US 7,396,829 B2 · Nitric oxide enhancing diuretic compounds, compositions and methods of use

Abstract

The invention describes novel compositions and kits comprising at least one nitric oxide enhancing diuretic compound, or pharmaceutically acceptable salts thereof, and, optionally, at least one nitric oxide enhancing compound and/or at least one therapeutic agent. The invention also provides methods for (a) treating conditions resulting from excessive water and/or electrolyte retention; (b) treating cardiovascular diseases; (c) treating renovascular diseases; (d) treating diabetes; (e) treating diseases resulting from oxidative stress; (f) treating endothelial dysfunctions; (g) treating diseases caused by endothelial dysfunctions; (h) treating cirrhosis; (j) treating pre-eclampsia; (k) treating osteoporosis; (l) treating nephropathy; (m) treating peripheral vascular diseases; (n) treating portal hypertension; (o) treating central nervous system disorders; (p) treating metabolic syndrome; (q) treating sexual dysfunctions; and (r) hyperlipidemia. The nitric oxide enhancing diuretic compounds comprise at least one nitric oxide enhancing group linked to the diuretic compound through one or more sites such as carbon, oxygen and/or nitrogen via a bond or moiety that cannot be hydrolyzed.

A compound of Formula (I), or a pharmaceutically acceptable salt thereof:

wherein the compound of Formula (I) is:
wherein:
X2 is —S(O)2;
Y2 is chlorine or CF3;
—V2—U2—W2— is:
(i) —NH—C(Rq)(Rr))—NRq—;
or
(ii) —NH—C(Rq)═N—;
Rq and Rr at each occurrence are independently a hydrogen, a lower alkyl group, a substituted alkyl group, an alkylaryl group, —CH2—S—CH—CH═CH2;
—CH2—S—CF3, —CH2—S—CH2—C6H5 or K′;
K′ is -G-Ec-(C(Re)(Rf))x—Wd—(C(Re)(Rf))y—Wi-Ej-Wg—(C(Re)(Rf))z—V4;
K is —(W)aEb-(C(Re)(Rf))p1-Ec-(C(Re)(Rf))x—(W)d—(C(Re)(Rf))y—(W)i-Ej-(W)g—(C(Re)(Rf))z—V4;
a, b, c, d, g, i and j are each independently an integer from 0 to 3;
p1, x, y and z are each independently an integer from 0 to 10;
G is a —CH2, oxygen or nitrogen;
V4 is V3, Re, —U3—V5 or V6;
V3 is:
R24 is —C6H4R29, —CN, —S(O)2—C6H4R29, —C(O)—N(Ra)(Ri), —NO2, —C(O)—OR25 or —S(O)2—R25;
R25 is an aryl group, a lower alkyl group, a haloalkyl group, a hydroxyalkyl group or an arylalkyl group;
R26 is —C(O)— or —S(O)2—;
R29 is a hydrogen, —CN, —S(O)2—R25, —C(O)—N(Ra)(Ri), —NO2 or —C(O)—OR25;
T′ is oxygen, sulfur or NR6;
R6 is a hydrogen, a lower alkyl group or an aryl group;
V6 is:
Z5 is —CH2 or oxygen;
Z6 is —CH or nitrogen;
k1 is an integer from 1 to 3;
W at each occurrence is independently —C(O)—, —C(S)—, -T3-, —(C(Re)(Rf))h—, —N(Ra)Ri, an alkyl group, an aryl group, a heterocyclic ring, an arylheterocyclic ring, —(CH2CH2O)q1— or a heterocyclic nitric oxide donor;
E at each occurrence is independently -T3-, an alkyl group, an aryl group, —(C(Re)(Rf))h—, a heterocyclic ring, an arylheterocyclic ring, —(CH2CH2O)q1— or Y4;
Y4 is:
T is a —S(O)o—;
a carbonyl or a covalent bond;
o is an integer from 0 to 2;
Rj and Rk are independently selected from an alkyl group, an aryl group, or Rj and Rk taken together with the nitrogen atom to which they are attached are a heterocylic ring;
T3 at each occurrence is independently a covalent bond, a carbonyl, an oxygen, —S(O)O—or —N(Ra)Ri;
h is an integer form 1 to 10;
q1 is an integer from 1 to 5;
Re and Rf are each independently a hydrogen, an alkyl, a cycloalkoxy, a halogen, a hydroxy, an hydroxyalkyl, an alkoxyalkyl, an arylheterocyclic ring, an alkylaryl, an alkylcycloalkyl, an alkylheterocyclic ring, a cycloalkylalkyl, a cycloalkylthio, an arylalklythio, an arylalklythioalkyl, an alkylthioalkyl, a cycloalkenyl, an heterocyclicalkyl, an alkoxy, a haloalkoxy, an amino, an alkylamino, a dialkylamino, an arylamino, a diarylamino, an alkylarylamino, an alkoxyhaloalkyl, a sulfonic acid, a sulfonic ester, an alkylsulfonic acid, an arylsulfonic acid, an arylalkoxy, an alkylthio, an arylthio, a cyano, an aminoalkyl, an aminoaryl, an aryl, an arylalkyl, an alkylaryl, a carboxamido, an alkylcarboxamido, an arylcarboxamido, an amidyl, a carboxyl, a carbamoyl, an alkylcarboxylic acid, an arylcarboxylic acid, an alkylcarbonyl, an arylcarbonyl, an ester, a carboxylic ester, an alkylcarboxylic ester, an arylcarboxylic ester, a sulfonamido, an alkylsulfonamido, an arylsulfonamido, an alkylsulfonyl, an alkylsulfonyloxy, an arylsulfonyl, arylsuiphonyloxy, a sulfonic ester, an alkyl ester, an aryl ester, a urea, a phosphoryl, a nitro, —U3—V5, V6, —(C(Ro)(Rp))k1—U3—V5, —(C(Ro)(Rp))k1—U3—V3, —(C(Ro)(Rp))k1—U3—V6, —(C(Ro)(Rp))k1—U3—C(O)—V6, or Re and Rf taken together with the carbons to which they are attached form a carbonyl, a methanthial, a heterocyclic ring, a cycloalkyl group, an aryl group, an oxime, an imine, a hydrazone, a bridged cycloalkyl group,
Ro and Rp are each independently a hydrogen, an alkyl, a cycloalkoxy, a halogen, a hydroxy, an hydroxyalkyl, an alkoxyalkyl, an arylheterocyclic ring, an alkylaryl, an alkylcycloalkyl, an alkylheterocyclic ring, a cycloalkylalkyl, a cycloalkylthio, an arylalklythio, an arylalklythioalkyl, an alkylthioalkyl a cycloalkenyl, an heterocyclicalkyl, an alkoxy, a haloalkoxy, an amino, an alkylamino, a dialkylamino, an arylamino, a diarylamino, an alkylarylamino, an alkoxyhaloalkyl, a sulfonic acid, a sulfonic ester, an alkylsulfonic acid, an arylsulfonic acid, an arylalkoxy, an alkylthio, an arylthio, a cyano an aminoalkyl, an aminoaryl, an aryl, an arylalkyl, an alkylaryl, a carboxamido, an alkylcarboxamido, an arylcarboxamido, an amidyl, a carboxyl, a carbamoyl, an alkylcarboxylic acid, an arylcarboxylic acid, an alkylcarbonyl, an arylcarbonyl, an ester, a carboxylic ester, an alkylcarboxylic ester, an arylcarboxylic ester, a sulfonamido, an alkylsulfonamido, an arylsulfonamido, an alkylsulfonyl, an alkylsulfonyloxy, an arylsulfonyl, arylsulphonyloxy, a sulfonic ester, an alkyl ester, an aryl ester, a urea, a phosphoryl, a nitro, —U3—V5, V6 or Ro and Rp taken together with the carbons to which they are attached form a carbonyl, a methanthial, a heterocyclic ring, a cycloalkyl group, an aryl group, an oxime, an imine, a hydrazone a bridged cycloalkyl group,
U3 is an oxygen, sulfur or —N(Ra)Ri;
V5 is —NO or —NO2 (i.e.an oxidized nitrogen);
k1 is an integer from 1 to 3;
Ra is a lone pair of electrons, a hydrogen or an alkyl group;
Ri is a hydrogen, an alkyl, an aryl, an alkylcarboxylic acid, an arylcarboxylic acid, an alkylcarboxylic ester, an arylcarboxylic ester, an alkylcarboxamido, an arylcarboxamido, an alkylaryl, an alkylsulfinyl, an alkylsulfonyl, an alkylsulfonyloxy, an arylsulfinyl, an arylsulfonyl, an arylsulphonyloxy, a sulfonamido, a carboxamido, a carboxylic ester, an aminoalkyl, an aminoaryl, —CH2—C—(U3—V5)(Re)(Rf), a bond to an adjacent atom creating a double bond to that atom or —(N2O2-).M1+, wherein M1+is an organic or inorganic cation;
and
with the proviso that the compound of Formula (I) must contain at least one nitric oxide enhancing group selected from a —ONO group, a —SNO group, a —KNO group, a —ONO2 group, —a SNO2 group, a —NNO2 group, a —(N2O2-).M1+group, a heterocyclic nitric oxide donor group and a nitroxide group where the nitric oxide enhancing group is linked to the compound of Formula (I)) through a carbon, oxygen or nitrogen atom via a bond that cannot be hydrolyzed.

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Nitric oxide enhancing diuretic compounds, compositions and methods of use

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Nitric oxide enhancing diuretic compounds, compositions and methods of use

Life of this patent

Abstract

Claims9