Patent EA-001963-B1 (EA)
Title: Atropisomers of3-aryl-4(3h)-quinazolinones and their use as ampa-receptor antagonists
Inventor: WELCH WILLIARD MCKOWAN JR
IPC: C07D405/06
Filed: 1998-02-06
Abstract: 1. An atropisomer of the formula   wherein R<2> is a phenyl group of the formula Ph<2> or a five or six membered heterocycle, wherein said 6-membered heterocycle has the formula   wherein "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" and "M" can be nitrogen and ii) when "K", "L" or "M" is nitrogen, then its respective substituent R<15>, R<16> or R<17> is absent; wherein said five membered heterocycle has the formula   wherein 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 (i) only one of "P", "Q" or "T" can be oxygen, NH or sulfur; (ii) at least one of "P", "Q" or "T" must be a heteroatom; and (iii) when "P" or "Q" is oxygen or sulphur then its respective substituent R<15> or R<16> is absent; wherein said Ph<2> is a group of the formula   R<3> is hydrogen, halo, -CN, -NO2, CF3, (C1-C6)alkyl or (C1-C6)alkoxy; R<5> is hydrogen, (C1-C6)alkyl, halo, CF3, (C1-C6)alkoxy or (C1-C6)alkylthiol; R<6> is hydrogen or halo; R<7> is hydrogen or halo; R<8> is hydrogen or halo; R<9> is hydrogen, halo, CF3, (C1-C6)alkyl optionally substituted with one to three halogen atoms, (C1-C6)alkoxy optionally substituted with one to three halogen atoms, (C1-C6)alkylthiol, amino-(CH2)s-, (C1-C6)alkyl-NH-(CH2)s-, di(C1-C6)alkyl-N-(CH2)s-, (C3-C7)cycloalkyl-NH-(CH2)s-, H2N-(C=O)-(CH2)s-, (C1-C6)alkyl-HN-(C=O)-(CH2)s-, di(C1-C6)alkyl-N-(C=O)-(CH2)s-, (C3-C7)cycloalkyl-NH-(C=O)-(CH2)s-, R<13>O-(CH2)s-, R<13>O-(C=O)-(CH2)s-, H(O=C)-NH-(CH2)s-, (C1-C6)alkyl-(O=C)-NH-(CH2)s-,   C1-C6(alkyl)-(C=O)-, hydroxy, hydroxy-(C1-C6)alkyl-, (C1-C6)alkyl-O-(C1-C6)alkyl-, and -CN; R<10> is hydrogen or halo; R<11> and R<14> are selected, independently, from hydrogen, halo, CF3, (C1-C6)alkyl optionally substituted with one to three halogen atoms, (C1-C6)alkoxy optionally substituted with one to three halogen atoms, (C1-C6)alkylthiol, amino-(CH2)p-, (C1-C6)alkyl-NH-(CH2)p-, di(C1-C6)alkyl-N-(CH2)p-, (C3-C7)cycloalkyl-NH-(CH2)p-, amino-(C1-C6)alkyl-NH-(CH2)p-, (C1-C6)alkyl-NH-(C1-C6)alkyl-NH-(CH2)p-, di(C1-C6)alkyl-N-(C1-C6)alkyl-NH-(CH2)p-,   -, H2N-(C=O)-(CH2)p-, (C1-C6)alkyl-HN-(C=O)-(CH2)p-, di(C1-C6)alkyl-N-(C=O)-(CH2)p-, (C3-C7)cycloalkyl-NH-(C=O)(CH2)p-, R<13>O-(CH2)p-, R<13>O-(C=O)-(CH2)p-, H(O=C)-O-, H(O=C)-O-(C1-C6)alkyl-, H(O=C)-NH-(CH2)p-, (C1-C6)alkyl-(O=C)-NH-(CH2)p-, -CHO, H-(C=O)-(CH2)p-, (C1-C6)alkyl-(C=O)-(CH2)p-,    (C1-C6)alkyl-(C=O)-O-(CH2)p-, amino-(C1-C6)alkyl-(C=O)-O-(CH2)p-, (C1-C6)alkyl-NH-(C1-C6)alkyl-(C=O)-O-(CH2)p-, di(C1-C6)alkyl-N-(C1-C6)alkyl-(C=O)-O-(CH2)p-, amino-(C1-C6)alkyl-O-(C=O)-(CH2)p-, (C1-C6)alkyl-NH-(C1-C6)alkyl-O-(C=O)-(CH2)p-, di(C1-C6)alkyl-N-(C1-C6)alkyl-O-(C=O)-O-(CH2)p-, hydroxy, hydroxy-(C1-C6)alkyl-, hydroxy-(C1-C6)alkyl-NH-(CH2)p-, (C1-C6)alkyl-O-(C1-C6)alkyl-, -CN, piperidine-(CH2)p-, pyrrolidine-(CH2)p-, or 