Patent ID: 6780996
Filing Date: 2004-08-24
Classification: A61P,C07D

Abstract:
A process for preparing a 7-substituted-3-quinoline or quinolone carbonitrile of Formula (I): wherein: is a ring formula andX is selected from â€”Oâ€”, â€”Sâ€”, â€”NHâ€”, and â€”NR2â€²â€”; Wâ€² is H or â€”OR3; q is an integer of 0-5; m is an integer of 0-2; n is an integer of 2-5; R1 is an alkyl group of 1 to 6 carbon atoms, a cycloalkyl group of 3 to 10 carbon atoms, or an aryl, or heteroaryl ring, said aryl or heteroaryl ring is optionally fused to an additional aryl or heteroaryl ring, said aryl or heteroaryl rings optionally fused may optionally be substituted with 1 to 4 substituents independently selected from the group consisting of â€”J, â€”NO2, â€”NH2, â€”OH, â€”SH, â€”CN, â€”N3, â€”COOH, â€”CONH2, â€”NHC(O)NH2, â€”C(O)H, â€”CF3, â€”OCF3, â€”R4, â€”OR4, â€”NHR4, â€”NR4R4, â€”S(O)mR4, â€”NHSO2R4, â€”R5OH, â€”R5OR4, â€”R5NH2, â€”R5NHR4, â€”R5NR4R4, â€”R5SH, â€”R5S(O)mR4, â€”NHR6OH, â€”N(R4)R6OH, â€”N(R4)R6OR4, â€”NHR6NH2, â€”NHR6NHR4, â€”NHR6NR4R4, â€”N(R4)R6NH2, â€”N(R4)R6NHR4, â€”N(R4)R6NHR4R4, â€”OR6OH, â€”OR6OR4, â€”OR6NH2, â€”OR6NHR4, â€”OR6NR4R4, â€”OC(O)R4, â€”NHC(O)R4, â€”NHC(O)NHR4, â€”OR5C(O)R4, â€”NHR5C(O)R4, â€”C(O)R4, â€”C(O)OR4, â€”C(O)NHR4, â€”C(O)NR4R4, â€”R5C(O)H, â€”R5C(O)R4, â€”R5C(O)OH, â€”R5C(O)OR4, â€”R5C(O)NH2, â€”R5C(O)NHR4, â€”R5C(O)NR4R4, â€”R5OC(O)R4, â€”R5OC(O)NH2, â€”R5OC(O)NHR4 and â€”R5OC(O)NR4R4, and â€”YR7 groups wherein Y is independently selected from â€”C(O)â€”, â€”C(O)Oâ€”, â€”OC(O)â€”, â€”C(O)NHâ€”, â€”NHC(O)â€”, â€”NHSO2â€”, â€”SO2NHâ€”, â€”C(OH)Hâ€”, â€”Q(C(R8)2)qâ€”, â€”(C(R8)2)qâ€”, â€”(C(R8)2)qQâ€”, â€”C&boxH;Câ€”, cis- and trans â€”CHâ‰¡CHâ€” and cycloalkyl of 3-10 carbon atoms; Q is â€”Oâ€”, â€”S(O)mâ€”, â€”NHâ€”, or â€”NR9â€”; J is halogen selected from fluoro, chloro, bromo and iodo; R2, R2â€² and R3 are each independently selected from an alkyl group of 1 to 6 carbon atoms, an alkenyl group of 2 to 6 carbon atoms or an alkynyl group of 2 to 6 carbon atoms, wherein each independent alkyl, alkenyl or alkynyl group is optionally substituted with â€”NO2, cyano, or â€”QR4, or R2, R2â€² and R3 are each independently selected from â€”(C(R8)2)q-aryl, â€”(C(R8)2)q-heteroaryl, â€”(C(R8)2)q-heterocyclyl, â€”(C(R8)2)nâ€”Qâ€”(C(R8)2)q-aryl, â€”(C(R8)2)nâ€”Qâ€”(C(R8)2)q-heteroaryl, â€”(C(R8)2)nâ€”Qâ€”(C(R8)2)q-heterocyclyl, â€”(C(R8)2)nâ€”Qâ€”(C(R8)2)nâ€”Q-aryl, â€”(C(R8)2)nâ€”Qâ€”(C(R8)2)n, â€”Q-heteroaryl, and â€”(C(R8)2)nâ€”Qâ€”(C(R8)2)nâ€”Q-heterocyclyl, wherein the heterocyclyl group may optionally be substituted on carbon or nitrogen with a group selected from â€”R4, â€”(C(R8)2)q-aryl, â€”(C(R8)2)q-heteroaryl, â€”(C(R8)2)q-heterocyclyl, â€”(C(R8)2)qâ€”SO2R4, or the heterocyclyl group may optionally be substituted on carbon by â€”(C(R8)2)qâ€”QR4, or the heterocyclyl group may optionally be substituted on nitrogen by â€”(C(R8)2)nâ€”QR4, and also wherein the aryl or heteroaryl group may optionally be substituted with a group selected from â€”NO2, cyano, â€”R4, â€”(C(R8)2)q-aryl, â€”(C(R8)2)q-heteroaryl, â€”(C(R8)2)q-heterocyclyl, â€”(C(R8)2)qâ€”SO2R4, and â€”(C(R8)2)qâ€”QR4 and further provided that R2 and R2â€² may optionally be taken together with the nitrogen to which they are attached, forming a heterocyclic