EA007737B1 - ГЕТЕРОАРИЛЗАМЕЩЕННЫЕ ПРОИЗВОДНЫЕ 2-ПИРИДИНИЛ- И 2-ПИРИМИДИНИЛ-6,7,8,9-ТЕТРАГИДРОПИРИМИДО[1,2-a]ПИРИМИДИН-4-ОНА - Google Patents
ГЕТЕРОАРИЛЗАМЕЩЕННЫЕ ПРОИЗВОДНЫЕ 2-ПИРИДИНИЛ- И 2-ПИРИМИДИНИЛ-6,7,8,9-ТЕТРАГИДРОПИРИМИДО[1,2-a]ПИРИМИДИН-4-ОНА Download PDFInfo
- Publication number
- EA007737B1 EA007737B1 EA200400936A EA200400936A EA007737B1 EA 007737 B1 EA007737 B1 EA 007737B1 EA 200400936 A EA200400936 A EA 200400936A EA 200400936 A EA200400936 A EA 200400936A EA 007737 B1 EA007737 B1 EA 007737B1
- Authority
- EA
- Eurasian Patent Office
- Prior art keywords
- pyrimidin
- tetrahydropyrimido
- ylmethyl
- pyridin
- dimethyl
- Prior art date
Links
- DNCYBUMDUBHIJZ-UHFFFAOYSA-N 1h-pyrimidin-6-one Chemical class O=C1C=CN=CN1 DNCYBUMDUBHIJZ-UHFFFAOYSA-N 0.000 title claims description 64
- 150000003839 salts Chemical class 0.000 claims abstract description 46
- 239000003814 drug Substances 0.000 claims abstract description 29
- 150000008318 pyrimidones Chemical class 0.000 claims abstract description 24
- 238000011282 treatment Methods 0.000 claims abstract description 24
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 23
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims abstract description 22
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 21
- 239000004480 active ingredient Substances 0.000 claims abstract description 20
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 20
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 19
- 125000005843 halogen group Chemical group 0.000 claims abstract description 18
- 230000004770 neurodegeneration Effects 0.000 claims abstract description 16
- 230000001225 therapeutic effect Effects 0.000 claims abstract description 16
- 208000015122 neurodegenerative disease Diseases 0.000 claims abstract description 15
- 208000024827 Alzheimer disease Diseases 0.000 claims abstract description 14
- 230000002159 abnormal effect Effects 0.000 claims abstract description 13
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 10
- 125000004430 oxygen atom Chemical group O* 0.000 claims abstract description 10
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 9
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 9
- 125000004434 sulfur atom Chemical group 0.000 claims abstract description 9
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 116
- -1 benzofuran-2-ylmethyl Chemical group 0.000 claims description 59
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 31
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 claims description 24
- 239000012453 solvate Substances 0.000 claims description 21
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 19
- 201000010099 disease Diseases 0.000 claims description 17
- 239000000126 substance Substances 0.000 claims description 17
- 230000000069 prophylactic effect Effects 0.000 claims description 15
- 229910052799 carbon Inorganic materials 0.000 claims description 14
- 206010028980 Neoplasm Diseases 0.000 claims description 11
- 125000003545 alkoxy group Chemical group 0.000 claims description 11
- LCKCIHLNWFCXLK-UHFFFAOYSA-N 1,4,7,8-tetrahydropyrimido[1,2-a]pyrimidin-6-one Chemical compound N1C=CCN2C(=O)CCN=C21 LCKCIHLNWFCXLK-UHFFFAOYSA-N 0.000 claims description 10
- 208000006011 Stroke Diseases 0.000 claims description 10
- 229940079593 drug Drugs 0.000 claims description 10
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 9
- 239000003112 inhibitor Substances 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 9
- 208000034799 Tauopathies Diseases 0.000 claims description 7
- 208000014674 injury Diseases 0.000 claims description 7
- 208000018737 Parkinson disease Diseases 0.000 claims description 6
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims description 6
- 229920006395 saturated elastomer Polymers 0.000 claims description 6
- 201000004384 Alopecia Diseases 0.000 claims description 5
- 208000004736 B-Cell Leukemia Diseases 0.000 claims description 5
- 206010006187 Breast cancer Diseases 0.000 claims description 5
- 208000026310 Breast neoplasm Diseases 0.000 claims description 5
- 208000010412 Glaucoma Diseases 0.000 claims description 5
- 208000008589 Obesity Diseases 0.000 claims description 5
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical group C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 5
- 206010038923 Retinopathy Diseases 0.000 claims description 5
- 208000024770 Thyroid neoplasm Diseases 0.000 claims description 5
- 201000004810 Vascular dementia Diseases 0.000 claims description 5
- 241000700605 Viruses Species 0.000 claims description 5
- 231100000360 alopecia Toxicity 0.000 claims description 5
- 206010015037 epilepsy Diseases 0.000 claims description 5
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 5
- 235000020824 obesity Nutrition 0.000 claims description 5
- 208000033808 peripheral neuropathy Diseases 0.000 claims description 5
- 201000000980 schizophrenia Diseases 0.000 claims description 5
- 230000005586 smoking cessation Effects 0.000 claims description 5
- 201000002510 thyroid cancer Diseases 0.000 claims description 5
- 230000008736 traumatic injury Effects 0.000 claims description 5
- 125000004429 atom Chemical group 0.000 claims description 4
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 3
- CSIYPJQZODIRND-UHFFFAOYSA-N 1-[2-(1h-indol-3-yl)ethyl]-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5-one Chemical compound N1=C2N(CCC=3C4=CC=CC=C4NC=3)CCN2C(=O)C=C1C1=CC=NC=C1 CSIYPJQZODIRND-UHFFFAOYSA-N 0.000 claims description 3
- YOBYLQSAZIBJKW-UHFFFAOYSA-N 1-[3-(1h-indol-3-yl)propyl]-7-pyridin-4-yl-2,3-dihydroimidazo[1,2-a]pyrimidin-5-one Chemical compound N1=C2N(CCCC=3C4=CC=CC=C4NC=3)CCN2C(=O)C=C1C1=CC=NC=C1 YOBYLQSAZIBJKW-UHFFFAOYSA-N 0.000 claims description 3
- 208000017442 Retinal disease Diseases 0.000 claims description 3
- 208000000389 T-cell leukemia Diseases 0.000 claims description 3
- 208000028530 T-cell lymphoblastic leukemia/lymphoma Diseases 0.000 claims description 3
- 208000029028 brain injury Diseases 0.000 claims description 3
- 201000011510 cancer Diseases 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical compound OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 claims description 3
