NL8801331A - Fosfor bevattende remmers van hmg-coa reductase, nieuwe tussenprodukten en werkwijze voor het toepassen daarvan. - Google Patents
Fosfor bevattende remmers van hmg-coa reductase, nieuwe tussenprodukten en werkwijze voor het toepassen daarvan. Download PDFInfo
- Publication number
- NL8801331A NL8801331A NL8801331A NL8801331A NL8801331A NL 8801331 A NL8801331 A NL 8801331A NL 8801331 A NL8801331 A NL 8801331A NL 8801331 A NL8801331 A NL 8801331A NL 8801331 A NL8801331 A NL 8801331A
- Authority
- NL
- Netherlands
- Prior art keywords
- hydroxybutyric acid
- phenyl
- fluorophenyl
- methyl
- ethyl
- Prior art date
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- 239000000543 intermediate Substances 0.000 title claims description 18
- 238000000034 method Methods 0.000 title description 9
- 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
- 239000000203 mixture Substances 0.000 claims description 226
- -1 hydroxyphosphinyl Chemical group 0.000 claims description 145
- 150000001875 compounds Chemical class 0.000 claims description 110
- 150000004702 methyl esters Chemical class 0.000 claims description 103
- 229910052739 hydrogen Inorganic materials 0.000 claims description 99
- 125000000217 alkyl group Chemical group 0.000 claims description 94
- SMBQBQBNOXIFSF-UHFFFAOYSA-N dilithium Chemical class [Li][Li] SMBQBQBNOXIFSF-UHFFFAOYSA-N 0.000 claims description 84
- 239000001257 hydrogen Substances 0.000 claims description 84
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 73
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 51
- 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 description 48
- 150000002431 hydrogen Chemical class 0.000 claims description 46
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 38
- 125000003545 alkoxy group Chemical group 0.000 claims description 37
- 239000002253 acid Substances 0.000 claims description 35
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 34
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 34
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 30
- 150000003839 salts Chemical class 0.000 claims description 30
- NJLHHACGWKAWKL-UHFFFAOYSA-N ClP(Cl)=O Chemical compound ClP(Cl)=O NJLHHACGWKAWKL-UHFFFAOYSA-N 0.000 claims description 28
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 26
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 25
- 150000002148 esters Chemical class 0.000 claims description 24
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 24
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 24
- 229910052799 carbon Inorganic materials 0.000 claims description 23
- 235000012000 cholesterol Nutrition 0.000 claims description 23
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 23
- 239000003960 organic solvent Substances 0.000 claims description 21
- 229910052801 chlorine Inorganic materials 0.000 claims description 20
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 19
- 229910052731 fluorine Inorganic materials 0.000 claims description 19
- 229910052736 halogen Inorganic materials 0.000 claims description 18
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 17
- 150000002367 halogens Chemical class 0.000 claims description 17
- 230000002209 hydrophobic effect Effects 0.000 claims description 15
- 102000004190 Enzymes Human genes 0.000 claims description 14
- 108090000790 Enzymes Proteins 0.000 claims description 14
- 229910052794 bromium Inorganic materials 0.000 claims description 13
- 125000001153 fluoro group Chemical group F* 0.000 claims description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 11
- 102100029077 3-hydroxy-3-methylglutaryl-coenzyme A reductase Human genes 0.000 claims description 10
- WHBMMWSBFZVSSR-UHFFFAOYSA-N 3-hydroxybutyric acid Chemical compound CC(O)CC(O)=O WHBMMWSBFZVSSR-UHFFFAOYSA-N 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- 125000001424 substituent group Chemical group 0.000 claims description 10
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 9
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical class C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 claims description 8
- 230000002401 inhibitory effect Effects 0.000 claims description 8
- 229910052760 oxygen Inorganic materials 0.000 claims description 8
