US 2010/0137291 A1 · NITROSATED NONSTEROIDAL ANTIINFLAMMATORY COMPOUNDS, COMPOSITIONS AND METHODS OF USE

Abstract

The invention describes novel nitrosated nonsteroidal antiinflammatory drugs (NSAIDs) and pharmaceutically acceptable salts thereof, and novel compositions comprising at least one nitrosated NSAID, and, optionally, at least one compound that donates, transfers or releases nitric oxide, stimulates endogenous synthesis of nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor or is a substrate for nitric oxide synthase, and/or at least one therapeutic agent. The invention also provides novel compositions comprising at least one nitrosated NSAID, and 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 and/or at least one therapeutic agent. The invention also provides novel kits comprising at least one nitrosated NSAID, and, optionally, at least one nitric oxide donor and/or at least one therapeutic agent. The invention also provides methods for treating inflammation, pain and fever; for treating gastrointestinal disorders; for facilitating wound healing; for treating and/or preventing gastrointestinal, renal and/or respiratory toxicities resulting from the use of nonsteroidal antiinflammatory compounds; for treating inflammatory disease states and/or disorders; and for treating and/or preventing ophthalmic diseases and/or disorders.

A compound of Formula (I), or a pharmaceutically acceptable salt thereof;

wherein the compound of Formula (I) is:
wherein:
Rm is a hydrogen or a lower alkyl group;
Rn is:
s is an integer of 0 or 1;
X is:
(1) —Y—(CH2)o—(W)q—(CH2)o—V—(CR4R4′)o-Q′-(CR4R4′)o—(CH2)—ONO2;
(2) —Y—(CR4R4′)o-Q′-(CR4R4′)o—V—(CR4R4′)o—(CH2)—ONO2;
(3) —Y—(CR4R4′)o-Q′-(CR4R4′)o—(W)q—(CR4R4′)o—(CH2)—ONO2;
(4) —Y—(CR4R4′)p-T-(CR4R4′)p-Q′-(CR4R4′)o—(CH2)—ONO2;
(5) —Y—(CR4R4′)p-Q′-(CR4R4′)o—(CH2)—ONO2;
(6) —Y—(CH—(CR4R4′)o-Q′-(CR4R4′)o—(CH2)—ONO2;
(7) —Y—(CR4R4′)o-Q′-(CR4R4′)o-T-(CR4R4′)o—(CH2)—ONO2;
(8) —Y—(CR4R4′)q—(W)q—(CR4R4′)o-Q′-(CR4R4′)o—(CH2)—ONO2;
(9) —Y—(CR4R4′)q—V—(CR4R4′)o-Q′-(CR4R4′)o—(CH2)—ONO2;
(10) —Y—(CR4R4′)o—V—(CR4R4′)o-Q′-(CR4R4′)o—(CH2)—ONO2;
(11) —Y—(CR4R4′)q—C(Z)-Q′-(CR4R4′)o—(CH2)—ONO2;
(12) —Y—(CR4R4′)p-(T)o-Q′-(T)o-(CR4R4′)q—(CH2)—ONO2;
(13) —Y—(CR4R4′)q—C(Z)—(CR4R4′)q—V—(CR4R4′)o-Q′-(CR4R4′)o—(CH2)—ONO2;
(14) —Y—(CR4R4′)q—C(Z)—(CR4R4′)q—(W)q—(CR4R4′)o-Q′-(CR4R4′)o—(CH2)—ONO2;
(15) —Y—(CR4R4′)o-Q′-(CR4R4′)o—ONO2;
or
(16) —Y—(CR4R4′)o—V—(CR4R4′)o-Q-(CR4R4′)o—ONO2;
R4 and R4′ at each occurrence are independently a hydrogen, lower alkyl group, —OH, —CH2OH, —ONO2, —NO2 or —CH2ONO2;
or R4 and R4′ taken together with the carbon atom to which they are attached are a cycloalkyl group or a heterocyclic ring;
V is —C(O)-T-, -T—C(O)—, -T-C(O)-T or T-C(O)—C(O)-T;
W is a covalent bond or a carbonyl group;
T at each occurrence is independently an oxygen, (S(O)o)o or NRj;
Rj is a hydrogen, an alkyl group, an aryl group, a heterocyclic ring, an alkylcarbonyl group, an alkylaryl group, an alkylsulfinyl group, an alkylsulfonyl group, an arylsulfinyl group, an arylsulfonyl group, a sulfonamido group, a N-alkylsulfonamido group, a N,N-diarylsulfonamido group, a N-arylsulfonamido group, a N-alkyl-N-arylsulfonamido group, a carboxamido group or a hydroxyl group;