- 208000020431 spinal cord injury Diseases 0.000 claims description 3
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 2
- OIJFGSXUGUNMMO-UHFFFAOYSA-N 1-[(5-methoxy-2,3-dihydro-1,4-benzodioxin-3-yl)methyl]-2,2-dimethyl-8-pyrimidin-4-yl-3,4-dihydropyrimido[1,2-a]pyrimidin-6-one Chemical compound O1C=2C(OC)=CC=CC=2OCC1CN(C(CCN1C(=O)C=2)(C)C)C1=NC=2C1=CC=NC=N1 OIJFGSXUGUNMMO-UHFFFAOYSA-N 0.000 claims description 2
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- JQBJQVCLAXDKFJ-UHFFFAOYSA-N 9-(3,4-dihydro-2h-chromen-2-ylmethyl)-8-methyl-2-pyridin-4-yl-7,8-dihydro-6h-pyrimido[1,2-a]pyrimidin-4-one Chemical compound C1CC2=CC=CC=C2OC1CN1C(C)CCN(C(C=2)=O)C1=NC=2C1=CC=NC=C1 JQBJQVCLAXDKFJ-UHFFFAOYSA-N 0.000 claims description 2
- ZQFVPBIVVLOQQN-UHFFFAOYSA-N 9-[(2-chloro-6,7-dihydro-5h-cyclopenta[b]pyridin-6-yl)methyl]-7,7-dimethyl-2-pyridin-4-yl-6,8-dihydropyrimido[1,2-a]pyrimidin-4-one Chemical compound C=1C(=O)N2CC(C)(C)CN(CC3CC4=NC(Cl)=CC=C4C3)C2=NC=1C1=CC=NC=C1 ZQFVPBIVVLOQQN-UHFFFAOYSA-N 0.000 claims description 2
- AKYVTEJEWKKJOO-UHFFFAOYSA-N 9-[(5-fluoro-8-methoxy-3,4-dihydro-2h-chromen-2-yl)methyl]-8-methyl-2-pyrimidin-4-yl-7,8-dihydro-6h-pyrimido[1,2-a]pyrimidin-4-one Chemical compound O1C=2C(OC)=CC=C(F)C=2CCC1CN1C(C)CCN(C(C=2)=O)C1=NC=2C1=CC=NC=N1 AKYVTEJEWKKJOO-UHFFFAOYSA-N 0.000 claims description 2
- UNOKUYNLMAKSQA-UHFFFAOYSA-N 9-[3-(1h-indol-3-yl)propyl]-2-pyridin-4-yl-7,8-dihydro-6h-pyrimido[1,2-a]pyrimidin-4-one Chemical compound N1=C2N(CCCC=3C4=CC=CC=C4NC=3)CCCN2C(=O)C=C1C1=CC=NC=C1 UNOKUYNLMAKSQA-UHFFFAOYSA-N 0.000 claims description 2
- 208000020925 Bipolar disease Diseases 0.000 claims description 2
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 2
- 208000028683 bipolar I disease Diseases 0.000 claims description 2
- 125000004122 cyclic group Chemical group 0.000 claims description 2
- 125000000814 indol-3-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C([*])C2=C1[H] 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 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 claims 2
- 229940126601 medicinal product Drugs 0.000 claims 2
- QMJBSXGXBOBMPC-UHFFFAOYSA-N 1,6,7,8-tetrahydropyrimido[1,2-a]pyrimidin-4-one Chemical compound N1CCCN2C(=O)C=CN=C21 QMJBSXGXBOBMPC-UHFFFAOYSA-N 0.000 claims 1
- QVYURLLEENPMIA-UHFFFAOYSA-N 1-[(5-fluoro-8-methoxy-3,4-dihydro-2h-chromen-2-yl)methyl]-2,2-dimethyl-8-pyrimidin-4-yl-3,4-dihydropyrimido[1,2-a]pyrimidin-6-one Chemical compound O1C=2C(OC)=CC=C(F)C=2CCC1CN(C(CCN1C(=O)C=2)(C)C)C1=NC=2C1=CC=NC=N1 QVYURLLEENPMIA-UHFFFAOYSA-N 0.000 claims 1
- BGBTXTRRHGZKOY-UHFFFAOYSA-N 1-[(5-methoxy-2,3-dihydro-1,4-benzodioxin-2-yl)methyl]-2,2-dimethyl-8-pyrimidin-4-yl-3,4-dihydropyrimido[1,2-a]pyrimidin-6-one Chemical compound C1OC=2C(OC)=CC=CC=2OC1CN(C(CCN1C(=O)C=2)(C)C)C1=NC=2C1=CC=NC=N1 BGBTXTRRHGZKOY-UHFFFAOYSA-N 0.000 claims 1
- WCQSQLRAQNHCQZ-UHFFFAOYSA-N 1-[(8-fluoro-5-methoxy-3,4-dihydro-2h-chromen-3-yl)methyl]-2,2-dimethyl-8-pyridin-4-yl-3,4-dihydropyrimido[1,2-a]pyrimidin-6-one Chemical compound C1C=2C(OC)=CC=C(F)C=2OCC1CN(C(CCN1C(=O)C=2)(C)C)C1=NC=2C1=CC=NC=C1 WCQSQLRAQNHCQZ-UHFFFAOYSA-N 0.000 claims 1
- UXBLDQMSOWQULB-UHFFFAOYSA-N 3-amino-2-methyl-6,7,8,9-tetrahydro-5h-cyclohepta[2,3]thieno[2,4-d]pyrimidin-4-one Chemical compound C1CCCCC2=C1SC1=C2C(=O)N(N)C(C)=N1 UXBLDQMSOWQULB-UHFFFAOYSA-N 0.000 claims 1
- GJBVQWVSBSUPPW-UHFFFAOYSA-N 4,6,7,8-tetrahydro-1H-pyrimido[1,2-a]pyrimidine Chemical compound N1C=2N(CCC1)CC=CN2 GJBVQWVSBSUPPW-UHFFFAOYSA-N 0.000 claims 1
- YCIPQJTZJGUXND-UHFFFAOYSA-N Aglaia odorata Alkaloid Natural products C1=CC(OC)=CC=C1C1(C(C=2C(=O)N3CCCC3=NC=22)C=3C=CC=CC=3)C2(O)C2=C(OC)C=C(OC)C=C2O1 YCIPQJTZJGUXND-UHFFFAOYSA-N 0.000 claims 1
- 102000004877 Insulin Human genes 0.000 claims 1
- 108090001061 Insulin Proteins 0.000 claims 1
- 206010012601 diabetes mellitus Diseases 0.000 claims 1
- 229940125396 insulin Drugs 0.000 claims 1
- 125000006514 pyridin-2-ylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims 1
- 108010051975 Glycogen Synthase Kinase 3 beta Proteins 0.000 abstract description 3
- 102000019058 Glycogen Synthase Kinase 3 beta Human genes 0.000 abstract 2
- 101150053721 Cdk5 gene Proteins 0.000 abstract 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 abstract 1
- 125000005678 ethenylene group Chemical group [H]C([*:1])=C([H])[*:2] 0.000 abstract 1
- 125000005677 ethinylene group Chemical group [*:2]C#C[*:1] 0.000 abstract 1
- 230000003449 preventive effect Effects 0.000 abstract 1
- 239000012458 free base Substances 0.000 description 74
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 60
- 238000000034 method Methods 0.000 description 58
- 239000000203 mixture Substances 0.000 description 58
- 239000000047 product Substances 0.000 description 50
- ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 49
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 48
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 43
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- 239000000243 solution Substances 0.000 description 35
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 31
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 27
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 23
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 22
- 239000000725 suspension Substances 0.000 description 19
- 239000002904 solvent Substances 0.000 description 17
- 239000011541 reaction mixture Substances 0.000 description 16
- 230000000694 effects Effects 0.000 description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
- 150000004677 hydrates Chemical class 0.000 description 13
- 229940098779 methanesulfonic acid Drugs 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical class N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- 239000012043 crude product Substances 0.000 description 11
- 239000012074 organic phase Substances 0.000 description 11
- 102000013498 tau Proteins Human genes 0.000 description 11
- 108010026424 tau Proteins Proteins 0.000 description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 11
- 239000002253 acid Substances 0.000 description 10
