MXPA01007162A - Novel aralkyl amines of spirofuropyridines useful in therapy - Google Patents
Novel aralkyl amines of spirofuropyridines useful in therapyInfo
- Publication number
- MXPA01007162A MXPA01007162A MXPA/A/2001/007162A MXPA01007162A MXPA01007162A MX PA01007162 A MXPA01007162 A MX PA01007162A MX PA01007162 A MXPA01007162 A MX PA01007162A MX PA01007162 A MXPA01007162 A MX PA01007162A
- Authority
- MX
- Mexico
- Prior art keywords
- azabicyclo
- furo
- pyridine
- aminospiro
- octan
- Prior art date
Links
- 238000002560 therapeutic procedure Methods 0.000 title claims abstract description 7
- 150000003974 aralkylamines Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 207
- -1 CO2R5 Chemical group 0.000 claims abstract description 114
- 238000000034 method Methods 0.000 claims abstract description 41
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 33
- 239000011780 sodium chloride Substances 0.000 claims abstract description 30
- 150000003839 salts Chemical class 0.000 claims abstract description 29
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 24
- 239000001257 hydrogen Substances 0.000 claims abstract description 24
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 23
- 230000000069 prophylaxis Effects 0.000 claims abstract description 22
- 150000002367 halogens Chemical class 0.000 claims abstract description 21
- 239000000203 mixture Substances 0.000 claims abstract description 19
- 125000001424 substituent group Chemical group 0.000 claims abstract description 15
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 15
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 13
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims abstract description 12
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 11
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims abstract description 10
- 201000010099 disease Diseases 0.000 claims abstract description 10
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 9
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims abstract description 9
- 206010061920 Psychotic disease Diseases 0.000 claims abstract description 8
- 125000003118 aryl group Chemical group 0.000 claims abstract description 8
- 125000004433 nitrogen atoms Chemical group N* 0.000 claims abstract description 8
- 125000004430 oxygen atoms Chemical group O* 0.000 claims abstract description 8
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 7
- 125000004434 sulfur atoms Chemical group 0.000 claims abstract description 7
- YRTCKZIKGWZNCU-UHFFFAOYSA-N furo[3,2-b]pyridine Chemical group C1=CC=C2OC=CC2=N1 YRTCKZIKGWZNCU-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims description 46
- 239000002904 solvent Substances 0.000 claims description 38
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 28
- 239000012442 inert solvent Substances 0.000 claims description 25
- 102000019315 Nicotinic acetylcholine receptors Human genes 0.000 claims description 18
- 108050006807 Nicotinic acetylcholine receptors Proteins 0.000 claims description 18
- 239000002585 base Substances 0.000 claims description 16
- 239000008194 pharmaceutical composition Substances 0.000 claims description 14
- 229960002715 Nicotine Drugs 0.000 claims description 13
- 206010001897 Alzheimer's disease Diseases 0.000 claims description 12
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 12
- SNICXCGAKADSCV-JTQLQIEISA-N Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 claims description 11
- 229930015196 nicotine Natural products 0.000 claims description 11
- 239000003153 chemical reaction reagent Substances 0.000 claims description 9
- 206010002855 Anxiety Diseases 0.000 claims description 8
- 206010057666 Anxiety disease Diseases 0.000 claims description 8
- 208000002193 Pain Diseases 0.000 claims description 8
- 206010061536 Parkinson's disease Diseases 0.000 claims description 8
- 208000000323 Tourette Syndrome Diseases 0.000 claims description 8
- 206010044126 Tourette's disease Diseases 0.000 claims description 8
- 150000001412 amines Chemical class 0.000 claims description 8
- 230000036506 anxiety Effects 0.000 claims description 8
- 239000003054 catalyst Substances 0.000 claims description 8
- 230000001713 cholinergic Effects 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 8
- 150000002431 hydrogen Chemical group 0.000 claims description 8
- 201000000980 schizophrenia Diseases 0.000 claims description 8
- 208000000044 Amnesia Diseases 0.000 claims description 7
- 206010004939 Bipolar I disease Diseases 0.000 claims description 7
- 206010004938 Bipolar disease Diseases 0.000 claims description 7
- 206010009900 Colitis ulcerative Diseases 0.000 claims description 7
- 201000001971 Huntington's disease Diseases 0.000 claims description 7
- 206010026749 Mania Diseases 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 230000036407 pain Effects 0.000 claims description 7
- 201000006704 ulcerative colitis Diseases 0.000 claims description 7
- 125000002524 organometallic group Chemical group 0.000 claims description 6
- 206010057852 Nicotine dependence Diseases 0.000 claims description 5
- 206010037211 Psychomotor hyperactivity Diseases 0.000 claims description 5
- 210000000225 Synapses Anatomy 0.000 claims description 5
- 238000005804 alkylation reaction Methods 0.000 claims description 5
- 208000009829 Lewy Body Disease Diseases 0.000 claims description 4
- 201000002832 Lewy body dementia Diseases 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 230000001603 reducing Effects 0.000 claims description 4
- 238000006722 reduction reaction Methods 0.000 claims description 4
- 230000000391 smoking Effects 0.000 claims description 4
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 3
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000006201 3-phenylpropyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- RMRFFCXPLWYOOY-UHFFFAOYSA-N Allyl radical Chemical group [CH2]C=C RMRFFCXPLWYOOY-UHFFFAOYSA-N 0.000 claims description 3
- 238000005917 acylation reaction Methods 0.000 claims description 3
- 239000000969 carrier Substances 0.000 claims description 3
- 238000005658 halogenation reaction Methods 0.000 claims description 3
- 230000001590 oxidative Effects 0.000 claims description 3
- 125000001462 1-pyrrolyl group Chemical group [*]N1C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 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 description 2
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000006479 2-pyridyl methyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims description 2
- 125000000389 2-pyrrolyl group Chemical group [H]N1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000001397 3-pyrrolyl group Chemical group [H]N1C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
- 125000000304 alkynyl group Chemical group 0.000 claims description 2
- 239000003701 inert diluent Substances 0.000 claims description 2
- 150000002978 peroxides Chemical class 0.000 claims description 2
- 239000000376 reactant Substances 0.000 claims description 2
- 206010053643 Neurodegenerative disease Diseases 0.000 claims 6
- 230000019771 cognition Effects 0.000 claims 6
- 206010012289 Dementia Diseases 0.000 claims 3
- 230000004913 activation Effects 0.000 claims 3
- 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 claims 2
- 206010003736 Attention deficit/hyperactivity disease Diseases 0.000 claims 2
- 206010012335 Dependence Diseases 0.000 claims 2
- 210000004558 Lewy Bodies Anatomy 0.000 claims 2
- 241001661355 Synapsis Species 0.000 claims 2
- 201000006287 attention deficit hyperactivity disease Diseases 0.000 claims 2
- 125000005843 halogen group Chemical group 0.000 claims 2
- 206010027175 Memory impairment Diseases 0.000 claims 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract description 10
- 101700033614 COR2 Chemical group 0.000 abstract description 3
- 101710008836 UQCRC2 Chemical group 0.000 abstract description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 abstract 2
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 abstract 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 abstract 1
- 239000011593 sulfur Substances 0.000 abstract 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 60
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 56
- 239000000243 solution Substances 0.000 description 35
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 30
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 20
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- BZKBCQXYZZXSCO-UHFFFAOYSA-N sodium hydride Chemical compound [H-].[Na+] BZKBCQXYZZXSCO-UHFFFAOYSA-N 0.000 description 18
- 239000007787 solid Substances 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 15
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 14
- 238000002360 preparation method Methods 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 12
- 239000002253 acid Substances 0.000 description 11
- 230000027455 binding Effects 0.000 description 11
- 229910000090 borane Inorganic materials 0.000 description 11
- 230000002829 reduced Effects 0.000 description 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 10
- MFRIHAYPQRLWNB-UHFFFAOYSA-N Sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 10
- 229910000085 borane Inorganic materials 0.000 description 10
- 239000003795 chemical substances by application Substances 0.000 description 10
- RAHZWNYVWXNFOC-UHFFFAOYSA-N sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 10
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 10
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 9
- 239000003638 reducing agent Substances 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 8
- 235000019341 magnesium sulphate Nutrition 0.000 description 8
- 239000000284 extract Substances 0.000 description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
- XHXFXVLFKHQFAL-UHFFFAOYSA-N Phosphoryl chloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
- 239000012299 nitrogen atmosphere Substances 0.000 description 6
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- 229910002027 silica gel Inorganic materials 0.000 description 6
- 125000003003 spiro group Chemical group 0.000 description 6
- NHQDETIJWKXCTC-UHFFFAOYSA-N Meta-Chloroperoxybenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 5
- XTHFKEDIFFGKHM-UHFFFAOYSA-N dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 5
- 238000003818 flash chromatography Methods 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 5
- 239000003446 ligand Substances 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- YOQDYZUWIQVZSF-UHFFFAOYSA-N sodium borohydride Substances [BH4-].[Na+] YOQDYZUWIQVZSF-UHFFFAOYSA-N 0.000 description 5
- 229910000033 sodium borohydride Inorganic materials 0.000 description 5
- 239000001187 sodium carbonate Substances 0.000 description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 description 5
- ODGROJYWQXFQOZ-UHFFFAOYSA-N sodium;boron(1-) Chemical compound [B-].[Na+] ODGROJYWQXFQOZ-UHFFFAOYSA-N 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid group Chemical group S(O)(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 5
- FKLJPTJMIBLJAV-UHFFFAOYSA-N 5-(7-(4-(4,5-DIHYDRO-2-OXAZOLYL)PHENOXY)HEPTYL)-3-METHYL ISOXAZOLE Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 4
- UAOMVDZJSHZZME-UHFFFAOYSA-N Diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N Triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 4
- 238000007792 addition Methods 0.000 description 4
- DMJZZSLVPSMWCS-UHFFFAOYSA-N diborane Chemical compound B1[H]B[H]1 DMJZZSLVPSMWCS-UHFFFAOYSA-N 0.000 description 4
- 229940079593 drugs Drugs 0.000 description 4
- NUCWDCRUEIUKPN-UHFFFAOYSA-J ethane-1,2-diamine;palladium(2+);phosphonato phosphate Chemical compound [Pd+2].[Pd+2].NCCN.NCCN.[O-]P([O-])(=O)OP([O-])([O-])=O NUCWDCRUEIUKPN-UHFFFAOYSA-J 0.000 description 4
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- 239000000843 powder Substances 0.000 description 4
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- 238000005932 reductive alkylation reaction Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
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- LCDJFVGAKJGCGB-UHFFFAOYSA-N 2-(4-nitrophenoxy)oxirane Chemical compound C1=CC([N+](=O)[O-])=CC=C1OC1OC1 LCDJFVGAKJGCGB-UHFFFAOYSA-N 0.000 description 3
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- NHKJPPKXDNZFBJ-UHFFFAOYSA-N Phenyllithium Chemical compound [Li]C1=CC=CC=C1 NHKJPPKXDNZFBJ-UHFFFAOYSA-N 0.000 description 3
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- 241000700159 Rattus Species 0.000 description 3
- BPLKQGGAXWRFOE-UHFFFAOYSA-M Trimethylsulfoxonium iodide Chemical compound [I-].C[S+](C)(C)=O BPLKQGGAXWRFOE-UHFFFAOYSA-M 0.000 description 3
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- 229910052500 inorganic mineral Inorganic materials 0.000 description 3
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- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
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- HUMNYLRZRPPJDN-UHFFFAOYSA-N Benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- 229940022766 EGTA Drugs 0.000 description 2
- GUBGYTABKSRVRQ-UUNJERMWSA-N Lactose Natural products O([C@@H]1[C@H](O)[C@H](O)[C@H](O)O[C@@H]1CO)[C@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1 GUBGYTABKSRVRQ-UUNJERMWSA-N 0.000 description 2
- YNESATAKKCNGOF-UHFFFAOYSA-N Lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 2
- ZCSHNCUQKCANBX-UHFFFAOYSA-N Lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L MgCl2 Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
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- FEWJPZIEWOKRBE-XIXRPRMCSA-L meso-tartrate(2-) Chemical compound [O-]C(=O)[C@@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-XIXRPRMCSA-L 0.000 description 1
- LMOYMHOTVOGFRM-UHFFFAOYSA-N methane;oxoplatinum Chemical compound C.[Pt]=O LMOYMHOTVOGFRM-UHFFFAOYSA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M methanoate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
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- QDHHCQZDFGDHMP-UHFFFAOYSA-N monochloramine Chemical compound ClN QDHHCQZDFGDHMP-UHFFFAOYSA-N 0.000 description 1
- 239000000472 muscarinic agonist Substances 0.000 description 1
- 125000004370 n-butenyl group Chemical group [H]\C([H])=C(/[H])C([H])([H])C([H])([H])* 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
- SECXISVLQFMRJM-UHFFFAOYSA-N n-methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000000626 neurodegenerative Effects 0.000 description 1
- 230000004112 neuroprotection Effects 0.000 description 1
- 238000002414 normal-phase solid-phase extraction Methods 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N o-xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical Effects 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000002924 oxiranes Chemical class 0.000 description 1
- 201000008125 pain agnosia Diseases 0.000 description 1
- 239000008024 pharmaceutical diluent Substances 0.000 description 1
- 229940100595 phenylacetaldehyde Drugs 0.000 description 1
- PWXJULSLLONQHY-UHFFFAOYSA-N phenylcarbamic acid Chemical group OC(=O)NC1=CC=CC=C1 PWXJULSLLONQHY-UHFFFAOYSA-N 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- OCFVSFVLVRNXFJ-UHFFFAOYSA-N potassium hydride Inorganic materials [H-].[K+] OCFVSFVLVRNXFJ-UHFFFAOYSA-N 0.000 description 1
- 238000004237 preparative chromatography Methods 0.000 description 1
- 238000002203 pretreatment Methods 0.000 description 1
- 230000002035 prolonged Effects 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- QJZUKDFHGGYHMC-UHFFFAOYSA-N pyridine-3-carbaldehyde Chemical compound O=CC1=CC=CN=C1 QJZUKDFHGGYHMC-UHFFFAOYSA-N 0.000 description 1
- BGUWFUQJCDRPTL-UHFFFAOYSA-N pyridine-4-carbaldehyde Chemical compound O=CC1=CC=NC=C1 BGUWFUQJCDRPTL-UHFFFAOYSA-N 0.000 description 1
- RYGIHSLRMNXWCN-UHFFFAOYSA-N quinoline-3-carbaldehyde Chemical compound C1=CC=CC2=CC(C=O)=CN=C21 RYGIHSLRMNXWCN-UHFFFAOYSA-N 0.000 description 1
- MGCGJBXTNWUHQE-UHFFFAOYSA-N quinoline-4-carbaldehyde Chemical compound C1=CC=C2C(C=O)=CC=NC2=C1 MGCGJBXTNWUHQE-UHFFFAOYSA-N 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 231100000486 side effect Toxicity 0.000 description 1
- 230000005586 smoking cessation Effects 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 235000015096 spirit Nutrition 0.000 description 1
- TYCHQBRUARUTCL-UHFFFAOYSA-N spiro[1-azabicyclo[2.2.2]octane-3,2'-oxirane] Chemical compound C1OC11C(CC2)CCN2C1 TYCHQBRUARUTCL-UHFFFAOYSA-N 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
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- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
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- 229960001367 tartaric acid Drugs 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 239000004149 tartrazine Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000001225 therapeutic Effects 0.000 description 1
- 230000002588 toxic Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- VFJYIHQDILEQNR-UHFFFAOYSA-M trimethylsulfanium;iodide Chemical compound [I-].C[S+](C)C VFJYIHQDILEQNR-UHFFFAOYSA-M 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
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- 239000008096 xylene Substances 0.000 description 1
Abstract
A compound of formula (I), wherein NRR1 is attached at the 5- or 6-position of the furopyridine ring;R is hydrogen, C1-C4 alkyl, or COR2;R1 is (CH2)nAr, CH2CH=CHAr, or CH2C=CAr;n is 0 to 3;A is N or NO;Ar is a 5- or 6-membered aromatic or heteroaromatic ring which contains zero to four nitrogen atoms, zero to one oxygen atoms, and zero to one sulfur atoms;or an 8-, 9- or 10-membered fused aromatic or heteroaromatic ring system containing zero to four nitrogen atoms, zero to one oxygen atoms, and zero to one sulfur, any of which may optionally be substituted with one to two substituents independently selected from:halogen, trifluoromethyl, or C1-C4 alkyl;R2 is hydrogen, C1-C4 alkyl, C1-C4 alkoxy or phenyl ring optionally substituted with one to three of the following substituents:halogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, OH;OC1-C4 alkyl, CO2R5, -CN, -NO2, -NR3R4, or -CF3;R3, R4 and R5 may be hydrogen, C1-C4 alkyl, or phenyl ring optionally substituted with one to three of the following substituents:halogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, OH;OC1-C4 alkyl, -CN, -NO2, or -CF3;and enantiomers thereof, and pharmaceutically acceptable salts thereof, processes for preparing them, composition containing them, and their use in therapy, especially in the treatment or prophylaxis of psychotic disorders and intellectual impairment disorders.