3-pyrroline-(CH2)p-, wherein said piperidine, pyrrolidine and 3-pyrroline of said piperidine-(CH2)p-, pyrrolidine-(CH2)p- and 3-pyrroline-(CH2)p- moieties may optionally be substituted on any of the ring carbon atoms capable of supporting an additional bond, preferably zero to two substituents, with a substituent independently selected from halo, CF3, (C1-C6)alkyl optionally substituted with one to three halogen atoms, (C1-C6)alkoxy optionally substituted with one to three halogen atoms, (C1-C6)alkylthiol, amino-(CH2)p-, (C1-C6)alkyl-NH-(CH2)p-, di(C1-C6)alkyl-N-(CH2)p-, (C3-C7)-cycloalkyl-NH-(CH2)p-, amino-(C1-C6)alkyl-NH-(CH2)p-, (C1-C6)alkyl-NH-(C1-C6)alkyl-NH-(CH2)p-, di(C1-C6)alkyl-N-(C1-C6)alkyl-NH-(CH2)p-, (C1-C6)alkyl-O-(C1-C6)alkyl-, di(C1-C6)alkyl-N-  , H2N-(C=O)-(CH2)p-, (C1-C6)alkyl-HN-(C=O)-(CH2)p-, di(C1-C6)alkyl-N-(C=O)-(CH2)p-, (C3-C7)cycloalkyl-NH-(C=O)-(CH2)p-, R<13>O-(C=O)-(CH2)p-, H(O=C)-O-, H(O=C)-O-(C1-C6)alkyl-, H(O=C)-NH-(CH2)p-, (C1-C6)alkyl-(O=C)-NH-(CH2)p-, -CHO, H-(C=O)-(CH2)p-, (C1-C6)alkyl-(C=O)-,     (C1-C6)alkyl-(C=O)-O-NH-(CH2)p-, amino-(C1-C6)alkyl-(C=O)-O-(CH2)p-, (C1-C6)alkyl-NH-(C1-C6)alkyl-(C=O)-O-(CH2)p-, di(C1-C6)alkyl-N-(C1-C6)alkyl-(C=O)-O-(CH2)p-, hydroxy, hydroxy-(C1-C6)alkyl-, hydroxy-(C1-C6)alkyl-NH-(CH2)p-, and -CN; R<12> is hydrogen, -CN or halo; R<13> is hydrogen, (C1-C6)alkyl, (C1-C6)alkyl-(C=O)-, (C1-C6)alkyl-O-(C=O)-, (C1-C6)alkyl-NH-(C1-C6)alkyl, di(C1-C6)alkyl-N-(C1-C6)alkyl-, (C1-C6)alkyl-NH-(C=O)-, or di(C1-C6)alkyl-N-(C=O)-; R<15> is hydrogen, -CN, (C1-C6)alkyl, halo, CF3, -CHO or (C1-C6)alkoxy; R<16> is hydrogen, -CN, (C1-C6)alkyl, halo, CF3, -CHO or (C1-C6)alkoxy; R<17> is hydrogen, -CN, (C1-C6)alkyl, amino-(C1-C6)alkyl-, (C1-C6)alkyl-NH-(C1-C6)alkyl-, di(C1-C6)alkyl-N-(C1-C6)alkyl-, halo, CF3, -CHO or (C1-C6)alkoxy; n is an integer from zero to 3; each p is independently an integer from zero to 4; s is an integer from zero to 4; wherein the dashed bond represented an optional double bond; and the pharmaceutically acceptable salts of such compounds. 2. A compound according to Claim 1 wherein R<3> is hydrogen, halo or (C1-C6)alkyl. 3. A compound according to Claim 1 wherein 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<5> is fluoro, bromo, chloro, methyl or trifluoromethyl. 5. A compound according to Claim 2 wherein R<5> is fluoro, bromo, chloro, methyl or trifluoromethyl. 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<11> is -CHO, chloro, fluoro, methyl, (C1-C6)alkyl-NH-(CH2)p-, di(C1-C6)alkyl-N-(CH2)p-, or cyano. 7. A compound according to Claim 2 wherein R<2> is Ph<2> and either R<9> is fluoro, chloro, -CN or hydroxy, or R<11> is -CHO, chloro, fluoro, methyl, (C1-C6)alkyl-NH-(CH2)p-, di(C1-C6)alkyl-N-(CH2)p-, or cyano. 8. A compound according to Claim 1 wherein R<2> is heteroaryl, 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. 9. 