BE1004193A3 - Inhibiteurs d'hmg-coa reductase contenant du phosphore, composes intermediaires et leur utilisation. - Google Patents

Inhibiteurs d'hmg-coa reductase contenant du phosphore, composes intermediaires et leur utilisation. Download PDF

Info

Publication number: BE1004193A3
Authority: BE; Belgium
Prior art keywords: group; lower alkyl; acid; mmol; methoxy
Prior art date: 1987-05-22

Application number

BE8800566A

Other languages

English (en)

French (fr)

Inventor

Donald Steven Karanewsky

Scott Adams Biller

Eric Michael Gordon

Original Assignee

Squibb & Sons Inc

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.)

1987-05-22

Filing date

1988-05-24

Publication date

1992-10-13

1988-05-24 Application filed by Squibb & Sons Inc filed Critical Squibb & Sons Inc

1992-10-13 Application granted granted Critical

1992-10-13 Publication of BE1004193A3 publication Critical patent/BE1004193A3/fr

Links

150000001875 compounds Chemical class 0.000 title claims abstract description 61
239000003112 inhibitor Substances 0.000 title abstract description 9
229910052698 phosphorus Inorganic materials 0.000 title description 5
239000011574 phosphorus Substances 0.000 title description 5
OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical class [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 title description 4
108090000895 Hydroxymethylglutaryl CoA Reductases Proteins 0.000 title description 2
102000004286 Hydroxymethylglutaryl CoA Reductases Human genes 0.000 title 1
125000000217 alkyl group Chemical group 0.000 claims abstract description 68
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 52
150000003839 salts Chemical class 0.000 claims abstract description 45
235000012000 cholesterol Nutrition 0.000 claims abstract description 26
125000003545 alkoxy group Chemical group 0.000 claims abstract description 21
230000015572 biosynthetic process Effects 0.000 claims abstract description 21
230000002209 hydrophobic effect Effects 0.000 claims abstract description 10
238000002360 preparation method Methods 0.000 claims abstract description 8
239000000203 mixture Substances 0.000 claims description 93
239000002253 acid Substances 0.000 claims description 52
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 33
229910052739 hydrogen Inorganic materials 0.000 claims description 32
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 31
239000001257 hydrogen Substances 0.000 claims description 29
150000004702 methyl esters Chemical class 0.000 claims description 23
ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 22
150000002148 esters Chemical class 0.000 claims description 16
239000004305 biphenyl Substances 0.000 claims description 14
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 13
235000010290 biphenyl Nutrition 0.000 claims description 13
125000005843 halogen group Chemical group 0.000 claims description 13
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 11
102000004190 Enzymes Human genes 0.000 claims description 10
108090000790 Enzymes Proteins 0.000 claims description 10
239000003814 drug Substances 0.000 claims description 9
125000001188 haloalkyl group Chemical group 0.000 claims description 8
239000000758 substrate Substances 0.000 claims description 6
125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 5
230000002401 inhibitory effect Effects 0.000 claims description 5
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 4
229910052799 carbon Inorganic materials 0.000 claims description 4
125000000490 cinnamyl group Chemical group C(C=CC1=CC=CC=C1)* 0.000 claims description 4
SMBQBQBNOXIFSF-UHFFFAOYSA-N dilithium Chemical class [Li][Li] SMBQBQBNOXIFSF-UHFFFAOYSA-N 0.000 claims description 4
125000005059 halophenyl group Chemical group 0.000 claims description 4
102100029077 3-hydroxy-3-methylglutaryl-coenzyme A reductase Human genes 0.000 claims description 3
230000000871 hypocholesterolemic effect Effects 0.000 claims description 3
101710158485 3-hydroxy-3-methylglutaryl-coenzyme A reductase Proteins 0.000 claims description 2
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
125000001589 carboacyl group Chemical group 0.000 claims description 2
239000003937 drug carrier Substances 0.000 claims description 2
239000012634 fragment Substances 0.000 claims description 2
125000004356 hydroxy functional group Chemical group O* 0.000 claims description 2
230000000055 hyoplipidemic effect Effects 0.000 claims description 2
125000004043 oxo group Chemical group O=* 0.000 claims description 2
WHBMMWSBFZVSSR-UHFFFAOYSA-N R3HBA Natural products CC(O)CC(O)=O WHBMMWSBFZVSSR-UHFFFAOYSA-N 0.000 claims 1
239000013067 intermediate product Substances 0.000 abstract 1
XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 106
239000000243 solution Substances 0.000 description 76
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 65
238000001704 evaporation Methods 0.000 description 61
230000008020 evaporation Effects 0.000 description 61
229910052786 argon Inorganic materials 0.000 description 53
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 51
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 49
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 47
239000003921 oil Substances 0.000 description 45
235000019198 oils Nutrition 0.000 description 45
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 44
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 42
UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 39
229910001868 water Inorganic materials 0.000 description 38
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 32
239000000047 product Substances 0.000 description 32
238000004809 thin layer chromatography Methods 0.000 description 32
-1 t-butoxy Chemical group 0.000 description 31
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 30
235000019439 ethyl acetate Nutrition 0.000 description 29
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 26
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 26
239000007787 solid Substances 0.000 description 25
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 24
239000012267 brine Substances 0.000 description 22
239000000741 silica gel Substances 0.000 description 22
229910002027 silica gel Inorganic materials 0.000 description 22
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 22
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 22
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
WGNSGQNASYNCBU-VKHMYHEASA-N (3s)-4-bromo-3-hydroxybutanoic acid Chemical compound BrC[C@@H](O)CC(O)=O WGNSGQNASYNCBU-VKHMYHEASA-N 0.000 description 18
VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 18
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
238000004587 chromatography analysis Methods 0.000 description 18
WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 17
239000000706 filtrate Substances 0.000 description 17
239000000725 suspension Substances 0.000 description 17
239000012074 organic phase Substances 0.000 description 16
