IE63760B1 - Phosphorus-containing HMG-CoA reductase inhibitors - Google Patents
Phosphorus-containing HMG-CoA reductase inhibitorsInfo
- Publication number
- IE63760B1 IE63760B1 IE154388A IE154388A IE63760B1 IE 63760 B1 IE63760 B1 IE 63760B1 IE 154388 A IE154388 A IE 154388A IE 154388 A IE154388 A IE 154388A IE 63760 B1 IE63760 B1 IE 63760B1
- Authority
- IE
- Ireland
- Prior art keywords
- lower alkyl
- compound
- salt
- mmole
- acid
- Prior art date
Links
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 title description 4
- 229910052698 phosphorus Inorganic materials 0.000 title description 4
- 239000011574 phosphorus Substances 0.000 title description 4
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 title description 2
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 title description 2
- 229940096701 plain lipid modifying drug hmg coa reductase inhibitors Drugs 0.000 title description 2
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 76
- 150000001875 compounds Chemical class 0.000 claims abstract description 58
- 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 50
- 150000003839 salts Chemical class 0.000 claims abstract description 27
- 235000012000 cholesterol Nutrition 0.000 claims abstract description 25
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 24
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 20
- 230000002209 hydrophobic effect Effects 0.000 claims abstract description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 6
- 239000000203 mixture Substances 0.000 claims description 75
- -1 87haloalkyl Chemical group 0.000 claims description 34
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 33
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 22
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 19
- 150000002148 esters Chemical class 0.000 claims description 19
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 17
- 229910052736 halogen Inorganic materials 0.000 claims description 12
- 150000002367 halogens Chemical class 0.000 claims description 12
- 102000004190 Enzymes Human genes 0.000 claims description 11
- 108090000790 Enzymes Proteins 0.000 claims description 11
- 235000010290 biphenyl Nutrition 0.000 claims description 10
- 239000004305 biphenyl Substances 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 8
- 230000002401 inhibitory effect Effects 0.000 claims description 8
- 102100029077 3-hydroxy-3-methylglutaryl-coenzyme A reductase Human genes 0.000 claims description 7
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 7
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical class [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 7
- 125000001188 haloalkyl group Chemical group 0.000 claims description 7
- 150000004702 methyl esters Chemical class 0.000 claims description 7
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 5
- SMBQBQBNOXIFSF-UHFFFAOYSA-N dilithium Chemical class [Li][Li] SMBQBQBNOXIFSF-UHFFFAOYSA-N 0.000 claims description 5
- 239000003937 drug carrier Substances 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
- 125000001589 carboacyl group Chemical group 0.000 claims description 4
- 125000000490 cinnamyl group Chemical group C(C=CC1=CC=CC=C1)* 0.000 claims description 4
- 125000005059 halophenyl group Chemical group 0.000 claims description 4
- 230000000055 hyoplipidemic effect Effects 0.000 claims description 4
- 230000000871 hypocholesterolemic effect Effects 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 101710158485 3-hydroxy-3-methylglutaryl-coenzyme A reductase Proteins 0.000 claims description 3
- VWYACSYWUFCXMS-INIZCTEOSA-N (3s)-4-[[2-(4-fluoro-3-methylphenyl)-4,6-dimethylphenyl]methoxy-hydroxyphosphoryl]-3-hydroxybutanoic acid Chemical compound CC1=CC(C)=C(COP(O)(=O)C[C@@H](O)CC(O)=O)C(C=2C=C(C)C(F)=CC=2)=C1 VWYACSYWUFCXMS-INIZCTEOSA-N 0.000 claims description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000004043 oxo group Chemical group O=* 0.000 claims description 2
- KRZJRNZICWNMOA-GXSJLCMTSA-N (3s,4r)-4,8-dihydroxy-3-methoxy-3,4-dihydro-2h-naphthalen-1-one Chemical compound C1=CC=C2[C@@H](O)[C@@H](OC)CC(=O)C2=C1O KRZJRNZICWNMOA-GXSJLCMTSA-N 0.000 claims 1
- SJHPCNCNNSSLPL-CSKARUKUSA-N (4e)-4-(ethoxymethylidene)-2-phenyl-1,3-oxazol-5-one Chemical class O1C(=O)C(=C/OCC)\N=C1C1=CC=CC=C1 SJHPCNCNNSSLPL-CSKARUKUSA-N 0.000 claims 1
- 125000006269 biphenyl-2-yl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C1=C(*)C([H])=C([H])C([H])=C1[H] 0.000 claims 1
- 229910052799 carbon Inorganic materials 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 8
- 239000003112 inhibitor Substances 0.000 abstract description 7
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 3
- 239000003529 anticholesteremic agent Substances 0.000 abstract description 2
- 239000000543 intermediate Substances 0.000 abstract description 2
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 abstract 1
- 229910000077 silane Inorganic materials 0.000 abstract 1
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 104
- 239000000243 solution Substances 0.000 description 72
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 64
- 229910052786 argon Inorganic materials 0.000 description 52
- 239000003921 oil Substances 0.000 description 46
- 235000019198 oils Nutrition 0.000 description 46
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 44
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 39
- 239000000047 product Substances 0.000 description 32
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 31
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 30
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 28
- 235000019439 ethyl acetate Nutrition 0.000 description 28
- 229910052739 hydrogen Inorganic materials 0.000 description 28
- 239000001257 hydrogen Substances 0.000 description 27
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 26
- 239000007787 solid Substances 0.000 description 25
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 23
- 239000012267 brine Substances 0.000 description 23
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 23
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 22
- 239000002253 acid Substances 0.000 description 22
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 22
- 239000000741 silica gel Substances 0.000 description 21
- 229910002027 silica gel Inorganic materials 0.000 description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 20
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 20
- 239000000725 suspension Substances 0.000 description 19
- 239000007832 Na2SO4 Substances 0.000 description 18
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- 229910052938 sodium sulfate Inorganic materials 0.000 description 18
- 235000011152 sodium sulphate Nutrition 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
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 16
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 15
- 238000003818 flash chromatography Methods 0.000 description 15
- 150000002431 hydrogen Chemical group 0.000 description 15
- 239000012074 organic phase Substances 0.000 description 15
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 14
- 125000003118 aryl group Chemical group 0.000 description 14
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 14
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 14
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 13
- 239000000460 chlorine Substances 0.000 description 13
- 125000001153 fluoro group Chemical group F* 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- KDCIHNCMPUBDKT-UHFFFAOYSA-N hexane;propan-2-one Chemical compound CC(C)=O.CCCCCC KDCIHNCMPUBDKT-UHFFFAOYSA-N 0.000 description 12
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 12
- 239000012043 crude product Substances 0.000 description 11
- 239000012528 membrane Substances 0.000 description 11
- 229920000515 polycarbonate Polymers 0.000 description 11
- 239000004417 polycarbonate Substances 0.000 description 11
- 229910004373 HOAc Inorganic materials 0.000 description 10
- 229940088598 enzyme Drugs 0.000 description 10
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 10
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 10
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 9
- 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
- 150000001299 aldehydes Chemical class 0.000 description 9
- 210000003494 hepatocyte Anatomy 0.000 description 9
- OSUKSSHOHKZSJC-UHFFFAOYSA-N 12591-02-5 Chemical compound ClP(=O)=O OSUKSSHOHKZSJC-UHFFFAOYSA-N 0.000 description 8
- 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 8
- 238000006243 chemical reaction Methods 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 239000003960 organic solvent Substances 0.000 description 8
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 229920006395 saturated elastomer Polymers 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
- 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
- 239000010779 crude oil Substances 0.000 description 7
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 7
- 239000002609 medium Substances 0.000 description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 7
- 239000011347 resin Substances 0.000 description 7
- 229920005989 resin Polymers 0.000 description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- 238000005481 NMR spectroscopy Methods 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
- 241000700159 Rattus Species 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 229910052731 fluorine Inorganic materials 0.000 description 6
- 239000011521 glass Substances 0.000 description 6
- 125000005843 halogen group Chemical group 0.000 description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- 150000002632 lipids Chemical class 0.000 description 6
- 239000010502 orange oil Substances 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
- 238000003786 synthesis reaction Methods 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
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 5
- JOOMLFKONHCLCJ-UHFFFAOYSA-N N-(trimethylsilyl)diethylamine Chemical compound CCN(CC)[Si](C)(C)C JOOMLFKONHCLCJ-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
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- 229910003002 lithium salt Inorganic materials 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
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 5
- 239000002244 precipitate Substances 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
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- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
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- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 4
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- 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
- 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
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- AHCYUBQQQZAYMH-HNNXBMFYSA-N OC(=O)C[C@H](O)CP(=O)OCOCC1=C(Cl)C=C(Cl)C=C1OCC1=CC=C(F)C=C1 Chemical compound OC(=O)C[C@H](O)CP(=O)OCOCC1=C(Cl)C=C(Cl)C=C1OCC1=CC=C(F)C=C1 AHCYUBQQQZAYMH-HNNXBMFYSA-N 0.000 description 3
- 102000004316 Oxidoreductases Human genes 0.000 description 3
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- 229910018540 Si C Inorganic materials 0.000 description 3
- 125000003282 alkyl amino group Chemical group 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 description 3
- 159000000007 calcium salts Chemical class 0.000 description 3
- 239000013553 cell monolayer Substances 0.000 description 3
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- 125000004093 cyano group Chemical group *C#N 0.000 description 3
- 150000005690 diesters Chemical class 0.000 description 3
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- 238000010348 incorporation Methods 0.000 description 3
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- 238000003756 stirring Methods 0.000 description 3
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- 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
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- 150000003904 phospholipids Chemical class 0.000 description 1
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- XRBCRPZXSCBRTK-UHFFFAOYSA-N phosphonous acid Chemical compound OPO XRBCRPZXSCBRTK-UHFFFAOYSA-N 0.000 description 1
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- 159000000001 potassium salts Chemical class 0.000 description 1
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- 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
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- 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
- 210000002966 serum Anatomy 0.000 description 1
- 238000000526 short-path distillation Methods 0.000 description 1
- 238000005584 silyl ether cleavage reaction Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 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
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- 241000894007 species Species 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
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- 125000004434 sulfur atom Chemical group 0.000 description 1
- 239000012730 sustained-release form Substances 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
- 238000002604 ultrasonography 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
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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 System
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/30—Phosphinic acids R2P(=O)(OH); Thiophosphinic acids, i.e. R2P(=X)(XH) (X = S, 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 System
- 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, i.e. RP(=X)(XH)2 (X = S, 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 System
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/30—Phosphinic acids R2P(=O)(OH); Thiophosphinic acids, i.e. R2P(=X)(XH) (X = S, 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 System
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/30—Phosphinic acids R2P(=O)(OH); Thiophosphinic acids, i.e. R2P(=X)(XH) (X = S, 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 System
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/30—Phosphinic acids R2P(=O)(OH); Thiophosphinic acids, i.e. R2P(=X)(XH) (X = S, 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 System
- 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, i.e. RP(=X)(XH)2 (X = S, Se)
- C07F9/3804—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, 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 System
- 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, i.e. RP(=X)(XH)2 (X = S, 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
Abstract
Compounds which are useful as inhibitors of cholesterol biosynthesis and thus as hypocholesterolemic agents have the structure <IMAGE> including salts thereof, wherein R is OH, lower alkoxy or lower alkyl; R<x> is H or alkyl; X is -O- or -NH-; n is 1 or 2 Z is a hydrophobic anchor, such as <IMAGE> wherein the dotted lines represent optional double bonds. New intermediates used in preparing the above compounds, e.g. compounds in which the OH group is silane blocked, pharmaceutical compositions containing such compounds and a method for using such compounds to inhibit cholesterol biosynthesis are also provided.
[DE3817375A1]
Description
PHQSPHORUS-CPNTAINING HMG-CoA REDUCTASE INHIBITORS The present invention concerns new phosphorus15 containing compounds which inhibit the activity of 3-hydroxy-3-methyl glutaryl-coenzyme A reductase and thus are helpful in inhibiting cholesterol biosynthesis, hypocholesterolemic compositions containing such compounds, and the use of such compounds for such purposes.
F. M. Singer et al., Proc. Soc. Exper.
Biol. Med., 102, 370 (1959) and F. H. Hulcher, Arch. Biochem. Biophys., 146, 422 (1971) disclose that certain mevalonate derivatives inhibit the biosynthesis of cholesterol.
Endo et al in U. S. Patents Nos. 4,049,495, 4,137,322 and 3,983,140 disclose a fermentation '4 product which is active in the inhibition of cholesterol biosynthesis. This product is called compactin and was reported by Brown et al., (J. Chem. Soc. Perkin 1. 1165 (1976)) to have a complex mevalonolactone structure.
G® Patent 1,5B6,152 discloses a group of synthetic compounds of the formula in which E represents a direct bond, a alkylene bridge or a vinylene bridge and the various R’s represent a variety of substituents.
The activity reported in the U.K. patent is less than 1% that of compactin.
U. S. Patent No. 4,375,475 to Willard et al discloses hypocholesterolemic and hypolipemic compounds having the structure -3wherein A is H or methyl; E is a direct bond, -CH2-, -CH2-CH2-, -C^-C^-C^- or -CH=CH-; R£ and are each selected from H, halogen, C1-4 alkyl, c1-4 haloalkyl, phenyl, phenyl substituted by halogen, C1-4 alkoxy, c2_e alkanoyloxy, c1-4 alkyl, or C1-4 haloalkyl, and 0R4 in which R4 is H, C2_a alkanoyl, benzoyl, phenyl, halophenyl, phenyl C1-3 alkyl, C1-9 alkyl, cinnamyl, c1-4 haloalkyl, allyl, cydoalkyl-C^-3 -alkyl, adamantyl-c^_3-alkyl, or substituted phenyl C^_3-alkyl in each of which the substituents are selected from halogen, C1-4 alkoxy, C14 alkyl, or cl-4 haloalkyl; and the corresponding dihydroxy acids resulting from the hydrolytic opening of the lactone ring, and the pharmaceutically acceptable salts of said acids, and the C1-3 alkyl and phenyl, d-imo-t-hyiamino or acetylamino substituted C1-3-alkyl esters of the dihydroxy acids; all of the compounds being the enantiomers having a 4 R configuration in the tetrahydropyran moiety of the traps racemate shown in the above formula.
