AU2005205016B2 - 1-benzyl-5-piperazin-1-yl-3,4 dihydro-1H-quinazolin-2-one derivatives and the respective 1H-benzo(1,2,6)thiadiazine-2,2-dioxide and 1,4-dihydro-benzo(D) (1,3)oxazin-2-one derivatives as modulators of the 5-hydroxytryptamine receptor (5-HT) for the treatment of diseases of the central nervous system - Google Patents

Info

Publication number

AU2005205016B2

AU2005205016B2 AU2005205016A AU2005205016A AU2005205016B2 AU 2005205016 B2 AU2005205016 B2 AU 2005205016B2 AU 2005205016 A AU2005205016 A AU 2005205016A AU 2005205016 A AU2005205016 A AU 2005205016A AU 2005205016 B2 AU2005205016 B2 AU 2005205016B2

Authority

AU

Australia

Prior art keywords

dihydro

benzyl

piperazin

quinazolin

compound

Prior art date

2004-01-16

Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

Ceased

Links

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• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims description 36
• 201000010099 disease Diseases 0.000 title claims description 24
• XCXVPQAXJPZYNW-UHFFFAOYSA-N 1h-2$l^{6},1,3-benzothiadiazine 2,2-dioxide Chemical compound C1=CC=C2C=NS(=O)(=O)NC2=C1 XCXVPQAXJPZYNW-UHFFFAOYSA-N 0.000 title claims description 7
• 238000011282 treatment Methods 0.000 title description 19
• QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 title description 18
• 210000003169 central nervous system Anatomy 0.000 title description 5
• SYZIUAAQNFJPJY-UHFFFAOYSA-N 1,4-dihydro-3,1-benzoxazin-2-one Chemical class C1=CC=C2COC(=O)NC2=C1 SYZIUAAQNFJPJY-UHFFFAOYSA-N 0.000 title description 3
• 108091032151 5-hydroxytryptamine receptor family Proteins 0.000 title description 3
• 102000014630 G protein-coupled serotonin receptor activity proteins Human genes 0.000 title 2
• QDEHEDMGJOKOIM-UHFFFAOYSA-N 1-benzyl-5-piperazin-1-yl-3,4-dihydroquinazolin-2-one Chemical class O=C1NCC2=C(N3CCNCC3)C=CC=C2N1CC1=CC=CC=C1 QDEHEDMGJOKOIM-UHFFFAOYSA-N 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims description 184
• -1 2-cyanophenyl Chemical group 0.000 claims description 155
• 229910052739 hydrogen Inorganic materials 0.000 claims description 80
• 239000001257 hydrogen Substances 0.000 claims description 78
• 125000000217 alkyl group Chemical group 0.000 claims description 73
• 239000000203 mixture Substances 0.000 claims description 53
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 51
• 238000000034 method Methods 0.000 claims description 50
• 125000005843 halogen group Chemical group 0.000 claims description 36
• FVACZQHQBKPPMX-UHFFFAOYSA-N quinazolin-2-one Chemical compound C1=C[CH]C2=NC(=O)N=CC2=C1 FVACZQHQBKPPMX-UHFFFAOYSA-N 0.000 claims description 29
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 27
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 26
• 125000001188 haloalkyl group Chemical group 0.000 claims description 26
• 125000003545 alkoxy group Chemical group 0.000 claims description 25
• 229910052757 nitrogen Inorganic materials 0.000 claims description 21
• 150000003839 salts Chemical class 0.000 claims description 21
• 238000002360 preparation method Methods 0.000 claims description 20
• 229910052701 rubidium Inorganic materials 0.000 claims description 20
• 125000001072 heteroaryl group Chemical group 0.000 claims description 17
• 125000004429 atom Chemical group 0.000 claims description 16
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 16
• 229910052799 carbon Inorganic materials 0.000 claims description 15
