US 6,297,260 B1 · Nitrosated and nitrosylated nonsteroidal antiinflammatory compounds, compositions and methods of use

Abstract

The present invention describes novel nitrosated and/or nitrosylated nonsteroidal antiinflammatory compounds, and novel compositions comprising at least one nitrosated and/or nitrosylated nonsteroidal antiinflammatory compound, and, optionally, at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase. The present invention also provides methods for treating, preventing and/or reducing inflammation, pain, and fever; decreasing or reversing the gastrointestinal, renal and other toxicities resulting from the use of nonsteroidal antiinflammatory drugs; treating and/or preventing gastrointestinal disorders; treating inflammatory disease states and disorders; and treating and/or preventing ophthalmic diseases or disorders.

A compound of formula (I), formula (II), formula (III), formula (IV), or a pharmaceutically acceptable salt thereof:

wherein the compound of formula (I) is:
wherein
Rg is a hydrogen atom or a lower alkyl group;
Rh is:
n is an integer of 0 or 1;
X is:
(i) —T—Bl—W—Bt—T—NOs;
(ii) —T—Bl—Ly—Bx—T—NOs;
(iii) —T—Bl—W—Bt—Wx—Bk—T—NOs;
(iv) —T—Bl—(C(Rb)(Rc))p—Ex—T—NOs;
(v) —T—Bl—G—Bt—Wz—Bk—Gx—Br—T—NOs;
(vi) —T—Bl—J—Ex—T—NOs;
or
(vii) —T—Bl—C(Rc)═N—Ez—T—NOs;
wherein
s is an integer of 1 or 2;
T at each occurrence is independently a covalent bond, a carbonyl, an oxygen, —S(O)o— or —N(Ra)(Ri)—;
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, —CH2—C(T—Q)(Re)(Rf), or —(N2O2−)−•M+, wherein M+ is an organic or inorganic cation;
L at each occurrence is independently —C(O)—, —C(S)—, —T—, a heterocyclic ring, an aryl group, an alkenyl group, an alkynyl group, an arylheterocyclic ring, or —(CH2CH2O)q;
q is an integer from 1 to 5;
B at each occurrence is independently an alkyl group, an aryl group, or —(C(Re)(Rf))p—, a heterocyclic ring, an aryl heterocyclic ring, or —(CH2CH2O)q;
p is an integer from 1 to 10;
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, 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 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 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 Re 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)—, —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 —C(O)—, —C(S)—, —T—, —(C(Re)(Rf))p—, an alkyl group, an aryl group, a heterocyclic ring, arylheterocyclic ring, or —(CH2CH2O)q;
W is oxygen, —S(O)o—, —N(Ra)(Ri)—, carbonyl, or methanthial;
with the proviso that when Ri is —CH2—C(T—NOs)(Re)(Rf) or —(N2O2−)−•M+, or Rb, Rc, Re or Rf are T—NOs or (C(Re)(Rf))k—T—NOs, then the “—T—NOs” subgroup designated in X can be a hydrogen, an alkyl, an alkoxy, an alkoxyalkyl, an aminoalkyl, a hydroxy, a heterocyclic ring or an aryl 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:
wherein
X is as defined herein;
Ri at each occurrence is independently Ri, wherein Ri is as defined herein;
Z is an aryl 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) C—Ro, wherein Ro at each occurrence is independently a hydrogen, an alkyl, an alkoxyalkyl, a halogen or a nitro group;
(2) N—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═Bb, wherein Ba and Bb are each independently a nitrogen atom or C—Ro wherein Ro is as defined herein;
wherein the compound of formula (IV) is:
wherein
Rm is an alkyl group or an aryl group;
and X, Z, A1, A2 and A3 are as defined herein.

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Nitrosated and nitrosylated nonsteroidal antiinflammatory compounds, compositions and methods of use

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Nitrosated and nitrosylated nonsteroidal antiinflammatory compounds, compositions and methods of use

Life of this patent

Abstract

Claims23