CA2307889A1 - Inhibiteurs phosphonate ester cyclique de proteine microsomale de transfert des triglycerides et procede associe - Google Patents
Inhibiteurs phosphonate ester cyclique de proteine microsomale de transfert des triglycerides et procede associe Download PDFInfo
- Publication number
- CA2307889A1 CA2307889A1 CA002307889A CA2307889A CA2307889A1 CA 2307889 A1 CA2307889 A1 CA 2307889A1 CA 002307889 A CA002307889 A CA 002307889A CA 2307889 A CA2307889 A CA 2307889A CA 2307889 A1 CA2307889 A1 CA 2307889A1
- Authority
- CA
- Canada
- Prior art keywords
- aryl
- alkyl
- amino
- oxo
- trifluoroethyl
- 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
- -1 Cyclic phosphonate ester Chemical class 0.000 title claims abstract description 94
- 238000000034 method Methods 0.000 title claims description 21
- 239000003112 inhibitor Substances 0.000 title abstract description 9
- 102100031545 Microsomal triglyceride transfer protein large subunit Human genes 0.000 title description 37
- 108010038232 microsomal triglyceride transfer protein Proteins 0.000 title description 37
- 150000001875 compounds Chemical class 0.000 claims abstract description 109
- 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 14
- 150000003626 triacylglycerols Chemical class 0.000 claims abstract description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 119
- 125000003118 aryl group Chemical group 0.000 claims description 117
- 125000001072 heteroaryl group Chemical group 0.000 claims description 66
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 50
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 48
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 47
- 125000003342 alkenyl group Chemical group 0.000 claims description 44
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 37
- 125000003545 alkoxy group Chemical group 0.000 claims description 34
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 34
- 125000001424 substituent group Chemical group 0.000 claims description 34
- 125000004104 aryloxy group Chemical group 0.000 claims description 33
- 229910052739 hydrogen Inorganic materials 0.000 claims description 33
- 125000000304 alkynyl group Chemical group 0.000 claims description 30
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 29
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 29
- 125000001188 haloalkyl group Chemical group 0.000 claims description 27
- 239000001257 hydrogen Substances 0.000 claims description 27
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 26
- 125000004414 alkyl thio group Chemical group 0.000 claims description 25
- 229910052760 oxygen Inorganic materials 0.000 claims description 25
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 24
- 125000005843 halogen group Chemical group 0.000 claims description 22
- 125000002947 alkylene group Chemical group 0.000 claims description 20
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 19
- 150000001204 N-oxides Chemical class 0.000 claims description 17
- 125000004432 carbon atom Chemical group C* 0.000 claims description 16
- 229910052717 sulfur Inorganic materials 0.000 claims description 16
- 235000010290 biphenyl Nutrition 0.000 claims description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 14
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 14
- 125000005553 heteroaryloxy group Chemical group 0.000 claims description 14
- 125000005368 heteroarylthio group Chemical group 0.000 claims description 14
- 150000002632 lipids Chemical class 0.000 claims description 14
- 239000001301 oxygen Substances 0.000 claims description 14
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 13
- 125000002102 aryl alkyloxo group Chemical group 0.000 claims description 13
- 125000005110 aryl thio group Chemical group 0.000 claims description 13
- 125000004450 alkenylene group Chemical group 0.000 claims description 12
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 claims description 12
- 229910052736 halogen Inorganic materials 0.000 claims description 12
- 150000002367 halogens Chemical class 0.000 claims description 12
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 12
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 claims description 11
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 11
- 229910052757 nitrogen Inorganic materials 0.000 claims description 11
- 201000001320 Atherosclerosis Diseases 0.000 claims description 10
- 125000003282 alkyl amino group Chemical group 0.000 claims description 10
- 125000004658 aryl carbonyl amino group Chemical group 0.000 claims description 10
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 10
- 125000005842 heteroatom Chemical group 0.000 claims description 10
- 125000004043 oxo group Chemical group O=* 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 10
