JP2014516074A - ピラゾロ［３，４−ｄ］ピリミジン化合物ならびにそのＰＤＥ２阻害剤および／またはＣＹＰ３Ａ４阻害剤としての使用 - Google Patents
ピラゾロ［３，４−ｄ］ピリミジン化合物ならびにそのＰＤＥ２阻害剤および／またはＣＹＰ３Ａ４阻害剤としての使用 Download PDFInfo
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- JP2014516074A JP2014516074A JP2014514172A JP2014514172A JP2014516074A JP 2014516074 A JP2014516074 A JP 2014516074A JP 2014514172 A JP2014514172 A JP 2014514172A JP 2014514172 A JP2014514172 A JP 2014514172A JP 2014516074 A JP2014516074 A JP 2014516074A
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- Prior art keywords
- alkyl
- methyl
- compound
- pharmaceutically acceptable
- acceptable salt
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- QUKPALAWEPMWOS-UHFFFAOYSA-N 1h-pyrazolo[3,4-d]pyrimidine Chemical class C1=NC=C2C=NNC2=N1 QUKPALAWEPMWOS-UHFFFAOYSA-N 0.000 title claims description 5
- 208000009011 Cytochrome P-450 CYP3A Inhibitors Diseases 0.000 title abstract description 6
- 229940121828 Phosphodiesterase 2 inhibitor Drugs 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 263
- 150000003839 salts Chemical class 0.000 claims abstract description 139
- 238000000034 method Methods 0.000 claims abstract description 70
- 201000000980 schizophrenia Diseases 0.000 claims abstract description 21
- 208000010877 cognitive disease Diseases 0.000 claims abstract description 9
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 119
- 125000000217 alkyl group Chemical group 0.000 claims description 106
- 125000000623 heterocyclic group Chemical group 0.000 claims description 71
- -1 4-Cyclopropylphenyl Chemical group 0.000 claims description 70
- 125000001424 substituent group Chemical group 0.000 claims description 46
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 41
- 125000001072 heteroaryl group Chemical group 0.000 claims description 41
- 229910052739 hydrogen Inorganic materials 0.000 claims description 39
- 125000005843 halogen group Chemical group 0.000 claims description 37
- 125000006647 (C3-C15) cycloalkyl group Chemical group 0.000 claims description 36
- 108010081668 Cytochrome P-450 CYP3A Proteins 0.000 claims description 33
- 239000001257 hydrogen Substances 0.000 claims description 33
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 30
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 30
- 125000004432 carbon atom Chemical group C* 0.000 claims description 29
- 230000000694 effects Effects 0.000 claims description 27
- 125000003342 alkenyl group Chemical group 0.000 claims description 26
- 229910052757 nitrogen Inorganic materials 0.000 claims description 26
- 125000000304 alkynyl group Chemical group 0.000 claims description 25
- 102100039205 Cytochrome P450 3A4 Human genes 0.000 claims description 24
- 125000004043 oxo group Chemical group O=* 0.000 claims description 22
- 125000003118 aryl group Chemical group 0.000 claims description 21
- 125000001153 fluoro group Chemical group F* 0.000 claims description 20
- 125000001188 haloalkyl group Chemical group 0.000 claims description 19
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 19
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 18
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 17
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 17
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 16
