AU753706B2 - Benzofuran derivatives, pharmaceutical composition containing the same, and a process for the preparation of the active ingredient - Google Patents
Benzofuran derivatives, pharmaceutical composition containing the same, and a process for the preparation of the active ingredient Download PDFInfo
- Publication number
- AU753706B2 AU753706B2 AU40529/99A AU4052999A AU753706B2 AU 753706 B2 AU753706 B2 AU 753706B2 AU 40529/99 A AU40529/99 A AU 40529/99A AU 4052999 A AU4052999 A AU 4052999A AU 753706 B2 AU753706 B2 AU 753706B2
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- Australia
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- dimethyl
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- 150000001907 coumarones Chemical class 0.000 title claims description 43
- 238000000034 method Methods 0.000 title claims description 33
- 238000002360 preparation method Methods 0.000 title claims description 27
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 26
- 239000004480 active ingredient Substances 0.000 title claims description 17
- 230000008569 process Effects 0.000 title claims description 17
- 150000001875 compounds Chemical class 0.000 claims description 184
- 239000011541 reaction mixture Substances 0.000 claims description 95
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 94
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 92
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 84
- -1 biphenylyl group Chemical group 0.000 claims description 72
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 49
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 48
- 150000003839 salts Chemical class 0.000 claims description 45
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 44
- 125000005843 halogen group Chemical group 0.000 claims description 42
- 239000002253 acid Substances 0.000 claims description 40
- 238000006243 chemical reaction Methods 0.000 claims description 38
- 125000000217 alkyl group Chemical group 0.000 claims description 32
- 125000000623 heterocyclic group Chemical group 0.000 claims description 30
- 125000003545 alkoxy group Chemical group 0.000 claims description 27
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 25
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 24
- 229910052757 nitrogen Inorganic materials 0.000 claims description 24
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 24
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 23
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 22
- 150000002118 epoxides Chemical class 0.000 claims description 21
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 20
- 150000004820 halides Chemical class 0.000 claims description 17
- 229920006395 saturated elastomer Polymers 0.000 claims description 17
- 150000003335 secondary amines Chemical class 0.000 claims description 17
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 16
- 125000001424 substituent group Chemical group 0.000 claims description 16
- 229910052717 sulfur Inorganic materials 0.000 claims description 15
- 125000004434 sulfur atom Chemical group 0.000 claims description 15
- 125000004076 pyridyl group Chemical group 0.000 claims description 13
- 125000003302 alkenyloxy group Chemical group 0.000 claims description 11
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 11
- 208000028867 ischemia Diseases 0.000 claims description 11
- 125000001624 naphthyl group Chemical group 0.000 claims description 10
- 125000003277 amino group Chemical group 0.000 claims description 9
- 150000002576 ketones Chemical class 0.000 claims description 9
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 9
- 210000004165 myocardium Anatomy 0.000 claims description 9
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 9
- 125000005842 heteroatom Chemical group 0.000 claims description 8
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 7
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 7
- 125000001544 thienyl group Chemical group 0.000 claims description 7
- HBEDSQVIWPRPAY-UHFFFAOYSA-N 2,3-dihydrobenzofuran Chemical compound C1=CC=C2OCCC2=C1 HBEDSQVIWPRPAY-UHFFFAOYSA-N 0.000 claims description 6
- 125000003342 alkenyl group Chemical group 0.000 claims description 6
- 150000004792 aryl magnesium halides Chemical class 0.000 claims description 5
- 230000006735 deficit Effects 0.000 claims description 5
- 230000010410 reperfusion Effects 0.000 claims description 5
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 4
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 4
- 241000124008 Mammalia Species 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 4
- VNZLQLYBRIOLFZ-UHFFFAOYSA-N 1-(2-methoxyphenyl)piperazine Chemical compound COC1=CC=CC=C1N1CCNCC1 VNZLQLYBRIOLFZ-UHFFFAOYSA-N 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 150000007522 mineralic acids Chemical class 0.000 claims description 3
- 150000007524 organic acids Chemical class 0.000 claims description 3
- 241000894007 species Species 0.000 claims description 3
- VHFVKMTVMIZMIK-UHFFFAOYSA-N 1-(3-chlorophenyl)piperazine Chemical compound ClC1=CC=CC(N2CCNCC2)=C1 VHFVKMTVMIZMIK-UHFFFAOYSA-N 0.000 claims description 2
- 239000012050 conventional carrier Substances 0.000 claims description 2
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims 2
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims 1
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims 1
- DMCVVFIWYIKAEJ-UHFFFAOYSA-N 4-phenylpiperidine-4-carbonitrile Chemical compound C=1C=CC=CC=1C1(C#N)CCNCC1 DMCVVFIWYIKAEJ-UHFFFAOYSA-N 0.000 claims 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims 1
- 101100534223 Caenorhabditis elegans src-1 gene Proteins 0.000 claims 1
- 235000009917 Crataegus X brevipes Nutrition 0.000 claims 1
- 235000013204 Crataegus X haemacarpa Nutrition 0.000 claims 1
- 235000009685 Crataegus X maligna Nutrition 0.000 claims 1
- 235000009444 Crataegus X rubrocarnea Nutrition 0.000 claims 1
- 235000009486 Crataegus bullatus Nutrition 0.000 claims 1
- 235000017181 Crataegus chrysocarpa Nutrition 0.000 claims 1
- 235000009682 Crataegus limnophila Nutrition 0.000 claims 1
- 235000004423 Crataegus monogyna Nutrition 0.000 claims 1
- 240000000171 Crataegus monogyna Species 0.000 claims 1
- 235000002313 Crataegus paludosa Nutrition 0.000 claims 1
- 235000009840 Crataegus x incaedua Nutrition 0.000 claims 1
- 239000002671 adjuvant Substances 0.000 claims 1
- 125000004429 atom Chemical group 0.000 claims 1
- 239000003085 diluting agent Substances 0.000 claims 1
- NWVNXDKZIQLBNM-UHFFFAOYSA-N diphenylmethylpiperazine Chemical compound C1CNCCN1C(C=1C=CC=CC=1)C1=CC=CC=C1 NWVNXDKZIQLBNM-UHFFFAOYSA-N 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 309
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 196
- 239000000243 solution Substances 0.000 description 149
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 129
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 117
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 99
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 99
- 229960004592 isopropanol Drugs 0.000 description 77
- 239000000203 mixture Substances 0.000 description 75
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 70
- 239000013078 crystal Substances 0.000 description 68
- GZBGWGUQAIPVIP-UHFFFAOYSA-N 2,2-dimethyl-7-(oxiran-2-ylmethoxy)-3h-1-benzofuran Chemical compound C=12OC(C)(C)CC2=CC=CC=1OCC1CO1 GZBGWGUQAIPVIP-UHFFFAOYSA-N 0.000 description 59
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 59
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 59
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 51
- 239000002904 solvent Substances 0.000 description 51
- 239000000047 product Substances 0.000 description 42
- 239000012074 organic phase Substances 0.000 description 40
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 39
- 238000001816 cooling Methods 0.000 description 38
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 32
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 27
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 27
- 239000012071 phase Substances 0.000 description 26
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 24
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 24
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 24
- 238000012360 testing method Methods 0.000 description 21
- 238000005192 partition Methods 0.000 description 20
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 18
- 238000003756 stirring Methods 0.000 description 17
- 239000002585 base Substances 0.000 description 16
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
- 238000001953 recrystallisation Methods 0.000 description 14
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 230000000694 effects Effects 0.000 description 12
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 10
- 230000003293 cardioprotective effect Effects 0.000 description 10
- 102000005962 receptors Human genes 0.000 description 10
- 108020003175 receptors Proteins 0.000 description 10
- 239000000126 substance Substances 0.000 description 10
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 description 9
- 241000700159 Rattus Species 0.000 description 9
- QWCRAEMEVRGPNT-UHFFFAOYSA-N buspirone Chemical compound C1C(=O)N(CCCCN2CCN(CC2)C=2N=CC=CN=2)C(=O)CC21CCCC2 QWCRAEMEVRGPNT-UHFFFAOYSA-N 0.000 description 9
- 229960002495 buspirone Drugs 0.000 description 9
- 239000008346 aqueous phase Substances 0.000 description 8
- 239000003054 catalyst Substances 0.000 description 8
- 238000004587 chromatography analysis Methods 0.000 description 8
- 239000003960 organic solvent Substances 0.000 description 8
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 7
- 150000007530 organic bases Chemical class 0.000 description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 description 7
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 7
- 150000005622 tetraalkylammonium hydroxides Chemical class 0.000 description 7
- ROLMZTIHUMKEAI-UHFFFAOYSA-N 4,5-difluoro-2-hydroxybenzonitrile Chemical compound OC1=CC(F)=C(F)C=C1C#N ROLMZTIHUMKEAI-UHFFFAOYSA-N 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 230000000949 anxiolytic effect Effects 0.000 description 6
- 238000009835 boiling Methods 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
- CVVIJWRCGSYCMB-UHFFFAOYSA-N hydron;piperazine;dichloride Chemical compound Cl.Cl.C1CNCCN1 CVVIJWRCGSYCMB-UHFFFAOYSA-N 0.000 description 6
- 239000005457 ice water Substances 0.000 description 6
- 150000007529 inorganic bases Chemical class 0.000 description 6
- 239000003921 oil Substances 0.000 description 6
- 238000005292 vacuum distillation Methods 0.000 description 6
- HAKSOKWVNPZVNM-UHFFFAOYSA-N 1,2,3,4-tetrahydropyridine;hydrochloride Chemical compound Cl.C1CNC=CC1 HAKSOKWVNPZVNM-UHFFFAOYSA-N 0.000 description 5
- WJGPNUBJBMCRQH-UHFFFAOYSA-N 2,2-dimethyl-2,3-dihydro-1-benzofuran-7-ol Chemical compound C1=CC(O)=C2OC(C)(C)CC2=C1 WJGPNUBJBMCRQH-UHFFFAOYSA-N 0.000 description 5
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 5
- RGFHJSYBDBNFMX-UHFFFAOYSA-N 4-(4-methoxyphenyl)piperidin-4-ol Chemical compound C1=CC(OC)=CC=C1C1(O)CCNCC1 RGFHJSYBDBNFMX-UHFFFAOYSA-N 0.000 description 5
- TVZCRIROJQEVOT-CABCVRRESA-N Cromakalim Chemical compound N1([C@@H]2C3=CC(=CC=C3OC([C@H]2O)(C)C)C#N)CCCC1=O TVZCRIROJQEVOT-CABCVRRESA-N 0.000 description 5
- 150000005325 alkali earth metal hydroxides Chemical class 0.000 description 5
- 229910052783 alkali metal Inorganic materials 0.000 description 5
- 150000001340 alkali metals Chemical class 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 239000003208 petroleum Substances 0.000 description 5
- 239000003444 phase transfer catalyst Substances 0.000 description 5
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 4
- TZGCBLLTLSJJBB-UHFFFAOYSA-N 5-bromo-2,2-dimethyl-7-(oxiran-2-ylmethoxy)-3h-1-benzofuran Chemical compound C=12OC(C)(C)CC2=CC(Br)=CC=1OCC1CO1 TZGCBLLTLSJJBB-UHFFFAOYSA-N 0.000 description 4
- NPPQSCRMBWNHMW-UHFFFAOYSA-N Meprobamate Chemical compound NC(=O)OCC(C)(CCC)COC(N)=O NPPQSCRMBWNHMW-UHFFFAOYSA-N 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- 206010062575 Muscle contracture Diseases 0.000 description 4
- 210000003169 central nervous system Anatomy 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 4
- 208000006111 contracture Diseases 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 239000000155 melt Substances 0.000 description 4
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- 125000005270 trialkylamine group Chemical group 0.000 description 4
- LKMZGTIBHBYUOW-UHFFFAOYSA-N (2,2-dimethyl-3h-1-benzofuran-7-yl) acetate Chemical compound CC(=O)OC1=CC=CC2=C1OC(C)(C)C2 LKMZGTIBHBYUOW-UHFFFAOYSA-N 0.000 description 3
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 description 3
- BIOFUDSSNYHMCZ-UHFFFAOYSA-N 2,2-dimethyl-5-nitro-7-(oxiran-2-ylmethoxy)-3h-1-benzofuran Chemical compound C=12OC(C)(C)CC2=CC([N+]([O-])=O)=CC=1OCC1CO1 BIOFUDSSNYHMCZ-UHFFFAOYSA-N 0.000 description 3
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 3
- RJFISGALWPADNA-UHFFFAOYSA-N 4-[3-(trifluoromethyl)phenyl]-1,2,3,6-tetrahydropyridine;hydrochloride Chemical compound Cl.FC(F)(F)C1=CC=CC(C=2CCNCC=2)=C1 RJFISGALWPADNA-UHFFFAOYSA-N 0.000 description 3
- ILKPZCKFWLTEBQ-UHFFFAOYSA-N 4-[3-(trifluoromethyl)phenyl]piperidin-4-ol Chemical compound C=1C=CC(C(F)(F)F)=CC=1C1(O)CCNCC1 ILKPZCKFWLTEBQ-UHFFFAOYSA-N 0.000 description 3
- ASXGJMSKWNBENU-UHFFFAOYSA-N 8-OH-DPAT Chemical compound C1=CC(O)=C2CC(N(CCC)CCC)CCC2=C1 ASXGJMSKWNBENU-UHFFFAOYSA-N 0.000 description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 3
- FKPSBYZGRQJIMO-UHFFFAOYSA-M benzyl(triethyl)azanium;hydroxide Chemical compound [OH-].CC[N+](CC)(CC)CC1=CC=CC=C1 FKPSBYZGRQJIMO-UHFFFAOYSA-M 0.000 description 3
- KXHPPCXNWTUNSB-UHFFFAOYSA-M benzyl(trimethyl)azanium;chloride Chemical compound [Cl-].C[N+](C)(C)CC1=CC=CC=C1 KXHPPCXNWTUNSB-UHFFFAOYSA-M 0.000 description 3
- NDKBVBUGCNGSJJ-UHFFFAOYSA-M benzyltrimethylammonium hydroxide Chemical compound [OH-].C[N+](C)(C)CC1=CC=CC=C1 NDKBVBUGCNGSJJ-UHFFFAOYSA-M 0.000 description 3
- 230000027455 binding Effects 0.000 description 3
- 208000015114 central nervous system disease Diseases 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 238000010908 decantation Methods 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 230000002140 halogenating effect Effects 0.000 description 3
- SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical compound OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 description 3
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 3
- 210000005240 left ventricle Anatomy 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 229960004815 meprobamate Drugs 0.000 description 3
- 125000003386 piperidinyl group Chemical group 0.000 description 3
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 3
- 239000013558 reference substance Substances 0.000 description 3
- 229940076279 serotonin Drugs 0.000 description 3
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
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- 210000000709 aorta Anatomy 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- BNBQRQQYDMDJAH-UHFFFAOYSA-N benzodioxan Chemical group C1=CC=C2OCCOC2=C1 BNBQRQQYDMDJAH-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- IZEKFCXSFNUWAM-UHFFFAOYSA-N dipyridamole Chemical compound C=12N=C(N(CCO)CCO)N=C(N3CCCCC3)C2=NC(N(CCO)CCO)=NC=1N1CCCCC1 IZEKFCXSFNUWAM-UHFFFAOYSA-N 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
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- 125000003700 epoxy group Chemical group 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 125000001207 fluorophenyl group Chemical group 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 210000005153 frontal cortex Anatomy 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- TVFIYRKPCACCNL-UHFFFAOYSA-N furan-2-carboxamide Chemical class NC(=O)C1=CC=CO1 TVFIYRKPCACCNL-UHFFFAOYSA-N 0.000 description 1
- 239000003365 glass fiber Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 229940077716 histamine h2 receptor antagonists for peptic ulcer and gord Drugs 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000007574 infarction Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 230000007786 learning performance Effects 0.000 description 1
- 210000005246 left atrium Anatomy 0.000 description 1
- 238000005567 liquid scintillation counting Methods 0.000 description 1
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Substances [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000007334 memory performance Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- 230000003680 myocardial damage Effects 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000004090 neuroprotective agent Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 230000009871 nonspecific binding Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 208000030212 nutrition disease Diseases 0.000 description 1
- 230000000050 nutritive effect Effects 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000035778 pathophysiological process Effects 0.000 description 1
- NCCBCEHAGCSKEA-UHFFFAOYSA-N pentaiodo-$l^{5}-phosphane Chemical compound IP(I)(I)(I)I NCCBCEHAGCSKEA-UHFFFAOYSA-N 0.000 description 1
- 229960001412 pentobarbital Drugs 0.000 description 1
- UXCDUFKZSUBXGM-UHFFFAOYSA-N phosphoric tribromide Chemical compound BrP(Br)(Br)=O UXCDUFKZSUBXGM-UHFFFAOYSA-N 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical compound O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 description 1
- HDOWRFHMPULYOA-UHFFFAOYSA-N piperidin-4-ol Chemical compound OC1CCNCC1 HDOWRFHMPULYOA-UHFFFAOYSA-N 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 229960004063 propylene glycol Drugs 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- GZRKXKUVVPSREJ-UHFFFAOYSA-N pyridinylpiperazine Chemical compound C1CNCCN1C1=CC=CC=N1 GZRKXKUVVPSREJ-UHFFFAOYSA-N 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 238000001525 receptor binding assay Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
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- 238000012552 review Methods 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000035488 systolic blood pressure Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- DGQOCLATAPFASR-UHFFFAOYSA-N tetrahydroxy-1,4-benzoquinone Chemical compound OC1=C(O)C(=O)C(O)=C(O)C1=O DGQOCLATAPFASR-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- HFRXJVQOXRXOPP-UHFFFAOYSA-N thionyl bromide Chemical compound BrS(Br)=O HFRXJVQOXRXOPP-UHFFFAOYSA-N 0.000 description 1
- 230000035922 thirst Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 229960002415 trichloroethylene Drugs 0.000 description 1
- UBOXGVDOUJQMTN-UHFFFAOYSA-N trichloroethylene Natural products ClCC(Cl)Cl UBOXGVDOUJQMTN-UHFFFAOYSA-N 0.000 description 1
- 230000002861 ventricular Effects 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Psychiatry (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- Pain & Pain Management (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
WO 99/58527 PCT/HU99/00038 -1- BENZOFURAN DERIVATIVES, PHARMACEUTICAL COMPOSITION CONTAINING THE SAME, AND A PROCESS FOR THE PREPARATION OF THE ACTIVE INGREDIENT The invention refers to novel benzofuran derivatives, pharmaceutical compositions containing the same as the active ingredient, and a process for the preparation of the active ingredient. The novel compounds influence the circulatory system and the heart, furthermore have an effect on the central nervous system.
More specifically, the invention refers to a novel benzofuran derivative of the formula R 0 1 Y 13 A B:I R N wherein R and R represent, independently, a hydrogen atom or a C 1 -4 alkyl group, X stands for an oxygen atom or a sulfur atom, Y means a hydrogen atom or a hydroxy group, Z represents a hydrogen atom, a halo atom, a C1- 4 alkyl group, a C 1 4 alkoxy group, an amino group, a nitro group, a cyano group, a trifluoromethyl group, a group of the formula -COOR -NHCOR or WO 99/58527 PCT/HU99/00038 -2-
-SO
2 NR R 4 wherein 3 R stands for a hydrogen atom or a C- 4 alkyl group, 4 R is a Cl-4 alkyl group, or 3 4 R and R form, together with the adjacent nitrogen atom, a saturated or unsaturated heterocyclic group having 5 to 10 members and optionally comprising one or more nitrogen atom(s) and/or one or more oxygen atom(s) and/or one or more sulfur atom(s) as the further heteroatom(s), A means a group of the formula CH, COH, C-CN,
C-COOR
3 or COR 4 wherein R 3 and R 4 are as defined above, B represents a methylene group, or A forms together with B a group of the formula Ar stands for a hydrogen atom, a C-_ 4 alkyl group, a phenyl(C_14 alkyl) group, a biphenylyl group, a naphthyl group, wherein said latter species are optionally substituted by a C1-4 alkoxy group or a C2- 4 alkenyl group; a partially saturated, or 6-membered heterocyclic group condensed with a phenyl group and containing one or two oxygen atom(s), said heterocyclic group being optionally substituted by one to three C_-4 alkyl group; a 5- or 6-membered, saturated or unsaturated heterocyclic group containing a nitrogen atom and/or an oxygen atom and/or a sulfur atom as the heteroatom; or a phenyl group -3substituted by the substituents
R
5
R
6 and R wherein 5 6 7 R and R mean, independently, a hydrogen atom, a halo atom, a trifluoromethyl group, a C 1 4 alkyl group, a methylenedioxy group, a phenoxy group optionally substituted by a C 1 4 alkoxy group or by a halo atom; a C2_ 4 alkenyl group, a C2_ 4 alkenyloxy group, a C_ 4 alkoxy group optionally substituted by a di(C 1 4 alkyl)amino group or by a 5- or 6-membered, saturated hetero cyclic group containing one or two nitrogen atom(s) or a nitrogen atom and an oxygen atom, wherein said heterocyclic group is optionally substituted by a Cl_ 4 alkyl group, or A-Ar stands for a group of the formula
N-(CH
2 wherein Ar' represents a diphenylmethyl group, a pyridyl group, a pyrimidinyl group, S: a naphthyl group, wherein said latter group is optionally substituted by a C 4 alkoxy group or a C alkenyloxy group; a partially saturated, 5- or 6-membered heterocyclic group condensed with a phenyl group and containing one or two oxygen atom(s), said heterocyclic group being optionally substituted by one to three C-4 alkyl 1-4 group(s); or a phenyl group substituted by the substituents R 5
R
6 and R 7 o: 26-JUL-2;000 12:46 FROM '1O37g0 ATO 00493025901840 P.03/05 Europ~ai atsflt
JULI
wherein
R
6 and R' are as defined above, nI has avalue of 0or 1, and Pharmaceutically suitable acid addition salts thereof According to the literature, certain furancarboxylic amides have antidepressant properties /Yakugaku Zas&hi 27 540 (1977);
C.A.,
L7j, 152 125d (1997)/, while beuzofuran derivatives having amino, arnidino, thiocarboxam~iidino or diaklaminoalkyl substituents on thefuran ring are H 2 receptor antagonists, and, consequently, possess antiulcer effect /publicated PCT application No. WO 86 02550; C.A., 105, 2 2 6586u (1986)/.
Tetrahydronaphtho-y derivatives having hypotensive activity a-rc known from DE-OS No. 22 35 597. The chemical structure of the known compounds resembles to that of the piperazinylalkylbenzofuran, derivatives of the formula Ia.
I -Phenoxyalclpiperidine derivatives useful in the treatment of cerebrovascular diseases are described in FR-A-26813 19.
4-Substituted piperidine derivatives are known from WO-A-97232 16. The known compounds are antagonists of NMDA receptor subtypes and can be also usefuld as neuroprotective agents i' several cardiovascular and CNS diseases.
The aim of the invention is to prepare novel benzofliran derivatives some representants of which influencing the circulatory system and the heart function, while other representarits of whichi having an effect on the central nervous system.
It was found that the above aim is achieved by the novel benzofuran derivatives of the formula
I
I
I
26!JUL-2000 12:47 FROPI 10G Qm578-.E.e, (,g"IV TO] 00493025901340 P. 04/05 4a In the description and claims, i the definition of the substituents, a halo atom WO 99/58527 PCT/HU99/00038 is, primarily, a fluoro, chloro, bromo or iodo atom, preferably a fluoro, chloro or bromo atom.
A C1- 4 alkyl group is a methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.-butyl, tert.-butyl or isobutyl group. Preferably, a C1-4 alkyl group is a methyl group.
A C2- 4 alkenyl group is a vinyl, allyl, methallyl or crotyl group, preferably an allyl or methallyl group.
A C 1 4 alkoxy group is, primarily, a methoxy, ethoxy, n-propoxy, isopropoxy or butoxy group, preferably a methoxy or isopropoxy group.
A C2- 4 alkenyloxy group is suitably an allyloxy or methallyloxy group.
A C 1 4 alkoxy group substituted by a di(Cl_ 4 alkyl)amino group is, in the first place, a 2-dimethylaminoethoxy, 3-dimethylaminopropoxy, 2-diethylaminoethoxy, 3-diethylaminopropoxy or 4-dimethylaminobutoxy group, preferably a 2-dimethylaminoethoxy group.
A partially saturated, 5- or 6-membered heterocyclic group condensed with a phenyl group and containing one or two oxygen atom(s) is a dihydrobenzofuran, benzodioxolan, dihydrobenzpyran or benzodioxan group.
A 5- or 6-membered, saturated or unsaturated heterocyclic group containing a nitrogen atom and/or an oxygen atom and/or a sulfur atom as the heteroatom is, preferably, a heterocyclic group wherein the heteroatom WO 99/58527 PCT/HU99/00038 -6consists of a nitrogen atom or an oxygen atom or a sulfur atom or a nitrogen atom and an oxygen atom, and the heterocyclic ring contains no double bond or one or more double bond(s).
