CA2438596C - Tetrahydro-pyrazino (1,2-a) indoles for the treatment of central nervous disorders - Google Patents

Info

Publication number

CA2438596C

CA2438596C CA002438596A CA2438596A CA2438596C CA 2438596 C CA2438596 C CA 2438596C CA 002438596 A CA002438596 A CA 002438596A CA 2438596 A CA2438596 A CA 2438596A CA 2438596 C CA2438596 C CA 2438596C

Authority

CA

Canada

Prior art keywords

methyl

pyrazino

indole

tetrahydro

disorders

Prior art date

2001-03-13

Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

Expired - Fee Related

Links

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• 238000011282 treatment Methods 0.000 title claims abstract description 49
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims abstract description 24
• AEIDURNZWCNQIM-UHFFFAOYSA-N 1,2,3,4-tetrahydropyrazino[1,2-a]indole Chemical class C1=CC=C2N3CCNCC3=CC2=C1 AEIDURNZWCNQIM-UHFFFAOYSA-N 0.000 title description 6
• 150000001875 compounds Chemical class 0.000 claims abstract description 290
• 208000001072 type 2 diabetes mellitus Diseases 0.000 claims abstract description 30
• 150000003839 salts Chemical class 0.000 claims abstract description 23
• 208000008589 Obesity Diseases 0.000 claims abstract description 21
• 235000020824 obesity Nutrition 0.000 claims abstract description 21
• 208000035475 disorder Diseases 0.000 claims abstract description 17
• 210000003169 central nervous system Anatomy 0.000 claims abstract description 13
• 230000002265 prevention Effects 0.000 claims abstract description 13
• 150000002148 esters Chemical class 0.000 claims abstract description 9
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• 208000018522 Gastrointestinal disease Diseases 0.000 claims abstract description 7
• 230000006378 damage Effects 0.000 claims abstract description 7
• 102100026383 Vasopressin-neurophysin 2-copeptin Human genes 0.000 claims abstract description 6
• 201000010064 diabetes insipidus Diseases 0.000 claims abstract description 6
• 201000002859 sleep apnea Diseases 0.000 claims abstract description 5
• 239000012453 solvate Substances 0.000 claims abstract description 4
• 239000000203 mixture Substances 0.000 claims description 89
• 125000000217 alkyl group Chemical group 0.000 claims description 55
• -1 arylsulfoxyl Chemical group 0.000 claims description 51
• 239000001257 hydrogen Substances 0.000 claims description 44
• 229910052739 hydrogen Inorganic materials 0.000 claims description 44
• 238000000034 method Methods 0.000 claims description 41
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 24
• 150000002431 hydrogen Chemical group 0.000 claims description 23
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 22
• 125000003545 alkoxy group Chemical group 0.000 claims description 19
• 239000003814 drug Substances 0.000 claims description 18
• 229910052736 halogen Inorganic materials 0.000 claims description 18
• 150000002367 halogens Chemical group 0.000 claims description 18
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 17
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 16
• AHLBNYSZXLDEJQ-FWEHEUNISA-N orlistat Chemical group CCCCCCCCCCC[C@H](OC(=O)[C@H](CC(C)C)NC=O)C[C@@H]1OC(=O)[C@H]1CCCCCC AHLBNYSZXLDEJQ-FWEHEUNISA-N 0.000 claims description 16
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• 125000004093 cyano group Chemical group *C#N 0.000 claims description 14
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• 238000004519 manufacturing process Methods 0.000 claims description 13
• 230000008569 process Effects 0.000 claims description 12
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
• 125000003118 aryl group Chemical group 0.000 claims description 10
• 125000004438 haloalkoxy group Chemical group 0.000 claims description 9
• 125000001188 haloalkyl group Chemical group 0.000 claims description 9
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 9
• 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 8
• 125000004414 alkyl thio group Chemical group 0.000 claims description 8
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 8
• 229940079593 drug Drugs 0.000 claims description 8
• 125000000623 heterocyclic group Chemical group 0.000 claims description 8
• 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 8
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• 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 6
• 125000005110 aryl thio group Chemical group 0.000 claims description 6
• 238000002360 preparation method Methods 0.000 claims description 6
• WCCMHJIGZQDECL-SECBINFHSA-N (4r)-6-fluoro-4,7-dimethyl-1,2,3,4-tetrahydropyrazino[1,2-a]indole Chemical compound C1=C(C)C(F)=C2N3[C@H](C)CNCC3=CC2=C1 WCCMHJIGZQDECL-SECBINFHSA-N 0.000 claims description 5
• PLPARSCPGGUWDI-SECBINFHSA-N (4r)-8-fluoro-4,7-dimethyl-1,2,3,4-tetrahydropyrazino[1,2-a]indole Chemical compound FC1=C(C)C=C2N3[C@H](C)CNCC3=CC2=C1 PLPARSCPGGUWDI-SECBINFHSA-N 0.000 claims description 5
• 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 5
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• 125000001153 fluoro group Chemical group F* 0.000 claims description 5
• 230000001524 infective effect Effects 0.000 claims description 5
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
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• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
• 231100000331 toxic Toxicity 0.000 claims description 5
