BR112012023664B1 - Compostos derivados de 2,3-di-hidro-1hinden-1-il-2,7- diazaspiro [3,5] nonano e composiçãofarmacêutica compreendendo os mesmos - Google Patents

Info

Publication number

BR112012023664B1

BR112012023664B1 BR112012023664A BR112012023664A BR112012023664B1 BR 112012023664 B1 BR112012023664 B1 BR 112012023664B1 BR 112012023664 A BR112012023664 A BR 112012023664A BR 112012023664 A BR112012023664 A BR 112012023664A BR 112012023664 B1 BR112012023664 B1 BR 112012023664B1

Authority

BR

Brazil

Prior art keywords

diazaspiro

dihydro

inden

nonane

acetyl

Prior art date

2010-03-19

Links

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• 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 19
• 150000001875 compounds Chemical class 0.000 title claims description 197
• 150000003839 salts Chemical class 0.000 claims abstract description 33
• -1 imidazo [2,1-b] [1,3] thiazolyl Chemical group 0.000 claims description 293
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 36
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 27
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 24
• 125000004076 pyridyl group Chemical group 0.000 claims description 22
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 19
• 125000001424 substituent group Chemical group 0.000 claims description 19
• HIZVCIIORGCREW-UHFFFAOYSA-N 1,4-dioxene Chemical compound C1COC=CO1 HIZVCIIORGCREW-UHFFFAOYSA-N 0.000 claims description 18
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 15
• 239000003085 diluting agent Substances 0.000 claims description 12
• 229910052739 hydrogen Inorganic materials 0.000 claims description 12
• 239000001257 hydrogen Substances 0.000 claims description 12
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 11
• 125000000714 pyrimidinyl group Chemical group 0.000 claims description 11
• 125000000335 thiazolyl group Chemical group 0.000 claims description 11
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 10
• ZIUDADZJCKGWKR-AREMUKBSSA-N 2-(2-methylimidazo[2,1-b][1,3]thiazol-6-yl)-1-[2-[(1r)-5-(6-methylpyrimidin-4-yl)-2,3-dihydro-1h-inden-1-yl]-2,7-diazaspiro[3.5]nonan-7-yl]ethanone Chemical compound C([C@H](C1=CC=2)N3CC4(CCN(CC4)C(=O)CC4=CN5C=C(SC5=N4)C)C3)CC1=CC=2C1=CC(C)=NC=N1 ZIUDADZJCKGWKR-AREMUKBSSA-N 0.000 claims description 9
• 125000002971 oxazolyl group Chemical group 0.000 claims description 9
• 125000003226 pyrazolyl group Chemical group 0.000 claims description 9
• 125000003373 pyrazinyl group Chemical group 0.000 claims description 8
• 125000002883 imidazolyl group Chemical group 0.000 claims description 7
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 7
• 125000001715 oxadiazolyl group Chemical group 0.000 claims description 7
• 125000002098 pyridazinyl group Chemical group 0.000 claims description 7
• 125000001425 triazolyl group Chemical group 0.000 claims description 7
• 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 5
• 125000003831 tetrazolyl group Chemical group 0.000 claims description 5
• 125000001113 thiadiazolyl group Chemical group 0.000 claims description 5
