Patent RU-2323215-C2 (RU)
Inventor: JUNG FREDERIK ANRI
IPC: A61P43/00
Filed: 2002-12-20
Granted: 2008-04-27
Abstract: FIELD: organic chemistry, medicine, biochemistry, pharmacy. 
     SUBSTANCE: invention relates to derivatives of quinazoline of the general formula (I):   and their pharmaceutically acceptable salts and in vivo hydrolyzed esters as aurorakinase inhibitors and their using, to a method for inhibition and pharmaceutical composition based on thereof, and to a method for their synthesis. In compound of the general formula (I) X represents -NR 6  wherein R 6  represents hydrogen atom or (C 1 -C 6 )-alkyl; R 5  represents group of the formula (a):   or (b):   wherein * means a point for adding to group X in compound of the formula (I); R 1 , R 2 , R 3  and R 4  are chosen independently from hydrogen atom or -X 1 R 9  wherein X 1  represents -O-, and R 9  is chosen from one of the following groups: (1) hydrogen atom or (C 1 -C 5 )-alkyl; (3) (C 1 -C 5 )-alkyl-X 3 R 20  wherein X 3  represents -O- or -NR 25  wherein R 25  represents hydrogen atom, (C 1 -C 3 )-alkyl or (C 1 -C 3 )-alkoxy-(C 2 -C 3 )-alkyl, and R 20  represents hydrogen atom, (C 1 -C 3 )-alkyl, cyclopentyl, cyclohexyl or 5- or 6-membered saturated heterocyclic group with 1 or 2 heteroatoms that are chosen independently from nitrogen atom (N) wherein (C 1 -C 3 )-alkyl group can carry 1 or 2 substitutes that are chosen from oxo, hydroxy group, halogen atom and (C 1 -C 4 )-alkoxy group, and wherein cyclic group can carry 1 or 2 substitutes that are chosen from (C 1 -C 4 )-alkyl; (4) (C 1 -C 5 )-alkyl-X 4 -(C 1 -C 5 )-alkyl-X 5 R 26  wherein X 4  and X 5  can be similar or different, and each means -O- or -NR 31 - wherein R 31  represents hydrogen atom, (C 1 -C 3 )-alkyl or (C 1 -C 3 )-alkoxy-(C 2 -C 3 )-alkyl, and R 26  represents hydrogen atom or (C 1 -C 3 )-alkyl; (5) R 32  wherein R 32  represents 5- or 6-membered saturated heterocyclic group added through carbon atom or nitrogen atom with 1 or 2 heteroatoms that are chosen independently from oxygen (O), sulfur (S) and N atoms wherein heterocyclic group can carry 1 or 2 substitutes that are chosen from hydroxy, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-hydroxyalkyl, (C 1 -C 4 )-alkoxy, (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl; (6) (C 1 -C 5 )-alkyl-R 32  wherein R 32  is given above; (18) (C 1 -C 5 )-alkyl optionally substituted with 1, 2 or 3 halogen atoms; (19) (C 1 -C 5 )-alkyl-X 10 -(C 1 -C 5 )-alkyl-X 11 R 90  wherein X 10  and X 11  that can be similar or different each means -O- or -NR 95 - wherein R 95  represents (C 1 -C 5 )-alkyl, (C 1 -C 3 )-alkyl substituted with 1, 2 or 3 halogen atoms, (C 1 -C 4 )-alkyl or (C 1 -C 4 )-alkoxy groups, (and wherein 2 (C 1 -C 4 )-alkoxy groups by (C 1 -C 4 )-alkyl groups alkoxy can form in common 5- or 6-membered saturated heterocyclic group that comprises 2 oxygen atoms), (C 2 -C 5 )-alkenyl, (C 2 -C 5 )-alkynyl, (C 3 -C 6 )-cycloalkyl, (C 3 -C 6 )-cycloalkyl-(C 1 -C 3 )-alkyl or (C 1 -C 3 )-alkoxy-(C 2 -C 3 )-alkyl; R 90  represents hydrogen atom or (C 1 -C 3 )-alkyl; (22) (C 1 -C 5 )-alkyl-R 96  wherein R 96  represents 5- or 6-membered heterocyclic group that can be saturated or unsaturated (added through carbon or nitrogen atom) with 1 or 2 heteroatoms that are chosen independently from N wherein heterocyclic group can carry 1 or 2 substitutes that are chosen from (C 1 -C 4 )-hydroxyalkyl, (C 1 -C 4 )-alkyl, hydroxy and (C 1 -C 4 )-alkoxy-(C 1 -C 4 )-alkyl, and wherein R 60  represents hydrogen atom; R 61  represents group of the subformula (k):   wherein p represents 0 or 1; q represents 1; R' 1  and R'' 1  represent independently hydrogen atom or (C 1 -C 10 )-alkyl; T represents C=O; V represents -N(R 63 )R 64  wherein R 63  represents -(CH 2 ) q' R 70  or phenyl optionally substituted with 1 or 2 groups chosen independently from halogen atom, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy, trifluoromethyl, trifluoromethoxy, nitro, difluoromethyl, difluoromethoxy and cyano group; R 64  represents hydrogen atom or (C 1 -C 3 )-alkyl; q' = 0; R 70  represents -K-J wherein K represents a bond, and J represents phenyl optionally substituted with 1, 2 or 3 groups that are chosen from halogen atom, (C 1 -C 3 )-alkyl, cyano, (C 1 -C 3 )-alkoxy, and R 62  represents hydrogen atom. Proposed compounds can be used in treatment and prophylaxis of diseases mediated by aurorakinase activity, for example, proliferative diseases, such as cancer. 
     EFFECT: valuable medicinal properties of compounds. 
     32 cl, 7 tbl, 2 sch, 147 ex