Nitrosated and nitrosylated compounds and compositions and their use for treating respiratory disorders

A composition comprising a compound of Formula (II) and a compound that donates, transfers or releases nitric oxide, elevates endogenous synthesis levels of nitric oxide or endothelium-derived relaxing factor, or is a substrate for nitric oxide synthase,

• wherein the compound of Formula (II) is:
• 15
• wherein,
• E is nitrogen or C—R7;
• R7 is hydrogen, halogen, —CH2O—Rj, or O—Rj;
• Rj is hydrogen, D or M;
• D is
• (i) hydrogen
• (ii) —NO
• (iii) —NO2
• (iv) —CH(Rd)—O—C(O)—Y—(C(Re)(Rf))p-T-Q;
• (v) —C(O)-T1-(C(Re)(Rf))p-T2-Q;
• or
• (vi) —C(O)-T-(C(Ry)(Rz))p;
• Rd is hydrogen, lower alkyl, cycloalkyl, aryl, alkylaryl or heteroaryl;
• Y is oxygen, sulfur or NRi;
• Ri is hydrogen, lower alkyl, lower haloalkyl or heteroaryl;
• Re and Rf are each independently hydrogen, lower alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl, alkylamino, dialkylamino, or carboxy, or Re and Rf taken together with the carbon atom to which they are attached are carbonyl, cycloalkyl or bridged cycloalkyl;
• p is an integer from 1 to 6;
• T, T1 and T2 are each independently a covalent bond, oxygen, sulfur or nitrogen;
• Q is —NO or —NO2;
• with the proviso that in “T-Q” and “T2-Q”, T and T2 cannot be a covalent bond;
• Ry and Rz are each independently -T1-(C(Re)(Rf))p-G-(C(Re)(Rf))p-T2-Q;
• G is a covalent bond, -T-C(O)—, —C(O)-T or Y;
• wherein Rd, Re, Rf, p, Q, T, T1, T2 and Y are as defined herein;
• M is:
• (i) —C(O)-T-(C(Re)(Rf))p-G-(C(Re)(Rf))p—N(N—(O−)·N═O)—Ri or
• (ii) —CH(Rd)—O—C(O)-T-(C(Re)(Rf))p-G-(C(Re)(Rf))p—N(N—(O−)·N═O)—Ri;
• wherein T, Re, Rf, p, G, Ri, and Rd are as defined herein;
• R8 and R9 are each independently amino, hydrogen, —CH2O—Rj, or —O—Rk;
• Rk is —C(O)—Rd or Rj;
• wherein Rd and Rj are as defined herein;
• S is:
• (1) —CH2—N(Z)—R10;
• wherein Z is hydrogen, —(N(O−)N═O), or M;
• wherein M is as defined herein;
• R10 is:
• (i) lower alkyl
• (ii) —(CH2)p—O—(CH2)a—C6H5;
• wherein a is an integer from 1 to 4 and p is as defined herein;
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• wherein Z is as defined herein;
• R11 is hydrogen, D, or M;
• with the proviso that R11 must be D or M if neither R8 or R9 include D or M and Z is a hydrogen;
• and
• with the proviso that the compounds of Formula (II) must contain at least one —NO group or at least one —NO2 group, and wherein the at least one —NO group or the at least one —NO2 group is linked to the compounds of Formula (II) through an oxygen atom, a nitrogen atom or a sulfur atom.

A kit comprising a compound of Formula (II) and a compound that donates, transfers or releases nitric oxide, elevates endogenous synthesis levels of nitric oxide or endothelium-derived relaxing factor, or is a substrate for nitric oxide synthase,

• wherein the compound of Formula (II) is:
• 17
• wherein,
• E is nitrogen or C—R7;
• R7 is hydrogen, halogen, —CH2O—Rj, or —O—Rj;
• Rj is hydrogen, D or M;
• D is
• (i) hydrogen
• (ii) —NO
• (iii) —NO2
• (iv) —CH(Rd)—O—C(O)—Y—(C(Re)(Rf))p-T-Q;
• (v) —C(O)-T1-(C(Re)(Rf))p-T2-Q;
• or
• (vi) —C(O)-T-(C(Ry)(Rz))p;
• Rd is hydrogen, lower alkyl, cycloalkyl, aryl, alkylaryl or heteroaryl;
• Y is oxygen, sulfur or NRi;
• Ri is hydrogen, lower alkyl, lower haloalkyl or heteroaryl;
• Re and Rf are each independently hydrogen, lower alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl, alkylamino, dialkylamino, or carboxy, or Re and Rf taken together with the carbon atom to which they are attached are carbonyl, cycloalkyl or bridged cycloalkyl;
• p is an integer from 1 to 6;
• T, T1 and T2 are each independently a covalent bond, oxygen, sulfur or nitrogen;
• Q is —NO or —NO2;
• with the proviso that in “T-Q” and “T2-Q”, T and T2 cannot be a covalent bond;
• Ry and Rz are each independently -T1-(C(Re)(Rf))p-G-(C(Re)(Rf))p-T2-Q;
• G is a covalent bond, -T-C(O)—, —C(O)-T or Y;
• wherein Rd, Re, Rf, p, Q, T, T1, T2 and Y are as defined herein;
• M is:
• (i) —C(O)-T-(C(Re)(Rf))p-G-(C(Re)(Rf))p—N(N—(O−)·N═O)—Ri or
• (ii) —CH(Rd)—O—C(O)-T-(C(Re)(Rf))p-G-(C(Re)(Rf))p—N(N—(O−).N═O)—Ri;
• wherein T, Re, Rf, p, G, Ri, and Rd are as defined herein;
• R8 and R9 are each independently amino, hydrogen, —CH2O—Rj, or —O—Rk;
• Rk is —C(O)—Rd or Rj;
• wherein Rd and Rj are as defined herein;
• S is:
• (1) —CH2—N(Z)—R10;
• wherein Z is hydrogen, —(N(O−)N═O), or M;
• wherein M is as defined herein;
• R10 is:
• (i) lower alkyl
• (ii) —(CH2)p—O—(CH2)a—C6H5;
• wherein a is an integer from 1 to 4 and p is as defined herein;
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• wherein Z is as defined herein;
• R11 is hydrogen, D, or M;
• with the proviso that R11 must be D or M if neither R8 or R9 include D or M and Z is a hydrogen;
• and
• with the proviso that the compounds of Formula (II) must contain at least one —NO group or at least one —NO2 group, and wherein the at least one —NO group or the at least one —NO2 group is linked to the compounds of Formula (II) through an oxygen atom, a nitrogen atom or a sulfur atom.