WO1998049145A1 - Substituted tetrahydroisoquinoline derivatives as modulators of dopamine d3 receptors - Google Patents
Substituted tetrahydroisoquinoline derivatives as modulators of dopamine d3 receptors Download PDFInfo
- Publication number
- WO1998049145A1 WO1998049145A1 PCT/EP1998/002581 EP9802581W WO9849145A1 WO 1998049145 A1 WO1998049145 A1 WO 1998049145A1 EP 9802581 W EP9802581 W EP 9802581W WO 9849145 A1 WO9849145 A1 WO 9849145A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- formula
- compound
- group
- 4alkyl
- tetrahydroisoquinoline
- Prior art date
Links
- 102000004073 Dopamine D3 Receptors Human genes 0.000 title claims description 8
- 108090000525 Dopamine D3 Receptors Proteins 0.000 title claims description 8
- 125000003039 tetrahydroisoquinolinyl group Chemical class C1(NCCC2=CC=CC=C12)* 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 98
- 150000003839 salts Chemical class 0.000 claims abstract description 26
- 125000005843 halogen group Chemical group 0.000 claims abstract description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 10
- 125000001424 substituent group Chemical group 0.000 claims abstract description 10
- 108050004812 Dopamine receptor Proteins 0.000 claims abstract description 9
- 102000015554 Dopamine receptor Human genes 0.000 claims abstract description 9
- 239000001257 hydrogen Substances 0.000 claims abstract description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 8
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 7
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 7
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims abstract description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 6
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 claims abstract description 5
- 125000003435 aroyl group Chemical group 0.000 claims abstract description 4
- 125000005533 aryl carboxamido group Chemical group 0.000 claims abstract description 4
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims abstract description 4
- 125000005279 aryl sulfonyloxy group Chemical group 0.000 claims abstract description 4
- 150000003976 azacycloalkanes Chemical class 0.000 claims abstract description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 4
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims abstract description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 4
- 125000005951 trifluoromethanesulfonyloxy group Chemical group 0.000 claims abstract description 3
- -1 trifluoromethylsulphonyloxy group Chemical group 0.000 claims description 27
- UWYZHKAOTLEWKK-UHFFFAOYSA-N tetrahydro-isoquinoline Natural products C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 claims description 25
- 238000000034 method Methods 0.000 claims description 21
- 238000006243 chemical reaction Methods 0.000 claims description 12
- 230000008569 process Effects 0.000 claims description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 208000028017 Psychotic disease Diseases 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 3
- 229910003844 NSO2 Inorganic materials 0.000 claims description 2
- 150000001638 boron Chemical group 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 229910052751 metal Chemical group 0.000 claims description 2
- 239000002184 metal Chemical group 0.000 claims description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 1
- 239000003210 dopamine receptor blocking agent Substances 0.000 claims 1
- 102000005962 receptors Human genes 0.000 abstract description 12
- 108020003175 receptors Proteins 0.000 abstract description 12
- 125000000217 alkyl group Chemical group 0.000 abstract description 8
- 239000000164 antipsychotic agent Substances 0.000 abstract description 5
- 230000009286 beneficial effect Effects 0.000 abstract description 3
- 125000002861 (C1-C4) alkanoyl group Chemical group 0.000 abstract 1
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 54
- 239000000203 mixture Substances 0.000 description 26
- 238000001819 mass spectrum Methods 0.000 description 23
- 239000003921 oil Substances 0.000 description 17
- 235000019198 oils Nutrition 0.000 description 17
- 239000000243 solution Substances 0.000 description 14
- 239000008186 active pharmaceutical agent Substances 0.000 description 13
- 210000004027 cell Anatomy 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
- 239000000556 agonist Substances 0.000 description 9
- 239000005557 antagonist Substances 0.000 description 9
- 239000000725 suspension Substances 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 8
- 239000000284 extract Substances 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 239000000872 buffer Substances 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical class OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 5
- 230000027455 binding Effects 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 239000002609 medium Substances 0.000 description 5
- 239000008188 pellet Substances 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- 125000002373 5 membered heterocyclic group Chemical group 0.000 description 4
- 125000004070 6 membered heterocyclic group Chemical group 0.000 description 4
- 229920000858 Cyclodextrin Polymers 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 4
- 239000002202 Polyethylene glycol Substances 0.000 description 4
- 239000003085 diluting agent Substances 0.000 description 4
- 229960003638 dopamine Drugs 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 229920001223 polyethylene glycol Polymers 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 201000000980 schizophrenia Diseases 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 238000010561 standard procedure Methods 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000000443 aerosol Substances 0.000 description 3
- 239000003125 aqueous solvent Substances 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 239000006184 cosolvent Substances 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 230000005714 functional activity Effects 0.000 description 3
- 125000005842 heteroatom Chemical group 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- HCKMONAVUWHQOT-JTQLQIEISA-N n-[[(2s)-1-ethylpyrrolidin-2-yl]methyl]-2-iodo-6-methoxy-3-sulfamoylbenzamide Chemical compound CCN1CCC[C@H]1CNC(=O)C1=C(I)C(S(N)(=O)=O)=CC=C1OC HCKMONAVUWHQOT-JTQLQIEISA-N 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 230000020477 pH reduction Effects 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- 230000002335 preservative effect Effects 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000000375 suspending agent Substances 0.000 description 3
- 150000003526 tetrahydroisoquinolines Chemical class 0.000 description 3