- 125000001589 carboacyl group Chemical group 0.000 claims description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims description 7
- 229910052698 phosphorus Inorganic materials 0.000 claims description 7
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 6
- 239000001301 oxygen Substances 0.000 claims description 6
- 125000003884 phenylalkyl group Chemical group 0.000 claims description 6
- 239000011574 phosphorus Substances 0.000 claims description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 5
- 125000001188 haloalkyl group Chemical group 0.000 claims description 5
- 239000000758 substrate Substances 0.000 claims description 5
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 4
- 101710158485 3-hydroxy-3-methylglutaryl-coenzyme A reductase Proteins 0.000 claims description 4
- 125000005059 halophenyl group Chemical group 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 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 claims description 3
- 150000001450 anions Chemical class 0.000 claims description 3
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 3
- 125000000490 cinnamyl group Chemical group C(C=CC1=CC=CC=C1)* 0.000 claims description 3
- KLIAJVJCJXRUFP-KRWDZBQOSA-N C=1C=CC=CC=1[Si](O[C@@H](CC(O)=O)CP(=O)OCO)(C(C)(C)C)C1=CC=CC=C1 Chemical compound C=1C=CC=CC=1[Si](O[C@@H](CC(O)=O)CP(=O)OCO)(C(C)(C)C)C1=CC=CC=C1 KLIAJVJCJXRUFP-KRWDZBQOSA-N 0.000 claims description 2
- 125000005002 aryl methyl group Chemical group 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 230000000055 hyoplipidemic effect Effects 0.000 claims description 2
- 230000000871 hypocholesterolemic effect Effects 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims 5
- GJAKLXGMROXGHH-UHFFFAOYSA-N OP(=O)C(C(=O)O)C(C)O Chemical compound OP(=O)C(C(=O)O)C(C)O GJAKLXGMROXGHH-UHFFFAOYSA-N 0.000 claims 2
- 235000010290 biphenyl Nutrition 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 230000001851 biosynthetic effect Effects 0.000 claims 1
- 239000004305 biphenyl Substances 0.000 claims 1
- 239000002184 metal Substances 0.000 claims 1
- 239000000376 reactant Substances 0.000 claims 1
- 125000003003 spiro group Chemical group 0.000 claims 1
- 125000000547 substituted alkyl group Chemical group 0.000 claims 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 646
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 307
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 264
- 239000000243 solution Substances 0.000 description 253
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 252
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 214
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 192
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 189
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 165
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 164
- 229910001868 water Inorganic materials 0.000 description 163
- 239000000741 silica gel Substances 0.000 description 139
- 229910002027 silica gel Inorganic materials 0.000 description 139
- 238000004809 thin layer chromatography Methods 0.000 description 132
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- 229910052786 argon Inorganic materials 0.000 description 126
- 235000019439 ethyl acetate Nutrition 0.000 description 123
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 83
- 239000000460 chlorine Substances 0.000 description 83
- 239000012267 brine Substances 0.000 description 78
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 78
- 239000000047 product Substances 0.000 description 77
- 229920006395 saturated elastomer Polymers 0.000 description 76
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 75
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 75
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 69
- 238000003756 stirring Methods 0.000 description 69
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- 238000004587 chromatography analysis Methods 0.000 description 66
- 238000001819 mass spectrum Methods 0.000 description 64
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 52
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 52
- 239000012043 crude product Substances 0.000 description 50
- 238000000921 elemental analysis Methods 0.000 description 49
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 48