- 239000012280 lithium aluminium hydride Substances 0.000 description 10
- 239000008194 pharmaceutical composition Substances 0.000 description 10
- 230000026731 phosphorylation Effects 0.000 description 10
- 238000006366 phosphorylation reaction Methods 0.000 description 10
- SIOXPEMLGUPBBT-UHFFFAOYSA-N picolinic acid Chemical compound OC(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-N 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- 239000002244 precipitate Substances 0.000 description 9
- 239000012312 sodium hydride Substances 0.000 description 9
- 229910000104 sodium hydride Inorganic materials 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 238000004587 chromatography analysis Methods 0.000 description 8
- 230000002401 inhibitory effect Effects 0.000 description 8
- 239000002480 mineral oil Substances 0.000 description 8
- 235000010446 mineral oil Nutrition 0.000 description 8
- 239000000741 silica gel Substances 0.000 description 8
- 229910002027 silica gel Inorganic materials 0.000 description 8
- 239000002585 base Substances 0.000 description 7
- 239000000546 pharmaceutical excipient Substances 0.000 description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 201000011240 Frontotemporal dementia Diseases 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000000460 chlorine Substances 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- UBLPNIGKZGWDKN-UHFFFAOYSA-N (2-chloro-6,7-dihydro-5h-cyclopenta[b]pyridin-6-yl)methanol Chemical compound C1=C(Cl)N=C2CC(CO)CC2=C1 UBLPNIGKZGWDKN-UHFFFAOYSA-N 0.000 description 5
- 102000004190 Enzymes Human genes 0.000 description 5
- 108090000790 Enzymes Proteins 0.000 description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 5
- 229910021529 ammonia Inorganic materials 0.000 description 5
- 239000012300 argon atmosphere Substances 0.000 description 5
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- 235000019198 oils Nutrition 0.000 description 5
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 4
- HBEDSQVIWPRPAY-UHFFFAOYSA-N 2,3-dihydrobenzofuran Chemical compound C1=CC=C2OCCC2=C1 HBEDSQVIWPRPAY-UHFFFAOYSA-N 0.000 description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 208000011990 Corticobasal Degeneration Diseases 0.000 description 4
- 206010012289 Dementia Diseases 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 4
- 108091000080 Phosphotransferase Proteins 0.000 description 4
- 235000011054 acetic acid Nutrition 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
- 206010064930 age-related macular degeneration Diseases 0.000 description 4
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- PCJNYGPKMQQCPX-UHFFFAOYSA-N ethyl 3-oxo-3-pyridin-4-ylpropanoate Chemical compound CCOC(=O)CC(=O)C1=CC=NC=C1 PCJNYGPKMQQCPX-UHFFFAOYSA-N 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 230000006951 hyperphosphorylation Effects 0.000 description 4
- WSFSSNUMVMOOMR-BJUDXGSMSA-N methanone Chemical compound O=[11CH2] WSFSSNUMVMOOMR-BJUDXGSMSA-N 0.000 description 4
- 210000002569 neuron Anatomy 0.000 description 4
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 4
- 208000027232 peripheral nervous system disease Diseases 0.000 description 4
- 102000020233 phosphotransferase Human genes 0.000 description 4
- 201000002212 progressive supranuclear palsy Diseases 0.000 description 4
- 125000000714 pyrimidinyl group Chemical group 0.000 description 4
- 210000000278 spinal cord Anatomy 0.000 description 4
- 230000004083 survival effect Effects 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 3
- YAYOVHRLVOHYMW-UHFFFAOYSA-N 1h-pyrimidin-6-one;hydrochloride Chemical compound Cl.O=C1C=CN=CN1 YAYOVHRLVOHYMW-UHFFFAOYSA-N 0.000 description 3
- 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 3
- ZCFPCDAOMSGDII-UHFFFAOYSA-N 7,7-dimethyl-2-pyridin-4-yl-6,8-dihydro-1h-pyrimido[1,2-a]pyrimidin-4-one Chemical compound C=1C(=O)N2CC(C)(C)CNC2=NC=1C1=CC=NC=C1 ZCFPCDAOMSGDII-UHFFFAOYSA-N 0.000 description 3
- MUZQOTCZAGDYCT-UHFFFAOYSA-N 7,7-dimethyl-2-pyrimidin-4-yl-6,8-dihydro-1h-pyrimido[1,2-a]pyrimidin-4-one Chemical compound C=1C(=O)N2CC(C)(C)CNC2=NC=1C1=CC=NC=N1 MUZQOTCZAGDYCT-UHFFFAOYSA-N 0.000 description 3
- 102000013455 Amyloid beta-Peptides Human genes 0.000 description 3
- 108010090849 Amyloid beta-Peptides Proteins 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 description 3
- 206010048010 Withdrawal syndrome Diseases 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- BNBQRQQYDMDJAH-UHFFFAOYSA-N benzodioxan Chemical compound C1=CC=C2OCCOC2=C1 BNBQRQQYDMDJAH-UHFFFAOYSA-N 0.000 description 3
- 210000004556 brain Anatomy 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 229960001701 chloroform Drugs 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000006378 damage Effects 0.000 description 3
- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- OIDIIAUKCZULOP-UHFFFAOYSA-N methanesulfonic acid;methoxymethane Chemical compound COC.CS(O)(=O)=O OIDIIAUKCZULOP-UHFFFAOYSA-N 0.000 description 3
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 238000007911 parenteral administration Methods 0.000 description 3
- 230000001575 pathological effect Effects 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000000829 suppository Substances 0.000 description 3
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 2
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 description 2
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- PBIUDEUWYGBHDW-UHFFFAOYSA-N 2-chloro-1-pyridin-3-ylethanone;hydrochloride Chemical compound Cl.ClCC(=O)C1=CC=CN=C1 PBIUDEUWYGBHDW-UHFFFAOYSA-N 0.000 description 2
- TUQPSMBVVMPFJS-UHFFFAOYSA-N 2-pyridin-4-yl-1,6,7,8-tetrahydropyrimido[1,2-a]pyrimidin-4-one Chemical compound N1=C2NCCCN2C(=O)C=C1C1=CC=NC=C1 TUQPSMBVVMPFJS-UHFFFAOYSA-N 0.000 description 2
- NDTLPGSBLDKERL-UHFFFAOYSA-N 5,5-difluoro-4,6-dihydro-1h-pyrimidin-2-amine Chemical compound NC1=NCC(F)(F)CN1 NDTLPGSBLDKERL-UHFFFAOYSA-N 0.000 description 2
- WCTDRGQIEULRBE-UHFFFAOYSA-N 6,7-dihydro-5h-cyclopenta[b]pyrazine Chemical compound C1=CN=C2CCCC2=N1 WCTDRGQIEULRBE-UHFFFAOYSA-N 0.000 description 2
