# Patent

## Title
Nitrooxyderivatives of carvedilol and other beta blockers as antihypertensive

## Abstract

The present invention relates to β-adrenergic blockers nitrooxyderivatives of general formula (I):

A-(Y—ONO2)s 

and enantiomers and diastereoisomers and pharmaceutically acceptable salts thereof, pharmaceutical compositions containing them and their use for the treatment of hypertension, cardiovascular diseases, glaucoma, migraine headache and vascular diseases.

## Background
The present invention relates to β-adrenergic blockers derivatives. More particularly, the present invention relates to β-adrenergic blockers nitrooxyderivatives, pharmaceutical compositions containing them and their use for the treatment of hypertension, cardiovascular diseases, glaucoma, migraine headache, vascular diseases and elevated intraocular pressure.
β-adrenergic blockers (β-blockers) are widely used in the treatment of hypertension and cardiovascular diseases including angina pectoris, arrhythmias, acute myocardial infarction, hypertrophic cardiomyopathy, congestive heart failure.
They work to block the effects of catecholamines at receptor sites in the heart, but they differ somewhat in their ability to block receptors in the blood vessels and lungs. Selective β-blockers have their major actions on the heart, some others are weak stimulators of the β-receptor while still blocking the major actions of catecholamines, some block both the β1 and β2 receptors in the heart and those in the blood vessels and have no stimulatory activity and some block other cathecolamine receptors that can lead to further vascular effects on blood vessels.
Several side effects are associated with this class of drugs such as muscle fatigue, sleep disturbances, decreased heart rate, hypotension, cold extremities, bronchospasm in asthmatic patients, hypoglycemia, increased in plasma lipids.
Moreover, abrupt withdrawal after long-term treatment with β-blockers has to be avoided, because an increased sensitivity to β-adrenergic system develops
U.S. Pat. No. 6,242,432 discloses derivatives of formula A-(X1—NO2)to having an antithrombotic activity, wherein A is the residue of a β-adrenergic blocker, X1 is a bivalent connecting bridge and to is 1 or 2. The invention is limited to particular residues of β-adrenergic blockers.
U.S. Pat. No. 5,502,237 and U.S. Pat. No. 5,639,904 disclose derivatives of formula R1—Ar—O—CH2—CH(OH)—CH2—NH—CH(CH3)2 used for the treatment of cardiovascular affections, wherein R1 is a chain having at least one nitrooxy group as substituent.
U.S. Pat. No. 4,801,596 discloses aminopropanol derivatives of formula




that can be used for prophylaxis and/or treatment of heart and circulatory diseases, wherein R3 is an alkyl or a nitrooxyalkyl radical containing 3 to 8 carbon atoms.

It was an object of the present invention to provide new β-adrenergic blockers nitrooxyderivatives having a significantly improved overall pharmacological profile as compared to native β-blockers that are able not only to eliminate or at least reduce the side effects associated with their parent compounds, but also having an improved pharmacological activity and tolerability.
It has been so surprisingly found that the β-adrenergic blockers nitrooxyderivatives of the present invention have a better pharmacological activity and organ protection properties, enhanced effects as anti-inflammatory, and on renal functions. In addition, they are effective in other pathologies including atherosclerosis, diabetes, peripheral vascular diseases (PVD) and elevated intraocular pressure.
In particular, it has been recognized that the β-adrenergic blockers nitrooxyderivatives of the present invention, differently from the above mentioned compounds of the prior art, exhibit an improved activity on the cardiovascular system and enhanced tolerability and can be employed for treating or preventing hypertension, cardiovascular diseases, glaucoma, migraine headache, vascular diseases and elevated intraocular pressure.
Object of the present invention are β-adrenergic blockers nitrooxyderivatives of general formula (I):

A-(Y—ONO2)s 

and enantiomers and diastereoisomers and pharmaceutically acceptable salts thereof,
wherein s is an integer equal to 1 or 2;
A is selected from the following β-adrenergic blocker residues of formula (II):




wherein
R1 is selected from the group consisting of:







R2 is selected from the group consisting of: —CH(CH3)2, —C(CH3)3 or




when the radical R1 has chosen from the formulae (IIa), (IIc), (IId), (IIg), (IIh), (IIi), (IIm), R2 is —CH(CH3)2;
when the radical R1 has chosen from the formulae (IIe), (IIf) or (IIn), R2 is —C(CH3)3;
when R1 is the radical (IIb), R2 is (IIIa);
when R1 is the radical (IIL), R2 is (IIIb);
Z is H or is a group capable of binding Y selected from the group consisting of:




wherein R′ and R′′ are the same or different, and are H or straight or branched C1-C4 alkyl;
Z1 is H or a —C(O)— capable of binding Y;
with the proviso that when s of formula (I) is 1, Z or Z1 is H;
preferably when s of formula (I) is 2, Z and Z1 are —C(O)—;
Y is a bivalent radical having the following meanings:
a)
straight or branched C1-C20 alkylene, preferably C1-C10 alkylene, more preferably C3-C6 alkylene, being optionally substituted with one or more of the substituents selected from the group consisting of: halogen atoms, hydroxy, —ONO2 or T, wherein T is —OC(O)(C1-C10alkyl)-ONO2, —O(C1-C10alkyl)-ONO2;
b)
cycloalkylene with 5 to 7 carbon atoms into cycloalkylene ring, the ring being optionally substituted with side chains T1, wherein T1 is straight or branched alkyl with from 1 to 10 carbon atoms, T1 is preferably CH3;
c)




wherein:
n is an integer from 0 to 20, preferably n is an integer from 0 to 10, more preferably n is 0 or 1,
n1 is an integer from 1 to 20, preferably from 1 to 10, more preferably n1 is 1;
n2, n3, n4 and n5 are integers equal or different from one another, equal to 0 or 1;
R3 and R4 are independently selected from H or CH3;
Y1 is —CH2— or —(CH2)na—CH═CH— wherein na is an integer from 0 to 20, preferably na is equal to 0;
X1 is —WC(O)— or —C(O)W—, wherein W is oxygen, sulfur or NH, preferably W is oxygen;
d)




wherein:
n1 is an integer from 1 to 20, preferably from 1 to 10;
X1 is —WC(O)— or —C(O)W—, wherein W is oxygen, sulfur or NH, preferably W is sulfur or NH,
n6 is an integer from 1 to 20, preferably from 1 to 5, more preferably n6 is 1,
n7 is an integer from 0 to 20, preferably from 0 to 5, more preferably n7 is 1,
R5, R5′, R6 and R6′ are independently selected from the group consisting of: H, CH3, OH, NH2, NHCOCH3, COOH, CH2SH and C(CH3)2SH;
when the bond between the CA and CB carbons is a double bond R5 and R6 or R6′ and R5′ are absent;
with the proviso that when Y is selected from the bivalent radicals mentioned under c)-d), the —ONO2 group is linked to the —(CH2)n1— group;
e)




wherein X2 is O or S,
n10a, n10 and n12 are integer independently selected from 0 to 20,
n10a is preferably selected from 0 to 10, more preferably n10a is 0 or 1,
n10 and n12 are preferably selected from 1 to 10, more preferably n10 and n12 are 1 or 2
n11 is an integer from 0 to 6, preferably from 0 to 4, more preferably n11 is 0 or 1,
R11 is H, CH3 or nitrooxy group, preferably R11 is H or a nitrooxy group and
R11a is CH3 or nitrooxy group;
f)




wherein
n8 is an integer from 0 to 10;
n9 is an integer from 1 to 10;
R9, R10, R8, R7 are same or different, and are H or straight or branched C1-C4 alkyl, preferably R9, R10, R8, R7 are H;
wherein the —ONO2 group is linked to




wherein n9 is as defined above;
Y2 is an heterocyclic saturated, unsaturated or aromatic 5 or 6 members ring, containing one or more heteroatoms selected from nitrogen, oxygen, sulfur,
and is selected from the group consisting of