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 9
- 125000004419 alkynylene group Chemical group 0.000 claims description 9
- 125000001769 aryl amino group Chemical group 0.000 claims description 9
- 229910052799 carbon Inorganic materials 0.000 claims description 9
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 9
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 9
- 150000002148 esters Chemical class 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 8
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 8
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 8
- 125000005135 aryl sulfinyl group Chemical group 0.000 claims description 8
- 125000004657 aryl sulfonyl amino group Chemical group 0.000 claims description 8
- 125000005241 heteroarylamino group Chemical group 0.000 claims description 8
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 8
- 239000011593 sulfur Substances 0.000 claims description 8
- 125000005018 aryl alkenyl group Chemical group 0.000 claims description 7
- 125000005114 heteroarylalkoxy group Chemical group 0.000 claims description 7
- 125000000623 heterocyclic group Chemical group 0.000 claims description 7
- 230000002401 inhibitory effect Effects 0.000 claims description 7
- 125000005592 polycycloalkyl group Chemical group 0.000 claims description 7
- 208000031226 Hyperlipidaemia Diseases 0.000 claims description 6
- 125000005015 aryl alkynyl group Chemical group 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- 125000004447 heteroarylalkenyl group Chemical group 0.000 claims description 6
- 125000005150 heteroarylsulfinyl group Chemical group 0.000 claims description 6
- 125000005143 heteroarylsulfonyl group Chemical group 0.000 claims description 6
- 208000008589 Obesity Diseases 0.000 claims description 5
- 206010033645 Pancreatitis Diseases 0.000 claims description 5
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 5
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 5
- 125000005100 aryl amino carbonyl group Chemical group 0.000 claims description 5
- 125000005129 aryl carbonyl group Chemical group 0.000 claims description 5
- 125000005160 aryl oxy alkyl group Chemical group 0.000 claims description 5
- 125000005164 aryl thioalkyl group Chemical group 0.000 claims description 5
- 125000004429 atom Chemical group 0.000 claims description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 5
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- 125000004438 haloalkoxy group Chemical group 0.000 claims description 5
- 125000005647 linker group Chemical group 0.000 claims description 5
- 235000020824 obesity Nutrition 0.000 claims description 5
- 125000005089 alkenylaminocarbonyl group Chemical group 0.000 claims description 4
- 125000005095 alkynylaminocarbonyl group Chemical group 0.000 claims description 4
- 125000001691 aryl alkyl amino group Chemical group 0.000 claims description 4
- 125000005199 aryl carbonyloxy group Chemical group 0.000 claims description 4
- 125000004350 aryl cycloalkyl group Chemical group 0.000 claims description 4
- 239000004305 biphenyl Chemical group 0.000 claims description 4
- 235000012000 cholesterol Nutrition 0.000 claims description 4
- 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 description 4
- 125000005223 heteroarylcarbonyl group Chemical group 0.000 claims description 4
- 125000005224 heteroarylcarbonylamino group Chemical group 0.000 claims description 4
- 125000005419 heteroarylsulfonylamino group Chemical group 0.000 claims description 4
- 201000001421 hyperglycemia Diseases 0.000 claims description 4
- 210000002966 serum Anatomy 0.000 claims description 4
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 3
- 208000035150 Hypercholesterolemia Diseases 0.000 claims description 3
- 150000001336 alkenes Chemical class 0.000 claims description 3
- 150000001345 alkine derivatives Chemical class 0.000 claims description 3
- 125000005133 alkynyloxy group Chemical group 0.000 claims description 3
- 125000003277 amino group Chemical group 0.000 claims description 3
- 125000002837 carbocyclic group Chemical group 0.000 claims description 3
- KXDHJXZQYSOELW-UHFFFAOYSA-N carbonic acid monoamide Natural products NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 claims description 3
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 3
- 201000005577 familial hyperlipidemia Diseases 0.000 claims description 3
- 208000020346 hyperlipoproteinemia Diseases 0.000 claims description 3
- 208000006575 hypertriglyceridemia Diseases 0.000 claims description 3
- 150000002576 ketones Chemical class 0.000 claims description 3
- KJAMZCVTJDTESW-UHFFFAOYSA-N tiracizine Chemical compound C1CC2=CC=CC=C2N(C(=O)CN(C)C)C2=CC(NC(=O)OCC)=CC=C21 KJAMZCVTJDTESW-UHFFFAOYSA-N 0.000 claims description 3