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
241001274216 Naso Species 0.000 description 15
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 15
CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 14
125000003118 aryl group Chemical group 0.000 description 13
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
239000012043 crude product Substances 0.000 description 12
125000001153 fluoro group Chemical group F* 0.000 description 12
230000008018 melting Effects 0.000 description 12
238000002844 melting Methods 0.000 description 12
FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 12
229910004373 HOAc Inorganic materials 0.000 description 11
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 11
239000012528 membrane Substances 0.000 description 11
UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 11
229920000515 polycarbonate Polymers 0.000 description 11
239000004417 polycarbonate Substances 0.000 description 11
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 11
238000004458 analytical method Methods 0.000 description 10
230000000694 effects Effects 0.000 description 10
210000003494 hepatocyte Anatomy 0.000 description 10
XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 10
239000010410 layer Substances 0.000 description 10
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 9
XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical class C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 9
238000007792 addition Methods 0.000 description 9
150000001299 aldehydes Chemical class 0.000 description 9
238000006243 chemical reaction Methods 0.000 description 9
KDCIHNCMPUBDKT-UHFFFAOYSA-N hexane;propan-2-one Chemical compound CC(C)=O.CCCCCC KDCIHNCMPUBDKT-UHFFFAOYSA-N 0.000 description 9
239000002609 medium Substances 0.000 description 9
229940079593 drug Drugs 0.000 description 8
229940088598 enzyme Drugs 0.000 description 8
150000002431 hydrogen Chemical group 0.000 description 8
238000011534 incubation Methods 0.000 description 8
239000003960 organic solvent Substances 0.000 description 8
239000011541 reaction mixture Substances 0.000 description 8
229920006395 saturated elastomer Polymers 0.000 description 8
238000003786 synthesis reaction Methods 0.000 description 8
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 8
CABVTRNMFUVUDM-VRHQGPGLSA-N (3S)-3-hydroxy-3-methylglutaryl-CoA Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)C[C@@](O)(CC(O)=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 CABVTRNMFUVUDM-VRHQGPGLSA-N 0.000 description 7
125000006273 (C1-C3) alkyl group Chemical group 0.000 description 7
125000004169 (C1-C6) alkyl group Chemical group 0.000 description 7
OSUKSSHOHKZSJC-UHFFFAOYSA-N 12591-02-5 Chemical compound ClP(=O)=O OSUKSSHOHKZSJC-UHFFFAOYSA-N 0.000 description 7
229910052783 alkali metal Inorganic materials 0.000 description 7
150000001408 amides Chemical class 0.000 description 7
125000003710 aryl alkyl group Chemical group 0.000 description 7
239000012298 atmosphere Substances 0.000 description 7
239000010779 crude oil Substances 0.000 description 7
239000013078 crystal Substances 0.000 description 7
238000001914 filtration Methods 0.000 description 7
229910052731 fluorine Inorganic materials 0.000 description 7
239000011347 resin Substances 0.000 description 7
229920005989 resin Polymers 0.000 description 7
RZYHXKLKJRGJGP-UHFFFAOYSA-N 2,2,2-trifluoro-n,n-bis(trimethylsilyl)acetamide Chemical compound C[Si](C)(C)N([Si](C)(C)C)C(=O)C(F)(F)F RZYHXKLKJRGJGP-UHFFFAOYSA-N 0.000 description 6
ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 6
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
235000019502 Orange oil Nutrition 0.000 description 6
ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical compound OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 6
IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 description 6
125000001309 chloro group Chemical group Cl* 0.000 description 6
125000004093 cyano group Chemical group *C#N 0.000 description 6
239000011521 glass Substances 0.000 description 6
RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
150000002596 lactones Chemical class 0.000 description 6
150000002632 lipids Chemical class 0.000 description 6
238000000034 method Methods 0.000 description 6
239000010502 orange oil Substances 0.000 description 6
238000010992 reflux Methods 0.000 description 6
FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
KJTLQQUUPVSXIM-ZCFIWIBFSA-N (R)-mevalonic acid Chemical class OCC[C@](O)(C)CC(O)=O KJTLQQUUPVSXIM-ZCFIWIBFSA-N 0.000 description 5
CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 5
QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 5
XJLXINKUBYWONI-DQQFMEOOSA-N [[(2r,3r,4r,5r)-5-(6-aminopurin-9-yl)-3-hydroxy-4-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2s,3r,4s,5s)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphate Chemical compound NC(=O)C1=CC=C[N+]([C@@H]2[C@H]([C@@H](O)[C@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-DQQFMEOOSA-N 0.000 description 5
150000007513 acids Chemical class 0.000 description 5
239000000460 chlorine Substances 0.000 description 5
239000000284 extract Substances 0.000 description 5
239000011737 fluorine Substances 0.000 description 5
235000019000 fluorine Nutrition 0.000 description 5
230000005764 inhibitory process Effects 0.000 description 5
238000002372 labelling Methods 0.000 description 5
210000004185 liver Anatomy 0.000 description 5
125000001624 naphthyl group Chemical group 0.000 description 5
ACVYVLVWPXVTIT-UHFFFAOYSA-N phosphinic acid Chemical compound O[PH2]=O ACVYVLVWPXVTIT-UHFFFAOYSA-N 0.000 description 5
239000002244 precipitate Substances 0.000 description 5
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 4
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 4
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
KJTLQQUUPVSXIM-UHFFFAOYSA-N DL-mevalonic acid Natural products OCCC(O)(C)CC(O)=O KJTLQQUUPVSXIM-UHFFFAOYSA-N 0.000 description 4
PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 4
JOOMLFKONHCLCJ-UHFFFAOYSA-N N-(trimethylsilyl)diethylamine Chemical compound CCN(CC)[Si](C)(C)C JOOMLFKONHCLCJ-UHFFFAOYSA-N 0.000 description 4
102000004316 Oxidoreductases Human genes 0.000 description 4
108090000854 Oxidoreductases Proteins 0.000 description 4
241000700159 Rattus Species 0.000 description 4
229910018540 Si C Inorganic materials 0.000 description 4
229960000583 acetic acid Drugs 0.000 description 4
125000003282 alkyl amino group Chemical group 0.000 description 4
125000004414 alkyl thio group Chemical group 0.000 description 4
150000001412 amines Chemical class 0.000 description 4
239000002585 base Substances 0.000 description 4
229910052794 bromium Inorganic materials 0.000 description 4
239000000872 buffer Substances 0.000 description 4
210000004027 cell Anatomy 0.000 description 4
239000006285 cell suspension Substances 0.000 description 4
229910052801 chlorine Inorganic materials 0.000 description 4