- ZPETZUBJYGWOOD-UHFFFAOYSA-N 8-methyl-2-pyridin-4-yl-1,6,7,8-tetrahydropyrimido[1,2-a]pyrimidin-4-one Chemical compound N1C(C)CCN(C(C=2)=O)C1=NC=2C1=CC=NC=C1 ZPETZUBJYGWOOD-UHFFFAOYSA-N 0.000 description 2
- YQQRUNHROWAJIV-UHFFFAOYSA-N 9-(6,7-dihydro-5h-cyclopenta[b]pyrazin-6-ylmethyl)-7,7-dimethyl-2-pyrimidin-4-yl-6,8-dihydropyrimido[1,2-a]pyrimidin-4-one Chemical compound C=1C(=O)N2CC(C)(C)CN(CC3CC4=NC=CN=C4C3)C2=NC=1C1=CC=NC=N1 YQQRUNHROWAJIV-UHFFFAOYSA-N 0.000 description 2
- CDCRELCQVYXHBD-UHFFFAOYSA-N 9-[2-(1h-indol-3-yl)ethyl]-2-pyridin-4-yl-7,8-dihydro-6h-pyrimido[1,2-a]pyrimidin-4-one Chemical compound N1=C2N(CCC=3C4=CC=CC=C4NC=3)CCCN2C(=O)C=C1C1=CC=NC=C1 CDCRELCQVYXHBD-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 101710137189 Amyloid-beta A4 protein Proteins 0.000 description 2
- 101710151993 Amyloid-beta precursor protein Proteins 0.000 description 2
- 102100022704 Amyloid-beta precursor protein Human genes 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- 208000037273 Pathologic Processes Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 208000000609 Pick Disease of the Brain Diseases 0.000 description 2
- 108091008611 Protein Kinase B Proteins 0.000 description 2
- 102100033810 RAC-alpha serine/threonine-protein kinase Human genes 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 208000027418 Wounds and injury Diseases 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 239000012190 activator Substances 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- DZHSAHHDTRWUTF-SIQRNXPUSA-N amyloid-beta polypeptide 42 Chemical compound C([C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O)[C@@H](C)CC)C(C)C)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C(C)C)C1=CC=CC=C1 DZHSAHHDTRWUTF-SIQRNXPUSA-N 0.000 description 2
- 150000001450 anions Chemical class 0.000 description 2
- 230000001640 apoptogenic effect Effects 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 150000007514 bases Chemical class 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 238000005341 cation exchange Methods 0.000 description 2
- 210000004027 cell Anatomy 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
- 210000003169 central nervous system Anatomy 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- VZWXIQHBIQLMPN-UHFFFAOYSA-N chromane Chemical compound C1=CC=C2CCCOC2=C1 VZWXIQHBIQLMPN-UHFFFAOYSA-N 0.000 description 2
- 229940110456 cocoa butter Drugs 0.000 description 2
- 235000019868 cocoa butter Nutrition 0.000 description 2
- 238000004891 communication Methods 0.000 description 2
- 210000004292 cytoskeleton Anatomy 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- WJSKHXMBIXCAJX-UHFFFAOYSA-N ethyl 2-furo[2,3-b]pyridin-3-ylacetate Chemical compound C1=CC=C2C(CC(=O)OCC)=COC2=N1 WJSKHXMBIXCAJX-UHFFFAOYSA-N 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- YRTCKZIKGWZNCU-UHFFFAOYSA-N furo[3,2-b]pyridine Chemical compound C1=CC=C2OC=CC2=N1 YRTCKZIKGWZNCU-UHFFFAOYSA-N 0.000 description 2
- 230000014509 gene expression Effects 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 125000001041 indolyl group Chemical group 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- TWBYWOBDOCUKOW-UHFFFAOYSA-N isonicotinic acid Chemical compound OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000000787 lecithin Substances 0.000 description 2
- 229940067606 lecithin Drugs 0.000 description 2
- 235000010445 lecithin Nutrition 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- 230000004807 localization Effects 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
- 230000001537 neural effect Effects 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 230000009054 pathological process Effects 0.000 description 2
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 2
- 229920000137 polyphosphoric acid Polymers 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000002953 preparative HPLC Methods 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 235000019260 propionic acid Nutrition 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 235000018102 proteins Nutrition 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 2
- XSCHRSMBECNVNS-UHFFFAOYSA-N quinoxaline Chemical compound N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 2
- 239000012429 reaction media Substances 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000007901 soft capsule Substances 0.000 description 2
- 238000004611 spectroscopical analysis Methods 0.000 description 2
- 238000010561 standard procedure Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 108010061506 tau-protein kinase Proteins 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- KQDBICCHTLJGMP-UHFFFAOYSA-N 1,4,5,6-tetrahydropyrimidin-2-amine;hydrobromide Chemical compound Br.NC1=NCCCN1 KQDBICCHTLJGMP-UHFFFAOYSA-N 0.000 description 1
- GRHGTRIHFULSAY-UHFFFAOYSA-N 1,4,5,6-tetrahydropyrimidin-2-amine;hydrochloride Chemical compound Cl.NC1=NCCCN1 GRHGTRIHFULSAY-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- KFDKBUVBJPDLIC-UHFFFAOYSA-N 1-(2,3-dihydro-1,4-benzodioxin-3-ylmethyl)-2,2-dimethyl-8-pyridin-4-yl-3,4-dihydropyrimido[1,2-a]pyrimidin-6-one Chemical compound C1OC2=CC=CC=C2OC1CN1C(C)(C)CCN(C(C=2)=O)C1=NC=2C1=CC=NC=C1 KFDKBUVBJPDLIC-UHFFFAOYSA-N 0.000 description 1
- CTUGPDIZVBGWCD-UHFFFAOYSA-N 1-(2,3-dihydro-1,4-benzodioxin-3-ylmethyl)-2,2-dimethyl-8-pyrimidin-4-yl-3,4-dihydropyrimido[1,2-a]pyrimidin-6-one Chemical compound C1OC2=CC=CC=C2OC1CN1C(C)(C)CCN(C(C=2)=O)C1=NC=2C1=CC=NC=N1 CTUGPDIZVBGWCD-UHFFFAOYSA-N 0.000 description 1
- QMDUEBURHKSKDG-UHFFFAOYSA-N 1-pyridin-3-ylethanol Chemical compound CC(O)C1=CC=CN=C1 QMDUEBURHKSKDG-UHFFFAOYSA-N 0.000 description 1
- KEOWKZFSSBVUIW-UHFFFAOYSA-N 1h-cyclopenta[b]pyrazine Chemical group C1=CNC2=CC=CC2=N1 KEOWKZFSSBVUIW-UHFFFAOYSA-N 0.000 description 1
- HFPPZQKUJWIBJI-UHFFFAOYSA-N 2,2-difluoropropane-1,3-diamine Chemical compound NCC(F)(F)CN HFPPZQKUJWIBJI-UHFFFAOYSA-N 0.000 description 1
- LWOIPPVWVLSHQJ-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-2-yl]ethanol Chemical compound OCCC1CN(CCO)CCN1 LWOIPPVWVLSHQJ-UHFFFAOYSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- 229940058020 2-amino-2-methyl-1-propanol Drugs 0.000 description 1
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 description 1
