DK3004079T3 - PYRIMIDE COMPOUNDS AND THEIR USE AS GAMMA SECRETASE MODULATORS - Google Patents

Info

Publication number

DK3004079T3

DK3004079T3 DK14727562.2T DK14727562T DK3004079T3 DK 3004079 T3 DK3004079 T3 DK 3004079T3 DK 14727562 T DK14727562 T DK 14727562T DK 3004079 T3 DK3004079 T3 DK 3004079T3

Authority

DK

Denmark

Prior art keywords

methyl

methoxy

imidazol

trifluoroethoxy

mmol

Prior art date

2013-06-04

Links

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• 150000001875 compounds Chemical class 0.000 title claims abstract description 286
• VHNYOQKVZQVBLC-RTCGXNAVSA-N (4r,7e,9as)-7-[[3-methoxy-4-(4-methylimidazol-1-yl)phenyl]methylidene]-4-(3,4,5-trifluorophenyl)-1,3,4,8,9,9a-hexahydropyrido[2,1-c][1,4]oxazin-6-one Chemical compound C1([C@@H]2COC[C@@H]3CC\C(C(N32)=O)=C/C=2C=C(C(=CC=2)N2C=C(C)N=C2)OC)=CC(F)=C(F)C(F)=C1 VHNYOQKVZQVBLC-RTCGXNAVSA-N 0.000 title 1
• 229940124648 γ-Secretase Modulator Drugs 0.000 title 1
• 150000003839 salts Chemical class 0.000 claims abstract description 40
• 238000011282 treatment Methods 0.000 claims abstract description 14
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 13
• 230000002265 prevention Effects 0.000 claims abstract description 9
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 8
• 201000010099 disease Diseases 0.000 claims abstract description 7
• 239000003814 drug Substances 0.000 claims abstract description 6
• OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 291
• -1 3-Methoxy -4- (4-methyl-1H-imidazol-1-yl) phenyl Chemical group 0.000 claims description 60
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 60
• 208000024827 Alzheimer disease Diseases 0.000 claims description 17
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 16
• 239000003795 chemical substances by application Substances 0.000 claims description 13
• 238000002560 therapeutic procedure Methods 0.000 claims description 13
• ASUTZQLVASHGKV-JDFRZJQESA-N galanthamine Chemical compound O1C(=C23)C(OC)=CC=C2CN(C)CC[C@]23[C@@H]1C[C@@H](O)C=C2 ASUTZQLVASHGKV-JDFRZJQESA-N 0.000 claims description 12
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
• KVWDHTXUZHCGIO-UHFFFAOYSA-N olanzapine Chemical compound C1CN(C)CCN1C1=NC2=CC=CC=C2NC2=C1C=C(C)S2 KVWDHTXUZHCGIO-UHFFFAOYSA-N 0.000 claims description 10
• 206010012289 Dementia Diseases 0.000 claims description 8
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
• 239000003085 diluting agent Substances 0.000 claims description 8
• 239000003937 drug carrier Substances 0.000 claims description 8
• 229960005017 olanzapine Drugs 0.000 claims description 8
• 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 claims description 8
