WO1996012721A1 - Indole derivatives useful as serotonergic agents - Google Patents
Indole derivatives useful as serotonergic agents Download PDFInfo
- Publication number
- WO1996012721A1 WO1996012721A1 PCT/US1995/013124 US9513124W WO9612721A1 WO 1996012721 A1 WO1996012721 A1 WO 1996012721A1 US 9513124 W US9513124 W US 9513124W WO 9612721 A1 WO9612721 A1 WO 9612721A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- hydrogen
- alkyl
- compound
- carbon atoms
- pharmaceutically acceptable
- Prior art date
Links
- 239000003762 serotonin receptor affecting agent Substances 0.000 title description 3
- 229940054051 antipsychotic indole derivative Drugs 0.000 title description 2
- 150000002475 indoles Chemical class 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 50
- 239000001257 hydrogen Substances 0.000 claims abstract description 38
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 38
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 24
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract description 21
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 19
- 150000003839 salts Chemical class 0.000 claims abstract description 18
- -1 polymethylene Polymers 0.000 claims abstract description 15
- GXGJIOMUZAGVEH-UHFFFAOYSA-N Chamazulene Chemical group CCC1=CC=C(C)C2=CC=C(C)C2=C1 GXGJIOMUZAGVEH-UHFFFAOYSA-N 0.000 claims abstract description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 12
- 125000006828 (C2-C7) alkoxycarbonyl group Chemical group 0.000 claims abstract description 8
- 125000006773 (C2-C7) alkylcarbonyl group Chemical group 0.000 claims abstract description 8
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims abstract description 8
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims abstract description 8
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 8
- 239000000460 chlorine Substances 0.000 claims abstract description 8
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 8
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims abstract description 7
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims abstract description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 7
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims abstract description 7
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 7
- 239000011737 fluorine Substances 0.000 claims abstract description 7
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims abstract description 6
- 125000004429 atom Chemical group 0.000 claims abstract description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 6
- 125000006826 (C2-C7) alkylcarbonyloxy group Chemical group 0.000 claims abstract description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 4
- 125000000000 cycloalkoxy group Chemical group 0.000 claims abstract description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 4
- 125000003831 tetrazolyl group Chemical group 0.000 claims abstract description 4
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims abstract description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract 5
- 125000000217 alkyl group Chemical group 0.000 claims description 20
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 8
- 208000019901 Anxiety disease Diseases 0.000 claims description 6
- 230000036506 anxiety Effects 0.000 claims description 6
- 230000000949 anxiolytic effect Effects 0.000 claims description 5
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 5
- 239000002249 anxiolytic agent Substances 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims 5
- 125000002249 indol-2-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([*])=C([H])C2=C1[H] 0.000 claims 3
- 125000003545 alkoxy group Chemical group 0.000 claims 2
- 241000124008 Mammalia Species 0.000 claims 1
- 125000003342 alkenyl group Chemical group 0.000 claims 1
- 208000024891 symptom Diseases 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 abstract description 2
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 abstract 1
- 230000000862 serotonergic effect Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 49
- 239000007787 solid Substances 0.000 description 49
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 36
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 36
- 239000003921 oil Substances 0.000 description 32
- 235000019198 oils Nutrition 0.000 description 32
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 27
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 26
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 24
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 21
- 239000002904 solvent Substances 0.000 description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 19
- 239000000203 mixture Substances 0.000 description 18
- 238000000921 elemental analysis Methods 0.000 description 17
- 229940093499 ethyl acetate Drugs 0.000 description 16
- 235000019439 ethyl acetate Nutrition 0.000 description 16
- 239000000463 material Substances 0.000 description 15
- 239000012044 organic layer Substances 0.000 description 15
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 14
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 13
- 238000000746 purification Methods 0.000 description 13
- 239000000243 solution Substances 0.000 description 13
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 12
- 238000001914 filtration Methods 0.000 description 11
- 239000007788 liquid Substances 0.000 description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 239000000741 silica gel Substances 0.000 description 10
- 229910002027 silica gel Inorganic materials 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 9
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 9
- 239000006260 foam Substances 0.000 description 9
- 238000001953 recrystallisation Methods 0.000 description 9
- 239000007858 starting material Substances 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N EtOH Substances CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 235000019341 magnesium sulphate Nutrition 0.000 description 8
- 102000005962 receptors Human genes 0.000 description 7
- 108020003175 receptors Proteins 0.000 description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 5
- 239000000969 carrier Substances 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- QWCRAEMEVRGPNT-UHFFFAOYSA-N buspirone Chemical compound C1C(=O)N(CCCCN2CCN(CC2)C=2N=CC=CN=2)C(=O)CC21CCCC2 QWCRAEMEVRGPNT-UHFFFAOYSA-N 0.000 description 4
- 229960002495 buspirone Drugs 0.000 description 4
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 102000040125 5-hydroxytryptamine receptor family Human genes 0.000 description 3
- 108091032151 5-hydroxytryptamine receptor family Proteins 0.000 description 3
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 3
- 239000000935 antidepressant agent Substances 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 238000007911 parenteral administration Methods 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 229940076279 serotonin Drugs 0.000 description 3
- CFTOTSJVQRFXOF-UHFFFAOYSA-N 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole Chemical compound N1C2=CC=CC=C2C2=C1CNCC2 CFTOTSJVQRFXOF-UHFFFAOYSA-N 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 230000001430 anti-depressive effect Effects 0.000 description 2
- 229940005513 antidepressants Drugs 0.000 description 2
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 208000015114 central nervous system disease Diseases 0.000 description 2
- 230000006835 compression Effects 0.000 description 2
- 238000007906 compression Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- WDCDAAMJNUHOIY-UHFFFAOYSA-N ethyl acetate;2-propan-2-yloxypropane Chemical compound CCOC(C)=O.CC(C)OC(C)C WDCDAAMJNUHOIY-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 239000004533 oil dispersion Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 239000008174 sterile solution Substances 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- ZXLDQJLIBNPEFJ-UHFFFAOYSA-N tetrahydro-beta-carboline Natural products C1CNC(C)C2=C1C1=CC=C(OC)C=C1N2 ZXLDQJLIBNPEFJ-UHFFFAOYSA-N 0.000 description 2
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 2
- AEIDURNZWCNQIM-UHFFFAOYSA-N 1,2,3,4-tetrahydropyrazino[1,2-a]indole Chemical compound C1=CC=C2N3CCNCC3=CC2=C1 AEIDURNZWCNQIM-UHFFFAOYSA-N 0.000 description 1
- UCDZCXROJJYDIF-UHFFFAOYSA-N 1-(azepan-1-yl)-4-chloro-2-phenylbutan-1-one Chemical compound C=1C=CC=CC=1C(CCCl)C(=O)N1CCCCCC1 UCDZCXROJJYDIF-UHFFFAOYSA-N 0.000 description 1
- 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 1
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-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
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 235000003911 Arachis Nutrition 0.000 description 1
- 244000105624 Arachis hypogaea Species 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- 206010012335 Dependence Diseases 0.000 description 1
- 208000020401 Depressive disease Diseases 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 208000030814 Eating disease Diseases 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 208000019454 Feeding and Eating disease Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 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 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 238000004296 chiral HPLC Methods 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 125000005265 dialkylamine group Chemical group 0.000 description 1
- WBKFWQBXFREOFH-UHFFFAOYSA-N dichloromethane;ethyl acetate Chemical compound ClCCl.CCOC(C)=O WBKFWQBXFREOFH-UHFFFAOYSA-N 0.000 description 1
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 1
- 235000014632 disordered eating Nutrition 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- HHFAWKCIHAUFRX-UHFFFAOYSA-N ethoxide Chemical compound CC[O-] HHFAWKCIHAUFRX-UHFFFAOYSA-N 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 235000003599 food sweetener Nutrition 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
- 150000002334 glycols Chemical class 0.000 description 1
- RERZNCLIYCABFS-UHFFFAOYSA-N harmaline Chemical class C1CN=C(C)C2=C1C1=CC=C(OC)C=C1N2 RERZNCLIYCABFS-UHFFFAOYSA-N 0.000 description 1
- QKGYJVXSKCDGOK-UHFFFAOYSA-N hexane;propan-2-ol Chemical compound CC(C)O.CCCCCC QKGYJVXSKCDGOK-UHFFFAOYSA-N 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 125000005948 methanesulfonyloxy group Chemical group 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- FUAXXSWWKCVWMD-UHFFFAOYSA-N n,n-dipropyl-1,2,3,4-tetrahydronaphthalen-1-amine Chemical compound C1=CC=C2C(N(CCC)CCC)CCCC2=C1 FUAXXSWWKCVWMD-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 150000004885 piperazines Chemical class 0.000 description 1
- 229920006316 polyvinylpyrrolidine Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- OGHBATFHNDZKSO-UHFFFAOYSA-N propan-2-olate Chemical compound CC(C)[O-] OGHBATFHNDZKSO-UHFFFAOYSA-N 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000008259 solid foam Substances 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 229940066771 systemic antihistamines piperazine derivative Drugs 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- AIFRHYZBTHREPW-UHFFFAOYSA-N β-carboline Chemical class N1=CC=C2C3=CC=CC=C3NC2=C1 AIFRHYZBTHREPW-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Definitions
- the compounds of this invention possess high affinity for the serotonin 5- HTIA receptor and as such are useful as antidepressant and anxiolytic agents for the treatment of a variety of central nervous system disorders such as depression, anxiety, eating disorders, sexual disfunction, addiction and related problems.