- ZWHOTPNCEFWATE-AWEZNQCLSA-N (3S)-3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-phenylpyrrolidine-1-carboxamide Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)O[C@@H]1CN(CC1)C(=O)NC1=CC=CC=C1 ZWHOTPNCEFWATE-AWEZNQCLSA-N 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- VKQVUQYZTXGZLW-UHFFFAOYSA-N 1-(7-bromo-3,4-dihydro-1h-isoquinolin-2-yl)-2,2,2-trifluoroethanone Chemical compound C1=C(Br)C=C2CN(C(=O)C(F)(F)F)CCC2=C1 VKQVUQYZTXGZLW-UHFFFAOYSA-N 0.000 description 2
- RIEVCJDAGDYFEP-UHFFFAOYSA-N 2,2,2-trifluoro-n-(4-oxobutyl)acetamide Chemical compound FC(F)(F)C(=O)NCCCC=O RIEVCJDAGDYFEP-UHFFFAOYSA-N 0.000 description 2
- NMOCOWABJRWQGY-UHFFFAOYSA-N 2-(4,4-diethoxybutyl)isoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(CCCC(OCC)OCC)C(=O)C2=C1 NMOCOWABJRWQGY-UHFFFAOYSA-N 0.000 description 2
- GFLPSABXBDCMCN-UHFFFAOYSA-N 4,4-diethoxybutan-1-amine Chemical compound CCOC(OCC)CCCN GFLPSABXBDCMCN-UHFFFAOYSA-N 0.000 description 2
- WMXADABRNBNSJC-UHFFFAOYSA-N 4-(1,3-dioxoisoindol-2-yl)butanal Chemical compound C1=CC=C2C(=O)N(CCCC=O)C(=O)C2=C1 WMXADABRNBNSJC-UHFFFAOYSA-N 0.000 description 2
- BPSLFSXCUJYFIR-UHFFFAOYSA-N 7-methoxy-1,2,3,4-tetrahydroisoquinoline Chemical compound C1CNCC2=CC(OC)=CC=C21 BPSLFSXCUJYFIR-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 2
- 101150049660 DRD2 gene Proteins 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 101150097070 Drd3 gene Proteins 0.000 description 2
- HCUARRIEZVDMPT-UHFFFAOYSA-N Indole-2-carboxylic acid Chemical compound C1=CC=C2NC(C(=O)O)=CC2=C1 HCUARRIEZVDMPT-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- 239000007832 Na2SO4 Substances 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 208000018737 Parkinson disease Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 239000004479 aerosol dispenser Substances 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 2
- 125000005620 boronic acid group Chemical group 0.000 description 2
- 229940098773 bovine serum albumin Drugs 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000001110 calcium chloride Substances 0.000 description 2
- 229910001628 calcium chloride Inorganic materials 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 210000000170 cell membrane Anatomy 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 2
- 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 2
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 2
- 229910000366 copper(II) sulfate Inorganic materials 0.000 description 2
- 229940097362 cyclodextrins Drugs 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 230000000142 dyskinetic effect Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- 239000007937 lozenge Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 229910001629 magnesium chloride Inorganic materials 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 239000003176 neuroleptic agent Substances 0.000 description 2
- 239000004031 partial agonist Substances 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000003380 propellant Substances 0.000 description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 description 2
- FTSUPYGMFAPCFZ-ZWNOBZJWSA-N quinpirole Chemical compound C([C@H]1CCCN([C@@H]1C1)CCC)C2=C1C=NN2 FTSUPYGMFAPCFZ-ZWNOBZJWSA-N 0.000 description 2
- 229950001037 quinpirole Drugs 0.000 description 2
- 239000002287 radioligand Substances 0.000 description 2
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 229940032147 starch Drugs 0.000 description 2
- 239000012258 stirred mixture Substances 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- 229910052725 zinc Inorganic materials 0.000 description 2
- HFVMEOPYDLEHBR-UHFFFAOYSA-N (2-fluorophenyl)-phenylmethanol Chemical compound C=1C=CC=C(F)C=1C(O)C1=CC=CC=C1 HFVMEOPYDLEHBR-UHFFFAOYSA-N 0.000 description 1
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- MJTTVLLQWNDHHK-WLHGVMLRSA-N (e)-but-2-enedioic acid;3-(dimethylamino)-1-[2-(trifluoromethyl)phenothiazin-10-yl]propan-1-one Chemical compound OC(=O)\C=C\C(O)=O.C1=C(C(F)(F)F)C=C2N(C(=O)CCN(C)C)C3=CC=CC=C3SC2=C1 MJTTVLLQWNDHHK-WLHGVMLRSA-N 0.000 description 1
- LJFNUFCUPDECPC-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline-7-carbonitrile Chemical compound C1CNCC2=CC(C#N)=CC=C21 LJFNUFCUPDECPC-UHFFFAOYSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- MMCDXESAXXRIIS-UHFFFAOYSA-N 2,2,2-trifluoro-n-[4-[7-(trifluoromethoxy)-3,4-dihydro-1h-isoquinolin-2-yl]butyl]acetamide Chemical compound C1CN(CCCCNC(=O)C(F)(F)F)CC2=CC(OC(F)(F)F)=CC=C21 MMCDXESAXXRIIS-UHFFFAOYSA-N 0.000 description 1
- GQFDPKXRYBGJLR-UHFFFAOYSA-N 2-(4-aminobutyl)-3,4-dihydro-1h-isoquinoline-7-carbonitrile Chemical compound C1=C(C#N)C=C2CN(CCCCN)CCC2=C1 GQFDPKXRYBGJLR-UHFFFAOYSA-N 0.000 description 1
- FQNHNYCDCKIHJU-UHFFFAOYSA-N 2-[4-(7-hydroxy-3,4-dihydro-1h-isoquinolin-2-yl)butyl]isoindole-1,3-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1CCCCN1CCC2=CC=C(O)C=C2C1 FQNHNYCDCKIHJU-UHFFFAOYSA-N 0.000 description 1
- JLVXJWJPHYNJGO-UHFFFAOYSA-N 2-[4-(7-methoxy-3,4-dihydro-1h-isoquinolin-2-yl)butyl]isoindole-1,3-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1CCCCN1CCC2=CC=C(OC)C=C2C1 JLVXJWJPHYNJGO-UHFFFAOYSA-N 0.000 description 1
- HHLGARPFXWIYTE-UHFFFAOYSA-N 2-[4-(trifluoromethoxy)phenyl]ethanamine Chemical compound NCCC1=CC=C(OC(F)(F)F)C=C1 HHLGARPFXWIYTE-UHFFFAOYSA-N 0.000 description 1
- VSWICNJIUPRZIK-UHFFFAOYSA-N 2-piperideine Chemical class C1CNC=CC1 VSWICNJIUPRZIK-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- QISOBCMNUJQOJU-UHFFFAOYSA-N 4-bromo-1h-pyrazole-5-carboxylic acid Chemical compound OC(=O)C=1NN=CC=1Br QISOBCMNUJQOJU-UHFFFAOYSA-N 0.000 description 1
- PXRKCOCTEMYUEG-UHFFFAOYSA-N 5-aminoisoindole-1,3-dione Chemical compound NC1=CC=C2C(=O)NC(=O)C2=C1 PXRKCOCTEMYUEG-UHFFFAOYSA-N 0.000 description 1
- OYODEQFZAJVROF-UHFFFAOYSA-N 7-bromo-1,2,3,4-tetrahydroisoquinoline Chemical compound C1CNCC2=CC(Br)=CC=C21 OYODEQFZAJVROF-UHFFFAOYSA-N 0.000 description 1
- KVQRYABFFFQRHE-UHFFFAOYSA-N 7-methylquinolin-6-amine Chemical compound C1=CC=C2C=C(N)C(C)=CC2=N1 KVQRYABFFFQRHE-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 235000003911 Arachis Nutrition 0.000 description 1
- 244000105624 Arachis hypogaea Species 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 229910020323 ClF3 Inorganic materials 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- 208000024254 Delusional disease Diseases 0.000 description 1
- 229940088353 Dopamine D3 receptor antagonist Drugs 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- 241000400611 Eucalyptus deanei Species 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 206010026749 Mania Diseases 0.000 description 1
- 208000026139 Memory disease Diseases 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 208000027099 Paranoid disease Diseases 0.000 description 1
