EP0766667A1 - Substituierte azetidinonverbindungen als hypocholesterolemische mittel - Google Patents
Substituierte azetidinonverbindungen als hypocholesterolemische mittelInfo
- Publication number
- EP0766667A1 EP0766667A1 EP95925237A EP95925237A EP0766667A1 EP 0766667 A1 EP0766667 A1 EP 0766667A1 EP 95925237 A EP95925237 A EP 95925237A EP 95925237 A EP95925237 A EP 95925237A EP 0766667 A1 EP0766667 A1 EP 0766667A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- phenyl
- oxo
- trans
- aryl
- azetidinyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- MNFORVFSTILPAW-UHFFFAOYSA-N azetidin-2-one Chemical class O=C1CCN1 MNFORVFSTILPAW-UHFFFAOYSA-N 0.000 title abstract description 16
- 239000003529 anticholesteremic agent Substances 0.000 title abstract description 7
- 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 90
- 150000001875 compounds Chemical class 0.000 claims abstract description 81
- 235000012000 cholesterol Nutrition 0.000 claims abstract description 33
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 32
- 238000000034 method Methods 0.000 claims abstract description 31
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 30
- 239000003112 inhibitor Substances 0.000 claims abstract description 22
- 125000003118 aryl group Chemical group 0.000 claims abstract description 18
- 150000003839 salts Chemical class 0.000 claims abstract description 13
- 239000001257 hydrogen Substances 0.000 claims abstract description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 10
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 9
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 5
- 150000002367 halogens Chemical class 0.000 claims abstract description 5
- 125000002993 cycloalkylene group Chemical group 0.000 claims abstract description 4
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims abstract description 4
- 125000001424 substituent group Chemical group 0.000 claims abstract description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 17
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 16
- -1 4-substituted phenyl Chemical group 0.000 claims description 12
- 201000001320 Atherosclerosis Diseases 0.000 claims description 11
- 239000003937 drug carrier Substances 0.000 claims description 9
- 230000009467 reduction Effects 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 6
- 241000124008 Mammalia Species 0.000 claims description 4
- 230000002265 prevention Effects 0.000 claims description 4
- YRMCNHBNNKOGOA-DQEYMECFSA-N ClC1=CC=C(C=C1)N1[C@H]([C@@H](C1=O)CCOC1=CC=C(C=C1)F)C1=CC=C(C=C1)C(C(=O)OC)=C Chemical compound ClC1=CC=C(C=C1)N1[C@H]([C@@H](C1=O)CCOC1=CC=C(C=C1)F)C1=CC=C(C=C1)C(C(=O)OC)=C YRMCNHBNNKOGOA-DQEYMECFSA-N 0.000 claims description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 2
- JPUJLIFMSYEYBN-XNMGPUDCSA-N methyl 3-[4-[(2s,3r)-1-(4-fluorophenyl)-4-oxo-3-(3-phenylpropyl)azetidin-2-yl]phenyl]propanoate Chemical compound C1=CC(CCC(=O)OC)=CC=C1[C@H]1N(C=2C=CC(F)=CC=2)C(=O)[C@@H]1CCCC1=CC=CC=C1 JPUJLIFMSYEYBN-XNMGPUDCSA-N 0.000 claims 2
- YZKKCEUGKWSCKS-CCMHZHPASA-N (E)-3-[4-[(2S,3R)-1-(4-fluorophenyl)-4-oxo-3-(3-phenylpropyl)azetidin-2-yl]phenyl]prop-2-enoic acid Chemical compound FC1=CC=C(C=C1)N1[C@@H]([C@H](C1=O)CCCC1=CC=CC=C1)C1=CC=C(C=C1)/C=C/C(=O)O YZKKCEUGKWSCKS-CCMHZHPASA-N 0.000 claims 1
- RUIBKXRBANYZKC-JIMLSGQQSA-N C(C)(=O)O.C(C)C1=CC=C(C=C1)[C@H]1N(C([C@@H]1CCCC1=CC=CC=C1)=O)C1=CC=C(C=C1)F Chemical compound C(C)(=O)O.C(C)C1=CC=C(C=C1)[C@H]1N(C([C@@H]1CCCC1=CC=CC=C1)=O)C1=CC=C(C=C1)F RUIBKXRBANYZKC-JIMLSGQQSA-N 0.000 claims 1