p at each occurrence is independently an integer from 1 to 6;
q at each occurrence is independently an integer from 1 to 3;
o at each occurrence is independently an integer from 0 to 2;
Y is oxygen or sulfur (—S—);
Q′ is a cycloalkyl group, a heterocyclic ring or an aryl group;
Z is (═O), (═N—OR5), (═N—NR5R′5) or (═CR5R′5);
R5 and R5′ at each occurrence are independently a hydrogen, a hydroxyl group, 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, an alkoxyaryl group, a cycloalkyl group or a heterocyclic ring;
and
with the proviso that for X in the compounds of Formula (I):
when Y is oxygen or sulfur in Formula 3, and W is a covalent bond, and R4 and R4′ are each independently a hydrogen or a lower alkyl group, Q′ cannot be a phenyl group or a saturated, unsaturated or aromatic heterocyclic ring having 5 or 6 atoms, containing one to three heteroatoms, wherein the heteroatoms are each independently nitrogen, oxygen or sulfur;
when Y is oxygen in Formula 3, and W is a covalent bond, and R4 and R4′ are hydrogen, Q′ cannot be a cycloalkyl group;
when Y is oxygen or sulfur in Formula 5, 6 or 15, and R4 and R4′ are each independently a hydrogen or a lower alkyl group, Q′ cannot be a phenyl group or a saturated, unsaturated or aromatic heterocyclic ring having 5 or 6 atoms, containing one to three heteroatoms, wherein the heteroatoms are each independently nitrogen, oxygen or sulfur;
when Y is oxygen in Formula 5, 6 or 15, and W is a covalent bond, and R4 and R4′ are hydrogen, Q′ cannot be a cycloalkyl group;
and
with the further proviso that the invention does not include the compounds of Formula (I), wherein Rm is a methyl group, Rn is structure 12 (i.e. naproxen) of ACS registry numbers 410071-57-7, 311336-62-6, 290335-27-2, 290335-26-1, 290335-25-0;
and the compounds of Formula (I) wherein Rm is a hydrogen, Rn is structure 16 (i.e. diclofenac) of ACS registry numbers 497818-55-0, 454170-89-9, 311336-61-5, 290335-37-4, 290335-36-3, 290335-35-2;
and the compounds of Formula (I) wherein Rm is a hydrogen, Rn is structure 8 (i.e. indomethacin) of ACS registry numbers 290335-34-1, 290335-33-0, 290335-32-9, 290335-31-8, 204268-63-3 and the compounds of ACS registry numbers 497818-54-9, 497818-52-7, 410071-65-7, 410071-64-6, 410071-63-5, 410071-62-4, 410071-61-3, 410071-60-2, 410071-59-9, 410071-58-8, 410071-21-5, 311336-60-4, 290335-34-1, 290335-33-0, 290335-32-9, 290335-31-8, 290335-30-7, 290335-29-4, 290335-28-3, 209002-87-9, 209002-86-8, 209002-85-7, 209002-84-6, 204268-63-3 and 174454-47-8.

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Nitrosated nonsteroidal antiinflammatory compounds, compositions and methods of use

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Nitrosated nonsteroidal antiinflammatory compounds, compositions and methods of use

Life of this patent

Abstract

Claims22