CA2105655A1 - Inhibiteurs de la squalene synthetase, a base de composes polyaromatiques renfermant une amine tertiaire - Google Patents
Inhibiteurs de la squalene synthetase, a base de composes polyaromatiques renfermant une amine tertiaireInfo
- Publication number
- CA2105655A1 CA2105655A1 CA002105655A CA2105655A CA2105655A1 CA 2105655 A1 CA2105655 A1 CA 2105655A1 CA 002105655 A CA002105655 A CA 002105655A CA 2105655 A CA2105655 A CA 2105655A CA 2105655 A1 CA2105655 A1 CA 2105655A1
- Authority
- CA
- Canada
- Prior art keywords
- compound according
- phenyl
- hydrogen
- hydroxy
- alkyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 239000004059 squalene synthase inhibitor Substances 0.000 title claims description 4
- 150000003512 tertiary amines Chemical class 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 80
- 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 claims abstract description 60
- 238000000034 method Methods 0.000 claims abstract description 25
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 18
- 238000011282 treatment Methods 0.000 claims abstract description 11
- -1 NR' SO Inorganic materials 0.000 claims description 55
- 229910052760 oxygen Inorganic materials 0.000 claims description 55
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims description 41
- 239000001257 hydrogen Substances 0.000 claims description 25
- 229910052739 hydrogen Inorganic materials 0.000 claims description 25
- 235000012000 cholesterol Nutrition 0.000 claims description 24
- 229910052799 carbon Inorganic materials 0.000 claims description 23
- 229910000085 borane Inorganic materials 0.000 claims description 22
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 22
- 125000000217 alkyl group Chemical group 0.000 claims description 21
- 229910052717 sulfur Inorganic materials 0.000 claims description 19
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 18
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 claims description 17
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 16
- 125000005843 halogen group Chemical group 0.000 claims description 15
- 150000003839 salts Chemical class 0.000 claims description 15
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 13
- 108010022535 Farnesyl-Diphosphate Farnesyltransferase Proteins 0.000 claims description 12
- 125000003118 aryl group Chemical group 0.000 claims description 12
- 125000003545 alkoxy group Chemical group 0.000 claims description 11
- 125000001624 naphthyl group Chemical group 0.000 claims description 10
- 229910052708 sodium Inorganic materials 0.000 claims description 10
- 125000001424 substituent group Chemical group 0.000 claims description 10
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
- 125000004104 aryloxy group Chemical group 0.000 claims description 7
- 125000004122 cyclic group Chemical group 0.000 claims description 7
- 230000005764 inhibitory process Effects 0.000 claims description 7
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 7
- 125000004423 acyloxy group Chemical group 0.000 claims description 6
- 125000003342 alkenyl group Chemical group 0.000 claims description 6
- 125000001188 haloalkyl group Chemical group 0.000 claims description 6
- 125000000623 heterocyclic group Chemical group 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 125000004442 acylamino group Chemical group 0.000 claims description 5
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 5
- 125000001041 indolyl group Chemical group 0.000 claims description 5
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 5
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 claims description 4
- 125000004429 atom Chemical group 0.000 claims description 4
- 125000002047 benzodioxolyl group Chemical group O1OC(C2=C1C=CC=C2)* 0.000 claims description 4
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 4
- 125000005842 heteroatom Chemical group 0.000 claims description 4
