CA2191455A1 - Substituted azetidinone compounds useful as hypocholesterolemic agents - Google Patents
Substituted azetidinone compounds useful as hypocholesterolemic agentsInfo
- Publication number
- CA2191455A1 CA2191455A1 CA002191455A CA2191455A CA2191455A1 CA 2191455 A1 CA2191455 A1 CA 2191455A1 CA 002191455 A CA002191455 A CA 002191455A CA 2191455 A CA2191455 A CA 2191455A CA 2191455 A1 CA2191455 A1 CA 2191455A1
- Authority
- CA
- Canada
- Prior art keywords
- phenyl
- oxo
- aryl
- trans
- lower alkyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 239000003529 anticholesteremic agent Substances 0.000 title abstract description 3
- MNFORVFSTILPAW-UHFFFAOYSA-N azetidin-2-one Chemical class O=C1CCN1 MNFORVFSTILPAW-UHFFFAOYSA-N 0.000 title abstract description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 83
- 238000000034 method Methods 0.000 claims abstract description 36
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 32
- 239000003112 inhibitor Substances 0.000 claims abstract description 26
- 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 23
- 125000003118 aryl group Chemical group 0.000 claims abstract description 21
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 20
- 150000003839 salts Chemical class 0.000 claims abstract description 13
- 239000001257 hydrogen Substances 0.000 claims abstract description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 10
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 8
- 235000012000 cholesterol Nutrition 0.000 claims abstract description 6
- 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
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 3
- 150000002367 halogens Chemical class 0.000 claims abstract description 3
- 125000001424 substituent group Chemical group 0.000 claims abstract description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract 3
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 24
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 22
- 230000009467 reduction Effects 0.000 claims description 8
- 241000124008 Mammalia Species 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 230000002265 prevention Effects 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims 4
- 201000001320 Atherosclerosis Diseases 0.000 claims 3
- 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
- MGROYOOFJHNERL-ILBGXUMGSA-N 2-[4-[(2s,3r)-1-(4-fluorophenyl)-4-oxo-3-(3-phenylpropyl)azetidin-2-yl]phenyl]acetic acid Chemical compound C1=CC(CC(=O)O)=CC=C1[C@H]1N(C=2C=CC(F)=CC=2)C(=O)[C@@H]1CCCC1=CC=CC=C1 MGROYOOFJHNERL-ILBGXUMGSA-N 0.000 claims 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-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
- 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 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
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims 1
- 239000003814 drug Substances 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
- 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 83
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 58
- 239000000203 mixture Substances 0.000 description 55
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 51
- 235000019439 ethyl acetate Nutrition 0.000 description 41
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 29
- 239000000047 product Substances 0.000 description 26
- 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
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- 239000000377 silicon dioxide Substances 0.000 description 20
- 238000003756 stirring Methods 0.000 description 19
- 239000007832 Na2SO4 Substances 0.000 description 17
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 17
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 17
- 229910052938 sodium sulfate Inorganic materials 0.000 description 17
- 235000011152 sodium sulphate Nutrition 0.000 description 17
- 239000003921 oil Substances 0.000 description 16
- 235000019198 oils Nutrition 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 15
- 239000000284 extract Substances 0.000 description 15
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 13
- 239000000843 powder Substances 0.000 description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 9
- 238000010791 quenching Methods 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- 150000002148 esters Chemical class 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 7
- 239000000460 chlorine Substances 0.000 description 7
- 235000005911 diet Nutrition 0.000 description 7
- 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 7
- 239000007787 solid Substances 0.000 description 7
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 6
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 6
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 6
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N EtOH Substances CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 150000002632 lipids Chemical class 0.000 description 5
- 210000004185 liver Anatomy 0.000 description 5
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 4
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 4
- 208000029078 coronary artery disease Diseases 0.000 description 4
- 230000000378 dietary effect Effects 0.000 description 4
- 239000006260 foam Substances 0.000 description 4
- 239000012458 free base Substances 0.000 description 4
- 239000008187 granular material Substances 0.000 description 4
- -1 hydroxyalkylamlnes Chemical compound 0.000 description 4
- 230000000968 intestinal effect Effects 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 210000002966 serum Anatomy 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- NIBFJPXGNVPNHK-UHFFFAOYSA-N 2,2-difluoro-1,3-benzodioxole-4-carbaldehyde Chemical group C1=CC(C=O)=C2OC(F)(F)OC2=C1 NIBFJPXGNVPNHK-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 230000037213 diet Effects 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 235000013305 food Nutrition 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 3
- 150000002466 imines Chemical class 0.000 description 3
- 230000003902 lesion Effects 0.000 description 3
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-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
- 238000010926 purge Methods 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- VNDYJBBGRKZCSX-UHFFFAOYSA-L zinc bromide Chemical compound Br[Zn]Br VNDYJBBGRKZCSX-UHFFFAOYSA-L 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- BWZVCCNYKMEVEX-UHFFFAOYSA-N 2,4,6-Trimethylpyridine Chemical compound CC1=CC(C)=NC(C)=C1 BWZVCCNYKMEVEX-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 241000282414 Homo sapiens Species 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 239000003810 Jones reagent Substances 0.000 description 2
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 2
- PCZOHLXUXFIOCF-UHFFFAOYSA-N Monacolin X Natural products C12C(OC(=O)C(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 PCZOHLXUXFIOCF-UHFFFAOYSA-N 0.000 description 2
- TUZYXOIXSAXUGO-UHFFFAOYSA-N Pravastatin Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(O)C=C21 TUZYXOIXSAXUGO-UHFFFAOYSA-N 0.000 description 2
- RYMZZMVNJRMUDD-UHFFFAOYSA-N SJ000286063 Natural products C12C(OC(=O)C(C)(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 RYMZZMVNJRMUDD-UHFFFAOYSA-N 0.000 description 2
- WGLPBDUCMAPZCE-UHFFFAOYSA-N Trioxochromium Chemical compound O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 2
- 241000857212 Varanus nebulosus Species 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 229910000085 borane Inorganic materials 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- YNHIGQDRGKUECZ-UHFFFAOYSA-N dichloropalladium;triphenylphosphanium Chemical compound Cl[Pd]Cl.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-N 0.000 description 2
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 2
- 230000002440 hepatic effect Effects 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 230000031891 intestinal absorption Effects 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 229960004844 lovastatin Drugs 0.000 description 2
- PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 description 2
- QLJODMDSTUBWDW-UHFFFAOYSA-N lovastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(C)C=C21 QLJODMDSTUBWDW-UHFFFAOYSA-N 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 238000005192 partition Methods 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 229960002965 pravastatin Drugs 0.000 description 2
- TUZYXOIXSAXUGO-PZAWKZKUSA-N pravastatin Chemical compound C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(O)=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)C[C@H](O)C=C21 TUZYXOIXSAXUGO-PZAWKZKUSA-N 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 229960002855 simvastatin Drugs 0.000 description 2
- RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000001632 sodium acetate Substances 0.000 description 2
- 235000017281 sodium acetate Nutrition 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 235000010265 sodium sulphite Nutrition 0.000 description 2
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
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Classifications
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- 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
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- 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
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- 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
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- 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
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Abstract
Substituted azetidinone hypocholesterolemic agents of formula (I) or a pharmaceutically acceptable salt thereof, wherein: Ar1 is aryl or R3-aryl; Ar2 is aryl or R4-aryl; R1 is selected from the group consisting of -(CH2)q-, wherein q is 2-6; -(CH2)e-Z-(CH2)r-, wherein Z is -O-, -C(O)-, phenylene, -NR10- or -S(O)0-2-, e is 0-5 and r is 0-5, provided that the sum of e and r is 1-6; -(C2-C6 alkenylene)-; and -(CH2)f-V-(CH2)g-, wherein V is C3-C6 cycloalkylene, f is 1-5 and g is 0-5, provided that the sum of f and g is 1-6;
R2 is -(lower alkylene)-COR5 or -(CH=CH)-COR5; R3 and R4 are independently 1-3 substituents selected from lower alkyl, -OR6, -O(CO)R6, -O(CO)OR9, -O(CH2)1-5OR6, -O(CO)NR6R7, -NR6R7, -NR6(CO)R7, -NR6(CO)OR9, -NR6(CO)NR7R8, -NR6SO2R9, -COOR6, -CONR6R7, -COR6, -SO2NR6R7, S(O)0-2R9, -O(CH2)1-10-COOR6, -O(CH2)1-10CONR6R7, -(lower alkylene)-COOR6, -CH=CH-COOR6, -CF3, -CN, -NO2 and halogen;
R5 is -OR or -NRR12; R, R6, R7, R8 and R12 are independently selected from hydrogen, lower alkyl, aryl and aryl-substituted lower alkyl; R9 is lower alkyl, aryl or aryl-substituted lower alkyl; and R10 is hydrogen, lower alkyl, aryl lower alkyl or -C(O)R6; are disclosed, as well as a method of lowering serum cholesterol by administering said compounds, alone or in combination with a cholesterol biosynthesis inhibitor, and pharmaceutical compositions containing them.
R2 is -(lower alkylene)-COR5 or -(CH=CH)-COR5; R3 and R4 are independently 1-3 substituents selected from lower alkyl, -OR6, -O(CO)R6, -O(CO)OR9, -O(CH2)1-5OR6, -O(CO)NR6R7, -NR6R7, -NR6(CO)R7, -NR6(CO)OR9, -NR6(CO)NR7R8, -NR6SO2R9, -COOR6, -CONR6R7, -COR6, -SO2NR6R7, S(O)0-2R9, -O(CH2)1-10-COOR6, -O(CH2)1-10CONR6R7, -(lower alkylene)-COOR6, -CH=CH-COOR6, -CF3, -CN, -NO2 and halogen;
R5 is -OR or -NRR12; R, R6, R7, R8 and R12 are independently selected from hydrogen, lower alkyl, aryl and aryl-substituted lower alkyl; R9 is lower alkyl, aryl or aryl-substituted lower alkyl; and R10 is hydrogen, lower alkyl, aryl lower alkyl or -C(O)R6; are disclosed, as well as a method of lowering serum cholesterol by administering said compounds, alone or in combination with a cholesterol biosynthesis inhibitor, and pharmaceutical compositions containing them.
Description
W0 95135277 ~ 17 SUBSTITUTED AZETIDINONE COMPOUNDS USEFUL AS
HYPOCHOLESTEROLEMIC AGENTS
BACKGROUND OF THE INVENTION
The present invention relates to .sllhstitllted ~:ti~i"ones useful as hypocholsble~lu~ c agents in the treatment and prevention of 1 5 dll lel us~ Ubib, and to the CC~ J;I ldiiui l of a sl Ihstitl l --~ d ~ i"~l~e of this invention and a ~,I ,olebl-;rul biosynthesis inhibitor for the treatment and prevention of dlllelUbCle,u:,ib.
All,eluscle,.: coronary heart disease (CHD) It:u1tls~"15 the major cause for death and cd,.liu~ bcular morbidity in the western world.
20 Risk factors for dll,erubclel.,~ic coronary heart disease include ,ertt:,laiùll, diabetes mellitus, family history, male gender, cigarette smoke and serum ul,~lebl~,ul. Atotal ~:lloleb~ ul level in excess of 225-250 mg/dl is ~I~bU~ d with significant elevation of risk of CHD.
Cholesteryl esters are a major c~",,uone"l of dll,elub.;le,.::
25 lesions and the major storage form of Clloleblt"ul in arterial wall cells.
Formation of ~:IIUl~bltllyl esters is also a key step in the intestinal dLb~l,UliUn of dietary cllùleblt~lul. Thus, inhibition of ~lloleblt~lyl ester formation and reduction of serum .,l ,~lebl~rul is likely to inhibit the plu~u,l~bbi~n of dlllt~luscl~lulic lesion formation, decrease the 30 accumulation of cl~ûlsbl~l~l esters in the arterial wall, and block the intestinal dLb~l,UliUn of dietary .:llOl~bl~lul.
A few ~,~tidil,ùnes have been reported as being useful in lowering ~:IIGl~bl~lul and/or in inhibiting the formation of ul~lebl~lul-containing lesions in l,,d,,,,,,dlial, arterial walls. U.S. 4,983,597 discloses 35 N-sulfonyl-2-d~t;u'i"ones as a,lti~:l,ûleblt,rul~",i~ agents and Ram, et al.,in In~iiAn J. Chem.. Sect. B. 29B. 12 (1990), p. 1134-7, disclose ethyl 4-(2-u~ ,-4-yl)phenoxy ~ .IUd~b as hy~ e",i.; agents. European Patent Publication 264,231 discloses 1-cllhctit~^d-4-phenyl-3-(2-oxo-alkylidene)-2-,~,~lid;"~nes as blood platelet ag,,,~:,,dliùn inhibitors.
wo ss/3s277 21914 5 5 ` ` r~ 7ll7 --European Patent 199,630 and European Patent Application 337,549 disclose elastase inhibitory s~bstitllt~d d~tllid;"ones said to be useful in treating i~,~ldllllll ~y conditions resulting in tissue destnuction which are :~c~ d with various disease states, e.g. dlll~luaCleruaia.
W093/02048, published February 4, 1993, discloses s~ -lactams useful as h~po-,l,oieal6rul~",i~ agents.
The regulation of whole-body .;I "~leal~rul l ,o" ,eo~ld ,i~ in humans and animals involves the regulation of dietary cl,ole ,l~,ul and modulation of cl~ûlealt,,ul biosy~lll,~ais, bile acid Li~sy"ll,asis and the 0 CdtabUI~II of the ul,~ rul-containing plasma li~uupr~ la. The liver is the major organ l~a,uollaibla for cl~ûlaalt,rul biosynthesis and cdld~ûli~
and for this rea~son, it is a prime dt:l~rlllilldlll of plasmâ ~.I,ul~s~rul levels.
The liver is the site of synthesis and secretion of very low density liuou~ul~ills (VLDL) which are subsequently Ill~ ûl;~d to low density li,u~prul~ s (LDL) in the circulation. LDL are the plt~dUlllilldl~l ~;IlOlea~ Ul-carrying li,uupiulei,,a in the plasma and an increase in their cûi,ce"l,dLi~n is correlated with increased dllleluacleluaia.
When intestinal ul~olealelul absorption is reduced, by whatever means, less ~:lloleal~rul is delivered to the liver. The consequence of this action is de~ dsed hepatic lipoprotein (VLDL) production and an increase in the hepatic clearance of plasma leal~,ul, mostly as LDL. Thus, the net effect of inhibiting intestinal ~,I,ùle:,le,,ul d~aOr~: ~ is a decrease in plasma cholesterol levels.
The inhibition of cll~leale,ul biûsyl,ll,a~i~ by 3-hydroxy-3-methylglutaryl coenzyme A ~HMG CoA) reductase (EC1.1.1.34) inhibitors has been shown to be an effective way to reduce plasma ullole (Witzum, Circulation, 80, 5 (1989), p. 1101-1114) and reduce aLilarua11eluai:,. CcJlll~ therapy of an HMG CoA reducta~se inhibltor and a bile acid sequestrant has been d~,,lul~sL,dl~d to be more effective in human hyperli,ui.ie,,,i.; patients than either agent in ,,,ûnull,~,d,uy (Tl" 1!3~ IIII, Dru~s, 36 (Suppl. 3) (1988), p. 63-71).
SUMMARY OF THE INVENTION
Novel hypo~l~ûlealt,,ula,,,i~ compounds of the present invention are ,~,u,~se" ~ by the formula I
W0 95135277 . , . r~ 17 ?191~S5 , ,~ ~s~
~R2 Ar1-R~
`Ar2 or a pharm~s~ salt thereof, wherein:
Ar1 is aryl or R3-s~ r.' aryl;
Ar2 is aryl or R4-sl Ihrt~ aryl;
R1 j5 selected from the sroup consisting of -(CH2)q-, wherein q is 2, 3, 4, 5 or 6;
-(CH2)e-Z-(CH2)r, wherein Z is -O-, -C(O)-, phenylene, -NR10-or -S(O)0 2-, e is 0-5 and r is 0-5, provided that the sum of e and r is 1-6;
-(C2-C6 alkenylene)-; and -(CH2)f-V-(CH2)g-, wherein V is C3-C6 cycloalkylene, f is 1-5 and g is 0-5, provided that the sum of f and 5 is 1-6;
R2 j5 -(lower alkylene)-COR5 or -(CH=CH)-CoR5;
R3 and R4 are i"~e~e,)d~"tly selected from the group consistins of 1-3 substituents i"d~l,end~"lly selected from the sroup consisting of lower alkyl,-OR6,-O(CO)R6,-O(CO)OR9,-O~CH2)1 sOR6,-O(CO)NR6R7, -NR6R7, -NR6(CO)R7, -NR6(CO)OR9, -NR6(CO)NR7R8, -NR6S02R9, -COOR6, -CoNR6R7, -COR6, -So2NR6R7, S(0)o 2R9, -O(CH2)1 10-COOR6,-O(CH2)1 1oCONR6R7,-(loweralkylene)-COOR6, -CH=CH-COOR6, -CF3, -CN, -NO2 and halosen;
R5 is -OR or-NRR12, wherein R and R12 are i,~d~e~ lllly selected from the group consisting of hydrogen, lower alkyl, aryl and aryl-.c,Ih~tit~ d lower alkyl;
R6, R7 and R8 are i"dep~"cl~"lly selected from the group consisting of hydrosen, lower alkyl, aryl and aryl-sl~h~,t;t~t~d lower alkyl;
R9 is lower alkyl, aryl or aryl-Q~h~tit~t~d lower alkyl; and R10 is hydrosen, lower alkyl, aryl lower alkyl or -C(O)R6.
