concentrated under reduced pressure affording the title compound as
an oil (0.04 g, 50%).
[0741] .sup.1H-NMR (DMSO-d.sub.6): 4.55 (2H, t); 4.13-3.96 (3H, m);
3.81 (1H, m); 3.68 (1H, bs); 2.66-2.51 (1H, m); 2.34-2.19 (1H, m);
1.81-1.31 (11H, m).
EXAMPLE 11
##STR00382##
[0742] (2S,3aS,6aS)-4-(nitrooxymethyl)benzyl octahydrocyclopenta
[b]pyrrole-2-carboxylate (corresponding to compound 520)
[0743] The title compound was prepared following the procedure
described in Example 10 using 4-(chloromethyl)benzyl alcohol
instead of 4-chloro-1-butanol in Step C.
[0744] .sup.1H-NMR (DMSO-d.sub.6): 7.51-7.21 (4H, m); 5.47 (2H, s);
5.09 (2H, s) 4.10 (1H, m); 3.82 (1H, m); 3.68 (1H, m); 2.62 (1H,
m); 2.38 (1H, m); 1.92-1.05 (9H, m)
EXAMPLE 12
##STR00383##
[0745]
4-[(nitrooxy)methyl]benzyl-2-amino-6-(tert-butoxycarbonylamino)hexa-
noate (corresponding to compound 24)
[0746] The title compound was prepared following procedure already
described in Examples 1 and 11 (0.010 g, 10%).
[0747] .sup.1H-NMR (DMSO-d.sub.6): 7.48-7.61 (8H, m); 6.78 (1H, t);
5.54 (2H, s); 5.15 (2H, s); 4.07 (1H, m); 2.87 (1H, m); 1.73-1.65
(2H, m); 1.36-1.22 (13H, m).
EXAMPLE 13
##STR00384##
[0748] 4-(nitrooxy)butyl
2-(tert-butoxycarbonylamino)-3-hydroxypropanoate (corresponding to
compound (45))
[0749] Starting from Boc-L-serine and following the procedure
described in Example 3 the title was obtained as an oil (0.350 g,
48%).
[0750] .sup.1H-NMR (CDCl.sub.3): 5.44 (1H, bs); 4.50 (2H, t); 4.38
(1H, m); 4.25 (2H, m); 3.97 (2H, m); 1.84 (4H, m); 1.47 (9H,
s).
##STR00385##
EXAMPLE 14
1-tert-butyl 2-(4-(nitrooxy)butyl)pyrrolidine-1,2-dicarboxylate
[0751] Starting from Boc-L-Proline and 4-chloro-1-butanol and
following the procedure described in Example 3 the title compound
was obtained as an oil.
[0752] .sup.1H-NMR (CDCl.sub.3): 4.50 (2H, t), 4.10-4.40 (3H, m),
3.65-3.33 (2H, m), 2.34-1.70 (8H, m), 1.45 (9H, d).
EXAMPLE 15
##STR00386##
[0753] 1-tert-butyl
2-(3-(nitrooxy)propyl)pyrrolidine-1,2-dicarboxylate
[0754] Starting from Boc-L-Proline and 3-bromo-1-propanol and
following the procedure described in Example 3 the title compound
was obtained as an oil.
[0755] .sup.1H-NMR (CDCl.sub.3): 4.56-4.52 (2H, m); 4.31-4.19 (3H,
m); 3.57-3.35 (2H, m); 2.28-1.80 (6H, m); 1.43 (9H, d).
EXAMPLE 16
##STR00387##
[0756]
2,2-dimethyl-15-(nitrooxy)-4,9-dioxo-3,8,10,13-tetraoxa-5-azapentad-
ecane-6-carboxylic acid (Corresponding to Compound 400)
[0757] Into a solution of N-Boc-L-Serine (1.66 g, 8.12 mmol),
di-isopropylethyl amine (DIPEA) (1.41 ml, 8.12 mmol),
N,N-dimethylaminopyridine (DMAP) (1.19 g, 9.74 mmol) and scandium
triflate (1.20 g, 2.43 mmol) in CH.sub.2Cl.sub.2 (40 ml), cooled to
-10.degree. C., a solution of 2-[2-(nitrooxy)ethoxy]ethyl
4-nitrophenyl carbonate in CH.sub.2Cl.sub.2 (40 ml) was added
drop-wise. The reaction was slowly warmed to room temperature and
stirred for 24 h. Then the organic phase was washed with pH 3
aqueous buffer and concentrated under reduced pressure. The crude
was partitioned between aqueous 5% aqueous Na.sub.2HPO.sub.4 and
diethyl ether and extracted twice with diethyl ether. The aqueous
phase was acidified to pH 3 and extracted with CH.sub.2Cl.sub.2.
