Use of EP4 receptor ligands in the treatment of IL-6 involved diseases

1. A method of treating atherosclerosis comprising administering to a mammal, in need thereof, an effective amount of an EP4 receptor antagonist; wherein said EP4 receptor antagonist is a compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein

one of Y 1 , Y 2 , Y 3 and Y 4 is N and the others are independently selected from CH or C(L);

R 1 is H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-7 cycloalkyl, C 1-8 alkoxy, halo-substituted C 1-8 alkoxy, C 1-8 alkyl-S(O)m-, Q 1 -, pyrrolidinyl, piperidyl, oxopyrrolidinyl, oxopiperidyl, amino, mono- or di-(C 1-8 alkyl)amino, C 1-4 alkyl-C(═O)—N(R 3 )— or C 1-4 alkyl-S(O)m-N(R 3 )—, wherein said C 1-8 alkyl, C 2-8 alkenyl and C 2-8 alkynyl are optionally substituted with halo, C 1-3 alkyl, hydroxy, oxo, C 1-4 alkoxy-, C 1-4 alkyl-S(O)m-, C 3-7 cycloalkyl-, cyano, indanyl, 1,2,3,4-tetrahydronaphtyl, 1,2-dihydronaphtyl, pyrrolidinyl, piperidyl, oxopyrrolidinyl, oxopiperidyl, Q 1 -, Q 1 -C(═O)—, Q 1 -O—, Q 1 -S(O)m-, Q 1 -C 1-4 alkyl-O—, Q 1 -C 1-4 alkyl-S(O)m-, Q 1 -C 1-4 alkyl-C(O)—N(R 3 )—, Q 1 -C 1-4 alkyl-N(R 3 )— or C 1-4 alkyl-C(O)—N(R 3 —;

Q 1 is a 5–12 membered monocyclic or bicyclic aromatic ring optionally containing up to 4 heteroatoms selected from O, N and S, and is optionally substituted with halo, C 1-4 alkyl, halo-substituted C 1-4 alkyl, hydroxy, C 1-4 alkoxy, halo-substituted C 1-4 alkoxy, C 1-4 alkylthio, nitro, amino, mono- or di-(C 1-4 alkyl)amino, cyano, HO—C 1-4 alkyl, C 1-4 alkoxy-C 1-4 alkyl, C 1-4 alkylsulfonyl, aminosulfonyl, C 1-4 alkylC(═O)—, HO(O═)C—, C 1-4 alkyl-O(O═)C—, R 3 N(R 4 )C(═O)—, C 1-4 alkylsulfonylamino, C 3-7 cycloalkyl, R 3 C(═O)N(R 4 )— or NH 2 (HN═)C—;

A is a 5–6 membered monocyclic aromatic ring optionally containing up to 3 heteroatoms selected from O, N and S, wherein said 5–6 membered monocyclic aromatic ring is optionally substituted with up to 3 substituents selected from halo, C 1-4 alkyl, halo-substituted C 1-4 alkyl, hydroxy, C 1-4 alkoxy, halo-substituted C 1-4 alkoxy, C 1-4 alkylthio, nitro, amino, mono- or di-(C 1-4 alkyl)amino, cyano, HO—C 1-4 alkyl, C 1-4 alkoxy-C 1-4 alkyl, C 1-4 alkylsulfonyl, aminosulfonyl, acetyl, R 3 N(R 4 )C(═O)—, HO(O═)C—, C 1-4 alkyl-O(O═)C—, C 1-4 alkylsulfonylamino, C 3-7 cycloalkyl, R 3 C(═O)N(R 4 )— and NH 2 (HN═)C—;

B is halo-substituted C 1-6 alkylene, C 3-7 cycloalkylene, C 2-6 alkenylene, C 2-6 alkynylene, —O—C 1-5 alkylene, C 1-2 alkylene-O—C 1-2 alkylene or C 1-6 alkylene optionally substituted with an oxo group or C 1-3 alkyl;

W is NH, N—C 1-4 alkyl, O, S, N—OR 5 or a covalent bond;

R 2 is H, C 1-4 alkyl, OH or C 1-4 alkoxy;