- buspirone US Patent 3,717,634
- Buspirone is used extensively for the treatment of anxiety and this anxiolytic activity is believed to be due, at least partially, to its 5-HTI A receptor affinity [VanderMaelen et al., Eut. J. Pharmacol. 1986, 129 (123-130)].
- WO 9,311,122-A and US 4,988,814 exemplify piperazine derivatives as compounds with affinity for the 5-HTJ receptor.
- This invention relates to a series of novel compounds which are useful as pharmaceuticals and in particular have activity as serotonergic agents and have the general formula A,
- R] and R5 are independently hydrogen, fluorine, chlorine, bromine, iodine, trifluoromethyl, cyano, nitro, CO2H, C ⁇ -C(, alkyl, C2-C10 alkenyl, Ci- alkoxy, C3-C8 cycloalkyl, cycloalkylalkyl where the alkyl group is of 1 to 6 carbon atoms and the cycloalkyl group has 3 to 8 carbon atoms, C3-C8 cycloalkyloxy, C2-C7 alkylcarbonyl, C2-C7 alkylcarbonyloxy, C2-C7 alkoxycarbonyl, mono- or di- alkylaminocarbonyl in which each alkyl group, independently, contains 1 to 6 carbon atoms, tetrazolyl, OH, -(CH 2 ) l - ⁇ OH, -SH, -NH 2 or -(CH 2 )i-6 R8R9 where Rg is hydrogen, Ci
- RlO and Ri 1 together represent dimethylene whilst R2 is hydrogen or -C6 alkyl or R2 and R 1 ] together represent dimethylene whilst R io is Hydrogen;
- R3 and R 4 are hydrogen or taken together with the carbon atoms to which they are attached form a double bond
- R>5 and R7 are independently H, C1-C 1 0 alkyl, C2-C 1 0 alkenyl, C3-C8 cycloalkyl, cycloalkylalkyl where the alkyl group is 1 to 6 carbon atoms and the cycloalkyl group is 3 to 8 carbon atoms or R ⁇ and R7 taken together are polymethylene, which, with the nitrogen atom to which they are attached, form a ring of 3 to 8 atoms; or a pharmaceutically acceptable salt thereof.
- R ⁇ and R5 independently, represent hydrogen, fluorine, chlorine, bromine, trifluoromethyl, CO2H, C1-C3 alkyl, C1-C3 alkoxy, C2- C4 alkoxycarbonyl, mono- or di-alkylaminocarbonyl in which each alkyl group, independently, contains 1 to 6 carbon atoms, -OH, -NH2 or -(CH2)i-3NRgR9 where R8 is hydrogen or C1-C3 alkyl and R9 is hydrogen or C1-C3 alkyl; R2 is H or C1-C3 alkyl; R3 and R4 are hydrogen or taken together with the carbon atoms to which they are attached form a double bond; and R and R7, taken together are polymethylene, which, with the nitrogen atom to which they are attached, form a ring of 5 to 8 atoms; or a pharmaceutically acceptable salt thereof.
- the pharmaceutically acceptable salts may be those derived from such organic and inorganic acids as: acetic, lactic, citric, tartaric, succinic, maleic, malonic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, and similarly known acceptable acids.
- salts may be formed with pharmaceutically acceptable bases to form alkali metal (such as Na, K or Li), alkaline earth metal (such as Ca or Mg), the ammonium or mono- or dialkylamine salts, the alkyl portion of said amine salts containing 1 to 6 carbon atoms.
- the compounds of this invention possess one or three chiral centers depending on the identity of R3 and R4. Therefore they present diastereoisomers and enantiomers, which may be separated by conventional procedures.
- diastereoisomers and enantiomers which may be separated by conventional procedures.
- the compounds having formula A and their pharmaceutically acceptable salts may be prepared by process which comprises reaction of a compound having formula B
- Rl, R2,R3,R4,R10 and Rl 1 are as defined above with a compound having the formula C:
- X is a leaving group, for example, chlorine, bromine or methanesulfonyloxy and R5,R6 and R7 are as defined above and, where appropriate, converting a resultant compound havineg formula A into a pharmaceutically acceptable salt thereof.
- X is a leaving group, for example, chlorine, bromine or methanesulfonyloxy
- R5,R6 and R7 are as defined above and, where appropriate, converting a resultant compound havineg formula A into a pharmaceutically acceptable salt thereof.
- the compounds of this invention are conveniently prepared by the route shown in the following scheme. Specific examples are given in the Experimental Section. These examples are for illustrative purposes only and are not to be construed as limitations for the disclosed invention. Those skilled in the art will be aware of other methods of preparing compounds of this invention.
- the starting materials or intermediates are available commercially or can be prepared by standard literature procedures.
- the compounds of this invention demonstrated high affinity for the serotonin 5-HTj A receptor subtype, and are therefore useful in the treatment of multi- CNS disorders amenable to treatment with antidepressant and anxiolytic agents.
- the Pyride [3,4-b] indole derivatives are preferred.
- the compounds of this invention are characterized as anxiolytic and/or antidepressant agents useful in the treatment of depression and in alleviating anxiety .
- the compounds may be administered orally or parentally.
- the compounds may be administered neat or with a pharmaceutical carrier to a patient in need thereof.
- the pharmaceutical carrier may be solid or liquid.
- the invention therefore also provides a pharmaceutical composition comprising a compound having formula A or a pharmaceutically acceptable salt thereof in association or combination with a pharmaceutical carrier.
- Applicable solid carriers can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintergrating agents or an encapsulating material.
- the carrier is a finely divided solid which is in admixture with the finely divided active ingredient.
- the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired.
- the powders and tablets preferably contain up to 99% of the active ingredient.
- Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
- Liquid carriers may be used in preparing solutions, suspensions, emulsions, syrups and elixirs.
- the active ingredient of this invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fat.
- the liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators.
- suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators.
- liquid carriers for oral and parenteral administration include water (panicularly containing additives as above e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil).
- the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate.
- Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration.
- Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Oral administration may be either liquid or solid composition form.
- the pharmaceutical composition is in unit dosage form, e.g. as tablets or capsules.
- the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient;
- the unit dosage forms can be packaged compositions, for example packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids.
- the unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.
- the dosage to be used in the treatment of a specific patient suffering from depression or anxiety must be subjectively determined by the attending physician.
- the variables involved include the specific state of anxiety or depression, and the size, age and response pattern of the patient.
- Triethylsilane (27.8 ml, 174 mmol) was added under nitrogen to a solution of 1, 2, 3, 4-tetrahydro-9H-pyrido [3,4-b]indole (10.0 g, 58 mmol) in 150 ml of trifluoroacetic acid and the reaction stirred at 50°C for approximately five days. The solvent was removed under reduced pressure to give 96.88 g of a two phase oil.