Description
NEW ARALQUIL AMPLES OF ESPIROFUROPIRIDINAS USEFUL IN THERAPY
TECHNICAL FIELD
This invention relates to novel substituted amines of spirophoropyridines or pharmaceutically acceptable salts thereof, processes for preparing them, pharmaceutical compositions containing them and their use in therapy. A further objective is to provide active compounds, which are potent ligands for nicotinic acetylcholine receptors (nAChR 's).
BACKGROUND OF THE INVENTION
The use of compounds that bind nicotinic acetylcholine receptors in the treatment of a range of conditions involving reduced cholinergic function, such as Alzheimer's disease, cognitive or attention disorders, anxiety, depression, smoking cessation, neuroprotection, schizophrenia, analgesia , Tourette syndrome and Parkinson's disease have been discussed in McDonald et al. (1995) "Nicotinic Acet lcholine Receptors: Molecular
REF: 131520 Biology, Chemistry and Pharmacology ", Chapter 5 in Annual Reports in Medicinal Chemistry, vol 30, pp. 41-50, Academic Press Inc., San Diego, CA; Williams et al. (1994)" Neuronal Nicotinic Acetylcholine Receptors, "Drug News &Perspectives, vol.7, pp. 205-223; and Lin and Meyer," Recent Developments in Neuronal Nicotinic Acetylcholine Receptor Modulators, "Exp. Opin. Ther. Patents. (1998), 8 ( 8): 991-1015 US Pat. No. 5,468,875 discloses 1-azabicyclo [2.2.1] hept-3-yl esters of N-alkylcarbamic acid which are centrally active muscarinic agents used in the treatment of Alzheimer's disease and other conditions. The 1-azobicyclo [2.2.2] oct an-3-yl esters of N- (2-alkoxyphenyl) carbamic acid are described in Pharmazie, vol 48, 465-466 (1993) together with their local anesthetic activity. The esters of 1-azabicyclo [2.2.2] octan-3-yl of the N-phenylcarbamic acid substituted in the ortho position on the phenyl ring are described as local anesthetics in Ac ta Pha rm. Sueci ca. 7, 239-246 (1970). Furopir idines used to control synaptic transmission are described in WO 97/05139.
BRIEF DESCRIPTION OF THE INVENTION
According to the invention, it has been found that the compounds of the formula I,
wherein NRRi is linked at position 5 or 6 of the furopyridine ring; R is hydrogen, C1-C4 alkyl, COR2; Ri is (CH2) nAr, CH2CH = CHAr or CH2C = CAr; n e s 0 to 3; A is N or NO; Ar is a 5 or 6 membered aromatic or heteroaromatic ring containing zero to four nitrogen atoms, zero to one oxygen atom and zero to one sulfur atom; or an 8, 9 or 10 membered aromatic or heteroaromatic ring system containing zero to four nitrogen atoms, zero to one oxygen atom and zero to one sulfur atom; any of which could optionally be substituted with one to two substituents independently selected from: halogen, trifluoromethyl or C? -C alkyl. R 2 is hydrogen, C 1 -C 4 alkyl; C4-C4 alkoxy; or phenyl ring optionally substituted with one to three of the following substituents: halogen, C alquilo alkyl;
C4; C2-C4 alkenyl; C2-C4 alkynyl, OH; OC-C4 alkyl;
C02R5, -CN, -N02, -NR3R4 or -CF3; R3, R4 and R5 are independently hydrogen; alkyl C? ~ C4; or phenyl ring optionally substituted with one to three of the following substituents: halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl; C2-C4 alkynyl, OH, OC1-C4 alkyl, C02R2, -CN; -N02 or -CF3; or an enantiomer thereof, and the pharmaceutically acceptable salts thereof, are potent ligands for the nicotinic acetylcholine receptors. Unless otherwise indicated, the C 1 -C 4 alkyl groups referred to herein, e.g. methyl, ethyl, n-propyl, n-butyl, i-propyl, i-butyl, t-butyl, s-butyl, could be straight or branched chain and the C3-C4 alkyl groups could also be cyclic, eg, cyclopropyl , cyclobutyl. Unless otherwise indicated, the C 1 -C 4 alkoxy groups referred to herein, e.g., methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, t-butoxy, s-butoxy, could be straight or branched chain. Unless indicated otherwise, the C2-C4 alkenyl groups referred to herein may contain one or two double bonds, e.g., ethenyl, i-propenyl, n-butenyl, i-butenyl, allyl, 1,3-butadienyl. Unless otherwise indicated, the C2-C alkynyl groups referred to herein contain a triple bond, e.g., ethynyl, propynyl, 1- or 2-butynyl. Halogen referred to herein could be fluoride, chloride, bromide or iodide. Unless otherwise indicated, (subst) phenyl refers to a phenyl ring optionally substituted with one to three of the following substituents: hydrogen, halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, OH , alkyl OC? ~ C4, CO2R5, -CN, -N02, -NR3R4, -CF3. Preferred compounds of the invention are compounds of the formula I wherein A is N. The compounds. Preferred of the invention are compounds of the formula I wherein Ri is (CH2) nAr.
Preferred compounds of the invention are compounds of formula I wherein Ri is CH2CH = CHAr. Preferred compounds of the invention are compounds of formula I wherein Ri is CH2C = CAr. Preferred compounds of the invention are compounds of formula I wherein Ar is selected from the group: phenyl ring optionally substituted with one to three of the following substituents: halogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl , OH, alkyl OC? -C4, C02R5, -CN, -N02, -NR3R4 and -CF3; 2-, 3- or 4-pyridyl; 2- or 3-furanyl; 2- or 3-thienyl; 2- or 4-imidazolyl; 1, 2- or 3-pyrrolyl; 2- or 4-oxazolyl and 3-or 4-isoxazolyl. Preferred compounds of the invention are compounds of formula I wherein Ar is selected from the group: 1- or 2-naphthyl; 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl; 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl; 2-, 4-, 5-, 6- or 7-benzoxazolyl; and 3-, 4-, 5-, 6- or 7 -benz isoxazolyl. Preferred compounds of the invention are compounds of the formula I, wherein R3, R4 and R5 are independently hydrogen or C1-C4 alkyl. Preferred compounds of the invention are compounds of formula I, wherein n is 1. Preferred compounds of the invention are compounds of formula I, wherein R is hydrogen. Preferred compounds of the invention are compounds of formula I, wherein Ar is a heteroaromatic ring. Preferred compounds of the invention are compounds of formula I, wherein n is 1, R is hydrogen and Ar is a heteroaromatic ring. Preferred compounds of the invention include the following:
R- (-) - 5 '-N- (Phenylmethyl) aminospiro [1-azabicyclo [2.2.2] octan-3, 2' - (3 [alpha] H) -furo [2,3-b] pyridine];
R- (-) - 5 '- (2-Pyridylmethyl) aminospiro [1-azabicyclo [2.2.2] octane-3,2' - (3'H) -furo [2,3-b] pyridine];
R- (-) - 5 '- (3-Pyridylmethyl) aminospiro [1-azabicyclo [2.2.2] octan-3, 2' - (3 'H) -furo [2,3-b] pyridine];
R- (-) - 5 '- (4-p-Pyridyl-methyl) -amino-spiro [1-azabicyclo [2.2.2] octan-3, 2' - (3 'H) -furo [2,3-b] pyridine];
R- (-) - 5 '- (2-Furanylmethyl) aminospiro [1-azabicyclo [2.2.2] octane-3,2' - (3'H) -furo [2,3-b] pyridine];
R- (-) - 5 '- (3-Furanylmethyl) aminospiro [1-azabicyclo [2.2.2] octan-3,2' - (3'H) -furo [2,3-b] pyridine];
R- (-) - 5 '- (2-Thienylmethyl) aminospiro [1-azabicyclo [2.2.2] octan-3,2' - (3'H) -furo [2,3-b] pyridine];
R- (-) - 5 '- (2-Imidazolylmethyl) aminospiro [1- azabicyclo [2.2.2] octane-3,2' - (3'H) -furo [2,3-b] pyridine];
R- (-) - 5 '- N- (4-Methoxyphenylmethyl) aminospiro [1-azabicyclo [2.2.2] octane-3,2, - (3'H) -furo [2,3-b] pyridine];
R- (-) - 5 '- N- (4-Chlorophenylmethyl) aminospiro [1-azabicyclo [2.2.2] octan-3, 2' - (3'H) -furo [2,3-b] pyridine];
R- (-) - 5 '- N - (4-Methylphenylmethyl) aminospiro [1-azabicyclo [2.2.2] octan-3,2' - (3'H) -furo [2,3-b] pyridine];
R- (-) -5 '-N- (3, -Dichlorophenylmethyl) aminospiro [1-azabicyclo [2.2.2] octan-3,2' - (3'H) -furo [2,3-b] pyridine]; R- (-) - 5 '- N-Acetyl-N- (phenylmethyl) aminospiro [1-azabicyclo [2.2.2] octan-3,2 * - (3'H) -furo [2,3-b] pyridine ];
R- (-) - 5 '- N-Methyl-N- (phenylmethyl) aminospiro [1-azabicyclo [2.2.2] octan-3,2' - (3'H) -furo [2, 3-b] pyridine ];
R- (-) - 5 '- N - (3-Pyridyl) aminospiro [1-azabicyclo [2.2.2] octane-3,2' (3'H) -furo [2,3-b] pyridine];
R- (-) -6 '-N- (Phenylmethyl) aminospiro [1-azabicyclo [2.2.2] octane-3,2' (3'H) -furo [2,3-b] pyridine];
R- (-) - 5 '- N - (3-Thienylmethyl) aminospiro [1-azabicyclo [2.2.2] octane-3,2' - (3'H) -furo [2,3-b] pyridine]; R - (-) - 5'-N- (2-Phenylethyl) aminospiro [1-azabicyclo [2.2.2] octane-3,2 '- (3'H) -furo [2,3-b] pyridine];
R- (-) - 5 '- N- (3-Phenylpropyl) aminospiro [1-azabicyclo [2.2.2] octan-3, 2' - (3 'H) -furo [2,3-b] pyridine];
R- (-) - 5 '- N- (Quinolin-3-ylmethyl) aminospiro [1-azabicyclo [2.2.2] octan-3,2' - (3'H) -furo [2,3-b] pyridine ];
R- (-) - 5 '- N- (Quinolin-4-ylmethyl) aminospiro [1-azabicyclo [2.2.2] octan-3, 2' - (3 'H) -furo [2,3-b] pyridine ]; R- (-) - 5 '-N- (1,4-Benzodioxan-6-ylmethyl) aminospiro [1-azabicyclo [2.2.2] octan-3,2' - (3'H) -furo [2,3 -b] pyridine]; R- (-) -5 '-N- (Imidazol-4-ylmethyl) aminospiro [1-azabicyclo [2.2.2] octan-3,2' - (3'H) -furo [2,3-b] pyridine ]; R- (-) - 5 '-N- (t-trans-3-phenylprop-2-enyl) aminospiro [1-azabicyclo [2.2.2] octane-3,2"- (3'H) -furo [2, 3-b] pyridine]; R - (-) - 5'-N- (Thiazol-2-ylmethyl) aminospiro [1-azabicyclo [2.2.2] octane-3,2 '- (3'H) -furo [ 2, 3-b] pyridine]; R- (-) -5 '-N- (3-Methylphenylmethyl) aminospiro [1-azabicyclo [2.2.2] octane-3,2' - (3'H) -furo [ 2, 3-b] pyridine]; R- (-) - 5 '-N- (2-Chlorophenylmethyl) aminospiro [1-azabicyclo [2.2.2] octane-3,2' - (3'H) -furo [ 2,3-b] pyridine]; R- (-) - 5 '-N- (3-Chlorophenylmethyl) aminospiro [1-azabicyclo [2.2.2] octane-3,2' - (3'H) -furo [ 2,3-b] pyridine]; R- (-) - 5 '-N- (3-Phenylpropynyl) aminospiro [1-azabicyclo [2.2.2] octane-3,2' - (3'H) -furo [ 2,3-b] pyridine]; R- (-) - 5 '-N- (3-Hydroxyphenylmethyl) aminospiro [1-azabicyclo [2.2.2] octane-3,2' - (3'H) -furo [ 2,3-b] pyridine]; R - (-) - 5'-N- (4-Hydroxyphenylmethyl) aminospiro [1-azabicyclo [2.2.2] octane-3,2 '- (3'H) -furo [ 2,3-b] pyridine]; R - (-) - 5'-N- [trans-3- (4-pyridinyl) prop-2-enyl] aminospiro [1-azabicyclo [2.2.2] octan-3, 2 '- (3' H) -furo [2, 3-b] pyridine];
R- (-) - 5 '- N-Acetyl-N- (3-thienylmethyl) aminospiro [1-azabicyclo [2.2.2] octan-3,2' - (3'H) -furo [2,3-b] ] pyridine];
R - (-) - 5'-N-Methyl-N- (4-pyridylmethyl) aminospiro [1-azabicyclo [2.2.2] octan-3, 2 '- (3' H) -furo [2, 3-b ] pyridine]; R- (-) - 5 '- N-Methyl-N- (3-pyridylmethyl) aminospiro [1-azabicyclo [2.2.2] octan-3,2' - (3'H) -furo [2,3-b] ] pyridine];
R - (-) - 5'-N- (2-Hydroxyethyl) -N- (3-thienylmethyl) aminospiro [1-azabicyclo [2.2.2] octan-3, 2 '- (3?) -furo [2, 3-b] pyridine]; and the enantiomers thereof, and the pharmaceutically acceptable salts thereof; Particularly preferred compounds of the invention are compounds of formula I, wherein n is
1; R is hydrogen and Ar is a heteroaromatic ring, which includes the following compounds: R- (-) - 5 '- (3-Pyridylmethyl) aminospiro [1-azabicyclo [2.2.2] octane-3,2' - (3 ') H) -furo [2,3-b] pyridine];
R- (-) - 5 '- (4-Pyridylmethyl) aminospiro [1-azabicyclo [2.2.2] octane-3,2' - (3'H) -furo [2,3-b] pyridine]; and the enantiomers thereof, and the pharmaceutically acceptable salts thereof. The compounds of the invention have the advantage that they could be less toxic, be more effective, be longer in action, have a wider range of activity, be more potent, produce fewer side effects, be more easily absorbed or have other pharmacological properties. tools.
Preparation Methods
In the reaction schemes and text that continues, R and Ri, unless otherwise indicated, are as defined above for formula I. Formula VIII represents a compound of formula I, wherein NRRi is linked in the position 5 of the furopyridine ring. Formula IX represents a compound of formula I, wherein NRRi is linked at position 6 of the furopyridine ring. A represents N; E represents halogen, N02 or NHR. The compounds of formula I could be prepared according to the methods depicted in Scheme 1.
VI HIV (I)
VII IX (I)
Scheme 1