Preferred are compounds of formula I wherein Ar1 is phenyl or R3-sl Ihstit~ ~t~od phenyl, especially (4-R3)-CI Ih~t~ t~d phenyl. Also preferred are compounds of formula I wherein Ar2 is phenyl or R4-Sll' "' '-?C phenyl, especially (4-R4)-sllhstit~ ~d phenyl.
R3, when present, is preferably a halogen. R4, when present, is preferably halosen or -OR6, wherein R6 j5 lower alkyl or W0 ~513!i277 21~14 ~ S ~ s ~ r~ /u7ll7 --hydrogen. Especially preferred are compounds wherein Ar2 jS 4 fluorophenyl.
R1 is preferably -(CH2)q- or-(CH2)e-Z-(CH2)r-, wherein referred values for q are 2 and 3; Z is preferabiy -O-; e is preferably 0;
5 and r is preferably 2.
R2 is preferably in the para-position. When R2 is -(lower alkylene)-COOR5, the lower alkylene portion is preferably methylene or ethylene. R5 is preferably lower alkyl, especially methyl, or hydrogen.
Another group of prefenred compounds is that wherein Ar1 is 10 phenyl or R3-s~hstit~ltRd phenyl, especially (4-R3)-sllhctitllt~Pd phenyl, Ar2 is phenyl or R4-sl~ctitl~ phenyl, especially (4-R4)-c~bstit~lt~ phenyl, and R1 is -(CH2)q- or-(CH2)e-Z-(CH2)r, wherein Z is -O-.
This invention also relates to a method of lowering the senum lil,ol~alerul level in a mammal in need of such treatment Cuill,uliaill~
15 dd~ lial~lilly an effective amount of a compound of formula I. That is, the use of a compound of the present invention as an h~po~:l,ule~l~rule,,,;~, agent is also claimed.
In still another aspect, the present invention relates to a pl1d""acdutical ~û~uoaitiùn cu,,,,uli~illu a serum cholesterol-lowering0 effective amount of a compound of fommula I in a pharm~-~RI l~l^AIly e carrier.
The present invention also relates to a method of reducing plasma il ,~leal~rul levels, and to a method of treating or preventing dllle,uacldluais, colll~uliaill~ ddllli~iaLdlilly to a mammal in need of such 25 treatment an effective amount of a C~ il ldli~ll of a Cl lhctitl ltpd ~ lidi"one ~il"~lea~t"ul dLa~,ution inhihitor of formula I and a "I,ol~s~t"ul biosynthesis inhibitor. That is, the present invention relates to the use of a cllh~t;tlltPd d~t~Li~ ol1e cl,oleal~lul abso,u~ion inhibitor of formula I for combined use with a cll~l~sl~ru~ sy"ll,asis inhibitor (and, similarly, use 30 of a cl ,oleatc~rul L,iosy. ,ll ,eai~ inhibitor for combined use with a s~ tPd ,li~i"ol-e ~I,ùle:,lt"ul aLa~l,uliul1 inhibitor of formula I) to treat or prQvent atheruscl~ruais or to reduce plasma ~:I,ùle~ rul levels.
In yet another aspect, the invention relates to a phd""ac~utical cul"poailiùn ~u"~,uriai~9 an effective amount of a 35 substituted d~t,tidi"~ne clloleial~lul abso~ inhibitor of formula 1, a 11,uleal~lul biosynthesis inhibitor, and a pl1dlllla~utically A~ 1e canier. In a final aspect, the invention relates to a kit cu,,,,urlaillg in one container an effective amount of a s~hctit~tPd d~ lune ~:I,ùleal~,ul Woss/3s277 lsl lSs ; - P ~ 7 db~ull ~icn inhibitûr of formula I in a pl1a""~e~ plJLr~ carrier, and in a separate container, an effective amount of a ul lultl~ ul biosynthesis inhibitor in a pl~d""~e.~ lly ~ e carrier.
5 DET~II Fn DE.~CRIPTION:
As used herein, the term ~lower alkyl" means straight or branched alkyl chains of 1 to 6 carbon atoms. Similarly, ~lower alkylene"
means a divalent alkyl chain, straight or branched, of 1 to 6 carbon atoms, and ~cycloalkylene" means a divalent cycloalkyl group.
1û "Aryl" means phenyl, naphthyl, indenyl, l~lldllj~Ulld,U~llllyl or indanyl. "Phenylene" means a divalent phenyl group.
~ Halogeno~ refers to fluorine, chlorine, bromine or iodine atoms.
Compounds of the invention have at least one asymmetric 15 carbon atom and therefore all isomers, including el-d"~iu",e,~ and ~iid~l~r~ulllel~ are c~, .Il~uldl~d as being part of this invention. The invention includes d and I isomers in both pure form and in admixture, including racemic mixtures. Isomers can be prepared using c~r,~ iunal techniques, either by reacting chiral starting materials or by separating 2û isomers of a compound of formuia 1. Isomers may also include geometric isomers, e.g. when a doubie bond is present. All such geometric isomers are c~r,l~,,,,uldlt,d for this invention.
Those skilled in the art will ap~":~idl~ that for some compounds of formula 1, one isomer will show greater plldllll~-:o 25 activity than another isomer.
Compounds of the invention with an amino group can form phar",a~;~utically ~c~ e salts with organic and inorganic acids.
Examples of suitable acids for salt formation are l,y~i~u~.lllùli.,, sulfuric, pl~:,,uhol;c, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, 30 ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known to those in the art. The salt is prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt.
The free base form may be ,~el~e.,dl~i by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous sodium 35 ~icd,u~ndle. The free base fonm differs from its respective sait form somewhat in certain physical properties, such as solubility in polar solvents, but the saLt is otherwise equivalent to its respective free base fomm for purposes of the invention.
l;Vo 95/35277 2 1 g ~ 17 Certain compounds of the invention are acidic (e.g., those compounds which possess a carboxyl group). These compounds form pharnl~t~l 'Iy A~C~ e salts with inorganic and orsanic bases.
Examples of such salts are the sodium, potassium, calcium, aluminum, sold and silYer salts. Also included are salts formed with phdl ",àceutically .t ~'.le. amines such as ammonia, alkyl amines, hydroxyalkylamlnes, N-methylglucamine and the like.
Choleaterol biosy"ll,6~ inhibitors for use in the ~""~;"
of the present invention include HMG CoA reductase inhibitors such as lovastatin, pravastatin, fluvastatin, simvastatin, and Cl-981; HMG CoA
synthetase inhibitors, for example L-659,699 ((E,E)-11-[3'R-(hydroxy-methyl)-4'-oxo-2'R-oxetanyl]-3,5,7R-trimethyl-2,4-~",decadi~n~i~ acid);
squalene synthesis inhibitors, for example .sq~ est~tirl 1; and squalene epoxidase inhibitors, for example, NB-598 ((E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-[(3,3'-bithiophen-5-yl)methoxy]benzene-",~ll,and",i"e ll,slluulllc,lid~) and other cl~ol~a~rul biosynthesis inhibitors such as DMP-565. Preferred HMG CoA reductase inhibitors are lovastatin, pravastatin and simvastatin.
Compounds of formula I can be prepared by known methods, for example those described in W093/02048 cited above.
Following are general schematic It~ a~llldliunS of typical procedures;
the examples below provide more detailed desu,, " ~s. Most of the abbreviations are defined in the examples below; those that are not include Pd(OAc)2 (palladium diacetate); Ph3P (triphenyl,ul)oal l,i"e); T~20 (triflic anhydride).
Method A:
Ar1_R1~ Pd(OAC)2, Ph3P Ar1-R~ C02Rs DMF, NaOAc N
O ~N`Ar2 ~,CO2Rs Ar2 Method B:
Ar1-R~10f~ PdlC, EtOAC Ar R~CO2Rs O `Ar2 H2 N~Ar2 Wo 951352~ 21 9 ~ P~
Method C:
Ar1-R~ Tf2O, DMAP Ar R~OTf O N~A 2 Collidine, CH2C12 N~Ar2 Vinyltributyltin, UCI R
Pd(Ph3P)4, Dioxane Nbr2 1) BH3THF, THF 0 C Ar1-R~OH
HYPOCHOLESTEROLEMIC AGENTS
BACKGROUND OF THE INVENTION
The present invention relates to .sllhstitllted ~:ti~i"ones useful as hypocholsble~lu~ c agents in the treatment and prevention of 1 5 dll lel us~ Ubib, and to the CC~ J;I ldiiui l of a sl Ihstitl l --~ d ~ i"~l~e of this invention and a ~,I ,olebl-;rul biosynthesis inhibitor for the treatment and prevention of dlllelUbCle,u:,ib.
All,eluscle,.: coronary heart disease (CHD) It:u1tls~"15 the major cause for death and cd,.liu~ bcular morbidity in the western world.
20 Risk factors for dll,erubclel.,~ic coronary heart disease include ,ertt:,laiùll, diabetes mellitus, family history, male gender, cigarette smoke and serum ul,~lebl~,ul. Atotal ~:lloleb~ ul level in excess of 225-250 mg/dl is ~I~bU~ d with significant elevation of risk of CHD.
Cholesteryl esters are a major c~",,uone"l of dll,elub.;le,.::
25 lesions and the major storage form of Clloleblt"ul in arterial wall cells.
Formation of ~:IIUl~bltllyl esters is also a key step in the intestinal dLb~l,UliUn of dietary cllùleblt~lul. Thus, inhibition of ~lloleblt~lyl ester formation and reduction of serum .,l ,~lebl~rul is likely to inhibit the plu~u,l~bbi~n of dlllt~luscl~lulic lesion formation, decrease the 30 accumulation of cl~ûlsbl~l~l esters in the arterial wall, and block the intestinal dLb~l,UliUn of dietary .:llOl~bl~lul.
A few ~,~tidil,ùnes have been reported as being useful in lowering ~:IIGl~bl~lul and/or in inhibiting the formation of ul~lebl~lul-containing lesions in l,,d,,,,,,dlial, arterial walls. U.S. 4,983,597 discloses 35 N-sulfonyl-2-d~t;u'i"ones as a,lti~:l,ûleblt,rul~",i~ agents and Ram, et al.,in In~iiAn J. Chem.. Sect. B. 29B. 12 (1990), p. 1134-7, disclose ethyl 4-(2-u~ ,-4-yl)phenoxy ~ .IUd~b as hy~ e",i.; agents. European Patent Publication 264,231 discloses 1-cllhctit~^d-4-phenyl-3-(2-oxo-alkylidene)-2-,~,~lid;"~nes as blood platelet ag,,,~:,,dliùn inhibitors.
wo ss/3s277 21914 5 5 ` ` r~ 7ll7 --European Patent 199,630 and European Patent Application 337,549 disclose elastase inhibitory s~bstitllt~d d~tllid;"ones said to be useful in treating i~,~ldllllll ~y conditions resulting in tissue destnuction which are :~c~ d with various disease states, e.g. dlll~luaCleruaia.
W093/02048, published February 4, 1993, discloses s~ -lactams useful as h~po-,l,oieal6rul~",i~ agents.
The regulation of whole-body .;I "~leal~rul l ,o" ,eo~ld ,i~ in humans and animals involves the regulation of dietary cl,ole ,l~,ul and modulation of cl~ûlealt,,ul biosy~lll,~ais, bile acid Li~sy"ll,asis and the 0 CdtabUI~II of the ul,~ rul-containing plasma li~uupr~ la. The liver is the major organ l~a,uollaibla for cl~ûlaalt,rul biosynthesis and cdld~ûli~
and for this rea~son, it is a prime dt:l~rlllilldlll of plasmâ ~.I,ul~s~rul levels.
The liver is the site of synthesis and secretion of very low density liuou~ul~ills (VLDL) which are subsequently Ill~ ûl;~d to low density li,u~prul~ s (LDL) in the circulation. LDL are the plt~dUlllilldl~l ~;IlOlea~ Ul-carrying li,uupiulei,,a in the plasma and an increase in their cûi,ce"l,dLi~n is correlated with increased dllleluacleluaia.
When intestinal ul~olealelul absorption is reduced, by whatever means, less ~:lloleal~rul is delivered to the liver. The consequence of this action is de~ dsed hepatic lipoprotein (VLDL) production and an increase in the hepatic clearance of plasma leal~,ul, mostly as LDL. Thus, the net effect of inhibiting intestinal ~,I,ùle:,le,,ul d~aOr~: ~ is a decrease in plasma cholesterol levels.
The inhibition of cll~leale,ul biûsyl,ll,a~i~ by 3-hydroxy-3-methylglutaryl coenzyme A ~HMG CoA) reductase (EC1.1.1.34) inhibitors has been shown to be an effective way to reduce plasma ullole (Witzum, Circulation, 80, 5 (1989), p. 1101-1114) and reduce aLilarua11eluai:,. CcJlll~ therapy of an HMG CoA reducta~se inhibltor and a bile acid sequestrant has been d~,,lul~sL,dl~d to be more effective in human hyperli,ui.ie,,,i.; patients than either agent in ,,,ûnull,~,d,uy (Tl" 1!3~ IIII, Dru~s, 36 (Suppl. 3) (1988), p. 63-71).
SUMMARY OF THE INVENTION
Novel hypo~l~ûlealt,,ula,,,i~ compounds of the present invention are ,~,u,~se" ~ by the formula I
W0 95135277 . , . r~ 17 ?191~S5 , ,~ ~s~
~R2 Ar1-R~
`Ar2 or a pharm~s~ salt thereof, wherein:
Ar1 is aryl or R3-s~ r.' aryl;
Ar2 is aryl or R4-sl Ihrt~ aryl;
R1 j5 selected from the sroup consisting of -(CH2)q-, wherein q is 2, 3, 4, 5 or 6;
-(CH2)e-Z-(CH2)r, wherein Z is -O-, -C(O)-, phenylene, -NR10-or -S(O)0 2-, e is 0-5 and r is 0-5, provided that the sum of e and r is 1-6;
-(C2-C6 alkenylene)-; and -(CH2)f-V-(CH2)g-, wherein V is C3-C6 cycloalkylene, f is 1-5 and g is 0-5, provided that the sum of f and 5 is 1-6;
R2 j5 -(lower alkylene)-COR5 or -(CH=CH)-CoR5;
R3 and R4 are i"~e~e,)d~"tly selected from the group consistins of 1-3 substituents i"d~l,end~"lly selected from the sroup consisting of lower alkyl,-OR6,-O(CO)R6,-O(CO)OR9,-O~CH2)1 sOR6,-O(CO)NR6R7, -NR6R7, -NR6(CO)R7, -NR6(CO)OR9, -NR6(CO)NR7R8, -NR6S02R9, -COOR6, -CoNR6R7, -COR6, -So2NR6R7, S(0)o 2R9, -O(CH2)1 10-COOR6,-O(CH2)1 1oCONR6R7,-(loweralkylene)-COOR6, -CH=CH-COOR6, -CF3, -CN, -NO2 and halosen;
R5 is -OR or-NRR12, wherein R and R12 are i,~d~e~ lllly selected from the group consisting of hydrogen, lower alkyl, aryl and aryl-.c,Ih~tit~ d lower alkyl;
R6, R7 and R8 are i"dep~"cl~"lly selected from the group consisting of hydrosen, lower alkyl, aryl and aryl-sl~h~,t;t~t~d lower alkyl;
R9 is lower alkyl, aryl or aryl-Q~h~tit~t~d lower alkyl; and R10 is hydrosen, lower alkyl, aryl lower alkyl or -C(O)R6.
Preferred are compounds of formula I wherein Ar1 is phenyl or R3-sl Ihstit~ ~t~od phenyl, especially (4-R3)-CI Ih~t~ t~d phenyl. Also preferred are compounds of formula I wherein Ar2 is phenyl or R4-Sll' "' '-?C phenyl, especially (4-R4)-sllhstit~ ~d phenyl.
R3, when present, is preferably a halogen. R4, when present, is preferably halosen or -OR6, wherein R6 j5 lower alkyl or W0 ~513!i277 21~14 ~ S ~ s ~ r~ /u7ll7 --hydrogen. Especially preferred are compounds wherein Ar2 jS 4 fluorophenyl.