One embodiment provides compounds of formula (I) wherein:
s is 2,
A is selected from the following β-adrenergic blocker residues of formula (II):




wherein
R1 is selected from the group consisting of:







R2 is selected from the group consisting of: —CH(CH3)2, —C(CH3)3 or




when the radical R1 has chosen from the formulae (IIa), (IIc), (IId), (IIg), (IIh), (IIi), (IIm), R2 is —CH(CH3)2;
when the radical R1 has chosen from the formulae (IIe), (IIf) or (IIn), R2 is —C(CH3)3;
when R1 is the radical (IIb), R2 is (IIIa);
when R1 is the radical (IIL), R2 is (IIIb);
Z is a group capable of binding Y selected from the group consisting of:
—C(O)—, —C(O)O— or




wherein R′ and R′′ are the same or different, and are H or straight or branched C1-C4 alkyl;
Z1 is H or a —C(O)— capable of binding Y, preferably Z and Z1 are —C(O)—;
Y is a bivalent radical having the following meaning:
a)
straight or branched C1-C20 alkylene, preferably C1-C10 alkylene, more preferably C3-C6 alkylene, being optionally substituted with one or more of the substituents selected from the group consisting of: halogen atoms, hydroxy, —ONO2 or T, wherein T is —OC(O)(C1-C10alkyl)-ONO2, —O(C1-C10alkyl)-ONO2;
b)
cycloalkylene with 5 to 7 carbon atoms into cycloalkylene ring, the ring being optionally substituted with side chains T1, wherein T1 is straight or branched alkyl with from 1 to 10 carbon atoms, T1 is preferably CH3;
c)




wherein:
n is an integer from 0 to 20, preferably n is an integer from 0 to 10, more preferably n is 0 or 1,
n1 is an integer from 1 to 20, preferably from 1 to 10, more preferably n1 is 1;
n2, n3, n4 and n5 are integers equal or different from one another, equal to 0 or 1;
R3 and R4 are independently selected from H or CH3;
Y1 is —CH2— or —(CH2)na—CH═CH— wherein na is an integer from 0 to 20, preferably na is equal to 0;
X1 is —WC(O)— or —C(O)W—, wherein W is oxygen, sulfur or NH, preferably W is oxygen;
d)




wherein:
n1 is an integer from 1 to 20, preferably from 1 to 10;
X1 is —WC(O)— or —C(O)W—, wherein W is oxygen, sulfur or NH, preferably W is sulfur or NH;
n6 is an integer from 1 to 20, preferably from 1 to 5, more preferably n6 is 1,
n7 is an integer from 0 to 20, preferably from 0 to 5, more preferably n7 is 1,
R5 and R5′ R6 and R6′ are independently selected from the group consisting of: H, CH3, OH, NH2, NHCOCH3, COOH, CH2SH and C(CH3)2SH;
when the bond between the CA and CB carbons is a double bond R5 and R6 or R6′ and R5′ are absent;
with the proviso that when Y is selected from the bivalent radicals mentioned under c)-d), the —ONO2 group is linked to the —(CH2)n1— group;
e)




wherein X2 is O or S,
n10a, n10 and n12 are integer independently selected from 0 to 20,
n10a is preferably selected from 0 to 10, more preferably n10a is 0 or 1;
n10 and n12 are preferably selected from 1 to 10, more preferably n10 and n12 are 1 or 2;
n11 is an integer from 0 to 6, preferably from 0 to 4, more preferably n11 is 0 or 1;
R11 is H, CH3 or nitrooxy group, preferably R11 is H or nitroxy;
R11a is CH3 or nitrooxy group;
f)




wherein
n8 is an integer from 0 to 10;
n9 is an integer from 1 to 10;
R9, R10, R8, R7 are same or different, and are H or straight or branched C1-C4 alkyl, preferably R9, R10, R8, R7 are H;
wherein the —ONO2 group is linked to




wherein n9 is as defined above;
Y2 is an heterocyclic saturated, unsaturated or aromatic 5 or 6 members ring, containing one or more heteroatoms selected from nitrogen, oxygen, sulfur,
and is selected from the group consisting of




Another embodiment provides compounds of formula (I) wherein:
s is 1,
A is selected from the following β-adrenergic blocker residues of formula (II):




wherein
R1 is selected from the group consisting of:







R2 is selected from the group consisting of: —CH(CH3)2, —C(CH3)3 or




when the radical R1 has chosen from the formulae (IIa), (IIc), (IId), (IIg), (IIh), (IIi), (IIm), R2 is —CH(CH3)2;
when the radical R1 has chosen from the formulae (IIe), (IIf) or (IIn), R2 is —C(CH3)3;
when R1 is the radical (IIb), R2 is (IIIa);
when R1 is the radical (IIL), R2 is (IIIb);
Z is H and Z1 a —C(O)— capable of binding Y;
Y is a bivalent radical having the following meaning:
a)
straight or branched C1-C20 alkylene, preferably C1-C10 alkylene, more preferably C3-C6 alkylene, being optionally substituted with one or more of the substituents selected from the group consisting of: halogen atoms, hydroxy, —ONO2 or T, wherein T is —OC(O)(C1-C10alkyl)-ONO2, —O(C1-C10alkyl)-ONO2;
b)
cycloalkylene with 5 to 7 carbon atoms into cycloalkylene ring, the ring being optionally substituted with side chains T1, wherein T1 is straight or branched alkyl with from 1 to 10 carbon atoms, T1 is preferably CH3;
c)




wherein:
n is an integer from 0 to 20, preferably n is an integer from 0 to 10, more preferably n is 0 or 1, and n1 is an integer from 1 to 20, preferably from 1 to 10, more preferably n1 is 1;
n2, n3, n4 and n5 are integers equal or different from one another, equal to 0 or 1;
R3 and R4 are independently selected from H or CH3;
Y1 is —CH2— or —(CH2)na—CH═CH— wherein na is an integer from 0 to 20, preferably na is equal to 0;
X1 is —WC(O)— or —C(O)W—, wherein W is oxygen, sulfur or NH, preferably W is oxygen;
d)




wherein:
n1 is an integer from 1 to 20, preferably from 1 to 10;
X1 is —WC(O)— or —C(O)W—, wherein W is oxygen, sulfur or NH, preferably W is sulfur or NH;
n6 is an integer from 1 to 20, preferably from 1 to 5, more preferably n6 is 1,
n7 is an integer from 0 to 20, preferably from 0 to 5, more preferably n7 is 1,
R5 and R5′ R6 and R6′ are independently selected from the group consisting of: H, CH3, OH, NH2, NHCOCH3, COOH, CH2SH and C(CH3)2SH;
when the bond between the CA and CB carbons is a double bond R5 and R6 or R6′ and R5′ are absent;
with the proviso that when Y is selected from the bivalent radicals mentioned under c)-d), the —ONO2 group is linked to a —(CH2)n1— group;
e)




wherein X2 is O or S,
n10a, n10 and n12 are integer independently selected from 0 to 20,
n10a is preferably selected from 0 to 10, more preferably n10a is 0 or 1;
n10 and n12 are preferably selected from 1 to 10, more preferably n10 and n12 are 1 or 2;
n11 is an integer from 0 to 6, preferably from 0 to 4, more preferably n11 is 0 or 1;
R11 is H, CH3 or nitrooxy group, preferably R11 is H or nitroxy;
R11a is CH3 or nitrooxy group;
f)




wherein
n8 is an integer from 0 to 10;
n9 is an integer from 1 to 10;
R9, R10, R8, R7 are same or different, and are H or straight or branched C1-C4 alkyl, preferably R9, R10, R8, R7 are H;
wherein the —ONO2 group is linked to




wherein n9 is as defined above;
Y2 is an heterocyclic saturated, unsaturated or aromatic 5 or 6 members ring, containing one or more heteroatoms selected from nitrogen, oxygen, sulfur,
and is selected from the group consisting of




