JPH08502731A - スクアレンシンターゼ阻害剤としてのキヌクリジン誘導体 - Google Patents

スクアレンシンターゼ阻害剤としてのキヌクリジン誘導体

Info

Publication number: JPH08502731A
Authority: JP; Japan
Prior art keywords: compound; formula; hydrogen; hydroxy; mixture
Prior art date: 1992-08-28
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.): Pending

Application number

JP6506955A

Other languages

English (en)

Japanese (ja)

Inventor

ブラウン，ジョージ・ロバート

マリオン，ケイス・ブレークニー

ホウィッタモア，ポール・ロバート・オーウェン

ブリタイン，デヴィッド・ロバート

Original Assignee

ゼネカ・リミテッド

Priority date (The priority date 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 date listed.)

1992-08-28

Filing date

1993-08-24

Publication date

1996-03-26

1993-08-24 Application filed by ゼネカ・リミテッド filed Critical ゼネカ・リミテッド

1996-03-26 Publication of JPH08502731A publication Critical patent/JPH08502731A/ja

Status Pending legal-status Critical Current

Links

239000004059 squalene synthase inhibitor Substances 0.000 title description 6
150000008584 quinuclidines Chemical class 0.000 title description 2
150000001875 compounds Chemical class 0.000 claims abstract description 278
-1 hydroxy, amino Chemical group 0.000 claims abstract description 154
229910052739 hydrogen Inorganic materials 0.000 claims abstract description 79
238000000034 method Methods 0.000 claims abstract description 77
239000001257 hydrogen Substances 0.000 claims abstract description 70
125000000217 alkyl group Chemical group 0.000 claims abstract description 55
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 50
125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 48
150000003839 salts Chemical class 0.000 claims abstract description 39
125000001424 substituent group Chemical group 0.000 claims abstract description 32
229910052757 nitrogen Inorganic materials 0.000 claims abstract description 24
125000003545 alkoxy group Chemical group 0.000 claims abstract description 19
125000005843 halogen group Chemical group 0.000 claims abstract description 19
150000002431 hydrogen Chemical class 0.000 claims abstract description 19
125000003342 alkenyl group Chemical group 0.000 claims abstract description 14
125000005236 alkanoylamino group Chemical group 0.000 claims abstract description 12
125000004414 alkyl thio group Chemical group 0.000 claims abstract description 12
125000000304 alkynyl group Chemical group 0.000 claims abstract description 11
125000001072 heteroaryl group Chemical group 0.000 claims abstract description 9
125000004453 alkoxycarbonyl group Chemical group 0.000 claims abstract description 8
125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims abstract description 7
125000003282 alkyl amino group Chemical group 0.000 claims abstract description 5
239000008194 pharmaceutical composition Substances 0.000 claims abstract description 5
229910052751 metal Inorganic materials 0.000 claims description 25
239000002184 metal Substances 0.000 claims description 25
239000003054 catalyst Substances 0.000 claims description 24
125000004429 atom Chemical group 0.000 claims description 23
238000004519 manufacturing process Methods 0.000 claims description 23
IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 23
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 20
229910052760 oxygen Inorganic materials 0.000 claims description 19
239000001301 oxygen Chemical group 0.000 claims description 19
NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 18
125000005842 heteroatom Chemical group 0.000 claims description 18
229910052717 sulfur Chemical group 0.000 claims description 18
239000011593 sulfur Chemical group 0.000 claims description 18
125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 18
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 16
239000000126 substance Substances 0.000 claims description 14
125000001140 1,4-phenylene group Chemical group [H]C1=C([H])C([*:2])=C([H])C([H])=C1[*:1] 0.000 claims description 12
239000002253 acid Substances 0.000 claims description 12
125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 12
239000003446 ligand Substances 0.000 claims description 12
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 12
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 10
125000001715 oxadiazolyl group Chemical group 0.000 claims description 10
125000004076 pyridyl group Chemical group 0.000 claims description 10
125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 8
QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 8
125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 7
125000005115 alkyl carbamoyl group Chemical group 0.000 claims description 6
125000002883 imidazolyl group Chemical group 0.000 claims description 6
150000002902 organometallic compounds Chemical class 0.000 claims description 6
ZKMZPXWMMSBLNO-UHFFFAOYSA-N 1-azabicyclo[2.2.2]octan-3-one Chemical compound C1CC2C(=O)CN1CC2 ZKMZPXWMMSBLNO-UHFFFAOYSA-N 0.000 claims description 5
239000003085 diluting agent Substances 0.000 claims description 4
125000006239 protecting group Chemical group 0.000 claims description 4
125000002098 pyridazinyl group Chemical group 0.000 claims description 4
