TW200538113A - Compounds - Google Patents
Compounds Download PDFInfo
- Publication number
- TW200538113A TW200538113A TW094105108A TW94105108A TW200538113A TW 200538113 A TW200538113 A TW 200538113A TW 094105108 A TW094105108 A TW 094105108A TW 94105108 A TW94105108 A TW 94105108A TW 200538113 A TW200538113 A TW 200538113A
- Authority
- TW
- Taiwan
- Prior art keywords
- methyl
- propyl
- azabicyclo
- thio
- hexane
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 305
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 339
- -1 haloC1-4alkoxy Chemical group 0.000 claims abstract description 150
- 238000000034 method Methods 0.000 claims abstract description 81
- 150000003839 salts Chemical class 0.000 claims abstract description 79
- 125000002619 bicyclic group Chemical group 0.000 claims abstract description 32
- 125000004076 pyridyl group Chemical group 0.000 claims abstract description 27
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 25
- 239000003814 drug Substances 0.000 claims abstract description 24
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 22
- 150000002367 halogens Chemical class 0.000 claims abstract description 22
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 21
- 125000001424 substituent group Chemical group 0.000 claims abstract description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 17
- 239000001257 hydrogen Substances 0.000 claims abstract description 16
- 239000000460 chlorine Substances 0.000 claims abstract description 14
- 125000000842 isoxazolyl group Chemical group 0.000 claims abstract description 13
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 12
- 125000000335 thiazolyl group Chemical group 0.000 claims abstract description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 7
- 102000004073 Dopamine D3 Receptors Human genes 0.000 claims abstract description 6
- 108090000525 Dopamine D3 Receptors Proteins 0.000 claims abstract description 6
- 125000001544 thienyl group Chemical group 0.000 claims abstract description 6
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims abstract description 5
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 5
- 125000001309 chloro group Chemical group Cl* 0.000 claims abstract description 4
- 238000002560 therapeutic procedure Methods 0.000 claims abstract description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 820
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 448
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 121
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 121
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 89
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 68
- 239000007789 gas Substances 0.000 claims description 53
- 125000001305 1,2,4-triazol-3-yl group Chemical group [H]N1N=C([*])N=C1[H] 0.000 claims description 43
- 125000000217 alkyl group Chemical group 0.000 claims description 42
- HGWUUOXXAIISDB-UHFFFAOYSA-N 3-azabicyclo[3.1.0]hexane Chemical compound C1NCC2CC21 HGWUUOXXAIISDB-UHFFFAOYSA-N 0.000 claims description 35
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 35
- 125000003545 alkoxy group Chemical group 0.000 claims description 34
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 30
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 claims description 27
- 229910052757 nitrogen Inorganic materials 0.000 claims description 27
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 23
- QRDSDKAGXMWBID-UHFFFAOYSA-N 5-azabicyclo[3.1.0]hexane Chemical compound C1CCN2CC21 QRDSDKAGXMWBID-UHFFFAOYSA-N 0.000 claims description 22
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 22
- 125000000623 heterocyclic group Chemical group 0.000 claims description 22
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 21
- SCVJRXQHFJXZFZ-KVQBGUIXSA-N 2-amino-9-[(2r,4s,5r)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-3h-purine-6-thione Chemical compound C1=2NC(N)=NC(=S)C=2N=CN1[C@H]1C[C@H](O)[C@@H](CO)O1 SCVJRXQHFJXZFZ-KVQBGUIXSA-N 0.000 claims description 20
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 18
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims description 18
- 239000011734 sodium Substances 0.000 claims description 17
- 239000000126 substance Substances 0.000 claims description 17
- 239000004305 biphenyl Substances 0.000 claims description 16
- 238000011282 treatment Methods 0.000 claims description 16
