HUE028302T2 - Quinuclidine Compounds As Alpha-7 Nicotine Acetylcholine Receptor Ligands - Google Patents

Info

Publication number

HUE028302T2

HUE028302T2 HUE09733949A HUE09733949A HUE028302T2 HU E028302 T2 HUE028302 T2 HU E028302T2 HU E09733949 A HUE09733949 A HU E09733949A HU E09733949 A HUE09733949 A HU E09733949A HU E028302 T2 HUE028302 T2 HU E028302T2

Authority

HU

Hungary

Prior art keywords

mmol

amine

octan

oxazole

bicyclo

Prior art date

2008-04-23

Links

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• 239000003446 ligand Substances 0.000 title description 4
• 102000047725 alpha7 Nicotinic Acetylcholine Receptor Human genes 0.000 title 1
• 108700006085 alpha7 Nicotinic Acetylcholine Receptor Proteins 0.000 title 1
• 150000008584 quinuclidines Chemical class 0.000 title 1
• -1 chloroisobutyl Chemical group 0.000 claims description 771
• 229910052739 hydrogen Inorganic materials 0.000 claims description 553
• 239000000203 mixture Substances 0.000 claims description 246
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 99
• 229910001868 water Inorganic materials 0.000 claims description 87
• 125000004076 pyridyl group Chemical group 0.000 claims description 37
• 150000003839 salts Chemical class 0.000 claims description 32
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 28
• 125000005843 halogen group Chemical group 0.000 claims description 22
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 17
• 229910052757 nitrogen Inorganic materials 0.000 claims description 16
• 239000001257 hydrogen Substances 0.000 claims description 8
• 210000004556 brain Anatomy 0.000 claims description 4
• 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 4
• 238000002560 therapeutic procedure Methods 0.000 claims description 4
• 239000002253 acid Substances 0.000 claims description 3
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
• ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
• 125000003545 alkoxy group Chemical group 0.000 claims description 2
• 239000011591 potassium Substances 0.000 claims description 2
• 229910052700 potassium Inorganic materials 0.000 claims description 2
• 235000010627 Phaseolus vulgaris Nutrition 0.000 claims 2
• 244000046052 Phaseolus vulgaris Species 0.000 claims 2
• 125000001309 chloro group Chemical group Cl* 0.000 claims 2
• TXFPEBPIARQUIG-UHFFFAOYSA-N 4'-hydroxyacetophenone Chemical compound CC(=O)C1=CC=C(O)C=C1 TXFPEBPIARQUIG-UHFFFAOYSA-N 0.000 claims 1
• PLIKAWJENQZMHA-UHFFFAOYSA-N 4-aminophenol Chemical compound NC1=CC=C(O)C=C1 PLIKAWJENQZMHA-UHFFFAOYSA-N 0.000 claims 1
• 102100020786 Adenylosuccinate synthetase isozyme 2 Human genes 0.000 claims 1
• 206010015535 Euphoric mood Diseases 0.000 claims 1
• 241001024304 Mino Species 0.000 claims 1
• 206010037660 Pyrexia Diseases 0.000 claims 1
• 150000001241 acetals Chemical class 0.000 claims 1
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims 1
• 238000004090 dissolution Methods 0.000 claims 1
• 210000000981 epithelium Anatomy 0.000 claims 1
• 230000002743 euphoric effect Effects 0.000 claims 1
• 239000000796 flavoring agent Substances 0.000 claims 1
• 235000019634 flavors Nutrition 0.000 claims 1
• 150000002334 glycols Chemical class 0.000 claims 1
• 239000004579 marble Substances 0.000 claims 1
• 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 claims 1
• 238000003801 milling Methods 0.000 claims 1
• 239000003973 paint Substances 0.000 claims 1
• 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims 1
• 238000004018 waxing Methods 0.000 claims 1
• 235000013618 yogurt Nutrition 0.000 claims 1
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 434
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 299
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 282
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 268
• 238000005160 1H NMR spectroscopy Methods 0.000 description 253
• 238000006243 chemical reaction Methods 0.000 description 218
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 203
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 181
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 157
• 235000019439 ethyl acetate Nutrition 0.000 description 149
• 239000007787 solid Substances 0.000 description 137
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 125
• TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 120
• 239000000047 product Substances 0.000 description 119
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 114
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 110
• 239000000843 powder Substances 0.000 description 102
• 239000000243 solution Substances 0.000 description 85
• 150000001875 compounds Chemical class 0.000 description 84
• 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 74
• 238000000034 method Methods 0.000 description 70
• 238000010898 silica gel chromatography Methods 0.000 description 67
• 239000011541 reaction mixture Substances 0.000 description 65
• 229960001701 chloroform Drugs 0.000 description 58
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 48
• 239000012043 crude product Substances 0.000 description 45
• QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 44
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 41
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• VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 37
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 37
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 37
• 235000011114 ammonium hydroxide Nutrition 0.000 description 36
• 239000002244 precipitate Substances 0.000 description 36
• 125000000714 pyrimidinyl group Chemical group 0.000 description 36
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 35
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 34
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 34
• 229910052938 sodium sulfate Inorganic materials 0.000 description 34
• 235000011152 sodium sulphate Nutrition 0.000 description 34
• 239000000725 suspension Substances 0.000 description 33
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 32
• 238000004587 chromatography analysis Methods 0.000 description 31
• OUKVGTYIZUXBIR-JZGIKJSDSA-N [(3s)-3-hydroxy-1-azoniabicyclo[2.2.2]octan-3-yl]methylazanium;dichloride Chemical compound Cl.Cl.C1CC2[C@@](CN)(O)CN1CC2 OUKVGTYIZUXBIR-JZGIKJSDSA-N 0.000 description 30
• 239000012267 brine Substances 0.000 description 29
• 238000004440 column chromatography Methods 0.000 description 29
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 29
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 28
• OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 28
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 27
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
• 229910000024 caesium carbonate Inorganic materials 0.000 description 27
• 239000003921 oil Substances 0.000 description 27
• 235000019198 oils Nutrition 0.000 description 27
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 26
• 238000003818 flash chromatography Methods 0.000 description 26
• 229910000085 borane Inorganic materials 0.000 description 25
• 239000010410 layer Substances 0.000 description 25
• 239000013058 crude material Substances 0.000 description 24
• OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 24
• 235000019341 magnesium sulphate Nutrition 0.000 description 24
• XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 23
• 125000001424 substituent group Chemical group 0.000 description 23
• 238000000746 purification Methods 0.000 description 22
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 21
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 21
• 239000012044 organic layer Substances 0.000 description 21
• 238000004809 thin layer chromatography Methods 0.000 description 21
• 238000001914 filtration Methods 0.000 description 20
• 239000012071 phase Substances 0.000 description 20
• 239000000741 silica gel Substances 0.000 description 20
• 229910002027 silica gel Inorganic materials 0.000 description 20
• 229960001866 silicon dioxide Drugs 0.000 description 20
• 238000003756 stirring Methods 0.000 description 20
• 125000000335 thiazolyl group Chemical group 0.000 description 20
• 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 19
• KXMMNJQMGILZDB-UHFFFAOYSA-N 1-(2-oxopyridine-1-carbothioyl)pyridin-2-one Chemical compound O=C1C=CC=CN1C(=S)N1C(=O)C=CC=C1 KXMMNJQMGILZDB-UHFFFAOYSA-N 0.000 description 17
• 238000003556 assay Methods 0.000 description 17
• HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 17
• INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 17
• 239000002904 solvent Substances 0.000 description 17
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 16
• OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 16
• 239000000908 ammonium hydroxide Substances 0.000 description 16
• 229940043379 ammonium hydroxide Drugs 0.000 description 16
• 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 16
• RAFNCPHFRHZCPS-UHFFFAOYSA-N di(imidazol-1-yl)methanethione Chemical compound C1=CN=CN1C(=S)N1C=CN=C1 RAFNCPHFRHZCPS-UHFFFAOYSA-N 0.000 description 16
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 15
• QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 14
• 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 14
• FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 14
• 210000004027 cell Anatomy 0.000 description 14
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• 230000003287 optical effect Effects 0.000 description 13
• 229910000029 sodium carbonate Inorganic materials 0.000 description 13
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 13
• 125000001425 triazolyl group Chemical group 0.000 description 13
• BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 12
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• 102000005962 receptors Human genes 0.000 description 12
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• DUKKRSPKJMHASP-UHFFFAOYSA-N 6-chloropyrimidin-4-amine Chemical compound NC1=CC(Cl)=NC=N1 DUKKRSPKJMHASP-UHFFFAOYSA-N 0.000 description 11
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• 125000004093 cyano group Chemical group *C#N 0.000 description 11
• 125000002887 hydroxy group Chemical group [H]O* 0.000 description 11
• 239000007858 starting material Substances 0.000 description 11
• 238000011282 treatment Methods 0.000 description 11
• XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 10
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• 239000004202 carbamide Substances 0.000 description 10
• 238000012512 characterization method Methods 0.000 description 10
• MHYCRLGKOZWVEF-UHFFFAOYSA-N ethyl acetate;hydrate Chemical compound O.CCOC(C)=O MHYCRLGKOZWVEF-UHFFFAOYSA-N 0.000 description 10
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• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 9
• 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 9
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• 201000000980 schizophrenia Diseases 0.000 description 9
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• 125000001544 thienyl group Chemical group 0.000 description 9
• UONKGCZCROZZCD-QMMMGPOBSA-N (3s)-3-(aminomethyl)-1-azabicyclo[2.2.2]octan-3-ol Chemical compound C1CC2[C@@](CN)(O)CN1CC2 UONKGCZCROZZCD-QMMMGPOBSA-N 0.000 description 8
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• 239000000543 intermediate Substances 0.000 description 8
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• 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 description 7
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
• 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 7
• 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 7
• 125000004612 furopyridinyl group Chemical group O1C(=CC2=C1C=CC=N2)* 0.000 description 7
• 239000007788 liquid Substances 0.000 description 7
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• 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 7
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• 208000019022 Mood disease Diseases 0.000 description 6
• PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 6
• CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical group C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 6
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• 125000001246 bromo group Chemical group Br* 0.000 description 6
• 239000003153 chemical reaction reagent Substances 0.000 description 6
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• FKGQRXQOODICAT-UHFFFAOYSA-N di(imidazol-1-yl)methanimine Chemical compound C1=CN=CN1C(=N)N1C=CN=C1 FKGQRXQOODICAT-UHFFFAOYSA-N 0.000 description 6
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• IWZSFFYAXNHSIT-UHFFFAOYSA-N n-(7-methoxy-5-methyl-[1,3]thiazolo[5,4-d]pyrimidin-2-yl)-1,1-bis(methylsulfanyl)methanimine Chemical compound COC1=NC(C)=NC2=C1N=C(N=C(SC)SC)S2 IWZSFFYAXNHSIT-UHFFFAOYSA-N 0.000 description 6
• ZNNZYHKDIALBAK-UHFFFAOYSA-M potassium thiocyanate Chemical compound [K+].[S-]C#N ZNNZYHKDIALBAK-UHFFFAOYSA-M 0.000 description 6
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