Patent ID: 6544979
Filing Date: 2003-04-08
Classification: A61K,A61P

Abstract:
A method for improving the bioavailability of a second pharmaceutical agent in a warm-blooded animal in need thereof wherein the second pharmaceutical agent interacts with a membrane-associated transporter comprising orally co-administering to the warm-blooded animal a first pharmaceutical compound of formula (I) a N-oxide form, a pharmaceutically acceptable addition salt or a stereochemically isomeric form thereof, whereinthe dotted line represents an optional bond; n is 1 or 2; R1 is hydrogen; halo; formyl; C1-4alkyl; C1-4alkyl substituted with 1 or 2 substituents each independently selected from hydroxy, C1-4alkyloxy, C1-4alkylcarbonyloxy, imidazolyl, thiazolyl or oxazolyl; or a radical of formula â€”Xâ€”COâ€”OR5â€ƒâ€ƒ(a-1); â€”Xâ€”COâ€”NR6R7â€ƒâ€ƒ(a-2); orâ€”Xâ€”COâ€”R10â€ƒâ€ƒ(a-3); â€ƒwherein â€”Xâ€” is a direct bond, C1-4alkanediyl or C2-6alkenediyl; R5is hydrogen; C1-12alkyl; Ar; Het; C1-6alkyl substituted with C1-4alkyloxy, C1-4alkyloxycarbonylC1-4alkyloxy, Ar or Het; R6 and R7 each independently are hydrogen or C1-4alkyl; R10 is imidazolyl, thiazolyl or oxazolyl; R2 is hydrogen, halo, C1-4alkyl, hydroxyC1-4alkyl, C1-4alkyloxycarbonyl, carboxyl, formyl or phenyl; R3 is hydrogen, C1-4alkyl or C1-4alkyloxy; R4 is hydrogen, halo, C1-4alkyl, C1-4alkyloxy or haloC1-4alkyl; Z is Z1 or Z2; wherein Z1 is a bivalent radical of formula â€”CH2â€”, â€”CH2â€”CH2â€” or â€”CH&boxH;CHâ€”; provided that when the dotted line is a bond, then Z1 is other than â€”CH2â€”; Z2 is a bivalent radical of formula â€”CHOHâ€”CH2â€”, â€”Oâ€”CH2â€”, â€”C(&boxH;O)â€”CH2â€”or â€”C(&boxH;NOH)â€”CH2â€”; â€”Aâ€”Bâ€” is a bivalent radical of formula â€”Yâ€”CR8&boxH;CHâ€”â€ƒâ€ƒ(b-1); â€”CH&boxH;CR8â€”Yâ€”â€ƒâ€ƒ(b-2); â€”CH&boxH;CR8â€”CH&boxH;CHâ€”â€ƒâ€ƒ(b-3); â€ƒâ€”CH&boxH;CHâ€”CR8&boxH;CHâ€”â€ƒâ€ƒ(b-4);orâ€”CH&boxH;CHâ€”CH&boxH;CR8â€”â€ƒâ€ƒ(b-5); â€ƒwherein each R8 independently is hydrogen, halo, C1-4alkyl, C1-4alkyloxy, hydroxyC1-4alkyl, hydroxycarbonylC1-4alkyl, formyl, carboxyl, ethenyl substituted with carboxyl, or ethenyl substituted with C1-4alkyloxycarbonyl; each Y independently is a bivalent radical of formula â€”Oâ€”, â€”Sâ€” or â€”NR9â€”; wherein R9 is hydrogen, C1-4alkyl or C1-4alkylcarbonyl; â€”A1â€” is a direct bond; C1-6alkanediyl; C1-6alkanediyl-oxy-C1-6alkanediyl; C1-6alkanediyloxy; carbonyl; C1-6alkanediylcarbonyl; C1-6alkanediyloxy substituted with hydroxy; or C1-6alkanediyl substituted with hydroxy or &boxH;NOH; â€”A2â€” is a direct bond or C1-6alkanediyl; Q is phenyl; phenyl substituted with one or two substituents selected from hydrogen, halo, hydroxy, C1-4alkyl, C1-4alkyloxy or haloC1-4alkyl; naphthalenyl; naphthalenyl substituted with one or two substituents selected from hydrogen, halo, hydroxy, C1-4alkyl, C1-4alkyloxy or haloC1-4alkyl; pyridinyl; pyridinyl substituted with one or two substituents selected from hydrogen, halo, hydroxy, C1-4alkyl, C1-4alkyloxy or haloC1-4alkyl; quinolinyl; or quinolinyl substituted with one or two substituents selected from hydrogen, halo, hydroxy, C1-4alkyl, C1-4alkyloxy or haloC1-4alkyl; Ar is phenyl or phenyl substituted with 1, 2 or 3 substituents each independently selected from hydrogen, halo, C1-4alkyl or C1-4alkyloxy; Het is furanyl; furanyl substituted with C1-4alkyl, C1-4alkyloxy or hydroxyC1-4alkyl; oxazolyl; oxazolyl substituted with C1-4alkyl or C1-4alkyloxy; or quinolinyl.