PCT Patent Application UO 04/02131 (PCT/EP03/OO3O8) filed in the name of Sandoz AG discloses heterocyclic analogs of meualono lactone and derivatives thereof having the structure -4wherein one of R and R„ is ‘4 and the R, a other is primary or secondary cj__6 alkyl, C3_g cycloalkyl or phenyl-(CH2)-, wherein R4 is hydrogen, Cj_4 alkyl, alkoxy, (except t-butoxy), trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, R5 is hydrogen, C1-3 alkyl, C 1-3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, R5a is hydrogen, ci-2alkoxy, fluoro or chloro, and m is 1, 2 or 3, with the provisos that both Rg and Rga must be hydrogen when R4 is hydrogen, Rga must be hydrogen when Rg is hydrogen, not more than one of R4 and Rg is trifluoromethyl, not more than one of R4 and Rg is phenoxy and not more than one of R^ and Rg is benzyloxy, R2 is hydrogen, C1-4 alkyl, C3_& cycloalkyl, C1-4 alkoxy (except t-butoxy), trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, R3 is hydrogen, C1-3 alkyl, Cj_3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, with the provisos that R3 must be hydrogen when R2 is hydrogen, not more than one of R2 and R3 is trifluoromethyl, not more than one of p R2 and R3 is phenoxy, and not more than one of R2 and R3 is benzyloxy. -510 X .is -(CH^- or Z is -CH=CH- (n=0, 4 3 j 2 1 -CH-CH- —C—CH- -COOH ! 2 7 2 OH OH 1, 2 or 3), II wherein R6 is hydrogen or C1-3 alkyl in free acid form or in the form of a physiologically hydrolysable and -acceptable ester or a δ lactone thereof or in salt form.
GB Patent Application 2162179 discloses naphthyl analogues of mevalolactone useful as cholesterol biosynthesis inhibitors having the structure = 1-3C alkyl; wherein Z is a gp. (Ζχ) CHCH^ 420¾ C00R7 OH OH R? = H, a hydrolysable ester gp. or a cation. -6European Patent Application 164698 discloses preparation of lactones useful as anti-hypercholesterolemic agents by treating an amide with an organic sulphonyl halide R5SO2X, then removing the protecting group Pr. wherein X = halo; Pr = a carbinol-protecting group; R1 = H or CH3; R3, R4 = H, 1-3C alkyl or phenyl-(l-3C alkyl), the phenyl being optionally substituted by 1-3C alkyl, 1-3C alkoxy or halo; R2 = a group of formula (A) or (B): (A) ik -7Q = R6-C- or R6-CH ; I ί I A R = H or OH; R = H or CHg,· a, b, c and d = optional double bonds; R7 = phenyl or benzyloxy, the ring in each case being optionally substituted by 1-3C alkyl or 10 halo; R8, R9 = 1-3C alkyl or halo; R5 = 1-3C alkyl, phenyl or mono- or di-(l-3C alkyl)phenvl.
Anderson, Paul Leroy, German Patent Application 3,525,256 discloses naphthyl analogs of mevalonolactones of the structure i 17 wherein R is alkyl, Z = Q, Q ; R = H, or a hydrolyzable ester group useful as inhibitors of cholesterol biosynthesis and in treatment of atherosclerosis.
PCT Patent Application li/O 84/02903 filed in the name of Sandoz AG discloses mevalono-lactone analogues useful as hypolipoproteinaemic agents having the structure groups Ro wherein the two of formula together form a radical or -(CH2)4wherein R2 is hydrogen, C}_4 alkyl, C1-4 alkoxy, (except t-butoxy), trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, R3 is hydrogen, C1-3 alkyl, C1-3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, with the provisos that not more than one of R2 and R3 is trifluoromethyl, not more than one of R2 and R3 is phenoxy, and not more than one of R2 and R3 is benzyloxy, R^ is hydrogen, alkyl, fluoro, chloro or benzyloxy, R4 is hydrogen, C^_4 alkyl, C-|__4 alkoxy, (except t-butoxy), trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, R5 is hydrogen, C^_3 alkyl, c-j_-3 alkoxy, trifluoromethyl, fluoro, chloro, phenoxy or benzyloxy, R5a is hydrogen, C^_2 alkyl, cq__2 alkoxy, fluoro or chloro, and with the provisos that not -9more than one of and Rg is tri fluoromethyl, not more than one of R^ and Rg is phenoxy and not more than one of R. and Rr is benzyloxy, -(CH2>g wherein n is 0, 1, 2 or 3 and both g's are 0 or one is 0 and the other is 1, Z is -CH-CH-—C-CH--COOH I 2 1 2 OH OH II wherein Rg is hydrogen or C1-3 alkyl, with the general proviso that -X-Z and the bearing phenyl group are ortho to each other; in free acid form or in the form of a physiologically-hydrolysable and acceptable ester or a δ lactone thereof or in salt form.
European Patent Application 127848 (Merck & Co, Inc.) discloses derivatives of 3-hydroxy-5« thia-w-aryl-alkanoic acids having the structural formula: HO I ox ^S(O). n is 0, 1 or 2; E IS — r — GH.*, "CH^ "CH2 "CH2 ", -CH=CH-CH2-; or -C^-C^CH-,· Rl' R2 and R-, are, e.g., hydrogen, chloro, bromo, fluoro, C^alkyl, phenyl, substituted phenyl or OR? in which R? is, e.g., hydrogen, C2_8alkanoyl, benzoyl, phenyl, substituted phenyl, C1-galkyl, cinnamyl, C^^haloalky 1, allyl, cycloalkyl-C1_3alkyl, adamantyl-C1_3~alkyl, or phenyl C. 3 alkyl; R , R5 and R6 are hydrogen, chloro, bromo, fluoro or C1-3 alkyl; and X is, e.g., hydrogen, C1-3 alkyl, a cation derived from an alkali metal or is ammonium.
Those compounds have antihypercholesterolemic activity by virtue of their ability to inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase and antifungal activity.
French Patent Application 2,596,393 filed on April 1, 1986 (Sanofi SA) discloses 3-carboxy-2-hydroxy-propane-phosphonic acid derivatives including salts thereof which are useful as hypolipaemic agents and have the formula: I Z \ OH 0R4 wherein and R2 = H, lower alkyl or optionally substituted aralkyl; R3 and R4 = H, lower alkyl or optionally substituted aryl or aralkyl.
These compounds are disclosed as giving greater reductions in cholesterol, triglyceride and phospholipid levels than meglutol.
European Patent Application 142146 (Merck Sc Co., Inc) discloses mevinolin-like compounds of the structural formula: E wherein R1 is, e.g., hydrogen or C1-4alkyl; E is -CH2CH2, -CH=CH-, or -(CH2)r-; and Z is 1) Ο 9 wherein X is -0- or -NR wherein R is hydrogen or cx.3alkyl? R7 is C2__8alkyl; and R8 is hydrogen or CH^; 2) wherein R10, R*1 and Ri2 are independently, e.g., hydrogen, halogen or Cl-4alkyl; 3) In accordance with the present invention, there are provided phosphorus-containing compounds capable of -13inhibiting the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA Reductase), having the formula I Ο H I R-P—CH--C—CH_-CO_RX I 2:22 X OH Z wherein R is OH, lower alkoxy or lower alkyl; Rx is H or lower alkyl; X is -Ό- or -NH-; n is 1 or 2; 15 Z is a hydrophobic anchor; and such compounds in salt form.
The term hydrophobic anchor as employed herein refers to a lipophilic group which when linked to the HMG-like upper side chain of the molecule by the appropriate linker (XM), binds to a hydrophobic pocket of the enzyme not utilized in binding the substrate HMG CoA, resulting in enhanced potency relative to compounds where Z=H.
The terms salt and salts refer to basic salts formed with inorganic and organic bases.
Such salts include ammonium salts, alkali metal salts like, lithium, sodium and potassium salts (which are preferred), alkaline earth metal salts like the calcium and magnesium salts, salts with organic bases, such as amine like salts, e.g., dicyclohexylamine salt, benzathine, N—methyl-Dglucamine, hydrahamine salts, salts with amino acids like arginine, lysine and the like. The nontoxic, pharmaceutically acceptable salts are preferred, although other salts are also useful, e.g., in isolating or purifying the product.
V Similarly when employed for treatment, if R is lower alkyl, the ester should be physiologicallyhydrolysable and physiologically-acceptable.
The hydrophobic anchors which are employed in accordance with the present invention are -15R6 wherein the dotted lines represent optional double bonds, for example, R wherein R1, R2, R2a and R2b may be the same or different and are each independently selected from H, halogen, lower alkyl, haloalkyl, phenyl, substituted phenyl or 0Ry wherein Ry is H, alkanoyl, benzoyl, phenyl, halophenyl, phenyl-lower alkyl, lower alkyl, cinnamyl, haloalkyl, allyl, cycloalkyl-lower alkyl, adamantyl-lower alkyl or substituted phenyl-lower alkyl. 175 5’ R and R are the same or different and are H, lower alkyl or OH; ll β ι* R is lower alkyl-C such as or arylCH2-; R6a is lower alkyl, hydroxy, oxo or halogen; g is 0, 1, 2 or 3, and R is H or lower alkyl .
Thus, the compounds of formula I encompass O' R-P-CH2-CH-CH2-CO2RX O OH and I· _ x -P-CH2-CH-CH2-CO2R NH OH The term ’’lower alkyl" or ’’alkyl as employed herein alone or as part of another group refers to -18both straight and branched chain hydrocarbons, containing 1 to 12 carbons in the normal chain, preferably 1 to 7 carbons, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl, the various branched chain isomers thereof, and the like as well as such groups including a halo-substituent, such as F, Br, Cl or I or CF3, an alkoxy substituent, an aryl substituent, an alkyl-aryl substituent, a haloaryl substituent, a cycloalkyl substituent, an alkylcycloalkyl substituent, hydroxy, and alkylamino substituent, an alkanoylamino substituent, an arylcarbonylamino substituent, a nitro substituent, a cyano substituent, a thiol substituent or an alkyl thio substituent.
The term cycloalkyl" as employed herein alone or as part of another group refers to saturated cyclic hydrocarbon groups containing 3 to carbons, preferably 3 to 8 carbons, which include cyclopropyl, cyclobutyl, cyclopentyl, * cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and cyclododecyl, any of which groups may be substituted with 1 or 2 halogens, 1 or 2 lower alkyl groups, 1 or 2 lower alkoxy groups, 1 or 2 hydroxy groups, 1 or 2 alkylamino groups, 1 or 2 alkanoylamino groups, 1 or 2 arylcarbonylamino groups-, 1 or 2 amino groups, 1 or 2 nitro groups, 1 or 2 cyano groups, 1 or 2 thiol groups, and/or 1 or 2 alkylthio groups.
The term aryl or Ar as employed herein refers to monocyclic or bicyclic aromatic groups 19containing from 6 to 10 carbons in the ring portion, such as phenyl, naphthyl, substituted phenyl or substituted naphthyl wherein the substituent on either the phenyl or naphthyl may be 1, 2 or 3 lower alkyl groups, halogens (Cl, Br or F), 1, 2 or 3 lower alkoxy groups, 1, 2 or 3 hydroxy groups, 1, 2 or 3 phenyl groups, 1, 2 or 3 alkanoyloxy group, 1, 2 or 3 benzoyloxy groups, 1, or 3 haloalkyl groups, 1, 2 or 3 halophenyl groups, 1, 2 or 3 allyl groups, 1, 2 or 3 cycloalkylalkyl groups, 1, 2 or 3 adamantyl alkyl groups, 1, 2 or 3 alkylamino groups, 1, 2 or 3 alkanoylamino groups, 1, 2 or 3 ary lcarbony lamino groups, 1, 2 or 3 amino groups, 1, 2 or 3 nitro groups, 1, 2 or 3 cyano groups, 1, 2 or 3 thiol groups, and/or 1, 2 or 3 alkylthio groups with the aryl group preferably containing 3 substituents.
The term aralkyl, aryl-alkyl or aryl-lower alkyl as used herein alone or as part of another group refers to lower alkyl groups as discussed above having an aryl substituent, such as benzyl.
The term lower alkoxy, alkoxy, or aryloxy or aralkoxy as employed herein alone or as part of another group refers to any of the above lower alkyl, alkyl, aralkyl or aryl groups linked to an oxygen atom.
The term lower alkylthio, alkylthio, arylthio or aralkylthio as employed herein alone or as pari-, of another group refers to any of the above lower alkyl, alkyl, aralkyl or aryl groups linked to a sulfur atom.
The term ’’lower alkylamino", ’’alkylamino1', arylamino, arylalkylamino as employed herein alone or as part of another group refers to any of the above lower alkyl, alkyl, aryl or arylalkyl groups linked to a nitrogen atom.
The term alkanoyl as used herein as part of another group refers to lower alkyl linked to a carbonyl group.
The term halogen or halo as used herein refers to chlorine, bromine, fluorine, iodine and CF3, with chlorine or fluorine being preferred.
Preferred are those compounds of formula I which have the following structure II R O I /x z CM— H z 2\ z c OH CH 2\ co2r wherein R is OH, OLi; Rx X is O or NH; and is Li or H; wherein R1 is phenyl which includes an alkyl and/or halo substitutent or R3, is benzyloxy which includes a halo substituent; R2 and R2a are the same and are halogen or lower alkyl; -2110 may also preferably be 2 wherein R and R are as defined immediately above with respect to the compound of formula II, or «6 Z is wherein R3 is H, CH.
CH -CH. or (substituted)phenylmethyl CH- R wherein R7 is H or CHg.