Such a heterocyclic group is, for example, a pyrrolyl, pyrrolidinyl, piperidinyl, pyridyl, morpholinyl, furyl or thienyl group. The above heterocyclic group is suitably a thienyl group.
A 5- or 6-membered, saturated heterocyclic group containing one or two nitrogen atom(s) or a nitrogen atom and an oxygen atom is, preferably, a pyrrolidinyl, piperidinyl, piperazinyl or morpholino group, the nitrogen atom of which is linked to the carbon atom of the C 1 4 alkoxy group.
A saturated or unsaturated heterocyclic group having 5 to 10 members is, for example, a pyrrolidinyl, pyrrolyl, piperidinyl, pyridyl, furyl, tetrahydrofuryl, morpholinyl, piperazinyl, imidazolidinyl, pyrimidinyl, pyrazolyl, pyrazolidinyl, thienyl, hexamethyleneimine-1-yl, heptamethyleneimine-l-yl etc. group.
A pharmaceutically suitable acid addition salt is an acid addition salt formed with an inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid etc. or with an organic acid such as acetic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid etc.
The invention includes any possible isomers of the compounds of the formula I WO 99/58527 PCT/HU99/00038 -7and the mixtures thereof.
A preferred subgroup of the benzofuran derivatives of the invention consists of the compounds of the formula I wherein R represents a hydrogen atom or a Cl-4 alkyl group, 2 R stands for a hydrogen atom, X means an oxygen atom, Y is a hydrogen atom or a hydroxy group, Z represents a hydrogen atom, a halo atom or a nitro group, A stands for a group of the formula CH, COH or C-CN, B means a methylene group, or A forms with B a group of the formula Ar represents a hydrogen atom, a benzyl group, a phenyl group substituted by substituents R R and R a biphenylyl group, a naphthyl group optionally substituted by a C 1 -4 alkoxy group; or a thienyl group, wherein
R
5
R
6 and R 7 mean, independently, a hydrogen atom, a halo atom, a trifluoromethyl group, a C 1 4 alkyl group, a C1- 4 alkoxy group, a C2_ 4 alkenyloxy group, a phenoxy group or a methylenedioxy group, and pharmaceutically suitable acid addition salts thereof.
Within the above subgroup, the suitable benzofuran derivatives of the invention consist of compounds of the formula. I wherein WO 99/58527 WO 9958527PCTIHU99/00038 -8- R 1represents a methyl group, R 2stands for a hydrogen atom, X means an oxygen atom, Y is a hydroxy group, Z represents a hydrogen atom, A is a group of the formula CH, COH or C-CN, B stands for a methylene group, or A forms with B a group of the formula Ar represents a phenyl group optionally substituted by a halo atom, a trifluoromethyl group, a methyl group or a methoxy group; or a methoxynaphthyl group, and pharmaceutically suitable acid addition salts thereof.
The especially preferred benzofuran derivatives of the formula I are as follows: 2-dimethyl-2, 3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl/-4- (3-trifluoromethylphenyl 6-tetrahydropyridine, 1-13- 2-dimethyl-2, 3 -dihydro-benzofuran-7-yloxy) -2-hydroxypropyl/-4-hydroxy-4-(3-trifluoromethylphenyl )piperidine, 1-/3-(2,2-dimethyl-2,3dihydrobenzofuran7..yl oxy)- 2 -hydroxypropyl/4hydroxy-4(4.fluorophenyl )piperidine, 2-dimethyl-2, 3 -dihydro-benzofuran-7-yloxy) 2 -hydroxypropyl/-4-hydroxy-4-phenylpiperidine, 2-dimethyl-2, 3 -dihydro-benzofuran-7-yloxy)- 2 -hydroxypropyl/4hydroxy-4-(3chlorophenyl )piperidine, 2-dimethyl-2, 3 -dihydro-benzofuran-7-yl- WO 99/58527 WO 9958527PCT/HU99/00038 -9oxy) -2-hydroxypropyl/-4-hydroxy-4.(3-methoxyphenyl )piperidine, 2-dimethyl-2, 3-dihydro-benzofuran-7yl oxy) -2-hydroxypropyl-4-hydroxy4-(4-methoxyphenyl )piperidine, 1-13- 2-dimethyl-2, 3-dihydro-benzofuran-7-yl> oxy)- 2 -hydroxypropyl/-4-(3-trjifluoromethylphenyl )piperidine, 2-dimethyl-2, 3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl-4-hydroxy4-( 4-methylphenyl )piperidine, 1-13- 2-dimethyl-2, 3-dihydro-benzofuran-7-yl.
oxy)- 2 -hydroxypropylI-4-cyano4phenyl.
piperidine, 1-13- 2-dimethyl-2, 3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl/-4-hydroxy.4-( 4-chiorophenyl )piperidine or l-/ 3 -(2,2-dimethyl-2,3dihydrobenzofuran7yloxy) -2-hydroxypropyl/-4hydroxy-4-(6-methoxynaphth-2-yl )piperidine, arnd pharmaceutically suitable acid addition salts thereof.
A further preferred subgroup of the benzofuran derivatives of the invention consists of the piperazinylalkylbenzofuran derivatives of the formula (H,Ar
(CH
2 )n Ia R 0r
RII-
WO 99/58527 PCT/HU99/00038 wherein 1 R represents a C 1 -4 alkyl group, 2 R stands for a hydrogen atom, X means an oxygen atom, Y is a hydroxy group, Z represents a hydrogen atom, Ar' represents a diphenylmethyl group, a pyridyl group, a partially saturated heterocyclic group containing two oxygen atoms and being condensed with a phenyl group, or a phenyl group substituted by substituents R 5
R
6 and R 7 wherein R R and R mean, independently, a hydrogen atom, a halo atom, a trifluoromethyl group, a Cl_ 4 alkyl group, a C1- 4 alkoxy group, or a methylenedioxy group, n has a value of O or 1, and pharmaceutically suitable acid addition salts thereof.
Within the subgroup of the formula Ia, the suitable piperazinylalkylbenzofuran derivatives of the invention consist of compounds of the formula Ia wherein R represents a methyl group, R stands for a hydrogen atom, X means an oxygen atom, Y is a hydroxy group, Z represents a hydrogen atom, Ar' represents a diphenylmethyl group, a pyridyl group, a benzo-1,3-dioxolanyl group WO 99/58527 WO 9958527PCT/HU99/00038 -11or a phenyl group optionally substituted by one or two halo atom(s), one or two methyl group(s), a methylenedioxy group, a trifluoromethyl group or a methoxy group, n has a value of 0 or 1, and pharmaceutically suitable acid addition salts thereof.
The especially preferred benzofuran derivatives of the formula Ia are as follows: 2-dimethyl-2, 3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl 1-4- (diphenylmethyl) piperazine, 1-13- 2-dimethyl-2, 3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl/-4- (4-f luorophenyl) piperazine, 1-13- 2-dimethyl-2, 3-dihydro-benzofuran-7-yl.
oxy) -2-hydroxypropyl/-4-hydroxy-4-(3-trifluoromethylphenyl )piperazine, 2-dimethyl-2, 3 -dihydro-benzofuran-7-y1oxy )-2-hydroxypropyl/-4- (4-methoxyphenyl) piperazine, 1-/ 3 -(2,2-dimethyl-2,3-dihydro-benzofuran-7.yloxy) -2-hydroxypropyl/-4- (benzo-1, -yl )piperazine, 2-dimethyl-2 ,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl/-4-(4-chlorophenyl) piperazine, l-/3-(2,2-dimethyl-2,3-dihydrobenzofuran7.yl oxy) 2 -hydroxypropyl/-4-benzylpiperazine, 1-/3-(2,2-dimethyl-2,3dihydro-benzofuran-7.yloxy )-2-hydroxypropyl/-4-.(2, 4-dichlorophenyl) piperazine, WO 99/58527 WO 9958527PCT/HU99/00038 -12- 1-13- 2-dimethyl-2, 3 -dihydro-benzofuran-7-y..
oxy)- 2 -hydroxypropylI-4-(3-chlorophenyl)piperaz The, 1-13- 2-dimethyl-2, 3 -dihydro-benzofuran-7yl.
oxy) -2-hydroxypropyl/-4 2-pyridyl )piperazine, 2-dirnethyl-2, 3-dihydro-benzofuran-7-y..
oxy)-2-hydroxypropyl/4-(2-methoxyphenyl)piperazine or l-/3-(2,2-dimethyl2,3dihydrobenzofuran7-yl oxy)-2-hydroxypropyl/4-(3-methoxyphenyl)piperazine, and pharmaceutically suitable acid addition salts thereof.
The compounds of the invention are prepared as follows: a) a halide of the formula R J4
R
2 wherein R 1, R 2, X, Y and Z are as defined in connection with formula I, Hal represents a halo atom, is reacted with a secondary amine of the formula r BE 'ArI HN ,v WO 99/58527 PCT/HU99/00038 -13wherein A, B and Ar are as stated in connection with formula I; or b) for the preparation of a benzofuran derivative of the formula I, wherein Y represents a hydroxy group, R R X, Z, A, B and Ar are as defined in connection with formula I, an epoxide of the formula R O z
III
R' X 0
R
2 wherein R R Z and X are as defined above, is reacted with a secondary amine of the formula IV, wherein A, B and Ar are as stated above; or c) a compound of the formula
V
R' 0 wherein R X and Z are as defined in connection with formula I, is reacted with a halo compound of the formula WO 99/58527 PCT/HU99/00038 -14- Y B, Ar Hal N1 A xI
R
wherein R2, Y, A, B and Ar are as stated in connection with formula I, Hal represents a halo atom; d) for the preparation of a benzofuran 1 2 derivative of the formula I, wherein R R 2 X, Z, A, B and Ar are as defined in connection with formula I, a compound of the formula V, wherein R
I
X and Z are as stated above, is reacted with an epoxide of the formula B Ar
R
wherein R A, B and Ar are as stated above; or e) for the preparation of a benzofuran derivative of the formula I, wherein A forms 1 2 with B a group of the formula R R X, Y, Z and Ar are as defined in connection with formula I, a benzofuran derivative of the formula I, wherein A stands for a group of the formula COH, B represents a methylene group, R R 2 X, Y, Z and Ar are as stated above, is dehydrated; or WO 99/58527 PCT/HU99/00038 f) for the preparation of a benzofuran derivative of the formula I, wherein A represents a group of the formula COH, B stands for a methylene group, R 1
R
2 X, Y, Z and Ar are as defined in connection with formula I, however, Ar is other than a hydrogen atom, a ketone of the formula
Z
R O X Y Y
XV
1 2 wherein R R X, Y and Z are as stated above, is reacted with an arylmagnesium halide of the formula Hal-Mg-Ar
XVI
wherein Ar is as stated above, Hal represents a halo atom, and the adduct formed is decomposed with water; or g) for the preparation of a benzofuran derivative of the formula I, wherein A represents a group of the formula COH, B stands 1 2 for a methylene group, R R X, Y, Z and Ar are as defined in connection with formula I, but Ar is other than a hydrogen atom, a ketone of the formula XV, wherein R 1
R
2 X, Y and Z are as stated above, is reacted with an aryl lithium compound of the formula WO 99/58527 PCT/HU99/00038 -16- Li-Ar
XVII
wherein Ar is as stated above, and the adduct formed is decomposed with water; or h) for the preparation of a benzofuran derivative of the formula I, wherein A represents a group of the formula CH, B stands for a methylene group, R R X, Y, Z and Ar are as defined in connection with formula I, a compound of the formula I, wherein A forms with B a group of the formula R R X, Y, Z and Ar are as stated above, is hydrogenized; or i) for the preparation of a benzofuran derivative of the formula I, wherein A represents a group of the formula CH, B stands for a methylene group, R R 2 X, Y, Z and Ar are as defined in connection with formula I, an epoxide of the formula III, wherein R R2, Z and X are as stated above, is reacted with a secondary amine of the formula IV, wherein A stands for a group of the formula CHOH, B and Ar are as stated above, under dehydrating reaction conditions, and the formed compound of the formula I, wherein A forms with B a group of the formula R 1
R
2 X, Y, Z and Ar are as stated above, is hydrogenized in the reaction mixture in which it was prepared; and if desired, an obtained base of the formula I is reacted with an inorganic or organic acid to form a pharmaceutically WO 99/58527 PCT/HU99/00038 -17suitable acid addition salt thereof, or liberated from the acid addition salt with a base.
In process a) of the invention, the reaction of the halide of the formula II with the secondary amine of the formula IV is suitably performed in an excess of the corresponding secondary amine of the formula IV. However, the reaction can be carried out also in an indifferent solvent in the presence of a suitable base, eventually in a two-phase system.
In the reaction, the solvent can be for example an alcohol, preferably methanol, ethanol or isopropanol, diisopropyl ether, dioxane, acetonitrile, dimethyl formamide, dimethyl sulfoxide, halogenated solvents, preferably dichloromethane, 1,2-dichloroethane or chlorobenzene.
In the reaction, the base can be an inorganic one such as an alkali metal hydroxide or an alkali earth metal hydroxide, preferably sodium or potassium hydroxide, or an organic base, preferably a trialkylamine or a tetraalkylammonium hydroxide. An especially preferred base is triethylamine. The base is used in a 0.8-1.1 molar equivalent, preferably 0.9-1.0 molar equivalent quantity, calculated to the compound of the formula
II.
The formed product of the formula I is separated from the reaction mixture by a method WO 99/58527 PCT/HU99/00038 -18known in itself. Thus, if the product crystallizes from the solvent employed in the reaction mixture or can be precipitated with another solvent that is miscible with the original solvent, then the product is filtered and purified by recrystallization or chromatography.
If the product does not crystallize from the reaction mixture, then the solution is evaporated, and the residue is recrystallized from a suitable solvent.
In some cases it is convenient to subject the evaporation residue to partition between water and an organic solvent that is immiscible with water, then to make the mixture alkaline, to separate the phases, to evaporate the organic phase, and to purify the residual base by recrystallization.
In process b) of the invention, the reaction of the epoxide of the formula III with the secondary amine of the formula IV is carried out in an indifferent solvent or in an excess of the secondary amine.
The solvent for the reaction can be, for example, methanol, ethanol, isopropanol, butanol, diisopropyl ether, acetonitrile, acetone, methyl ethyl ketone, dimethyl formamide, water or mixtures thereof, preferably ethanol, isopropanol or 5-20 mass preferably 10 mass solutions thereof in water.
Each mole of the epoxide of the formula WO 99/58527 PCT/HU99/00038 -19- III is reacted with 0.8-2.0, preferably 0.85-1.2 moles of the secondary amine of the formula IV. If used as a base, the secondary amine of the formula IV is added directly to the reaction mixture. If a salt of the secondary amine of the formula IV is employed, the base can be liberated in the reaction mixture in situ by adding a molar equivalent quantity of inorganic or organic base calculated to the amount of the salt of the secondary amine.
As the inorganic base, primarily a 5-40 mass preferably 10-25 mass solution of an alkali metal or alkali earth metal hydroxide, preferably sodium or potassium hydroxide in water is used.
As the organic base, preferably a trialkylamine or a tetraalkylammonium hydroxide, specifically triethylamine is employed.
In general, the reaction is performed at the boiling point of the solvent employed or at a lower temperature.
The product is separated from the reaction mixture as described under process a) above.
In process c) of the invention, the reaction of the compound of the formula V with the halo compound of the formula XI is carried out in an indifferent solvent in the presence of an inorganic or organic base and a phase transfer catalyst.
The inorganic base is primarily a WO 99/58527 PCT/HU99/00038 hydroxide or carbonate of an alkali metal or alkali earth metal, preferably sodium or potassium hydroxide or potassium carbonate.
The organic base is a trialkylamine or a tetraalkylammonium hydroxide, preferably triethylamine. The base is taken in 1-2, preferably 1.2 molar equivalent quantity, calculated to the compound of the formula
V.
The halo compound of the formula XI is used in 1-3, preferably 1.8-2 molar equivalent quantity, calculated to the compound of the formula V.
The solvent for the reaction can be, for example, methanol, ethanol, propanol, butanol, acetone, methyl ethyl ketone, diethyl ketone, acetonitrile, dimethyl formamide, water, preferably ethanol, acetone or methyl ethyl ketone.
The phase transfer catalyst can be a tetraalkylammonium hydroxide or halide, preferably trimethylbenzylammonium hydroxide, triethylbenzylammonium hydroxide, trimethylbenzylammonium chloride, tetrabutylammonium bromide or tetrabutylammonium hydrosulfate.
The reaction is carried out at a temperature of 40 to 100 OC, preferably to 80 0
C.
The product is separated in a manner known in itself. After the end of the reaction, the reaction mixture is, for example, evaporated to dryness under reduced pressure, WO 99/58527 PCT/HU99/00038 -21the residue is subjected to partition between water and an organic solvent that is immiscible with water, the separated organic phase is dried, evaporated to dryness under reduced pressure, and the residue is purified by recrystallization from a suitable solvent or by vacuum distillation.
In process d) of the invention, the compound of the formula V is reacted with the epoxide of the formula XII in an indifferent solvent.
The solvent can be, for example, methanol, ethanol, isopropanol, butanol, diisopropyl ether, acetonitrile, acetone, methyl ethyl ketone, dimethyl formamide, water or a mixture thereof, preferably ethanol, isopropanol or a 5-20 mass preferably 10 mass mixture thereof in water.
The compound of the formula V is used in 0.8-2.0, preferably 0.85-1.2 molar equivalent quantity, calculated to the epoxide of the formula XII.
In general, the reaction is carried out at the boiling point of the solvent employed, or at a lower temperature.
The product can be separated from the reaction mixture as described in connection with process c) above.
In process e) of the invention, the dehydration of the compound of the formula I, wherein A represents a group of the formula COH, B stands for a methylene group, is carried WO 99/58527 PCT/HU99/00038 -22out by means of a strong mineral acid, preferably hydrochloric acid, in an indifferent solvent, preferably an alcohol, especially preferably in ethanol under heating, preferably boiling. It is convenient to use the starting compound in a solution having a concentration of 5-40 preferably 15-25 If the product separates from the solution after cooling, then it is filtered; in the opposite case, a solution that does not dissolve the product, however, being miscible with the solvent used in the reaction, preferably ether is added to the reaction mixture, and the crystals precipitated are filtered.
In processes f) and g) of the invention, the ketone of the formula XV is reacted with the arylmagnesium halide of the formula XVI or the aryllithium compound of the formula XVII in an indifferent aprotic organic solvent, preferably ether, tetrahydrofuran or dioxane at a temperature between -10 0 C and the boiling point of the solvent, preferably O10 to 0 C. The product can be obtained from the reaction mixture after decomposing the complex formed in the reaction with an acid and evaporating the solvent by simple recrystallization or salt formation. If the product or the salt thereof does not crystallize, the reaction mixture decomposed with an acid is made alkaline, the product is dissolved in an organic solvent being immiscible with water, the organic phase is WO 99/58527 PCT/HU99/00038 -23dried, evaporated, and the base obtained is purified by crystallization or chromatography.
In processes h) and i) of the invention, the compound of the formula I, wherein A forms with B a group of the formula is conveniently reduced by catalytic hydrogenation using a noble metal catalyst on a carbon carrier, preferably palladium on carbon, especially preferably 10 palladium on carbon catalyst in an alcohol, preferably methanol.
After removing the catalyst by filtration, the product is separated by evaporating the solvent and crystallizing the residue. As an alternative, the evaporation residue can be converted to a salt.
If the product or the salt thereof does not crystallize, the reaction mixture is subjected to partition between water and an organic solvent being immiscible with water, the organic phase is dried, evaporated, and the residual base is purified by crystallization or chromatography.
The reduction can be performed also in the reaction mixture in which the starting compound was prepared.
The halides of the formula II are novel compounds, thus, the invention includes these compounds, too.
The halides of the formula II can be prepared by reacting a compound of the formula V with a dihaloalkane of the formula WO 99/58527 PCT/HU99/00038 -24-
Y
Hal Hal
R'
R
2 wherein Y, R and Hal are as defined above.
Alternatively, the halide of the formula II can be prepared by reacting a compound of the formula V with a haloalkanol derivative of the formula
Y
Hal OH VII
R'
2R wherein Y, R and Hal are as defined above, then converting the hydroxy group of the formed hydroxyalkyl derivative of the formula R' I Y VIII R' X OH
R
2 1 2 wherein R R X, Y and Z are as defined above, to a halo atom.
The compound of the formula V is reacted with the dihaloalkane of the formula VI in an indifferent solvent in the presence of an inorganic or organic base and a phase WO 99/58527 PCT/HU99/00038 transfer catalyst.
The inorganic base is, primarily, an alkali metal or alkali earth metal hydroxide or carbonate, preferably sodium or potassium hydroxide or potassium carbonate. The organic base is a trialkylamine or a tetraalkylammonium hydroxide, preferably triethylamine. The base is employed in 1 to 1.5 molar quantity, calculated to the compound of the formula
V.
The dihaloalkane of the formula VI is taken in 1-3, preferably 1.8-2 molar equivalent quantity, calculated to the compound of the formula V.
In the reaction, the solvent can be, for example, methanol, ethanol, propanol, butanol, acetone, methyl ethyl ketone, acetonitrile, dimethyl formamide, water, preferably ethanol, acetone or methyl ethyl ketone.
The phase transfer catalyst can be a tetraalkylammonium hydroxide or halide, preferably trimethylbenzylammonium hydroxide, triethylbenzylammonium hydroxide, trimethylbenzylammonium chloride, tetrabutylammonium bromide or tetrabutylammonium hydrosulfate.
The reaction can be carried out at a temperature of 40 to 100 0 C, preferably to 80 OC.
The product is separated from the reaction mixture in a manner known in itself. For example, after the end of the reaction, the WO 99/58527 PCT/HU99/00038 -26reaction mixture is evaporated to dryness under reduced pressure, the residue is subjected to partition between water and an organic solvent being immiscible with water, the organic phase is separated, dried, evaporated to dryness under reduced pressure, and the residue is purified by recrystallization from a suitable solvent or by vacuum distillation.
The reaction of the compound of the formula V with the haloalkanol derivative of the formula VII is carried out in an analogous manner as described in connection with the reaction of the compound of the formula V with the dihaloalkane of the formula
VI.
The formed hydroxyalkyl derivatives of the formula VIII are converted to the desired halides of the formula II using a halogenating agent such as thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, thionyl bromide, phosphorus oxybromide, phosphorus pentabromide, phosphorus pentaiodide, phosphorus tribromide, preferably thionyl chloride.
The halogenating agent is used in an excess of 1-4 moles, preferably 1.2-2.2 moles for each mole of the starting hydroxyalkyl derivative of the formula VIII.
The reaction is carried out in an indifferent solvent, preferably halogenated alkanes, especially chloroform, dichloromethane WO 99/58527 PCT/HU99/00038 -27or 1,2-dichloroethane, or an excess of the halogenating agent is used as the solvent.
After evaporating the solvent, the product is separated in the same manner as described in connection with the reaction of the compound of the formula V and the dihaloalkane of the formula VI.
Some of the epoxides of the formula III are known from the literature /Japane Patent Application published under No. J6 0258-174-A; 104, 207136k (1986)/. They are prepared from the compounds of the formula V by reaction with epichlorohydrin in alkaline medium. As an alternative, they can be prepared by reacting the compound of the formula V with a halide of the formula
RT
Ha Ix wherein R 2 and Hal are as defined above, and oxidizing the formed allyl derivative of the formula
Z
R
x 1 2 wherein R R X and Z are as stated above.
The compound of the formula V is reacted WO 99/58527 PCT/HU99/00038 -28with 1-3 molar equivalent quantity of epichlorohydrin in the presence of an alkali metal or alkali earth metal hydroxide, preferably sodium or potassium hydroxide used in 1-3 molar equivalent quantity.
The reaction is carried out in methanol, ethanol, propanol, acetone, methyl ethyl ketone, acetonitrile, dimethyl formamide, water or a mixture thereof, preferably aqueous methanol or aqueous ethanol, conveniently at the boiling point of the solvent or at a lower temperature.
The epoxide of the formula III that forms in the reaction can be separated in a manner known in itself. For example, after the end of the reaction, the reaction mixture is evaporated to dryness under reduced pressure, the residue is subjected to partition between water and an organic solvent being immiscible with water, the separated organic phase is dried, and evaporated to dryness under reduced pressure. In general, the residue is pure enough for the further reactions. If necessary, the product can be purified by chromatography or crystallization.
One of the allyl derivatives of the formula X, wherein X represents an oxygen atom, R 1 stands for a methyl group, R 2 means a hydrogen atom and Z is a hydrogen atom, is known from the literature /Aust. J. Chem., 36 1263 (1983)/. It is prepared from the compound of the formula V which is reacted WO 99/58527 PCT/HU99/00038 -29with a halide of the formula IX in an alkaline medium in the presence of a phase transfer catalyst.