Abstract
The compound of formula (A), where R1 and R5 are independently hydrogen, fluorine, chlorine, bromine, iodine, trifluoromethyl, cyano, nitro, CO2H, C1-C6 alkyl, C2-C10 alkenyl, C1-C6 alkoxy, C3-C8 cycloalkyl, cycloalkylalkyl, C3-C8 cycloalkyloxy, C2-C7 alkylcarbonyl, C2-C7 alkylcarbonyloxy, C2-C7 alkoxycarbonyl, mono- or di-alkylaminocarbonyl, tetrazolyl, -OH, -(CH2)1-6OH, -SH, -NH2 or -(CH2)1-6NR8R9 where R8 is hydrogen, C1-C6 alkyl, C2-C7 alkylcarbonyl, C2-C7 alkoxycarbonyl and R9 is hydrogen or C1-C6 alkyl; R10 and R11 together represent dimethylene whilst R2 is hydrogen or C1-C6 alkyl or R2 and R11 together represent dimethylene whilst R10 is hydrogen; R3 and R4 are hydrogen or taken together with the carbon atoms to which they are attached form a double bond; R6 and R7 are independently H, C1-C10 alkyl, C2-C10 alkenyl, C3-C8 cycloalkyl, cycloalkylalkyl or R6 and R7 taken together are polymethylene, which, with the nitrogen atom to which they are attached, form a ring of 3 to 8 atoms; or a pharmaceutically acceptable salt thereof is useful as a serotonergic agent.
Description
ΪNnθl-F. DERIVATIVES USEFUL AS SEROTONERGIC AGENTS
Background of Invention
The compounds of this invention possess high affinity for the serotonin 5- HTIA receptor and as such are useful as antidepressant and anxiolytic agents for the treatment of a variety of central nervous system disorders such as depression, anxiety, eating disorders, sexual disfunction, addiction and related problems. As an example buspirone (US Patent 3,717,634 ) is known to display potent affinity for the 5-HTIA serotonin receptor. Buspirone is used extensively for the treatment of anxiety and this anxiolytic activity is believed to be due, at least partially, to its 5-HTI A receptor affinity [VanderMaelen et al., Eut. J. Pharmacol. 1986, 129 (123-130)].
WO 9,311,122-A and US 4,988,814 exemplify piperazine derivatives as compounds with affinity for the 5-HTJ receptor.
DESCRIPTION OF THE INVENTION
This invention relates to a series of novel compounds which are useful as pharmaceuticals and in particular have activity as serotonergic agents and have the general formula A,
where
R] and R5 are independently hydrogen, fluorine, chlorine, bromine, iodine, trifluoromethyl, cyano, nitro, CO2H, C\-C(, alkyl, C2-C10 alkenyl, Ci- alkoxy, C3-C8 cycloalkyl, cycloalkylalkyl where the alkyl group is of 1 to 6 carbon atoms and the cycloalkyl
group has 3 to 8 carbon atoms, C3-C8 cycloalkyloxy, C2-C7 alkylcarbonyl, C2-C7 alkylcarbonyloxy, C2-C7 alkoxycarbonyl, mono- or di- alkylaminocarbonyl in which each alkyl group, independently, contains 1 to 6 carbon atoms, tetrazolyl, OH, -(CH2)l -όOH, -SH, -NH2 or -(CH2)i-6 R8R9 where Rg is hydrogen, Ci - alkyl, C2 - C7 alkylcarbonyl, C2- C7 alkoxycarbonyl and R9 is hydrogen or
alkyl;
RlO and Ri 1 together represent dimethylene whilst R2 is hydrogen or -C6 alkyl or R2 and R 1 ] together represent dimethylene whilst R io is Hydrogen;
R3 and R4 are hydrogen or taken together with the carbon atoms to which they are attached form a double bond;
R>5 and R7 are independently H, C1-C10 alkyl, C2-C10 alkenyl, C3-C8 cycloalkyl, cycloalkylalkyl where the alkyl group is 1 to 6 carbon atoms and the cycloalkyl group is 3 to 8 carbon atoms or Rό and R7 taken together are polymethylene, which, with the nitrogen atom to which they are attached, form a ring of 3 to 8 atoms; or a pharmaceutically acceptable salt thereof.
The compounds where Ri o and R\ \ together represent dimethylene are Pyrido[3,4-b] indole derivatives. Those where R2 and R J I together represent dimethylene are pyrazino[ l,2-a] indole derivatives. Of both these kinds of compounds, a preferred group from the viewpoint of facile production and economic considerations, are those in which R\ and R5, independently, represent hydrogen, fluorine, chlorine, bromine, trifluoromethyl, CO2H, C1-C3 alkyl, C1-C3 alkoxy, C2- C4 alkoxycarbonyl, mono- or di-alkylaminocarbonyl in which each alkyl group, independently, contains 1 to 6 carbon atoms, -OH, -NH2 or -(CH2)i-3NRgR9 where R8 is hydrogen or C1-C3 alkyl and R9 is hydrogen or C1-C3 alkyl; R2 is H or C1-C3 alkyl; R3 and R4 are hydrogen or taken together with the carbon atoms to which they are attached form a double bond; and R and R7, taken together are polymethylene, which, with the nitrogen atom to which they are attached, form a ring of 5 to 8 atoms; or a pharmaceutically acceptable salt thereof.
The pharmaceutically acceptable salts may be those derived from such organic and inorganic acids as: acetic, lactic, citric, tartaric, succinic, maleic, malonic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, and similarly known acceptable acids. Where the compounds of this invention contain acidic substituents such as the carboxylic acid group, salts may be formed with pharmaceutically acceptable bases to form alkali metal (such as Na, K or Li), alkaline earth metal (such as Ca or Mg), the ammonium or mono- or dialkylamine salts, the alkyl portion of said amine salts containing 1 to 6 carbon atoms.
The compounds of this invention possess one or three chiral centers depending on the identity of R3 and R4. Therefore they present diastereoisomers and enantiomers, which may be separated by conventional procedures. In naming the compounds throughout this disclosure and in the appended claims it is to be understood that it is intended to embrace the isomers as their mixtures and in their pure form.
The compounds having formula A and their pharmaceutically acceptable salts may be prepared by process which comprises reaction of a compound having formula B
B
where Rl, R2,R3,R4,R10 and Rl 1 are as defined above with a compound having the formula C:
where X is a leaving group, for example, chlorine, bromine or methanesulfonyloxy and R5,R6 and R7 are as defined above and, where appropriate, converting a resultant compound havineg formula A into a pharmaceutically acceptable salt thereof. In particular the compounds of this invention are conveniently prepared by the route shown in the following scheme. Specific examples are given in the Experimental Section. These examples are for illustrative purposes only and are not to be construed as limitations for the disclosed invention. Those skilled in the art will be aware of other methods of preparing compounds of this invention. The starting materials or intermediates are available commercially or can be prepared by standard literature procedures.
High affinity for the serotonin 5-HTJ A receptor for the compounds of this invention was established by testing them in accordance with the standard pharmacological test procedure in which the compound's ability to displace [3H] 8- OHDPAT (dipropylaminotetralin) from the 5-HTI A serotonin receptor was determined following the procedure of Hall et al., J. Neurochem. 44 1685 (1985). This procedure is employed to analogize the properties of the claimed compounds with that of buspirone, which is a standard for anxiolytic activity, and, like the compounds of this invention, displays potent affinity for the 5-HTIA serotonin receptor subtype. The anxiolytic activity of buspirone is believed to be, at least partially, due to its 5-HTIA receptor affinity [VanderMaelen et al., Eur. J. Pharmacol. 1986, 129 (123-130)]. The results of this experimental test procedure are given in the following table:
TABLE
5-HTIA_Binding (ICSQ) Example 1 30.9 nM Example 2 33.3 nM
Example 3 37.1 nM
Example 4 67.4 nM
Example 6 85.3nM
Hence, the compounds of this invention demonstrated high affinity for the serotonin 5-HTj A receptor subtype, and are therefore useful in the treatment of multi- CNS disorders amenable to treatment with antidepressant and anxiolytic agents. The Pyride [3,4-b] indole derivatives are preferred.
Based upon this receptor binding data, the compounds of this invention are characterized as anxiolytic and/or antidepressant agents useful in the treatment of depression and in alleviating anxiety . The compounds may be administered orally or parentally. As such , the compounds may be administered neat or with a pharmaceutical carrier to a patient in need thereof. The pharmaceutical carrier may be solid or liquid. The invention therefore also provides a pharmaceutical composition comprising a compound having formula A or a pharmaceutically acceptable salt thereof in association or combination with a pharmaceutical carrier.
Applicable solid carriers can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintergrating agents or an encapsulating material. In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99% of the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
Liquid carriers may be used in preparing solutions, suspensions, emulsions, syrups and elixirs. The active ingredient of this invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fat. The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators. Suitable examples
of liquid carriers for oral and parenteral administration include water (panicularly containing additives as above e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil). For parenteral administration the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration.
Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Oral administration may be either liquid or solid composition form.
Preferably the pharmaceutical composition is in unit dosage form, e.g. as tablets or capsules. In such form, the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient; the unit dosage forms can be packaged compositions, for example packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids. The unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.
The dosage to be used in the treatment of a specific patient suffering from depression or anxiety must be subjectively determined by the attending physician. The variables involved include the specific state of anxiety or depression, and the size, age and response pattern of the patient.
EXAMPLE 1
1.A7eDan-1.vl-2.Dhenv[.4-ri.3.4.9-tetrahvdro-2H-nvridor3.4.h1indol.2.vn- l?utan-l- ng
A mixture of l ,2,3,4-terrahydro-9H-pyrido[3,4-b]indole (520 mg, 3.0 mmol), l -(azepan- l -yl)-4-chloro-2-phenyl-butan-l -one (840 mg, 3.0 mmol), N,N- diisopropylethylamine (520 μl, 3.0 mmol) and potassium iodide (500 mg, 3.0 mmol) in 15 ml of anhydrous dimethylformamide was heated under nitrogen at 80°C for five hours. The reaction was partitioned between ethyl acetate and water. The aqueous layer was separated and the organic layer washed five times with water. The organic layer was dried (MgSO4) and the solvent removed under reduced pressure to give 1.16 g of a brown oil. Purification of the oil on 200 g of silica gel (230-400 mesh) eluting with 75% ethyl acetate-hexane gave 441 mg of a solid foam. The foam was dissolved in diethyl ether containing a small amount of methylene chloride. To this solution was added 1.1 ml of I N ethereal HC1. An oil precipitated, which after concentration of the supernatant liquid, solidified. The solid was collected by filtration and then recrystallized from isopropyl alcohol - ethanol to give 329 mg (22%) of the title compound as a light brown solid, hydrochloride, 0.375 isopropanolate, 0.375 ethanolate, mp 238-239°C.
Elemental Analysis for C27H34CIN3OO.375 C H8O»0.375 C2H6O Calc'd: C, 70.51; H, 8.04; N, 8.54 Found: C, 70.51; H, 7.86; N, 8.75
EXAMPLE 2
l-A7eπan.l.vl-4-r9.ιnethvl.l.3.4.9.tetrahvdro.2H.nvridor3.4.h1.indol.2.vn.2. phenvl-hutan-l-one
A solution of benzyl chloroformate (8.3 ml, 58 mmol) in 20 ml of anhydrous tetrahydrofuran was added dropwise under nitrogen to a warm solution of 1,2,3,4- tetrahydro-9H-pyrido[3,4-b] indole (10.0 g, 58 mmol) and triethylamine (8.1 ml, 58 mmol) in 200 ml of anhydrous tetrahydrofuran. After the addition, the reaction was stirred at room temperature for four hours. The solvent was removed under reduced
pressure and the residue partitioned between ethyl acetate and IN HCl. The organic layer was separated, extracted one time with IN HCl, dried (MgSO 4) and the solvent removed under reduced pressure to give 15.7 g of an off-white solid. Recrystallization of the solid from 100 ml of 25% hexane-ethyl acetate gave 4.23 g (24%) of the benzyloxycarbonyl derivative of the starting material as a white solid. Recrystallization of the mother liquors from ethyl acetate-diisopropyl ether gave an additional 5.84 g (33%) of material, mp 102-104°C.
Elemental Analysis for C19H 18 2O2 Calc'd: C, 74.49; H, 5.92; N, 9.14
Found: C, 74.44; H, 5.96; N, 9.30
Sodium hydride [1.5 g of a 60% oil dispersion (37 mmol)] was added in portions over fifteen minutes to a solution of the material prepared in the previous paragraph (9.5 g, 31 mmol) in 100 ml of anhydrous dimethylformamide under nitrogen at room temperature. After the addition was complete the reaction was stirred for three hours. Methyl iodide (5.8 ml, 93 mmol) was then added and the reaction stirred at room temperature overnight. The reaction was quenched by the slow addition of IN HCl. The reaction was then partitioned between IN HCl and ethyl acetate. The organic layer was separated, extracted three times with water, dried (MgSO4) and the solvent removed under reduced pressure to give 10.4 g of a light yellow solid. Recrystallization of the solid from 100 ml of 20% ethyl acetate- diisopropyl ether gave 7.59 g (76%) of the 9-methyl derivative of the starting material as a white solid, mp 100-101°C.
Elemental Analysis for C20H20N2O2
Calc'd: C, 74.97; H, 6.29; N, 8.79 Found: C, 74.95; H, 6.30; N, 8.77
A mixture of the material prepared in the previous paragraph (4.0 g, 12 mmol) and 500 mg of 10% Pd/C in 40 ml of ethyl acetate was hydrogenated at room temperature and 40 psi for 5.5 hours. The catalyst was removed by filtration through celite and then rinsed thoroughly with ethanol and then dimethylformamide. The filtrate was concentrated under reduced pressure to give 2.39 g of an oil. The oil was dissolved in 15 ml of ethanol and 10 ml of IN ethereal HCl was added. A solid
formed which was collected by filtration, rinsed with diethyl ether, and dried under high vacuum to give 2.23 g (80%) of l,2,3,4-tetrahydro-9-methyl-pyrido[3,4-b]indole as the hydrochloride salt, mp > 250°C.
Elemental Analysis for C12H15CIN2
Calc'd: C, 64.71; H, 6.79; N, 12.58 Found: C, 64.50; H, 6.73; N, 12.51
A mixture of the material prepared in the previous paragraph (1.56 g, 7.0 mmol), l-(azepan- l-yl)-4-chloro-2-phenyl-butan- l-one (2.0 g, 7.0 mmol), N,N- diisopropylethylamine (2.4 ml, 14.0 mmol) and potassium iodide (1.2 g, 7.0 mmol) in
50 ml of anhydrous dimethylformamide was heated under nitrogen at 80°C for five hours and then left at room temperature overnight. The reaction was partitioned between ethyl acetate and water. The aqueous layer was separated and the organic layer washed five times with water. The organic layer was dried (MgSO4) and the solvent removed under reduced pressure to give 2.89 g of a brown foam. Purification of the foam on 400 g of silica gel (230-400 mesh) eluting with 75% ethyl acetate- hexane gave 2.34 g of an off-white foam. The foam was dissolved in diethyl ether and to this solution was added 7 ml of IN ethereal HCl. The solid formed was collected by filtration, rinsed with diethyl ether, and dried under high vacuum to give as a light yellow solid the title compound (2.00g, 58%) as a hydrochloride, hydrate,
0.08 diethyl etherate, mp 105-170°C.
Elemental Analysis for C28H38CIN3O2O.O8 C4H10O Calc'd: C, 69.41 ; H, 7.98; N, 8.87
Found: C, 69.47; H, 7.78; N, 8.64
EXAMPLE 3
l-A7enan-1.vl-4.fftrans>.9.melhvl.1., .4.4a.9-9a-hexahvdro-2H-Dvridor3.4- blindol-2-yl)-2-phenyl-butan-l-one
A mixture of l,2,3,4-tetrahydro-9-methyl-pyrido[3,4-b]indole hydrochloride, prepared in the third paragraph of Example 2 (4.50 g, 20 mmol), potassium carbonate (14.0 g, 100 mmol) and benzyl chloride (2.3 ml, 20 mmol) in 45 ml of water plus 45
ml of tetrahydrofuran was stirred at room temperature overnight. The reaction was partitioned between water and ethyl acetate. The organic layer was separated, extracted one time with saturated sodium chloride, one time with water, dried (MgSO4) and the solvent removed under reduced pressure to give 4.12 g of a yellow solid. Purification of the solid on 200 g of silica gel (230-400 mesh) eluting with hexane-ethyl acetate gave 3.67 g (66%) of the 2-benzyl derivative of the starting material as a white solid, mp 109-110°C.
