2-phenyl benzimidazole derivatives as MCP-1 antagonists

A method for the treatment of inflammatory disease or condition, atherosclerosis, restenosis, chronic or acute immune disorders, or transplant rejection in a mammal in need thereof comprising administering to such mammal an effective amount of a compound of Formula I

• wherein A is N;
• W, X, Y, and Z can be independently C—R2, C—R3, C—R4, or C—R5,
• R2, R3, R4, and R5 can be independently
• H,
• C1-20 alkyl,
• halogen,
• nitro,
• —SO2NR8R9,
• alkoxy of from 1-4 carbon atoms;
• —S(O)pR where p is an integer from 0 to 2;
• —(CH2)mOR,
• —(CH2)mCOOR,
• —(CH2)mNR8R9,
• —(CH2)mCONR8R9,
• —(CH2)mCOR, or
• —CF3;
• benzyl, or
• phenyl wherein benzyl or phenyl is optionally substituted with one or two substituents each independently selected from alkyl, halogen, hydrogen, hydroxy, or alkoxy;
• m is an integer of from 0 to 4,
• R is hydrogen, lower alkyl of from 1-4 carbon atoms, aryl of from 6-10 carbon atoms, or benzyl;
• R′2 is:
• H,
• C1-20 alkyl,
• halogen,
• nitro,
• —SO2NR8R9,
• alkoxy of from 1-4 carbon atoms,
• —S(O)pR wherein p is an integer of from 0 to 2,
• —(CH2)mOR1—(CH2)COOR,
• —(CH2)mNR8R9,
• —(CH2)mCONR8R9,
• —(CH2)mCOR, or
• —CF3;
• R1 can be H, lower alkyl of from 1-4 carbon atoms, or —(CH2)m-Ph;
• R6 is hydrogen or alkyl of from 1-6 carbon atoms or R7;
• R7 is (CH2)nNR10R11;
• n is an integer from 2 to 6;
• R8 and R9 can be independently hydrogen, lower alkyl of from 1-4 carbon atoms, or can be taken together to form a ring of from 3-8 atoms having up to one additional heteroatom as O, S, SO2, or N—R12;
• R10 and R11 can independently be lower alkyl,
• —(CH2)mPh, unsubstituted or substituted with up to three R2 substituents, or
• R10 and R11 can be taken together to form a ring of from 3-8 atoms which may contain oxygen or NR12;
• R12 is
• hydrogen,
• lower alkyl,
• —(CH2)tPh, where Ph is phenyl unsubstituted or substituted with up to three R2 substituents;
• t is an integer of from 0 to 2;
• or a pharmaceutically acceptable salt thereof.

A method for the treatment of atherosclerosis in a mammal in need thereof comprising administering to such mammal an effective amount of a compound of Formula I

• wherein A is N;
• W, X, Y, and Z can be independently C—R2, C—R3, C—R4, C—R5,
• R2, R3, R4, and R5 can be independently:
• H,
• C1-20 alkyl,
• halogen,
• nitro,
• —SO2NR8R9,
• alkoxy of from 1-4 carbon atoms;
• —S(O)pR where p is an integer from 0 to 2;
• —(CH2)mOR,
• —(CH2)mCOOR,
• —(CH2)mNR8R9,
• —(CH2)mCONR8R9,
• —(CH2)mCOR, or
• —CF3;
• m is an integer of from 0 to 4,
• R is hydrogen, lower alkyl of from 1-4 carbon atoms, aryl of from 6-10 carbon atoms, or benzyl;
• R1 can be H, lower alkyl of from 1-4 carbon atoms, or —(CH2)m-Ph;
• R6 is hydrogen or alkyl of from 1-6 carbon atoms or R7;
• R7 is (CH2)nNR10R11;
• n is an integer from 2 to 6;
• R8 and R9 can be independently hydrogen, lower alkyl of from 1-4 carbon atoms, or can be taken together to form a ring of from 3-8 atoms having up to one additional heteroatom as O, S, SO2, or N—R12;
• R10 and R11 can independently be lower alkyl,
• —(CH2)mPh, unsubstituted or substituted with up to three R2 substituents, or
• R10 and R11 can be taken together to form a ring of from 3-8 atoms which may contain oxygen or NR12;
• R12 is
• hydrogen,
• lower alkyl,
• —(CH2)tPh, where Ph is phenyl unsubstituted or substituted with up to three R2 substituents;
• t is an integer of from 0 to 2;
• or a pharmaceutically acceptable salt thereof.

A method of inhibiting the binding of Monocyte Chemoattractant Protein-1 to a receptor thereof in a mammal in need thereof comprising administering to such mammal an effective inhibiting amount of a compound of Formula I

• wherein A is N;
• W, X, Y, and Z can be independently C—R2, C—R3, C—R4, C—R5,
• R2, R3, R4, and R5 can be independently
• H,
• C1-20 akyl,
• halogen,
• nitro,
• —SO2NR8R9,
• alkoxy of from 1-4 carbon atoms,
• —S(O)pR where p is an integer of from 0 to 2,
• —(CH2)mOR,
• —(CH2)mCOOR,
• —(CH2)mNR8R9,
• —(CH2)mCONR8R9,
• —(CH2)mCOR,
• —CF3,
• -benzyl, or
• phenyl wherein benzyl or phenyl is optionally substituted with one or two substituents each independently selected from alkyl, halogen, hydrogen, hydroxy, or alkoxy;
• m is an integer of from 0 to 4,
• R is hydrogen, lower alkyl of from 1-4 carbon atoms, aryl of from 6-10 carbon atoms, or benzyl;
• when X and Y are substituted by alkyl, they can be joined to form a ring fused at X and Y;
• R1 can be H, lower alkyl of from 1-4 carbon atoms, or —(CH2)m-Ph;
• R′2 is:
• H,
• C1-20 alkyl,
• halogen,
• nitro,
• —SO2NR8R9,
• alkoxy of from 1-4 carbon atoms,
• —S(O)pR wherein p is an integer of from 0 to 2,
• —(CH2)mOR1—CH2COOR,
• —(CH2)mNR8R9,
• —(CH2)mCONR8R9,
• —(CH2)mCOR, or
• —CF3;
• R6 is hydrogen or alkyl of from 1-6 carbon atoms or R7;
• R7 is (CH2)nNR10R11;
• n is an integer from 2 to 6;
• R8 and R9 can be independently hydrogen, lower alkyl of from 1-4 carbon atoms, or can be taken together to form a ring of from 3-8 atoms having up to one additional heteroatom as O, S, SO2, or N—R12;
• R10 and R11 can independently be lower alkyl,
• —(CH2)mPh, unsubstituted or substituted with up to three R2 substituents, or
• R10 and R11 can be taken together to form a ring of from 3-8 atoms which may contain oxygen or NR12;
• R12 is
• hydrogen,
• lower alkyl,
• —(CH2)tPh, where Ph is phenyl unsubstituted or substituted with up to three R2 substituents;
• t is an integer of from 0 to 2;
• or a pharmaceutically acceptable salt thereof.