The present invention also provides a hypocholesterolemic or hypolipemic composition conprising a canpound as defined above and a pharmaceutically acceptable carrier therefor, with the provisos that if Rx is lover alkyl the ester is physiologically-hydrolysable and physiologically-acceptable and that if the compound is in salt form it is in pharmaceutically acceptable form, and a pharmaceutically acceptable carrier therefor.
The present invention further provides use of a canpound as χ defined above with the provisos that if R is lower alkyl the ester is physiologically-hydrolysable and physiologically-acceptable and that if the canpound is in salt form it is in pharmaceutically acceptable form, for the manufacture of a medicament for a treatment involving inhibiting cholesterol biosynthesis. , The compounds of formula I of the invention may be prepared according to the following reaction sequence and description thereof.
C,HI6 5 OSi-C (C»3) 3 C6»5 -CH2-C-Cll2-CO2alkyl H R -P (Oalkyl)2 III Arbuzov Reaction Q (R = lower alkyl or lower alkoxy) R -P-CH2-CH-CH2-CO2alkyl Oalkyl^3b-C(CH3) 3C6H5 C6H5 IV IV I. (c»3)3—SiBr, CH2C12 > 2. H2O Ra -P-CH2-CH-CH2-CO2alky1 Oil j) -ZZ Phosphorus ester cleavage a I a VB. - R =0H where R was lower alkoxy RbOH-DCC VB (R3’ = OH) ._b . ... .
(R = lower alkyl) Pyridine (Esterification, O . ·» RDO-P-Cil2-CH-CH2CO2alkyl OH I I Si-C(CH3,3C6U5 C6H5 23VI VI 1) (COC1)2; CH2C12 (Acid Cl Formation) or 2) Ζ-(ΟΙ2)η~ΧΗ (coupling reaction) VA. -:(C_H_),N, DMAP i 3 J o c " R -^-CII2-CH-CH2CO2alky 1 1) (n-CJIJ.NF, CIKCOOH, THF (silyl 4 ether cleavage) 2) OH , dioxane (Hydrolysis, -;-> (Rc = lower alkyl or lower alkoxy) I· x R-P-CII.-CH-CH„-CO_R 2 - 2 2 OH γ'2’η I. 244) -25As seen in the above reaction sequence, compounds of Formula I may be prepared by subjecting iodide A to an Arbuzov reaction by heating iodide A Ο,Η. |6 5 O-Si-C(CH-)f I 3 3 I C6H5 A I-CH2-C-CH2-CO2alkyl H and phosphonite/phosphite III III Ra-P(Oalkyl)215 wherein Ra is lower alkyl or lower alkoxy, employing standard Arbuzov conditions and procedures to form phosphinate/phosphonate IV O a IV R-P CH- CH-CH--CO-alkyl I 2 S 2 2 Oalkyl (58i-C(CH3 )3C6H5 \H5 Phosphinate/phosphonate IV is a novel compound and is claimed in the Applicants' British Patent Specification No. GB 2 235 924.
Phosphmate/phosphonate IV is then subjected to a phosphorus ester cleavage by treating a solution of compound IV in an inert organic solvent, such as methylene chloride, sequentially with bis (trimethylsilyl)trifluoroacetamide (BSTFA) and trimethylsilyl bromide, under an inert atmosphere such as argon to form the phosphinic acid VA where Ra in IV is lower alkyl, that is, O H VA lower alkyl-CH2-CE-CH2-CO2alkyl OH δ I (CH^ ) 3 or phosphonic acid VB (wherein Ra in IV is lower alkoxy), that is O tt VB HO-y-CH2-CH-CH2-CO2alkyl OH O I Si-C(CH3 )3 C6H5 C6H5 Compounds VA and VB are novel intermediates and are claimed in the Applicants' British Patent Specification No. GB 2 235 924.
Where phosphonic acid VB is obtained,.it is esterified by treating VB in dry pyridine with alcohol VC RbOH (where Rb is lower alkyl) and dicyclohexyl carbodiimide and the resulting reaction mixture is stirred under an inert atTnngphArps such as argon, to form phosphonic mono alkyl ester VI -27O VI RbO-P-CH2-CH-CH2CO2alkyl OH O ^Sl-C(CH3)3 ^6^5 *"6^5 Ester VI or phosphinic acid VA is then dissolved in an inert organic solvent, such as, methylene chloride, benzene or tetrahydrofuran (THF) and treated with trimethylsilyldiethylamine and stirred under an inert atmosphere such as argon; the mixture is evaporated and then dissolved in methylene chloride (or other appropriate inert organic solvent). The resulting solution is cooled to a temperature within the range of from about 0°C to about 25°C, treated with oxalyl chloride and then evaporated to give crude phosphonochloridate. The phosphonochloridate is dissolved in inert organic solvent such as methylene chloride, benzene, pyridine or THF; the solution is cooled to a temperature within the range of from about -20°C to about 0°C and treated with B Z-(CH2)n-XH employing a molar ratio of VI or VA:B of within the range of from about 0.5:1 to about 3:1 and preferably from about 1:1 to about 2:1, followed by triethylamine and catalytic 4-dimethylaminopyridine (DMAP) to form adduct VII -28VII CH2-CH-CH2-CO2alkyl "rH2>n wherein Rc is lower alkyl or lower alkoxy.
Compound VII is subjected to silyl ether cleavage by treating a VII in an inert organic solvent, such as tetrahydrofuran, with glacial acetic acid and tetrabutylammonium fluoride to form ester VIII VIII x I (Rx = alkyl) The ester VIII may then be hydrolyzed to the corresponding alkali metal salt or acid, that is, where Rx is alkali metal or H by treatment with strong base such as lithium hydroxide in the presence of dioxane, tetrahydrofuran or other inert organic solvent, under an inert atmosphere such as argon, at 25°C, employing a molar ratio of base:ester VIII of within the range of from about. 1:1 to about 1.1:1 to form the corresponding alkali metal salt -29V.
VII ΙΑ Ο Η R-P-CHI 2 X (Ι?Η2>η Z wherein R is CH-CH2-CO2alkali metal OH lower alkyl or lower alkoxy.
Compound VIIIA may then be .treated with strong acid such as HCl to form the corresponding acid VIIIB O H viiib r-^>-ch2-ch-ch2-co2h X 0H Wn Z The ester VIII wherein R is lower alkoxy may be converted to the corresponding di-alkali metal salt by treating ester VIII with strong base at 50-60®C employing a molar ratio of base:ester VIII of within the range of from about 2:1 to about 4:1 to form VIIIC -30The di-alkali metal salt VIIIC may be converted to the corresponding acid wherein R is OH by treatment with strong acid such as HCl to form VIIID VIIID HO-P-CH--CH-CH--CO-H I 2 5 Z Z X OH I Z The iodide starting material A may be prepared starting with the bromide C OH I Br-CH2-CH-CH2C02alkyl (prepared employing procedures as described in Tetrahedron Lett. 26, 2951 (1985)) which is dissolved in solution in dimethylformamide (DMF) with imidazole and 4-dimethylamino pyridine and the resulting solution is treated with t-butyldiphenyl silyl chloride under an inert atmosphere such as argon to form the silyl ether D D OSi-C(CH-)I 3 3 Br-CH2-CH-CH2 CO2 alkyl -31A solution of silyl ether D in an inert organic solvent such as methyl ethyl ketone or DMF is treated with sodium iodide under an inert atmosphere such as argon, to form iodide A.
The starting compound B B Z-(CH2)n-XH may be prepared as described below depending upon 10 the definition of Z and X.
Thus, compounds of formula B wherein Z is and X is 0, that is, compounds of the structure may be prepared by treating aldehyde E with a reducing agent such as lithium aluminum hydride or sodium borohydride.
Compounds of formula B where Z is may be prepared by oxidizing the aldehyde E by treating E in solution with acetone with, for example, Jones reagent to form the acid F i, L which in suspension with methylene chloride is treated with oxalyl chloride to form the corresponding acid chloride which is dissolved in an inert organic solvent such as tetrahydrofuran, and treated with a mixture of concentrated ammonium hydroxide in tetrahydrofuran to form an amide of the structure Amide G is then reduced to the corresponding amide 2 B by treating G with a reducing agent such as lithium aluminum hydride.
Starting compounds of formula B wherein 2 is -3410 and X is Ο structure Η' •20 where X is Ο J. Org. Chem. 50, 1190 (1985). Compounds of formula H’ were X is NH may be prepared by the reductive amination of J (prepared as disclosed by C. H. Heathcock et al, supra) -35by treating J with ammonium acetate and sodium cyanoborohydride in the presence of an alcohol solvent such as methanol.
Starting compound of formula B wherein Z is and X is O, that is, compounds of the structure are disclosed in WO 8402-903-A and GB 2,162,179A both filed in the name of Sandoz.
Starting compounds of formula B wherein Z is and X is NH, that, is, compounds of the structure may be prepared by the reductive amination of the aldehyde 0 by treating O with ammonium acetate and sodium cyanoborohydride in the presence of an alcohol solvent such as methanol. -37The compounds of the invention may be prepared as racemic mixtures and may later be resolved to obtain the S-isomer which is preferred. However, the compounds of the invention may be prepared directly in the form of their S-isomers as described herein and in the working examples set out hereinafter.
The compounds of the invention are inhibitors of 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase and thus are useful in inhibiting cholesterol biosynthesis as demonstrated by the following tests. 1) Rat Hepatic HMG-CoA Reductase Rat hepatic HMG-CoA reductase activity is measured using a modification of the method described by Edwards (Edwards, P.A., et al., J. Lipid Res. 20:40, 1979). Rat hepatic microsomes are used as a source of enzyme, and the enzyme activity is determined by measuring the 14 conversion of the C-HMG-CoA substrate to 14 C-mevalonic acid. a. Preparation of Microsomes Livers are'removed from 2-4 cholestyramine-fed, decapitated, Sprague Dawley rats, and homogenized in phosphate buffer A (potassium phosphate, 0.04 M, pH 7.2; KC1, 0.05 M; sucrose, 0.1 M; EDTA, 0.03 M; aprotinin, 500 KI units/ml). The homogenate is spun at 16,000 x g for 15 minutes at 4°C. The supernatant is removed and recentrifuged under the same conditions a second time. The second 16,000 x g supernatant is -38spun at 100,000 x g for 70 minutes at 4°C.
Pelleted microsomes are resuspended in a minimum volume of buffer A (3-5 ml per liver), and homogenized in a glass/glass homogenizer. Dithiothreitol is added (10 mM), and the preparation is aliquoted, quick frozen in acetone/dry ice, and stored at -80°C. The specific activity of the first microsomal preparation was 0.68 nmole mevalonic acid/mg protein/minute. b i Enzyme Assay The reductase is assayed in 0.25 ml which contains the following components at the indicated final concentrations: 0.04 M Potassium phosphate, pH 7.0 0.05 M KC1 0.10 M Sucrose 0.03 M EDTA 0.01 M Dithiothreitol 3.5 mM NaCl 1% Dimethylsulfoxide 50-200 pg Microsomal protein 100 pM14C»-[DL]HMG-CoA (0.05 pCi, 30-60 mCi/mmole) 2.7 mM NADPH (nicotinamide adenine dinucleotide phosphate) Reaction mixtures are incubated at 37°C. Under conditions described, enzyme activity increases linearly up to 300 pg microsomal protein per reaction mixture, and is linear with respect to -39incubation time up to 30 minutes. The standard incubation time chosen for drug studies is 20 minutes, which results in 12-15% conversion of HMG-CoA substrate to the mevalonic acid product.
[DL-]HMG-CoA substrate is used at 100 μΜ, twice the concentration needed to saturate the enzyme under the conditions described. NADPH is used in excess at a level 2.7 times the concentration required to achieve maximum enzyme velocity.
Standardized assays for the evaluation of inhibitors are conducted according to the following procedure. Microsomal enzyme is incubated in the presence of NADPH at 37°C for 15 minutes. DMSO vehicle with or without test compound is added, and the mixture further incubated for 15 minutes at 37°C. The enzyme 14 assay is initiated by adding C-HMG-CoA substrate. After 20 minutes incubation at 37°C the reaction is stopped by the addition of 25 μΐ Of 33% KOH. 3H-mevalonic acid (0.05 pCi) is added, and the reaction mixture allowed to stand at room temperature for 30 minutes. Fifty μΐ 5N HCl is added to lactonize the mevalonic acid.
Bromophenol blue is'added as a pH indicator to monitor an adequate drop in pH. Lactonization is allowed to proceed for 30 minutes at room temperature. Reaction mixtures are centrifuged for 15 minutes at 2800 rpm. The supernatants are layered onto 2 grams AG 1-X8 anion exchange resin (Biorad, formate form) poured in 0.7 cm (id) glass columns, and eluted with 2.0 ml H2O. The first 0.5 ml is discarded, and the next 1.5 ml is -40collected and counted for both tritium and carbon 14 in 10.0 ml Opti-fluor scintillation fluid. Results are calculated as nmoles mevalonic acid produced per 20 minutes, and are corrected to 100% recovery of tritium. Drug effects are expressed, as Ι^θ values (concentration of drug producing 50% inhibition of enzyme activity) derived from composite dose response data with the 95% confidence interval indicated.