Another embodiment provides compounds of formula (I) wherein
s is 1,
A is selected from the following β-adrenergic blocker residues of formula (II):




wherein
R1 is selected from the group consisting of:







R2 is selected from the group consisting of: —CH(CH3)2, —C(CH3)3 or




when the radical R1 has chosen from the formulae (IIa), (IIc), (IId), (IIg), (IIh), (IIi), (IIm), R2 is —CH(CH3)2;
when the radical R1 has chosen from the formulae (IIe), (IIf) or (IIn), R2 is —C(CH3)3;
when R1 is the radical (IIL), R2 is (IIIb);
Z1 is H;
Z is a group capable of binding Y selected from the group consisting of:
—C(O)—, —C(O)O— or




wherein R′ and R′′ are the same or different, and are H or straight or branched C1-C4 alkyl;
Y is a bivalent radical having the following meaning:
c)




wherein:
n is an integer from 0 to 20, preferably n is an integer from 0 to 10, more preferably n is 0 or 1,
n1 is an integer from 1 to 20, preferably from 1 to 10, more preferably n1 is 1;
n2, n3, n4 and n5 are integers equal or different from one another, equal to 0 or 1;
R3 and R4 are independently selected from H or CH3;
Y1 is —CH2— or —(CH2)na—CH═CH— wherein na is an integer from 0 to 20, preferably na is equal to 0;
X1 is —WC(O)— or —C(O)W—, wherein W is oxygen, sulfur or NH, preferably W is oxygen;
e)




wherein
X2 is O or S,
n10a is 0 or 1,
n11 is 0 or 1,
n10 and n12 are or 2;
R11 is H, CH3 or nitrooxy group;
R11a is CH3 or nitrooxy group;
f)




wherein
n8 is an integer from 0 to 10;
n9 is an integer from 1 to 10;
R9, R10, R8, R7 are same or different, and are H or straight or branched C1-C4 alkyl, preferably R9, R10, R8, R7 are H;
wherein the —ONO2 group is linked to




wherein n9 is as defined above;
Y2 is an heterocyclic saturated, unsaturated or aromatic 5 or 6 members ring, containing one or more heteroatoms selected from nitrogen, oxygen, sulfur,
and is selected from the group consisting of







Another embodiment provides compounds of formula (I) wherein
s is an integer equal to 1 or 2
A is the β-adrenergic blocker residue of formula (II):




wherein
R1 is (IIb)




R2 is (IIa)




Z is H or is a group capable of binding Y selected from the group consisting of:




wherein R′ and R′′ are the same or different, and are H or straight or branched C1-C4 alkyl;
Z1 is H or a —C(O)— capable of binding Y;
with the proviso that when s of formula (I) is 1, Z or Z1 is H;
preferably when s of formula (I) is 2, Z and Z1 are —C(O)—;
Y is a bivalent radical having the following meaning:
a)
straight or branched C1-C20 alkylene, preferably; C1-C10 alkylene, more preferably C3-C6 alkylene, being optionally substituted with one or more of the substituents selected from the group consisting of: halogen atoms, hydroxy, —ONO2 or T, wherein T is —OC(O)(C1-C10alkyl)-ONO2, —O(C1-C10alkyl)-ONO2;
b)
cycloalkylene with 5 to 7 carbon atoms into cycloalkylene ring, the ring being optionally substituted with side chains T1, wherein T1 is straight or branched alkyl with from 1 to 10 carbon atoms, T1 is preferably CH3;
c)




wherein:
n is an integer from 0 to 20, preferably n is an integer from 0 to 10, more preferably n is 0 or 1,
n1 is an integer from 1 to 20, preferably from 1 to 10, more preferably n1 is 1,
n2, n3, n4 and n5 are integers equal or different from one another, equal to 0 or 1,
R3 and R4 are independently selected from H or CH3;
Y1 is —CH2— or —(CH2)na—CH═CH— wherein na is an integer from 0 to 20, preferably na is equal to 0;
X1 is —WC(O)— or —C(O)W—, wherein W is oxygen, sulfur or NH, preferably W is oxygen;
d)




wherein:
n1 is an integer from 1 to 20, preferably from 1 to 10;
X1 is —WC(O)— or —C(O)W—, wherein W is oxygen, sulfur or NH, preferably W is sulfur or NH;
n6 is an integer from 1 to 20, preferably from 1 to 5, more preferably n6 is 1,
n7 is an integer from 0 to 20, preferably from 0 to 5, more-preferably n7 is 1,
R5 and R5′ R6 and R6 are independently selected from the group consisting of: H, CH3, OH, NH2, NHCOCH3, COOH, CH2SH and C(CH3)2SH;
when the bond between the CA and CB carbons is a double bond R5 and R6 or R6′ and R5′ are absent;
with the proviso that when Y is selected from the bivalent radicals mentioned under c)-d), the —ONO2 group is linked to a —(CH2)n1— group;
e)




wherein X2 is O or S, n10a, n10 and n12 are integer independently selected from 0 to 20,
n10a is preferably selected from 0 to 10, more preferably n10a is 0 or 1;
n10 and n12 are preferably selected from 1 to 10, more preferably n10 and n12 are 1 or 2,
n11 is an integer from 0 to 6, preferably from 0 to 4, more preferably n11 is 0 or 1;
R11 is H, CH3 or nitrooxy group, preferably R11 is H or a nitrooxy group,
R11a is CH3 or nitrooxy group;
f)




wherein
n8 is an integer from 0 to 10;
n9 is an integer from 1 to 10;
R9, R10, R8, R7 are same or different, and are H or straight or branched C1-C4 alkyl, preferably R9, R10, R8, R7 are H;
wherein the —ONO2 group is linked to




wherein n9 is as defined above;
Y2 is an heterocyclic saturated, unsaturated or aromatic 5 or 6 members ring, containing one or more heteroatoms selected from nitrogen, oxygen, sulfur,
and is selected from the group consisting of