- 208000027089 Parkinsonian disease Diseases 0.000 description 1
- 206010034010 Parkinsonism Diseases 0.000 description 1
- 241000270295 Serpentes Species 0.000 description 1
- 201000001880 Sexual dysfunction Diseases 0.000 description 1
- 206010043118 Tardive Dyskinesia Diseases 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric Acid Chemical compound [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- GVBVSRVHHWBZHF-UHFFFAOYSA-N [2-[4-(1,3-dioxoisoindol-2-yl)butyl]-3,4-dihydro-1h-isoquinolin-7-yl] trifluoromethanesulfonate Chemical compound O=C1C2=CC=CC=C2C(=O)N1CCCCN1CCC2=CC=C(OS(=O)(=O)C(F)(F)F)C=C2C1 GVBVSRVHHWBZHF-UHFFFAOYSA-N 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000008484 agonism Effects 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000005278 alkyl sulfonyloxy group Chemical group 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 230000000561 anti-psychotic effect Effects 0.000 description 1
- 239000003416 antiarrhythmic agent Substances 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 239000008365 aqueous carrier Substances 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000004604 benzisothiazolyl group Chemical group S1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000004603 benzisoxazolyl group Chemical group O1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 235000011148 calcium chloride Nutrition 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- 229960003920 cocaine Drugs 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 239000008139 complexing agent Substances 0.000 description 1
- 239000000356 contaminant Substances 0.000 description 1
- 238000011340 continuous therapy Methods 0.000 description 1
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 description 1
- 229960000913 crospovidone Drugs 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- ZHXTWWCDMUWMDI-UHFFFAOYSA-N dihydroxyboron Chemical group O[B]O ZHXTWWCDMUWMDI-UHFFFAOYSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- VRHAQNTWKSVEEC-UHFFFAOYSA-N ethyl 1,3-dioxoisoindole-2-carboxylate Chemical compound C1=CC=C2C(=O)N(C(=O)OCC)C(=O)C2=C1 VRHAQNTWKSVEEC-UHFFFAOYSA-N 0.000 description 1
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 1
- UREBWPXBXRYXRJ-UHFFFAOYSA-N ethyl acetate;methanol Chemical compound OC.CCOC(C)=O UREBWPXBXRYXRJ-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 230000002538 fungal effect Effects 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 238000000703 high-speed centrifugation Methods 0.000 description 1
- 238000000265 homogenisation Methods 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 108010024941 iodothyronine deiodinase type II Proteins 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 229960001375 lactose Drugs 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 208000024714 major depressive disease Diseases 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000004458 methylaminocarbonyl group Chemical group [H]N(C(*)=O)C([H])([H])[H] 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- UADUXXNRAYZZQQ-UHFFFAOYSA-N n-[4-(7-cyano-3,4-dihydro-1h-isoquinolin-2-yl)butyl]-2,2,2-trifluoroacetamide Chemical compound C1=C(C#N)C=C2CN(CCCCNC(=O)C(F)(F)F)CCC2=C1 UADUXXNRAYZZQQ-UHFFFAOYSA-N 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 230000000701 neuroleptic effect Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 230000009871 nonspecific binding Effects 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 229940100692 oral suspension Drugs 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000004043 oxo group Chemical group O=* 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 208000002851 paranoid schizophrenia Diseases 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 235000010603 pastilles Nutrition 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 125000005543 phthalimide group Chemical group 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000005495 pyridazyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 239000011369 resultant mixture Substances 0.000 description 1
- 238000007790 scraping Methods 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 231100000872 sexual dysfunction Toxicity 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 229940080313 sodium starch Drugs 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 238000004114 suspension culture Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 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 effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 1
- WTVXIBRMWGUIMI-UHFFFAOYSA-N trifluoro($l^{1}-oxidanylsulfonyl)methane Chemical group [O]S(=O)(=O)C(F)(F)F WTVXIBRMWGUIMI-UHFFFAOYSA-N 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
- C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
-
- 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
- C07D409/02—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
Definitions
- the present invention relates to novel tetrahydroisoquinoline derivatives, processes for their preparation, pharmaceutical compositions containing them and their 5 use in therapy, as modulators of dopamine D3 receptors, in particular as antipsychotic agents.
- Rl, R ⁇ and R ⁇ are each inter alia hydrogen;
- X is inter alia (CH2)mNR ⁇ CO;
- m is 2-4; and
- Ar ⁇ is an optionally substituted heterocyclic ring or an 15 optionally substituted phenyl ring.
- the compounds are said to be useful as antiarrhythmic agents.
- Rl represents a substituent selected from: a hydrogen or halogen atom; a hydroxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, trifluoromethanesulfonyloxy, pentafluoroethyl, Cj ⁇ alkyl, C1.4al.coxy, arylCj ⁇ alkoxy, Cj ⁇ alkylthio, C ⁇ _4alkoxyC ⁇ _4alkyl, C3_6cycloalkylC ⁇ _4alkoxy, C j ⁇ alkanoyl, C ⁇ alkoxycarbonyl,
- Ar represents an optionally substituted phenyl ring or an optionally substituted 5- or 6- membered aromatic heterocyclic ring; or an optionally substituted bicyclic ring system; and salts thereof.
- alkyl group or moiety may be straight or branched.
- Alkyl groups which may be employed include methyl, ethyl, n-propyl, n- butyl, n-pentyl, n-hexyl and any branched isomers thereof such as isopropyl, t-butyl, sec-pentyl, and the like.
- Examples of compounds of formula (I) include those in which Ar is a bicyclic aromatic or heteroaromatic ring system and in which R ⁇ is other than pentafluoroethyl.
- R! represents an arylC ⁇ alkoxy, arylsulphonyl, arylsulphonyloxy, arylsulphonylC ⁇ _4alkyl, arylsulphonamido, arylcarboxamido, arylsulphonamidoC ⁇ alkyl, arylcarboxamidoC ⁇ _4alkyl, aroyl, aroylC ⁇ alkyl, or arylC ⁇ _4alkanoyl group
- the aryl moiety may be selected from an optionally substituted phenyl ring or an optionally substituted 5- or 6-membered heterocyclic ring.