239000007789 gas Substances 0.000 description 4
229910052744 lithium Inorganic materials 0.000 description 4
230000003228 microsomal effect Effects 0.000 description 4
125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 4
108090000623 proteins and genes Proteins 0.000 description 4
102000004169 proteins and genes Human genes 0.000 description 4
229910010271 silicon carbide Inorganic materials 0.000 description 4
239000007858 starting material Substances 0.000 description 4
238000003756 stirring Methods 0.000 description 4
125000001424 substituent group Chemical group 0.000 description 4
238000012360 testing method Methods 0.000 description 4
LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 4
125000004178 (C1-C4) alkyl group Chemical group 0.000 description 3
OBTZDIRUQWFRFZ-UHFFFAOYSA-N 2-(5-methylfuran-2-yl)-n-(4-methylphenyl)quinoline-4-carboxamide Chemical compound O1C(C)=CC=C1C1=CC(C(=O)NC=2C=CC(C)=CC=2)=C(C=CC=C2)C2=N1 OBTZDIRUQWFRFZ-UHFFFAOYSA-N 0.000 description 3
NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 3
NPOAOTPXWNWTSH-UHFFFAOYSA-N 3-hydroxy-3-methylglutaric acid Chemical compound OC(=O)CC(O)(C)CC(O)=O NPOAOTPXWNWTSH-UHFFFAOYSA-N 0.000 description 3
101000856746 Bos taurus Cytochrome c oxidase subunit 7A1, mitochondrial Proteins 0.000 description 3
FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 3
NHEULQMXMXIOJY-UHFFFAOYSA-N Cl[PH2]=O Chemical compound Cl[PH2]=O NHEULQMXMXIOJY-UHFFFAOYSA-N 0.000 description 3
KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 3
WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 3
FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 3
239000007832 Na2SO4 Substances 0.000 description 3
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
150000001340 alkali metals Chemical class 0.000 description 3
125000001246 bromo group Chemical group Br* 0.000 description 3
239000003795 chemical substances by application Substances 0.000 description 3
238000003776 cleavage reaction Methods 0.000 description 3
239000012230 colorless oil Substances 0.000 description 3
150000005690 diesters Chemical class 0.000 description 3
230000002255 enzymatic effect Effects 0.000 description 3
210000002950 fibroblast Anatomy 0.000 description 3
125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
238000010348 incorporation Methods 0.000 description 3
239000000543 intermediate Substances 0.000 description 3
239000012280 lithium aluminium hydride Substances 0.000 description 3
239000011777 magnesium Substances 0.000 description 3
229910052749 magnesium Inorganic materials 0.000 description 3
GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 3
JYVXNLLUYHCIIH-LURJTMIESA-N mevalonolactone Chemical group C[C@]1(O)CCOC(=O)C1 JYVXNLLUYHCIIH-LURJTMIESA-N 0.000 description 3
229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 3
229910052757 nitrogen Inorganic materials 0.000 description 3
239000008188 pellet Substances 0.000 description 3
ACVYVLVWPXVTIT-UHFFFAOYSA-M phosphinate Chemical compound [O-][PH2]=O ACVYVLVWPXVTIT-UHFFFAOYSA-M 0.000 description 3
210000003240 portal vein Anatomy 0.000 description 3
238000012545 processing Methods 0.000 description 3
230000007017 scission Effects 0.000 description 3
239000011734 sodium Substances 0.000 description 3
229910052938 sodium sulfate Inorganic materials 0.000 description 3
235000011152 sodium sulphate Nutrition 0.000 description 3
239000006228 supernatant Substances 0.000 description 3
125000004765 (C1-C4) haloalkyl group Chemical group 0.000 description 2
USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 2
239000005695 Ammonium acetate Substances 0.000 description 2
PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
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125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
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
230000003111 delayed effect Effects 0.000 description 1
235000014113 dietary fatty acids Nutrition 0.000 description 1
NSSMTQDEWVTEKN-UHFFFAOYSA-N diethoxy(methyl)phosphane Chemical compound CCOP(C)OCC NSSMTQDEWVTEKN-UHFFFAOYSA-N 0.000 description 1
239000003085 diluting agent Substances 0.000 description 1
125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
238000004821 distillation Methods 0.000 description 1
239000002552 dosage form Substances 0.000 description 1
238000001035 drying Methods 0.000 description 1
239000003480 eluent Substances 0.000 description 1
238000007824 enzymatic assay Methods 0.000 description 1
238000006911 enzymatic reaction Methods 0.000 description 1
230000032050 esterification Effects 0.000 description 1
238000005886 esterification reaction Methods 0.000 description 1
OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 1
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
230000007717 exclusion Effects 0.000 description 1
229930195729 fatty acid Natural products 0.000 description 1
239000000194 fatty acid Substances 0.000 description 1
150000004665 fatty acids Chemical class 0.000 description 1
238000000855 fermentation Methods 0.000 description 1
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239000012894 fetal calf serum Substances 0.000 description 1
239000012530 fluid Substances 0.000 description 1
235000019256 formaldehyde Nutrition 0.000 description 1
239000000499 gel Substances 0.000 description 1
239000011491 glass wool Substances 0.000 description 1
229940045189 glucose-6-phosphate Drugs 0.000 description 1
239000008187 granular material Substances 0.000 description 1
239000001963 growth medium Substances 0.000 description 1
150000004820 halides Chemical class 0.000 description 1
238000010438 heat treatment Methods 0.000 description 1
229960002897 heparin Drugs 0.000 description 1
229920000669 heparin Polymers 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
125000000623 heterocyclic group Chemical group 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
XHJJEWBMBSQVCJ-UHFFFAOYSA-N homocamfin Chemical compound CC(C)C1CC(C)=CC(=O)C1 XHJJEWBMBSQVCJ-UHFFFAOYSA-N 0.000 description 1
229950007035 homocamfin Drugs 0.000 description 1
239000008240 homogeneous mixture Substances 0.000 description 1
239000012456 homogeneous solution Substances 0.000 description 1
238000000265 homogenisation Methods 0.000 description 1
XGIHQYAWBCFNPY-AZOCGYLKSA-N hydrabamine Chemical class C([C@@H]12)CC3=CC(C(C)C)=CC=C3[C@@]2(C)CCC[C@@]1(C)CNCCNC[C@@]1(C)[C@@H]2CCC3=CC(C(C)C)=CC=C3[C@@]2(C)CCC1 XGIHQYAWBCFNPY-AZOCGYLKSA-N 0.000 description 1
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239000007924 injection Substances 0.000 description 1
238000002347 injection Methods 0.000 description 1
150000007529 inorganic bases Chemical class 0.000 description 1
229910052740 iodine Inorganic materials 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
125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
238000002955 isolation Methods 0.000 description 1
238000007273 lactonization reaction Methods 0.000 description 1
