Nitric Oxide Enhancing Pyruvate Compounds, Compositions and Methods of Use

A nitric oxide enhancing pyruvate compound of Formula (I) or (II), or a pharmaceutically acceptable salt thereof:

• wherein the compound of Formula (I) is:
• wherein:
• R1 is K′ or —(C(Re)(Rf))aa-T3-A;
• R2 is K, K′ or
• A is a hydrogen, K, K′,
• Rb is a hydrogen, a lower alkyl group or —COCH3;
• Rc is a hydrogen or a lower alkyl group;
• D is a hydrogen, V4, K or K′;
• Z is an oxo, an oxime, a hydrozone, ═N—O-A, —N—(OA)-R82, ═N—N-(A)(R82) or ═N—(R82);
• R82 is a hydrogen, K, K′, an alkyl group, an aryl group, an alkylsulfonyl group, an arylsulfonyl group, a carboxylic ester, an alkylcarbonyl group, an arylcarbonyl group, a carboxamido group, an alkoxyalkyl group or an alkoxyaryl group;
• K is —Wa-Eb-(C(Re)(Rf))pl-Ec-(C(Re)(Rf))x—Wd—(C(Re)(Rf))y—Wi-Ej—Wg—(C(Re)(Rf))z—(U)bb—V4;
• K′ is —Wa-Eb-(C(Re)(Rf))pl-Ec-(C(Re)(Rf))x—Wd—(C(Re)(Rf))y—Wi-Ej—Wg—(C(Re)(Rf))z—Re;
• V6 is:
• Z5 is —CH2 or oxygen;
• Z6 is —CH or nitrogen;
• aa is an integer from 0 to 5;
• bb is an integer from 0 to 1;
• a, b, c, d, g, i and j are each independently an integer from 0 to 3;
• p, x, y and z are each independently an integer from 0 to 10;
• 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)ql— 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)ql— 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 arylalkylthio, an arylalkylthioalkyl, 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, —(C(Ro)(Rp))kl—U3—V5, —(C(Ro)(Rp))kl—U3—V4, —(C(Ro)(Rp))kl—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 arylalkylthio, an arylalkylthioalkyl, 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,
• V4 is V3 or V6;
• V3 is:
• R24 is —C6H4R27, —CN, —S(O)2—C6H4R27, —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—;
• R27 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, an aryl 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 pyruvate compounds of Formula (I) must contain at least heterocyclic nitric oxide donor group and/or nitroxide group linked to the pyruvate compound of Formula (I) through an oxygen atom, a nitrogen atom or a sulfur atom via a bond or moiety that can be hydrolyzed;
• wherein the compound of Formula (II) is):
• wherein Z, T3 and R2 are as defined herein, and
• with the proviso that the pyruvate compounds of Formula (II) must contain at least heterocyclic nitric oxide donor group and/or nitroxide group linked to the pyruvate compound of Formula (II) through an oxygen atom, a nitrogen atom or a sulfur atom via a bond or moiety that can be hydrolyzed.