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
• CEUORZQYGODEFX-UHFFFAOYSA-N Aripirazole Chemical compound ClC1=CC=CC(N2CCN(CCCCOC=3C=C4NC(=O)CCC4=CC=3)CC2)=C1Cl CEUORZQYGODEFX-UHFFFAOYSA-N 0.000 claims description 6
• XSVMFMHYUFZWBK-NSHDSACASA-N Rivastigmine Chemical compound CCN(C)C(=O)OC1=CC=CC([C@H](C)N(C)C)=C1 XSVMFMHYUFZWBK-NSHDSACASA-N 0.000 claims description 6
• 239000003693 atypical antipsychotic agent Substances 0.000 claims description 6
• QZUDBNBUXVUHMW-UHFFFAOYSA-N clozapine Chemical compound C1CN(C)CCN1C1=NC2=CC(Cl)=CC=C2NC2=CC=CC=C12 QZUDBNBUXVUHMW-UHFFFAOYSA-N 0.000 claims description 6
• 229960004640 memantine Drugs 0.000 claims description 6
• RAPZEAPATHNIPO-UHFFFAOYSA-N risperidone Chemical compound FC1=CC=C2C(C3CCN(CC3)CCC=3C(=O)N4CCCCC4=NC=3C)=NOC2=C1 RAPZEAPATHNIPO-UHFFFAOYSA-N 0.000 claims description 6
• 229960001685 tacrine Drugs 0.000 claims description 6
• YLJREFDVOIBQDA-UHFFFAOYSA-N tacrine Chemical compound C1=CC=C2C(N)=C(CCCC3)C3=NC2=C1 YLJREFDVOIBQDA-UHFFFAOYSA-N 0.000 claims description 6
• MVWVFYHBGMAFLY-UHFFFAOYSA-N ziprasidone Chemical compound C1=CC=C2C(N3CCN(CC3)CCC3=CC=4CC(=O)NC=4C=C3Cl)=NSC2=C1 MVWVFYHBGMAFLY-UHFFFAOYSA-N 0.000 claims description 6
• 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 5
• 229960004431 quetiapine Drugs 0.000 claims description 5
• URKOMYMAXPYINW-UHFFFAOYSA-N quetiapine Chemical compound C1CN(CCOCCO)CCN1C1=NC2=CC=CC=C2SC2=CC=CC=C12 URKOMYMAXPYINW-UHFFFAOYSA-N 0.000 claims description 5
• RTHCYVBBDHJXIQ-MRXNPFEDSA-N (R)-fluoxetine Chemical compound O([C@H](CCNC)C=1C=CC=CC=1)C1=CC=C(C(F)(F)F)C=C1 RTHCYVBBDHJXIQ-MRXNPFEDSA-N 0.000 claims description 4
• IOBDVBVNPMCPMC-UHFFFAOYSA-N 2-[6-(methoxymethyl)-2-[3-methoxy-4-(4-methylimidazol-1-yl)anilino]pyrimidin-4-yl]propan-2-ol Chemical compound COCC1=CC(C(C)(C)O)=NC(NC=2C=C(OC)C(=CC=2)N2C=C(C)N=C2)=N1 IOBDVBVNPMCPMC-UHFFFAOYSA-N 0.000 claims description 4
• 229960004372 aripiprazole Drugs 0.000 claims description 4
• 229960004170 clozapine Drugs 0.000 claims description 4
• 208000010877 cognitive disease Diseases 0.000 claims description 4
• 229960002464 fluoxetine Drugs 0.000 claims description 4
• 229960003980 galantamine Drugs 0.000 claims description 4
• ASUTZQLVASHGKV-UHFFFAOYSA-N galanthamine hydrochloride Natural products O1C(=C23)C(OC)=CC=C2CN(C)CCC23C1CC(O)C=C2 ASUTZQLVASHGKV-UHFFFAOYSA-N 0.000 claims description 4
• YAAWASYJIRZXSZ-UHFFFAOYSA-N pyrimidine-2,4-diamine Chemical compound NC1=CC=NC(N)=N1 YAAWASYJIRZXSZ-UHFFFAOYSA-N 0.000 claims description 4
• 229960001534 risperidone Drugs 0.000 claims description 4
• 229960004136 rivastigmine Drugs 0.000 claims description 4