- an aryl moiety may be optionally substituted by one or more substituents selected from hydrogen, halogen, amino, cyano, C1 _4alkyl, C]_4alkylamino, C ⁇ _ 4dialkylamino, Cj ⁇ alkylamido, C ⁇ alkanoyl, or R ⁇ R ⁇ NCO where each of R ⁇ and R ⁇ independently represents a hydrogen atom or C ⁇ _4alkyl group.
- a halogen atom present in the compounds of formula (I) may be fluorine, chlorine, bromine or iodine.
- the substituents R may be the same or different.
- An optionally substituted 5- or 6-membered heterocyclic aromatic ring, as defined for either of the groups Ar or Ar ⁇ may contain from 1 to 4 heteroatoms selected from O, N or S. When the ring contains 2-4 heteroatoms, one is preferably selected from O, N and S and the remaining heteroatoms are preferably N.
- Examples of 5 and 6- membered heterocyclic groups include furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, triazolyl, triazinyl, pyridazyl, pyrimidinyl and pyrazolyl.
- bicyclic, for example bicyclic aromatic or heteroaromatic, ring systems for Ar include naphthyl, indazolyl, indolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzisothiazolyl, quinolinyl, quinoxolinyl, quinazolinyl, cinnolinyl, isoquinolinyl, pyrazolo[l,5- a]pyrimidyl, pyrrolo[3,2-b]pyridyl, pyrrolo[3,2-c]pyridyl, thieno[3,2-b]thiophenyl, 1,2- dihydro-2-oxo-quinolinyl, 2,3-dihydro-3-oxo-4H-benzoxazinyl, 1 ,2-dihydro-2-oxo-3 ⁇ - indoly
- the group Ar may be optionally substituted by one or more substituents selected from: a hydrogen or halogen atom, or a hydroxy, oxo, cyano, nitro, C1.4a.kyl,
- Ar may be optionally substituted by one or more 5- or 6- membered heterocyclic rings, as defined above, optionally substituted by a C]_2 alkyl or R 7 R 8 N- group; wherein R 7 and R 8 are as defined above.
- substituents positioned ortho to one another may be linked to form a 5- or 6- membered ring.
- salts of formula (I) should be physiologically acceptable.
- suitable physiologically acceptable salts will be apparent to those skilled in the art and include for example acid addition salts formed with inorganic acids eg. hydrochloric, hydrobromic, sulphuric, nitric or phosphoric acid; and organic acids eg. succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, p- toluenesulphonic, methanesulphonic or naphthalenesulphonic acid.
- Other non- physiologically acceptable salts eg. oxalates, may be used, for example in the isolation of compounds of formula (I) and are included within the scope of this invention.
- R ⁇ represents a substituent selected from: a halogen atom, methyl, cyano, trifluoromethylsulfonyloxy, trifluoromethyl, pentafluoroethyl, or trifluoromethoxy group.
- the group Ar is optionally substituted by one or more substituents selected from: a hydrogen or halogen atom, cyano, methoxy, methylenedioxy, acetyl, acetylamino, methylsulfonyl, methylsulfonyloxy, methylaminosulfonyl, methylsulfonylamino, or methylaminocarbonyl group.
- substituents selected from: a hydrogen or halogen atom, cyano, methoxy, methylenedioxy, acetyl, acetylamino, methylsulfonyl, methylsulfonyloxy, methylaminosulfonyl, methylsulfonylamino, or methylaminocarbonyl group.
- Certain of the substituted heteroaromatic ring systems included in compounds of formula (I) may exist in one or more tautomeric forms.
- the present invention includes within its scope all such tautomeric forms, including mixtures.
- Particular compounds according to the invention include:
- the present invention also provides a process for preparing compounds of formula (I) and salts thereof which process comprises : (a) reacting a compound of formula (II):
- R ⁇ a represents a group W wherein W is a halogen atom or a trifluoromethylsulphonyloxy group, or W is a group M selected from a boron derivative e.g. a boronic acid function B(OH)2 or a metal function such as trialkylstannyl e.g. SnBu3, zinc halide or magnesium halide, and when q is 2 the other R ⁇ a is R!
- W* is a halogen atom or a trifluoromethylsulphonyloxy group when W is a group M or W ⁇ is a group M when W is a halogen atom or a trifluoromethylsulphonyloxy group;
- Process (a) requires the presence of a reducing agent.
- Suitable reducing agents which may be employed include sodium borohydride, cyanoborohydride or triacetoxyborohydride under acidic conditions, or catalytic hydrogenation.
- the reaction may conveniently be effected in a solvent such as ethanol or dichloroethane.
- Process (b) may be effected by methods well known in the art for formation of an amide bond.
- Reaction of a compound of formula (VI) with Ar ⁇ Wl, according to process (c) may be effected in the presence of a transition metal eg palladium catalyst such as bis- triphenylphosphinepalladium dichloride or tetrafa ' s-triphenylphosphinepalladium (0).
- a transition metal eg palladium catalyst
- M represents a boronic acid function such as B(OH) 2
- the reaction may be carried out under basic conditions, for example using aqueous sodium carbonate in a suitable solvent such as dioxane.
- M is trialkylstannyl
- the reaction may be carried out in an inert solvent, such as xylene or dioxane optionally in the presence of LiCl.
- M is a zinc or magnesium halide
- the reaction may be effected in an aprotic solvent such as tetrahydrofuran.
- the substituent W is preferably a halogen atom such as bromine, or a sulphonyloxy group such as trifluoromethylsulphonyloxy; and W ⁇ is preferably a goup M, such as trialkylstannyl or B(OH)2-
- the reagent serving to introduce the group Ar* is preferably a compound of formula Ar ⁇ -Hal, wherein Hal is a halogen atom.
- the reaction may be effected in the presence of a base, such as potassium carbonate, in a solvent such as dimethylformamide.
- Interconversion reactions according to process (e) may be effected using methods well known in the art.
- Compounds of formula (II) may be prepared by methods known in the art.
- a compound of formula (IV) may be prepared by alkylation of a compound (II) by standard methods.
- a compound of formula (II) may be reacted with N-(4-bromobutylphthalimide) followed by removal of the phthalimide group to give a compound of formula (IV) where R ⁇ is hydrogen.
- R ⁇ is hydrogen
- Compounds where R ⁇ is alkyl may be prepared by subsequent reaction with the appropriate aldehyde using conditions analogous to process (a) above.