Conversion of drugs in lactone form to their sodium salts is accomplished by solubilizing the lactone in DMSO, adding a 10-fold molar excess of NaOH, and allowing the mixture to stand at room temperature for 15 minutes. The mixture is then partially neutralized'(pH 7.5-8.0) using IN HCl, and diluted into the enzyme reaction mixture. 2) Cholesterol Synthesis in Freshly Isolated Rat Hepatocytes_ Compounds which demonstrate activity as inhibitors of HMG-CoA reductase are evaluated for . . 14 their ability to inhibit C-acetate incorporation into cholesterol in freshly isolated rat hepatocyte suspensions using methods originally described by *» Capuzzi et al. (CapuzJsi, D.M. and Margolis, S., Lipids, 6:602, 1971). a. Isolation of Rat Hepatocytes Sprague Dawley rats (180-220 grams) are anesthetized with Nembutol (50 mg/kg). The abdomen is opened and the first branch of the portal vein is tied closed. Heparin (100-200 units) is injected directly into the abdominal -41vena cava. A single closing suture is placed on the distal section of the portal vein, and the portal vein is canulated between the suture and the first branching vein. The liver is perfused at a rate of 20 ml/minute with prewarmed (37°C), oxygenated buffer A (HBSS without calcium or magnesium containing 0.5 mM EDTA) after severing the vena cava to allow drainage of the effluent. The liver is additionally perfused with 200 ml of prewarmed buffer B (HBSS containing 0.05% bacterial collagenase). Following perfusion with buffer B, the liver is excised and decapsulated in 60 ml Waymouth's medium allowing free cells to disperse into the medium. Hepatocytes are isolated by low speed centrifugation for 3 minutes at 50xg at room temperature. Pelleted hepatocytes are washed once in Waymouth's medium, counted and assayed for viability by trypan blue exclusion. These hepatocyte enriched cell suspensions routinely show 70-90% viability. b. C-Acetate Incorporation into Cholesterol_ Hepatocytes are resuspended at 5xl06 cells per 2.0 ml in incubation medium (IM) [0.02 M Tris-HCl (pH 7.4), 0.1 M KCl, 3.3 mM sodium citrate, 6.7 mM nicotinamide, 0.23 mM NADP, 1.7 mM glucose-6-phosphate].
Test compounds are routinely dissolved in DMSO or DMSO:H2O (1:3) and added to the IM. Final DMSO concentration in the IM is <_ 1.0%, and has no significant effect on cholesterol synthesis. -42Incubation is initiated by adding 14 C-acetate (58 mCi/mmol, 2 pCi/ml), and placing the cell suspensions (2.0 ml) in 35 mm tissue culture dishes, at 37°C for 2.0 hours. Following incubation, cell suspensions are transferred to glass centrifuge tubes and spun at 50xg for 3 minutes at room temperature. Cell pellets are resuspended and lysed in 1.0 ml H20, and placed in an ice bath.
Lipids are extracted essentially as described by Bligh, E. G. and W. J. Dyer, Can. J. Biochem. and Physiol., 32:911, 1959. The lower organic phase is removed and dried under a stream of nitrogen, and the residue resuspended in (100 μΐ) chloroform:methanol (2:1). The total sample is spotted on silica gel (LK6D) thin-layer plates and developed in hexane:ethyl ether:acetic acid (75:25:1). Plates are scanned and counted using a BioScan automated scanning system. Radiolabel in the cholesterol peak (RF 0.28) is determined and expressed at total counts per peak and as a percent of the label in the total lipid extract. Cholesterol peaks in control cultures routinely contain 800-1000 cpm, and are 9-20% of the label present in the total lipid extract; results compatable with Capuzzi, et al., indicating 9% of extracted label in cholesterol.
Drug effects (% inhibition of cholesterol synthesis) are determined by comparing % of label in cholesterol for control and drug treated cultures. Dose response curves are constructed from composite data from two or more studies, and -43results are expressed as Ι5θ values with a 95% confidence interval. 3) Cholesterol Synthesis in Human Skin Fibroblasts 5 Compound selectivity favoring greater inhibitory activity in hepatic tissue would be an attribute for a cholesterol synthesis inhibitor. Therefore, in addition to evaluating cholesterol synthesis inhibitors in hepatocytes, these compounds are also tested for their activity as inhibitors of cholesterol synthesis in cultured fibroblasts. a. Human Skin Fibroblast Cultures Human skin fibroblasts (passage 7-27) are grown in Eagles' minimal essential medium (EM) containing 10% fetal calf serum. For each experiment, stock cultures are trypsonized to disperse the cell monolayer, counted, and plated in 35 mm tissue culture wells (5xl05 cells/2.0 ml). Cultures are incubated for 18 hours at 37°C in 5% CO2/95% humidified room air. Cholesterol biosynthetic enzymes are induced by removing the serum containing medium, washing the cell monolayers, and adding 1.0 ml of EM containing 1.0% fatty acid free bovine serum albumin, and incubating the cultures an additional 24 hours. b. C-Acetate Incorporation into Cholesterol_ Induced fibroblast cultures are washed with ΕΜΕΜ1θθ (Earle's minimal essential medium). Test compounds are dissolved in DMSO or DMSO:EM (1:3) -44(final DMSO concentration in cell cultures £ 1.0%), added to the cultures, and the cultures preincubated for 30 minutes at 37°G in 5% C02/95% humidified room air. Following preincubation with drugs, [l-14C]Na acetate (2.0 pCi/ml, 58 mCi/mmole) is added, and the cultures reincubated for 4 hours. After incubation, the culture medium is removed, and the cell monolayer (200 pg cell protein per culture) is scraped into 1.0 ml of E^O. Lipids; in the lysed cell suspension are extracted into chloroform:methanol as described for hepatocyte suspensions. The organic phase is dried under nitrogen, and the residue resuspended in chloroform:methanol (2:1) (100 μΐ), and the total sample spotted on silica gel (LK6D) thin-layer plates, and analyzed as described for hepatocytes.
Inhibition of cholesterol synthesis is determined by comparing the percent of label in the cholesterol peak from control and drug-treated cultures. Results are expressed as values, and are derived from composite dose response curves from two or more experiments. A 95% confidence interval for the Ι^θ value is also calculated from the composite dose response curves.
A further aspect of the present invention is a pharmaceutical composition comprising at least one of the compounds of formula I in association with a pharmaceutical carrier (vehicle or diluent). The pharmaceutical composition can be formulated employing conventional solid or liquid vehicles of diluents and pharmaceutical additives of a type appropriate to the mode of desired administration. The compounds can be administered -45by an oral route, for example, in the form of tablets, capsules, granules or powders, or they can be administered by a parenteral route in the form of injectable preparations, such dosage forms containing from 1 to 2000 mg of active compound per dosage, for use in the treatment. The dose to be administered depends on the unitary dose, the symptoms, and the age and the body weight of the patient.
The compounds of formula I may be administered in a similar manner as known compounds suggested for use in inhibiting cholesterol biosynthesis, such as lovastatin, in mammalian species such as humans, dogs, cats and the like. Thus, the compounds of the invention may be administered in an amount from about 4 to 2000 mg in a single dose or in the form of individual doses from 1 to 4 times per day, preferably 4 to 200 mg in divided dosages of 1 to 100 mg, suitably 0.5 to 50 mg 2 to 4 times daily or in sustained release form. -46The following working Examples represent preferred embodiments of the present invention. Unless otherwise indicated, all temperatures are expressed in degrees Centigrade. Flash chromatography was performed on either Merck 60 or Whatmann LPS-I silica gel. Reverse phase chromatography was performed on CHP-20 MCI gel resin supplied by Mitsubishi, Ltd.
Example 1 (S)-4-[[[4'-Fluoro-3,3’,5-trimethyl[1,1’-biphenyl]2-yl]methoxy]methoxyphosphinyl]-3-hydroxy-butanoic acid, monolithium salt A. N- (2,4-Dimethylbenzylidene)benzeneamine Ref. Merck U. S. Patent No. 4,375,475, pg. 39.
A solution of freshly distilled 2,4-dimethylbenzaldehyde (Aldrich, 6.97 ml, 50 mmole) and distilled aniline (Aldrich, 4.56 ml, 50 mmole) in dry toluene (80.0 ml) was refluxed for 3.0 hours under argon in a flask equipped with a Dean-Stark apparatus. The mixture was cooled, then evaporated in vacuo to a yellow oil. The crude oil was purified by Kugelrohr distillation (0.5 mm Hg, 160-180°C) to give 8.172 g (78.1%) of desired title benzerieimine as a light yellow oil which crystallized on standing to a low melting solid. TLC (4:1) Hex-acetone, RF=0.67 and 0.77 (geometric isomers), U.V. and I2-47- Ref. Merck U.S. Patent No. 4,375,475, pg. 39.
A mixture of Part A benzeneimine (6.0 g, 28.7 mmol) in glacial HOAc (144 ml) was treated with palladium (II) acetate (6.44 g, 28.7 mmole) and the clear, red homogeneous solution refluxed under argon for one hour. The resulting turbid mixture was filtered warm through a packed ^s bed of Celite into 900 ml of H2O. Precipitated orange solid was collected by filtration and dried in vacuo at 65°C over P20g ^or 16,0 k°urs to 9ive 10.627 g (85.5%) of desired title palladium complex as an orange solid with m.p. = 194°-196°C. (Literature m.p. of a recrystallized analytical sample = 203°-205°C).
C. 4’-Fludro-S,3',5-trimethyl[1,1*biphenyl]-2-carboxaldehyde (1) Bromo[4-fluoro-3-methylphenyl]magnesium_ Ref. Merck U. S. Patent No. 4,375,475, pp. 37 and 38.
The title Part C(l) Grignard reagent was prepared by adding 5-bromo-2-fluorotoluene (22.5 g, 60.9 mmole, Fairfield Chemical Co.) dropwise -48at a rate sufficient to maintain the reaction at reflux to stirred magnesium turnings (1.35 g, 55.4 mmole, 8.0 eg.) in dry Et2O (70.0 ml). The reaction was initiated in an.ultrasound device. After bromide addition was complete, the mixture was stirred for one hour under argon at room temperature, refluxed for 15 minutes and then allowed to cool to room temperature. (2) 4’-Fluoro-3,3 * ,5-trimethyl[1,1’biphenyl]-2-carboxaldehyde In a second flask, a mixture of the Part B dipalladium complex (3.0 g, 6.92 mmole) and triphenylphosphine (14.52 g, 55.4 mmole, 8.0 eq.) in dry benzene (100 ml) was stirred at room temperature under argon for 30 minutes. Freshly prepared and filtered (glass wool plug) Part C (1) Grignard reagent was then added in one portion by means of a cannula to this solution and the mixture was stirred for 1.5 hours at room temperature under argon. 6.0 N HC1 (35 ml) was added, the mixture stirred an additional hour at room temperature, then filtered through packed Celite (V bed). The filtrate was extracted with Et2O (250 ml), the extract washed with brine (2 x 100 ml), dried over anhydrous MgS04 and evaporated in vacuo to give 13.35 g of a viscous orange oil which crystallized on standing. The crude orange solid was purified by flash chromatography on silica gel' (700 g) eluting with hexane, followed by (95:5) hexane-Et2O. Product fractions were evaporated to give 1.507 g (89.9%) of desired title aldehyde as a light yellow solid with m.p.. = -4972°-75°C) (Literature reports m.p. = 73°-74°C). TLC: (95:5) Hex-Et2O, Rf = 0.40., U.V. and PMA.
D. 4'-Fluoro-3,3',5-trimethyl[1,1'biphenyl1-2-methanol_ A cooled (0°C, ice bath) solution of dry Et2O (15.0 ml) was treated with LiAlH^ (259 mg, 6.82 mmole, 0.55 eq.) and the gray suspension treated dropwise over 15 minutes with a solution of the Part C aldehyde (3.0 g, 12.4 mmole) in dry Et2O (15 ml). The mixture was stirred at room temperature under argon for 30 minutes, then cooled back to 0°C and quenched by sequential dropwise addition of 260 μΐ H2O, 260 μΐ of 15% NaOH and 780 μΐ H20. The suspension was diluted with EtOAc, filtered through anhydrous Na2SO4 over packed Celite (V bed) and the colorless filtrate evaporated in vacuo to give 2.99 g (98.8%) of a white solid. Trituration of the crude solid with cold hexane and drying in vacuo afforded 2.467 g (81.6%) of desired title alcohol as a white solid with m.p. 102-103°C. TLC: (9:1) Hex-EtOAc, Rf = 0.24, U.V. and PMA.
E. (S)—3-[[(1,1-DimethylethylJdiphenylsilyl]oxy]-4-(hydroxymethoxyphosphinyl) butanoic acid, methyl ester_ (1) (S)-4-Bromo-3-hydroxybutanoic acid, methyl ester (1)(a) [R-(R*,R*)]-2,3,4-trihydroxybutanoic acid, calcium salt, hydrate -50Ref. Carbohydrate Research 72, pp. 301-304 (1979).
Calcium carbonate (50 g) was added to a solution of D-isoascorbic acid (44.0 g, 250 mmol) in H2O (625 ml), the suspension cooled to 0°C (ice bath) and treated portionwise with 30% H2°2 (100 ml). The mixture was stirred at 30°-40°C (oil bath) for 30 minutes. Darco (10 g) was added and the black suspension heated on a steam bath until evolution of O2 ceased. The suspension was filtered through Celite, evaporated in vacuo (bath temperature 40°C). The residue was taken up in H^O (50 ml), warmed on a steam bath and CH^OH was added until the solution was turbid. The gummy precipitated solid was collected by filtration and air dried to give 30.836 g (75.2%) of desired calcium salt as a powdery white solid.
TLC (7:2:1) iPrOH-NH4OH-H2O, Rf = 0.19, PMA. (l)(b) (S-(R*,S*)]-2,4-Dibromo-3hydroxybutanoic acid, methyl ester_ Ref. Bock, K. et al., Acta Scandinavica (B) 32, ' pp. 341-344 (1983) Part (l)(a) calcium salt (30 g) was dissolved in 30-32% HBr in acetic acid (210 ml) and stirred at room temperature for 24 hours. Methanol (990 ml) was then added to the brown solution and it was stirred overnight. The mixture was evaporated to an orange oil, taken up in CH^OH (75 ml), refluxed for 2.0 hours and evaporated.
The residue was partitioned between EtOAc (100 ml) and H2O, the organic phase washed with H2O (2x) and brine then dried over anhydrous Na2SO4 and -51evaporated to give 22.83 g (90.5%) of crude dibromide as a light orange oil. TLC (1:1) EtOAc-Hex, Rf = 0.69, UV & PMA. (1)(c) (S)-4-Bromo-3-hydroxybutanoic acid, methyl ester Ref. the same as for preparation of (l)(b).