• 125000004306 triazinyl group Chemical group 0.000 claims description 5
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
• JYDQZHGILUYIQT-HHHXNRCGSA-N 1-[2-[(1r)-5-(5-ethylpyrimidin-2-yl)-2,3-dihydro-1h-inden-1-yl]-2,7-diazaspiro[3.5]nonan-7-yl]-2-(5-methoxypyridin-2-yl)ethanone Chemical compound N1=CC(CC)=CN=C1C1=CC=C([C@@H](CC2)N3CC4(C3)CCN(CC4)C(=O)CC=3N=CC(OC)=CC=3)C2=C1 JYDQZHGILUYIQT-HHHXNRCGSA-N 0.000 claims description 4
• 125000005955 1H-indazolyl group Chemical group 0.000 claims description 4
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
• KVGZZAHHUNAVKZ-UHFFFAOYSA-N 1,4-Dioxin Chemical compound O1C=COC=C1 KVGZZAHHUNAVKZ-UHFFFAOYSA-N 0.000 claims description 3
• RIMZMWDWQJSJAV-RUZDIDTESA-N 2-(2-methylimidazo[2,1-b][1,3,4]thiadiazol-6-yl)-1-[2-[(1r)-5-(6-methylpyrimidin-4-yl)-2,3-dihydro-1h-inden-1-yl]-2,7-diazaspiro[3.5]nonan-7-yl]ethanone Chemical compound C([C@H](C1=CC=2)N3CC4(CCN(CC4)C(=O)CC4=CN5N=C(SC5=N4)C)C3)CC1=CC=2C1=CC(C)=NC=N1 RIMZMWDWQJSJAV-RUZDIDTESA-N 0.000 claims description 3
• CWWWNUAQMXMSGC-MUUNZHRXSA-N 1-[2-[(1r)-5-(2,6-dimethylpyrimidin-4-yl)-2,3-dihydro-1h-inden-1-yl]-2,7-diazaspiro[3.5]nonan-7-yl]-2-(5-methoxypyridin-2-yl)ethanone Chemical compound N1=CC(OC)=CC=C1CC(=O)N1CCC2(CN(C2)[C@H]2C3=CC=C(C=C3CC2)C=2N=C(C)N=C(C)C=2)CC1 CWWWNUAQMXMSGC-MUUNZHRXSA-N 0.000 claims description 2
• NOLZCWDIRAGCGH-XMMPIXPASA-N 2-(5-methoxypyridin-2-yl)-1-[2-[(1r)-5-(triazol-2-yl)-2,3-dihydro-1h-inden-1-yl]-2,7-diazaspiro[3.5]nonan-7-yl]ethanone Chemical compound N1=CC(OC)=CC=C1CC(=O)N1CCC2(CN(C2)[C@H]2C3=CC=C(C=C3CC2)N2N=CC=N2)CC1 NOLZCWDIRAGCGH-XMMPIXPASA-N 0.000 claims description 2
• JXSRLENOQQOMED-HHHXNRCGSA-N 2-imidazo[1,2-a]pyridin-2-yl-1-[2-[(1r)-5-(6-methylpyrimidin-4-yl)-2,3-dihydro-1h-inden-1-yl]-2,7-diazaspiro[3.5]nonan-7-yl]ethanone Chemical compound C1=NC(C)=CC(C=2C=C3CC[C@H](C3=CC=2)N2CC3(C2)CCN(CC3)C(=O)CC=2N=C3C=CC=CN3C=2)=N1 JXSRLENOQQOMED-HHHXNRCGSA-N 0.000 claims description 2
• METKIMKYRPQLGS-UHFFFAOYSA-N atenolol Chemical compound CC(C)NCC(O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-UHFFFAOYSA-N 0.000 claims description 2
• 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims 4
• YKXOWLUZZIFXMJ-UHFFFAOYSA-N 1,2-diazaspiro[3.5]nonane Chemical compound C1NNC11CCCCC1 YKXOWLUZZIFXMJ-UHFFFAOYSA-N 0.000 claims 1
• WUKHDLMVEFYYHY-AREMUKBSSA-N 2-(5-ethylpyridin-2-yl)-1-[2-[(1r)-5-pyrimidin-2-yl-2,3-dihydro-1h-inden-1-yl]-2,7-diazaspiro[3.5]nonan-7-yl]ethanone Chemical compound N1=CC(CC)=CC=C1CC(=O)N1CCC2(CN(C2)[C@H]2C3=CC=C(C=C3CC2)C=2N=CC=CN=2)CC1 WUKHDLMVEFYYHY-AREMUKBSSA-N 0.000 claims 1
• KEHVZGBXBDJDMH-AREMUKBSSA-N 2-(5-methoxypyridin-2-yl)-1-[2-[(1r)-5-(4-methylpyrimidin-2-yl)-2,3-dihydro-1h-inden-1-yl]-2,7-diazaspiro[3.5]nonan-7-yl]ethanone Chemical compound N1=CC(OC)=CC=C1CC(=O)N1CCC2(CN(C2)[C@H]2C3=CC=C(C=C3CC2)C=2N=C(C)C=CN=2)CC1 KEHVZGBXBDJDMH-AREMUKBSSA-N 0.000 claims 1
• SEGKTHKDKIHNOM-AREMUKBSSA-N 2-(5-methoxypyridin-2-yl)-1-[2-[(1r)-5-(5-methylpyrimidin-2-yl)-2,3-dihydro-1h-inden-1-yl]-2,7-diazaspiro[3.5]nonan-7-yl]ethanone Chemical compound N1=CC(OC)=CC=C1CC(=O)N1CCC2(CN(C2)[C@H]2C3=CC=C(C=C3CC2)C=2N=CC(C)=CN=2)CC1 SEGKTHKDKIHNOM-AREMUKBSSA-N 0.000 claims 1