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 15
- 208000028017 Psychotic disease Diseases 0.000 claims description 15
- 208000011117 substance-related disease Diseases 0.000 claims description 15
- 201000009032 substance abuse Diseases 0.000 claims description 14
- 125000002971 oxazolyl group Chemical group 0.000 claims description 13
- 102000005962 receptors Human genes 0.000 claims description 13
- 108020003175 receptors Proteins 0.000 claims description 13
- WGSXKYXKAARAKD-UHFFFAOYSA-N 1-fluoro-3-isocyanato-5-(trifluoromethyl)benzene Chemical group FC1=CC(N=C=O)=CC(C(F)(F)F)=C1 WGSXKYXKAARAKD-UHFFFAOYSA-N 0.000 claims description 11
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 11
- SMUQFGGVLNAIOZ-UHFFFAOYSA-N quinaldine Chemical compound C1=CC=CC2=NC(C)=CC=C21 SMUQFGGVLNAIOZ-UHFFFAOYSA-N 0.000 claims description 11
- 229910052708 sodium Inorganic materials 0.000 claims description 11
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 claims description 10
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 9
- 125000003118 aryl group Chemical group 0.000 claims description 9
- 231100000736 substance abuse Toxicity 0.000 claims description 9
- OFJBYLCQNJHFMI-UHFFFAOYSA-N 2,5-dihydro-1,2-oxazole Chemical compound C1ONC=C1 OFJBYLCQNJHFMI-UHFFFAOYSA-N 0.000 claims description 8
- PZOUSPYUWWUPPK-UHFFFAOYSA-N 4-methyl-1h-indole Chemical compound CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 241000124008 Mammalia Species 0.000 claims description 8
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 8
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 claims description 8
- 201000000980 schizophrenia Diseases 0.000 claims description 8
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 7
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 claims description 7
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 7
- 125000004304 oxazol-5-yl group Chemical group O1C=NC=C1* 0.000 claims description 7
- XAGZJIQIVXSURR-UHFFFAOYSA-N 1-[4-(trifluoromethyl)phenyl]piperidin-2-one Chemical group C1=CC(C(F)(F)F)=CC=C1N1C(=O)CCCC1 XAGZJIQIVXSURR-UHFFFAOYSA-N 0.000 claims description 6
- 150000002148 esters Chemical class 0.000 claims description 6
- 125000001425 triazolyl group Chemical group 0.000 claims description 6
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 5
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 5
- 150000002576 ketones Chemical class 0.000 claims description 5
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 5
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 claims description 5
- 239000002689 soil Substances 0.000 claims description 5
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical compound [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims description 5
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 claims description 4
- 101150026303 HEX1 gene Proteins 0.000 claims description 4
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000007983 Tris buffer Substances 0.000 claims description 4
- 125000004799 bromophenyl group Chemical group 0.000 claims description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 201000010099 disease Diseases 0.000 claims description 4
- 229960003638 dopamine Drugs 0.000 claims description 4
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 claims description 4
- 150000004687 hexahydrates Chemical class 0.000 claims description 4
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 4
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 4
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 4
- 125000005493 quinolyl group Chemical group 0.000 claims description 4
- 150000003573 thiols Chemical class 0.000 claims description 4
- 150000003852 triazoles Chemical class 0.000 claims description 4
- ZZLCFHIKESPLTH-UHFFFAOYSA-N 4-Methylbiphenyl Chemical compound C1=CC(C)=CC=C1C1=CC=CC=C1 ZZLCFHIKESPLTH-UHFFFAOYSA-N 0.000 claims description 3
- BIUDHHGROGJSHN-UHFFFAOYSA-N 4-fluoro-3-(trifluoromethyl)benzaldehyde Chemical group FC1=CC=C(C=O)C=C1C(F)(F)F BIUDHHGROGJSHN-UHFFFAOYSA-N 0.000 claims description 3
- OQLZINXFSUDMHM-UHFFFAOYSA-N Acetamidine Chemical compound CC(N)=N OQLZINXFSUDMHM-UHFFFAOYSA-N 0.000 claims description 3
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 3