R1 is preferably -(CH2)q- or-(CH2)e-Z-(CH2)r-, wherein referred values for q are 2 and 3; Z is preferabiy -O-; e is preferably 0;
5 and r is preferably 2.
R2 is preferably in the para-position. When R2 is -(lower alkylene)-COOR5, the lower alkylene portion is preferably methylene or ethylene. R5 is preferably lower alkyl, especially methyl, or hydrogen.
Another group of prefenred compounds is that wherein Ar1 is 10 phenyl or R3-s~hstit~ltRd phenyl, especially (4-R3)-sllhctitllt~Pd phenyl, Ar2 is phenyl or R4-sl~ctitl~ phenyl, especially (4-R4)-c~bstit~lt~ phenyl, and R1 is -(CH2)q- or-(CH2)e-Z-(CH2)r, wherein Z is -O-.
This invention also relates to a method of lowering the senum lil,ol~alerul level in a mammal in need of such treatment Cuill,uliaill~
15 dd~ lial~lilly an effective amount of a compound of formula I. That is, the use of a compound of the present invention as an h~po~:l,ule~l~rule,,,;~, agent is also claimed.
In still another aspect, the present invention relates to a pl1d""acdutical ~û~uoaitiùn cu,,,,uli~illu a serum cholesterol-lowering0 effective amount of a compound of fommula I in a pharm~-~RI l~l^AIly e carrier.
The present invention also relates to a method of reducing plasma il ,~leal~rul levels, and to a method of treating or preventing dllle,uacldluais, colll~uliaill~ ddllli~iaLdlilly to a mammal in need of such 25 treatment an effective amount of a C~ il ldli~ll of a Cl lhctitl ltpd ~ lidi"one ~il"~lea~t"ul dLa~,ution inhihitor of formula I and a "I,ol~s~t"ul biosynthesis inhibitor. That is, the present invention relates to the use of a cllh~t;tlltPd d~t~Li~ ol1e cl,oleal~lul abso,u~ion inhibitor of formula I for combined use with a cll~l~sl~ru~ sy"ll,asis inhibitor (and, similarly, use 30 of a cl ,oleatc~rul L,iosy. ,ll ,eai~ inhibitor for combined use with a s~ tPd ,li~i"ol-e ~I,ùle:,lt"ul aLa~l,uliul1 inhibitor of formula I) to treat or prQvent atheruscl~ruais or to reduce plasma ~:I,ùle~ rul levels.
In yet another aspect, the invention relates to a phd""ac~utical cul"poailiùn ~u"~,uriai~9 an effective amount of a 35 substituted d~t,tidi"~ne clloleial~lul abso~ inhibitor of formula 1, a 11,uleal~lul biosynthesis inhibitor, and a pl1dlllla~utically A~ 1e canier. In a final aspect, the invention relates to a kit cu,,,,urlaillg in one container an effective amount of a s~hctit~tPd d~ lune ~:I,ùleal~,ul Woss/3s277 lsl lSs ; - P ~ 7 db~ull ~icn inhibitûr of formula I in a pl1a""~e~ plJLr~ carrier, and in a separate container, an effective amount of a ul lultl~ ul biosynthesis inhibitor in a pl~d""~e.~ lly ~ e carrier.
5 DET~II Fn DE.~CRIPTION:
As used herein, the term ~lower alkyl" means straight or branched alkyl chains of 1 to 6 carbon atoms. Similarly, ~lower alkylene"
means a divalent alkyl chain, straight or branched, of 1 to 6 carbon atoms, and ~cycloalkylene" means a divalent cycloalkyl group.
1û "Aryl" means phenyl, naphthyl, indenyl, l~lldllj~Ulld,U~llllyl or indanyl. "Phenylene" means a divalent phenyl group.
~ Halogeno~ refers to fluorine, chlorine, bromine or iodine atoms.
Compounds of the invention have at least one asymmetric 15 carbon atom and therefore all isomers, including el-d"~iu",e,~ and ~iid~l~r~ulllel~ are c~, .Il~uldl~d as being part of this invention. The invention includes d and I isomers in both pure form and in admixture, including racemic mixtures. Isomers can be prepared using c~r,~ iunal techniques, either by reacting chiral starting materials or by separating 2û isomers of a compound of formuia 1. Isomers may also include geometric isomers, e.g. when a doubie bond is present. All such geometric isomers are c~r,l~,,,,uldlt,d for this invention.
Those skilled in the art will ap~":~idl~ that for some compounds of formula 1, one isomer will show greater plldllll~-:o 25 activity than another isomer.
Compounds of the invention with an amino group can form phar",a~;~utically ~c~ e salts with organic and inorganic acids.
Examples of suitable acids for salt formation are l,y~i~u~.lllùli.,, sulfuric, pl~:,,uhol;c, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, 30 ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known to those in the art. The salt is prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt.
The free base form may be ,~el~e.,dl~i by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous sodium 35 ~icd,u~ndle. The free base fonm differs from its respective sait form somewhat in certain physical properties, such as solubility in polar solvents, but the saLt is otherwise equivalent to its respective free base fomm for purposes of the invention.
l;Vo 95/35277 2 1 g ~ 17 Certain compounds of the invention are acidic (e.g., those compounds which possess a carboxyl group). These compounds form pharnl~t~l 'Iy A~C~ e salts with inorganic and orsanic bases.
Examples of such salts are the sodium, potassium, calcium, aluminum, sold and silYer salts. Also included are salts formed with phdl ",àceutically .t ~'.le. amines such as ammonia, alkyl amines, hydroxyalkylamlnes, N-methylglucamine and the like.
Choleaterol biosy"ll,6~ inhibitors for use in the ~""~;"
of the present invention include HMG CoA reductase inhibitors such as lovastatin, pravastatin, fluvastatin, simvastatin, and Cl-981; HMG CoA
synthetase inhibitors, for example L-659,699 ((E,E)-11-[3'R-(hydroxy-methyl)-4'-oxo-2'R-oxetanyl]-3,5,7R-trimethyl-2,4-~",decadi~n~i~ acid);
squalene synthesis inhibitors, for example .sq~ est~tirl 1; and squalene epoxidase inhibitors, for example, NB-598 ((E)-N-ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-[(3,3'-bithiophen-5-yl)methoxy]benzene-",~ll,and",i"e ll,slluulllc,lid~) and other cl~ol~a~rul biosynthesis inhibitors such as DMP-565. Preferred HMG CoA reductase inhibitors are lovastatin, pravastatin and simvastatin.
Compounds of formula I can be prepared by known methods, for example those described in W093/02048 cited above.
Following are general schematic It~ a~llldliunS of typical procedures;
the examples below provide more detailed desu,, " ~s. Most of the abbreviations are defined in the examples below; those that are not include Pd(OAc)2 (palladium diacetate); Ph3P (triphenyl,ul)oal l,i"e); T~20 (triflic anhydride).
Method A:
Ar1_R1~ Pd(OAC)2, Ph3P Ar1-R~ C02Rs DMF, NaOAc N
O ~N`Ar2 ~,CO2Rs Ar2 Method B:
Ar1-R~10f~ PdlC, EtOAC Ar R~CO2Rs O `Ar2 H2 N~Ar2 Wo 951352~ 21 9 ~ P~
Method C:
Ar1-R~ Tf2O, DMAP Ar R~OTf O N~A 2 Collidine, CH2C12 N~Ar2 Vinyltributyltin, UCI R
Pd(Ph3P)4, Dioxane Nbr2 1) BH3THF, THF 0 C Ar1-R~OH
2) NaOH, 30% H2O2 N~Ar2 ~COOH
CrO3, H2S4 Arl-Rl~
Acetone ~ ~Ar2 CH3oH~ EDCI Arl-R~l - co2cH3 NMM, HOBT O Ar2 Method D:
A~1_R1~ Pd(Ph3P)4 )~CO2Me N Et3N, CH3CN N~Ar2 Ar2 ~CO2Me ~,CO2Me 6~ CO Me Ar1-R~ 10% Pd/C, H2 ~ 2 `Ar2 EtOAc/MeOH ~ ~Ar2 1~
W0 9~/35277 ~ 5 ~ P~ 17 --- -.a `,. ' Method E:
HO~ CO2Me HO~ CO2H
Ar~-R1~ , , ,~
Ar2 Ar2 MethQd F:
Ar1 R1~ Pd(Ph3P)4, NaOAc \~CO2Me O N~A 2 DMF, ~CO2Me ~Ar2 Method G: ~
SiMe3 Arl- R1y~ (Ph3P)2Pdcl2~ Ar1- R
O `Ar2 _ SlMe3 ~Ar2 ~,SiMe3 Ar~ - Rl~ 1 ) Di~ ,lùl ICAyiJU~ dl ,c, THF Ar~ - R~ CO2H
`Ar2 2) H2O2, NaOH N~A
~ CO2H ~CO2Me Arl-R~ ~JJ MeOH, EDCI, NMM Ar1-R1 ~
I ~ n O ~N`Ar2 HOBT. CH2C12 o4~ - N~A
10 MethQd H:
Ar1-R1~ (Ph3P)2Pdcl2~ Ar~-R~
O `Ar2 Cul, i'P~2NH ~Ar2 W0 95135277 9 ~ 7 117 CH20H ~ (CH2~30H
~ Ar1- R1 Ar1-R~ J~ 10% PdlC, H
Ar1_ ~ Cr~2, 1125O, Ar O N~A acetone ~Ar2 ~,(CH2)2C02H ~cH2)2co2Me Ar~-R1~ 2 MeOH. EDCI. I~MM Ar -R~
O~N`A HOBT, CH2CI2, THF O Ar2 Method l: ~r ~,CH2GO2Et Arl-R~ n-Bu3SnCH2CO2Et Ar1_R1"~
O~ ArZ DMF o~N~Ar MethQd J: Br ,~CO2Me Ar~-R~ ~C02Me, CH3CN Ar1-R
oJ--N~A 2 Pd(Ph3)4, Et3N O~ N~A
~,CO2Me Arl- R1 '~CO2H
Arl-R~ ~ UOH H O ~
o~LN~A, T'HF2 ' o,~N~Ar Method K: (CHz)2C02H ~CH2)2CONEt2 Ar1-R1~ Et2NH, EDCI, NMM Ar1-R
oJ--N~A HOBT. CH2CI2 od~ ~Ar2 ~JO95/35277 ~,.J ~ PCT/US95/07117 ~
Starting compounds for the above reactions are all either coi"",~,.;i '!y available or well known in the art and can be prepared via known methods.
Reactive groups not involved in the above processes can be 5 protected during the reactions with conventional protecting groups which can be removed by standard procedures after the reaction. The following Table 1 shows some typical protecting groups:
Group to be Grr~up to be Protected and Protected Protecting Group -COOH --COOalkyl, -COObenzyl,-COOphenyl _NH / NCOalkyl,~ NCObenzyl,, NCOphenyl ,NCH2OCH2CH2Si(CH3)3 NC(O)OC(CH3)3, cr3 ~N-benzyl, ~NSi(CH3)3, NSi-C(CH)3 --NH2 -N~
o ICH3 --OH --OCH3,--OCH2OCH3, --OSil-C(CH)3 --OSi(CH3)3, or--OCH2phenyl We have found that the compounds of this invention lower senum lipid levels, in particular serum ullol~bl~rul levels. Compounds of this invention have been found to inhibit the intestinal absorption of cl~ rul and to si~ d"lly reduce the formation of liver ~I)olebllilyl esters in animal models. Thus, compounds of this invention a e hy~o~l,olasl~rule",i~ agents by Yirtue of their ability to inhibit the intestinal absorption and/or ~bl~ icdlion of uI)(.lebl~rul; they are, therefore, useful in the treatment and prevention of dll,arusclelusis in mammals, in particular in humans.
The in vivo activity of the compounds of formula I can be d~,.",i"ed by the following procedure:
Wo ss/3s277 ~ r~ 7 In Vivo Assav of I Iy~ ",i.; AQents Usin~ the Hy~erliuid~l,lic H~m~tPr Hamsters are separated into groups of six and given a controlled cl~ol~alalul diet (Purina Chow #5001 containing 0.5%
ul,ol~al~rul) for seven days. Diet consumption is monitored to determine 5 dietary cl,ol~at~rul exposure in the face of test compounds. The animals are dosed with the test compound once daily beginning with the initiation of diet. Dosing is by oral savage of 0.2 mL of com oil alone (control group) or solution (or suspension) of test compound in corn oil. All animals moribund or in poor physical condition are euthanized. Aner 10 seven days, the animals are d,~ ti~ed by intramuscular (IM) injection of ketamine and sacrificed by cle~ n. Blood is collected into vacutainer tubes containing EDTA for plasma lipid analysis and the liver sxcised for tissue lipid analysis Lipid analysis is conducted as per published procedures (Schnitzer-Polokoff, R, et al, Comp Biochem.
Physiol., 99A, 4 (1991), p. 665-670) and data is reported as percent reduction of lipid versus control.
The present invention also relates to a plld""dceutical cur,,~uosiliùn ~U~ UIisil~g a compound of formula I and a ,cl,a""aceutically 2û ,~ carrier. The compounds of formulal can be d.l,ni"i~lt,t,d in any ~;u"~,"'i~ )dl dosage form, preferably an oral dosage form such as a capsule, tablet, powder, cachet, suspension or solution. The formulations and ,uI,d,,,,aceutical c~",,uo~it;ons can be prepared using conventional pharrrl~e~ r Ar~ e excipients and additives and conventional 25 techniques. Such pl,d""aue.ltically ~rcert~hle excipients and additives include non-toxic compatible fillers, binders, .lisi, ~, dllt~, buffers, preservatives, anti-oxidants, lubricants, flavorings, II,iuh~r,e,:7, coloring agents, emulsifiers and the like.
The daily hypocholesteremic dose of a compound of formula 30 I is about 0.1 to about 30 mg/kg of body weight per day, preferably about 0.1 to about 15 ms/kg. For an average body weight of 70kg, the dosage level is therefore from about 5 mg to about 1000 mg of dnug per day, given in a single dose or 2-4 divided doses . The exact dose, however, is d~ ,"~,i"ed by the attending clinician and is depen~"l on the potency of 35 the compound aJ",i"ialt~ , the a~e, weight, condition and response of the patient.
For the co",Li"dli~,)s of this invention wherein the hydroxy h5titll~ 5 a~ ,o~-e is a~l";"i~ in C;u~lUil ) with a ~ ùle~ ul WO 95135277 2 1 9 ~ 4 ~ S PCIIUS9~/~7117 biosynthesis inhibitor, the typica! daily dose of the cllol~altllul biosynthesisinhibitor is 0.1 to 80 mg/kg of Illall,ll, ' -l weight per d2y dd",il,isl~r~d insingle ûr divided dosages, usually once or twice a day: for example, for HMG CoA reductase inhibitors, about 10 to about 40 mg per dose is given 1 to 2 times a day, giYing a total daily dose of about 10 to 80 mg per day, and forthe other .:I~ol~sL~,ul ~ius~"~l,eais inhibitors, about 1 to 1000 mg per dose is given 1 to 2 times a day, giving a total daily dose of about 1 ms to about 2000 mg per day. The exact dose of any cu",,uo,~e"l of the COIllbilld~iùll to be ~II"i"is~ is d~l~""i,)ed by the attending clinician and is d~pQIld~,lt on the potency of the compound acllll;lliaLt:l~d, the age, weight, condition and response of the patient.
Where the cu",,uone"ts of a cul"l.i,~alion are ad",i,~ialt"~d separately, the number of doses of eæh cu",poller,t given per day may not necessd,i!y be the same, e.g. where one cc.""uùne"l may have a greater duration of activity, and will therefore need to be ~I",i"ial~r~d less frequently.
Since the present invention relates to the reduction of plasma cllul~ ,ul levels by treatment with a culllL,ill ti~n of active i~u~l:di~ wherein said active i"~,tdie"La may be a,ll"i"i~L~I~d separately, the invention also relates to combining separate plIdl11 ,a~eutical Cul~ - 15 in kit form. That is, a kit is L;unLt"", ' wherein two separate units are combined: a cl,oleaLt,lul biusy~ esis inhibitor pl,dl",dceutical cullluuailiù~l and a s~hstit~lted ~t~ une cholesterol abâorption inhibitor ph~""aceutical Culll,uoSilioll. The kit will preferably include directions for the a~",i, lia~l~L;oll of the separate cull,,uo"~,fLa. The kit form is particularly advantageous when the separate colllpoi~ellla must be ~IIIlillial~ in different dosage forms (e.g. oral and p~,~"~rdl) or are a.ll"i"i~ ,t,d at different dosage intervals.
Following are examples of preparing compounds of formula 1. The b~ u~llelllially listed is relative aL~ ,LIullli:,LIr unless otherwise noted. The temms cis and trans refer to the relative orie, I ~s at the aLtltiU'ill~1~6 3- and 4-positions unless otherwise indicated.