An argon purged solution of the dibromide (20.80 g, 75.4 mmol) and anhydrous NaOAc (21.0 g) in EtOAc (370 ml) and glacial HOAc (37 ml) was treated with 5% Pd/C (1.30 g) and the black suspension stirred under of H2 (1 atm) while monitoring H2 uptake. After 2.0 hours H2 uptake was complete, the mixture was filtered through Celite, the filtrate washed with saturated NaHCOg and brine then dried over anhydrous MgS04 and evaporated to give crude dibromoester as a brown oil. The crude oil was combined with another batch (starting from 36.77 g of the dibromide) and vacuum distilled to give .77 g (61.3%) of desired title bromoester as a clear oil with b.p. = 79°-80°C (1.0 mm Hg).
TLC (1:1) EtOAc-Hex, Rf = 0.44, PMA.
Anal Calcd for CgHgO^Br: C, 30.48; H, 4.60; Br, 40.56 Found: C, 29.76; H, 4.50; Br, 39.86 (2) (S)-4-Bromo-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy]butanoic acid, methyl ester_ A solution of part E(l) bromohydrin (4.0 g, .4 mmol), imidazole (6.94 g, 5.0 eq.), and -524-dimethylamino pyridine (4-DMAP) (12 mg, 0.005 eq.) in dry DMF (40 ml) was treated with t-butyldiphenylsilyl chloride (5.84 ml, 1.1 eq.) and the homogeneous mixture stirred overnight under argon at room temperature. The mixture was partitioned between 5% KHSO^ and EtOAc, the organic phase washed with I^O and brine, dried over anhydrous Na2SO4 and evaporated to give 9.32 g (100%) of crude silyl ether as a clear, viscous oil. TLC (3:1) Hex-EtOAc, Rf silyl ether = 0.75, U.V. and PMA. (3) (S)-4-Iodo-3-[[(1,1-dimethylethyl)diphenylsilyl]oxy(butanoic acid, methyl ester A solution of the crude Part E(2) bromide (9.32 g, 201 mmole) in methyl ethyl ketone (60 ml, dried over 4A sieves) was treated with sodium iodide (15.06 g, 100.5 mmole, 5.0 eq.) and the yellow suspension refluxed for 5.0 hours under argon. The mixture was cooled, diluted with EtOAc, filtered, the filtrate washed with dilute NaHSO^ (until colorless) and brine then dried over anhydrous Na2S04 and evaporated in vacuo to give 10.17 g of a yellow.'oil. The crude oil was purified by flash chromatography on silica gel (600 g) eluting with (3:1) Hexane-CH2C12. Product fractions were combined and evaporated to give 7.691 g (74.2%, overall yield for both steps) of desired title iodide as a clear, colorless, viscous oil. TLC (3:1) Hex-EtOAc, product. Rf = 0.75, U.V. and PMA. (Note: product iodide co-spots with starting bromide). -53(4) (S)-4-(Diethoxyphosphinyl)-3-[[(1,1dimethylethyl)diphenylsilyl]oxy]butanoic acid, methyl ester A solution of the iodide (7.691 g) in triethyl phosphite (20 ml) was heated at 155°C (oil bath) for 3.5 hours under argon. The mixture was cooled and excess phosphite distilled off in vacuo (0.5 mm Hg, 75°C) to leave a yellow oil (~8.0 g). The crude oil was purified by flash chromatography on silica gel (400 g) eluting with (4:1) Hexane-acetone. Product fractions were evaporated to give 3.222 ,g (41.1%) of desired title phosphonate as a clear, colorless, viscous oil.
TLC (1:1) Hex-acetone, Rf = 0.51, U.V. and PMA. Additionally 2.519 g (61.1% corrected yield) of starting Part (3) iodide was recovered. (5) (S)-3-[[(l,l-Dimethylethyl)diphenylsilyl]oxy]-4-phosphonobutanoic acid, methyl ester A solution of the Part (4) phosphonate (9.85 g, 20.0 mmole) in dry CH2C12 (60 ml) was treated sequentially with bistrimethylsilyltrifluoroacetamide (BSTFA) (5.31 ml, 32.0 mmole, 1.6 eq.) and trimethylsilyl bromide (TMSBr) (6.60 ml 50.0 mmole, 2.5 eq.) and the clear mixture stirred overnight under argon at room temperature. · 5% KHSO4 (80 ml) was added and the mixture was extracted with EtOAc. The aqueous phase was saturated with NaCl and re-extracted with EtOAc.
The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and evaporated in vacuo to give crude title phosphonic acid as a -54viscous oil. TLC (7:2:1) iPrOH-NH^H-^O, Rf = 0.30, U.V. and PMA. (6) (S)-3-([(1,1-Dimethylethyl)diphenylsi lyl]oxy]-4-(hydroxymethoxyphosphinyl)butanoic acid, methyl ester Part (5) crude phosphonic acid (^20.0 mmole) in dry pyridine (25 ml) was treated with dried CHgOH (over 3A sieves, 1.62 ml, 40.0 mmole, 2.0 eq.) and dicyclohexyl carbodiimide (DCC) (4.54 gm, 22.0 mmole, 1.10 eg.) and the resulting white suspension stirred under argon at room temperature overnight. Pyridine was removed in vacuo, then azeotroped with benzene (2 x 15 ml). The residual oil was dissolved in EtOAc, filtered and washed with 1.0 N HCl and brine, dried over anhydrous Na2SO4 and evaporated in vacuo to give 8.272 g of crude title ester as an oil containing a small amount of precipitated dicyclohexyl urea (DCU). TLC (7:2:1) iPrOH-NH4-OH H2O, Rf = 0.60, U.V. and PMA.
F. (S)-4-[[[4’-Fluoro-3,3’,5-trimethyl[1,1*-biphenyl]-2-yl]methoxyphosphinyl]. ·. \ 3-t-butyldiphenylsily1oxybutanoic acid, methyl ester__ Part E crude phosphonic acid mono methyl ester (6.595 gm, -^14.7 mmole) was dissolved in dry CH2C12 (30 ml), treated with distilled trimethylsilyldiethylamine (5.60 ml, 29.4 mmole, 2.0 eq.) and stirred under argon at room temperature for 1 hour. The mixture was evaporated in vacuo, chased with benzene (1 x 30 ml) and dried in vacuo. -55The light yellow viscous oil was dissolved in dry CH2C12 (30 ml) and DMF (dried over 4A sieves, 2 drops)> the clear solution cooled to -10°C (salt/ice bath) and treated dropwise via syringe with distilled oxalyl chloride (1.41 ml, 16.2 mmole, 1.1 eq.). vigorous gas evolution was evident and the solution became deeper yellow in color. The mixture was stirred under argon at -10°C for 15 minutes then allowed to stir at room temperature for 1 hour. The mixture was evaporated in vacuo, chased with benzene (1 x 30 ml) and dried in vacuo:to give crude phosphonochloridate as a yellow oil.
To a solution of the crude phosphonochloridate (^ 14.7 mmole) in dry CH2C12 (10 ml) was added dropwise a solution of the Part D biphenyl alcohol (2.06 g, 8.43 mmole) in dry pyridine (15 ml) and the resulting mixture stirred at room temperature under argon for 16 hours.
The mixture was evaporated to dryness and the residue partitioned between 5% KHS04 and EtOAc.
The organic phase washed with saturated NaHCO^ and brine then dried over anhydrous Na2SO4 and evaporated in vacuo to give 8.290 g of a brown oil. The crude product was purified by flash chromatography on silica gel (370 g) eluting with (70:30) Hexane-acetone. Product fractions were combined and evaporated to give 3.681 g (66%) of the desired title phosphonate as a pale yellow oil. TLC (3:2) Hexane-acetone, Rf = 0.59, U.V. and PMA. -56G. (S)-4-[[[4’-Fluoro-3,3’,5-trimethyl[1,1'-biphenyl]-2-yl]methoxyphosphinyl]3-hydroxybutanoic acid, methyl ester A mixture of the Part F silyl ether (1.103 g, 1.66 mmole) in dry THF (20.0 ml) was treated with glacial acetic acid (380 pi, 6.64 mmole, 4.0 eq.) and a 1.0 M tetrabutyl ammonium fluoride solution (4.98 ml, 4.98 mmole, 3.0 eq.) and the clear yellow solution stirred overnight at room temperature under argon. The mixture was partitioned between cold H2O and EtOAc, the organic phase washed with saturated NaHCO3 and brine, dried over anhydrous Na2SO4 and evaporated to a viscous yellow oil (1.174 g). The crude oil was purified by flash chromatography on silica gel (47 g) eluting with (85:15) CH2C12-Acetone. Product fractions were evaporated to give 679 mg (93.1%) of desired title alcohol as a clear viscous oil. TLC (1:1) Hexane-acetone, Rf = 0.41, U.V. and PMA.
H. (S)-4-[[[4'-Fluoro-3,3’,5-trimethyl[1,1'-biphenyl]-2-yl]methoxy]methoxyphosphinyl]-3-hydroxy-butanoic acid, monolithium salt A solution of the Part G methyl ester (184 mg, 0.420 mmole) in dioxane (5.0 ml) was treated with 1.0 N LiOH (0.50 ml, 1.2 eq.) and the mixture stirred at room temperature under argon for 3 hours. The mixture was diluted with H2O, filtered through a 0.4 pm polycarbonate membrane and evaporated in vacuo. The residue dissolved in H.?O (75 ml), frozen and lyophilized. The crude acid -57was dissolved in a minimum amount of H20 and chromatographed on a 100 ml bed of CHP-20 resin eluting with a H2O/CH3CN linear gradient system. Product fractions were evaporated, dissolved in H2O (50 ml), filtered through 0.4 pm polycarbonate membrane and lyophilized to give 174 mg (89.1% based on weight of hydrate) of desired title mono-lithium salt as a white solid. TLC (7:2:1) iPrOH-NH4OH-H2O, Rf = 0.58 , U.V. and PMA.
Anal Calcd for C2lH25 O&PFLi + 1.95 moles Η£0 (MW 465.46): C, 54.19; H, 6.26; F, 4.08; P. 6.65 Found: C, 54.19; H, 6.21; F, 4.29; P, 6.43 H1 NMR (400 HMz): δ 1.74-2.08 ppm (2H, m, -PO(OCH3)CH2-) 2.30 (3H, s, aromatic methyl) 2.32 (3H, d, aromatic methyl a to 2.35-2.62 fluorine, Jgp.2.2 Hz) (2H, m, -CH2CO2Li) 2.46 (3H, s, aromatic methyl) 3.57 & 3.63 (3H, 2 doublets, -OP(OCH3)-, 2 diastereomers, J„ = 10.3 u-p .···. 1 Hz) 4.28 (1H, m, -CH2CH(OH)CH2CO2Li) • 0 II 4.97 (2H, m, PhCH2OP(OCH3)R) 6.87-7.25 (5H, m, aromatic H's) -58Example 2 (S)-4-[[[4'-Fluoro-3, 3',5-trimethyl[1,1'biphenyl ] -2-yl] methoxy ] hydroxyphosphinyl] -3hydroxybutanoic acid, dilithium salt A solution of the Example 1 diester (374 mg, 0.853 mmole) in dioxane (8.0 ml) was treated with 1.0 N LiOH (2.6 ml, 3.0 eq.) and heated at 50°C (oil bath) for 5.0 hours under argon. A white precipitate was evident. The mixture was diluted with H20 and filtered. The aqueous solution was extracted once with Et2O, filtered through a 0.4 pm polycarbonate membrane and concentrated in vacuo. The crude product was chromatographed on CHP-20 resin (100 ml bed) eluting with a H2O/CH3CN linear gradient system. Product fractions were evaporated in vacuo, taken up in H2O (50 ml), filtered through a 0.4 pm polycarbonate membrane and lyophilized to give 260 mg (67.1% based on hydrate weight) of desired title di-lithium salt as a white solid. TLC (7:2:1).
• PrOH-NH4OH-H2O, Rf=0.47, U.V. and PMA.
Anal Calcd for C2QH220gPFLi2 + 1.77 moles H2O: C, 52.88, H, 5.67; F, 4.18; P, 6.82 Found: C, 52.88; H, £.26; F, 4.24; P, 6.43 H1 NMR (400 MHz, CD3OD): O II ό 1.69 ppm (2H, m, -OPCH2CH(OH)-) 2.26-2.42 (2H, m, CH2CO2Li) 2.30 (3H, s, aromatic methyl) 2.31 (3H, d, aromatic methyl a to F, Jhf=1.9 Hz) 38 (3H, s, aromatic methyl) 22 (1H, m, -CH(OH)CH2-) 0 ll . 75 (2H, m, PhCH2OP-) I 23 (5H, m, 1 aromatic protons) Example 3 (3S)-4-([[4'-Fluoro-3,3',5-trimethyl[1,1’-biphenyl] 2-yl ]methoxy]me thy lphosphinyl] -3-hydroxybutanoic acid, monolithium salt A. (S)-4-[(Chloro)methylphosphinyl]-3 [[(1,1-dimethylethyl)diphenylsilyl]oxy]butanoic acid, methyl ester_ The title phosphinochloridate compound is prepared as described in Example 6 Part B first three paragraphs.
B. (3S )-4-([[4'-Fluoro-3,3',5-trimethyl[1,1'-biphenyl]-2-yl]methoxy]methylphosphinyl]-3-t-butyldiphenylsilyloxybutanoic acid, methyl ester_ A cooled (0°C, ice bath) solution of Part A phosphinochloridate (~2.2 mmole) and Example 1 Part C(2) biphenyl' alcohol (429 mg, 2.2 mmole, 1.0 eq) in dry CH2C12 (10 ml) was treated with EtgN (425 μΐ, 3.04 mmole, 1.4 eq) and 4-DMAP (27 mg, 0.22 mmole) and the orange solution stirred at room temperature overnight under argon. The mixture was partitioned between 5% KHSO^ and EtOAc, the organic layer washed with brine, dried over anhydrous Na2SO4 and evaporated to give 1.1 g of an orange oil. The crude oil was purified by flash -60chromatography on LPS-1 silica gel (44 g) eluting with (1:1) EtOAc:Hexane. Product fractions were combined and evaporated to give 298 mg (21%) of desired coupled title product as a pale yellow oil. Also 460 mg (67% corrected yield) of starting Example 1 Part C(2) biphenyl alcohol was recovered. TLC (1:1) EtOAc:Hex, Rf=0.18 UV and PMA.