In the reaction, the alkaline medium is achieved by means of an alkali metal or alkali earth metal hydroxide or carbonate, preferably sodium or potassium hydroxide or potassium carbonate. The bases listed are used in 12 molar equivalent quantity.
In the reaction, the solvent is, for example, methanol, ethanol, propanol, butanol, acetone, methyl ethyl ketone, diethyl ketone, acetonitrile, dimethyl formamide, water or a mixture thereof, preferably ethanol, acetone or methyl ethyl ketone.
As the phase transfer catalyst, a tetraalkylammonium hydroxide or halide, preferably trimethylbenzylammonium hydroxide, triethylbenzylammonium hydroxide, trimethylbenzylammonium chloride, tetrabutylammonium bromide or tetrabutylammonium hydrosulfate can be used.
The reaction is performed at a temperature of 40 to 100 preferably 60 to 80 °C.
The product is separated in a manner known in itself. For example, after the end of the reaction, the reaction mixture is evaporated to dryness under reduced pressure, the residue is subjected to partition between water and an organic solvent being immiscible with water, the organic phase separated is dried, evaporated to dryness under reduced WO 99/58527 PCT/HU99/00038 pressure, and the residue is purified by recrystallization from a suitable solvent or by vacuum distillation.
The allyl derivative of the formula X is oxidized to the corresponding epoxide of the formula III with an organic oxidizing agent such as m-chloroperbenzoic acid, peracetic acid, perphthalic acid, 2,3-dichloro-5,5-dicyano-l,4-benzoquinone (DDQ), preferably m-chloroperbenzoic acid at a temperature of 0 to 40 preferably to 30 0
C.
In the reaction, the solvent is dichloromethane, 1,2-dichloroethane, chloroform, 1,1,2-trichloroethylene, chlorobenzene, preferably dichloromethane or 1,2-dichloroethane.
The product is separated in a manner known in itself. For example, after the end of the reaction, water is added to the reaction mixture, the solution is made alkaline by the addition of sodium carbonate, the phases are separated, the organic phase is dried, then evaporated to dryness under reduced pressure. The residue is purified by recrystallization from a suitable solvent or by chromatography.
Some of the halo compounds of the formula XI are known /Peltz, Protiva, Coll.
Czech. Chem. Commun., 32 2840 (1967), US-P No. 4,110,536; Chem. Abstr., 90, P 121596r)/. They are prepared by reacting a WO 99/58527 PCT/HU99/00038 -31corresponding secondary amine of the formula IV with a corresponding dihaloalkane of the formula VI. The other halo compounds of the formula XI are also easily prepared according to the above processes.
Some of the epoxides of the formula XII are also known. They are prepared from a corresponding compound of the formula IV that is reacted with epichlorohydrin in alkaline medium /CH-P No. 474,511; Chem. Abstr., 72, 55506m (1970)/. Certain compounds of the formula XII can be also prepared by reacting a corresponding secondary amine of the formula IV with a corresponding halide of the formula IX, and converting the double bond of the formed compound of the formula R ,B A r N A
XIV
wherein R 2 A, B and Ar are as defined above, to an epoxy group under the conditions described in connection with the oxidation of the compounds of the formula X. The other epoxides of the formula XII can be also easily prepared according to the processes described above.
The ketones of the formula XV are novel compounds, thus, the invention includes these compounds, too. They are prepared by reacting a halide of the formula II or an epoxide of WO 99/58527 PCT/HU99/00038 -32the formula III with the piperidone of the formula HNO 0
XIII
The reaction conditions are identical with those employed in processes a) and b) of the invention.
The ketone of the formula XV is reacted with the arylmagnesium halide of the formula XVI as described in the literature /J-P No.
14,632 Chem. Abstr., 68, 114618s (1968)/.
The reaction of the aryllithium derivatives of the formula XVII with the ketone of the formula XV can be also carried out in the manner known from the literature /Elpern, Wetteran, Carabates, Ph., Grunbach, J. Am. Chem. Soc., 80, 4916 (1958)/.
The arylmagnesium halides of the formula XVI and the aryllithium derivatives of the formula XVII are commercially available.
The secondary amines of the formula IV are, in general, commercially available, or can be easily prepared by known methods.
The biological activity of the compounds of the invention was studied in the following tests.
WO 99/58527 PCT/HU99/00038 -33- 1. Measurement of the cardioprotective effect in ischemic rat heart (Langendorff) preparation Cardioprotective compounds protect the myocardium from any impairment during ischemia and/or reperfusion. Of the numerous methods used for the determination of cardioprotective effect, one of the best known and often employed test consists in the isolated perfused rat heart subjected to global ischemia /Longman, S.D. and Hamilton, Medicinal Research Reviews, 12/. During global ischemia, myocardial contracture comes about due to a rise of the calcium concentration in the myocardium. The time lapsed after starting global ischemia until the beginning of contracture time to contracture TTC) is prolonged by several cardioprotective compounds, thus, the effectiveness of the compounds can be examined by measuring TTC.
Male Sprague-Dawley rats weighing 300 to 350 g were injected with 2500 IU (0.5 ml) of heparin i.p. and 10 minutes later the animals were anaesthetized with sodium pentobarbital 2 4 6 (lH, 3 H,5H)-pyrimidinetrione sodium salt/ in a dose of 60 mg/kg i.p. The heart was quickly excised, and the aorta was connected to a cannula fixed to a Langendorff apparatus.
The heart was perfused at a constant pressure (8000 Pa) with a modified carbogenized WO 99/58527 PCT/HU99/00038 -34- Krebs-Henseleit solution. The composition of the solution was the following (in mM): NaCl 118, KC1 4.7, MgSO 4 1.6, CaCl 2 2.5, NaHCO 3 24.88, KH2PO 4 1.18, EDTA 0.5, glucose 11.
Partial CO 2 pressure and pH of the solution were maintained within the physiological limits (pCO 2 4000-4650 Pa, pH 7.3-7.45).
A hole was cut in the wall of the left atrium and a water-filled plastic balloon attached to a metal cannula was inserted into the left ventricle. End diastolic pressure of the left ventricle was set to a value between 666-1333 Pa during the equilibration period by changing the volume of the liquid in the balloon, however, later it was not modified.
After a 20 minutes' equilibration period, the hearts were perfused for 10 minutes with the vehicle (0.04 of dimethyl sulfoxide), in case of the control group, or with a solution of the test substance at 10 6 or 10 5 105 M concentration, in case of the treated groups. The activity of the test compound was not examined further when, at the end of the 10 minutes' period, the systolic pressure of the left ventricle was reduced by more than 20 compared to the control value determined before the treatment.
Global ischemia was initiated by completely shutting off the perfusate flow and carbogenization for 25 minutes. The time period from the beginning of ischemia until WO 99/58527 PCT/HU99/00038 the formation of myocardial contracture i.e.
an increase of 666 Pa in left ventricular end diastolic pressure (TTC) was measured.
3 parallel experiments were performed with the test compounds at each concentration and parameters of 3 additional vehicle (0.04 dimethyl sulfoxide) treated hearts were measured along with the test substance.
Individual TTC values were averaged, and the effect of the test substances was expressed as a percentage change compared to the vehicle treated group. Compounds that prolong TTC compared to the control group are cardioprotective. As a reference substance, lemakalim i.e. (3S)-trans-3,4-dihydro-3- -hydroxy-2,2-dimethyl-4-(2-oxo-l- -pyrrolidinyl)- 2 H-l-benzpyrane-6-carbonitrile was used. The results obtained are shown in Table I.
WO 99/58527 PCT/HU99/00038 -36- Table I TTC prolonging effect in isolated Langendorff rat hearts Compound TTC change (in at (No. of Example) 10 5 M 10-6M lemakalim 55 9 no data 8 90 43 65 18 24 no data 47 16 78 26 no data 43 59 2 41 53 32 63 111 -3 66 66 68 43 0 73 49 19 76 80 Several representants of the benzofuran derivatives examined caused a remarkably higher TTC prolongation at a concentration of 10 6 M than the reference substance lemakalim.
The compounds of the invention caused a considerable prolongation of TTC in isolated perfused rat heart during ischemia. This fact is a proof of the cardioprotective effect.
WO 99/58527 PCT/HU99/00038 -37- The compound of Example 9 surpasses remarkably also the effect of lemakalim determined at -6 a concentration of 10 6 M. Thus, the cardioprotective effect of the compounds of the invention can be used for human therapy.
The above cardioprotective effect raises the possibility of preventing the unfavourable effects of serious coronary arrhythmia that frequently occur in ischemic heart disease by prolonged administration of active substances. Especially the treatment of changing anginal patients seems to be suitable since in this disease considered as a state that precedes myocardial infarction, the treatment employed can reduce the rate of an irreversible myocardial damage caused by a later myocardia. infarction. A further use of the compounds can be a cardioprotective therapy before surgery, for example in case of temporarily blocked coronary circulation (coronary dilatation by balloon) or stopped heart due to surgery causes. A faster and more complete regulation of heart function can be obtained by a cardioprotective treatment of the heart prepared for transplantation.
In this case, the compound of the invention is added to the nutritive solution of the heart.
WO 99/58527 PCT/HU99/00038 -38- 2. Determination of the influence on serotonin neurotransmission receptor binding assay receptor assay was performed according to Peroutka's method /Peroutka, J. Neurochem., 47, 529 (1986)/. The binding was determined in membrane fragments prepared from rat frontal cortex using tritium-labelled 8 -hydroxy-N,N-dipropyl-2-aminotetraline as specific ligand. Non-specific binding was determined in the presence of 10 microM of /5-hydroxytriptamine/. The final incubation volume was 250 microliters. The assay samples were incubated at 25 °C for minutes. The reaction was stopped by the addition og 9 ml of an ice-cold solution of tris(hydroxymethyl)aminomethane hydrochloride having a pH value of 7.7 followed by quick filtration under reduced pressure. The filtration was carried out using a Whatman GFIB glass-fibre filter paper soaked in a 0.05 solution of polyethyleneimine for 2 to 3 hours before use. The radioactivity retained on the filters was determined by liquid scintillation counting.
The results obtained are summarized in Table II. As the reference compound, buspirone i.e. 4 -(2-pyrimidinyl)-l- -piperazinyl Jbutyl-8-azaspiro/4,5/decan- -7,9-dione was used.
WO 99/58527 PCT/HU99/00038 -39- Table II Effect of the compounds on 5-HTIA receptor binding Compound Inhibition of receptor binding (No. of Example) K. in nmole/litre 9 6 24 12 14 16 3 26 3 23 12 0.7 28 9 buspirone 19 From the data of Table II it can be seen that the compounds of the invention have considerable affinity to serotonin 5-HT1A receptors. Most of the compounds examined were superior to buspirone used as the reference compound.
WO 99/58527 PCT/HU99/00038 Elevated plus-maze test on rats The test was carried out according to a modified method of Pelow et al. Neurosci.
Methods, 14, 149 (1985)/. The elevated plus-maze consists of two open and two cm wall enclosed arms of the same size x 15 cm) arranged in the shape of a cross.
The arms of the same type are opposite to each other. The junction of the four arms forms a central square area (15 x 15 cm).
The apparatus is made of a wooden material elevated to a height of 50 cm and illuminated by a dim light from above. Male Sprague-Dawley rats weighing 220 to 260 g were used for the experiment.
The rats were treated with the test or reference compounds 60 minutes prior to the test. The animals were then placed onto a central square area and were subjected to the test for 5 minutes. The following 4 different parameters were determined: time spent in the open arms; time spent in the closed arms; number of entries into the open arms; number of entries into the closed arms.
A compound was considered to be effective where significant increase was found either in the time spent in the open arms (in sec) or in the number of entries into the open arms when compared to the control animals (in percentage). Minimum effective doses (MED) WO 99/58527 PCT/HU99/00038 -41were determined based on the time spent in the open arms for each compound examined.
The results obtained are shown in Table III.
Buspirone was used as the reference material.
Table III Compound MED (in mg/kg) (No. of Example) p.o.
16 1 23 3 24 3 0.3 buspirone 3 From Table III it can be seen that the compound of Example 25 is superior by one order of magnitude to buspirone in the above test characterizing the anxiolytic effect.
It is to be noted that buspirone binds strongly to the 5-HTIA receptor is widely used in the clinical practice.
On the basis of the results obtained in studies connected with the influence on the serotonin neurotransmission, the compounds of the invention can be used in various diseases primarily due to disorders of the central nervous system.
Many clinical and preclinical studies WO 99/58527 PCT/HU99/00038 -42suggest that 5-HTIA receptors may have a role in different pathophysiological processes.
Buspirone used in our studies as a reference material and acting through 5-HTIA receptors inhibited the aggressive behavior of rhesus monkeys /Tomkins, Clemento, Taylor, Perlach, Res. Commun. Physiol.
Psychiat. Behav., 5, 337 (1980)/ and indicated an anxiolytic effect in clinical trials /Goldberg, H.L. and Finnerty, Am. J.
Psychiatry, 136, 1184 (1979)/. In our examinations, several compounds of the invention surpassed the anxiolytic activity of buspirone.
It is supposed that 5-HTIA receptors play a role also in depression clinical patterns since it was shown that 5-HTIA ligands had also an antidepressant potential in test models using animals /Porsolt, Roux, S. and Wettstein, Pharmacol. Res., 31, 169 (1995)/. A further therapeutical possibility consists in the therapy of cognitive defficiencies in case of drugs acting on the 5-HTIA receptor. The administration of 8-hydroxy-N,N-dipropyl-2-aminotetraline to rats improved the memory and learning performances /Carli, M. and Samanin, Br.
J. Pharmacol., 105, 720 (1992)/. In addition to the clinical patterns mentioned above, in case of active substances acting through the 5-HTIA receptor, the use in various nutritional diseases is possible. This WO 99/58527 PCT/HU99/00038 -43hypothesis is based on the fact that the 8 -hydroxy-N,N-dipropyl-2-aminotetraline acting through the 5-HTIA receptor, under certain conditions, enhanced the food intake, while under other conditions, it reduced the food intake /Dourish, Hutson, P.H. and Curzon, Psychopharmacology, 86, 197 (1985); Dourish, Hutson, P.H. and Curzon, G., Brain Res. Bull., 15, 377 (1985)/. Thus, the compounds of the invention can be effective in several clinical patterns connected with a disease of the central nervous system wherein symptoms such as anxiety, depression, cognitive defficiencies or nutritional disorder appear.
The above hypothesis is also confirmed by the following test.
3. Determination of the anxiolytic effect on the basis of Vogel's conflict test The anxiolytic effect was examined by the method of Vogel et al. /Vogel, Beer, Clody, Psychopharmacologia (Berl.), 21, 1 (1971)/. Male Wistar rats weighing 180 to 200 g were left to be thirsty for 48 hours and starved for 24 hours before the test.
The substances to be examined and the carriers, respectively, were administered to the animals half an hour before the examination. In the test chamber, the rats were allowed to drink from the drinking tube protruding into the chamber. Following every 20th lick, the WO 99/58527 PCT/HU99/00038 -44apparatus emitted an electric shock of 0.7 mA through the drinking tube. During the test lasting for 5 minutes, the number of those electric shocks was registered which the animals accepted in order to quench their thirst. The effect of the compounds was expressed as the increase of the tolerated number of electric shocks in percentage. The minimum effective dose (MED) was determined for each compound.
Meprobamate /2-methyl-2-propyltrimethylenecarbamate/ was used as the reference substance. The results obtained are summarized in Table IV.
Table IV Anxiolytic effect Compound
MED
(No. of Example) in mg/kg ip.
68 meprobamate From Table IV it is apparant that the benzofurane derivative examined surpassed the effect of the meprobamate used as the reference in the Vogel's conflict test by a factor of higher than 2.
Summing up, the above tests indicate unanimously that the compounds of the invention have a valuable effect on the heart. Simultaneously, due to their mechanism of action, the compound of the invention can be suitable for the treatment of diseases of the central nervous system such as depression, anxiety, cerebral ischemia, schizophrenia etc.
Thus, the novel benzofuran derivatives of the invention can be used as active ingredients in pharmaceutical compositions.
The pharmaceutical compositions of the invention contain a therapeutically active amount of the compound of the formula 1 or a pharmaceutically suitable acid addition salt thereof and one or more conventional carrier(s).
Accordingly, the invention also provides a method of protecting the myocardium of a mammal from impairment during ischemia and/or reperfusion, which method comprises administering to said mammal in an amount which effectively protects said myocardium, a benzofuran derivative or a pharmaceutical composition of the invention.
The invention further provides the use of a benzofuran derivative I or a piperazinyl-alkylbenzofuran derivative la of the invention for the preparation of a medicament for protecting the myocardium from impairment during ischemia 20 and/or reperfusion.
The pharmaceutical compositions of the invention are suitable for peroral, parenteral or rectal administration or for local treatment, and can be solid or liquid.
The solid pharmaceutical compositions suitable for peroral administration may be powders, capsules, tablets, film-coated tablets, microcapsules etc., and can comprise binding agents such as gelatine, sorbitol, poly (vinyl-pyrrolidone) etc.; fillings agents such as lactose, glucose, starch, calcium phosphate etc.; auxiliary substances for tabletting such as-magnesium stearate, talc, poly (ehtyleneglycol), silica etc.; wetting WO 99/58527 PCT/HU99/00038 -46agents such as sodium laurylsulfate etc. as the carrier.
The liquid pharmaceutical compositions suitable for peroral administration may be solutions, suspensions or emulsions and can comprise e.g. suspending agents such as gelatine, carboxymethylcellulose etc.; emulsifiers such as sorbitane monooleate etc.; solvents such as water, oils, glycerol, propyleneglycol, ethanol etc.; preservatives such as methyl p-hydroxybenzoate etc. as the carrier.
Pharmaceutical compositions suitable for parenteral administration consist of sterile solutions of the active ingredient, in general.
Dosage forms listed above as well as other dosage forms are known per se, see e.g.
Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Co., Easton, USA (1990).
The pharmaceutical compositions of the invention contain, in general, 0.1 to 95.0 per cent by mass of a compound of the formula I or a pharmaceutically suitable acid addition salt thereof. A typical dose for adult patients amounts to 0.1 to 1000 mg of the compound of the formula I or a pharmaceutically suitable acid addition salt, daily. The above dose can be administered in one or more portions.
The actual dosage depends on many factors and is determined by the doctor.
WO 99/58527 PCT/HU99/00038 -47- The pharmaceutical compositions of the invention are prepared by admixing a compound of the formula I or a pharmaceutically suitable acid addition salt thereof to one or more carrier(s), and converting the mixture obtained to a pharmaceutical composition in a manner known per se. Useful methods are known from the literature, e.g. Remington's Pharmaceutical Sciences.
A preferred subgroup of the pharmaceutical compositions of the invention contains a benzofuran derivative of the formula I, wherein 1 R represents a hydrogen atom or a CI_ 4 alkyl group, R stands for a hydrogen atom, X means an oxygen atom, Y is a hydrogen atom or a hydroxy group, Z represents a hydrogen atom, a halo atom or a nitro group, A stands for a group of the formula CH, COH or C-CN, B means a methylene group, or A forms with B a group of the formula Ar represents a hydrogen atom, a benzyl group, a phenyl group substituted by substituents R R and R a biphenylyl group, a naphthyl group optionally substituted by a C 1 4 alkoxy group; or a thienyl group, wherein R R and R mean, independently, a hydrogen atom, a halo atom, a trifluoromethyl group, a C1- 4 alkyl WO 99/58527 PCT/HU99/00038 -48group, a C 1 -4 alkoxy group, a C2- 4 alkenyloxy group, a phenoxy group or a methylenedioxy group, or a pharmaceutically suitable acid addition salt thereof as the active ingredient.
Suitably, within the above subgroup, the pharmaceutical compositions of the invention comprise a benzofuran derivative of the formula I, wherein R represents a methyl group,
R
2 stands for a hydrogen atom, X means an oxygen atom, Y is a hydroxy group, Z represents a hydrogen atom, A is a group of the formula CH, COH or C-CN, B stands for a methylene group, or A forms with B a group of the formula Ar represents a phenyl group optionally substituted by a halo atom, a trifluoromethyl group, a methyl group or a methoxy group; or a methoxynaphthyl group, or a pharmaceutically suitable acid addition salt thereof as the active ingredient.
A further preferred subgroup of the pharmaceutical compositions of the invention contains a piperazinylalkylbenzofuran derivative of the formula Ia, wherein R represents a Cl-4 alkyl group, R stands for a hydrogen atom, X means an oxygen atom, Y is a hydroxy group, Z represents a hydrogen atom, WO 99/58527 PCT/HU99/00038 -49- Ar' represents a diphenylmethyl group, a pyridyl group, a partially saturated heterocyclic group containing two oxygen atoms and being condensed with a phenyl group, or a phenyl group substituted by substituents R 5
R
and R 7 wherein
R
5
R
6 and R 7 mean, independently, a hydrogen atom, a halo atom, a trifluoromethyl group, a C_-4 alkyl group, a C1- 4 alkoxy group, or a methylenedioxy group, n has a value of O or 1, or a pharmaceutically suitable acid addition salt thereof as the active ingredient.
Suitably, within the above subgroup, the pharmaceutical compositions of the invention contain a piperazinylalkylbenzofuran derivative of the formula Ia, wherein R represents a methyl group,
R
2 stands for a hydrogen atom, X means an oxygen atom, Y is a hydroxy group, Z represents a hydrogen atom, Ar' represents a diphenylmethyl group, a pyridyl group, a benzo-1,3-dioxolanyl group or a phenyl group optionally substituted by one or two halo atom(s), one or two methyl group(s), a methylenedioxy group, a trifluoromethyl group or a methoxy group, n has a value of O or 1, or a pharmaceutically suitable acid addition WO 99/58527 WO 9958527PCT/HU99/00038 salt thereof as the active ingredient.
The especially preferred pharmaceutical compositions of the invention comprise one of the following benzofuran derivatives or a pharmaceutically suitable acid addition salt thereof as the active ingredient: 1-13- 2-dimethyl-2, 3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-(3-trifluoromethylphenyl) 6-tetrahydropyridine, 1-/3-(2,2-dimethyl-2,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl/-4-hydroxy-4-(3-trifluoromethyiphenyl )piperidine, 2-dimethyl-2, 3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl/-4-hydroxy-4- (4-f luorophenyl )piperidine, 1-/3-(2,2-dimethyl-2,3-dihydrobenzofura...yl.
oxy )-2-hydroxypropyl/-4-hydrcxy-4-pheny1piperidine, 1-/3-(2,2-dimethyl-2,3-dihydro-benzofuran-7.yl oxy) -2-hydroxypropyl/-4-hydroxy-4-( 3-chlorophenyl )piper idine, 1-13-( 2 ,2-dimethyl-2, 3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl/-4-hydroxy-4- (3-methoxyphenyl )piperidine, 1-13- 2-dimethyl-2 ,3-dihydro-benzofuran-7-yloxy) -2-hydroxypropyl/-4-hydroxy-4-(4-methoxyphenyl)piperidine, 2-dimethyl-2, 3-dihydro-benzof uran-7-yloxy) -2-hydroxypropyl/-4- (3-trifluoromethylphenyl )piperidine, 2, 2-dimethyl-2, 3 -dihydro-benzofuran-7-yloxy) -2-hydroxypropyl/-4-hyroxy4( 4-methyl- WO 99/58527 WO 9958527PCT/HiU99/00038 -51pheriyl)piperidine, 2-dimethyl-2, 3-dihydro-berizofuran-7-ypoxy)- 2 -hydroxypropyl/-4-cyano4phenylpiperidiie, 1-/ 3 2 2 -dimethyl-2,3-dihydro-benzofuran7yloxy)-2-hydroxypropyl/-4-hydroxy-4-(4-chiorophenyl )piperidine, l-/ 3 -(2,2-dimethyl-2,3-dihydro-benzofuran.7.yl oxy)-2-hydroxypropyl/-4-hydroxy4( 6-methoxynaphth-2-y piperidine, 1-13- 2-dimethyl-2, 3-dihydro-benzofuran-7-y..
oxy) -2-hydroxypropyl/-4- (diphenylmethyl) piperazine, 1-13- 2-dimethyl-2, 3-dihydro-benzofuran-7-ylv oxy) -2-hydroxypropyl/-4- (4-f luorophenyl) piperazine, l-/3-(2,2-dimethyl-2,3-dihydro-.benzofuran-7.yl.
oxy)-2-hydroxypropyl/-4hydroxy4( 3-trifluoromethyiphenyl )piperazine, 1-/ 3 -(2,2-dimethyl-2,3dihydrobenzofuran7yloxy) -2-hydroxypropyl/-4-(4-methoxyphenyl) piperazine, 2-dimethyl-2, 3-dihydro-benzofuran-7-ylN oxy)- 2 -hydroxypropyl/4(benzo-13dioxolan-5- -yl )piperazine, 2-dirnethyl-2, 3-dihydro-benzofuran-7.yl> oxy) -2-hydroxypropyl/-4-(4-chiorophenyl) piperazine, l-/ 3 -(2,2-dimethyl2,3dihydrobenzofuran7yloxy) 2 -hydroxypropyl/-4benzylpiperazine, l-/ 3 -(2,2-dimethyl2,3-dihydro-benzofuran7yloxy) -2-hydroxypropyl/-4-(2, 4-dichlorophenyl) WO 99/58527 WO 9958527PCT/HU99/00038 -52piperazine, 1-13- 2-dimethyl-2, 3-dihydro-benzofuran-7-yloxy)-2-hydroxypropyl/-4-(3-chlorophenyl).
piperazine, 2-dimethyl-2, 3-dihydro-benzofuran-7-yloxy)- 2 -hydroxypropyl/-4-(2-pyridyl)piperazine, 2 ,2-dimethyl-2,3-dihydrobenzofuran7yl.
oxy) -2-hydroxypropyl/-4- (2-methoxyphenyl) piperazine or 1-/ 3 -(2,2-dimethy1-2,3-dihydrobenzofuran7yloxy) -2-hydroxypropyl/-4- (3-methoxyphenyl) piperazine.