The compounds of the formula I wherein A represents NO, could be prepared from the compounds of the formula I, wherein A represents N by oxidation with a peroxide reactant in an appropriate solvent, followed by the reduction of the tertiary amine oxides in an appropriate solvent. Oxidation agents include hydrogen peroxide, m-chloroperbenzoic acid, peracetic acid or magnesium monoperoxyphthalate. The preferred oxidant is m-chloroperbenzoic acid. Suitable inert solvents include chloroform, methylene chloride and 1,2-dichloroethane. The preferred solvent is dichloromethane. The reaction is usually carried out at a temperature of -20 ° C to 66 ° C, preferably 0 ° C to 20 ° C. Reducing agents include sulfur dioxide and triphenylphosphine. The preferred reagent is sulfur dioxide. Suitable inert solvents include water and alcohols. The preferred solvent is ethanol. The reaction is usually carried out at a temperature of -20 ° C to 50 ° C, preferably 0 ° C to 25 ° C. The compounds of formula I, wherein R represents COR2 could be prepared from the compounds of formula I wherein R represents hydrogen, using an appropriate acylation procedure. Typical acylation procedures include treatment with a carboxylic acid and a coupling agent, for example dicyclohexylcarbodiimide, in an appropriate solvent, for example tetrahydrofuran, or treatment with a chloride or carboxylic acid anhydride in the presence of a base. The preferred method is treatment with a carboxylic anhydride. Appropriate bases include triethylamine, 4- (N, N-dimethylamino) pyridine or pyridine.
The preferred base is pyridine. The reaction is usually carried out at a temperature of 0 ° C to 120 ° C, preferably 80 ° C to 100 ° C. Compounds IX could be prepared from compound VII by reaction with a halogenation reagent, such as phosphorus oxychloride, phosphorus oxybromide., phosphorus pentachloride or phosphorus pentabromide, followed by reaction with an amine in an inert solvent. The preferred halogenating agent is phosphorus oxychloride. The halogenation reaction is usually carried out at a temperature of 0 ° C to 150 ° C, preferably 80 ° C to 120 ° C. The amine component could be any NHRRi amine defined above. Suitable inert solvents include alcoholic solvents, such as methanol and ethanol, as well as aromatic solvents, such as benzene, toluene or xylene. The preferred inert solvent is ethanol. The reaction is usually carried out at a temperature of 20 ° C to 200 ° C, preferably 100 ° C to 170 ° C. The reaction with the amine could be facilitated by the presence of an appropriate organometallic catalyst and a base. Suitable organometallic catalysts include palladium phosphine complexes, which could be formed in itself from a source of palladium and an appropriate phosphine. The preferred source of palladium is tris (dibenzylidinacetone) dipalladium (0). The preferred phosphine is 2-2'-bis (diphenylphosphino) 1,1'-biphenyl. Suitable bases include lithium bis (trimethylsilyl) amide or sodium t-butoxide, preferably sodium t-butoxide. Inert solvents suitable for the reaction in the presence of an organometallic catalyst include tetrahydrofuran, 1,2-dimethoxyethane or 1,4-dioxane, preferably 1,2-dimethoxyethane, and the reaction is usually carried out at a temperature of 60 ° C. at 120 ° C, preferably 80 ° C to 110 ° C. The compounds of the formula VIII could be prepared from the compounds of the formula VI, wherein E represents NHR by an appropriate alkylation process. Typical alkylation procedures include treatment with an appropriate alkyl halide or sulfonate ester and base, for example sodium hydride, in an appropriate solvent, for example DMF or reductive alkylation using the appropriate aromatic aldehyde together with an appropriate reducing agent in a inert solvent. The preferred method is reductive alkylation. Suitable aromatic aldehydes include Ar (CH2) mCHO, ArCH = CHCHO or ArC = CCHO, where m could be 0-2 and Ar is defined as above. Suitable alkylating reagents include sodium borohydride and sodium cyanoborohydride. The preferred reducing agent is sodium borohydride. Suitable inert solvents include water, methanol or ethanol. The preferred solvent is methanol. The reaction is usually carried out at a temperature of 0 ° C to 100 ° C, preferably 20 ° C to 65 ° C. The compounds of the formula VIII could be prepared from the compounds of the formula VI, wherein E represents halogen, by reaction with an amine of the formula RRiNH in the presence of an appropriate organometallic catalyst, base and solvent. Suitable organometallic catalysts include palladium phosphine complexes, which could be formed in itself from a palladium source and an appropriate phosphine. The preferred palladium source is tris (dibenzyl idinacetone) dipalladium (0). The preferred phosphine is 2-2'-bis (diphenylphosphino) 1,1'-biphenyl. Suitable bases include lithium bis (trimethylsilyl) amide or sodium t-butoxide, preferably sodium t-butoxide. Suitable inert solvents include tetrahydrofuran, 1,2-dimethoxyethane or 1,4-dioxane. The preferred solvent is 1,2-dimethoxyethane. The reaction is usually carried out at a temperature of 60 ° C to 120 ° C, preferably 80 ° C to 110 ° C. Compound VII could be prepared from compound V by oxidation with a peroxidic reagent in an appropriate solvent, followed by reduction of the tertiary amine oxides in an appropriate solvent. Oxidation agents include hydrogen peroxide, m-chloroperbenzoic acid, peracetic acid or magnesium monoperoxyphthalate. The preferred oxidant is m-chloroperbenzoic acid. Suitable inert solvents include chloroform, methylene chloride and 1,2-dichloroethane. The preferred solvent is dichloromethane. The reaction is usually carried out at a temperature of -20 ° C to 66 ° C, preferably 0 ° C to 20 ° C. Reducing agents include sulfur dioxide and triphenylphosphine. The preferred reagent is sulfur dioxide. Suitable inert solvents include water and alcohols. The preferred solvent is ethanol. The reaction is usually carried out at a temperature of -20 ° C to 50 ° C, preferably 0 ° C to 25 ° C. The compounds of the formula VI, wherein E represents NHR and R represents an alkyl group could be prepared from the compounds of the formula VI, wherein E represents NH2 by an appropriate alkylation process. Typical alkylation procedures include treatment with an appropriate alkyl halide or sulfonate ester and base, for example sodium hydride, in an appropriate solvent, for example DMF, or reductive alkylation using the appropriate aldehyde or ketone, together with a reducing agent appropriate in an inert solvent. The preferred method is reductive alkylation. Suitable reducing agents include sodium borohydride and sodium cyanoborohydride. The preferred reducing agent is sodium borohydride. Suitable inert solvents include water, methanol or ethanol. The preferred solvent is methanol. The reaction is usually carried out at a temperature of 0 ° C to 100 ° C, preferably 20 ° C to 65 ° C. The compounds of the formula VI in which E represents NH 2 could be prepared from the compounds of the formula VI, wherein E represents N 0 2 by reduction in an appropriate solvent. Suitable reducing agents include hydrogen in the presence of a catalyst, for example 5-10% palladium on carbon, platinum oxide or rhodium on carbon. The preferred reducing agent is hydrogen in the presence of 10% palladium on carbon. Suitable inert solvents include water, methanol or ethanol. The preferred solvent is methanol. The reaction is usually carried out at a temperature of 0 ° C to 65 ° C, preferably 15 ° C to 30 ° C. Compound VI in which E represents N02 could be prepared from compound V by reaction with a nitrating agent in an appropriate solvent. The preferred nitrating agent is fuming nitric acid; the preferred solvent is sulfuric acid. The reaction is usually carried out at a temperature of -10 ° C to 100 ° C, preferably 50 ° C to 80 ° C. Compounds of formula VI, wherein E represents halogen could be prepared from a compound V by reaction with a halogenating agent in an appropriate solvent, for example bromine in acetic acid. The reaction is usually carried out at a temperature of 0 ° C to 110 ° C, preferably 60 ° C to 110 ° C. Compound V could be prepared from the cyclization of compound IV in the presence of a base in an inert solvent, followed by deprotection of the compound which is cyclized using acid in an appropriate solvent. Suitable bases include sodium hydride, sodium amide, potassium hydride, potassium t-amylate, potassium t-butoxide, and potassium bis (trimethylsilyl) amide. The preferred base is sodium hydride. Suitable inert solvents include N, N-dimethylformamide, N-methylpyrrolidin-2-one, ethers such as diethyl ether, tetrahydrofuran and 1,4-dioxane and dimethisulfoxide. The preferred inert solvent is N, N-dimethylformamide. The reaction is usually carried out at a temperature of -10 ° C to 100 ° C, preferably 20 ° C to 6 ° C. Suitable acids for the deprotection of the compound that is subjected to cyclization include mineral, organic and Lewis acids, for example, hydrochloric and hydrobromic acid, sulfuric acid, triflic acid, methanesulfonic acid and boron trifluoride etherate. The preferred acid is bromhydric acid. Suitable solvents include acetone, butanone, ethanone and pinacolone. The preferred solvent is acetone. The reaction is usually carried out at a temperature of -10 ° C to 100 ° C, preferably 0 ° C to 60 ° C. Alternatively, the deprotection could be carried out by heating the borane complex in alcoholic solvents. A preferred method is by refluxing an ethanolic solution of the complex. Compound IV could be prepared from compound III using a lithium base and a proton transfer agent in an inert solvent. Suitable lithium bases include lithium diisopropylamide, n-butyl lithium, sec-butyl lithium, tert-butyl lithium and phenyl lithium. The preferred lithium base is phenyllithium. Suitable proton transfer agents include sterically hindered secondary amines, such as diisopropylamine and 2,2,6,6-tetramethylpiperidine. The appropriate proton transfer agent is diisopropylamine. Suitable inert solvents include diethyl ether, tetrahydrofuran and 1,4-dioxane. The preferred inert solvent is tetrahydrofuran. The reaction is usually carried out at a temperature of -100 ° C to 0 ° C, preferably -78 ° C to -25 ° C. Compound III could be prepared from the reaction of compound II with an anion of a reagent well known in the art for the preparation of oxiranes from ketones (see, for example, the reactions referenced in J. March, "Advanced Organic Chemistry". 1992) 4th Edition, pages 974-975), followed by reaction with borane (BH3 or B2He) in an inert solvent. Borane is preferred in tetrahydrofuran. Suitable inert solvents include diethyl ether, tetrahydrofuran and 1,4-dioxane. The preferred inert solvent is tetrahydrofuran. The reaction is usually carried out at a temperature of -10 ° C to 66 ° C, preferably 0 ° C to 20 ° C. Suitable epoxidation agents include trimethylsulfoxonium iodide, trimethylsulfonium iodide and diazomethane. The preferred reagent is trimethylsulfoxonium iodide. Suitable inert solvents include dipolar aprotic solvents. The preferred solvent is dimethisulfoxide. The reaction is usually carried out at a temperature of -10 ° C to 100 ° C, preferably 50 ° C to 75 ° C. When necessary, hydroxy, amino or other reactive groups could be protected using a protecting group as described in the standard text
"Protecting groups in Organic Synthesis", 2nd Edition
(1991) by Greene and Wuts. The reactions described above, unless otherwise indicated, are usually carried out at a pressure of one to three atmospheres, preferably at ambient pressure (about one atmosphere). Unless stated otherwise, the reactions described above are carried out under an inert atmosphere, preferably under a nitrogen atmosphere. The compounds and intermediates of the invention could be isolated from their reaction mixtures by standard techniques. The acid addition salts of the compounds of the formula I which may be mentioned include salts of mineral acids, for example the hydrochloride and hydrobromide salts; and salts formed with organic acids such as formate, acetate, maleate, benzoate, tartrate and fumarate salts. The acid addition salts of the compounds of the formula I could be formed by the reaction of the free base or a salt, enantiomer or protected derivative thereof, with one or more equivalents of the appropriate acid. The reaction could be carried out in a solvent or medium in which the salt is insoluble or in a solvent in which the salt is soluble, eg, water, dioxane, ethanol, tetrahydrofuran or diethyl ether, or a mixture of solvents, which they could be removed by vacuum or by freeze drying. The reaction could be a metathetic process or it could be carried out on an ion exchange resin. The compounds of the formula I exist in the tautomeric or enantiomeric forms, all of which are included within the scope of the invention. Various optical isomers could be isolated by separation of a racemic mixture of the compounds using conventional techniques, e.g. fractional crystallization or chiral HPLC. Alternatively, the individual enantiomers could be made by reacting the optically active initiator materials suitable under the reaction conditions that will not cause racemization.