Example 1 Methvl 4-~1-(4-fluoroDhenvl)-4-oxo-3-(2-(4-fluu,u~her,o~y)-ethyl)-2-"~ljL~en~nRt~
Reflux a solution of 4-formyl ",~ iue" tt (3.0 9,18.3 mmol) and 4-fluoroaniline (2.0 9, 18.3 mmol) in toluene (2ûO mL) -W0 95/35277 P~ 17 , 2191~5S
overnight with azeotropic removal of water via a Dean-Stark trap, monitoring conversion to the cor,~b,uorniing imine by 1H NMR of the crude mixture. Remove the Dean-Stark trap and add n-tributylamine (13.0 mL,54.8 mmol). Add 4-fluolu,uhe,,u,~yL,~Ityryl chloride (27.4 mL, 27.4 mmol, 1M in toluene) slowly and reflux overnight""u,~ i"y consumption of the imine by 1 H NMR. Cool the mixture to room temperature, quench with 1 M
HCI and stir for ~30 min. Dilute the resulting solution with ethyl acetate (EtOAc), wash with 1 M HCI, water and brine, dry over anhydrous NazSO4 and ~,unc~,,l,dLt, to an amber oil. To reduce unreacted starting aldehyde, redissolve the oil in 5û% CH30H/tetrahydrofuran (THF) (10û mL) and add NaBH4 (1.22 9, 32 mmol). After gas evolution ceases (~15 min), quench the reaction with 1 M HCI, dilute with EtOAc, wash with 1 M HCI, water and brine, dry over anhydrous Na2SO4 and col,c~r,l,d~d onto enough silica gel to obtain a free flowing powder. Load this powder onto a ul~ dluyld~l~y column prepacked with 20% EtOAc/hexanes and silica. Elute with 2û%
EtOAc/hexanes to obtain 2.48 9 (31 %) of the title compound as an 8/1 trans/cis mixture. Purify by HPLC (silica gel, 15% EtOAC/hexanes) to obtain pure cis and trans diabl~ru,,,er~.
In a similar manner, prepare the following compound:
1A: Trans 1-(4-methoxyphenyl~-3-(3-vl~en~lv,u~yl)-4-(4-bromoDvhenyl~-2~ L;~ ne.
Exampl~ 2 Tr~ns Methyl 3-[4-~1-(4-MethoxyDhenyl)-4-oxo-3-(3-DhenylDrovYI)-Z-~Pt~ yllDhenyl~-2-Druve~
Add Pd(OAc)2 (û.036 9, 0.16 mol) and triphenylpl~o~,ul,il~e (Ph3P) (0.097 9, 0.32 mmol) to anhydrous .ii",e:lllyll.J""d",ide (DMF) (3 mL) under N2. Stirthe mixture at room temperature until l1~lllo~t:"~us (5 min) and then add to a mixture of the product of Example 1A (3.6 9, 8.8 mmol ), sodium acetate (0.72 9, 8.8 mmol), methyl acrylate (û.79 mL, 8.8 mmol) and DMF (10 ml) under N2. Heat the resulting mixture to 130 C
- overnight. Cool the reaction mixture to room temperature, and partionbetween ether and water. Wash the ether layer with water (5X) and brine, dry over Na2SO4 and conc~"l,dld to an oil. Clllul~ vyla,uh on silica gel (25% EtOAc/hexanes) to obtain 1.27 9 (35%) of the title compound as a colorless oil. MS (El): 455(M+, 17), 306(54), Z15(45), 188(41), 149(100), 91 (68).
. .
WO 9~135277 A ~,~ 7 2191455~
Example 3 Tri~ns methyl 3-~4-[1 -(4-",HII lù~y.,he~ ,yl)-4-oxo-3-(3-Dhenyll~roDyl)-2-~7Ptidinyl]Dhenyll-Druvd, 1. .,.ld Disslove the product of Example 2 (0.35 5, 0.77 mmol) in EtOAc (6 mL) and purge with N2. Add 10% Pd/C (0.082 9), purge the resuHing suspension with H2 and stir under a balloon of H2 for 3 h. Filter the mixture through celite, wash the filter cak~ with EtOAc and Gollce"~ t~
the filtrate to obtain 0.35 9 (100%) of the title compound as a clear oil.
MS (El): 455(M+, 13), 308(31), 217(78),185(25), 149(52), 129(100).
In a similiar manner, prepare:
3A: Tr~ns methyl 3-~(3R. 2S)-4-[1-(4-methoxyphenyl)-4-oxo-
CrO3, H2S4 Arl-Rl~
Acetone ~ ~Ar2 CH3oH~ EDCI Arl-R~l - co2cH3 NMM, HOBT O Ar2 Method D:
A~1_R1~ Pd(Ph3P)4 )~CO2Me N Et3N, CH3CN N~Ar2 Ar2 ~CO2Me ~,CO2Me 6~ CO Me Ar1-R~ 10% Pd/C, H2 ~ 2 `Ar2 EtOAc/MeOH ~ ~Ar2 1~
W0 9~/35277 ~ 5 ~ P~ 17 --- -.a `,. ' Method E:
HO~ CO2Me HO~ CO2H
Ar~-R1~ , , ,~
Ar2 Ar2 MethQd F:
Ar1 R1~ Pd(Ph3P)4, NaOAc \~CO2Me O N~A 2 DMF, ~CO2Me ~Ar2 Method G: ~
SiMe3 Arl- R1y~ (Ph3P)2Pdcl2~ Ar1- R
O `Ar2 _ SlMe3 ~Ar2 ~,SiMe3 Ar~ - Rl~ 1 ) Di~ ,lùl ICAyiJU~ dl ,c, THF Ar~ - R~ CO2H
`Ar2 2) H2O2, NaOH N~A
~ CO2H ~CO2Me Arl-R~ ~JJ MeOH, EDCI, NMM Ar1-R1 ~
I ~ n O ~N`Ar2 HOBT. CH2C12 o4~ - N~A
10 MethQd H:
Ar1-R1~ (Ph3P)2Pdcl2~ Ar~-R~
O `Ar2 Cul, i'P~2NH ~Ar2 W0 95135277 9 ~ 7 117 CH20H ~ (CH2~30H
~ Ar1- R1 Ar1-R~ J~ 10% PdlC, H
Ar1_ ~ Cr~2, 1125O, Ar O N~A acetone ~Ar2 ~,(CH2)2C02H ~cH2)2co2Me Ar~-R1~ 2 MeOH. EDCI. I~MM Ar -R~
O~N`A HOBT, CH2CI2, THF O Ar2 Method l: ~r ~,CH2GO2Et Arl-R~ n-Bu3SnCH2CO2Et Ar1_R1"~
O~ ArZ DMF o~N~Ar MethQd J: Br ,~CO2Me Ar~-R~ ~C02Me, CH3CN Ar1-R
oJ--N~A 2 Pd(Ph3)4, Et3N O~ N~A
~,CO2Me Arl- R1 '~CO2H
Arl-R~ ~ UOH H O ~
o~LN~A, T'HF2 ' o,~N~Ar Method K: (CHz)2C02H ~CH2)2CONEt2 Ar1-R1~ Et2NH, EDCI, NMM Ar1-R
oJ--N~A HOBT. CH2CI2 od~ ~Ar2 ~JO95/35277 ~,.J ~ PCT/US95/07117 ~
Starting compounds for the above reactions are all either coi"",~,.;i '!y available or well known in the art and can be prepared via known methods.
Reactive groups not involved in the above processes can be 5 protected during the reactions with conventional protecting groups which can be removed by standard procedures after the reaction. The following Table 1 shows some typical protecting groups:
Group to be Grr~up to be Protected and Protected Protecting Group -COOH --COOalkyl, -COObenzyl,-COOphenyl _NH / NCOalkyl,~ NCObenzyl,, NCOphenyl ,NCH2OCH2CH2Si(CH3)3 NC(O)OC(CH3)3, cr3 ~N-benzyl, ~NSi(CH3)3, NSi-C(CH)3 --NH2 -N~
o ICH3 --OH --OCH3,--OCH2OCH3, --OSil-C(CH)3 --OSi(CH3)3, or--OCH2phenyl We have found that the compounds of this invention lower senum lipid levels, in particular serum ullol~bl~rul levels. Compounds of this invention have been found to inhibit the intestinal absorption of cl~ rul and to si~ d"lly reduce the formation of liver ~I)olebllilyl esters in animal models. Thus, compounds of this invention a e hy~o~l,olasl~rule",i~ agents by Yirtue of their ability to inhibit the intestinal absorption and/or ~bl~ icdlion of uI)(.lebl~rul; they are, therefore, useful in the treatment and prevention of dll,arusclelusis in mammals, in particular in humans.
The in vivo activity of the compounds of formula I can be d~,.",i"ed by the following procedure:
Wo ss/3s277 ~ r~ 7 In Vivo Assav of I Iy~ ",i.; AQents Usin~ the Hy~erliuid~l,lic H~m~tPr Hamsters are separated into groups of six and given a controlled cl~ol~alalul diet (Purina Chow #5001 containing 0.5%
ul,ol~al~rul) for seven days. Diet consumption is monitored to determine 5 dietary cl,ol~at~rul exposure in the face of test compounds. The animals are dosed with the test compound once daily beginning with the initiation of diet. Dosing is by oral savage of 0.2 mL of com oil alone (control group) or solution (or suspension) of test compound in corn oil. All animals moribund or in poor physical condition are euthanized. Aner 10 seven days, the animals are d,~ ti~ed by intramuscular (IM) injection of ketamine and sacrificed by cle~ n. Blood is collected into vacutainer tubes containing EDTA for plasma lipid analysis and the liver sxcised for tissue lipid analysis Lipid analysis is conducted as per published procedures (Schnitzer-Polokoff, R, et al, Comp Biochem.
Physiol., 99A, 4 (1991), p. 665-670) and data is reported as percent reduction of lipid versus control.
The present invention also relates to a plld""dceutical cur,,~uosiliùn ~U~ UIisil~g a compound of formula I and a ,cl,a""aceutically 2û ,~ carrier. The compounds of formulal can be d.l,ni"i~lt,t,d in any ~;u"~,"'i~ )dl dosage form, preferably an oral dosage form such as a capsule, tablet, powder, cachet, suspension or solution. The formulations and ,uI,d,,,,aceutical c~",,uo~it;ons can be prepared using conventional pharrrl~e~ r Ar~ e excipients and additives and conventional 25 techniques. Such pl,d""aue.ltically ~rcert~hle excipients and additives include non-toxic compatible fillers, binders, .lisi, ~, dllt~, buffers, preservatives, anti-oxidants, lubricants, flavorings, II,iuh~r,e,:7, coloring agents, emulsifiers and the like.
The daily hypocholesteremic dose of a compound of formula 30 I is about 0.1 to about 30 mg/kg of body weight per day, preferably about 0.1 to about 15 ms/kg. For an average body weight of 70kg, the dosage level is therefore from about 5 mg to about 1000 mg of dnug per day, given in a single dose or 2-4 divided doses . The exact dose, however, is d~ ,"~,i"ed by the attending clinician and is depen~"l on the potency of 35 the compound aJ",i"ialt~ , the a~e, weight, condition and response of the patient.
For the co",Li"dli~,)s of this invention wherein the hydroxy h5titll~ 5 a~ ,o~-e is a~l";"i~ in C;u~lUil ) with a ~ ùle~ ul WO 95135277 2 1 9 ~ 4 ~ S PCIIUS9~/~7117 biosynthesis inhibitor, the typica! daily dose of the cllol~altllul biosynthesisinhibitor is 0.1 to 80 mg/kg of Illall,ll, ' -l weight per d2y dd",il,isl~r~d insingle ûr divided dosages, usually once or twice a day: for example, for HMG CoA reductase inhibitors, about 10 to about 40 mg per dose is given 1 to 2 times a day, giYing a total daily dose of about 10 to 80 mg per day, and forthe other .:I~ol~sL~,ul ~ius~"~l,eais inhibitors, about 1 to 1000 mg per dose is given 1 to 2 times a day, giving a total daily dose of about 1 ms to about 2000 mg per day. The exact dose of any cu",,uo,~e"l of the COIllbilld~iùll to be ~II"i"is~ is d~l~""i,)ed by the attending clinician and is d~pQIld~,lt on the potency of the compound acllll;lliaLt:l~d, the age, weight, condition and response of the patient.
Where the cu",,uone"ts of a cul"l.i,~alion are ad",i,~ialt"~d separately, the number of doses of eæh cu",poller,t given per day may not necessd,i!y be the same, e.g. where one cc.""uùne"l may have a greater duration of activity, and will therefore need to be ~I",i"ial~r~d less frequently.
Since the present invention relates to the reduction of plasma cllul~ ,ul levels by treatment with a culllL,ill ti~n of active i~u~l:di~ wherein said active i"~,tdie"La may be a,ll"i"i~L~I~d separately, the invention also relates to combining separate plIdl11 ,a~eutical Cul~ - 15 in kit form. That is, a kit is L;unLt"", ' wherein two separate units are combined: a cl,oleaLt,lul biusy~ esis inhibitor pl,dl",dceutical cullluuailiù~l and a s~hstit~lted ~t~ une cholesterol abâorption inhibitor ph~""aceutical Culll,uoSilioll. The kit will preferably include directions for the a~",i, lia~l~L;oll of the separate cull,,uo"~,fLa. The kit form is particularly advantageous when the separate colllpoi~ellla must be ~IIIlillial~ in different dosage forms (e.g. oral and p~,~"~rdl) or are a.ll"i"i~ ,t,d at different dosage intervals.
Following are examples of preparing compounds of formula 1. The b~ u~llelllially listed is relative aL~ ,LIullli:,LIr unless otherwise noted. The temms cis and trans refer to the relative orie, I ~s at the aLtltiU'ill~1~6 3- and 4-positions unless otherwise indicated.
Example 1 Methvl 4-~1-(4-fluoroDhenvl)-4-oxo-3-(2-(4-fluu,u~her,o~y)-ethyl)-2-"~ljL~en~nRt~
Reflux a solution of 4-formyl ",~ iue" tt (3.0 9,18.3 mmol) and 4-fluoroaniline (2.0 9, 18.3 mmol) in toluene (2ûO mL) -W0 95/35277 P~ 17 , 2191~5S
overnight with azeotropic removal of water via a Dean-Stark trap, monitoring conversion to the cor,~b,uorniing imine by 1H NMR of the crude mixture. Remove the Dean-Stark trap and add n-tributylamine (13.0 mL,54.8 mmol). Add 4-fluolu,uhe,,u,~yL,~Ityryl chloride (27.4 mL, 27.4 mmol, 1M in toluene) slowly and reflux overnight""u,~ i"y consumption of the imine by 1 H NMR. Cool the mixture to room temperature, quench with 1 M
HCI and stir for ~30 min. Dilute the resulting solution with ethyl acetate (EtOAc), wash with 1 M HCI, water and brine, dry over anhydrous NazSO4 and ~,unc~,,l,dLt, to an amber oil. To reduce unreacted starting aldehyde, redissolve the oil in 5û% CH30H/tetrahydrofuran (THF) (10û mL) and add NaBH4 (1.22 9, 32 mmol). After gas evolution ceases (~15 min), quench the reaction with 1 M HCI, dilute with EtOAc, wash with 1 M HCI, water and brine, dry over anhydrous Na2SO4 and col,c~r,l,d~d onto enough silica gel to obtain a free flowing powder. Load this powder onto a ul~ dluyld~l~y column prepacked with 20% EtOAc/hexanes and silica. Elute with 2û%
EtOAc/hexanes to obtain 2.48 9 (31 %) of the title compound as an 8/1 trans/cis mixture. Purify by HPLC (silica gel, 15% EtOAC/hexanes) to obtain pure cis and trans diabl~ru,,,er~.
In a similar manner, prepare the following compound:
1A: Trans 1-(4-methoxyphenyl~-3-(3-vl~en~lv,u~yl)-4-(4-bromoDvhenyl~-2~ L;~ ne.
Exampl~ 2 Tr~ns Methyl 3-[4-~1-(4-MethoxyDhenyl)-4-oxo-3-(3-DhenylDrovYI)-Z-~Pt~ yllDhenyl~-2-Druve~
Add Pd(OAc)2 (û.036 9, 0.16 mol) and triphenylpl~o~,ul,il~e (Ph3P) (0.097 9, 0.32 mmol) to anhydrous .ii",e:lllyll.J""d",ide (DMF) (3 mL) under N2. Stirthe mixture at room temperature until l1~lllo~t:"~us (5 min) and then add to a mixture of the product of Example 1A (3.6 9, 8.8 mmol ), sodium acetate (0.72 9, 8.8 mmol), methyl acrylate (û.79 mL, 8.8 mmol) and DMF (10 ml) under N2. Heat the resulting mixture to 130 C
- overnight. Cool the reaction mixture to room temperature, and partionbetween ether and water. Wash the ether layer with water (5X) and brine, dry over Na2SO4 and conc~"l,dld to an oil. Clllul~ vyla,uh on silica gel (25% EtOAc/hexanes) to obtain 1.27 9 (35%) of the title compound as a colorless oil. MS (El): 455(M+, 17), 306(54), Z15(45), 188(41), 149(100), 91 (68).