Elemental Analysis for C19H20N2 Calc'd: C, 82.57; H, 7.29; N, 10.14
Found: C, 82.29; H, 7.29; N, 10.01
A solution of 1M BH3 THF (49.2 ml, 49.2 mmol) was added under nitrogen dropwise over ten minutes to a solution of the material prepared in the previous paragraph (3.63 g, 13 mmol) in 250 ml of anhydrous tetrahydrofuran at ice bath temperature. After the addition the cooling bath was removed and the reaction stirred at room temperature for thirty minutes and then refluxed for thirty minutes. After cooling to room temperature the solvent was removed under reduced pressure. To this residue 80 ml of one to one glacial acetic acid - IN HCl was added cautiously. After the evolution of gas ceased the reaction was refluxed for fifteen minutes and then stirred overnight at room temperature. The reaction was again refluxed for forty- five minutes and then cooled in an ice bath before 50% aqueous NaOH was added until the reaction was basic. The reaction was extracted with methylene chloride, dried (MgSO4) and the solvent removed under reduced pressure to give 5 g of a clear oil. Purification of the oil on 600 g of silica gel (230-400 mesh) eluting with 10% ethyl acetate - hexane gave 3.70 g of a white solid. Recrystallization of the solid from diisopropyl ether gave 2.61 g (71%) of the hexahydro derivative of the starting material as a white solid, mp 59-60°C.
Elemental Analysis for C19H22 2
Calc'd: C, 81.97; H, 7.97; N, 10.06 Found: C, 81.84; H, 7.95; N, 10.05
A mixture of the material prepared in the preceding paragraph (2.48 g, 8.9 mmol) and 1.2 g of 10% Pd/C in 250 ml of absolute ethanol was hydrogenated at room temperature and 40 psi for 24 hours. The catalyst was removed by filtration
through celite and the filtrate concentrated to dryness under reduced pressure to give 1.49 g of a tan solid. Recrystallization of the solid from diisopropyl ether gave 617 mg (37%) of the debenzylated derivative of the starting material as an off-white solid, mp 68-70°C.
Elemental Analysis for C12H16N2
Calc'd: C, 76.55; H, 8.57; N, 14.88
Found: C, 76.47; H, 8.68; N, 14.77
A mixture of the material produced in the previous paragraph (1.355 g, 7.2 mmol), l-(azepan- l -yl)-4-chloro-2-phenyl-butan- l-one (2.0 g, 7.2 mmol), N,N- diisopropylethylamine (1.3 ml, 7.2 mmol) and potassium iodide (1.2 g, 7.2 mmol) in 30 ml of anhydrous dimethylformamide was heated under nitrogen at 80°C for five hours. The reaction was partitioned between ethyl acetate and water. The organic layer was separated, washed four times with water, dried (MgSO4) and the solvent removed under reduced pressure to give 2.95 g of a brown solid. Purification of the solid on 300 g of silica gel (230-400 mesh) eluting with 50% hexane - ethyl acetate gave 2.30 g of an off-white solid. Recrystallization of the solid two times from isopropyl alcohol gave 0.542 g (17%) of the title compound as a white solid. NMR analysis of this material indicated it to be a single diastereomer, mp 1 1 1-1 13°C.
Elemental Analysis for C28H37N3O
Calc'd: C, 77.92; H, 8.64; N, 9.74
Found: C, 77.52; H, 8.70; N, 9.63
The mother liquor from the above recrystallization was purified by HPLC (hexane-isopropyl alcohol) to give 169 mg of a yellow oil. The oil was dissolved in diethyl ether plus a small amount of CH2CI2- One equivalent of IN ethereal HCl was added and the solvent was concentrated to approximately half its volume. Diethyl ether was added and a solid formed. The solid was collected by filtration, rinsed with diethyl ether and dried under high vacuum to give 88.4 mg of a brown solid. NMR analysis indicated the solid to be the other diastereomer formed in the reaction, melting range 150-200 'C.
Elemental Analysis for C28H37N3O»HC1«4H2O«0.1 C4H10O Calc'd: C, 62.30; H, 8.65; N, 7.67 Found: C, 62.81; H, 7.37; N, 7.60
EXAMPLE 4
l-AzeDan-1-yl-4-((cisV1.3.4.4a.9.9a-hexahvdro-2H-pyridor3.4-b1indol-2-vn-2- phenvl-butan-1-Qne
Triethylsilane (27.8 ml, 174 mmol) was added under nitrogen to a solution of 1, 2, 3, 4-tetrahydro-9H-pyrido [3,4-b]indole (10.0 g, 58 mmol) in 150 ml of trifluoroacetic acid and the reaction stirred at 50°C for approximately five days. The solvent was removed under reduced pressure to give 96.88 g of a two phase oil. Purification of the oil by HPLC eluting with 2:1 : 1 ethyl acetate:methanol:ammonium hydroxide gave 3.83 g of the hexahydro derivative (trifluroacetic acid salt) of the starting material as a white solid, mp 146-149°C.
Elemental Analysis for CnHi4N2»CF3CO2H Calc'd: C, 54.17; H, 5.24; N, 9.72.
Found: C, 54.26; H, 5.20; N, 9.70.
A mixture of the material produced in the previous paragraph (4.0 g, 14 mmol), l-(azepan- l-yl)-4-chloro-2-phenyl-butan- l-one (3.89 g, 14 mmol), N,N- diisopropylethylamine (4.85 ml, 28 mmol) and potassium iodide (2.31 g, 14 mmol) in 250 ml of anhydrous dimethylformamide was heated under nitrogen at 75°C for six hours. The reaction was partitioned between ethyl acetate and water. The organic layer was separated, washed multiple times with water, dried (MgSO4) and the solvent removed under reduced pressure to give 5.33 g of a brown oil. Purification of the oil by HPLC eluting with methanol-methylene chloride gave 1.14 g of a yellow oil. The oil was dissolved in diethyl ether containing a small amount of methylene chloride. One equivalent of ethereal HCl was added and the solid formed was collected by filtration and dried under high vacuum to give the title compound as a light brown solid, hydrochloride, hydrate, 0.2 diethyl etherate. NMR analysis and chiral HPLC showed the material to be a mixture of diastereomers and their enantiomers, mp 105-130°C.
Elemental Analysis for C27H35N3OΗCIΗ2OO.2 C4H10O Calc'd: C, 68.57; H, 8.28; N, 8.63. Found: C, 68.51; H, 8.19; N, 8.57.
EXAMPLE 5
l.AzeDan-l-vl-4-f(cis>-9-methvl-1.3.4.4a.9.9a-hexahvdro-2H-Dvridor3.4-hlindol-
2-vn.2-Dhenvl-hutane-1.one
A solution of benzyl chloroformate (3.80 mL, 26.6 mmol) in 100 mL of anhydrous dimethyl- formamide was added under nitrogen dropwise over two hours to a solution of the material prepared in paragraph 1 of Example 4 (7.64 g, 26.6 mmol) and triethylamine (7.42, 53.2 mmol) in 100 ml of anhydrous dimethylformamide at ice bath temperature. After the addition the reaction was stirred at ice bath temperature for two hours and at room temperature overnight. The reaction was diluted with ethyl acetate, washed multiple times with water, dried (MgSO4) and the solvent removed under reduced pressure to give 5.74g of an oil. Purification of the oil on 450g of silica gel (230-400 mesh) eluting with hexane-ethyl acetate gave 2.04g of a solid. Recrystallization of the solid from isopropyl alcohol gave 1.44g (18%) of the benzyloxycarbonyl derivative of the starting material, mp 88-90 *C.
Elemental Analysis for C19H20N2O2 Calc'd: C, 74.00; H, 6.54; N, 9.08
Found: C, 73.96; H, 6.54; N, 9.03
Sodium hydride (271 mg of a 60% oil dispersion containing 6.78 mmol) was added in portions under nitrogen to a solution of the material prepared in the preceding paragraph (1.74g, 5.65 mmol) in 20 ml anhydrous dimethylformamide at room temperature. After the addition , the reaction was stirred a room temperature for two hours. Methyl iodide (1.06 ml, 16.95 mmol) was added and the reaction stirred at room temperature overnight. The reaction was diluted with ethyl acetate, washed multiple times with water, dried (MgSO4) and the solvent removed under reduced pressure to give l.Og of an oil. Purification of the oil on 450g of silica gel (230-400
mesh) eluting with hexane- ethyl acetate gave 850 mg (47%) of the methyl derivative of the starting material as a clear oil, MS m/e 322 [M+].