Intermediaries
A further aspect of the invention relates to new intermediaries. Special interest among these novel intermediates are the compounds of formula VI and VII in Scheme I. These intermediates are useful in the synthesis of the compounds of formula I, but their use is not limited to the synthesis of these compounds. The formulas for these compounds are presented below:
Compounds of formula VI
SAW
wherein E is N02, NHR or halogen; and the compounds of formula VII VII
Intermediate compounds also exist in the enantiomeric forms and could be used as enantiomers, racemates or purified mixtures. The use of compounds VI and VII as intermediates in a synthesis of a ligand for nicotinic acetylcholine receptors is another aspect of the invention.
Pharmaceutical compositions
A further aspect of the invention relates to a pharmaceutical composition for treating or preventing a condition or condition as exemplified below, which results from dysfunction of the neurotransmission of the nicotinic acetylcholine receptor in a mammal, preferably a human, comprising an amount of a compound of the formula I, an enantiomer thereof and a pharmaceutically acceptable salt thereof, effective to treat or prevent such a condition or condition and a pharmaceutically acceptable inert carrier. For the uses mentioned above, of course, the dose administered will vary with the compound employed, the manner of administration and the desired treatment. However, in general, satisfactory results will be obtained when administering the compounds of the invention at a daily dosage of 0.1 mg to 20 mg per kg of body weight of the mammal, preferably given in divided doses 1 to 4 times a day or in prolonged release form. For men, the total daily dose is in the range of 5 mg to 1, 400 mg, more preferably 10 mg to 100 mg and the unit dosage forms suitable for oral administration comprise from 2 mg to 1400 mg of the compound mixed with a solid or liquid pharmaceutical carrier or diluent. The compounds of the formula I, or an enantiomer thereof, and the pharmaceutically acceptable salts thereof, could be used singly or in the form of medicinal preparations suitable for enteral, parenteral, oral, rectal or nasal administration. According to a further aspect of the invention, there is provided a pharmaceutical composition, preferably comprising less than 80% and more preferably less than 50% by weight of a compound of the invention in admixture with a pharmaceutically acceptable inert diluent or carrier. Examples of suitable diluents and vehicles are: for tablets and dragees: lactose, starch, talc, stearic acid; for capsules: tartaric acid or lactose; for injectable solutions: water, alcohols, glycerin, vegetable oils; for suppositories: natural or hardened oils or waxes. A process for the preparation of such a pharmaceutical composition is also provided, which comprises mixing the ingredients simultaneously or sequentially.
Utility
A further aspect of the invention is the use of a compound according to the invention, or an enantiomer thereof, and a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prophylaxis of one of the diseases or conditions mentioned below; and a method of treatment or prophylaxis of one of the diseases or conditions mentioned below, which comprises administering a therapeutically effective amount of a compound according to the invention, or an enantiomer thereof, and a pharmaceutically acceptable salt thereof to a patient. The compounds according to the invention are agonists of nicotinic acetylcholine receptors. While not limited by theory, it is believed that agonists of subtype 7 nAChR (nicotinic acetylcholine receptor) should be useful in the treatment or prophylaxis of psychotic conditions and intellectual damage conditions and have advantages over compounds that are, or they are also agonists of the subtype or4 nAChR. Therefore, compounds that are selective for subtype a7 nAChR are preferred. The compounds of the invention are intended as pharmaceuticals, in particular in the treatment or prophylaxis of psychotic conditions and sufferings of intellectual damage. Examples of psychotic conditions include schizophrenia, mania or manic depression and anxiety. Examples of intellectual damage conditions include Alzheimer's disease, learning deficit, cognitive deficit, attention deficit, memory loss, Lewy body dementia and hyperactivity disorder of attention deficit. The compounds of the invention could also be useful as analgesics in the treatment of pain (including chronic pain) and in the treatment or prophylaxis of Parkinson's disease, Huntington's disease, Tourette's syndrome and neurodegenerative conditions in which there is loss of cholinergic synapses . The compounds could also be indicated for the treatment or prophylaxis of temporary fatigue (refers to a temporary condition causing fatigue, insomnia and other symptoms as a result of air travel through the time zones), for use in the induction of cessation of smoking and for the treatment or prophylaxis of nicotine addiction (including that resulting from exposure to products containing nicotine). It is also believed that the compounds according to the invention are useful in the treatment and prophylaxis of ulcerative colitis.
Pharmacology
The pharmacological activity of the compounds of the invention could be measured in the tests set forth below:
Test A - Test for affinity in subtype 7 nAChR Linkage of 125I- -Bungarotoxin (BTX) to rat hippocampal membranes. Rat hippocampi were homogenized in 20 volumes of cold homogenization buffer (HB: concentrations of the constituents (mM): tris (hydroxymethyl) aminomethane 50, MgCl2 1, NaCl 120, KCl 5, pH 7.4). The homogenate was centrifuged for 5 minutes at 1000 x g, the supernatant was collected and the granule was re-extracted. The divided supernatants were centrifuged for 20 minutes at 12,000 x g, washed and resuspended in HB. The membranes (30-80 μg) were incubated with 5 nM [125 I] a-BTX. 1 mg / mL of BSA (bovine serum albumin), test drug, and either 2 mM CaCl 2 or 0.5 mM EGTA [ethylene glycol bis (β-aminoethyl ether)] for 2 hours at 21 ° C, and then filtered and washed 4 times on Whatman glass fiber filters (thickness C) using a Brandel cell harvester. Pre-treatment of the filters for 3 hours with 1% (BSA / PEI at 0.01%
(polyethyleneimine)) in water was critical for lower filtering targets (0.07% of total counts per minute). The non-specific binding was described by
(-) - 100 μM nicotine and the specific binding was typically 75%.
Test B - Test for affinity to subtype a4 nAChR Enlazamiento of [3H] - (-) - nicotine. Using a modified procedure from Mart ino-Barrows and Kellar
(Mol Pharm (1987) 31: 169-174), the rat brain (cortex and hippocampus) was homogenized as in the [125I] a-BTX binding test, centrifuged for 20 minutes at 12,000 xg, washed twice , and then resuspended in HB containing 100 μM diisopropyl fluorophosphate. After 20 minutes at 4 ° C, the membranes (approximately 0.5 mg) were incubated with
[3 H] - (-) -nicotine 3 nM, test drug, 1 μM atropine and either 2 mM CaCl 2 or 0.5 mM EGTA for 1 hour at 4 ° C, and then filtered on glass fiber filters
Whatman (thickness C) (pretreated for 1 hour with 0.5% PEI) using a Brandel cell harvester. The non-specific binding was described by 100 μM carbachol, and the specific binding was typically 84%.
Analysis of link results for Tests A and B
The IC50 and pseudo Hill coefficients (nH) were calculated using the ALLFIT non-linear curve fitting program (DeLean A, Munson P J and Rodbard D (1977) Am. J. Physiol., 235: E97-E102). The saturation curves were fitted to a site model, using the non-linear regression program ENZFITTER (Leatherbarrow, RJ (1987)), yielding KD values of 1.67 and 1.70 nM for the ligands 125I-a-BTX and [3H] - (-) ~ nicotine, respectively. The Ki values were estimated using the Cheng-Prusoff general equation:
K _- [IC50] / ((2+ ([ligand] / [KD]) nn) li // nn 1)
wherein a value of n = l was used provided that nH < 1.5 and a value of n = 2 was used when nH = 1.5. The samples were tested in triplicate and were typically ± 5%. Ki values were determined using 6 or more concentrations of the drug. The compounds of the invention are compounds with binding affinities (Kx) less than 1000 nM in either Test A or Test B, indicating that they are expected to have useful therapeutic activity.
EXAMPLES
Commercial reagents were used without further purification. Mass spectra were recorded using a Hewlett Packard 5988A or Quattro-1 mass spectrometer and reported as m / z for the parent molecular ion with its relative intensity. The ambient temperature refers to 20-25 ° C. The following examples are preferred non-limiting examples that model the preferred aspects of the invention.
Preparation 1 Spiro complex [1-azabicyclo [2.2.2] octan-3, 2'-oxirane]
N-borane (compound III)
A mixture of trimethylsulfoxonium iodide (16.10 g, 73.2 mmol) and a dispersion of sodium hydride (60% in oil, 3.00 g, 75.0 mmol) in anhydrous dimethyl sulfoxide was stirred at room temperature under nitrogen for 30 minutes. Then quinuclidin-3-one (II) (7.05 g, 56.3 mmol) was added as a solid portion, and the resulting mixture was stirred at 65-70 ° C under nitrogen for 1 hour. The reaction mixture was cooled, water (200 ml) was added and the resulting solution was extracted with chloroform (3 x 200 ml). The chloroform extracts were combined and reextracted with water (4 x 200 ml). The chloroform layer was then dried (MgSO 4), filtered and evaporated under reduced pressure to provide spiro [1-a-zabicyclo [2.2.2] octane-3, 2'-oxirane] (6.51 g, 46.8 mmol, 83 %) as a clear, colorless liquid. To a stirred solution of spirofl-azabicyclo [2.2.2] octane-3, 2'-oxirane] (5.3 g, 38.1 mmol) in anhydrous tetrahydrofuran (100 ml) at 0 ° C was added dropwise a solution of borane in tetrahydrofuran (1.0 M, 38.1 mL, 38.1 mmol), and the resulting solution was stirred at 0 ° C under nitrogen for 30 minutes. Brine (100 ml) was added cautiously to the reaction solution, and the resulting aqueous mixture was extracted with ethyl acetate (2 x 100 ml). The organic extracts were combined, dried (MgSO4), filtered and evaporated under reduced pressure to give the title compound (III) (4.3 g, 28.1 mmol, 74%) as a white solid: elect roatomized MS 152 ( [MH] +, 15).