125000001113 thiadiazolyl group Chemical group 0.000 claims description 4
125000004432 carbon atom Chemical group C* 0.000 claims description 3
150000001768 cations Chemical class 0.000 claims description 3
125000002541 furyl group Chemical group 0.000 claims description 3
125000001041 indolyl group Chemical group 0.000 claims description 3
125000001786 isothiazolyl group Chemical group 0.000 claims description 3
125000002971 oxazolyl group Chemical group 0.000 claims description 3
125000003226 pyrazolyl group Chemical group 0.000 claims description 3
125000000168 pyrrolyl group Chemical group 0.000 claims description 3
125000005493 quinolyl group Chemical group 0.000 claims description 3
125000000335 thiazolyl group Chemical group 0.000 claims description 3
125000001544 thienyl group Chemical group 0.000 claims description 3
125000001425 triazolyl group Chemical group 0.000 claims description 3
XFZZBSVADYAQES-JXMROGBWSA-N 3-[(e)-2-[4-(5-ethyl-1,2,4-oxadiazol-3-yl)phenyl]ethenyl]-1-azabicyclo[2.2.2]octan-3-ol Chemical compound O1C(CC)=NC(C=2C=CC(\C=C\C3(O)C4CCN(CC4)C3)=CC=2)=N1 XFZZBSVADYAQES-JXMROGBWSA-N 0.000 claims description 2
MLWYTCBWAVPQJV-UHFFFAOYSA-N 3-[2-(4-pyridin-3-ylphenyl)ethenyl]-1-azabicyclo[2.2.2]octan-3-ol Chemical compound C1N(CC2)CCC2C1(O)C=CC(C=C1)=CC=C1C1=CC=CN=C1 MLWYTCBWAVPQJV-UHFFFAOYSA-N 0.000 claims description 2
150000001450 anions Chemical class 0.000 claims description 2
125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 2
125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 2
125000005956 isoquinolyl group Chemical group 0.000 claims description 2
125000000842 isoxazolyl group Chemical group 0.000 claims description 2
125000003373 pyrazinyl group Chemical group 0.000 claims description 2
FSXBRBLSPAJQLQ-UHFFFAOYSA-N 3-[2-[4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]ethenyl]-1-azabicyclo[2.2.2]octan-3-ol Chemical compound O1C(C)=NC(C=2C=CC(C=CC3(O)C4CCN(CC4)C3)=CC=2)=N1 FSXBRBLSPAJQLQ-UHFFFAOYSA-N 0.000 claims 1
125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims 1
239000003814 drug Substances 0.000 abstract description 9
125000001188 haloalkyl group Chemical group 0.000 abstract description 3
125000004181 carboxyalkyl group Chemical group 0.000 abstract description 2
125000004663 dialkyl amino group Chemical group 0.000 abstract description 2
125000005118 N-alkylcarbamoyl group Chemical group 0.000 abstract 2
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 148
239000000203 mixture Substances 0.000 description 145
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 141
239000007787 solid Substances 0.000 description 125
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 122
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 103
238000005481 NMR spectroscopy Methods 0.000 description 93
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 89
239000000243 solution Substances 0.000 description 88
238000002844 melting Methods 0.000 description 67
230000008018 melting Effects 0.000 description 67
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 61
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 61
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 60
229910001868 water Inorganic materials 0.000 description 58
QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 54
235000019439 ethyl acetate Nutrition 0.000 description 50
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 46
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 44
238000006243 chemical reaction Methods 0.000 description 44
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 43
239000000741 silica gel Substances 0.000 description 39
229910002027 silica gel Inorganic materials 0.000 description 39
239000003480 eluent Substances 0.000 description 38
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 37
239000002904 solvent Substances 0.000 description 37
239000007858 starting material Substances 0.000 description 37
HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 35
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 34
HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 34
239000003921 oil Substances 0.000 description 33
UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 32
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 30
229910021529 ammonia Inorganic materials 0.000 description 27
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 24
238000010992 reflux Methods 0.000 description 24
OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 23
CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 23
KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 22
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 21
238000003818 flash chromatography Methods 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
229910000085 borane Inorganic materials 0.000 description 20
239000002585 base Substances 0.000 description 19
125000002346 iodo group Chemical group I* 0.000 description 19
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 18
238000004440 column chromatography Methods 0.000 description 18
238000004452 microanalysis Methods 0.000 description 17