Preferred compounds are those of formula (I) wherein:
s is 2,
A is a β-adrenergic blocker residues of formula (II) as above defined
Z and Z1 are —(CO)—
Y is a bivalent radical having the following meanings:
a) straight C1-C10 alkylene, preferably C3-C6 alkylene;
c)




wherein the —ONO2 group is bound to (CH2)n1;
n, n2, n3, n4, n5 are equal to 0, n1 is 1 and the —(CH2)n1— group is bound to the phenyl ring through the [C]2 or [C]3 or [C]4;
or n, n2, n5 are 1, n3 and n4 are equal to 0, and
n1 is an integer from 1 to 10,
Y1 is —(CH2)na—CH═CH— wherein na is 0, X1 is —WC(O)— wherein W is oxygen and the WC(O) group is bound to the phenyl ring through the [C]4, R4 is CH3 and the (OR4) group is bound to the phenyl ring through the [C]3;
d)




wherein
n1 is an integer from 1 to 10,
n6 and n7 are 1,
X1 is —WC(O)— wherein W is sulfur,
R5, R5′ and R6′ are H, R6 is NHCOCH3 and
the —ONO2 is bound to the —(CH2)n1— group;
e)




wherein
X2 is O or S, and n11 is 0,
n10a is an integer from 0 to 10,
n12 is an integer from 1 to 10,
R11 is H or a nitrooxy group
and the —ONO2 group is bound to (CH2)n12;
Another group of preferred compounds comprises compounds of formula (I)
wherein
s is 1,
A is a β-adrenergic blocker residues of formula (II) as above defined,
Z is H,
Z1 is —(CO)—
Y is a bivalent radical having the following meanings:
a) straight C1-C10 alkylene, preferably C3-C6 alkylene;
c)




wherein the —ONO2 group is bound to (CH2)n1;
n, n2, n3, n4, n5 are equal to 0, n1 is 1 and the —(CH2)n1— group is bound to the phenyl ring through the [C]2 or [C]3 or [C]4;
or n, n2, n5 are 1, n3 and n4 are equal to 0, and n1 is an integer from 1 to 10, Y1 is —(CH2)na—CH═CH— wherein na is 0, X1 is —WC(O)— wherein W is oxygen and the WC(O) group is bound to the phenyl ring through the [C]4, R4 is CH3 and the (OR4) group is bound to the phenyl ring through the [C]3;
d)




wherein
n1 is an integer from 1 to 10;
X1 is —WC(O)— wherein W is sulfur;
n6 is 1
n7 is 1,
R5, R5′ and R6′ are H, R6 is, NHCOCH3 and
the —ONO2 is bound to the —(CH2)n1— group;
e)




wherein
X2 is O or S, and n11 is 0,
n10a is an integer from 0 to 10,
n12 is an integer from 1 to 10,
R11 is H or a nitrooxy group
and the —ONO2 group is bound to (CH2)n12;
Another group of preferred compounds comprises compounds of formula (I)
wherein
s is 1,
A is a β-adrenergic blocker residues of formula (II) as above defined,
Z1 is H,
Z is —(CO)— or —C(O)O— and
Y is a bivalent radical having the following meanings:
c)




wherein the —ONO2 group is bound to (CH2)n1;
n, n2, n3, n4, n5 are equal to 0,
n1 is 1 and the —(CH2)n1— group is bound to the phenyl ring through the [C]2 or [C]3 or [C]4;
or in formula (IV)
n, n2, n5 are 1,
n3 and n4 are equal to 0,
n1 is an integer from 1 to 10,
Y1 is —(CH2)na—CH═CH— wherein na is 0, X1 is —WC(O)— wherein W is oxygen and the WC(O) group is bound to the phenyl ring through the [C]4, R4 is CH3 and the (OR4) group is bound to the phenyl ring through the [C]3;
Another groups of preferred compounds comprises compounds of formula (I) wherein:
s is 1,
A is the β-adrenergic blocker residues of formula (II) wherein
R1 is




R2 is




Z1 is H and Z is —(CO)— or —C(O)O— and
Y is a bivalent radical having the following meanings:
a) straight C1-C10 alkylene, preferably C3-C6 alkylene;
c)




wherein the —ONO2 group is bound to (CH2)n1;
n, n2, n3, n4, n5 are equal to 0, n1 is 1 and the —(CH2)n1— group is bound to the phenyl ring through the [C]2 or [C]3 or [C]4;
or in formula (IV)
n, n2, n5 are 1, n3 and n4 are equal to 0,
n1 is an integer from 1 to 10,
Y1 is —(CH2)na—CH═CH— wherein na is 0,
X1 is —WC(O)— wherein W is oxygen and the WC(O) group is bound to the phenyl ring through the [C]4, R4 is CH3 and the (OR4) group is bound to the phenyl ring through the [C]3;
d)




wherein
n1 is an integer from 1 to 10,
n6 and n7 are 1,
X1 is —WC(O)— wherein W is sulfur,
R5, R5′ and R6′ are H, R6 is NHCOCH3 and
the —ONO2 is bound to the —(CH2)n1— group;
e)




wherein
X2 is O or S, and n11 is 0,
n10a is an integer from 0 to 10,
n12 is an integer from 1 to 10,
R11 is H or a nitrooxy group
and the —ONO2 group is bound to (CH2)n12.
Most preferred compounds of formula (I) according to the present invention are the following:























































Examples of “straight or branched C1-C20 alkylene” include, but are not limited to, methylene, ethylene, propylene, isopropylene, n-butylene, pentylene, n-hexylene and the like.
As stated above, the invention includes also the pharmaceutically acceptable salts of the compounds of formula (I) and stereoisomers thereof.
Examples of pharmaceutically acceptable salts are either those with inorganic bases, such as sodium, potassium, calcium and aluminium hydroxides, or with organic bases, such as lysine, arginine, triethylamine, dibenzylamine, piperidine and other acceptable organic amines.
The compounds according to the present invention, when they contain in the molecule one salifiable nitrogen atom, can be transformed into the corresponding salts by reaction in an organic solvent such as acetonitrile, tetrahydrofuran with the corresponding organic or inorganic acids.
Examples of pharmaceutical acceptable organic acids are: oxalic, tartaric, maleic, succinic, citric acids. Examples of pharmaceutical acceptable inorganic acids are: nitric, hydrochloric, sulphuric, phosphoric acids. Salts with nitric acid are preferred.
The compounds of the invention which have one or more asymmetric carbon atoms can exist as optically pure enantiomers, pure diastereomers, enantiomers mixtures, diastereomers mixtures, enantiomer racemic mixtures, racemates or racemate mixtures. Within the object of the invention are also all the possible isomers, stereoisomers and their mixtures of the compounds of formula (I).
The compounds and compositions of the present invention can be administered by any available and effective delivery system including but not limited to, orally, bucally, parenterally, by inhalation spray, by topical application, by injection, transdermally, or rectally (e.g. by the use of suppositories) in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles. Parenteral includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion technique.
Solid dosage forms for oral administration can include for example capsule, tablets, pills, powders, granules and gel. In such solid dosage forms, the active compounds can be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage form can also comprise, as normal practice, additional substance other than inert diluent, e.g., lubricating agent such as magnesium stearate.
Injectable preparations, for example sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing agents, wetting agents and/or suspending agents.
The composition of this invention can further include conventional excipients, i.e., pharmaceutical acceptable organic or inorganic substances which do not deleteriously react with the active compounds.
The doses of β-adrenergic blockers nitrooxyderivatives can be determinated by standard clinique technique and are in the same ranges or less than as described for commercially available compounds as reported in the: Physician's Desk Reference, Medical Economics Company, Inc., Oradell, N. J., 58th Ed., 2004; The pharmacological basis of therapeutics, Goodman and Gilman, J. G. Hardman, L. e. Limbird, 20th Ed.
EXPERIMENTAL
Synthesis Procedure
Compounds of the invention can be synthesized as shown in Schemes 1 to 6. Compounds of general formula (I) A-(Y—ONO2)s, defined in Scheme 1-3 as compounds of formula D, wherein s is 1, Y is as above defined and A is a 0-adrenergic blocker residue of formula (II), wherein Z is —C(O)— and Z1 is H, the enantiomers, diastereoisomer and a pharmaceutically acceptable salt thereof, can be prepared as outlined in Schemes 1-3.