C. (3S)—4—[[[4'-Fluoro-3,3',5-trimethyl[1,1’-biphenyl]-2-yl]methoxy]methylphosphinyl]-3-hydroxybutanoic acid, methyl ester A solution of the Part B silyl ether (298 mg, 0.46 mmole) in dry THF (6.0 ml) was treated with glacial HOAc (110 μΐ, 1.84 mmole, 4.0 eq) and a 1.0 M in THF solution of tetrabutylammonium fluoride (1.43 ml, 3.1 eq) and the resulting solution stirred overnight under argon at room temperature. The mixture was partitioned between cold H2O and EtOAc, the organic phase washed with saturated NaHCO^ and brine, dried over anhydrous Na2S04 and evaporated to a yellow oil (273 mg). The crude oil was purified by flash chromatography on LPS-1 silica gel (11 g) eluting with (3:2) Hex-acetone. Product fractions were combined and evaporated to give 150 mg (80%) of desired title alcohol as a viscous oil.
TLC (1:1) Hex:acetone, Rf=0.23, UV and PMA.
D. (3S)-4-([[4'-Fluoro-3,3',5-trimethyl[1,1*-biphenyl]-2-yl(methoxy]methy1phosphinyl]-3-hydroxybutanoic acid, monolithium salt -61A solution of the Part C methyl ester (150 mg, 0.367 mmole) in dioxane (3.0 ml) was treated with 1.0 N LiOH (0.44 ml, 1.2 eq.) and the resulting white suspension was stirred at room temperature under argon for 2 hours. The mixture was diluted with H2O, filtered through a 0.4 pm polycarbonate membrane and evaporated in vacuo to a colorless glass.
The crude product was taken up in a minimum amount of H2O and chromatographed on HP-20 (100 ml bed) eluting with a H2O/CH3CN linear gradient. Product fractions were evaporated, taken up in H20 (50 ml), filtered through a 0.4 pm polycarbonate membrane and lyophilized to give 130 mg (79% based on hydrate weight) of desired title lithium salt as a white solid. TLC (8:1:1) CH2Cl2-CH3OH-HOAc, Rf=0.52, UV and PMA.
Anal Calcd for C21H25O5FLiP (MW 445.49): C, 56.61; H, 6 Found: C, 56.67; H, 6 + 1 .73 moles h2o 44; F. 4.26; P, 6.95 36; F, 4.31; P, 7.43 (400 MHz): δ 1.49 ppm (3H, d, 1.83-2.0 (2H, m, 2.27-2.40 (2H, nt, 2.30 (6H, s, 2.44 (3H, s, 4.26 (1H, nt, 0--OP(CH3)-, JH_p=14.7 Hz) O p-(ch3)ch2-) CH^COnLi) aromatic methyl’s) aromatic methyl) -CH2CH(OH)CH2CO2Li) -620 η 4.87 (2Η, m, ArCH2OP(CH3)-) 6.90-7.20 (5H, m, aromatic H’s) Example 4 (S)-4-[ [ [2,4-Dichloro-6-[(4-fluorophenyl)methoxy]phenyl]methoxy]methoxyphosphinyl]-3-hydroxybutanoic acid, monolithium salt A. 2,4-Dichloro-6-(4-fluorophenylmethoxy)benzaldehyde (Ref.: J. Med Chem., 1986, 29, 167) A solution of 13.77 g (72.5 mmol) of 4,6-dichloro-2-hydroxybenzaldehyde in 100 ml of DMF was stirred and 12.02 g (87 mmol) of K2CO3 was added. This mixture was heated to ~70°C for 60 minutes, then 11.7 ml of 4-fluorobenzyl bromide was added. The resulting solution was stirred at 70°C for 3.5 hours, then this was poured onto ice H2O (1.5 1), filtered and washed with H2O, and recrystallized from Et2O/petroleum ether.
Yield: 17.88 g (83%) of off-white crystals, m.p. 107-108°C.
B. 2,4-Dichloro-6-[(4-fluorophenyl)methoxy]benzenemethanol_ Cold (0°C, ice bath), dry Et2O (10.0 ml) was treated with LiAlH4 (158 mg, 4.16 mmole, 0.6 eq.) and the grey suspension treated dropwise with a solution of Part A aldehyde (2.06 g, 6.93 mmole) in 10 ml dry THF. The mixture was warmed to room temperature and stirred for an hour under argon. The mixture was cooled back to 0°C (ice bath) and quenched by sequential dropwise addition -63of H20 (160 μΐ), 15% NaOH (160 μΐ) and H2O (475 μΐ) Precipitated salts were removed by filtration through anhydrous Na2SO4 over packed Celite (¼11 bed).' The clear filtrate was evaporated to give 2.052 g (98.9%) of crude alcohol as white crystals. One trituration with cold hexane afforded 1.892 g (91.2%) of pure title alcohol as a white crystalline solid with m.p. = 72-73°C.
TLC (4:1) Hex-acetone, Rf=0.31, UV and PMA.
Anal Calcd for c14H11°2cl2F 301-142): C, 55.84; H, 3.68; Cl, 23.55; F, 6.31 . Found: C, 55.97; H, 3.71; Cl, 23.42; F, 6.30 C. (S )-4-[[[2,4-Dichloro-6-[(4-fluorophenyl )methoxy]phenyl]methoxy]methoxyphosphinyl] -3- t-buty ldiphenyls ilyloxy20 butanoic acid, methyl ester_· A solution of the Example 1 Part E(6) methyl ester (^3.84 mmole) in dry CH2C12 (10 ml) was treated with distilled trimethylsilyl diethylamine (1.46 ml, 7.68 mmole, 2.0 eg.) and the resulting solution stirred at room temperature under argon for 1.0 hour. The mixture was evaporated in vacuo, chased with benzene (1 x 20 ml) and dried in vacuo to give crude silylated phosphonic acid mono methyl ester as a colorless oil.
A solution of the crude ester (^3.84 mmole) in dry CH2C12 (10 ml) and dry DMF (1 drop) was cooled to -10°C (salt, ice bath) and treated -64dropwise with distilled oxalyl chloride (368 μ1·, 4.22 mmole, 1.1 eq.). Gas evolution was evident from the clear yellow mixture. The mixture was stirred at room temperature under argon for one hour, evaporated in vacuo, chased with benzene (2 x 20 ml) to give crude phosphonochloridate as a viscous yellow oil.
The crude phosphonochloridate (^3.84 mmole) in dry CH2C12 (10 ml) at 0°C (ice bath) was treated with Part B alcohol (1.15 g, 3.84 mmole, 1.0 eg.) followed by Et^N (805 μΐ, 5.76 mmole, 1.5 eq.) and 4-DMAP (47 mg, 0.384 mmole, 0.1 eq. ) and the brown mixture stirred overnight at room temperature, under argon. The mixture was partitioned between 5% KHSO4 and EtOAc, the organic phase washed with brine, dried over anhydrous Na2SO4 and evaporated to give 3.197 g of a dark brown oil. The crude product was purified by flash chromatography on silica gel (160 g) eluting with (7:3) Hex-EtOAc. Product fractions were combined and evaporated to give 594 mg (21.1%) of desired title phosphonate as a yellow oil. Additionally, 688 mg (52.4% corrected yield ) 'of starting Part B alcohol was recovered.
TLC (1:1) Hex-acetone, Rf=0.29, UV and PMA.
D. (S)-4-[[[2,4-Dichloro-6-[(4-fluorophenyl )methoxy]phenyl]methoxy]methoxyphosphinyl ] -3-hydroxy butanoic acid, methyl ester__ A solution of the Part C silyl ester (578 mg, 0.788 mmole) in dry THF (8 ml) was treated with glacial HOAc (180 μΐ, 3.2 mmole, 4.0 eq.) followed by 1.0 M solution of n-Bu4NF in THF (2.36 -65ml, 2.36 mmole, 3.0 eq.) and the resulting pale yellow solution stirred overnight under argon at room temperature. The mixture was poured into cold H2O and extracted with EtOAc (2X). The organic phase was washed with saturated NaHCOg and brine, dried over anhydrous Na2S04 and evaporated to give 625 mg of a yellow oil. The crude product was purified by flash chromatography on silica gel (31 g) eluting with (7:3) Hexane-acetone. Product fractions were combined and evaporated to give 339 mg (86.9%) of desired title alcohol as a clear, colorless, viscous oil.
TLC (1:1) Hex-acetone, Rf = 0.25, UV and PMA.
E. (S)-4-[[[2,4-Dichloro-6-[(4-fluorophenyl ) methoxy]phenyl]methoxy]methoxyphosphinyl]-3-hydroxybutanoic acid, monolithium salt A solution of the Part D phosphonate (132 mg, 0.267 mmole) in dioxane (2.5 ml) was treated with 1.0 N LiOH (0.32 ml, 1.2 eq.) and the mixture stirred under argon at room temperature for 4.0 hours. A white precipitate was noted. The mixture was diluted with H2O, filtered and the filtrate evaporated to dryness in vacuo. The residue was chromatographed on HP-20 resin (100 ml bed) eluting with a H2O/CH3CN linear gradient system. Product fractions were combined and evaporated, taken up in H2O, filtered through a 0.4 pm polycarbonate membrane and lyophilized to give 108 mg (79% based on hydrate weight) of desired title lithium salt as a white solid. -66TLC (20:1:1) CH2Cl2- C^OH-HOAC, Rf ~ 0.41, UV and PMA.
Anal Calcd for CigHigO7Cl2Fli2P + 1.42 moles H2O (MW 511.72): C, 44.59; H, 4.10; Cl, 13.86; F, 3.71; P, 6.05 Found: C, 44.22; H, 4.09; Cl, 13.91; F, 3.72; P, 6.11 H1 NMR (400 MHZ): δ U 1.98-2.11 ppm (2H, m, OP(OCH3)CH2CH(0H)- 2.26-2.45 ppm (2H, m, -CH(OH)CH2CO2Li) 3.63 & 3.62 (3H, 2 doublets, 2 diastereomers OP(OCH3)CH2-, Jgp-ll HZ) 4.23 (1H, m, (-CH2CH(OH)CH2CO2Li) 5.16 (2H, s, F-PhCH2O) 5.24 (2H, d, ArCH2OP, ^=6.2 Hz) 7.13-7.53 (6H, m, aromatic H’s) Example 5 (3S )-4-[[[2,4-Dichloro-6-[(4-fluorophenyl)methoxy]phenyl]methox£]hydroxyphosphinyl]-3hydroxybutanoic acid, dilithium salt_ A mixture of the Example 4 Part D diester (210 mg, 0.424 mmole) in dioxane (4.0 ml) was treated with 1.0 N LiOH (1.30 ml, 3.0 eq.) and the colorless solution heated at 50°C (oil bath) under argon for 3.5 hours. A white precipitate was evident after 15 minutes. The mixture was diluted with H2O, filtered and the filtrate evaporated -67in vacuo. The residue was dissolved in a minimum amount of E^O and chromatographed on HP-20 resin (100 ml bed) eluting with a H2O/CH3CN linear, gradient. Product fractions were combined and evaporated. The residue was taken up in H2O (50 ml), filtered through a 0.4 pm polycarbonate membrane and lyophilized to give 175 mg (81% based on hydrate weight) of desired title dilithium salt as a white solid.
TLC (8:1:1) CH2Cl2-CH3OH-HOAc, Rf = 0.07, UV and PMA.
Anal Cacld for ClgH16O7Cl2FLi2P + 1.70 moles H2<0 (MW 509.62): C, 42.42; H, 3.84; F, 3.73; Cl, 13.91; P, 6.08 Found: C, 42.46; H, 3.90; F, 3.93; Cl, 13.42; P, 5.66 H1NMR (400 MHz): O U 1.73-1.92 ppm (2H, m, -OP (OLi)-CH2 CH(OH)- 2.27 (1H, Hz) dd, -CH(OH)CH2CO2Li, J. 2.39 (1H, .ΉΖ) dd, -CH(OH)CH2CO2Li, J. 4.26 (1H, m, CH2 CH(OH)CH2 CO2 Li ) 5.08 (2H, s, F-Ph-CH2OAr) 7.03-7.53 (6H, m, aromatic H’s). -68Example 6 (3S)-4-[(2,4-Dichloro-6-[(4-fluorophenyl)methoxy]phenyl]methoxy]raethylphosphinyl]-3-hydroxybutanoic acid, methyl ester_ A. (S)3-[[(l,1-Dimethylethyl)diphenylsily1] oxy]-4-(ethoxymethylphosphinyl)butanoic acid, methyl ester_ A mixture of the Example 1 Part E(3) iodide (4.68 g, 9.18 mmole) in methyl diethoxyphosphine (Strem Chemicals, 5.0 g, 36.7 mmole) was heated at 100°C (oil bath) for 2.5 hours, then at 150°C for three additional hours under argon. A white precipitate slowly formed in the yellow solution. Excess phosphine was distilled off in vacuo (0.5 mm Hg) and the crude product purified by flash chromatography on silica gel eluting with (65:35) Hexane-acetone. Product fractions were combined and evaporated to give 1.590 g (38%) of desired title phosphinic ester (mixture of diastereomers) as a clear viscous oil.
TLC (3:2) Hex-acetone, Rf (2 diastereomers) = 0.19 and 0.22, UV and PMA.