238000003475 lamination Methods 0.000 description 1
239000007788 liquid Substances 0.000 description 1
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159000000002 lithium salts Chemical class 0.000 description 1
210000001853 liver microsome Anatomy 0.000 description 1
210000005228 liver tissue Anatomy 0.000 description 1
PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 description 1
229960004844 lovastatin Drugs 0.000 description 1
QLJODMDSTUBWDW-UHFFFAOYSA-N lovastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(C)C=C21 QLJODMDSTUBWDW-UHFFFAOYSA-N 0.000 description 1
159000000003 magnesium salts Chemical class 0.000 description 1
238000004519 manufacturing process Methods 0.000 description 1
229960001961 meglutol Drugs 0.000 description 1
MBBQAVVBESBLGH-BYPYZUCNSA-N methyl (3s)-4-bromo-3-hydroxybutanoate Chemical compound COC(=O)C[C@H](O)CBr MBBQAVVBESBLGH-BYPYZUCNSA-N 0.000 description 1
229940057061 mevalonolactone Drugs 0.000 description 1
238000012986 modification Methods 0.000 description 1
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238000012544 monitoring process Methods 0.000 description 1
125000002950 monocyclic group Chemical group 0.000 description 1
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230000003000 nontoxic effect Effects 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
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
125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
239000007800 oxidant agent Substances 0.000 description 1
230000003647 oxidation Effects 0.000 description 1
238000007254 oxidation reaction Methods 0.000 description 1
230000001590 oxidative effect Effects 0.000 description 1
125000004430 oxygen atom Chemical group O* 0.000 description 1
229910052763 palladium Inorganic materials 0.000 description 1
LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 1
YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
235000019371 penicillin G benzathine Nutrition 0.000 description 1
125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
239000003208 petroleum Substances 0.000 description 1
239000007793 ph indicator Substances 0.000 description 1
239000008024 pharmaceutical diluent Substances 0.000 description 1
239000000546 pharmaceutical excipient Substances 0.000 description 1
125000003884 phenylalkyl group Chemical group 0.000 description 1
239000008363 phosphate buffer Substances 0.000 description 1
150000003904 phospholipids Chemical class 0.000 description 1
125000005541 phosphonamide group Chemical group 0.000 description 1
XRBCRPZXSCBRTK-UHFFFAOYSA-N phosphonous acid Chemical compound OPO XRBCRPZXSCBRTK-UHFFFAOYSA-N 0.000 description 1
229910000073 phosphorus hydride Inorganic materials 0.000 description 1
159000000001 potassium salts Chemical class 0.000 description 1
238000011533 pre-incubation Methods 0.000 description 1
230000001737 promoting effect Effects 0.000 description 1
BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
150000003254 radicals Chemical class 0.000 description 1
238000000163 radioactive labelling Methods 0.000 description 1
238000011084 recovery Methods 0.000 description 1
238000001953 recrystallisation Methods 0.000 description 1
230000009467 reduction Effects 0.000 description 1
238000006722 reduction reaction Methods 0.000 description 1
238000006268 reductive amination reaction Methods 0.000 description 1
238000011160 research Methods 0.000 description 1
238000004366 reverse phase liquid chromatography Methods 0.000 description 1
XMVJITFPVVRMHC-UHFFFAOYSA-N roxarsone Chemical group OC1=CC=C([As](O)(O)=O)C=C1[N+]([O-])=O XMVJITFPVVRMHC-UHFFFAOYSA-N 0.000 description 1
238000000926 separation method Methods 0.000 description 1
210000002966 serum Anatomy 0.000 description 1
239000002002 slurry Substances 0.000 description 1
229910052708 sodium Inorganic materials 0.000 description 1
239000012279 sodium borohydride Substances 0.000 description 1
229910000033 sodium borohydride Inorganic materials 0.000 description 1
239000011780 sodium chloride Substances 0.000 description 1
239000001509 sodium citrate Substances 0.000 description 1
NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
159000000000 sodium salts Chemical class 0.000 description 1
241000894007 species Species 0.000 description 1
239000000126 substance Substances 0.000 description 1
125000003107 substituted aryl group Chemical group 0.000 description 1
125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
229910052717 sulfur Inorganic materials 0.000 description 1
125000004434 sulfur atom Chemical group 0.000 description 1
208000024891 symptom Diseases 0.000 description 1
239000003826 tablet Substances 0.000 description 1
LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
150000003573 thiols Chemical group 0.000 description 1
BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 description 1
UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 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
238000005292 vacuum distillation Methods 0.000 description 1
239000003981 vehicle Substances 0.000 description 1
210000003462 vein Anatomy 0.000 description 1
238000005406 washing Methods 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
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/30—Phosphinic acids [R2P(=O)(OH)]; Thiophosphinic acids ; [R2P(=X1)(X2H) (X1, X2 are each independently O, S or Se)]
- 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
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl
- 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
- 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
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/30—Phosphinic acids [R2P(=O)(OH)]; Thiophosphinic acids ; [R2P(=X1)(X2H) (X1, X2 are each independently O, S or Se)]
- C07F9/301—Acyclic saturated acids which can have further substituents on alkyl
- 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
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/30—Phosphinic acids [R2P(=O)(OH)]; Thiophosphinic acids ; [R2P(=X1)(X2H) (X1, X2 are each independently O, S or Se)]
- C07F9/32—Esters thereof
- C07F9/3205—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/3211—Esters of acyclic saturated acids which can have further substituents on alkyl
- 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
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/30—Phosphinic acids [R2P(=O)(OH)]; Thiophosphinic acids ; [R2P(=X1)(X2H) (X1, X2 are each independently O, S or Se)]
- C07F9/36—Amides thereof
- 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
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
- C07F9/3808—Acyclic saturated acids which can have further substituents on alkyl
- 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
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/44—Amides thereof
- C07F9/4403—Amides thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4407—Amides of acyclic saturated acids which can have further substituents on alkyl

