NZ579360A

NZ579360A - Tricyclic isoquinoline derivatives for treatment of obesity

Tricyclic isoquinoline derivatives for treatment of obesity

Info

Publication number: NZ579360A
Authority: NZ; New Zealand
Prior art keywords: tetrahydro; azepino; indole; alkyl; methyl
Prior art date: 2007-03-13

Application number

NZ579360A

Other languages

English (en)

Inventor

Johan Angbrant

Peter Brandt

Rune Ringom

Bengt Lindqvist

Original Assignee

Proximagen Ltd

Priority date

2007-03-13

Filing date

2008-03-13

Publication date

2011-06-30

2008-03-13 Application filed by Proximagen Ltd filed Critical Proximagen Ltd

2011-06-30 Publication of NZ579360A publication Critical patent/NZ579360A/en

Links

238000011282 treatment Methods 0.000 title claims abstract description 14
208000008589 Obesity Diseases 0.000 title abstract description 9
235000020824 obesity Nutrition 0.000 title abstract description 9
125000002183 isoquinolinyl group Chemical class C1(=NC=CC2=CC=CC=C12)* 0.000 title description 2
150000001875 compounds Chemical class 0.000 claims abstract description 190
230000000694 effects Effects 0.000 claims abstract description 9
-1 imidazolyl-methyl Chemical group 0.000 claims description 131
125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 113
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 67
125000003118 aryl group Chemical group 0.000 claims description 47
AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 claims description 43
SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 38
239000001257 hydrogen Substances 0.000 claims description 36
229910052739 hydrogen Inorganic materials 0.000 claims description 36
150000003839 salts Chemical class 0.000 claims description 36
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 30
125000001072 heteroaryl group Chemical group 0.000 claims description 30
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 27
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 22
JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 21
125000001424 substituent group Chemical group 0.000 claims description 21
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 21
125000004093 cyano group Chemical group *C#N 0.000 claims description 20
229910052736 halogen Inorganic materials 0.000 claims description 20
150000002367 halogens Chemical class 0.000 claims description 20
125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 18
PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 18
RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 18
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 16
125000004432 carbon atom Chemical group C* 0.000 claims description 15
229910052799 carbon Inorganic materials 0.000 claims description 13
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 12
229910052757 nitrogen Inorganic materials 0.000 claims description 10
239000008194 pharmaceutical composition Substances 0.000 claims description 10
125000006413 ring segment Chemical group 0.000 claims description 10
239000003814 drug Substances 0.000 claims description 9
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 8
241001465754 Metazoa Species 0.000 claims description 8
125000004429 atom Chemical group 0.000 claims description 8
125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 7
125000001153 fluoro group Chemical group F* 0.000 claims description 7
125000000623 heterocyclic group Chemical group 0.000 claims description 7
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 7
230000003287 optical effect Effects 0.000 claims description 7
238000011321 prophylaxis Methods 0.000 claims description 7
125000001309 chloro group Chemical group Cl* 0.000 claims description 6
235000012631 food intake Nutrition 0.000 claims description 6
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
230000009467 reduction Effects 0.000 claims description 6
125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 5