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 claims description 4
- 230000002401 inhibitory effect Effects 0.000 claims description 4
- 229940123495 Squalene synthetase inhibitor Drugs 0.000 claims description 3
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 3
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 3
- 229910052744 lithium Inorganic materials 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 125000001544 thienyl group Chemical group 0.000 claims description 3
- 239000003529 anticholesteremic agent Substances 0.000 claims description 2
- 239000003524 antilipemic agent Substances 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 125000004434 sulfur atom Chemical group 0.000 claims description 2
- 150000002431 hydrogen Chemical group 0.000 claims 12
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims 2
- 201000001320 Atherosclerosis Diseases 0.000 claims 1
- BSGHUPVVNKNZRA-VOTSOKGWSA-N C1N(C2)CC3CC2CC1C3OCC(C=C1)=CC=C1\C=C\C1=CC=CC=C1 Chemical compound C1N(C2)CC3CC2CC1C3OCC(C=C1)=CC=C1\C=C\C1=CC=CC=C1 BSGHUPVVNKNZRA-VOTSOKGWSA-N 0.000 claims 1
- UYANAUSDHIFLFQ-UHFFFAOYSA-N borinic acid Chemical compound OB UYANAUSDHIFLFQ-UHFFFAOYSA-N 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 230000000871 hypocholesterolemic effect Effects 0.000 claims 1
- 125000004430 oxygen atom Chemical group O* 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 10
- 125000002619 bicyclic group Chemical group 0.000 abstract description 6
- 125000003367 polycyclic group Chemical group 0.000 abstract description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 abstract description 4
- 125000001302 tertiary amino group Chemical group 0.000 abstract description 4
- 230000001603 reducing effect Effects 0.000 abstract description 3
- 239000002207 metabolite Substances 0.000 abstract description 2
- 125000002950 monocyclic group Chemical group 0.000 abstract description 2
- 239000008196 pharmacological composition Substances 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 86
- 239000000203 mixture Substances 0.000 description 76
- 239000000243 solution Substances 0.000 description 57
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 53
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 42
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 42
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 42
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 42
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 32
- 238000006243 chemical reaction Methods 0.000 description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 23
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 239000000047 product Substances 0.000 description 18
- 239000010410 layer Substances 0.000 description 17
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 17
- 235000019341 magnesium sulphate Nutrition 0.000 description 16
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 15
- 239000007787 solid Substances 0.000 description 15
- 150000002500 ions Chemical class 0.000 description 13
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 12
- 239000000725 suspension Substances 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- 108090000895 Hydroxymethylglutaryl CoA Reductases Proteins 0.000 description 11
- 102000004286 Hydroxymethylglutaryl CoA Reductases Human genes 0.000 description 11
- 238000003556 assay Methods 0.000 description 11
- DIOQZVSQGTUSAI-UHFFFAOYSA-N n-butylhexane Natural products CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 description 11
- 102000004190 Enzymes Human genes 0.000 description 10
- 108090000790 Enzymes Proteins 0.000 description 10
- 239000003208 petroleum Substances 0.000 description 10
- 239000002244 precipitate Substances 0.000 description 10
- 229940031439 squalene Drugs 0.000 description 10
- TUHBEKDERLKLEC-UHFFFAOYSA-N squalene Natural products CC(=CCCC(=CCCC(=CCCC=C(/C)CCC=C(/C)CC=C(C)C)C)C)C TUHBEKDERLKLEC-UHFFFAOYSA-N 0.000 description 10