- UENSRVLXNOIBQC-UHFFFAOYSA-N 2-furo[2,3-b]pyridin-3-ylethanol Chemical compound C1=CC=C2C(CCO)=COC2=N1 UENSRVLXNOIBQC-UHFFFAOYSA-N 0.000 description 1
- OHQHYECMOFDXPV-UHFFFAOYSA-N 2-methoxy-2,3-dihydro-1-benzofuran Chemical compound C1=CC=C2OC(OC)CC2=C1 OHQHYECMOFDXPV-UHFFFAOYSA-N 0.000 description 1
- ZFMVWTHVXNBHNJ-UHFFFAOYSA-N 2-methylpropane-1,3-diamine;hydrochloride Chemical compound Cl.NCC(C)CN ZFMVWTHVXNBHNJ-UHFFFAOYSA-N 0.000 description 1
- GKECDORWWXXNRY-UHFFFAOYSA-N 2h-pyridin-3-one Chemical compound O=C1CN=CC=C1 GKECDORWWXXNRY-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- HOTUUKXLXZBJMR-UHFFFAOYSA-N 3-methoxy-3,4-dihydro-2h-chromene Chemical compound C1=CC=C2CC(OC)COC2=C1 HOTUUKXLXZBJMR-UHFFFAOYSA-N 0.000 description 1
- JPQIZEWXWKGDNS-UHFFFAOYSA-N 5,5-dimethyl-4,6-dihydro-1h-pyrimidin-2-amine;hydrochloride Chemical compound Cl.CC1(C)CNC(N)=NC1 JPQIZEWXWKGDNS-UHFFFAOYSA-N 0.000 description 1
- QTFVHGKLPDHRSZ-UHFFFAOYSA-N 5-methyl-1,4,5,6-tetrahydropyrimidin-2-amine;hydrochloride Chemical compound Cl.CC1CNC(N)=NC1 QTFVHGKLPDHRSZ-UHFFFAOYSA-N 0.000 description 1
- AVGXFYDTYMYUGL-UHFFFAOYSA-N 6,7-dihydro-5h-cyclopenta[b]pyrazin-6-ylmethanol Chemical compound C1=CN=C2CC(CO)CC2=N1 AVGXFYDTYMYUGL-UHFFFAOYSA-N 0.000 description 1
- ZNOIAHOPHBDPRB-UHFFFAOYSA-N 6-methyl-1,4,5,6-tetrahydropyrimidin-2-amine;hydrochloride Chemical compound Cl.CC1CCN=C(N)N1 ZNOIAHOPHBDPRB-UHFFFAOYSA-N 0.000 description 1
- QOXNOHZFVBFFTF-UHFFFAOYSA-N 7,7-difluoro-2-pyridin-4-yl-6,8-dihydro-1h-pyrimido[1,2-a]pyrimidin-4-one Chemical compound C=1C(=O)N2CC(F)(F)CNC2=NC=1C1=CC=NC=C1 QOXNOHZFVBFFTF-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 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 1
- NJQXYRMVUXRIJL-UHFFFAOYSA-N 9-(2,3-dihydro-1,4-benzodioxin-3-ylmethyl)-8-methyl-2-pyridin-4-yl-7,8-dihydro-6h-pyrimido[1,2-a]pyrimidin-4-one Chemical compound C1OC2=CC=CC=C2OC1CN1C(C)CCN(C(C=2)=O)C1=NC=2C1=CC=NC=C1 NJQXYRMVUXRIJL-UHFFFAOYSA-N 0.000 description 1
- JUXRIVHZKOKMLC-UHFFFAOYSA-N 9-(2,3-dihydro-1,4-benzodioxin-3-ylmethyl)-8-methyl-2-pyrimidin-4-yl-7,8-dihydro-6h-pyrimido[1,2-a]pyrimidin-4-one Chemical compound C1OC2=CC=CC=C2OC1CN1C(C)CCN(C(C=2)=O)C1=NC=2C1=CC=NC=N1 JUXRIVHZKOKMLC-UHFFFAOYSA-N 0.000 description 1
- VIDOYKVNXIELAK-UHFFFAOYSA-N 9-(2-furo[2,3-b]pyridin-3-ylethyl)-7,7-dimethyl-2-pyrimidin-4-yl-6,8-dihydropyrimido[1,2-a]pyrimidin-4-one Chemical compound C=1C(=O)N2CC(C)(C)CN(CCC=3C4=CC=CN=C4OC=3)C2=NC=1C1=CC=NC=N1 VIDOYKVNXIELAK-UHFFFAOYSA-N 0.000 description 1
- BLVXKNQSJLZZDB-UHFFFAOYSA-N 9-(2-furo[2,3-b]pyridin-3-ylethyl)-7,7-dimethyl-2-pyrimidin-4-yl-6,8-dihydropyrimido[1,2-a]pyrimidin-4-one;hydrochloride Chemical compound Cl.C=1C(=O)N2CC(C)(C)CN(CCC=3C4=CC=CN=C4OC=3)C2=NC=1C1=CC=NC=N1 BLVXKNQSJLZZDB-UHFFFAOYSA-N 0.000 description 1
- CTIQKVVDITXIHF-UHFFFAOYSA-N 9-(furo[3,2-b]pyridin-2-ylmethyl)-7,7-dimethyl-2-pyridin-4-yl-6,8-dihydropyrimido[1,2-a]pyrimidin-4-one Chemical compound C=1C(=O)N2CC(C)(C)CN(CC=3OC4=CC=CN=C4C=3)C2=NC=1C1=CC=NC=C1 CTIQKVVDITXIHF-UHFFFAOYSA-N 0.000 description 1
- JPRWBLCLDKHFOJ-UHFFFAOYSA-N 9-(furo[3,2-b]pyridin-2-ylmethyl)-8-methyl-2-pyridin-4-yl-7,8-dihydro-6h-pyrimido[1,2-a]pyrimidin-4-one Chemical compound C=1C2=NC=CC=C2OC=1CN1C(C)CCN(C(C=2)=O)C1=NC=2C1=CC=NC=C1 JPRWBLCLDKHFOJ-UHFFFAOYSA-N 0.000 description 1
- MYYURDXLYVASIE-UHFFFAOYSA-N 9-[(5-methoxy-2,3-dihydro-1,4-benzodioxin-2-yl)methyl]-8-methyl-2-pyrimidin-4-yl-7,8-dihydro-6h-pyrimido[1,2-a]pyrimidin-4-one Chemical compound C1OC=2C(OC)=CC=CC=2OC1CN1C(C)CCN(C(C=2)=O)C1=NC=2C1=CC=NC=N1 MYYURDXLYVASIE-UHFFFAOYSA-N 0.000 description 1
- YMFHUQQSCHDPMI-UHFFFAOYSA-N 9-[(5-methoxy-2,3-dihydro-1,4-benzodioxin-3-yl)methyl]-8-methyl-2-pyridin-4-yl-7,8-dihydro-6h-pyrimido[1,2-a]pyrimidin-4-one Chemical compound O1C=2C(OC)=CC=CC=2OCC1CN1C(C)CCN(C(C=2)=O)C1=NC=2C1=CC=NC=C1 YMFHUQQSCHDPMI-UHFFFAOYSA-N 0.000 description 1
- HXIQVEBSSYOTBD-UHFFFAOYSA-N 9-[(5-methoxy-2,3-dihydro-1,4-benzodioxin-3-yl)methyl]-8-methyl-2-pyrimidin-4-yl-7,8-dihydro-6h-pyrimido[1,2-a]pyrimidin-4-one Chemical compound O1C=2C(OC)=CC=CC=2OCC1CN1C(C)CCN(C(C=2)=O)C1=NC=2C1=CC=NC=N1 HXIQVEBSSYOTBD-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 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
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 108020005544 Antisense RNA Proteins 0.000 description 1
- 102100021569 Apoptosis regulator Bcl-2 Human genes 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 108091007914 CDKs Proteins 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 102000008130 Cyclic AMP-Dependent Protein Kinases Human genes 0.000 description 1
- 102000003903 Cyclin-dependent kinases Human genes 0.000 description 1
- 108090000266 Cyclin-dependent kinases Proteins 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 101710088194 Dehydrogenase Proteins 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- IYXGSMUGOJNHAZ-UHFFFAOYSA-N Ethyl malonate Chemical class CCOC(=O)CC(=O)OCC IYXGSMUGOJNHAZ-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 108010001483 Glycogen Synthase Proteins 0.000 description 1
- 102100038104 Glycogen synthase kinase-3 beta Human genes 0.000 description 1
- 102100039121 Histone-lysine N-methyltransferase MECOM Human genes 0.000 description 1
- 108010033040 Histones Proteins 0.000 description 1
- 102000006947 Histones Human genes 0.000 description 1
- 101000971171 Homo sapiens Apoptosis regulator Bcl-2 Proteins 0.000 description 1
- 101001033728 Homo sapiens Histone-lysine N-methyltransferase MECOM Proteins 0.000 description 1
- 101001059454 Homo sapiens Serine/threonine-protein kinase MARK2 Proteins 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 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
- 239000004472 Lysine Substances 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 108091054455 MAP kinase family Proteins 0.000 description 1
- 102000043136 MAP kinase family Human genes 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 102000029749 Microtubule Human genes 0.000 description 1
- 108091022875 Microtubule Proteins 0.000 description 1
