CA2469278A1 - Isochroman compounds for treatment of cns disorders - Google Patents
Isochroman compounds for treatment of cns disorders Download PDFInfo
- Publication number
- CA2469278A1 CA2469278A1 CA002469278A CA2469278A CA2469278A1 CA 2469278 A1 CA2469278 A1 CA 2469278A1 CA 002469278 A CA002469278 A CA 002469278A CA 2469278 A CA2469278 A CA 2469278A CA 2469278 A1 CA2469278 A1 CA 2469278A1
- Authority
- CA
- Canada
- Prior art keywords
- dihydro
- benzopyran
- compound according
- hydrogen
- ethyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- HEBMCVBCEDMUOF-UHFFFAOYSA-N isochromane Chemical class C1=CC=C2COCCC2=C1 HEBMCVBCEDMUOF-UHFFFAOYSA-N 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 213
- 239000003814 drug Substances 0.000 claims abstract description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 101
- 239000001257 hydrogen Substances 0.000 claims description 100
- 238000000034 method Methods 0.000 claims description 63
- -1 morpholino, pyrrolidino Chemical group 0.000 claims description 53
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 47
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 47
- 229910052757 nitrogen Inorganic materials 0.000 claims description 40
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 37
- 150000003839 salts Chemical class 0.000 claims description 30
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 14
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 claims description 13
- 210000003169 central nervous system Anatomy 0.000 claims description 10
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 10
- 150000002825 nitriles Chemical group 0.000 claims description 8
- 241000124008 Mammalia Species 0.000 claims description 7
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 6
- 125000004442 acylamino group Chemical group 0.000 claims description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 229940076279 serotonin Drugs 0.000 claims description 5
- HDYHZDJVNOQYNZ-WINIVTDRSA-N (1s)-1-[2-[(2r)-4-(1,2-dihydroacenaphthylen-5-yl)-2-methylpiperazin-1-yl]ethyl]-3,4-dihydro-1h-isochromene-6-carboxamide Chemical compound C1CC2=CC=CC3=C2C1=CC=C3N1C[C@@H](C)N(CC[C@H]2C3=CC=C(C=C3CCO2)C(N)=O)CC1 HDYHZDJVNOQYNZ-WINIVTDRSA-N 0.000 claims description 4
- 230000004064 dysfunction Effects 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 241001465754 Metazoa Species 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000003386 piperidinyl group Chemical group 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 6
- 125000001475 halogen functional group Chemical group 0.000 claims 4
- 229910052717 sulfur Inorganic materials 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 23
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 138
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 108
- 238000006243 chemical reaction Methods 0.000 description 94
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 81
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 78
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 76
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 69
- 239000000243 solution Substances 0.000 description 69
- 239000000203 mixture Substances 0.000 description 66
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 57
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 54
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 53
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 51
- 239000000543 intermediate Substances 0.000 description 49
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 47
- 239000002904 solvent Substances 0.000 description 41
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 38
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 34