- COLOHWPRNRVWPI-UHFFFAOYSA-N 1,1,1-trifluoroethane Chemical compound [CH2]C(F)(F)F COLOHWPRNRVWPI-UHFFFAOYSA-N 0.000 claims description 2
- 101100495918 Arabidopsis thaliana CHR23 gene Proteins 0.000 claims description 2
- 125000003302 alkenyloxy group Chemical group 0.000 claims description 2
- 125000000033 alkoxyamino group Chemical group 0.000 claims description 2
- 125000004992 haloalkylamino group Chemical group 0.000 claims description 2
- 125000002883 imidazolyl group Chemical group 0.000 claims 3
- 125000004076 pyridyl group Chemical group 0.000 claims 3
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical group C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims 2
- 125000003396 thiol group Chemical class [H]S* 0.000 claims 2
- 125000001589 carboacyl group Chemical group 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 111
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 87
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 70
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 56
- 239000000243 solution Substances 0.000 description 52
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- 238000006243 chemical reaction Methods 0.000 description 48
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 36
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- 239000007787 solid Substances 0.000 description 30
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- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 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 description 1
- 238000007257 deesterification reaction Methods 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 230000003412 degenerative effect Effects 0.000 description 1
- 239000003398 denaturant Substances 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 239000003599 detergent Substances 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 235000020805 dietary restrictions Nutrition 0.000 description 1
- 235000015872 dietary supplement Nutrition 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 1
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 125000003438 dodecyl 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])C([H])([H])C([H])([H])* 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 210000001842 enterocyte Anatomy 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- KGAWPIXNSIYQPC-UHFFFAOYSA-N ethyl piperidine-2-carboxylate;hydrochloride Chemical compound Cl.CCOC(=O)C1CCCCN1 KGAWPIXNSIYQPC-UHFFFAOYSA-N 0.000 description 1
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000037406 food intake Effects 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- 230000009395 genetic defect Effects 0.000 description 1
- JFCQEDHGNNZCLN-UHFFFAOYSA-N glutaric acid Chemical compound OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 239000012133 immunoprecipitate Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 239000012948 isocyanate Substances 0.000 description 1
- 150000002513 isocyanates Chemical class 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 1
- 229910001416 lithium ion Inorganic materials 0.000 description 1
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 1
- 210000001853 liver microsome Anatomy 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 238000006140 methanolysis reaction Methods 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- QAFJIJWLEBLXHH-UHFFFAOYSA-N methyl 2-fluorobenzoate Chemical compound COC(=O)C1=CC=CC=C1F QAFJIJWLEBLXHH-UHFFFAOYSA-N 0.000 description 1
- 210000001589 microsome Anatomy 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- SDXHXQHPTCVQKW-UHFFFAOYSA-N n-(1,3-dihydroxypropan-2-yl)-2-[4-(trifluoromethyl)phenyl]benzamide Chemical compound OCC(CO)NC(=O)C1=CC=CC=C1C1=CC=C(C(F)(F)F)C=C1 SDXHXQHPTCVQKW-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 125000001400 nonyl 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])[H] 0.000 description 1
- HEGSGKPQLMEBJL-RKQHYHRCSA-N octyl beta-D-glucopyranoside Chemical compound CCCCCCCCO[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O HEGSGKPQLMEBJL-RKQHYHRCSA-N 0.000 description 1
- 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 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- MPQXHAGKBWFSNV-UHFFFAOYSA-N oxidophosphanium Chemical class [PH3]=O MPQXHAGKBWFSNV-UHFFFAOYSA-N 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- RLZZZVKAURTHCP-UHFFFAOYSA-N phenanthrene-3,4-diol Chemical compound C1=CC=C2C3=C(O)C(O)=CC=C3C=CC2=C1 RLZZZVKAURTHCP-UHFFFAOYSA-N 0.000 description 1
- DDBREPKUVSBGFI-UHFFFAOYSA-N phenobarbital Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NC(=O)NC1=O DDBREPKUVSBGFI-UHFFFAOYSA-N 0.000 description 1
- 125000005538 phosphinite group Chemical group 0.000 description 1
- AQSJGOWTSHOLKH-UHFFFAOYSA-N phosphite(3-) Chemical class [O-]P([O-])[O-] AQSJGOWTSHOLKH-UHFFFAOYSA-N 0.000 description 1