Compounds of formula (i) wherein R1, R2, Z and Y are as above defined, P1 is an amine protecting group such as tert-butyloxycarbonyl ester (t-Boc) and X3 is an halogen atom preferably Cl, Br and I, are converted to compounds of formula (L) wherein R1, R2, P1, Z and Y are as above defined, by reaction with AgNO3 in a suitable organic solvent such as acetonitrile, tetrahydrofurane, a silver nitrate molar excess is preferably used and the reaction is carried out, in the dark, at a temperature from room temperature to the boiling temperature of the solvent. The compounds of formula (L) are converted to the compounds of formula (D) by deprotecting the amine group (strong acid, such as HCl in dioxane or trifluoroacetic acid, is used to remove a t-butyl carbamate). Other preferred methods for removing the amine protecting groups are those described in T. W. Greene “Protective groups in organic synthesis”, Harvard University Press, 1980.
The compounds of formula (H) wherein R1, R2, Z, P1 and Y are as above defined, are converted to the esters of formula (i) wherein R1, R2, Y, Z, X3 and P1 are as above defined, by reaction with an appropriate acid (Q1) of formula X3—Y—COOH wherein Y and X3 are as above defined. The reaction is generally carried out in an inert organic solvent such as N,N′-dimethylformamide, tetrahydrofuran, benzene, toluene, dioxane, a polyhalogenated aliphatic hydrocarbon at a temperature from 0° C. to 50° C. in presence of a dehydrating agent such as dycyclohexylcarbodiimide DCC or 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDAC HCl) with a catalyst, such as 4-N,N-dimethylaminopyridine (DMAP).
The compounds of formula (H) wherein R1, R2 and P1 are as above defined, can be obtained by deprotecting the hydroxylic group of the compounds of formula (G) wherein R1, R2 are as above defined and P is a hydroxylic protecting group such as silyl ethers, such as trimethylsilyl or tert-butyl-dimethylsilyl and those described in T. W. Greene “Protective groups in organic synthesis”, Harvard University Press, 1980. Fluoride ion is the preferred method for removing silyl ether protecting group.
The compounds of formula (G) wherein R1, R2, P and P1 are as above defined, can be obtained by reacting the compounds of formula (F) wherein R1, R2 and P are as above defined with a suitable amine protecting group (P1) as above described.
The alcohol group of the compounds of formula (A) wherein R1, R2 are as above defined, is protected to afford the compounds of formula (F) wherein R1, R2 are as above defined Preferred protecting group for the alcohol moiety are silyl ethers, such as trimethylsilyl or tert-butyl-dimethylsilyl.
The compounds (A) wherein R1, R2 are as above defined are commercially available, the acids of formula X3—Y—COOH wherein X3 is as above defined, are commercially available.




Compounds of formula (B) wherein R1, R2, Z, Y are as above defined and X3 is an halogen atom, such as Cl, Br and 1, are converted to compounds of formula (D) wherein R1, R2, Z and Y are as above defined, by reaction with AgNO3 in a suitable organic solvent such as acetonitrile, tetrahydrofurane, a silver nitrate molar excess is preferably used and the reaction is carried out, in the dark, at a temperature from room temperature and the boiling temperature of the solvent.
The compounds of formula (B) wherein R1, R2, Z, Y and X3 are as above defined can be obtained by reaction of the compounds of formula (A) with an appropriate acyl chloride (Q) of formula X3—Y—C(O)Cl, wherein X3 is chosen among chlorine, bromine, and Y is as above defined. The esterification is carried out in an inert organic solvent such as N,N′-dimethylformamide, tetrahydrofuran, benzene, toluene, chloroform in presence of a base as triethylamine, pyridine at a temperature from room temperature and 50° C. The reaction is completed within a time range from 30 minutes to 24 hours.
Alternatively the compounds of formula (B) can be obtained by reaction of compounds of formula (A) with an acid (Q1) of formula X3—Y—C(O)OH in the presence of a dehydrating agent as dicyclohexylcarbodiimide (DCC) or N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (EDAC) and a catalyst, such as N,N-dimethylamino pyridine. The reaction is carried out in an inert organic solvent such as as N,N′-dimethylformamide, tetrahydrofuran, benzene, toluene, dioxane, a polyhalogenated aliphatic hydrocarbon at a temperature from 0° C. and 50° C. The reaction is completed within a time range from 30 minutes to 36 hours.
The compounds of formula (Q1), where X3 is an halogen atom are commercially available or can be obtained from the corresponding commercially available hydroxy acid by well known reactions, for example by reaction with thionyl or oxalyl chloride, halides of PIII or PV in solvents inert such as toluene, chloroform, DMF, etc.
The compounds (A) wherein R1, R2 are as above defined are commercially available




Alternatively the compounds of formula (D) can be obtained as described below. The compounds of formula are converted to the compounds (D) by reaction of hydroxy group with a nitrooxy derivative, containing activated acylating group, of formula Cl(O)C—Y—ONO2.
The nitrooxy compounds can be obtained from the corresponding alcohols of formula Cl(O)C—Y—OH by reaction with nitric acid and acetic anhydride in a temperature range from −50° C. to 0° C. or from the corresponding halogen derivatives of formula Cl(O)C—Y-Hal by reaction with silver nitrate in the presence of an inert solvent such as acetonitrile, tetrahydrofurane. A silver nitrate molar excess is preferably used and the reaction is carried out, in the dark, a temperature from the boiling temperature and room temperature. The reaction is completed within a time range from 30 minutes to 3 days.
The compounds of general formula (I) A-(Y—ONO2)s, defined in Scheme 4 as compounds of formula (D1), wherein s is 1, Y is as above defined and A is a β-adrenergic blocker residue of formula (II), wherein Z is —C(O)O— and Z1 is H, the enantiomers, diastereoisomer and a pharmaceutically acceptable salt thereof, can be prepared as outlined in Scheme 4.




The compounds of formula (B1) wherein R1, R2, Y are as above defined and X3 is an halogen atom, such as Cl, Br and I, are converted to compounds of formula (D1) wherein R1, R2, and Y are as above defined, by reaction with AgNO3 in a suitable organic solvent such as acetonitrile, tetrahydrofurane, a silver nitrate molar excess is preferably used and the reaction is carried out, in the dark, at a temperature from room temperature and the boiling temperature of the solvent.
The compounds of formula (A) wherein R1 and R2 are as above defined are converted to the compounds (B1) by reaction with an appropriate compound (Q2) having formula X3—Y—OC(O)Cl wherein X3 is Cl, Br or I, and Y is as defined above. The reaction is generally carried out in presence of a base in an aprotic polar or non-polar solvent such as THF or CH2Cl2 at temperature range between 0°-65° C. or in a double phase system H2O/Et2O at temperature range between 20°-40° C.
The compounds of formula (Q2) are commercially available or can be obtained from the corresponding alcohols by reaction with triphosgene in presence of an organic base.
The compounds of general formula (I) A-(Y—ONO2)s, defined in Scheme 5 as compounds of formula (D), wherein s is 1, Y is as above defined and A is a β-adrenergic blocker residue of formula (II), wherein Z is




wherein R′ and R′′ are H or straight or branched C1-C4 alkyl and Z1 is H, the enantiomers, diastereoisomer and a pharmaceutically acceptable salts thereof, may be prepared as outlined in Scheme 5:





The compounds of formula (i) wherein R1, R2, Z and Y are as above defined, P1 is an amine protecting group such as tert-butyloxycarbonyl ester (t-Boc) and X3 is an halogen atom such as Cl, Br and I, are converted to compounds of formula (L) wherein R1, R2, P1, Z and Y are as above defined, by reaction with AgNO3 in a suitable organic solvent such as acetonitrile, tetrahydrofurane, a silver nitrate molar excess is preferably used and the reaction is carried out, in the dark, at a temperature from room temperature and the boiling temperature of the solvent. The compounds of formula (L) are converted to the compounds of formula (D) by deprotecting the amine group (strong acid, such as HCl in dioxane or trifluoroacetic acid, is used to remove a t-butyl carbamate). Other preferred methods for removing the amine protecting groups are those described in T. W. Greene “Protective groups in organic synthesis”, Harvard University Press, 1980.
The compounds of formula (i) wherein R1, R2, Y, X3, Z and P1 are as above defined, can be obtained by reacting the compounds of formula (M) wherein R1, R2, P1, R′, R′′ and X3 are as above defined, with an acid (Q1) of formula X3—Y—COOH wherein X3 is an halogen atom and Y is as above defined. The reaction is carried out in an inert organic solvent such as N,N′-dimethylformamide, tetrahydrofuran, benzene, toluene, dioxane, a polyhalogenated aliphatic hydrocarbon at a temperature range from 0° C. and 50° C. in the presence of a dehydrating agent such as dycyclohexylcarbodiimide DCC or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDAC HCl) with a catalyst, such as 4-N,N-dimethylaminopyridine (DMAP).
The reaction is complete within a time ranges from 30 minutes to 24 hours.
The compounds of formula (M) wherein R1, R2, P1, R′, R′′ and X3 are as above defined, can be obtained by reacting the compounds the of formula (H) with a compound (S) of formula X3—C(R′)(R′′)—OC(O)X3 wherein X3 is an halogen atom. The reaction is carried out in presence of an organic or inorganic base in a polar solvent as DMF, THF, acetonitrile at a temperature in the range from −5° C. to 60° C. or in a double phase system according to methods well known in the literature.
The amine group of the compounds (A) is protected to afford the compounds of formula (H) wherein P1 is a suitable amine protecting group such as tert-butyloxycarbonyl ester (t-Boc) The compounds (S) are commercially available.
The compounds of general formula (I) A-(Y—ONO2)s, defined in Scheme 6 as compounds of formula (E), wherein s is 2, Y is as above defined and A is a β-adrenergic blocker residue of formula (II), wherein Z1 and Z are —C(O)—, the enantiomers, diastereoisomer and a pharmaceutically acceptable salt thereof, can be synthesized as shown in Scheme 6.




Compounds of formula (C) wherein R1, R2, Z, Z1 and Y are as above defined and X3 is an halogen atom, such as Cl, Br and I, are converted to compounds of formula (E) wherein R1, R2, Z and Y are as above defined, by reaction with AgNO3 in a suitable organic solvent such as acetonitrile, tetrahydrofurane, a silver nitrate molar excess is preferably used and the reaction is carried out, in the dark, at a temperature from room temperature and the boiling temperature of the solvent.
The compounds of formula (C) wherein R1, R2, Z, Z1, Y and X3 are as above defined can be obtained by reaction of the compounds of formula (A) with an appropriate acyl halide (Q) of formula X3—Y—C(O)Cl, wherein X3 is chosen among chlorine, bromine, and Y is as above defined. The reaction is carried out in an inert organic solvent such as N,N′-dimethylformamide, tetrahydrofuran, benzene, toluene, chloroform in presence of a base as triethylamine, pyridine at a temperature from room temperature and 50° C. The reaction is completed within a time range from 30 minutes to 24 hours.
Alternatively the compounds of formula (C) can be obtained by reaction of the compounds of formula (A) with an acid (Q1) of formula X3—Y—COOH in the presence of a dehydrating agent such as dicyclohexylcarbodiimide (DCC) or N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (EDAC) and a catalytic amount of N,N-dimethylamino pyridine. The reaction is carried out in an inert organic solvent such as N,N′-dimethylformamide, tetrahydrofuran, benzene, toluene, dioxane, a polyhalogenated aliphatic hydrocarbon at a temperature from 0° C. and 50° C. The reaction is completed within a time range from 30 minutes to 36 hours.
The compounds of formula (Q1), where X3 is an halogen atom are commercially available or can be obtained from the corresponding commercially available hydroxy acid by well known reactions, for example by reaction with thionyl or oxalyl chloride, halides of PIII or PV in solvents inert such as toluene, chloroform, DMF, etc.
The compounds (A) wherein R1, R2 are as above defined are commercially available.
The compounds of formula (E) can also be obtained as described below. The compounds of formula A are converted to the compounds (E) by reaction with a nitrooxy derivative of formula Cl(O)C—Y—ONO2 containing an activated acylating group.
The nitrooxycompounds can be obtained from the corresponding alcohols of formula Cl(O)C—Y—OH by reaction with nitric acid and acetic anhydride in a temperature range from −50° C. to 0° C. or from the corresponding halogen derivatives of formula Cl(O)C—Y-Hal by reaction with silver nitrate in the presence of an inert solvent such as acetonitrile, tetrahydrofurane. A silver nitrate molar excess is preferably used and the reaction is carried out, in the dark, a temperature from the boiling temperature and room temperature. The reaction is completed within a time range from 30 minutes to 3 days.


EXAMPLES
The following non-limiting examples further describe and enable one of ordinary skilled in the art to make and use the present invention.
Example 1
4-(Nitrooxymethyl)benzoic acid 1-(9H-carbazol-4-yloxy)-3-[[2-(2-methoxyphenoxy)ethyl]amino]-2-propanoate of formula (8)




1a. 4-(Chloromethyl)benzoic acid 1-(9H-carbazol-4-yloxy)-3-[[2-(2-methoxyphenoxy)ethyl]amino]-2-propanoate
To a solution of carvedilol (2 g, 5 mmol) in chloroform (50 ml) 4-chloromethyl benzoic acid (0.9 g, 5.5 mmol), EDAC (1.15 g, 6 mmol) and N,N-dimethylaminopyridine (catalytic amount) were added. The reaction was stirred at room temperature for 24 hours. The solution was treated with water and the organic layer was dried over sodium sulphate. The solvent was evaporated and the residue was purified by flash chromatography eluting with n-hexane/ethyl acetate 6/4 (Rf=0.2). The title product 0.27 g was obtained as a white powder.
1b. 4-(Nitrooxymethyl)benzoic acid 1-(9H-carbazol-4-yloxy)-3-[[2-(2-methoxyphenoxy)ethyl]amino]-2-propanoate
A solution of the product of Example 1a (0.27 g, 0.48 mmol) and silver nitrate (0.16 g, 0.96 mmol) in acetonitrile (30 ml) was stirred at 60° C., in the dark, for 36 hours. The precipitated (silver salts) was filtered off and the solvent was evaporated under vacuum. The residue was treated with chloroform and water. The organic layer was dried over sodium sulphate. The solvent was evaporated and the residue was purified by flash chromatography eluting with ethyl acetate/n-hexane 6/4. The title product 0.03 g was obtained as a white powder.
1H-NMR (DMSO) δ (ppm): 11.31 (1H,s); 8.15 (2H,m); 7.8-7.5 (2H,m); 7.43 (1H,d); 7.30 (2H,m); 7.15-6.85 (7H,m); 6.77 (1Hd); 6.03 (1H,m); 5.65 (2H,s); 4.55 (2H,m); 4.33 (2H,m); 4.0-3.7 (5H,m); 3.51 (2H,m).
Example 2
4-(Nitrooxymethyl)benzoic acid 1-(9H-carbazol-4-yloxy)-3-[[2-(2-methoxyphenoxy)ethyl][(4-nitrooxymethyl)benzoyl]amino]-2-propanoate of formula (11)