- Compounds of formula (VI), and (VII) may be prepared by processes analogous to (a) or (b) described above.
- Compounds Ar Wl an( j Ar ⁇ Hal are commercially available or may be prepared by standard methods.
- Compounds of formula (I) have been found to exhibit affinity for dopamine receptors, in particular the D3 receptor, and are expected to be useful in the treatment of disease states which require modulation of such receptors, such as psychotic conditions. Compounds of formula (I) have also been found to have greater affinity for dopamine D3 than for D2 receptors.
- antipsychotic agents neuropeptides
- eps extrapyramidal side effects
- Preferred compounds of the present invention are therefore those which have higher affinity for dopamine D3 than dopamine D receptors (such affinity can be measured using standard methodology for example using cloned dopamine receptors). Said compounds may advantageously be used as selective modulators of D3 receptors.
- D3 antagonists are of potential use as antipsychotic agents for example in the treatment of schizophrenia, schizo-affective disorders, psychotic depression, mania, paranoid and delusional disorders.
- Conditions which may be treated by dopamine D3 receptor agonists include dyskinetic disorders such as Parkinson's disease, neuroleptic-induced parkinsonism and tardive dyskinesias; depression; anxiety, memory disorders, sexual dysfunction and drug (eg.
- the present invention provides a method of treating conditions which require modulation of dopamine D3 receptors, for example psychoses such as schizophrenia, which comprises administering to a subject in need thereof an effective amount of a compound of formula (I) or a physiologically acceptable salt thereof.
- the invention also provides the use of a compound of formula (I) or a physiologically acceptable salt thereof in the manufacture of a medicament for the treatment of conditions which require modulation of dopamine D3 receptors, for example psychoses such as schizophrenia.
- a preferred use for D3 antagonists according to the present invention is in the treatment of psychoses such as schizophrenia.
- a preferred use for D3 agonists according to the present invention is in the treatment of dyskinetic disorders such as Parkinson's disease.
- the compounds of the present invention are usually administered as a standard pharmaceutical composition.
- the present invention therefore provides in a further aspect pharmaceutical compositions comprising a novel compound of formula (I) or a physiologically acceptable salt thereof and a physiologically acceptable carrier.
- the compounds of formula (I) may be administered by any convenient method, for example by oral, parenteral, buccal, sublingual, nasal, rectal or transdermal administration and the pharmaceutical compositions adapted accordingly.
- the compounds of formula (I) and their physiologically acceptable salts which are active when given orally can be formulated as liquids or solids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges.
- a liquid formulation will generally consist of a suspension or solution of the compound or physiologically acceptable salt in a suitable liquid carrier(s) for example an aqueous solvent such as water, ethanol or glycerine, or a non-aqueous solvent, such as polyethylene glycol or an oil.
- a suitable liquid carrier(s) for example an aqueous solvent such as water, ethanol or glycerine, or a non-aqueous solvent, such as polyethylene glycol or an oil.
- the formulation may also contain a suspending agent, preservative, flavouring or colouring agent.
- a composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations.
- suitable pharmaceutical carrier(s) include magnesium stearate, starch, lactose, sucrose and cellulose.
- a composition in the form of a capsule can be prepared using routine encapsulation procedures.
- pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.
- Typical parenteral compositions consist of a solution or suspension of the compound or physiologically acceptable salt in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
- a sterile aqueous carrier or parenterally acceptable oil for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
- the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration.
- compositions for nasal administration may conveniently be formulated as aerosols, drops, gels and powders.
- Aerosol formulations typically comprise a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomising device.
- the sealed container may be a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal once the contents of the container have been exhausted.
- the dosage form comprises an aerosol dispenser
- a propellant which can be a compressed gas such as compressed air or an organic propellant such as a fluorochlorohydrocarbon.
- the aerosol dosage forms can also take the form of a pump-atomiser.
- compositions suitable for buccal or sublingual administration include tablets, lozenges and pastilles, wherein the active ingredient is formulated with a carrier such as sugar and acacia, tragacanth, or gelatin and glycerin.
- Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter.
- compositions suitable for transdermal administration include ointments, gels and patches.
- composition is in unit dose form such as a tablet, capsule or ampoule.
- Each dosage unit for oral administration contains preferably from 1 to 250 mg (and for parenteral administration contains preferably from 0.1 to 25 mg) of a compound of the formula (I) or a physiologically acceptable salt thereof calculated as the free base.
- the physiologically acceptable compounds of the invention will normally be administered in a daily dosage regimen (for an adult patient) of, for example, an oral dose of between 1 mg and 500 mg, preferably between 10 mg and 400 mg,e.g. between 10 and 250 mg or an intravenous, subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg, preferably between 0.1 mg and 50 mg, e.g. between 1 and 25 mg of the compound of the formula (I) or a physiologically acceptable salt thereof calculated as the free base, the compound being administered 1 to 4 times per day.
- the compounds will be administered for a period of continuous therapy, for example for a week or more.
- the ability of the compounds to bind selectively to human D3 dopamine receptors can be demonstrated by measuring their binding to cloned receptors.
- the inhibition constants (Kj) of test compounds for displacement of [ ⁇ 1] iodosulpride binding to human D3 dopamine receptors expressed in CHO cells were determined as follows. The cell lines were shown to be free from bacterial, fungal and mycoplasmal contaminants, and stocks of each were stored frozen in liquid nitrogen. Cultures were grown as monolayers or in suspension in standard cell culture media. Cells were recovered by scraping (from monolayers) or by centrifugation (from suspension cultures), and were washed two or three times by suspension in phosphate buffered saline followed by collection by centrifugation. Cell pellets were stored frozen at -
- Crude cell membranes were prepared by homogenisation followed by high-speed centrifugation, and characterisation of cloned receptors achieved by radioligand binding.
- the membrane pellet was resuspended in ice-cold 50 mM Tris salts (pH 7.4 @ 37°C), using an Ultra-Turrax, and recentrifuged at 18,000 r.p.m for 15 min at 4°C in a Sorvall RC5C. The membranes were washed two more times with ice-cold 50 mM Tris salts (pH 7.4 @ 37°C). The final pellet was resuspended in 50 mM Tris salts (pH 7.4 @ 37°C), and the protein content determined using bovine serum albumin as a standard (Bradford, M. M. (1976) Anal. Biochem. 72, 248-254).
- the functional activity of compounds at human D2 and human D3 receptors may be determined using a Cytosensor Microphysiometer (McConnell HM et al Science 1992 257 1906-1912)
- McConnell HM et al Science 1992 257 1906-1912 a Cytosensor Microphysiometer
- cells hD2_CHO or hD3_CHO were seeded into 12mm Transwell inserts (Costar) at 300000 cells/cup in foetal calf serum (FCS)-containing medium. The cells were incubated for 6h at 37°C in 5%CO2, before changing to FCS-free medium.