- ZUSWDTWYONAOPH-UHFFFAOYSA-N [2-(trifluoromethyl)phenyl]hydrazine;hydrochloride Chemical group [Cl-].[NH3+]NC1=CC=CC=C1C(F)(F)F ZUSWDTWYONAOPH-UHFFFAOYSA-N 0.000 claims description 3
- 125000001589 carboacyl group Chemical group 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 125000001041 indolyl group Chemical group 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 claims description 3
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 3
- 125000001766 1,2,4-oxadiazol-3-yl group Chemical group [H]C1=NC(*)=NO1 0.000 claims description 2
- 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 claims description 2
- SNTWKPAKVQFCCF-UHFFFAOYSA-N 2,3-dihydro-1h-triazole Chemical compound N1NC=CN1 SNTWKPAKVQFCCF-UHFFFAOYSA-N 0.000 claims description 2
- NXFFJDQHYLNEJK-UHFFFAOYSA-N 2-[4-[(4-chlorophenyl)methyl]-7-fluoro-5-methylsulfonyl-2,3-dihydro-1h-cyclopenta[b]indol-3-yl]acetic acid Chemical compound C1=2C(S(=O)(=O)C)=CC(F)=CC=2C=2CCC(CC(O)=O)C=2N1CC1=CC=C(Cl)C=C1 NXFFJDQHYLNEJK-UHFFFAOYSA-N 0.000 claims description 2
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)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
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 2
- 125000001207 fluorophenyl group Chemical group 0.000 claims description 2
- 125000002541 furyl group Chemical group 0.000 claims description 2
- 229940067157 phenylhydrazine Drugs 0.000 claims description 2
- 125000005936 piperidyl group Chemical group 0.000 claims description 2
- 210000003296 saliva Anatomy 0.000 claims description 2
- 229930192474 thiophene Natural products 0.000 claims description 2
- AKIKYWSEBGSZBD-UHFFFAOYSA-N 2-methyl-1h-isoquinoline Chemical compound C1=CC=C2C=CN(C)CC2=C1 AKIKYWSEBGSZBD-UHFFFAOYSA-N 0.000 claims 3
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical group OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims 3
- YBUMNVFXMLIKDZ-UHFFFAOYSA-N 2,4-Dimethyl-1H-indole Chemical compound C1=CC=C2NC(C)=CC2=C1C YBUMNVFXMLIKDZ-UHFFFAOYSA-N 0.000 claims 2
- HIZVCIIORGCREW-UHFFFAOYSA-N 1,4-dioxene Chemical compound C1COC=CO1 HIZVCIIORGCREW-UHFFFAOYSA-N 0.000 claims 1
- ZCHCHJQEWYIJDQ-UHFFFAOYSA-N 2-methyl-1,3-oxazole Chemical compound CC1=NC=CO1 ZCHCHJQEWYIJDQ-UHFFFAOYSA-N 0.000 claims 1
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims 1
- GVSNQMFKEPBIOY-UHFFFAOYSA-N 4-methyl-2h-triazole Chemical compound CC=1C=NNN=1 GVSNQMFKEPBIOY-UHFFFAOYSA-N 0.000 claims 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims 1
- YXLXNENXOJSQEI-UHFFFAOYSA-L Oxine-copper Chemical compound [Cu+2].C1=CN=C2C([O-])=CC=CC2=C1.C1=CN=C2C([O-])=CC=CC2=C1 YXLXNENXOJSQEI-UHFFFAOYSA-L 0.000 claims 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims 1
- JAPMJSVZDUYFKL-UHFFFAOYSA-N bicyclo[3.1.0]hexane Chemical compound C1CCC2CC21 JAPMJSVZDUYFKL-UHFFFAOYSA-N 0.000 claims 1
- 229910052805 deuterium Inorganic materials 0.000 claims 1
- 150000002500 ions Chemical class 0.000 claims 1
- 150000004032 porphyrins Chemical class 0.000 claims 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims 1
- 125000005504 styryl group Chemical group 0.000 claims 1
- 125000004496 thiazol-5-yl group Chemical group S1C=NC=C1* 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 175
- 229940079593 drug Drugs 0.000 abstract description 20
- 230000008569 process Effects 0.000 abstract description 8
- 239000000543 intermediate Substances 0.000 abstract description 7
- 125000002861 (C1-C4) alkanoyl group Chemical group 0.000 abstract 3
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 abstract 3
- 239000000164 antipsychotic agent Substances 0.000 abstract 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 abstract 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 270
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 188
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 162
- 239000007787 solid Substances 0.000 description 119
- 239000000243 solution Substances 0.000 description 94
- 239000000203 mixture Substances 0.000 description 92
- 235000019439 ethyl acetate Nutrition 0.000 description 90
- 239000000047 product Substances 0.000 description 88
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 67
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 63
- 239000002904 solvent Substances 0.000 description 50
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 49
- 239000002585 base Substances 0.000 description 47
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 46