Preparation 2 Complex of 3- (2-chloropyridin-3-ylmethyl) -3-hydroxy-l-azabicyclo [2.2.2] octane N-borane (compound IV)
A solution of phenyl-lithium (1.8 M in cyclohexane / ether [7: 3], 167 ml, 0.3 mol, 3 eq.) Was added via a cannula to anhydrous tetrahydrofuran (350 ml) at -60 ° C under a nitrogen atmosphere. Then, diisoproylethylamine was added dropwise, followed by a dropwise addition of 2-chloropyridine (28.4 ml, 3 eq.) For ten minutes. The resulting solution was stirred at -40 ° C under nitrogen for 1.5 hours. Then, the solution was cooled to -60 ° C and a solution of the spiro [1-azabicyclo [2.2.2] octan-3, 2'-oxirane] N-borane complex (15.3 g, 0.1 mol) was added dropwise. in tetrahydrofuran (75 ml). The resulting reaction mixture was then stirred at -40 ° C under nitrogen. After 3 hours, a saturated solution of sodium bicarbonate (150 ml) was slowly added, followed by water (400 ml), and the resulting aqueous mixture was allowed to warm to room temperature. The layers were separated and the aqueous phase was extracted with ethyl acetate (3 x 100 ml). The organic layers were combined, dried (MgSO 4), filtered and evaporated under reduced pressure. Column chromatography using silica gel and elution with ethyl acetate / hexanes [3: 2] gave the title compound IV as a tan solid (17.5 g, 65.6 mmol, 66%): electroatomized MS 269 ([ MH] + with 37C1, 10), 267 ([MH] + with 35C1, 26).
Preparation 3 Spiro [l-azabicyclo [2.2.2] octane-3,2 '(3'H) -furo [2,3-b] pyridine] (compound V)
Complex 3- (2-chloropyridin-3-ylmethyl) -3-hydroxy-l-azabicyclo [2.2.2] octane N-borane (17.4 g, 65.3 mmol) was dissolved in anhydrous N, N-dimethylformamide (500 mL), The resulting solution was cooled to 0 ° C under nitrogen, and a dispersion of sodium hydride (60% in oil, 6.55 g, 163 mmol, 2.5 eq.) was added portion by portion. The resulting solution was stirred at room temperature under nitrogen for 16 hours. Then a saturated solution of ammonium chloride (50 ml) was added at 0 ° C, followed by cold water (500 ml), and the resulting aqueous mixture was extracted with chloroform (4 x 125 ml). The organic extracts were combined, dried (MgSO4) and evaporated under reduced pressure to give an orange solid. Purification through a short column of silica gel eluting with chloroform / acetone [95: 5 to 85:15], followed by stirring in hexanes (100 ml) and filtration, gave a yellow solid (12.7 g, 55.2 mmol, 84%) of the complex spiro [l-azabicyclo [2.2.0] octan-3, 2 '(3' H) -furo [2, 3-b] pyridine] N-borane, electroatomized MS 231 ([MH] +, 65). The spiro [l-azabicyclo [2.2.2] octane-3, 2 '(3' H) -furo [2,3-b] pyridine] N-borane complex (12.2 g, 53 mmol) was dissolved in 150 ml of acetone, the solution was cooled to 0 ° C and an aqueous solution of HBr (24%, 50 mL) was added. The resulting solution was stirred at room temperature under nitrogen for 24 hours. The reaction was concentrated under reduced pressure, and the aqueous residue was treated with saturated aqueous sodium carbonate solution (50 ml). The solution was basified to pH > 10 using sodium carbonate and the resulting solution was extracted with chloroform (3x100 ml). The organic extracts were combined, dried (MgSO 4), filtered and evaporated under reduced pressure to provide the title compound VI (11.2 g, 51.8 mmol, 98%, 54% overall) as an almost white solid; Electroatomized MS 217 ([MH] +, 72). The title compound was separated into its (R) and (S) enantiomers by the following methods:
Method A - 250 mg of the title compound was separated by chiral HPLC, using a 2 cm X 25 cm CHIRALCEL-OD column in a Waters Delta Prep 3000 Preparative Chromatography System, eluting with 2,2,4-trimethylpentane / ethanol ( 92: 8 to 9: 1) at a flow rate of 20 ml / min. This yielded 111 mg of the (S) -enantiomer ([] 23 = +59.7 (c = 1, methanol)) and 90 mg of the (R) -enantiomer ([a] 23 = -63.9 (c = 1, methanol)).
Method B - 1 g (4.62 mmol) of the title compound was treated with L- (+) - tartaric acid (694 mg, 4.62 mmol) in 15% aqueous ethanol (10 mL) and recrystallized three times to obtain the enantiomer (S) L- (+) - tartrate (650 mg; 1.77 mmol; [] 23 = +57.7 (c = 2, H20)). The filtrates were concentrated under reduced pressure and the aqueous residue was basified to pH > 10 using solid sodium carbonate. The resulting mixture was extracted with chloroform (3 x 25 ml) and the combined organic extracts were dried (MgSO 4) and evaporated under reduced pressure. The residue (650 mg, 3 mmol) was treated with D- (-) - tartaric acid (452 mg, 0.3 mmol) and recrystallized as above to give the (R) - (-) - tartrate (775) enantiomer mg; 2.11 mmol; [] 23 = -58.2 ° (c = 2, H20)).
Preparation 4 (R) - (-) - 5 '- Nitrospiro [1-azabicyclo [2.2.2] octan-3, 2' (3?) -furo [2, 3-b] pyridine] (compound VI, E = NQ2).
(R) - (-) - Spiro [1-azabicyclo [2.2.2] octan-3'2 (3'H) -furo [2,3-b] pyridine] (3.03 g, 14 mmol) was dissolved in acid concentrated sulfuric acid (7 ml) at 0-5 ° C, fuming nitric acid (3.3 ml, 70.2 mmol) was added over 10 minutes, the mixture was stirred for 1 hour and heated at 65-70 ° C for 24 hours, cooled, poured onto ice (200 g), 300 ml of water was added, basified to pH 10 with solid potassium carbonate, stirred for 1 hour, filtered and dried, the solid title compound was provided (3.6 g, 13.8 mmol, 98%); Electroato i zado MS 262 ([MH] +, 100). Preparation 5 (R) - (-) - 5 '-Aminospiro [1-azabicyclo [2.2.2] octan-3, 2' (3 'H) -furo [2,3-b] pyridine] (compound VI, E = NH2).
A mixture of the (R) - (-) - 5 'nitrospiro [1-azabicyclo [2.2.2] octane-3,2' (3'H) -furo [2,3-b] pyridine] enantiomer (3.8 g, 13.3 mmol) and 10% palladium on carbon (48% moisture in water, 270 g) in methanol (90 ml) was hydrogenated for 1 hour at 3.4 atmospheres of hydrogen. The catalyst was filtered through a pad of celite and the solvent was evaporated under reduced pressure; the residue was purified by flash chromatography
(eluting with chloroform in ammonia / methanol, 95: 5 a
85:15), gave the title compound (2.5 g, 10.8 mmol, 81%); electroatomized MS (m / z, relative intensity) 232 ([MH] +, 100).
Preparation 6 (R) - (-) - Spiro [l-azabicyclo [2.2.2] octane-3,2 '(3'H) -furo [2, 3-b] pyridine-N-oxide] (compound VII) .
A solution of 2.03 g (9.38 mmol) of (R) - (-) - spiro [1-azabicyclo [2.2.2] octan-3, 2 '(3' H) -furo [2,3-b] pyridine] in 100 ml of methylene chloride was cooled in an ice bath, to which 6.90 g (22.8 mmol) of 57-86% m-chloroperbenzoic acid was added, in portions over 5 minutes. The reaction was allowed to warm gradually to room temperature and was stirred for 24 hours total. The solvent was removed in vacuo and the solid residue was dissolved in 100 ml of absolute ethanol, cooled in an ice bath and sulfur dioxide was bubbled until the solution changed to cloudy. The reaction was stirred for 4 hours, then the solvent was stirred in vacuo. The solid residue was dissolved in 150 ml of a 9: 1 mixture of chloroform and methanol, then extracted with 50 ml of 10% aqueous sodium hydroxide. The organic layer was dried with magnesium sulfate, concentrated in vacuo and subjected to flash chromatography through neutral silica gel using a 9: 1 mixture of chloroform and 2.0M ammonia in methanol as the eluent, giving 1.30 g ( 60%) of the title compound after crystallization from ethyl acetate / hexane (1: 1): [] 23 = -56.82 (c = 1.09, EtOH), electroatomized MS 233 ([MH] +, 100) .
Preparation 7A 5'-Bromoespiro [l-azabicyclo [2.2.2] octane-3,2 '(3'H) -furo [2, 3-b] pyridine] (compound VI, E = Br).
A solution of spiro [1-azabicyclo [2.2.2] octan-3, 2 '(3?) -furo [2, 3-b] pyridine] (100 mg, 0.462 mmol) and sodium acetate (410 mg, mmol) in 5% aqueous acetic acid (4 ml) was heated at 60 ° C. Bromine (0.100 ml, 1.94 mmol) was added via a syringe for 10 minutes, and the solution was then heated to reflux for 1 hour. The mixture was allowed to cool to room temperature, basified to pH > 10 with sodium carbonate, and extracted with chloroform (3 x 15 ml). The combined extracts were dried (MgSO 4), filtered and evaporated under reduced pressure to give the title compound (110 mg, 0.37 mmol, 81%) as an almost white solid: electroatomized MS 295 ([MH] +, with 79 Br, 100), 297 ([MH +], with 81 Br, 98).
Preparation 7B (R) - (-) -5'-Bromoespiro [1-azabicyclo [2.2.2] octan-3, 2 '(3' H) -furo [2, 3-b] pyridine] (compound VI, E = Br)
The (R) - (-) -spiro [1-azabicyclo [2.2.2] octan-3,2 * (3'H) -furo [2,3-b] pyridine] (1.95 g, 9 mmol) enantiomer treated in the same manner as described in Preparation 7A provided the title compound (1.77 g, 6 mmol, 67%) ([a] 23 = -45.5 ° (c = 1, MeOH)).
Example 1 R- (-) -5 '-N- (Phenylmethyl) aminospiro [1-azabicyclo [2.2.2] octan-3,2' - (3'H) -furo [2,3-b] pyridine]
Sodium spheres of mineral spirits were dried with absorbent paper, weighed (100 mg, 4.3 mmol) and gradually added to 2 ml of anhydrous methanol, while stirring under a nitrogen atmosphere at 0 ° C. The reaction was stirred at 0 ° C for 25 minutes, during which time the vigorous bubbling was stopped and almost all the solid dissolved. 5'-Aminospiro [l-azabicyclo [2.2.2] octan-3,2 '- (3'H) -furo [2, 3-b] pyridine] (230 mg, 1.0 mmol) and benzaldehyde (0.23 ml) were added. , 1.0 mmol), the ice bath was removed and 2 ml of additional anhydrous methanol was added. The solution was stirred at room temperature for two days, then heated at 50 ° C for 2 h. Sodium borohydride (106 mg, 2.8 mmol) was added and the reaction was heated to reflux for 90 minutes. Due to cooling to room temperature, the methanol was stirred in vacuo and the residue was partitioned between 8 ml of chloroform and 2 ml of water. The aqueous layer was extracted twice more with 8 ml of chloroform and the organic layers were combined and dried with magnesium sulfate. The chloroform was fractionated in vacuo, and the crude product was purified on a flash silica column using a gradient of methanol in 0-10% ammonia / chloroform, giving 0.25 g (77%) of the title compound as a white powder : electroatomized MS 322 ([MH] +, 100).
Example 2 R- (-) - 5 '- N - (2-Pyridyl-rtethyl) aminospiro [1-azabicyclo [2.2.2] octane-3,2' - (3'H) -furo [2,3-b ] pyridine]
The title compound was prepared by the procedure used in Example 1 from 115 mg (0.5 mmol) of 5 '-aminoespiro [1-a-zabicyclo [2.2.2] octane-3,2'- (3'H) -furo [2, 3-b] pyridine] and 0.114 ml (1.2 mmol) of 2-pyridine carboxaldehyde to give 84 mg of the title compound as a beige powder (52%): elect roatomized MS 323 ([MH +], 100 ).
Example 3 R- (-) - 5 '- N - (3-pyridylmethyl) aminospiro [1-azabicyclo [2.2.2] octan-3,2' - (3'H) -furo [2,3-b] pyridine ]
The title compound was prepared by the procedure used in Example 1 from 115 mg (0.5 mmol) of 5 '-aminoespiro [1-azabicyclo [2.2.2] octane-3, 2' - (3?) -furo [2, 3-b] pyridine] and 3-pyridinecarboxaldehyde to give 81 mg, (50%) of the title compound as a beige powder: electroatomized MS 323 ([MH +], 100).
Example 4 R- (-) - 5 '- N - (4-pyridylmethyl) aminospiro [1-azabicyclo [2.2.2] octan-3,2' - (3'H) -furo [2,3-b] pyridine ]
The title compound was prepared by the procedure used in Example 1 from 115 mg (0.5 mmol) of 5 '-aminoespiro [1-azabicyclo [2.2.2] octan-3, 2' - (3'H) - furo [2, 3-b] pyridine] and 4-pyridinecarboxaldehyde to give 84 mg (52%) of the title compound as a light yellow powder: electroatomized MS 323 ([MH +], 100).
Example 5 R- (-) - 5 '- N - (2-Furanyl ethyl) aminospiro [1-azabicyclo [2.2.2] octan-3,2' - (3'H) -furo [2,3-b] pyridine]
The title compound was prepared by the procedure used in Example 1 from 50 mg (0.22 mmol) of 5 '-aminoespiro [1-azabicyclo [2.2.2] octan-3, 2' - (3?) -furo [2, 3-b] pyridine] and 2-furaldehyde (43 mL, 0.52 mmol), giving 30 mg of the title compound as a dark yellow semi-solid: electroatomized MS 312 ([MH +], 100).
Example 6 R- (-) - 5 '-N- (3-Furanylmethyl) aminospiro [1-azabicyclo [2.2.2] octan-3,2' - (3'H) -furo [2,3-b] pyridine ]
The title compound was prepared by the procedure used in Example 1 from 50 mg (0.22 mmol) of 5 '-aminoespiro [1-azabicyclo [2.2.2] octan-3, 2' - (3 'H) - furo [2, 3-b] pyridine] and 3-furaldehyde to give 25 mg of the title compound: electroatomized MS 312 ([MH +], 100).