- XRBCRPZXSCBRTK-UHFFFAOYSA-N phosphonous acid Chemical class OPO XRBCRPZXSCBRTK-UHFFFAOYSA-N 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 238000002264 polyacrylamide gel electrophoresis Methods 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910052705 radium Inorganic materials 0.000 description 1
- 230000011514 reflex Effects 0.000 description 1
- 229910052701 rubidium Inorganic materials 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000006884 silylation reaction Methods 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 1
- BAZAXWOYCMUHIX-UHFFFAOYSA-M sodium perchlorate Chemical compound [Na+].[O-]Cl(=O)(=O)=O BAZAXWOYCMUHIX-UHFFFAOYSA-M 0.000 description 1
- 229910001488 sodium perchlorate Inorganic materials 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 125000004385 trihaloalkyl group Chemical group 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Substances C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 125000002948 undecyl 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])[H] 0.000 description 1
- 241000701447 unidentified baculovirus Species 0.000 description 1
- 239000002691 unilamellar liposome Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 235000019155 vitamin A Nutrition 0.000 description 1
- 239000011719 vitamin A Substances 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 235000019168 vitamin K Nutrition 0.000 description 1
- 239000011712 vitamin K Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 150000003738 xylenes Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
- C07F9/6571—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms
- C07F9/657163—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms the ring phosphorus atom being bound to at least one carbon atom
- C07F9/657181—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and oxygen atoms as the only ring hetero atoms the ring phosphorus atom being bound to at least one carbon atom the ring phosphorus atom and, at least, one ring oxygen atom being part of a (thio)phosphonic acid derivative
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- 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
-
- 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
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Obesity (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Child & Adolescent Psychology (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Nouveaux inhibiteurs phosphonate ester cyclique de MTP de structure (I) dans laquelle R?2¿, L?2¿, A, B, L?1¿, R?1¿ et R?5a¿ sont tels que décrits dans le descriptif. Ces composés sont utiles pour abaisser le taux sérique de cholestérol et de triglycérides.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US6334797P | 1997-10-28 | 1997-10-28 | |
| US60/063,347 | 1997-10-28 | ||
| PCT/US1998/021750 WO1999021564A1 (fr) | 1997-10-28 | 1998-10-14 | Inhibiteurs phosphonate ester cyclique de proteine microsomale de transfert des triglycerides et procede associe |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2307889A1 true CA2307889A1 (fr) | 1999-05-06 |
Family
ID=22048585
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002307889A Abandoned CA2307889A1 (fr) | 1997-10-28 | 1998-10-14 | Inhibiteurs phosphonate ester cyclique de proteine microsomale de transfert des triglycerides et procede associe |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP1039915A4 (fr) |
| JP (1) | JP2001521001A (fr) |
| AU (1) | AU753520B2 (fr) |
| CA (1) | CA2307889A1 (fr) |
| WO (1) | WO1999021564A1 (fr) |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2562543B1 (fr) * | 1984-04-10 | 1987-09-25 | Elf Aquitaine | Nouveaux phosphonites cycliques, leur preparation et applications |
| CA2236684A1 (fr) * | 1996-01-16 | 1997-07-24 | William A. Slusarchyk | Composes aromatiques a conformation restreinte servant d'inhibiteurs de la proteine de transfert de triglyceride microsomique et procede associe |
| US5760246A (en) * | 1996-12-17 | 1998-06-02 | Biller; Scott A. | Conformationally restricted aromatic inhibitors of microsomal triglyceride transfer protein and method |
-
1998
- 1998-10-14 AU AU10876/99A patent/AU753520B2/en not_active Ceased
- 1998-10-14 WO PCT/US1998/021750 patent/WO1999021564A1/fr not_active Application Discontinuation
- 1998-10-14 CA CA002307889A patent/CA2307889A1/fr not_active Abandoned
- 1998-10-14 EP EP98953531A patent/EP1039915A4/fr not_active Withdrawn
- 1998-10-14 JP JP2000517722A patent/JP2001521001A/ja active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| WO1999021564A1 (fr) | 1999-05-06 |
| EP1039915A4 (fr) | 2001-02-14 |
| EP1039915A1 (fr) | 2000-10-04 |
| AU1087699A (en) | 1999-05-17 |
| AU753520B2 (en) | 2002-10-17 |
| JP2001521001A (ja) | 2001-11-06 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Dead |