Patent EA-002905-B1 (EA)
Title: 2,3 disubstituted -4 (3h)-quinazolinones and pharmaceutcal composition comprising thereon
Inventor: ELLIOTT MRK LEONARD
IPC: C07D239/91
Filed: 1997-02-17
Abstract: 1. 2,3-disubstituted -4 (3H)- quinazolinones of the formula   where in R<1> is optionally substituted phenyl of the formula Ph<1> or heteroaryl wherein said heteroaryl is selected from the group consisting of pyridin-2-yl, pyridin-3-yl, and pyridin4-yl, wherein said heteroaryl may optionally be substituted by a substituent in second position selected from (C1-C6)alkyl and halogen; said Ph<1> is a group of the formula   R<2> is phenyl of the formula ph<2> or a five or six membered heterocycle, wherein said 6-membered heterocycle has the formula   where in "N" is nitrogen; wherein said ring positions "K", "L" and "M" may be independently selected from carbon or nitrogen, with the proviso that i) only one of "K", "L" or "M" can be nitrogen and ii) when "K", "L" or "M" is nitrogen then its respective R<15>, R<16> or R<17> is absent; where in said five membered heterocycle has the formula   where in said "T" is -CH-, N, NH, O or S; wherein said ring positions "P" and "Q" may be independently selected from carbon, nitrogen, oxygen or sulfur; with the proviso that only one of "P," "Q" or "T" can be oxygen or sulfur and at least one of "P," "Q" or "T" must be a heteroatom; where in said ph<2> is a group of the formula   R<3> is hydrogen, halo or (C1-C6)alkyl; R<5> is hydrogen, (C1-C6)alkyl, halo; R<6> is hydrogen or halo; R<7> is hydrogen or halo; R<8> is hydrogen or halo; R<9> is hydrogen, halo, (C1-C6)alkyl, di(C1-C6)alkyl-N-(CH2)p-, hydroxy or -CH; R<10> is hydrogen, (C1-C6)alkyl, di(C1-C6)alkyl-N-(CH2)p-,CHO or HO-(C1-C6)alkyl: R<11> is hydrogen or halo; R<12> is hydrogen, -CH or halo; R<13> is (C1-C6)alkyl- (C=O); R<14> is selected from hydrogen, halo, (C1-C6)alkyl, optionally substituted with one to three halogen atoms,   di(C1-C6)alkyl-N-(C1-C6)alkyl-(C=O)-O-(CH2)p-, hydroxy-(C1-C6)alkyl-, -(C1-C6)alkyl-O--(C1-C6)alkyl-, -CN, piperidine-(CH2)p-, pyrrolidine--(CH2)p-, and 3-pyrroline-(CH2)p-, wherein said piperidine of -(CH2)p moiety may optionally be substituted on any of the ring carbon atoms capable o f supporting and additional bond, with a substituent -(C1-C6)alkyl. R<15> is hydrogen or (C1-C6)alkyl; R<16> is hydrogen or (C1-C6)alkyl; R<17> is hydrogen, -CN, di(C1-C6)alkyl -N- (C1-C6)alkyl-, (C1-C6)alkoxy group or CHF2 each p is independently an integer from zero to 4; wherein the dashed bond represented an optional double bond; with the proviso that: 1) when R<9> is hydrogen, one of R<11> and R<12> is other than hydrogen, 2) when R3 is hydrogen, R<6>, R<7>, and R<8> are hydrogen; and R<5> is chloro or methyl, then (a) R<2> can not be unsubstituted phenyl, thienyl or furyl or (b) R<9> can not be hydroxy or methyl; 3) when R<3> is hydrogen or chloro, R<5> is methyl, R<6>, R<7>, and R<8> are hydrogen, and K, L and M equal carbon, then (a) one of R<14> through R<17> must be other than hydrogen or (b) R<17> must be other than hydrogen; 4) when R<1> is unsubstituted pyridin-2-yl, and R<3> is hydrogen, bromo or iodo then R2 can not be unsubstituted phenyl; 5) when R<7> is chloro; R<5>, R<6> and R<8> are hydrogen, and R<3> is hydrogen, then (a) R<2> can not be unsubstituted phenyl, pyridyl, thienyl or furyl or (b) R<9> can not be hydroxy when R<10> and R<11> are hydrogen; 6) when R<2> is unsubstituted pyridin-2-yl, R<5> and R7 are hydrogen, and R<3> is hydrogen, then R<6> or R<8> must be other than chloro; 7) when R<2> is unsubstituted phenyl, R<3> is hydrogen, and R<5> and R<7> are hydrogen, then one of R<6> or R<7> must be other than chloro; and the pharmaceutically acceptable salts of such compounds. 2. A compound according to Claim 1 wherein R<3> is fluoro. 3. A compound according to Claim 1 wherein R<1> is Ph<1> and one of R<5>, R<6>, R<7> or R<8> is fluoro, bromo, chloro, methyl or trifluoromethyl. 