Furthermore, the invention refers to a method for the treatment of diseases which comprises administering a therapeutically effective non-toxic amount of a benzofuran derivative of the formula I or a pharmaceutically suitable acid addition salt thereof to a patient suffering from especially a heart disease or a disease of the central nervous system.
The invention is further elucidated by means of the following Examples.
Preparation of halides of the formula II 1) 7 3 -Bromopropyloxy)2,2dimethyl2,3dihydrobenzofuran To a solution of 32.8 g (0.2 moles) of 2, 2-dimethyl-2, 3 -dihydrobenzofuran-7.o1 in 600 ml of acetone, 80.8 g (0.4 moles) of WO 99/58527 PCT/HU99/00038 -53- 1,3-dibromopropane and 83.0 g (0.6 moles) of anhydrous potassium carbonate are added, and the reaction mixture is boiled under stirring for 24 hours. After cooling, the inorganic salts are filtered, and the filtrate is evaporated to dryness under reduced pressure. The residual product is recrystallized from methanol, filtered, then dried at room temperature.
Thus, 34.7 g (61 of the title compound are obtained, 54-56 °C.
Preparation of epoxides of the formula III 2) 5-Bromo-2, 2 -dimethyl-7-oxiranylmethoxy- 2,3-dihydrobenzofuran a) 7-Acetoxy-2,2-dimethyl-2,3-dihydrobenzofuran To a solution of 16.4 g (0.1 moles) of 2,2-dimethyl-2,3-dihydrobenzofuran-7-ol in ml of glacial acetic acid, 12.2 g (0.12 moles) of acetic anhydride are added, the reaction mixture is boiled for 30 minutes, then evaporated to dryness under reduced pressure. The residual oily product is rubbed with 60 ml of ice-water, the white crystalline product is filtered, washed with ice-water, and dried under reduced pressure.
Thus, 20.4 g (99 of the title compound are obtained. After recrystallization from methanol, 49-50 OC.
WO 99/58527 PCT/HU99/00038 -54b) 7 -Acetoxy-5-bromo-2,2-dimethyl-2,3- -dihydrobenzofuran A solution of 16.0 g (0.1 moles) of bromine in 40 ml of glacial acetic acid are added, drop by drop, to a salution of 20.6 g (0.1 moles) of 7-acetoxy-2,2-dimethyl- -2,3-dihydrobenzofuran in 150 ml of chloroform under stirring and cooling at a temperature of 15-20 °C in 30 minutes. The solution obtained is stirred for 15 minutes, then evaporated to dryness under reduced pressure.
The residual honeylike product is rubbed with 150 ml of icewater, the crystals precipitated are filtered, then washed with ice-water until neutrality. The thus-obtained crystals are suspended in 80 ml of methanol at 0 OC, filtered again, and dried under reduced pressure.
Thus, 22.0 g (77 of the title compound are obtained. 76 0
C.
c) 5-Bromo-2,2-dimethyl-2,3-dihydrobenzofuran-7-ol 24.2 g (0.085 moles) of -2,2-dimethyl-2, 3 -dihydrobenzofuran are stirred in a mixture of 70 ml of methanol and 68 ml of 10 aqueous sodium hydroxide at 20-25 C for 3 hours. The reaction mixture is acidified with concentrated hydrochloric acid to a pH value of 2, the methanol is distilled WO 99/58527 PCT/HU99/00038 off under reduced pressure, and the residue is extracted 3 times using 50 ml of dichloromethane each time. The combined organic phases are washed twice using 20 ml of water each time to remove traces of the acid, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure.
The residue is rubbed with n-hexane to obtain a crystalline substance that is filtered, and dried under reduced pressure.
Thus, 19.9 g (96.4 of the title compound are obtained. 70 °C.
d) 5-Bromo-2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran To a solution of 19.9 g (0.082 moles) of 5-bromo-2,2-dimethyl-2,3-dihydrobenzofuran- -7-ol in 60 ml of 10 aqueous sodium hydroxide, 13.65 g (0.147 moles) of epichlorohydrin are added, and the reaction mixture is stirred at 45-50 °C for 3 hours.
After cooling, the separated oil is dissolved in 100 ml of dichloromethane, the aqueous phase is extracted with 30 ml of dichloromethane, the combined organic phases are extracted twice with 20 ml of water each time, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure.
Thus, 23.5 g (98 of the title compound are obtained as a honeylike matter that is WO 99/58527 PCT/HU99/00038 -56used directly for the preparation of the compounds of the formula I. On standing for a long time, the product crystallizes. M.p.: 46-48 0
C.
3) 2 ,2-Dimethyl-7-oxiranylmethoxy-2,3- -dihydrobenzofuran To a solution of 15.0 g (0.09 moles) of 2,2-dimethyl2, 3 -dihydrobenzofuran-7-ol in 100 ml of 10 aqueous sodium hydroxide, 20.0 g (0.216 moles) of epichlorohydrin are added, and the reaction mixture is stirred at 48 to 50 °C for 2.5 hours. After cooling, the oil separated is dissolved in 100 ml of dichloromethane, the aqueous phase is extracted with 50 ml of dichloromethane, the combined organic phases are extracted twice using ml of water each time, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The title compound is obtained as a thick honeylike substance that is rubbed with 60 ml of n-hexane to obtain white crystals. The crystals precipitated are filtered, and dried under reduced pressure.
Thus, 19.5 g (97 of the title compound are obtained. 51-52 OC.
4) 2 2 -Dimethyl-7-oxiranylmethoxy-2,3- -dihydrobenzofuran WO 99/58527 PCT/HU99/00038 -57- 0.35 g of 82 m-chloroperbenzoic acid are added to a solution of 0.204 g (0.001 moles) of 2 ,2-dimethyl-7-(2-propenyloxy)- 2,3-dihydrobenzofuran in 5 ml of dichloromethane, and the reaction mixture is stirred for 10 hours. To the reaction mixture, 5 ml of 10 aqueous sodium hydrocarbonate solution are added, the phases are separated, the organic phase is dried over anhydrous sodium sulfate, filtered, and the solvent is removed under reduced pressure. The residual oily product is purified by column chromatography (the column is filled with silica gel and eluted with a mixture of 24 volumes of dichloromethane and 1 volume of acetone).
Thus, 0.068 g (31 of the title compound are obtained. 49-51 OC.
2, 2 -Dimethyl-5-nitro-7-oxiranylmethoxy- -2,3-dihydrobenzofuran a) 7 -Acetoxy-2,2-dimethyl-5-nitro-2,3- -dihydrobenzofuran To a solution of 16.5 g (0.08 moles) of 7-acetoxy-2,2-dimethyl-2,3-dihydrobenzofuran in 60 ml of chloroform, 6 ml (0.06 moles) of acetic anhydride are added under stirring and cooling at 15 to 20 °C in 30 minutes.
To the stirred and cooled solution obtained, 4 ml (5.53 g, 0.06 moles) of concentrated nitric acid (density: 1.42; 65 are added, WO 99/58527 PCT/HU99/00038 -58drop by drop, in 30 to 40 minutes taking care that the temperature of the mixture should be within 25 to 28 To the reaction mixture stirred for further 10 minutes, 100 ml of ice water are added, the phases are separated, the organic phase is washed with ice water until neutral, dried over anhydrous sodium sulfate, filtered, and the solvent is removed under reduced pressure. The crystalline product obtained is suspended in 40 ml of methanol having a temperature of O filtered, and dried under reduced pressure.
Thus, 14.8 g (74 of the title compound are obtained. 142-143 OC.
b) 2 ,2-Dimethyl-5-nitro-2,3-dihydrobenzofuran-7-ol 13.3 g (0.053 moles) of 7-acetoxy-2,2- -dimethyl-5-nitro-2,3-dihydrobenzofuran are stirred in a mixture of 40 ml of methanol and 42.5 ml of 10 aqueous sodium hydroxide at 20 to 25 C for 30 minutes. The obtained solution of purpur colour is acidified to a pH value of 1 with concentrated hydrochloric acid, the methanol is distilled off under reduced pressure, and the residue is extracted with 50 ml of dichloromethane. The phases are separated, the aqueous phase is extracted twice using 25 ml of dichloromethane each time. The combined organic phases are extracted twice with 20 ml of water each time to remove WO 99/58527 PCT/HU99/00038 -59the acid, then dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The residue is rubbed with n-hexane to obtain a crystalline substance that is filtered and dried under reduced pressure.
Thus, 10.8 g (97.8 of the title compound are obtained. 96-97 0
C.
c) 2, 2 -Dimethyl-5-nitro-7-oxiranylmethoxy- -2,3-dihydrobenzofuran 14.5 g (0.156 moles) of epichlorohydrin are added to a solution of 10.8 g (0.052 moles) of 2,2-dimethyl-5-nitro-2,3-dihydrobenzofuran- -7-ol in 62 ml of 10 aqueous sodium hydroxide, and the reaction mixture is stirred at 48 to 52 °C for 2.5 hours. After cooling, the oil separated is dissolved in 60 ml of dichloromethane, the aqueous phase is extracted twice using 60 ml of dichloromethane each time, the combined organic phases are extracted twice with 20 ml of water each time, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure.
The residue is rubbed with n-hexane, then filtered and dried under reduced pressure.
Thus, 13.3 g (96.7 of the title compound are obtained. 108 0 C (after recrystallization from methanol).
WO 99/58527 PCT/HU99/00038 6) 2,2-Dimethyl-7-(2-allyloxy)-2,2- -dihydrobenzofuran To a solution of 8.20 g (0.05 moles) of 2,2-dimethyl-2,3-dihydrobenzofuran-7-ol in 100 ml of acetone, 12.1 g (0.12 moles) of allyl bromide and 20.75 g (0.15 moles) of anhydrous potassium carbonate are added, and the reaction mixture is boiled for 12 hours under stirring. After cooling, the inorganic salts are filtered, and the filtrate is evaporated under reduced pressure to remove the solvent. The residual oily product is purified by vacuum distillation.
Thus, 9.20 g (90 of the title compound are obtained. 77 OC/53.3 Pa.
7) 2 2 -Dimethyl-7-(2-allyloxy)-2,3- -dihydrobenzofuran To a solution of 8.20 g (0.05 moles) of 2,2-dimethyl-2, 3 -dihydrobenzofuran-7-ol in 100 ml of acetone, 7.63 g (0.10 moles) of allyl chloride and 20.7 g (0.15 moles) of anhydrous potassium carbonate are added, and the reaction mixture is boiled for 12 hours under stirring. After cooling, the inorganic salts are filtered, and the filtrate is evaporated under reduced pressure to remove the solvent. The residual oily product is purified by vacuum distillation.
Thus, 8.90 g (87 of the title compound WO 99/58527 PCT/HU99/00038 -61are obtained. 77 0 C/53.3 Pa.
Preparation of compounds of the formula X 8) 2,2-Dimethyl-7-(2-methyl-2-propenyloxy)- -2,3-dihydrobenzofuran To a solution of 24.6 g (0.15 moles) of 2,2-dimethyl-2,3-dihydrobenzofuran-7-ol in 350 ml of acetone, 27.1 g (0.3 moles) of methallyl chloride and 62.25 g (0.45 moles) of anhydrous potassium carbonate are added, and the reaction mixture is boiled for 22 hours under stirring. After cooling, the inorganic salts are filtered, and the filtrate is evaporated under reduced pressure to remove the solvent. The residual oily product is purified by vacuum distillation.
Thus, 25.0 g (76.5 of the title compound are obtained. 80-83 OC/27-40 Pa.
Preparation of benzofuran derivatives of the formula I Example 1 1-/3-(2,2-Dimethyl-2,3-dihydrobenzofuran- 7 -yloxy)propyl/-4-(4-methoxyphenyl)-1,2,3,6- -tetrahydropyridine hydrochloride To a solution of 4.0 g (0.14 moles) of 7-(3-bromopropyloxy)-2,2-dimethyl-2,3-dihydro- WO 99/58527 PCT/HU99/00038 -62benzofuran in 60 ml of dichloromethane, 2.28 g (0.012 moles) of 4-(4-methoxyphenyl)-1,2,3,6- -tetrahydropyridine hydrochloride and 12 ml of 10 aqueous sodium hydroxide solution are added. The reaction mixture is stirred at room temperature for 12 hours, then the two phases are separated. The organic phase is extracted twice with 50 ml of water each time, dried over anhydrous sodium sulfate, filtered, then evaporated under reduced pressure to remove the solvent. The residue is dissolved in 30 ml of ethanol containing of hydrogen chloride, and evaporated to dryness over a water bath under reduced pressure. The residual product is rubbed with ml of ethyl acetate, and the crystalline product precipitated is filtered.
Thus, 3.75 g (72.8 of the title compound are obtained. 165 OC.
Example 2 1-/3-(2,2-Dimethyl-2, 3 -dihydrobenzofuran- 7 -yloxy)propyl/-4-(4-methoxyphenyl)-1,2,3,6- -tetrahydropyridine A mixture of 2.15 g (0.005 moles) of 1-/3-(2,2-dimethyl-2, 3 -dihydrobenzofuran-7- -yloxy)propyl/-4-(4-methoxyphenyl)-1,2,3,6tetrahydropyridine hydrochloride, 20 ml of dichloromethane and 3 ml of 10 aqueous sodium hydroxide is stirred for 10 minutes. The two phases are separated, the organic phase is WO 99/58527 PCT/HU99/00038 -63extracted twice with 5 ml of water each time, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The evaporation residue is recrystallized from a low amount of ethanol.
Thus, 1.54 g (78.5 of the title base are obtained. 96-97 0
C.
Example 3 1-/3-(2,2-Dimethyl-2,3-dihydrobenzofuran-7- -yloxy)propyl/-4-(4-methoxyphenyl)-1,2,3,6- -tetrahydropyridine hydrochloride To a solution of 3.0 g (0.0105 moles) of 7 3 -bromopropyloxy)-2,2-dimethyl-2,3- -dihydrobenzofuran in 50 ml of dichloromethane, 2.07 g (0.01 moles) of 4-hydroxy-4-(4- -methoxyphenyl)piperidine and 5 ml of 10 aqueous sodium hydroxide are added, and the reaction mixture is stirred at room temperature for 14 hours. The phases are separated, the organic phase is extracted twice using ml of water each time, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to remove the solvent. The residue (4.15 g) is dissolved in 30 ml of ethanol containing 5 of hydrogen chloride at 40 C, the solution obtaines is maintained at the above temperature for 5 minutes, then evaporated again under reduced pressure. The residue is rubbed with 30 ml of ethyl acetate, filtered, and dried under reduced pressure.
WO 99/58527 PCT/HU99/00038 -64- Thus, 2.79 g (85 of the title compound are obtained. 165 OC.
Example 4 1-/3-(2,2-Dimethyl-2,3-dihydrobenzofuran-7- -yloxy)propyl/-4-(4-methoxyphenyl)-l,2,3,6- -tetrahydropyridine hydrochloride 0.82 g (0.002 moles) of -dimethyl-2,3-dihydrobenzofuran-7-yloxy)- -propyl/-4-(4-methoxyphenyl)-1,2,3,6- -tetrahydropyridine are stirred in 10 ml of ethanol containing 5 of hydrogen chloride at 40 °C for 5 minutes, then the solution is evaporated under reduced pressure. The residue is rubbed with 30 ml of ethyl acetate, filtered, and dried under reduced pressure.
Thus, 0.75 g (87 of the title compound are obtained. 165 OC.
Example 1-/3-(2,2-Dimethyl-2,3-dihydrobenzofuran-7- -yloxy)propyl/-4-hydroxy-4-(4-methoxyphenyl)- -piperidine To a solution of 0.57 g (0.002 moles) of 7 3 -bromopropyloxy)-2,2-dimethyl-2,3dihydrobenzofuran in 10 ml of dichloromethane, 0.41 g (0.002 moles) of 4-hydroxy-4-(4methoxyphenyl)piperidine and 1 ml of 10 aqueous sodium hydroxide are added. The reaction mixture is stirred at room temperature WO 99/58527 PCT/HU99/00038 for 14 hours, then the phases are separated.
The organic phase is extracted twice with ml of water each time, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to remove the solvent. The residue is recrystallized from 3 ml of ethanol.
Thus, 0.35 g (43 of the title compound are obtained. 116-117 °C.
Example 6 1-/3-(2,2-Dimethyl-2,3-dihydrobenzofuran-7- -yloxy)propyl/-4-(3-trifluoromethylphenyl)- -1,2,3,6-tetrahydropyridine hydrochloride To a solution of 3.00 g (0.0105 moles) of 7 -(3-bromopropyloxy)-2,2-dimethyl-2,3- -dihydrobenzofuran in 50 ml of dichloromethane, 2.63 g (0.01 moles) of 4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride and 10 ml of 10 aqueous sodium hydroxide are added. The reaction mixture is stirred at room temperature for 24 hours, then the phases are separated. The organic phase is extracted twice using 10 ml of water each time, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to remove the solvent. The residue (4.68 g) is dissolved in 20 ml of ethanol containing of hydrogen chloride, and evaporated to dryness again under reduced pressure. The crystalline residue is rubbed with ether, filtered, and dried under reduced pressure.
WO 99/58527 PCT/HU99/00038 -66- Thus, 3.86 g (82.5 of the title compound are obtained. 186-187 OC.
Example 7 1-/3-(2,2-Dimethyl-2,3-dihydrobenzofuran-7- -yloxy)propyl/-4-hydroxy-4-(3-trifluoromethylphenyl)piperidine hydrochloride To a solution of 3.00 g (0.0105 moles) of 7-(3-bromo-propyloxy)-2,2-dimethyl-2,3- -dihydrobenzofuran in 50 ml of dichloromethane, 2.45 g (0.01 moles) of 4-hydroxy-4-(3- -trifluoromethylphenyl)piperidine and 5 ml of 10 aqueous sodium hydroxide are added.
The reaction mixture is stirred at room temperature for 24 hours, then the phases are separated. The organic phase is extracted twice with 10 ml of water each time, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to remove the solvent. The residue (4.91 g) is dissolved in 20 ml of ethanol containing 5 of hydrogen chloride, and the solution is evaporated to dryness again under reduced pressure. The crystalline residue is rubbed with ether, filtered, and dried under reduced pressure.
Thus, 3.30 g (67.9 of the title compound are obtained. 154-155 0
C.
WO 99/58527 PCT/HU99/00038 -67- Example 8 1-/3-(2,2-Dimethyl-2,3-dihydrobenzofuran-7- -yloxy)-2-hydroxypropyl/-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride To a solution of 1.20 g (0.0055 moles) of 2,2-dimethyl-7-oxiranylmethoxy-2,3dihydrobenzofuran in 10 ml of isopropanol, 1.30 g (0.005 moles) of 4 -(3-trifluoromethylphenyl)-1,2,3, 6 -tetrahydropyridine hydrochloride and 1.1 ml of 20 aqueous sodium hydroxide are added. The reaction mixture is boiled for 5 hours, then evaporated under reduced pressure. The residue is subjected to partition between 15 ml of dichloromethane and 10 ml of water, the organic layer is extracted twice with 10 ml of water, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to remove the solvent.
The residue (2.42 g) is dissolved in ml of ethanol containing 5 of hydrogen chloride, and the solution obtained is evaporated again under reduced pressure. The crystalline residue is rubbed with ether, filtered, and dried under reduced pressure.
Thus, 2.02 g (83.5 of the title compound are obtained. 160-162 OC (after recrystallization from isopropanol).
WO 99/58527 PCT/HU99/00038 -68- Example 9 1-/3-(2,2-Dimethyl-2,3-dihydrobenzofuran-7- -yloxy)-2-hydroxypropyl/-4-hydroxy-4-(3-trifluoromethylphenyl)piperidine hydrochloride To a solution of 4.40 g (0.02 moles) of 2,2-dimethyl-7-oxiranylmethoxy-2,3- -dihydrobenzofuran in 30 ml of isopropanol, 4.90 g (0.02 moles) of 4-hydroxy-4-(3-trifluoromethylphenyl)piperidine are added. The reaction mixture is boiled for 6 hours, then evaporated to dryness under reduced pressure.
The oily residue is dissolved in 15 ml of methanol, and, to the cooled solution, a mixture of 3 ml of concentrated hydrochloric acid and 3 ml of water are added at a temperature of 15 to 20 0 C. The crystals precipitated are filtered, washed with cold methanol, and dried under reduced pressure.
Thus, 8.06 g (86 of the title compound are obtained. 156-158 OC (recrystallized from isopropanol).
Example 1-/3-(2,2-Dimethyl-2,3-dihydrobenzofuran-7- -yloxy)- 2 -hydroxypropyl/-4-(4-chlorophenyl)- -1,2,3, 6 -tetrahydropyridine hydrochloride To a solution of 2.80 g (0.013 moles) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 20 ml of isopropanol, 2.30 g (0.01 moles) of 4 -(4-chlorophenyl)-l,2,3,6- WO 99/58527 PCT/HU99/00038 -69- -tetrahydropyridine hydrochloride and 2.2 ml of 20 aqueous sodium hydroxide are added.
The reaction mixture is boiled for 6 hours, then evaporated under reduced pressure. The residue is subjected to partition between ml of chloroform and 20 ml of water, the organic phase is extracted twice with 20 ml of water each time, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to remove the solvent.
The residue (4.3 g) is dissolved in ml of ethanol containing 10 of hydrogen chloride, and the solution obtained is evaporated to dryness again. The crystalline residue is rubbed with ether, filtered, and dried under reduced pressure.
Thus, 3.48 g (77.3 of the title compound are obtained. 164-166 oC (after recrystallization from isopropanol).
Example 11 1-/3-(2,2-Dimethyl-2,3-dihydrobenzofuran-7- -yloxy)- 2 -hydroxypropyl/-4-(2-thienyl)-1,2,3,6- -tetrahydropyridine hydrochloride To a solution of 2.80 g (0.013 moles) of 2, 2 -dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 20 ml of isopropanol, 2.04 g (0.01 moles) of 4 -(2-thienyl)-1,2,3,6- -tetrahydropyridine hydrochloride and 2.2 ml of 20 aqueous sodium hydroxide are added.
The reaction mixture is boiled for 6 hours, WO 99/58527 PCT/HU99/00038 then evaporated under reduced pressure. The residue is subjected to partition between ml of chloroform and 20 ml of water, the organic phase is extracted twice using ml of water each time, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to remove the solvent. The residue is dissolved in 15 ml of ethanol containing 10 of hydrogen chloride, and the solution obtained is evaporated to dryness again under reduced pressure. The crystalline residue is rubbed with ether, filtered, and dried under reduced pressure.
Thus, 3.50 g (82 of the title compound are obtained. 180 0
C.
Example 12 1-/3-(2,2-Dimethyl-2,3-dihydrobenzofuran-7- -yloxy)-2-hydroxypropyl/-4-(4-fluorophenyl)- -1,2,3, 6 -tetrahydropyridine hydrochloride To a solution of 2.80 g (0.013 moles) of 2, 2 -dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 20 ml of isopropanol, 2.13 g (0.01 moles) of 4 -(4-fluorophenyl)-l,2,3,6- -tetrahydropyridine hydrochloride and 2.2 ml of 20 aqueous sodium hydroxide are added.
The reaction mixture is boiled for 6 hours, then evaporated under reduced pressure. The residue is subjected to partition between ml of chloroform and 20 ml of water, the organic phase is extracted twice with 20 ml WO 99/58527 PCT/HU99/00038 -71of water each time, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to remove the solvent. The residue is dissolved in 15 ml of ethanol containing of hydrogen chloride, and the solution obtained is evaporated to dryness again under reduced pressure. The crystalline residue is rubbed with ether, filtered, and dried under reduced pressure.
Thus, 3.2 g (73.8 of the title compound are obtained. 153-155 OC.