- cups were loaded into the sensor chambers of the Cytosensor Microphysiometer (Molecular Devices) and the chambers perfused with running medium (bicarbonate-free Dulbecco's modified Eagles medium containing 2 mM glutamine and 44 mM NaCl) at a flow rate of 100 ul/min. Each pump cycle lasted 90s. The pump was on for the first 60s and the acidification rate determined between 68 and 88s, using the Cytosoft programme. Agonists and antagonists were diluted in running medium. In experiments to determine agonist activity, cells were exposed (4.5 min for hD2, 7.5 min for hD3) to increasing concentrations of putative agonist at half hour intervals. Seven concentrations of agonist were used.
- Peak acidification rate to each agonist concentration was determined and concentration-response curves fitted using Robofit [Tilford, N.S., Bowen, W.P. & Baxter, G.S. Br. J. Pharmacol. (1995) in press].
- cells were treated at 30 min intervals with five pulses of a submaximal concentration of quinpirole (100 nM for hD2 cells, 30 nM for hD3 cells), before exposure to the lowest concentration of putative antagonist. At the end of the next 30 min interval, cells were pulsed again with quinpirole (in the continued presence of the antagonist) before exposure to the next highest antagonist concentration. In all, five concentrations of antagonist were used in each experiment. Peak acidification rate to each agonist concentration was determined and concentration- inhibition curves fitted using Robofit.
- compositions represent typical pharmaceutical formulations according to the present invention, which may be prepared using standard methods.
- Buffer Suitable buffers include citrate, phosphate, sodium hydroxide/hydrochloric acid.
- Solvent Typically water but may also include cyclodextrins (1-100 mg) and co- solvents such as propylene glycol, polyethylene glycol and alcohol. Tablet
- Diluent e.g. Microcrystalline cellulose, lactose, starch
- Binder e.g. Polyvinylpyrrolidone, hydroxypropymethylcellulose
- Disintegrant e.g. Sodium starch glycollate, crospovidone Lubricant : e.g. Magnesium stearate, sodium stearyl fumarate.
- Suspending agent e.g. Xanthan gum, microcrystalline cellulose
- Diluent e.g. sorbitol solution, typically water
- Preservative e.g. sodium benzoate
- Buffer e.g. citrate
- Co-solvent e.g. alcohol, propylene glycol, polyethylene glycol, cyclodextrin
- Trifluoromethylsulfonic anhydride (33ml, 0.194 mmol) was added dropwise with stirring to an ice-cooled solution of 7-hydroxy-2-(4-phthalimidobutyl)- 1,2,3,4- tetrahydroisoquinoline (51.3g, 0.146 mmol) in anhydrous pyridine (150ml). After stirring at room temperature for 18h the reaction mixture was added to 10% aqueous Copper (II) sulfate (IL) and extracted into ethyl acetate (IL). The organic layer was separated, washed with 10% aqueous copper (II) sulfate (2x500ml), dried (Na j SO 4 ) and evaporated in vacuo. Chromatography on silica gel using 10-100% ethyl acetate- hexane gradient elution gave the title compound as a green oil (49.4g, 40%).
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Psychiatry (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP98929278A EP0981516A1 (en) | 1997-04-30 | 1998-04-27 | Substituted tetrahydroisoquinoline derivatives as modulators of dopamine d?3 receptors |
JP54662098A JP2001522366A (ja) | 1997-04-30 | 1998-04-27 | ドーパミンd▲上3▼受容体のモジュレーターとしての置換テトラヒドロイソキノリン誘導体 |
CA002288308A CA2288308A1 (en) | 1997-04-30 | 1998-04-27 | Substituted tetrahydroisoquinoline derivatives as modulators of dopamine d3 receptors |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB9708694.6A GB9708694D0 (en) | 1997-04-30 | 1997-04-30 | Compounds |
GB9708694.6 | 1997-04-30 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1998049145A1 true WO1998049145A1 (en) | 1998-11-05 |
Family
ID=10811545
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP1998/002581 WO1998049145A1 (en) | 1997-04-30 | 1998-04-27 | Substituted tetrahydroisoquinoline derivatives as modulators of dopamine d3 receptors |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP0981516A1 (ja) |
JP (1) | JP2001522366A (ja) |
CA (1) | CA2288308A1 (ja) |
GB (1) | GB9708694D0 (ja) |
WO (1) | WO1998049145A1 (ja) |
Cited By (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1999059974A1 (en) * | 1998-05-20 | 1999-11-25 | Smithkline Beecham Plc | Tetraisoquinololine derivatives as modulators of dopamine d3 receptors |
US6274593B1 (en) | 1997-05-01 | 2001-08-14 | Smithkline Beecham P.L.C. | Substituted tetrahydro isoquinolines as modulators of dopamine D3 receptors |
US6465485B1 (en) | 1997-05-03 | 2002-10-15 | Smithkline Beecham P.L.C. | Tetrahydroisoquinoline derivatives as modulators of dopamine D3 receptors |
JP2002534519A (ja) * | 1999-01-12 | 2002-10-15 | ビーエーエスエフ アクチェンゲゼルシャフト | ドーパミン−d3−レセプター親和性を有するトリアゾール化合物 |
US6605607B1 (en) | 1998-10-08 | 2003-08-12 | Smithkline Beecham P.L.C. | Tetrahydrobenzazepine derivatives useful as modulators of dopamine D3 receptors (antipsychotic agents) |
WO2006008133A2 (en) * | 2004-07-20 | 2006-01-26 | Siena Biotech S.P.A. | Modulators of alpha7 nicotinic acetylcholine receptors and therapeutic uses thereof |
US8163729B2 (en) | 2007-01-16 | 2012-04-24 | Wyeth | Modulators of α7 nicotinic acetylcholine receptors and therapeutic uses thereof |
US10005792B2 (en) | 2014-09-03 | 2018-06-26 | Ctxt Pty. Ltd. | Aminoindane-, aminotetrahydronaphthalene- and aminobenzocyclobutane-derived PRMT5-inhibitors |