Elemental Analysis for C20H22N2O2 Calc'd: C, 74.51 ; H, 6.88; N, 8.69
Found: C, 73.35; H, 6.85; N, 8.52
A mixture of the material prepared in the preceding paragraph (800 mg, 2.48 mmol) and 120 mg of 10% Pd/C in 80 ml of ethanol was hydrogenated at room temperature and 40 psi for 17 hours. The catalyst was removed by filtration through celite and the solvent was removed under reduced pressure to give 426 mg (91%) of a brown oil which was used in the next step without purification.
A mixture of the material prepared in the preceding paragraph (382 mg, 2.03 mmol), l-(azepan-l-yl)-4-chloro-2-phenyl-butan-l-one (568 mg, 2.03 mmol), N,N- diisopropylethylamine (353 μl, 2.03 mmol)and potassium iodide (337 mg, 2.03 mmol) in 15 ml of anhydrous dimethylformamide was stirred under nitrogen at 80*C for five hours. The reaction was partitioned between ethyl acetate and water. The aqueous layer was separated and the organic layer washed multiple times with water. The organic layer was dried (MgSO4) and the solvent removed under reduced pressure to give 739 mg of a brown oil. Purification of the oil on 200 g of silica gel (230-400 mesh) eluting with ethyl acetate-methylene chloride gave 361 mg of an off- white solid. This solid was further purified by trituration with hexane to give 205 mg of a solid. The solid (195 mg, 0.45 mmol) was dissolved in diethyl ether and 452 μl (0.45 mmol) of IN ethereal HCl was added. The solid formed was collected by filtration and dried under high vacuum to give as an off-white solid the title compound (120 mg, 12%) as a hydrochloride, sesquihydrate, 0.2 diethyl etherate, MS, m/e 431 (M+ - HCl).
Elemental Analyses for C28H37N3θ«HCl' 1.5 H2θ« 0.2 C4H 10O Calc'd: C, 67.84; H, 8.30; N, 8.24 Found: C, 68.09; H, 8.43; N, 8.48
EXAMPLE fi
1.AzeDan-1.vl.4.(3. 4.dihvdro-1H.Dvrazinori. 2-alindol-2.vl 2-Dhenvl- tnιtan-1-pne
A mixture of 1, 2, 3, 4-tetrahydropyrazino [1, 2-a]indole (2.35 g, 12 mmol), 1-
(azepan- l -yl)-4-chloro-2-phenyl-butan- l-one (2.72 g, 10 mmol), N, N- diisopropylethylamine (1.7 ml, 10 mmol) and potassium iodide (1.6 g, 10 mmol) in
50 ml of anhydrous dimethylformamide was heated under nitrogen at 80°C for five hours. The reaction was partitioned between ethyl acetate and water. The aqueous layer was separated and the organic layer washed five times with water. The organic layer was dried (MgSO4) and the solvent removed under reduced pressure to five 4.25 g of a brown oil. Purification of the oil on 400 g of silica gel (230-400 mesh) eluting with 30% ethyl acetate-hexane gave 3.70 g (92%) of a yellow foam. The foam (2.0 g) was dissolved in 30 ml of diethyl ether and 5 ml of IN ethereal HCl was added. The solid formed was collected by filtration, rinsed with diethyl ether and dried under high vacuum. Recrystallization of the solid from ethyl acetate gave the title compound as a light yellow solid, hydrochloride, hemihydrate, 0.233 ethylacetate, mp 145-150°C.
Elemental Analysis for C27H33N3O«HC1'0.5 H2O«0.233 C4H8O2 Calc'd: C, 69.66; H, 7.72; N, 8.72 Found: C, 69.91; H, 7.61; N, 8.65
EXAMPLE
1-AzeDan.l.vl-2-nhenvi-4.r3. 4. 10. lOa-te.rahvdro-IH.nvrazinori. 2-alindol-2- vl i-hntan-l-one
A mixture of 1, 2, 3, 4, 10, 10a-hexahydro-pyrazino[l, 2-a]indole (735.9 mg,
4.22 mmol), l-(azepan-l-yl)-4-chloro-2-phenyl-butan-l-one (1.18 g, 4.22 mmol), N, N-diisopropylethylamine (736 μl, 4.22 mmol) and potassium iodide (701 mg, 4.22 mmol) in 20 ml of anhydrous dimethylformamide was heated under nitrogen at 80°C for five hours. The reaction was partitioned between ethyl acetate and water. The aqueous layer was separated and the organic layer washed five times with water. The
organic layer was dried (MgSO4) and the solvent removed under reduced pressure to give 1.64 g of a dark brown oil. Purification of the oil on 400 g of silica gel (230-400 mesh) eluting with ethyl acetate gave 710 mg (40%) of a brown oil. The oil (610 mg) was dissolved in 10 ml of diethyl ether and 1.44 ml of IN ethereal HCl was added. The solid formed was collected by filtration. The solid on standing turned to a foam which was dried under high vacuum to give the title compound as a light tan foam, hydrochloride, sesquihydrate, 0.1 diethyl etherate, MS m e 417 M+.
Elemental Analysis for C27H35N3OΗCM .5 H2OO.IC4H10O Calc'd: C, 67.39; H, 8.25; N, 8.60
Found: C, 67.08; H, 8.00; N, 8.35
Claims
(1) A compound of the formula:
where Rl and R5 are independently hydrogen, fluorine, chlorine, bromine, iodine, trifluoromethyl, cyano, nitro, CO2H, Ci-Cό alkyl, C2-C1 0 alkenyl, Cj-Cό alkoxy, C3 - C8 cycloalkyl, cycloalkylalkyl where the alkyl group is of 1 to 6 carbon atoms and the cycloalkyl group has 3 to 8 carbon atoms, C3-C8 cycloalkyloxy, C2-C7 alkylcarbonyl, C2-C7 alkylcarbonyloxy, C2-C7 alkoxycarbonyl, mono- or di-alkylaminocarbonyl in which each alkyl group, independently, contains 1 to 6 carbon atoms, tetrazolyl, -OH, -(CH2)i-όOH, -SH, -NH2 or -(CH2)i-6NRsR9 where R8 is hydrogen, -C6 alkyl, C2-C7 alkylcarbonyl, C2-C7 alkoxycarbonyl and R9 is hydrogen or C1-C6 alkyl;
RlO and Rl 1 together represent dimethylene whilst R2 is hydrogen or C1-C6 hydrogen;
R3 and R4 are hydrogen or taken together with the carbon atoms to which they are attached form a double bond;
R6 and R7 are independently H, C1-C10 alkyl, C2-C10 alkenyl, C3-C8 cycloalkyl, cycloalkylalkyl where the alkyl group is 1 to 6 carbon atoms and the cycloalkyl group is 3 to 8 carbon atoms or R$ and R7 taken together are polymethylene, which, with the nitrogen atom to which they are attached, form a ring of 3 to 8 atoms; or a pharmaceutically acceptable salt thereof.
(2) A compound of Claim 1 in which Rio and Rπ together represent dimethylene whilst R2 is hydrogen or Ci-C alkyl.
(3) A compound of Claim 2 in which Ri and R5, independently, represent hydrogen, fluorine, chlorine, bromine, trifluoromethyl, CO2H, C1-C3 alkyl, C1-C3 alkoxy, C2-C4 alkoxycarbonyl, mono- or di-alkylaminocarbonyl in which each alkyl group, independently, contains 1 to 6 carbon atoms, -OH, -NH2 or -(CH2)i-3NR8R9 where Rs is hydrogen or C1-C3 alkyl and R9 is hydrogen or C1-C3 alkyl; R2 is H or C1-C3 alkyl; R3 and R4 are hydrogen or taken together with the carbon atoms to which they are attached form a double bond; and R6 and R t taken together are polymethylene, which, with the nitrogen atom to which they are attached, form a ring of 5 to 8 atoms; or a pharmaceutically acceptable salt thereof.
(4) The compound of Claim 2 which is l -azepan- l -yl-2-phenyl-4-( 1,3,4,9- tetrahydro-2H-pyrido[3,4-b]indol-2-yl]-butan-l-one or a pharmaceutically acceptable salt thereof.
(5) The compound of Claim 2 which is l-azepan-l -yl-4-(9-methyl- 1,3,4,9- tetrahydro-2H-pyrido[3,4-b]indol-2-yl]-2-phenyl-butan-l-one or a pharmaceutically acceptable salt thereof.
(6) The compound of Claim 2 which is l-azepan-l-yl-4-((trans)-9-methyl- l,3,4,4a,9,9a-hexahydro-2H-pyrido[3,4-b]indol-2-yl)-2-phenyl-butan-l-one or a pharmaceutically acceptable salt thereof.