Example 13 1-/3-(2,2-Dimethyl-2, 3 -dihydrobenzofuran-7- -yloxy)- 2 -hydroxypropyl/-4-benzylpiperidine hydrochloride To a solution of 2 2 -dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 30 ml of isopropanol, 2.62 g (0.015 moles) of 4-benzylpiperidine are added. The reaction mixture is boiled for 6 hours, then evaporated under reduced pressure. The residue is subjected to partition between 20 ml of chloroform and ml of water, the organic phase is extracted twice with 20 ml of water each time, dried over anhydrous sodium sulfate, filtered, then evaporated under reduced pressure to remove the solvent. The residue is dissolved in ml of ethanol containing 10 of hydrogen chloride, and the solution obtained is also evaporated to dryness under reduced pressure.
WO 99/58527 WO 9958527PCT/HU99/00038 -72- The crystalline residue is rubbed with ether, filtered, and dried under reduced pressure.
Thus, 2.67 g (62 of the title compound are obtained. 130-132 0
C.
Example 14 1-/ 3 -(2,2-Dimethyl-2,3-dihydrobenzofuran.7 -yloxy) -2-hydroxypropyl/--4-hydroxy-4- (4-chlorophenyl )piper idine To a solution of 3.40 g (0.015 moles) of 2, 2-dimethyl-7-oxiranylmethoxy-2, 3-benzofuran in 30 ml of isopropanol, 3.15 g (0.015 moles) of 4-hydroxy-4- (4-chlorophenyl) piperidine are added. The reaction mixture is boiled for 6 hours, cooled, the crystals precipitated are filtered, washed with isopropanol, and dried under reduced pressure.
Thus, 5.40 g (83.4 of the title compound are obtained. 148-150 0
C
(recrystallized from acetone).
Example 1-/3-(2,2-Dimethyl-2,3-dihydrobenzofuran.7 -yloxy)-2-hydroxypropyl/-4-hydroxy4(4chloro.
phenyl )piperidine hydrochloride 0.86 g (0.002 moles) of -dimethyl-2, 3 -dihydrobenzofuran-7-yloxy) -2-hydroxypropyl/-4-hydroxy-4-.(4--chlorophenyl)piperidine are dissolved in 10 ml of methanol, and, to the solution obtained, 2 WO 99/58527 PCT/HU99/00038 -73ml of methanol containing 5 of hydrogen chloride are added under cooling with ice.
The solution is evaporated to dryness under reduced pressure, the crystalline residue is rubbed with ether, filtered, then dried under reduced pressure.
Thus, 0.87 g (93 of the title compound are obtained. 172-174 OC.
Example 16 1-/3-(2,2-Dimethyl-2,3-dihydrobenzofuran-7- -yloxy)- 2 -hydroxypropyl/-4-hydroxy-4-(4-fluorophenyl)piperidine To a solution of 3.4 g (0.015 moles) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 30 ml of isopropanol, 2.53 g (0.013 moles) of 4-hydroxy-4-(4-fluorophenyl)piperidine are added, and the reaction mixture is boiled for 4 hours. The isopropanol is distilled off under reduced pressure, the residue is rubbed with 120 ml of petroleum ether 60 the crystals precipitated are filtered, washed with a mixture of 1 volume of acetone and 4 volumes of petroleum ether, and dried under reduced pressure.
Thus, 4.55 g (84 of the title compound are obtained. 147-148 OC (after recrystallization from ethanol).
WO 99/58527 PCT/HU99/00038 -74- Example 17 1-/3-(2,2-Dimethyl-2,3-dihydrobenzofuran-7- -yloxy)-2-hydroxypropyl/-4-hydroxy-4-(4-fluorophenyl)piperidine hydrochloride 0.83 g (0.002 moles) of -dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2- -hydroxypropyl/-4-hydroxy-4-(4-fluorophenyl)piperidine are dissolved in 10 ml of methanol, and, to the solution obtained, 2 ml of methanol containing 5 of hydrogen chloride are added under cooling with ice. The solution is evaporated to dryness under reduced pressure, the crystalline residue is rubbed with ether, filtered, and dried under reduced pressure.
Thus, 0.79 g (87.5 of the title compound are obtained. 173-175 OC.
Example 18 1-/3-(2,2-Dimethyl-2,3-dihydrobenzofuran-7- -yloxy)-2-hydroxypropyl/-4-phenyl)-1,2,3,6- -tetrahydropyridine hydrochloride To a solution of 1.40 g (0.0063 moles) of 2, 2 -dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 10 ml of isopropanol, 0.98 g (0.005 moles) of 4-(4-phenyl)-1,2,3,6- -tetrahydropyridine hydrochloride and 1.1 ml of 20 aqueous sodium hydroxide are added.
The reaction mixture is boiled for 5 hours, then evaporated under reduced pressure. The residue is subjected to partition between WO 99/58527 PCT/HU99/00038 ml of chloroform and 10 ml of water, the organic phase is extracted twice using ml of water each time, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to remove the solvent. The residue is dissolved in 15 ml of ethanol containing 5 of hydrogen chloride, and the solution obtained is also evaporated under reduced pressure. The crystalline residue is rubbed with ether, filtered, and dried under reduced pressure.
Thus, 1.93 g (92.8 of the title compound are obtained. 166-167 OC.
Example 19 1-/3-(2,2-Dimethyl-2,3-dihydrobenzofuran-7- -yloxy)-2-hydroxypropyl/piperidine To a solution of 2.30 g (0.0105 moles) of 2, 2 -dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 10 ml of isopropanol, 0.85 g (0.01 moles) of piperidine are added. The solution obtained is boiled for 3 hours, cooled, and 20 ml of isopropanol containing of hydrogen chloride are added under cooling at 15 to 20 0 C. The reaction mixture is evaporated to dryness under reduced pressure, the residue is recrystallized from a mixture of ethanol and ether, the crystals separated are filtered, washed with ether, and dried under reduced pressure.
Thus, 2.60 g (76 of the title compound WO 99/58527 PCT/HU99/00038 -76are obtained. 128-130 0
C.
Example 1-/3-(2,2-Dimethyl-2,3-dihydrobenzofuran-7- -yloxy)-2-hydroxypropyl/-4-hydroxy-4-phenylpiperidine hydrochloride To a solution of 3.3 g (0.015 moles) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 20 ml of ethanol, 2.5 g (0.014 moles) of 4 -hydroxy-4-phenylpiperidine are added. The solution obtained is boiled for 3 hours, then cooled to 15 and 10 ml of ethanol containing 10 of hydrogen chloride are added under cooling at 15 to 20 The reaction mixture is evaporated to dryness under reduced pressure, the residue is rubbed with ether, the crystals precipitated are filtered, and dried under reduced pressure.
Thus, 3.62 g (60 of the title compound are obtained. 176-177 OC.
Example 21 1-/3-(2,2-Dimethyl-2,3-dihydrobenzofuran-7- -yloxy)- 2 -hydroxypropyl/-4-hydroxy-4-phenylpiperidine 1.4 g (0.003 moles) of 1-/3-(2,2-dimethyl- -2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-hydroxy-4-phenylpiperidine hydrochloride are dissolved in 50 ml of warm water, and, to the solution obtained, 5 ml of WO 99/58527 PCT/HU99/00038 -77aqueous sodium hydroxide are added. The crystals precipitated are filtered, washed with water, then recrystallized from methanol.
Thus, 1.00 g (78 of the title base are obtained. 127-129 OC.
Example 22 1-/3-(2,2-Dimethyl-2, 3 -dihydrobenzofuran-7- -yloxy)-2-hydroxypropyl/-4-(2-methoxyphenyl)piperidine hydrochloride To a solution of 3.40 g (0.0153 moles) of 2, 2 -dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 30 ml of isopropanol, 3.10 g (0.015 moles) of 4-hydroxy-4-(2-methoxyphenyl)piperidine are added. The reaction mixture is boiled for 5 hours, cooled to C, and 4 ml of ethanol containing 15 of hydrogen chloride are added under cooling at 15 to 20 The solution obtained is evaporated to dryness under reduced pressure, and the residue is recrystallized from a mixture of ethanol and ether. The crystals precipitated are filtered, and dried under reduced pressure.
Thus, 4.73 g (68 of the title compound are obtained. 102-104 0
C.
Example 23 1-/3-(2,2-Dimethyl-2,3-dihydrobenzofuran-7- -yloxy)- 2 -hydroxypropyl/-4-(6-methoxynaphth-2- -yl)piperidine hydrochloride WO 99/58527 PCT/HU99/00038 -78- To a solution of 2.42 g (0.011 moles) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 20 ml of ethanol, 2.6 g (0.01 moles) of 4-hydroxy-4-(6-methoxynaphth- -2-yl)piperidine are added. The solution obtained is boiled for 6 hours, cooled to and 3 ml of ethanol containing 15 of hydrogen chloride are added. The reaction mixture is evaporated to dryness under reduced pressure, and the residue is rubbed with ether.
The crystals precipitated are filtered, recrystallized from a mixture of ethyl acetate and ethanol, filtered again, and dried under reduced pressure.
Thus, 4.6 g (89.5 of the title compound are obtained. 125-127 OC.
Example 24 1-/3-(2,2-Dimethyl-2,3-dihydrobenzofuran-7- -yloxy)-2-hydroxypropyl/-4-hydroxy-4-(3-chlorophenyl)-piperidine hydrochloride To a solution of 2.64 g (0.012 moles) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 15 ml of ethanol, 2.12 g (0.01 moles) of 4-hydroxy-4-(3-chlorophenyl)piperidine are added. The solution obtained is boiled for 6 hours, cooled to 15 0 C, and 3 ml of ethanol containing 15 of hydrogen chloride are added under cooling at 15 to The reaction mixture is evaporated to dryness under reduced pressure, and the WO 99/58527 PCT/HU99/00038 -79residue is rubbed with ether. The crystals precipitated are filtered, recrystallized from a mixture of ethyl acetate and ethanol, filtered again, and dried under reduced pressure.
Thus, 3.64 g (77.8 of the title compound are obtained. 138-140 0
C.
Example 1-/3-(2,2-Dimethyl-2,3-dihydrobenzofuran-7- -yloxy)-2-hydroxypropyl/-4-hydroxy-4-(3- -methoxyphenyl)-piperidine hydrochloride To a solution of 3.80 g (0.0173 moles) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 30 ml of isopropanol, 3.10 g (0.015 moles) of 4-hydroxy-4-(3-methoxyphenyl)piperidine are added. The solution obtained is boiled for 4 hours, then evaporated to dryness under reduced pressure. The residue is dissolved in 40 ml of ethyl acetate, cooled to 15 C, and 6 ml of ethanol containing of hydrogen chloride are added under cooling at 15 to 20 The reaction mixture is evaporated to dryness under reduced pressure, and the residue is rubbed with ether. The crystals precipitated are filtered, recrystallized from a mixture of acetone and ether, filtered again, and dried under reduced pressure.
Thus, 5.90 g (84.8 of the title compound are obtained. 128-130 OC.
WO 99/58527 PCT/HU99/00038 Example 26 l-/3-(2,2-Dimethyl-2,3-dihydrobenzofuran-7- -yloxy)-2-hydroxypropyl/-4-hydroxy-4-(4- -methoxyphenyl)-piperidine To a solution of 3.80 g (0.0173 moles) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 20 ml of ethanol, 3.10 g (0.015 moles) of 4-hydroxy-4-(4-methoxyphenyl)piperidine are added. The solution obtained is boiled for 4 hours, then evaporated to dryness under reduced pressure. The residue is rubbed with 40 ml of ethyl acetate, the crystals precipitated are filtered, and dried under reduced pressure.
Thus, 4.70 g (73.4 of the title compound are obtained. 144-146 OC.
Example 27 1-/3-(2,2-Dimethyl-2,3-dihydrobenzofuran-7- -yloxy)- 2 -hydroxypropyl/-4-hydroxy-4-(5-fluoro- -2-methoxyphenyl)piperidine hydrochloride To a solution of 3.80 g (0.0173 moles) of 2, 2 -dimethyl- 7 -oxiranylmethoxy-2,3-dihydrobenzofuran in 20 ml of ethanol, 3.37 g (0.015 moles) of 4-hydroxy-4-(5-fluoro-2-methoxyphenyl)piperidine are added. The solution obtained is boiled for 6 hours, cooled to and 4 ml of ethanol containing 15 of hydrogen chloride are added under cooling at 15 to 20 C. The reaction mixture is WO 99/58527 PCT/HU99/00038 -81evaporated to dryness under reduced pressure, and the residue is rubbed with ether. The crystals precipitated are filtered, and recrystallized from 40 ml of ethyl acetate.
Thus, 5.60 g (77.5 of the title compound are obtained. 156-158 °C.
Example 28 l-/3-(2,2-Dimethyl-2,3-dihydrobenzofuran-7- -yloxy)- 2 -hydroxypropyl/-4-hydroxy-4-(3-trifluoromethylphenyl)piperidine hydrochloride To a solution of 3.96 g (0.018 moles) of 2, 2 -dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 30 ml of ethanol, 3.34 g (0.015 moles) of 4-( 3 -trifluoromethylphenyl)piperidine hydrochloride and 2 ml of 40 aqueous sodium hydroxide are added. The reaction mixture is boiled for 6 hours, then evaporated to dryness under reduced pressure.
The residue is subjected to partition between ml of water and 50 ml of dichloromethane, the phases are separated, the organic phase is extracted twice using 20 ml of water each time, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The residue is dissolved in 25 ml of ethanol containing 5 of hydrogen chloride, and the solution is evaporated to dryness under reduced pressure. The crystalline residue is rubbed with ether, the crystals WO 99/58527 PCT/HU99/00038 -82separated are filtered, and dried under reduced pressure.
Thus, 5.15 g (77.1 of the title compound are obtained. 172-174 °C.
Example 29 l-/3-(2,2-Dimethyl-2,3-dihydrobenzofuran-7- -yloxy)-2-hydroxypropyl/-4-hydroxy-4-(4-methylphenyl)piperidine To a solution of 3.4 g (0.0153 moles) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 20 ml of ethanol, 2.86 g (0.015 moles) of 4-hydroxy-4-(4-methylphenyl)piperidine are added. The solution obtained is boiled for 5 hours. After cooling, the solution is further cooled to 5 °C in ice bath, the crystals precipitated are filtered, and dried under reduced pressure.
Thus, 5.17 g (83.8 of the title compound are obtained. 138-139 °C.
Example 1-/3-(2,2-Dimethyl-2,3-dihydrobenzofuran-7- -yloxy)-2-hydroxypropyl/-4-hydroxy-4-(4-methylphenyl)piperidine hydrochloride 4.11 g (0.01 moles) of 1-/3-(2,2-dimethyl- 2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-hydroxy-4-(4--methylphenyl)piperidine are dissolved in 15 ml of methanol, and, to the solution cooled with ice, 12 ml of methanol WO 99/58527 PCT/HU99/00038 -83containing 5 of hydrogen chloride are added.
The solution is evaporated to dryness under reduced pressure, the crystalline residue is rubbed with ether, filtered, and dried under reduced pressure.
Thus, 4.17 g (93 of the title compound are obtained. 164-166 0
C.
Example 31 1-/3-(2,2-Dimethyl-2,3-dihydrobenzofuran-7- -yloxy)-2-hydroxypropyl/-4-(4-methoxyphenyl)- -1,2,3,6-tetrahydropyridine To a solution of 3.52 g (0.016 moles) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 25 ml of ethanol, 3.37 g (0.015 moles) of 4-(4-methoxyphenyl)-l,2,3,6- -tetrahydropyridine hydrochloride and 2 ml of 40 aqueous sodium hydroxide are added.
The reaction mixture is boiled for 6 hours, then evaporated to dryness under reduced pressure, the residue is diluted with 50 ml of water, the crystals precipitated are filtered, and dried under reduced pressure.
Thus, 6.1 g (92.8 of the title compound are obtained. 104-105 °C (after recrystallization from petroleum ether having a boiling point of 120 0
C).
WO 99/58527 PCT/HU99/00038 -84- Example 32 1-/3-(2,2-Dimethyl-2,3-dihydrobenzofuran-7- -yloxy)-2-hydroxypropyl/-4-(4-methoxyphenyl)- -1,2,3,6-tetrahydropyridine hydrochloride 4.09 g (0.01 moles) of 1-/3-(2,2-dimethyl- 2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-(4-methoxyphenyl)-1,2,3,6-tetrahydropyridine are dissolved in 15 ml of methanol, and, to the solution cooled with ice, 12 ml of methanol containing 5 of hydrogen chloride are added. The solution is evaporated to dryness under reduced pressure, the crystalline residue is rubbed with ether, filtered, and dried under reduced pressure.
Thus, 4.05 g (91 of the title compound are obtained. 162-164 OC.
Example 33 1-/3-(2,2-Dimethyl-2,3-dihydrobenzofuran-7-ylox y)- 2 -hydroxypropyl/-4-(4-methoxyphenyl)-1,2,3,6 -tetrahydropyridine hydrochloride 1.10 g (0.0025 moles) of -dimethyl- 2, 3 -dihydrobenzofuran-7-yloxy)- -2-hydroxypropyl/-4-(4-methoxyphenyl)-1,2,3,6- -tetrahydropyridine are dissolved in 5 ml of ethanol containing 20 of hydrogen chloride, and the solution is boiled for minutes. After cooling, the solution is diluted with 50 ml of ether, the crystals precipitated are filtered, washed with ether, and dried WO 99/58527 WO 9958527PCT/iHU99/00038 under reduced pressure.
Thus, 0.98 g (93 of the title compound are obtained. 161-163 0
C.
Example 34 l-/ 3 -(2,2-Dimethyl-2,3-dihydrobenzofuran-7 -yloxy) -2-hydroxypropyl/-4-hydroxy-4-(3,5- -dimethyl-4-methoxyphenyl )piperidine hydrochloride To a solution of 3.60 g (0.0165 moles) of 2 2 -dimethyl-7-oxiranylmethoxy)-2,3.dihydrobenzofuran in 20 ml of ethanol, 3.45 g (0.015 moles) of 4-hydroxy-4-( 3 ,5-dimethyl-4-methoxyphenyl)piperidine are added. The reaction mixture is reacted at 55 to 60 0 C for 2 hours, then cooled to 0 0 C, and 5 ml of ethanol containing 10 of hydrogen chloride are added under cooling. The reaction mixture is evaporated to dryness under reduced pressure, and the residue is rubbed with ether. The crystals precipitated are filtered, and dried under reduced pressure.
Thus, 6.42 g (87 of the title compound are obtained. 92-96 0
C.
Example 1-/3-(2,2-Dimethyl-2,3-dihydrobenzofuran-7 -yloxy)- 2 -hydroxypropyl/-4-hydroxy-4-(3,5- -dimethyl-4-methoxyphenyl )piperidine hydrochloride WO 99/58527 PCT/HU99/00038 -86- To 1.26 g (0.0057 moles) of 2,2-dimethyl- -7-oxiranylmethoxy-2,3-dihydrobenzofuran, 1.18 g (0.005 moles) of 4-hydroxy-4-(3,5- -dimethyl-4-methoxyphenyl)piperidine are added, and the reaction mixture is reacted at C for 1 hour. The melt is cooled, then dissolved in ether, and, to the solution obtained, 1 ml of ethanol containing 20 of hydrogen chloride are added. The crystals precipitated are filtered, washed with ether, and dried under reduced pressure.
Thus, 2.04 g (83 of the title compound are obtained. 94-96 0
C.
Example 36 l-/3-(2,2-Dimethyl-2,3-dihydrobenzofuran-7- -yloxy)-2-hydroxypropyl/-4-hydroxy-4-(3,4- -methylenedioxyphenyl)piperidine To a solution of 2.42 g (0.011 moles) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 20 ml of ethanol, 2.57 g (0.01 moles) of 4-hydroxy-4-(3,4-methylenedioxyphenyl)piperidine hydrochloride and 4.2 ml of 10 aqueous sodium hydroxide are added.
The reaction mixture is boiled for 5 hours, then evaporated to dryness under reduced pressure. The residue is subjected to partition between 20 ml of water and 50 ml of dichloromethane, the phases are separated, the organic phase is extracted twice with 20 ml of water each time, dried over anhydrous sodium sulfate, WO 99/58527 PCT/HU99/00038 -87filtered, and evaporated to dryness under reduced pressure. The residue is recrystallized from a mixture of ethyl acetate and n-hexane, the crystals precipitated are filtered, and dried under reduced pressure.
Thus, 3.01 g (73 of the title compound are obtained. 128-130 OC.
Example 37 1-/3-(2,2-Dimethyl-2,3-dihydrobenzofuran-7- -yloxy)-2-hydroxypropyl/-4-hydroxy-4-/4-(2- -methyl-2-propenyloxy)phenyl/piperidine To a solution of 4.8 g (0.022 moles) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 20 ml of diisopropyl ether, 4.94 g (0.02 moles) of 4-hydroxy-4-/4-(2- -methyl-2-propenyloxy)phenylpiperidine are added. The reaction mixture is boiled for 6 hours, then cooled to O the crystals precipitated are filtered, washed with diisopropyl ether, then dried under reduced pressure.
Thus, 7.95 g (85 of the title compound are obtained. 108-110 0
C.
Example 38 1-/3-(2,2-Dimethyl-2, 3 -dihydrobenzofuran-7- -yloxy)-2-hydroxypropyl/-4-hydroxy-4-(4- -biphenylyl)piperidine hydrochloride To a solution of 2.64 g (0.012 moles) WO 99/58527 PCT/HU99/00038 -88of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 16 ml of ethanol, 2.53 g (0.01 moles) of 4-hydroxy-4-(4-biphenylyl)piperidine are added. The reaction mixture is stirred at 70 oC for 1 hour, then evaporated to dryness under reduced pressure. The residue is dissolved in 50 ml of ether, and, to the solution obtained, 1.5 ml of ethanol containing of hydrogen chloride are added under cooling. The crystals precipitated are filtered, washed with ether, then dried under reduced pressure.
Thus, 4.45 g (87 of the title compound are obtained. 166-167 OC.
Example 39 1-/3-(2,2-Dimethyl-2,3-dihydrobenzofuran-7- -yloxy)-2-hydroxypropyl/-4-hydroxy-4-(4- -phenoxyphenyl)piperidine To a solution of 2.64 g (0.012 moles) of 2, 2 -dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 16 ml of ethanol, 2.70 g (0.01 moles) of 4-hydroxy-4-(4-phenoxyphenyl)piperidine are added. The reaction mixture is stirred at 70 OC for 1 hour, then evaporated to dryness under reduced pressure. The residue is recrystallized from a low amount of methanol, filtered, and dried under reduced pressure.
Thus, 4.47 g (91 of the title compound are obtained. 113-115 °C.
WO 99/58527 PCT/HU99/00038 -89- Example 2 -Dimethyl-2,3-dihydrobenzofuran-7- -yloxy)-2-hydroxypropyl/-4-hydroxy-4-(4-chloro- -3-trifluoromethylphenyl)piperidine hydrochloride To a solution of 3.90 g (0.0177 moles) cf 2 2 -dimethyl-7-oxiranylmethoxy-2,3- -dihydrobenzofuran in 20 ml of ethanol, 4.19 g (0.015 moles) of 4-hydroxy-4-(4-chloro- -3-trifluoromethylphenyl)piperidine are added.
The reaction mixture is stirred at 60 oC for 2 hours, then evaporated to dryness under reduced pressure. The residue is dissolved in 60 ml of ether, and, to the solution obtained, 2.5 ml of ethanol containing of hydrogen chloride are added. The crystals precipitated are filtered, washed with ether, and dried under reduced pressure.
Thus, 7.00 g (88 of the title compound are obtained. 146-148 0
C.
Example 41 1-/3-(2,2-Dimethyl-2,3-dihydrobenzofuran-7- -yloxy)- 2 -hydroxypropyl/-4-cyano-4-phenylpiperidine hydrochloride To a solution of 0.20 g (0.005 moles) of sodium hydroxide in 15 ml of isopropanol, 1.21 g (0.0055 moles) of 2,2-dimethyl-7- -oxiranylmethoxy-2, 3 -dihydrobenzofuran and 1.11 g (0.005 moles) of 4-cyano-4-phenyl- WO 99/58527 PCT/HU99/00038 piperidine hydrochloride are added. The reaction mixture is boiled under stirring for 6 hours, then evaporated to dryness under reduced pressure. The residue is subjected to partition between 50 ml of water and ml of dichloromethane, the phases are separated, the organic phase is extracted twice using 20 ml of water each time, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure.
The residue is dissolved in 50 ml of ether, and, to the solution obtained, 1 ml of ethanol containing 20 of hydrogen chloride are added under cooling. The crystals precipitated are filtered, washed with ether, then dried under reduced pressure.
Thus, 1.60 g (74 of the title compound are obtained. 204-206 0
C.