. .
WO 9~135277 A ~,~ 7 2191455~
Example 3 Tri~ns methyl 3-~4-[1 -(4-",HII lù~y.,he~ ,yl)-4-oxo-3-(3-Dhenyll~roDyl)-2-~7Ptidinyl]Dhenyll-Druvd, 1. .,.ld Disslove the product of Example 2 (0.35 5, 0.77 mmol) in EtOAc (6 mL) and purge with N2. Add 10% Pd/C (0.082 9), purge the resuHing suspension with H2 and stir under a balloon of H2 for 3 h. Filter the mixture through celite, wash the filter cak~ with EtOAc and Gollce"~ t~
the filtrate to obtain 0.35 9 (100%) of the title compound as a clear oil.
MS (El): 455(M+, 13), 308(31), 217(78),185(25), 149(52), 129(100).
In a similiar manner, prepare:
3A: Tr~ns methyl 3-~(3R. 2S)-4-[1-(4-methoxyphenyl)-4-oxo-
3-~3-vi,e,,yl~ruvyl)-2-~ inyl~Dhenyl]vr~lr)~nnrllH: (prepared from trans methyl 3-[(3R, 2S)-4-[1-(4-1"t:lll.,,~pll~"yl)-4-oxo-3-(3-ph~"yl~.,uf.~1)-2-~H~ .,he"yl]-2-~,uuellodlH, prepared as described in Example 9.
M.p. 91-92C. HRMS calc'd for C2gH31NO4: 457.2252; found 457.2274.
(El): 457(M+, 100), 308(52), 252(59),160(46).
Example 4 Tr~ns Methyl 2-~4-[1-(4-MethoxyDhenyl)-4-oxo-3(R)-(3-DhenylproDyl)-2(S)-,~ i. ,yllullel lyl~Hll ~an,~
Step 1: (5S)-1-(5-Phenyl-1-oxo-pentanyl)-5-p~,e,~ylùxdl~ ne:
Slowly add 5-phenylvaleryl chloride (15.4 9, 78.1 mmol) in CH2C12 (40 mL) via cannula to a 0 C solution of (5S)-5-phenyl-~ " " lone (10.6 9, 65.1 mmol), triethylamine (Et3N) (21.8 mL, 156.2 mmol) and dimethylaminûpyridine (DMAP) (0.56 9, 4.56 mmol) in CH2CI2 (160 mL).
After addition, allow the mixture to warm to room temperature overnight.
Add water and stir the mixture for 30 min.; wash with 1 M HCI, water, NaHCO3 (sat'd), water and brine, dry over anhydrous Na2SO4 and CO~lC~ ldlt, to obtain the title compound of Step 1 as an amber oll, 24.29 (~ 100%).
Step 2:
Add TiCI4 (38 mL, 38 mmol, 1 M in CH2CI2) dropwise to a -40 C
solution of (5S)-1-(5-phenyl-1-oxo-pentanyl)-5-phenyl-~.~dlu~i~i,,one (12.3 5, 38.0 mmol) in CH2CI2 (125 mL) over 10 min. Stir for an additional 35 10 min., then add Hunig's base (13.2 mL, 76 mmol) over 8 min. while Illdill~c~illill9 the temperature at -40 C. Stir the resulting solution for 30 min. Add N-(4-be"~lu,~1,6"~yli.iene)-4-methoxyaniline (21.6 9, 68.2 mmol) in CH2CI2 (450 mL) via cannula over 40 min., again Illdillldilli s'' ~
the reaction l~",~ re at -50 to -40 C. Stir the mixture for 3 h and allow to warm to -20 C. Quench the reaction by slowly adding acetic acid (20 - ml) in CH2CI2 (100 mL), stir the mixture for 30 min. and then pour into a 0 C solution of 2N H2SO4 (500 mL) and EtOAc (500 mL) and stir rapidly 5 for 1 h. Filter the resulting mixture, extract the filtrate with EtOAc, wash the combined extracts with NaHCO3 (sat'd) and brine, dry over Na2SO4 and con~t" ,I, to a beige solid (20 g). Reui y~ " ~ from EtOAc to obtain 8.08 g (34%) of an off white solid.
Step 3: Trans (3R,4S)- 1-(-~ uxy~pller~l)-3-(3-phenylpropyl)-4-(4-1 0 benxylo~ypl~e"yl)-2-d~li(ii.,dl~e.
Add N,O-L.is(llilll~llly;~ l)d..~Ld"lide (4.6 ml, 18.8 mmol) to a 90 C
solution of the product of Step 2 (8.03 9, 12.5 mmol) in toluene (100 mL) and stir for 1 h. Add tetrabutylammonium fluoride (0.16 9, 0.63 mmol) and stir the mixture at 90 C for an additional hour. Cool the mixture to room temperature and quench the reaction with CH30H (10 mL). Dilute the mixture with EtOAc, wash with 1 M HCI, NaHCO3 (sat'd), water and brine, then uui~C~It~ to a white solid. Purify the solid further by oll~u~ y on silica gel (30% EtOAC/hexane) to obtain 5.46 9 (91%) of the title compound of Step 3 as a white solid.
Step 4: Trans (3R,4S)- 1-(-methoxyphenyl)-3-(3-plle,,ylplu,u~l)-4-(4-hydroxyphenyl)-2-A t!lidi~ùlle Hl,u,u~e, a suspension of the product of Step 3 in 50%
CH30H/EtOAc (100 mL) with 1 û% Pd/C (0.42 9) on a Parr aparatus at 60 psi overnight. Filterthe reaction mixture through celite and con~i~"l,dle the filtrate to provide 5 9 of a foam. Purify the foam by silica gel ~:IIlUllldlU~U,ld,U~ly (40-100% EtOAc/hexane) to provide 4.05 9 (92%) of the title compound of Step 4 as a white solid.
Step 5: Trans (3R,4S)- 1-(-,n~ll,u,.ypl~er,yl)-3-(3-phenylpropyl)-4-(4-triflu~rui,,t,~l~al~e~ lfonyl)phenyl)-2-~ lidilldne:
Add trifilic anhydride (0.57 mL, 3.4 mmol) to a 0 C solution of the product of Step 4 (1.2 ~, 3.1 mmol), DMAP (0.1 9) and 2,4,6-collidine (0.44 - mL, 3.4 mmol) in CH2CI2 (15 mL). After 30 min., quench the reaction with water and extract with EtOAc. Combine the extracts, wash with NH4CI
(sat'd), NaHCO3 (sat'd), water and brine, dry over Na2SO4 and concer,l,dl~ to obtain 1.7 9 (100%) of the title compound of Step 5 as an oil.
Step 6: Trans (3R,4S)-1-(4-Methoxyphenyl)- 3-(3-phenylpropyl)-4-(4-vinylphenyl)-2-A,el;ui, ,~"e:
wo ssl3s277 2 1 9 1 ~ ~ 5 ~ P ~
Dissolve the product of Step 5 (1.229, 2.35 mmol) in dioxane (30 mL), add LiCI (0.30 9, 7.04 mmol) and palladium I~L,dki~ i,uller,yl-phosphine (Pd(Ph3P)4) (0.28 9, 0.24 mmol). Add vinyltributyltin (0.83 ml, 2.82 mmol) and heat the mixture to 90 C""on ' ~i"g the reaction by TLC
5 (25% EtOAc/hexanes). Cool the mixture to room temp., treat with 2.5 M KF
(30 mL) and stir the mixture ovennight. Filter the resulting solution, dilut~
with EtOAc, wash with water and brine, dry over Na2SO4 and cOI~c~ laL~
to a yellow oil. Cll~u~ luyld~ull on silica gel (20% EtOAc/hexane) to obtain 0.447 g (50%) of the title compound of Step 6 as an oil.
10 Step 7: Trans Methyl 4-[1-(4-Me,ll,~A~pllellyl)-4-oxo-3(R)-(3-phen propyl)-2(S)-azetidinyl]phenyl-2-ethanol:
Add borane I~I,dl.Jdluf-Jran complex (3.4 mL, 3.4 mmol) to a 0 C
solution of the product of Step 6 (0.45 9, 1.12 mmol) in THF (15 mL) and allow the mixture to wamm to room temperature overnight. Add 2N NaOH
(1.7 ml) followed by 30% H2O2 (1.2 mL) and stir the mixture for 3h.
Quench the mixture by addins 0.8M Na2SO3 solution (2 mL). Extract the mixture ether, wash the etheral extracts with water and brine, dry over Na2SO4 and COIl.~ l Ch~u~ uyldpll on silica (30% EtOAc/hexanes) to obtain 0.18 9 (41%) of the title compound of Step 7 as an oil.
Step 8: Trans Methyl 2-[4-[1~(4-Mt~llu~y,uh~ 1)-4-oxO-3(R)-(3-~1 ,e"y~ul u,uyl)-2(S)-azetidinyl]phenyl]-acetic acid:
Add Jones Reagent (0.4 ml, prepared by dissolving 6.7 9 chromic acid in cu,l~ t,d~t:d H2S04 and diluting with distilled water to 50 mL) to a solution of the product of Step 7 (0.15 9, 0.36 mmol) in acetone (4 mL), ~"oi- i"g the reaction by TLC (5% MeOH/CH2CI2). Add CH30H (2 mL) and stir the mixture for 30 min. Con~;t",l,dl~ the mixture, partition the residue between water and CH2CI2, and extract with CH2CI2. Combine the extracts, wash with Na2SO3 (sat'd), water and brine, dry over Na2SO4 and ,unC~lltldl~ to obtain 0.144 9 (93%) of the title compound of Step 8 as 3û a yellow foam.
Step 9:
Using a well known procedure, add 1-(3-dimethyld",i"op,upyl)-3-yl-;dlL "' "ide l,Jd,u.,l,lûri~ (EDCI) to a solution of the product of Step 8, ethanol, I,,~ ybel,~u~lia~ (HOBT) and N-llle:lllyl~llùl,ul~
(NMM) in CH2CI2 and stir the mixture overnight. Dilute the resulting reaction mixture with CH2CI2, wash with 1 M HCI, water and brine, dry over anhydrous Na2SO4 and cûnc~,ltldle to an oil. C~ulll_ u~ld,ull the residue on silica (3% CH30H/CH2CI2) to obtain 0.090 9 (61 %) of the title _ _ _ _ _ WO 95135277 P~ 17 2~
compound. HRMS calc'd for C2gH2gNO4: 443.2097; found 443.2093.
MS (Cl): 444 (M+1, 100).
- Example 5 TrArls methyl 3-~3-ben7yloxv-4-[1-(4-fluorui~he,,~rl)-4-oxo-3-(3-phenyl-propyl)-2-u,~ r.he,,yll~lu~elln~lle Combine trans-1 -(-flu~,upller,yl)-3-(3-ph~ ,ru,uyl)-4-(4-bromo-2-benx~l~xyphe"yl)-2-~ i"one (0.55 9, 1.û mmol) (prepared according to the procedure of Example 1), triethylamine (0.28 mL, 2.0 mmol), methyl acrylate (0.18 mL, 2.0 mmol) and Pd(Ph3P)4 (0.û58 9, 0.05 mmol) in CH3CN (2 mL) and heat to 80 C over night. Monitor the reaction by TLC
(25% EtOAC/hexane); add methyl acrylate (0.18 mL, 2.0 mmol) and Pd(Ph3P)4 (0.058 9, 0.05 mmol) and heat the mixture for an additional 20 h. at 80 C. Cool the reaction mixture to room temperature, dilute with EtOAc, wash with 0.1 N HCI, water and brine, dry over Na2SO4 and ~ûnc~r~t~dl~. Ch~ullldluyld~uh the residue on silica (20% EtOAc/hexane) to obtain 0.27 9 (48%) of the title compound as a yellow soiid.
5A: In a similar manner, prepare trAns methyl 3-[4-[1-(4-fluorophenyl)-4-oxo-3-(3-phenylpro~Dyl)-2-A7Ptjdinyl~phenyl~Jrupennrllp Example 6 trArls methyl 3-[3-hydroxy-4-[1-(4-fluorophenyl)-4-oxo-3-(3-phenylpropyl)-2-~ yl!~,)l1enyUI"upion~l~
Dissolve the product of Example 5 (û.266 9, 0.48 mmol) in EtOAc (16 mL), dilute with CH30H (2û mL) and purse with N2 Add 20%
Pd/C (0.05 9), purge the mixture with H2 and then stir under a balloon of H2 overnight. Filter the reaction mixture through celite. Wash the filter cake with EtOAc and cu,,c6,,l,dle the filtrate to give 0.156 9 of the title compound as a colorless oil. HRMS calc'd for C2gH2gNO4: M+H
462.2081; found 462.2070. MS (Cl): 462 (M+1,37), 351(17), 293(41), 1 38(1 00).
Example 7 trArls 3-[3-hydroxy-4-[1-r4-flllnrophenyl~-4-oxo-3-(3-phenylDrowV-2-A7~ti~irlyl]Dhen~l]~lu~ A~ir~
Dissolve the product of Example 6 (0.0669, 0.14 mmol) in THF (3 mL), add LiOH (0.04 9, û.86 mmol) and stirthe mixture at room 35 temperature overnight. Acidify the solution to pH 3 with 1 M HCI, dilute with EtOAc, wash with water and brine, dry over Na2SO4 and cu~ rltldL~
to give 0.061 9, (91%) of the title compound as an oil. HRMS calc'd for C27H26NO4F: M+H 448.1924; found 448.1911. (FAB): 444 (M+1,100).
WO 9~135277 , ~ I PCTIUS9~107117 2 1 9 ~
Example 8 Tr~ns Methyl 3-[3-[1-~henyl-4-oxo-3-(3-~henylrDro~yl)-2-çl70tidinyl]c)he" jUvr. ~r~nn:3to ~: Prepare trans 1 -phenyl-3-(3-phenylpropyl)-4-(3-benzyl-oxyphenyl)-2-~ " ,ùne in a manner simiiar to that described in Example 1.
~L2: Using the procedure of Example 4, Step 4, treat the product of Step 1 to obtain trans 1-phenyl-3-(3-phenylpropyl)-4-(3-hydroxyphenyl)-2-~li ;li"o~le.
~: Using the procedure of Example 4, Step 5, treat the product of Step 2 to obtain trans 1-phenyl-3-(3-phenylpropyl)-4-((3-trifluu,ul,,t,ll,;l-sulfonyl))phenyl)-2-~lid;"one .
SteD 4: UsinQ the procedure of Example 5, treat the product of Step 3 to obtain compound 8-1, trans methyl 3-[3-[1-phenyl-4-oxo-3-(3-phenylpropyl)-2-azetidinyl]phenyl]-2-prupe~ ,odle.
Using the procedure of Example 3, treat the product of Step 4 to obtain the title compound (8-2). HRMS calc'd for C2sH29NO3: M+H
428.2226; found 428.2235. MS (Cl): 428 (M+1,100).
Example 9 TrAns (3~ ~)-Methyl 3-[4-[1-(4-methoxyDhenYI)-4-oxo-3-~3-Dhenyl-,Dro~Dyl)-2-~ Dhenyl]-2-~Dru~e, ~ R
Heat the product of Example 4, Step 5 (0.51 9, 0.98 mmol), sodium acetate (0.1 ~,1.1 mmol), DMF (6 mL) and methyl acrylate (0.1 mL, 1.1 mmol) to 130 C. Add Pd(Ph3P)4 (0.1 9, 0.11 mmol) and stir the mixture at 130 C overnight. Cool the mixture to room l~",,ue, ~e, partition between water and ether, and extract with ether. Combine the etheral extracts, wash with water and brine, dry over Na2SO4 and cù~luellllldl~. C~llu~ldluyld~Jh the residue on silica (25% EtOAc/l~e,~dnes) to provide 0.18 g (40%) of the title compound as a clear oil. HRMS calc'd for C2gH2gN04: 455.2097; found 455.2û80. MS (El): 455 (M+,72), 371(40), 306(56), 252(100).
