NZ618944B2 - Crystal of fused heterocyclic compound - Google Patents
Crystal of fused heterocyclic compound Download PDFInfo
- Publication number
- NZ618944B2 NZ618944B2 NZ618944A NZ61894412A NZ618944B2 NZ 618944 B2 NZ618944 B2 NZ 618944B2 NZ 618944 A NZ618944 A NZ 618944A NZ 61894412 A NZ61894412 A NZ 61894412A NZ 618944 B2 NZ618944 B2 NZ 618944B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- crystal
- imidazo
- methyl
- pyridin
- dihydro
- Prior art date
Links
- 150000002391 heterocyclic compounds Chemical class 0.000 title description 3
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 41
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 35
- 239000003112 inhibitor Substances 0.000 claims abstract description 26
- 201000000980 schizophrenia Diseases 0.000 claims abstract description 22
- 101710031109 PDE10A Proteins 0.000 claims abstract description 7
- 102100017569 PDE10A Human genes 0.000 claims abstract description 7
- 238000002844 melting Methods 0.000 claims abstract description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 72
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 70
- 239000003814 drug Substances 0.000 claims description 51
- -1 3-methyl-3H- imidazo[4,5-b]pyridinyl Chemical group 0.000 claims description 50
- 229940079593 drugs Drugs 0.000 claims description 40
- 239000000843 powder Substances 0.000 claims description 15
- 241000124008 Mammalia Species 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 230000000069 prophylaxis Effects 0.000 claims description 5
- 230000001225 therapeutic Effects 0.000 claims description 5
- 238000005259 measurement Methods 0.000 abstract description 13
- JRFDBVSKHNNCIC-UHFFFAOYSA-N 1-ethyl-7-methyl-3-[4-(3-methylimidazo[4,5-b]pyridin-2-yl)oxyphenyl]imidazo[4,5-b]pyridin-2-one Chemical compound C1=CN=C2N(C)C(OC3=CC=C(C=C3)N3C4=NC=CC(C)=C4N(C3=O)CC)=NC2=C1 JRFDBVSKHNNCIC-UHFFFAOYSA-N 0.000 abstract description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 75
- 239000000203 mixture Substances 0.000 description 74
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 33
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 32
- 239000003795 chemical substances by application Substances 0.000 description 31
- 239000000243 solution Substances 0.000 description 28
- 230000035492 administration Effects 0.000 description 26
- 239000007787 solid Substances 0.000 description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- 238000001914 filtration Methods 0.000 description 19
- 239000002904 solvent Substances 0.000 description 18
- 101710031992 pRL90232 Proteins 0.000 description 17
- 101710035540 plaa2 Proteins 0.000 description 16
- 150000002500 ions Chemical class 0.000 description 15
- 230000002829 reduced Effects 0.000 description 15
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 14
- 239000012453 solvate Substances 0.000 description 14
- 150000001875 compounds Chemical class 0.000 description 13
- FXHOOIRPVKKKFG-UHFFFAOYSA-N DMA Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 11
- 230000037361 pathway Effects 0.000 description 11
- 239000011780 sodium chloride Substances 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 10
- 201000010099 disease Diseases 0.000 description 10
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 10
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 10
- 150000003839 salts Chemical class 0.000 description 10
- 239000000126 substance Substances 0.000 description 10
- PUOAETJYKQITMO-FYJGNVAPSA-N (3E)-1-[1-(4-fluorophenyl)ethyl]-3-[[3-methoxy-4-(4-methylimidazol-1-yl)phenyl]methylidene]piperidin-2-one Chemical compound C=1C=C(N2C=C(C)N=C2)C(OC)=CC=1\C=C(C1=O)/CCCN1C(C)C1=CC=C(F)C=C1 PUOAETJYKQITMO-FYJGNVAPSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 8
- 229920002472 Starch Polymers 0.000 description 8
- 230000003042 antagnostic Effects 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M buffer Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- 230000000051 modifying Effects 0.000 description 8
- 239000002244 precipitate Substances 0.000 description 8
- 239000008107 starch Substances 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- 102000004190 Enzymes Human genes 0.000 description 7
- 108090000790 Enzymes Proteins 0.000 description 7
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 7
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 7
- 239000008186 active pharmaceutical agent Substances 0.000 description 7
- 230000037396 body weight Effects 0.000 description 7
- 229920002678 cellulose Polymers 0.000 description 7
- 239000001913 cellulose Substances 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 239000000741 silica gel Substances 0.000 description 7
- 229910002027 silica gel Inorganic materials 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- 235000019698 starch Nutrition 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- 210000004556 Brain Anatomy 0.000 description 6
- ZOOGRGPOEVQQDX-KHLHZJAASA-N Cyclic Guanosine Monophosphate Chemical compound C([C@H]1O2)O[P@](O)(=O)O[C@@H]1[C@H](O)[C@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-KHLHZJAASA-N 0.000 description 6
- 206010012289 Dementia Diseases 0.000 description 6
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinylpyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 6
- WVDDGKGOMKODPV-UHFFFAOYSA-N benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 6
- 230000005712 crystallization Effects 0.000 description 6
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- JXXWJMUPNZDILL-UHFFFAOYSA-N imidazo[4,5-b]pyridin-2-one Chemical compound C1=CC=NC2=NC(=O)N=C21 JXXWJMUPNZDILL-UHFFFAOYSA-N 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- 239000011777 magnesium Chemical class 0.000 description 6
- 229910052749 magnesium Inorganic materials 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 230000004770 neurodegeneration Effects 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- BZKBCQXYZZXSCO-UHFFFAOYSA-N sodium hydride Chemical compound [H-].[Na+] BZKBCQXYZZXSCO-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- PGDIPOWQYRAOSK-UHFFFAOYSA-N 1,3-dihydroimidazo[4,5-b]pyridin-2-one Chemical compound C1=CN=C2NC(=O)NC2=C1 PGDIPOWQYRAOSK-UHFFFAOYSA-N 0.000 description 5
- 229920002261 Corn starch Polymers 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N DMSO-d6 Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 5
- 229940088598 Enzyme Drugs 0.000 description 5
- 102000004877 Insulin Human genes 0.000 description 5
- 108090001061 Insulin Proteins 0.000 description 5
- 239000002202 Polyethylene glycol Substances 0.000 description 5
- 206010061920 Psychotic disease Diseases 0.000 description 5
- 230000004913 activation Effects 0.000 description 5
- 239000000556 agonist Substances 0.000 description 5
- 239000005557 antagonist Substances 0.000 description 5
- 230000006399 behavior Effects 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 239000008120 corn starch Substances 0.000 description 5
- 229940099112 cornstarch Drugs 0.000 description 5
- 239000007884 disintegrant Substances 0.000 description 5
- FYYHWMGAXLPEAU-UHFFFAOYSA-N magnesium Chemical class [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 5
- 239000008194 pharmaceutical composition Substances 0.000 description 5
- 229920001223 polyethylene glycol Polymers 0.000 description 5
- 238000001144 powder X-ray diffraction data Methods 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 239000000758 substrate Substances 0.000 description 5
- 229920003169 water-soluble polymer Polymers 0.000 description 5
- VVQNEPGJFQJSBK-UHFFFAOYSA-N 2-methyl-2-propenoic acid methyl ester Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 4
- 229960005069 Calcium Drugs 0.000 description 4
- FBPFZTCFMRRESA-KAZBKCHUSA-N D-Mannitol Natural products OC[C@@H](O)[C@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KAZBKCHUSA-N 0.000 description 4
- 101700040453 DRD2 Proteins 0.000 description 4
- 206010012378 Depression Diseases 0.000 description 4
- 229920003134 Eudragit® polymer Polymers 0.000 description 4
- ASUTZQLVASHGKV-JDFRZJQESA-N Galantamine 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 description 4
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 4
- GUBGYTABKSRVRQ-UUNJERMWSA-N Lactose Natural products O([C@@H]1[C@H](O)[C@H](O)[C@H](O)O[C@@H]1CO)[C@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1 GUBGYTABKSRVRQ-UUNJERMWSA-N 0.000 description 4
- FBPFZTCFMRRESA-KVTDHHQDSA-N Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- 238000007792 addition Methods 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 239000011230 binding agent Substances 0.000 description 4
- 238000004166 bioassay Methods 0.000 description 4
- OYPRJOBELJOOCE-UHFFFAOYSA-N calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 4
- 239000011575 calcium Substances 0.000 description 4
- 229910052791 calcium Inorganic materials 0.000 description 4
- 239000000969 carrier Substances 0.000 description 4
- 210000004027 cells Anatomy 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 4
- 239000003086 colorant Substances 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N deuterated chloroform Substances [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 235000002864 food coloring agent Nutrition 0.000 description 4
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- GUBGYTABKSRVRQ-XLOQQCSPSA-N 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 4
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Chemical compound [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 4
- 235000010355 mannitol Nutrition 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L mgso4 Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N n-butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 4
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 4
- 239000011148 porous material Substances 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- DTEXGEJZUVIVGK-UHFFFAOYSA-N 3-methyl-2-methylsulfonylimidazo[4,5-b]pyridine Chemical compound C1=CN=C2N(C)C(S(C)(=O)=O)=NC2=C1 DTEXGEJZUVIVGK-UHFFFAOYSA-N 0.000 description 3
- 206010001897 Alzheimer's disease Diseases 0.000 description 3
- 206010004938 Bipolar disease Diseases 0.000 description 3
- ADEBPBSSDYVVLD-UHFFFAOYSA-N Donepezil Chemical compound O=C1C=2C=C(OC)C(OC)=CC=2CC1CC(CC1)CCN1CC1=CC=CC=C1 ADEBPBSSDYVVLD-UHFFFAOYSA-N 0.000 description 3
- LNEPOXFFQSENCJ-UHFFFAOYSA-N Haloperidol Chemical compound C1CC(O)(C=2C=CC(Cl)=CC=2)CCN1CCCC(=O)C1=CC=C(F)C=C1 LNEPOXFFQSENCJ-UHFFFAOYSA-N 0.000 description 3
- 201000001971 Huntington's disease Diseases 0.000 description 3
- 208000001365 Hyperprolactinemia Diseases 0.000 description 3
- ZLNQQNXFFQJAID-UHFFFAOYSA-L Magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 3
- XAPRFLSJBSXESP-UHFFFAOYSA-N Oxycinchophen Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=C(O)C=1C1=CC=CC=C1 XAPRFLSJBSXESP-UHFFFAOYSA-N 0.000 description 3
- 206010061536 Parkinson's disease Diseases 0.000 description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N Potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 3
- RAPZEAPATHNIPO-UHFFFAOYSA-N Risperidone Chemical compound FC1=CC=C2C(C3CCN(CC3)CCC=3C(=O)N4CCCCC4=NC=3C)=NOC2=C1 RAPZEAPATHNIPO-UHFFFAOYSA-N 0.000 description 3
- 229960001534 Risperidone Drugs 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 230000033228 biological regulation Effects 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 238000002447 crystallographic data Methods 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- 230000003001 depressive Effects 0.000 description 3
- 229960003530 donepezil Drugs 0.000 description 3
- 229960003638 dopamine Drugs 0.000 description 3
- 239000002702 enteric coating Substances 0.000 description 3
- 238000009505 enteric coating Methods 0.000 description 3
- 235000003599 food sweetener Nutrition 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 229960003878 haloperidol Drugs 0.000 description 3
- 239000008079 hexane Substances 0.000 description 3
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 3
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 3
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 3
- 210000003702 immature single positive T cell Anatomy 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 3
- 231100000053 low toxicity Toxicity 0.000 description 3
- 239000001095 magnesium carbonate Substances 0.000 description 3
- 239000011776 magnesium carbonate Substances 0.000 description 3
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 3
- 230000036651 mood Effects 0.000 description 3
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- 239000001184 potassium carbonate Substances 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 231100000486 side effect Toxicity 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 230000002459 sustained Effects 0.000 description 3
- 239000003765 sweetening agent Substances 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 3
- 230000001131 transforming Effects 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
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2R,3R,4S,5R,6S)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2S,3R,4S,5R,6R)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2R,3R,4S,5R,6R)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 2
- BXQABIOBEFRESA-UHFFFAOYSA-N 1-ethyl-7-methyl-3-(4-phenylmethoxyphenyl)imidazo[4,5-b]pyridin-2-one Chemical compound O=C1N(CC)C2=C(C)C=CN=C2N1C(C=C1)=CC=C1OCC1=CC=CC=C1 BXQABIOBEFRESA-UHFFFAOYSA-N 0.000 description 2
- VUKAUDKDFVSVFT-UHFFFAOYSA-N 2-[6-[4,5-bis(2-hydroxypropoxy)-2-(2-hydroxypropoxymethyl)-6-methoxyoxan-3-yl]oxy-4,5-dimethoxy-2-(methoxymethyl)oxan-3-yl]oxy-6-(hydroxymethyl)-5-methoxyoxane-3,4-diol Chemical compound COC1C(OC)C(OC2C(C(O)C(OC)C(CO)O2)O)C(COC)OC1OC1C(COCC(C)O)OC(OC)C(OCC(C)O)C1OCC(C)O VUKAUDKDFVSVFT-UHFFFAOYSA-N 0.000 description 2
- CDMARAGGTGQTDJ-UHFFFAOYSA-N 3-[4-(3-methylimidazo[4,5-b]pyridin-2-yl)oxyphenyl]-1-propylimidazo[4,5-b]pyridin-2-one Chemical compound C1=CN=C2N(C)C(OC3=CC=C(C=C3)N3C4=NC=CC=C4N(C3=O)CCC)=NC2=C1 CDMARAGGTGQTDJ-UHFFFAOYSA-N 0.000 description 2
- XAUBEYHIVLSHOG-UHFFFAOYSA-N 3-methylimidazo[4,5-b]pyridine Chemical compound C1=CN=C2N(C)C=NC2=C1 XAUBEYHIVLSHOG-UHFFFAOYSA-N 0.000 description 2
- 229960000836 Amitriptyline Drugs 0.000 description 2
- KRMDCWKBEZIMAB-UHFFFAOYSA-N Amitriptyline Chemical compound C1CC2=CC=CC=C2C(=CCCN(C)C)C2=CC=CC=C21 KRMDCWKBEZIMAB-UHFFFAOYSA-N 0.000 description 2
- SESFRYSPDFLNCH-UHFFFAOYSA-N Benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- 229950008138 Carmellose Drugs 0.000 description 2
- AHOUBRCZNHFOSL-YOEHRIQHSA-N Casbol Chemical compound C1=CC(F)=CC=C1[C@H]1[C@H](COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-YOEHRIQHSA-N 0.000 description 2
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 2
- QZUDBNBUXVUHMW-UHFFFAOYSA-N Clozapine Chemical compound C1CN(C)CCN1C1=NC2=CC(Cl)=CC=C2NC2=CC=CC=C12 QZUDBNBUXVUHMW-UHFFFAOYSA-N 0.000 description 2
- 206010057668 Cognitive disease Diseases 0.000 description 2
- 229960000913 Crospovidone Drugs 0.000 description 2
- 102000008130 Cyclic AMP-Dependent Protein Kinases Human genes 0.000 description 2
- 108010049894 Cyclic AMP-Dependent Protein Kinases Proteins 0.000 description 2
- 102000004654 Cyclic GMP-Dependent Protein Kinases Human genes 0.000 description 2
- 108010003591 Cyclic GMP-Dependent Protein Kinases Proteins 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N D-Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- HCYAFALTSJYZDH-UHFFFAOYSA-N Desimpramine Chemical compound C1CC2=CC=CC=C2N(CCCNC)C2=CC=CC=C21 HCYAFALTSJYZDH-UHFFFAOYSA-N 0.000 description 2
- XSVMFMHYUFZWBK-NSHDSACASA-N EXELON Chemical compound CCN(C)C(=O)OC1=CC=CC([C@H](C)N(C)C)=C1 XSVMFMHYUFZWBK-NSHDSACASA-N 0.000 description 2
- 206010015037 Epilepsy Diseases 0.000 description 2
- 229960002464 Fluoxetine Drugs 0.000 description 2
- 229960003980 Galantamine Drugs 0.000 description 2
- 102000014150 Interferons Human genes 0.000 description 2
- 108010050904 Interferons Proteins 0.000 description 2
- 102000004310 Ion Channels Human genes 0.000 description 2
- 108090000862 Ion Channels Proteins 0.000 description 2
- VTHJTEIRLNZDEV-UHFFFAOYSA-L Magnesium hydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 2
- 206010057840 Major depression Diseases 0.000 description 2
- 108020004999 Messenger RNA Proteins 0.000 description 2
- 229960003105 Metformin Drugs 0.000 description 2
- 229960002900 Methylcellulose Drugs 0.000 description 2
- RTHCYVBBDHJXIQ-UHFFFAOYSA-N N-methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propan-1-amine Chemical compound C=1C=CC=CC=1C(CCNC)OC1=CC=C(C(F)(F)F)C=C1 RTHCYVBBDHJXIQ-UHFFFAOYSA-N 0.000 description 2
- 210000001577 Neostriatum Anatomy 0.000 description 2
- 229960001158 Nortriptyline Drugs 0.000 description 2
- PHVGLTMQBUFIQQ-UHFFFAOYSA-N Nortryptiline Chemical compound C1CC2=CC=CC=C2C(=CCCNC)C2=CC=CC=C21 PHVGLTMQBUFIQQ-UHFFFAOYSA-N 0.000 description 2
- 208000008589 Obesity Diseases 0.000 description 2
- KVWDHTXUZHCGIO-UHFFFAOYSA-N Olanzapine Chemical compound C1CN(C)CCN1C1=NC2=CC=CC=C2NC2=C1C=C(C)S2 KVWDHTXUZHCGIO-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 206010034721 Personality disease Diseases 0.000 description 2
- WRMNZCZEMHIOCP-UHFFFAOYSA-N Phenethyl alcohol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 2
- DDBREPKUVSBGFI-UHFFFAOYSA-N Phenobarbital Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NC(=O)NC1=O DDBREPKUVSBGFI-UHFFFAOYSA-N 0.000 description 2
- 229960002695 Phenobarbital Drugs 0.000 description 2
- 229940068984 Polyvinyl Alcohol Drugs 0.000 description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 description 2
- 229960003975 Potassium Drugs 0.000 description 2
- BWPIARFWQZKAIA-UHFFFAOYSA-N Protriptyline Chemical compound C1=CC2=CC=CC=C2C(CCCNC)C2=CC=CC=C21 BWPIARFWQZKAIA-UHFFFAOYSA-N 0.000 description 2
- 229960002073 Sertraline Drugs 0.000 description 2
- VGKDLMBJGBXTGI-SJCJKPOMSA-N Sertraline Chemical compound C1([C@@H]2CC[C@@H](C3=CC=CC=C32)NC)=CC=C(Cl)C(Cl)=C1 VGKDLMBJGBXTGI-SJCJKPOMSA-N 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N Sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N Stearic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- YLJREFDVOIBQDA-UHFFFAOYSA-N Tacrine Chemical compound C1=CC=C2C(N)=C(CCCC3)C3=NC2=C1 YLJREFDVOIBQDA-UHFFFAOYSA-N 0.000 description 2
- 229960001685 Tacrine Drugs 0.000 description 2
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000000111 anti-oxidant Effects 0.000 description 2
- 230000000561 anti-psychotic Effects 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 235000019445 benzyl alcohol Nutrition 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 2
- 230000002490 cerebral Effects 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 229960004106 citric acid Drugs 0.000 description 2
- 229960004170 clozapine Drugs 0.000 description 2
- 239000011247 coating layer Substances 0.000 description 2
- 229960003914 desipramine Drugs 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- KLBQZWRITKRQQV-UHFFFAOYSA-N dl-Thioridazine Chemical compound C12=CC(SC)=CC=C2SC2=CC=CC=C2N1CCC1CCCCN1C KLBQZWRITKRQQV-UHFFFAOYSA-N 0.000 description 2
- 239000008298 dragée Substances 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 239000007941 film coated tablet Substances 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 229920001519 homopolymer Polymers 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 229940079322 interferon Drugs 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 230000003834 intracellular Effects 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 239000000347 magnesium hydroxide Substances 0.000 description 2
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 2
- 239000000395 magnesium oxide Substances 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 201000003895 major depressive disease Diseases 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 230000003340 mental Effects 0.000 description 2
- 229920002106 messenger RNA Polymers 0.000 description 2
- 229920003145 methacrylic acid copolymer Polymers 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000006011 modification reaction Methods 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N n-heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- 210000002569 neurons Anatomy 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 235000020824 obesity Nutrition 0.000 description 2
- 229960005017 olanzapine Drugs 0.000 description 2
- 239000006191 orally-disintegrating tablet Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 229960002296 paroxetine Drugs 0.000 description 2