Example 42 1-/3-(2,2-Dimethyl-2,3-dihydrobenzofuran-7- -yloxy)- 2 -hydroxypropyl/-4-cyano-4-(3-trifluoromethylphenyl)piperidine hydrochloride To a solution of 0.20 g (0.005 moles) of sodium hydroxide in 15 ml of isopropanol, 1.21 g (0.0055 moles) of 2,2-dimethyl- -7-oxiranylmethoxy-2,3-dihydrobenzofuran and 1.40 g (0.005 moles) of 4-cyano-4-(3-trifluoromethylphenyl)piperidine hydrochloride are added. The reaction mixture is boiled for 6 hours under stirring, then evaporated to WO 99/58527 PCT/HU99/00038 -91dryness under reduced pressure. The residue is subjected to partition between 50 ml of water and 50 ml of dichloromethane, the phases are separated, the organic phase is extracted twice using 20 ml of water each time, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure.
The residue is dissolved in 50 ml of ether, and, to the solution obtained, 1 ml of ethanol containing 20 of hydrogen chloride is added.
The crystals precipitated is filtered, washed with ether, and dried under reduced pressure.
Thus, 1.48 g (59.2 of the title compound are obtained. 213-216 0
C.
Example 43 1-/3-(5-Bromo-2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)- 2 hydroxypropyl/-4-hydroxy- -4-(4-methoxyphenyl)piperidine To a solution of 2.63 g (0.0088 moles) of 5-bromo-2, 2 -dimethyl-7-oxiranylmethoxy- 2,3-dihydrobenzofuran in 10 ml of isopropanol, 1.66 g (0.008 moles) of 4-hydroxy-4-(4- -methoxyphenyl)piperidine are added. The reaction mixture is boiled under stirring for 10 hours, then cooled to 0 The crystals precipitated are filtered, washed with cold isopropanol, and dried under reduced pressure.
Thus, 2.67 g (66 of the title compound are obtained. 120-121 °C (after recrystallization from isopropanol).
WO 99/58527 WO 9958527PCTAiHU99/00038 -92- Example 44 1-13- (5-Bromo-2, 2-dimethyl-2, 3-dihydrobenzofuran-7-yloxy) 2 hydroxypropyl-4-hydroxy.
4 -chloro-3-trifluoromethylphenyl )piperidine hydrochloride To a solution of 3.30 g (0.011 moles) of 5-bromo-2, 2 -dimethyl-7-oxiranylmethoxy.
-2,3-dihydrobenzofuran in 20 ml of ethanol, 2.80 g (0.01 moles) of 4 -hydroxy-4-(4-chloro- 3 -trifluoromethylphenyl )piperidine are added.
The reaction mixture is stirred at 60 0 C for 2 hours, then evaporated to dryness under reduced pressure. The residue is dissolved in 60 ml of ether, and, to the solution obtained, 2.5 ml of ethanol containing of hydrogen chloride are added under cooling.
The crystals separated are filtered, washed with ether, and dried under reduced pressure.
Thus, 4.86 g (79 of the title compound are obtained. 108-110 0 C.
Example 1-/3-(2,2-Dimethyl-5-nitro-2,3-dihydrobenzo.
furan-7-yloxy) 2 -hydroxypropyl/-4-hydroxy- (4-methoxyphenyl )piperidine To a solution of 2.62 g (0.01 moles) of 2, 2 -dimethyl-5-nitro.7oxiranylrethoxy-2,3- -dihydrobenzofuran in 8 ml of isopropanol, 1.86 g (0.009 moles) of 4-hydroxy-4-(4- -methoxyphenyl)piperidine are added. The WO 99/58527 PCT/HU99/00038 -93reaction mixture is boiled for 2 hours under stirring, then cooled to 2 The crystals precipitated are filtered, washed with cold isopropanol, then dried under reduced pressure.
Thus, 3.48 g (81.8 of the title compound are obtained. 136-138 OC.
Example 46 1-/3-(2,2-Dimethyl-5-nitro-2,3-dihydrobenzofuran-7-yloxy)-2--hydroxypropyl/-4-(3- -trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride To a solution of 2.46 g (0.012 moles) of 2, 2 -dimethyl-5-nitro-7-oxiranylmethoxy- -2,3-dihydrobenzofuran in 20 ml of isopropanol, 2.11 g (0.01 moles) of 4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride and 2.2 ml of 20 aqueous sodium hydroxide are added. The reaction mixture is boiled for 5 hours under stirring, then evaporated under reduced pressure. The residue is subjected to partition between 30 ml of dichloromethane and 10 ml of water, the organic phase is extracted twice with 20 ml of water each time, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to remove the solvent. The residue is dissolved in 50 ml of ethanol containing 5 os hydrogen chloride, and the solution obtained is also evaporated to dryness under reduced pressure.
The crystalline residue is rubbed with ether, WO 99/58527 WO 9958527PCTAFIU99/00038 -94filtered, and dried under reduced pressure.
Thus, 3.89 g (73.7 of the title compound are obtained. 162-165 0
C.
Example 47 l-/3-(2,2-Dimethyl-2,3-dihydrobenzofuran-7- -yloxy) -2-hydroxypropyl/-4- (6-methoxynaphth- 2 -yl)-l,2,3,6-tetrahydropyridine hydrochloride A solution of 3.34 g (0.0065 moles) of 1-13- 2-dimethyl-2, 3-dihydrobenzofuran-7- -yloxy) -2-hydroxypropyl/-4-- (6-methoxynaphth- -2-yl)piperidine hydrochloride in 15 ml of ethanol containing 20 of hydrogen chloride is boiled for 20 minutes, then evaporated to dryness under reduced pressure. The crystalline residue is rubbed with 30 ml of ether, filtered, and dried under reduced pressure.
Thus, 2.96 g (92 of the title compound are obtained. 186-188 0
C.
Example 48 (5-Bromo-2, 2-dimethyl-2, 3-dihydrobenzofuran- 7 -yloxy)-2-hydroxypropyl/4(3-trifluoromethylphenyl ,6-tetrahydropyridine hydrochloride To a solution of 2.63 g (0.0088 moles) of 5-bromo-2, 2 -dimethyl-7-oxiranylmethoxy- 2 3 -dihydrobenzofuran in 15 ml of ethanol, 2.11 g (0.008 moles) of 4 3 -trifluoromethyl- WO 99/58527 PCT/HU99/00038 phenyl)-1,2,3,6-tetrahydropyridine hydrochloride and 3.2 ml of 10 aqueous sodium hydroxide are added. The reaction mixture is boiled for 6 hours under stirring, then evaporated under reduced pressure. The residue is subjected to partition between 50 ml of dichloromethane and 50 ml of water. The organic phase is extracted twice with 20 ml of water each time, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to remove the solvent. The residue is dissolved in 10 ml of ethanol containing 10 of hydrogen chloride, and the solution obtained is also evaporated to dryness under reduced pressure.
The crystalline residue is boiled with ml of ethyl acetate, the crystals are filtered from the hot mixture, and dried under reduced pressure.
Thus, 3.78 g (89.8 of the title compound are obtained. 112-114 OC.
Example 49 1-/3-(5-Bromo-2,2-dimethyl-2,3-dihydrobenzofuran-7-yloxy)-2-hydroxypropyl/-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride To a solution of 2.30 g (0.0077 moles) of 5-bromo-2,2-dimethyl-7-oxiranylmethoxy-2,3- -dihydrobenzofuran in 15 ml of ethanol, 1.72 g (0.007 moles) of 4-(3-trifluoromethylphenyl)- -1,2,3,6-tetrahydropyridine are added, and WO 99/58527 PCT/HU99/00038 -96the reaction mixture is boiled for 6 hours under stirring, then evaporated under reduced pressure. The residue is boiled in 10 ml of ethanol containing 20 of hydrogen chloride for 30 minutes, and the mixture is also evaporated under reduced pressure. The crystalline residue is boiled with 30 ml of ethyl acetate for 5 minutes, the crystals are filtered, and dried under reduced pressure.
Thus, 3.42 g (92.8 of the title compound are obtained. 112-114 OC.
Example 1-/3-(2,2-Dimethyl-2,3-dihydrobenzofuran-7- -yloxy)-2-hydroxypropyl/-4-(3-trifluoromethylphenyl)piperidine hydrochloride A solution of 1.78 g (0.004 moles) of 1-/3-(2,2-dimethyl-2,3-dihydrobenzofuran-7- -yloxy)-2-hydroxypropyl/-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride in 20 ml of methanol is hydrogenized in the presence of 0.1 g of 10 palladium/carbon catalyst at 20 °C and atmospheric pressure. As soon as the calculated amount of hydrogen (96 ml) is taken up, the catalyst is removed by filtration, and the solution is evaporated under reduced pressure.
The crystalline residue is rubbed with ml of ether, the crystals are filtered, and dried under reduced pressure.
Thus, 1.75 g (98 of the title compound WO 99/58527 PCT/HU99/00038 -97are obtained. 172-174 OC.
Example 51 1-/3-(2,2-Dimethyl-2,3-dihydrobenzofuran-7- -yloxy)- 2 -hydroxypropyl/-4-(3-trifluoromethylphenyl)piperidine hydrochloride A mixture of 2.31 g (0.0105 moles) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran and 2.45 g (0.01 moles) of 4-hydroxy-4-( 3 -trifluoromethylphenyl)piperidine is melted at 80 °C for 1 hour, then dissolved in 10 ml of ethanol containing 20 of hydrogen chloride, and the mixture is boiled for minutes. The solution is diluted with 10 ml of ethanol, cooled to 30 OC, 0.1 g of 10 palladium/carbon catalyst are added, and the mixture is hydrogenized. As soon as the calculated amount of hydrogen (240 ml) is taken up, the catalyst is removed by filtration, and the solution is evaporated under reduced pressure. The crystalline residue is rubbed with ether, the crystals are filtered, and dried under reduced pressure.
Thus, 4.05 g (91 of the title compound are obtained. 172-174 0
C.
Example 52 1-/3-(2,2-Dimethyl-2,3-dihydrobenzofuran-7- -yloxy)- 2 -hydroxypropyl/-4-hydroxypiperidine hydrochloride WO 99/58527 PCT/HU99/00038 -98- To a solution of 1.32 g (0.006 moles) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 10 ml of tetrahydrofuran, 0.55 g (0.0055 moles) of 4-hydroxypiperidine are added. The reaction mixture is boiled for 3 hours under stirring, then evaporated to dryness under reduced pressure. The residue is dissolved in a mixture of 5 ml of 2-propanol and 1.5 ml of 2-propanol containing 16 of hydrogen chloride, the solution obtained is evaporated under reduced pressure, the residue is dissolved in 8 ml of 2-propanol, and allowed to stand at O °C for 5 days. The crystals precipitated are filtered, recrystallized from 2-propanol, filtered, and dried under reduced pressure.
Thus, 1.22 g (57 of the title compound are obtained. 139-141 0
C.
Example 53 1-/3-(2,2-Dimethyl-2,3-dihydrobenzofuran-7- -yloxy)- 2 -hydroxypropyl/-4-methylpiperidine hydrochloride A mixture of 1.32 g (0.006 moles) of 2, 2 -dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran, 0.44 g (0.0045 moles) of 4-methylpiperidine and 8 ml of water is boiled for 9 hours. The oillike phase of the mixture formed is dissolved in 20 ml of ether, washed with water, dried over anhydrous sodium sulfate, evaporated under reduced pressure, WO 99/58527 PCT/HU99/00038 -99dissolved in 3 ml of 2-propanol containing 16 of hydrogen chloride, and evaporated under reduced pressure. The residue is dissolved in ethyl acetate, precipitated with ether, the crystals are filtered, dissolved in hot 2-propanol, precipitated again with ether, the crystals are filtered, and dried under reduced pressure.
Thus, 1.25 g (59 of the title compound are obtained. 146-148 OC.
Example 54 1-/3-(2,2-Dimethyl-2,3-dihydrobenzofuran-4- -yloxy)- 2 -hydroxypropyl/-4-hydroxy-4-(4-trifluoromethylphenyl)piperidine hydrochloride 3.28 g (0.02 moles) of 2,2-dimethyl- -2,3-dihydrobenzofuran-4-ol are dissolved in 25 ml of 10 aqueous sodium hydroxide.
To the solution, 3.70 g (0.04 moles) of epichlorohydrin are added, and the reaction mixture is stirred at 45 to 50 °C for 3 hours.
After cooling, the oily product that separates is dissolved in 30 ml of dichloromethane, the phases are separated, the organic phase is washed twice with 20 ml of water each time, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The residual thick honeylike epoxide (3.78 g, 85.3 is dissolved in 40 ml of ethanol, to the solution obtained, 3.80 g (0.0155 moles) of 4 -hydroxy-4-(3-trifluoro- WO 99/58527 PCT/HU99/00038 -100methylphenyl)piperidine are added, and the reaction mixture is boiled for 6 hours. After cooling, to the solution obtained, 15 ml of ethanol containing 5 of hydrogen chloride are added at a temperature of less than C, and the mixture is evaporated to dryness under reduced pressure. The crystalline residue is recrystallized from a mixture of ethanol and ether, filtered, washed with ether.
Thus, 5.60 g (72 of the title compound are obtained. 162-164 0
C.
Example 1-/3-(2,2-Dimethyl-2,3-dihydrobenzofuran-4- -yloxy)- 2 -hydroxypropyl/-4-hydroxy-4-(6- -methoxynaphth-2-yl)piperidine hydrochloride The procedure of Example 54 is followed with the difference that the epoxide obtained in the first reaction step (3.75 g, 85.2 is dissolved in 50 ml of ethanol. To the solution, 3.94 g (0.0153 moles) of 4-hydroxy- -4-(6-methoxy-naphth-2-yl)piperidine are added, and the reaction mixture is boiled for 4 hours.
After cooling, to the solution, 13 ml of ethanol containing 5 of hydrogen chloride are added, and the reaction mixture is evaporated to dryness under reduced pressure.
The residual crystalline product is recrystallized from a mixture of ethanol and ether.
Thus, 5.35 g (68 of the title compound WO 99/58527 PCT/HU99/00038 -101are obtained. 118-120 0
C.
Example 56 1-/3-(2,2-Dimethyl-2,3-dihydrobenzofuran-5- -yloxy)-2-hydroxypropyl/-4-hydroxy-4-(4-trifluoromethylphenyl)piperidine hydrochloride 3.28 g (0.02 moles) of 2,2-dimethyl- -2,3-dihydrobenzofuran-5-ol are dissolved in 30 ml of aqueous solution containing 3 g of sodium hydroxide. To the solution obtained, 3.70 g (0.04 moles) of epichlorohydrin are added, and the reaction mixture is stirred at 48 to 50 0 C for 3 hours. After cooling, the oily product that separates is dissolved in 30 ml of dichloromethane, the phases are separated, the organic phase is washed twice with 20 ml of water each time, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The residual thick waxlike epoxide (3.85 g, 87.3 is dissolved in 50 ml of ethanol, to the solution, 3.80 g (0.0155 moles) of 4-hydroxy-4-(trifluoromethylphenyl)piperidine are added, and the reaction mixture is boiled for 5 hours. After cooling, to the solution obtained, 15 ml of ethanol containing of hydrogen chloride are added at a temperature of less than 15 OC, and the mixture is evaporated to dryness under reduced pressure. The residue that crystallizes is recrystallized from a mixture of ethanol and WO 99/58527 PCT/HU99/00038 -102ether, filtered, and washed with ether.
Thus, 4.97 g (64 of the title compound are obtained. 172-173 OC.
Example 57 1-/3-(2,2-Dimethyl-2,3-dihydrobenzofuran-6- -yloxy)-2-hydroxypropyl/-4-hydroxy-4-phenylpiperidine hydrochloride 1.64 g (0.01 moles) of 2,2-dimethyl- -2,3-dihydro-benzofuran-6-ol are dissolved in 15 ml of 10 aqueous sodium hydroxide.
To the solution, 1.85 g (0.02 moles) of epichlorohydrin are added, and the reaction mixture is stirred at 48 to 52 °C for hours. After cooling, the oily product that separates is dissolved in 25 ml of dichloromethane, the phases are separated, the organic phase is washed twice with 15 ml of water each time, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The residual thick honeylike epoxide (2.10 g, 95 is dissolved in ml of ethanol, to the solution obtained, 1.52 g (0.0086 moles) of 4-hydroxy-4-phenylpiperidine are added, and the reaction mixture is boiled for 6 hours. After cooling, to the solution obtained, 10 ml of ethanol containing of hydrogen chloride are added at a temperature of less than 15 OC, and the mixture is evaporated to dryness under reduced pressure. The residue that crystallizes is WO 99/58527 PCT/HU99/00038 -103recrystallized from a mixture of ethanol and ether, filtered, and washed with ether.
Thus, 4.97 g (64 of the title compound are obtained. 184-186 °C.
Example 58 1-/3-(2,2-Dimethyl-2,3-dihydrobenzofuran-7- -yloxy)-2-hydroxypropyl/-4-methoxy-4-(3-trifluoromethylphenyl)piperidine hydrochloride To a solution of 0.20 g (0.005 moles) of sodium hydroxide in 15 ml of isopropanol, 1.21 g (0.0055 moles) of 2,2-dimethyl-7oxiranylmethoxy-2,3-dihydrobenzofuran and 1.48 g (0.005 moles) of 4-methoxy-4-(3-trifluoromethylphenyl)piperidine hydrochloride are added. The reaction mixture is boiled for 6 hours under stirring, then evaporated to dryness under reduced pressure. The residue is subjected to partition between 50 ml of water and 50 ml of dichloromethane, the phases are separated, the organic phase is extracted twice with 20 ml of water each time, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure.
The residue is dissolved in 50 ml of ether, and, to the solution, 1 ml of ethanol containing 20 of hydrogen chloride is added under cooling, the crystals precipitated are filtered, washed with ether, and dried under reduced pressure.
Thus, 1.62 g (62.8 of the title WO 99/58527 PCT/HU99/00038 -104compound are obtained. 192-195 0
C.
Example 59 1-/3-(2,2-Dimethyl-2,3-dihydrobenzofuran-7- -yloxy)-2-hydroxypropyl/-4-(diphenylmethyl)piperazine A solution of 2.20 g (0.01 moles) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzo furan and 2.52 g (0.01 moles) of l-(diphenylmethyl)piperazine in 30 ml of isopropanol is boiled for 6 hours. The solution is evaporated to dryness under reduced pressure, the residual product is rubbed with n-hexane, and filtered. The thus-obtained crude product (4.53 g) is recrystallized from 25 ml of ethanol, filtered, and dried under reduced pressure.
Thus, 3.89 g (82 of the title compound are obtaimed. 129-130 0
C.
Example 1-/3-(2,2-Dimethyl-2,3-dihydrobenzofuran-7- -yloxy)-2-hydroxypropyl/-4-(diphenylmethyl)piperazine A mixture of 2.20 g (0.01 moles) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran and 2.52 g (0.01 moles) of l-(diphenylmethyl)piperazine is melted at C and maintained at the above temperature for an hour. The obtained mass that solidifies WO 99/58527 PCT/HU99/00038 -105is recrystallized from 25 ml of ethanol, filtered, and dried under reduced pressure.
Thus, 3.92 g (83 of the title compound are obtained. 129-130 °C.
Example 61 1-/3-(2,2-Dimethyl-2,3-dihydrobenzofuran-7- -yloxy)- 2 -hydroxypropyl/-4-(diphenylmethyl)piperazine A mixture of 2.20 g (0.01 moles) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran and 2.52 g (0.01 moles) of l-(diphenylmethyl)piperazine is melted at °C and maintained at the above temperature for an hour. The obtained mass that solidifies is recrystallized from 25 ml of ethanol, filtered, and dried under reduced pressure.
Thus, 3.82 g (81 of the title compound are obtained. 129-130 0
C.
Example 62 l-/3-(2,2-Dimethyl-2,3-dihydrobenzofuran-7- -yloxy)-2-hydroxypropyl/-4-(diphenylmethyl)piperazine To a solution of 2.31 g (0.011 moles) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran in 20 ml of ethanol, 2.52 g (0.01 moles) of l-(diphenylmethyl)piperazine are added, and the reaction mixture is boiled for 4 hours. After cooling, the crystals WO 99/58527 PCT/HU99/00038 -106precipitated are filtered, and dried under reduced pressure.
Thus, 3.87 g (81 of the title compound are obtained. 129-130 °C.
Example 63 1-/3-(2,2-Dimethyl-2,3-dihydrobenzofuran-7- -yloxy)- 2 -hydroxypropyl/-4-(4-fluorophenyl)piperazine A solution of 4.40 g (0.02 moles) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran and 3.60 g (0.02 moles) of l-(4-fluorophenyl)piperazine in 30 ml of ethanol is boiled for 5 hours. The solution is evaporated to dryness under reduced pressure, the residual product is subjected to chromatography on a column filled with Kieselgel 60 using a mixture of 30 volumes of chloroform and 1 volume of ethanol as the eluent. The fractions containing the product are evaporated, the residual product is rubbed with n-hexane, and filtered, dried under reduced pressure.
Thus, 7.30 g (91 of the title compound are obtained. 80-82 0
C.
Example 64 1-/3-(2,2-Dimethyl-2,3-dihydrobenzofuran-7- -yloxy)-2-hydroxypropyl/-4-(4-fluorophenyl)piperazine WO 99/58527 PCT/HU99/00038 -107- A mixture of 2.31 g (0.011 moles) of 2, 2 -dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran and 1.80 g (0.01 moles) of l-(4-fluorophenyl)piperazine is melted at 60 OC, and maintained at the above temperature for an hour. The melt obtained is subjected to chromatography on a column filled with Kieselgel 60 using a mixture consisting og volumes of chloroform and 1 volume of ethanol as the eluent. The fractions containing the product are evaporated, and the residue is rubbed with n-hexane, then filtered, and dried under reduced pressure.
Thus, 3.72 g (93 of the title compound are obtained. 80-82 0
C.
Example 1-/3-(2,2-Dimethyl-2, 3 -dihydrobenzofuran-7- -yloxy)-2-hydroxypropyl/-4-(4-fluorophenyl)piperazine A mixture of 2.20 g (0.011 moles) of 2, 2 -dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran and 1.80 g (0.01 moles) of l-( 4 -fluorophenyl)piperazine is melted at C and maintained at the latter temperature for 1 hour. To the melt obtained, 60 ml of n-hexane are added, the mixture is cooled, the crystals precipitated are filtered, dried under reduced pressure.
Thus, 3.26 g (81 of the title compound are obtained. 80-82 °C.
WO 99/58527 PCT/HU99/00038 -108- Example 66 1-/3-(2,2-Dimethyl-2,3-dihydrobenzofuran-7- -yloxy)-2-hydroxypropyl/-4-(3-fluorophenyl)piperazine A solution of 2.20 g (0.01 moles) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran and 2.30 g (0.01 moles) of l-(3-trifluoromethylphenyl)piperazine in 20 ml of isopropanol is boiled for 4 hours. The solution is evaporated to dryness under reduced pressure, the residue is subjected to chromatography on a column filled with Kieselgel 60 and using a mixture of 30 volumes of chloroform and 1 volume of ethanol as the eluent. The fractions containing the product are evaporated, the product obtained is rubbed with n-hexane, filtered, and dried under reduced pressure.
Thus, 3.76 g (84 of the title compound are obtained. 82-84 °C.
Example 67 1-/3-(2,2-Dimethyl-2,3-dihydrobenzofuran-7- -yloxy)- 2 -hydroxypropyl/-4-(3-fluorophenyl)piperazine A mixture of 2.20 g (0.01 moles) of 2, 2 -dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran and 2.30 g (0.01 moles) of l-(3-trifluoromethylphenyl)piperazine is melted at and maintained at the latter temperature WO 99/58527 PCT/HU99/00038 -109for 1.5 hours. To the melt obtained, 60 ml of n-hexane are added, the mixture is cooled, the crystals precipitated are filtered, and dried under reduced pressure.
Thus, 3.77 g (84 of the title compound are obtained. 82-84 0
C.
Example 68 1-/3-(2,2-Dimethyl-2,3-dihydrobenzofuran-7- -yloxy)-2-hydroxypropyl/-4-(4-methoxyphenyl)piperazine A solution of 3.80 g (0.017 moles) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran and 2.88 g (0.015 moles) of l-( 4 -methoxyphenyl)piperazine in 40 ml of methyl tert.-butyl ether is boiled for 8 hours, then cooled to 0 The crystals precipitated are filtered, and dried under reduced pressure.
Thus, 5.21 g (84 of the title compound are obtained. 93-94 0
C.
Example 69 l-/3-(2,2-Dimethyl-2,3-dihydrobenzofuran-7- -yloxy)-2-hydroxypropyl/-4-(4-methoxyphenyl)piperazine A mixture of 1.10 g (0.005 moles) of 2, 2 -dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran and 0.96 g (0.005 moles) of l-( 4 -methoxyphenyl)piperazine is melted at OC, and maintained at the latter temperature WO 99/58527 PCT/HU99/00038 -110for 1 hour. To the warm melt obtained, ml of methyl tert.-butyl ether are added, the mixture is cooled, the crystals precipitated are filtered, and dried under reduced pressure.
