TW201016677A - Novel derivatives - Google Patents

Info

Publication number

TW201016677A

TW201016677A TW098123842A TW98123842A TW201016677A TW 201016677 A TW201016677 A TW 201016677A TW 098123842 A TW098123842 A TW 098123842A TW 98123842 A TW98123842 A TW 98123842A TW 201016677 A TW201016677 A TW 201016677A

Authority

TW

Taiwan

Prior art keywords

phenyl

trifluoromethyl

mmol

carbonyl

sulfonyl

Prior art date

2008-07-17

Links

• Espacenet
• Global Dossier
• Discuss

• 238000000034 method Methods 0.000 claims abstract description 97
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 7
• 238000002560 therapeutic procedure Methods 0.000 claims abstract description 5
• 150000001875 compounds Chemical class 0.000 claims description 219
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 139
• -1 2-methyl-3-acridinyl Chemical group 0.000 claims description 100
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 91
• 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 88
• 150000003839 salts Chemical class 0.000 claims description 55
• 229910052739 hydrogen Inorganic materials 0.000 claims description 53
• 239000001257 hydrogen Substances 0.000 claims description 52
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 46
• 239000002253 acid Substances 0.000 claims description 43
• OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine group Chemical group NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 40
• 125000000217 alkyl group Chemical group 0.000 claims description 37
• JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 36
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 35
• 208000002193 Pain Diseases 0.000 claims description 30
• 230000036407 pain Effects 0.000 claims description 27
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 25
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 23
• 239000000463 material Substances 0.000 claims description 22
• 125000004076 pyridyl group Chemical group 0.000 claims description 19
• 229910052757 nitrogen Inorganic materials 0.000 claims description 18
• 125000003545 alkoxy group Chemical group 0.000 claims description 17
• 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 17
• 239000003814 drug Substances 0.000 claims description 15
• 229910052736 halogen Inorganic materials 0.000 claims description 15
• 150000002367 halogens Chemical class 0.000 claims description 14
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 14
• 150000002431 hydrogen Chemical class 0.000 claims description 12
• 238000003971 tillage Methods 0.000 claims description 11
• 125000001188 haloalkyl group Chemical group 0.000 claims description 10
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 9
• 125000006661 (C4-C6) heterocyclic group Chemical group 0.000 claims description 7
• MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Natural products C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 claims description 7
• 125000004438 haloalkoxy group Chemical group 0.000 claims description 7
• 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 7
• 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims description 6
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
• 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 5
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 5
• 239000002689 soil Substances 0.000 claims description 5
• 239000000126 substance Substances 0.000 claims description 5
• 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 5
• YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 4
• 230000000739 chaotic effect Effects 0.000 claims description 4
• 125000006612 decyloxy group Chemical group 0.000 claims description 4
• 229910052805 deuterium Inorganic materials 0.000 claims description 4
• 238000004519 manufacturing process Methods 0.000 claims description 4
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
• 125000003396 thiol group Chemical group [H]S* 0.000 claims description 4
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 3
• 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 3
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
• 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
• 125000000623 heterocyclic group Chemical group 0.000 claims description 3
• 125000002757 morpholinyl group Chemical group 0.000 claims description 3
• 229910052760 oxygen Inorganic materials 0.000 claims description 3
• 239000001301 oxygen Substances 0.000 claims description 3
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
• 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims 2
• KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims 2
• XTFIVUDBNACUBN-UHFFFAOYSA-N 1,3,5-trinitro-1,3,5-triazinane Chemical group [O-][N+](=O)N1CN([N+]([O-])=O)CN([N+]([O-])=O)C1 XTFIVUDBNACUBN-UHFFFAOYSA-N 0.000 claims 1
• 125000005577 anthracene group Chemical group 0.000 claims 1
• 125000002393 azetidinyl group Chemical group 0.000 claims 1
• 229910052754 neon Inorganic materials 0.000 claims 1
• GKAOGPIIYCISHV-UHFFFAOYSA-N neon atom Chemical compound [Ne] GKAOGPIIYCISHV-UHFFFAOYSA-N 0.000 claims 1
• 230000008569 process Effects 0.000 abstract description 36
• 238000002360 preparation method Methods 0.000 abstract description 15
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 12
• 101000935123 Homo sapiens Voltage-dependent N-type calcium channel subunit alpha-1B Proteins 0.000 abstract description 10
• 102100025342 Voltage-dependent N-type calcium channel subunit alpha-1B Human genes 0.000 abstract description 10
• 201000010099 disease Diseases 0.000 abstract description 8
• 230000000903 blocking effect Effects 0.000 abstract description 3
• 230000009286 beneficial effect Effects 0.000 abstract 1
• 150000004885 piperazines Chemical class 0.000 abstract 1
• 229940066771 systemic antihistamines piperazine derivative Drugs 0.000 abstract 1
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 362
• 235000019439 ethyl acetate Nutrition 0.000 description 179
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 135
• 239000000243 solution Substances 0.000 description 105
• 239000000203 mixture Substances 0.000 description 99
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 91
• 239000011541 reaction mixture Substances 0.000 description 76
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 69
• 206010057190 Respiratory tract infections Diseases 0.000 description 66
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 62
• 238000006243 chemical reaction Methods 0.000 description 53
• 239000002585 base Substances 0.000 description 50
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 45
• 229910001868 water Inorganic materials 0.000 description 42
• 239000012044 organic layer Substances 0.000 description 41
• XKRFYHLGVUSROY-UHFFFAOYSA-N argon Substances [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 40
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 40