- 229920003199 poly(diethylsiloxane) Polymers 0.000 description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 description 2
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 2
- 239000001253 polyvinylpolypyrrolidone Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N potassium Chemical class [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Chemical class 0.000 description 2
- 230000002335 preservative Effects 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Chemical group CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 2
- 229960002601 protriptyline Drugs 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 229960004136 rivastigmine Drugs 0.000 description 2
- 230000000580 secretagogue Effects 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- 239000003772 serotonin uptake inhibitor Substances 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 238000007613 slurry method Methods 0.000 description 2
- 239000001187 sodium carbonate Substances 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000007901 soft capsule Substances 0.000 description 2
- 239000007940 sugar coated tablet Substances 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 229960002784 thioridazine Drugs 0.000 description 2
- 230000002588 toxic Effects 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 239000001069 triethyl citrate Substances 0.000 description 2
- 235000013769 triethyl citrate Nutrition 0.000 description 2
- 239000003643 water by type Substances 0.000 description 2
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 description 1
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 1
- PUSNGFYSTWMJSK-GSZQVNRLSA-N (2R,3R,4S,5R,6R)-2,3,4-trimethoxy-6-(methoxymethyl)-5-[(2S,3R,4S,5R,6R)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxyoxane;1-[[(2R,3R,4S,5R,6S)-3,4,5-tris(2-hydroxypropoxy)-6-[(2R,3R,4S,5R,6R)-4,5,6-tris(2-hydroxypropoxy)-2-(2-hydroxypropoxymethyl)oxan- Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](OC)O[C@@H]1COC.CC(O)CO[C@@H]1[C@@H](OCC(C)O)[C@H](OCC(C)O)[C@@H](COCC(O)C)O[C@H]1O[C@H]1[C@H](OCC(C)O)[C@@H](OCC(C)O)[C@H](OCC(C)O)O[C@@H]1COCC(C)O PUSNGFYSTWMJSK-GSZQVNRLSA-N 0.000 description 1
- YLOCGHYTXIINAI-XKUOMLDTSA-N (2S)-2-amino-3-(4-hydroxyphenyl)propanoic acid;(2S)-2-aminopentanedioic acid;(2S)-2-aminopropanoic acid;(2S)-2,6-diaminohexanoic acid Chemical compound C[C@H](N)C(O)=O.NCCCC[C@H](N)C(O)=O.OC(=O)[C@@H](N)CCC(O)=O.OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 YLOCGHYTXIINAI-XKUOMLDTSA-N 0.000 description 1
- XUFXOAAUWZOOIT-WVJZLWNXSA-N (2S,3R,4R,5S,6R)-5-[(2R,3R,4R,5S,6R)-5-[(2R,3R,4S,5S,6R)-3,4-dihydroxy-6-methyl-5-[[(1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl)cyclohex-2-en-1-yl]amino]oxan-2-yl]oxy-3,4-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-6-(hydroxymethyl)oxane-2,3,4-triol Chemical compound O([C@H]1O[C@H](CO)[C@H]([C@@H]([C@H]1O)O)O[C@H]1O[C@@H]([C@H]([C@H](O)[C@H]1O)N[C@@H]1[C@@H]([C@@H](O)[C@H](O)C(CO)=C1)O)C)[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O XUFXOAAUWZOOIT-WVJZLWNXSA-N 0.000 description 1
- MKJIEFSOBYUXJB-HOCLYGCPSA-N (3S,11bS)-9,10-dimethoxy-3-isobutyl-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-one Chemical compound C1CN2C[C@H](CC(C)C)C(=O)C[C@H]2C2=C1C=C(OC)C(OC)=C2 MKJIEFSOBYUXJB-HOCLYGCPSA-N 0.000 description 1
- KQBDLOVXZHOAJI-UHFFFAOYSA-N (4-phenylmethoxyphenyl)azanium;chloride Chemical compound Cl.C1=CC(N)=CC=C1OCC1=CC=CC=C1 KQBDLOVXZHOAJI-UHFFFAOYSA-N 0.000 description 1
- RHKBUWXYXKWOEB-WLHGVMLRSA-L (E)-but-2-enedioate;3-[2-[4-(6-fluoro-1,2-benzoxazol-3-yl)piperidin-1-yl]ethyl]-9-hydroxy-2-methyl-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidin-4-one Chemical compound [O-]C(=O)\C=C\C([O-])=O.FC1=CC=C2C(C3CCN(CC3)CCC=3C(=O)N4CCCC(O)C4=NC=3C)=NOC2=C1 RHKBUWXYXKWOEB-WLHGVMLRSA-L 0.000 description 1
- BGRJTUBHPOOWDU-NSHDSACASA-N (S)-(-)-sulpiride Chemical compound CCN1CCC[C@H]1CNC(=O)C1=CC(S(N)(=O)=O)=CC=C1OC BGRJTUBHPOOWDU-NSHDSACASA-N 0.000 description 1
- KWTSXDURSIMDCE-QMMMGPOBSA-N (S)-amphetamine Chemical compound C[C@H](N)CC1=CC=CC=C1 KWTSXDURSIMDCE-QMMMGPOBSA-N 0.000 description 1
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 description 1
- JZMBBGGWOWOXDZ-UHFFFAOYSA-N 1-methyl-2,3-dihydroimidazo[4,5-b]pyridine Chemical compound C1=CC=C2N(C)CNC2=N1 JZMBBGGWOWOXDZ-UHFFFAOYSA-N 0.000 description 1
- RHQDFWAXVIIEBN-UHFFFAOYSA-N 2,2,2-trifluoroethyl alcohol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 description 1
- YGZFYDFBHIDIBH-UHFFFAOYSA-N 2-[bis(2-hydroxyethyl)amino]icosan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCC(CO)N(CCO)CCO YGZFYDFBHIDIBH-UHFFFAOYSA-N 0.000 description 1
- WBEHKXQILJKFIN-UHFFFAOYSA-N 2-amino-2-methyltetradecanoic acid Chemical compound CCCCCCCCCCCCC(C)(N)C(O)=O WBEHKXQILJKFIN-UHFFFAOYSA-N 0.000 description 1
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-butanone Chemical group CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 1
- QDUJVEOOSNUDDW-UHFFFAOYSA-N 2-chloropyrimidine-4,5-diamine Chemical compound NC1=CN=C(Cl)N=C1N QDUJVEOOSNUDDW-UHFFFAOYSA-N 0.000 description 1
- YQEMORVAKMFKLG-UHFFFAOYSA-N 2-stearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 description 1
- PGRHXDWITVMQBC-UHFFFAOYSA-N 3-acetyl-6-methylpyran-2,4-dione Chemical compound CC(=O)C1C(=O)OC(C)=CC1=O PGRHXDWITVMQBC-UHFFFAOYSA-N 0.000 description 1
- WTDRDQBEARUVNC-LURJTMIESA-N 3-hydroxy-L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 description 1
- RKWGIWYCVPQPMF-UHFFFAOYSA-N 4-chloro-N-[(propylamino)carbonyl]benzenesulfonamide Chemical compound CCCNC(=O)NS(=O)(=O)C1=CC=C(Cl)C=C1 RKWGIWYCVPQPMF-UHFFFAOYSA-N 0.000 description 1
- PQUGCKBLVKJMNT-UHFFFAOYSA-N 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)pyrazole Chemical compound C1=CC(OC)=CC=C1N1C(C=2C=CC(Cl)=CC=2)=CC(C(F)(F)F)=N1 PQUGCKBLVKJMNT-UHFFFAOYSA-N 0.000 description 1
- CWSZBVAUYPTXTG-UHFFFAOYSA-N 5-[6-[[3,4-dihydroxy-6-(hydroxymethyl)-5-methoxyoxan-2-yl]oxymethyl]-3,4-dihydroxy-5-[4-hydroxy-3-(2-hydroxyethoxy)-6-(hydroxymethyl)-5-methoxyoxan-2-yl]oxyoxan-2-yl]oxy-6-(hydroxymethyl)-2-methyloxane-3,4-diol Chemical compound O1C(CO)C(OC)C(O)C(O)C1OCC1C(OC2C(C(O)C(OC)C(CO)O2)OCCO)C(O)C(O)C(OC2C(OC(C)C(O)C2O)CO)O1 CWSZBVAUYPTXTG-UHFFFAOYSA-N 0.000 description 1
- PVXPPJIGRGXGCY-IPFGBZKGSA-N 6-O-α-D-glucopyranosyl-β-D-fructofuranose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@](O)(CO)O1 PVXPPJIGRGXGCY-IPFGBZKGSA-N 0.000 description 1
- OIRDTQYFTABQOQ-GAWUUDPSSA-N 9-β-D-XYLOFURANOSYL-ADENINE Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@H](O)[C@H]1O OIRDTQYFTABQOQ-GAWUUDPSSA-N 0.000 description 1
- 206010065040 AIDS dementia complex Diseases 0.000 description 1
- 229940005529 ANTIPSYCHOTICS Drugs 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- OIRDTQYFTABQOQ-SXVXDFOESA-N Adenosine Natural products Nc1ncnc2c1ncn2[C@@H]3O[C@@H](CO)[C@H](O)[C@@H]3O OIRDTQYFTABQOQ-SXVXDFOESA-N 0.000 description 1
- 102000009346 Adenosine receptors Human genes 0.000 description 1
- 108050000203 Adenosine receptors Proteins 0.000 description 1
- 208000000044 Amnesia Diseases 0.000 description 1
- 206010001954 Amnestic disease Diseases 0.000 description 1
- 229940025084 Amphetamine Drugs 0.000 description 1
- 229960004543 Anhydrous Citric Acid Drugs 0.000 description 1
- 206010057666 Anxiety disease Diseases 0.000 description 1
- 206010059512 Apoptosis Diseases 0.000 description 1
- CEUORZQYGODEFX-UHFFFAOYSA-N Aripirazole Chemical compound ClC1=CC=CC(N2CCN(CCCCOC=3C=C4NC(=O)CCC4=CC=3)CC2)=C1Cl CEUORZQYGODEFX-UHFFFAOYSA-N 0.000 description 1
- IAOZJIPTCAWIRG-QWRGUYRKSA-N Aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 1
- 229960003438 Aspartame Drugs 0.000 description 1
- 108010011485 Aspartame Proteins 0.000 description 1
- 206010003736 Attention deficit/hyperactivity disease Diseases 0.000 description 1
- 206010003805 Autism Diseases 0.000 description 1
- 229920003084 Avicel® PH-102 Polymers 0.000 description 1
- 229960002170 Azathioprine Drugs 0.000 description 1
- 229960000686 Benzalkonium Chloride Drugs 0.000 description 1
- GIJXKZJWITVLHI-PMOLBWCYSA-N Benzatropine Chemical compound O([C@H]1C[C@H]2CC[C@@H](C1)N2C)C(C=1C=CC=CC=1)C1=CC=CC=C1 GIJXKZJWITVLHI-PMOLBWCYSA-N 0.000 description 1
- 229960001950 Benzethonium Chloride Drugs 0.000 description 1
- UREZNYTWGJKWBI-UHFFFAOYSA-M Benzethonium chloride Chemical compound [Cl-].C1=CC(C(C)(C)CC(C)(C)C)=CC=C1OCCOCC[N+](C)(C)CC1=CC=CC=C1 UREZNYTWGJKWBI-UHFFFAOYSA-M 0.000 description 1
- 229940093239 Benztropine Drugs 0.000 description 1
- 206010004940 Bipolar II disease Diseases 0.000 description 1
- 206010006360 Brief psychotic disease Diseases 0.000 description 1
- OZVBMTJYIDMWIL-AYFBDAFISA-N Bromocriptine Chemical compound C1=CC(C=2[C@H](N(C)C[C@@H](C=2)C(=O)N[C@]2(C(=O)N3[C@H](C(N4CCC[C@H]4[C@]3(O)O2)=O)CC(C)C)C(C)C)C2)=C3C2=C(Br)NC3=C1 OZVBMTJYIDMWIL-AYFBDAFISA-N 0.000 description 1
- 229960002802 Bromocriptine Drugs 0.000 description 1
- 229960001058 Bupropion Drugs 0.000 description 1
- SNPPWIUOZRMYNY-UHFFFAOYSA-N Bupropion Chemical compound CC(C)(C)NC(C)C(=O)C1=CC=CC(Cl)=C1 SNPPWIUOZRMYNY-UHFFFAOYSA-N 0.000 description 1
- ZASLMJSZKYXRFO-UHFFFAOYSA-N C(C)N1CN(C2=NC=CC(=C21)C)C2=CC=C(C=C2)O Chemical compound C(C)N1CN(C2=NC=CC(=C21)C)C2=CC=C(C=C2)O ZASLMJSZKYXRFO-UHFFFAOYSA-N 0.000 description 1
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 1
- 102100007493 CNTF Human genes 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L Caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 102000003922 Calcium Channels Human genes 0.000 description 1
- 108090000312 Calcium Channels Proteins 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L Calcium hydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000218236 Cannabis Species 0.000 description 1
- FFGPTBGBLSHEPO-UHFFFAOYSA-N Carbamazepine Chemical compound C1=CC2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 FFGPTBGBLSHEPO-UHFFFAOYSA-N 0.000 description 1
- 229940063834 Carboxymethylcellulose Sodium Drugs 0.000 description 1
- 229960001777 Castor Oil Drugs 0.000 description 1
- 206010007776 Catatonia Diseases 0.000 description 1
- 208000009810 Catatonic Schizophrenia Diseases 0.000 description 1
- 229920002301 Cellulose acetate Polymers 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 206010008118 Cerebral infarction Diseases 0.000 description 1
- ZPEIMTDSQAKGNT-UHFFFAOYSA-N Chlorpromazine Chemical compound C1=C(Cl)C=C2N(CCCN(C)C)C3=CC=CC=C3SC2=C1 ZPEIMTDSQAKGNT-UHFFFAOYSA-N 0.000 description 1
- 229960001076 Chlorpromazine Drugs 0.000 description 1
- 229960001761 Chlorpropamide Drugs 0.000 description 1
- 108010005939 Ciliary Neurotrophic Factor Proteins 0.000 description 1
- 235000008733 Citrus aurantifolia Nutrition 0.000 description 1
- 235000005979 Citrus limon Nutrition 0.000 description 1
- 240000002268 Citrus limon Species 0.000 description 1
- 229960001681 Croscarmellose Sodium Drugs 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- UNXHWFMMPAWVPI-QWWZWVQMSA-N D-Threitol Natural products OC[C@@H](O)[C@H](O)CO UNXHWFMMPAWVPI-QWWZWVQMSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N D-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
- 229940099371 DIACETYLATED MONOGLYCERIDES Drugs 0.000 description 1
- 101700062901 DPP Proteins 0.000 description 1
- 102100012353 DPP4 Human genes 0.000 description 1
- 101700039720 DPP4 Proteins 0.000 description 1
- 239000004287 Dehydroacetic acid Substances 0.000 description 1
- 206010012218 Delirium Diseases 0.000 description 1
- 206010012256 Delusional disease Diseases 0.000 description 1
- 206010012401 Depressive disease Diseases 0.000 description 1
- 206010012601 Diabetes mellitus Diseases 0.000 description 1
- UXZFQZANDVDGMM-UHFFFAOYSA-N Diiodohydroxyquinoline Chemical compound C1=CN=C2C(O)=C(I)C=C(I)C2=C1 UXZFQZANDVDGMM-UHFFFAOYSA-N 0.000 description 1
- 208000001495 Disorganized Schizophrenia Diseases 0.000 description 1
- XIQVNETUBQGFHX-UHFFFAOYSA-N Ditropan Chemical compound C=1C=CC=CC=1C(O)(C(=O)OCC#CCN(CC)CC)C1CCCCC1 XIQVNETUBQGFHX-UHFFFAOYSA-N 0.000 description 1
- 206010013663 Drug dependence Diseases 0.000 description 1
- ZEUITGRIYCTCEM-KRWDZBQOSA-N Duloxetine Chemical compound C1([C@@H](OC=2C3=CC=CC=C3C=CC=2)CCNC)=CC=CS1 ZEUITGRIYCTCEM-KRWDZBQOSA-N 0.000 description 1
- 206010049669 Dyscalculia Diseases 0.000 description 1
- 206010058319 Dysgraphia Diseases 0.000 description 1
- 206010013932 Dyslexia Diseases 0.000 description 1
- 229940022766 EGTA Drugs 0.000 description 1
- 206010048653 Enzyme inhibition Diseases 0.000 description 1
- CXOFVDLJLONNDW-UHFFFAOYSA-N Epinat Chemical compound N1C(=O)NC(=O)C1(C=1C=CC=CC=1)C1=CC=CC=C1 CXOFVDLJLONNDW-UHFFFAOYSA-N 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 239000004386 Erythritol Substances 0.000 description 1
- 229940009714 Erythritol Drugs 0.000 description 1
- UNXHWFMMPAWVPI-ZXZARUISSA-N Erythritol Chemical compound OC[C@H](O)[C@H](O)CO UNXHWFMMPAWVPI-ZXZARUISSA-N 0.000 description 1
- WSEQXVZVJXJVFP-FQEVSTJZSA-N Escitalopram Chemical compound C1([C@]2(C3=CC=C(C=C3CO2)C#N)CCCN(C)C)=CC=C(F)C=C1 WSEQXVZVJXJVFP-FQEVSTJZSA-N 0.000 description 1
- HAPOVYFOVVWLRS-UHFFFAOYSA-N Ethosuximide Chemical compound CCC1(C)CC(=O)NC1=O HAPOVYFOVVWLRS-UHFFFAOYSA-N 0.000 description 1
- 229960002767 Ethosuximide Drugs 0.000 description 1
- 238000005079 FT-Raman Methods 0.000 description 1
- WKGXYQFOCVYPAC-UHFFFAOYSA-N Felbamate Chemical compound NC(=O)OCC(COC(N)=O)C1=CC=CC=C1 WKGXYQFOCVYPAC-UHFFFAOYSA-N 0.000 description 1
- 229940099239 Felbatol Drugs 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 235000016623 Fragaria vesca Nutrition 0.000 description 1
- 240000009088 Fragaria x ananassa Species 0.000 description 1
- 235000011363 Fragaria x ananassa Nutrition 0.000 description 1
- 229960004580 GLIBENCLAMIDE Drugs 0.000 description 1
- UGJMXCAKCUNAIE-UHFFFAOYSA-N Gabapen Chemical compound OC(=O)CC1(CN)CCCCC1 UGJMXCAKCUNAIE-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 229940042385 Glatiramer Drugs 0.000 description 1
- ZNNLBTZKUZBEKO-UHFFFAOYSA-N Glibenclamide Chemical compound COC1=CC=C(Cl)C=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZNNLBTZKUZBEKO-UHFFFAOYSA-N 0.000 description 1
- WIGIZIANZCJQQY-RUCARUNLSA-N Glimepiride Chemical compound O=C1C(CC)=C(C)CN1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)N[C@@H]2CC[C@@H](C)CC2)C=C1 WIGIZIANZCJQQY-RUCARUNLSA-N 0.000 description 1
- ZJJXGWJIGJFDTL-UHFFFAOYSA-N Glipizide Chemical compound C1=NC(C)=CN=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZJJXGWJIGJFDTL-UHFFFAOYSA-N 0.000 description 1
- 229960001381 Glipizide Drugs 0.000 description 1
- 229960004666 Glucagon Drugs 0.000 description 1
- 108060003199 Glucagon Proteins 0.000 description 1
- MASNOZXLGMXCHN-ZLPAWPGGSA-N Glucagonum Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 MASNOZXLGMXCHN-ZLPAWPGGSA-N 0.000 description 1
- 229940095884 Glucophage Drugs 0.000 description 1
- 208000002705 Glucose Intolerance Diseases 0.000 description 1
- 206010018429 Glucose tolerance impaired Diseases 0.000 description 1
- 229940014653 Glyburide Drugs 0.000 description 1
- 102000010726 Glycine Plasma Membrane Transport Proteins Human genes 0.000 description 1
- 108010063380 Glycine Plasma Membrane Transport Proteins Proteins 0.000 description 1
- 229920002907 Guar gum Polymers 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 229940031574 HYDROXYMETHYL CELLULOSE Drugs 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 241000257303 Hymenoptera Species 0.000 description 1
- 206010020993 Hypoglycaemia Diseases 0.000 description 1
- 206010021118 Hypotonia Diseases 0.000 description 1
- 206010061216 Infarction Diseases 0.000 description 1
- 206010022114 Injury Diseases 0.000 description 1
- 229940120520 Iodoquinol Drugs 0.000 description 1
- JEIPFZHSYJVQDO-UHFFFAOYSA-N Iron(III) oxide Chemical compound O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
- SFLSHLFXELFNJZ-MRVPVSSYSA-N L-Noradrenaline Natural products NC[C@@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-MRVPVSSYSA-N 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- 229960004873 LEVOMENTHOL Drugs 0.000 description 1
- 229940031703 LOW SUBSTITUTED HYDROXYPROPYL CELLULOSE Drugs 0.000 description 1
- 206010024094 Learning disease Diseases 0.000 description 1
- 229940067606 Lecithin Drugs 0.000 description 1
- 239000004367 Lipase Substances 0.000 description 1
- 229940040461 Lipase Drugs 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N Malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- VQHSOMBJVWLPSR-WUJBLJFYSA-N Maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 description 1
- 206010026749 Mania Diseases 0.000 description 1
- BUGYDGFZZOZRHP-UHFFFAOYSA-N Memantine Chemical compound C1C(C2)CC3(C)CC1(C)CC2(N)C3 BUGYDGFZZOZRHP-UHFFFAOYSA-N 0.000 description 1
- 229940041616 Menthol Drugs 0.000 description 1
- FEWJPZIEWOKRBE-XIXRPRMCSA-N Mesotartaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-XIXRPRMCSA-N 0.000 description 1
- 208000001145 Metabolic Syndrome Diseases 0.000 description 1
- 102000016193 Metabotropic Glutamate Receptors Human genes 0.000 description 1
- 108010010914 Metabotropic Glutamate Receptors Proteins 0.000 description 1
- IBAQFPQHRJAVAV-ULAWRXDQSA-N Miglitol Chemical compound OCCN1C[C@H](O)[C@@H](O)[C@H](O)[C@H]1CO IBAQFPQHRJAVAV-ULAWRXDQSA-N 0.000 description 1
- 229960001785 Mirtazapine Drugs 0.000 description 1
- RONZAEMNMFQXRA-UHFFFAOYSA-N Mirtazapine Chemical compound C1C2=CC=CN=C2N2CCN(C)CC2C2=CC=CC=C21 RONZAEMNMFQXRA-UHFFFAOYSA-N 0.000 description 1
- 208000001089 Multiple System Atrophy Diseases 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- CZFNISFYDPIDNM-UHFFFAOYSA-N N,N-dimethylformamide;oxolane Chemical compound CN(C)C=O.C1CCOC1 CZFNISFYDPIDNM-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000009025 Nervous System Disease Diseases 0.000 description 1
- 206010029305 Neurological disorder Diseases 0.000 description 1
- 231100000618 Neurotoxin Toxicity 0.000 description 1
- 229960002748 Norepinephrine Drugs 0.000 description 1
- 229940005483 OPIOID ANALGESICS Drugs 0.000 description 1
- AHLBNYSZXLDEJQ-FWEHEUNISA-N Orlistat Chemical compound CCCCCCCCCCC[C@H](OC(=O)[C@H](CC(C)C)NC=O)C[C@@H]1OC(=O)[C@H]1CCCCCC AHLBNYSZXLDEJQ-FWEHEUNISA-N 0.000 description 1
- BRUQQQPBMZOVGD-XFKAJCMBSA-N Oxycontin Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(OC)C2=C5[C@@]13CCN4C BRUQQQPBMZOVGD-XFKAJCMBSA-N 0.000 description 1
- 229940088417 PRECIPITATED CALCIUM CARBONATE Drugs 0.000 description 1
- 108060002038 Pde4 Proteins 0.000 description 1
- 101700034712 Pde6 Proteins 0.000 description 1
- YYPWGCZOLGTTER-MZMPZRCHSA-N Pergolide Chemical compound C1=CC=C2[C@H]3C[C@@H](CSC)CN(CCC)[C@@H]3CC3=CN=C1[C]32 YYPWGCZOLGTTER-MZMPZRCHSA-N 0.000 description 1
- 229960004851 Pergolide Drugs 0.000 description 1
- 102000003728 Peroxisome Proliferator-Activated Receptors Human genes 0.000 description 1
- 108090000029 Peroxisome Proliferator-Activated Receptors Proteins 0.000 description 1
- JTJMJGYZQZDUJJ-UHFFFAOYSA-N Phencyclidine Chemical compound C1CCCCN1C1(C=2C=CC=CC=2)CCCCC1 JTJMJGYZQZDUJJ-UHFFFAOYSA-N 0.000 description 1
- 229960002036 Phenytoin Drugs 0.000 description 1
- 229960005095 Pioglitazone Drugs 0.000 description 1
- HYAFETHFCAUJAY-UHFFFAOYSA-N Pioglitazone Chemical compound N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 HYAFETHFCAUJAY-UHFFFAOYSA-N 0.000 description 1
- 206010070606 Post stroke depression Diseases 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M Potassium bicarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229940097325 Prolactin Drugs 0.000 description 1
- 102000003946 Prolactin Human genes 0.000 description 1
- 108010057464 Prolactin Proteins 0.000 description 1
- 206010037175 Psychiatric disease Diseases 0.000 description 1
- 239000004373 Pullulan Substances 0.000 description 1
- 229920001218 Pullulan Polymers 0.000 description 1
- URKOMYMAXPYINW-UHFFFAOYSA-N Quetiapine Chemical compound C1CN(CCOCCO)CCN1C1=NC2=CC=CC=C2SC2=CC=CC=C12 URKOMYMAXPYINW-UHFFFAOYSA-N 0.000 description 1
- 229960005197 Quetiapine fumarate Drugs 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 206010037999 Reading disease Diseases 0.000 description 1
- YASAKCUCGLMORW-UHFFFAOYSA-N Rosiglitazone Chemical compound C=1C=CC=NC=1N(C)CCOC(C=C1)=CC=C1CC1SC(=O)NC1=O YASAKCUCGLMORW-UHFFFAOYSA-N 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N Saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 Saccharin Drugs 0.000 description 1
- 206010039637 Schizophrenia, catatonic type Diseases 0.000 description 1