ZUSWDTWYONAOPH-UHFFFAOYSA-N [2-(trifluoromethyl)phenyl]hydrazine;hydrochloride Chemical group [Cl-].[NH3+]NC1=CC=CC=C1C(F)(F)F ZUSWDTWYONAOPH-UHFFFAOYSA-N 0.000 claims description 5
125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 5
125000002883 imidazolyl group Chemical group 0.000 claims description 5
150000003951 lactams Chemical class 0.000 claims description 5
125000002950 monocyclic group Chemical group 0.000 claims description 5
IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 5
239000012453 solvate Substances 0.000 claims description 5
125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims description 5
125000001544 thienyl group Chemical group 0.000 claims description 5
125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 4
239000004480 active ingredient Substances 0.000 claims description 4
125000004104 aryloxy group Chemical group 0.000 claims description 4
125000002619 bicyclic group Chemical group 0.000 claims description 4
125000000723 dihydrobenzofuranyl group Chemical group O1C(CC2=C1C=CC=C2)* 0.000 claims description 4
239000003085 diluting agent Substances 0.000 claims description 4
125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 4
230000037406 food intake Effects 0.000 claims description 4
125000002541 furyl group Chemical group 0.000 claims description 4
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
125000000842 isoxazolyl group Chemical group 0.000 claims description 4
125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
125000004076 pyridyl group Chemical group 0.000 claims description 4
238000002560 therapeutic procedure Methods 0.000 claims description 4
125000000335 thiazolyl group Chemical group 0.000 claims description 4
125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 claims description 3
125000001731 2-cyanoethyl group Chemical group [H]C([H])(*)C([H])([H])C#N 0.000 claims description 3
125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 3
125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 3
125000004861 4-isopropyl phenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 3
108091005435 5-HT6 receptors Proteins 0.000 claims description 3
QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims description 3
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
125000005553 heteroaryloxy group Chemical group 0.000 claims description 3
QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 3
125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims description 3
125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 3
125000004496 thiazol-5-yl group Chemical group S1C=NC=C1* 0.000 claims description 3
125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 claims description 3
125000006528 (C2-C6) alkyl group Chemical group 0.000 claims description 2
WKKRCJNLADPSGP-UHFFFAOYSA-N 3-(benzenesulfonyl)-11-ethyl-3,11-diazatricyclo[6.4.1.04,13]trideca-1,4,6,8(13)-tetraene Chemical compound C1=C(C2=3)CN(CC)CCC2=CC=CC=3N1S(=O)(=O)C1=CC=CC=C1 WKKRCJNLADPSGP-UHFFFAOYSA-N 0.000 claims description 2
IQCBTUNXAQRCPO-UHFFFAOYSA-N 3-(benzenesulfonyl)-11-methyl-3,11-diazatricyclo[6.4.1.04,13]trideca-1,4,6,8(13)-tetraene Chemical compound C1=C(C2=3)CN(C)CCC2=CC=CC=3N1S(=O)(=O)C1=CC=CC=C1 IQCBTUNXAQRCPO-UHFFFAOYSA-N 0.000 claims description 2
BIUDHHGROGJSHN-UHFFFAOYSA-N 4-fluoro-3-(trifluoromethyl)benzaldehyde Chemical group FC1=CC=C(C=O)C=C1C(F)(F)F BIUDHHGROGJSHN-UHFFFAOYSA-N 0.000 claims description 2
PMYJVMYDCUOWSM-UHFFFAOYSA-N 5-(3,10-diazatricyclo[6.4.1.04,13]trideca-1,4,6,8(13)-tetraen-3-ylsulfonyl)-2-fluorobenzonitrile Chemical compound C1=C(C#N)C(F)=CC=C1S(=O)(=O)N1C(C=CC=C2CNCC3)=C2C3=C1 PMYJVMYDCUOWSM-UHFFFAOYSA-N 0.000 claims description 2
CUGMEDIZNAIZJK-UHFFFAOYSA-N 5-methyl-1-(phenylsulfonyl)-3,4,5,6-tetrahydro-1h-azepino[5,4,3-cd]indole Chemical compound C=12C3=CC=CC=1CN(C)CCC2=CN3S(=O)(=O)C1=CC=CC=C1 CUGMEDIZNAIZJK-UHFFFAOYSA-N 0.000 claims description 2