Example 1û
(3S. 2~) trans methyl 4-[1-(4-ul~lu~ulJh~ 1)-4-oxo-3-(2-(4-fluoro-~henoxy~ethyl~-2-~7otirlinylJDhenvl-2-Druoer~ Q (lOA) ~nd (3R. 2S) tr~ns methyl 4-[1-(4-11,1u,u~ e"yl)-4-oxo-3-(2-(4-fluoro-,Dhenoxy)ethyl)-2-~ "yl]~Dhenyl-2-Dro~enn~t~ (10B) Add 4-(4-flu~ruuhe~,u,~y)butyryl chloride (0.72 9. 3.34 mmol) dropwise to a solution of 4-formyl ~ lllyl!JlulJ~nodl~ 4-~illlurudl " ,e imine WO 95/35277 21 91 4 ~ pCTlUSgs/07117 (0.5 9, 1.67 mmol) and Hunis's base (0.87 mL, 5.0 mmol) in dichloro-ethane (46 mL) at 80 C. Reflux the mixture ovemight, cool to room I~,,,,u~, ~re, quench with 1 M HCI and stir for 15 min. Wash the mixture with NaHCO3 (sat'd), water and brine, dry over Na2SO4 and cùnc6, Itld~
5 Ci"u", _ d,ull the residue ûn silica (40% EtOAc/hexane). To remove 4-formyl ~ ll,yi.~ ual~ ~OIItdlll Idlll, dissolve the product in 50%
CH30H/THF and treat with NaBH4 (1.5 g). After 30 min, quench with NH4CI (sat'd), wash with NH4CI (sat'd), water and brine, dry ov0r Na2SO4 and uùnc6lltldi~. C~u~ O d,UII the residue on silica (35%
10 EtOAc/l~e~dn~s) to provide 0.575 (33%) of trans methyl 4-[1-(4-.:I,I~ropi~e,,yl)-4-oxo-3-(2-(4-fluo,uphel~o,~y)ethyl)-2-a_etidinyi]phenyl-2-~c,u~ dle. Resolve the iidal6lulll~la by chiral HPLC (Chiracel AS
column, 30% iau,u,upanol/hexanes, 70 mL/min) to give 0.128 9 compound 10A and 0.139 9 compound 10B.
15 10A: HRMScalc'dforC27H23NO4CI: 480.1378; found480.1378.
(Cl): 480(M+, 100), 215(99).
10B: HRMS calc'd for C27H23NO4CI: 480.1378; found 48û.1369.
(Cl): 480(M+, 88), 215(100).
Example 1 1 Tr~ns 3-~4-~1 -(4-Methoxyphenyl)-4-oxo-3-(3-phenylpropyl)-2-~7Ptir~ ylluher~ lr~J~n~; Arir~
Step 1: Hydrolyze the product of Example 2 according to the procedure described in Example 7 to obtain trans 3-[4-[1-(4-methoxyphenyl)-4-oxo-3-(3-ph~"~l~,,uu~1)-2-a_etidinyl]phenyl]-2-propenoic acid (compound 11-1).
Step 2: 1 Iyd~uyer,d~ the product of Step 1 according to the procedure described in Example 3 to obtain the title compound (11-2). H~MS caic'd for C2gH3~ NO4: M+H 444.2175; found 444.2165. (FAB): 444(M+1, 1 0û).
Example 1 2 Trans Methyl (3R. 2S)-4-[1-(4-fluorophenyl)-4-oxo-3-(3-pl-e"ylv,uvyl)-2-~7~tidinyl]i.~"cel ,evr~ ~n~.~n~
Step 1: Trans (3R, 4S)-1-(4-fluorophenyl)-4-(4-((~,i",t~l,ylailyl)acetylenyl)-phenyl)-3-(3-pll6~ ru,uyl)-2-d~ ol)e:
Heat a mixture of trans (3R, 4S)-1-(4-fluorophenyl)-4-(4-bromo-phenyl)-3-(3-phenylpropyl)-2-d~';di,~ e (0.69 9, 1.57 mmol) (preparedfrom N-(4-u,u,noi~ ylidene)-4-fluulud,,ili,,~ and (5S)-1-(5-phenyl-1-oxo-pentanyl)-5-pl,6";'~ ' "nol~e using the procedure described in steps 2 and 3 of Example 4), (trimethylsilyl)acetylene (0.33 mL, 2.36 mmol), i,is(l,i~ullerly~,llr~a~ull;lle)palladium (Il) chloride ((Ph3P)2PdC12) (0.0559, W09~135277 2191455 r~l,u )ll7 --7 ~
i.~,,~
0.079 mmol) and di;~opru,uyl...,,i, ,e (6 mL) to 80 C. Monitor the reaction by TLC. After 80 min, add additional (trimethylsilyl)acetylene (0.33 mL, 2.36 mmol). After an additional 50 min, cool the mixture to room temperature, filter throush celite and wash the filter cake with CH2C12.
5 Co,)c~r,~,dt~ the fiUrate onto enough silica so that a free flowing powder is obtained. Lûad the resulting powder onto a ~ lU~ u,U,ld~lly column p,~,d..l~d with silica and 10% EtOAc/hexane. Elute with 10%
EtOAc/hexane to obtain 0.595 9 (83%) of the title compound of Step 1 as a light brown solid. MS(FAB): 456 (M+, 100), 318(37), 296(35).
Step 2: Trans (3R, 2S) 4-[1-(4-fluorophenyl)-4-oxo-3-(3-ph~ ,,u,uyl)-2-d~lidil ljll' en~eneac~ acid:
Add cycl~ Adne (1 .û8 mL, 1 û.64 mmol) to a û C solution of borane (5.3 mL, 5.3 mmol, 1 M in THF). Stir at 0 C for 1 h. Dropwise add the product of step 1 (û.485 g, 1.07 mmol) in THF (7.5 mL) and keep the mixture at 0 C overnight (22h). Sequentially add CH30H (0.43 mL), 3N
NaOH (1.06 mL) and 30 % H2O2 (1.2 mL) to the 0 C mixture. Allow the mixture to warm to room tPnlrPratl Ire and stir for 3 h. Pour the mixture into brine and acidify with 1 M HCI. Extract with EtOAc, combine the extracts, wash with water and brine, dry over anhydrous Na2SO4 and ~u,~c~"l, onto ~nough silica that a free flowing powder is obtained. Load the ~esulting powder onto a ~,lllull._~Jyld~u~ly column pr~,ua~ ed with silica and 5% CH3OH/CH2CI2. Elute with 5% CH3OH/CH2CI2 to obtain the title compound of Step 2, 0.227 9 (52%). HRMS calc'd for C26H2sNO3F:
(M+H) 418.1818; found 418.1820. MS(CI): 418 (M+H, 18), 235(29), 145(55), 83(100).
Step 3: Using a procedure similar to that of Example 4, step 9, treat the product of step 3 to obtain the title compound, 0.023 9 (25%). HRMS
calc'd for C28H2gNO3F: (M+H) 446.2131; found 446.2150. MS(CI): 446 (M+H, 1 00), 277(1 3),1 38(44).
3û Exsmpl~ 13 Trans Methyl (3R. 2S)-4-[1-~4-fl~u,uvher,yl)-4-oxo-3-(3-~he,,;l~,uvyl~-2-a7Pt~ ylll~pn~rieGruv~l~n Step 1: Trans (3R, 4S)-1-(4-fluorophenyl)-4-(4-(3-hydroxy-1-propynyl)-phenyl)-3-(3-~ r,~ u~,yl)-2-d~ û~
Use a procedure similar to that of Example 12, Step 1, ~, Ih~ I Iy propargyl alcohol (0.20 mL, 3.49 mmol) for (I,i",~ll"~ l)acetylene and refluxing overnight. Filter and ~ dpl l as in Example 12, Step 1, using a column p,~paci~d with silica and 30% EtOAc/hexane. Elute with W0 95/35277 ~ 17 30% EtOAc/hexane to obtain the title compound of Step 1, 0.73g (75%), as a yellow oil. HRMS calc'd for C27H2sNO2F: (M+H) 414.1869; found 414.1854. MS(CI): 414 (M+H, 72), 259(32), 138(100).
Step 2: Trans (3R, 4S)-1-(4-flu~,oph~"yl)-4-(4-(3-hydroxy-1-propyl)-5 phenyl)-3-(3-plle"yl~ lup~1)-2-~li.li"ùne:
Using the procedure of Example 6, treat the product of Step 1 to obtain 0.42 9 (100%) of the title compound of Step 2. MS(CI): 418 (M I H, 100), 138(55).
Step3: Trans (3R,2S)-4-[1-(4-fluu,u,ùhe,,,rl)-4-oxo-3-(3-pl,~,,y;~,,upyl)-2-10 d~tidillyl;' r~ne~U~Udlluic acid:
Add Jone's Reagent (1.0 mL, prepared as described in Example 4,step 7) to a 0 C solution of the product of Step 2 in acetone (8 mL).
Monitor the reaction by TLC (5% CH3OHICH2CI2). Upon consumption of starting material, quench the reaction by the addition of CH30H and -15 COll-,elllldl~ in vacuo. Dissolve the residue in water, and adjust to pH 13 with NaOH. Extract the resulting solution with ether, acidify the aqueous layer to pH 3 with HCI (conc.) and extract with EtOAc. Combine the extracts, wash with 10% NaHSO3, water and brine, dry over anhydrous Na2S04 and ~;ui~ce~lt~dl~ onto enough silica that a free flowing powder is 20 obtained. Load the resulting powder onto a ull,u,ll _ d,uhy column ~,,t",dcl~ed with silica and 5% CH30H/CH2C12. Elute with 5-8%
CH3OH/CH2CI2 to obtain 0.2439 (53%) of the title compound of Step 3 as a white foam. HRMS calc'd for C27H27NO3F:( M+H) 432.1975; found 432.1 972. MS(CI) : 432 (M+H , 100).
25 Step 4: Using a procedure similar to that of Example 4, step 9, but using THF, treat the product of step 3 to obtain the title compound, û.54 9 (57%).
HRMS calc'd for C2gH2gNO3F: (M+H) 446.2131; found 446.2150.
MS(CI): 446 (M+H, 100), 277(13),138(44).
Exsmple 14 TrAns Etilyl (3R. 2S)-4-[1-(4-fluu,u~he,,~1)-4-oxo-3-(3-Dlle,,ylvru~1)-2-A7Qt~ yl]ben7Qr~e A~t~tQ
Dry ZnBr2 (0.335 9, 1.49 mmol) at 130 C under vacuum overnight, then cool to room temperature under nitrogen. Add a solution of trans (3R, 4S)-1-(4-fluorophenyl)-4-(4-~,u",ùplle"yl)-3-(3-phenyl-35 propyl)-2-~- ~t;~i"~l~e (0Ø50 9, 1.14 mmol) and ethyl 2-tributyltin acetate (0.56 9, 1.49 mmol) in DMF (3 mL) via cannula under nitrogen. Heat the mixture to 80 C. Monitor consumption of starting material by TLC (15%
EtOAclhexane) and upon U~lllr~ , cool to room It7""u- Ire, filter WO 95/35277 2 1 9 1 4 5 5 ~ s 3 P~ 7 through celite, and wash the filter cake with EtOAc. Add 2.5 M KF (10 mL) to the filtrate, stir for 3h, dilute with EtOAc, wash with water and brine, dry over anhydrous Na2SO4 and cor,c6"1,dl~ onto enough silica that a free flowing powder is obtained. Load the resulting powder is loaded onto a 5 ~;I"u", " ~,ul,y column ~,~uac~d with silica and 15% EtOAc/hexane.
Elute with 15% EtOAC/Il~Adlle to obtain the title compound as a yellow oil, 0.4169 (82%). HRMS calc'd for C2gH2gNO3F: (M+H) 446.2131; found 446.2123. MS(FAB): 446 (M+H, 100), 308(18), 286(24).
Example 1 5 Tr~ns ~3R. 2S)-3-[4-~1 -(4-FI~ uuhe, ,yl)-4-oxo-3-(3-r henylDroDyl)-2-;."",~l,er,~ll E-2-~Dro~enoic ~
Step 1: Trans methyl (3R, 2S)-3-[4-[1-(4-fluorophenyl)-4-oxo-3-(3-phenyl-propyl)-2-d~lidi"yl]~ e, Iyl]-E-2-prupen~dld Treat trans (3R, 4S)-1-(4-fluorophenyl)-4-(4-bromophenyl)-3-(3-ph6,,yl~.rupyl)-2-d~ i,,ù,~e methyl acrylate in a manner similar to that described in Example 5 to obtain the title compound of Step 1. HRMS
calc'd for C2gH27NO3F: (M+H) 444.1975; found 444.1971. MS(CI): 444 (M+H, 100).
Step 2: TrQat the product of step 1 as described in Example 7, purifying by ulllullldlu~ ,ully on a column pre:,uaclied with silica and 0.5% HOAc/2.5%
EtOH/97% CH2CI2, eluting with the same eluant to obtain the title compound. HRMS calc'd for C27H2sNO3F: (M+H) 430.1818; found 430.1810. MS(CI): 430 ~M+H, 100), 293(26),177(74). 138(52).
E%ample 1 6 Tr~ns N.N-Diethyl-(3R. 2S)-4-~1-(4-fluoroDhenyl)-4-oxo-3-(3-Dher~yl~roDyl)-2-i~Atidinyl]be"~end~rur~"~";de Add EDCI (0.û58 9, 0.303 mmol) to a mixture of the product of Step 3 of Example 13 (0.092 9, 0.213 mmol), HOBT hydrate (.035 9, 0.256 mmol), NMM (0.û29 mL, 0.277 mmol) and Et2N (0.044 mL, 0.427 mmol) in CH2CI2 (2.5 mL). Stir the resulting mixture overnight until TLC
(50% EtOAc/hexane) indicates consumption of starting material. Dilute the mixture with CH2CI2, wash with 0.2N HCI, water and brine, dry over anhydrous Na2SO4 and Col,C611l,dl~ onto enough silica such that a free flowing powder is obtained. Load the resulting powder is loaded onto a ~:lllu~lldiv5,ld,ully column ~ ~tluacl~6d with silica and 35% EtOAc/hexane.
Elute with 35-50% EtOAc/hexane to obtain an oil which is further purified by silica ~:lllulll_~uuld~lly, eluting with 35-50% EtOAc/hexanes to obtain the title compound, 0.689 (73%), as an oil. MS(CI): 487 (M+, 100), Wo 9sl3s2M 91 qSS P~ 7 350(19), 318(37). HRMS(FAB): calcd. for C31H36N2O2F(M+1), 487.2761;
found 487.2783.
The following formulations exemplify some of the dosage 5 fomms of this invention. In each the term "active compound" d~siy, Id~S a campound of formula I.
FXAMPI F A
[~
No, Ina, re~iPrlt ma/tablet ma,/tablet Active Compound 100 500 2Lactose USP 122 113 3Corn Starch, Food Grade, as a 10% 30 40 paste in Purified Water 4Corn Starch, Food Grade 45 40 5MaQnesium Stearate 3 ~, Total 300 700 10 Method of Man~If~tllre Mix Item Nos. 1 and 2 in suitable mixer for 10-15 minutes.
Granulate the mixture with Itsm No. 3. Mill the damp granules through a coarse screen (e.g., 114", 0.63 cm) if necessary. Dry the damp granules.
Screen the dried granules if necessary and mix with Item No. 4 and mix for 10-15 minutes. Add Item No. 5 and mix for 1-3 minutes. Compress the mixture to ap~.,uprid~a size and weight on a suitable tablet machine.
FXAMPI F B
!;:ap ~s~les No. Inaredient m~ltablet m~/tablet Active Compound 100 500 2Lactose USP 106 123 3Corn Starch, Food Grade 40 70 4Magnesium Stearate NF 4 7 Total 250 700 20 Method of Manl~f~rh~re Mix Item Nos. 1, 2 and 3 in a suitable blender for 10-15 minutes. Add Item No. 4 and mix for 1-3 minutes. Fill the mixture into w09s/3ri277 2~455` r~ 7--suitable two-piece hard gelatin capsules on a suitable erl~rs~ y machine.
Rffp,t,serlLd~h/~ formulations CO~ liailly a uI,oles~, biuay, ,~l ,esis inhibitor are well known in the art. It is cu~ vldLad that 5 where the two active il~y~ ta are a~",i~isl~r~d as a single cul"r ii~ ~, the dosage forms disclosed above for sl ~hstit~ I~Ad i"ui1e compounds may readiiy be modified using the kl,ûJ.~;lye of one skilled in the art.
Using the test procedures described above, the following l~L
yiy~L data were obtained for ,~,ur~ae" ~to compounds of formula 1.
Compounds are referred to by the c~r~:a,uO~i,ly example number; data is reported as percent change (i.e., percent reduction in ~ vl~sLl:,ul esters) Yersus control, therefore, negative numbers indicate a positive lipid-15 lowering effect.
% Recuction Ex. No. Serum Cholesterol Dose Cholesterol Esters mglkg -28 -76 5û
16 û -19 1û
For racemic compounds of formula I or active diaal~ ullltlla or e,~d"liul"era of compounds of formula 1, compounds ad",i";aLff,~d at 2û dosages of 1-50 mg/kg show a range of -97 to -12% reduction in ul)olffal~rul esters, and a-49 to 0% reduction in senum ullultla~fflul. The reductiorl in ~:llùl~a~tllul esters is the more important measure of activit,Y, and active compounds preferably show a range of -3û to -97% reduction in dlùl~ lul esters.