- 206010039640 Schizophrenia, residual type Diseases 0.000 description 1
- 229940053479 Selective serotonin reuptake inhibitors Drugs 0.000 description 1
- 229940076279 Serotonin Drugs 0.000 description 1
- 208000007929 Shared Paranoid Disorder Diseases 0.000 description 1
- 206010040535 Shared psychotic disease Diseases 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- UNAANXDKBXWMLN-UHFFFAOYSA-N Sibutramine Chemical compound C=1C=C(Cl)C=CC=1C1(C(N(C)C)CC(C)C)CCC1 UNAANXDKBXWMLN-UHFFFAOYSA-N 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N Silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 229940005550 Sodium alginate Drugs 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- NNMHYFLPFNGQFZ-UHFFFAOYSA-M Sodium polyacrylate Chemical compound [Na+].[O-]C(=O)C=C NNMHYFLPFNGQFZ-UHFFFAOYSA-M 0.000 description 1
- 229940075582 Sorbic Acid Drugs 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 240000001132 Stevia rebaudiana Species 0.000 description 1
- CZMRCDWAGMRECN-GDQSFJPYSA-N Sucrose Natural products O([C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1)[C@@]1(CO)[C@H](O)[C@@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-GDQSFJPYSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-L Sulphite Chemical class [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 description 1
- 108020003835 TX1 Proteins 0.000 description 1
- FKHIFSZMMVMEQY-UHFFFAOYSA-N Talc Chemical compound [Mg+2].[O-][Si]([O-])=O FKHIFSZMMVMEQY-UHFFFAOYSA-N 0.000 description 1
- MIQPIUSUKVNLNT-UHFFFAOYSA-N Tasmar Chemical compound C1=CC(C)=CC=C1C(=O)C1=CC(O)=C(O)C([N+]([O-])=O)=C1 MIQPIUSUKVNLNT-UHFFFAOYSA-N 0.000 description 1
- 210000001550 Testis Anatomy 0.000 description 1
- 229960005333 Tetrabenazine Drugs 0.000 description 1
- OGIDPMRJRNCKJF-UHFFFAOYSA-N TiO Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- 235000015450 Tilia cordata Nutrition 0.000 description 1
- 235000011941 Tilia x europaea Nutrition 0.000 description 1
- URAYPUMNDPQOKB-UHFFFAOYSA-N Triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 1
- 229960002622 Triacetin Drugs 0.000 description 1
- HWHLPVGTWGOCJO-UHFFFAOYSA-N Trihexyphenidyl Chemical group C1CCCCC1C(C=1C=CC=CC=1)(O)CCN1CCCCC1 HWHLPVGTWGOCJO-UHFFFAOYSA-N 0.000 description 1
- 229960001032 Trihexyphenidyl Drugs 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Tris Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K Trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
- GXPHKUHSUJUWKP-UHFFFAOYSA-N Troglitazone Chemical compound C1CC=2C(C)=C(O)C(C)=C(C)C=2OC1(C)COC(C=C1)=CC=C1CC1SC(=O)NC1=O GXPHKUHSUJUWKP-UHFFFAOYSA-N 0.000 description 1
- 208000001072 Type 2 Diabetes Mellitus Diseases 0.000 description 1
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Vitamin C Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 1
- 235000010724 Wisteria floribunda Nutrition 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- CXNIUSPIQKWYAI-UHFFFAOYSA-N Xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N Xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 Xylitol Drugs 0.000 description 1
- NWONKYPBYAMBJT-UHFFFAOYSA-L Zinc sulfate Chemical compound [Zn+2].[O-]S([O-])(=O)=O NWONKYPBYAMBJT-UHFFFAOYSA-L 0.000 description 1
- 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 description 1
- 238000000862 absorption spectrum Methods 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 229960002632 acarbose Drugs 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- IYKJEILNJZQJPU-UHFFFAOYSA-N acetic acid;butanedioic acid Chemical compound CC(O)=O.OC(=O)CCC(O)=O IYKJEILNJZQJPU-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000000996 additive Effects 0.000 description 1
- 229960005305 adenosine Drugs 0.000 description 1
- GFFGJBXGBJISGV-UHFFFAOYSA-N adenyl group Chemical group N1=CN=C2N=CNC2=C1N GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 1
- 230000001058 adult Effects 0.000 description 1
- 230000001476 alcoholic Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 230000003281 allosteric Effects 0.000 description 1
- RJZNFXWQRHAVBP-UHFFFAOYSA-I aluminum;magnesium;pentahydroxide Chemical compound [OH-].[OH-].[OH-].[OH-].[OH-].[Mg+2].[Al+3] RJZNFXWQRHAVBP-UHFFFAOYSA-I 0.000 description 1
- 229960002734 amfetamine Drugs 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 239000000883 anti-obesity agent Substances 0.000 description 1
- 239000000164 antipsychotic agent Substances 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 239000002830 appetite depressant Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229960004372 aripiprazole Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 239000000605 aspartame Substances 0.000 description 1
- 235000010357 aspartame Nutrition 0.000 description 1
- 239000012131 assay buffer Substances 0.000 description 1
- 201000002055 autistic disease Diseases 0.000 description 1
- LMEKQMALGUDUQG-UHFFFAOYSA-N azathioprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC=NC2=C1NC=N2 LMEKQMALGUDUQG-UHFFFAOYSA-N 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 230000003542 behavioural Effects 0.000 description 1
- 229960001081 benzatropine Drugs 0.000 description 1
- 229960002903 benzyl benzoate Drugs 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- 229940058933 biguanide antimalarials Drugs 0.000 description 1
- 229940090145 biguanide blood glucose lower drugs Drugs 0.000 description 1
- 150000004283 biguanides Chemical class 0.000 description 1
- 230000027455 binding Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- VTYYLEPIZMXCLO-UHFFFAOYSA-L calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 238000007707 calorimetry Methods 0.000 description 1
- 230000002149 cannabinoid Effects 0.000 description 1
- 229930003827 cannabinoid Natural products 0.000 description 1
- 239000003557 cannabinoid Substances 0.000 description 1
- 210000000692 cap cell Anatomy 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- 229960000623 carbamazepine Drugs 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 229920003123 carboxymethyl cellulose sodium Polymers 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000010800 chemical transportation method Methods 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229960003920 cocaine Drugs 0.000 description 1
- ZPUCINDJVBIVPJ-LJISPDSOSA-N cocaine Chemical compound O([C@H]1C[C@@H]2CC[C@@H](N2C)[C@H]1C(=O)OC)C(=O)C1=CC=CC=C1 ZPUCINDJVBIVPJ-LJISPDSOSA-N 0.000 description 1
- ZPUCINDJVBIVPJ-BARDWOONSA-N cocaine Natural products O([C@@H]1C[C@H]2CC[C@H](N2C)[C@@H]1C(=O)OC)C(=O)C1=CC=CC=C1 ZPUCINDJVBIVPJ-BARDWOONSA-N 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 230000001808 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 230000004059 degradation Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000000593 degrading Effects 0.000 description 1
- 229940061632 dehydroacetic acid Drugs 0.000 description 1
- 235000019258 dehydroacetic acid Nutrition 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- KLGZELKXQMTEMM-OUBTZVSYSA-N deuteride Chemical compound [2H-] KLGZELKXQMTEMM-OUBTZVSYSA-N 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- JAUGGEIKQIHSMF-UHFFFAOYSA-N dialuminum;dimagnesium;dioxido(oxo)silane;oxygen(2-);hydrate Chemical compound O.[O-2].[O-2].[Mg+2].[Mg+2].[Al+3].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O.[O-][Si]([O-])=O JAUGGEIKQIHSMF-UHFFFAOYSA-N 0.000 description 1
- PWZFXELTLAQOKC-UHFFFAOYSA-A dialuminum;hexamagnesium;carbonate;hexadecahydroxide;tetrahydrate Chemical compound O.O.O.O.[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Al+3].[Al+3].[O-]C([O-])=O PWZFXELTLAQOKC-UHFFFAOYSA-A 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 238000000113 differential scanning calorimetry Methods 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 229960000691 diiodohydroxyquinoline Drugs 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- ZLSFWAPBBIIMKI-KVINTPOGSA-M dipotassium;(2S,4aS,6aR,6aS,6bR,8aR,10S,12aS,14bR)-2,4a,6a,6b,9,9,12a-heptamethyl-10-oxido-13-oxo-3,4,5,6,6a,7,8,8a,10,11,12,14b-dodecahydro-1H-picene-2-carboxylate Chemical compound [K+].[K+].C([C@H]1C2=CC(=O)[C@H]34)[C@@](C)(C([O-])=O)CC[C@]1(C)CC[C@@]2(C)[C@]4(C)CC[C@@H]1[C@]3(C)CC[C@H]([O-])C1(C)C ZLSFWAPBBIIMKI-KVINTPOGSA-M 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 229960002866 duloxetine Drugs 0.000 description 1
- 230000001544 dysphoric Effects 0.000 description 1
- 238000005868 electrolysis reaction Methods 0.000 description 1
- 238000000132 electrospray ionisation Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000012055 enteric layer Substances 0.000 description 1
- 235000019414 erythritol Nutrition 0.000 description 1
- 229960004341 escitalopram Drugs 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 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 1
- 238000001704 evaporation Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 229960003472 felbamate Drugs 0.000 description 1
- 238000007716 flux method Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 238000002194 freeze distillation Methods 0.000 description 1
- 201000011240 frontotemporal dementia Diseases 0.000 description 1
- 229960002870 gabapentin Drugs 0.000 description 1
- 238000010574 gas phase reaction Methods 0.000 description 1
- 238000010582 gas stream method Methods 0.000 description 1
- 238000002309 gasification Methods 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
- 229960004346 glimepiride Drugs 0.000 description 1
- 230000004110 gluconeogenesis Effects 0.000 description 1
- 230000004116 glycogenolysis Effects 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 239000000665 guar gum Substances 0.000 description 1
- 235000010417 guar gum Nutrition 0.000 description 1
- 229960002154 guar gum Drugs 0.000 description 1
- 239000000380 hallucinogen Substances 0.000 description 1
- 230000002440 hepatic Effects 0.000 description 1
- UKJFVOWPUXSBOM-UHFFFAOYSA-N hexane;oxolane Chemical compound C1CCOC1.CCCCCC UKJFVOWPUXSBOM-UHFFFAOYSA-N 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 229920001477 hydrophilic polymer Polymers 0.000 description 1
- 229960001545 hydrotalcite Drugs 0.000 description 1
- 229910001701 hydrotalcite Inorganic materials 0.000 description 1
- 238000001027 hydrothermal synthesis Methods 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 229940071826 hydroxyethyl cellulose Drugs 0.000 description 1
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 1
- 230000002218 hypoglycaemic Effects 0.000 description 1
- 230000001505 hypomanic Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000000752 ionisation method Methods 0.000 description 1
- 229910000460 iron oxide Inorganic materials 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical group CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- 201000003723 learning disability Diseases 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229960004502 levodopa Drugs 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000004571 lime Substances 0.000 description 1
- 235000019421 lipase Nutrition 0.000 description 1
- 102000004882 lipase Human genes 0.000 description 1
- 108090001060 lipase Proteins 0.000 description 1
- 230000004132 lipogenesis Effects 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229960001078 lithium Drugs 0.000 description 1
- 229960003511 macrogol Drugs 0.000 description 1
- 239000000391 magnesium silicate Substances 0.000 description 1
- 229910052919 magnesium silicate Inorganic materials 0.000 description 1
- 235000019792 magnesium silicate Nutrition 0.000 description 1
- VPBIQXABTCDMAU-UHFFFAOYSA-N magnesium;oxido(oxo)alumane Chemical compound [Mg+2].[O-][Al]=O.[O-][Al]=O VPBIQXABTCDMAU-UHFFFAOYSA-N 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 229940099690 malic acid Drugs 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 235000010449 maltitol Nutrition 0.000 description 1
- 239000000845 maltitol Substances 0.000 description 1
- 229940035436 maltitol Drugs 0.000 description 1
- 230000000873 masking Effects 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000010297 mechanical methods and process Methods 0.000 description 1
- 229960004640 memantine Drugs 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- WVJKHCGMRZGIJH-UHFFFAOYSA-N methanetriamine Chemical compound NC(N)N WVJKHCGMRZGIJH-UHFFFAOYSA-N 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 229960001110 miglitol Drugs 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 201000008895 mood disease Diseases 0.000 description 1
- 201000009457 movement disease Diseases 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 230000003551 muscarinic Effects 0.000 description 1
- 230000036640 muscle relaxation Effects 0.000 description 1
- 230000000626 neurodegenerative Effects 0.000 description 1
- 230000004031 neuronal differentiation Effects 0.000 description 1
- 239000002581 neurotoxin Substances 0.000 description 1
- 108090000590 neurotransmitter receptors Proteins 0.000 description 1
- 102000004108 neurotransmitter receptors Human genes 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000002767 noradrenalin uptake inhibitor Substances 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 201000008430 obsessive-compulsive disease Diseases 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 230000003364 opioid Effects 0.000 description 1
- 230000003287 optical Effects 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 229960001243 orlistat Drugs 0.000 description 1
- 229960005434 oxybutynin Drugs 0.000 description 1
- 229960002085 oxycodone Drugs 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N p-acetaminophenol Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- 230000036961 partial Effects 0.000 description 1
- 108060002036 pde-2 Proteins 0.000 description 1
- 108060002037 pde-3 Proteins 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229950010883 phencyclidine Drugs 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 239000002587 phosphodiesterase IV inhibitor Substances 0.000 description 1
- 239000002590 phosphodiesterase V inhibitor Substances 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 230000001817 pituitary Effects 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 230000000607 poisoning Effects 0.000 description 1
- 231100000572 poisoning Toxicity 0.000 description 1
- 229920001495 poly(sodium acrylate) polymer Polymers 0.000 description 1
- 229920000307 polymer substrate Polymers 0.000 description 1
- 201000008839 post-traumatic stress disease Diseases 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Inorganic materials [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 230000000770 pro-inflamatory Effects 0.000 description 1
- WYDUSKDSKCASEF-UHFFFAOYSA-N procyclidine Chemical compound C1CCCCC1C(C=1C=CC=CC=1)(O)CCN1CCCC1 WYDUSKDSKCASEF-UHFFFAOYSA-N 0.000 description 1
- 229960005253 procyclidine Drugs 0.000 description 1
- 230000002250 progressing Effects 0.000 description 1
- 230000001737 promoting Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propanol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 239000003801 protein tyrosine phosphatase 1B inhibitor Substances 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 235000019423 pullulan Nutrition 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 229960004431 quetiapine Drugs 0.000 description 1
- ZTHJULTYCAQOIJ-WXXKFALUSA-N quetiapine fumarate Chemical compound [H+].[H+].[O-]C(=O)\C=C\C([O-])=O.C1CN(CCOCCO)CCN1C1=NC2=CC=CC=C2SC2=CC=CC=C12.C1CN(CCOCCO)CCN1C1=NC2=CC=CC=C2SC2=CC=CC=C12 ZTHJULTYCAQOIJ-WXXKFALUSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 230000014786 regulation of synaptic transmission Effects 0.000 description 1
- 229960004586 rosiglitazone Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 201000000261 schizophreniform disease Diseases 0.000 description 1
- 238000010581 sealed tube method Methods 0.000 description 1
- MEZLKOACVSPNER-GFCCVEGCSA-N selegiline Chemical compound C#CCN(C)[C@H](C)CC1=CC=CC=C1 MEZLKOACVSPNER-GFCCVEGCSA-N 0.000 description 1
- 229960003946 selegiline Drugs 0.000 description 1
- 231100000489 sensitizer Toxicity 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 229960004425 sibutramine Drugs 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 238000010583 slow cooling Methods 0.000 description 1
- MSXHSNHNTORCAW-UHFFFAOYSA-M sodium 3,4,5,6-tetrahydroxyoxane-2-carboxylate Chemical compound [Na+].OC1OC(C([O-])=O)C(O)C(O)C1O MSXHSNHNTORCAW-UHFFFAOYSA-M 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- ZNJHFNUEQDVFCJ-UHFFFAOYSA-M sodium;2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid;hydroxide Chemical compound [OH-].[Na+].OCCN1CCN(CCS(O)(=O)=O)CC1 ZNJHFNUEQDVFCJ-UHFFFAOYSA-M 0.000 description 1
- WSWCOQWTEOXDQX-UHFFFAOYSA-N sorbic acid Chemical compound CC=CC=CC(O)=O WSWCOQWTEOXDQX-UHFFFAOYSA-N 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical compound OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 description 1
- 229960004940 sulpiride Drugs 0.000 description 1
- 230000004083 survival Effects 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000000892 thaumatin Substances 0.000 description 1
- 235000010436 thaumatin Nutrition 0.000 description 1
- 238000002076 thermal analysis method Methods 0.000 description 1
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 1
- 229910001929 titanium oxide Inorganic materials 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- 229960004603 tolcapone Drugs 0.000 description 1
- 229960004045 tolterodine Drugs 0.000 description 1
- OOGJQPCLVADCPB-HXUWFJFHSA-N tolterodine Chemical compound C1([C@@H](CCN(C(C)C)C(C)C)C=2C(=CC=C(C)C=2)O)=CC=CC=C1 OOGJQPCLVADCPB-HXUWFJFHSA-N 0.000 description 1
- 230000000699 topical Effects 0.000 description 1
- 108090000464 transcription factors Proteins 0.000 description 1
- 102000003995 transcription factors Human genes 0.000 description 1
- 230000005068 transpiration Effects 0.000 description 1
- 125000003258 trimethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 239000003174 triple reuptake inhibitor Substances 0.000 description 1
- 239000011778 trisodium citrate Substances 0.000 description 1
- VOBHRQFELWTZFS-AWLRYRRCSA-K trisodium;(4Z)-3-oxo-4-[(4-sulfonatonaphthalen-1-yl)hydrazinylidene]naphthalene-2,7-disulfonate Chemical compound [Na+].[Na+].[Na+].C1=CC=C2C(N/N=C3/C4=CC=C(C=C4C=C(C3=O)S(=O)(=O)[O-])S([O-])(=O)=O)=CC=C(S([O-])(=O)=O)C2=C1 VOBHRQFELWTZFS-AWLRYRRCSA-K 0.000 description 1
- UJMBCXLDXJUMFB-UHFFFAOYSA-K trisodium;5-oxo-1-(4-sulfonatophenyl)-4-[(4-sulfonatophenyl)diazenyl]-4H-pyrazole-3-carboxylate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)C1=NN(C=2C=CC(=CC=2)S([O-])(=O)=O)C(=O)C1N=NC1=CC=C(S([O-])(=O)=O)C=C1 UJMBCXLDXJUMFB-UHFFFAOYSA-K 0.000 description 1
- 229960001641 troglitazone Drugs 0.000 description 1
- 229960004688 venlafaxine Drugs 0.000 description 1
- PNVNVHUZROJLTJ-UHFFFAOYSA-N venlafaxine Chemical compound C1=CC(OC)=CC=C1C(CN(C)C)C1(O)CCCCC1 PNVNVHUZROJLTJ-UHFFFAOYSA-N 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- VWQVUPCCIRVNHF-UHFFFAOYSA-N yttrium Chemical compound [Y] VWQVUPCCIRVNHF-UHFFFAOYSA-N 0.000 description 1
- 229910052727 yttrium Inorganic materials 0.000 description 1
- 239000011686 zinc sulphate Substances 0.000 description 1
- 235000009529 zinc sulphate Nutrition 0.000 description 1
- 229960000607 ziprasidone Drugs 0.000 description 1
- 238000004857 zone melting Methods 0.000 description 1
Classifications
-
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Abstract
Disclosed herein is a crystal of 1-ethyl-7-methyl-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one which is thermodynamically, chemically and physically stable. The crystal shows an X-ray powder diffraction pattern having characteristic peaks at interplaner spacings (d) of 13.59 ± 0.2, 6.76 ± 0.2, 9.22 ± 0.2, 7.88 ± 0.2, 6.21 ± 0.2, 6.13 ± 0.2, 5.73 ± 0.2, 4.64 ± 0.2, 3.79 ± 0.2 and 3.75 ± 0.2 Angstroms in powder X-ray diffraction. The crystal also shows an initial temperature of 222-224 °C of an endothermic behaviour caused by melting in DSC measurement (temperature increase rate 5 °C/min). The crystal is a phosphodiesterase 10A (PDE10A) inhibitor useful in the treatment of schizophrenia. terplaner spacings (d) of 13.59 ± 0.2, 6.76 ± 0.2, 9.22 ± 0.2, 7.88 ± 0.2, 6.21 ± 0.2, 6.13 ± 0.2, 5.73 ± 0.2, 4.64 ± 0.2, 3.79 ± 0.2 and 3.75 ± 0.2 Angstroms in powder X-ray diffraction. The crystal also shows an initial temperature of 222-224 °C of an endothermic behaviour caused by melting in DSC measurement (temperature increase rate 5 °C/min). The crystal is a phosphodiesterase 10A (PDE10A) inhibitor useful in the treatment of schizophrenia.