B. (3S)-4-([2,4-Dichloro-6-[(4-fluorophenyl ) methoxy ] phenyl ] methoxy ] methyl phosphinyl]-3-t-butyldiphenylsilylbutanoic acid, methyl ester_ A solution of Part A phosphinic ester (605 mg, 1.3 mmole) in dry CH2C12 (6.0 ml) was treated with bis(trimethylsilyl)trifluoroacetamide (BSTFA) (280 μΐ, 1.05 mmole, 0.8 eg.) and trimethylsilyl bromide (TMSBr) (210 μΐ, 1.57 mmole, 1.2 eq.) and the resulting solution stirred at room temperature -69under argon overnight. 5% KHSO^ (15 ml) was added and the mixture extracted with EtOAc. The organic phase was washed with brine, dried over anhydrous Na2SO4 and evaporated in vacuo to give crude phosphinic acid as a colorless oil.
A solution of the crude phosphinic acid (^1.3 mmole) in dry CH2Cl2 (6.0 ml) was treated with distilled trimethylsilyl diethylamine (270 μΐ, 1.44 mmole, 1.1 eq.) and the clear mixture was stirred at room temperature under argon for 1.0 hour. The mixture was evaporated in vacuo, chased with benzene (1 x 15 ml), and dried in vacuo.
A cooled (0°C, ice bath) solution of the crude silylated phosphinic acid (^1.3 mmole) in dry CH2C12 (6.0 ml) and DMF (1 drop) was treated dropwise via syringe with distilled oxalyl chloride (130 μΐ, 1.44 mmole, 1.1 eq.). Gas evolution was evident. The mixture was stirred at room temperature under argon for one hour then evaporated in vacuo, chased with benzene (2 x 15 ml) and dried in vacuo to give crude phosphinochloridate as a yellow oil.
A cooled (0°, ice bath) solution of phosphinochoridate (~1.3 mmole) and Example 1 Part E(6) alcohol (392 mg, 1.3 mmole) in dry CH2C12 (6.0 ml) was treated with Et3N (275 μΐ, 1.97 mmole, 1.5 eq.) and 4-DMAP (16 mg, 0.13 mmole, 0.1 eq) and the resulting yellow mixture stirred under argon at room temperature overnight. The mixture was partitioned between 5% KHS04 and EtOAc, the organic phase washed with brine, dried over anhydrous Na2SO4 and evaporated to give 908 mg of -ΊΟcrude product as a dark yellow oil. The crude product was purified by flash chromatography on silica gel (45 g) eluting with (3:2) Hex-EtOAc. Product fractions were combined and evaporated to give 266 mg (28.3%) of desired title product as a clear, colorless oil. Also 197 mg (57%, corrected yield) of the starting alcohol was recovered.
C. (3S)-4-[[2,4-Dichloro-6-[(4-fluoro10 phenylJmethoxy]phenyllmethoxyJmethylphosphinyl]-3-hydroxybutanoic acid, methyl ester A solution of the Part B silyl ester (275 mg, 0.38 mmole) in dry THF (6.0 ml) was treated with glacial HOAc (90 μΐ, 1.53 mmole, 4.0 eq.) and a 1.0 M solution in THF of tetrabutylammonium fluoride (1.2 ml, 3.1 eq.). The resulting solution was stirred overnight under argon at room temperature. The mixture was partitioned between cold H2O and EtOAc, the organic phase washed with saturated NaHC03 and brine, dried over anhydrous Na2SO4 and evaporated to give 258 mg of a yellow oil. The crude product was purified by flash chromatography on LPS-1 silica gel (8 g) eluting with (1:1) Hexane-acetone. Product fractions were combined and evaporated to give 142 mg (77%) of desired title alcohol as a clear, colorless, oil.
TLC (1:1) Hexane-acetone, Rf = 0.20, UV and PMA. -71D. (3S)-4-[[2,4-Dichloro-6-[(4-fluorophenyl)methoxy]phenyl]methoxy]methylphosphinyl]-3-hydroxybutanoic acid, monolithium salt_ A solution of the Part C methyl ester (142 mg, 0.296 mmole) in dioxane (3.0 ml) was treated with 1.0 N LiOH (0.36 ml, 1.2 eq.) and the resulting white suspension stirred under argon at room temperature for 2.0 hours. The mixture was diluted with H2O, filtered through a 0.4 pm polycarbonate membrane and the filtrate evaporated in vacuo.
The crude product was dissolved in a minimum amount of H2O and chromatographed on a 100 ml bed of HP-20 resin eluting with a H2O/CH3.CN linear gradient. Product fractions were combined and evaporated. The residue was taken up in H2O, filtered through a polycarbonate membrane and lyophilized to give 93 mg (63% based on hydrate weight) of desired title lithium salt as a white solid.
TLC (8:1:1) CH2C12- CH3OH-HOAc, Rf = 0.51, UV and PMA.
Anal Calcd for C^HigO7Cl2FLiP + 1.38 moles H20 (MW 495.94): C, 46.01; H, 4.42; F, 3.83; Cl, 14.30; P, 6.24 Found: C, 46.10; H, 4.49; F, 3.82; Cl, 14.32; P, 6.43 H1 NMR (400 MHz): -720 If δ 1.53 ppm (3H, d, -OP (CH^ ) CH2 -, JH_p = 14.6 Hz) 1.87-2.10 (2H, m, -OP(OCH3)CH2-) 2.27 (1H, JH- dd, -CH(OH)CH2CO2Li, h=8.4 Hz, JH_p=l.l Hz) 2.38 (1H, JH- dd, -CH(OH)CH2CO2Li, h=4.7 Hz, JH_p=l.l Hz) 4.29 (1H, m, -CH2CH(OH)CH2CO2Li) 5.16+5.18 (4H, m, ArCH20P and F-PhCH2O)-) 7.11-7.52 (6H, m, aromatic) Example 7 (S)-4-[[[4'-Fluoro-3, 3',5-trimethyl[1,1'-biphenyl2-y1]methyl]amino]methoxyphosphinyl]-3-hydroxybutanoic acid, monolithium salt___ A. 4'-Fluoro-3,3',5-trimethyl[1,1'biphenyl]-2-carboxylic acid A solution of the Example 1 Part C(2) aldehyde (1.0 g, 4.13 mmole) in acetone (10.0 ml) at 0°C (ice bath) was treated dropwise with 8.0 N Jones reagent (4.1 ml, excess) and the resulting brown-green suspension stirred overnight under argon at room temperature. Excess oxidant was destroyed by adding isopropanol (10.0 ml) and precipitated chromium salts removed by filtration through a %'· pad of Celite. The filtrate was evaporated, taken up in EtOAc, washed with 1.0 N HCl (2X), saturated NH4C1 (2X) and brine, then dried over anhydrous Na2SO4 and evaporated to give 1.011 g of a green solid with m.p. 153-154°C. -73The crude acid was purified via the dicyclohexylamine salt. To a solution of the crude acid in EtOAc (5.0 ml) was added dicyclohexyl amine (DOHA) (823 μΐ, 1.0 eq.). The solution diluted with hexane and precipitated crystalline salt was collected to give 997 mg (55% from aldehyde, m.p. 181-183°C) of desired product as an off-white crystalline DOHA salt.
The title free acid was regenerated from the DOHA salt by partitioning the salt between 5% KHSO4 and EtOAc. The organic phase was washed with brine, dried over anhydrous Na2SO4 and evaporated in vacuo to give 554 mg (52% from aldehyde) of desired title acid.
TLC (9:1) CH2C12-CH3OH, Rf=0.37, UV and PMA.
B. 4'-Fluoro-3,3’,5-trimethyl[1,11biphenyl]-2-carboxamide_ A suspension of the Part A acid (554 mg, 2.14 mmole) in dry CH2C12 (6.0 ml) and dry DMF (1 drop) at 0°C (ice bath) was treated dropwise via syringe with distilled oxalyl chloride (205 μΐ, 2.35 mmole, 1.1 eq.).and the clear yellow solution stirred under argon at room temperature for one hour. The mixture was evaporated in vacuo, chased with benzene (2X) and dried in vacuo to give crude acid chloride as a yellow oil.
A cooled (0°C, ice bath) mixture of THF (3.0 ml) and concentrated NH40H (2.0 ml, excess) was treated dropwise with a THF solution (3.0 ml) of the crude acid chloride and the bright orange solution stirred at room temperature under argon for 1.0 hour. The mixture was partitioned -74between H2O and EtOAc, the organic phase washed with saturated NaHCOg, H2O and brine, then dried over anhydrous Na2SO4 and evaporated to give 528 mg (96.1%) of crude amide as a light orange solid. One recrystallization from EtOAc-hexane afforded 435 mg (79.1%) of purified title amide as pale yellow needles with m.p. 197-198°C. TLC (1:1) Et20-Acetone Rf=0.83, UV and PMA.
C. 4'-Fluoro-3,3’,5-trimethyl[1,1'biphenyl]-2-methanamine A cooled (0°C, ice bath) solution of dry THF (5.0 ml) was treated with solid LiAlH4 (125 mg, 3.3 mmole) and the gray suspension treated dropwise over five minutes with a solution of the Part B amide (424 mg, 1.65 mmole) in 'THF (5.0 ml). The resulting suspension was stirred at room temperature under argon for 2.5 hours, then refluxed for 45 minutes. The mixture was cooled to 0°C (ice bath) and quenched by sequential dropwise addition of 125 μΐ H2O, 125 μΐ of 15% NaOH and 375 μΐ H2O. Precipitated aluminum salts were removed by filtration through anhydrous Na2SO4 over packed Celite. The clear filtrate was evaporated in vacuo to give the'crude amine as a clear oil.
TLC (7:3) Et20-acetone, Rf=0.60, UV and PMA. The amine was purified as the HCl salt.
A solution of the crude amine (~1.65 mmole) in absolute EtOH (8.0 ml) was treated with concentrated HCl (152 μΐ, 1.82 mmole) and the mixture stirred for 15 minutes at room temperature under argon. The mixture was evaporated in vacuo to a white crystalline solid. -75The solid was triturated with cold Et2O, collected by filtration and dried in vacuo to give 426 mg (92.4%) of title amine-HCl as fine white crystals.
D. (S)-4-[[[[4’-Fluoro-3,3’,5-trimethyl[1,1’-biphenyl]-2-yl]methyl]amino]methoxyphosphinyl]-3-t-butyldiphenylsilyloxy butanoic acid, methyl ester A solution of Example 1 Part E(6) methyl ester (~2.0 mmole) in dry CH2C12 (5.0 ml) was treated with distilled trimethylsilyl diethylamine (758 μΐ, 4.0 mmole, 2.0 eq.) and the clear mixture stirred at room temperature under argon for one hour. The mixture was evaporated in vacuo, chased with benzene (lx 15 ml) and dried in vacuo A cooled (0°C) solution of the crude silyl phosphonate in dry CH2C12 (7.0 ml) and DMF (1 drop) was treated dropwise with distilled oxalyl chloride (192 μΐ, 2.2 mmole, 1.1 eq.). Gas evolution was evident from the clear yellow mixture. The solution was stirred at room temperature for one hour, evaporated in vacuo, chased with benzene (2 x 15 ml), and dried in vacuo to give the crude phosphonochloridate as . - 1 a yellow, viscous oil.
A cooled (0°C) solution of the phosphonochloridate and Part C biphenyl amine-HCl (416 mg, 1.49 mmole) in dry CH2Cl2 (10 ml) was treated with EtgN (641 μΐ, 4.6 mmole, 2.3 eg.) and 4-DMAP (24 mg, 0.2 mmole, 0.1 eq.) and the clear yellow mixture stirred overnight at room temperature under argon. The mixture was partitioned between 5% KHSO4 and EtOAc, the 76organic phase washed with brine, dried over anhydrous Na^SO^ and evaporated in vacuo to give 1.19 g of a yellow oil'. The crude product was purified by flash chromatography on silica gel (60 g) eluting with (7:3) hexane-acetone. Product fractions were evaporated to give 588 mg (59.5%) of desired title phosphonamide as a pale yellow, viscous oil.
TLC (7:3) Hexane-acetone, Rf=0.20, UV and PMA.
E. (S)-4-([[[4*-Fluoro-3,3’,5-trimethyl[1,1’-biphenyl)-2-yljmethyl]amino]methoxyphosphinyl]-3-hydroxybutanoic acid, methyl ester A solution of Part D silyl ether (588 mg, 0.888 mmole) in dry THF (10.0 ml) was treated with glacial HOAc (203 μΐ, 3.55 mmole, 4.0 eq.) and a 1.0 M solution in THF of tetrabutylammonium fluoride (2.66 ml, 2.66 mmole, 3.0 eq.) and the resulting solution stirred overnight under argon at room temperature. The mixture was poured into cold H2O and extracted with EtOAc. The organic phase was washed with saturated NaHCO3 and brine, then dried over anhydrous Na2SO4 and evaporated in vacuo to give 605 mg of an orange oil. The crude product was purified by flash chromatography on silica gel (36 g) eluting with (1:1) Hexaneacetone. Product fractions were combined and evaporated to give 196 mg (50.4%) of desired title alcohol as a light orange oil.
TLC (1:1) Hexane-acetone, Rf=0.16, UV and PMA. -77F. (S)-4-[[[[4'-Fluoro-3,3',5-trimethyl[1,1*-biphenyl]-2-yl]methyl]amino]methoxyphosphinyl]-3-hydroxybutanoic acid, monolithium salt_ A solution of the Part E diester (105 mg, 0.240 mmole) in dioxane (2.0 ml) was treated with 1.0 N LiOH (288 pi, 1.2 eg.) and the white suspension stirred under argon at room temperature for 4.0 hours. The mixture was diluted with H2O, filtered, the filtrate evaporated in vacuo. The residue was chromatographed on HP-20 (100 ml bed) resin eluting with a H2O/CH3CN linear gradient. Product fractions were combined and evaporated.
The residue was taken up in H2O (50 ml), filtered through a 0.4 pm polycarbonate membrane and lyophilized to give 70 mg (62.7% based on weight of hydrate) of desired title lithium salt as a white solid.
TLC (20:1:1) CH2Cl2-CH3OH-HOAc, Rf=0.19, UV and PMA.