ring having 3 to 8 ring members one of which is optionally an additional heteroatom selected from nitrogen, oxygen and sulfur, wherein said formed heterocyclic ring may optionally be substituted on carbon or nitrogen with a group â€”R4, or said heterocyclic ring may optionally be substituted on carbon by â€”(C(R8)2)qâ€”QR4, or said heterocyclic ring may optionally be substituted on nitrogen by â€”(C(R8)2)nâ€”QR4; R4 is a monovalent group independently selected from alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, and alkynyl of 2 to 6 carbon atoms; R5 is a divalent group independently selected from alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, and alkynyl of 2 to 6 carbon atoms; R6 is a divalent alkyl group of 2 to 6 carbon atoms; R7 is a cycloalkyl ring of 3 to 10 carbon atoms optionally substituted with one or more alkyl groups of 1 to 6 carbon atoms or an aryl or heteroaryl ring, optionally fused to an additional aryl or heteroaryl ring, wherein said aryl or heteroaryl ring optionally fused, may optionally be substituted with 1 to 4 substituents selected from the group consisting of aryl, â€”CH2-aryl, â€”NH-aryl, â€”O-aryl, â€”S(O)m-aryl, â€”J, â€”NO2, â€”NH2, â€”OH, â€”SH, â€”CN, â€”N3, â€”COOH, â€”CONH2, â€”NHC(O)NH2, â€”C(O)H, â€”CF3, â€”OCF3, â€”R4, â€”OR4, â€”NHR4, â€”NR4R4, â€”S(O)mR4, â€”NHSO2R4, â€”R5OH, â€”R5OR4, â€”R5NH2, â€”R5NHR4, â€”R5NR4R4, â€”R5SH, â€”R5S(O)mR4, â€”NHR6OH, â€”NHR8OR4, â€”N(R4)R6OH, â€”N(R4)R6OR4, â€”NHR6NH2, â€”NHR6NHR4, â€”NHR6NR4R4, â€”N(R4)R6NH2, â€”N(R4)R6NHR4, â€”N(R4)R8NHR4R4, â€”OR6OH, â€”OR6OR4, â€”OR6NH2, â€”OR6NHR4, â€”OR6NR4R4, â€”OC(O)R4, â€”NHC(O)R4, â€”NHC(O)NHR4, â€”OR5C(O)R4, â€”NHR5C(O)R4,C(O)R4, â€”C(O)OR4, â€”C(O)NHR4, â€”C(O)NR4R4, â€”R5C(O)H, â€”R5C(O)R4, â€”R5C(O)OH, â€”R5C(O)OR4, â€”R5C(O)NH2, â€”R5C(O)NHR4, â€”R5C(O)NR4R4, â€”R5OC(O)R4, â€”R5OC(O)NH2, â€”R5OC(O)NHR4 and â€”R5OC(O)NR4R4; R8 is independently â€”H or â€”R4; R9 is a monovalent alkyl group of 1 to 6 carbon atoms; wherein aryl as used herein denotes a mono or bi-cyclic aromatic ring having 6 to 12 carbon atoms, heteroaryl as used herein denotes a 5 or 6 membered aromatic ring, which contains 1 to 4 heteroatoms which may be the same or different selected from nitrogen, oxygen and sulfur; and heterocyclyl denotes a saturated or partially unsaturated monocyclic radical containing 3 to 8 ring atoms selected from carbon, nitrogen, oxygen and sulfur with at least 1 and preferably 1 to 4, more preferably 1 to 2 nitrogen, oxygen or sulfur as ring atoms; which comprises reacting a corresponding compound of Formula (IIA) â€ƒwherein: â€ƒis as defined above; with a compound of the formula R2XH, where X is selected from â€”Sâ€”, â€”Oâ€”, â€”NHâ€”, and â€”NR2â€²â€” and where R2â€² and R2 are as defined above or R2â€² and R2 may optionally be taken together with the nitrogen to which each is attached to form a heterocyclic ring, and in the presence of a base, when X is â€”Oâ€” or â€”Sâ€”, to provide a 7-substituted-3-quinolinecarbonitrile of Formula (IA) â€ƒand if so desired converting a compound of Formula (IA) to a corresponding pharmaceutically acceptable salt by conventional means, and if so desired, converting the corresponding pharmaceutically acceptable salt to a compound of Formula (IA) by conventional means.