Nicotinamide derivatives and a tiotropium salt in combination for the treatment of diseases

A pharmaceutical composition comprising a compound of formula (1)

• 49
• wherein:
• m is 0, 1, 2 or 3;
• n is 0, 1, 2 or 3;
• R1 and R2 are each independently hydrogen, halo, cyano, (C1-C4)alkyl or (C1-C4)alkoxy;
• X is —O—, —S— or —NH—;
• R3 is:
• (a) phenyl, naphthyl, heteroaryl or (C3-C8)cycloalkyl, each optionally substituted independently with 1 to 3 halo, cyano, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)thioalkyl, —C(═O)N H2, —C(═O)NH((C1-C4)alkyl), hydroxy, —O—C(═O)(C1-C4)alkyl, —C(═O)—O—(C1-C4)alkyl or hydroxy(C1-C4)alkyl;
• or
• (b) a bicyclic group of the following formula:
• 50
• where the symbol “*” in the definition of R3 indicates the point of attachment of each partial formula (1.1) through (1.4) to the remaining portion of formula (1);
• Y is
• 51
• where the symbol “*” in the definition of Y indicates the point of attachment of each partial formula (1.5) through (1.11) to the remaining portions —NH— of formula (1) and “**” in the definition of Y indicates the point of attachment of each partial formula (1.5) through (1.11) to the remaining portions —R4 of formula (1);
• and
• R4 is:
• (a) phenyl, naphthyl or heteroaryl, each optionally substituted independently with 1 to 3 carboxy, —C(═O)—O—(C1-C4)alkyl, halo, cyano, —C(═O)NH2, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, hydroxy or hydroxy(C1-C4)alkyl;
• or
• (b) (C1-C4)alkyl optionally substituted with hydroxy, carboxyl, C(═O)—O—(C1-C4)alkyl, phenyl, naphthyl or heteroaryl wherein said phenyl, naphthyl and heteroaryl are each optionally substituted independently with 1 to 3 carboxy, —C(═O)O(C1-C4)alkyl, halo, cyano, —C(═O)NH2, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, hydroxy or hydroxy(C1-C4)alkyl;
• or a pharmaceutically acceptable salt thereof, tiotropium or a derivative thereof and a pharmaceutically acceptable excipient and/or additive.

A method of treating a disease, disorder or condition mediated by the PDE4 isozyme in a mammal, said method comprising administering to said mammal in need of such mediation, a therapeutically effective amount of a compound of formula (1)

• 52
• wherein:
• m is 0, 1, 2 or 3;
• n is 0, 1, 2 or 3;
• R1 and R2 are each independently hydrogen, halo, cyano, (C1-C4)alkyl or (C1-C4)alkoxy;
• X is —O—, —S— or —NH—;
• R3 is:
• (a) phenyl, naphthyl, heteroaryl or (C3-C8)cycloalkyl, each optionally substituted independently with 1 to 3 halo, cyano, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)thioalkyl, —C(═O)N H2, —C(═O)NH((C1-C4)alkyl), hydroxy, —O—C(═O)(C1-C4)alkyl, —C(═O)—O—(C1-C4)alkyl or hydroxy(C1-C4)alkyl;
• or
• (b) a bicyclic group of the following formula:
• 53
• where the symbol “*” in the definition of R3 indicates the point of attachment of each partial formula (1.1) through (1.4) to the remaining portion of formula (1);
• Y is
• 54
• where the symbol “*” in the definition of Y indicates the point of attachment of each partial formula (1.5) through (1.11) to the remaining portions —NH— of formula (1) and “**” in the definition of Y indicates the point of attachment of each partial formula (1.5) through (1.11) to the remaining portions —R4 of formula (1);
• and
• R4 is:
• (a) phenyl, naphthyl or heteroaryl, each optionally substituted independently with 1 to 3 carboxy, —C(═O)—O—(C1-C4)alkyl, halo, cyano, —C(═O)NH2, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, hydroxy or hydroxy(C1-C4)alkyl;
• or
• (b) (C1-C4)alkyl optionally substituted independently with hydroxy, carboxyl, C(═O)—O—(C1-C4)alkyl, phenyl, naphthyl or heteroaryl wherein said phenyl, naphthyl and heteroaryl are each optionally substituted independently with 1 to 3 carboxy, —C(═O)O(C1-C4)alkyl, halo, cyano, —C(═O)NH2, (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, hydroxy or hydroxy(C1-C4)alkyl;
• or a pharmaceutically acceptable salt thereof and tiotropium or a derivative thereof.