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Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
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Life Sciences & Earth Sciences (AREA)
General Health & Medical Sciences (AREA)
Biochemistry (AREA)
Molecular Biology (AREA)
Engineering & Computer Science (AREA)
Bioinformatics & Cheminformatics (AREA)
Pharmacology & Pharmacy (AREA)
Veterinary Medicine (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Public Health (AREA)
Medicinal Chemistry (AREA)
General Chemical & Material Sciences (AREA)
Chemical Kinetics & Catalysis (AREA)
Animal Behavior & Ethology (AREA)
Heart & Thoracic Surgery (AREA)
Cardiology (AREA)
Diabetes (AREA)
Hematology (AREA)
Obesity (AREA)
Vascular Medicine (AREA)
Urology & Nephrology (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Pyrane Compounds (AREA)
Steroid Compounds (AREA)
Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

BE8800566A 1987-05-22 1988-05-24 Inhibiteurs d'hmg-coa reductase contenant du phosphore, composes intermediaires et leur utilisation. BE1004193A3 (fr)

Applications Claiming Priority (2)

Application Number	Priority Date	Filing Date	Title
US5328187A	1987-05-22	1987-05-22
US10968087A	1987-10-19	1987-10-19

Publications (1)

Publication Number	Publication Date
BE1004193A3 true BE1004193A3 (fr)	1992-10-13

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ID=26731667

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
BE8800566A BE1004193A3 (fr)	1987-05-22	1988-05-24	Inhibiteurs d'hmg-coa reductase contenant du phosphore, composes intermediaires et leur utilisation.

Country Status (24)

Country	Link
JP (1)	JP2680347B2 (pl)
KR (1)	KR880013958A (pl)
CN (1)	CN88103091A (pl)
AU (1)	AU610591B2 (pl)
BE (1)	BE1004193A3 (pl)
CH (1)	CH676984A5 (pl)
DE (1)	DE3817375C2 (pl)
DK (1)	DK277488A (pl)
ES (1)	ES2009918A6 (pl)
FI (1)	FI89493C (pl)
FR (1)	FR2615508B1 (pl)
GB (1)	GB2205837B (pl)
GR (1)	GR1000959B (pl)
HU (1)	HU205125B (pl)
IE (2)	IE63760B1 (pl)
IL (1)	IL86464A (pl)
IT (1)	IT1217685B (pl)
NL (1)	NL8801330A (pl)
NO (1)	NO882218L (pl)
NZ (1)	NZ224733A (pl)
PH (1)	PH25350A (pl)
PL (1)	PL154877B1 (pl)
PT (1)	PT87539B (pl)
SE (1)	SE503210C2 (pl)