The organic phase was finally dried over sodium sulphate and
concentrated under reduced pressure to give the title compound as
an oil. (2.4 g, 80%)
[0758] .sup.1H-NMR (CDCl.sub.3): 5.54 (1H, bs); 4.63 (2H, m); 4.52
(3H, m); 4.29 (2H, m); 3.86-3.69 (4H, m); 1.46 (9H, s).
EXAMPLE 17
##STR00388##
[0759] 2-(tert-butoxycarbonylamino)-4-methylpentyl
4-hydroxybutanoate (corresponding to compound (510))
Step A: 2-(tert-butoxycarbonylamino)-4-methylpentyl
4-bromobutanoate
[0760] tert-Butyl 1-hydroxy-4-methylpentan-2-ylcarbamate (2.00 g,
9.20 mmol) and 4-bromo-butyric acid (2.57 g, 15.38 mmol) were
dissolved in CH.sub.2Cl.sub.2 (40 ml) and the mixture was cooled to
0.degree. C. EDC (4.20 g, 21.90 mmol) and DMAP (0.27 g, 2.21 mmol)
were added and the reaction was slowly warmed to room temperature
and stirred overnight. Then the reaction was treated with a
solution of 5% aqueous NaH.sub.2PO.sub.4 (100 ml). The organic
layer was washed with a solution of 10% aqueous Na.sub.2CO.sub.3
(100 ml) and brine, dried over Na.sub.2SO.sub.4, filtered and
concentrated. The obtained crude clear oil corresponding to the
title compound (3.30 g) was used without any further
purification.
Step B: 2-(tert-Butoxycarbonylamino)-4-methylpentyl
4-(nitrooxy)butanoate
[0761] To a solution of crude
2-(tert-butoxycarbonylamino)-4-methylpentyl 4-bromobutanoate (3.30
g) in CH.sub.3CN (60 ml), AgNO.sub.3 (4.20 g, 24.52 mmol) was
added. The resulting solution (divided into 5 vials) was heated in
a microwave apparatus (120.degree. C., 9 minutes). Then the formed
salts were filtered off, the solvent was concentrated and the
residue purified by flash chromatography (n-hexane/EtOAc 80:20 as
eluent) affording the title compound (1.05 g, yield: 33.5%) as a
clear oil.
[0762] .sup.1H-NMR (CDCl.sub.3): 4.54 (2H, t); 4.48-4.34 (1H, m);
2.49 (2H, t); 2.18-1.99 (2H, m); 1.79-1.57 (1H, m); 1.39-1.22 (2H,
m); 1.00-0.86 (6H, m).
EXAMPLE 18
##STR00389##
[0763] 2-Amino-4-methylpentyl 4-(nitrooxy)butanoate hydrochloride
(corresponding to compound 507)
[0764] The title compound was prepared from
2-(tert-butoxycarbonylamino)-4-methylpentyl 4-(nitrooxy)butanoate
(described in Example 17) following the procedure described in
Example 4 (0.71 g, 90%).
[0765] .sup.1H-NMR (DMSO-d.sub.6): 4.56 (2H, t); 4.27-4.22 (1H, m);
4.11-4.06 (1H, m); 3.39-3.32 (2H, m); 2.51 (2H, t); 2.01-1.92 (2H,
m); 1.75-1.68 (1H, m); 1.51-1.38 (2H, m); 0.90 (6H, d).
EXAMPLE 19
##STR00390##
[0766] 4-[(Nitrooxy)methyl]benzyl
2-(tert-butoxycarbonylamino)-4-phenylbutanoate (corresponding to
compound 13)
[0767] The title compound was prepared as a clear oil from
2-(tert-butoxycarbonylamino)-4-phenylbutanoic acid following
procedure described in Example 3.
