KR20110025984A - 포스포디에스테라제 １０ 억제제로서의 이치환된 페닐 화합물 - Google Patents
포스포디에스테라제 １０ 억제제로서의 이치환된 페닐 화합물 Download PDFInfo
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- KR20110025984A KR20110025984A KR1020117001927A KR20117001927A KR20110025984A KR 20110025984 A KR20110025984 A KR 20110025984A KR 1020117001927 A KR1020117001927 A KR 1020117001927A KR 20117001927 A KR20117001927 A KR 20117001927A KR 20110025984 A KR20110025984 A KR 20110025984A
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- Prior art keywords
- compound
- substituted
- unsubstituted
- alkyl
- benzo
- Prior art date
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 title claims abstract description 22
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 title abstract description 10
- 239000003112 inhibitor Substances 0.000 title abstract description 9
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 title abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 205
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 23
- 238000011282 treatment Methods 0.000 claims abstract description 20
- 238000000034 method Methods 0.000 claims abstract description 18
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 10
- -1 cyano, amino Chemical group 0.000 claims description 273
- 125000000217 alkyl group Chemical group 0.000 claims description 59
- 229910052736 halogen Inorganic materials 0.000 claims description 59
- 150000002367 halogens Chemical class 0.000 claims description 58
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 47
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 43
- 125000006413 ring segment Chemical group 0.000 claims description 37
- 125000003545 alkoxy group Chemical group 0.000 claims description 34
- 125000003118 aryl group Chemical group 0.000 claims description 34
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 34
- 125000005112 cycloalkylalkoxy group Chemical group 0.000 claims description 34
- 125000001072 heteroaryl group Chemical group 0.000 claims description 34
- 125000001424 substituent group Chemical group 0.000 claims description 33
- 125000005605 benzo group Chemical group 0.000 claims description 29
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 29
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 26
- 229910052799 carbon Inorganic materials 0.000 claims description 25
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 24
- 229910052757 nitrogen Inorganic materials 0.000 claims description 24
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 23
- 125000003282 alkyl amino group Chemical group 0.000 claims description 21
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 21
- 201000000980 schizophrenia Diseases 0.000 claims description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims description 16
- 239000001257 hydrogen Substances 0.000 claims description 15
- 150000003839 salts Chemical class 0.000 claims description 15
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 14
- 125000004001 thioalkyl group Chemical group 0.000 claims description 14
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 13
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 13
- 125000005885 heterocycloalkylalkyl group Chemical group 0.000 claims description 12
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 12
- 125000003368 amide group Chemical group 0.000 claims description 11
- 150000002431 hydrogen Chemical class 0.000 claims description 11
- 229910052760 oxygen Inorganic materials 0.000 claims description 11
- 229910052717 sulfur Inorganic materials 0.000 claims description 11
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 10
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 10
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 9
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 9
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims description 9
- 208000008589 Obesity Diseases 0.000 claims description 8
- KPCZJLGGXRGYIE-UHFFFAOYSA-N [C]1=CC=CN=C1 Chemical group [C]1=CC=CN=C1 KPCZJLGGXRGYIE-UHFFFAOYSA-N 0.000 claims description 8
- 125000002950 monocyclic group Chemical group 0.000 claims description 8
- 235000020824 obesity Nutrition 0.000 claims description 8
- 208000023105 Huntington disease Diseases 0.000 claims description 7
- 125000004414 alkyl thio group Chemical group 0.000 claims description 7
- 125000004104 aryloxy group Chemical group 0.000 claims description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 7
- 125000005553 heteroaryloxy group Chemical group 0.000 claims description 7
- 125000005842 heteroatom Chemical group 0.000 claims description 7
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 6
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 208000001145 Metabolic Syndrome Diseases 0.000 claims description 5
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 claims description 5
- 125000004076 pyridyl group Chemical group 0.000 claims description 5
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 4
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 4
- 239000001301 oxygen Substances 0.000 claims description 4
- 208000019116 sleep disease Diseases 0.000 claims description 4
- 239000011593 sulfur Substances 0.000 claims description 4
- 208000014094 Dystonic disease Diseases 0.000 claims description 3
- 208000030814 Eating disease Diseases 0.000 claims description 3
- 208000019454 Feeding and Eating disease Diseases 0.000 claims description 3
- 206010034158 Pathological gambling Diseases 0.000 claims description 3
- 206010043118 Tardive Dyskinesia Diseases 0.000 claims description 3
- 125000002102 aryl alkyloxo group Chemical group 0.000 claims description 3
- 208000015114 central nervous system disease Diseases 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 206010012601 diabetes mellitus Diseases 0.000 claims description 3
- 208000035475 disorder Diseases 0.000 claims description 3
- 235000014632 disordered eating Nutrition 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 201000003631 narcolepsy Diseases 0.000 claims description 3
- 208000012201 sexual and gender identity disease Diseases 0.000 claims description 3
- 208000015891 sexual disease Diseases 0.000 claims description 3
- 230000005586 smoking cessation Effects 0.000 claims description 3
- 125000005647 linker group Chemical group 0.000 claims description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 2
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims 2
- 125000006625 (C3-C8) cycloalkyloxy group Chemical group 0.000 claims 2
- 150000002828 nitro derivatives Chemical class 0.000 claims 2
- 125000001113 thiadiazolyl group Chemical group 0.000 claims 1
- 210000003169 central nervous system Anatomy 0.000 abstract description 8
- 208000024891 symptom Diseases 0.000 abstract description 8
- 201000010099 disease Diseases 0.000 abstract description 7
- 241000124008 Mammalia Species 0.000 abstract description 5
- 208000012902 Nervous system disease Diseases 0.000 abstract description 5
- 208000025966 Neurological disease Diseases 0.000 abstract description 5
- 208000015122 neurodegenerative disease Diseases 0.000 abstract description 5
- 208000020016 psychiatric disease Diseases 0.000 abstract description 4
- 230000007278 cognition impairment Effects 0.000 abstract description 3
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- 230000000698 schizophrenic effect Effects 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 289
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 231
- 239000000203 mixture Substances 0.000 description 230
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 165
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 156
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 136
- 239000000243 solution Substances 0.000 description 133
- 235000019439 ethyl acetate Nutrition 0.000 description 127
- 229910052786 argon Inorganic materials 0.000 description 78
- 239000002904 solvent Substances 0.000 description 77
- 239000007787 solid Substances 0.000 description 74
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 64
- 239000000741 silica gel Substances 0.000 description 58
- 229910002027 silica gel Inorganic materials 0.000 description 58
- 239000011541 reaction mixture Substances 0.000 description 54
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 51
- 239000011734 sodium Substances 0.000 description 50
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 44
- 238000010992 reflux Methods 0.000 description 42
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 42
- 238000003818 flash chromatography Methods 0.000 description 41
- 238000004587 chromatography analysis Methods 0.000 description 39
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 38
- 239000000706 filtrate Substances 0.000 description 34
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 34
- 238000003786 synthesis reaction Methods 0.000 description 31
- 230000015572 biosynthetic process Effects 0.000 description 27
- 239000012074 organic phase Substances 0.000 description 26
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 description 26
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 24
- 239000007864 aqueous solution Substances 0.000 description 22
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 22
- 229920006395 saturated elastomer Polymers 0.000 description 22
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- 239000012267 brine Substances 0.000 description 20
- 238000009472 formulation Methods 0.000 description 20
- QLULGIRFKAWHOJ-UHFFFAOYSA-N pyridin-4-ylboronic acid Chemical compound OB(O)C1=CC=NC=C1 QLULGIRFKAWHOJ-UHFFFAOYSA-N 0.000 description 20
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 20
- 239000003921 oil Substances 0.000 description 19
- 235000019198 oils Nutrition 0.000 description 19
- 239000000725 suspension Substances 0.000 description 19
- 235000008504 concentrate Nutrition 0.000 description 16
- 239000012141 concentrate Substances 0.000 description 16
- SMUQFGGVLNAIOZ-UHFFFAOYSA-N quinaldine Chemical compound C1=CC=CC2=NC(C)=CC=C21 SMUQFGGVLNAIOZ-UHFFFAOYSA-N 0.000 description 16
- 238000010898 silica gel chromatography Methods 0.000 description 16
- 239000001993 wax Substances 0.000 description 16
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 15
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 15
- 238000012360 testing method Methods 0.000 description 15
- 235000002639 sodium chloride Nutrition 0.000 description 14
- 239000003814 drug Substances 0.000 description 13
- 238000000746 purification Methods 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 12
- 235000017557 sodium bicarbonate Nutrition 0.000 description 12
- VNLSTUJKUKLXCE-UHFFFAOYSA-N 2-[[4-(2-nitro-6-pyridin-4-ylphenyl)phenoxy]methyl]quinoline Chemical compound C=1C=C(OCC=2N=C3C=CC=CC3=CC=2)C=CC=1C=1C([N+](=O)[O-])=CC=CC=1C1=CC=NC=C1 VNLSTUJKUKLXCE-UHFFFAOYSA-N 0.000 description 11
- 229940079593 drug Drugs 0.000 description 11
- 230000000694 effects Effects 0.000 description 11
- 238000001914 filtration Methods 0.000 description 11
- 239000012044 organic layer Substances 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 239000008346 aqueous phase Substances 0.000 description 10
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 10
- 229910000024 caesium carbonate Inorganic materials 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- 239000000164 antipsychotic agent Substances 0.000 description 9
- 125000004429 atom Chemical group 0.000 description 9
- 239000012230 colorless oil Substances 0.000 description 9
- 239000006260 foam Substances 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
- KPMBJFBCGUKSKZ-UHFFFAOYSA-N 3-pyridin-4-yl-2-[4-(quinolin-2-ylmethoxy)phenyl]aniline Chemical compound C=1C=C(OCC=2N=C3C=CC=CC3=CC=2)C=CC=1C=1C(N)=CC=CC=1C1=CC=NC=C1 KPMBJFBCGUKSKZ-UHFFFAOYSA-N 0.000 description 8
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 8
- 101100272976 Panax ginseng CYP716A53v2 gene Proteins 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
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- 239000002552 dosage form Substances 0.000 description 8
- 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 8
- 238000001802 infusion Methods 0.000 description 8
- HRVRWIBVVHOHNN-UHFFFAOYSA-N 2-bromo-3-nitrophenol Chemical compound OC1=CC=CC([N+]([O-])=O)=C1Br HRVRWIBVVHOHNN-UHFFFAOYSA-N 0.000 description 7
- WUZBJBRSKNHZJA-UHFFFAOYSA-N 3-nitro-2-(4-phenylmethoxyphenyl)phenol Chemical compound OC1=CC=CC([N+]([O-])=O)=C1C(C=C1)=CC=C1OCC1=CC=CC=C1 WUZBJBRSKNHZJA-UHFFFAOYSA-N 0.000 description 7
- SVIAEKFXYHOOIZ-UHFFFAOYSA-N 4-(2-nitro-6-pyridin-4-ylphenyl)phenol Chemical compound C1=CC(O)=CC=C1C1=C(C=2C=CN=CC=2)C=CC=C1[N+]([O-])=O SVIAEKFXYHOOIZ-UHFFFAOYSA-N 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 7
- 241000699670 Mus sp. Species 0.000 description 7
- 208000028017 Psychotic disease Diseases 0.000 description 7
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- 238000002347 injection Methods 0.000 description 7
- 239000007924 injection Substances 0.000 description 7
- 238000001990 intravenous administration Methods 0.000 description 7
- UISDUKOOLHTIRD-UHFFFAOYSA-N 4-[3-nitro-2-(4-phenylmethoxyphenyl)phenyl]pyridine Chemical compound C=1C=C(OCC=2C=CC=CC=2)C=CC=1C=1C([N+](=O)[O-])=CC=CC=1C1=CC=NC=C1 UISDUKOOLHTIRD-UHFFFAOYSA-N 0.000 description 6
- 241000699666 Mus <mouse, genus> Species 0.000 description 6
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 6
- 125000005083 alkoxyalkoxy group Chemical group 0.000 description 6
- 229940005529 antipsychotics Drugs 0.000 description 6
- 239000007900 aqueous suspension Substances 0.000 description 6
- 210000004556 brain Anatomy 0.000 description 6
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 6
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 6
- 238000001425 electrospray ionisation time-of-flight mass spectrometry Methods 0.000 description 6
- 125000005412 pyrazyl group Chemical group 0.000 description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 6
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 6
- DCTWUFRRAQEPTP-UHFFFAOYSA-N 2-[[4-(3-methyl-2-pyridin-4-ylphenyl)phenoxy]methyl]quinoline Chemical compound CC1=CC=CC(C=2C=CC(OCC=3N=C4C=CC=CC4=CC=3)=CC=2)=C1C1=CC=NC=C1 DCTWUFRRAQEPTP-UHFFFAOYSA-N 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 5
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- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 5
- 239000000499 gel Substances 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 238000004949 mass spectrometry Methods 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 5
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- DMJHEIDWSIAXCS-UHFFFAOYSA-N (4-phenylmethoxyphenyl)boronic acid Chemical compound C1=CC(B(O)O)=CC=C1OCC1=CC=CC=C1 DMJHEIDWSIAXCS-UHFFFAOYSA-N 0.000 description 4
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 4
- VTWAIOQJNHBREO-UHFFFAOYSA-N 2-(2-bromo-4-chlorophenoxy)oxane Chemical compound BrC1=CC(Cl)=CC=C1OC1OCCCC1 VTWAIOQJNHBREO-UHFFFAOYSA-N 0.000 description 4
- LKIIAXCVHKLFLL-UHFFFAOYSA-N 2-(2-bromo-4-fluorophenoxy)oxane Chemical compound BrC1=CC(F)=CC=C1OC1OCCCC1 LKIIAXCVHKLFLL-UHFFFAOYSA-N 0.000 description 4
- RMPVKDAXBCLEHT-UHFFFAOYSA-N 2-(2-bromo-4-methylphenoxy)oxane Chemical compound BrC1=CC(C)=CC=C1OC1OCCCC1 RMPVKDAXBCLEHT-UHFFFAOYSA-N 0.000 description 4
- HKLQJDBXYVBQEB-UHFFFAOYSA-N 2-(2-bromo-6-fluorophenoxy)oxane Chemical compound FC1=CC=CC(Br)=C1OC1OCCCC1 HKLQJDBXYVBQEB-UHFFFAOYSA-N 0.000 description 4
- DSHDIYIOTRZOBW-UHFFFAOYSA-N 2-(2-bromo-6-methylphenoxy)oxane Chemical compound CC1=CC=CC(Br)=C1OC1OCCCC1 DSHDIYIOTRZOBW-UHFFFAOYSA-N 0.000 description 4
- CJQQCJCXPNMAEN-UHFFFAOYSA-N 2-(2-chloro-6-iodophenoxy)oxane Chemical compound ClC1=CC=CC(I)=C1OC1OCCCC1 CJQQCJCXPNMAEN-UHFFFAOYSA-N 0.000 description 4
- WDETYCRYUBGKCE-UHFFFAOYSA-N 2-(chloromethyl)quinolin-1-ium;chloride Chemical compound Cl.C1=CC=CC2=NC(CCl)=CC=C21 WDETYCRYUBGKCE-UHFFFAOYSA-N 0.000 description 4
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- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
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- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
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- GZKLJWGUPQBVJQ-UHFFFAOYSA-N sertindole Chemical compound C1=CC(F)=CC=C1N1C2=CC=C(Cl)C=C2C(C2CCN(CCN3C(NCC3)=O)CC2)=C1 GZKLJWGUPQBVJQ-UHFFFAOYSA-N 0.000 description 1
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- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
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- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
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- HBDDRESWUAFAHY-UHFFFAOYSA-N thiomorpholin-3-one Chemical compound O=C1CSCCN1 HBDDRESWUAFAHY-UHFFFAOYSA-N 0.000 description 1
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- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
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- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
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- A—HUMAN NECESSITIES
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- 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
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- 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
- A61P25/20—Hypnotics; Sedatives
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
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- Diabetes (AREA)
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- Obesity (AREA)
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- Endocrinology (AREA)
- Psychiatry (AREA)
- Pain & Pain Management (AREA)
- Emergency Medicine (AREA)
- Child & Adolescent Psychology (AREA)
- Anesthesiology (AREA)
- Psychology (AREA)
- Reproductive Health (AREA)
- Nutrition Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Quinoline Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
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| US13885608P | 2008-12-18 | 2008-12-18 | |
| US61/138,856 | 2008-12-18 |
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| EP (1) | EP2297131A2 (enExample) |
| JP (1) | JP2011526294A (enExample) |
| KR (1) | KR20110025984A (enExample) |
| CN (1) | CN102131798A (enExample) |
| AU (1) | AU2009262150A1 (enExample) |
| BR (1) | BRPI0914775A2 (enExample) |
| CA (1) | CA2729220A1 (enExample) |
| MX (1) | MX2011000177A (enExample) |
| RU (1) | RU2011102587A (enExample) |
| WO (1) | WO2009158467A2 (enExample) |
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| AU2010311493B2 (en) * | 2009-10-30 | 2014-06-05 | Janssen Pharmaceutica Nv | Radiolabelled PDE10 ligands |
| EP2423181A1 (en) | 2010-07-28 | 2012-02-29 | Prous Institute For Biomedical Research S.A. | Multitarget substituted biphenyl diol derivatives |
| CN107141309A (zh) | 2011-01-11 | 2017-09-08 | 桑诺维恩药品公司 | 杂芳基化合物及其使用方法 |
| CN103476757A (zh) | 2011-02-18 | 2013-12-25 | 阿勒根公司 | 作为磷酸二酯酶10(pde10a)的抑制剂的取代的6,7-二烷氧基-3-异喹啉醇衍生物 |
| US20120309796A1 (en) | 2011-06-06 | 2012-12-06 | Fariborz Firooznia | Benzocycloheptene acetic acids |
| GB201113538D0 (en) * | 2011-08-04 | 2011-09-21 | Karobio Ab | Novel estrogen receptor ligands |
| JP6299591B2 (ja) | 2012-07-03 | 2018-03-28 | 小野薬品工業株式会社 | ソマトスタチン受容体作動活性を有する化合物およびその医薬用途 |
| AU2013289284B2 (en) * | 2012-07-09 | 2017-03-30 | Janssen Pharmaceutica Nv | Inhibitors of phosphodiesterase 10 enzyme |
| WO2014071044A1 (en) | 2012-11-01 | 2014-05-08 | Allergan, Inc. | Substituted 6,7-dialkoxy-3-isoquinoline derivatives as inhibitors of phosphodiesterase 10 (pde10a) |
| US8906951B1 (en) | 2013-06-24 | 2014-12-09 | Tigercat Pharma, Inc. | Use of NK-1 receptor antagonists in pruritus |
| US9198898B2 (en) | 2013-06-24 | 2015-12-01 | Tigercat Pharma, Inc. | Use of NK-1 receptor antagonists in pruritus |
| EP2860177A3 (en) * | 2013-09-20 | 2015-06-10 | Bayer Intellectual Property GmbH | Synthesis of functionalized arenes |
| US9200016B2 (en) | 2013-12-05 | 2015-12-01 | Allergan, Inc. | Substituted 6, 7-dialkoxy-3-isoquinoline derivatives as inhibitors of phosphodiesterase 10 (PDE 10A) |
| IL269241B (en) | 2017-03-16 | 2022-09-01 | Crinetics Pharmaceuticals Inc | Somatostatin modulators and uses thereof |
| EP3752498B1 (en) | 2018-02-12 | 2023-06-28 | Crinetics Pharmaceuticals, Inc. | Somatostatin modulators and uses thereof |
| CN112074505B (zh) | 2018-03-08 | 2024-04-05 | 因赛特公司 | 作为PI3K-γ抑制剂的氨基吡嗪二醇化合物 |
| US11046658B2 (en) | 2018-07-02 | 2021-06-29 | Incyte Corporation | Aminopyrazine derivatives as PI3K-γ inhibitors |
| EP4548974A3 (en) | 2018-09-18 | 2025-08-13 | Crinetics Pharmaceuticals, Inc. | Somatostatin modulators and uses thereof |
| TWI841768B (zh) * | 2019-08-14 | 2024-05-11 | 美商克林提克斯醫藥股份有限公司 | 非肽生長抑制素(somatostatin)5型受體激動劑及其用途 |
| KR102811543B1 (ko) | 2019-10-16 | 2025-05-23 | 삼성디스플레이 주식회사 | 유기 전계 발광 소자 및 유기 전계 발광 소자용 다환 화합물 |
| WO2022029640A1 (en) * | 2020-08-04 | 2022-02-10 | Precision Bio-Therapeutics S.R.L. | Quinoline compounds as selective and/or dual modulators of bile acid receptors and leukotriene cysteinyl receptors |
| IL305011A (en) | 2021-02-17 | 2023-10-01 | Crinetics Pharmaceuticals Inc | Crystalline forms of a somatostatin modulator |
| AU2023396827A1 (en) | 2022-12-13 | 2025-06-19 | Crinetics Pharmaceuticals, Inc. | Somatostatin subtype-2 receptor (sst2r) targeted therapeutics and uses thereof |
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| EP0453210A3 (en) * | 1990-04-19 | 1993-01-13 | Imperial Chemical Industries Plc | Pyridine derivatives |
| NZ238624A (en) * | 1990-06-19 | 1994-08-26 | Meiji Seika Co | Pyridine derivatives, compositions, preparations and use thereof |
| GB2264710A (en) * | 1992-03-04 | 1993-09-08 | Merck & Co Inc | Quinoline and azaquinoline angiotensin ii antagonists incorporating a substituted biphenyl element |
| EP1541149A1 (en) * | 2002-06-26 | 2005-06-15 | Kyowa Hakko Kogyo Co., Ltd. | Phosphodiesterase inhibitor |
| US7524870B2 (en) * | 2004-12-03 | 2009-04-28 | Hoffmann-La Roche Inc. | Biaryloxymethylarenecarboxylic acids as glycogen synthase activators |
| WO2007129183A2 (en) * | 2006-05-02 | 2007-11-15 | Pfizer Products Inc. | Bicyclic heteroaryl compounds as pde10 inhibitors |
| WO2008033455A2 (en) * | 2006-09-13 | 2008-03-20 | The Institutes For Pharmaceutical Discovery, Llc | Biphenyl and heteroaryl phenyl derivatives as protein tyrosine phosphatases inhibitors |
-
2009
- 2009-06-25 BR BRPI0914775A patent/BRPI0914775A2/pt not_active IP Right Cessation
- 2009-06-25 CN CN2009801332872A patent/CN102131798A/zh active Pending
- 2009-06-25 CA CA2729220A patent/CA2729220A1/en not_active Abandoned
- 2009-06-25 WO PCT/US2009/048608 patent/WO2009158467A2/en not_active Ceased
- 2009-06-25 US US13/001,361 patent/US20110224204A1/en not_active Abandoned
- 2009-06-25 KR KR1020117001927A patent/KR20110025984A/ko not_active Ceased
- 2009-06-25 JP JP2011516646A patent/JP2011526294A/ja active Pending
- 2009-06-25 EP EP09770999A patent/EP2297131A2/en not_active Withdrawn
- 2009-06-25 MX MX2011000177A patent/MX2011000177A/es not_active Application Discontinuation
- 2009-06-25 AU AU2009262150A patent/AU2009262150A1/en not_active Abandoned
- 2009-06-25 RU RU2011102587/04A patent/RU2011102587A/ru not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| WO2009158467A3 (en) | 2010-07-29 |
| AU2009262150A1 (en) | 2009-12-30 |
| EP2297131A2 (en) | 2011-03-23 |
| US20110224204A1 (en) | 2011-09-15 |
| BRPI0914775A2 (pt) | 2015-10-20 |
| WO2009158467A2 (en) | 2009-12-30 |
| MX2011000177A (es) | 2011-06-20 |
| RU2011102587A (ru) | 2012-07-27 |
| JP2011526294A (ja) | 2011-10-06 |
| CN102131798A (zh) | 2011-07-20 |
| CA2729220A1 (en) | 2009-12-30 |
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