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* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
IT1217684B (it) *	1987-05-22	1990-03-30	Squibb & Sons Inc	Inibitori della hmg coa riduttasi contenenti fosforo,nuovi intermedi e procedimento
CA2007643A1 (en) *	1989-02-01	1990-08-01	Donald S. Karanewsky	Combination of an hmg coa reductase inhibitor and a squalene synthetase inhibitor and method for lowering serum cholesterol using such combination
CA2042526A1 (en) *	1990-06-11	1991-12-12	Adeoye Y. Olukotun	Method for preventing a second heart attack employing an hmg coa reductase inhibitor
US5202327A (en) *	1991-07-10	1993-04-13	E. R. Squibb & Sons, Inc.	Phosphorus-containing hmg-coa reductase inhibitors
GB9126144D0 (en) *	1991-12-10	1992-02-12	British Bio Technology	Compounds
US20010006644A1 (en)	1997-07-31	2001-07-05	David J. Bova	Combinations of hmg-coa reductase inhibitors and nicotinic acid and methods for treating hyperlipidemia once a day at night
GEP20033045B (en)	1998-09-17	2003-08-25	Bristol Myers Squibb Co	Method for Treating Diabetes
AU2002254567B2 (en)	2001-04-11	2007-10-11	Bristol-Myers Squibb Company	Amino acid complexes of C-aryl glucosides for treatment of diabetes and method
KR20040054729A (ko)	2001-10-18	2004-06-25	브리스톨-마이어스 스큅 컴퍼니	인간 글루카곤-유사-펩티드-1 모방체, 및 당뇨병 및 이와관련된 증상의 치료에 있어서 이의 용도
US7238671B2 (en)	2001-10-18	2007-07-03	Bristol-Myers Squibb Company	Human glucagon-like-peptide-1 mimics and their use in the treatment of diabetes and related conditions
US6806381B2 (en)	2001-11-02	2004-10-19	Bristol-Myers Squibb Company	Process for the preparation of aniline-derived thyroid receptor ligands
US7057046B2 (en)	2002-05-20	2006-06-06	Bristol-Myers Squibb Company	Lactam glycogen phosphorylase inhibitors and method of use
ATE469645T1 (de)	2002-10-23	2010-06-15	Bristol Myers Squibb Co	Auf glycinnitril basierende hemmer der dipeptidylpeptidase iv
US7098235B2 (en)	2002-11-14	2006-08-29	Bristol-Myers Squibb Co.	Triglyceride and triglyceride-like prodrugs of glycogen phosphorylase inhibiting compounds
TW200504021A (en)	2003-01-24	2005-02-01	Bristol Myers Squibb Co	Substituted anilide ligands for the thyroid receptor
US7459474B2 (en)	2003-06-11	2008-12-02	Bristol-Myers Squibb Company	Modulators of the glucocorticoid receptor and method
US6995183B2 (en)	2003-08-01	2006-02-07	Bristol Myers Squibb Company	Adamantylglycine-based inhibitors of dipeptidyl peptidase IV and methods
US8158362B2 (en)	2005-03-30	2012-04-17	Decode Genetics Ehf.	Methods of diagnosing susceptibility to myocardial infarction and screening for an LTA4H haplotype
KR101494067B1 (ko)	2004-03-05	2015-02-16	더 트러스티스 오브 더 유니버시티 오브 펜실바니아	부작용을 최소화하면서 과지질혈증 및 과콜레스테롤혈증과 연관된 질환 또는 질병의 치료 방법
US7145040B2 (en)	2004-07-02	2006-12-05	Bristol-Myers Squibb Co.	Process for the preparation of amino acids useful in the preparation of peptide receptor modulators
US7534763B2 (en)	2004-07-02	2009-05-19	Bristol-Myers Squibb Company	Sustained release GLP-1 receptor modulators
TW200611704A (en)	2004-07-02	2006-04-16	Bristol Myers Squibb Co	Human glucagon-like-peptide-1 modulators and their use in the treatment of diabetes and related conditions
AR051446A1 (es)	2004-09-23	2007-01-17	Bristol Myers Squibb Co	Glucosidos de c-arilo como inhibidores selectivos de transportadores de glucosa (sglt2)
US7517991B2 (en)	2004-10-12	2009-04-14	Bristol-Myers Squibb Company	N-sulfonylpiperidine cannabinoid receptor 1 antagonists
US7589088B2 (en)	2004-12-29	2009-09-15	Bristol-Myers Squibb Company	Pyrimidine-based inhibitors of dipeptidyl peptidase IV and methods
US7635699B2 (en)	2004-12-29	2009-12-22	Bristol-Myers Squibb Company	Azolopyrimidine-based inhibitors of dipeptidyl peptidase IV and methods
WO2006076598A2 (en)	2005-01-12	2006-07-20	Bristol-Myers Squibb Company	Bicyclic heterocycles as cannabinoid receptor modulators
WO2006076569A2 (en)	2005-01-12	2006-07-20	Bristol-Myers Squibb Company	Bicyclic heterocycles as cannabinoid receptor modulators
US7368458B2 (en)	2005-01-12	2008-05-06	Bristol-Myers Squibb Company	Bicyclic heterocycles as cannabinoid receptor modulators
US20060160850A1 (en)	2005-01-18	2006-07-20	Chongqing Sun	Bicyclic heterocycles as cannabinoid receptor modulators
US20060235028A1 (en)	2005-04-14	2006-10-19	Li James J	Inhibitors of 11-beta hydroxysteroid dehydrogenase type I
US7521557B2 (en)	2005-05-20	2009-04-21	Bristol-Myers Squibb Company	Pyrrolopyridine-based inhibitors of dipeptidyl peptidase IV and methods
US7629342B2 (en)	2005-06-17	2009-12-08	Bristol-Myers Squibb Company	Azabicyclic heterocycles as cannabinoid receptor modulators
US7632837B2 (en)	2005-06-17	2009-12-15	Bristol-Myers Squibb Company	Bicyclic heterocycles as cannabinoid-1 receptor modulators
US7452892B2 (en)	2005-06-17	2008-11-18	Bristol-Myers Squibb Company	Triazolopyrimidine cannabinoid receptor 1 antagonists
TW200726765A (en)	2005-06-17	2007-07-16	Bristol Myers Squibb Co	Triazolopyridine cannabinoid receptor 1 antagonists
US7317012B2 (en)	2005-06-17	2008-01-08	Bristol-Myers Squibb Company	Bicyclic heterocycles as cannabinoind-1 receptor modulators
AR056155A1 (es)	2005-10-26	2007-09-19	Bristol Myers Squibb Co	Antagonistas del receptor 1 de la hormona de concentracion de melanina no basica
EP1943215A2 (en)	2005-10-31	2008-07-16	Brystol-Myers Squibb Company	Pyrrolidinyl beta-amino amide-based inhibitors of dipeptidyl peptidase iv and methods
US7592461B2 (en)	2005-12-21	2009-09-22	Bristol-Myers Squibb Company	Indane modulators of glucocorticoid receptor, AP-1, and/or NF-κB activity and use thereof
US7553836B2 (en)	2006-02-06	2009-06-30	Bristol-Myers Squibb Company	Melanin concentrating hormone receptor-1 antagonists
US20100022457A1 (en)	2006-05-26	2010-01-28	Bristol-Myers Squibb Company	Sustained release glp-1 receptor modulators
US7919598B2 (en)	2006-06-28	2011-04-05	Bristol-Myers Squibb Company	Crystal structures of SGLT2 inhibitors and processes for preparing same
WO2008057862A2 (en)	2006-11-01	2008-05-15	Bristol-Myers Squibb Company	MODULATORS OF GLUCOCORTICOID RECEPTOR, AP-1, AND/OR NF-ϰB ACTIVITY AND USE THEREOF
TW200904405A (en)	2007-03-22	2009-02-01	Bristol Myers Squibb Co	Pharmaceutical formulations containing an SGLT2 inhibitor
PE20090696A1 (es)	2007-04-20	2009-06-20	Bristol Myers Squibb Co	Formas cristalinas de saxagliptina y procesos para preparar las mismas
EP2581081A3 (en)	2007-06-01	2013-07-31	The Trustees Of Princeton University	Treatment of viral infections by modulation of host cell metabolic pathways
US20090011994A1 (en)	2007-07-06	2009-01-08	Bristol-Myers Squibb Company	Non-basic melanin concentrating hormone receptor-1 antagonists and methods
ES2408384T3 (es)	2007-07-27	2013-06-20	Bristol-Myers Squibb Company	Nuevos activadores de glucoquinasa y procedimientos de uso de los mismos
BRPI0817211A2 (pt)	2007-09-20	2017-05-16	Irm Llc	composto composições como moduladores da atividade de gpr119
PE20091928A1 (es)	2008-05-29	2009-12-31	Bristol Myers Squibb Co	Tienopirimidinas hidroxisustituidas como antagonistas de receptor-1 de hormona concentradora de melanina no basicos
MX2011009852A (es)	2009-03-27	2011-09-29	Bristol Myers Squibb Co	Metodos para prevenir episodios cardiovasculares adversos mayores con inhibidores de dipeptidil peptidasa iv.
WO2011014520A2 (en)	2009-07-29	2011-02-03	Irm Llc	Compounds and compositions as modulators of gpr119 activity
WO2011044001A1 (en)	2009-10-09	2011-04-14	Irm Llc	Compounds and compositions as modulators of gpr119 activity
ES2689107T3 (es)	2009-11-13	2018-11-08	Astrazeneca Ab	Formulaciones de tabletas bicapa
EP2498759B1 (en)	2009-11-13	2018-08-01	AstraZeneca AB	Immediate release tablet formulations
WO2011060255A1 (en)	2009-11-13	2011-05-19	Bristol-Myers Squibb Company	Reduced mass metformin formulations
US8394858B2 (en)	2009-12-03	2013-03-12	Novartis Ag	Cyclohexane derivatives and uses thereof
TWI562775B (en)	2010-03-02	2016-12-21	Lexicon Pharmaceuticals Inc	Methods of using inhibitors of sodium-glucose cotransporters 1 and 2
CN102971313A (zh)	2010-04-14	2013-03-13	百时美施贵宝公司	新颖的葡糖激酶激活剂及其使用方法
MY161846A (en)	2010-07-09	2017-05-15	James Trinca Green	Combination immediate/delayed release delivery system for short half-life pharmaceuticals including remogliflozin
US8697739B2 (en)	2010-07-29	2014-04-15	Novartis Ag	Bicyclic acetyl-CoA carboxylase inhibitors and uses thereof
TWI631963B (zh)	2011-01-05	2018-08-11	雷西肯製藥股份有限公司	包含鈉－葡萄糖共同輸送體１與２之抑制劑的組合物與應用方法
WO2014052619A1 (en)	2012-09-27	2014-04-03	Irm Llc	Piperidine derivatives and compositions as modulators of gpr119 activity
US9200025B2 (en)	2012-11-20	2015-12-01	Lexicon Pharmaceuticals, Inc.	Inhibitors of sodium glucose cotransporter 1
US9593113B2 (en)	2013-08-22	2017-03-14	Bristol-Myers Squibb Company	Imide and acylurea derivatives as modulators of the glucocorticoid receptor
CN104610262B (zh) *	2013-11-01	2017-06-06	上海医药工业研究院	联苯类化合物、中间体、制备方法、药物组合物及其应用
TW201702271A (zh)	2015-04-30	2017-01-16	哈佛大學校長及研究員協會	治療代謝病症之抗－ａｐ２抗體及抗原結合劑
MA53175A (fr)	2018-07-19	2021-05-26	Astrazeneca Ab	Méthodes de traitement de hfpef au moyen de dapagliflozine et compositions comprenant celle-ci
US10968192B2 (en)	2018-09-26	2021-04-06	Lexicon Pharmaceuticals, Inc.	Crystalline solid forms of N-(1-((2-(dimethylamino)ethyl)amino)-2-methyl-1-oxopropan-2-yl)-4-(4-(2-methyl-5-((2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(methylthio)tetrahydro-2H-pyran-2-yl)benzyl)phenyl)butanamide and methods of their synthesis
CA3186856A1 (en)	2020-07-29	2022-02-03	Ruth NALLEN	Lomitapide for use in methods of treating hyperlipidemia and hypercholesterolemia in pediatric patients