[0768] .sup.1H-NMR (CDCl.sub.3): 7.34 (4H, m); 5.07-5.04 (1H, m);
4.49 (2H, t); 4.36-4.34 (1H, m); 4.23-4.11 (2H, m); 2.70 (2H, t);
2.19-2.11 (1H, m); 2.02-1.94 (1H, m); 1.92-1.76 (4H, m); 1.61 (9H,
s).
EXAMPLE 20
##STR00391##
[0769] 3-[(Nitrooxy)methyl]phenyl
2-(tert-butoxycarbonylamino)-4-phenylbutanoate (corresponding to
compound 86)
[0770] Starting from 2-(tert-butoxycarbonylamino)-4-phenylbutanoic
acid and 3-(bromomethyl)phenyl alcohol and following the procedure
reported in Example 3 the title compound was obtained as an
oil.
[0771] .sup.1H-NMR (CDCl.sub.3): 7.50-7.16 (7H, m); 7.15-7.05 (2H,
m); 5.42 (2H, s); 5.07 (1H, d); 4.65-4.47 (1H, m); 2.80 (2H, t);
2.44-2.23 (1H, m); 2.23-1.99 (1H, m); 1.48 (9H, s).
##STR00392##
EXAMPLE 21
2-(2-(Nitrooxy)ethoxy)ethyl
2-(tert-butoxycarbonylamino)-4-phenylbutanoate
[0772] Starting from 2-(tert-butoxycarbonylamino)-4-phenylbutanoic
acid and 2-chloroethoxyethyl alcohol and following the procedure
reported in Example 3 the title compound was obtained as an
oil.
[0773] .sup.1H-NMR (CDCl.sub.3): 7.19-7.03 (5H, m); 5.08 (1H, d);
4.50-4.45 (2H, m); 4.22-4.06 (3H, m); 3.65-3.55 (4H, m); 2.56 (2H,
t); 2.08-1.80 (2H, m); 1.32 (9H, s).
EXAMPLE 22
##STR00393##
[0774]
2,2-Dimethyl-14-(nitrooxy)-4,9-dioxo-3,8,10-trioxa-5-azatetradecane-
-6-carboxylic acid (corresponding to compound (401))
[0775] The title compound was prepared from N-Boc-L-serine and
4-chlorobutyl chloroformate following procedure described in
Example 16.
[0776] .sup.1H-NMR (CDCl.sub.3): 5.50 (1H, d); 4.52-4.40 (5H, m);
4.19 (2H, t); 1.88-1.75 (4H, m); 1.46 (9H, s).
##STR00394##
2-amino-3-((4-(nitrooxy)butoxy)carbonyloxy)propanoic acid
hydrochloride (corresponding to compound (407))
[0777] The title compound was obtained as a white solid from
2,2-dimethyl-14-(nitrooxy)-4,9-dioxo-3,8,10-trioxa-5-azatetradecane-6-car-
boxylic acid (described in Example 22) following procedure
described in Example 4.
[0778] .sup.1H-NMR (DMSO-d.sub.6): 4.60-4.41 (4H, m); 4.18-4.13
(3H, m); 1.78-1.65 (4H, m).
EXAMPLE 24
##STR00395##
[0779] 4-(nitrooxy)butyl
2-(tert-butoxycarbonylamino)-3-(4-hydroxyphenyl)propanoate
(corresponding to compound 67)
[0780] To a solution of Boc-(L)-tyrosine (5.0 g, 17.77 mmol) in
N,N-dimethylformamide (40 ml) cesium carbonate (5.79 g, 17.77 mmol)
was added. The reaction was cooled at 0.degree. C. and a solution
of 4-bromobutyl nitrate (17.77 mmol) in dichloromethane (20% w/w,
17.06 g) was added drop wise. The reaction was stirred at 0.degree.
C. for 20 minutes and then at room temperature for 22 hours. The
mixture was poured into a 5% aqueous NaH.sub.2PO.sub.4 solution and
extracted with diethyl ether (40.times.4 ml), the organic layers
were dried over sodium sulfate and concentrated under reduced
pressure. The residue was purified by flash chromatography
(n-hexane/EtOAc from 9:1 to 1:1 as eluent affording the title
compound.
