Patent EA-003188-B1 (EA)
Title: Substituted pyrido- or pyrimido- containing 6,6- or 6,7- bicyclic derivatives
Inventor: CHEN YUHPYNG LIANG
IPC: A61P25/22
Filed: 1997-07-23
Abstract: 1. A compound of the formula: wherein: the dashed lines represent optional double bonds; A is nitrogen or CR<7>; B is -CR<1>R<2>R<10>,-CR<2>R<10>NHR<1>,-CR<2>R<10>OR<1>, -CR<2>R<10>SR<1> or -COR<2>, and is single bonded to D; D is nitrogen or CR<4> and is single bonded to all atoms to which it is attached, E is oxygen, C=O, CR<6>R<12>; K is C=O, C=S, oxygen, or NR<8> when single bonded to both adjacent ring atoms, or CR<2> when it is double bonded to an adjacent ring atom; G is NR<8> when single bonded to both adjacent ring atoms, either N or CR<8> when it is double bonded to an adjacent ring atom; the 6-membered ring that contains D, E, K and G may contain from one to three double bonds, from zero to two heteroatoms selected from oxygen, nitrogen and sulfur, and from zero to two C=O groups, wherein the carbon atoms of such groups are part of the ring and the oxygen and sulfur atoms are substituents on the ring; R<1> is C1-C6alkyl; R<2> is C1-C12; C3-C8 cycloalkyl or (C1-C6 alkylene)(C3-C8 cycloalkyl); R<3> is C1-C4 alkyl, -O(C1-C4 alkyl), or S(C1-C4 alkyl);R<4> is hydrogen, each R<6> and R<8> that is attached to a carbon atom is selected, independently, from hydrogen, C1-C2 alkyl, -O(C1-C2 alkyl), -S(C1-C2 alkyl), or -C(=O)O(C1-C2 alkyl); R<5> is substituted phenyl, naphthyl, wherein each of the foregoing R<5> groups is substituted with two or three substituents R<15>, selected, independently, C1-C6 alkyl, -O(C1-C6 alkyl) and -S(C1-C6 alkyl); R<7> is hydrogen; R<10> is hydrogen; R<12> is hydrogen; and Z is NH, oxygen, sulfur, -N(C1-C4 alkyl) with the proviso that: (a) in the six-membered rings of structures in formula I, there can not be two double bonds adjacent to each other; or a pharmaceutically acceptable salt of such compound. 2. A compound according to claim 1 wherein B is -CHR<1>R<2> and R<1> is C1-C6 alkyl, R<2> is C1-C6 alkyl. 3. A compound according to claim 2 wherein R is methyl, ethyl, or methoxy; 4. A compound according to claim 3 wherein A is CH. 5. A compound according to claim 4 wherein D is N; E--K--G is CR<6>R<12>C(=O)-NH, CR<6>R<12>C(=O)-NCH3, C(=O)-CR<8>=CR<8>, C(=O) -C(=O) -NH. 6. A compound according to claim 5, wherein CR<6>R<12> is CH<2>. 7. A compound according to claim 5, wherein CR<8> is CH. 8. A compound according to claim 5, wherein CR<6>R12 is CH2 and CR<8> is CH. 9. A compound according to claim 8, wherein R<5> is di- or tri-substituted phenyl, in which the two or three substituents are independently selected from C1-C4 alkyl, O-(C1-C4 alkyl). 10. A compound according to claim 2, wherein B is CHR<1>R<2>; and the ring containing D, E, K and G is a benzo, pyrido, or pyrimido ring. 11. A compound according to claim 10, wherein R<5> is di- or tri-substituted phenyl, in which the two or three substituents are independently selected from C1-C4 alkyl, and O-(C1-C4 alkyl). 12. A compound according to claim 2, wherein R<5> is di- or tri-substituted phenyl, in which the two or three substituents are independently selected from C1-C4 alkyl, 0-(C1-C4 alkyl). 13. A compound according to claim 1 wherein R<3> is methyl, ethyl, or methoxy; R<6> and R<8> are selected, independently, from hydrogen and methyl; R<5> is di- or tri-substituted phenyl, in which two or three of the substitutents can be selected, independently, from C1-C4 alkyl, -O-(C1-C4 alkyl) and Z is oxygen or NH. 14. A compound according to claim 1 wherein A is N or CH. 15. A compound according to claim 1 wherein D is nitrogen, E = K is CH2-C=O. 16. A compound according to claim 1 wherein D is nitrogen, E = K is CH2-C=O, or CH2-O and G is NH or NCH3. 17. A compound according to claim 1 that is selected from: 1-(1-ethyl-propyl)-7-methyl-5-(2,4,6-trimethyl-phenoxy)-1,4-dihydro-2H-pyrido [3,4-b] pyrazin-3-one; 1-(1-ethyl-propyl)-4,7-dimethyl-5-(2,4,6-trimethyl-phenoxy)-1,4-dihydro-2H-pyrido [3,4-b]pyrazin-3-one: 1-(1-ethyl-propyl)-4,7-dimethyl-5-(2,4,6-trimethyl-phenoxy)-1,2,3,4-tetrahydro-pyrido [3,4-b]pyrazine; 1-(1-ethyl-propyl)-7-methyl-5-(2,4,6-trimethyl-phenoxy)-1,2,3,4-tetrahydro-pyrido[3,4-b]pyrazine; 1-(1-ethyl-propyl)-7-methyl-2-oxo-5-(2,4,6-trimethyl-phenoxy)-1,2,3,4-tetrahydro-(1,6)naphthyridine-3-carboxylic acid methyl ester, 1-(1-ethyl-propyl)-7-methyl-2-oxo-5-(2,4,6-trimethyl-phenoxy)-1,2,3,4-tetrahydro-[1,6)naphthyridine-3-carboxylic acid isopropyl ester, 1-(1-ethyl-propyl)-7-methyl-5-(2,4,6-trimethyl-phenoxy)-3,4-dihydro-1H-[1,6]naphthyridin-2-one; 1-(1-ethyl-propyl}-7-methyl-5-(2,4,6-trimethyl-phenoxy)-1,2,3,4-tetrahydro-[1,6]naphthyridine; 1-(1-ethyl-propyl)-7-methyl-5-(2,4,6-trimethyl-phenoxy)-1,4-dihydro-2H-3-oxa-1,6-diaza-naphthalene; 1-(1-ethyl-propyl)-4,7-dimethyl-5-(2,4,6-trimethyl-phenoxy)-1,4-dihydro-2H-3-oxa-1,6-diaza-naphthalene; 1-(1-ethyl-propyl)-3,7-dimethyl-5-(2,4,6-trimethyl-phenoxy)-3,4-dihydro-1H-3-oxa-[1,6]-naphthyridin-2-one; and 1-(1-ethyl-propyl)-3,3,6-trimethyl-4-(2,4,6-trimethyl-phenoxy)-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine.