Compositions and methods for the inhibition of phospholipase A2
The present invention relates to various novel substituted dipeptide derived nitrogen-containing heterocyclic compounds, their pharmaceutically acceptable salt derivatives, and their methods of use.
1 . A compound for inhibiting a PLA2 enzyme comprising the formula I:
or a pharmaceutically acceptable salt thereof,
wherein, W is a member selected from the group consisting of —C(R 5 )(R 5a )—; —C(R 6 )(R 6a )—C(R 7 )(R 7a )—; —C(R 8 )═C(R 9 )—; —N(R 10 ), and combinations thereof;
X is a member selected from the group consisting of —N(R 1a )C(═Y)N(R 4 )—; —OC(═Y)N(R 4 )—; —N(R 1a )C(═Y)O—; —N(R 1a )S(═O)N(R 4 )—; —N(R 1a )S(═O) 2 N(R 4 )—; —C(R 1a )(R 3a )C(═Y)N(R 4 )—, and combinations thereof;
Y and Z represent, each independent from the other, a member selected from the group consisting of oxygen (“O”) and sulfur (“S”); and
R 1 , R 1a , R 2 , R 3 , R 3a , R 4 , R 5 , R 5a , R 6 , R 6a , R 7 , R 7a , R 8 , R 9 , and R 10 represent, each independent from the other, a member selected from the group consisting of: a hydrogen atom; an amino acid side chain; a (C1-C10) alkyl; (C1-C10) alkenyl; (C1-C10) alkynyl; (C5-C12) monocyclic or bicyclic aryl; (C5-C14) monocyclic or bicyclic aralkyl; monocyclic or bicyclic (C5-C14) heteroaralkyl; and (C1-C10) monocyclic or bicyclic heteroaryl group having up to 5 heteroatoms selected from N, O, S, and P said groups being able to be non-substituted or substituted by 1 to 6 substituents further selected from the group consisting of: a halogen atom, an NO 2 , OH, amidine, benzamidine, imidazole, 1,2,3-triazole, alkoxy, (C1-C4), amino, piperazine, piperidine, dialkylamino, guanidine group, bis alkylated or bis acylated guanido group, carboxylic acid, carboxamide, ester, hydroxamic acid, phosphinic acid, phosphonate, phosphonamidate, sulfhydryl and any combination thereof.
2 . A therapeutic composition for treating or preventing an inflammatory condition in an individual comprising an effective amount of a compound of formula I:
or a pharmaceutically acceptable salt thereof,
wherein, W is a member selected from the group consisting of —C(R 5 )(R 5a )—; —C(R 6 )(R 6a )—C(R 7 )(R 7a )—; —C(R 8 )═C(R 9 )—; —N(R 10 ), and combinations thereof;
X is a member selected from the group consisting of —N(R 1a )C(═Y)N(R 4 )—; —OC(═Y)N(R 4 )—; —N(R 1a )C(═Y)O—; —N(R 1a )S(═O)N(R 4 )—; —N(R 1a )S(═O) 2 N(R 4 )—; —C(R 1a )(R 3a )C(═Y)N(R 4 )—, and combinations thereof;
Y and Z represent, each independent from the other, a member selected from the group consisting of oxygen (“O”) and sulfur (“S”); and
R 1 , R 1a , R 2 , R 3 , R 3a , R 4 , R 5 , R 5a , R 6 , R 6a , R 7 , R 7a , R 8 , R 9 , and R 10 represent, each independent from the other, a member selected from the group consisting of: a hydrogen atom; an amino acid side chain; a (C1-C10) alkyl; (C1-C10) alkenyl; (C1-C10) alkynyl; (C5-C12) monocyclic or bicyclic aryl; (C5-C14) monocyclic or bicyclic aralkyl; monocyclic or bicyclic (C5-C14) heteroaralkyl; and (C1-C10) monocyclic or bicyclic heteroaryl group having up to 5 heteroatoms selected from N, O, S, and P said groups being able to be non-substituted or substituted by 1 to 6 substituents further selected from the group consisting of: a halogen atom, an NO 2 , OH, amidine, benzamidine, imidazole, 1,2,3-triazole, alkoxy, (C1-C4), amino, piperazine, piperidine, dialkylamino, guanidine group, bis alkylated or bis acylated guanido group, carboxylic acid, carboxamide, ester, hydroxamic acid, phosphinic acid, phosphonate, phosphonamidate, sulfhydryl and any combination thereof.
3 . The therapeutic composition of claim 2 , further comprising at least one of a pharmaceutically acceptable carrier, excipient, adjuvant, another biologically active agent or a combination thereof.
4 . The therapeutic composition of claim 3 , wherein the biologically active agent comprises at least one of a steroid, non-steroidal anti-inflammatory, acetylsiacylic acid, a cyclooxygenase inhibitor or a combination thereof.
5 . The therapeutic composition of claim 3 , wherein the therapeutic is present in a pharmaceutically acceptable form.
6 . The therapeutic of claim 5 , wherein the pharmaceutically acceptable form comprises a tablet or capsule comprising an enteric coating.
7 . A method for the treatment or prevention of an inflammatory disease or condition comprising:
administering to an individual in need thereof, an effective amount of the therapeutic of claim 2 .
8 . The method of claim 7 , wherein the therapeutic further comprises at least one other ingredient selected from the group consisting of a pharmaceutically acceptable carrier, excipient, adjuvant, another biologically active agent or a combination thereof.
9 . The method of claim 8 , wherein the biologically active agent comprises a steroid, non-steroidal anti-inflammatory, acetylsiacylic acid, a cyclooxygenase inhibitor or a combination thereof.
10 . The method of claim 7 , wherein the therapeutic is administered in a pharmaceutically acceptable form.
11 . The method of claim 10 , wherein the pharmaceutically acceptable form comprises a tablet or capsule comprising an enteric coating for oral administration.
12 . The method of claim 7 , wherein the therapeutic is administered parenterally.
13 . The method of claim 7 , wherein the inflammatory disease or condition is selected from the group consisting of tissue injury, rheumatoid arthritis, osteoarthritis, eczema, lupus, IBD, Crohn's disease, ARDS, colitis, psoriasis, asthma, cystic fibrosis, AIDS, stenosis, restenosis, Alzheimer's disease, Parkinson's disease, cancer, atherosclerosis, arteriosclerosis, and cardiopulmonsary disease.
14 . A kit for treating or preventing a physiological condition associated with inflammation, said kit comprising a plurality of containers, wherein at least one of said containers contains the therapeutic of claim 2 or a pharmaceutically acceptable salt thereof.