2a. 4-(Chloromethyl)benzoic acid 1-(9H-carbazol-4-yloxy)-3-[[2-(2-methoxyphenoxy)ethyl][(4-chloromethyl)benzoyl]amino]-2-propanoate
To a solution of carvedilol (2 g, 5 mmol) in chloroform (50 ml) 4-chloromethyl benzoic acid (0.9 g, 5.5 mmol), EDAC (1.15 g, 6 mmol) and N,N-dimethylaminopyridine (catalytic amount) were added. The reaction was stirred for 24 hours at room temperature. The solution was treated with water and the organic layer was dried over sodium sulfate and filtered. The solvent was evaporated and the residue was purified by flash chromatography eluting with n-hexane/ethyl acetate 1/1 (Rf=0.42). The title product (0.06 g) was obtained as a white powder.
2b. 4-(Nitrooxymethyl)benzoic acid 1-(9H-carbazol-4-yloxy)-3-[[2-(2-methoxyphenoxy)ethyl][(4-nitrooxymethyl)benzoyl]amino]-2-propanoate
A solution of the product of example 2a (0.06 g, 0.08 mmol) and silver nitrate (0.06 g, 0.32 mmol) in acetonitrile (20 ml) was stirred at 60° C., in the dark, for 36 hours. The precipitated (silver salts) was removed by filtration. The filtrate was concentrated and the residue was treated with chloroform and water. The combined organic layer extracts were dried over sodium sulfate and filtered. The solvent was evaporated and the residue was purified by flash chromatography eluting with n-hexane/ethyl acetate 6/4. The title product 0.015 g was obtained as a powder.
1H-NMR (DMSO) δ (ppm): 1.24 (1H,s); 8.1 (3H,m); 7.7-7.2 (8H,m); 7.2-6.7 (8H,m); 6.05 (1H,m); 5.6-5.8 (4H,d); 4.55 (1H,m); 4.30 (2H,m); 4.15 (3H,m); 3.71 (5H,s).
Example 3
1-(9H-carbazolyloxy)-3-[[2-(2-methoxyphenoxy)ethyl][(4-nitrooxymethyl)benzoyl]amino]-2-propanol of formula (15)




3a. 1-(9H-carbazol-4-yloxy)-3-[[2-(2-methoxyphenoxy)ethyl][(4-chloromethyl)benzoyl]amino]-2-propanol
To a solution of carvedilol (2 g, 5 mmol) in chloroform (50 ml) 4-chloromethyl benzoic acid (0.9 g, 5.5 mmol), EDAC (1.15 g, 6 mmol) and N,N-dimethylaminopyridine (catalytic amount) were added. The reaction was stirred for 24 hours at room temperature. The solution was treated with water and the organic layer was dried over sodium sulfate and filtered. The solvent was evaporated and the residue was purified by flash chromatography eluting with n-hexane/ethyl acetate 6/4 (Rf=0.42). The title product 1.05 g was obtained as a white powder.
3b. 1-(9H-carbazol-4-yloxy)-3-[[2-(2-methoxyphenoxy)ethyl][(4-nitrooxymethyl)benzoyl]amino]-2-propanol
A solution of the product of example 3a (1.0 g, 1.78 mmol) and silver nitrate (0.6 g, 3.6 mmol) in acetonitrile (100 ml) was stirred at 65° C., in the dark, for 32 hours. The precipitated (silver salts) was removed by filtration. The filtrate was concentrated and the residue was treated with methylene chloride and water. The combined organic layer extracts were dried over sodium sulphate. The solvent was evaporated and the residue was purified by flash chromatography eluting with n-hexane/ethyl acetate 1/1. The title product 0.4 g was obtained as yellow powder.
1H-NMR (DMSO) δ (ppm): 11.24 (1H,s); 8.40-6.50 (15H,m); 5.61 (2H,m); 5.51 (1H,m); 5.36 (1H,m); 4.40-3.90 (4H,m); 3.74-3.71 (7H,m).
Example 4
1-(9H-carbazol-4-yloxy)-3-[[2-(2-methoxyphenoxy)ethyl][(3-nitrooxypropanoyl)amino]-2-propanol of formula (112)




The compound was synthesized under the analogous procedure described in example 3 starting from carvedilol and 3-bromopropanoic acid.
1H-NMR (DMSO) δ (ppm): 11.24 (1H, s); 8.25 (1H, dd); 7.46 (1H, dd); 7.29 (2H, m); 7.08 (2H, m); 6.90 (4H, m); 6.70 (1H, dd); 5.50 (1H, d); 4.80 (2H, m); 4.35 (1H, m); 4.20-3.6 (9H, m); 3.6-2.8 (4H, m).
Example 5
1-(9H-carbazol-4-yloxy)-3-[[2-(2-methoxyphenoxy)ethyl][(6-nitrooxyhexanoyl)amino]-2-propanol of formula (113)




The compound was synthesized under the analogous procedure described in example 3 starting from carvedilol and 6-bromohexanoic acid.
1H-NMR (DMSO) δ (ppm): 11.24 (1H, s); 8.25 (1H, dd); 7.46 (1H, dd); 7.29 (2H, m); 7.08 (2H, m); 6.90 (4H, m); 6.70 (1H, dd); 5.40 (1H, d); 4.50-3.50 (13H, m); 2.6-2.3 (2H, m); 1.70-0.50 (6H, m).
Example 6
6-(nitrooxy)hexanoic acid 1-(9H-carbazol-4-yloxy)-3-[[2-(2-methoxyphenoxy)ethyl]-[(6-nitrooxyhexanoyl]amino]-2-propanol of formula (111)




The compound was synthesized under the analogous procedure described in example 2 starting from carvedilol and 6-bromohexanoic acid.
1H-NMR (DMSO) δ (ppm): 11.24 (1H, s); 8.15 (1H, dd); 7.46 (1H, dd); 7.29 (2H, m); 7.08 (2H, m); 6.90 (4H, m); 6.70 (1H, dd); 5.65 (1H, m); 4.6-4.20 (6H, m); 4.2-3.5 (9H, m); 2.50 (2H, m); 2.29 (2H, m); 1.70-0.60 (12H, m).
Example 7
6-(nitrooxy)hexanoic acid 1-(9H-carbazol-4-yloxy)-3-[[2-(2-methoxyphenoxy)ethyl]amino]-2-propanol hydrochloride of formula (110)




The compound was synthesized under the analogous procedure described in example 1 starting from carvedilol and 6-bromohexanoic acid.
1H-NMR (DMSO) δ (ppm): 11.30 (1H, s); 8.15 (1H, dd); 7.44 (1H, dd); 7.32 (2H, m); 7.10-6.90 (6H, m); 6.70 (1H, dd); 5.65 (1H, m); 4.50-4.20 (7H, m); 3.90-3.40 (7H, m); 2.40 (2H, m); 1.60-1.10 (6H, m).
Example 8
Measurements of cGMP in Rat PC12 Cell Line
cGMP contributes to the function and interaction of several vascular cell types and its dysfunction is involved in major cardiovascular diseases such as hypertension, diabetic complications, atherosclerosis, and tissue infarction. Therefore the extent of cGMP formation elicited by the compounds of the inventions was evaluated in the rat pheochromocytoma (PC12) cell line.
Tested Compounds