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 34
- 239000002585 base Substances 0.000 description 32
- 125000006239 protecting group Chemical group 0.000 description 31
- 239000007787 solid Substances 0.000 description 30
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 29
- 125000000217 alkyl group Chemical group 0.000 description 26
- 239000012043 crude product Substances 0.000 description 26
- 239000000284 extract Substances 0.000 description 26
- 239000003960 organic solvent Substances 0.000 description 26
- 239000011541 reaction mixture Substances 0.000 description 26
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
- 239000000377 silicon dioxide Substances 0.000 description 23
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 22
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 22
- 238000003756 stirring Methods 0.000 description 21
- 238000003786 synthesis reaction Methods 0.000 description 20
- 150000001298 alcohols Chemical class 0.000 description 19
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 18
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 18
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 17
- 238000003818 flash chromatography Methods 0.000 description 17
- 238000010992 reflux Methods 0.000 description 16
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 15
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 15
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 15
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 15
- 239000003054 catalyst Substances 0.000 description 15
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 15
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 14
- 239000002253 acid Substances 0.000 description 14
- 239000012267 brine Substances 0.000 description 14
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 14
- 238000000746 purification Methods 0.000 description 14
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 14
- VHJPENWPAHZKRQ-LBPRGKRZSA-N 2-[(1s)-6-carbamoyl-3,4-dihydro-1h-isochromen-1-yl]ethyl methanesulfonate Chemical compound NC(=O)C1=CC=C2[C@H](CCOS(=O)(=O)C)OCCC2=C1 VHJPENWPAHZKRQ-LBPRGKRZSA-N 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 13
- 239000012044 organic layer Substances 0.000 description 13
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 12
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 12
- 239000003638 chemical reducing agent Substances 0.000 description 12
- 239000010410 layer Substances 0.000 description 11
- 229910000027 potassium carbonate Inorganic materials 0.000 description 11
- 229910052763 palladium Inorganic materials 0.000 description 10
- 230000002829 reductive effect Effects 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 9
- 208000035475 disorder Diseases 0.000 description 9
- 239000012279 sodium borohydride Substances 0.000 description 9
- 229910000033 sodium borohydride Inorganic materials 0.000 description 9
- 239000000725 suspension Substances 0.000 description 9
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 9
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- 150000002148 esters Chemical class 0.000 description 8
- 125000005843 halogen group Chemical group 0.000 description 8
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 8
- 238000006722 reduction reaction Methods 0.000 description 8
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 8
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 7
- BLDKDRFRRQRQKG-NSHDSACASA-N 2-[(1s)-6-bromo-3,4-dihydro-1h-isochromen-1-yl]ethanol Chemical compound BrC1=CC=C2[C@H](CCO)OCCC2=C1 BLDKDRFRRQRQKG-NSHDSACASA-N 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 7
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 7