- 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 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- BHEOSNUKNHRBNM-UHFFFAOYSA-N Tetramethylsqualene Natural products CC(=C)C(C)CCC(=C)C(C)CCC(C)=CCCC=C(C)CCC(C)C(=C)CCC(C)C(C)=C BHEOSNUKNHRBNM-UHFFFAOYSA-N 0.000 description 9
- 239000002253 acid Substances 0.000 description 9
- PRAKJMSDJKAYCZ-UHFFFAOYSA-N dodecahydrosqualene Natural products CC(C)CCCC(C)CCCC(C)CCCCC(C)CCCC(C)CCCC(C)C PRAKJMSDJKAYCZ-UHFFFAOYSA-N 0.000 description 9
- ZHVULPDNOFUIML-UHFFFAOYSA-N octane;hydrochloride Chemical compound Cl.CCCCCCCC ZHVULPDNOFUIML-UHFFFAOYSA-N 0.000 description 9
- 239000011734 sodium Substances 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- 239000003112 inhibitor Substances 0.000 description 8
- 210000004185 liver Anatomy 0.000 description 8
- 229910000104 sodium hydride Inorganic materials 0.000 description 8
- 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 7
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 7
- 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 7
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 7
- 238000009833 condensation Methods 0.000 description 7
- 230000005494 condensation Effects 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- 239000012312 sodium hydride Substances 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 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 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 6
- 239000012267 brine Substances 0.000 description 6
- 239000006185 dispersion Substances 0.000 description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- 238000010792 warming Methods 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 5
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 5
- 229930182558 Sterol Natural products 0.000 description 5
- 125000003277 amino group Chemical group 0.000 description 5
- 239000000872 buffer Substances 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 150000003432 sterols Chemical class 0.000 description 5
- 235000003702 sterols Nutrition 0.000 description 5
- 230000001629 suppression Effects 0.000 description 5
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 description 4
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 150000001299 aldehydes Chemical class 0.000 description 4
- 239000012131 assay buffer Substances 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 125000002837 carbocyclic group Chemical group 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 150000002576 ketones Chemical class 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 229910052751 metal Inorganic materials 0.000 description 4
- 239000002184 metal Substances 0.000 description 4
- BKIMMITUMNQMOS-UHFFFAOYSA-N nonane Chemical compound CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- 235000019198 oils Nutrition 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- 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 4
- KJTLQQUUPVSXIM-ZCFIWIBFSA-M (R)-mevalonate Chemical compound OCC[C@](O)(C)CC([O-])=O KJTLQQUUPVSXIM-ZCFIWIBFSA-M 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 102000003960 Ligases Human genes 0.000 description 3
- 108090000364 Ligases Proteins 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 150000004678 hydrides Chemical class 0.000 description 3
- ATADHKWKHYVBTJ-UHFFFAOYSA-N hydron;4-[1-hydroxy-2-(methylamino)ethyl]benzene-1,2-diol;chloride Chemical compound Cl.CNCC(O)C1=CC=C(O)C(O)=C1 ATADHKWKHYVBTJ-UHFFFAOYSA-N 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000011777 magnesium Substances 0.000 description 3
- 230000003228 microsomal effect Effects 0.000 description 3
- 230000037361 pathway Effects 0.000 description 3
- 239000008188 pellet Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 3
- HVVNWCUEJXPERA-UHFFFAOYSA-N 1-(bromomethyl)-4-(2-phenylethenyl)benzene Chemical compound C1=CC(CBr)=CC=C1C=CC1=CC=CC=C1 HVVNWCUEJXPERA-UHFFFAOYSA-N 0.000 description 2