WO2019146739A1 (ja) | 2018-01-26 | 2019-08-01 | 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縮環化合物 |
US10421743B2 (en) | 2016-03-09 | 2019-09-24 | Ctxt Pty Ltd | Tetrahydroisoquinolines as PRMT5 inhibitors |
US10494376B2 (en) | 2014-09-03 | 2019-12-03 | Ctxt Pty. Ltd. | Tetrahydroisoquinoline derived PRMT5-inhibitors |
US10519167B2 (en) | 2016-03-09 | 2019-12-31 | Ctxt Pty Ltd | 3-oxa-8-azabicyclo[3.2.1]octane derivatives and their use in the treatment of cancer and hemoglobinopathies |
US10550096B2 (en) | 2016-03-09 | 2020-02-04 | Ctxt Pty Ltd | Tetrahydroisoquinolines as PRMT5 inhibitors |
US10647708B2 (en) | 2014-09-03 | 2020-05-12 | Ctxt Pty. Ltd | Tetrahydroisoquinoline derived PRMT5-inhibitors |
US10745380B2 (en) | 2016-03-09 | 2020-08-18 | Ctxt Pty Ltd | Pyridine derivatives and their use in the treatment of cancer and hemoglobinopathies |
US10787434B2 (en) | 2016-03-09 | 2020-09-29 | Ctxt Pty, Ltd | Benzopiperdine derivatives and their use in the treatment of cancer and hemoglobinopathies |
US10870660B2 (en) | 2016-07-28 | 2020-12-22 | Shionogi & Co., Ltd. | Nitrogen-containing condensed ring compounds having dopamine D3 antagonistic effect |
US10961256B2 (en) | 2016-03-09 | 2021-03-30 | Ctxt Pty Ltd | PRMT5 inhibitors |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1660137A4 (en) * | 2003-07-31 | 2008-11-12 | Univ St Louis | SIGMA 2 RECEPTOR RADIOACTIVE TRACTORS FOR IMAGING THE STATE OF PROLIFERATION OF SOLID TUMORS |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0300865A1 (fr) * | 1987-07-16 | 1989-01-25 | Synthelabo | Dérivés de N-aminobutyl N-phényl arylamides, leur préparation et leur application en thérapeutique |
US5294621A (en) * | 1992-10-07 | 1994-03-15 | Ortho Pharmaceutical Corporation | Thieno tetrahydropyridines useful as class III antiarrhythmic agents |
WO1996002246A1 (de) * | 1994-07-15 | 1996-02-01 | Basf Aktiengesellschaft | Verwendung heterocyclischer verbindungen als dopamin-d3 liganden |
WO1997043262A1 (en) * | 1996-05-11 | 1997-11-20 | Smithkline Beecham P.L.C. | Tetrahydroisoquinoline derivatives as modulators of dopamine d3 receptors |
WO1998006699A1 (en) * | 1996-08-14 | 1998-02-19 | Smithkline Beecham Plc | Tetrahydroisoquinoline derivatives and their pharmaceutical use |
-
1997
- 1997-04-30 GB GBGB9708694.6A patent/GB9708694D0/en active Pending
-
1998
- 1998-04-27 CA CA002288308A patent/CA2288308A1/en not_active Abandoned
- 1998-04-27 EP EP98929278A patent/EP0981516A1/en not_active Withdrawn
- 1998-04-27 JP JP54662098A patent/JP2001522366A/ja active Pending
- 1998-04-27 WO PCT/EP1998/002581 patent/WO1998049145A1/en not_active Application Discontinuation
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0300865A1 (fr) * | 1987-07-16 | 1989-01-25 | Synthelabo | Dérivés de N-aminobutyl N-phényl arylamides, leur préparation et leur application en thérapeutique |
US5294621A (en) * | 1992-10-07 | 1994-03-15 | Ortho Pharmaceutical Corporation | Thieno tetrahydropyridines useful as class III antiarrhythmic agents |
WO1996002246A1 (de) * | 1994-07-15 | 1996-02-01 | Basf Aktiengesellschaft | Verwendung heterocyclischer verbindungen als dopamin-d3 liganden |
WO1997043262A1 (en) * | 1996-05-11 | 1997-11-20 | Smithkline Beecham P.L.C. | Tetrahydroisoquinoline derivatives as modulators of dopamine d3 receptors |
WO1998006699A1 (en) * | 1996-08-14 | 1998-02-19 | Smithkline Beecham Plc | Tetrahydroisoquinoline derivatives and their pharmaceutical use |
Non-Patent Citations (1)
Title |
---|
JERZY L. MOKROSZ ET AL: "8-[4-[2-(1,2,3,4-tetrahydroisoquinolinyl)]butyl]-8-azaspiro[4,5]decane-7,9-dione:A new 5-HT1a receptor ligand with the same activity profile as buspirone", JOURNAL OF MEDICINAL CHEMISTRY., vol. 39, no. 5, 1996, WASHINGTON US, pages 1125 - 1129, XP002074949 * |
Cited By (31)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6274593B1 (en) | 1997-05-01 | 2001-08-14 | Smithkline Beecham P.L.C. | Substituted tetrahydro isoquinolines as modulators of dopamine D3 receptors |
US6465485B1 (en) | 1997-05-03 | 2002-10-15 | Smithkline Beecham P.L.C. | Tetrahydroisoquinoline derivatives as modulators of dopamine D3 receptors |
US6414154B1 (en) | 1998-05-20 | 2002-07-02 | Smithkline Beecham P.L.C. | Tetraisoquinoline derivatives as modulators of dopamine D3 receptors |
WO1999059974A1 (en) * | 1998-05-20 | 1999-11-25 | Smithkline Beecham Plc | Tetraisoquinololine derivatives as modulators of dopamine d3 receptors |
US6605607B1 (en) | 1998-10-08 | 2003-08-12 | Smithkline Beecham P.L.C. | Tetrahydrobenzazepine derivatives useful as modulators of dopamine D3 receptors (antipsychotic agents) |
CZ303926B6 (cs) * | 1999-01-12 | 2013-06-26 | Abbott Gmbh & Co. Kg. | Derivát triazolu a farmaceutický prostredek s jeho obsahem |
US6583166B1 (en) | 1999-01-12 | 2003-06-24 | Abbott Laboratories | Triazole compounds with dopamine-D3-receptor affinity |
US6602867B1 (en) | 1999-01-12 | 2003-08-05 | Abbott Laboratories | Triazole compounds with dopamine-D3-receptor affinity |
US6579892B1 (en) | 1999-01-12 | 2003-06-17 | Abbott Laboratories | Triazole compounds with dopamine-D3-receptor affinity |
BG65086B1 (bg) * | 1999-01-12 | 2007-02-28 | Basf Aktiengesellschaft | Триазоли с допамин-d3 рецепторен афинитет |
BG65105B1 (bg) * | 1999-01-12 | 2007-02-28 | Basf Aktiengesellschaft | Триазоли с допамин-d3 рецепторен афинитет |