- OWYNIKONTOYLMC-BDYUSTAISA-N C1(=CC=CC=C1)N1[C@H]([C@@H](C1=O)CCCC1=CC=CC=C1)C=1C=C(C=CC=1)CCC(=O)OC Chemical compound C1(=CC=CC=C1)N1[C@H]([C@@H](C1=O)CCCC1=CC=CC=C1)C=1C=C(C=CC=1)CCC(=O)OC OWYNIKONTOYLMC-BDYUSTAISA-N 0.000 claims 1
- FUGYGVRJDOXLCO-BDYUSTAISA-N COC1=CC=C(C=C1)N1[C@H]([C@@H](C1=O)CCCC1=CC=CC=C1)C1=CC=C(C=C1)CC(=O)OC Chemical compound COC1=CC=C(C=C1)N1[C@H]([C@@H](C1=O)CCCC1=CC=CC=C1)C1=CC=C(C=C1)CC(=O)OC FUGYGVRJDOXLCO-BDYUSTAISA-N 0.000 claims 1
- PXMIQFARRIZZDX-BDYUSTAISA-N COC1=CC=C(C=C1)N1[C@H]([C@@H](C1=O)CCCC1=CC=CC=C1)C1=CC=C(C=C1)CCC(=O)O Chemical compound COC1=CC=C(C=C1)N1[C@H]([C@@H](C1=O)CCCC1=CC=CC=C1)C1=CC=C(C=C1)CCC(=O)O PXMIQFARRIZZDX-BDYUSTAISA-N 0.000 claims 1
- SBEJWWXTKUMFLD-BDYUSTAISA-N FC1=CC=C(C=C1)N1[C@H]([C@@H](C1=O)CCCC1=CC=CC=C1)C1=CC=C(C=C1)C=CC(=O)OC Chemical compound FC1=CC=C(C=C1)N1[C@H]([C@@H](C1=O)CCCC1=CC=CC=C1)C1=CC=C(C=C1)C=CC(=O)OC SBEJWWXTKUMFLD-BDYUSTAISA-N 0.000 claims 1
- VHNAMJILPLUEMS-XCZPVHLTSA-N methyl 3-[4-[(2R,3S)-1-(4-methoxyphenyl)-4-oxo-3-(3-phenylpropyl)azetidin-2-yl]phenyl]prop-2-enoate Chemical compound COC1=CC=C(C=C1)N1[C@H]([C@@H](C1=O)CCCC1=CC=CC=C1)C1=CC=C(C=C1)C=CC(=O)OC VHNAMJILPLUEMS-XCZPVHLTSA-N 0.000 claims 1
- YDBAAXKMLWWEOT-XCZPVHLTSA-N methyl 3-[4-[(2R,3S)-1-(4-methoxyphenyl)-4-oxo-3-(3-phenylpropyl)azetidin-2-yl]phenyl]propanoate Chemical compound COC(=O)CCc1ccc(cc1)[C@H]1[C@H](CCCc2ccccc2)C(=O)N1c1ccc(OC)cc1 YDBAAXKMLWWEOT-XCZPVHLTSA-N 0.000 claims 1
- YNSUSYHVGWMPGV-PQHLKRTFSA-N n,n-diethyl-3-[4-[(2s,3r)-1-(4-fluorophenyl)-4-oxo-3-(3-phenylpropyl)azetidin-2-yl]phenyl]propanamide Chemical compound C1=CC(CCC(=O)N(CC)CC)=CC=C1[C@H]1N(C=2C=CC(F)=CC=2)C(=O)[C@@H]1CCCC1=CC=CC=C1 YNSUSYHVGWMPGV-PQHLKRTFSA-N 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 85
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 68
- 239000000203 mixture Substances 0.000 description 56
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 50
- 235000019439 ethyl acetate Nutrition 0.000 description 42
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 28
- 239000000047 product Substances 0.000 description 26
- 239000012141 concentrate Substances 0.000 description 25
- 238000003756 stirring Methods 0.000 description 23
- 239000000243 solution Substances 0.000 description 22
- 239000012267 brine Substances 0.000 description 21
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 21
- 239000000377 silicon dioxide Substances 0.000 description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- 239000003921 oil Substances 0.000 description 16
- 235000019198 oils Nutrition 0.000 description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 15
- 239000000284 extract Substances 0.000 description 15
- 239000000843 powder Substances 0.000 description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 238000004587 chromatography analysis Methods 0.000 description 9
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 9
- 238000010791 quenching Methods 0.000 description 9
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- 229940122502 Cholesterol absorption inhibitor Drugs 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
- 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 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
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- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 4
- 108010007622 LDL Lipoproteins Proteins 0.000 description 4
- 102000007330 LDL Lipoproteins Human genes 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 230000003143 atherosclerotic effect Effects 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 150000001840 cholesterol esters Chemical class 0.000 description 4