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 15
• 125000001153 fluoro group Chemical group F* 0.000 claims description 15
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 13
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 12
• JZFICWYCTCCINF-UHFFFAOYSA-N Thiadiazin Chemical compound S=C1SC(C)NC(C)N1CCN1C(=S)SC(C)NC1C JZFICWYCTCCINF-UHFFFAOYSA-N 0.000 claims description 11
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 10
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• 239000008194 pharmaceutical composition Substances 0.000 claims description 10
• 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 claims description 9
• 208000036864 Attention deficit/hyperactivity disease Diseases 0.000 claims description 8
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
• 125000002252 acyl group Chemical group 0.000 claims description 7
• 208000015802 attention deficit-hyperactivity disease Diseases 0.000 claims description 7
• 239000003814 drug Substances 0.000 claims description 7
• 125000004404 heteroalkyl group Chemical group 0.000 claims description 7
• 125000001624 naphthyl group Chemical group 0.000 claims description 7
• 229910052717 sulfur Inorganic materials 0.000 claims description 7
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 6
• 208000035231 inattentive type attention deficit hyperactivity disease Diseases 0.000 claims description 6
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 5
• 239000003937 drug carrier Substances 0.000 claims description 5
• 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 5
• 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims description 4
• 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 claims description 4
• 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 claims description 4
• 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 4
• 208000024827 Alzheimer disease Diseases 0.000 claims description 4
• 208000020925 Bipolar disease Diseases 0.000 claims description 4
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• 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 4
• 208000015114 central nervous system disease Diseases 0.000 claims description 4
• 210000001035 gastrointestinal tract Anatomy 0.000 claims description 4
• 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 claims description 4
• 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims description 4
• 201000000980 schizophrenia Diseases 0.000 claims description 4
• 125000003107 substituted aryl group Chemical group 0.000 claims description 4
• UCKBESNKIBVXOX-UHFFFAOYSA-N 1-[(4-fluorophenyl)methyl]-5-piperazin-1-yl-3,4-dihydroquinazolin-2-one Chemical compound C1=CC(F)=CC=C1CN1C2=CC=CC(N3CCNCC3)=C2CNC1=O UCKBESNKIBVXOX-UHFFFAOYSA-N 0.000 claims description 3
• OAMKXXZOKAQMFE-UHFFFAOYSA-N 1-benzyl-6-fluoro-5-piperazin-1-yl-3,4-dihydroquinazolin-2-one Chemical compound O=C1NCC2=C(N3CCNCC3)C(F)=CC=C2N1CC1=CC=CC=C1 OAMKXXZOKAQMFE-UHFFFAOYSA-N 0.000 claims description 3
• 208000023105 Huntington disease Diseases 0.000 claims description 3
• 208000028683 bipolar I disease Diseases 0.000 claims description 3
• ZYFGPTIXKRIOIL-UHFFFAOYSA-N 1-[(2-fluorophenyl)methyl]-5-piperazin-1-yl-3,4-dihydroquinazolin-2-one Chemical compound FC1=CC=CC=C1CN1C2=CC=CC(N3CCNCC3)=C2CNC1=O ZYFGPTIXKRIOIL-UHFFFAOYSA-N 0.000 claims description 2
• 208000026139 Memory disease Diseases 0.000 claims description 2
• 208000012902 Nervous system disease Diseases 0.000 claims description 2
• CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 claims description 2
• DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims 2
• RUOOEFDLFQQWNN-UHFFFAOYSA-N 1-[(2,2-dimethyl-3h-1-benzofuran-7-yl)methyl]-5-piperazin-1-yl-3,4-dihydroquinazolin-2-one Chemical compound C=12OC(C)(C)CC2=CC=CC=1CN(C1=CC=C2)C(=O)NCC1=C2N1CCNCC1 RUOOEFDLFQQWNN-UHFFFAOYSA-N 0.000 claims 1
• CQGNOOPIHCBULX-UHFFFAOYSA-N 1-[(2,3-dichlorophenyl)methyl]-5-piperazin-1-yl-3,4-dihydroquinazolin-2-one Chemical compound ClC1=CC=CC(CN2C3=CC=CC(=C3CNC2=O)N2CCNCC2)=C1Cl CQGNOOPIHCBULX-UHFFFAOYSA-N 0.000 claims 1
• ZREQQLIQGVXRAC-UHFFFAOYSA-N 1-[(2,3-difluorophenyl)methyl]-5-piperazin-1-yl-3,4-dihydro-2$l^{6},1,3-benzothiadiazine 2,2-dioxide Chemical compound FC1=CC=CC(CN2S(NCC3=C(N4CCNCC4)C=CC=C32)(=O)=O)=C1F ZREQQLIQGVXRAC-UHFFFAOYSA-N 0.000 claims 1
• HKUVDSQISIOHAM-UHFFFAOYSA-N 1-[(2,6-dimethylphenyl)methyl]-5-piperazin-1-yl-3,4-dihydroquinazolin-2-one Chemical compound CC1=CC=CC(C)=C1CN1C2=CC=CC(N3CCNCC3)=C2CNC1=O HKUVDSQISIOHAM-UHFFFAOYSA-N 0.000 claims 1
• PEAADNBWFCCMCV-UHFFFAOYSA-N 1-[(2-fluorophenyl)methyl]-5-piperazin-1-yl-4h-3,1-benzoxazin-2-one Chemical compound FC1=CC=CC=C1CN1C2=CC=CC(N3CCNCC3)=C2COC1=O PEAADNBWFCCMCV-UHFFFAOYSA-N 0.000 claims 1
• VQAUFXIQDMQEPX-UHFFFAOYSA-N 1-[(3-chloro-2-fluorophenyl)methyl]-5-piperazin-1-yl-3,4-dihydro-2$l^{6},1,3-benzothiadiazine 2,2-dioxide Chemical compound FC1=C(Cl)C=CC=C1CN1S(=O)(=O)NCC2=C(N3CCNCC3)C=CC=C21 VQAUFXIQDMQEPX-UHFFFAOYSA-N 0.000 claims 1
• MDKXZMBGVZHRCL-UHFFFAOYSA-N 1-[(3-fluorophenyl)methyl]-5-piperazin-1-yl-3,4-dihydroquinazolin-2-one Chemical compound FC1=CC=CC(CN2C3=CC=CC(=C3CNC2=O)N2CCNCC2)=C1 MDKXZMBGVZHRCL-UHFFFAOYSA-N 0.000 claims 1
• CZRPTAXTPDFGFM-UHFFFAOYSA-N 1-[(3-fluorophenyl)methyl]-5-piperazin-1-yl-4h-3,1-benzoxazin-2-one Chemical compound FC1=CC=CC(CN2C3=CC=CC(=C3COC2=O)N2CCNCC2)=C1 CZRPTAXTPDFGFM-UHFFFAOYSA-N 0.000 claims 1
• LGRNEPWCKFRPPA-UHFFFAOYSA-N 1-[(4-chlorophenyl)methyl]-5-piperazin-1-yl-3,4-dihydro-2$l^{6},1,3-benzothiadiazine 2,2-dioxide Chemical compound C1=CC(Cl)=CC=C1CN1S(=O)(=O)NCC2=C(N3CCNCC3)C=CC=C21 LGRNEPWCKFRPPA-UHFFFAOYSA-N 0.000 claims 1
• NEJULOZWVLPODE-UHFFFAOYSA-N 1-[(4-fluorophenyl)methyl]-5-piperazin-1-yl-3,4-dihydro-2$l^{6},1,3-benzothiadiazine 2,2-dioxide Chemical compound C1=CC(F)=CC=C1CN1S(=O)(=O)NCC2=C(N3CCNCC3)C=CC=C21 NEJULOZWVLPODE-UHFFFAOYSA-N 0.000 claims 1
• LQXBXVDFUCCDJA-UHFFFAOYSA-N 1-benzyl-5-piperazin-1-yl-3,4-dihydro-2$l^{6},1,3-benzothiadiazine 2,2-dioxide Chemical compound O=S1(=O)NCC2=C(N3CCNCC3)C=CC=C2N1CC1=CC=CC=C1 LQXBXVDFUCCDJA-UHFFFAOYSA-N 0.000 claims 1
• RPPKAAXCQQTHKG-UHFFFAOYSA-N 1-benzyl-5-piperazin-1-yl-7-(trifluoromethyl)-3,4-dihydroquinazolin-2-one Chemical compound C=12CNC(=O)N(CC=3C=CC=CC=3)C2=CC(C(F)(F)F)=CC=1N1CCNCC1 RPPKAAXCQQTHKG-UHFFFAOYSA-N 0.000 claims 1
• IHRSNZQEIJEURL-UHFFFAOYSA-N 2-(1-benzyl-2-oxo-5-piperazin-1-yl-4h-quinazolin-3-yl)acetamide Chemical compound O=C1N(CC(=O)N)CC2=C(N3CCNCC3)C=CC=C2N1CC1=CC=CC=C1 IHRSNZQEIJEURL-UHFFFAOYSA-N 0.000 claims 1
• HSBCWXOUIRFTQI-UHFFFAOYSA-N 3-[(3-methyl-2-oxo-5-piperazin-1-yl-4h-quinazolin-1-yl)methyl]benzonitrile Chemical compound O=C1N(C)CC2=C(N3CCNCC3)C=CC=C2N1CC1=CC=CC(C#N)=C1 HSBCWXOUIRFTQI-UHFFFAOYSA-N 0.000 claims 1
• 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims 1
• 125000005605 benzo group Chemical group 0.000 claims 1
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 121
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