Thus, 1.88 g (91 of the title compound are obtained. 93-94 0
C.
Example l-/3-(2,2-Dimethyl-2,3-dihydrobenzofuran-7- -yloxy)-2-hydroxypropyl/-4-(benzo-1,3dihydrochloride A solution of 3.80 g (0.017 moles) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran and 3.30 g (0.015 moles) of l-(benzo-l, 3 -dioxolane-5-yl)piperazine in ml of ethanol is boiled for 10 hours. The solution is evaporated to dryness under reduced pressure, the residue (8.0 g) is dissolved in 30 ml of ethanol containing 4.0 g of hydrogen chloride. From the homogeneous solution, crystals begin to separate. The suspension is diluted with 60 ml of methyl tert.-butyl ether, filtered, and the crystals are dried under reduced pressure.
Thus, 5.40 g (70 of the title compound are obtained. 216-218 °C.
WO 99/58527 PCT/HU99/00038 -111- Example 71 1-/3-(2,2-Dimethyl-2, 3 -dihydrobenzofuran-7- -yloxy)-2-hydroxypropyl/-4-(benzo-1,3dihydrochloride A solution of 3.80 g (0.017 moles) of 2, 2 -dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran and 3.30 g (0.015 moles) of in ml of isopropanol is boiled for 6 hours.
The solution is evaporated to dryness under reduced pressure, the residue is dissolved in 20 ml of ethanol containing 15 of hydrogen chloride. From the homogeneous solution, crystals begin to separate. The suspension is diluted with 60 ml of methyl tert.-butyl ether, filtered, and the crystals are dried under reduced pressure.
Thus, 5.43 g (71 of the title compound are obtained. 216-218 0
C.
Example 72 1-/3-(2,2-Dimethyl-2, 3 -dihydrobenzofuran-7- -yloxy)-2-hydroxypropyl/-4-(benzo-1,3dihydrochloride A solution of 2.31 g (0.011 moles) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran and 2.20 g (0.01 moles) of l-(benzo-l, 3 -dioxolane-5-yl)piperazine in ml of diisopropyl ether is boiled for 6 hours, then, 7 ml of ethanol containing WO 99/58527 PCT/HU99/00038 -112of hydrogen chloride are added. The crystals precipitated are cooled, filtered, and dried under reduced pressure.
Thus, 4.41 g (86 of the title compound are obtained. 216-218 0
C.
Example 73 1-/3-(2,2-Dimethyl-2,3-dihydrobenzofuran-7- -yloxy)-2-hydroxypropyl/-4-(4-chlorophenyl)piperazine A mixture of 2.42 g (0.0115 moles) of 2, 2 -dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran, 2.70 g (0.01 moles) of l-(4-chlorophenyl)piperazine dihydrochloride, 26 ml of ethanol, 3 ml of water and 0.9 g (0.0225 moles) of sodium hydroxide is boiled for 6 hours under stirring, then evaporated to dryness under reduced pressure. The residue is subjected to partition between 80 ml of dichloromethane and 50 ml of water, the organic phase is extracted twice using 30 ml of water each time, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The residue is recrystallized from 8 ml of methanol, the crystals precipitated are filtered, and dried under reduced pressure.
Thus, 3.25 g (78 of the title compound are obtained. 96-98 OC.
WO 99/58527 PCT/HU99/00038 -113- Example 74 1-/3-(2,2-Dimethyl-2,3-dihydrobenzofuran-7- -yloxy)-2-hydroxypropyl/-4-(4-chlorophenyl)piperazine To a solution of 2.70 g (0.01 moles) of 1-(4-chlorophenyl)piperazine dihydrochloride in 26 ml of ethanol, 3 ml of water and 0.9 g (0.0225 moles) of sodium hydroxide are added, and the mixture is boiled for 10 minutes.
Then, to the reaction mixture, 2.40 g (0.011 moles) of 2, 2 -dimethyl-7-oxiranylmethoxy- 2 ,3-dihydrobenzofuran are added under stirring, and the mixture is boiled for further 4 hours, then evaporated to dryness under reduced pressure. To the residue, 50 ml of water are added, the water above the substance that slowly hardens is decanted, and the residue is rubbed with a further portion of water. The crystals precipitated are filtered, washed with water, recrystallized from methanol, filtered, and dried under reduced pressure.
Thus, 3.17 g (80 of the title compound are obtained. 96-98 0
C.
Example 1-/3-(2,2-Dimethyl-2, 3 -dihydrobenzofuran-7- -yloxy)- 2 -hydroxypropyl/-4-(4-chlorophenyl)piperazine dihydrochloride To a solution of 0.40 g (0.001 moles) WO 99/58527 PCT/HU99/00038 -114of 1-/ 3 2 2 -dimethyl-2,3-dihydrobenzofuran- 7 -yloxy)- 2 -hydroxypropyl/-4-(4-chlorophenyl)piperazine in 5 ml of ethanol, 1 ml of ethanol containing 20 of hydrogen chloride is added, and the mixture is evaporated to dryness under reduced pressure. The residue is boiled with ml of ethyl acetate for 5 minutes, the hot suspension is filtered, and the crystals are dried under reduced pressure.
Thus, 0.43 g (91 of the title compound are obtained. 168-170 0
C.
Example 76 1-/3-(2,2-Dimethyl-2,3-dihydrobenzofuran-7- -yloxy)-2-hydroxypropyl/-4-(3-methoxyphenyl)piperazine dihydrochloride A mixture of 1.32 g (0.006 moles) of 2, 2 -dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran, 1.46 g (0.0055 moles) of 1-(3- -methoxyphenyl)piperazine dihydrochloride, 0.44 g (0.011 moles) of sodium hydroxide, ml of ethanol, 3 ml of dimethylformamide and 10 ml of water is boiled for 3 hours.
The reaction mixture is cooled to 20 OC, the phases are separated, the lower (organic) phase is dissolved in 20 ml of ether, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure. The residue is dissolved in 3 ml of 2-propanol, to the solution formed, 3 ml of 2-propanol containing 16 of hydrogen chloride are added, and the WO 99/58527 PCT/HU99/00038 -115reaction mixture is maintained at O °C for days. The crystals precipitated are filtered, recrystallized from 2-propanol, filtered again, and dried under reduced pressure.
Thus, 1.48 g (60 of the title compound are obtained. 168-170 OC.
Example 77 1-/3-(2,2-Dimethyl-2,3-dihydrobenzofuran-7- -yloxy)-2-hydroxypropyl/-4-benzylpiperazine dihydrochloride A mixture of 1.32 g (0.006 moles) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran, 0.97 g (0.0055 moles) of 1-benzylpiperazine and 8 ml of 2-propanol is boiled for 4 hours, then cooled to 20 To the reaction mixture, 20 ml of petroleum ether are added, the mixture is maintained at O C for 5 days, the crystals formed are filtered, then recrystallized from n-hexane.
The crystals precipitated are dissolved in ml of 2-propanol, and, to the solution obtained, 1.5 ml of 2-propanol containing 16 of hydrogen chloride are added. After cooling, the crystalline salt precipitated is filtered, and dried under reduced pressure.
Thus, 1.50 g (58 of the title compound are obtained. 188-191 OC.
WO 99/58527 PCT/HU99/00038 -116- Example 78 1-/3-(2,2-Dimethyl-2,3-dihydrobenzofuran-7- -yloxy)-2-hydroxypropyl/-4-(2,4-dichlorophenyl)piperazine hydrochloride A mixture of 1.32 g (0.006 moles) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran, 1.15 g (0.005 moles) of 1-(2,4- -dichlorophenyl)piperazine and 8 ml of 2-propanol is boiled for 5 hours, then cooled to 20 To the reaction mixture, 3.6 ml of 2-propanol and 2.4 ml of 2-propanol containing 16 of hydrogen chloride are added, and the mixture is stirred at room temperature for 5 hours. The crystals precipitated are filtered, recrystallized from 2-propanol, filtered, then dried under reduced pressure.
Thus, 1.19 g (45 of the title compound are obtained. 169-171 °C.
Example 79 1-/3-(2,2-Dimethyl-2,3-dihydrobenzofuran-7- -yloxy)-2-hydroxypropyl/-4-(3-chlorophenyl)piperazine hydrochloride A mixture of 2.64 g (0.012 moles) of 2, 2 -dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran, 2.36 g (0.012 moles) of 1-(3- -chlorophenyl)piperazine and 16 ml of 2-propanol is boiled for 3 hours. After cooling, to the solution obtained, 7 ml of 2-propanol containing 16 of hydrogen chloride WO 99/58527 PCT/HU99/00038 -117are added at 20 The reaction mixture is maintained at 0 °C for 2 days, the crystals precipitated are filtered, recrystallized from 2-propanol, filtered again, and dried under reduced pressure.
Thus, 2.88 g (53 of the title compound are obtained. 187-190 OC.
Example 1-/3-(2,2-Dimethyl-2,3-dihydrobenzofuran-7- -yloxy)-2-hydroxypropyl/-4-(2-pyridyl)piperazine trihydrochloride A mixture of 1.32 g (0.006 moles) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran, 0.78 g (0.0048 moles) of 1-(2- -pyridyl)piperazine and 8 ml of petroleum ether is boiled for 6 hours. After cooling to 20 C, the phases that form are separated, to the lower phase, 20 ml of 2-propanol and ml of 2-propanol containing 16 of hydrogen chloride are added, and the reaction mixture is maintained at 0 °C for 5 days.
The crystals separated are filtered, recrystallized from 2-propanol, filtered, and dried under reduced pressure.
Thus, 1.68 g (71 of the title compound are obtained. 133-136 OC.
WO 99/58527 PCT/HU99/00038 -118- Example 81 1-/3-(2,2-Dimethyl-2,3-dihydrobenzofuran-7- -yloxy)-2-hydroxypropyl/-4-(2-methoxyphenyl)piperazine dihydrochloride A mixture of 2.64 g (0.012 moles) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran, 2.36 g (0.011 moles) of 1-(2- -methoxyphenyl)piperazine and 16 ml of 2-propanol is boiled for 5.5 hours. After cooling to 20 0 C, to the reaction mixture, ml of 2-propanol and 8 ml of 2-propanol containing 16 of hydrogen chloride are added, and the reaction mixture is maintained at 0 °C for 2 days. The crystals precipitated are filtered using reduced pressure, washed with 2-propanol, recrystallized from 2-propanol, filtered again, and dried under reduced pressure.
Thus, 2.53 g (47 of the title compound are obtained. 128-130 0
C.
Example 82 1-/3-(2,2-Dimethyl-2,3-dihydrobenzofuran-7- -yloxy)-2-hydroxypropyl/-4-(3,4-dimethylphenyl)piperazine dihydrochloride A mixture of 1.32 g (0.006 moles) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran, 0.95 g (0.005 moles) of 1-(3,4- -dimethylphenyl)piperazine and 8 ml of ethanol is boiled for 6 hours. After cooling to WO 99/58527 PCT/HU99/00038 -119- C, the reaction mixture is filtered, and the filtrate is evaporated to dryness under reduced pressure. To the residue, 5 ml of 2-propanol containing 16 of hydrogen chloride are added, the reaction mixture is maintained at 0 OC for 2 days, the crystals precipitated are filtered, recrystallized from 2-propanol, filtered again, and dried under reduced pressure.
Thus, 1.50 g (62 of the title compound are obtained. 119-122 OC.
Example 83 1-/3-(2,2-Dimethyl-2,3-dihydrobenzofuran-7- -yloxy)-2-hydroxypropyl/-4-(2-pyrimidyl)piperazine dihydrochloride A mixture of 1.32 g (0.006 moles) of 2, 2 -dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran, 0.65 g (0.004 moles) of 2- -pyrimidylpiperazine and 8 ml of tetrahydrofuran is boiled for 12 hours, then cooled to 20 To the oil that forms, 20 ml of ether and 1.5 ml of 2-propanol containing of hydrogen chloride are added, the reaction mixture is maintained at 0 °C for days, the crystals precipitated are filtered, dried under reduced pressure, and recrystallized from 2 -propanol.
Thus, 1.50 g (82 of the title compound are obtained. 128-130 OC.
WO 99/58527 PCT/HU99/00038 -120- Example 84 l-/ 3 2 2 -Dimethyl-2,3-dihydrobenzofuran-7- -yloxy)- 2 -hydroxypropyl/-4-(4-chloro-2-methylphenyl)piperazine hydrochloride A mixture of 2.64 g (0.012 moles) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran, 2.27 g (0.008 moles) of 1-(4- -chloro-2-methylphenyl)piperazine hydrochloride, 0.64 g (0.016 moles) of sodium hydroxide and 16 ml of water is boiled for 3 hours, then cooled to 20 The aqueous phase is decanted, to the organic phase, ml of ether are added, and stirred for an hour. The crystals precipitated are filtered, dried under reduced pressure, and recrystallized from acetonitrile.
Thus, 2.07 g (60 of the title compound are obtained. 68-70 OC.
Example 1-/3-(2,2-Dimethyl-2, 3 -dihydrobenzofuran-7- -yloxy)- 2 -hydroxypropyl/-4-methylpiperazine dihydrochloride A mixture of 1.32 g (0.006 moles) of 2, 2 -dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran, 0.45 g (0.0045 moles) of 4-methylpiperazine and 8 ml of ethanol is boiled for 3 hours, then cooled to 20 To the mixture, 4 ml of 2-propanol containing 30 of hydrogen chloride are added, the reaction mixture is WO 99/58527 PCT/HU99/00038 -121maintained at -15 °C for 2 days, the crystals precipitated are filtered, dried under reduced pressure, dissolved in hot 2-propanol, and precipitated from the solution by diethyl ether.
Thus, 1.15 g (65 of the title compound are obtained. 119-122 0
C.
Example 86 1-/3-(2,2-Dimethyl-2,3-dihydrobenzofuran-7- -yloxy)-2-hydroxypropyl/-4-(trifluoromethylbenzyl)piperazine dihydrochloride A mixture of 1.32 g (0.006 moles) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran, 1.43 g (0.0045 moles) of 4-(3- -trifluoromethyl)benzylpiperazine dihydrochloride, 0.36 g (0.009 moles) of sodium hydroxide and 8 ml of water is boiled for hours, then cooled to 20 the aqueous phase is removed by decantation, to the organic phase, 2 ml of 2-propanol containing 30 of hydrogen chloride are added, the crystals precipitated are filtered, dried under reduced pressure, and recrystallized from 2-propanol.
Thus, 1.39 g (57 of the title compound are obtained. 209-211 OC.
Example 87 1-/3-(2,2-Dimethyl-2,3-dihydrobenzofuran-7- -yloxy)-2-hydroxypropyl/-4-(3,4-dichlorophenyl)piperazine hydrochloride WO 99/58527 PCT/HU99/00038 -122- A mixture of 1.32 g (0.006 moles) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran, 1.04 g (0.0045 moles) of 1-(3,4- -dichlorophenyl)piperazine and 8 ml of 2-propanol is boiled for 3 hours, then cooled to 20 0 C. To the reaction mixture, a mixture of 10 ml of 2-propanol and 2 ml of 2-propanol containing 30 of hydrogen chloride are added, the reaction mixture is stirred for 5 hours, the crystals precipitated are filtered, dried under reduced pressure, and recrystallized from 2-propanol.
Thus, 1.63 g (62 of the title compound are obtained. 180-182 0
C.
Example 88 1-/3-(2,2-Dimethyl-2,3-dihydrobenzofuran-7- -yloxy)- 2 -hydroxypropyl/-4-(2,6-dimethylphenyl)piperazine dihydrochloride A mixture of 1.32 g (0.006 moles) of 2,2-dimethyl-7-oxiranylmethoxy-2,3-dihydrobenzofuran, 0.90 g (0.004 moles) of 1-(2,6- -dimethylphenyl)piperazine hydrochloride, 0.32 g (0.008 moles) of sodium hydroxide and 8 ml of water is boiled for 2 hours, then cooled to 20 C. The aqueous phase of the mixture formed is removed by decantation, to the organic phase, 2.5 ml of 2-propanol containing 30 of hydrogen chloride are added, the reaction mixture is maintained at C for 2 days, then 10 ml of.
2 -propanol are 123 added, the crystals precipitated are filtered, dried under reduced pressure, and recrystallized from 2-propanol.
Thus, 1.00g of the title compound are obtained. 115-1170C.
Example 89 1 -/3-(2,2-Dimethyl-2,3-dihyd robenzofuran-7-yloxy)-2-hyd roxypropyl/-4-(4-chloro- 2-methyl-phenyl)piperazine A mixture of 0.5g (0.0016 moles) of 1-bromo-3-(2,2-dimethyl-2,3dihydrobenzofuran-7-yloxy)-2-propanol, 0.45g (0.0016 moles) of 4-chloro-2methylphenylpiperazine, 0.25g (0.0063 moles) of sodium hydroxide and 6.5ml of water is boiled for 3 hours, then cooled to 200C. The aqueous phase is removed by decantation, the residual oil is rubbed with ether, the crystals precipitated are filtered, dried under reduced pressure, and recrystallized from acetonitrile.
Thus, 0.25g of the title compound are obtained.
M.p.:68-70 0
C.
As employed above and throughout this disclosure (including the claims), the following terms, unless otherwise indicated, shall be understood to have the following meanings: "comprises" (or grammatical variations thereof) when used in this 20 specifciation is taken to specify the presence of stated features, integers, steps or components but does not preclude the presence or addition of one or more other S. features, integers, steps, components or groups thereof.
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Claims (14)
1. A novel benzofuran derivative of the formula R Y B A Ar R' X N R 2 wherein R and R represent, independently, a hydrogen atom or a C_-4 alkyl group, X stands for an oxygen atom or a sulfur atom, Y means a hydrogen atom or a hydroxy group, Z represents a hydrogen atom, a halo atom, a C1-4 alkyl group, a C 1 4 alkoxy group, an amino group, a nitro group, a cyano group, a trifluoromethyl group, a group of the formula -COOR 3 -NHCOR 3 or -S02NR3R4, wherein 3 R stands for a hydrogen atom or a C-4 alkyl group, 4 R is a C 1 4 alkyl group, or 3 4 R and R form, together with the adjacent nitrogen atom, a saturated or unsaturated heterocyclic group having 5 to 10 members and optionally comprising one or more nitrogen atom(s) and/or one or more oxygen atom(s) and/or one or more sulfur atom(s) as the further heteroatom(s), A means a group of the formula CH, COH, C-CN, C-COOR 3 or COR 4 wherein R 3 and R are WO 99/58527 PCT/HU99/00038 -125- as defined above, B represents a methylene group, or A forms together with B a group of the formula Ar stands for a hydrogen atom, a C -4 alkyl group, a phenyl(C 1 4 alkyl) group, a biphenylyl group, a naphthyl group, wherein said latter species are optionally substituted by a C1-4 alkoxy group or a C2- 4 alkenyl group; a partially saturated, or 6-membered heterocyclic group condensed with a phenyl group and containing one or two oxygen atom(s), said heterocyclic group being optionally substituted by one to three C1-4 alkyl group; a 5- or
6-membered, saturated or unsaturated hetero cyclic group containing a nitrogen atom and/or an oxygen atom and/or a sulfur atom as the heteroatom; or a phenyl group substituted by the substituents R 5 R 6 and R wherein R 5 R 6 and R 7 mean, independently, a hydrogen atom, a halo atom, a trifluoro- methyl group, a C1-4 alkyl group, a methylenedioxy group, a phenoxy group optionally substituted by a C -4 alkoxy group or by a halo atom; a C 2 4 alkenyl group, a C2_ 4 alkenyloxy group, a C 1 -4 alkoxy group optionally substituted by a di(Cl_ 4 alkyl)amino group or by a 5- or 6 -membered, saturated hetero- cyclic group containing one or two -126- nitrogen atom(s) or a nitrogen atom and an oxygen atom, wherein said heterocyclic group is optionally substituted by a C 1 4 alkyl group, or A-Ar stands for a group of the formula N-(CH 2 wherein Ar' represents a diphenylmethyl group, a pyridyl group, a pyrimidinyl group, a naphthyl group, wherein said latter group is optionally substituted by a C1-4 alkoxy group or a C2- 4 alkenyloxy group; a partially saturated, 5- or 6-membered heterocyclic group condensed with a phenyl group and containing one or two oxygen atom(s), said hetero- cyclic group being optionally substituted by one to three C 1 -4 alkyl group(s); or a phenyl group substituted by the substituents R 5 R 6 and R 7 wherein R R and R are as defined above, n has a value of O or 1, and pharmaceutically suitable acid addition salts thereof. 2. A benzofuran derivative as claimed in Claim 1, wherein in formula I R represents a hydrogen atom or a C 4 alkyl *a group, R2 stands for a hydrogen atom, X means an oxygen atom, Y is a hydrogen atom or a hydroxy group, Z represents a hydrogen atom, a halo atom WO 99/58527 PCT/HU99/00038 -127- or a nitro group, A stands for a group of the formula CH, COH or C-CN, B means a methylene group, or A forms with B a group of the formula Ar represents a hydrogen atom, a benzyl group, a phenyl group substituted by substituents R R and R 7 a biphenylyl group, a naphthyl group optionally substituted by a C 1 -4 alkoxy group; or a thienyl group, wherein R and R 7 mean, independently, a hydrogen atom, a halo atom, a trifluoro- methyl group, a C 1 -4 alkyl group, a C1- 4 alkoxy group, a C2_ 4 alkenyloxy group, a phenoxy group or a methylenedioxy group, and pharmaceutically suitable acid addition salts thereof. 3. A benzofuran derivative as claimed in Claim 1 or 2, wherein in formula I R represents a methyl group, R stands for a hydrogen atom, X means an oxygen atom, Y is a hydroxy group, Z represents a hydrogen atom, A is a group of the formula CH, COH or C-CN, B stands for a methylene group, or A forms with B a group of the formula Ar represents a phenyl group optionally substituted by a halo atom, a trifluoro- methyl group, a methyl group or a methoxy WO 99/58527 PCT/HU99/00038 -128- group; or a methoxynaphthyl group, and pharmaceutically suitable acid addition salts thereof. 4. A piperazinylalkylbenzofuran derivative of the formula ,Ar (CH)n Ia R as claimed in Claim 1, wherein R represents a C 1 -4 alkyl group, R stands for a hydrogen atom, X means an oxygen atom, Y is a hydroxy group, Z represents a hydrogen atom, Ar' represents a diphenylmethyl group, a pyridyl group, a partially saturated heterocyclic group containing two oxygen atoms and being condensed with a phenyl group, or a phenyl group substituted by substituents R 5 R 6 and R wherein R R and R mean, independently, a hydrogen atom, a halo atom, a trifluoro- methyl group, a Cl_ 4 alkyl group, a Cl-4 alkoxy group, or a methylenedioxy group, n has a value of O or 1, and pharmaceutically suitable acid addition salts thereof. WO 99/58527 WO 9958527PCT/HU99/00038 -129- A piperazinylalkylbenzofuran derivative as claimed in Claim 4, wherein in formula Ia R 1represents a methyl group, R 2stands for a hydrogen atom, X means an oxygen atom, Y is a hydroxy group, Z represents a hydrogen atom, Ar' represents a diphenylmethyl group, a pyridyl group, a benzo-l,3--dioxolanyl group or a phenyl group optionally substituted by one or two halo atom(s), one or two methyl group(s), a methylenedioxy group, a trifluoromethyl group or a methoxy group, n has a value of 0 or 1, and pharmaceutically suitable acid addition salts thereof. 6. 1-/3 -(2,2-dimethyl-2,3-dihydro-benzo- furan-7-yloxy) 2 -hydroxypropyl/-4-(3-trifluoro- methylphenyl) 6 -tetrahydropyridine, 1-/3-(2,2dimethyl2,3dihydrobenzofuran7yl- oxy)-2-hydroxypropyl/4hydroxy-4-(3-trifluoro- methyiphenyl )piper idine, 1-13- 2-dimethyl-2, 3 -dihydro-benzofuran-7-yl. oxy)-2-hydroxypropyl/-4hydroxy4( 4-f luoro- phenyl )piperidine, 1-/3-(2,2-dimethyl-2,3dihyrobenzofuran.7yl- oxy)- 2 -hydroxypropyl/.4-ydroxy4phenyl1 piperidine, 1-/3-(2,2-dimethyl-2,3-dihydro-benzofuran-7yl- oxy) 2 -hydroxypropyl/.4-hydroxy-4-(3-chioro- phenyl )piperidine, -130- 1 methy1233dihydr-enobrn-f 7 yl- o~xy) 2 -hydroxypropy/4hydroxy4(3-methoy phenyl)piperidine, 1-13- 2-dirnethy1-2, 3 -dihydro-benzofuran7-yl oxy) 2 -hydroxypropyl/4-ydroxy- 4 -(4-rnethoxy- phenyl )piperidine, 1-/3-(2,2dimethy23dihydrobenzofura 7 yl- oxy)- 2 -hydroxypropylp4-( -trifluoromethyl. pheriyl )piper idine, i-/3-(2,2dimethyl2J,3d ydbnofuref. 7 oxy)- 2 -hydroxypropyl/4hydr 4( 4 thyl phenyl )piperidine, 2-dimethyN2 3 -dihydro-benzofuran7yl- oxy) 2 -hydroxypropyl/4cyano-4phenyl- piperidine, 1-/3-(2,2dimethy1223-dihy-rnorn-o 7 -i- oxy) 2 -hydroxypropy/4hydroxy4( 4 -hlo phenyl )piperidine, 2dimethy1.23 3diydrbnobrn-o 7 yl- oxy X) 2 -hydroxypropy/4hydroxy 4 -(6mtoy *naphth-2-yl)piperidine, 1-/ 3 -(2,2-dimethyl12,3.dihydrobenzofuran 7 yl- oxy)- 2 -hydroxypropy/4(diphenylthyl) piperazine, oxy) -2-hydroxypropyl/- 4 4 -fluoropheny piperazine, 0 -/3-(22dimethyl223dihyd*bzfua-yl oxy)- 2 -hydroxypropy/4h'ydroxy 4 -(3trif1ur methyiphenyl )piperidine, 1-3 0i/J(2 2dimeth2 .33-ihdo-benobrn- 7 yl- o~xy) 2 -hydroxypropyl/-4-( 4 -rnethoxypheny1)- -131- piperazine, 2 -dimethy1-2, dihydrobenzfuran 7 y oxy) 2 -hydroxypropyl/-4. (benzo-l, -yl piperazine, 1-/ 3 2ddimetyl2,23 dihh d rnobefan 7 oxy) 2 -hydroxypropyl/-4. 4 -chlorophenyl)- piperazine, 2-dirnethyl-2, 3 -dihydro-benzof uran 7 -y oxy) 2 -hydroxypropyl/4benzylpiprzie 2-dimethyl-2, 3 -dihydro.benzofuran7-yi oxy) 2 hydroxypropy14-( 2 4 dh.oohnl piperazine, oxy) 2 hydroxypropyl/-4 3 -chlorophenyl piperazine, 2-dimethyl-2, 3 -dihydro-benzofuran.7-yl- oxy) -2-hydroxypropyl/ 4 2 p.idyl) pprzn 2 d methyl233d ihydr-enobefan 7 y oxy) 7 2 -hydroxypropy/- 4 2 -methoxyphenyl piperazine. or
7. imthN2Adh rbenzofuran eiaiesbtnill PpaZin,XYABadAarasefndi Cad Po harmaceutically suitable acid dto asdherin descthriedf wiharefernced toiny oneao bnoan deraivae of the formula I hri WO 99/58527 PCT/HU99/00038 -132- R Y II R' X Hal R 2 1 2 wherein R R X, Y and Z are as defined in connection with formula I, Hal represents a halo atom, is reacted with a secondary amine of the formula B, AAr HN I wherein A, B and Ar are as stated in connection with formula I; or b) for the preparation of a benzofuran derivative of the formula I, wherein Y represents a hydroxy group, R R 2 X, Z, A, B and Ar are as defined in connection with formula I, an epoxide of the formula OO III R' X' SRC 1 2 wherein R R Z and X are as defined above, is reacted with a secondary amine of the WO 99/58527 PCT/HU99/00038 -133- formula IV, wherein A, B and Ar are as stated above; or c) a compound of the formula R' R' wherein R X and Z are as defined in connection with formula I, is reacted with a halo compound of the formula H r AAr xI aL4--NQ R wherein R 2 Y, A, B and Ar are as stated in connection with formula I, Hal represents a halo atom; d) for the preparation of a benzofuran derivative of the formula I, wherein R R 2 X, Z, A, B and Ar are as defined in connection with formula I, a compound of the formula V, wherein R1, X and Z are as stated above, is reacted with an epoxide of the formula 0 (B, A Ar r B A r X I R2 WO 99/58527 PCT/HU99/00038 -134- wherein R 2 A, B and Ar are as stated above; or e) for the preparation of a benzofuran derivative of the formula I, wherein A forms 1 2 with B a group of the formula R R X, Y, Z and Ar are as defined in connection with formula I, a benzofuran derivative of the formula I, wherein A stands for a group of the formula COH, B represents a methylene group, R R 2 X, Y, Z and Ar are as stated above, is dehydrated; or f) for the preparation of a benzofuran derivative of the formula I, wherein A represents a group of the formula COH, B stands for a methylene group, R R 2 X, Y, Z and Ar are as defined in connection with formula I, however, Ar is other than a hydrogen atom, a ketone of the formula z R Y xv 2O N wherein R R X, Y and Z are as stated above, is reacted with an arylmagnesium halide of the formula Hal-Mg-Ar XVI wherein Ar is as stated above, Hal represents WO 99/58527 PCT/HU99/00038 -135- a halo atom, and the adduct formed is decomposed with water; or g) for the preparation of a benzofuran derivative of the formula I, wherein A represents a group of the formula COH, B stands 1 2 for a methylene group, R R X, Y, Z and Ar are as defined in connection with formula I, but Ar is other than a hydrogen atom, a ketone of the formula XV, wherein R R 2 X, Y and Z are as stated above, is reacted with an aryl lithium compound of the formula Li-Ar XVII wherein Ar is as stated above, and the adduct formed is decomposed with water; or h) for the preparation of a benzofuran derivative of the formula I, wherein A represents a group of the formula CH, B stands for a methylene group, R R 2 X, Y, Z and Ar are as defined in connection with formula I, a compound of the formula I, wherein A forms with B a group of the formula R R 2 X, Y, Z and Ar are as stated above, is hydrogenized; or i) for the preparation of a benzofuran derivative of the formula I, wherein A represents a group of the formula CH, B stands 1 2 for a methylene group, R R X, Y, Z and Ar are as defined in connection with formula I, an epoxide of the formula III, wherein 1 2, R R Z and X are as stated above, is reacted -136- with a secondary amine of the formula IV, wherein A stands for a group of the formula CHOH, B and Ar are as stated above, under dehydrating reaction conditions, and the formed compound of the formula I, wherein A forms with B a group of the formula R, R 2 X, Y, Z and Ar are as stated above, is hydrogenized in the reaction mixture in which it was prepared; and if desired, an obtained base of the formula I is reacted with an inorganic or organic acid to form a pharmaceutically suitable acid addition salt thereof, or liberated from the acid addition salt with a base.