Description
CRYSTAL OE FUSED HETEROCYCLIC COMPOUND
TECHNICAL FIELD OF THE INVENTION
The t invention s to a crystal of a fused
heterocyclic compound, which has a superior phosphodiesterase
10A inhibitory action, and is useful as an agent for the
treatment or prophylaxis of schizophrenia etc., and the like.
(Background of the Invention)
Phosphodiesterases (PDEs) are a superfamily of enzymes
d by 21 genes and subdivided into ll distinct families
ing to structural and functional properties. These
enzymes metabolically inactivate the ubiquitous intracellular
second messengers, cyclic adenosine osphate (CAMP) and
cyclic guanosine monophosphate (cGMP); PDEs selectively
catalyze the hydrolysis of the 3’-ester bond, forming the
inactive 5’—monophosphate. Oh the basis of substrate
specificity, the PDE families can be further classified into
three groups: i) the cAMP—PDEs (PDE4, PDE7, PDE8), ii) the
cGMP—PDEs (PDES, PDE6 and PDE9), and iii) the dual—substrate
PDES (PDEI, PDEZ, PDE3, PDEIO and PDEIl).
The CAMP and cGMP are involved in the regulation of
virtually every physiolOgical process such as pro—inflammatory
or production and action, ion channel function, muscle
relaxation, learning and memory ion, differentiation,
apoptosis, lipogenesis, glycogenolysis and gluconeogenesis.
Especially, in neurOns, these second messengers have important
role in the regulation of synaptic transmission as well as in
neuronal differentiation and survival (non—patent document 1).
Regulation of these processes by cAMP and cGMP are accompanied
by activation of protein kinase A (PKA) and protein kinase G
(PKG), which in turn phosphorylate a variety of substrates,
including transcription factors, ion channels and receptors
W0 2012/176934
that regulate a variety of physiological ses.
Intracellular CAMP and CGMP concentrations seem to be
temporally, Spatially, and functionally compartmentalized by
regulation of adenyl and guanyl es in se to
extracellular signaling and their degradation by PDEs (non—
patent document 2). PDEs provide the only means of degrading
the cyclic nucleotides CAMP and cGMP in cells, thus PDEs play
an essential role in cyclic nucleotide signal transduction.
Thereby, PDEs could be promising targets for various
therapeutic drugs.
nPhosphodiesterase'lOA (EDElOA) was discovered in 1999
(non—patent documents 3—5).I ExpresSion studies have shown that
PDElOA has the most restricted distribution within the all
known PDE families; the PDElOA mRNA is highly expressed only
in brain and testes (non—patent documents 6 and 7). In the
brain, mRNA and protein of PDElOA are highly enriched in
medium spiny neurons (MSNs) of the striatum (non—patent
documents 8 and 9). MSNs are classified into two groups: the
MSN that express D1 dopamine ors responsible for a direct
tonigral) pathway and the MSN that express D2 dopamine
receptors responsible for an indirect (striatopallidal)
pathway. The function of direct pathway is to plan and
execution, while indirect pathway is to act as a brake on
behavioral activation. As PDElOA is expressed in both MSNs,
PDElOA inhibitors could activate both of these ys. The
antipsychotic efficacy of current tions, D2 or Dz/S—HTfl;
antagonists, mainly s from their activation of the
indirect pathway in the striatum. As PDElOA inhibitors are
able to activate this pathway, this suggests that PDElOA
inhibitors are promising as ychotic drugs. The excessive
D2 receptor antagonism in the brain by D2 antagonists causes
problems of extrapyramidal side-effects and
hyperprolactinaemia. However the expression of PDElOA is
limited to these striatal pathways in the brain, thus side
WO 76934
effects by PDElOA inhibitors were expected to be weaker
compared with current D2 nists. ing
hyperprolactinaemia, PDElOA inhibitors would e no
prolactin elevation due to lack of D2 receptor antagonism in
the pituitary, Moreover, the presence of PDElOA in a direct
pathway makes it likely that PDElOA inhibitors will have some
advantage over current D2 antagonists; the direct pathway is
thought to promote desired action, and activation of this
pathway by PDElOA inhibitors may counteract extrapyramidal
ms induced by excessive D2 receptor antagonism. In
addition, activation of this pathway could facilitate
striatal—thalamic w, promoting the execution of
procedural strategies. Furthermore, enhancement of second
messenger levels without blockade of ne and/or other
neurotransmitter receptors may also provide therapeutic
advantages with fewer adverse side—effects ed with
current antipsychotics (e.g., hyperprolactinaemia and weight
gain). This unique distribution and function in the brain
tes that PDElOA represents an important new target for
the treatment of neurological and psychiatric disorders, in
particular psychotic disorders like schizophrenia.
Patent document 1 describes, as a phosphodiesterase (PDE)
inhibitor, a compound represented by the formula:
[0006]
R10 0/
7E"\M,,&
R11/U\ /
wherein each symbol is as defined in patent document 1,
W0 2012/176934
and the following compounds:
Patent document 2 describes, as a odiesterase (PDE)
inhibitor, a compound represented by the formula:
(R3 )p (R )m4
0 X9 ,X1‘\~X2
N \ \X8” .‘X1O Z/X5 \
u /N )l(7 {£01 A >\X:,
wherein each symbol is as defined in patent document 2,
and the following compounds:
(Rm .
- Patent document 3 describes, as a odiesterase (PDE)
inhibitor, a compound represented by the formula:
(R2)I1(R3)px1§y(R4)m)n\l\/R1Kro\lx8X7:/|)|(1D Z’XS;
x6 N
’/ 12,x11Y/L\ ;>“gN
wherein each symbol is as defined in patent document 3,
and the following compounds:
Patent document 4 describes, as a phosphodiesterase (PDE)
10 inhibitor, a compound represented by the a:
n Z is
wherein each symbol is as defined in patent document 4.
[0020]
Patent document 5 describes, as a phosphodiesterase (PDE)
inhibitor, a compound represented by the formula:'
VV()2012/176934
wherein each symbol is as defined in patent document 5.
Patent document 6 describes, as a phosphodiesterase (PDE)
inhibitor, a compound represented by the a:
wherein each symbol is as d in patent document 6.
[Document List]
[patent documents]
patent document 1 W02008/004ll7
patent document 2 W02010/057l2l
patent document 3: WO20lO/057126
patent document 4 /072828
patent document 5 W02008/001182
patent document 6: W02010/090737
[non—patent documents]
non—patent document 1: Nat. Rev. Drug Discov. 2006, vol. 5, p.
660—670
non—patent document 2: Circ. Res. 2007, vol. 100(7), p. 950—
non—patent document 3: Proc. Natl. Acad. Sci. USA, 1999, vol.
96, p. 8991—8996
non—patent document 4: J. Biol. Chem. 1999, vol. 274, p.
18438—18445
tent docUment 5: Gene, 1999, vol. 234, p. 109—117
non—patent document 6: Eur. J. Biochem. 1999, Vol. 266, p.
1118—1127
non—patent document 7: J. Biol. Chem. 1999, vol. 274, p.
18438—18445
non—patent document 8: Eur. J. Biochem. 1999, vol. 266, p.
1118—1127
tent document 9: Brain Res. 2003, vol. 985, p. 113-126
Y OF THE INVENTION
Problems to be Solved by the Invention
'The development of a compound having a superior PDElOA
inhibitory action, which is useful as an agent for the
treatment or laxis of phrenia etc. and the like,
and has properties superior in the stability, has been desired.
Means of Solving the Problems
[0029]
The present inventors have conducted intensive studies in
an attempt to solve the aforementioned problems and
successfully obtained l—ethyl~7—methyl—3—{4—[(3~methyl—3H—
imidazo[4,5—b]pyridin—2—y1)oxy]phenyl}—1,3—dihydro—2H—
imidazo[4,5-b]pyridin—2—one as a crystal which is
thermodynamically, ally and physically highly stable. In
addition, they have found that the crystal has a
, or
PDElOA inhibitory action, and is sufficiently satisfactory as
a medicament for the treatment or prophylaxis of schizophrenia
and the like. They have completed the present invention baSed
on these findings.
Accordingly, the present ion relates to
a crystal of 1-ethylmethyl{4-[(3-methyl-3H-
imidazo[4,5-b]pyridinyl)oxy]phenyl}-1,3-dihydro-2H-
imidazo[4,5-b]pyridinone showing an X-ray powder
diffraction pattern having characteristic peaks at interplaner
spacings (d) of 13.59±0.2 and 6.76±0.2 Angstroms in powder X-
ray diffraction nafter sometimes to be referred to as
the crystal of the present invention). More specifically, the
present invention provides a crystal of 1-ethylmethyl{4-
[(3-methyl-3H-imidazo[4,5-b]pyridinyl)oxy]phenyl}-1,3-
dihydro-2H-imidazo[4,5-b]pyridinone showing an X-ray powder
diffraction pattern having characteristic peaks at lanar
spacings (d) of 13.59±0.2, 9.22±0.2, 7.88±0.2, 6.76±0.2,
6.21±0.2, .2, 5.73±0.2, 4.64±0.2, 3.79±0.2 and 3.75±0.2
Angstroms in powder X-ray diffraction;
the crystal of the mentioned [1], which shows an X-
ray powder diffraction pattern having further characteristic
peaks at interplaner spacings (d) of 9.22±0.2, .2,
6.21±0.2, 6.13±0.2, 5.73±0.2, 4.64±0.2, 3.79±0.2 and 3.75±0.2
Angstroms in powder X-ray diffraction;
the crystal of the above-mentioned [2], which shows an X-
ray powder diffraction pattern having further characteristic
peaks at laner gs (d) of 7.48±0.2, 5.24±0.2,
.13±0.2, 4.27±0.2, .2, 4.06±0.2, 3.99±0.2, 3.93±0.2,
3.60±0.2, 3.41±0.2, 3.16±0.2, 3.10±0.2, 3.06±0.2, 2.89±0.2,
2.83±0.2, 2.73±0.2 and 2.58±0.2 Angstroms in powder X-ray
diffraction;
the crystal of the above-mentioned [1], which shows an
initial temperature of about 222 - about 224°C of an
endothermic or caused by melting in DSC measurement
(temperature increase rate 5°C/min);
(Followed by page 8a)
a medicament comprising the l of the above-mentioned
the medicament of the above-mentioned [5], which is a
phosphodiesterase 10A inhibitor;
the medicament of the above-mentioned [5], which is a
prophylactic or therapeutic agent for schizophrenia;
a method of preventing or treating schizophrenia in a
mammal, comprising administering an effective amount of the
crystal of the mentioned [1] to the mammal;
(Followed by page 9)
WO 76934 V
use of the crystal of the above-mentioned [1] for the
production of a prophylactic or therapeutic drug for
schizophrenia;
the crystal of the aboye—mentioned [l] for use for the
laxis or treatment of schizophrenia;
and the like.
Effect of the Invention
Since the crystal of the present invention shows a
superior PDElOA inhibitory action, is low toxic and is.
superior in stability, it is useful as a pharmaceutical
product.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. I shows a powder X—ray diffraction pattern of the
crystal of Reference Example l—l.
Fig. 2 shows a powder X—ray diffraction n of the
crystal of Reference Example 2.
Fig. 3 shows a powder X—ray diffraction pattern of the
l of Reference Example 3.
Fig. 4 shows a powder X—ray diffraction pattern of the
crystal of Reference Example 4.
Fig. 5 shows a powder X—ray diffraction pattern of the
crystal of Reference Example 5.
Fig. 6 shows a powder X—ray ction pattern of the
crystal of Reference Example 6.
Fig. 7 shows a powder X—ray diffraction pattern of the
crystal of Reference Example 7.
Fig. 8 shows a powder X—ray diffraction pattern of the
crystal of Example 1(2).
Fig. 9 shows DSC thermoanalytical data of the crystal of
Example 1(2).
Description of Embodiments
(DETAILED DESCRIPTION OF THE INVENTION)
yThe crystal of 1—ethyl—7—methyl—3—{4—[(3—methyl—3H—
imidazo[4,5-b]pyridin—2—yl)oxy]phenyl}—1,3—dihydro-2H~
imidazO[4,5—b]pyridin—2—one in the present ion may be a
solvate such as e and the like, or a lvate such as
nonhydrate rate) and the like.
[Examples of the “hydrate” include 0.5 e to 5.0
hydrate. Among these, 0.5 hydrate, 1.0 hydrate, 1.5 hydrate,
2.0 hydrate and 2.5 hydrate are preferable. Particularly
preferred are 0.5 hydrate, 1.0 hydrate and 1.5 hydrate. In
addition, the aforementioned “hydrate” may also be a “variable
hydrate” containing a variable amount of water in the crystal
structure according to the humidity environment. The water
content of the variable hydrate varies within the range of
about 4.0 — about 14.5 wt%.
l—Ethyl—7—methyl-3—{4—[(3—methyl—3H—imidazo[4,5—
b]pyridin—2—yl)oxy]phenyl}~1,3-dihydro—2H—imidazo[4,5—
b]pyridin—2—one in the present ion may also be a
2O deuteride thereof.
In addition, the crystal of 1—ethyl—7—methyl—3—{4—[(3—
methyl—3H—imidazo[4,5—b]pyridin-2—yl)oxy]phenyl]—l,3~dihydro—
2H~imidazo[4,5—b]pyridin—2—one in the present ion may
also be a solvate other than a hydrate.
es of the solvate crystal of 1—ethyl—7~methyl—3—{4—
[(3—methyl—3H—imidazo[4,5-b]pyridin—2—yl)oxy]phenyl}—l,3~
dihydronH—imidazo[4,5-b]pyridin—2—one include alcohol solvate
crystals such as methanol solvate crystal, ethanol solvate
crystal and the like (preferably Cyfi alcohol solvate crystal),
organic solvent hydrate l to which water and organic
solvent are added (e.g., alcohol hydrate crystals such as
methanol hydrate, ethanol hydrate, etc., preferably Cbfi alcohol
hydrate crystal) and the like.
The l of the present invention can be produced by
crystal transformation of ous l-ethyl—7-methyl—3—{4—[(3—
methyl—3H-imidazo[4,5—b]pyridin—2—yl)oxy]phenyl}—l,3—dihydro—
2H—imidazo[4,5—b]pyridin32—one or other crystals ding
hydrate crystal) of l—ethyl—7—methyl~3—{4—[(3—methyl~3H—
imidazo[4,5—b]pyridin—2—yl)oxy]phenyl}-l,3—dihydro—2H~
imidazo[4,5—b]pyridin—2—one.
The crystal transformation is a phenomenon where a
crystal structure changes when the temperature or pressure
exceeds a certain level.
As the “crystal transformation ”, a method known
per se can be ned and, for example, crystallization from
a solution (e.g., concentration , slow cooling method,
reaction method (diffusion method, electrolysis method),
hydrothermal growth method, flux method and the like),
crystallization from the above (e.g., a gasification method
(sealed tube method, gas stream method), a gas phase reaction
method, a chemical transportation method), crystallization
from molten form (e.g., a normal freezing method ng—up
method, temperature gradient method, Bridgman method), a zone
melting method (zone leveling method, float zone method), a
special growth method (VLS method, liquid phase epitaxis
method), a transpiration method (a method ing dissolving
a crystal in a solvent, filtering and evaporating the solvent
under ambient conditions), a slurry method (a method including
adding a crystal to a solvent such that an excess solid
s to give a suspension, stirring the suspension at
ambient temperature or under heating or cooling, and
collecting the solid), drying under reduced pressure, ng,
pulverization, pressurization and the like can be mentioned.
To obtain the crystal of the present invention, a slurry
method is preferable from among the above.
[0040]
For analyzing the l obtained, X—ray diffraction
crystallographic analysis is commonly used. In.addition,
crystal orientation can also be determined by a mechanical
method, an optical method (e.g., FT—Raman um, solid—
(J1 state NMR spectrum), etc. In addition, crystal thermoanalysis
(Differential Scanning Calorimetry (DSC)), infrared absorption
spectrum is (KBr) and the like can also be performed
according to conventional methods.