239000011541 reaction mixture Substances 0.000 description 17
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 17
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 16
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 16
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 16
LJLUTMJIZANZQO-UHFFFAOYSA-N 3-ethenyl-1-azabicyclo[2.2.2]octan-3-ol Chemical compound C1CC2C(O)(C=C)CN1CC2 LJLUTMJIZANZQO-UHFFFAOYSA-N 0.000 description 15
108010022535 Farnesyl-Diphosphate Farnesyltransferase Proteins 0.000 description 15
238000002360 preparation method Methods 0.000 description 15
XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 14
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 14
238000012360 testing method Methods 0.000 description 14
102100037997 Squalene synthase Human genes 0.000 description 13
230000015572 biosynthetic process Effects 0.000 description 13
125000001309 chloro group Chemical group Cl* 0.000 description 13
239000000284 extract Substances 0.000 description 13
125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 description 12
125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 12
235000012000 cholesterol Nutrition 0.000 description 12
238000001914 filtration Methods 0.000 description 12
238000001953 recrystallisation Methods 0.000 description 12
239000012300 argon atmosphere Substances 0.000 description 11
238000001704 evaporation Methods 0.000 description 11
230000008020 evaporation Effects 0.000 description 11
229910052736 halogen Inorganic materials 0.000 description 11
229910000029 sodium carbonate Inorganic materials 0.000 description 11
125000001153 fluoro group Chemical group F* 0.000 description 10
150000002367 halogens Chemical class 0.000 description 10
HRDXJKGNWSUIBT-UHFFFAOYSA-N methoxybenzene Chemical group [CH2]OC1=CC=CC=C1 HRDXJKGNWSUIBT-UHFFFAOYSA-N 0.000 description 10
230000009467 reduction Effects 0.000 description 10
239000000725 suspension Substances 0.000 description 10
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
239000007789 gas Substances 0.000 description 9
230000005764 inhibitory process Effects 0.000 description 9
229910052943 magnesium sulfate Inorganic materials 0.000 description 9
235000019341 magnesium sulphate Nutrition 0.000 description 9
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 9
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 9
238000000746 purification Methods 0.000 description 9
125000001246 bromo group Chemical group Br* 0.000 description 8
201000010099 disease Diseases 0.000 description 8
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 8
230000002401 inhibitory effect Effects 0.000 description 8
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 8
229910000027 potassium carbonate Inorganic materials 0.000 description 8
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 8
229920006395 saturated elastomer Polymers 0.000 description 8
238000004454 trace mineral analysis Methods 0.000 description 8
ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 7
QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 7
229910052786 argon Inorganic materials 0.000 description 7
229910052796 boron Inorganic materials 0.000 description 7
LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 7
229940079593 drug Drugs 0.000 description 7
239000000706 filtrate Substances 0.000 description 7
239000007788 liquid Substances 0.000 description 7
210000004185 liver Anatomy 0.000 description 7
230000008569 process Effects 0.000 description 7
238000003786 synthesis reaction Methods 0.000 description 7
201000001320 Atherosclerosis Diseases 0.000 description 6
UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 6
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 6
PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 6
229920002472 Starch Polymers 0.000 description 6
239000012442 inert solvent Substances 0.000 description 6
239000000047 product Substances 0.000 description 6
239000011734 sodium Substances 0.000 description 6
229910052708 sodium Inorganic materials 0.000 description 6
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
238000010561 standard procedure Methods 0.000 description 6
239000008107 starch Substances 0.000 description 6
235000019698 starch Nutrition 0.000 description 6
238000003756 stirring Methods 0.000 description 6
RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
ZSLUVFAKFWKJRC-IGMARMGPSA-N 232Th Chemical compound [232Th] ZSLUVFAKFWKJRC-IGMARMGPSA-N 0.000 description 5
FCHUOBPHXDXZBK-UHFFFAOYSA-N 3-(4-bromophenyl)pyridine Chemical compound C1=CC(Br)=CC=C1C1=CC=CN=C1 FCHUOBPHXDXZBK-UHFFFAOYSA-N 0.000 description 5
239000004215 Carbon black (E152) Substances 0.000 description 5
WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 5
239000004472 Lysine Substances 0.000 description 5
KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 5
MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 5
241000700159 Rattus Species 0.000 description 5
230000002378 acidificating effect Effects 0.000 description 5
239000007864 aqueous solution Substances 0.000 description 5