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• KYWYASJHTQNPQN-SNVBAGLBSA-N (4r)-4,6-dimethyl-1,2,3,4-tetrahydropyrazino[1,2-a]indole Chemical compound C1=CC(C)=C2N3[C@H](C)CNCC3=CC2=C1 KYWYASJHTQNPQN-SNVBAGLBSA-N 0.000 claims description 4
• QCCLCOBTVCROQM-MRVPVSSYSA-N (4r)-7-chloro-4-methyl-1,2,3,4-tetrahydropyrazino[1,2-a]indole Chemical compound C1=C(Cl)C=C2N3[C@H](C)CNCC3=CC2=C1 QCCLCOBTVCROQM-MRVPVSSYSA-N 0.000 claims description 4
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 4
• 125000005078 alkoxycarbonylalkyl group Chemical group 0.000 claims description 4
• 125000003806 alkyl carbonyl amino group Chemical group 0.000 claims description 4
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 4
• 125000005129 aryl carbonyl group Chemical group 0.000 claims description 4
• 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 4
• 125000005242 carbamoyl alkyl group Chemical group 0.000 claims description 4
• 125000004181 carboxyalkyl group Chemical group 0.000 claims description 4
• 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 4
• 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 4
• FDDMFHHTGQNMSI-SNVBAGLBSA-N (4r)-4,6,10-trimethyl-1,2,3,4-tetrahydropyrazino[1,2-a]indole Chemical compound C1=CC(C)=C2N3[C@H](C)CNCC3=C(C)C2=C1 FDDMFHHTGQNMSI-SNVBAGLBSA-N 0.000 claims description 3
• FZBQGXPBXAHHRF-SECBINFHSA-N (4r)-4-methyl-1,2,3,4-tetrahydropyrazino[1,2-a]indole-6-carbonitrile Chemical compound C1=CC(C#N)=C2N3[C@H](C)CNCC3=CC2=C1 FZBQGXPBXAHHRF-SECBINFHSA-N 0.000 claims description 3
• HAZWRUAJTCVCEE-MRVPVSSYSA-N (4r)-4-methyl-6-(trifluoromethyl)-1,2,3,4-tetrahydropyrazino[1,2-a]indole Chemical compound C1=CC(C(F)(F)F)=C2N3[C@H](C)CNCC3=CC2=C1 HAZWRUAJTCVCEE-MRVPVSSYSA-N 0.000 claims description 3
• FVONZVAYLZSBOJ-SECBINFHSA-N (4r)-6-ethyl-8-fluoro-4-methyl-1,2,3,4-tetrahydropyrazino[1,2-a]indole Chemical compound C1=C2CNC[C@@H](C)N2C2=C1C=C(F)C=C2CC FVONZVAYLZSBOJ-SECBINFHSA-N 0.000 claims description 3
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• 206010006550 Bulimia nervosa Diseases 0.000 claims description 3
• 206010008874 Chronic Fatigue Syndrome Diseases 0.000 claims description 3
• 206010012289 Dementia Diseases 0.000 claims description 3
• 208000026139 Memory disease Diseases 0.000 claims description 3
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• 208000019695 Migraine disease Diseases 0.000 claims description 3
• 208000027626 Neurocognitive disease Diseases 0.000 claims description 3
• 208000021384 Obsessive-Compulsive disease Diseases 0.000 claims description 3
• 206010036618 Premenstrual syndrome Diseases 0.000 claims description 3
• 208000028017 Psychotic disease Diseases 0.000 claims description 3
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• 206010041250 Social phobia Diseases 0.000 claims description 3
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• 125000005843 halogen group Chemical group 0.000 claims description 3
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• 208000029766 myalgic encephalomeyelitis/chronic fatigue syndrome Diseases 0.000 claims description 3
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• 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
• 208000010643 digestive system disease Diseases 0.000 claims description 2
• 208000018685 gastrointestinal system disease Diseases 0.000 claims description 2
• IZBGCWZNRUPEDO-LLVKDONJSA-N (4r)-4-methyl-6-thiophen-2-yl-1,2,3,4-tetrahydropyrazino[1,2-a]indole Chemical compound C([C@H](N1C2=3)C)NCC1=CC2=CC=CC=3C1=CC=CS1 IZBGCWZNRUPEDO-LLVKDONJSA-N 0.000 claims 1
• 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 219
• 238000007429 general method Methods 0.000 description 112
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 108
• 239000007787 solid Substances 0.000 description 101
• 239000000243 solution Substances 0.000 description 100
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 91
• 229940093499 ethyl acetate Drugs 0.000 description 73
• 235000019439 ethyl acetate Nutrition 0.000 description 73
• 239000000543 intermediate Substances 0.000 description 72
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 58
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 56
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 56
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 55
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• 238000002451 electron ionisation mass spectrometry Methods 0.000 description 49
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 48
• ZGFOJWQAHCHOLG-LURJTMIESA-N tert-butyl (5s)-5-methyl-2,2-dioxooxathiazolidine-3-carboxylate Chemical compound C[C@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1 ZGFOJWQAHCHOLG-LURJTMIESA-N 0.000 description 47
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• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 35
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• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 33
• KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 33
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• 235000019441 ethanol Nutrition 0.000 description 15
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 15
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• NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 14
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