• 229960000607 ziprasidone Drugs 0.000 claims description 4
• YJQWOLFZVCPXGK-UHFFFAOYSA-N 1-[2-[3-methoxy-4-(4-methoxyimidazol-1-yl)anilino]-6-(2,2,2-trifluoroethoxymethyl)pyrimidin-4-yl]ethanol Chemical compound C1=NC(OC)=CN1C(C(=C1)OC)=CC=C1NC1=NC(COCC(F)(F)F)=CC(C(C)O)=N1 YJQWOLFZVCPXGK-UHFFFAOYSA-N 0.000 claims description 3
• XAOCKFGTPHMXGH-UHFFFAOYSA-N 1-[2-[3-methoxy-4-(4-methylimidazol-1-yl)anilino]-6-(2,2,2-trifluoroethoxymethyl)pyrimidin-4-yl]-2-methylpropan-1-ol Chemical compound C=1C=C(N2C=C(C)N=C2)C(OC)=CC=1NC1=NC(COCC(F)(F)F)=CC(C(O)C(C)C)=N1 XAOCKFGTPHMXGH-UHFFFAOYSA-N 0.000 claims description 3
• BUBAHBRWIZRTJR-UHFFFAOYSA-N 1-[2-[3-methoxy-4-(4-methylimidazol-1-yl)anilino]-6-(2,2,2-trifluoroethoxymethyl)pyrimidin-4-yl]ethanol Chemical compound C=1C=C(N2C=C(C)N=C2)C(OC)=CC=1NC1=NC(COCC(F)(F)F)=CC(C(C)O)=N1 BUBAHBRWIZRTJR-UHFFFAOYSA-N 0.000 claims description 3
• CDUINTDPTHLEDE-UHFFFAOYSA-N 1-[[2-[3-methoxy-4-(4-methylimidazol-1-yl)anilino]-6-(2,2,2-trifluoroethoxymethyl)pyrimidin-4-yl]amino]-2-methylpropan-2-ol Chemical compound C=1C=C(N2C=C(C)N=C2)C(OC)=CC=1NC1=NC(COCC(F)(F)F)=CC(NCC(C)(C)O)=N1 CDUINTDPTHLEDE-UHFFFAOYSA-N 0.000 claims description 3
• OQPFNFZAOVYKTL-UHFFFAOYSA-N 2-[2-[3-methoxy-4-(4-methylimidazol-1-yl)anilino]-6-(2,2,2-trifluoroethoxymethyl)pyrimidin-4-yl]butan-2-ol Chemical compound CCC(C)(O)C1=CC(COCC(F)(F)F)=NC(NC=2C=C(OC)C(=CC=2)N2C=C(C)N=C2)=N1 OQPFNFZAOVYKTL-UHFFFAOYSA-N 0.000 claims description 3
• HWFMQHNCLUXIHR-UHFFFAOYSA-N 2-[2-[3-methoxy-4-(4-methylimidazol-1-yl)anilino]-6-(2,2,2-trifluoroethoxymethyl)pyrimidin-4-yl]propan-2-ol Chemical compound C=1C=C(N2C=C(C)N=C2)C(OC)=CC=1NC1=NC(COCC(F)(F)F)=CC(C(C)(C)O)=N1 HWFMQHNCLUXIHR-UHFFFAOYSA-N 0.000 claims description 3
• FGEODWQZAMQRTK-UHFFFAOYSA-N 2-[2-[3-methoxy-4-(4-methylimidazol-1-yl)anilino]-6-(3,3,3-trifluoropropoxymethyl)pyrimidin-4-yl]propan-2-ol Chemical compound C=1C=C(N2C=C(C)N=C2)C(OC)=CC=1NC1=NC(COCCC(F)(F)F)=CC(C(C)(C)O)=N1 FGEODWQZAMQRTK-UHFFFAOYSA-N 0.000 claims description 3
• KNWHEQXEAMCNQN-UHFFFAOYSA-N 2-[6-(cyclopropylmethoxymethyl)-2-[3-methoxy-4-(4-methylimidazol-1-yl)anilino]pyrimidin-4-yl]propan-2-ol Chemical compound C=1C=C(N2C=C(C)N=C2)C(OC)=CC=1NC(N=C(C=1)C(C)(C)O)=NC=1COCC1CC1 KNWHEQXEAMCNQN-UHFFFAOYSA-N 0.000 claims description 3
• CUYWDQUWJUSFRW-UHFFFAOYSA-N 2-cyclopropyl-1-[2-[3-methoxy-4-(4-methylimidazol-1-yl)anilino]-6-(2,2,2-trifluoroethoxymethyl)pyrimidin-4-yl]ethanol Chemical compound C=1C=C(N2C=C(C)N=C2)C(OC)=CC=1NC(N=1)=NC(COCC(F)(F)F)=CC=1C(O)CC1CC1 CUYWDQUWJUSFRW-UHFFFAOYSA-N 0.000 claims description 3