239000003638 chemical reducing agent Substances 0.000 description 5
ONCCWDRMOZMNSM-FBCQKBJTSA-N compound Z Chemical compound N1=C2C(=O)NC(N)=NC2=NC=C1C(=O)[C@H]1OP(O)(=O)OC[C@H]1O ONCCWDRMOZMNSM-FBCQKBJTSA-N 0.000 description 5
238000009472 formulation Methods 0.000 description 5
238000010438 heat treatment Methods 0.000 description 5
229930195733 hydrocarbon Natural products 0.000 description 5
150000002430 hydrocarbons Chemical class 0.000 description 5
125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 5
229910052744 lithium Inorganic materials 0.000 description 5
229960003646 lysine Drugs 0.000 description 5
SBYHFKPVCBCYGV-UHFFFAOYSA-N quinuclidine Chemical group C1CC2CCN1CC2 SBYHFKPVCBCYGV-UHFFFAOYSA-N 0.000 description 5
239000003826 tablet Substances 0.000 description 5
YYGNTYWPHWGJRM-UHFFFAOYSA-N (6E,10E,14E,18E)-2,6,10,15,19,23-hexamethyltetracosa-2,6,10,14,18,22-hexaene Chemical compound CC(C)=CCCC(C)=CCCC(C)=CCCC=C(C)CCC=C(C)CCC=C(C)C YYGNTYWPHWGJRM-UHFFFAOYSA-N 0.000 description 4
XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 4
125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 4
VWFJDQUYCIWHTN-YFVJMOTDSA-N 2-trans,6-trans-farnesyl diphosphate Chemical compound CC(C)=CCC\C(C)=C\CC\C(C)=C\CO[P@](O)(=O)OP(O)(O)=O VWFJDQUYCIWHTN-YFVJMOTDSA-N 0.000 description 4
125000006306 4-iodophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1I 0.000 description 4
DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 4
VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
229910021595 Copper(I) iodide Inorganic materials 0.000 description 4
VWFJDQUYCIWHTN-UHFFFAOYSA-N Farnesyl pyrophosphate Natural products CC(C)=CCCC(C)=CCCC(C)=CCOP(O)(=O)OP(O)(O)=O VWFJDQUYCIWHTN-UHFFFAOYSA-N 0.000 description 4
208000035150 Hypercholesterolemia Diseases 0.000 description 4
GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 4
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239000003125 aqueous solvent Substances 0.000 description 1
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MXOQNVMDKHLYCZ-UHFFFAOYSA-N benzamidoxime Chemical compound ON=C(N)C1=CC=CC=C1 MXOQNVMDKHLYCZ-UHFFFAOYSA-N 0.000 description 1
SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
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QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 1
239000001273 butane Substances 0.000 description 1
KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
YHASWHZGWUONAO-UHFFFAOYSA-N butanoyl butanoate Chemical compound CCCC(=O)OC(=O)CCC YHASWHZGWUONAO-UHFFFAOYSA-N 0.000 description 1
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JHIWVOJDXOSYLW-UHFFFAOYSA-N butyl 2,2-difluorocyclopropane-1-carboxylate Chemical compound CCCCOC(=O)C1CC1(F)F JHIWVOJDXOSYLW-UHFFFAOYSA-N 0.000 description 1
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239000007963 capsule composition Substances 0.000 description 1
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230000003197 catalytic effect Effects 0.000 description 1
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ACTIUHUUMQJHFO-UPTCCGCDSA-N coenzyme Q10 Chemical compound COC1=C(OC)C(=O)C(C\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CCC=C(C)C)=C(C)C1=O ACTIUHUUMQJHFO-UPTCCGCDSA-N 0.000 description 1
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XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
238000005984 hydrogenation reaction Methods 0.000 description 1
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QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 description 1
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KFBKRCXOTTUAFS-UHFFFAOYSA-N nickel;triphenylphosphane Chemical compound [Ni].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 KFBKRCXOTTUAFS-UHFFFAOYSA-N 0.000 description 1
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JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
235000005985 organic acids Nutrition 0.000 description 1
239000012044 organic layer Substances 0.000 description 1
239000012074 organic phase Substances 0.000 description 1
WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 1
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238000005192 partition Methods 0.000 description 1
239000008177 pharmaceutical agent Substances 0.000 description 1
239000000825 pharmaceutical preparation Substances 0.000 description 1
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UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
RPGWZZNNEUHDAQ-UHFFFAOYSA-N phenylphosphine Chemical compound PC1=CC=CC=C1 RPGWZZNNEUHDAQ-UHFFFAOYSA-N 0.000 description 1
NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
239000010452 phosphate Substances 0.000 description 1
239000002504 physiological saline solution Substances 0.000 description 1
229910052697 platinum Inorganic materials 0.000 description 1
239000003495 polar organic solvent Substances 0.000 description 1
239000003505 polymerization initiator Substances 0.000 description 1
229950008882 polysorbate Drugs 0.000 description 1
229920000136 polysorbate Polymers 0.000 description 1
239000001267 polyvinylpyrrolidone Substances 0.000 description 1