- NIPNSKYNPDTRPC-UHFFFAOYSA-N N-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 NIPNSKYNPDTRPC-UHFFFAOYSA-N 0.000 description 1
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 1
- 108010025020 Nerve Growth Factor Proteins 0.000 description 1
- 102000007072 Nerve Growth Factors Human genes 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 101700056750 PAK1 Proteins 0.000 description 1
- 208000024571 Pick disease Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- LCTONWCANYUPML-UHFFFAOYSA-M Pyruvate Chemical compound CC(=O)C([O-])=O LCTONWCANYUPML-UHFFFAOYSA-M 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 102100028904 Serine/threonine-protein kinase MARK2 Human genes 0.000 description 1
- 102100031206 Serine/threonine-protein kinase N1 Human genes 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 102000017299 Synapsin-1 Human genes 0.000 description 1
- 108050005241 Synapsin-1 Proteins 0.000 description 1
- 101150038925 TPK2 gene Proteins 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 102000044159 Ubiquitin Human genes 0.000 description 1
- 108090000848 Ubiquitin Proteins 0.000 description 1
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 1
- 229960004373 acetylcholine Drugs 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 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
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- CBTVGIZVANVGBH-UHFFFAOYSA-N aminomethyl propanol Chemical compound CC(C)(N)CO CBTVGIZVANVGBH-UHFFFAOYSA-N 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 230000002424 anti-apoptotic effect Effects 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- RFRXIWQYSOIBDI-UHFFFAOYSA-N benzarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC=C(O)C=C1 RFRXIWQYSOIBDI-UHFFFAOYSA-N 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 210000005013 brain tissue Anatomy 0.000 description 1
- 150000001649 bromium compounds Chemical group 0.000 description 1
- ZSOMHSLKERBJSE-UHFFFAOYSA-N bromo methanesulfonate Chemical compound CS(=O)(=O)OBr ZSOMHSLKERBJSE-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 230000003920 cognitive function Effects 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 230000002301 combined effect Effects 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 230000003831 deregulation Effects 0.000 description 1
- 230000001687 destabilization Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- OCXGTPDKNBIOTF-UHFFFAOYSA-N dibromo(triphenyl)-$l^{5}-phosphane Chemical compound C=1C=CC=CC=1P(Br)(C=1C=CC=CC=1)(Br)C1=CC=CC=C1 OCXGTPDKNBIOTF-UHFFFAOYSA-N 0.000 description 1
- 150000005690 diesters Chemical class 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 238000011037 discontinuous sequential dilution Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- IGRUUQSUGJLZCM-UHFFFAOYSA-N ethyl 3-oxo-3-pyrimidin-4-ylpropanoate Chemical compound CCOC(=O)CC(=O)C1=CC=NC=N1 IGRUUQSUGJLZCM-UHFFFAOYSA-N 0.000 description 1
- VNNBHOWNGMPSRP-UHFFFAOYSA-N ethyl 6,7-dihydro-5h-cyclopenta[b]pyrazine-6-carboxylate Chemical compound C1=CN=C2CC(C(=O)OCC)CC2=N1 VNNBHOWNGMPSRP-UHFFFAOYSA-N 0.000 description 1
- IIEWJVIFRVWJOD-UHFFFAOYSA-N ethyl cyclohexane Natural products CCC1CCCCC1 IIEWJVIFRVWJOD-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
- FQYYIPZPELSLDK-UHFFFAOYSA-N ethyl pyridine-2-carboxylate Chemical compound CCOC(=O)C1=CC=CC=N1 FQYYIPZPELSLDK-UHFFFAOYSA-N 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- OIMBQDHQXBDNFX-UHFFFAOYSA-N furo[3,2-b]pyridin-2-ylmethanol Chemical compound C1=CC=C2OC(CO)=CC2=N1 OIMBQDHQXBDNFX-UHFFFAOYSA-N 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
- 229940097043 glucuronic acid Drugs 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 229960004275 glycolic acid Drugs 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 229960000789 guanidine hydrochloride Drugs 0.000 description 1
- PJJJBBJSCAKJQF-UHFFFAOYSA-N guanidinium chloride Chemical compound [Cl-].NC(N)=[NH2+] PJJJBBJSCAKJQF-UHFFFAOYSA-N 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 230000006882 induction of apoptosis Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 125000002510 isobutoxy group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])O* 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- HEBMCVBCEDMUOF-UHFFFAOYSA-N isochromane Chemical compound C1=CC=C2COCCC2=C1 HEBMCVBCEDMUOF-UHFFFAOYSA-N 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229940080428 lactose 200 mg Drugs 0.000 description 1
- 235000019860 lauric fat Nutrition 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 125000005905 mesyloxy group Chemical group 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 210000004688 microtubule Anatomy 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000007923 nasal drop Substances 0.000 description 1
- 229940100662 nasal drops Drugs 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 210000001577 neostriatum Anatomy 0.000 description 1
- 210000005044 neurofilament Anatomy 0.000 description 1
- 230000014511 neuron projection development Effects 0.000 description 1
- 230000006576 neuronal survival Effects 0.000 description 1
- 230000002981 neuropathic effect Effects 0.000 description 1
- 230000002887 neurotoxic effect Effects 0.000 description 1
- 239000002581 neurotoxin Substances 0.000 description 1
- 230000000508 neurotrophic effect Effects 0.000 description 1
- 239000003900 neurotrophic factor Substances 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 230000036963 noncompetitive effect Effects 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 230000000865 phosphorylative effect Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000000861 pro-apoptotic effect Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 125000001500 prolyl group Chemical group [H]N1C([H])(C(=O)[*])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000026938 proteasomal ubiquitin-dependent protein catabolic process Effects 0.000 description 1
- 229940043437 protein kinase A inhibitor Drugs 0.000 description 1
- 239000012656 protein kinase A inhibitor Substances 0.000 description 1
- 230000009822 protein phosphorylation Effects 0.000 description 1