Citations (3)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
EP0080889A1 (en) *	1981-12-01	1983-06-08	Philip A. Hunt Chemical Corporation	Herbicidal compositions containing and method using phosphonoalkanoic acids, esters and salts thereof
FR2596393A1 (fr) *	1986-04-01	1987-10-02	Sanofi Sa	Derives de l'acide hydroxy-3 dihydroxyoxophosphorio-4 butanoique, leur procede de preparation, leur application comme medicament et les compositions les renfermant
FR2615516A1 (fr) *	1987-05-22	1988-11-25	Squibb & Sons Inc	Inhibiteurs de la hmg-coa reductase, contenant du phosphore, nouveaux intermediaires de ces inhibiteurs et procede pour leur preparation

1988
- 1988-05-20 ES ES8801610A patent/ES2009918A6/es not_active Expired
- 1988-05-20 PT PT87539A patent/PT87539B/pt not_active IP Right Cessation
- 1988-05-20 NO NO882218A patent/NO882218L/no unknown
- 1988-05-20 IL IL86464A patent/IL86464A/xx not_active IP Right Cessation
- 1988-05-20 IT IT20682/88A patent/IT1217685B/it active
- 1988-05-20 DE DE3817375A patent/DE3817375C2/de not_active Expired - Fee Related
- 1988-05-20 DK DK277488A patent/DK277488A/da not_active Application Discontinuation
- 1988-05-20 PH PH36956A patent/PH25350A/en unknown
- 1988-05-20 IE IE154388A patent/IE63760B1/en not_active IP Right Cessation
- 1988-05-20 IE IE930324A patent/IE930324L/xx unknown
- 1988-05-20 HU HU882614A patent/HU205125B/hu not_active IP Right Cessation
- 1988-05-20 FI FI882384A patent/FI89493C/fi not_active IP Right Cessation
- 1988-05-20 AU AU16508/88A patent/AU610591B2/en not_active Ceased
- 1988-05-20 GR GR880100331A patent/GR1000959B/el unknown
- 1988-05-20 GB GB8811929A patent/GB2205837B/en not_active Expired - Fee Related
- 1988-05-20 SE SE8801903A patent/SE503210C2/sv not_active IP Right Cessation
- 1988-05-20 NZ NZ224733A patent/NZ224733A/en unknown
- 1988-05-21 JP JP63124809A patent/JP2680347B2/ja not_active Expired - Lifetime
- 1988-05-21 PL PL1988272597A patent/PL154877B1/pl unknown
- 1988-05-21 KR KR1019880006020A patent/KR880013958A/ko not_active Ceased
- 1988-05-21 CN CN198888103091A patent/CN88103091A/zh active Pending
- 1988-05-24 CH CH1967/88A patent/CH676984A5/fr not_active IP Right Cessation
- 1988-05-24 FR FR8806885A patent/FR2615508B1/fr not_active Expired - Fee Related
- 1988-05-24 BE BE8800566A patent/BE1004193A3/fr not_active IP Right Cessation
- 1988-05-24 NL NL8801330A patent/NL8801330A/nl not_active Application Discontinuation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
EP0080889A1 (en) *	1981-12-01	1983-06-08	Philip A. Hunt Chemical Corporation	Herbicidal compositions containing and method using phosphonoalkanoic acids, esters and salts thereof
FR2596393A1 (fr) *	1986-04-01	1987-10-02	Sanofi Sa	Derives de l'acide hydroxy-3 dihydroxyoxophosphorio-4 butanoique, leur procede de preparation, leur application comme medicament et les compositions les renfermant
FR2615516A1 (fr) *	1987-05-22	1988-11-25	Squibb & Sons Inc	Inhibiteurs de la hmg-coa reductase, contenant du phosphore, nouveaux intermediaires de ces inhibiteurs et procede pour leur preparation