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 7
- 150000001412 amines Chemical class 0.000 description 7
- 229910021529 ammonia Inorganic materials 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 229910000024 caesium carbonate Inorganic materials 0.000 description 7
- 238000009833 condensation Methods 0.000 description 7
- 230000005494 condensation Effects 0.000 description 7
- 238000010511 deprotection reaction Methods 0.000 description 7
- 125000002346 iodo group Chemical group I* 0.000 description 7
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 7
- 239000012312 sodium hydride Substances 0.000 description 7
- 229910000104 sodium hydride Inorganic materials 0.000 description 7
- FJXLTZLEPWTCNA-LLVKDONJSA-N (3r)-1-(6-fluoronaphthalen-1-yl)-3-methylpiperazine Chemical compound C1CN[C@H](C)CN1C1=CC=CC2=CC(F)=CC=C12 FJXLTZLEPWTCNA-LLVKDONJSA-N 0.000 description 6
- OKVBZMBTWUQVHH-GFCCVEGCSA-N 5-[(3r)-3-methylpiperazin-1-yl]naphthalene-2-carbonitrile Chemical compound C1CN[C@H](C)CN1C1=CC=CC2=CC(C#N)=CC=C12 OKVBZMBTWUQVHH-GFCCVEGCSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 6
- 125000003277 amino group Chemical group 0.000 description 6
- 125000001246 bromo group Chemical group Br* 0.000 description 6
- 239000000872 buffer Substances 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- 125000001153 fluoro group Chemical group F* 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
- ZXNJREJHAWLHTA-NSHDSACASA-N (1s)-1-(2-hydroxyethyl)-3,4-dihydro-1h-isochromene-6-carboxamide Chemical compound OCC[C@@H]1OCCC2=CC(C(=O)N)=CC=C21 ZXNJREJHAWLHTA-NSHDSACASA-N 0.000 description 5
- DIOHEXPTUTVCNX-UHFFFAOYSA-N 1,1,1-trifluoro-n-phenyl-n-(trifluoromethylsulfonyl)methanesulfonamide Chemical compound FC(F)(F)S(=O)(=O)N(S(=O)(=O)C(F)(F)F)C1=CC=CC=C1 DIOHEXPTUTVCNX-UHFFFAOYSA-N 0.000 description 5
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 5
- JTASHBQGWFAFFN-SNVBAGLBSA-N 3-[(3r)-3-methylpiperazin-1-yl]-1-benzothiophene-6-carbonitrile Chemical compound C1CN[C@H](C)CN1C1=CSC2=CC(C#N)=CC=C12 JTASHBQGWFAFFN-SNVBAGLBSA-N 0.000 description 5
- QALKJGMGKYKMKE-UHFFFAOYSA-N 5-bromo-1,2-dihydroacenaphthylene Chemical group C1CC2=CC=CC3=C2C1=CC=C3Br QALKJGMGKYKMKE-UHFFFAOYSA-N 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 5
- PLUBXMRUUVWRLT-UHFFFAOYSA-N Ethyl methanesulfonate Chemical compound CCOS(C)(=O)=O PLUBXMRUUVWRLT-UHFFFAOYSA-N 0.000 description 5
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 5
- 125000006241 alcohol protecting group Chemical group 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 239000002244 precipitate Substances 0.000 description 5
- 238000010561 standard procedure Methods 0.000 description 5
- 125000001424 substituent group Chemical group 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- XLYALKKNTXLCBP-WINIVTDRSA-N (1S)-1-[2-[(2R)-2-methyl-4-(3-thiatricyclo[7.3.1.05,13]trideca-1(13),5,7,9,11-pentaen-8-yl)piperazin-1-yl]ethyl]-3,4-dihydro-1H-isochromene-6-carboxamide Chemical compound C1SCC2=CC=CC3=C2C1=CC=C3N1C[C@@H](C)N(CC[C@H]2C3=CC=C(C=C3CCO2)C(N)=O)CC1 XLYALKKNTXLCBP-WINIVTDRSA-N 0.000 description 4
- LXAMNENMWIGGES-DWXRJYCRSA-N (1s)-1-[2-[(2r)-4-(6-fluoronaphthalen-1-yl)-2-methylpiperazin-1-yl]ethyl]-3,4-dihydro-1h-isochromen-6-amine Chemical compound FC1=CC=C2C(N3C[C@H](N(CC3)CC[C@H]3C4=CC=C(N)C=C4CCO3)C)=CC=CC2=C1 LXAMNENMWIGGES-DWXRJYCRSA-N 0.000 description 4
- CVTMHSYEBIYHBH-GFCCVEGCSA-N (3r)-1-(1,2-dihydroacenaphthylen-5-yl)-3-methylpiperazine Chemical compound C1CN[C@H](C)CN1C1=CC=C2C3=C1C=CC=C3CC2 CVTMHSYEBIYHBH-GFCCVEGCSA-N 0.000 description 4
- FMSOZQMEGAYAOA-GFCCVEGCSA-N (3r)-3-methyl-1-(1h,3h-naphtho[1,8-cd]pyran-6-yl)piperazine Chemical compound C1CN[C@H](C)CN1C1=CC=C2C3=C1C=CC=C3COC2 FMSOZQMEGAYAOA-GFCCVEGCSA-N 0.000 description 4