Z is a 5–12 membered monocyclic or bicyclic aromatic ring optionally containing up to 3 heteroatoms selected from O, N and S, wherein said 5–12 membered monocyclic or bicyclic aromatic ring is optionally substituted with halo, C 1-4 alkyl, halo-substituted C 1-4 alkyl, C 1-4 alkenyl, C 1-4 alkynyl, hydroxy, C 1-4 alkoxy, halo-substituted C 1-4 alkoxy, C 1-4 alkylthio, nitro, amino, mono- or di-(C 1-4 alkyl)amino, cyano, HO—C 1-4 alkyl, C 1-4 alkoxy-C 1-4 alkyl, C 1-4 alkylsulfonyl, aminosulfonyl, C 1-4 alkylC(═O)—, R 3 C(═O)N(R 4 )—, HO(O═)C—, C 1-4 alkyl-O(O═)C—, C 1-4 alkylsulfonylamino, C 3-7 cycloalkyl, NH 2 (HN═)C—, Q 2 -S(O)m-, Q 2 -O—, Q 2 N(R 3 )— or Q 2 -;

L is halo, C 1-4 alkyl, halo-substituted C 1-4 alkyl, hydroxy, C 1-4 alkoxy, halo-substituted C 1-4 alkoxy, C 1-4 alkylthio, nitro, amino, mono- or di-(C 1-4 alkyl)amino, cyano, HO—C 1-4 alkyl, C 1-4 alkoxy-C 1-4 alkyl, C 1-4 alkylsulfonyl, aminosulfonyl, C 1-4 alkylC(═O)—, HO(O═)C—, C 1-4 alkyl-O(O═)C—, C 1-4 alkylsulfonylamino, C 3-7 cycloalkyl, R 3 C(═O)N(R 4 )—, NH 2 (HN═)C—, R 3 N(R 4 )C(═O)—, R 3 N(R 4 )S(O)m-, Q 2 -, Q 2 -C(═O)—, Q 2 -O—, Q 2 -C 1-4 alkyl-O—, or two adjacent L groups are optionally joined together to form an alkylene chain having 3 or 4 members in which one or two (non-adjacent) carbon atoms are optionally replaced by oxygen atoms;

m is 0, 1 or 2;

R 3 and R 4 are independently selected from H and C 1-4 alkyl;

R 5 is H, C 1-4 alkyl, C 1-4 alkyl-(O═)C— or C 1-4 alkyl-O—(O═)C—; and

Q 2 is a 5–12 membered monocyclic or bicyclic aromatic ring, or a 5–12 membered tricyclic ring optionally containing up to 3 heteroatoms selected from O, N and S, wherein said 5–12 membered monocyclic or bicyclic aromatic ring is optionally substituted with halo, C 1-4 alkyl, halo-substituted C 1-4 alkyl, C 1-4 alkenyl, C 1-4 alkynyl, hydroxy, C 1-4 alkoxy, halo-substituted Cl 1-4 alkoxy, C 1-4 alkylthio, nitro, amino, mono- or di-(C 1-4 alkyl)amino, cyano, HO—C 1-4 alkyl, C 1-4 alkoxy-C 1-4 alkyl, C 1-4 alkylsulfonyl, aminosulfonyl, C 1-4 alkyl-(O═)C—, R 3 (R 4 )C(═O)N—, HO(O═)C—, C 1-4 alkyl-O(O═)C—, C 1-4 alkylsulfonylamino, C 3-7 cycloalkyl, C 1-4 alkyl-C(═O)NH— or NH 2 (HN═)C—.

2. The method according to claim 1 , wherein said EP4 receptor antagonist is N-[({2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethyl}amino)carbonyl]-4-methylbenzene sulfonamide or a pharmaceutically acceptable of salt thereof.

3. The method according to claim 1 , wherein said EP4 receptor antagonist is 2-ethyl-4,6-dimethyl-1-(4-{2-[({[(4-methylphenyl)sulfonyl]amino}carbonyl)amino]ethyl}phenyl)-1H-imidazo[4,5-c]pyridine or a pharmaceutically acceptable salt thereof.