JP2002534519A (ja) * | 1999-01-12 | 2002-10-15 | ビーエーエスエフ アクチェンゲゼルシャフト | ドーパミン−d3−レセプター親和性を有するトリアゾール化合物 |
WO2006008133A2 (en) * | 2004-07-20 | 2006-01-26 | Siena Biotech S.P.A. | Modulators of alpha7 nicotinic acetylcholine receptors and therapeutic uses thereof |
WO2006008133A3 (en) * | 2004-07-20 | 2006-03-23 | Siena Biotech Spa | Modulators of alpha7 nicotinic acetylcholine receptors and therapeutic uses thereof |
US8163729B2 (en) | 2007-01-16 | 2012-04-24 | Wyeth | Modulators of α7 nicotinic acetylcholine receptors and therapeutic uses thereof |
US10494376B2 (en) | 2014-09-03 | 2019-12-03 | Ctxt Pty. Ltd. | Tetrahydroisoquinoline derived PRMT5-inhibitors |
US10005792B2 (en) | 2014-09-03 | 2018-06-26 | Ctxt Pty. Ltd. | Aminoindane-, aminotetrahydronaphthalene- and aminobenzocyclobutane-derived PRMT5-inhibitors |
US10647708B2 (en) | 2014-09-03 | 2020-05-12 | Ctxt Pty. Ltd | Tetrahydroisoquinoline derived PRMT5-inhibitors |
US10745380B2 (en) | 2016-03-09 | 2020-08-18 | Ctxt Pty Ltd | Pyridine derivatives and their use in the treatment of cancer and hemoglobinopathies |
US10519167B2 (en) | 2016-03-09 | 2019-12-31 | Ctxt Pty Ltd | 3-oxa-8-azabicyclo[3.2.1]octane derivatives and their use in the treatment of cancer and hemoglobinopathies |
US10550096B2 (en) | 2016-03-09 | 2020-02-04 | Ctxt Pty Ltd | Tetrahydroisoquinolines as PRMT5 inhibitors |
US10421743B2 (en) | 2016-03-09 | 2019-09-24 | Ctxt Pty Ltd | Tetrahydroisoquinolines as PRMT5 inhibitors |
US10787434B2 (en) | 2016-03-09 | 2020-09-29 | Ctxt Pty, Ltd | Benzopiperdine derivatives and their use in the treatment of cancer and hemoglobinopathies |
US10961256B2 (en) | 2016-03-09 | 2021-03-30 | Ctxt Pty Ltd | PRMT5 inhibitors |
US11028101B2 (en) | 2016-03-09 | 2021-06-08 | Ctxt Pty Ltd | 3-oxa-8-azabicyclo[3.2.1]octane derivatives and their use in the treatment of cancer and hemoglobinopathies |
US10870660B2 (en) | 2016-07-28 | 2020-12-22 | Shionogi & Co., Ltd. | Nitrogen-containing condensed ring compounds having dopamine D3 antagonistic effect |
US11345716B2 (en) | 2016-07-28 | 2022-05-31 | Shionogi & Co., Ltd. | Nitrogen-containing condensed ring compounds having dopamine D3 antagonistic effect |
US11897899B2 (en) | 2016-07-28 | 2024-02-13 | Shionogi & Co., Ltd. | Nitrogen-containing condensed ring compounds having dopamine D3 antagonistic effect |
WO2019146739A1 (ja) | 2018-01-26 | 2019-08-01 | 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縮環化合物 |
KR20200112910A (ko) | 2018-01-26 | 2020-10-05 | 시오노기 앤드 컴파니, 리미티드 | 도파민 d3 수용체 길항 작용을 갖는 축환 화합물 |
US11578084B2 (en) | 2018-01-26 | 2023-02-14 | Shionogi & Co., Ltd. | Condensed ring compounds having dopamine D3 receptor antagonistic effect |
Also Published As
Publication number | Publication date |
---|---|
EP0981516A1 (en) | 2000-03-01 |
GB9708694D0 (en) | 1997-06-18 |
CA2288308A1 (en) | 1998-11-05 |
JP2001522366A (ja) | 2001-11-13 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO1998049145A1 (en) | Substituted tetrahydroisoquinoline derivatives as modulators of dopamine d3 receptors | |
EP0917530B1 (en) | Tetrahydroisoquinoline derivatives as modulators of dopamine d3 receptors | |
EP1335915B1 (en) | Tetrahydrobenzazepine derivatives useful as modulators of dopamine d3 receptors (antipsychotic agents) | |
EP1119563B1 (en) | Tetrahydrobenzazepine derivatives useful as modulators of dopamine d3 receptors (antipsychotic agents) | |
US6465485B1 (en) | Tetrahydroisoquinoline derivatives as modulators of dopamine D3 receptors | |
EP0922035B1 (en) | Tetrahydroisoquinoline derivatives and their pharmaceutical use | |
US6274593B1 (en) | Substituted tetrahydro isoquinolines as modulators of dopamine D3 receptors | |
WO1998051671A1 (en) | Substituted tetrahydroisoquinoline derivatives as modulators of dopamine d3 receptors | |
EP1119562B1 (en) | 2,3-dihydro-1h-isoindole derivatives useful as modulators of dopamine d3 receptors (antipsychotic agents) | |
US6358974B1 (en) | Isoquinoline derivatives | |
EP1086095B1 (en) | Tetrahydroisoquinoline derivatives as modulators of dopamine d3 receptors | |
US6414154B1 (en) | Tetraisoquinoline derivatives as modulators of dopamine D3 receptors | |
US6855717B2 (en) | Tetrahydroisoquinoline derivatives as modulators of dopamine D3 receptors | |
MXPA01003645A (en) | Tetrahydrobenzazepine derivatives useful as modulators of dopamine d3 receptors (antipsychotic agents) |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): CA JP US |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE |
|
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
ENP | Entry into the national phase |
Ref country code: JP Ref document number: 1998 546620 Kind code of ref document: A Format of ref document f/p: F |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1998929278 Country of ref document: EP |
|
ENP | Entry into the national phase |
Ref document number: 2288308 Country of ref document: CA Ref country code: CA Ref document number: 2288308 Kind code of ref document: A Format of ref document f/p: F |
|
WWE | Wipo information: entry into national phase |
Ref document number: 09403840 Country of ref document: US |
|
WWP | Wipo information: published in national office |
Ref document number: 1998929278 Country of ref document: EP |
|
WWW | Wipo information: withdrawn in national office |
Ref document number: 1998929278 Country of ref document: EP |