[0781] .sup.1H-NMR (CDCl.sub.3): 7.00 (2H, d, J=8 Hz); 6.76 (2H, d,
J=8 Hz); 5.01 (1H, bd, J=8 Hz); 4.51 (1H, m); 4.42 (2H, t, J=6 Hz);
4.12 (2H, m); 3.00 (2H, d, J=6 Hz); 1.69 (4H, m); 1.44 (9H, s).
##STR00396##
EXAMPLE 25
4-(nitrooxy)butyl 2-amino-3-(4-hydroxyphenyl)propanoate
(corresponding to compound (58)
[0782] The title compound was obtained from 4-(nitrooxy)butyl
2-(tert-butoxycarbonylamino)-3-(4-hydroxyphenyl)propanoate
(described in Example 24) following procedure described in Example
4.
[0783] .sup.1H-NMR (CDCl.sub.3): 7.05 (2H, dd, J=9 and 3 Hz); 6.74
(2H, dd, J=9 and 3 Hz); 4.45 (2H, t, J=6 Hz); 4.15 (2H, t, J=6 Hz);
3.73 (1H, m); 2.93 (2H, m); 1.73 (4H, m).
EXAMPLE 26
##STR00397##
[0784] 2-(R)-5,6-bis(nitrooxy)hexyl 1-tert-butyl
pyrrolidine-1,2-dicarboxylate (corresponding to compound
4,5-(R)-isomer)
[0785] To a solution of N-Boc-L-Proline (288 mg, 1.34 mmol) and
(2R)-6-hydroxypentane-1,2-diyl dinitrate (obtained as described in
WO2005070868(A1)) (300 mg, 1.34 mmol) in CH.sub.2Cl.sub.2 (6 mL)
was added at 0.degree. C. EDAC (257 mg, 1.34 mmol), and then DMAP
(catalytic). The reaction was stirred overnight at rt. The organic
layer was washed successively with H.sub.2O, HCl 0.1M, H.sub.2O and
brine, dried over Na.sub.2SO.sub.4, filtered and evaporated. The
residue was purified by column chromatography on silica (15% to 25%
AcOEt in n-Hexane in 20 CV, then 25% to 35% in 5 CV) to give the
title compound (413 mg, 73%).
[0786] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.5.30 (m, 1H), 4.77
(m, 1H), 4.50 (m, 1H), 4.31 (d, J=11.5 Hz, 1H), 4.19 (m, 2H), 3.47
(m, 2H), 1.94 (m, 3H), 1.76 (m, 4H), 1.56 (m, 3H), 1.45 (d, J=12.67
Hz, 9H).
EXAMPLE 27
##STR00398##
[0787] (R)-5,6-bis(nitrooxy)hexyl pyrrolidine-2-carboxylate
(corresponding to compound 1; 5(R)-isomer)
[0788] To a solution of [(5R)-5,6-dinitroxyloxane-1-yl]
N-tButoxy-L-proline ester (410 mg, 0.97 mmol) in CH.sub.2Cl.sub.2
(3 mL) was added TFA (223 .mu.L, 2.91 mmol, 3 eq). The reaction was
stirred at RT for 3 hrs. The organic layer was washed with
H.sub.2O, K.sub.2CO.sub.3 diluted, H.sub.2O and brine, dried over
Na.sub.2SO.sub.4, filtered and evaporated yielding the title
compound (215 mg, 69%).
[0789] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.5.31 (ddd, J=13.23,
6.51, 3.09 Hz, 1H), 4.77 (dd, J=12.88, 3.07 Hz, 1H), 4.50 (dd,
J=12.87, 6.46 Hz, 1H), 4.17 (t, J=6.30 Hz, 2H), 3.82 (dd, J=8.46,
5.25 Hz, 1H), 3.13 (dd, J=16.88, 6.54 Hz, 1H), 2.42 (s, 2H), 2.17
(m, 1H), 1.78 (m, 6H), 1.52 (m, 3H).