Example 7 R- (-) - 5 '- N - (2-Thienylmethyl) aminospiro [l-azabicyclo [2.2.2] octan-3,2' - (3'H) -furo [2,3-b] pyridine
The title compound was prepared by the procedure used in Example 1 from 50 mg
(0.22 mmol) of 5 '-aminoespiro [1-azabicyclo [2.2.2] octan-3, 2' - (3 * H) -furo [2, 3-b] pyridine] and 4-thiophenecarboxaldehyde, giving 9 mg of the composed of title: electroatomizado MS 328 ([MH +], 100).
Example 8 R- (-) - 5 '-N- (4-Methoxyphenylmethyl) aminospiro [1-azabicyclo [2.2.2] octan-3,2' - (3'H) -furo [2,3-b] pyridine ]
The title compound was prepared by the procedure used in Example 1 from 50 mg (0.22 mmol) of 5 '-aminoespiro [1-azabicyclo [2.2.2] octan-3, 2' - (3 'H) - furo [2, 3-b] pyridine] and 4-methoxybenzaldehyde, affording 18 mg of the title compound: electroatomized MS 352 ([MH +], 100).
Example 9 R- (-) - 5 '-N- (4-Chlorophenylmethyl) aminospiro [1-azabicyclo [2.2.2] octan-3,2' - (3'H) -furo [2,3-b] pyridine ]
The title compound was prepared by the procedure used in Example 1 from 50 mg
(0.22 mmol) of 5 '-aminoespiro [1-azabicyclo [2.2.2] octan-3, 2' - (3 'H) -furo [2, 3-b] pyridine] and 4-chlorobenzaldehyde, to give 62 mg of the title compound: electroatomizado
MS 356 [MH] +, 37C1 358.
Example 10 R- (-) - 5 '- N - (4-Methylphenylmethyl) aminospiro [1-azabicyclo [2.2.2] octan-3,2' - (3'H) -furo [2,3-b] pyridine The title compound was prepared by the procedure used in Example 1 from 50 mg (0.22 mmol) of 5 '-aminoespiro [1-azabicyclo [2.2.2] octan-3, 2' - (3?) - furo [2, 3-b] pyridine] and 4-tolualdehyde, giving 6 mg of the title compound: electroatomized MS 336 ([MH] +, 100).
Example 11 R- (-) - 5 '- N - (3,4-Dichlorophenylmethyl) aminospiro [1-azabicyclo [2.2.2] octan-3,2' - (3'H) -furo [2,3-b] ] pyridine]
The title compound was prepared by the procedure used in Example 1 from 50 mg (0.22 mmol) of 5 '-aminoespiro [1-azabicyclo [2.2.2] octan-3, 2' - (3?) -furo [2, 3-b] pyridine] and 3,4-dichlorobenzaldehyde, to give 19 mg of the title compound: electroatomized MS 390 [MH] +, 37Cl? 392, 37C12 394.
Example 12 R- (-) - 5 '- N - (2-Imidazolylmethyl) aminospiro [1-azabicyclo [2.2.2] octane-3,2' - (3'H) -furo [2,3-b] pyridine] The title compound was prepared by the procedure used in Example 1 from 50 mg (0.22 mmol) of 5 '-aminoespiro [1-azabicyclo [2.2.2] octan-3, 2' - (3?) -furo [2, 3-b] pyridine] and 2-imidazolylcarboxaldehyde, giving 57 mg of the title compound: electroatomized MS 312 ([MH] +, 100).
Example 13 R- (-) - 5 '- N-Acetyl-N- (phenylmethyl) aminospiro [1-azabicyclo [2.2.2] octan-3,2' - (3'H) -furo [2,3-b] ] pyridine]
Acetic anhydride (25 μl, 0.26 mmol) was added to a solution of R- (-) - 5 '-N- (phenylmethyl) aminospiro [1-azabicyclo [2.2.2] octan-3,2' - (3'H ) -furo [2,3-b] pyridine]
(50 mg, 0.22 mmol) in 1 ml of anhydrous pyridine under nitrogen. The reaction was heated to 95 ° C with an oil bath, then cooled to room temperature and poured into saturated sodium carbonate. The product was extracted with four portions of chloroform. The organic layers were combined, dried with magnesium sulfate and fractionated in vacuo. The crude product was passed through a Supelco Visiprep using chloroform and then a gradient of methanol in ammonia / chloroform at 5-15%. The solvents were removed in vacuo, and the purified product was dissolved in methanol and acidified with 0.9 ml of 1.0 M hydrogen chloride in ether, to give 59 mg (61%) of the title compound as a white semi-solid : Electroatomized MS 364 ([MH] +, 100).
Example 14 R- (-) - 5 '- N-Methyl-N- (phenylmethyl) aminospiro [1-azabicyclo [2.2.2] octan-3,2' - (3'H) -furo [2,3-b ] pyridine]
Under a nitrogen atmosphere, sodium cyanoborohydride (39 mg, 0.62 mmol) was added to a solution of 50 mg, (0.22 mmol) of R - (-) - 5'-N- (phenylmethyl) aminospiro [1-azabicyclo [ 2.2.2] octan-3, 2 '- (3?) -furo [2, 3-b] pyridine] and 165 μl (2.2 mmol) of 37% aqueous formaldehyde in 1 ml of deionized water adjusted to pH 3 using Concentrated hydrochloric acid. The reaction was stirred at room temperature, adding acid to adjust the pH as long as it rises above 6. After one hour, the reaction was poured into saturated sodium carbonate and this was extracted with four portions of chloroform. The organic layers were combined, dried with magnesium sulfate and fractionated in va cuo. The residue was passed through a Supelco Visiprep using a gradient of methanol in ammonia / chloroform. The solvents were removed in vacuo and the residue was placed in methanol and acidified with 0.9 ml of 1.0 M hydrogen chloride in ether. Removal of the solvent went to give 64 mg (98%) of the HCl salt of the title compound as a light yellow semi-solid: electroatomized: MS 336 ([MH] +, 100).
Example 15 R- (-) - 5 '- N - (3-Pyridylamino) spiro [1-azabicyclo [2.2.2] octane-3,2' (3'H) -furo [2,3-b] pyridine]
In a pressure sealed tube under nitrogen, R- (-) -5'-bromo spiro [1-azabicyclo [2.2.2] octane-3,2 '(3'H) -furo was heated and stirred at 100 ° C. 2,3-b] pyridine] (105.1 mg, 0.36 mmol), 3-aminopyridine (69 mg, 0.73 mmol), tris (dibenzyl-idinacetone) dipaium (0) (21 mg, 0.023 mmol), 2-2 '-bis ( diphenylphosphino) 1, 1'-racemic (34 mg, 0.055 mmol), sodium t-butoxide (0.105 g, 1.09 mmol) and 1,2-dimethoxyethane (5 mL). After 3 days, the solution was allowed to cool and was divided between water and chloroform. The chloroform layer was then dried by the addition of magnesium sulfate and filtered through a solid phase extraction cartridge containing 5 g of silica. The crude product was eluted from the cartridge with a 1: 1 v / v mixture of methanolic ammonia and chloroform; the resulting solution was evaporated. The residue was purified by reverse phase HPLC on a C-18 column using a gradient of 0-50% acetonitrile and 0.1% trifluoroacetic acid as the eluent. The fractions containing the product were evaporated and the product was dissolved in a small volume of methanol (ca. 5 ml), and excess hydrogen chloride (1M solution in ether, approximately 5 ml) was added. The solution was re-evaporated to give the title compound (54 mg, 0.13 mmol) as a salt of hydrochloride: electroatomized MS 309 ([MH] +, 100); [a] 58 nm = -42.0 (c = 0.1, MeOH).
Example 16 R- (-) -6 '-N- (Phenylmethyl) aminospiro [1-azabicyclo [2.2.2] octan-3,2' - (3'H) -furo [2,3-b] pyridine]
(R) - (-) - spiro [l-azabicyclo [2.2.2] octane-3,2 '(3'H) -furo [2, 3-b] pyridine-N-oxide] (VII) [970 mg (4.20 mmol)] was dissolved in 10 ml of phosphorus oxychloride, while stirring in an ice bath. The suspension was then heated to reflux and stirred for 5 hours. Once cooled to room temperature, the reaction was poured onto 100 g of ice, diluted with 100 ml of water, made basic with potassium carbonate and extracted with chloroform (3 x 50 ml). The combined organic extract was dried with anhydrous magnesium sulfate, concentrated in vacuo, and subjected to flash chromatography through neutral silica gel using a 95: 5 mixture of chloroform and ammonia 2. ON in methanol to give 700 mg of R - (-) - 6-chlorospiro [l-azabicyclo [2.2.2] octane-3,2 '(3'H) -furo [2,3-b] pyridine] as an almost white solid. A solution of 85 mg (0.34 mmol) of the chloride in 3.0 ml of benzylamine was heated to reflux, under a nitrogen atmosphere, for 23 hours. Once cooled to room temperature, the solution was subjected to flash chromatography through neutral silica gel using a 9: 1 mixture of chloroform and 2N ammonia in methanol, providing 22 mg (20%) of the title compound, electroatomized MS 322 ([MH] +, 100).
Example 17 R- (-) - 5 '- N - (3-Thienylmethyl) aminospiro [1-azabicyclo [2.2.2] octan-3,2' - (3'H) -furo [2,3-b]? iridina]
The title compound was prepared by the procedure used in Example 1 from 50 mg
(0.22 mmol) of R (-) - 5 '-aminoespiro [1-azabicyclo [2.2.2] octan-3, 2! - (3'H) -furo [2, 3-b] pyridine] and 3-thiophenecarboxaldehyde , giving 61 mg (85%) of the title compound: electroatomized MS 328 ([MH] +, 100)
Example 18 R- (-) -5 '-N- (2-Phenylethyl) aminospiro [1-azabicyclo [2.2.2] octan-3,2' - (3'H) -furo [2,3-b] pyridine ]
The title compound was prepared by the procedure used in Example 1 from 50 mg (0.22 mmol) of R (-) - 5 '-aminoespiro [1-azabicyclo [2.2.2] octan-3, 2' - ( 3'H) -furo [2, 3-b] pyridine] and phenylacetaldehyde, giving 31 mg of the title compound: electroatomized MS 336 ([MH +], 100).
Example 19 R- (-) -5 '-N- (3-Phenylpropyl) aminospiro [1-azabicyclo [2.2.2] octan-3,2' - (3'H) -furo [2,3-b] pyridine ]
The title compound was prepared by the procedure used in Example 1 from 50 mg (0.22 mmol) of R (-) - 5 '-aminoespiro [1-azabicyclo [2.2.2] octan-3, 2' - ( 3?) -furo [2, 3-b] pyridine] and 3-phenylpropionaldehyde, giving 42 mg of the title compound: electroatomized MS 350 ([MH] +, 100).
EXAMPLE 20 R- (-) - 5 '- N - (Quinolin-3-ylmethyl) aminospiro [1-azabicyclo [2.2.2] octan-3,2' - (3'H) -furo [2,3-b] ] pyridine] The title compound was prepared by the procedure used in Example 1 from 50 mg (0.22 mmol) of R (-) - 5 '-aminoespiro [1-azabicyclo [2.2.2] octan-3, 2 '- (3'H) -furo [2,3-b] pyridine] and 3-quinolinecarboxaldehyde, giving 47 mg of the title compound: electroatomized MS 373 ([MH] +, 100).
Example 21 R- (-) - 5 '- N - (Quinolin-4-ylmethyl) aminospiro [1-azabicyclo [2.2.2] octan-3,2' - (3'H) -furo [2,3-b] ] pyridine]
The title compound was prepared by the procedure used in Example 1 from 50 mg (0.22 mmol) of R (-) - 5 '-aminoespiro [1-azabicyclo [2.2.2] octan-3, 2' - ( 3 * H) -furo [2, 3-b] pyridine] and 4-quinolinecarboxaldehyde, giving 3 mg of the title compound: electroatomized MS 373 ([MH] +, 100).
Example 22 R- (-) - 5 '- N - (1,4-Benzodioxan-6-ylmethyl) aminospiro [1-azabicyclo [2.2.2] octane-3,2' - (3'H) -furo [2 , 3-b] pyridine] The title compound was prepared by the procedure used in Example 1 from 50 mg (0.22 mmol) of R (-) - 5 '-aminoespiro [1-azabicyclo [2.2.2] octan -3,2 '- (3'H) -furo [2,3-b] pyridine] and 1,4-benzodioxan-6-ylcarboxaldehyde, giving 31 mg of the title compound: electroatomized MS 380 ([MH] +, 100).
EXAMPLE 23 R- (-) - 5 '- N - (Imidazol-4-ylmethyl) aminospiro [1-azabicyclo [2.2.2] octan-3,2' - (3'H) -furo [2,3-b] ] pyridine]
The title compound was prepared by the procedure used in Example 1 from 50 mg (0.22 mmol) of R (-) - 5 '-aminoespiro [1-azabicyclo [2.2.2] octan-3, 2' - ( 3 'H) -furo [2, 3-b] pyridine] and 4 (5) -imidazolecarboxaldehyde, yielding 1 mg of the title compound: electroatomized MS 312 ([MH +], 100).