9. A process for the preparation of a benzofuran derivative, which process is substantially as herein described with reference to any one of Examples 1 to 89.
10. A pharmaceutical composition comprising a benzofuran derivative of the formula R O Y B 'A Ar S..R X R 2 wherein R and R 2 represent, independently, a hydrogen atom or a C 1 -4 alkyl group, X stands for an oxygen atom or a sulfur atom, Y means a hydrogen atom or a hydroxy group, Z represents a hydrogen atom, a halo atom, "Rfj a C 1 -4 alkyl group, a C 1 -4 alkoxy group, s7 an amino group, a nitro group, a cyano RTO WO 99/58527 PCT/HU99/00038 -137- group, a trifluoromethyl group, a group of the formula -COOR -NHCOR or -SO2NR R4, wherein 3 R stands for a hydrogen atom or a C 4 alkyl group, 4 R is a Cl-4 alkyl group, or 3 4 R and R form, together with the adjacent nitrogen atom, a saturated or unsaturated heterocyclic group having 5 to 10 members and optionally comprising one or more nitrogen atom(s) and/or one or more oxygen atom(s) and/or one or more sulfur atom(s) as the further heteroatom(s), A means a group of the formula CH, COH, C-CN, C-COOR 3 or COR 4 wherein R 3 and R 4 are as defined above, B represents a methylene group, or A forms together with B a group of the formula Ar stands for a hydrogen atom, a Cl-4 alkyl group, a phenyl(Cl_ 4 alkyl) group, a biphenylyl group, a naphthyl group, wherein said latter species are optionally substituted by a C1-4 alkoxy group or a C2-4 alkenyl group; a partially saturated, or 6-membered heterocyclic group condensed with a phenyl group and containing one or two oxygen atom(s), said heterocyclic group being optionally substituted by one to three C 1 4 alkyl group; a 5- or 6-membered, saturated or unsaturated hetero cyclic group containing a nitrogen atom -138- and/or an oxygen atom and/or a sulfur atom as the heteroatom; or a phenyl group substituted by the substituents R 5 R 6 and R wherein 5 6 7 R R and R mean, independently, a hydrogen atom, a halo atom, a trifluoro- methyl group, a Cl-4 alkyl group, a methylenedioxy group, a phenoxy group optionally substituted by a C 1 4 alkoxy group or by a halo atom; a C 2 4 alkenyl group, a C2_ 4 alkenyloxy group, a C14 alkoxy group optionally substituted by a di(Cl_ 4 alkyl)amino group or by a 5- or 6-membered, saturated hetero- cyclic group containing one or two nitrogen atom(s) or a nitrogen atom and an oxygen atom, wherein said heterocyclic group is optionally substituted by a C 1 4 alkyl group, or A-Ar stands for a group of the formula N-(CH 2 wherein Ar' represents a diphenylmethyl group, a pyridyl group, a pyrimidinyl group, a naphthyl group, wherein said latter group is optionally substituted by a C 1 4 alkoxy group or a C2-4 alkenyloxy ,group; a partially saturated, 5- or 6 -membered heterocyclic group condensed with a phenyl group and containing one or two oxygen atom(s), said hetero- cyclic group being optionally *o oo substituted by one to three Cl_4 alkyl -139- group(s); or a phenyl group substituted by the substituents R 5 R 6 and R 7 5 6 7 wherein R R and R are as defined above, n has a value of O or 1, or a pharmaceutically suitable acid addition salt thereof as the active ingredient and one or more conventional carrier(s).
11. A pharmaceutical composition as claimed in Claim 10, comprising a benzofuran derivative of the formula I, wherein R represents a hydrogen atom or a C- 4 alkyl group, R 2 stands for a hydrogen atom, X means an oxygen atom, Y is a hydrogen atom or a hydroxy group, Z represents a hydrogen atom, a halo atom or a nitro group, A stands for a group of the formula CH, COH or C-CN, B means a methylene group, or A forms with B a group of the formula Ar represents a hydrogen atom, a benzyl group, a phenyl group substituted by substituents 5 6 7 R R and R a biphenylyl group, a naphthyl group optionally substituted by a Cl 4 alkoxy group; or a thienyl group, wherein 5 6 7 R R and R mean, independently, a hydrogen atom, a halo atom, a trifluoro- methyl group, a C_ 4 alkyl group, a Cl-4 alkoxy group, a C2- 4 alkenyloxy -140- group, a phenoxy group or a methylenedioxy group, or a pharmaceutically suitable acid addition salt thereof as the active ingredient.
12. A pharmaceutical composition as claimed inClaim 10 or 11,comprising a benzofuran derivative of the formula I, wherein R represents a methyl group, R stands for a hydrogen atom, X means an oxygen atom, Y is a hydroxy group, Z represents a hydrogen atom, A is a group of the formula CH, COH or C-CN, B stands for a methylene group, or A forms with B a group of the formula Ar represents a phenyl group optionally substituted by a halo atom, a trifluoro- methyl group, a methyl group or a methoxy group; or a methoxynaphthyl group, :or a pharmaceutically suitable acid addition salt thereof as the active ingredient.
13. A pharmaceutical composition as claimed in Claim l0 comprising a piperazinyl- alkylbenzofuran derivative of the formula i -Ar R Y (CH2)n -R X a a wherein -141- R represents a C 1 4 alkyl group, R stands for a hydrogen atom, X means an oxygen atom, Y is a hydroxy group, Z represents a hydrogen atom, Ar' represents a diphenylmethyl group, a pyridyl group, a partially saturated heterocyclic group containing two oxygen atoms and being condensed with a phenyl group, or a phenyl group substituted by substituents R 5 R 6 and R wherein R 5 R and R mean, independently, a hydrogen atom, a halo atom, a trifluoro- methyl group, a Cl-4 alkyl group, a C 1 4 alkoxy group, or a methylenedioxy group, n has a value of 0 or 1, or a pharmaceutically suitable acid addition salt thereof as the active ingredient.
14. A pharmaceutical composition as S:"claimed in Claim 13 comprising a piperazinyl- Salkylbenzofuran derivative of the formula Ia, wherein 1 R represents a methyl group, R stands for a hydrogen atom, X means an oxygen atom, Y is a hydroxy group, SZ represents a hydrogen atom, *5 Ar' represents a diphenylmethyl group, a pyridyl group, a benzo-1,3-dioxolanyl group or a phenyl group optionally substituted -142- by one or two halo atom(s), one or two methyl group(s), a methylenedioxy group, a trifluoromethyl group or a methoxy group, n has a value of 0 or 1, or a pharmaceutically suitable acid addition salt thereof as the active ingredient. A pharmaceutical composition as claimed in Claim 10, comprising one of the following compounds: 2-dimethyl-2, J-dihydro-benzofuran- 7 -yloxy)-2-hydroxypropyl/4(3-trifluoo methylphenyj) 2,3, 6 -tetrahydropyridine, l-/3-(2,2-dimethyl-2, 3 -dihydro-benzofuran7yl- oxy)- 2 -hydroxypropyl/4hydroxy 4 (3-trif1ur methyiphenyl )piperidine, l-/3(2-ddm mehy h-2,dihydb dzfranb 7 oxy)- 2 hydroxypropy1/44hydroy 4 4 -flur- phenyl)piperidine, 1-13- 2-dimethyl-2, 3 -dihydrobenzofuran7yl- oxy) 2 -hdoyrl-4-hoxpropyl/hydroxy lh Spiperidine, l-/3(2,2dm metyll2,3-dhydr-ezfrabf 7 S. .oxy)- 2 hydroxypropyl/ 4hhyroy 4 3 hlo phenyl) piperidine, 5555 l/3-(2,2-dimethyl-2,3 -dihydrobenzofuran7yl- oxy)- 2 hydroxyprop 4-y/4hy-4-(3mtoy phenyl ),piperidine, l-/3-(2,2dmethyl-2,3dihydrbenzdfuran 7 lyi oxy)- 2 hydxpoy4hdrxyroyl-h 4 -4mtoy 0 phenyl )piperidine, 2 -dimethyi-2, 3 -dihydro-benzofuran7yl- 055 5oxy)- 2 -hydroxypropyl/ 4 3 -trif1urmeh WO 99/58527 PCTJ-IU99/00038 -143- phenyl )piperidine, 2-dimethyl-2, J-dihydro-benzofuran7-yI oxy)- 2 hydroxypropy1/44hydr roxy( 4 mth l- phenyl )piperidine, l-/3-(2,2-dimethylN2, 3 -dihydro-benzofuran7yl- oxy) 2 -hydroxypropyl/4cyano4phenvl- piper idine, 2-dimethyl-2, 3 -dihydro-benzofuran7-vl oxy) 2 -hydroxypropyl/4-ydroxy-4-(4-chloro- pheny.) piperidine, 1-13- 2-dimethyl..2, 3 -dihydro-benzofuran-7y. oxy)- 2 hydroxypropy1-4-hydro 4 (-thoy naphth-2-yl )piperidine, 2-dimethyl-2, 3 -dihydro-benzofuran7-y oxy) -2-hydroxypropyl/.4-(diphenylmethyl) piperazine, 1-13- 2-dimethyl-2, 3 -dihydro-benzofuran7-yl oxy)- 2 -hydroxypropyi/4(4flurophnl)- piperazine, 1-/3(2,2di methyl 12,3dhydr-ezfraf 7 yl- oxy)- 2 -hydroxypropy/4hydroxy 4 (3trfluoo 0. -4 methyiphenyl )piperidine, l-/ 3 (2,2di ethy1.3di hydrenobernzf 7 -y ox)2hyrxpopl 4 -methoxyphenyl) piperazine, 1-13- 2-dimethyl-2,3-dihydro-benzofuran7y1 oxy)- 2 -hydroxypropy/4(benzol,3 -yl )piperazine, l-/3(2,2im mehy y12,3 diydrobnofuenzf 7 y *SSoxy)- 2 .hyd droxro opy1/4-4-chorhehl)- piperazine, 2-dimethyl-2, 3 -dihydrobenzofuran7y> -144- oxy)- 2 -hydroxypropy/4benzylpieaie 2-dimethyl-2, 3 -dihydro-benzofuran 7 yl- oxy)- 2 -hydroxypropy/4(2,4-dichlorophenyl)- piperazine, 1-/3-(2,2dienethyl2-dihydrbnofua-y oxy) -2-hydroxypropyl/-4-( 3 -chlorophenyl) piperazine, 2dietethy3dihydr be ofuar-yl oxy)-~ 2 hydroxypro opy1/-(2-pidvl,.praie 1-13- 2-dimethyl-2, 3 -dihydro.-benzofuran-7-yL- oxy) 2 -hydroxypropyl/-4. 2 -methoxyphenyl) piperazine or 2-dimethyl.2, 3 -dihydrobenzofuran7yl- oxy)- 2 hydroxypropylI44(3-metyhnl piperazine, or a pharmaceutically suitable acid addition salt thereof as the active ingredient.
16. A pharmaceutical composition comprising a benzofuran derivative of claim 7 together with a pharmaceutically acceptable carrier, diluent, excipient and/or adjuvant. -145-
17. A halide of the formula R II R' X Hal R 2 R wherein R 1 and R 2 represents, independently, a hydrogen atom or a C 1 4 alkyl group, X stands for an oxygen atom or a sulfur atom, Y means a hydrogen atom or a hydroxy group, Z represents a hydrogen atom, a halo atom, a C 1 -4 alkyl group, a C 1 4 alkoxy group, an amino group, a nitro group, a cyano group, a trifluoromethyl group or a group of the formula -COOR 3 -NHCOR or -SO 2 N 3 R 4 wherein 3 R stands for a hydrogen atom or a C14 alkyl group, 4 R means a C Smeans a1-4 alkyl group, or R and R form, together with the adjacent nitrogen atom, a saturated or unsaturated heterocyclic group having 5 to 10 members "and optionally comprising one or more nitrogen atom(s) and/or one or more °oxygen atom(s) and/or one or more sulfur atom(s), Hal represents a halo atom. a ft a a a a a.. a -146-
18. A method of preparing a halide of formula II as defined in claim 17, which method is substantially as herein described with reference to the Example entitled "Preparation of halides of the formula II".
19. A ketone of the formula z R- Y 0 XV R XN wherein R and R represents, independently, a hydrogen atom or a C 1 4 alkyl group, X stands for an oxygen atom or a sulfur atom, Y means a hydrogen atom or a hydroxy group, Z represents a hydrogen atom, a halo atom, a C 1 _4 alkyl group, a C 1 4 alkoxy group, an amino group, a nitro group, a cyano group, a trifluoromethyl group or a group 3 3 34 of the formula -COOR 3 -NHCOR or -SO 2 NR R4 0 wherein 3 R stands for a hydrogen atom or a C 4 *1-4 alkyl group, 4 R means a C-4 alkyl group, or 1-4 R and R form, together with the adjacent nitrogen atom, a saturated or unsaturated -147- heterocyclic group having 5 to 10 members and optionally comprising one or more nitgroen atom(s) and/or one or more oxygen atom(s) and/or one or more sulfur atom(s). A method of protecting the myocardium of a mammal from impairment during ischemia and/or reperfusion, which method comprises administering to said mammal in an amount which effectively protects said myocardium, a benzofuran derivative I or la as claimed in any one of claims 1 to 7 and/or a pharmaceutical composition as claimed in any one of claims 10 to 16.
21. The use of a benzofuran derivative I or a piperazinyl- alkylbenzofuran derivative la as claimed in any one of claims 1 to 7 for the preparation of a medicament for protecting the myocardium from impairment during ischemia and/or reperfusion. DATED this 13th day of August 2002 EGIS GYOGYSZERGYAR WATERMARK PATENT TRADEMARK ATTORNEYS 290 BURWOOD ROAD HAWTHORN VICTORIA 3122 AUSTRALIA P18540AU00 p6
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HU9801086 | 1998-05-14 | ||
HU9801086A HUP9801086A3 (en) | 1998-05-14 | 1998-05-14 | Benzofurane derivatives, pharmaceutical compositions containing them as active ingredient process for producing the active ingredient and intermediates of them |
HU9801085 | 1998-05-14 | ||
HU9801085A HUP9801085A3 (en) | 1998-05-14 | 1998-05-14 | Piperazinyl-alkyl-benzofurane derivatives, pharmaceutical compositions containing them as active ingredient and process for producing the active ingredient |
PCT/HU1999/000038 WO1999058527A2 (en) | 1998-05-14 | 1999-05-13 | Benzofuran derivatives, pharmaceutical composition containing the same, and a process for the preparation of the active ingredient |
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US6835733B2 (en) | 1999-12-20 | 2004-12-28 | Eli Lilly And Company | Tropane linked benzofuran derivatives |
AU2049601A (en) | 1999-12-20 | 2001-07-03 | Eli Lilly And Company | Benzofuran derivatives |
FR2845992B1 (en) * | 2002-10-16 | 2005-02-04 | Pf Medicament | 3- (CYCLOPENTEN-1YL) -BENZYL-OU3- (CYCLOPENTEN-1YL) -HETEROARYLMETHYL-AMINE DERIVATIVES AND THEIR USE AS MEDICAMENTS FOR THE TREATMENT OF SCHIZOPHRENIA |
WO2006088963A1 (en) * | 2005-02-17 | 2006-08-24 | Bayer Cropscience Ag | Improved process for preparing (disubstitutedpropenyl) phenylalkyl substituted dihydrobenzofurans |
HU230761B1 (en) * | 2007-05-30 | 2018-03-28 | Egis Gyógyszergyár Nyilvánosan Működő Részvénytársaság | New benzofuran derivatives as selective inhibitors of 5-ht6 and process for their preparation |
HU230729B1 (en) * | 2007-05-30 | 2017-12-28 | Egis Gyógyszergyár Nyilvánosan Működő Részvénytársaság | New benzofuran derivatives as selective inhibitors of 5-ht7 and process for their preparation |
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CH474511A (en) * | 1966-06-24 | 1969-06-30 | F. Hoffmann-La Roche & Co. Aktiengesellschaft | |
DE2235597A1 (en) * | 1972-07-20 | 1974-01-31 | Boehringer Mannheim Gmbh | SINGLE SQUARE CLIP ON 3- (5,6,7,8TETRAHYDRONAPHTH-1-YL-OXY) -PROPYL SQUARE CLIP FOR -PIPERAZINE DERIVATIVES AND METHOD FOR THEIR PRODUCTION |
FR2353291A1 (en) * | 1976-05-31 | 1977-12-30 | Parcor | NEW DERIVATIVES OF BENZOFURANNE |
US4110536A (en) * | 1977-04-18 | 1978-08-29 | Miles Laboratories, Inc. | Derivatives of 5-(indol-3-yl)hydantoin |
US4612309A (en) * | 1984-10-23 | 1986-09-16 | William H. Rorer, Inc. | Antisecretory bicyclic benzo-oxy heterocyclic ethers and thioethers |
US4966907A (en) * | 1988-08-12 | 1990-10-30 | Merck & Co., Inc. | 6-substituted 5-hydroxy-2,3-dihydrobenzofurans as inhibitors of leukotriene biosynthesis |
GB9005014D0 (en) * | 1990-03-06 | 1990-05-02 | Janssen Pharmaceutica Nv | N.(4.piperidinyl)(dihydrobenzofuran or dihydro.2h.benzopyran)carboxamide derivatives |
FR2681319B1 (en) * | 1991-09-12 | 1995-02-17 | Synthelabo | 1- (PHENOXYALKYL) PIPERIDINE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION. |
AU699152B2 (en) * | 1994-09-27 | 1998-11-26 | Janssen Pharmaceutica N.V. | N-substituted piperidinyl bicyclic benzoate derivatives |
TW490465B (en) * | 1994-11-24 | 2002-06-11 | Janssen Pharmaceutica Nv | Enterokinetic benzamide, the preparation process and the pharmaceutical compositions thereof |
GB9507882D0 (en) * | 1995-04-18 | 1995-05-31 | Pharmacia Spa | Substituted dihydrobenzofuran derivatives as 5-ht4 agonists |
ZA9610745B (en) * | 1995-12-22 | 1997-06-24 | Warner Lambert Co | 4-Subsituted piperidine analogs and their use as subtype selective nmda receptor antagonists |
NZ330263A (en) * | 1996-02-15 | 1999-06-29 | Janssen Pharmaceutica Nv | Esters of 3-hydroxy-piperidinemethanol derivatives to improve gastric emptying |
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JP2002514643A (en) | 2002-05-21 |
WO1999058527A2 (en) | 1999-11-18 |
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CA2332275A1 (en) | 1999-11-18 |
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PL345309A1 (en) | 2001-12-03 |
HRP20000750A2 (en) | 2001-06-30 |
SK17212000A3 (en) | 2001-05-10 |
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