EXAMPLE 28
##STR00399##
[0790] 2-(tert-butoxycarbonylamino)ethyl 4-(nitrooxy)butanoate
(corresponding to compound (508))
Step A: 2-(tert-butoxycarbonylamino)ethyl 4-bromobutanoate
[0791] N-Boc-ethanolamine (2.10 g; 13.0 mmol), 4-Bromobutyric acid
(2.18 g; 13.0 mmol) and N,N-dimethylaminopyridine (0.318 g; 2.60
mmol) were dissolved in CH.sub.2Cl.sub.2 (35 mL) and the mixture
was cooled to 0.degree. C.; EDAC (3.75 g; 19.6 mmol) was added and
the reaction was slowly warmed to room temperature and stirred for
18 hours. Then the mixture was diluted with CH.sub.2Cl.sub.2,
washed with aqueous Na.sub.2HPO.sub.4 (5%, 2.times.50 ml) aqueous
NaH.sub.2PO.sub.4 (5%, 2.times.50 ml) and brine (1.times.40 ml).
The organic layer was dried over sodium sulfate and concentrated
under reduced pressure.
[0792] The residue was purified by flash chromatography
(hexane/EtOAc=75/25; R.sub.f=0.40), yielding the title compound
(3.03 g, 75%).
Step B: 2-(tert-butoxycarbonylamino)ethyl 4-(nitrooxy)butanoate
[0793] To a solution of 2-(tert-butoxycarbonylamino)ethyl
4-bromobutanoate (3.03 g; 9.77 mmol) in CH.sub.3CN (80 mL),
AgNO.sub.3 (4.15 g; 24.4 mmol) was added and the reaction was
performed at the microwave (120.degree. C., 7 min). The formed
salts were filtered off and the solvent was concentrated; then the
residue was diluted with EtOAc and washed with water (40 ml); the
organic layer was dried over sodium sulfate and concentrated under
reduced pressure.
[0794] The residue was purified by flash chromatography
(hexane/EtOAc=7/3; R.sub.f=0.40), yielding the title compound (1.48
g, 52%).
[0795] .sup.1H-NMR (300 MHz, CDCl.sub.3): 4.77 (1H, s); 4.54 (2H,
t); 4.17 (2H, t); 3.44-3.38 (2H, m); 2.49 (2H, t); 2.13-2.04 (2H,
m); 1.46 (9H, s).
EXAMPLE 29
##STR00400##
[0796] 2-aminoethyl 4-(nitrooxy)butanoate hydrochloride
(corresponding to compound (509))
[0797] The title compound was obtained as a white solid starting
from 2-(tert-butoxycarbonylamino)ethyl 4-(nitrooxy)butanoate,
prepared as described in Example 28 following the procedure
described in Example 4 (1.16 g; quantitative yield).
[0798] .sup.1H-NMR (DMSO-d.sub.6): 8.25 (2H, s); 4.56 (2H, t); 4.23
(2H, t); 3.06 (2H, t); 2.51 (2H, t); 2.01-1.91 (2H, m).
##STR00401##
EXAMPLE 30
(S)-2-(tert-butoxycarbonylamino)-3-phenylpropyl
4-(nitrooxy)butanoate (corresponding to compound (511))
[0799] The title compound was prepared from (S)-tert-butyl
1-hydroxy-3-phenylpropan-2-ylcarbamate and 4-Bromobutyric acid
following the procedure described in Example 29.
[0800] .sup.1H-NMR (300 MHz, CDCl.sub.3): 7.35-7.25 (5H, m);
4.56-4.54 (1H, m); 4.52 (2H, t); 4.15-4.04 (3H, m); 2.84-2.81 (2H,
m); 2.50 (2H, t); 2.13-2.04 (2H, m); 1.32 (9H, s).
EXAMPLE 31
##STR00402##
[0801] (S)-4-(nitrooxy)butyl
2-(tert-butoxycarbonylamino)-3-phenylpropanoate (corresponding to
compound (15))
[0802] The title compound was prepared from
(S)-2-(tert-butoxycarbonylamino)-3-phenylpropanoic acid and
4-chloro-1-butanol following the procedure described in Example
3.
[0803] .sup.1H-NMR (300 MHz, CDCl.sub.3): 7.31 (3H, m), 7.16 (2H,
d), 4.98 (1H, bd), 4.56 (1H, bm), 4.41 (2H, t), 4.12 (2H, m), 3.08
(2H, d), 1.69 (4H, m), 1.93 (9H, s).
EXAMPLE 32
##STR00403##
[0804] (S)-4-hydroxybutyl pyrrolidine-2-carboxylate
[0805] The title compound was prepared from Boc-Proline and
4-chloro-1-butanol following the procedure described in Example 3,
eventually hydrolyzing the Boc protective group as described in
Example 4.