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 2
- TZMSYXZUNZXBOL-UHFFFAOYSA-N 10H-phenoxazine Chemical compound C1=CC=C2NC3=CC=CC=C3OC2=C1 TZMSYXZUNZXBOL-UHFFFAOYSA-N 0.000 description 2
- HBEDSQVIWPRPAY-UHFFFAOYSA-N 2,3-dihydrobenzofuran Chemical compound C1=CC=C2OCCC2=C1 HBEDSQVIWPRPAY-UHFFFAOYSA-N 0.000 description 2
- LULAYUGMBFYYEX-UHFFFAOYSA-N 3-chlorobenzoic acid Chemical compound OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 2
- IVLICPVPXWEGCA-UHFFFAOYSA-N 3-quinuclidinol Chemical compound C1C[C@@H]2C(O)C[N@]1CC2 IVLICPVPXWEGCA-UHFFFAOYSA-N 0.000 description 2
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 2
- 125000006281 4-bromobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Br)C([H])([H])* 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- ACTIUHUUMQJHFO-UHFFFAOYSA-N Coenzym Q10 Natural products COC1=C(OC)C(=O)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)CCC=C(C)C)=C(C)C1=O ACTIUHUUMQJHFO-UHFFFAOYSA-N 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- KJTLQQUUPVSXIM-UHFFFAOYSA-N DL-mevalonic acid Natural products OCCC(O)(C)CC(O)=O KJTLQQUUPVSXIM-UHFFFAOYSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
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- 229940081974 saccharin Drugs 0.000 description 1
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- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000003333 secondary alcohols Chemical class 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
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- 229910000077 silane Inorganic materials 0.000 description 1
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- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
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- YYGNTYWPHWGJRM-AAJYLUCBSA-N squalene Chemical compound CC(C)=CCC\C(C)=C\CC\C(C)=C\CC\C=C(/C)CC\C=C(/C)CCC=C(C)C YYGNTYWPHWGJRM-AAJYLUCBSA-N 0.000 description 1
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- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
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- 239000012085 test solution Substances 0.000 description 1
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 1
- 150000003536 tetrazoles Chemical group 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 229940086542 triethylamine Drugs 0.000 description 1
- VNMXZSWOKNCHAM-UHFFFAOYSA-N trimethyl 4-oxocyclohexane-1,1,3-tricarboxylate Chemical compound COC(=O)C1CC(C(=O)OC)(C(=O)OC)CCC1=O VNMXZSWOKNCHAM-UHFFFAOYSA-N 0.000 description 1
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
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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
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Obesity (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US66768691A | 1991-03-08 | 1991-03-08 | |
| US667,686 | 1991-03-08 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2105655A1 true CA2105655A1 (fr) | 1992-09-09 |
Family
ID=24679220
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002105655A Abandoned CA2105655A1 (fr) | 1991-03-08 | 1992-03-03 | Inhibiteurs de la squalene synthetase, a base de composes polyaromatiques renfermant une amine tertiaire |
Country Status (5)
| Country | Link |
|---|---|
| JP (1) | JPH06506467A (fr) |
| AU (1) | AU1752792A (fr) |
| CA (1) | CA2105655A1 (fr) |
| MX (1) | MX9201030A (fr) |
| WO (1) | WO1992015579A1 (fr) |
Families Citing this family (62)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9122988D0 (en) * | 1991-10-30 | 1991-12-18 | Ici Plc | Heterocyclic compounds |
| GB9127279D0 (en) * | 1991-12-23 | 1992-02-19 | Ici Plc | Heterocyclic derivatives |
| GB9201749D0 (en) * | 1992-01-28 | 1992-03-11 | Smithkline Beecham Plc | Medicaments |
| US5726306A (en) * | 1992-04-20 | 1998-03-10 | Takeda Chemical Industries, Ltd. | 4,1-benzoxazepin derivatives and their use |
| JPH06508377A (ja) * | 1992-04-10 | 1994-09-22 | ゼネカ リミテッド | ヘテロ環式化合物 |