Example 24 R- (-) - 5'-N- (trans-3-pyridinylprop-2-enyl) aminospiro [1-azabicyclo [2.2.2] octane-3,2 '- (3'H) -furo [2 , 3-b] pyridine]
The title compound was prepared by the procedure used in Example 1 from 50 mg (0.22 mmol) of R (-) - 5 '-aminoespiro [1-azabicyclo [2.2.2] octan-3, 2' - ( 3 'H) -furo [2, 3-b] pyridine] and cinnamaldehyde, giving 43 mg of the title compound: electroatomized MS 348 ([MH] +, 100).
Example 25 R- (-) - 5'-N- (Thiazol-2-ylmethyl) aminospiro [1-azabicyclo [2.2.2] octan-3,2 '- (3'H) -furo [2,3-b] ] pyridine]
The title compound was prepared by the procedure used in Example 1 from 50 mg
(0.22 mmol) of R (-) - 5 '-aminoespiro [1-azabicyclo [2.2.2] octan-3, 2' - (3'H) -furo [2, 3-b] pyridine] and
2-t iazolcarboxaldehyde, giving 13 mg of the title compound: electroatomized MS 329 ([MH] +, 100).
Example 26 R- (-) -5 '-N- (3-Methylphenylmethyl) aminospiro [1-azabicyclo [2.2.2] octan-3,2' - (3'H) -furo [2,3-b] pyridine ]
Titanium tetrachloride (0.5 ml of a l.OM solution in dichloromethane) was added to a solution of 50 mg (0.22 mmol) of R (-) - 5 '-aminoespiro [1-azabicyclo [2.2.2] octan-3, 2 '- (3'H) -furo [2, 3-b] pyridine], 0.066 ml (0.47 mmol) of triethylamine and 0.026 ml (0.22 mmol) of m-tolualdehyde in 2 ml of chloroform, under a nitrogen atmosphere . After stirring for 16 h, a solution of 0.65 mmol of sodium cyanoborohydride in 0.55 ml of methanol was added; The resulting solution was stirred for 20 min, then poured into 20 ml of aqueous sodium carbonate and extracted with chloroform (4 x 10 ml). The combined organic extract was dried with magnesium sulfate, concentrated in vacuo and subjected to flash chromatography through neutral silica gel using a gradient of methanol in 0-15% ammonia / chloroform, giving 60 mg
(81%) of the title compound: electroatomized MS 336
([MH] +, 100).
Example 27 R- (-) -5 '-N- (2-Chlorophenylmethyl) aminospiro [1-azabicyclo [2.2.2] octan-3,2' - (3'H) -furo [2,3-b] pyridine ]
The title compound was prepared by the procedure used in Example 26 from 50 mg
(0.22 mmol) of R (-) - 5 '-aminoespiro [1-azabicyclo [2.2.2] octan-3, 2' - (3?) -furo [2, 3-b] pyridine] and
2-chlorobenzaldehyde, giving 63 mg of the title compound: electroatomized MS 356 ([MH] +, 100).
Example 28 R- (-) -5 '-N- (3-Chlorophenylmethyl) aminospiro [1-azabicyclo [2.2.2] octan-3,2' - (3'H) -furo [2,3-b] pyridine The title compound was prepared by the procedure used in Example 26 from 50 mg (0.22 mmol) of R (-) - 5 '-aminoespiro [1-azabicyclo [2.2.2] octane-3, 2'- (3?) -furo [2, 3-b] pyridine] and 2-chlorobenzaldehyde, giving 50 mg of the title compound: electroatomized MS 356 ([MH] +, 100).
Example 29 R- (-) -5 '-N- (3-Phenylpropynyl) aminospiro [1-azabicyclo [2.2.2] octan-3,2' - (3'H) -furo [2,3-b] pyridine ]
The title compound was prepared by the procedure used in Example 26 from 400 mg (1.76 mmol) of R (-) - 5 '-aminoespiro [1-azabicyclo [2.2.2] octane-3,2' - ( 3'H) -furo [2, 3-b] pyridine] and 3-phenylpropargyl aldehyde, giving 212 mg of the title compound: electroatomized MS 346 ([MH] +, 100).
EXAMPLE 30 R- (-) - 5 '- N - (3-Hydroxyphenylmethyl) aminospiro [1-azabicyclo [2.2.2] octan-3,2' - (3'H) -furo [2,3-b] pyridine The title compound was prepared by the procedure used in Example 26 from 250 mg
(1.10 mmol) of R (-) - 5 '-aminoespiro [1-azabicyclo [2.2.2] octan-3, 2 • - (3' H) -furo [2, 3-b] pyridine] and 3-hydroxybenzaldehyde , giving 117 mg of the title compound: electroatomized MS 338 ([MH] +, 100).
Example 31 R- (-) - 5 '- N - (4-Hydroxyphenylmethyl) aminospiro [1-azabicyclo [2.2.2] octan-3,2' - (3'H) -furo [2,3-b] pyridine ]
The title compound was prepared by the procedure used in Example 26 from 250 mg (1.10 mmol) of R (-) - 5 '-aminoespiro [1-azabicyclo [2.2.2] octan-3, 2' - ( 3'H) -furo [2, 3-b] pyridine] and 4-hydroxybenzaldehyde, giving 31 mg of the title compound: electroatomized MS 338 ([MH] +, 100).
Example 32 R- (-) - 5 '-N- [t ra n s- 3- (4-pyridinyl) prop-2-enyl] aminospiro [1-azabicyclo [2.2.2] octan-3, 2' - ( 3 'H) -furo [2, 3-b] pyridine]
He prepared himself. Title compound by the procedure used in Example 26 from 250 mg (1.10 mmol) of R (-) - 5 '-aminoespiro [1-azabicyclo [2.2.2] octane-3,2' - (3'H ) -furo [2, 3-b] pyridine] and trans-3-pyridylpropenal, giving 77 mg of the title compound: electroatomized MS 349 ([MH] +, 100).
EXAMPLE 33 R- (-) - 5 '- N-Acetyl-N- (3-thienylmethyl) aminospiro [1-azabicyclo [2.2.2] octane-3,2' - (3'H) -furo [2,3 -b] pyridine]
The title compound was prepared by the procedure used in Example 13 from 100 mg of R (-) - 5'-N- (3-thienylmethyl) aminospiro [l-azabicyclo [2.2.2] octane-3, 2 '- (3?) -furo [2, 3-b] pyridine] and acetic anhydride, giving 25 mg of the title compound: electroatomized MS 370 ([MH] +, 100).
Example 34 R- (-) - 5 '- N-Methyl-N- (-pyridylmethyl) aminospiro [1-azabicyclo [2.2.2] octan-3,2' - (3'H) -furo [2,3- b] pyridine]
The title compound was prepared by the procedure used in Example 14 from 100 mg of R (-) - 5 '-N- (4-pyridylmethyl) aminospiro [1-azabicyclo [2.2.2] octan-3, 2 '- (3'H) -furo [2, 3-b] pyridine] and 37% aqueous formaldehyde, giving 26 mg of the title compound: electroatomized MS 337 ([MH] +, 100).
Example 35 R- (-) - 5 '- N-Methyl-N- (3-pyridylmethyl) aminospiro [1-azabicyclo [2.2.2] octan-3,2' - (3'H) -furo [2,3 -b] pyridine;
The title compound was prepared by the procedure used in Example 14 from 200 mg of R (-) - 5 '- N - (3-pyridylmethyl) aminospiro [1-azabicyclo [2.2.2] octane-3, 2 '- (3' H) -furo [2, 3-b] pyridine] and 37% aqueous formaldehyde, giving 190 mg of the title compound: electroatomized MS 337 ([MH] +, 100).
Example 36 R- (-) -5 '-N- (2-Hydroxyethyl) -N- (3-thienylmethyl) aminospiro [1-azabicyclo [2.2.2] octan-3, 2' (3?) -furo [2 , 3-b] pyridine]
The title compound was prepared by the procedure used in Example 14 from 100 mg of R (-) - 5 '-N- (3-thienylmethyl) aminospiro [1-azabicyclo [2.2.2] octan-3, 2 '- (3' H) -furo [2, 3-b] pyridine] and glyoxal, giving 54 mg of the title compound: electroatomized MS 372 ([MH] +, 100).
It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.
Claims (43)
1. A compound of formula I, characterized because NRRi is linked in position 5 or 6 of the furopyridine ring; R is hydrogen, C 1 -C 4 alkyl, COR 2; Ri is (CH2) nAr, CH2CH = CHAr or CH2C = CAr; n is 0 to 3; A is N or NO; Ar is a 5 or 6 membered aromatic or heteroaromatic ring containing zero to four nitrogen atoms, zero to one oxygen atom and zero to one sulfur atom; or an 8, 9 or 10 membered aromatic or heteroaromatic ring system containing zero to four nitrogen atoms, zero to one oxygen atom and zero to one sulfur atom; any of which could optionally be substituted with one to two substituents independently selected from: halogen, trifluoromethyl or C? -C alkyl. R 2 is hydrogen, C 1 -C 4 alkyl; C4-C4 alkoxy; or phenyl ring optionally substituted with one to three of the following substituents: halogen, Ci- C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl, OH; OC1-C4 alkyl; CO2R5, -CN, -N02. -NR3R4 or -CF3; R3, R4 and R5 are independently hydrogen; C? -C4 alkyl; or phenyl ring optionally substituted with one to three of the following substituents: halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl; C2-C4 alkynyl, OH, OC1-C4 alkyl, -CN; -N02 or -CF3; or an enantiomer thereof, and pharmaceutically acceptable salts thereof.
2. A compound according to claim 1, characterized in that A is N; or an enantiomer thereof, and pharmaceutically acceptable salts thereof.
3. A compound according to claim 1 or 2, characterized in that Ri is (CH2) nAr or an enantiomer thereof, and pharmaceutically acceptable salts thereof.
4. A compound according to claim 1 or 2, characterized in that Ri is CH2CH = CHAr; or an enantiomer thereof, and pharmaceutically acceptable salts thereof.
5. A compound according to claim 1 or 2, characterized in that Ri is CH2C = CAr; or an enantiomer thereof, and pharmaceutically acceptable salts thereof.
6. A compound according to any of claims 1 to 5, characterized in that Ar is selected from the group: phenyl ring optionally substituted with one to three of the following substituents: halogen, C1-C alkyl; C2-C4 alkenyl; C2-C alkynyl, OH; alkyl OC? ~ C4; CO2R5, -CN, -N02, -NR3R4 and -CF3; 2-, 3- or 4-pyridyl; 2- or 3-furanyl; 2- or 3-thienyl; 2- or 4-imidazolyl; 1, 2- or 3-pyrrolyl; 2- or 4-oxazolyl and 3- o-isoxazolyl; or an enantiomer thereof, and pharmaceutically acceptable salts thereof.
7. A compound according to any of claims 1 to 5, characterized in that Ar is selected from the group: - 1- or 2-naphthyl; 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl; 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl; 2-, 4-, 5-, 6- or 7-benzoxazolyl; and 3-, 4-, 5-, 6- or 7-benzisoxazolyl; or an enantiomer thereof, and pharmaceutically acceptable salts thereof.
8. A compound according to any of claims 1 to 6, characterized in that R3, R4 and R5 are independently hydrogen or C? -C4 alkyl; or an enantiomer thereof, and pharmaceutically acceptable salts thereof.
9. A compound according to any of claims 1 to 8, characterized in that n is 1.
10. A compound according to any of claims 1 to 8, characterized in that R is hydrogen.
11. A compound according to any of claims 1 to 8, characterized in that Ar is a heteroaromatic ring.
12. A compound according to any of claims 1 to 8, characterized in that n is 1; R is hydrogen and Ar is a heteroaromatic ring.