Anal Calcd for C21H2&NO5PFLi + 2.41 moles H2O (MW 472.75): C, 53.35; H, 6.57; N, 2.96; F, 4.02; P, 6.55 Found: C, 53.35; H, 6.52; N, 2.98; F, 4.05; P, 6.59 -78H1 NMR (400 MHz): 1.79-1 ppm (2H, m, -P(OCH3)CH2~) 26-2.44 ppm (2H, m, -CH2CO2Li 2.29 (3H, s, aromatic methyl) 2.31 (3H, d, aromatic methyl a 2.47 to (3H, fluorine, Jgp=1.4 Hz) aromatic methyl) 3.46 & 3.50 (3H, 2 doublets, 2 3.96 diastereomers, 1^=10.5 Hz) O II (2H, m, -PhCH2NHP(OCH3)- 4.17 (1H, m, (-CH2CH(OH)CH2CO2Li) 6.84-7.21 (5H, m, aromatic protons) Examples 8 to 20 Following the procedures as outlined heretofore and as described in the previous working Examples, the following additional compounds may be prepared.
O 1' R-P-CHI + f2>n H I __ x C-CH2-CO2-RX OH -79Ex.
No. _R 8. OH C2K5° .
C3H7 11. CH3O 12. OH H NH CH3 Li NH H 0 H η X Rx 13. CKO 4 9 CH2-0 oio C2H5 Li ExNo . R _ Z η X RX 14.
C5S11 NH CH.
CH -0 C2H5 H 19. HO 0 Li . ch3o owo NH -82Example 21 (S)-4-Diisopropyloxyphosphinyl)-3- [[(1,1-dimethyl ethyl)diphenylsilyl] oxy]-butanoic acid, methyl ester The Example 1 Part E(3) iodide (45.1 mmol.., 21.70 g) was stirred under high vacuum for 30 minutes. Freshly distilled triisopropyl phosphite (0.451 mol., 93.92 g, 113.37 ml.) was added in one portion and the reaction mixuture was stirred under argon and heated in a 155°C oil bath for 16.5 hours. The mixture was then cooled to room temperature. Excess triisopropyl phosphite and volatile reaction products were removed by short path distillation (10 mm Hg) followed by Kugelrohr distillation (0.50 mm Hg, 100°C, 8 hours). The product was further purified via flash chromatography (95 mm diam. column, 6’’/Merck silica gel, 6/3/1 Hexane/acetone/toluene eluent, 2/rain flow rate, 50 ml fractions) to afford 17.68.g (33.96 mmol, 75% yield) of the title isopropylphosphonate as a clear viscous oil.
TLC: Silica gel Rf=0.32 (6:3:1 Hexane/acetone 1HNMR δ toluene) (270 ΜΗ , cdci3) 7.70-7.65 (m,4H) 7.45-7.35 (m,6H) 4.57-4.44 (m,3H) 3.59 (s,3 H) 2.94 and 2.88 (2xd, 1H J=3. 2.65 and 2.60 (2xd, 1H J=7. 2.24-1.87 (Series of m, 2H) 1.19 and 1.12 (2xd, 12H J=6 1.01 (s, 9H) -83Example 22 S)-4-(Hydroxymethoxyphosphinyl)-3- [ [ (1,1-dimethylethyl ) diphenylsilyl] oxy] butanoic acid, methyl ester, dicyclohexylamine (1:1) salt The Example 21 isopropyl phosphonate (30.5 mmol, 10.66 g) was stirred under argon, at room temperature, in 80 ml of dry CH2Cl2· This solution was treated dropwise (5 min) with bistrimethylsilyltrifluoroacetamide (BSTFA) (32.8 . mmol, 8.44 g, 8.71 ml), followed by dropwise addition (10 min) of trimethyisilylbromide (TMSBr) (51.3 mmol, 7.84 g, 6.75 ml). After stirring at room temperature for 20 hours, the reaction mixture was quenched with 200 ml of 5% aqueous KHSO4 and stirred vigorously for 15 minutes. The aqueous layer was extracted 3 times with ethylacetate. The organic extracts were combined, washed once with brine, dried over Na2S04 and concentrated in vacuo. The residue was azeotroped 2 times with 50 ml of toluene. The precipitate which formed was suspended in toluene and filtered. The filtrate was concentrated and the azeotrope/filter process repeated. The resulting filtrate was evaporated in vacuo and then pumped under high vacuum 'for 5 hours. The resulting viscous clear oil was stirred under argon, at room temperature, in 50 ml of dry pyridine. This solution was treated in one portion with dicyclohexylcarbodiimide (DCC) (22.6 mmol, 4.65 g), followed by addition of methanol (41.0 mmol, 1.31 g, 1.67 ml). After stirring at room temperature for 20 hours, the reaction mixture was filtered through a celite pad in a sintered glass funnel. 84The celite was washed with ethyl acetate and the combined filtrates were evaporated in vacuo. The residue was redissolved in ethyl acetate and washed 2 times with 5% aqueous KHS04 and once with brine. The organic extract was dried over Na2SG4, filtered, the filtrate concentrated and azeotroped 2 times with toluene, suspended in toluene and filtered. The resulting filtrate was again concentrated, azeotroped, filtered and the filtrate evaporated in vacuo and placed under high vacuum for 6 hours to afford the phosphonate monoester as a clear viscous oil (10.2 g, >100% yield). TLC: silica gel R^=0.50 (7:2:1 nPrOH/NH4OH/H2O). The phosphonate monoester [1.21 g was pumped under high vacuum for 4 hours, affording 1.16 g (2.57 mmol)] was dissolved in 10 ml of dry ethyl ether and treated dropwise with dicyclohexylamine (2.65 mmol, 0.481 g, 0.528 ml). The resulting homogeneous solution sat at room temperature for 7 hours resulting in significant crystal formation. The mixture was stored at -20°C for 16 hours and then warmed to room temperature and filtered. The crystals were washed with cold, dry ethyl ether and then pumped . λ 1 under high vacuum over Ρ2θ5 for 18 hours. The crystals were subsequently pumped under high vacuum at 45°C for 4 hours, affording 1.25g (1.98 mmol, 77% yield) of the title dicyclohexylamine salt as a white powdery solid, m.p. 155-156°C.
TLC: Silica gel Rf=0.57 (20% MeOH/CH2Cl2) Ή NMR: (270 MH2, CDC13) 7.71-7.65 (m, 4H) 7.40-7.32 (m, 6H) 4.02 (m, 1H) 3.52 (s, 3H) 3.28 and 3.22 (m, 1H) 3.11 (d, 3H J: =11 : Hz) 2.77-2.64 (m, 2H) 2.62-2.56 (m, 1H) 1.92-1.08 (Se: ries of m 1.00 (S, 9H) Mass Spec: (FAB) 632 (M&H)+ IR:(KBr) 3466-3457 (broad) 3046, 3016, 2997, 2937, 2858, 2836, 2798, 2721, 2704, 2633, 2533, 2447, 1736, 1449, 1435, 1426, 1379, 1243, 1231, 1191, 1107, 1074, 1061, 1051, 820 CM-1 Anal Calcd for c22H3i °6PS^*C12H23N: C,64.63; H,8.61; N,2.22 Found: C, 64.51; H, 8.49; N, 2.18
Claims (8)
1. A compound capable of inhibiting the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase, having the formula O R-P-C^ -CH-C^-CO^R X OH Wn z X wherein R is OH. lower alkoxy or lower alkyl and R is H or lower alkyl; X is -O- or -ΝΞ-; n is 1 or 2 Z is a hydrophobic anchor which is wherein the dotted lines represent optional double bonds, wherein R 1 , R 2 , R 2a and R 21 * “ay be the same or different and are H, halogen, lower alkyl, 87haloalkyl, phenyl/ substituted phenyl ox OR y in which R y is H, alkanoyl, benzoyl, phenyl, halophenyl, phenyl-lower alkyl, lower alkyl, cinnamyl, haloalkyl, allyl, cycloalkyl-lower alkyl, adamantyl-lower alkyl or substituted phenyl-lower alkyl; e ci R and R are the same.or different and , 5 5» are H, lower alkyl or OH, one or R and R being present when the carbon to which it is attached is linked to a double bond; O R 3 * 5 is alkyl-C-or arylCH^-; R 6a is lower alkyl, hydroxy, oxo or halogen, and g is 0, 1, 2. or 3, or such a compound in salt form.
2. The compound as defined in Claim 1 wherein X is -O-, R is alkoxy, and Z is
3. The compound as defined in Claim 1 wherein X is -NH-, R is alkoxy and is CH-,, and Z is
4. The compound as defined in claim 2 having the name (S)-4-[[[4’-fluoro-3,3’,5trimethyl [1,1* -biphenyl ] -2-yl lmethoxy] methoxypho sphinyl]-3-hydroxy-butanoic acid, methyl ester or its monolithium salt, (S )-4- [ [ [4’-fluoro-3,3', 5-trimethyl [1,1’biphenyl ] -2-yl ] methoxy ] hydroxyphosphinyl ] -3 hydroxybutanoic acid, dilithium salt, (3S)—4— £ [ [4’ -fluoro-3, 3 ’,5-trimethyl[1,1‘biphenyl ] -2-yl ] me thoxy ]methylpho sphinyl ] -3hydroxybutanoic acid, monolithium salt, (S )-4- £ [ [2,4-dichloro-6-[ (4-fluorophenyl )methoxy] phenyl ] methoxy] methoxyphosphinyl ] -3 hydroxybutanoic acid, monolithium salt, (3S) -4- [[[2,4-dichloro-6- [ (4-fluorophenyl) methoxy jphenyl ] methoxy] hydroxyphosphinyl ] -3 hydroxybutanoic acid, dilithium salt, (3S) -4- [ [2,4-dichloro-6- L( 4-fluorophenyl) methoxy Jphenyl ] methoxy ] methy lphosphinyl ] -3 hydroxybutanoic acid, or its methyl ester, or (s)-4-£££[4’-fluoro-3,3*,5-trimethyl .£ 1,1 ’biphenyl-2-yl ] methyl ] amino ] methoxyphosphinyl ] -3 hydroxybutanoic acid, monolithium salt.
5. A hypocholesterolemic or hypolipemic composition comprising a compound as defined in any preceding claim and a pharmaceutically acceptable carrier X therefor, with the provisos that if R is lower alkyl the ester is physiologically-hydrolysable and physiologicallyacceptable and that if the compound is in salt form it is in pharmaceutically acceptable form, and a pharmaceutically acceptable carrier therefor.
6. A compound as. defined in any one of claims X 1 -4 with the provisos that if R is lower alkyl the ester is physiologically-hydrolysable and physiologically.-acceptable and that if the compound is in salt form it is in pharmaceutically acceptable form, for use in a treatment involving inhibiting cholesterol biosynthesis.
7. Use of a compound as defined in any one of X claims 1 -4 with the provisos that if R is lower alkyl the ester is physiologically-hydrolysable and physiologicallyacceptable and that if the compound is in salt form it is in pharmaceutically acceptable form, for the manufacture of a medicament for a treatment involving inhibiting cholesterol biosynthesis.
8. A compound according to Claim 1, substantially as herein described in the Examples.
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US5328187A | 1987-05-22 | 1987-05-22 | |
US10968087A | 1987-10-19 | 1987-10-19 |
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IE881543L IE881543L (en) | 1988-11-22 |
IE63760B1 true IE63760B1 (en) | 1995-06-14 |
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IE154388A IE63760B1 (en) | 1987-05-22 | 1988-05-20 | Phosphorus-containing HMG-CoA reductase inhibitors |
IE930324A IE930324L (en) | 1987-05-22 | 1988-05-20 | PHOSPHORUS-CONTAINING HMG-CoA REDUCTASE INHIBITORS, NEW¹INTERMEDIATES AND METHOD |
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KR (1) | KR880013958A (en) |
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AU (1) | AU610591B2 (en) |
BE (1) | BE1004193A3 (en) |
CH (1) | CH676984A5 (en) |
DE (1) | DE3817375C2 (en) |
DK (1) | DK277488A (en) |
ES (1) | ES2009918A6 (en) |
FI (1) | FI89493C (en) |
FR (1) | FR2615508B1 (en) |
GB (1) | GB2205837B (en) |
GR (1) | GR1000959B (en) |
HU (1) | HU205125B (en) |
IE (2) | IE63760B1 (en) |
IL (1) | IL86464A (en) |
IT (1) | IT1217685B (en) |
NL (1) | NL8801330A (en) |
NO (1) | NO882218L (en) |
NZ (1) | NZ224733A (en) |
PH (1) | PH25350A (en) |
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FR2596393B1 (en) * | 1986-04-01 | 1988-06-03 | Sanofi Sa | HYDROXY-3 DIHYDROXYOXOPHOSPHORIO-4 BUTANOIC ACID DERIVATIVES, THEIR PREPARATION PROCESS, THEIR USE AS MEDICAMENTS AND THE COMPOSITIONS CONTAINING THEM |
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1988
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- 1988-05-20 GB GB8811929A patent/GB2205837B/en not_active Expired - Fee Related
- 1988-05-20 IE IE930324A patent/IE930324L/en unknown
- 1988-05-20 HU HU882614A patent/HU205125B/en not_active IP Right Cessation
- 1988-05-21 KR KR1019880006020A patent/KR880013958A/en not_active Application Discontinuation
- 1988-05-21 PL PL1988272597A patent/PL154877B1/en unknown
- 1988-05-21 JP JP63124809A patent/JP2680347B2/en not_active Expired - Lifetime
- 1988-05-21 CN CN198888103091A patent/CN88103091A/en active Pending
- 1988-05-24 FR FR8806885A patent/FR2615508B1/en not_active Expired - Fee Related
- 1988-05-24 BE BE8800566A patent/BE1004193A3/en not_active IP Right Cessation
- 1988-05-24 NL NL8801330A patent/NL8801330A/en not_active Application Discontinuation
- 1988-05-24 CH CH1967/88A patent/CH676984A5/fr not_active IP Right Cessation
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Legal Events
Date | Code | Title | Description |
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MM4A | Patent lapsed |