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- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 4
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- 235000005911 diet Nutrition 0.000 description 3
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- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
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- 230000003902 lesion Effects 0.000 description 3
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 3
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 3
- 229940096701 plain lipid modifying drug hmg coa reductase inhibitors Drugs 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
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- ROMLTSOUSBNAAT-DHIUTWEWSA-N (3r,4s)-4-(4-bromophenyl)-1-(4-fluorophenyl)-3-(3-phenylpropyl)azetidin-2-one Chemical compound C1=CC(F)=CC=C1N1C(=O)[C@H](CCCC=2C=CC=CC=2)[C@H]1C1=CC=C(Br)C=C1 ROMLTSOUSBNAAT-DHIUTWEWSA-N 0.000 description 2
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- VJBOVHAWAZTZQJ-UHFFFAOYSA-N 4-(4-fluorophenoxy)butanoyl chloride Chemical compound FC1=CC=C(OCCCC(Cl)=O)C=C1 VJBOVHAWAZTZQJ-UHFFFAOYSA-N 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
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- 239000003755 preservative agent Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- TVDSBUOJIPERQY-UHFFFAOYSA-N prop-2-yn-1-ol Chemical group OCC#C TVDSBUOJIPERQY-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- JBYXPOFIGCOSSB-UQGDGPGGSA-N rumenic acid Chemical compound CCCCCC\C=C/C=C/CCCCCCCC(O)=O JBYXPOFIGCOSSB-UQGDGPGGSA-N 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 150000003378 silver Chemical class 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 239000000779 smoke Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229940031439 squalene Drugs 0.000 description 1
- TUHBEKDERLKLEC-UHFFFAOYSA-N squalene Natural products CC(=CCCC(=CCCC(=CCCC=C(/C)CCC=C(/C)CC=C(C)C)C)C)C TUHBEKDERLKLEC-UHFFFAOYSA-N 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- QIWRFOJWQSSRJZ-UHFFFAOYSA-N tributyl(ethenyl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C=C QIWRFOJWQSSRJZ-UHFFFAOYSA-N 0.000 description 1
- DFKDOZMCHOGOBR-NCSQYGPNSA-N zaragozic acid A Chemical compound C([C@@H](C)[C@H](OC(C)=O)C(=C)CC[C@]12[C@H](O)[C@H]([C@](O2)(C(O)=O)[C@@](O)([C@H](O1)C(O)=O)C(O)=O)OC(=O)/C=C/[C@@H](C)C[C@@H](C)CC)C1=CC=CC=C1 DFKDOZMCHOGOBR-NCSQYGPNSA-N 0.000 description 1
- DFKDOZMCHOGOBR-UHFFFAOYSA-N zaragozic acid A Natural products O1C(C(O)(C(O2)C(O)=O)C(O)=O)(C(O)=O)C(OC(=O)C=CC(C)CC(C)CC)C(O)C21CCC(=C)C(OC(C)=O)C(C)CC1=CC=CC=C1 DFKDOZMCHOGOBR-UHFFFAOYSA-N 0.000 description 1
- 150000003952 β-lactams Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
- 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
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
- C07D205/085—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams with a nitrogen atom directly attached in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
- C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
-
- 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
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
Definitions
- the regulation of whole-body cholesterol homeostasis in humans and animals involves the regulation of dietary cholesterol and modulation of cholesterol biosynthesis, bile acid biosynthesis and the catabolism of the cholesterol-containing plasma lipoproteins.
- the liver is the major organ responsible for cholesterol biosynthesis and catabolism and for this reason, it is a prime determinant of plasma cholesterol levels.