- ZXTHMIRFPYPAQI-FOEZPWHWSA-N 1-[2-[(2r)-4-(6-fluoronaphthalen-1-yl)-2-methylpiperazin-1-yl]ethyl]-3,4-dihydro-1h-isochromene-6-carbonitrile Chemical compound FC1=CC=C2C(N3C[C@H](N(CC3)CCC3C4=CC=C(C=C4CCO3)C#N)C)=CC=CC2=C1 ZXTHMIRFPYPAQI-FOEZPWHWSA-N 0.000 description 4
- QWENRTYMTSOGBR-UHFFFAOYSA-N 1H-1,2,3-Triazole Chemical compound C=1C=NNN=1 QWENRTYMTSOGBR-UHFFFAOYSA-N 0.000 description 4
- YJAXXBXMTQOVBP-WINIVTDRSA-N 5-[(3r)-4-[2-[(1s)-6-amino-3,4-dihydro-1h-isochromen-1-yl]ethyl]-3-methylpiperazin-1-yl]naphthalene-2-carbonitrile Chemical compound N#CC1=CC=C2C(N3C[C@H](N(CC3)CC[C@H]3C4=CC=C(N)C=C4CCO3)C)=CC=CC2=C1 YJAXXBXMTQOVBP-WINIVTDRSA-N 0.000 description 4
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 4
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 4
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 4
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- 125000003545 alkoxy group Chemical group 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000012298 atmosphere Substances 0.000 description 4
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 4
- 238000004296 chiral HPLC Methods 0.000 description 4
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 150000002373 hemiacetals Chemical class 0.000 description 4
- YAMHXTCMCPHKLN-UHFFFAOYSA-N imidazolidin-2-one Chemical compound O=C1NCCN1 YAMHXTCMCPHKLN-UHFFFAOYSA-N 0.000 description 4
- 239000012280 lithium aluminium hydride Substances 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
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- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/76—Benzo[c]pyrans
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07—ORGANIC CHEMISTRY
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- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
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- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
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- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- Organic Chemistry (AREA)
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- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Psychiatry (AREA)
- Hospice & Palliative Care (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0130339.5 | 2001-12-19 | ||
| GBGB0130339.5A GB0130339D0 (en) | 2001-12-19 | 2001-12-19 | Isochroman compounds |
| PCT/US2002/036148 WO2003053948A1 (en) | 2001-12-19 | 2002-12-06 | Isochroman compounds for treatment of cns disorders |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2469278A1 true CA2469278A1 (en) | 2003-07-03 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002469278A Abandoned CA2469278A1 (en) | 2001-12-19 | 2002-12-06 | Isochroman compounds for treatment of cns disorders |
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|---|---|
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| JP (1) | JP2005516952A (enExample) |
| CN (1) | CN1312148C (enExample) |
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| AT (1) | ATE355283T1 (enExample) |
| AU (1) | AU2002359378B8 (enExample) |
| BR (1) | BR0214859A (enExample) |
| CA (1) | CA2469278A1 (enExample) |
| CY (1) | CY1106552T1 (enExample) |
| DE (1) | DE60218529T2 (enExample) |
| DK (1) | DK1458703T3 (enExample) |
| ES (1) | ES2280606T3 (enExample) |
| GB (1) | GB0130339D0 (enExample) |
| MX (1) | MXPA04006085A (enExample) |
| PE (1) | PE20030728A1 (enExample) |
| PT (1) | PT1458703E (enExample) |
| SI (1) | SI1458703T1 (enExample) |
| SV (1) | SV2004001441A (enExample) |
| TW (1) | TW200301116A (enExample) |
| WO (1) | WO2003053948A1 (enExample) |