- 239000000284 extract Substances 0.000 description 44
- 239000011734 sodium Substances 0.000 description 42
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 39
- 239000000725 suspension Substances 0.000 description 39
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 38
- 239000000706 filtrate Substances 0.000 description 36
- 239000012074 organic phase Substances 0.000 description 36
- 239000010410 layer Substances 0.000 description 34
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 33
- WDYVUKGVKRZQNM-UHFFFAOYSA-N 6-phosphonohexylphosphonic acid Chemical compound OP(O)(=O)CCCCCCP(O)(O)=O WDYVUKGVKRZQNM-UHFFFAOYSA-N 0.000 description 33
- 238000001816 cooling Methods 0.000 description 31
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 31
- WGNSGQNASYNCBU-VKHMYHEASA-N (3s)-4-bromo-3-hydroxybutanoic acid Chemical compound BrC[C@@H](O)CC(O)=O WGNSGQNASYNCBU-VKHMYHEASA-N 0.000 description 29
- 229960000583 acetic acid Drugs 0.000 description 29
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- 238000005160 1H NMR spectroscopy Methods 0.000 description 27
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 26
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- 150000001299 aldehydes Chemical class 0.000 description 26
- FMSFYLBGEMAMPE-UHFFFAOYSA-N C#C.O[PH2]=O Chemical compound C#C.O[PH2]=O FMSFYLBGEMAMPE-UHFFFAOYSA-N 0.000 description 25
- 238000005481 NMR spectroscopy Methods 0.000 description 25
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
- 238000010792 warming Methods 0.000 description 23
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- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 21
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 20
- 230000015572 biosynthetic process Effects 0.000 description 20
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- 229910052757 nitrogen Inorganic materials 0.000 description 20
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- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 13
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- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 12
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- 238000012360 testing method Methods 0.000 description 11
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- 101150041968 CDC13 gene Proteins 0.000 description 6
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- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 6
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- 238000000746 purification Methods 0.000 description 6
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- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 description 1
- 125000003258 trimethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 238000002525 ultrasonication Methods 0.000 description 1
- 238000002211 ultraviolet spectrum 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
- 238000005292 vacuum distillation Methods 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- ZTWTYVWXUKTLCP-UHFFFAOYSA-N vinylphosphonic acid Chemical compound OP(O)(=O)C=C ZTWTYVWXUKTLCP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/30—Phosphinic acids [R2P(=O)(OH)]; Thiophosphinic acids ; [R2P(=X1)(X2H) (X1, X2 are each independently O, S or Se)]
- C07F9/301—Acyclic saturated acids which can have further substituents on alkyl
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/30—Phosphinic acids [R2P(=O)(OH)]; Thiophosphinic acids ; [R2P(=X1)(X2H) (X1, X2 are each independently O, S or Se)]
- C07F9/302—Acyclic unsaturated acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/30—Phosphinic acids [R2P(=O)(OH)]; Thiophosphinic acids ; [R2P(=X1)(X2H) (X1, X2 are each independently O, S or Se)]
- C07F9/303—Cycloaliphatic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/30—Phosphinic acids [R2P(=O)(OH)]; Thiophosphinic acids ; [R2P(=X1)(X2H) (X1, X2 are each independently O, S or Se)]
- C07F9/306—Arylalkanephosphinic acids, e.g. Ar-(CH2)n-P(=X)(R)(XH), (X = O,S, Se; n>=1)
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/30—Phosphinic acids [R2P(=O)(OH)]; Thiophosphinic acids ; [R2P(=X1)(X2H) (X1, X2 are each independently O, S or Se)]
- C07F9/32—Esters thereof