(7) The compound of Claim 2 which is l-azepan-l-yl-4-((cis)- l,3,4,4a,9,9a- hexahydro-2H-pyrido[3,4-b]indol-2-yl)-2-phenyl-butan-l-one or a pharmaceutically acceptable salt thereof.
(8) The compound of Claim 2 which is l-azepan-l-yl-4-((cis)-9-methyl- l,3,4,4a,9,9a-hexahydro-2H-pyrido[3,4-b]indol-2-yl)-2-phenyl-butane-l-one
(9) A compound of Claim 1, in which R2 and Ri i together represent dimethylene whilst Rio is hydrogen.
(10) A compound of Claim 9 in which R\ and R5, independently, represent hydrogen, fluorine, chlorine, bromine, trifluoromethyl, CO2H, C1-C3 alkyl, C1-C3 alkoxy, C2-C4 alkoxycarbonyl, mono- or di-alkylaminocarbonyl in which each alkyl group, independently, contains 1 to 6 carbon atoms, -OH, -NH2 or -(CH2)i-3NRsR9 where Rs is hydrogen or C1-C3 alkyl and R9 is hydrogen or C1-C3 alkyl; R3 and R4 are hydrogen or taken together with the carbon atoms to which they are attached form a double bond; and R(, and R7 taken together are polymethylene, which, with the nitrogen atom to which they are attached, form a ring of 5 to 8 atoms; or a pharmaceutically acceptable salt thereof.
(11) The compound of Claim 9 which is l-azepan- l -yl-4-(3, 4-dihydro-lH- pyrazinof l, 2-a]indol-2-yl)-2-phenyl-butan-l-one or a pharmaceutically acceptable salt thereof.
(12) The compound of Claim 9 which is l-azepan-l-yl-2-phenyl-4-(3, 4, 10, 10a- tetrahydro-l H-pyrazino[l , 2-a]indol-2-yl)-butane- l -one or a pharmaceutically acceptable salt thereof.
(13) A pharmaceutical composition of matter comprising a compound of as claimed in any one of Claims 1 to 12 in combination or association with a pharmaceutically acceptable carrier.
(14) A process for the preparation of a compound as claimed in Claim 1, which comprises reaction of a compound having formula B:
B
where Rl, R2, R3, R4, Rl0> and Rl 1 are as defined in claim 1 with a compound having the formula C
where X is a leaving group and R5, R6 and R7 are as defined in Claim 1 and, where appropriate, converting a resultant compound having the formula A into a pharmaceutically acceptable salt thereof.
(15) A method for relieving symptoms of anxiety which comprises administering a compound as claimed in any one of Claims 1 to 12 in an anxiolytic amount to a mammal in need thereof.
A ENDED CLAIMS
[received by the International Bureau on 19 February 1996 (19.02.96); original claim 1 amended; remaining claims unchanged (1 page)]
( 1 ) A compound of the formula:
where R\ and R5 are independently hydrogen, fluorine, chlorine, bromine, iodine, trifluoromethyl, cyano, nitro, CO2H, Cj-C6 alkyl, C2-C10 alkenyl, C\-C(, alkoxy, C3-C8 cycloalkyl, cycloalkylalkyl where the alkyl group is of 1 to 6 carbon atoms and the cycloalkyl group has 3 to 8 carbon atoms, C3-C8 cycloalkyloxy, C2-C7 alkylcarbonyl, C2-C7 alkylcarbonyloxy, C2-C7 alkoxycarbonyl, mono- or di- alkylaminocarbonyl in which each alkyl group, independently, contains 1 to 6 carbon atoms, tetrazolyl, -OH, -(CH2)i-6OH, -SH, -NH2 or -(CH2)i-6NRgR9 where R8 is hydrogen, Ci-Cβ alkyl, C2-C7 alkylcarbonyl, C2-C7 alkoxycarbonyl and R9 is hydrogen or Cj-Cό alkyl;
RlO and Ri 1 together represent dimethylene whilst R2 is hydrogen oτ C\-C(, alkyl or R2 and Ri 1 together represent dimethylene whilst R10 is hydrogen;
R3 and R4 are hydrogen or taken together with the carbon atoms to which they are attached form a double bond;
STATEMENT UNDER ARTICLE 19
The amendment at page 18 consists in the correction of an obvious error in the definition of the symbols R2, RlO and Rll- The error resided in the omission of the words "alkyl or R2 and Rn together represent dimethylene whilst Rio is". The correction does not involve the introduction of new matter because the correct definition of the aforesaid symbols can be seen from page 2, lines 9 to 11 and claims 2 and 9 as originally filed.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU38314/95A AU3831495A (en) | 1994-10-20 | 1995-10-03 | Indole derivatives useful as serotonergic agents |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US32643394A | 1994-10-20 | 1994-10-20 | |
US08/326,433 | 1994-10-20 | ||
US08/326,435 | 1994-10-20 | ||
US08/326,435 US5466688A (en) | 1994-10-20 | 1994-10-20 | Pyrido[3,4-B]indole derivatives as serotonergic agents |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1996012721A1 true WO1996012721A1 (en) | 1996-05-02 |
Family
ID=26985403
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1995/013124 WO1996012721A1 (en) | 1994-10-20 | 1995-10-03 | Indole derivatives useful as serotonergic agents |
Country Status (2)
Country | Link |
---|---|
AU (1) | AU3831495A (en) |
WO (1) | WO1996012721A1 (en) |
Cited By (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002072584A2 (en) * | 2001-03-13 | 2002-09-19 | F. Hoffmann-La Roche Ag | Tetrahydro-pyrazino (1,2-a) indoles for the treatment of central nervous disorders |
US8618299B2 (en) | 2009-07-01 | 2013-12-31 | Albany Molecular Research, Inc. | Azinone-substituted azapolycycle MCH-1 antagonists, methods of making, and use thereof |
US8629158B2 (en) | 2009-07-01 | 2014-01-14 | Albany Molecular Research, Inc. | Azabicycloalkane-indole and azabicycloalkane-pyrrolo-pyridine MCH-1 antagonists, methods of making, and use thereof |
US8637501B2 (en) | 2009-07-01 | 2014-01-28 | Albany Molecular Research, Inc. | Azinone-substituted azepino[b]indole and pyrido-pyrrolo-azepine MCH-1 antagonists, methods of making, and use thereof |
US8697700B2 (en) | 2010-12-21 | 2014-04-15 | Albany Molecular Research, Inc. | Piperazinone-substituted tetrahydro-carboline MCH-1 antagonists, methods of making, and uses thereof |
US8716308B2 (en) | 2008-01-11 | 2014-05-06 | Albany Molecular Research, Inc. | (1-azinone)-substituted pyridoindoles |
US8993765B2 (en) | 2010-12-21 | 2015-03-31 | Albany Molecular Research, Inc. | Tetrahydro-azacarboline MCH-1 antagonists, methods of making, and uses thereof |
US9006245B2 (en) | 2012-03-16 | 2015-04-14 | Vitae Pharmaceuticals, Inc. | Liver X receptor modulators |
US9073925B2 (en) | 2009-07-01 | 2015-07-07 | Albany Molecular Research, Inc. | Azinone-substituted azabicycloalkane-indole and azabicycloalkane-pyrrolo-pyridine MCH-1 antagonists, methods of making, and use thereof |
US9073931B2 (en) | 2012-03-16 | 2015-07-07 | Vitae Pharmaceuticals, Inc. | Liver X receptor modulators |
JP2016516829A (en) * | 2013-04-23 | 2016-06-09 | ラボラトリオス・デル・ドクトル・エステベ・ソシエダッド・アノニマ | Pyrazino [1,2-a] indole compounds, their preparation and use as pharmaceuticals |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3641030A (en) * | 1968-10-21 | 1972-02-08 | American Home Prod | 4 5-dihydro-n-(4-phenyl-1-piperazinylcarbonyl-1h( 14)-diazepino (12-a)indole |
US4754038A (en) * | 1987-02-26 | 1988-06-28 | American Home Products Corporation | Carboline histamine H1 antagonists |