- QLULGIRFKAWHOJ-UHFFFAOYSA-N pyridin-4-ylboronic acid Chemical compound OB(O)C1=CC=NC=C1 QLULGIRFKAWHOJ-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- ZFCHNZDUMIOWFV-UHFFFAOYSA-N pyrimidine-2-carboxylic acid Chemical compound OC(=O)C1=NC=CC=N1 ZFCHNZDUMIOWFV-UHFFFAOYSA-N 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000018406 regulation of metabolic process Effects 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 125000005920 sec-butoxy group Chemical group 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 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
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 125000005424 tosyloxy group Chemical group S(=O)(=O)(C1=CC=C(C)C=C1)O* 0.000 description 1
- GGUBFICZYGKNTD-UHFFFAOYSA-N triethyl phosphonoacetate Chemical compound CCOC(=O)CP(=O)(OCC)OCC GGUBFICZYGKNTD-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/14—Drugs for dermatological disorders for baldness or alopecia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/34—Tobacco-abuse
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- 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
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Diabetes (AREA)
- Psychiatry (AREA)
- Ophthalmology & Optometry (AREA)
- Hematology (AREA)
- Addiction (AREA)
- Pain & Pain Management (AREA)
- Obesity (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Endocrinology (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Psychology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Dermatology (AREA)
- Epidemiology (AREA)
- Hospice & Palliative Care (AREA)
- Emergency Medicine (AREA)
- Agronomy & Crop Science (AREA)
- Pest Control & Pesticides (AREA)
- Plant Pathology (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP02290486A EP1348708A1 (en) | 2002-02-28 | 2002-02-28 | Heteroaryl substituted 2-pyrimidinyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 7-pyrimidinyl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)one derivatives |
| EP02290485A EP1340758A1 (en) | 2002-02-28 | 2002-02-28 | Heteroaryl substituted 2-pyridinyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 7-pyridinyl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)one derivatives |
| PCT/EP2003/002651 WO2003072579A1 (en) | 2002-02-28 | 2003-02-26 | HETEROARYL SUBSTITUTED 2-PYRIDINYL AND 2-PYRIMIDINYL -6,7,8,9- TETRAHYDROPYRIMIDO[1,2-a] PYRIMIDIN-4-ONE DERIVATIVES |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| EA200400936A1 EA200400936A1 (ru) | 2005-02-24 |
| EA007737B1 true EA007737B1 (ru) | 2006-12-29 |
Family
ID=27767034
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EA200400936A EA007737B1 (ru) | 2002-02-28 | 2003-02-26 | ГЕТЕРОАРИЛЗАМЕЩЕННЫЕ ПРОИЗВОДНЫЕ 2-ПИРИДИНИЛ- И 2-ПИРИМИДИНИЛ-6,7,8,9-ТЕТРАГИДРОПИРИМИДО[1,2-a]ПИРИМИДИН-4-ОНА |
Country Status (22)
| Country | Link |
|---|---|
| US (2) | US7232827B2 (OSRAM) |
| EP (1) | EP1480983B1 (OSRAM) |
| JP (1) | JP4458851B2 (OSRAM) |
| KR (1) | KR101030629B1 (OSRAM) |
| CN (1) | CN1315832C (OSRAM) |
| AR (1) | AR038619A1 (OSRAM) |
| AT (1) | ATE309247T1 (OSRAM) |
| AU (1) | AU2003221500B9 (OSRAM) |
| BR (1) | BR0308109A (OSRAM) |
| CA (1) | CA2474823C (OSRAM) |
| DE (1) | DE60302221T2 (OSRAM) |
| DK (1) | DK1480983T3 (OSRAM) |
| EA (1) | EA007737B1 (OSRAM) |
| ES (1) | ES2250883T3 (OSRAM) |
| IL (1) | IL163287A (OSRAM) |
| MX (1) | MXPA04008364A (OSRAM) |
| NO (1) | NO329805B1 (OSRAM) |
| NZ (1) | NZ534466A (OSRAM) |
| PL (1) | PL372465A1 (OSRAM) |
| SI (1) | SI1480983T1 (OSRAM) |
| TW (1) | TWI303637B (OSRAM) |
| WO (1) | WO2003072579A1 (OSRAM) |
Families Citing this family (23)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AR043486A1 (es) | 2003-03-07 | 2005-08-03 | Sanofi Aventis | Derivados de 2-(diaza-biciclo-alquil)-pirimidona |
| EP1454910A1 (en) | 2003-03-07 | 2004-09-08 | Sanofi-Synthelabo | Substituted pyrimidinyl-2-(diaza-bicyclo-alkyl)-pyrimidone derivatives |
| EP1557417B1 (en) * | 2003-12-19 | 2007-03-07 | Sanofi-Aventis | Substituted 8'-pyri(mi)dinyl-dihydrospiro-[cycloalkylamine]-pyrimido[1,2-a] pyrimidin-6-one derivatives |
| EP1723427A2 (en) * | 2004-02-26 | 2006-11-22 | Bayer HealthCare AG | Diagnostics and therapeutics for diseases associated with glycogen synthase kinase 3 beta (gsk3b) |
| DE102004010194A1 (de) * | 2004-03-02 | 2005-10-13 | Aventis Pharma Deutschland Gmbh | 4-Benzimidazol-2-yl-pyridazin-3-on-Derivate, ihre Herstellung und Verwendung in Arzneimitteln |
| DE102004010207A1 (de) | 2004-03-02 | 2005-09-15 | Aventis Pharma S.A. | Neue 4-Benzimidazol-2-yl-pyridazin-3-on-Derivate |
| US7678363B2 (en) | 2005-08-26 | 2010-03-16 | Braincells Inc | Methods of treating psychiatric conditions comprising administration of muscarinic agents in combination with SSRIs |
| EP2258359A3 (en) | 2005-08-26 | 2011-04-06 | Braincells, Inc. | Neurogenesis by muscarinic receptor modulation with sabcomelin |
| WO2007047978A2 (en) | 2005-10-21 | 2007-04-26 | Braincells, Inc. | Modulation of neurogenesis by pde inhibition |
| AU2006308889A1 (en) | 2005-10-31 | 2007-05-10 | Braincells, Inc. | GABA receptor mediated modulation of neurogenesis |
| US20100216734A1 (en) | 2006-03-08 | 2010-08-26 | Braincells, Inc. | Modulation of neurogenesis by nootropic agents |
| CA2651813A1 (en) | 2006-05-09 | 2007-11-22 | Braincells, Inc. | Neurogenesis by modulating angiotensin |
| US20100184806A1 (en) | 2006-09-19 | 2010-07-22 | Braincells, Inc. | Modulation of neurogenesis by ppar agents |
| WO2010099217A1 (en) | 2009-02-25 | 2010-09-02 | Braincells, Inc. | Modulation of neurogenesis using d-cycloserine combinations |
| FR2947551B1 (fr) * | 2009-07-02 | 2012-05-18 | Sanofi Aventis | Nouveaux derives de 1,2,3,4-tetrahydro-pyrimido{1,2-a)pyrimidin-6-one, leur preparation et leur utilisation pharmaceutique comme inhibiteurs de phosphorylation d'akt (pkb) |
| FR2947550B1 (fr) * | 2009-07-02 | 2012-05-18 | Sanofi Aventis | Nouveaux derives de 2,3-dihydro-1h-imidazo{1,2-a}pyrimidin-5-one, leur preparation et leur utilisation pharmaceutique comme inhibiteurs de phosphorylation d'akt (pkb) |
| LT2448939T (lt) * | 2009-07-02 | 2017-06-12 | Sanofi | 2,3-dihidro-1h-imidazo {1,2-a} pirimidin-5-ono dariniai, jų gamyba ir farmacinis panaudojimas |