| GB9207961D0 (en) * | 1992-04-10 | 1992-05-27 | Ici Plc | Heterocyclic derivatives |
| DE69332792T2 (de) * | 1992-04-20 | 2004-01-15 | Takeda Chemical Industries Ltd | 4,1-Benzoxazepinderivate als Squalen-Synthetase Inhibitoren und ihre Verwendung zur Behandlung von Hypercholesterämie und als Fungizide |
| GB9211796D0 (en) * | 1992-06-04 | 1992-07-15 | Ici Plc | Heterocyclic derivatives |
| GB9216721D0 (en) * | 1992-08-06 | 1992-09-23 | Ici Plc | Therapeutic heterocyclic derivatives |
| GB9218334D0 (en) * | 1992-08-28 | 1992-10-14 | Ici Plc | Heterocyclic compounds |
| WO1994014803A1 (fr) * | 1992-12-21 | 1994-07-07 | Zeneca Limited | Derives de quinuclidine comme inhibiteurs de la squalene synthetase |
| GB9226577D0 (en) * | 1992-12-21 | 1993-02-17 | Ici Plc | Heterocyclic derivatives |
| GB9226573D0 (en) * | 1992-12-21 | 1993-02-17 | Ici Plc | Heterocyclic compounds |
| US5451596A (en) * | 1992-12-29 | 1995-09-19 | Rhone Poulenc Rorer Pharmaceuticals Inc. | Cycloalkyl amine bis-aryl squalene synthase inhibitors |
| CA2115183A1 (fr) * | 1993-02-12 | 1994-08-13 | Takashi Nomoto | Derives de substitution d'acide amique |
| IL109451A0 (en) * | 1993-04-29 | 1994-07-31 | Zeneca Ltd | Heterocyclic derivatives |
| AU678503B2 (en) * | 1993-09-24 | 1997-05-29 | Takeda Chemical Industries Ltd. | Condensed heterocyclic compounds and their use as squalene synthetase inhibitors |
| GB9412145D0 (en) * | 1994-06-17 | 1994-08-10 | Zeneca Ltd | Heterocycles |
| US5556990A (en) * | 1994-12-16 | 1996-09-17 | Rhone-Poulenc Rorer Pharmaceuticals Inc. | Polyarylcarbamoylaza- and -carbamoylalkanedioic acids |
| US6297198B1 (en) | 1996-05-14 | 2001-10-02 | Syngenta Participations Ag | Isoxazole derivatives and their use as herbicides |
| SE9902987D0 (sv) | 1999-08-24 | 1999-08-24 | Astra Pharma Prod | Novel compounds |
| ES2252063T3 (es) * | 1999-09-28 | 2006-05-16 | Eisai Co., Ltd. | Compuesto de quinuclidina y medicamento que comprende el compuesto como principio activo. |
| US6492385B2 (en) | 2000-08-18 | 2002-12-10 | Pharmacia & Upjohn Company | Quinuclidine-substituted heteroaryl moieties for treatment of disease |
| US6479510B2 (en) | 2000-08-18 | 2002-11-12 | Pharmacia & Upjohn Company | Quinuclidine-substituted aryl compounds for treatment of disease |
| US6486172B2 (en) | 2000-08-18 | 2002-11-26 | Pharmacia & Upjohn Company | Quinuclidine-substituted aryl compounds for treatment of disease |
| WO2002017358A2 (fr) | 2000-08-21 | 2002-02-28 | Pharmacia & Upjohn Company | Fractions heteroaryle substituees par quinuclidine destinees au traitement de maladies |
| US6599916B2 (en) | 2000-08-21 | 2003-07-29 | Pharmacia & Upjohn Company | Quinuclidine-substituted heteroaryl moieties for treatment of disease |
| GB0104050D0 (en) | 2001-02-19 | 2001-04-04 | Astrazeneca Ab | Chemical compounds |
| GB0107228D0 (en) | 2001-03-22 | 2001-05-16 | Astrazeneca Ab | Chemical compounds |
| 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 |
| PE20021019A1 (es) | 2001-04-19 | 2002-11-13 | Upjohn Co | Grupos azabiciclicos sustituidos |
| BR0212101A (pt) | 2001-08-24 | 2004-08-24 | Pharmacia & Up John Company | 7-aza [2.2.1] biciclo-heptanos substituìdos com heteroarila para o tratamento de doenças |
| US6919359B2 (en) | 2001-11-08 | 2005-07-19 | Pfizer Inc | Azabicyclic-substituted-heteroaryl compounds for the treatment of disease |
| SE0103818D0 (sv) | 2001-11-15 | 2001-11-15 | Astrazeneca Ab | Chemical compounds |
| US6852716B2 (en) | 2002-02-15 | 2005-02-08 | Pfizer Inc | Substituted-aryl compounds for treatment of disease |
| EP1542999A1 (fr) | 2002-08-01 | 2005-06-22 | Pharmacia & Upjohn Company LLC | Composes azabicyclique de 1h-pyrazole et 1h-pyrrole servant a effectuer un traitement therapeutique |
| GB0220581D0 (en) | 2002-09-04 | 2002-10-09 | Novartis Ag | Organic Compound |
| SE0301369D0 (sv) | 2003-05-09 | 2003-05-09 | Astrazeneca Ab | Chemical compounds |
| DE10334724A1 (de) * | 2003-07-30 | 2005-02-24 | Bayer Healthcare Ag | N-Biarylamide |