EP0302788A1 (en) * | 1987-08-07 | 1989-02-08 | Synthelabo | 2-[Methyl(4-piperidinyl)]-1,2,3,4-tetrahydro-9H-pyrido[3,4-b] indole derivatives, their preparation and therapeutical use |
-
1995
- 1995-10-03 AU AU38314/95A patent/AU3831495A/en not_active Abandoned
- 1995-10-03 WO PCT/US1995/013124 patent/WO1996012721A1/en active Application Filing
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3641030A (en) * | 1968-10-21 | 1972-02-08 | American Home Prod | 4 5-dihydro-n-(4-phenyl-1-piperazinylcarbonyl-1h( 14)-diazepino (12-a)indole |
US4754038A (en) * | 1987-02-26 | 1988-06-28 | American Home Products Corporation | Carboline histamine H1 antagonists |
EP0302788A1 (en) * | 1987-08-07 | 1989-02-08 | Synthelabo | 2-[Methyl(4-piperidinyl)]-1,2,3,4-tetrahydro-9H-pyrido[3,4-b] indole derivatives, their preparation and therapeutical use |
Non-Patent Citations (1)
Title |
---|
Z. J. VEJDELEK ET AL: "Synthetic experiments in the group of hypotensive alkaloids. XXI. Chemistry of 1,2,3,4-tetrahydronorharmane-1-carboxylic acid and derivatives", JOURNAL OF MEDICINAL AND PHARMACEUTICAL CHEMISTRY, vol. 3, no. 3, 1961, pages 427 - 440 * |
Cited By (20)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002072584A3 (en) * | 2001-03-13 | 2003-01-03 | Hoffmann La Roche | Tetrahydro-pyrazino (1,2-a) indoles for the treatment of central nervous disorders |
US6844345B2 (en) | 2001-03-13 | 2005-01-18 | Hoffman-La Roche Inc. | Piperazine derivatives |
WO2002072584A2 (en) * | 2001-03-13 | 2002-09-19 | F. Hoffmann-La Roche Ag | Tetrahydro-pyrazino (1,2-a) indoles for the treatment of central nervous disorders |
US9296743B2 (en) | 2008-01-11 | 2016-03-29 | Albany Molecular Research, Inc. | (1-azinone)-substituted pyridoindoles |
US8716308B2 (en) | 2008-01-11 | 2014-05-06 | Albany Molecular Research, Inc. | (1-azinone)-substituted pyridoindoles |
US9650378B2 (en) | 2008-01-11 | 2017-05-16 | Albany Molecular Research, Inc. | (1-azinone)-substituted pyridoindoles |
US8618299B2 (en) | 2009-07-01 | 2013-12-31 | Albany Molecular Research, Inc. | Azinone-substituted azapolycycle MCH-1 antagonists, methods of making, and use thereof |
US8629158B2 (en) | 2009-07-01 | 2014-01-14 | Albany Molecular Research, Inc. | Azabicycloalkane-indole and azabicycloalkane-pyrrolo-pyridine MCH-1 antagonists, methods of making, and use thereof |
US8637501B2 (en) | 2009-07-01 | 2014-01-28 | Albany Molecular Research, Inc. | Azinone-substituted azepino[b]indole and pyrido-pyrrolo-azepine MCH-1 antagonists, methods of making, and use thereof |
US9073925B2 (en) | 2009-07-01 | 2015-07-07 | Albany Molecular Research, Inc. | Azinone-substituted azabicycloalkane-indole and azabicycloalkane-pyrrolo-pyridine MCH-1 antagonists, methods of making, and use thereof |
US8697700B2 (en) | 2010-12-21 | 2014-04-15 | Albany Molecular Research, Inc. | Piperazinone-substituted tetrahydro-carboline MCH-1 antagonists, methods of making, and uses thereof |
US8993765B2 (en) | 2010-12-21 | 2015-03-31 | Albany Molecular Research, Inc. | Tetrahydro-azacarboline MCH-1 antagonists, methods of making, and uses thereof |
US9006244B2 (en) | 2012-03-16 | 2015-04-14 | Vitae Pharmaceuticals, Inc. | Liver X receptor modulators |
US9073931B2 (en) | 2012-03-16 | 2015-07-07 | Vitae Pharmaceuticals, Inc. | Liver X receptor modulators |
US9388190B2 (en) | 2012-03-16 | 2016-07-12 | Vitae Pharmaceuticals, Inc. | Liver X receptor modulators |
US9416135B2 (en) | 2012-03-16 | 2016-08-16 | Vitae Pharmaceuticals, Inc. | Liver X receptor modulators |
US9006245B2 (en) | 2012-03-16 | 2015-04-14 | Vitae Pharmaceuticals, Inc. | Liver X receptor modulators |
US9707232B2 (en) | 2012-03-16 | 2017-07-18 | Vitae Pharmaceuticals, Inc. | Liver X receptor modulators |
US9814715B2 (en) | 2012-03-16 | 2017-11-14 | Vitae Pharamceuticals, Inc. | Liver X receptor modulators |
JP2016516829A (en) * | 2013-04-23 | 2016-06-09 | ラボラトリオス・デル・ドクトル・エステベ・ソシエダッド・アノニマ | Pyrazino [1,2-a] indole compounds, their preparation and use as pharmaceuticals |
Also Published As
Publication number | Publication date |
---|---|
AU3831495A (en) | 1996-05-15 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
KR100341190B1 (en) | Piperidine and Piperazine | |
HU211566A9 (en) | New benzimidazoline-2-oxo-1-carboxylic acid derivatives useful as 5-ht receptor antagonists | |
AU2002345266B2 (en) | 3,6-disubstituted azabicyclo [3.1.0]hexane derivatives useful as muscarinic receptor antagonists | |
IL110622A (en) | Bicyclic carboxamides n-substituted by bridged bicyclic amines | |
JPWO2002074746A1 (en) | Benzoazepine derivatives | |
KR100361950B1 (en) | 3-indolylpiperidine | |
JPH04290884A (en) | Alpha-oxoacetamide derivative | |
CA2042860A1 (en) | Bicyclic 1-aza-cycloalkanes | |
EP0339950A2 (en) | Dibenzofurancarboxamides, their use as pharmaceutical agents, a composition containing the same, and a process for the preparation thereof | |
WO1996012721A1 (en) | Indole derivatives useful as serotonergic agents | |
US5527794A (en) | Pyrido[3,4-b]indole derivatives as serotonergic agents | |
IE913987A1 (en) | New tricyclic compounds | |
US6057321A (en) | 1,4-diazabicyclo [2.2.2] oct-2-ylmethyl derivatives, their preparation and therapeutic application | |
US5439915A (en) | Pyrido[3,4-B]indole carboxamide derivatives as serotonergic agents | |
JP3315144B2 (en) | Derivatives of substituted imidazol-2-ones and methods for their production | |
IE862996L (en) | PHENOXY-SUBSTITUTED ß-CARBOLINE DERIVATIVES | |
EP1819709B1 (en) | Novel diazabicyclic aryl derivatives as cholinergy ligands | |
ITMI980305A1 (en) | ESTERS AND AMID OF ACID 2-OXO-2,3-DIHYDRO-BENZIMIDAZOL-1- CARBOXYLIC | |
EP0737677A1 (en) | 4-Indolylpiperazinyl derivates | |
RU2194047C2 (en) | Benzylpiperidines, method of their synthesis and pharmaceutical composition based on thereof | |
IE913005A1 (en) | Indolonaphthyridines | |
ES2239226T3 (en) | DERIVATIVES OF 6H-OXAZOLO (4,5-E) INDOL AS LIGANDS OF NICOTINIC ACETILCOLINE RECEPTORS AND / OR SEROTONERGIC LIGANDS. | |
CA2042443A1 (en) | Tricyclic compounds | |
IE59757B1 (en) | 5-Aminoalkyl- beta -carboline derivatives, their production and their use as durgs | |
EP1421086B1 (en) | 2-(AMINOMETHYL)-TETRAHYDRO-9-OXA-1,3-DIAZA-CYCLOPENTA a|NAPHTHALENYL DERIVATIVES WITH ANTIPSYCHOTIC ACTIVITY |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AM AU BB BG BR BY CA CN CZ EE FI GE HU IS JP KG KP KR KZ LK LR LT LV MD MG MK MN MX NO NZ PL RO RU SD SE SG SI SK TJ TM TT UA UG UZ VN |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): KE MW SD SZ UG AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG |
|
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 | ||
122 | Ep: pct application non-entry in european phase | ||
NENP | Non-entry into the national phase |
Ref country code: CA |