229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
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235000011009 potassium phosphates Nutrition 0.000 description 1
CUQOHAYJWVTKDE-UHFFFAOYSA-N potassium;butan-1-olate Chemical compound [K+].CCCC[O-] CUQOHAYJWVTKDE-UHFFFAOYSA-N 0.000 description 1
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JKANAVGODYYCQF-UHFFFAOYSA-N prop-2-yn-1-amine Chemical compound NCC#C JKANAVGODYYCQF-UHFFFAOYSA-N 0.000 description 1
BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
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125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
102000004169 proteins and genes Human genes 0.000 description 1
108090000623 proteins and genes Proteins 0.000 description 1
238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
125000004944 pyrazin-3-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 description 1
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229940005657 pyrophosphoric acid Drugs 0.000 description 1
230000002285 radioactive effect Effects 0.000 description 1
229910052705 radium Inorganic materials 0.000 description 1
HCWPIIXVSYCSAN-UHFFFAOYSA-N radium atom Chemical compound [Ra] HCWPIIXVSYCSAN-UHFFFAOYSA-N 0.000 description 1
239000002994 raw material Substances 0.000 description 1
239000000376 reactant Substances 0.000 description 1
NPCOQXAVBJJZBQ-UHFFFAOYSA-N reduced coenzyme Q9 Natural products COC1=C(O)C(C)=C(CC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C)C(O)=C1OC NPCOQXAVBJJZBQ-UHFFFAOYSA-N 0.000 description 1
238000006722 reduction reaction Methods 0.000 description 1
238000004007 reversed phase HPLC Methods 0.000 description 1
238000002390 rotary evaporation Methods 0.000 description 1
238000007127 saponification reaction Methods 0.000 description 1
229910010271 silicon carbide Inorganic materials 0.000 description 1
125000004469 siloxy group Chemical group [SiH3]O* 0.000 description 1
125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 1
URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
235000017557 sodium bicarbonate Nutrition 0.000 description 1
229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
239000011780 sodium chloride Substances 0.000 description 1
CWXOAQXKPAENDI-UHFFFAOYSA-N sodium methylsulfinylmethylide Chemical group [Na+].CS([CH2-])=O CWXOAQXKPAENDI-UHFFFAOYSA-N 0.000 description 1
159000000000 sodium salts Chemical class 0.000 description 1
239000008279 sol Substances 0.000 description 1
125000004079 stearyl 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])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])[H] 0.000 description 1
150000003432 sterols Chemical class 0.000 description 1
235000003702 sterols Nutrition 0.000 description 1
210000002784 stomach Anatomy 0.000 description 1
229910021653 sulphate ion Inorganic materials 0.000 description 1
229940065721 systemic for obstructive airway disease xanthines Drugs 0.000 description 1
239000011975 tartaric acid Substances 0.000 description 1
235000002906 tartaric acid Nutrition 0.000 description 1
102000055501 telomere Human genes 0.000 description 1
108091035539 telomere Proteins 0.000 description 1
210000003411 telomere Anatomy 0.000 description 1
150000003505 terpenes Chemical class 0.000 description 1
150000003536 tetrazoles Chemical class 0.000 description 1
125000003831 tetrazolyl group Chemical group 0.000 description 1
VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
ZCUFMDLYAMJYST-UHFFFAOYSA-N thorium dioxide Chemical compound O=[Th]=O ZCUFMDLYAMJYST-UHFFFAOYSA-N 0.000 description 1
230000000699 topical effect Effects 0.000 description 1
238000012876 topography Methods 0.000 description 1
230000001988 toxicity Effects 0.000 description 1
231100000419 toxicity Toxicity 0.000 description 1
238000012549 training Methods 0.000 description 1
229910052723 transition metal Inorganic materials 0.000 description 1
150000003624 transition metals Chemical class 0.000 description 1
DBGVGMSCBYYSLD-UHFFFAOYSA-N tributylstannane Chemical compound CCCC[SnH](CCCC)CCCC DBGVGMSCBYYSLD-UHFFFAOYSA-N 0.000 description 1
125000005951 trifluoromethanesulfonyloxy group Chemical group 0.000 description 1
BPLKQGGAXWRFOE-UHFFFAOYSA-M trimethylsulfoxonium iodide Chemical compound [I-].C[S+](C)(C)=O BPLKQGGAXWRFOE-UHFFFAOYSA-M 0.000 description 1
WIOADUFWOUUQCV-UHFFFAOYSA-N triphenylphosphanium dichloride Chemical compound [Cl-].[Cl-].C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 WIOADUFWOUUQCV-UHFFFAOYSA-N 0.000 description 1
LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
238000001665 trituration Methods 0.000 description 1
229940035936 ubiquinone Drugs 0.000 description 1
208000011733 vascular alteration Diseases 0.000 description 1
230000004869 vascular alteration Effects 0.000 description 1
239000000052 vinegar Substances 0.000 description 1
235000021419 vinegar Nutrition 0.000 description 1
229910052726 zirconium Inorganic materials 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
- C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Landscapes

Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Health & Medical Sciences (AREA)
Engineering & Computer Science (AREA)
Bioinformatics & Cheminformatics (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Life Sciences & Earth Sciences (AREA)
Cardiology (AREA)
Heart & Thoracic Surgery (AREA)
Chemical Kinetics & Catalysis (AREA)
General Chemical & Material Sciences (AREA)
Medicinal Chemistry (AREA)
Urology & Nephrology (AREA)
Pharmacology & Pharmacy (AREA)
Vascular Medicine (AREA)
Animal Behavior & Ethology (AREA)
General Health & Medical Sciences (AREA)
Public Health (AREA)
Veterinary Medicine (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Plural Heterocyclic Compounds (AREA)
Enzymes And Modification Thereof (AREA)
Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Nitrogen Condensed Heterocyclic Rings (AREA)

JP6506955A 1992-08-28 1993-08-24 スクアレンシンターゼ阻害剤としてのキヌクリジン誘導体 Pending JPH08502731A (ja)

Applications Claiming Priority (3)

Application Number	Priority Date	Filing Date	Title
GB929218334A GB9218334D0 (en)	1992-08-28	1992-08-28	Heterocyclic compounds
GB9218334.2		1992-08-28
PCT/GB1993/001802 WO1994005660A1 (en)	1992-08-28	1993-08-24	Quinuclidine derivatives as squalene synthase inhibitors

Publications (1)

Publication Number	Publication Date
JPH08502731A true JPH08502731A (ja)	1996-03-26

Family

ID=10721113

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
JP6506955A Pending JPH08502731A (ja)	1992-08-28	1993-08-24	スクアレンシンターゼ阻害剤としてのキヌクリジン誘導体