4. A compound according to Claim 1 wherein R<1> is Ph<1> and R<5> is fluoro, bromo, chloro, methyl or methyl. 5. A compound according to Claim 2 wherein R<1> is Ph<1> and R<5> is fluoro, bromo, chloro, methyl or methyl. 6. A compound according to Claim 1 wherein R<2> is Ph<2> and either R<9> is fluoro, chloro, -CN or hydroxy, or R<10> is -CHO, methyl, or di(C1-C6)alkyl-N-(CH2)p-. 7. A compound according to Claim 2 wherein R<2> is Ph2 and either R<9> is fluoro, chloro, -CN or hydroxy, or R<10> is -CHO, methyl, or di(C1-C6)alkyl-N-(CH2)p-. 8. A compound according to Claim 1 wherein R<1> is heteroaryl optionally substituted at the second position with halo, or (C1-C6)alkyl. 9. A compound according to Claim 2 wherein R<1> is heteroaryl optionally substituted at the second position with halo, (C1-C6)alkyl. 10. A compound according to Claim 6 wherein R<1> is heteroaryl optionally substituted at the second position with halo, (C1-C6)alkyl. 11. A compound according to Claim 1 wherein R<1> is pyridin-3-yl substituted at thr second position of the pyridine ring with chloro or methyl. 12. A compound according to Claim 1 wherein R<2> is heteroaryl are those wherein said heteroaryl is either an optionally substituted six-membered heterocycle wherein "K", "L" and "M" are carbon, or "K" and "L" are carbon and "M" is nitrogen (i.e. pyrimidin-2-yl), or said heteroaryl is an optionally substituted five membered heterocycle wherein "T" is nitrogen, "P" is sulfur and "Q" is carbon, or "T" is nitrogen or sulfur, "Q" is nitrogen or sulfur and "P" is carbon or "T" is oxygen and "P" and "Q" are each carbon. 13. A compound according to Claim 1 wherein R<2> is an optionally substituted six-membered heterocycle wherein "K", "L" and "M" are carbon are those wherein R<14> is hydrogen, -CHO, chloro, fluoro, methyl, (C1-C6)alkyl-NH-(CH2)p-,di(C1-C6)alkyl-N-(CH2)p- or cyano; R<17> is hydrogen or di(C1-C6)alkyl-N- C1-C6)alkyl; or R<15> or R<16> are independently hydrogen or methyl. 14. A compound according to Claim 1 wherein R<2> is an optionally substituted six-membered heterocycle wherein "K", "L" and "M" are carbon and R<14> is hydrogen, CHO, methyl, (C1-C6)alkyl-NH-(CH2)p-,di(C1-C6)alkyl-N-(CH2)p- or cyano. 15. A compound according to Claim 1 wherein R<2> is an optionally substituted five-membered heterocycle wherein "T" is nitrogen, "P" is sulfur and "Q" is carbon and R<14> is chloro, fluoro or methyl; and R<15> and R<16> are each independently hydrogen or methyl. 16. A compound according to Claim 1 wherein R<2> is an optionally substituted five-membered heterocycle wherein "T" is nitrogen or sulfur, "Q" is sulfur or nitrogen and "P" is carbon and R<14> is selected from hydrogen, chloro, flouro and methyl; and R<15> is selected from hydrogen and methyl. 17. A compound according to Claim 1 wherein said compound is selected from the group consisting of: 3-(2-chloro-phenyl)-2-[2-(5-diethylaminomethyl-2-fluoro-phenyl)-vinyl]-6-fluoro-3H-quinazolin-4-one; 3-(2-chloro-phenyl)-2-[2-(6-diethylaminomethyl-pyridin-2-yl)-vinyl]-6-fluoro-3H-quinazolin-4-one; 3-(2-chloro-phenyl)-2-[2-(4-diethylaminomethyl-pyridin-2-yl)-vinyl]-6-fluoro-3H-quinazolin-4-one; 3-(2-chloro-phenyl)-2-[2-(6-ethylaminomethyl-pyridin-2-yl)-vinyl]-6-fluoro-3H-quinazolin-4-one; 3-(2-bromo-phenyl)-2-[2-(6-diethylaminomethyl-pyridin-2-yl)-vinyl]-6-fluoro-3H-quinazolin-4-one; 3-(2-chloro-phenyl)-6-fluoro-2-[2-(6-methoxymethyl-pyridin-2-yl)-vinyl]-3H-quinazolin-4-one; 6-fluoro-3-(2-methyl-pyridin-3-yl)-2-[2-(2-methyl-thiazol-4-yl)-vinyl]-3H-quinazolin-4-one; 3-(2-chloro-phenyl)-6-fluoro-2-[2-(4-methyl-pyrimidine-2-yl)-vinyl]- 3H-quinazolin-4-one; 3-(2-chloro-phenyl)-6-fluoro-2-{2-[6-(isopropylamino-methyl)-pyridin-2-yl]-ethyl}-3H-quinazolin-4-one; and 2-[2-(5-diethylaminomethyl-2-fluoro-phenyl)-vinyl]-6-fluoro-3-(2-methyl-pyridin-3-yl)-3H-quinazolin4-one. 18 A pharmaceutical composition having an AMPA receptor antagonizing activity and comprising an effective amount of a compound of the formula 1 according to Claim 1 and a pharmaceutically acceptable carrier.