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 40
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 32
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 32
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 32
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 31
• 238000003756 stirring Methods 0.000 description 31
• KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 30
• 239000007787 solid Substances 0.000 description 30
• 239000002904 solvent Substances 0.000 description 30
• 239000000047 product Substances 0.000 description 29
• 239000010410 layer Substances 0.000 description 28
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 26
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 25
• UXRDAJMOOGEIAQ-CKOZHMEPSA-N [(8r,9s,10r,13s,14s,17r)-17-acetyl-10,13-dimethyl-16-methylidene-3-oxo-1,2,8,9,11,12,14,15-octahydrocyclopenta[a]phenanthren-17-yl] acetate Chemical compound C1=CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC(=C)[C@](OC(=O)C)(C(C)=O)[C@@]1(C)CC2 UXRDAJMOOGEIAQ-CKOZHMEPSA-N 0.000 description 23
• 239000013058 crude material Substances 0.000 description 22
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
• 229910052786 argon Inorganic materials 0.000 description 21
• 210000004027 cell Anatomy 0.000 description 21
• 239000003921 oil Substances 0.000 description 21
• 235000019198 oils Nutrition 0.000 description 21
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 20
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 19
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
• 239000007789 gas Substances 0.000 description 17
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 16
• 230000002829 reductive effect Effects 0.000 description 16
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
• VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
• 125000000717 hydrazino group Chemical group [H]N([*])N([H])[H] 0.000 description 15
• 239000003643 water by type Substances 0.000 description 15
• BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 14
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 13
• 239000007821 HATU Substances 0.000 description 13
• IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 13
• 150000002148 esters Chemical class 0.000 description 12
• 239000012071 phase Substances 0.000 description 12
• 238000000746 purification Methods 0.000 description 12
• 229920006395 saturated elastomer Polymers 0.000 description 12
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 11
• 244000166102 Eucalyptus leucoxylon Species 0.000 description 11
• 235000004694 Eucalyptus leucoxylon Nutrition 0.000 description 11
• 239000000460 chlorine Substances 0.000 description 11
• OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 11
• UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 11
• 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 11
• YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 10
• QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 10
• 235000015165 citric acid Nutrition 0.000 description 10
• 238000012360 testing method Methods 0.000 description 10
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 9
• 241000400611 Eucalyptus deanei Species 0.000 description 9
• 239000003795 chemical substances by application Substances 0.000 description 9
• 230000002209 hydrophobic effect Effects 0.000 description 9
• 239000003446 ligand Substances 0.000 description 9
• AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 8
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• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
• 239000000706 filtrate Substances 0.000 description 8
• 238000001914 filtration Methods 0.000 description 8
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 7
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 7
• 229910052801 chlorine Inorganic materials 0.000 description 7
• HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 7
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• 239000012458 free base Substances 0.000 description 7
• BRZYSWJRSDMWLG-CAXSIQPQSA-N geneticin Chemical compound O1C[C@@](O)(C)[C@H](NC)[C@@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](C(C)O)O2)N)[C@@H](N)C[C@H]1N BRZYSWJRSDMWLG-CAXSIQPQSA-N 0.000 description 7
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• 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 6
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• 150000001412 amines Chemical class 0.000 description 6
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• 229910052794 bromium Inorganic materials 0.000 description 6
• MWKFXSUHUHTGQN-UHFFFAOYSA-N decan-1-ol Chemical compound CCCCCCCCCCO MWKFXSUHUHTGQN-UHFFFAOYSA-N 0.000 description 6
• 238000001704 evaporation Methods 0.000 description 6
• 230000008020 evaporation Effects 0.000 description 6
• 238000003818 flash chromatography Methods 0.000 description 6
• NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 6
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 6
• 235000019341 magnesium sulphate Nutrition 0.000 description 6
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
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• 239000007858 starting material Substances 0.000 description 6
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• 208000024827 Alzheimer disease Diseases 0.000 description 5
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• 206010012289 Dementia Diseases 0.000 description 5
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• 239000005557 antagonist Substances 0.000 description 5
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• 125000001246 bromo group Chemical group Br* 0.000 description 5
• 125000005843 halogen group Chemical group 0.000 description 5
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• YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 4
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• YQYJSBFKSSDGFO-UHFFFAOYSA-N Epihygromycin Natural products OC1C(O)C(C(=O)C)OC1OC(C(=C1)O)=CC=C1C=C(C)C(=O)NC1C(O)C(O)C2OCOC2C1O YQYJSBFKSSDGFO-UHFFFAOYSA-N 0.000 description 4
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• 239000000556 agonist Substances 0.000 description 4
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• LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 4
• 239000000052 vinegar Substances 0.000 description 4
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• 239000011701 zinc Substances 0.000 description 4
• 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 3
• 125000002373 5 membered heterocyclic group Chemical group 0.000 description 3
• JWWGTYCXARQFOT-UHFFFAOYSA-N 6-sulfanylidene-1h-pyridine-3-carboxylic acid Chemical compound OC(=O)C1=CC=C(S)N=C1 JWWGTYCXARQFOT-UHFFFAOYSA-N 0.000 description 3
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
• OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 3
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