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 44
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 42
- 229910001868 water Inorganic materials 0.000 description 42
- 101150041968 CDC13 gene Proteins 0.000 description 40
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 40
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 40
- 238000004808 supercritical fluid chromatography Methods 0.000 description 39
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 37
- 239000003795 chemical substances by application Substances 0.000 description 35
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 32
- YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Natural products ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 31
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 31
- 238000000926 separation method Methods 0.000 description 29
- 239000002253 acid Substances 0.000 description 28
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 27
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 26
- 235000019253 formic acid Nutrition 0.000 description 26
- 239000000463 material Substances 0.000 description 26
- 239000011541 reaction mixture Substances 0.000 description 26
- 239000012265 solid product Substances 0.000 description 24
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 23
- 230000003287 optical effect Effects 0.000 description 23
- 238000004458 analytical method Methods 0.000 description 22
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 22
- 238000001228 spectrum Methods 0.000 description 22
- 238000000825 ultraviolet detection Methods 0.000 description 22
- 238000006243 chemical reaction Methods 0.000 description 21
- 239000012458 free base Substances 0.000 description 21
- 239000003480 eluent Substances 0.000 description 20
- 238000003756 stirring Methods 0.000 description 20
- 206010036790 Productive cough Diseases 0.000 description 19
- 208000035475 disorder Diseases 0.000 description 19
- 210000003802 sputum Anatomy 0.000 description 19
- 208000024794 sputum Diseases 0.000 description 19
- 239000012043 crude product Substances 0.000 description 18
- 239000012071 phase Substances 0.000 description 18
- 230000002829 reductive effect Effects 0.000 description 17
- 238000012360 testing method Methods 0.000 description 17
- ZPUCINDJVBIVPJ-LJISPDSOSA-N cocaine Chemical compound O([C@H]1C[C@@H]2CC[C@@H](N2C)[C@H]1C(=O)OC)C(=O)C1=CC=CC=C1 ZPUCINDJVBIVPJ-LJISPDSOSA-N 0.000 description 16
- 231100000572 poisoning Toxicity 0.000 description 16
- 230000000607 poisoning effect Effects 0.000 description 16
- 239000000725 suspension Substances 0.000 description 16
- 238000001914 filtration Methods 0.000 description 15
- 238000004128 high performance liquid chromatography Methods 0.000 description 15
- 230000014759 maintenance of location Effects 0.000 description 15
- IPCSVZSSVZVIGE-UHFFFAOYSA-N palmitic acid group Chemical group C(CCCCCCCCCCCCCCC)(=O)O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 15
- 238000007792 addition Methods 0.000 description 14
- 239000000706 filtrate Substances 0.000 description 14
- 239000002249 anxiolytic agent Substances 0.000 description 13
- 230000000147 hypnotic effect Effects 0.000 description 13
- 239000012044 organic layer Substances 0.000 description 13
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 239000003326 hypnotic agent Substances 0.000 description 12
- 229920006395 saturated elastomer Polymers 0.000 description 12
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- A—HUMAN NECESSITIES
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| WO2007006117A1 (en) * | 2005-07-13 | 2007-01-18 | Nicogen Inc. | Novel cyp2a6 inhibitors |
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| AR060237A1 (es) * | 2006-04-03 | 2008-06-04 | Glaxo Group Ltd | Compuesto de 3-azabiciclo[3.1.0]hexano como moduladores del receptor de dopamina d3, su uso para la preparacion de un medicamento para el tratamiento de afecciones psicoticas y composicion farmaceutica que lo comprende. |
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| GB0607899D0 (en) * | 2006-04-03 | 2006-05-31 | Glaxo Group Ltd | Process for preparing heterocyclic derivatives |
| US8222266B2 (en) * | 2006-04-03 | 2012-07-17 | Glaxo Group Limited | Azabicyclo [3.1.0] hexyl derivatives as modulators of dopamine D3 receptors |