- C07F9/3205—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/3211—Esters of acyclic saturated acids which can have further substituents on alkyl
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/30—Phosphinic acids [R2P(=O)(OH)]; Thiophosphinic acids ; [R2P(=X1)(X2H) (X1, X2 are each independently O, S or Se)]
- C07F9/32—Esters thereof
- C07F9/3205—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/3217—Esters of acyclic unsaturated acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/30—Phosphinic acids [R2P(=O)(OH)]; Thiophosphinic acids ; [R2P(=X1)(X2H) (X1, X2 are each independently O, S or Se)]
- C07F9/32—Esters thereof
- C07F9/3205—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/3241—Esters of arylalkanephosphinic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/572—Five-membered rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/572—Five-membered rings
- C07F9/5728—Five-membered rings condensed with carbocyclic rings or carbocyclic ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
- C07F9/6503—Five-membered rings
- C07F9/65031—Five-membered rings having the nitrogen atoms in the positions 1 and 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
- C07F9/6503—Five-membered rings
- C07F9/6506—Five-membered rings having the nitrogen atoms in positions 1 and 3
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- Urology & Nephrology (AREA)
- Obesity (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US5323887A | 1987-05-22 | 1987-05-22 | |
US5323887 | 1987-05-22 | ||
US10968187A | 1987-10-19 | 1987-10-19 | |
US10968187 | 1987-10-19 |
Publications (1)
Publication Number | Publication Date |
---|---|
NL8801331A true NL8801331A (nl) | 1988-12-16 |
Family
ID=26731613
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NL8801331A NL8801331A (nl) | 1987-05-22 | 1988-05-24 | Fosfor bevattende remmers van hmg-coa reductase, nieuwe tussenprodukten en werkwijze voor het toepassen daarvan. |
Country Status (24)
Country | Link |
---|---|
JP (1) | JPH01139589A (sv) |
KR (1) | KR880013959A (sv) |
CN (1) | CN1030761A (sv) |
AU (2) | AU610174B2 (sv) |
BE (1) | BE1002251A3 (sv) |
CH (3) | CH678626A5 (sv) |
DE (1) | DE3817298C2 (sv) |
DK (1) | DK277388A (sv) |
ES (1) | ES2009919A6 (sv) |
FI (1) | FI87927C (sv) |
FR (1) | FR2615516B1 (sv) |
GB (1) | GB2205838B (sv) |
GR (1) | GR880100332A (sv) |
HU (1) | HU201085B (sv) |
IE (1) | IE63715B1 (sv) |
IL (1) | IL86463A (sv) |
IT (1) | IT1217684B (sv) |
NL (1) | NL8801331A (sv) |
NO (1) | NO882219L (sv) |
NZ (1) | NZ224734A (sv) |
PH (2) | PH25581A (sv) |
PL (1) | PL157761B1 (sv) |
PT (1) | PT87540B (sv) |
SE (3) | SE501541C2 (sv) |
Families Citing this family (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU610591B2 (en) * | 1987-05-22 | 1991-05-23 | E.R. Squibb & Sons, Inc. | Phosphorus-containing hmg-coa reductase inhibitors, new intermediates and method |
US5112819A (en) * | 1989-10-10 | 1992-05-12 | Glaxo Group Limited | Imidazole derivatives, pharmaceutical compositions and use |
US5025000A (en) * | 1990-03-02 | 1991-06-18 | E. R. Squibb & Sons, Inc. | Phosphorus-containing HMG-CoA reductase inhibitor compounds |
US5124453A (en) * | 1990-03-02 | 1992-06-23 | E. R. Squibb & Sons, Inc. | Process for preparing certain 5,6,7,8-tetrahydroindolizinyl (ethyl or ethynyl)-hydroxy or methoxy-phosphinyl-3-hydroxy-butanoates and derivatives thereof |
CA2042526A1 (en) * | 1990-06-11 | 1991-12-12 | Adeoye Y. Olukotun | Method for preventing a second heart attack employing an hmg coa reductase inhibitor |
CA2043525A1 (en) * | 1990-06-24 | 1991-12-25 | Donald S. Karanewsky | Phosphorus-containing hmg-coa reductase inhibitors, new intermediates and method |
DE4023308A1 (de) * | 1990-07-21 | 1992-01-23 | Bayer Ag | Substituierte pyrido-oxazine |
DE4025818A1 (de) * | 1990-08-16 | 1992-02-20 | Bayer Ag | Phenylsulfonamid substituierte pyridinalken- und -aminooxyalkancarbonsaeure-derivate |
NZ241574A (en) * | 1991-02-22 | 1993-08-26 | Ishihara Sangyo Kaisha | Substituted phenyl derivatives of hydrazone and pesticidal compositions |
US5202327A (en) * | 1991-07-10 | 1993-04-13 | E. R. Squibb & Sons, Inc. | Phosphorus-containing hmg-coa reductase inhibitors |
US5256692A (en) * | 1992-01-07 | 1993-10-26 | E. R. Squibb & Sons, Inc. | Sulfur-containing HMG-COA reductase inhibitors |