• NATXGJPPVHDYCP-HHHXNRCGSA-N 2-(5-methoxypyridin-2-yl)-1-[2-[(1r)-5-(6-methylpyrimidin-4-yl)-2,3-dihydro-1h-inden-1-yl]-2,7-diazaspiro[3.5]nonan-7-yl]ethanone Chemical compound N1=CC(OC)=CC=C1CC(=O)N1CCC2(CN(C2)[C@H]2C3=CC=C(C=C3CC2)C=2N=CN=C(C)C=2)CC1 NATXGJPPVHDYCP-HHHXNRCGSA-N 0.000 claims 1
• ZWFXCKJHCJRMDP-XMMPIXPASA-N 2-(5-methylpyridin-2-yl)-1-[2-[(1r)-5-(triazol-2-yl)-2,3-dihydro-1h-inden-1-yl]-2,7-diazaspiro[3.5]nonan-7-yl]ethanone Chemical compound N1=CC(C)=CC=C1CC(=O)N1CCC2(CN(C2)[C@H]2C3=CC=C(C=C3CC2)N2N=CC=N2)CC1 ZWFXCKJHCJRMDP-XMMPIXPASA-N 0.000 claims 1
• WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims 1
• GNKDKYIHGQKHHM-RJKLHVOGSA-N ghrelin Chemical compound C([C@H](NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)CN)COC(=O)CCCCCCC)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1N=CNC=1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C1=CC=CC=C1 GNKDKYIHGQKHHM-RJKLHVOGSA-N 0.000 abstract description 59
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• XVWYVEFVHFPPNL-UHFFFAOYSA-N 3-(2,3-dihydro-1h-inden-1-yl)-2,7-diazaspiro[3.5]nonane Chemical class C1NC(C2C3=CC=CC=C3CC2)C11CCNCC1 XVWYVEFVHFPPNL-UHFFFAOYSA-N 0.000 abstract description 2
• 102000012004 Ghrelin Human genes 0.000 abstract 1
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 250
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 246
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 209
• 239000000203 mixture Substances 0.000 description 194
• 238000006243 chemical reaction Methods 0.000 description 170
• OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 156
• 239000000243 solution Substances 0.000 description 155
• 238000005481 NMR spectroscopy Methods 0.000 description 141
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• 235000019439 ethyl acetate Nutrition 0.000 description 96
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 93
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 84
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• 229940125425 inverse agonist Drugs 0.000 description 57
• 229910052757 nitrogen Inorganic materials 0.000 description 57
• 102100033367 Appetite-regulating hormone Human genes 0.000 description 52
• IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 50
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 50
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• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 42
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• 238000000746 purification Methods 0.000 description 40
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• ZIUDADZJCKGWKR-UHFFFAOYSA-N 2-(2-methylimidazo[2,1-b][1,3]thiazol-6-yl)-1-[2-[5-(6-methylpyrimidin-4-yl)-2,3-dihydro-1h-inden-1-yl]-2,7-diazaspiro[3.5]nonan-7-yl]ethanone Chemical compound N1=C2SC(C)=CN2C=C1CC(=O)N(CC1)CCC1(C1)CN1C(C1=CC=2)CCC1=CC=2C1=CC(C)=NC=N1 ZIUDADZJCKGWKR-UHFFFAOYSA-N 0.000 description 1