[0806] .sup.1H-NMR (CDCl.sub.3): 4.5 (3H, m), 4.3 (2H, bt), 3.57
(2H, m), 2.45 (1H, m) 2.13 (3H, m), 1.87 (4H, m).
EXAMPLE 33
##STR00404##
[0807] ((S)-bis(4-(nitrooxy)butyl)
2-(tert-butoxycarbonylamino)succinate (corresponding to compound
(468))
[0808] The title compound was prepared from L-Boc-Aspartic acid and
4-chloro-1-butanol following the procedure described in Example 3.
.sup.1H-NMR (CDCl.sub.3): 5.48 (1H, bd), 4.58 (1H, bd), 4.51 (4H,
t), 4.23 (2H, t), 2.93 (2H, m), 1.81 (8H, m), 1.47 (9H, s).
EXAMPLE 34
##STR00405##
[0809] (S)--((R)-5,6-bis(nitrooxy)hexyl)
2-(tert-butoxycarbonylamino)-3-phenylpropanoate (corresponding to
compound (123, 5(R)-isomer))
[0810] The title compound was prepared from Boc-L-Phenylalanine and
(2R)-6-hydroxypentane-1,2-diyl dinitrate (obtained as described in
WO2005070868(A1)) following the procedure described in Example
26.
EXAMPLE 35
##STR00406##
[0811] (S)--((R)-5,6-bis(nitrooxy)hexyl) 2-amino-3-phenylpropanoate
(corresponding to compound 14 5(R)-isomer)
[0812] The title compound was prepared from
(S)--((R)-5,6-bis(nitrooxy)hexyl)
2-(tert-butoxycarbonylamino)-3-phenylpropanoate (prepared as
described in Example 34) following procedure described in Example
4.
[0813] .sup.1H-NMR (CDCl.sub.3): 9.04-8.65 (2H, m), 7.47-7.14 (5H,
m), 5.31-5.15 (1H, m), 4.80-4.65 (1H, m) 4.55-4.31 (1H, m),
4.23-3.96 (2H, m); 3.60-3.42 (1H, m); 3.42-3.23 (1H, m); 1.74-1.46
(4H, m); 1.45-1.15 (2H, m).
##STR00407##
EXAMPLE 35
4-[(nitrooxy)methyl]benzyl 2-(tert-butoxycarbonylamino)acetate
(corresponding to compound (87))
[0814] The title compound was prepared from N-Boc-Glycine
N-hydroxysuccinimido ester and 4-(chloromethyl)benzyl alcohol
following procedures reported in Example 3.
[0815] .sup.1H-NMR (CDCl.sub.3): 7.41 (4H, s), 5.44 (2H, s), 5.19
(2H, s), 5.02 (1H, bs), 3.97 (2H, d), 1.47 (9H, s).
EXAMPLE 36
##STR00408##
[0816] 4-[(nitrooxy)methyl]benzyl 2-aminoacetate (corresponding to
compound (33))
[0817] The title compound was prepared from
4-[(nitrooxy)methyl]benzyl 2-(tert-butoxycarbonylamino)acetate
(prepared in Example 35) following procedures reported in Example
4.
[0818] .sup.1H-NMR (CDCl.sub.3): 8.66-8.34 (2H, m), 7.59-7.40 (4H,
m), 5.59 (2H, s), 5.26 (2H, s) 3.87 (2H, s).
EXAMPLE 37
##STR00409##
[0819] (S)-bis(4-(nitrooxy)butyl)
2-(tert-butoxycarbonylamino)pentanedioate (corresponding to
compound (472))
[0820] The title compound was prepared from L-Boc-Glutamic acid and
4-chloro-1-butanol following the procedure described in Example 3,
eventually hydrolyzing the Boc protective group as described in
Example 4.
[0821] .sup.1H-NMR (CDCl.sub.3): 5.28 (1H, bd), 4.48 (1H, bd), 4.19
(2H, t), 4.07 (2H, t), 2.40 (3H, m), 2.03 (1H, m), 1.72 (8H, m),
1.45 (9H, s).