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| US7538113B2 (en) | 2005-02-18 | 2009-05-26 | Wyeth | 4-substituted imidazo[4,5-c]pyridine antagonists of gonadotropin releasing hormone receptor |
| US7582634B2 (en) | 2005-02-18 | 2009-09-01 | Wyeth | 7-substituted imidazo[4,5-c]pyridine antagonists of gonadotropin releasing hormone receptor |
| US7534796B2 (en) | 2005-02-18 | 2009-05-19 | Wyeth | Imidazo[4,5-b]pyridine antagonists of gonadotropin releasing hormone receptor |
| US7531542B2 (en) | 2005-05-18 | 2009-05-12 | Wyeth | Benzooxazole and benzothiazole antagonists of gonadotropin releasing hormone receptor |
| US7582636B2 (en) | 2005-05-26 | 2009-09-01 | Wyeth | Piperazinylimidazopyridine and piperazinyltriazolopyridine antagonists of Gonadotropin Releasing Hormone receptor |
| NL2000351C2 (nl) | 2005-12-22 | 2007-09-11 | Pfizer Prod Inc | Estrogeen-modulatoren. |
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| US4247553A (en) * | 1977-10-31 | 1981-01-27 | The Upjohn Company | Methods of treating psychosis |
| DE69419778T2 (de) * | 1993-12-28 | 1999-12-09 | Pharmacia & Upjohn Co., Kalamazoo | Heterozyklische verbindungen für die behandlung von kardiovaskular- und zentralnervensystem störungen |
| MX9710260A (es) * | 1995-06-30 | 1998-03-29 | Upjohn Co | Isocromanos 1, 6-disustituidos para el tratamiento de migrañas. |
| GB2370270A (en) * | 2000-12-20 | 2002-06-26 | Lilly Co Eli | Pharmaceutical compounds |
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2001
- 2001-12-19 GB GBGB0130339.5A patent/GB0130339D0/en not_active Ceased
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2002
- 2002-11-18 TW TW091133608A patent/TW200301116A/zh unknown
- 2002-12-06 CA CA002469278A patent/CA2469278A1/en not_active Abandoned
- 2002-12-06 PT PT02793911T patent/PT1458703E/pt unknown
- 2002-12-06 JP JP2003554664A patent/JP2005516952A/ja not_active Ceased
- 2002-12-06 CN CNB028281209A patent/CN1312148C/zh not_active Expired - Fee Related
- 2002-12-06 BR BR0214859-5A patent/BR0214859A/pt not_active IP Right Cessation
- 2002-12-06 DE DE60218529T patent/DE60218529T2/de not_active Expired - Lifetime
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- 2002-12-06 WO PCT/US2002/036148 patent/WO2003053948A1/en not_active Ceased
- 2002-12-06 AT AT02793911T patent/ATE355283T1/de not_active IP Right Cessation
- 2002-12-06 EP EP02793911A patent/EP1458703B1/en not_active Expired - Lifetime
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- 2002-12-13 PE PE2002001229A patent/PE20030728A1/es not_active Application Discontinuation
- 2002-12-18 AR ARP020104961A patent/AR038662A1/es unknown
- 2002-12-19 SV SV2002001441A patent/SV2004001441A/es not_active Application Discontinuation
-
2007
- 2007-04-26 CY CY20071100573T patent/CY1106552T1/el unknown
Also Published As
| Publication number | Publication date |
|---|---|
| MXPA04006085A (es) | 2004-09-27 |
| SI1458703T1 (sl) | 2007-08-31 |
| GB0130339D0 (en) | 2002-02-06 |
| ES2280606T3 (es) | 2007-09-16 |
| SV2004001441A (es) | 2004-05-07 |
| AU2002359378B2 (en) | 2008-08-21 |
| WO2003053948A1 (en) | 2003-07-03 |
| AU2002359378B8 (en) | 2008-09-11 |
| AU2002359378A1 (en) | 2003-07-09 |
| EP1458703A1 (en) | 2004-09-22 |
| PT1458703E (pt) | 2007-05-31 |
| JP2005516952A (ja) | 2005-06-09 |
| PE20030728A1 (es) | 2003-08-29 |
| TW200301116A (en) | 2003-07-01 |
| CY1106552T1 (el) | 2012-01-25 |
| CN1620447A (zh) | 2005-05-25 |
| AR038662A1 (es) | 2005-01-26 |
| DK1458703T3 (da) | 2007-06-11 |
| DE60218529T2 (de) | 2007-11-22 |
| DE60218529D1 (de) | 2007-04-12 |
| ATE355283T1 (de) | 2006-03-15 |
| BR0214859A (pt) | 2004-11-03 |
| CN1312148C (zh) | 2007-04-25 |
| EP1458703B1 (en) | 2007-02-28 |
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| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Discontinued |