The peak of the spectrum obtained by the above—mentioned
analysis method inevitably contains a certain measurement
error by its nature. A crystal with a spectrum peak within the
error range is also encompassed in the crystal of the present
invention. For e, “i0.2” or “i0.l” in the interplanar
spacing (d) of powder X—ray diffraction means that the error
is ble.
The crystal of the present invention produced by the
aforementioned method is a novel crystal showing an X—ray
powder diffraction n having characteristic peaks at
interplanar spacings (d) of l3.59i0.2 and 6.76i0.2 Angstroms,
by powder X—ray diffraction, and is preferably a crystal of non—
solvate (e.g., anhydrate).
The crystal of the t invention is preferably a
crystal showing an X—ray powder diffraction pattern having
[characteristic peaks at interplanar gs (d) of 13.59i0.2,
9.22i0.2, .2, 6.76i0.2, 6.21i0.2, 6.13i0.2, 5.73i0.2,
4.64i0.2, 3.79i0.2 and 3.75i0.2 Angstroms, by powder X—ray
diffraction, and is preferably a crystal of non—solvate (e.g.,
anhydrate).
The crystal of the present invention is more preferably a
crystal g an X—ray powder diffraction pattern having
Characteristic peaks at lanar spacings (d) of 13.59i0.2,
9.22i0.2, 7.88i0.2, 7.48i0.2, 6.76i0.2, 6.21i0.2, 6.13i0.2,
.73i0.2, 5.24i0.2, 5.13i0.2, .2, 4.27i0.2, 4.l6i0.2,
3.99i0.2, 3.93i0.2, 3;79i0.2, .2, 3.60i0.2, 3.4li0.2,
2.89i0.2, 2,73i0.2 and 2.58i0.2 Angstroms, by powder X—ray
action, and is preferably a crystal of non—solvate (e.g.,
anhydrate).
The crystal of the present invention is further more
preferably a crystal showing an X—ray powder diffraction pattern
having characteristic peaks at interplanar spacings (d) of
l3.59i0.2, .2, 7.88i0.2, .2, 6.76i0.2, 6.21i0.2,
6.13i0.2, 5.73i0.2, 5.24i0.2, 5.13i0.2, 4.64i0.2, 4.27i0.2,
4.16i0.2, 4.06i0.2, 3.99i0.2, 3.93i0.2, 3.79:0.2, 3.75i0.2,
.2, 3.4li0.2, 3.16i0.2, 3.10i0.2, 3.06i0.2, 2.89i0.2,
2.83i0.2, 2.73i0.2 and 2.58i0.2 Angstroms, by powder X—ray
diffraction, and is preferably a crystal of non—solvate (e.g.,
anhydrate).
As another embodiment, the crystal of the present
invention produced by the aforementioned method is a novel
crystal showing an X—ray powder diffraction pattern having
characteristic peaks at interplanar spacings (d) of l3.59i0.l
and 6.76i0.l Angstroms, by powder X-ray ction, and is
preferably a crystal of non~solvate (e.g., anhydrate).
]
The crystal of the present invention is preferably a
crystal showing an X~ray powder diffraction pattern having
characteristic peaks at interplanar spacings (d) of 13.59i0.l,
.l, 7.88i0.l, 6.76i0.l, 6.21i0.l, 6.13i0.l, 5.73i0.l,
4.64i0.l, .l and 3.75i0.l Angstroms, by powder X-ray
diffraction, and is preferably a crystal of non—solvate (e.g.,
anhydrate).
The crystal of the t invention is more preferably a
l g an X—ray powder diffraction pattern having
characteristic peaks at interplanar spacings (d) of l3.59i0.l,
9.22i0.l, 7.88i0.l, 7.48i0.1, 6.76i0.l, 6.21i0.l, 6.13i0.l,
.73i0.l, 5.24f0.l, 5.13i0.l, 4.64i0.1, 4.27i0.1, 4.16i0.1,
3.99i0.l, 3.93i0.l, .l,'3.75i0.l, 3.60i0.l, 3.41i0.l,
2.89i0.l, 2.73i0.l and 2.58i0.l Angstroms, by powder X—ray
diffraction, and is preferably a crystal of lvate (e.g.,
anhydrate).
The crystal of the t invention is further more
preferably a l showing an X—ray powder ction pattern
having characteristic peaks at interplanar spacings (d) of
l3.59i0.1, 9.22i0.l, 7.88i0.l, .l, 6.76i0.l, 6.21i0.l,
6.13i0.l, 5.73i0.l, 5.24i0.l, 5.13i0.l,°4.64f0.l, 4.27i0.l,
4.16i0.l, 4.06i0.l, 3.99i0.l, 3.93i0.l, .1, 3.75i0.l,
.l, .l, 3.l6iO.l, 3.l0i0.l, 3.06i0.l, 2.89i0.l,
2.83i0.l, 2.73i0.l and 2.58i0.l Angstroms, by powder X-ray
diffraction, and is preferably a crystal of non-solvate (e.g.,
anhydrate). The crystal of the present invention is preferably
anhydrous crystal.
[0050]
The crystal of the present invention shows an initial
temperature of about 222 — about 224°C, preferably about 223°C,
of an endothermic behavior caused by melting in DSC
ement under the conditions of temperature increase rate
n, wherein the “about” here means il°C.
The crystal of the present invention shows a peak
temperature of about 223°C — about 225°C, preferably about 224°C,
of an endothermic behavior caused by melting in DSC
measurement under conditions of ature increase rate
°C/min, wherein the “about” here means il°C. The peak
temperature of an endothermic behavior is higher than the
initial temperature.
The crystal of the present invention does not have two or
W0 2012/176934
more endothermic behaviors between room temperature and about
240°C (it has only a peak of an ermic behavior caused by
one melting) in DSC measurement under conditions of
temperature increase rate 5°C/min, wherein the ” here
means il°C.
The purity of the crystal of the t invention is
about 95% — 100%, preferably about'97% — 100%, more preferably
[about 99% — 100%.
[0054]
AThe thus—obtained crystal of the present invention has a
or PDElOA inhibitory action, is low toxic and is useful
as a pharmaceutical product. Moreover, since the crystal of
the present invention is superior in stability, it can be
handled easily and can be processed into a solid
pharmaceutical composition with good reproducibility.
The crystal of the present ion is useful for the
prophylaxis and/or treatment of, for example, the following
es or symptoms, in mammals (e.g., , cows, horses,
dogs, cats, monkeys, mice, rats, etc. ularly humans):
psychotic disorder (e.g., brief psychotic disorder, shared
psychotic disorder);
psychosis induced by alcohol, amphetamine, cannabis,
cocaine, hallucinogens, obesity, inhalants, opioids, or
phencyclidine;
delusional er;
anxiety disorder;
movement disorder;
mood disorder;
major depressive disorder;
a major depressive disorder superimposed on a psychotic
disorder comprising a delusional disorder or schizophrenia;
major depressive episode of the mild, moderate or severe
type;
W0 2012/176934
manic or mixed mood episode;
hypomanic mood episode;
depressive episode with atypical features;
depressive episode with melancholic features;
depressive e with catatonic features;
mood episode with postpartum onset;
post—stroke depression;
mic disorder;
minor depressive disorder;
autism;
drug addiction;
neurodegenerative er;
neurodegeneration associated with cerebral ;
neurodegeneration associated with ;
neurodegeneration ated with cerebral infarct;
hypoglycemia—induced neurodegeneration;
neurodegeneration associated with epileptic seizure;
neurodegeneration associated with neurotoxin poisoning;
multi—system atrophy;
Alzheimer’s disease;
dementia;
infarct dementia;
alcoholic dementia or other drug—related dementia;
dementia associated with ranial tumors or cerebral
trauma;
dementia associated with Huntington’s disease or
Parkinson’s disease;
AIDS—related dementia;
frontotemporal dementia;
delirium;
amnestic disorder;
post—traumatic stress disorder;
mental ation;
learning disorder (e.g., reading disorder, mathematics
disorder, or a disorder of written expression);
attention—deficit/hyperactivity disorder;
age—related cognitive decline;
Ipremenstrual dysphoric disorder;
post-psychotic depressive er of phrenia;
bipolar disorders comprising r I disorder and
bipolar II disorder;
cyclothymic‘disorder;
Parkinsonis disease;
Huntington’s disease;
paranoid;
schizophrenia (e.g., id schizophrenia, disorganized
schizophrenia, catatonic schizophrenia, undifferentiated
phrenia, residual schizophrenia);
schizophreniform disorder;
affective er of the delusional type or the'
depressive type;
personality disorder of the paranoid type;
personality disorder of the schizoid type;
obesity;
metabolic syndrome;
non—insulin ent diabetes mellitus (NIDDM);
glucose intolerance;
and the like, particularly for the prophylaxis and/or
treatment of schizophrenia.
[0056]
The crystal of the present invention is of low toxicity
and can be safely stered orally or non—orally (e.g.,
l, rectal and intravenous administration, etc.), as such
or in the form of pharmaceutical compositions formulated with
a pharmacologically acceptable carrier, e.g., tablets
(including sugar—coated tablets and film—coated tablets),
powders, granules, capsules (including soft capsules), orally
disintegrating tablets, orally disintegrating films, liquids,
injectable preparations, suppositories, sustained—release
preparations and patches, in accordance with a commonly known
W0 2012/176934
method.
The content of the crystal of the present invention in
the pharmaceutical composition is about 0.01 to 100% by weight
of the entire composition. While the dose varies depending on
the subject of administration, administration route, target
disease, symptom and the like, for example, for oral
administration to a patient with schizOphrenia (adult, about
60 kg body weight), a single dose is generally within the
range of about 0.1 — about 20 mg/kg body weight, preferably
about 0.2 — about 10 mg/kg body , more preferably about
0.5 — about 10 mg/kg body weight. Such dose is preferably
administered one - several times (e.g., 3 times) per day.
Pharmacologically acceptable carriers that may be used to
produce the ceutical composition of the present
invention include various c or inorganic carrier
substances in common use as pharmaceutical materials,
including ents, lubricants, binders, disintegrants,
water—soluble rs and basic inorganic salts for solid
preparations; and solvents, lizing agents, ding
agents, isotonizing agents, buffers and soothing agents for
liquid preparations. Other ordinary pharmaceutical ves
such as preservatives, antioxidants, colorants, sweetening
agents, souring agents, bubbling agents, flavorings and the
like may also be used as necessary.
Such “excipients” include, for example, lactose, sucrose,
itol, starch, cornstarch, crystalline cellulose, light
anhydrous silicic acid, titanium oxide and the like.
Such “lubricants” include, for example, magnesium
stearate, e ester of fatty acids, polyethylene glycol,
talc and stearic acid.
[0061]
Such “binders” include, for example, hydroxypropyl
cellulose, hydroxypropyl methylcellulose, crystalline
cellulose, d-starch, nylpyrrolidone, gum arabic powder,
gelatin, pullulan, low—substituted hydroxypropyl cellulose and_
the like.
Such “disintegrants” e (1) crospovidone, (2) what
is called super—disintegrants such as croscarmellose sodium
(FMC—Asahi Chemical) and carmellose calcium (GOTOKU CHEMICAL
CO., LTD.), (3) sodium ymethyl starch (e.g., product of
Matsutani Chemical), (4) bstituted hydroxypropyl
ose (e.g., product of Shin-Etsu Chemical),_(5)"
cornstarch, and so forth. Said “crospovidone” may be any
crosSlinked r having the chemical name l—ethenyl42—
pyrrolidinone homopolymer, including polyvinylpolypyrrolidone
(PVPP) and l—vinyl—Z—pyrrolidinone homopolymer, and is
exemplified by Colidon CL (produced by BASF), Polyplasdon XL
(produced by ISP), Polyplasdon XL—lO (produced by ISP),
Polyplasdon INF—10 (produced by ISP) and the like.
[0063]
Such “water—soluble polymers” e, for example,
ethanol—soluble water—soluble polymers and the like [e.g.,
cellulose derivatives such as hydroxypropyl cellulose
(hereinafter also referred to as HPC), polyvinylpyrrolidone]
and ethanol—insoluble water—soluble polymers [e.g., ose
derivatives such as hydroxypropyl methylcellulose nafter
also referred to as HPMC), methyl cellulose and carboxymethyl
cellulose sodium, sodium polyacrylate, polyvinyl alcohol,
sodium alginate, guar gum and the like].
[0064]
Such “basic inorganic salts” include, for example, basic
nic salts of sodium, potassium, magnesium and/or calcium.
Preferred are basic inorganic salts of magnesium and/or
calcium. More preferred are basic inorganic salts of magnesium.
Such basic inorganic salts of sodium include, for example,
sodium carbonate, sodium hydrogen carbonate, disodium
hydrogenphosphate, etc. Such basic inorganic salts of
potassium include, for example, potassium carbonate, potassium
hydrogen carbonate, etc. Such basic nic salts of
magnesium include, for example, heavy magnesium carbonate,
magnesium ate, magnesium oxide, magnesium hydroxide,
magnesium aluminometasilicate, magnesium silicate, magnesium
aluminate, synthetic hydrotalcite [MgJUQ(OH)m-CO3HMQO] and
aluminum magnesium hydroxide. Among others, red is heavy
magnesium carbonate, magnesium carbonate, magnesium oxide,
magnesium hydroxide, etc. Such basic inorganic salts of
calcium include, for eXample, precipitated calcium carbonate,
calcium hydroxide, etc.
Such nts" include, for example, water for injection,
alcohol, propylene , macrogol, sesame oil, corn oil,
olive oil, etc.
Such “solubilizing agents” e, for example,
polyethylene glycol, propylene glycol, D—mannitol,
benzylbenzoate, ethanol, tris—aminomethane, terol,
triethanolamine, sodium carbonate, sodium citrate and the like.
Such “suspending agents” include, for example,
tants such as stearyl triethanolamine, sodium lauryl
sulfate, lauryl aminopropionic acid, lecithin, benzalkonium
chloride, benzethonium chloride, glycerol monostearate and the
like; hydrophilic polymers such as polyvinyl alcohol,
polyvinylpyrrolidone, sodium carboxymethylcellulose,
methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose,
hydroxypropyl ose etc. and the like.
Such “isotonizing agents” include, for example, glucose,
itol, sodium chloride, glycerol, D—mannitol and the like.
[0069]
Such “buffers” include, for example, buffer solutions of
phosphates, acetates, ates, citrates, etc.
Such “soothing agents” include, for example, benzyl
alcohol and the like.
Such “preservatives” include, for example, p—oxybenzoic
acid esters, butanol, benzyl alcohol, phenethyl alcohol,
dehydroacetic acid, sorbic acid and the like.
[0072]
Such “antioxidants” include, for example, sulfites,
ascorbic acid, d-tocopherol and the like.
Such “colorants” include, for example, food colors such
as Food Color Yellow No. 5, Food Color Red No. 2 and Food
Color Blue No. 2; and food lake colors, red ferric oxide and
the like.
Such “sweetening agents” include, for example, saccharin
, dipotassium glycyrrhetinate, aspartame, stevia,
thaumatin and the like.
Such “souring agents” include, for example, citric acid
(anhydrous citric acid), tartaric acid, malic acid and the
like.
Such ing ” include, for example, sodium
bicarbonate and the like.
Such “flavorings” may be synthetic substances or
naturally occurring substances, and include, for example,
lemon, lime, , menthol, strawberry and the like.
The crystal of the present invention may be prepared as a
preparation for oral administration in accordance with a
commonly known method, by, for example, Ssion—shaping it
in the presence of an excipient, a disintegrant, a binder, a
ant, or the like, and subsequently coating it as
necessary by a commonly known method for the purpose of taste
masking, c dissolution or sustained release. For an
enteric preparation, an intermediate layer may be provided by
a commonly known method between the enteric layer and the
drug—containing layer for the purpose of separation of the two
layers.
[0079]
For preparing the crystal of the present ion as an
orally disintegrating tablet, available methods include, for
example, a method in which a core containing crystalline
cellulose and e is coated with the crystal of the
present ion and a basic inorganic salt, and is further
coated with a coating layer containing a water—soluble polymer
to give a ition, which is coated with an enteric coating
layer containing polyethylene glycol, further coated with an
c coating layer containing triethyl citrate, still
further coated with an enteric coating layer containing
polyethylene glycol, and still yet further coated with
mannitol to give fine granules, which are mixed with additives
and shaped, and the like. The above—mentioned “enteric coating
layer” includes, for example, aqueous enteric polymer
substrates such as cellulose acetate phthalate (CAP),
hydroxypropyl cellulose phthalate, ymethyl
cellulose acetate succinate, methacrylic acid copolymers [e.g.,
Eudragit L3OD—55 (trade name; produced by Rohm), Colicoat
MAEBODP (trade name; produced by BASF), d PA3O (trade
name; produced by Sanfyo Chemical) and the like],
carboxymethyl ethyl ose, shellac and the like;
sustained~release substrates such as methacrylic acid
copolymers [e.g., Eudragit NEBOD (trade name), Eudragit RL3OD
(trade name), Eudragit RSBOD (trade name), etc.] and the like;
water—soluble polymers; plasticizers such as triethyl citrate,
polyethylene glycol, acetylated monoglycerides, triacetine,
castor oil and the like; and mixtures thereof, and the like.
The above-mentioned “additive” includes, for example, watersoluble
sugar alcohols (e.g., sorbitol, mannitol, maltitol,
reduced starch rides, xylitol, reduced palatinose,
erythritol, etc.), crystalline cellulose [e.g., Ceolas KG 801,
Avicel PH 101, Avicel PH 102, Avicel PH 301, Avicel PH 302,
Avicel RC-591 (crystalline cellulose carmellose sodium) and
the like], low-substituted ypropyl cellulose [e.g., LH-
22, LH-32, LH-23, LH-33 (Shin-Etsu Chemical) and mixtures
thereof and the like] and the like; binders, souring ,
ng agents, sweetening agents, flavorings, ants,
colorants, stabilizers, excipients, disintegrants etc. are
also used.
[0080]
The crystal of the present invention can be administered
as the sole active agent or in combination with other
medicaments such as other agents used in the treatment of
psychosis, especially schizophrenia and bipolar disorder,
obsessive-compulsive disorder, major depression, Parkinson’s
disease, Alzheimer’s disease, cognitive impairment and/or
memory loss [e.g., nicotinic ?7 agonists, nicotinic ?7 partial
ts, nicotinic ?7 positive allosteric modulators, PDE2
inhibitors, PDE4 inhibitors, PDE5 inhibitors, other PDE
inhibitors, calcium channel rs, muscarinic m1 and m2
modulators, adenosine receptor modulators, ampakines, Glycine
transporter 1 inhibitors, NMDA-R modulators, mGluR modulators,
dopamine modulators, serotonin modulators, selective serotonin
reuptake inhibitors, serotonin and norepinephrine reuptake
inhibitors, norepinephrine and dopamine ke inhibitors,
triple reuptake inhibitors, cannabinoid modulators, and
esterase tors (e.g., donepezil, rivastigmine, and
galanthamine)]. In such ations, each active ient
can be administered either in accordance with their usual
dosage range or a dose below their usual dosage range, and can
be administered either simultaneously or sequentially.
Drugs suitable in combination with the crystal of the
present ion include, but are not limited to, other
suitable schizophrenia drugs such as Haloperidol, Clozapine,
Olanzapine, Risperidone, razole, Ziprasidone,
Paliperidone, and Quetiapine fumarate; bipolar disorder drugs,
including, but not limited to, Lithium, Olanzapine,
Aripiprazole, and ic acid; Parkinson’s disease drugs,
ing, but not limited to, Levodopa, Bromocriptine,
Pergolide, exole, Tolcapone, Procyclidine,
Trihexyphenidyl, and Benztropine; agents used in the treatment
of major depression, including, but not limited to,
Amitriptyline, Protriptyline, Desipramine, Nortriptyline,
Paroxetine, Fluoxetine, Sertraline, Bupropion, Escitalopram,
Mirtazapine, Venlafaxine, Duloxetine; agents used in the
treatment of Alzheimer’s disease, including, but not limited
to, Galanthamine, Tacrine, Donepezil, Rivastigmine, Memantine,
pin, Selegiline, Estrogen and Iodoquinol; agents used in
the treatment of ia, including, but not limited to,
Thioridazine, Haloperidol, Risperidone, Tacrine, Donepezil,
and igmine; agents used in the treatment of epilepsy,
including, but not limited to, Phenytoin, Phenobarbital,
Carbamazepine, ic acid, Ethosuximide, Gabapentin,
Phenobarbital, Solfeton and Felbatol; agents used in the
treatment of multiple sclerosis, including, but not limited to,
Tolterodine, Oxybutynin, Oxycodone, Interferon ?-1b,
Interferon ?-1a, Azathioprine, Methotrexate and Glatiramer;
agents used in the treatment of Huntington’s disease,
including, but not limited to, Amitriptyline, Protriptyline,
Desipramine, Nortriptyline, Paroxetine, Fluoxetine, Sertraline,
Tetrabenazine, Haloperidol, Chlorpromazine, Thioridazine,
Sulpiride, Quetiapine, Clozapine, and Risperidone; agents used
in the ent of es, including, but not limited to,
PPAR ligands (e.g., agonists, antagonists, such as
Rosiglitazone, Troglitazone and Pioglitazone), insulin
secretagogues (e.g., sulfonylurea drugs, such as Glyburide,
Glimepiride, Chlorpropamide, amide, and Glipizide, and
non-sulfonyl secretagogues), ?-glucosidase inhibitors (e.g.,
Acarbose, Miglitol, and ose), insulin sensitizers (such
as the PPAR-? agonists, e.g., glitazones; biguanides, PTP-1B
inhibitors, DPP-IV inhibitors, and 11?-HSD inhibitors),
hepatic glucose output lowering compounds (such as glucagon
antagonists and metformin, e.g., Glucophage and Glucophage XR),
insulin and n derivatives (both long and short acting
forms and formulations of insulin); and antiobesity drugs,
including, but not limited to, ?-3 agonists, CB-1 agonists,
eptide Y5 inhibitors, Ciliary Neurotrophic Factor and
derivatives (e.g., e), appetite suppressants (e.g.,
Sibutramine), and lipase inhibitors (e.g., Orlistat).
[0081]
The form of administration of concomitant drugs with the
crystal of the t invention is not particularly limited
and is acceptable as long as the l of the t
invention is combined with concomitant drugs at the time of
administration. Examples of such forms of administration are
as follows:
(1) administration of a single formula obtained by
simultaneous formulation of the crystal of the present
ion with a concomitant drug,
(2) aneous administration via the same
administration route for two kinds of formulas obtained by
independent formulations of the crystal of the present
invention and a concomitant drug,
(3) administrations at different times via the same
administration route for two kinds of formulas obtained by
independent formulations of the crystal of the present
invention and a concomitant drug,
(4) simultaneous stration via different
administration routes for two kinds of formulas obtained by
independent formulations of the crystal of the present
invention and a concomitant drug,
(5) administrations at different times via different
stration routes for two kinds Of formulas obtained by
independent formulations of the crystal of the present
ion and a itant drug (e.g., administration in the
order of the crystal of the present invention and then a
concomitant drug, or administration in the reversed order).
These forms of administration are summarized below and
abbreviated as a itant agent of the present invention.
When administering the concomitant agent of the t
invention, a itant drug_and the crystal of the present
inventiOn can be stered at the Same time, but the
crystal of the present invention can be administered after a
concomitant drug is administered or after the crystal of the
present invention is administered, a concomitant drug can be
administered. When administering at different times, the time
difference depends upon the active ingredients to be
administered, drug forms and methods of administration. For
example, when a itant drug is administered first, the
crystal of the present invention can be administered within 1
min to 3 days, preferably within 10 min to 1 day and more
preferably within 15 min to 1 hour after the concomitant drug
is administered. However, if the crystal of the present
invention is administered first, a concomitant drug can be
administered within 1 min to 1 day, preferably within 10 min
to 6 hours and more preferably within 15 min to 1 hour after
the crystal of the present invention is administered.
If there are no problems with side effects of the
concomitant drugs, any dosages can be set. A daily dosage as a
concomitant drug depends upon dosages, administration subjects,
administration , target diseases, symptoms, etc. For
example, in the case of oral administration in patients with
schizophrenia s, bodyweight of approximately 60 kg), a
normal daily dosage ranges from about 0.1 to about 20 mg/kg
bodyweight, preferably from about 0.2 to about 10 mg/kg
bodyweight and more ably from about 0.5 to about 10
mg/kg bodyweight. It is preferable that this dosage is
administered once daily to l times daily (e.g., 3 .
If the crystal of the present invention is used in
combination with a concomitant drug, the respective s
can be d within a safe range with consideration of the
opposite effects of the respective drugs.
The concomitant agent of the present invention exhibits
low toxicity. For e, the crystal of the present
invention or(and) the aforementioned concomitant drug can be
combined with a pharmaceutically acceptable carrier according
to the known method to prepare a pharmaceutical composition
such as tablets (including sugar—coated tablets and film—
coated tablets), powder agents, granular , capsules
(including soft capsules), liquids, injection solutions,
suppositories, sustained—release agents, etc. These
compositions can be administered safely orally or non—orally
(e.g., including topical, rectal and enous routes).
_[OO84]
The pharmaceutically acceptable carriers that can be used
for manufacturing the concomitant agent of the present
invention can be the same as those used in the pharmaceutical
composition of the present invention as mentioned above.
A mixing ratio n the crystal of the present
invention and a concomitant drug in the concomitant agent of
the t invention can be selected appropriately based on
the administration subjects, administration routes and
diseases.
The aforementioned concomitant drugs can be combined at
an appropriate ratio if two or more drugs are combined.
A dosage of the concomitant drug can be selected
appropriately based on the dosages used clinically. In
addition, a mixing ratio n the crystal of the present
invention and a concomitant drug can be selected appropriately
based on the administration subjects, administration routes,
target diseases, ms, combinations, etc. For example, if
the administration subject is humans, a concomitant drug can
be used in an amount ranging from 0.01 tb 100 parts by weight
relative to 1 part by weight of the crystal of the present
ion.
For example, the content of the crystal of the present
invention in the concomitant agent of the present invention
varies with the form of formulations. lly, it is present
in a range from about 0.01 to 99.9 wt%, preferably from about
0.1 to 50 wt% and more preferably from about 0.5 to 20 wt%
relative to the entire formula.
The content of a concomitant drug in the concomitant
agent of the present invention varies with the form of
.formulations. Generally-it is present in a range from about
0.01 to 99.9 wt%, preferably from about 0.1 to 50 wt% and more
preferably from about 0.5 to 20 wt% relative to the entire
formula.
The content of an ve such as carriers in the
concomitant agent of the present ion varies with the
form of formulations. lly it is present in a range from
about 1 to 99.99 wt% and preferably from about 10 to 90 wt%
relative to the entire formula.
When the crystal of the present invention and a
concomitant drug are formulated independently, the same
contents can be applied.
Since the s may fluctuate under various conditions
as mentioned above, a dosage less than the aforementioned
s may be sufficient or it may be ary to administer
at a dosage exceeding the range.
Examples
IThe present ion is explained in detail by referring
to the following Reference Examples, Examples, Formulation
Examples, and Experimental es. These examples are mere
embodiments, which do not limit the present invention, and can
be modified within the range not deviating from the scope of
the present invention.
The “room temperature” in the following Reference
Examples and-Examples is generally about 10°C to about 35°C. 0
in the yield means mol/mol%, O
6 of solvent used for
chromatography means % by volume, and % used for others means
wt%. In proton NMR spectrum, OH and NH protons and the like
that cannot be identified since they are broad bands are not
recorded in the data. In silica gel chromatography, silica gel
60 (230—400 mesh) manufactured by Merk & Co., Inc. was used,
and aminopropylsilane—bonded silica gel atorex NH
manufactured by Fuji SilySia Chemical Ltd.) was used for basic
silica gel chromatography described as “NH silica gel”.
Other abbreviations used in the text mean the following.
: singlet
d: doublet
dd: doublet of doublets
dt: t of triplets
t: triplet
tt: triplet of triplets
td: t of doublets
q: quartet
septet: septet
m: multiplet
br: broad
J: coupling constant
Hz: Hertz
WC 2012/176934
CDCl3: deuterated chloroform
DMSO—d6: deuterated dimethyl sulfoxide
1H NMR: proton r magnetic resonance
HPLC: high performance liquid chromatography
THF: tetrahydrofuran
DMF: N,N*dimethylformamide
DMSO: dimethyl ide
IPE: isopropyl ether
DMA: N,N—dimethylacetamide
DIPEA: N,N—diisopropylethylamine
Pd2(dba)3: tris(dibenzylideneacetone)dipalladium(0)
LC—MS: liquid chromatography—mass spectrometry spectrum
ESI: electrospray—ionization method
API: atmospheric pressure ionization method
[0092]
All reagents and solvents were of commercial y and
used without further cation. The compounds and/or
intermediates were purified by preparative high performance
liquid chromatography (prep. HPLC) using a Gilson High through
Put purification system.
The columns Were reversed phase YMC CombiPrep Pro C18, S-
um, 19 x 50 mm. A gradient elution was used (flow rate 20
), typically starting with 5% acetonitrile/95% water and
progressing to 100% acetonitrile over a Period of 7 minutes.
All solvents contained 0.1% trifluoroacetic acid (TFA).
Mass ometric analysis was performed according to
liquid chromatography/mass spectroscopy (LCMS) methods. The
method employed a Waters LC—MS System (Agilent HPllOO HPLC and
a Micromass ZMD mass spectrometer for the LCMS instrument, a
CAPCELL PAK C18, UGlZO, s—3 m, 1.5 x 35 mm for the
chromatography ), and a solvent system that was a 5-95%
gradient of acetonitrile in water with 0.04% TFA (flow rate
0.5 mL/min; molecular weight range 200—800; cone Voltage 20 V;
column temperature 40°C). All masses were reported as those of
the protonated parent ions.
Powder X—ray diffraction analysis was measured Using RINT
Ultima—IV (manufactured by Rigaku Corporation).
Differential ng calorimetry (DSC) was measured
using a differential scanning calorimeter (DSCl (manufactured
by r-Toledo)) at a temperature rise rate 5°C/min within
the range of 25°C to 240°C.
Heating was performed by Heatblock (manufactured by
TAITEC CO., Ltd.).
Reference Example 1—1j
Crystal of l-7—methyl—3—{4—I(3~methyl—3H—imidazo[4,5?
b]pyridin—2-yl)oxy]phenyl}—1,3—dihydro—2H—imidazo[4,5—
bprridinf2—one (Form A)
a)3—[4—(benzyloxy)phenyl]—7-methy1—1,3—dihydro—2H—imidazo[4,5—
in—Z—one
N fi\%
6%,,,,,,,,,hf as.
%..........4}"NkrNH
A mixture of tertvbutyl (2—chloro—4~methylpyridin—3—
yl)carbamate (2.00 g), 4—(benzyloxy)aniline hydrochloride
(2.91 g), 9,9—dimethyl—4,5—bis(diphenylphosphino)xanthene (381
mg), sodium tert—butoxide (1.90 g) and Pd2(dba)3 (302 mg) in 2~
propanol (6 mL) and toluene (24 mL) was stirred under a
nitrogen atmosphere at 100°C for 24 hr. The reaction mixture
was concentrated under reduced re. The residue was
dissolved in methanol, and the precipitates were filtered off.
The filtrate was concentrated, and the residue was purified by
column chromatography (NH silica gel, eluted with 15% — 50%
ethyl acetate in hexane) to give 3;[4—(benzyloxy)phenyl]—7§
methyl—1,3—dihydro—2H—imidazo[4,5—b]pyridin~2—one (988 mg) as
a colorless solid.
MS (API+): [M+H]+ 332.3.
1H NMR (300 MHz, 00013) 5 2.39 (3H, s), 5.12 (2H, s), 6.87 (1H,
d, J = 5.3 Hz), 7.12 (2H, d,‘J = 9.0 Hz), 7.28—7.50 (5H, m),
7.57 (2H, d, J z 8.7 Hz), 7.96 (1H, d, J =’5.3 Hz), 9.93 (1H,
brs).
b) 3—[4—(benzyloxy)phenyl]—1—ethyl—7—methyl—1,3*dihydro—2H-
imidazo[4,5—b]pyridin—2—one
Iodoethane (0.289 mL) was added to a mixture of 3—[4—
(benzyloxy)pheny1]—7—methyl—1,3—dihydro-2H-imidazo[4,5—
b]pyridin52—one (998 mg) and cesium carbonate (1.96 g) in DMF
(10 mL) at room temperature. The mixture was d at 50°C
for 4 hr. The mixture was diluted with water at room
temperature, and the mixture was extracted with ethyl acetate.
The organic layer was separated, washed with water and brine,
dried over magnesium sulfate, and then concentrated under
reduced pressure. The residue was purified by column
chromatography (silica gel, eluted with 15% — 30% ethyl
acetate in ) to give 3—[4—(benzyloxy)phenyl]—1—ethyl—7—
methyl—1,3-dihydro—2H—imidazo[4,5—b]pyridin—2—one(801 mg) as a
white solid.
MS (API+): [M+H]+ 360.4.
1H NMR (300 MHz, c0c13) 5 1.41 (3H, t, J = 7.2 Hz), 2.61 (3H,
s), 4.19 (2H, q, J'= 7.2 Hz), 5.11 (2H, s), 6.81 (1H, d, J =
.3 Hz), 7.10 (2H, d, J = 8.7 Hz), 7.30—7.47 (5H, m), 7.53 (2H,
d, J = 9.1 Hz), 7.91 (1H, d, J = 5.3 Hz).
[0100]
c) 1—7—methyl—3—{4—[(3—methyl~3H—imidazo[4,5-b]pyridin—
2—yl)oxy]phenyl}~1,3—dihydro—2H—imidazo[4,5—b]pyridin—2—one
w") __\ ’fi
N’”“O~<J~ll
57/ \
o r
A mixture of 3—[4—(benzyloxy)phenyl]—l—ethyl—7—methyl-
1,3—dihydro—2H—imidazo[4,5—b]pyridin—2—one (800 mg) and 10%
Pd—C (118 mg) in ethanol (20 mL) was hydrogenated overnight
under a balloon pressure at room temperature. The catalyst was
filtered off, and the filtrate was concentrated in vacuo to
give l—B—(4-hydroxyphenyl)—7—methyl~1,3—dihydro—2H—
imidazo[4,5—b]pyridin-2—one as a colorless solid. To a mixture
of this solid and 3—methyl—2-(methylsulfonyl)—3H—imidazo[4,5—
bprridine (480 mg) in DMF (10 mL) was added 60% sodium
hydride (58.9 mg) at 100°C. The mixture was heated under
microwave irradiation at 180°C for 30 min. The on
mixture was diluted with methanol and concentrated in vacuo.
The e was purified by column chromatography (NH silica
gel, eluted with 30% — 50% ethyl acetate in hexane, and silica
gel, eluted-with 15% — 30% ethyl acetate in hexane). The crude
nce was purified by HPLC (C18, eluted with
water/acetonitrile containing 0.1% trifluoroacetic acid). To
the obtained solution was added aqueous ted sodium
hydrogen carbonate, and the mixture was extracted with ethyl
acetate. The extract was dried over magnesium sulfate, and
then trated in vacuo to give l~ethyl—7-methyl—3—{4—[(3—
methyl—3H—imidazo[4,5—b]pyridin—2~yl)oxy]phenyl}—l,3*dihydro—
2H—imidazo[4,5—b]pyridin—2—one (119 mg) as colorless crystals
(Form A).
MS (API+): [M+H]+ 401.3.
Reference Example 1-2
Crystal of l—ethyl—7—methyl—3—{4—[(3—methyl—3H—imidazo[4,5-
b] pyridin—Z-yl) oxy] phenyl } —1, 3—dihydro—2H—imidazo [4, 5—
din—2—one (Form A)
a) 1~ethyl—3-(4—hydroxyphenyl)~7—methyl~1,3-dihydro—2H—
imidazo[4,5-b]pyridin~2—one‘
[0105]
m— {in21:»
”our________x;x N :5
o i
A mixture of 3—[4—(benzyloxy)pheny1]—1—ethy1—7—methyl—
1,3—dihydro—2H—imidazo[4,5—b]pyridin—2—one (21.4 g) and 10%
Pd—C (3.17 g) in ethanol (400 mL) was hydrogenated under a
n pressure at room temperature for 2 hr. The catalyst
was ed off, and the filtrate was concentrated in vacuo.
The solid was washed with THF—hexane to give 1—ethy1—3—(4-
hydroxyphenyl)—7-methyl-1,3-dihydro—2H-imidazo[4,5—b]pyridinf
2—one (10.90 g) as a solid.
Ms (API+): [M+H]+ 270.4.
_b) 1*ethyl—7—methyl—3—{4—[(3—methyl—3H—imidazo[4,5tb]pyridin—
2—y1)oxy]pheny1}—1,3—dihydro-2H—imidazo[4,5—b]pyridin—2—one
[0108]
Q"? '—"\ ”firl“
«frag
1 2;
I?” 7
To a solution of 3—methyl—2—(methylsulfony1)—3H—
imidazo[4,5—b]pyridine (1.0 g) and 1-ethyl-3—(4—
hydroxyphenyl)—7—methy1—1,3—dihydro—2H~imidazo[4,5—b]pyridin—
2—0ne (1.3 g) in DMF (10 mL) was added 60% sodium hydride
(0.23 g) at room temperature, and the mixture was stirred
under microwave irradiation at 180°C for 30 min. To the
mixture was added ethanol (10 mL). The formed crystals were
collected by filtration, and washed with ethanol. This
microwave reaction was repeated two additional times using the
same amount of starting materials. The combined crystals were
recrystallized from ethanol containing 5% distilled water (270
m1) and dried under reduced pressure to give l-7—methyl—
3—{4-[(3—methyl—3H—imidazo[4,5-b]pyridin—2—y1)oxy]pheny1)—1,3—
dihydro—ZH—imidazo[4,5-b]pyridin—2—one (3.3 g) as white
crystals (Form A).
MS (API+): [M+H]+ 401.3.
1H NMR (300 MHZ, DMSO—de) 5 1.32 (311, t, J = 7.2 Hz), 2.61 (3H,
s), 3.77 (3H, s), 4.12 (2H, q, J = 7.2 Hz), 7.00 (1H, d, J =
.7 Hz), 7.20 (1H, dd, J ='.7.>'9, 4.9 Hz), 7.58—7.66 (2H, m),
7.71-7.78 (2H, m), 7.80 (1H, dd, J = 7.9, 1.1 Hz), 7.87 (1H, d,
J = 4.9 Hz), 8.22 (1H, dd, J = 4.9, 1.5 Hz).
Anal. Calcd for C3H2&%02: C, 65.99; H, 5.03; N, 20.99. Found: C,
65.76; H, 5.07; N, 20.85.
The ement s of powder X—ray diffraction of
Form A crystals obtained in Reference Example 1—1 are shown in
'20 the following Table 1 and Fig. 1.
[Table 1]
Powder X~ray diffraction data (Form A crystals)
2 9 (O ) d value CA) relative intenSit§
_ (%71
7.88 3 5
9-5 9.302 26
.9 8.1102 38
14.06 6.2937 8
14.58 6.0704 11
.74 5.6255 . 57
16.14 5.487 22
16.76 5.2854 . 10
18.3 4.8439 _ 81
19.6 4.5255 6
-3 4.371 61
21.22 .4.1835 6
21.84 4.0661 12
22.3 3.9833 10
22.76 3.9038 14
23.72 3.7479 19
24.68 3.6043 58
.36 3.5092 23
26.32 3.3833 11
27.1 3.2877 6
27.7 3.2178 100
28.36 3.1444 12
29.94 2.982 3
.48 2.9304 3
.9 2.8915 5
31.7 2.8203 5
32.84 2.725 3
33.14 ,2-701 3
33.94 2.6391 4 J
Reference Example 2
Crystal of l—ethy1—7—methyl—3—{4—[(3—methyl—3H—imidazo[4,5—
b]pyridin*2—yl)oxy]phenyl}—l,3—dihydro—2H—imidazo[4,5—
b]pyridin—2—one (Form B)
The crystals of l~ethyl—7—methyl—3—{4—[(3—methyl—3H—
imidazo[4,5—b]pyridin—2—yl)oxy]phenyl}-l,3—dihydro—2H—
imidazo[4,5~b]pyridin~2—one (Form A) (20 mg, 0.05 mmol)
obtained in Reference Example 1—1 were mixed with acetonitrile
(3 mL), and dissolved at an inside temperature of 60°C. This
solution was filtered through a filter with 0.22 pm pore size,
and cooled to 0 ~ 5°C with stirring. The e was stirred
for 8 hr in a cooled state at O — 5°C. The crystals were
collected by tion to give l—ethyl—7*methyl—3-{4~[(3—
methyl—3H—imidaio[4,5—b]pyridin—2—yl)oxy]phenyl}—l,3—dihydro—
2H—imidazo[4L5-b]pyridin—2—one als of Form B).
The measurement results of powder X—ray diffraction of
the obtained crystals are shown in the following Table 2 and
Fig. 2.
[Table 2]
Powder X—ray diffraction data (Form B crystals)
r—-—
2 6 (o ) d value (A) relative ity (%)
4.82 18.3182 ' 37
.12 » 17.2455 19
.5 . 15.7584 12
.7 15.492 11
.08 1 14.5245 7
9.25 9.5425 20
9.52 9.1852 17
.22 8.5482 13
11.34 ‘ 7.7955 96
11.35 7.7828 100
11.92 7.4184 23
.7 5.5398
15_9 5.5593 5
17.18 5.1571 4
18.54 4.7553 6
22.88 3.8835 12
24.58 3.5187 7
24.72 3.5985 11
3.5589 5
.02 3.4215 6
29.85 2.9898 6
29.98 2.9781 6
.1 2.9555 5
.25 2.9512 7
Reference Example 3
Crystal of l—ethyl—7—methyl—3—{4—[(3-methyl-3H-imidazo[4,5—
b]pyridin—2—yl)oxy]phenyl}—l,3*dihydro—2H—imidazo[4,5—
in—Z—one (Form D)
The crystals of l—ethyl—7—methyl—3—{4~[(3—methyl—3H—
imidazo[4,5—b]pyridin—2—yl)oxy]phenyl}—l,3—dihydro—2H—
imidazo[4,5—b]pyridin—2—one (Form A) (20 mg, 0.05 mmol)
obtained in Reference Example l~l were mixed with
trifluoroethanol (0.5 mL) and dissolved at room temperature.
oroethanol was evaporated under a nitrogen stream while
cooling to O — 5°C. The crystals were collected by filtration
to give l—ethyl—7—methyl—3—{4—[(3—methyl~3H-imidazo[4,5—
b]pyridin—2—yl)oxy]phenyl}~l,3—dihydro—2H—imidazo[4,5—
b]pyridin—2~one (crystals of Form D).-
The measurement results of powder X~ray diffraction of
the obtained crystals are shown in the following Table 3 and
Fig. 3.