EXAMPLE 38
##STR00410##
[0822] (S)-4-(nitrooxy)butyl 2-amino-3-phenylpropanoate
(corresponding to compound (40))
[0823] The title compound was prepared from (S)-4-(nitrooxy)butyl
2-(tert-butoxycarbonylamino)-3-phenylpropanoate (prepared as
described in Example 31) following procedure described in Example
4.
[0824] .sup.1H-NMR (DMSO): 8.7 (3H, bs), 7.30 (5H, m), 4.47 (2H,
d), 4.25 (1H, t), 4.08 (2H, t), 3.15 (2H, m), 1.54 (4H, m).
PHARMACOLOGICAL EXAMPLE
[0825] The ability of the compounds of the present invention to
release nitric oxide was assessed testing their vasorelaxant
activity in isolated rabbit thoracic aorta preparations (Wanstall
J. C. et al., Br. J. Pharmacol., 134:463-472, 2001).
[0826] The compounds of the invention that were tested are the
compounds of the following formulas: 7, 8, 9, 12, 13, 15, 86, 87,
123, 407, 508, 511;
and compounds reported in Examples 14, 15, and 21.
Method
[0827] Male New Zealand rabbits were anaesthetized with
thiopental-Na (50 mg/kg, iv), sacrificed by exsanguinations and
then the thorax was opened and the aorta dissected. Single ring
preparations (4 mm in length) of thoracic aorta were set up in
physiological salt solution (PSS) at 37.degree. C. in small organ
chambers (5 ml). The composition of PSS was (mM): NaCl 130,
NaHCO.sub.3 14.9, KH.sub.2PO.sub.4 1.2, MgSO.sub.4 1.2, HEPES 10,
CaCl.sub.2, ascorbic acid 170 and glucose 1.1 (95% O.sub.2/5%
CO.sub.2; pH 7.4). Each ring was mounted under 2 g passive tension
in 5 ml organ bath. Isometric tension was recorded with a Grass
transducer (Grass FT03) attached to a BIOPAC MP150 System.
Preparations were allowed to equilibrate for 1 h, then contracted
submaximally with noradrenaline (NA, 1 .mu.M) and, when the
contraction was stable, acetylcholine (ACh, 10 .mu.M) was added. A
relaxant response to ACh indicated the presence of a functional
endothelium. When a stable precontraction was reached, a cumulative
concentration-response curve to either of the vasorelaxant agents
was obtained in the presence of a functional endothelium. Time
intervals between different concentrations were based on the time
needed to reach a full response.
[0828] Moreover, the nitric oxide-dependent vascular relaxation
elicited by the tested compounds was examined preincubating the
aortic rings with the soluble guanylyl cyclase inhibitor ODQ
(1-H-(1,2,4)-oxadiazol(4,3-a)quinoxalin-1-one) at 10 .mu.M for 20
min. Responses to vasorelaxing agents were measured from the
plateau of NA contraction. The IC.sub.50 (concentration giving 50%
reversal of NA contraction) was interpolated from the plots of
relaxant-response vs log molar concentration of tested
compound.
[0829] During the experimental period, the plateau obtained with NA
was stable without significant spontaneous loss of contraction in
the aortic rings.
[0830] As shown in the following Table 1, the compounds of the
invention were able to induce relaxation in a
concentration-dependent manner. Furthermore, in experiments
performed in the presence of ODQ (10 .mu.M), the vascular
relaxation of the tested compounds was inhibited.
TABLE-US-00001 TABLE 1 Compound IC.sub.50 (.mu.M) .+-. sem Example
15 1.2 .+-. 0.33 Example 14 1.9 .+-. 0.4 Compound 8 2.6 .+-. 0.6
Compound 7 2.4 .+-. 0.5 Compound 9 4.5 .+-. 1.4 Compound 86 5.2
.+-. 0.9 Compound 13 10.2 .+-. 0.5 Example 21 8.0 .+-. 1.8 Compound
87 2.1 .+-. 0.4 Compound 12 10.2 .+-. 4.2 Compound 508 4.4 .+-. 0.7
Compound 15 12.6 .+-. 6.4 Compound 511 9.5 .+-. 3.6 Compound 123
0.64 .+-. 0.14 Compound 407 16 .+-. 6.4 IC.sub.50 is the
concentration which inhibits 50% of the response.
* * * * *