Country Status (13)

Country	Link
US (1)	US5714496A (2)
EP (1)	EP0656897B1 (2)
JP (1)	JPH08502731A (2)
AT (1)	ATE161843T1 (2)
AU (1)	AU4969193A (2)
CA (2)	CA2143430A1 (2)
DE (1)	DE69316224D1 (2)
FI (1)	FI950893A0 (2)
GB (2)	GB9218334D0 (2)
IL (1)	IL106797A0 (2)
TW (1)	TW231293B (2)
WO (1)	WO1994005660A1 (2)
ZA (1)	ZA936201B (2)

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JP2005512974A (ja) *	2001-10-17	2005-05-12	ユセベソシエテアノニム	キヌクリジン誘導体、その調製方法、及びｍ２及び／又はｍ３ムスカリン受容体阻害剤としてのその使用
JP2015523402A (ja) *	2012-07-30	2015-08-13	アスターバイオテックリミテッドライアビリティカンパニー	タンパク質キナーゼ阻害薬

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1992
- 1992-08-28 GB GB929218334A patent/GB9218334D0/en active Pending
1993
- 1993-08-18 GB GB939317153A patent/GB9317153D0/en active Pending
- 1993-08-24 EP EP93919477A patent/EP0656897B1/en not_active Expired - Lifetime
- 1993-08-24 JP JP6506955A patent/JPH08502731A/ja active Pending
- 1993-08-24 DE DE69316224T patent/DE69316224D1/de not_active Expired - Lifetime
- 1993-08-24 CA CA002143430A patent/CA2143430A1/en not_active Abandoned
- 1993-08-24 AT AT93919477T patent/ATE161843T1/de not_active IP Right Cessation
- 1993-08-24 AU AU49691/93A patent/AU4969193A/en not_active Abandoned
- 1993-08-24 ZA ZA936201A patent/ZA936201B/xx unknown
- 1993-08-24 WO PCT/GB1993/001802 patent/WO1994005660A1/en not_active Ceased
- 1993-08-25 US US08/392,928 patent/US5714496A/en not_active Expired - Fee Related
- 1993-08-25 IL IL106797A patent/IL106797A0/xx unknown
- 1993-08-27 CA CA002104981A patent/CA2104981A1/en not_active Abandoned
- 1993-08-31 TW TW082107086A patent/TW231293B/zh active
1995
- 1995-02-27 FI FI950893A patent/FI950893A0/fi not_active Application Discontinuation

Cited By (5)

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US6599917B1 (en)	1999-09-28	2003-07-29	Eisai Co., Ltd.	Quinuclidine compounds and drugs containing the same as the active ingredient
JPWO2002076973A1 (ja) *	2001-03-27	2004-10-21	エーザイ株式会社	Ｎ−アリール環状アミン誘導体およびそれを有効成分として含有する医薬
US7112593B2 (en)	2001-03-27	2006-09-26	Eisai Co., Ltd.	N-aryl-substituted cyclic amine derivative and medicine containing the same as active ingredient
JP2005512974A (ja) *	2001-10-17	2005-05-12	ユセベソシエテアノニム	キヌクリジン誘導体、その調製方法、及びｍ２及び／又はｍ３ムスカリン受容体阻害剤としてのその使用
JP2015523402A (ja) *	2012-07-30	2015-08-13	アスターバイオテックリミテッドライアビリティカンパニー	タンパク質キナーゼ阻害薬

Also Published As

Publication number	Publication date
IL106797A0 (en)	1993-12-08
GB9317153D0 (en)	1993-10-06
US5714496A (en)	1998-02-03
AU4969193A (en)	1994-03-29
EP0656897A1 (en)	1995-06-14
ZA936201B (en)	1994-02-28
CA2104981A1 (en)	1994-03-01
FI950893A7 (fi)	1995-02-27
ATE161843T1 (de)	1998-01-15
WO1994005660A1 (en)	1994-03-17
DE69316224D1 (de)	1998-02-12
EP0656897B1 (en)	1998-01-07
GB9218334D0 (en)	1992-10-14
CA2143430A1 (en)	1994-03-17
TW231293B (2)	1994-10-01
FI950893A0 (fi)	1995-02-27

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