[Table 3]
Powder X—ray diffraction data (Form D ls)
2 9 (o ) d value (A) relative intensity (%)
L_—_i
,72 15.4378 12
11.52 7.6757 100
11.96 7.3937 13
12,4 7.1323 24
.62 5.6685 14
16.26 5.4468 8
16.52 5.3616 11
19.28 4.5999 7
23.26' 3.821 18
24.18 3.6777 ’ 29
24.56 3.6216 11
24.68 3.6043 10
.54 3.4848 10
26.28 3.3884 13
26.5 3.3607 18
28.14 3.1685 10
29.82 2.9937 8
29.92 2.9839 7
.2 2.9569 9
31.18 2.8661 4 __J
Reference Example 4
l of l—7—methyl~3—{4w[(3—methyl—3H—imidazo[4,5—
b]pyridin-2+yl)oxy]phenyl}—l,3—dihydro—2H—imidazo[4,5~
b]pyridin—2—one (Form E)
The crystals of lrethyl—7—methyl—3—{4-[(3—methyl—3H—
imidazo[4,5—b]pyridin—2-yl)oxylphenyl}—l,3—dihydro—2H—
imidazo[4,5—b]pyridin—2—one (Form A) (20 mg, 0.05 mmol)
obtained in Reference Example 1—1 were mixed with acetone (4
mL) and dissolved at inside temperature 50°C. This solution
was filtered through a filter with 0.22 um pore size, water (3'
mL) heated to 50°C was added, and cooled to"0 e 5°C with
stirring. The mixture was stirred for 8 hr in a cooled state
at O — 5°C. The crystals were collected by filtration to give
l-ethyl—7—methyl—3-{4—[(3—methyl—3H—imidazo[4,5—b]pyridin—2—
yl)oxy]phenyl}—l,3-dihydro~2H—imidazo[4,5—b]pyridin~2—one
(crystals of Form E). -
The measurement results of powder X—ray ction of
the obtained crystals are shown in the following Table 4 and
Fig. 4.
[Table 4]
WO 76934
Powder Xeray diffraction data (Form E crystals)
2 6 (o ) d value (21) ve intensity (%)
,64 15.6566 15
11.32 7.8102 100
11_9 7.4308 4
,4 5.749 1
17.02 5.2052 3
.06 4.4227 1
.32 4.3667 1
22.76 3.9038 4
23.92 3.7171 1
24.5 3.6304 1
.52 3.4875 2
26.04 3.419 1
28.6 3.1186 1
29.96 2.98 3
.26 2.9512 2
30_9 2.8915 2
34.48 2.599 2
Reference Example 5
Crystal of l—ethyl—7—methyl~3—{4—[(3Fmethyl—3H—imidazo[4,5—
b]pyridin—2~yl)oxy]phenyl}—l,3—dihydro—2H—imidazo[4,5—
b]pyridin—2—one (Form F)
The crystals of l—ethyl—7-methyl-3—{4—[(3—methyl—3H—
imidazo[4,5—b]pyridin—2—yl)oxy]phenyl}—l,3—dihydro-2H—
imidazo[4,5-b]pyridin—2—one (Form A) (20 mg, 0.05 mmol)
obtained in Reference Example 1—1 were mixed with anol
(10 mL) and dissolved at inside temperature 60°C. This
solution was filtered through a filter with 0.22 um pore size,
n—heptane (10 mL) heated to 60°C was added, and cooled to 0 -
°C with stirring. The mixture was stirred for 8 hr in a
cooled state at 0 — 5°C. The crystals were collected by
filtration to give l—ethyl—7-methyl—3-{4—[(3-methyle3H—
imidazo[4,5-b]pyridin~2—yl)oxy]phenyl}-l,3—dihydro—2H—
imidazo[4,5—b]pyridin—2*one (crystals of Form F).
The measurement results of powder X—ray diffraction of
the obtained crystals are shown in the following Table 5 and
Fig. 5.
[Table 5]
Powder X—ray diffraction data (Form F crystals)
2 6 (0 ) d value (A) relativelintensity (%)
7_33 11 9687 5 *ii
.42 8 4827 100
14.32. , 6.18 3
14.86 6.9666 2
16.66 6.3488 3
.92 4.2428 6
.98 4.2308 5
22.28 3.9868 2
23_5 3.7826 6
23.78 3.7386 4
,5 3.4902 2
26.98 3.4268 2
26.82 3.3214 18
27.62 3.2269 2
31.66 2.8238 12
33.44 2.6774 2
Reference Example 6
Crystal of l—ethyl—7—methyl—3-{4—[(3-methyl—3H—imidazo[4,5—
in—Z-yl)oxy]phenyl}—l,3—dihydro—2H—imidazo[4,5—
b]pyridin—2—one variable hydrate (Form H)
The crystals of l—ethyl—7—methyl—3—{4—[(3—methyl-3H—
imidazo[4,5—b]pyridin—2~yl)oxy]phenyl}—l,3-dihydro~2H—
o[4,5-b]pyridin—2—one (Form A) (20 mg, 0.05 mmol)
obtained in Reference Example 1—1 were mixed with
acetonitrile/water (9:1) (1 mL) and the mixture was stirred at
room temperature for a week. The crystals were collected by
filtration to give 1—ethyl—7—methyl—3~{4—[(3—methyl—3H—
imidazo[4,5—b]pyridin—Z—ylfoxy]phenyl}—1,3-dihydro—2H—
o[4,5—b]pyridin-2—one variable hydrate (water content of
the variable hydrate varied within the range of about 4 —
about 14 wt%) (crystals of Form H).
The measurement results of powder X—ray diffraction of
the obtained ls are shown in the following Table 6 and
Fig. 6.
[Table 6]
Powder X—ray diffraction data (Form H crystals}
relative intensity (%)
6.06 14.5724 23
7.9 11.182 ' 4
9.24 9.5631 18
.96 8.0659 28
.86 5.5832 29
16.2 5.4668 5
17.14 ' 5.1691
17.76 4.99 4
18.62 4.7614 ~ 9
.42 4.3456 12
24.04 3.6988 8
24.8 3.5871 100
26.54 3.3558 29
27.2 3.2758 .24
27.54 3.2361 6
29.28 3.0477 3
29.6 3.0154 9
31.46 2.8413 6
33.48 2.6743 5
nce Example 7
Crystal of l-ethyl—7—methyl—3—{4~[(3—methyl—3H-imidazo[4,5—
bprridin—Z—yl)oxy]phenyl}—l,3—dihydro—2H—imidazo[4,5—
b]pyridin—2-one monohydrate (Form I)
The crystals of l—ethyl—7—methyl—3—{4—[(3—methyl—3H-
imidazo [4 , 5—b] pyridin—2—yl) oxy] phenyl } ~l
, 3—dihydro—2H—
imidazo[4,5—b]pyridin—2-one (Form A) (20 mg, 0.05 mmol)
obtained in Reference Example 1—1 were mixed with
ethanol/water (9:1) (1 mL) and the mixture was stirred at room
ature for a week. The crystals were collected by
filtration to give l—ethyl—7—methyl—3-{4—[(3—methyl—3H—
imidazo[4,5—b]pyridin—2—yl)oxy]phenyl}—l,3—dihydro—2H—
imidazo[4,5—b]pyridin—2~one monohydrate (crystals of Form I).
The measurement results of powder X—ray diffraction of
the obtained ls are shown in the following Table 7 and
Fig. 7.
[Table 7]
VV()2012/176934
Powder X—ray diffraction data (Form I ls)
2 9 (° ) d value (A) relative intensity (%)
8.24 10.7213 11
.6 8.339 41
11.44 7.7285 33
12.64 6.9974 5
13.72 6.4489 17
13.94 6.3476 12
14.7 6.0211 16
.64 5.6613 50
17.68 5.0124 20
18.46 . 4.8023 31
18.96 4.6768 6
.62 4.3039 19
» 20.92 4.2428 6
22.62 3.9277 12
22.92 3.8769 8
23.16 3.8373 5
24.5 3.6304 10
.52 3.4875 100
26.1 3.4113 37
27.72 3.2155 42
29.6 3.0154 8
29.78 2.9976 22
Example 1
l of l—ethyl—7—methyl*3~{4—[(3—methyl—3H—imidazo[4,5—
b]pyridin—2—yl)oxy]phenyl}—l,3—dihydro—2H~imidazo[4,5—
b]pyridin—2—one (Form G)
(l) The crystals of l—ethyl—7-methyl—3—{4—[(3-methyl—3H—
imidazo[4,5—b]pyridin—2—yl)oxy]phenyl}~1,3—dihydro—2H-
imidazoI4,5—b]pyridin—2—one (Form A: 100 mg) were dissolved in
ethanol (20 mL) at 80°C, and the solution was allowed to cool
to room temperature. The mixture was stirred at room-
W0 2012/176934
temperature for 350 hr. The solids were collected by
filtration to give l~7*methyl-3—{4-[(3~methyl—3H-
imidazo[4,5—b]pyridin—2—yl)oxy]phenyl}—l,3~dihydro—2H—
o[4,5~b]pyridinone (50 mg) as crystals (Form G).
(2) The crystals of l—ethyl-7~methyl—3—{4—[(3—methyl—3H—
imidazo[4,5—b]pyridin—2—yl)oxy]phenyl}—l,3—dihydro~2H~
imidazo[4,5—b]pyridin—2-one (Form A: 40.0 g) were dissolved in
DMSO (400 mL) at 95°C, and the solution was allowed to cool to
85°C. To the solution was slowly added ethanol (400 mL) at
85°C, and the mixture was allowed to cool to 80°C. To the
solution was added a seed l (Form G, 50 mg) at 80°C. The
mixture was stirred and maintained at 73°C for 20 hr. Thef'
solids were collected by filtration, and washed with ethanol
(500 mL) to give l—7-methyl-3—{4—[(3—methyl-3H*
'imidazo[4,5—b]pyridin—2—yl)oxy]phenyl}—1,3—dihydro—2H—
imidazo[4,5—b]pyridin—2—one (19.5 g) as white crystals (Form
Example 2
Crystal of l—ethyl—7—methyl—3—{4—[(3—methyl—3H—imidazo[4,5-
bprridin—Z-yl)oxy]phenyl}—l,3—dihydro—2H—imidazo[4,5—
b]pyridin—2~one (Form G)
The crystals of l—ethyl-7—methyl—3—{4—[(3—methyl—3H—
imidazo[4,5—b]pyridin-2—yl)oxy]phenyl}—l,3—dihydro-2H—
o[4,5—b]pyridin—2—one (Form A: 600 mg) were d in
ethanol (60 mL) at room temperature for 168 hr. The solids
were collected by filtration to give l—ethyl—7—methyl—3—{4—
[(3—methyl—3H—imidazo[4,5—b]pyridin—2—yl)oxy]phenyl}—l,3—
dihydro—2H-imidazo[4,5—b]pyridin—2—one (350 mg) as crystals,
(Form G).
M8 (APl+): [M+H]+ 401.1.
1H NMR (400 MHz, DMSO—d6) 5 1.25—1.38 (3H, m), 2.61 (3H, s),
3.78 (3H, s), 4.04—4.18.(2H, m), 6.96—7.04 (1H, m), 7.17—7.25
(1H, m), 7.59—7.66 (2H, m), 7.71—7.77 (2H, m), 7.78—7.83 (1H,
m), 7.85—7.91 (1H, m), 8.16—8.28 (1H, m).
Anal. Calcd for Cszfikozz C, 65.99; H, 5.03; N, 20.99. Found: C,
65.73; H, 5.12; N, 20.85.
Example 3
Crystal of 1—ethyl—7—methyl~3—{4—[(3-methyl—3H—imidazo[4,5—
b]pyridin—2—yl)oxy]phenyl}—1,3—dihydro—2H—imidazo[4,5—
b]pyridin—2;one (Form G)
The crystals (3.0 g) of l—ethyl*7—methyl—3—{4~[(3—methyl—
3H-imidazo[4,5—b]pyridin—2—yl)oxy]phenyl}—l,3—dihydro—2H—
imidazo[4,5—b1pyridin—2—one obtained in Example 7 a) were
dissolved in DMSO (33 mL) at 90°C. To the solution was slowly
added ethanol (30 mL) at 80 — 90°C. The l (Form G)
obtained in Example 2 was added as a seed crystal at 80 — 90°C.
The mixture was stirred at 60 — 65°C for 6 hr, and at room
temperature for 18 hr. The solids were collected by filtration,
and washed with ethanol (15 mL) to give l—7—methyl—3-{4-
[(3—methyl—3H—imidazo[4,5—b]pyridin—2—yl)oxy]phenyl}—1,3—
dihydro-2H—imidazo[4,5-b]pyridin-2—one (1.3 g) as white
crystals (Form G).
[0127]
Example 4
Crystal of l—ethyl—7—methyl—3—{4—[(3—methyl—3H—imidazo[4,5—
b]pyridin—2—yl)oxy]phenyl}—l,3—dihydro—2H—imidazo[4,5-
b]pyridin—2—one (Form G)
The crystals (3.0 g) of l—ethyl—7—methyl—3—{4—[(3—methyl—
3H—imidazo[4,5-b]pyridin~2—yl)oxy]phenyl}—1,3fdihydro-2H—
imidazo[4,5—b]pyridin~2—one obtained in Example 7 a) were
dissolved in DMSO (33 mL) at 90 — 95°C. To the on was
slowly added ethyl acetate (30 mL) at 70 — 90°C. The crystal
(Form G) obtained in e 3 was added as a seed crystal at
80 — 90°C. The mixture was d at 45 — 50°C for 25 min and
at 70 — 75°C for 3 hr. The mixture was cooled to O — 5°C, and
stirred for 1 hr. The solids were collected by filtration and
washed with ethyl acetate (15 mL) to give l~ethyl—7—methyl—3—
{4—[(3—methyl—3H—imidazo[4,5—b]pyridin—2—yl)oxy]phenyl}—l,3—
dihydro—ZH—imidazo[4,5—b]pyridin-2—one (2.6 g) as crystals
(Form G).
Example 5
l of l-ethyl~7-methyl—3—{4—[(3—methyl-3H—imidazo[4,5-
b]pyridin—2—yl)oxy]phenyl}—1,3—dihydro—2H—imidazo[4,5—
bprridin—Z—one (Form G)
A solution of 3—methyl—2-(methylsulfonyl)—3H—imidazo[4,5-
b]pyridine (20.4 g, 96.55 mmol) in DMA (117 mL) was added to a
solution of l—ethyl—3—(4—hydroxyphenyl)—7—methyl—l,3—dihydro—
2H~imidazo[4,5—b]pyridin—2—one (26.0 g, 96.55 mmol) and
potassium tert—butoxide (11.4 g) in DMA (96 mL) at room
temperature. The mixture was stirred at 95 - 100°C for 1.5 hr.
Water (221 mL) was added at 80 — 100°C. The precipitates were
collected at room temperature and dried under d pressure
to give 1—ethylmethy1-3—{4—[(3—methyl-3H—imidazo[4,5—
b]pyridin—2*yl)oxy]phenyl}—l,3—dihydro—2H—imidazo[4,5—
b]pyridin—2—one (35.8 g) as a crude t.
The crude 1-ethyl—7—methyl—3—{4—[(3—methyl—3H—
imidazo[4,5—b]pyridin—2—yl)oxy]phenyl}—l,3—dihydro—2H—
imidazo[4,5—b]pyridin—2—one (10.0 g) was dissolved in DMSO
(150 mL) at 90 — 100°C. The solution was filtered through a
ipaper filter, and washed with DMSO (10 mL). The combined
filtrate was slowly added to a e of the crystals (Form
GE 100 mg) (as a seed l) obtained in Example 4 in ethyl
acetate (100 mL) at 5 — 30°C. The mixture was stirred at room
temperature for 17 hr and at 70°C for 1 hr. The mixture was
slowly cooled to 25°C and stirred for 2 hr. The mixture was
stirred at O — 10°C for 1 hr, and at room temperature for 1 hr.
The solids were ted by filtration, and dried under
reduced pressure at 50°C to give l~ethyl—7—methyl~3—{4—[(3—
methyl+3H-imidazo[4,5—b]pyridin—2—yl)oxy]phenyl}—1,3—dihydro—
2H—imidazo[4,5—b]pyridin~2—one (8.0 g) as white crystals (Form
[0129]
Example 6
Crystal of 1-ethyl-7~methyl-3—{4~[(3—methyl—3H—imidazo[4,5—
b]pyridin—2—yl)oxy]phenyl}~1,3—dihydro—2H—imidazo[4,5—
b]pyridin—2—one (Form G)
A solution of 3—methyl—2—(methylsulfonyl)-3H—imidazo[4,5—
b]pyridine (40.8 g, 193.09 mmol) in DMA (234 mL) was added to
a solution of 1—ethy1—3—(4—hydroxyphenyl)—7—methyl—1,3—
dihydro—ZH—imidazo[4,5—b]pyridin—2—one (52.0 g, 193.09 mmol)
and potassium tert—butoxide (22.8 g) in DMA (192 mL) at room
temperature. The mixture was stirred at 90 — 100°C for 1 hr.
Water (442 mL) was added at 80 — 100°C. The precipitates were
collected at room temperature and dried under reduced pressure
to give 1—ethyl—7—methyl—3—{4—[(3—methyl—3H—imidazo[4,5—
b]pyridin—2—yl)oxy]phenyl}—1,3—dihydro—2H—imidazo[4,5—
b]pyridin—2—one (72.4 g) as a crude product.
The crude 1—7—methyl—3—{4-[(3—methyl—3H—
o[4,5-b]pyridin—2—yl)oxy]phenyl}—1,3—dihydro—2H—
imidazo[4,5—b]pyridin—2—one (60.0 g) was dissolved in DMSO
(900 mL) at 90 ~ 100°C. The solution was filtered through a
paper , and washed with DMSO (60 mL). The combined
filtrate was slowly added to a mixture of the crystals (Form
G: 600 mg) (as a seed l) obtained in Example 5 in ethyl
acetate (600 mL) at 0 — 30°C. The mixture was stirred at 70°C
for 0.5 hr and cooled to room temperature. The mixture was
stirred at room ature for 1 hr, at 0 — 10°C for 1 hr, and
at room ature for 1 hr. The solids were collected by
filtration, and dried under reduced pressure at 50°C to give 1—
ethyl—7—methyl—3—{4—[(3—methyl—3H—imidazo[4,5—b]pyridin—2-
yl)oxy]phenyl}—1,3—dihydro—2H—imidazo[4,5—b]pyridin—2—one
(47.9 g) as white crystals (Form G).
MS 0351+): [M+H]+ 401.2.
1H NMR (500 MHZ, CDCl3) 5 1.42 (3H, t), 2.62 (3H, s), 3.84 (3H,
s), 4.15—4.27 (2H, m), 6.81~6.92 (1H, m), 7.10-7.18 (1H, m),
7.52—7.61 (2H, m), 7.7377.80 (1H, m), 7.82—7.87 (2H, m), 7.91—
7.95 (1H, m), 8.20~8.29 (1H, m).
Example 7
Crystal of 1—ethyl~7—methy1—3—{4—[(3—methyl—3H—imidazo[4,5~
b]pyridin—2—yl)oxy]phenyl}—1,3—dihydro-2H-imidazo[4,5—
blpyridin—2—one (Form G)
a) A solution of 3—methy1—2—(methylsulfonyl)—3H—imidazo[4,5—
b]pyridine (78.4 g, 371.33 mmol) in DMA (420 mL) was added to
a solution of l—3—(4—hydroxyphenyl)—7—methyl—1,3-
dihydro—ZH—imidazo[4,5—b]pyridinone (100.0 9, 371.33 mmol)
and potassium tert—butoxide (51.5 g) in DMA (370 mL) at room
temperature. The e was stirred at 90 — 100°C for 1 hr.