M.p. 91-92C. HRMS calc'd for C2gH31NO4: 457.2252; found 457.2274.
(El): 457(M+, 100), 308(52), 252(59),160(46).
Example 4 Tr~ns Methyl 2-~4-[1-(4-MethoxyDhenyl)-4-oxo-3(R)-(3-DhenylproDyl)-2(S)-,~ i. ,yllullel lyl~Hll ~an,~
Step 1: (5S)-1-(5-Phenyl-1-oxo-pentanyl)-5-p~,e,~ylùxdl~ ne:
Slowly add 5-phenylvaleryl chloride (15.4 9, 78.1 mmol) in CH2C12 (40 mL) via cannula to a 0 C solution of (5S)-5-phenyl-~ " " lone (10.6 9, 65.1 mmol), triethylamine (Et3N) (21.8 mL, 156.2 mmol) and dimethylaminûpyridine (DMAP) (0.56 9, 4.56 mmol) in CH2CI2 (160 mL).
After addition, allow the mixture to warm to room temperature overnight.
Add water and stir the mixture for 30 min.; wash with 1 M HCI, water, NaHCO3 (sat'd), water and brine, dry over anhydrous Na2SO4 and CO~lC~ ldlt, to obtain the title compound of Step 1 as an amber oll, 24.29 (~ 100%).
Step 2:
Add TiCI4 (38 mL, 38 mmol, 1 M in CH2CI2) dropwise to a -40 C
solution of (5S)-1-(5-phenyl-1-oxo-pentanyl)-5-phenyl-~.~dlu~i~i,,one (12.3 5, 38.0 mmol) in CH2CI2 (125 mL) over 10 min. Stir for an additional 35 10 min., then add Hunig's base (13.2 mL, 76 mmol) over 8 min. while Illdill~c~illill9 the temperature at -40 C. Stir the resulting solution for 30 min. Add N-(4-be"~lu,~1,6"~yli.iene)-4-methoxyaniline (21.6 9, 68.2 mmol) in CH2CI2 (450 mL) via cannula over 40 min., again Illdillldilli s'' ~
the reaction l~",~ re at -50 to -40 C. Stir the mixture for 3 h and allow to warm to -20 C. Quench the reaction by slowly adding acetic acid (20 - ml) in CH2CI2 (100 mL), stir the mixture for 30 min. and then pour into a 0 C solution of 2N H2SO4 (500 mL) and EtOAc (500 mL) and stir rapidly 5 for 1 h. Filter the resulting mixture, extract the filtrate with EtOAc, wash the combined extracts with NaHCO3 (sat'd) and brine, dry over Na2SO4 and con~t" ,I, to a beige solid (20 g). Reui y~ " ~ from EtOAc to obtain 8.08 g (34%) of an off white solid.
Step 3: Trans (3R,4S)- 1-(-~ uxy~pller~l)-3-(3-phenylpropyl)-4-(4-1 0 benxylo~ypl~e"yl)-2-d~li(ii.,dl~e.
Add N,O-L.is(llilll~llly;~ l)d..~Ld"lide (4.6 ml, 18.8 mmol) to a 90 C
solution of the product of Step 2 (8.03 9, 12.5 mmol) in toluene (100 mL) and stir for 1 h. Add tetrabutylammonium fluoride (0.16 9, 0.63 mmol) and stir the mixture at 90 C for an additional hour. Cool the mixture to room temperature and quench the reaction with CH30H (10 mL). Dilute the mixture with EtOAc, wash with 1 M HCI, NaHCO3 (sat'd), water and brine, then uui~C~It~ to a white solid. Purify the solid further by oll~u~ y on silica gel (30% EtOAC/hexane) to obtain 5.46 9 (91%) of the title compound of Step 3 as a white solid.
Step 4: Trans (3R,4S)- 1-(-methoxyphenyl)-3-(3-plle,,ylplu,u~l)-4-(4-hydroxyphenyl)-2-A t!lidi~ùlle Hl,u,u~e, a suspension of the product of Step 3 in 50%
CH30H/EtOAc (100 mL) with 1 û% Pd/C (0.42 9) on a Parr aparatus at 60 psi overnight. Filterthe reaction mixture through celite and con~i~"l,dle the filtrate to provide 5 9 of a foam. Purify the foam by silica gel ~:IIlUllldlU~U,ld,U~ly (40-100% EtOAc/hexane) to provide 4.05 9 (92%) of the title compound of Step 4 as a white solid.
Step 5: Trans (3R,4S)- 1-(-,n~ll,u,.ypl~er,yl)-3-(3-phenylpropyl)-4-(4-triflu~rui,,t,~l~al~e~ lfonyl)phenyl)-2-~ lidilldne:
Add trifilic anhydride (0.57 mL, 3.4 mmol) to a 0 C solution of the product of Step 4 (1.2 ~, 3.1 mmol), DMAP (0.1 9) and 2,4,6-collidine (0.44 - mL, 3.4 mmol) in CH2CI2 (15 mL). After 30 min., quench the reaction with water and extract with EtOAc. Combine the extracts, wash with NH4CI
(sat'd), NaHCO3 (sat'd), water and brine, dry over Na2SO4 and concer,l,dl~ to obtain 1.7 9 (100%) of the title compound of Step 5 as an oil.
Step 6: Trans (3R,4S)-1-(4-Methoxyphenyl)- 3-(3-phenylpropyl)-4-(4-vinylphenyl)-2-A,el;ui, ,~"e:
wo ssl3s277 2 1 9 1 ~ ~ 5 ~ P ~
Dissolve the product of Step 5 (1.229, 2.35 mmol) in dioxane (30 mL), add LiCI (0.30 9, 7.04 mmol) and palladium I~L,dki~ i,uller,yl-phosphine (Pd(Ph3P)4) (0.28 9, 0.24 mmol). Add vinyltributyltin (0.83 ml, 2.82 mmol) and heat the mixture to 90 C""on ' ~i"g the reaction by TLC
5 (25% EtOAc/hexanes). Cool the mixture to room temp., treat with 2.5 M KF
(30 mL) and stir the mixture ovennight. Filter the resulting solution, dilut~
with EtOAc, wash with water and brine, dry over Na2SO4 and cOI~c~ laL~
to a yellow oil. Cll~u~ luyld~ull on silica gel (20% EtOAc/hexane) to obtain 0.447 g (50%) of the title compound of Step 6 as an oil.
10 Step 7: Trans Methyl 4-[1-(4-Me,ll,~A~pllellyl)-4-oxo-3(R)-(3-phen propyl)-2(S)-azetidinyl]phenyl-2-ethanol:
Add borane I~I,dl.Jdluf-Jran complex (3.4 mL, 3.4 mmol) to a 0 C
solution of the product of Step 6 (0.45 9, 1.12 mmol) in THF (15 mL) and allow the mixture to wamm to room temperature overnight. Add 2N NaOH
(1.7 ml) followed by 30% H2O2 (1.2 mL) and stir the mixture for 3h.
Quench the mixture by addins 0.8M Na2SO3 solution (2 mL). Extract the mixture ether, wash the etheral extracts with water and brine, dry over Na2SO4 and COIl.~ l Ch~u~ uyldpll on silica (30% EtOAc/hexanes) to obtain 0.18 9 (41%) of the title compound of Step 7 as an oil.
Step 8: Trans Methyl 2-[4-[1~(4-Mt~llu~y,uh~ 1)-4-oxO-3(R)-(3-~1 ,e"y~ul u,uyl)-2(S)-azetidinyl]phenyl]-acetic acid:
Add Jones Reagent (0.4 ml, prepared by dissolving 6.7 9 chromic acid in cu,l~ t,d~t:d H2S04 and diluting with distilled water to 50 mL) to a solution of the product of Step 7 (0.15 9, 0.36 mmol) in acetone (4 mL), ~"oi- i"g the reaction by TLC (5% MeOH/CH2CI2). Add CH30H (2 mL) and stir the mixture for 30 min. Con~;t",l,dl~ the mixture, partition the residue between water and CH2CI2, and extract with CH2CI2. Combine the extracts, wash with Na2SO3 (sat'd), water and brine, dry over Na2SO4 and ,unC~lltldl~ to obtain 0.144 9 (93%) of the title compound of Step 8 as 3û a yellow foam.
Step 9:
Using a well known procedure, add 1-(3-dimethyld",i"op,upyl)-3-yl-;dlL "' "ide l,Jd,u.,l,lûri~ (EDCI) to a solution of the product of Step 8, ethanol, I,,~ ybel,~u~lia~ (HOBT) and N-llle:lllyl~llùl,ul~
(NMM) in CH2CI2 and stir the mixture overnight. Dilute the resulting reaction mixture with CH2CI2, wash with 1 M HCI, water and brine, dry over anhydrous Na2SO4 and cûnc~,ltldle to an oil. C~ulll_ u~ld,ull the residue on silica (3% CH30H/CH2CI2) to obtain 0.090 9 (61 %) of the title _ _ _ _ _ WO 95135277 P~ 17 2~
compound. HRMS calc'd for C2gH2gNO4: 443.2097; found 443.2093.
MS (Cl): 444 (M+1, 100).
- Example 5 TrArls methyl 3-~3-ben7yloxv-4-[1-(4-fluorui~he,,~rl)-4-oxo-3-(3-phenyl-propyl)-2-u,~ r.he,,yll~lu~elln~lle Combine trans-1 -(-flu~,upller,yl)-3-(3-ph~ ,ru,uyl)-4-(4-bromo-2-benx~l~xyphe"yl)-2-~ i"one (0.55 9, 1.û mmol) (prepared according to the procedure of Example 1), triethylamine (0.28 mL, 2.0 mmol), methyl acrylate (0.18 mL, 2.0 mmol) and Pd(Ph3P)4 (0.û58 9, 0.05 mmol) in CH3CN (2 mL) and heat to 80 C over night. Monitor the reaction by TLC
(25% EtOAC/hexane); add methyl acrylate (0.18 mL, 2.0 mmol) and Pd(Ph3P)4 (0.058 9, 0.05 mmol) and heat the mixture for an additional 20 h. at 80 C. Cool the reaction mixture to room temperature, dilute with EtOAc, wash with 0.1 N HCI, water and brine, dry over Na2SO4 and ~ûnc~r~t~dl~. Ch~ullldluyld~uh the residue on silica (20% EtOAc/hexane) to obtain 0.27 9 (48%) of the title compound as a yellow soiid.
5A: In a similar manner, prepare trAns methyl 3-[4-[1-(4-fluorophenyl)-4-oxo-3-(3-phenylpro~Dyl)-2-A7Ptjdinyl~phenyl~Jrupennrllp Example 6 trArls methyl 3-[3-hydroxy-4-[1-(4-fluorophenyl)-4-oxo-3-(3-phenylpropyl)-2-~ yl!~,)l1enyUI"upion~l~
Dissolve the product of Example 5 (û.266 9, 0.48 mmol) in EtOAc (16 mL), dilute with CH30H (2û mL) and purse with N2 Add 20%
Pd/C (0.05 9), purge the mixture with H2 and then stir under a balloon of H2 overnight. Filter the reaction mixture through celite. Wash the filter cake with EtOAc and cu,,c6,,l,dle the filtrate to give 0.156 9 of the title compound as a colorless oil. HRMS calc'd for C2gH2gNO4: M+H
462.2081; found 462.2070. MS (Cl): 462 (M+1,37), 351(17), 293(41), 1 38(1 00).
Example 7 trArls 3-[3-hydroxy-4-[1-r4-flllnrophenyl~-4-oxo-3-(3-phenylDrowV-2-A7~ti~irlyl]Dhen~l]~lu~ A~ir~
Dissolve the product of Example 6 (0.0669, 0.14 mmol) in THF (3 mL), add LiOH (0.04 9, û.86 mmol) and stirthe mixture at room 35 temperature overnight. Acidify the solution to pH 3 with 1 M HCI, dilute with EtOAc, wash with water and brine, dry over Na2SO4 and cu~ rltldL~
to give 0.061 9, (91%) of the title compound as an oil. HRMS calc'd for C27H26NO4F: M+H 448.1924; found 448.1911. (FAB): 444 (M+1,100).
WO 9~135277 , ~ I PCTIUS9~107117 2 1 9 ~
Example 8 Tr~ns Methyl 3-[3-[1-~henyl-4-oxo-3-(3-~henylrDro~yl)-2-çl70tidinyl]c)he" jUvr. ~r~nn:3to ~: Prepare trans 1 -phenyl-3-(3-phenylpropyl)-4-(3-benzyl-oxyphenyl)-2-~ " ,ùne in a manner simiiar to that described in Example 1.
~L2: Using the procedure of Example 4, Step 4, treat the product of Step 1 to obtain trans 1-phenyl-3-(3-phenylpropyl)-4-(3-hydroxyphenyl)-2-~li ;li"o~le.
~: Using the procedure of Example 4, Step 5, treat the product of Step 2 to obtain trans 1-phenyl-3-(3-phenylpropyl)-4-((3-trifluu,ul,,t,ll,;l-sulfonyl))phenyl)-2-~lid;"one .
SteD 4: UsinQ the procedure of Example 5, treat the product of Step 3 to obtain compound 8-1, trans methyl 3-[3-[1-phenyl-4-oxo-3-(3-phenylpropyl)-2-azetidinyl]phenyl]-2-prupe~ ,odle.
Using the procedure of Example 3, treat the product of Step 4 to obtain the title compound (8-2). HRMS calc'd for C2sH29NO3: M+H
428.2226; found 428.2235. MS (Cl): 428 (M+1,100).
Example 9 TrAns (3~ ~)-Methyl 3-[4-[1-(4-methoxyDhenYI)-4-oxo-3-~3-Dhenyl-,Dro~Dyl)-2-~ Dhenyl]-2-~Dru~e, ~ R
Heat the product of Example 4, Step 5 (0.51 9, 0.98 mmol), sodium acetate (0.1 ~,1.1 mmol), DMF (6 mL) and methyl acrylate (0.1 mL, 1.1 mmol) to 130 C. Add Pd(Ph3P)4 (0.1 9, 0.11 mmol) and stir the mixture at 130 C overnight. Cool the mixture to room l~",,ue, ~e, partition between water and ether, and extract with ether. Combine the etheral extracts, wash with water and brine, dry over Na2SO4 and cù~luellllldl~. C~llu~ldluyld~Jh the residue on silica (25% EtOAc/l~e,~dnes) to provide 0.18 g (40%) of the title compound as a clear oil. HRMS calc'd for C2gH2gN04: 455.2097; found 455.2û80. MS (El): 455 (M+,72), 371(40), 306(56), 252(100).
Example 1û
(3S. 2~) trans methyl 4-[1-(4-ul~lu~ulJh~ 1)-4-oxo-3-(2-(4-fluoro-~henoxy~ethyl~-2-~7otirlinylJDhenvl-2-Druoer~ Q (lOA) ~nd (3R. 2S) tr~ns methyl 4-[1-(4-11,1u,u~ e"yl)-4-oxo-3-(2-(4-fluoro-,Dhenoxy)ethyl)-2-~ "yl]~Dhenyl-2-Dro~enn~t~ (10B) Add 4-(4-flu~ruuhe~,u,~y)butyryl chloride (0.72 9. 3.34 mmol) dropwise to a solution of 4-formyl ~ lllyl!JlulJ~nodl~ 4-~illlurudl " ,e imine WO 95/35277 21 91 4 ~ pCTlUSgs/07117 (0.5 9, 1.67 mmol) and Hunis's base (0.87 mL, 5.0 mmol) in dichloro-ethane (46 mL) at 80 C. Reflux the mixture ovemight, cool to room I~,,,,u~, ~re, quench with 1 M HCI and stir for 15 min. Wash the mixture with NaHCO3 (sat'd), water and brine, dry over Na2SO4 and cùnc6, Itld~
5 Ci"u", _ d,ull the residue ûn silica (40% EtOAc/hexane). To remove 4-formyl ~ ll,yi.~ ual~ ~OIItdlll Idlll, dissolve the product in 50%
CH30H/THF and treat with NaBH4 (1.5 g). After 30 min, quench with NH4CI (sat'd), wash with NH4CI (sat'd), water and brine, dry ov0r Na2SO4 and uùnc6lltldi~. C~u~ O d,UII the residue on silica (35%
10 EtOAc/l~e~dn~s) to provide 0.575 (33%) of trans methyl 4-[1-(4-.:I,I~ropi~e,,yl)-4-oxo-3-(2-(4-fluo,uphel~o,~y)ethyl)-2-a_etidinyi]phenyl-2-~c,u~ dle. Resolve the iidal6lulll~la by chiral HPLC (Chiracel AS
column, 30% iau,u,upanol/hexanes, 70 mL/min) to give 0.128 9 compound 10A and 0.139 9 compound 10B.
15 10A: HRMScalc'dforC27H23NO4CI: 480.1378; found480.1378.