Also Published As

Publication number	Publication date
GB2205837B (en)	1991-11-20
CH676984A5 (pl)	1991-03-28
SE8801903D0 (sv)	1988-05-20
FI882384A0 (fi)	1988-05-20
IE930324L (en)	1988-11-22
DK277488D0 (da)	1988-05-20
GB8811929D0 (en)	1988-06-22
IL86464A (en)	1993-06-10
SE503210C2 (sv)	1996-04-22
IL86464A0 (en)	1988-11-15
JP2680347B2 (ja)	1997-11-19
PT87539B (pt)	1992-09-30
FI882384A7 (fi)	1988-11-23
GR1000959B (el)	1993-03-16
IE881543L (en)	1988-11-22
DE3817375C2 (de)	1997-04-30
PL154877B1 (en)	1991-09-30
FR2615508A1 (fr)	1988-11-25
ES2009918A6 (es)	1989-10-16
GR880100331A (en)	1989-02-23
AU610591B2 (en)	1991-05-23
JPS6456689A (en)	1989-03-03
NO882218D0 (no)	1988-05-20
DK277488A (da)	1988-11-23
FI89493B (fi)	1993-06-30
FI89493C (fi)	1993-10-11
DE3817375A1 (de)	1988-12-08
HUT49358A (en)	1989-09-28
KR880013958A (ko)	1988-12-22
SE8801903L (sv)	1988-11-23
HU205125B (en)	1992-03-30
IT8820682A0 (it)	1988-05-20
IE63760B1 (en)	1995-06-14
AU1650888A (en)	1988-11-24
FR2615508B1 (fr)	1994-11-25
PL272597A1 (en)	1989-03-06
PH25350A (en)	1991-05-13
GB2205837A (en)	1988-12-21
PT87539A (pt)	1989-05-31
IT1217685B (it)	1990-03-30
NZ224733A (en)	1990-12-21
NL8801330A (nl)	1988-12-16
NO882218L (no)	1988-11-23
CN88103091A (zh)	1988-12-21

Legal Events

Date	Code	Title	Description
2005-11-30	RE	Patent lapsed	Effective date: 20050531
2007-12-31	RE	Patent lapsed	Effective date: 20050531

Publication	Publication Date	Title
BE1004193A3 (fr)	1992-10-13	Inhibiteurs d'hmg-coa reductase contenant du phosphore, composes intermediaires et leur utilisation.
US4904646A (en)	1990-02-27	Phosphorus-containing HMG-COA reductase inhibitors
US5017716A (en)	1991-05-21	Phosphorous-containing HMG-CoA reductase inhibitors, new intermediates and method
AU612475B2 (en)	1991-07-11	Phenol substituted gem-diphosphonate derivatives, process for their preparation and pharmaceutical compositions containing them
US5025000A (en)	1991-06-18	Phosphorus-containing HMG-CoA reductase inhibitor compounds
WO1996026948A1 (en)	1996-09-06	Phosphate derivatives of disubstituted ureas and thioureas
EP3277662B1 (en)	2025-01-22	Hydrogen sulfide precursors and conjugates thereof
EP1453840A1 (fr)	2004-09-08	Phosphonates utiles comme modulateurs de l'activite des lymphocytes t-gamma-9-delta-2
HU201085B (en)	1990-09-28	Process for producing phosphor-containing compounds and pharmaceutical compositions containing them as active components
CA2078771A1 (en)	1991-10-18	2(5h)-furanones substituted in the 5 and or in the 4 position, as anti-inflammatory agents
EP0593595B1 (en)	2000-01-05	Derivatives of inositol, preparations containing them and their use
US5227508A (en)	1993-07-13	3-deoxy-3-substituted analogs of phosphatidylinositol
EP0787135B1 (fr)	2000-05-24	Derives hydrosolubles d'epipodophyllotoxine, leur procede de preparation, leur utilisation a titre de medicament, et leur utilisation destinee aux traitements anticancereux
US4702864A (en)	1987-10-27	Analogs of platelet activating factor
US5407923A (en)	1995-04-18	Substituted derivatives of deoxymyoinositol, process for their preparation and their use in medicaments
Wróblewski et al.	2002	Synthesis of (1R, 2S)-and (1S, 2S)-3-azido-1, 2-dihydroxypropylphosphonates
GB2235924A (en)	1991-03-20	Phosphorus-containing 3-hydroxy-butanoic acid intermediates
PH26228A (en)	1992-04-01	An intermediate for the preparation of phosphorous containing CoA reductase inhibitors
CN102079760A (zh)	2011-06-01	α-二氟亚甲基膦内酯的合成方法
JPH04270276A (ja)	1992-09-25	２−テトラヒドロフラン誘導体の鏡像異性体、その中間体およびそれらの製造方法
WO1991016330A1 (fr)	1991-10-31	Prodrogues d'amethopterine(methotrexate), produits intermediaires, procede de preparation et compositions les contenant
EP0366469A2 (en)	1990-05-02	Phosphorus containing enzyme inhibitors
FR2876104A1 (fr)	2006-04-07	Composes fluorophosphonocinnamiques, systhese et aplications
DD270714A5 (de)	1989-08-09	Verfahren zur herstellung von phosphorhaltigen hmg-coa reduktase-inhibitoren
JPH072886A (ja)	1995-01-06	血小板増多剤ロイストロダクシンｈ