Patent ID: 6593347
Filing Date: 2003-07-15
Classification: A61K,A61P,C07C,C07D,C07F

Abstract:
A composition comprising at least one compound of formula (I), formula (II), formula (III), formula (IV), or a pharmaceutically acceptable salt thereof, and at least one compound that donates, transfers, or releases nitric oxide, induces the production of endogenous nitric oxide or endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase, or a pharmaceutically acceptable salt thereof,wherein the compound of formula (I) is: â€ƒwherein Rg is a hydrogen atom or a lower alkyl group; Rh is: â€ƒn is an integer of 0 or 1; X is: (i) -T-B1â€”Wâ€”Bt-T-NOs; (ii) -T-B1-Ly-Bx-T-NOs; (iii) -T-B1â€”Wâ€”Btâ€”Wxâ€”Bk-T-NOs; (iv) -T-B1(C(Rb)(Rc))p-ExX-T-NOs; (v) -T-B1-G-Bt-Wz-Bk-Gx-Br-T-NOs; (vi) -T-B1-J-Ex-T-NOs; or (vii) -T-B1-C(Re)&boxH;N-Ez-T-NOs; whereins is an integer of 1 or 2; T at each occurrence is independently a covalent bond, a carbonyl, an oxygen, â€”S(O)oâ€” or â€”N(Ra)(Ri)â€”; o is an integer from 0 to 2; Ra is a lone pair of electrons, a hydrogen or an alkyl group; Ri is a hydrogen, an alkyl group, an aryl group, an alkylcarboxylic acid group, an aryl carboxylic acid group, an alkylcarboxylic ester group, an arylcarboxylic ester group, an alkylcarboxamido, an arylcarboxamido, an alkylaryl, an alkylsulfinyl, an alkylsulfonyl, an arylsulfinyl, an arylsulfonyl, a sulfonamido, a carboxamido, a carboxylic ester group, an amino alkyl, an amino aryl, â€”CH2â€”C(T-Q)(Re)(Rf), or â€”(N2O2âˆ’)âˆ’Â·M+, wherein M+ is an organic or inorganic cation; L at each occurrence is independently â€”C(O)â€”, â€”C(S)â€”, -T-, a heterocyclic ring, an aryl group, an alkenyl group, an alkynyl group, an arylheterocyclic ring, or â€”(CH2CH2O)q; q is an integer from 1 to 5; B at each occurrence is independently an alkyl group, an aryl group, or â€”(C(Re)(Rf))pâ€”, a heterocyclic ring, an aryl heterocyclic ring, or â€”(CH2CH2O)q; p is an integer from 1 to 10; Re and Rf are each independently a hydrogen, an alkyl group, 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, -T-NOs, or (C(Re)(Rf))k-T-NOs, or Re and Rf taken together with the carbon atoms to which they are attached are a heterocyclic ring, a cycloalkyl group or a bridged cycloalkyl group; Rb and Rc are each independently a haloalkyl, an alkenyl group, an alkynyl group, a bridged cycloalkyl group, a heterocyclic ring, a cycloalkoxy, a halogen, a hydroxy, an hydroxyalkyl, an alkoxyalkyl, an aryiheterocyclic 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 arylalkyl, an alkylaryl, a carboxamido, an 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, -T-NOs, or (C(Re)(Rf))k-T-NOs, or Rb and Rc 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; G is a covalent bond, -T-C(O)â€”, â€”C(O)-T- or T; J is a carbonyl, a phosphoryl or a silyl; k, l, t and z are each independently an integer from 1 to 3; y is an integer from 1 to 3; x and r are each independently an integer from 0 to 3; E at each occurrence is independently â€”C(O)â€”, â€”C(S)â€”, -T-, â€”(C(Ra)(Rf))pâ€”, an alkyl group, an aryl group, a heterocyclic ring, arylheterocyclic ring, or (CH2CH2O)q; W is oxygen, â€”S(O)oâ€”, N(Ra)(Ri), carbonyl, or methanthial; with the proviso that when Ri is â€”CH2â€”C(T-NOs)(Re)(Rf) or â€”(N2O2âˆ’)âˆ’Â·M+, or Rb, Rc, Re or Rf are T-NOs or (C(Re)(Rf))k-T-NOs, then the â€œ-T-NOs â€  subgroup designated in X can be a hydrogen, an alkyl, an alkoxy, an alkoxyalkyl, an aminoalkyl, a hydroxy, a heterocyclic ring or an aryi group; wherein the compound of formula (II) is: wherein Rk is: and X is as defined as herein;wherein the compound of formula (III) is: whereinX is as defined herein; Ri at each occurrence is independently Ri, wherein Ri is as defined herein; Z is an aryi group; and A1, A2 and A3 comprise the other subunits of a 5- or 6-membered monocyclic aromatic ring and each of A1, A2 and A3 is independently: (1) Câ€”Ro, wherein Ro at each occurrence is independently a hydrogen, an alkyl, an alkoxyalkyl, a halogen or a nitro group; (2) Nâ€”Rp, wherein Rp at each occurrence is independently a covalent bond to an adjacent ring atom in order to render the ring aromatic, a hydrogen, an alkyl, an arylalkyl, an aryl or a heteroaryl group; (3) a sulfur atom; (4) an oxygen atom; or (5) Ba&boxH;Bb, wherein Ba and Bb are each independently a nitrogen atom or Câ€”Ro wherein Ro is as defined herein; wherein the compound of formula (IV) is: whereinRm is an alkyl group or an aryl group; and X, Z, A1, A2 and A3 are as defined herein.