| US8163927B2 (en) * | 2006-04-03 | 2012-04-24 | Glaxo Group Limited | Azabicyclo [3.1.0] hexane derivatives as modulators of dopamine D3 receptors |
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| US20080045725A1 (en) | 2006-04-28 | 2008-02-21 | Murry Jerry A | Process For The Synthesis of (+) And (-)-1-(3,4-Dichlorophenyl)-3-Azabicyclo[3.1.0]Hexane |
| GB0616574D0 (en) * | 2006-08-21 | 2006-09-27 | Glaxo Group Ltd | Compounds |
| US8138377B2 (en) | 2006-11-07 | 2012-03-20 | Dov Pharmaceutical, Inc. | Arylbicyclo[3.1.0]hexylamines and methods and compositions for their preparation and use |
| US20090069374A1 (en) * | 2007-06-06 | 2009-03-12 | Phil Skolnick | Novel 1-Heteroaryl-3-Azabicyclo[3.1.0]Hexanes, Methods For Their Preparation And Their Use As Medicaments |
| US9133159B2 (en) | 2007-06-06 | 2015-09-15 | Neurovance, Inc. | 1-heteroaryl-3-azabicyclo[3.1.0]hexanes, methods for their preparation and their use as medicaments |
| GB0719235D0 (en) * | 2007-10-02 | 2007-11-14 | Glaxo Group Ltd | Novel compounds |
| GB0719234D0 (en) * | 2007-10-02 | 2007-11-14 | Glaxo Group Ltd | Novel compounds |
| CN102816106A (zh) | 2008-06-24 | 2012-12-12 | 默沙东公司 | 用于制备基本上立体异构纯的稠合二环脯氨酸化合物的生物催化方法 |
| US8536185B2 (en) | 2008-09-22 | 2013-09-17 | Cayman Chemical Company, Incorporated | Multiheteroaryl compounds as inhibitors of H-PGDS and their use for treating prostaglandin D2 mediated diseases |
| BR112012000657A2 (pt) | 2009-06-26 | 2016-11-16 | Panacea Biotec Ltd | novos azabicilohexanos |
| US20140206740A1 (en) | 2011-07-30 | 2014-07-24 | Neurovance, Inc. | Use Of (1R,5S)-(+)-(Napthalen-2-yl)-3-Azabicyclo[3.1.0]Hexane In The Treatment Of Conditions Affected By Monoamine Neurotransmitters |
| US20160279098A1 (en) * | 2013-11-11 | 2016-09-29 | Euthymics Bioscience, Inc. | Novel methods |
| HK1250029A1 (zh) | 2015-08-05 | 2018-11-23 | Indivior Uk Limited | 具有双环结构的多巴胺d3受体拮抗剂 |
| JP7250405B2 (ja) | 2018-01-26 | 2023-04-03 | 塩野義製薬株式会社 | ドーパミンｄ３受容体拮抗作用を有する環式化合物 |
| CN116113627B (zh) | 2020-06-22 | 2025-06-03 | 科赛普特治疗公司 | 季吲哚糖皮质激素受体拮抗剂 |
| US12115154B2 (en) | 2020-12-16 | 2024-10-15 | Srx Cardio, Llc | Compounds for the modulation of proprotein convertase subtilisin/kexin type 9 (PCSK9) |
| IL313667A (en) | 2021-12-21 | 2024-08-01 | Corcept Therapeutics Inc | Glucocorticoid receptor antagonists INDAZOL CYCLES |
| CA3243549A1 (en) | 2021-12-21 | 2023-06-29 | Corcept Therapeutics Incorporated | INDAZOLE PIPERAZINE-BASED GLUCOCORTICOID RECEPTOR ANTAGONISTS |
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| TWI274750B (en) * | 1999-01-12 | 2007-03-01 | Abbott Gmbh & Co Kg | Triazole compounds showing high affinity to dopamine D3 receptor and pharmaceutical composition comprising the same |
| GB0015562D0 (en) * | 2000-06-23 | 2000-08-16 | Pfizer Ltd | Heterocycles |
| JP4272423B2 (ja) | 2000-11-14 | 2009-06-03 | スミスクライン ビーチャム ピー エル シー | ドーパミンｄ３受容体のモジュレーターとして有用なテトラヒドロベンズアゼピン誘導体（抗精神病剤） |
| US6569887B2 (en) * | 2001-08-24 | 2003-05-27 | Dov Pharmaceuticals Inc. | (−)-1-(3,4-Dichlorophenyl)-3-azabicyclo[3.1.0]hexane, compositions thereof, and uses as a dopamine-reuptake |
| EP1440059B1 (en) | 2001-10-22 | 2008-04-16 | Pfizer Products Inc. | 3-azabicyclo(3.1.0)hexane derivatives as opioid receptor antagonists |
| IL166510A0 (en) * | 2002-08-09 | 2006-01-15 | Nps Pharma Inc | 1,2,4"oxadiazole as modulators of metabotropic glutamate receptor-5 |
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2005
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-
2006
- 2006-07-31 IL IL177184A patent/IL177184A0/en unknown
- 2006-08-22 MA MA29286A patent/MA28438B1/fr unknown
- 2006-09-22 NO NO20064309A patent/NO20064309L/no not_active Application Discontinuation
-
2009
- 2009-09-01 AU AU2009212887A patent/AU2009212887A1/en not_active Abandoned
- 2009-12-16 US US12/639,129 patent/US8263782B2/en not_active Expired - Fee Related
- 2009-12-16 US US12/639,282 patent/US8283474B2/en not_active Expired - Fee Related
-
2010
- 2010-03-01 CY CY20101100197T patent/CY1109854T1/el unknown
-
2011
- 2011-10-26 HR HR20110781T patent/HRP20110781T1/hr unknown
- 2011-11-07 CY CY20111101073T patent/CY1112011T1/el unknown
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2012
- 2012-03-29 HR HR20120281T patent/HRP20120281T1/hr unknown
- 2012-04-11 CY CY20121100356T patent/CY1113029T1/el unknown
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