    1) Carvedilol (parent drug)
    2) 1-(9H-carbazol-4-yloxy)-3-[[2-(2-methoxyphenoxy)ethyl][(4-nitrooxymethyl)benzoyl]amino]-2-propanol (compound of example 3);
    3) 4-(Nitrooxymethyl)benzoic acid 1-(9H-carbazol-4-yloxy)-3-[[2-(2-methoxyphenoxy)ethyl]amino]-2-propanoate (compound of example 1);
    4) 1-(9H-carbazol-4-yloxy)-3-[[2-(2-methoxyphenoxy)ethyl][(3-nitrooxypropanoyl)amino]-2-propanol (compound of example 4);
    5) 1-(9H-carbazol-4-yloxy)-3-[[2-(2-methoxyphenoxy)ethyl][(6-nitrooxyhexanoyl)amino]-2-propanol (compound of example 5).

Method



Cells were maintained at 37° C. in DMEM medium enriched with 10% horse serum and 5% foetal bovine serum under 5% CO2 atmosphere. At the time of experiments the cells were washed once with Hank's Balanced Salt Solution (HBSS) supplemented with 0.05% ascorbic acid and preincubated in the same buffer for 10 min in a floating water bath. After the preincubation step, cells were exposed for additional 45 min to either control conditions or increasing concentrations of test compounds ranging from 0.1 to 25 μM, in the presence of the phosphodiesterase inhibitor, IBMX (100 μM) and the NO-independent activator of soluble guanylyl cyclase, YC-1 (20 μM). The reaction was terminated by the removal of the incubating buffer and consecutive addition of 100 μl of absolute ethanol. The organic extracts were then evaporated to dryness and the residues dissolved in aqueous buffer for quantitative determination of intracellular cGMP levels using the cGMP enzyme immunoassay kit.
The obtained results reported in Table 1 are expressed as EC50 (μM) and efficacy Emax (% of vehicle). As shown in the table the nitroderivatives of carvedilol induced a consistent increase of intracellular cGMP formation in PC12 cell line. Conversely, this effect was not induced by the parent compound.







TABLE 1







Effects of the nitroxyderivatives of carvedilol and


the carvedilol on cGMP accumulation in PC12 cells











Compound
EC50 (μM)
Emax (% of vehicle)







Carvedilol
Not effective
Not effective



Compound of example 3
1.8
565



Compound of example 1
2.3
480



Compound of example 4
1.7
395



Compound of example 5
0.6
322

## Claims

1. A compound of general formula A-(Y—ONO2)s (I) and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof, wherein
s is an integer equal to 1;
A is selected from the following β-adrenergic blockers residues of formula (II):




wherein
R1 is




R2 is




Z is —C(O)—;
Z1 is H;
Y is a bivalent radical selected from the group consisting of:
a)
straight or branched C1-C20 alkylene being optionally substituted with one or more of the substituents selected from the group consisting of: halogen atoms, hydroxy, —ONO2 or T, wherein T is —OC(O)(C1-C10alkyl)-ONO2, —O(C1-C10alkyl)-ONO2;

b)




wherein:
n is an integer from 0 to 20,
n1 is an integer from 1 to 20;
n2, n3, n4 and n5 are integers equal or different from each other, equal to 0 or 1,
R3 and R4 are independently selected from H or CH3,
Y1 is —CH2— or —(CH2)na—CH═CH— wherein na is an integer from 0 to 20;
X1 is —WC(O)— or —C(O)W—, wherein W is oxygen, sulfur or NH; and
c)




wherein
X2 is O or S,
n10a, n10 and n12 are integer independently selected from 0 to 20,
n11 is an integer from 0 to 6;
R11 is H, CH3 or nitrooxy group;
R11a is CH3 or nitrooxy group;
and wherein (Y—ONO2)s bonds with Z of formula (II).

2. A compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 1 wherein Y is a straight or branched C1-C10 alkylene.

3. A compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 1 wherein
Y is




wherein
n is an integer from 0 to 20,
n1 is an integer from 1 to 20;
n2, n3, n4 and n5 are integers equal or different from each other, equal to 0 or 1;
R3 and R4 are independently selected from H or CH3;
Y1 is —CH2— or —CH2)na—CH═CH— wherein na is an integer from 0 to 20;
X1 is —WC(O)— or —C(O)W—, wherein W is oxygen, sulfur or NH.

4. A compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 3 wherein
n2, n3, n4, n5 are equal to 0,
n1 is 1,
n is an integer from 0 to 10,
Y1 is CH2.

5. A compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 3 wherein
n, n2, n5 are 1,
n3 and n4 are equal to 0, and
n1 is an integer from 1 to 10,
Y1 is —(CH2)na—CH═CH— wherein na is 0,
X1 is —WC(O)— wherein W is oxygen and X1 is bound to the phenyl ring through the [C]4,
R4 is CH3 and the group (OR4) is bound to the phenyl ring through the [C]3.

6. A compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 1 wherein
Y is




wherein
X2 is O or S,
n10a, n10 and n12 are integers independently selected from 0 to 20;
n11 is an integer from 0 to 6;
R11 is H, CH3 or a nitrooxy group;
R11a is CH3 or a nitrooxy group.

7. A compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 6 wherein
Y is




wherein
X2 is O or S,
n10a is an integer from 0 to 10
n11 are 0,
n12 is an integer from 1 to 10,
R11 is H or a nitrooxy group;
wherein the —ONO2 group is bound to the —(CH2)n12— group.

8. A compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 1 wherein
Y is a straight or branched C1-C20 alkylene being optionally substituted with one or more of the substituents selected from the group consisting of halogen atoms, hydroxy, —ONO2 or T, wherein T is —OC(O)(C1-C10alkyl)-ONO2, —O(C1-C10alkyl)-ONO2.

9. A compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to claim 8 wherein Y is a straight or branched C3-C6 alkylene.

10. Compounds and the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof according to any one of claims 1, 8 or 9 wherein the compounds are:

11. A compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts according to claim 1, that is 4-(Nitrooxymethyl)benzoic acid 1-(9H-carbazol-4-yloxy)-3-[[2-(2-methoxyphenoxy)ethyl]amino]-2-propanoate.

12. A compound and the enantiomers, diastereoisomers and pharmaceutically acceptable salts according to any one of claim 1, 8 or 9, that is 6-(nitrooxy)hexanoic acid 1-(9H-carbazol-4-yloxy)-3-[[2-(2-methoxyphenoxy)ethyl]amino]-2-propanol hydrochloride.

13. A medicament comprising a compound of formula (I) and/or the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof as defined in claim 1.

14. A method for the treatment or prophylaxis of hypertension, cardiovascular and vascular diseases using a drug comprising a compound of formula (I) and/or the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof as defined in claim 1.

15. A method for the treatment of glaucoma and elevated intraocular pressure using a drug comprising a compound of formula (I) and/or the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof as defined in claim 1.

16. A pharmaceutical composition comprising a compound of formula (I) and/or the enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof as defined in claim 1 and at least one pharmaceutically acceptable carrier.