Nitrosated and nitrosylated α-adrenergic receptor antagonist, compositions and methods of use

A compound of formula (VIIIa), or a pharmaceutically acceptable salt thereof:

• wherein
• a is an integer of 2 or 3;
• Rv and Rw are each independently a hydrogen, a lower alkyl, a cycloalkyl, an aryl, or Rv and Rw when taken together with the nitrogen atom to which they are attached are a heterocyclic ring;
• Rx is hydrogen or lower alkyl;
• R′x is independently selected from Rx;
• D2 is:
• (i) —C(O)—Yl—Z1—(G—(C(Ry)(Rz))q′—Tl—Q)p;
• (ii) —P—Z1—(G—(C(Ry)(Rz))q′—Tl—Q)p;
• (iii) —P—B1—V—Bt—Kr—Es—(C(Ry)(Rz))w—Ec—(C(Ry) (Rz))x—Kd—(C(Ry)(Rz))y—Ki—Ej—Kg—(C(Ry)(Rz))z—Tl—Q;
• or
• (iv) —P—F′n—Kr—Es—(C(Ry)(Rz))w—Ec—(C(Ry)(Rz))x—Kd—(C(Ry)(Rz))y—Ki—Ej—Kg—(C(Ry)(Rz))z—Tl—Q;
• Yl is oxygen, S(O)o, lower alkyl or NR′i;
• o is an integer from 0 to 2;
• R′i is a hydrogen, an alkyl, an aryl, an alkylcarboxylic acid, an aryl carboxylic acid, an alkylcarboxylic ester, an arylcarboxylic ester, an alkylcarboxamido, an arylcarboxamido, an alkylaryl, an alkylsulfinyl, an alkylsulfonyl, an arylsulfinyl, an arylsulfonyl, a sulfonamido, a carboxamido, a carboxylic ester, —CH2—C(Tl—Q)(Ry)(Rz), or —(N2O2−).M+, wherein M+ in an organic or inorganic cation;
• Ry and Rz are each independently a hydrogen, an alkyl, a cycloalkoxy, a halogen, a hydroxy, an hydroxyalkyl, an alkoxyalkyl, an arylheterocyclic ring, an alkylaryl, a cycloalkylalkyl, a heterocyclicalkyl, an alkoxy, a haloalkoxy, an amino, an alkylamino, a dialkylamino, an arylamino, a diarylamino, an alkylarylamino, an alkoxyhaloalkyl, a haloalkoxy, a sulfonic acid, an alkylsulfonic acid, an arylsulfonic acid, an arylalkoxy, an alkylthio, an arylthio, a cyano, an aminoalkyl, an aminoaryl, an alkoxy, an aryl, an arylalkyl, an alkylaryl, a carboxamido, a alkyl carboxamido, an aryl carboxamido, an amidyl, a carboxyl, a carbamoyl, an alkylcarboxylic acid, an arylcarboxylic acid, an ester, a carboxylic ester, an alkylcarboxylic ester, an arylcarboxylic ester, a haloalkoxy, a sulfonamido, an alkylsulfonamido, an arylsulfonamido, a urea, a nitro, —Tl—Q, or (C(Ry)(Rz))k—Tl—Q, or Ry and Rz taken together with the carbon atoms to which they are attached are a carbonyl, a methanthial, a heterocyclic ring, a cycloalkyl group or a bridged cycloalkyl group;
• k is an integer from 1 to 3;
• Tl is independently a covalent bond, oxygen, S(O)o or NRi;
• Zl is a covalent bond, an alkyl, an aryl, an alkylaryl, an arylalkyl, a heteroalkyl, or (C(Ry)(Rz))p;
• G is a covalent bond, —Tl—C(O)—, —C(O)—Tl— or Tl;
• q′ is an integer from 0 to 5;
• P is a carbonyl, a phosphoryl or a silyl;
• l and t are each independently an integer from 1 to 3;
• r, s, c, d, g, i and j are each independently an integer from 0 to 3;
• w, x, y and z are each independently an integer from 0 to 10;
• p is an integer from 1 to 10;
• B at each occurrence is independently an alkyl, an aryl, or (C(Ry)(Rz))p,;
• E at each occurrence is independently —Ti—, an alkyl, an aryl, or —(CH2CH2O)q;
• K at each occurrence is independently —C(O)—, —C(S)—, —Tl—, a heterocyclic ring, an aryl, an alkenyl, an alkynyl, an arylheterocyclic ring, or —(CH2CH2O)q;
• q is an integer of from 1 to 5;
• V is oxygen, S(O)o, or NR′i;
• F′ at each occurrence is independently B or carbonyl;
• n is an integer from 2 to 5;
• and
• Q is —NO or —NO2;
• with the proviso that when R′i is —CH2—C(Tl—Q)(Ry)(Rz) or —(N2O2−).M−, or Ry or Rz are Tl—Q, or (C(Ry)(Rz))k—Tl—Q then the “—Tl—Q” subgroup designated in D can be a hydrogen, an alkyl, an alkoxy, an alkoxyalkyl, an aminoalkyl, a hydroxy, or an aryl.