Water (780 mL) was added at 90 — 100°C. The precipitates were
collected at room ature and dried under reduced pressure
to give 1-ethyl—7—methyl—3-{4-[(3—methyl—3H—imidazo[4,5—
b] pyridin—Z-yl) oxy] phenyl } —1 , 3—dihydro—2H—imidazo [4 , 5—
b]pyridin—2—one (127.7 g) as crystals. The ed crystals
(125.0 g) were dissolved in DMSO (1375 mL) at 90 - 95°C. To
the solution was slowly added ethanol (1250 mL) at 80 — 95°C,
and the mixture was d to cool to room temperature. The
solids were collected by filtration, washed with ethanol (625
mL) to give l—7-methyl—3-{4—[(3—methyl—3H-imidazo[4,5—
b]pyridin—2—y1)oxy]phenyl}—1,3—dihydro—2H—imidazo[4,5—
b]pyridin—2-one (103.9 g) as crystals.
b) A mixture of the obtained crystals (55.0 g) in a on
of DMSO (275 mL) and ethanol (275 mL) was stirred at 70 — 75°C
for 0.5 hr, and the mixture was allowed to cool to room
temperature. The solids were collected by filtration, and
washed with ethanol (165 mL) to give 1—ethy1—7—methy1—3—{4—
[(3—methyl-3H—imidazo[4,5—b1pyridin—2eyl)oxy]phenyl}—1,3—
dihydro—ZH—imidazo[4,5—b]pyridin—2—one (52.2 g) as crystals.
The obtained crystals (5.0 g) were dissolved in DMSO (50 mL)
at 95°C. The solution was filtered through a paper filter and
washed with DMSO (5 mL). To the combined filtrate was slowly
added ethanol (50 mL) at 73 — 95°C. To the solution were added
the crystals obtained in Example 4 (Form G: 5 mg) as a seed
crystal at 73°C. The mixture was allowed to cool to room
ature. The mixture was stirred at 70 - 75°C for 7 hr,
and allowed to cool to room temperature. The mixture was
stirred at 70 ~ 75°C for 8 hr, and cooled to room ature.
The mixture was stirred at 70 — 75°C for 2 hr, and the e
was stirred at room temperature for 1 hr, and 0 — 10°C for 1 hr.
The solids were collected by tion, and dried under
reduced pressure at 50°C to give l—7—methyl—3—{4—[(3—
methyl—3H—imidazo[4,5~b]pyridin—2—yl)oxy]phenyl}—1,3—dihydro—
2H—imidazo[4,5—b]pyridin—2~one (4.5 g) as white crystals (Form
Example 8
Crystal of 1—ethyl—7—methyl—3—{4—[(3—methyl—3H—imidazo[4.5—
bprridin—2—yl)oxy]phenyl}—1,3-dihydro—2H—imidazo[4,5—
b]pyridin—2—one (Form G)
3—Methyl—2—(methylsulfonyl)—3H—imidazo[4,5—b1pyridine_
(8.62 g, 40.8 mmol) was added to a mixture of 1—ethyl—3—(4—
hydroxyphenyl)-7—methyl—1,3—dihydro—2H—imidazo[4,5—b]pyridin~
2—one (10.0 g, 37.1 mmol), potassium carbonate (6.15 g) and
water (4.25 mL) in DMA (75 mL) at room temperature. The
mixture was stirred at 80 - 90°C for 1 hr. Water (135 mL) was
added at 45°C. The precipitates were collected at room
temperature, and dried under reduced pressure to give 1—ethyl—
7—methyl—3—{4—[(3—methyl—3H—imidazo[4,5—b]pyridin—2—
yl)oxy]phenyl}—1,3—dihydro—2H—imidazo[4,5—b]pyridin—2—one
(14.13 g) as a crude product.
The crude l—ethyl—7—methyl—3—{4~[(3—methyl—3H—
imidazo[4,5—b]pyridin—2—yl)oxy]phenyl}—l,3—dihydro—2H—
imidazo[4,5-b]pyridin—2—one (12.0 g) was dissolved in DMSO
(228 mL) at 90°C. The solution was filtered through glass
filter. The filtrate was heated to 90°C and stirred at 30°C
for 1 hr. Ethanol (72 mL) was added and the e was
stirred for 1 hr. After stirring at 60°C for 4.5 hr, the
mixture was cooled to room temperature. After stirring at 10°C
W0 2012/176934
for 4.5 hr, the precipitates were collected and dried under
reduced pressure to give 1~ethyl—7—methyl—3—{4—[(3—methyl—3H-
imidazo[4,5—b]pyridin—2—yl)oxy]phenyl}—1,3—dihydro—2H—
imidaio[4,5—b]pyridin—2—one (10.32 g) as white crystals (Form
Example 9
Crystal of 1'ethy1—7-methyl—3—{4—[(3—methyl—3Heimidazo[4,5—
din—2~yl)oxy]phenyl}~1,3—dihydro—2H-imidazo[4,5-
b]pyridin—2—one (Form G)
3—Methyl—2—(methylsulfonyl)—3H—imidazo[4,5—b]pyridine
(258.9 g, 1.22 mmol) was added tofa mixture of 1—ethy1—3—(4—
hydroxyphenyl)—7—methyl-1,3—dihydro42H—imidazo[4,5—b]pyridin—
2—one (300.0 g, 1.11 mmol), potassium carbonate (184.7 g) and
water (127.5 mL) in DMA (1950 mL) at room temperature. DMA
(300 mL) was further added and the mixture was stirred at 86 —
87°C for 1 hr. Water (4050 mL) was added at 45°C. The
precipitates were collected at 25°C, and dried under reduced
pressure to give 1-ethy1—7~methyl-3—{4—[(3—methyl—3H—
imidazo[4,5—b]pyridin—2—y1)oxy]phenyl}—1,3—dihydro—2H—
imidazo[4,5—b]pyridin—2—one (435.87 g) as a crude product.
The crude 1-ethy1—7—methyl—3—{4—[(3—methy1—3H—
imidazo[4,5-blpyridinyl)oxy]phenyl}—1,3-dihydro—2H—
imidazo[4,5—b]pyridin—2—one (400.0 g) was dissolved in DMSO
(7600 mL) at 80 — 90°C. The solution was filtered through a
glass . The filtrate was heated to 80 ~ 90°C, and the
crystals (Form G: 4 g) obtained in e 8 were added to the
solution at 50°C as a seed crystal. After cooling to 30°C,
l (2400 mL) was added. The mixture was heated to 60 ~
70°C and cooled to room ature. After stirring under ice—
cooling, the precipitates were collected and dried under
reduced pressure to give l—7—methy1—3—{4—[(3—methyl~3H—
imidazo[4,5—b]pyridin—2—yl)oxy]phenyl}—1,3-dihydro—2H—
imidazo[4,5—b]pyridin~2-one (344.04 g) as white crystals (Form
G).
The measurement results of powder X—ray diffraction of
the Form G crystals ed in Example 1(2) are shown in the
following Table 8 and Fig. 8. In addition, the DSC
thermoanalytical data of the crystals are shown in Fig. 9.
[Table 8]
‘Powder X~ray diffraction data (Form G Crystals)
2 9 (° ) 01 value (A) relative intensity (‘3)
6.5 13.5869 8
9.58 9.2245 38
11.22 7.8796 82
11.82 7.4809 17
13.08 6.763 25
14.26 6.2059 47
14.44 6.1289 49
.46 5.7268 58
16.9 5.2419 12
17.28 5 29
19.12 4.638 45
.8 4.267 25
21.32 4.1641 16
21.88 4.0588 5
22.24 3.9939 30
22. 58 3.9345 44
23.44 3.7921 100
23.27 3.7479 100
24.74 3.5957 15
26.12 3.4088 17
28.24 . 3.1575 5
28. 82 3. 0953 10
29.18 3.0579 20
.88 2.8933 13
31. 64 2. 8255 6
32.78 2.7298 7
34. 68 2. 5845 7
Formulation Example 1
(1) Crystal of Example 1 10.0 g
(2) Lactose 70.0 g
(3) Cornstarch 50.0 g
2012/066461
(4) Soluble starch 7.0 g
(5) Magnesium stearate 3.0 g
After 10.0 g of the crystal of Example 1 and 3.0 g of
-magnesium te are granulated in 70 mL of aqueous solution
of soluble starch (7.0 g as soluble starch) and then dried,
the ing mixture is mixed with 70.0 g of lactose and 50.0
g of cornstarch (lactose, cornstarch, soluble starch and
magnesium stearate are all products in compliance with
~ Japanese Pharmacopoeia). The mixture is compressed to obtain a
tablet.
Experimental Example 1 Study of crystallization from various
solvents
The crystals of l—ethyl—7—methyl—3—{4—[(3—methyl—3H—
imidazo[4,5—b]pyridin—2-yl)oxy]phenyl}—l,3—dihydro—2H—
imidazo[4,5—b]pyridin—2—one (Form A) (20 mg, 0.05 mmol)
obtained in Reference Example 1—1 were maintained at 55°C, and
various ts were added until almost the whole amount was
dissolved. This solution was filtered through a filter with
0.22 um pore size, and cooled to O — 5°C with stirring. The
mixture was stirred for 8 hr under cooling at O — 5°C. The
crystals of l—ethyl—7—methyl—3—{4—[(3—methyl—3H—imidazo[4,5—
bprridin—Z—yl)oxy]phenyl}—l,3—dihydro—2H—imidazo[4,5~
din—2~one formed were collected by filtration, and the
l form of the crystalline products was confirmed. The
results are shown in Table 9.
[Table 9]
LSOlVGDt solubility at 55°C (mg/mL) _LEryStal form
methanol 5.6
. Form A
l 2.6 Form A
F2_propano 1 <2 . 7 L— A
[acetone '
6.5' VA
Lmethylethylketone 6.8 —J A
ethyl acetate 3.4 A
a ton1tr i le ~r
ce 8.1 B
rtoluene 5.2 G
chloroform 1‘ >200 A
Ltetrahydrofuran 26 A
Ltrifluoroethanol >200 D
L__ _J
As shown above, in the crystallization from various
solvents, Form A crystals were preferentially crystallized,
and Form G crystals were crystallized only under the toluene
condition where use for the production of a drug substance for
pharmaceutical products is limited from the aspect of residual
solvent.
Experimental e 2 Solvent suspending test of crystal form
mixture
Crystal form mixtures containing the same weight of each
crystal form of l—ethyl—7—methyl—3e{4—[(3~methyl—3H—
imidazo[4,5—b]pyridin—2—yl)oxy]phenyl}—l,3—dihydro—2H—
imidazo[4,5-b]pyridin—2-one obtained in nce Examples 1—1,
3 and 4, and Example 1 were ed to the total amount of 20
mg. The crystal form mixtures were mixed with ethanol (1 mL),
and the mixtures were stirred at room temperature. After
stirring for one week, and after stirring for 2 weeks, the
crystals of l—7—methyl—3~{4—[(3-methyl—3H—imidazo[4,5—
b]pyridin—2—yl)oxy]phenyl}—1,3—dihydro—2H—imidazo[4,5-
din—2—one formed were collected by filtration, and the
crystal form of the crystalline products was confirmed. The
. 2012/066461
results are shown in Table 10.
[Table 10]
crystal form
crystal form mixture
1 week later 2 weeks later
Form A+Form G Form G Form G
Form A+Form E Form A + Form G Form G
Form A+Form D+Form E+Form G [ Form G Form G
As shown above, the mixtures of various crystal forms
transformed into Form G l 2 weeks later at room
temperature and under suspending in ethanol. The results have
clarified that the crystal (Form G) of the present invention
is dynamically stable under suspending in ethanol at
room temperature.
Experimental Example 3 Solvent suspending test of Form A
crystal in various solvents
The crystals of l—ethyl—7—methyl—3—{4—[(3-methyl—3H-
imidaZo[4,5—b]pyridinyl)oxy]phenyl}-l,3—dihydro—2H—
imidazo[4,5—b]pyridin-2—one (Form A) (20 mg, 0:05 mmol)
obtained in Reference Example 1—1 were mixed with various
solvents (1 mL) and the mixture was stirred at room
temperature. After stirring for one week, and after ng
for 2 weeks, the crystals of lsethyl—7~methyl—3-[4—[(3—methyl—
dazo[4,5—b]pyridin—2—yl)oxy]phenyl}—l,3—dihydro—2H—
imidazo[4,5—b]pyridin—2—one formed were collected by
filtration, and the crystal form of the crystalline products
was confirmed. The results are shown in Table 11.
[0143]
WO 76934
[Table 11]
t crystal form
1 week later 2 weeks later
methanol Form G Form G “—1
isopropyl alcohol Form A *——T_ Form A
acetone Form G Form G
methylethylketone Form G Form G
ethyl e Form AfForm G Form G
toluene ‘[—__ Form G Form G __J
tetrahydrofuran Form G —_—T Form G
1—butanol‘
As shown above, Form A crystal was transformed into Form
G crystal when suspended in many of the solvents. The results
have revealed that the crystal (Form G) of the present
invention is thermodynamically more stable when suspended in
various solvents at room temperature than Form A
preferentially ed by crystallization from a solution.
[0145]
Experimental Example 4 Preservation stability test
The crystals of l—ethyl-7—methyl—3—{4—[(3—methyl—3H-
imidazo[4,5—b]pyridin—2—yl)oxy]phenyl}—l,3—dihydro—2H—
o[4,5—b]pyridin—2—one (Form G, 5 — 10 mg) obtained in
Example 1 were placed in a glass bottle, sealed with a metal
cap and preserved at 80°C. The sample was taken out 1 week and
2 weeks later, dissolved in a water/acetonitrile mixed
solution at a concentration of 0.2 mg/mL and analogs were
measured by Alliance HPLC 2695 (Waters Corporation). The
results are shown in Table 12.
[Table 12]
area tage
storage crystal
appearance (%) of HPLC peak
condition . form
area of main form
h' .
w lte crystalline
prestorage 99.7 Form G
powder
80°C, 1 week no change 99.7 ::r Form G
[80°C, 2 weeks no change 99.6 _L_Form G
From the above—mentioned results, it has been clarified
that the crystal (Form G) of the present invention has very
high al and al stability.
mental Example 5 PDE enzyme inhibition
Human PDElOA enzyme was generated from Sf9 or COS—7 cells
transfected with the full—length gene. The cloned enzyme was
extracted from homogenized cell pellets. The extracted enzyme
from Sf9 cells was partially purified using His—tag affinity
column. The enzyme was stored at —70°C until use. PDE
activity was measured using an SPA illation Proximity
Assay) (GE Healthcare). To evaluate the inhibitory activity,
10 uL of serially diluted l—ethyl-7—methyl—3—{4—[(3—methyl—3H~
imidazo[4,5—b]pyridin-2—yl)oxy]phenyl}~l,3—dihydro—2H—
imidazo[4,5—b1pyridin—2—one was incubated with 20 uL of PDE
enzyme in an assay buffer (50 mM HEPES—NaOH, 8.3 mM MgClz, 1.7
mM EGTA, 0.1% BSA (pH 7.4))_for 30 min at room temperature.
The final concentration of DMSO in the assay was 1 percent as
compounds were tested in duplicate in 96-well half—area plates
(Corning). To start the reaction, 10 uL of substrate [3H] cGMP
(25 or 50 nM; enclosed in SPA kits from GE Healthcare or
purchased from PerkinElmer, respectively) was added to a final
assay volume of 40 uL. After 60 min of tion at room
temperature, yttrium SPA beads containing zinc sulphate were
added (6 mg/mL, 20 uL) to terminate the PDE reaction. After
standing still for 60 min, the assay plates were counted on a
scintillation counter (PerkinElmer) and the tion rate
was calculated. The tion rate was calculated based on
the control wells containing DMSO as 0% and control wells
without enzyme as 100%. The s are shown in Table 13.
[Table 13]
Inhibition rate (%) (10 uM] Inhibition rate (%) (1 pM)
106 109
INDUSTRIAL APPLICABILITY
Since the crystal of the present invention shows a
superior PDElOA inhibitory action, it can provide a
prophylactic or therapeutic drug ally useful for a
disease such as schizophrenia and the like. In addition, since
the crystal of the present invention is superior in the
efficacy, low toxicity, stability, in vivo kinetics etc.
(particularly, stability), it is useful as a medicament.
[0151]
While some of the ments of the present invention‘
have been described in detail in the above, it is, however,‘
possible for those of ordinary skill in the art to make various
modifications and changes to the particular embodiments shown
t substantially departing from the teaching and ages
of the present invention. Such modifications and changes are
encompassed in the spirit and scope of the t invention as
set forth in the appended claims.
This application is based on patent application No.
2011-138920 filed in Japan, the contents of which are
incorporated in full herein by this reference}
Claims (12)
1. A crystal of lmethyl{4-[(3-methyl-3H- imidazo[4,5-b]pyridinyl)oxy]phenyl}-1,3-dihydro-2H- imidazo[4,5-b]pyridinone showing an X-ray powder diffraction pattern having characteristic peaks at interplanar spacings (d) of 13.59±0.2, 9.22±0.2, 7.88±0.2, 6.76±0.2, 6.21±0.2, 6.13±0.2, 5.73±0.2, 4.64±0.2, .2 and 3.75±0.2 Angstroms in powder X-ray ction.
2. The crystal according to claim 1, which shows an X-ray powder diffraction pattern having further characteristic peaks at interplanar spacings (d) of 7.48±0.2, 5.24±0.2, 5.13±0.2, 4.27±0.2, 4.16±0.2, 4.06±0.2, 3.99±0.2, 3.93±0.2, 3.60±0.2, .2, 3.16±0.2, .2, 3.06±0.2, 2.89±0.2, 2.83±0.2, 2.73±0.2 and 2.58±0.2 Angstroms in powder X-ray diffraction.
3. The crystal according to claim 1, which shows an initial temperature of about 222 - about 224 °C of an endothermic behavior caused by melting in DSC ement (temperature increase rate n).
4. A medicament comprising the crystal according to claim
5. The medicament according to claim 4, which is a phosphodiesterase 10A inhibitor.
6. The ment according to claim 4, which is a prophylactic or therapeutic agent for schizophrenia.
7. A method of preventing or treating schizophrenia in a mammal, comprising administering an effective amount of the crystal according to claim 1 to the mammal, wherein the mammal is a non-human subject.
8. Use of the crystal according to claim 1 for the production of a prophylactic or therapeutic drug for schizophrenia.
9. The crystal according to claim 1 for use for the prophylaxis or treatment of schizophrenia.
10. The crystal according to claim 1, substantially as herein described with reference to any one of the examples and/or s.
11. The medicament according to claim 4, substantially as herein described with reference to any one of the examples and/or figures.
12. The use according to claim 8, substantially as herein described with nce to any one of the examples and/or figures.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2011-138920 | 2011-06-22 | ||
JP2011138920 | 2011-06-22 | ||
PCT/JP2012/066461 WO2012176934A1 (en) | 2011-06-22 | 2012-06-21 | Crystal of fused heterocyclic compound |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ618944A NZ618944A (en) | 2015-08-28 |
NZ618944B2 true NZ618944B2 (en) | 2015-12-01 |
Family
ID=
Similar Documents
Publication | Publication Date | Title |
---|---|---|
TWI397530B (en) | Substituted triazolopyridines and analogs thereof | |
TWI480282B (en) | Fused heterocyclic derivative and use thereof | |
EP2248816B1 (en) | 2-ALKYLAMINO-3-ARYLSULFONYL-CYCLOALCANO [e OR d] PYRAZOLO[1,5-A]PYRIMIDINES AS ANTAGONISTS OF SEROTONIN 5-HT6 RECEPTORS, METHODS FOR THE PRODUCTION AND THE USE THEREOF | |
KR101965326B1 (en) | Novel 2,3,5-substituted thiophene compounds as protein kinase inhibitors | |
TW200804387A (en) | Novel imidazopyrazines as cyclin dependent kinase inhibitors | |
SG186341A1 (en) | Fused heterocyclic compounds as phosphodiesterases (pdes) inhibitors | |
US20090163539A1 (en) | Enantiomer of tenatoprazole and the use thereof in therapy | |
TW201245199A (en) | 6-cycloalkyl-pyrazolopyrimidinones for the treatment of CNS disorders | |
CN105793245B (en) | Medical compounds | |
TW201004952A (en) | Substituted pyrimidin-4-one derivatives | |
CN107530350A (en) | Inhibitor of cellular necrosis and correlation technique | |
TW200936140A (en) | Substituted arylamide oxazepinopyrimidone derivatives | |
CZ20021703A3 (en) | 2,4-Diaminopyrimidine compounds usable as immunosuppressants | |
TW200835495A (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 | |
SA06270365B1 (en) | New 3H-Imidazo[4,5-b]pyridine Derivatives | |
CA2839825C (en) | Crystal of fused heterocyclic compound | |
NZ618944B2 (en) | Crystal of fused heterocyclic compound | |
TWI670271B (en) | [1,2,4]triazolo[4,3-a]pyrazin-6(5h)-one derivatives | |
US11919894B2 (en) | Pro drugs of PDE10 compounds | |
EP3099690B1 (en) | (hetero)aryl imidazoles/pyrazoles for treatment of neurological disorders | |
CN105061423B (en) | Pyridine salt JAK inhibitor containing halogeno-benzene structure, preparation method and its usage | |
CN116514845A (en) | USP1 inhibitors and uses thereof | |
TW201305155A (en) | Triazolopyridine compounds |