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, -CHO, chloro, fluoro, methyl, (C1-C6)alkyl-NH-(C1-C6)alkyl, di(C1-C6)alkyl-N-(C1-C6)alkyl, or cyano; or R<15> or R<16> are independently hydrogen, -CHO, chloro, fluoro, methyl or cyano. 10. 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. 11. 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>, R<15> or R<16> are each independently hydrogen, chloro, fluoro, methyl or cyano. 12. 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> or R<15> are independently selected from hydrogen, chloro, fluoro, methyl or cyano. 13. A compound according to Claim 1 wherein said compound is selected from the group consisting of: (S)-3-(2-chlorophenyl)-2-[2-(5-diethylaminomethyl-2-fluorophenyl)-vinyl]-6-fluoro-3H-quinazolin-4-one; (S)-3-(2-chlorophenyl)-2-[2-(6-diethylaminomethylpyridin-2-yl)-vinyl]-6-fluoro-3H-quinazolin-4-one; (S)-3-(2-chlorophenyl)-2-[2-(4-diethylaminomethylpyridin-2-yl)-vinyl]-6-fluoro-3H-quinazolin-4-one; (S)-3-(2-chlorophenyl)-2-[2-(6-ethylaminomethylpyridin-2-yl)-vinyl]-6-fluoro-3H-quinazolin-4-one; (S)-3-(2-bromophenyl)-2-[2-(6-diethylaminomethylpyridin-2-yl)-vinyl]-6-fluoro-3H-quinazolin-4-one; (S)-3-(2-chlorophenyl)-6-fluoro-2-[2-(6-methoxymethylpyridin-2-yl)vinyl]-3H-quinazolin-4-one; (S)-3-(2-chlorophenyl)-6-fluoro-2-[2-(4-methylpyrimidine-2-yl)-vinyl]-3H-quinazolin-4-one; (S)-3-(2-chlorophenyl)-6-fluoro-2-{2-[6-(isopropylaminomethyl)pyridin-2-yl]ethyl}-3H-quinazolin-4-one; and (S)-6-fluoro-2-[2-(2-methylthiazol-4-yl)vinyl]-3-(2-methylphenyl)-3H-quinazolin-4-one. 14. A pharmaceutical composition for treating or preventing a condition selected from cerebral deficits subsequent to or resulting from cardiac bypass surgery and grafting, stroke, cerebral ischemia, spinal cord trauma, head trauma, Alzheimer's disease, Huntington's chorea, amyotrophic lateral sclerosis, epilepsy, AIDS-induced dementia, perinatal hypoxia, hypoxia (such as conditions caused by strangulation, surgery, smoke inhalation, asphyxiation, drowning, choking, electrocution or drug or alcohol overdose), cardiac arrest, hypoglycemic neuronal damage, opiate tolerance, addiction withdrawal (such as alcoholism and drug addiction including opiate, cocaine and nicotine addiction), idiopathic and drug induced Parkinson's disease or brain edema; muscular spasms, migraine headaches, urinary incontinence, psychosis, convulsions, chronic or acute pain, ocular damage, retinopathy, retinal neuropathy, tinnitus, anxiety, emesis and tardive dyskinesia, in a mammal, comprising an amount of a compound according to Claim 1 effective in treating or preventing such condition and a pharmaceutically acceptable carrier. 15. A method for treating or preventing a condition selected from cerebral deficits subsequent to or resulting from cardiac bypass surgery and grafting, stroke, cerebral schema, spinal cord trauma, head trauma, Alzheimer's disease, Huntington's chorea, amyotrophic lateral scleros