• ZNSHPICMEBTIDG-UHFFFAOYSA-N 3-[[2-[3-methoxy-4-(4-methylimidazol-1-yl)anilino]-6-(2,2,2-trifluoroethoxymethyl)pyrimidin-4-yl]amino]propanenitrile Chemical compound C=1C=C(N2C=C(C)N=C2)C(OC)=CC=1NC1=NC(COCC(F)(F)F)=CC(NCCC#N)=N1 ZNSHPICMEBTIDG-UHFFFAOYSA-N 0.000 claims description 3
• WETTXVVWUDYFEV-UHFFFAOYSA-N 4-(azetidin-1-yl)-n-[3-methoxy-4-(4-methylimidazol-1-yl)phenyl]-6-(2,2,2-trifluoroethoxymethyl)pyrimidin-2-amine Chemical compound C=1C=C(N2C=C(C)N=C2)C(OC)=CC=1NC(N=1)=NC(COCC(F)(F)F)=CC=1N1CCC1 WETTXVVWUDYFEV-UHFFFAOYSA-N 0.000 claims description 3
• MYGVFZNIOCVSMR-UHFFFAOYSA-N 4-[(3-fluoroazetidin-1-yl)methyl]-n-[3-methoxy-4-(4-methylimidazol-1-yl)phenyl]-6-(2,2,2-trifluoroethoxymethyl)pyrimidin-2-amine Chemical compound C=1C=C(N2C=C(C)N=C2)C(OC)=CC=1NC(N=1)=NC(COCC(F)(F)F)=CC=1CN1CC(F)C1 MYGVFZNIOCVSMR-UHFFFAOYSA-N 0.000 claims description 3
• HEYWBCWIRSVHLW-UHFFFAOYSA-N 4-[(dimethylamino)methyl]-n-[3-methoxy-4-(4-methylimidazol-1-yl)phenyl]-6-(2,2,2-trifluoroethoxymethyl)pyrimidin-2-amine Chemical compound C=1C=C(N2C=C(C)N=C2)C(OC)=CC=1NC1=NC(COCC(F)(F)F)=CC(CN(C)C)=N1 HEYWBCWIRSVHLW-UHFFFAOYSA-N 0.000 claims description 3
• NXIJKQAXXRFXRS-UHFFFAOYSA-N 4-n-(2-methoxyethyl)-2-n-[3-methoxy-4-(4-methylimidazol-1-yl)phenyl]-6-(2,2,2-trifluoroethoxymethyl)pyrimidine-2,4-diamine Chemical compound COCCNC1=CC(COCC(F)(F)F)=NC(NC=2C=C(OC)C(=CC=2)N2C=C(C)N=C2)=N1 NXIJKQAXXRFXRS-UHFFFAOYSA-N 0.000 claims description 3
• MXANQQONSNDYOB-UHFFFAOYSA-N 4-n-benzyl-2-n-[3-methoxy-4-(4-methylimidazol-1-yl)phenyl]-4-n-methyl-6-(2,2,2-trifluoroethoxymethyl)pyrimidine-2,4-diamine Chemical compound C=1C=C(N2C=C(C)N=C2)C(OC)=CC=1NC(N=1)=NC(COCC(F)(F)F)=CC=1N(C)CC1=CC=CC=C1 MXANQQONSNDYOB-UHFFFAOYSA-N 0.000 claims description 3
• NWAZCFKNPYIPFM-UHFFFAOYSA-N 4-n-cyclopropyl-2-n-[3-methoxy-4-(4-methylimidazol-1-yl)phenyl]-6-(2,2,2-trifluoroethoxymethyl)pyrimidine-2,4-diamine Chemical compound C=1C=C(N2C=C(C)N=C2)C(OC)=CC=1NC(N=1)=NC(COCC(F)(F)F)=CC=1NC1CC1 NWAZCFKNPYIPFM-UHFFFAOYSA-N 0.000 claims description 3
• OOFOLNCXBGEMHJ-UHFFFAOYSA-N 6-(cyclopropylmethoxymethyl)-2-n-[3-methoxy-4-(4-methylimidazol-1-yl)phenyl]-4-n-methylpyrimidine-2,4-diamine Chemical compound N=1C(NC=2C=C(OC)C(=CC=2)N2C=C(C)N=C2)=NC(NC)=CC=1COCC1CC1 OOFOLNCXBGEMHJ-UHFFFAOYSA-N 0.000 claims description 3
• 208000000044 Amnesia Diseases 0.000 claims description 3
• 108010090849 Amyloid beta-Peptides Proteins 0.000 claims description 3
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• 208000026139 Memory disease Diseases 0.000 claims description 3
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• 229940121363 anti-inflammatory agent Drugs 0.000 claims description 3
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