• IHFYSFFWDWXLJS-UHFFFAOYSA-N 2-(2-methylimidazo[2,1-b][1,3]thiazol-6-yl)-1-[2-[5-(triazol-2-yl)-2,3-dihydro-1h-inden-1-yl]-2,7-diazaspiro[3.5]nonan-7-yl]ethanone Chemical compound N1=C2SC(C)=CN2C=C1CC(=O)N(CC1)CCC1(C1)CN1C(C1=CC=2)CCC1=CC=2N1N=CC=N1 IHFYSFFWDWXLJS-UHFFFAOYSA-N 0.000 description 1
• LAHGWWGYBMWICT-UHFFFAOYSA-N 2-(2h-indazol-3-yl)-1-[2-(5-pyrimidin-2-yl-2,3-dihydro-1h-inden-1-yl)-2,7-diazaspiro[3.5]nonan-7-yl]ethanone Chemical compound N=1NC2=CC=CC=C2C=1CC(=O)N(CC1)CCC1(C1)CN1C(C1=CC=2)CCC1=CC=2C1=NC=CC=N1 LAHGWWGYBMWICT-UHFFFAOYSA-N 0.000 description 1
• MLPMUDNDESIAHM-UHFFFAOYSA-N 2-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)acetic acid Chemical compound C1CCCN2N=C(CC(=O)O)C=C21 MLPMUDNDESIAHM-UHFFFAOYSA-N 0.000 description 1
• RQUMQZKTCZFHMQ-UHFFFAOYSA-N 2-(4-ethylphenyl)-1-[2-(5-pyrimidin-2-yl-2,3-dihydro-1h-inden-1-yl)-2,7-diazaspiro[3.5]nonan-7-yl]ethanone Chemical compound C1=CC(CC)=CC=C1CC(=O)N1CCC2(CN(C2)C2C3=CC=C(C=C3CC2)C=2N=CC=CN=2)CC1 RQUMQZKTCZFHMQ-UHFFFAOYSA-N 0.000 description 1
• TYYSKYJWHWZGJF-RUZDIDTESA-N 2-(4-methoxyphenyl)-1-[2-[(1r)-5-(triazol-2-yl)-2,3-dihydro-1h-inden-1-yl]-2,7-diazaspiro[3.5]nonan-7-yl]ethanone Chemical compound C1=CC(OC)=CC=C1CC(=O)N1CCC2(CN(C2)[C@H]2C3=CC=C(C=C3CC2)N2N=CC=N2)CC1 TYYSKYJWHWZGJF-RUZDIDTESA-N 0.000 description 1
• TVENWCAZFIVAQU-UHFFFAOYSA-N 2-(4-methoxyphenyl)-1-[2-[5-(1,3-oxazol-2-yl)-2,3-dihydro-1h-inden-1-yl]-2,7-diazaspiro[3.5]nonan-7-yl]ethanone Chemical compound C1=CC(OC)=CC=C1CC(=O)N1CCC2(CN(C2)C2C3=CC=C(C=C3CC2)C=2OC=CN=2)CC1 TVENWCAZFIVAQU-UHFFFAOYSA-N 0.000 description 1
• MYFNSSGRTXSXDT-UHFFFAOYSA-N 2-(4-methoxyphenyl)-1-[2-[5-(2-methylpyrimidin-4-yl)-2,3-dihydro-1h-inden-1-yl]-2,7-diazaspiro[3.5]nonan-7-yl]ethanone Chemical compound C1=CC(OC)=CC=C1CC(=O)N1CCC2(CN(C2)C2C3=CC=C(C=C3CC2)C=2N=C(C)N=CC=2)CC1 MYFNSSGRTXSXDT-UHFFFAOYSA-N 0.000 description 1
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• ZFBVFLGNDAWLDS-UHFFFAOYSA-N 2-(5-methoxypyridin-2-yl)-1-[2-[5-(5-methylpyridin-2-yl)-2,3-dihydro-1h-inden-1-yl]-2,7-diazaspiro[3.5]nonan-7-yl]ethanone Chemical compound N1=CC(OC)=CC=C1CC(=O)N1CCC2(CN(C2)C2C3=CC=C(C=C3CC2)C=2N=CC(C)=CC=2)CC1 ZFBVFLGNDAWLDS-UHFFFAOYSA-N 0.000 description 1
• SEGKTHKDKIHNOM-UHFFFAOYSA-N 2-(5-methoxypyridin-2-yl)-1-[2-[5-(5-methylpyrimidin-2-yl)-2,3-dihydro-1h-inden-1-yl]-2,7-diazaspiro[3.5]nonan-7-yl]ethanone Chemical compound N1=CC(OC)=CC=C1CC(=O)N1CCC2(CN(C2)C2C3=CC=C(C=C3CC2)C=2N=CC(C)=CN=2)CC1 SEGKTHKDKIHNOM-UHFFFAOYSA-N 0.000 description 1
• IDTDGFHEYCPFTC-UHFFFAOYSA-N 2-(5-methoxypyridin-2-yl)-1-[2-[5-(6-methylpyridin-2-yl)-2,3-dihydro-1h-inden-1-yl]-2,7-diazaspiro[3.5]nonan-7-yl]ethanone Chemical compound N1=CC(OC)=CC=C1CC(=O)N1CCC2(CN(C2)C2C3=CC=C(C=C3CC2)C=2N=C(C)C=CC=2)CC1 IDTDGFHEYCPFTC-UHFFFAOYSA-N 0.000 description 1
• NATXGJPPVHDYCP-UHFFFAOYSA-N 2-(5-methoxypyridin-2-yl)-1-[2-[5-(6-methylpyrimidin-4-yl)-2,3-dihydro-1h-inden-1-yl]-2,7-diazaspiro[3.5]nonan-7-yl]ethanone Chemical compound N1=CC(OC)=CC=C1CC(=O)N1CCC2(CN(C2)C2C3=CC=C(C=C3CC2)C=2N=CN=C(C)C=2)CC1 NATXGJPPVHDYCP-UHFFFAOYSA-N 0.000 description 1
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