- the liver is the site of synthesis and secretion of very low density lipoproteins (VLDL) which are subsequently metabolized to low density lipoproteins (LDL) in the circulation.
- VLDL very low density lipoproteins
- LDL low density lipoproteins
- LDL low density lipoproteins
- Step 2 Trans (3R, 4S)-1-(4-fluorophenyl)-4-(4-(3-hydroxy-1-propyl)- phenyl)-3-(3-phenylpropyl)-2-azetidinone:
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US26178594A | 1994-06-20 | 1994-06-20 | |
| US261785 | 1994-06-20 | ||
| PCT/US1995/007117 WO1995035277A1 (en) | 1994-06-20 | 1995-06-15 | Substituted azetidinone compounds useful as hypocholesterolemic agents |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP0766667A1 true EP0766667A1 (de) | 1997-04-09 |
Family
ID=22994864
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP95925237A Withdrawn EP0766667A1 (de) | 1994-06-20 | 1995-06-15 | Substituierte azetidinonverbindungen als hypocholesterolemische mittel |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP0766667A1 (de) |
| JP (1) | JPH10501811A (de) |
| AU (1) | AU2943095A (de) |
| CA (1) | CA2191455A1 (de) |
| MX (1) | MX9606319A (de) |
| WO (1) | WO1995035277A1 (de) |
Families Citing this family (26)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5633246A (en) * | 1994-11-18 | 1997-05-27 | Schering Corporation | Sulfur-substituted azetidinone compounds useful as hypocholesterolemic agents |
| PL362512A1 (en) | 2000-12-21 | 2004-11-02 | Avantis Pharma Deutschland Gmbh | Diphenyl azetidinone derivatives, method for the production thereof, medicaments containing these compounds, and their use |
| IL156552A0 (en) | 2000-12-21 | 2004-01-04 | Aventis Pharma Gmbh | Diphenyl azetidinone derivatives, method for the production thereof, medicaments containing these compounds, and their use |
| EP1864680A3 (de) * | 2001-01-26 | 2012-03-28 | Schering Corporation | Kombinationen von Peroxisom-Proliferator-aktivierten Rezeptor-(PPAR)-Aktivator(en) und Sterolabsorptionshemmer(n) sowie entsprechende Behandlung für vaskuläre Indikationen |
| AU2006202618B2 (en) * | 2001-01-26 | 2007-04-19 | Organon Llc | Combinations of peroxisome proliferator-activated receptor (PPAR) activator(s) and sterol absorption inhibitor(s) and treatments for vascular indications |
| CN101297969B (zh) * | 2001-01-26 | 2011-03-09 | 先灵公司 | 过氧化物酶体增殖物激活受体(ppar)活化剂和甾醇吸收抑制剂的组合药 |
| RU2003126186A (ru) * | 2001-01-26 | 2005-03-10 | Шеринг Корпорейшн (US) | Комбинации ингибитора (ингибиторов) всасывания стерина с сердечно-сосудистым агентом (агентами), предназначенные для лечения патологических состояний сосудов |
| AU2006203175B2 (en) * | 2001-01-26 | 2008-07-24 | Organon Llc | Combinations of peroxisome proliferator-activated receptor (PPAR) activators(s) and sterol absorption inhibitors(s) and treatments for vascular indications |
| AU2007201970B2 (en) * | 2001-01-26 | 2008-04-17 | Organon Llc | Combinations of peroxisome proliferator-activated receptor (PPAR) activator(s) and sterol absorption inhibitor(s) and treatments for vascular indications |
| WO2002058685A2 (en) * | 2001-01-26 | 2002-08-01 | Schering Corporation | Combinations of nicotinic acid and derivatives thereof and sterol absorption inhibitor(s) and treatments for vascular indications |
| TWI337083B (en) * | 2001-01-26 | 2011-02-11 | Schering Corp | Combinations of peroxisome proliferator-activated receptor (ppar) activator(s) and sterol absorption inhibitor(s) and treatments for vascular indications |