US20010006644A1 (en) | 1997-07-31 | 2001-07-05 | David J. Bova | Combinations of hmg-coa reductase inhibitors and nicotinic acid and methods for treating hyperlipidemia once a day at night |
AU2003218758A1 (en) * | 2002-03-14 | 2003-09-22 | Syngenta Participations Ag | Derivatives of 1-phenyl-3-phenylpyrazole as herbicides |
JP4407237B2 (ja) * | 2002-12-24 | 2010-02-03 | 三菱化学株式会社 | 非水系電解液及びそれを用いる非水系電解液二次電池 |
JP4485169B2 (ja) | 2003-05-16 | 2010-06-16 | 花王株式会社 | 腸管ミネラル吸収能改善剤 |
CN1760363B (zh) * | 2004-10-14 | 2010-04-28 | 蒋继宏 | 杜仲3-羟基-3-甲基戊二酰辅酶a还原酶蛋白编码序列 |
WO2007081019A1 (ja) * | 2006-01-16 | 2007-07-19 | Sankyo Agro Company, Limited | (3-硫黄原子置換フェニル)ピラゾール誘導体 |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR339233A (fr) * | 1903-12-23 | 1905-01-26 | Cyanidgesellschaft Mit Beschra | Nouveau procédé pour l'obtention d'explosifs |
DE803645C (de) * | 1949-10-11 | 1951-04-05 | Dynamit Act Ges Vormals Alfred | Schagwettersichere Sprengkapsel in Verbindung mit elektrischen Zuendern |
DE918196C (de) * | 1952-12-23 | 1954-09-20 | J G W Berckholtz Fa | Masse zur Erzeugung von farbigem Rauch |
US3274035A (en) * | 1964-06-15 | 1966-09-20 | Lohr A Burkardt | Metallic composition for production of hygroscopic smoke |
US3862866A (en) * | 1971-08-02 | 1975-01-28 | Specialty Products Dev Corp | Gas generator composition and method |
DE2841815C2 (de) * | 1978-09-26 | 1985-02-21 | Buck Chemisch-Technische Werke GmbH & Co, 7347 Bad Überkingen | Verfahren zur Herstellung einer Geschoßfüllung |
US4438700A (en) * | 1982-07-19 | 1984-03-27 | The United States Of America As Represented By The Secretary Of The Army | White smoke spotting composition for training ammunition |
FR2596393B1 (fr) * | 1986-04-01 | 1988-06-03 | Sanofi Sa | Derives de l'acide hydroxy-3 dihydroxyoxophosphorio-4 butanoique, leur procede de preparation, leur application comme medicament et les compositions les renfermant |
AU610591B2 (en) * | 1987-05-22 | 1991-05-23 | E.R. Squibb & Sons, Inc. | Phosphorus-containing hmg-coa reductase inhibitors, new intermediates and method |
-
1988
- 1988-05-20 SE SE8801904A patent/SE501541C2/sv not_active IP Right Cessation
- 1988-05-20 PT PT87540A patent/PT87540B/pt not_active IP Right Cessation
- 1988-05-20 IL IL8646388A patent/IL86463A/en not_active IP Right Cessation
- 1988-05-20 ES ES8801611A patent/ES2009919A6/es not_active Expired
- 1988-05-20 GB GB8811931A patent/GB2205838B/en not_active Expired - Fee Related
- 1988-05-20 GR GR880100332A patent/GR880100332A/el unknown
- 1988-05-20 IT IT20681/88A patent/IT1217684B/it active
- 1988-05-20 HU HU882613A patent/HU201085B/hu not_active IP Right Cessation
- 1988-05-20 AU AU16502/88A patent/AU610174B2/en not_active Ceased
- 1988-05-20 PH PH36953A patent/PH25581A/en unknown
- 1988-05-20 DK DK277388A patent/DK277388A/da not_active Application Discontinuation
- 1988-05-20 DE DE3817298A patent/DE3817298C2/de not_active Expired - Fee Related
- 1988-05-20 NZ NZ224734A patent/NZ224734A/en unknown
- 1988-05-20 FI FI882385A patent/FI87927C/sv not_active IP Right Cessation
- 1988-05-20 NO NO882219A patent/NO882219L/no unknown
- 1988-05-20 IE IE154488A patent/IE63715B1/en not_active IP Right Cessation
- 1988-05-21 CN CN88103699A patent/CN1030761A/zh active Pending
- 1988-05-21 KR KR1019880006019A patent/KR880013959A/ko not_active Application Discontinuation
- 1988-05-21 PL PL1988286491A patent/PL157761B1/pl unknown
- 1988-05-23 JP JP63125630A patent/JPH01139589A/ja active Pending
- 1988-05-24 CH CH1463/90A patent/CH678626A5/fr not_active IP Right Cessation
- 1988-05-24 CH CH1462/90A patent/CH678625A5/fr not_active IP Right Cessation
- 1988-05-24 FR FR888806884A patent/FR2615516B1/fr not_active Expired - Fee Related
- 1988-05-24 CH CH1966/88A patent/CH675582A5/fr not_active IP Right Cessation
- 1988-05-24 BE BE8800565A patent/BE1002251A3/fr not_active IP Right Cessation
- 1988-05-24 NL NL8801331A patent/NL8801331A/nl not_active Application Discontinuation
-
1989
- 1989-05-19 PH PH38673A patent/PH26578A/en unknown
-
1991
- 1991-02-21 AU AU71266/91A patent/AU643501B2/en not_active Ceased
-
1992
- 1992-05-14 SE SE9201587A patent/SE9201587D0/sv not_active Application Discontinuation
- 1992-05-20 SE SE9201588A patent/SE9201588A0/sv not_active Application Discontinuation
Also Published As
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