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 16
- 125000001246 bromo group Chemical group Br* 0.000 claims description 16
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 16
- 150000002431 hydrogen Chemical class 0.000 claims description 16
- 125000004566 azetidin-1-yl group Chemical group N1(CCC1)* 0.000 claims description 11
- 125000005842 heteroatom Chemical group 0.000 claims description 10
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 9
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 7
- 230000002401 inhibitory effect Effects 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 5
- 230000004060 metabolic process Effects 0.000 claims description 5
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 4
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 4
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 4
- SCCSYDABXJGYAW-UHFFFAOYSA-N 4-(azetidin-1-yl)-1-methyl-3-[1-methyl-5-(4-methylphenyl)pyrazol-4-yl]pyrazolo[3,4-d]pyrimidine Chemical compound C1=CC(C)=CC=C1C1=C(C=2C3=C(N4CCC4)N=CN=C3N(C)N=2)C=NN1C SCCSYDABXJGYAW-UHFFFAOYSA-N 0.000 claims description 3
- YTHKCXNSTDQKHK-UHFFFAOYSA-N 4-(azetidin-1-yl)-1-methyl-3-[1-methyl-5-[5-(trifluoromethyl)pyridin-2-yl]pyrazol-4-yl]pyrazolo[3,4-d]pyrimidine Chemical compound C=1C=C(C(F)(F)F)C=NC=1C=1N(C)N=CC=1C(C=12)=NN(C)C2=NC=NC=1N1CCC1 YTHKCXNSTDQKHK-UHFFFAOYSA-N 0.000 claims description 3
- 125000004399 C1-C4 alkenyl group Chemical group 0.000 claims description 3
- ATNFIPKAFIUZOM-UHFFFAOYSA-N 3-[5-(4-cyclopropylphenyl)-1-methylpyrazol-4-yl]-4-(3,3-difluoroazetidin-1-yl)-1-methylpyrazolo[3,4-d]pyrimidine Chemical compound C=1C=C(C2CC2)C=CC=1C=1N(C)N=CC=1C(C=12)=NN(C)C2=NC=NC=1N1CC(F)(F)C1 ATNFIPKAFIUZOM-UHFFFAOYSA-N 0.000 claims description 2
- JDMKZMZRNRRQDF-UHFFFAOYSA-N 3-[5-(4-ethylphenyl)-1-methylpyrazol-4-yl]-4-(3-fluoroazetidin-1-yl)-1-methylpyrazolo[3,4-d]pyrimidine Chemical compound C1=CC(CC)=CC=C1C1=C(C=2C3=C(N4CC(F)C4)N=CN=C3N(C)N=2)C=NN1C JDMKZMZRNRRQDF-UHFFFAOYSA-N 0.000 claims description 2
- XRDSERGKQSDYOF-UHFFFAOYSA-N 4-(3,3-difluoroazetidin-1-yl)-1-methyl-3-[1-methyl-5-[4-(trifluoromethyl)phenyl]pyrazol-4-yl]pyrazolo[3,4-d]pyrimidine Chemical compound C=1C=C(C(F)(F)F)C=CC=1C=1N(C)N=CC=1C(C=12)=NN(C)C2=NC=NC=1N1CC(F)(F)C1 XRDSERGKQSDYOF-UHFFFAOYSA-N 0.000 claims description 2
- SMARPIIFKRVNEM-UHFFFAOYSA-N 4-(3,3-difluoroazetidin-1-yl)-3-[5-(4-ethylphenyl)-1-methylpyrazol-4-yl]-1-methylpyrazolo[3,4-d]pyrimidine Chemical compound C1=CC(CC)=CC=C1C1=C(C=2C3=C(N4CC(F)(F)C4)N=CN=C3N(C)N=2)C=NN1C SMARPIIFKRVNEM-UHFFFAOYSA-N 0.000 claims description 2
- MGBHLGVDDNUFLX-UHFFFAOYSA-N 4-(3-fluoroazetidin-1-yl)-1-methyl-3-[1-methyl-5-[4-(trifluoromethyl)phenyl]pyrazol-4-yl]pyrazolo[3,4-d]pyrimidine Chemical compound C=1C=C(C(F)(F)F)C=CC=1C=1N(C)N=CC=1C(C=12)=NN(C)C2=NC=NC=1N1CC(F)C1 MGBHLGVDDNUFLX-UHFFFAOYSA-N 0.000 claims description 2
- SHAVEYUXRBIMLA-UHFFFAOYSA-N 4-(azetidin-1-yl)-1-methyl-3-[1-methyl-5-[4-(trifluoromethyl)phenyl]pyrazol-4-yl]pyrazolo[3,4-d]pyrimidine Chemical compound C=1C=C(C(F)(F)F)C=CC=1C=1N(C)N=CC=1C(C=12)=NN(C)C2=NC=NC=1N1CCC1 SHAVEYUXRBIMLA-UHFFFAOYSA-N 0.000 claims description 2
- MIOZWWXFVVGLKA-UHFFFAOYSA-N 4-(azetidin-1-yl)-3-[5-(3-fluoro-4-methoxyphenyl)-1-methylpyrazol-4-yl]-1-methylpyrazolo[3,4-d]pyrimidine Chemical compound C1=C(F)C(OC)=CC=C1C1=C(C=2C3=C(N4CCC4)N=CN=C3N(C)N=2)C=NN1C MIOZWWXFVVGLKA-UHFFFAOYSA-N 0.000 claims description 2
- WORSSTXTYKCIPJ-UHFFFAOYSA-N 4-(azetidin-1-yl)-3-[5-(4-bromophenyl)-1-methylpyrazol-4-yl]-1-methylpyrazolo[3,4-d]pyrimidine Chemical compound C=1C=C(Br)C=CC=1C=1N(C)N=CC=1C(C=12)=NN(C)C2=NC=NC=1N1CCC1 WORSSTXTYKCIPJ-UHFFFAOYSA-N 0.000 claims description 2
- YSTWEXHDLNQGDV-UHFFFAOYSA-N 4-(azetidin-1-yl)-3-[5-(4-cyclopropylphenyl)-1-methylpyrazol-4-yl]-1-methylpyrazolo[3,4-d]pyrimidine Chemical compound C=1C=C(C2CC2)C=CC=1C=1N(C)N=CC=1C(C=12)=NN(C)C2=NC=NC=1N1CCC1 YSTWEXHDLNQGDV-UHFFFAOYSA-N 0.000 claims description 2
- MLERDBQFQWJIBU-UHFFFAOYSA-N 4-(azetidin-1-yl)-3-[5-(4-ethylphenyl)-1-methylpyrazol-4-yl]-1-methylpyrazolo[3,4-d]pyrimidine Chemical compound C1=CC(CC)=CC=C1C1=C(C=2C3=C(N4CCC4)N=CN=C3N(C)N=2)C=NN1C MLERDBQFQWJIBU-UHFFFAOYSA-N 0.000 claims description 2
- 102100039208 Cytochrome P450 3A5 Human genes 0.000 claims 2
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 49
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 19
- 238000002360 preparation method Methods 0.000 abstract description 19
- 239000000126 substance Substances 0.000 abstract description 19
- 208000035475 disorder Diseases 0.000 abstract description 17
- 241000124008 Mammalia Species 0.000 abstract description 12
- 206010012289 Dementia Diseases 0.000 abstract description 9
- 239000000543 intermediate Substances 0.000 abstract description 6
- 210000003169 central nervous system Anatomy 0.000 abstract description 5
- 201000010099 disease Diseases 0.000 abstract description 2
- 230000009885 systemic effect Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 89
- 238000006243 chemical reaction Methods 0.000 description 62
- 239000000243 solution Substances 0.000 description 59
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 57
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 51
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 48
- 239000000047 product Substances 0.000 description 44
- 238000003786 synthesis reaction Methods 0.000 description 42
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 40
- 230000015572 biosynthetic process Effects 0.000 description 39
- 239000011541 reaction mixture Substances 0.000 description 38
- 238000005481 NMR spectroscopy Methods 0.000 description 36
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 30
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 29
- 239000002585 base Substances 0.000 description 29
- 239000002904 solvent Substances 0.000 description 29
- 239000007787 solid Substances 0.000 description 28
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 26
- 230000035484 reaction time Effects 0.000 description 25
- 125000004429 atom Chemical group 0.000 description 23
- 101100135859 Dictyostelium discoideum regA gene Proteins 0.000 description 22
- 101100082606 Plasmodium falciparum (isolate 3D7) PDEbeta gene Proteins 0.000 description 22
- 101100135860 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) PDE2 gene Proteins 0.000 description 22
- 239000002253 acid Substances 0.000 description 21
- 229910052799 carbon Inorganic materials 0.000 description 21
- 239000003153 chemical reaction reagent Substances 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 21
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 20
- 229910052794 bromium Inorganic materials 0.000 description 20
- 229920006395 saturated elastomer Polymers 0.000 description 20
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 20
- 239000000460 chlorine Substances 0.000 description 19
- 239000003814 drug Substances 0.000 description 19
- 238000010898 silica gel chromatography Methods 0.000 description 19
- 230000005764 inhibitory process Effects 0.000 description 17
- 238000000746 purification Methods 0.000 description 17
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 16
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 16
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 16
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 16
- 229940079593 drug Drugs 0.000 description 16
- 239000003960 organic solvent Substances 0.000 description 16
- 230000002829 reductive effect Effects 0.000 description 16
- 239000007810 chemical reaction solvent Substances 0.000 description 15
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 14
- 102000004190 Enzymes Human genes 0.000 description 13
- 108090000790 Enzymes Proteins 0.000 description 13
- 229910052801 chlorine Inorganic materials 0.000 description 13
- 239000012044 organic layer Substances 0.000 description 13
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 13
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 11
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 11
- 229910052938 sodium sulfate Inorganic materials 0.000 description 11
- 235000011152 sodium sulphate Nutrition 0.000 description 11
- 0 *c1c(-c2n[n](*)c3ncnc(*)c23)[n](*)nc1* Chemical compound *c1c(-c2n[n](*)c3ncnc(*)c23)[n](*)nc1* 0.000 description 10
- 101001098858 Homo sapiens cGMP-dependent 3',5'-cyclic phosphodiesterase Proteins 0.000 description 10
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
- 102100038953 cGMP-dependent 3',5'-cyclic phosphodiesterase Human genes 0.000 description 10
- 150000001721 carbon Chemical group 0.000 description 10
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- ZOOGRGPOEVQQDX-UUOKFMHZSA-N 3',5'-cyclic GMP Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-UUOKFMHZSA-N 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 8
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- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 8
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 8
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 8
- 150000002148 esters Chemical class 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 8
- 229910000029 sodium carbonate Inorganic materials 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 125000001425 triazolyl group Chemical group 0.000 description 8
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 7
- 102000004328 Cytochrome P-450 CYP3A Human genes 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- 238000003556 assay Methods 0.000 description 7
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- MGNBKNBEZGLHNF-UHFFFAOYSA-N (2-methylpyrazol-3-yl)boronic acid Chemical compound CN1N=CC=C1B(O)O MGNBKNBEZGLHNF-UHFFFAOYSA-N 0.000 description 6
- UBCBMOUQUMSFEP-UHFFFAOYSA-N (4,6-dichloropyrimidin-5-yl)-[1-methyl-5-(4-methylphenyl)pyrazol-4-yl]methanone Chemical compound C1=CC(C)=CC=C1C1=C(C(=O)C=2C(=NC=NC=2Cl)Cl)C=NN1C UBCBMOUQUMSFEP-UHFFFAOYSA-N 0.000 description 6
- VTQZNXFVIPXTRQ-UHFFFAOYSA-N 3-(4-ethylphenyl)imidazole-4-carbaldehyde Chemical compound C1=CC(CC)=CC=C1N1C(C=O)=CN=C1 VTQZNXFVIPXTRQ-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 238000005859 coupling reaction Methods 0.000 description 6
- 125000004122 cyclic group Chemical group 0.000 description 6
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- DEQYTNZJHKPYEZ-UHFFFAOYSA-N ethyl acetate;heptane Chemical compound CCOC(C)=O.CCCCCCC DEQYTNZJHKPYEZ-UHFFFAOYSA-N 0.000 description 6
- 229910052736 halogen Inorganic materials 0.000 description 6
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- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 6
- 125000003386 piperidinyl group Chemical group 0.000 description 6
- 230000008569 process Effects 0.000 description 6
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 description 6
- 239000000758 substrate Substances 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 6
- XMAYWYJOQHXEEK-OZXSUGGESA-N (2R,4S)-ketoconazole Chemical compound C1CN(C(=O)C)CCN1C(C=C1)=CC=C1OC[C@@H]1O[C@@](CN2C=NC=C2)(C=2C(=CC(Cl)=CC=2)Cl)OC1 XMAYWYJOQHXEEK-OZXSUGGESA-N 0.000 description 5
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- WPLOVIFNBMNBPD-ATHMIXSHSA-N subtilin Chemical compound CC1SCC(NC2=O)C(=O)NC(CC(N)=O)C(=O)NC(C(=O)NC(CCCCN)C(=O)NC(C(C)CC)C(=O)NC(=C)C(=O)NC(CCCCN)C(O)=O)CSC(C)C2NC(=O)C(CC(C)C)NC(=O)C1NC(=O)C(CCC(N)=O)NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C1NC(=O)C(=C/C)/NC(=O)C(CCC(N)=O)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)CNC(=O)C(NC(=O)C(NC(=O)C2NC(=O)CNC(=O)C3CCCN3C(=O)C(NC(=O)C3NC(=O)C(CC(C)C)NC(=O)C(=C)NC(=O)C(CCC(O)=O)NC(=O)C(NC(=O)C(CCCCN)NC(=O)C(N)CC=4C5=CC=CC=C5NC=4)CSC3)C(C)SC2)C(C)C)C(C)SC1)CC1=CC=CC=C1 WPLOVIFNBMNBPD-ATHMIXSHSA-N 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000003956 synaptic plasticity Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- MCZDHTKJGDCTAE-UHFFFAOYSA-M tetrabutylazanium;acetate Chemical compound CC([O-])=O.CCCC[N+](CCCC)(CCCC)CCCC MCZDHTKJGDCTAE-UHFFFAOYSA-M 0.000 description 1
- 125000004192 tetrahydrofuran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea group Chemical group NC(=S)N UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 1
- 238000003354 tissue distribution assay Methods 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 230000003936 working memory Effects 0.000 description 1
- 239000002676 xenobiotic agent Substances 0.000 description 1
- 229910052727 yttrium Inorganic materials 0.000 description 1
- VWQVUPCCIRVNHF-UHFFFAOYSA-N yttrium atom Chemical compound [Y] VWQVUPCCIRVNHF-UHFFFAOYSA-N 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
- 229960000607 ziprasidone Drugs 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
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Psychiatry (AREA)
- Hospice & Palliative Care (AREA)
- Pain & Pain Management (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201161494070P | 2011-06-07 | 2011-06-07 | |
| US61/494,070 | 2011-06-07 | ||
| PCT/IB2012/052627 WO2012168817A1 (en) | 2011-06-07 | 2012-05-24 | Pyrazolo[3,4-d]pyrimidine compounds and their use as pde2 inhibitors and/or cyp3a4 inhibitors |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2014516074A true JP2014516074A (ja) | 2014-07-07 |
| JP2014516074A5 JP2014516074A5 (enExample) | 2015-07-09 |
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Family Applications (1)
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| JP2014514172A Ceased JP2014516074A (ja) | 2011-06-07 | 2012-05-24 | ピラゾロ［３，４−ｄ］ピリミジン化合物ならびにそのＰＤＥ２阻害剤および／またはＣＹＰ３Ａ４阻害剤としての使用 |
Country Status (11)
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|---|---|
| US (1) | US8829010B2 (enExample) |
| EP (1) | EP2718295A1 (enExample) |
| JP (1) | JP2014516074A (enExample) |
| KR (1) | KR101626681B1 (enExample) |
| CN (1) | CN103596956A (enExample) |
| AU (1) | AU2012265970A1 (enExample) |
| CA (1) | CA2836851C (enExample) |
| IL (1) | IL229606A0 (enExample) |
| MX (1) | MX2013014470A (enExample) |
| SG (1) | SG195085A1 (enExample) |
| WO (1) | WO2012168817A1 (enExample) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2017536410A (ja) * | 2014-12-06 | 2017-12-07 | イントラ−セルラー・セラピーズ・インコーポレイテッドＩｎｔｒａ−Ｃｅｌｌｕｌａｒ Ｔｈｅｒａｐｉｅｓ， Ｉｎｃ． | 有機化合物 |
Families Citing this family (25)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TW201100441A (en) | 2009-06-01 | 2011-01-01 | Osi Pharm Inc | Amino pyrimidine anticancer compounds |
| EP2646448B1 (en) | 2010-11-29 | 2017-08-30 | OSI Pharmaceuticals, LLC | Macrocyclic kinase inhibitors |
| WO2014126954A1 (en) * | 2013-02-13 | 2014-08-21 | OSI Pharmaceuticals, LLC | Regioselective synthesis of substituted pyrimidines |
| CN104098574A (zh) * | 2013-04-12 | 2014-10-15 | 苏州科捷生物医药有限公司 | 氮杂环丁烷取代嘧啶类化合物及其用途 |
| WO2015026646A1 (en) * | 2013-08-20 | 2015-02-26 | E. I. Du Pont De Nemours And Company | Fungicidal pyrazoles |
| US9815796B2 (en) | 2013-12-23 | 2017-11-14 | Merck Sharp & Dohme Corp. | Pyrimidone carboxamide compounds as PDE2 inhibitors |
| JP6696904B2 (ja) | 2014-01-08 | 2020-05-20 | イントラ−セルラー・セラピーズ・インコーポレイテッドＩｎｔｒａ−Ｃｅｌｌｕｌａｒ Ｔｈｅｒａｐｉｅｓ， Ｉｎｃ． | 製剤および医薬組成物 |
| MA50375A (fr) | 2014-04-23 | 2021-05-26 | Dart Neuroscience Cayman Ltd | Compositions contenant des composés substitués de [1,2,4]triazolo[1,5-a]pyrimidine-7-yl utilisés en tant qu'inhibiteurs pde2 |
| JP2017114764A (ja) * | 2014-04-25 | 2017-06-29 | 武田薬品工業株式会社 | 片頭痛治療剤 |
| WO2016073424A1 (en) | 2014-11-05 | 2016-05-12 | Dart Neuroscience, Llc | Substituted 5-methyl-[1, 2, 4] triazolo [1,5-a) pyrimidin-2-amine compounds as pde2 inhibitors |
| KR102562576B1 (ko) | 2014-12-06 | 2023-08-01 | 인트라-셀룰라 써래피스, 인코퍼레이티드. | 유기 화합물 |
| JP2017538769A (ja) | 2014-12-22 | 2017-12-28 | ファイザー・インク | プロスタグランジンｅｐ３受容体の拮抗薬 |
| WO2016145614A1 (en) | 2015-03-17 | 2016-09-22 | Merck Sharp & Dohme Corp. | Triazolyl pyrimidinone compounds as pde2 inhibitors |
| US10287269B2 (en) | 2015-03-26 | 2019-05-14 | Merck Sharp & Dohme Corp. | Pyrazolyl pyrimidinone compounds as PDE2 inhibitors |
| US10195201B2 (en) | 2015-05-05 | 2019-02-05 | Merck Sharp & Dohme Corp. | Heteroaryl-pyrimidinone compounds as PDE2 inhibitors |
| WO2016183741A1 (en) | 2015-05-15 | 2016-11-24 | Merck Sharp & Dohme Corp. | Pyrimidinone amide compounds as pde2 inhibitors |
| WO2016191935A1 (en) | 2015-05-29 | 2016-12-08 | Merck Sharp & Dohme Corp. | 6-alkyl dihydropyrazolopyrimidinone compounds as pde2 inhibitors |
| WO2016192083A1 (en) | 2015-06-04 | 2016-12-08 | Merck Sharp & Dohme Corp. | Dihydropyrazolopyrimidinone compounds as pde2 inhibitors |
| WO2016209749A1 (en) | 2015-06-25 | 2016-12-29 | Merck Sharp & Dohme Corp. | Substituted pyrazolo/imidazolo bicyclic compounds as pde2 inhibitors |
| WO2017000276A1 (en) | 2015-07-01 | 2017-01-05 | Merck Sharp & Dohme Corp. | Bicyclic heterocyclic compounds as pde2 inhibitors |
| WO2017000277A1 (en) | 2015-07-01 | 2017-01-05 | Merck Sharp & Dohme Corp. | Substituted triazolo bicycliccompounds as pde2 inhibitors |
| WO2018091687A1 (en) | 2016-11-18 | 2018-05-24 | Integrative Research Laboratories Sweden Ab | Novel azetidine derivatives useful as modulators of cortical catecholaminergic neurotransmission |
| CN111447930A (zh) | 2017-11-23 | 2020-07-24 | 奥斯陆大学医院公司 | 心动过速的治疗 |
| BR112022008786A2 (pt) * | 2019-11-09 | 2022-07-26 | Shanghai Simr Biotechnology Co Ltd | Composto, composição, uso do composto ou da composição, e, método para tratar ou prevenir uma complicação diabética, doença relacionada à neuroinflamação ou aterosclerose |
| CN113244395B (zh) * | 2020-02-10 | 2024-07-23 | 广州市妇女儿童医疗中心 | 纤维化疾病机制及其治疗药物 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2007534687A (ja) * | 2004-04-23 | 2007-11-29 | エグゼリクシス， インコーポレイテッド | キナーゼ調節因子および使用方法 |
| JP2008526717A (ja) * | 2005-01-05 | 2008-07-24 | ニコメッド ゲゼルシャフト ミット ベシュレンクテル ハフツング | トリアゾロフタラジン |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102491969B (zh) | 2005-01-07 | 2015-08-19 | 辉瑞产品公司 | 杂芳族喹啉化合物及其作为pde10抑制剂的用途 |
| CN102020645B (zh) * | 2010-09-30 | 2012-12-12 | 中山大学 | 吡唑并嘧啶酮衍生物及其可药用盐、其制备方法和应用 |
-
2012
- 2012-05-24 SG SG2013086178A patent/SG195085A1/en unknown
- 2012-05-24 CA CA2836851A patent/CA2836851C/en not_active Expired - Fee Related
- 2012-05-24 CN CN201280027766.8A patent/CN103596956A/zh active Pending
- 2012-05-24 MX MX2013014470A patent/MX2013014470A/es unknown
- 2012-05-24 JP JP2014514172A patent/JP2014516074A/ja not_active Ceased
- 2012-05-24 AU AU2012265970A patent/AU2012265970A1/en not_active Abandoned
- 2012-05-24 US US14/116,064 patent/US8829010B2/en not_active Expired - Fee Related
- 2012-05-24 WO PCT/IB2012/052627 patent/WO2012168817A1/en not_active Ceased
- 2012-05-24 EP EP12727686.3A patent/EP2718295A1/en not_active Withdrawn
- 2012-05-24 KR KR1020147000046A patent/KR101626681B1/ko not_active Expired - Fee Related
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2013
- 2013-11-25 IL IL229606A patent/IL229606A0/en unknown
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2007534687A (ja) * | 2004-04-23 | 2007-11-29 | エグゼリクシス， インコーポレイテッド | キナーゼ調節因子および使用方法 |
| JP2008526717A (ja) * | 2005-01-05 | 2008-07-24 | ニコメッド ゲゼルシャフト ミット ベシュレンクテル ハフツング | トリアゾロフタラジン |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2017536410A (ja) * | 2014-12-06 | 2017-12-07 | イントラ−セルラー・セラピーズ・インコーポレイテッドＩｎｔｒａ−Ｃｅｌｌｕｌａｒ Ｔｈｅｒａｐｉｅｓ， Ｉｎｃ． | 有機化合物 |
Also Published As
| Publication number | Publication date |
|---|---|
| CA2836851C (en) | 2016-06-21 |
| MX2013014470A (es) | 2014-03-21 |
| EP2718295A1 (en) | 2014-04-16 |
| US20140080806A1 (en) | 2014-03-20 |
| CA2836851A1 (en) | 2012-12-13 |
| KR101626681B1 (ko) | 2016-06-01 |
| US8829010B2 (en) | 2014-09-09 |
| AU2012265970A1 (en) | 2013-11-28 |
| WO2012168817A1 (en) | 2012-12-13 |
| CN103596956A (zh) | 2014-02-19 |
| IL229606A0 (en) | 2014-01-30 |
| KR20140019466A (ko) | 2014-02-14 |
| SG195085A1 (en) | 2013-12-30 |
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