WMHLDULSLHZDIB-UHFFFAOYSA-N 6-methyl-1-(phenylsulfonyl)-3,4,5,6-tetrahydro-1h-azepino[5,4,3-cd]indol-7-ol Chemical compound C=12C3=CC=C(O)C=1C(C)NCCC2=CN3S(=O)(=O)C1=CC=CC=C1 WMHLDULSLHZDIB-UHFFFAOYSA-N 0.000 claims description 2
FNTIMKOXGDBGCH-UHFFFAOYSA-N 6-methyl-1-(phenylsulfonyl)-3,4,5,6-tetrahydro-1h-azepino[5,4,3-cd]indole Chemical compound C=12C3=CC=CC=1C(C)NCCC2=CN3S(=O)(=O)C1=CC=CC=C1 FNTIMKOXGDBGCH-UHFFFAOYSA-N 0.000 claims description 2
125000001246 bromo group Chemical group Br* 0.000 claims description 2
150000002431 hydrogen Chemical class 0.000 claims description 2
FGFUBBNNYLNVLJ-UHFFFAOYSA-N indol-3-one Chemical compound C1=CC=C2C(=O)C=NC2=C1 FGFUBBNNYLNVLJ-UHFFFAOYSA-N 0.000 claims description 2
238000004519 manufacturing process Methods 0.000 claims description 2
230000000052 comparative effect Effects 0.000 claims 3
XPDWGBQVDMORPB-UHFFFAOYSA-N Fluoroform Chemical compound FC(F)F XPDWGBQVDMORPB-UHFFFAOYSA-N 0.000 claims 2
LHRXWSTUFXVPDK-UHFFFAOYSA-N 3-(1-benzofuran-2-ylsulfonyl)-3,10-diazatricyclo[6.4.1.04,13]trideca-1,4,6,8(13)-tetraene Chemical compound C1CNCC2=CC=CC3=C2C1=CN3S(=O)(=O)C1=CC2=CC=CC=C2O1 LHRXWSTUFXVPDK-UHFFFAOYSA-N 0.000 claims 1
DFTKOYUJDUEEOW-UHFFFAOYSA-N 3-(2,5-difluorophenyl)sulfonyl-3,10-diazatricyclo[6.4.1.04,13]trideca-1,4,6,8(13)-tetraene Chemical compound FC1=CC=C(F)C(S(=O)(=O)N2C=3C=CC=C4CNCCC(C=34)=C2)=C1 DFTKOYUJDUEEOW-UHFFFAOYSA-N 0.000 claims 1
SXCMVHPFIXZXMR-UHFFFAOYSA-N 3-(2-chlorophenyl)sulfonyl-3,10-diazatricyclo[6.4.1.04,13]trideca-1,4,6,8(13)-tetraene Chemical compound ClC1=CC=CC=C1S(=O)(=O)N1C(C=CC=C2CNCC3)=C2C3=C1 SXCMVHPFIXZXMR-UHFFFAOYSA-N 0.000 claims 1
LGQZNSKGYATOKG-UHFFFAOYSA-N 3-(3,4-difluorophenyl)sulfonyl-3,10-diazatricyclo[6.4.1.04,13]trideca-1,4,6,8(13)-tetraene Chemical compound C1=C(F)C(F)=CC=C1S(=O)(=O)N1C(C=CC=C2CNCC3)=C2C3=C1 LGQZNSKGYATOKG-UHFFFAOYSA-N 0.000 claims 1
HDXZZLXIBGNKHC-UHFFFAOYSA-N 3-(3,5-dimethylphenyl)sulfonyl-3,10-diazatricyclo[6.4.1.04,13]trideca-1,4,6,8(13)-tetraene Chemical compound CC1=CC(C)=CC(S(=O)(=O)N2C=3C=CC=C4CNCCC(C=34)=C2)=C1 HDXZZLXIBGNKHC-UHFFFAOYSA-N 0.000 claims 1
CIQXLKCGLOJSAU-UHFFFAOYSA-N 3-(3-fluorophenyl)sulfonyl-3,10-diazatricyclo[6.4.1.04,13]trideca-1,4,6,8(13)-tetraene Chemical compound FC1=CC=CC(S(=O)(=O)N2C=3C=CC=C4CNCCC(C=34)=C2)=C1 CIQXLKCGLOJSAU-UHFFFAOYSA-N 0.000 claims 1
RLVJETJHQDOMPZ-UHFFFAOYSA-N 3-(4-propylphenyl)sulfonyl-3,10-diazatricyclo[6.4.1.04,13]trideca-1,4,6,8(13)-tetraene Chemical compound C1=CC(CCC)=CC=C1S(=O)(=O)N1C(C=CC=C2CNCC3)=C2C3=C1 RLVJETJHQDOMPZ-UHFFFAOYSA-N 0.000 claims 1
238000001282 Kruskal–Wallis one-way analysis of variance Methods 0.000 claims 1
238000000585 Mann–Whitney U test Methods 0.000 claims 1
125000001183 hydrocarbyl group Chemical group 0.000 claims 1
108091053735 lin-4 stem-loop Proteins 0.000 claims 1
108091032363 lin-4-1 stem-loop Proteins 0.000 claims 1
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238000010972 statistical evaluation Methods 0.000 claims 1
RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims 1
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 20
210000003169 central nervous system Anatomy 0.000 abstract description 6
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229940124801 5-HT6 antagonist Drugs 0.000 abstract 1
239000003751 serotonin 6 antagonist Substances 0.000 abstract 1
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 92
238000000034 method Methods 0.000 description 75
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 74
239000000047 product Substances 0.000 description 67
DRYBMFJLYYEOBZ-UHFFFAOYSA-N methyl 1h-indole-5-carboxylate Chemical compound COC(=O)C1=CC=C2NC=CC2=C1 DRYBMFJLYYEOBZ-UHFFFAOYSA-N 0.000 description 62
239000000203 mixture Substances 0.000 description 60
BEUJAVGQOANFRI-UHFFFAOYSA-N 1h-indole;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.C1=CC=C2NC=CC2=C1 BEUJAVGQOANFRI-UHFFFAOYSA-N 0.000 description 40
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238000002953 preparative HPLC Methods 0.000 description 24
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