| CA2434504A1 (en) * | 2001-01-26 | 2002-08-01 | Teddy Kosoglou | Combinations of sterol absorption inhibitor(s) with blood modifiers for treating vascular conditions |
| EP1911462A3 (de) * | 2001-01-26 | 2011-11-30 | Schering Corporation | Zusammensetzungen enthaltend einen Sterolabsorptionshemmer |
| SI1363668T1 (sl) * | 2001-01-26 | 2007-12-31 | Schering Corp | Kombinacija sekvestranta(-ov) in zaviralca(-ev) absorpcije sterola ter zdravljenje vaskularnih indikacij |
| AU2008201609B8 (en) * | 2001-01-26 | 2009-01-08 | Organon Llc | Combinations of peroxisome proliferator-activated receptor (ppar) activator(s) and sterol absorption inhibitors(s) and treatments for vascular indications |
| GB0215579D0 (en) | 2002-07-05 | 2002-08-14 | Astrazeneca Ab | Chemical compounds |
| AR040588A1 (es) | 2002-07-26 | 2005-04-13 | Schering Corp | Formulacion farmaceutica que comprende un inhibidor de la absorcion del colesterol y un inhibidor de una hmg- co a reductasa |
| BRPI0418004A (pt) | 2003-12-23 | 2007-04-17 | Astrazeneca Ab | composto ou um sal, solvato, solvato de um tal sal ou uma pró-droga deste farmaceuticamente aceitáveis, métodos para tratar ou prevenir condições hiperlipidêmicas, aterosclerose, mal de alzheimer, e tumores associados com colesterol, formulação farmacêutica, combinação, e, processo para preparar um composto ou um sal, solvato, solvato de um tal sal ou uma pró-droga deste farmaceuticamente aceitáveis |
| SA06270191B1 (ar) | 2005-06-22 | 2010-03-29 | استرازينيكا ايه بي | مشتقات من 2- أزيتيدينون جديدة باعتبارها مثبطات لامتصاص الكوليسترول لعلاج حالات فرط نسبة الدهون في الدم |
| TW200806623A (en) * | 2005-10-05 | 2008-02-01 | Merck & Co Inc | Anti-hypercholesterolemic compounds |
| AR060623A1 (es) | 2006-04-27 | 2008-07-02 | Astrazeneca Ab | Compuestos derivados de 2-azetidinona y un metodo de preparacion |
| WO2008108486A1 (ja) | 2007-03-06 | 2008-09-12 | Teijin Pharma Limited | １－ビアリールアゼチジノン誘導体 |
| EP2965752A1 (de) | 2007-12-10 | 2016-01-13 | ratiopharm GmbH | Pharmazeutische formulierung enthaltend ezetimib |
| CA2754384A1 (en) | 2009-03-06 | 2010-09-10 | Lipideon Biotechnology Ag | Pharmaceutical hypocholesterolemic compositions |
| CN101993403B (zh) | 2009-08-11 | 2012-07-11 | 浙江海正药业股份有限公司 | 氮杂环丁酮类化合物及医药应用 |
| WO2015092448A1 (en) * | 2013-12-18 | 2015-06-25 | Rudjer Boskovic Institute | Beta-lactam cholesterol absorption inhibitors |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HUT67341A (en) * | 1991-07-23 | 1995-03-28 | Schering Corp | Substituted beta-lactam compounds useful as hypocholesterolemic agents, pharmaceutical compositions containing the same and process for the production thereof |
| US5631365A (en) * | 1993-09-21 | 1997-05-20 | Schering Corporation | Hydroxy-substituted azetidinone compounds useful as hypocholesterolemic agents |
-
1995
- 1995-06-15 AU AU29430/95A patent/AU2943095A/en not_active Abandoned
- 1995-06-15 JP JP8502289A patent/JPH10501811A/ja active Pending
- 1995-06-15 CA CA002191455A patent/CA2191455A1/en not_active Abandoned
- 1995-06-15 MX MX9606319A patent/MX9606319A/es unknown
- 1995-06-15 EP EP95925237A patent/EP0766667A1/de not_active Withdrawn
- 1995-06-15 WO PCT/US1995/007117 patent/WO1995035277A1/en not_active Application Discontinuation
Non-Patent Citations (1)
| Title |
|---|
| See references of WO9535277A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| WO1995035277A1 (en) | 1995-12-28 |
| MX9606319A (es) | 1997-05-31 |
| CA2191455A1 (en) | 1995-12-28 |
| JPH10501811A (ja) | 1998-02-17 |
| AU2943095A (en) | 1996-01-15 |
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