13. A compound according to claim 1, characterized in that the compound is: R- (-) - 5 '-N- (Phenylmethyl) aminospiro [1-azabicyclo [2.2.2] octan-3,2' - (3'H) -furo [2,3-b] pyridine]; R- (-) - 5 '- (2-Pyridylmethyl) aminospiro [1-azabicyclo [2.2.2] octane-3,2' - (3'H) -furo [2,3-b] pyridine]; R- (-) - 5 '- (3-Pyridylmethyl) aminospiro [l-azabicyclo [2.2.2] octane-3,2' - (3'H) -furo [2,3-b] pyridine]; R - (-) - 5 '- (4-p-Pyridylmethyl) aminospiro [1-azabicyclo [2.2.2] octane-3,2' - (3'H) -furo [2, 3-b] pyridine]; R - (-) - 5 '- (2-Furanylmethyl) aminospiro [l-azabicyclo [2.2.2] octan-3,2' - (3?) - furo [2,3-b] pyridine]; R- (-) - 5 '- (3-Furanylmethyl) aminospiro [1-azabicyclo [2.2.2] octan-3, 2' - (3 'H) -furo [2, 3-b] pyridine]; R- (-) - 5 '- (2-Thienylmethyl) aminospiro [1-azabicyclo [2.2.2] octan-3,2' - (3'H) -furo [2,3-b] pyridine]; R- (-) - 5 '- (2-Imidazolylmethyl) aminospiro [1-azabicyclo [2.2.2] octan-3, 2' - (3?) -furo [2, 3-b] pyridine]; R- (-) - 5'-N- (4-Methoxyphenylmethyl) aminospiro [1-azabicyclo [2.2.2] octan-3, 2'- (3?) - furo [2, 3-b] pyridine]; R- (-) - 5 '- N- (4-Chlorophenylmethyl) aminospiro [1-azabicyclo [2.2.2] octane-3,2, - (3'H) -furo [2,3-b] pyridine]; R- (-) - 5 '- N- (4-Methylphenylmethyl) aminospiro [1-azabicyclo [2.2.2] octan-3,2 * - (3'H) -furo [2,3-b] pyridine]; R- (-) - 5 '- N - (3,4-Dichlorophenylmethyl) aminospiro [1-azabicyclo [2.2.2] octan-3,2' - (3?) - furo [2,3-b] pyridine]; R- (-) - 5 '- N-Acetyl-N- (phenylmethyl) aminospiro [1-azabicyclo [2.2.2] octan-3,2' - (3'H) -furo [2,3-b] pyridine ]; R- (-) -5 * -N-Methyl-N- (phenylmethyl) aminospiro [1-azabicyclo [2.2.2] octan-3, 2 '- (3' H) -furo [2, 3-b] pyridine ]; R - (-) - 5'-N- (3-Pyridyl) aminospiro [1-azabicyclo [2.2.2] octane-3,2 '(3'H) -furo [2,3-b] pyridine]; R- (-) -6 '-N- (Phenylmethyl) aminospiro [1-azabicyclo [2.2.2] octane-3,2' (3 'H) -furo [2,3-b] pyridine]; R- (-) - 5 '- N- (3-thienylmethyl) aminospiro [1-azabicyclo [2.2.2] octan-3, 2' - (3?) -furo [2, 3-b] pyridine]; R - (-) - 5'-N- (2-Phenylethyl) aminospiro [1-azabicyclo [2.2.2] octane-3,2 '- (3'H) -furo [2,3-b] pyridine]; R- (-) - 5 '- N - (3-Phenylpropyl) aminospiro [1-azabicyclo [2.2.2] octan-3, 2' - (3 • H) -furo [2, 3-b] pyridine]; R- (-) - 5 '- N- (Quinolin-3-ylmethyl) aminospiro [1-azabicyclo [2.2.2] octan-3,2' - (3'H) -furo [2,3-b] pyridine ]; R- (-) - 5 '- N - (Quinolin-4-ylmethyl) aminospiro [1-azabicyclo [2.2.2] octan-3,2' - (3'H) -furo [2,3-b] pyridine ]; R- (-) - 5 '-N- (1,4-Benzodioxan-6-ylmethyl) aminospiro [1-azabicyclo [2.2.2] octan-3,2' - (3'H) -furo [2,3 -b] pyridine]; R- (-) -5 '-N- (Imidazol-4-ylmethyl) aminospiro [1-azabicyclo [2.2.2] octan-3, 2' - (3 • H) -furo [2, 3-b] pyridine ]; R- (-) - 5 '-N- (trans-3-Phenylprop-2-enyl) aminospiro [1-azabicyclo [2.2.2] octan-3, 2' - (3 * H) -furo [2, 3 -b] pyridine]; R- (-) - 5 '- N - (Thiazol-2-ylmethyl) aminospiro [1-azabicyclo [2.2.2] octan-3, 2' - (3 'H) -furo [2,3-b] pyridine ]; R- (-) - 5 '- N - (3-Methylphenylmethyl) aminospiro [1-azabicyclo [2.2.2] octane-3,2' - (3'H) -furo [2,3-b] pyridine]; R- (-) - 5 '- N- (2-Chlorophenylmethyl) aminospiro [1-azabicyclo [2.2.2] octan-3, 2' - (3 'H) -furo [2,3-b] pyridine]; R- (-) - 5 '- N- (3-Chlorophenylmethyl) aminospiro [1-azabicyclo [2.2.2] octane-3,2' - (3'H) -furo [2,3-b] pyridine]; R- (-) - 5 '- N - (3-Phenylpropynyl) aminospiro [1-azabicyclo [2.2.2] octan-3, 2' - (3 'H) -furo [2,3-b] pyridine]; R- (-) - 5 '- N- (3-Hydroxyphenylmethyl) aminospiro [1-azabicyclo [2.2.2] octan-3,2' - (3'H) -furo [2,3-b] pyridi a]; R- (-) - 5 '- N - (4-Hydroxyphenylmethyl) aminospiro [1-azabicyclo [2.2.2] octane-3,2' - (3'H) -furo [2,3-b] pyridine]; R - (-) - 5'-N- [tra.s-3- (4-pyridinyl) prop-2-enyl] aminospiro [l-azabicyclo [2.2.2] octan-3,2 '- (3'H ) -furo [2,3-b] pyridine]; R- (-) -51-N-Acetyl-N- (3-thienylmethyl) aminospiro [l-azabicyclo [2.2.2] octan-3, 2 '- (3' H) -furo [2, 3-b] pyridine]; R- (-) - 5 '- N-Methyl-N- (4-pyridylmethyl) aminospiro [1-azabicyclo [2.2.2] octan-3,2' - (3'H) -furo [2,3-b] ] pyridine]; R- (-) - 5 '- N-Methyl-N- (3-pyridyl ethyl) aminospiro [1-azabicyclo [2.2.2] octan-3,2' - (3?) - furo [2,3-b] ] pyridine]; R- (-) -5 '-N- (2-Hydroxyethyl) -N- (3-thienylmethyl) aminospiro [1-azabicyclo [2.2.2] octan-3, 2' - (3 'H) -furo [2 , 3-b] pyridine]; or an enantiomer thereof, and pharmaceutically acceptable salts thereof.
14. A compound according to claim 1, characterized in that the compound is R- (-) - 5 '- (3-Pyridylmethyl) aminospiro [1-azabicyclo [2.2.2] octan-3, 2' - (3 'H) -furo [2,3-b] pyridine]; R- (-) - 5 '- (4-Pyridylmethyl) aminospiro [1-azabicyclo [2.2.2] octan-3,2' - (3'H) -furo [2,3-b] pyridine]; or an enantiomer thereof, and pharmaceutically acceptable salts thereof.
15. A compound according to any of claims 1 to 14, characterized in that it is used in therapy.
16. A pharmaceutical composition, characterized in that it includes a compound as defined in claims 1 to 14, in admixture with a pharmaceutically acceptable inert diluent or carrier.
17. The pharmaceutical composition according to claim 16, characterized in that it is used in the treatment or prophylaxis of psychotic conditions or sufferings of intellectual damage.
18. The pharmaceutical composition according to claim 16, characterized in that it is used in the treatment or prophylaxis of diseases in the human or conditions in which the activation of the nicotinic receptor 7 is beneficial.
19. The pharmaceutical composition according to claim 16, characterized in that it is used in the treatment or prophylaxis of Alzheimer's disease, learning deficit, cognition deficit, attention deficit, memory loss, attention deficit hyperactivity disorder, dementia of the Lewy body, anxiety, schizophrenia, mania or manic depression, Parkinson's disease, Huntington's disease, Tourette's syndrome and neurodegenerative diseases in which there is loss of cholinergic synapsis, temporary fatigue, cessation of smoking, nicotine addiction including results from exposure to products that contain nicotine, pain or ulcerative colitis.
The pharmaceutical composition according to claim 19, characterized in that it is used in the treatment or prophylaxis of Alzheimer's disease, learning deficit, cognition deficit, attention deficit, Lewy body dementia, memory loss or suffering from hyperactivity of attention deficit.
21. The pharmaceutical composition according to claim 19, characterized in that it is used in the treatment or prophylaxis of anxiety, schizophrenia, mania or manic depression.
22. The pharmaceutical composition according to claim 19, characterized in that it is used in the treatment or prophylaxis of Parkinson's disease, Huntington's disease, Tourette's syndrome or neurodegenerative diseases in which there is loss of cholinergic synapses.
23. The pharmaceutical composition according to claim 19, characterized in that it is used in the treatment or prophylaxis of temporary fatigue, nicotine addiction including that resulting from exposure to products containing nicotine, pain or ulcerative colitis.
24. The pharmaceutical composition according to claim 19, characterized in that it is used in the treatment or prophylaxis of Alzheimer's disease.
25. The use of a compound as defined in any of claims 1 to 14, in the manufacture of a medicament for the treatment or prophylaxis of psychotic conditions or conditions of intellectual damage.
26. The use of a compound as defined in any of claims 1 to 14, in the manufacture of a medicament for the treatment or prophylaxis of diseases in the human or conditions in which the activation of the nicotinic receptor a7 is beneficial.
27. The use according to claim 25 or claim 26, characterized in that the condition or condition is Alzheimer's disease, learning deficit, cognition deficit, attention deficit, memory loss, hyperactivity disorder of attention deficit, dementia of the body of Lewy, anxiety, schizophrenia, mania or manic depression, Parkinson's disease, Huntington's disease, Tourette's syndrome and neurodegenerative diseases in which there is loss of cholinergic synapsis, temporary fatigue, cessation of smoking, nicotine addiction including that resulting from exposure to products containing nicotine, pain or ulcerative colitis.
28. The use according to claim 27, characterized in that the condition or condition is Alzheimer's disease, learning deficit, cognition deficit, attention deficit, Lewy body dementia, memory loss or deficit hyperactivity disorder. Attention.
29. The use according to claim 27, characterized in that the condition or condition is anxiety, schizophrenia, mania or manic depression.
30. The use according to claim 27, characterized in that the condition or condition is Parkinson's disease, Huntington's disease, Tourette's syndrome or neurodegenerative diseases in which there is loss of cholinergic synapses.
31. The use according to claim 27, characterized in that the condition or condition is temporary fatigue, addiction to nicotine including that resulting from exposure to nicotine-containing products, pain or ulcerative colitis.
32. The use according to claim 27, characterized in that the condition or condition is Alzheimer's disease.
A method for the treatment or prophylaxis of psychotic conditions or conditions of intellectual damage, characterized in that it comprises administering a therapeutically effective amount of a compound as defined according to any of claims 1 to 14.
34. A method for the treatment or prophylaxis of diseases in the human or conditions in which activation of the nicotinic receptor 7 is beneficial, characterized in that it comprises administering a therapeutically effective amount of a compound as defined according to any of claims 1 to 14.
35. The method according to claim 33 or claim 34, characterized in that the condition or condition is Alzheimer's disease, learning deficit, cognition deficit, attention deficit, memory loss, attention deficit hyperactivity disorder, dementia of the Lewy body, anxiety, schizophrenia, mania or manic depression, Parkinson's disease, Huntington's disease, Tourette's syndrome, neurodegenerative diseases in which there is cholinergic synapse loss, temporary fatigue, cessation of smoking, nicotine addiction including results from exposure to products that contain nicotine, pain or ulcerative colitis.
36. The method according to claim 33 or claim 34, characterized in that the condition or condition is Alzheimer's disease, learning deficit, cognition deficit, attention deficit, Lewy body dementia, memory loss or suffering from hyperactivity of attention deficit.
37. The method according to claim 33 or claim 34, characterized in that the condition or condition is anxiety, schizophrenia, mania or manic depression.
38. The method according to claim 33 or claim 34, characterized in that the condition or condition is Parkinson's disease, Huntington's disease, Tourette's syndrome or neurodegenerative diseases in which there is loss of cholinergic synapses.
39. The method according to claim 33 or claim 34, characterized in that the condition or condition is temporary fatigue, addiction to nicotine including that resulting from exposure to nicotine-containing products, pain or ulcerative colitis.
40. The method according to claim 33 or claim 34, characterized in that the condition or condition is Alzheimer's disease.
41. A process for preparing a compound of formula I, as defined according to any of claims 1 to 14, or an enantiomer thereof, and pharmaceutically acceptable salts thereof, characterized in that it comprises: a) preparing compounds wherein NRRi is placed in the 5 'position, alkylation or acylation compounds of the formula VI, wherein E is halogen, N02 or NHR in an appropriate solvent: or b) preparing compounds wherein NRRX is placed in the 5 'position, reacting the compounds of the formula VI, wherein E is halogen, N02 or NHR, with an amine in the presence of an appropriate organometallic catalyst, base or solvent: VI VIII (I) or c) preparing compounds wherein NRRi is placed in the 6"position, reacting the compounds of formula VII, with a halogenation reagent, followed by reaction with an amine in an inert solvent: or d) preparing compounds wherein NRRi is placed in the 6 'position, oxidizing the compounds of the formula VIII or IX with a peroxide reactant in an appropriate solvent, followed by partial reduction.
42. A compound of the formula Vile
43. A compound of the formula SAW characterized in that E is N02, NHR or halogen NEW ARCHAIL AMPHAS OF ESPIROFUROPIRIDINAS USEFUL IN THERAPY SUMMARY OF THE INVENTION The present invention describes a compound of the formula (I), wherein NRRi is linked at the 5 or 6 position of the furopyridine ring; R is hydrogen, C 1 -C 4 alkyl or COR 2; Ri is (CH2) nAr, CH2CH = CHAr or CH2C = CAr; n is 0 to 3; A is N or NO; Ar is a 5 or 6 membered aromatic or heteroaromatic ring containing zero to four nitrogen atoms, zero to one oxygen atom and zero to one sulfur atom; or an 8, 9 or 10 membered aromatic or heteroaromatic ring system containing zero to four nitrogen atoms, zero to one oxygen atom and zero to one sulfur atom; any of which could be optionally substituted with one to two substituents independently selected from: halogen, trifluoromethyl or C? -C4 alkyl; R 2 is hydrogen, C 1 -C 4 alkyl; C4-C4 alkoxy; or phenyl ring optionally substituted with one to three of the following substituents: halogen, C 1 -C 4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl, OH; alkyl 0C? ~ C4; CO2R5, -CN, -N02, -NR3R4 or -CF3; R3, R4 and Rs could be hydrogen; alkyl C? ~ C4; or phenyl ring optionally substituted with one to three of the following substituents: halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl; C2-C4 alkynyl, OH, OC1-C4 alkyl, -CN; -N02 or -CF3; or the enantiomers thereof, and pharmaceutically acceptable salts thereof, processes for preparing them, compositions containing them, and their use in therapy, especially in the treatment or prophylaxis of psychotic conditions and sufferings of intellectual damage.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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SE9900100-0 | 1999-01-15 |
Publications (1)
Publication Number | Publication Date |
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MXPA01007162A true MXPA01007162A (en) | 2002-03-05 |
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