| US7160876B2 (en) | 2003-12-22 | 2007-01-09 | Abbott Laboratories | Fused bicycloheterocycle substituted quinuclidine derivatives |
| US20050245531A1 (en) * | 2003-12-22 | 2005-11-03 | Abbott Laboratories | Fused bicycloheterocycle substituted quinuclidine derivatives |
| EP1824848A1 (fr) * | 2004-12-10 | 2007-08-29 | Abbott Laboratories | Derives polycycliques de quinuclidine substitues par un bicycloheterocycle condense |
| US7655657B2 (en) | 2003-12-22 | 2010-02-02 | Abbott Laboratories | Fused bicycloheterocycle substituted quinuclidine derivatives |
| PE20060437A1 (es) | 2004-06-18 | 2006-06-08 | Novartis Ag | COMPUESTOS AZA-BICICLONONANOS COMO LIGANDOS COLINERGICOS DE nAChR |
| US7781478B2 (en) | 2004-07-14 | 2010-08-24 | Ptc Therapeutics, Inc. | Methods for treating hepatitis C |
| GB0415746D0 (en) | 2004-07-14 | 2004-08-18 | Novartis Ag | Organic compounds |
| GB0611907D0 (en) | 2006-06-15 | 2006-07-26 | Glaxo Group Ltd | Compounds |
| EP1856126A2 (fr) | 2005-02-17 | 2007-11-21 | Wyeth a Corporation of the State of Delaware | Derive d'indole, benzothiophene, benzofurane et indene a fusion cycloalkyle |
| GB0521508D0 (en) | 2005-10-21 | 2005-11-30 | Novartis Ag | Organic compounds |
| GB0525672D0 (en) | 2005-12-16 | 2006-01-25 | Novartis Ag | Organic compounds |
| GB0525673D0 (en) | 2005-12-16 | 2006-01-25 | Novartis Ag | Organic compounds |
| US8314119B2 (en) | 2006-11-06 | 2012-11-20 | Abbvie Inc. | Azaadamantane derivatives and methods of use |
| CN103180321A (zh) | 2010-09-23 | 2013-06-26 | Abbvie公司 | 氮杂金刚烷衍生物的一水合物 |
| US20170298081A1 (en) * | 2014-08-08 | 2017-10-19 | Kasuma Partners Inc. | Condensed heterocyclic compound |
| LT3416962T (lt) | 2016-02-15 | 2021-07-12 | Sanofi | 6,7-dihidro-5h-benzo[7]anuleno dariniai kaip estrogenų recepptoriaus moduliatoriai |
| ES3039455T3 (en) | 2016-11-17 | 2025-10-21 | Sanofi Sa | Novel substituted n-(3-fluoropropyl)-pyrrolidine compounds, processes for their preparation and therapeutic uses thereof |
| EP3434272A1 (fr) | 2017-07-25 | 2019-01-30 | Sanofi | Combinaison comprenant du palbociclib et 6-(2,4-dichlorophényl)-5-[4-[(3s)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7h-benzo[7]annulène-2-acide carboxylique |
| JP7413363B2 (ja) | 2018-09-07 | 2024-01-15 | サノフイ | メチル６－（２，４－ジクロロフェニル）－５－［４－［（３ｓ）－１－（３－フルオロプロピル）ピロリジン－３－イル］オキシフェニル］－８，９－ジヒドロ－７ｈ－ベンゾ［７］アヌレン－２－カルボキシレートの調製方法 |
| WO2021063967A1 (fr) | 2019-10-01 | 2021-04-08 | Sanofi | Nouveaux composés 6,7-dihydro-5h-benzo[7]annulène substitués, procédés permettant leur préparation et leurs utilisations thérapeutiques |
| KR20220113695A (ko) | 2019-12-09 | 2022-08-16 | 사노피 | 7h-벤조[7]아눌렌-2-카르복실산 유도체의 결정질 형태 |
| TW202146007A (zh) | 2020-02-27 | 2021-12-16 | 法商賽諾菲公司 | 包含阿培利司（ａｌｐｅｌｉｓｉｂ）與６－（２，４－二氯苯基）－５－［４－［（３ｓ）－１－（３－氟丙基）吡咯啶－３－基］氧苯基］－８，９－二氫－７ｈ－苯并［７］輪烯－２－羧酸之組合 |
| WO2022084280A1 (fr) | 2020-10-19 | 2022-04-28 | Sanofi | Composés 6,7-dihydro-5h-benzo[7]annulène substitués et leurs dérivés, processus permettant leur préparation et utilisations thérapeutiques associées |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH667657A5 (de) * | 1985-01-07 | 1988-10-31 | Sandoz Ag | Carbocyclische und heterocyclische carbonylmethylen- und methylpiperidine und -pyrrolidine. |
-
1992
- 1992-03-03 CA CA002105655A patent/CA2105655A1/fr not_active Abandoned
- 1992-03-03 WO PCT/US1992/001773 patent/WO1992015579A1/fr not_active Ceased
- 1992-03-03 AU AU17527/92A patent/AU1752792A/en not_active Abandoned
- 1992-03-03 JP JP4509423A patent/JPH06506467A/ja active Pending
- 1992-03-09 MX MX9201030A patent/MX9201030A/es unknown
Also Published As
| Publication number | Publication date |
|---|---|
| JPH06506467A (ja) | 1994-07-21 |
| AU1752792A (en) | 1992-10-06 |
| WO1992015579A1 (fr) | 1992-09-17 |
| MX9201030A (es) | 1992-09-01 |
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Legal Events
| Date | Code | Title | Description |
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| FZDE | Dead |