| SI2448940T1 (sl) * | 2009-07-02 | 2014-10-30 | Sanofi | Derivati 6,7,8,9-tetrahidro-pirimido(1,2-a)pirimidin-4-ona, njihova priprava in njihova farmacevtska uporaba |
| CN102715186A (zh) * | 2012-06-15 | 2012-10-10 | 王学权 | 一种增效除草组合物 |
| FR2992314B1 (fr) | 2012-06-22 | 2015-10-16 | Sanofi Sa | Nouveaux derives de 2,3-dihydro-1h-imidazo{1,2-a}pyrimidin-5-one et 1,2,3,4-tetrahydro-pyrimido{1,2-a}pyrimidin-6-one comportant une morpholine substituee, leur preparation et leur utilisation pharmaceutique |
| WO2015150957A1 (en) * | 2014-04-01 | 2015-10-08 | Pfizer Inc. | Chromene and 1,1 a,2,7b-tetrahydrocyclopropa[c]chromene pyridopyrazinediones as gamma-secretase modulators |
| WO2015155738A2 (en) | 2014-04-09 | 2015-10-15 | Christopher Rudd | Use of gsk-3 inhibitors or activators which modulate pd-1 or t-bet expression to modulate t cell immunity |
| ES2968804T3 (es) * | 2017-05-24 | 2024-05-14 | Abbisko Therapeutics Co Ltd | Derivado de azaarilo, método de preparación del mismo y uso farmacéutico del mismo |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000018758A1 (en) * | 1998-09-25 | 2000-04-06 | Mitsubishi Chemical Corporation | Pyrimidone derivatives |
| WO2002018386A1 (en) * | 2000-09-01 | 2002-03-07 | Sanofi-Synthelabo | 2-PYRIDINYL-6,7,8,9-TETRAHYDROPYRIMIDO[1,2-a]PYRIMIDIN-4-ONE AND 7-PYRIDINYL-2,3-DIHYDROIMIDAZO[1,2-a]PYRIMIDIN-5(1H)ONE DERIVATI VES |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998024782A2 (en) * | 1996-12-05 | 1998-06-11 | Amgen Inc. | Substituted pyrimidine compounds and their use |
-
2003
- 2003-02-26 ES ES03717210T patent/ES2250883T3/es not_active Expired - Lifetime
- 2003-02-26 US US10/504,677 patent/US7232827B2/en not_active Expired - Fee Related
- 2003-02-26 AU AU2003221500A patent/AU2003221500B9/en not_active Ceased
- 2003-02-26 AT AT03717210T patent/ATE309247T1/de active
- 2003-02-26 CN CNB038092549A patent/CN1315832C/zh not_active Expired - Fee Related
- 2003-02-26 JP JP2003571285A patent/JP4458851B2/ja not_active Expired - Fee Related
- 2003-02-26 DE DE60302221T patent/DE60302221T2/de not_active Expired - Lifetime
- 2003-02-26 PL PL03372465A patent/PL372465A1/xx not_active IP Right Cessation
- 2003-02-26 SI SI200330138T patent/SI1480983T1/sl unknown
- 2003-02-26 NZ NZ534466A patent/NZ534466A/en not_active IP Right Cessation
- 2003-02-26 BR BR0308109-5A patent/BR0308109A/pt active Search and Examination
- 2003-02-26 DK DK03717210T patent/DK1480983T3/da active
- 2003-02-26 KR KR1020047013466A patent/KR101030629B1/ko not_active Expired - Fee Related
- 2003-02-26 CA CA2474823A patent/CA2474823C/en not_active Expired - Fee Related
- 2003-02-26 EP EP03717210A patent/EP1480983B1/en not_active Expired - Lifetime
- 2003-02-26 WO PCT/EP2003/002651 patent/WO2003072579A1/en not_active Ceased
- 2003-02-26 MX MXPA04008364A patent/MXPA04008364A/es active IP Right Grant
- 2003-02-26 EA EA200400936A patent/EA007737B1/ru not_active IP Right Cessation
- 2003-02-27 TW TW092104217A patent/TWI303637B/zh not_active IP Right Cessation
- 2003-02-28 AR ARP030100657A patent/AR038619A1/es unknown
-
2004
- 2004-07-29 IL IL163287A patent/IL163287A/en not_active IP Right Cessation
- 2004-08-26 NO NO20043565A patent/NO329805B1/no not_active IP Right Cessation
-
2007
- 2007-05-16 US US11/749,349 patent/US7465737B2/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000018758A1 (en) * | 1998-09-25 | 2000-04-06 | Mitsubishi Chemical Corporation | Pyrimidone derivatives |
| WO2002018386A1 (en) * | 2000-09-01 | 2002-03-07 | Sanofi-Synthelabo | 2-PYRIDINYL-6,7,8,9-TETRAHYDROPYRIMIDO[1,2-a]PYRIMIDIN-4-ONE AND 7-PYRIDINYL-2,3-DIHYDROIMIDAZO[1,2-a]PYRIMIDIN-5(1H)ONE DERIVATI VES |
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US7465737B2 (en) | Heteroaryl substituted 2-pyridinyl and 2-pyrimidinyl -6,7,8,9-tetrahydropyrimido[1,2-a] pyrimidin-4-one derivatives | |
| JP5501355B2 (ja) | 置換アルキルピリミジン−４−オン誘導体 | |
| KR101070075B1 (ko) | 치환된8-퍼플루오로알킬-6,7,8,9-테트라히드로피리미도[1,2-ａ]피리미딘-4-온 유도체 | |
| EP2593450A1 (en) | Substituted imidazoquinoline derivatives as kinase inhibitors | |
| EA006859B1 (ru) | ПРОИЗВОДНЫЕ ЗАМЕЩЕННОГО 2-ПИРИДИНИЛ-6,7,8,9-ТЕТРАГИДРОПИРИМИДО[1,2-a]ПИРИМИДИН-4-ОНА И 7-ПИРИДИНИЛ-2,3-ДИГИДРОИМИДАЗО[1, 2-a]ПИРИМИДИН-5(1H)ОНА | |
| EP4308564A1 (en) | Polycyclic inhibitors of plasma kallikrein | |
| EP1295885A1 (en) | Substituted 2-pyridinyl-6,7,8,9-tetrahydropyrimido(1,2-a)pyrimidin-4-one and 7-pyridinyl-2,3-dihydroimidazo(1,2-a)pyrimidin-5(1H)one derivatives | |
| JP5501354B2 (ja) | 神経変性疾患に対する置換三環式誘導体 | |
| EA007459B1 (ru) | Производные 1-[алкил]-, 1-[(гетероарил)алкил]- и 1-[(арил)алкил]-7-(пиримидин-4-ил)имидазо[1,2-a]пиримидин-5(1h)-она | |
| CN115667251A (zh) | 杂芳基衍生物化合物、及其用途 | |
| EP1348708A1 (en) | Heteroaryl substituted 2-pyrimidinyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 7-pyrimidinyl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)one derivatives | |
| EP1340758A1 (en) | Heteroaryl substituted 2-pyridinyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 7-pyridinyl-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)one derivatives | |
| HK1137750A (en) | Substituted 8-piperidinyl-2-pyridinyl-pyrimido [1,2-a]pyrimidin-6-one and 8-piperidinyl-2-pyrimidinyl-pyrimido[1,2-a]pyrimidin-6-one derivatives | |
| HK1088893B (en) | SUBSTITUTED 8-PERFLUOROALKYL-6,7,8,9-TETRAHYDROPYRIMIDO[1,2-a] PYRIMIDIN-4-ONE DERIVATIVES | |
| HK1086012A1 (en) | 8-substituted-6, 7, 8, 9-tetrahydropyrimido[1,2-a] pyrimidin-4-one derivatives | |
| HK1086012B (en) | 8-substituted-6, 7, 8, 9-tetrahydropyrimido[1,2-a] pyrimidin-4-one derivatives | |
| HK1232540A1 (en) | Indoloquinolone compounds as anaplastic lymphoma kinase (alk) inhibitors | |
| HK1232540B (en) | Indoloquinolone compounds as anaplastic lymphoma kinase (alk) inhibitors |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MM4A | Lapse of a eurasian patent due to non-payment of renewal fees within the time limit in the following designated state(s) |
Designated state(s): AM AZ BY KZ KG MD TJ TM |
|
| MM4A | Lapse of a eurasian patent due to non-payment of renewal fees within the time limit in the following designated state(s) |
Designated state(s): RU |