(Cl): 480(M+, 100), 215(99).
10B: HRMS calc'd for C27H23NO4CI: 480.1378; found 48û.1369.
(Cl): 480(M+, 88), 215(100).
Example 1 1 Tr~ns 3-~4-~1 -(4-Methoxyphenyl)-4-oxo-3-(3-phenylpropyl)-2-~7Ptir~ ylluher~ lr~J~n~; Arir~
Step 1: Hydrolyze the product of Example 2 according to the procedure described in Example 7 to obtain trans 3-[4-[1-(4-methoxyphenyl)-4-oxo-3-(3-ph~"~l~,,uu~1)-2-a_etidinyl]phenyl]-2-propenoic acid (compound 11-1).
Step 2: 1 Iyd~uyer,d~ the product of Step 1 according to the procedure described in Example 3 to obtain the title compound (11-2). H~MS caic'd for C2gH3~ NO4: M+H 444.2175; found 444.2165. (FAB): 444(M+1, 1 0û).
Example 1 2 Trans Methyl (3R. 2S)-4-[1-(4-fluorophenyl)-4-oxo-3-(3-pl-e"ylv,uvyl)-2-~7~tidinyl]i.~"cel ,evr~ ~n~.~n~
Step 1: Trans (3R, 4S)-1-(4-fluorophenyl)-4-(4-((~,i",t~l,ylailyl)acetylenyl)-phenyl)-3-(3-pll6~ ru,uyl)-2-d~ ol)e:
Heat a mixture of trans (3R, 4S)-1-(4-fluorophenyl)-4-(4-bromo-phenyl)-3-(3-phenylpropyl)-2-d~';di,~ e (0.69 9, 1.57 mmol) (preparedfrom N-(4-u,u,noi~ ylidene)-4-fluulud,,ili,,~ and (5S)-1-(5-phenyl-1-oxo-pentanyl)-5-pl,6";'~ ' "nol~e using the procedure described in steps 2 and 3 of Example 4), (trimethylsilyl)acetylene (0.33 mL, 2.36 mmol), i,is(l,i~ullerly~,llr~a~ull;lle)palladium (Il) chloride ((Ph3P)2PdC12) (0.0559, W09~135277 2191455 r~l,u )ll7 --7 ~
i.~,,~
0.079 mmol) and di;~opru,uyl...,,i, ,e (6 mL) to 80 C. Monitor the reaction by TLC. After 80 min, add additional (trimethylsilyl)acetylene (0.33 mL, 2.36 mmol). After an additional 50 min, cool the mixture to room temperature, filter throush celite and wash the filter cake with CH2C12.
5 Co,)c~r,~,dt~ the fiUrate onto enough silica so that a free flowing powder is obtained. Lûad the resulting powder onto a ~ lU~ u,U,ld~lly column p,~,d..l~d with silica and 10% EtOAc/hexane. Elute with 10%
EtOAc/hexane to obtain 0.595 9 (83%) of the title compound of Step 1 as a light brown solid. MS(FAB): 456 (M+, 100), 318(37), 296(35).
Step 2: Trans (3R, 2S) 4-[1-(4-fluorophenyl)-4-oxo-3-(3-ph~ ,,u,uyl)-2-d~lidil ljll' en~eneac~ acid:
Add cycl~ Adne (1 .û8 mL, 1 û.64 mmol) to a û C solution of borane (5.3 mL, 5.3 mmol, 1 M in THF). Stir at 0 C for 1 h. Dropwise add the product of step 1 (û.485 g, 1.07 mmol) in THF (7.5 mL) and keep the mixture at 0 C overnight (22h). Sequentially add CH30H (0.43 mL), 3N
NaOH (1.06 mL) and 30 % H2O2 (1.2 mL) to the 0 C mixture. Allow the mixture to warm to room tPnlrPratl Ire and stir for 3 h. Pour the mixture into brine and acidify with 1 M HCI. Extract with EtOAc, combine the extracts, wash with water and brine, dry over anhydrous Na2SO4 and ~u,~c~"l, onto ~nough silica that a free flowing powder is obtained. Load the ~esulting powder onto a ~,lllull._~Jyld~u~ly column pr~,ua~ ed with silica and 5% CH3OH/CH2CI2. Elute with 5% CH3OH/CH2CI2 to obtain the title compound of Step 2, 0.227 9 (52%). HRMS calc'd for C26H2sNO3F:
(M+H) 418.1818; found 418.1820. MS(CI): 418 (M+H, 18), 235(29), 145(55), 83(100).
Step 3: Using a procedure similar to that of Example 4, step 9, treat the product of step 3 to obtain the title compound, 0.023 9 (25%). HRMS
calc'd for C28H2gNO3F: (M+H) 446.2131; found 446.2150. MS(CI): 446 (M+H, 1 00), 277(1 3),1 38(44).
3û Exsmpl~ 13 Trans Methyl (3R. 2S)-4-[1-~4-fl~u,uvher,yl)-4-oxo-3-(3-~he,,;l~,uvyl~-2-a7Pt~ ylll~pn~rieGruv~l~n Step 1: Trans (3R, 4S)-1-(4-fluorophenyl)-4-(4-(3-hydroxy-1-propynyl)-phenyl)-3-(3-~ r,~ u~,yl)-2-d~ û~
Use a procedure similar to that of Example 12, Step 1, ~, Ih~ I Iy propargyl alcohol (0.20 mL, 3.49 mmol) for (I,i",~ll"~ l)acetylene and refluxing overnight. Filter and ~ dpl l as in Example 12, Step 1, using a column p,~paci~d with silica and 30% EtOAc/hexane. Elute with W0 95/35277 ~ 17 30% EtOAc/hexane to obtain the title compound of Step 1, 0.73g (75%), as a yellow oil. HRMS calc'd for C27H2sNO2F: (M+H) 414.1869; found 414.1854. MS(CI): 414 (M+H, 72), 259(32), 138(100).
Step 2: Trans (3R, 4S)-1-(4-flu~,oph~"yl)-4-(4-(3-hydroxy-1-propyl)-5 phenyl)-3-(3-plle"yl~ lup~1)-2-~li.li"ùne:
Using the procedure of Example 6, treat the product of Step 1 to obtain 0.42 9 (100%) of the title compound of Step 2. MS(CI): 418 (M I H, 100), 138(55).
Step3: Trans (3R,2S)-4-[1-(4-fluu,u,ùhe,,,rl)-4-oxo-3-(3-pl,~,,y;~,,upyl)-2-10 d~tidillyl;' r~ne~U~Udlluic acid:
Add Jone's Reagent (1.0 mL, prepared as described in Example 4,step 7) to a 0 C solution of the product of Step 2 in acetone (8 mL).
Monitor the reaction by TLC (5% CH3OHICH2CI2). Upon consumption of starting material, quench the reaction by the addition of CH30H and -15 COll-,elllldl~ in vacuo. Dissolve the residue in water, and adjust to pH 13 with NaOH. Extract the resulting solution with ether, acidify the aqueous layer to pH 3 with HCI (conc.) and extract with EtOAc. Combine the extracts, wash with 10% NaHSO3, water and brine, dry over anhydrous Na2S04 and ~;ui~ce~lt~dl~ onto enough silica that a free flowing powder is 20 obtained. Load the resulting powder onto a ull,u,ll _ d,uhy column ~,,t",dcl~ed with silica and 5% CH30H/CH2C12. Elute with 5-8%
CH3OH/CH2CI2 to obtain 0.2439 (53%) of the title compound of Step 3 as a white foam. HRMS calc'd for C27H27NO3F:( M+H) 432.1975; found 432.1 972. MS(CI) : 432 (M+H , 100).
25 Step 4: Using a procedure similar to that of Example 4, step 9, but using THF, treat the product of step 3 to obtain the title compound, û.54 9 (57%).
HRMS calc'd for C2gH2gNO3F: (M+H) 446.2131; found 446.2150.
MS(CI): 446 (M+H, 100), 277(13),138(44).
Exsmple 14 TrAns Etilyl (3R. 2S)-4-[1-(4-fluu,u~he,,~1)-4-oxo-3-(3-Dlle,,ylvru~1)-2-A7Qt~ yl]ben7Qr~e A~t~tQ
Dry ZnBr2 (0.335 9, 1.49 mmol) at 130 C under vacuum overnight, then cool to room temperature under nitrogen. Add a solution of trans (3R, 4S)-1-(4-fluorophenyl)-4-(4-~,u",ùplle"yl)-3-(3-phenyl-35 propyl)-2-~- ~t;~i"~l~e (0Ø50 9, 1.14 mmol) and ethyl 2-tributyltin acetate (0.56 9, 1.49 mmol) in DMF (3 mL) via cannula under nitrogen. Heat the mixture to 80 C. Monitor consumption of starting material by TLC (15%
EtOAclhexane) and upon U~lllr~ , cool to room It7""u- Ire, filter WO 95/35277 2 1 9 1 4 5 5 ~ s 3 P~ 7 through celite, and wash the filter cake with EtOAc. Add 2.5 M KF (10 mL) to the filtrate, stir for 3h, dilute with EtOAc, wash with water and brine, dry over anhydrous Na2SO4 and cor,c6"1,dl~ onto enough silica that a free flowing powder is obtained. Load the resulting powder is loaded onto a 5 ~;I"u", " ~,ul,y column ~,~uac~d with silica and 15% EtOAc/hexane.
Elute with 15% EtOAC/Il~Adlle to obtain the title compound as a yellow oil, 0.4169 (82%). HRMS calc'd for C2gH2gNO3F: (M+H) 446.2131; found 446.2123. MS(FAB): 446 (M+H, 100), 308(18), 286(24).
Example 1 5 Tr~ns ~3R. 2S)-3-[4-~1 -(4-FI~ uuhe, ,yl)-4-oxo-3-(3-r henylDroDyl)-2-;."",~l,er,~ll E-2-~Dro~enoic ~
Step 1: Trans methyl (3R, 2S)-3-[4-[1-(4-fluorophenyl)-4-oxo-3-(3-phenyl-propyl)-2-d~lidi"yl]~ e, Iyl]-E-2-prupen~dld Treat trans (3R, 4S)-1-(4-fluorophenyl)-4-(4-bromophenyl)-3-(3-ph6,,yl~.rupyl)-2-d~ i,,ù,~e methyl acrylate in a manner similar to that described in Example 5 to obtain the title compound of Step 1. HRMS
calc'd for C2gH27NO3F: (M+H) 444.1975; found 444.1971. MS(CI): 444 (M+H, 100).
Step 2: TrQat the product of step 1 as described in Example 7, purifying by ulllullldlu~ ,ully on a column pre:,uaclied with silica and 0.5% HOAc/2.5%
EtOH/97% CH2CI2, eluting with the same eluant to obtain the title compound. HRMS calc'd for C27H2sNO3F: (M+H) 430.1818; found 430.1810. MS(CI): 430 ~M+H, 100), 293(26),177(74). 138(52).
E%ample 1 6 Tr~ns N.N-Diethyl-(3R. 2S)-4-~1-(4-fluoroDhenyl)-4-oxo-3-(3-Dher~yl~roDyl)-2-i~Atidinyl]be"~end~rur~"~";de Add EDCI (0.û58 9, 0.303 mmol) to a mixture of the product of Step 3 of Example 13 (0.092 9, 0.213 mmol), HOBT hydrate (.035 9, 0.256 mmol), NMM (0.û29 mL, 0.277 mmol) and Et2N (0.044 mL, 0.427 mmol) in CH2CI2 (2.5 mL). Stir the resulting mixture overnight until TLC
(50% EtOAc/hexane) indicates consumption of starting material. Dilute the mixture with CH2CI2, wash with 0.2N HCI, water and brine, dry over anhydrous Na2SO4 and Col,C611l,dl~ onto enough silica such that a free flowing powder is obtained. Load the resulting powder is loaded onto a ~:lllu~lldiv5,ld,ully column ~ ~tluacl~6d with silica and 35% EtOAc/hexane.
Elute with 35-50% EtOAc/hexane to obtain an oil which is further purified by silica ~:lllulll_~uuld~lly, eluting with 35-50% EtOAc/hexanes to obtain the title compound, 0.689 (73%), as an oil. MS(CI): 487 (M+, 100), Wo 9sl3s2M 91 qSS P~ 7 350(19), 318(37). HRMS(FAB): calcd. for C31H36N2O2F(M+1), 487.2761;
found 487.2783.
The following formulations exemplify some of the dosage 5 fomms of this invention. In each the term "active compound" d~siy, Id~S a campound of formula I.
FXAMPI F A
[~
No, Ina, re~iPrlt ma/tablet ma,/tablet Active Compound 100 500 2Lactose USP 122 113 3Corn Starch, Food Grade, as a 10% 30 40 paste in Purified Water 4Corn Starch, Food Grade 45 40 5MaQnesium Stearate 3 ~, Total 300 700 10 Method of Man~If~tllre Mix Item Nos. 1 and 2 in suitable mixer for 10-15 minutes.
Granulate the mixture with Itsm No. 3. Mill the damp granules through a coarse screen (e.g., 114", 0.63 cm) if necessary. Dry the damp granules.
Screen the dried granules if necessary and mix with Item No. 4 and mix for 10-15 minutes. Add Item No. 5 and mix for 1-3 minutes. Compress the mixture to ap~.,uprid~a size and weight on a suitable tablet machine.
FXAMPI F B
!;:ap ~s~les No. Inaredient m~ltablet m~/tablet Active Compound 100 500 2Lactose USP 106 123 3Corn Starch, Food Grade 40 70 4Magnesium Stearate NF 4 7 Total 250 700 20 Method of Manl~f~rh~re Mix Item Nos. 1, 2 and 3 in a suitable blender for 10-15 minutes. Add Item No. 4 and mix for 1-3 minutes. Fill the mixture into w09s/3ri277 2~455` r~ 7--suitable two-piece hard gelatin capsules on a suitable erl~rs~ y machine.
Rffp,t,serlLd~h/~ formulations CO~ liailly a uI,oles~, biuay, ,~l ,esis inhibitor are well known in the art. It is cu~ vldLad that 5 where the two active il~y~ ta are a~",i~isl~r~d as a single cul"r ii~ ~, the dosage forms disclosed above for sl ~hstit~ I~Ad i"ui1e compounds may readiiy be modified using the kl,ûJ.~;lye of one skilled in the art.
Using the test procedures described above, the following l~L
yiy~L data were obtained for ,~,ur~ae" ~to compounds of formula 1.
Compounds are referred to by the c~r~:a,uO~i,ly example number; data is reported as percent change (i.e., percent reduction in ~ vl~sLl:,ul esters) Yersus control, therefore, negative numbers indicate a positive lipid-15 lowering effect.
% Recuction Ex. No. Serum Cholesterol Dose Cholesterol Esters mglkg -28 -76 5û
16 û -19 1û
For racemic compounds of formula I or active diaal~ ullltlla or e,~d"liul"era of compounds of formula 1, compounds ad",i";aLff,~d at 2û dosages of 1-50 mg/kg show a range of -97 to -12% reduction in ul)olffal~rul esters, and a-49 to 0% reduction in senum ullultla~fflul. The reductiorl in ~:llùl~a~tllul esters is the more important measure of activit,Y, and active compounds preferably show a range of -3û to -97% reduction in dlùl~ lul esters.
Claims (9)
1. A compound represented by the formula or a pharmaceutically acceptable salt thereof, wherein:
Ar1 is aryl or R3-substituted aryl;
Ar2 is aryl or R4-subtituted aryl;
R1 is selected from the group consisting of -(CH2)q-, wherein q is 2, 3, 4, 5 or 6;
-(CH2)e-Z-(CH2)r, wherein Z is -O-, -C(O)-, phenylene, -NR10- or -S(O)0-2-, e is 0-5 and r is 0-5, provided that the sum of e and r is 1-6;
-(C2-C6 alkenylene)-; and -(CH2)t-V-(CH2)?-, wherein V is C3-C6 cycloalkylene, f is 1-5 and g is 0-5, provided that the sum of f and 9 is 1-6;
R2 is -(lower alkylene)-COR5 or -(CH=CH)-COR5;
R3 and R4 are independently selected from the group consisting of 1-3 substituents independently selected from the group consisting of lower alkyl, -OR6, -O(CO) R6, -O(CO)OR9, -O(CH2)1-5OR6, -O(CO)NR6R7, -NR6R7, -NR6(CO)R7, -NR6(CO)OR9, -NR6(CO)NR7R8, -NR6SO2R9, -COOR6, -CONR6R7, -COR6, -SO2NR6R7, S(O)0-2R9, -O(CH2)1-10-COOR6,-O(CH2)1-10CONR6R7,-(lower alkylene)-COOR6, -CH=CH-COOR6, -CF3, -CN, -NO2 and halogen;
R5 is -OR or -NRR12, wherein R and R12 are independently selected from the group consisting of hydrogen, lower alkyl, aryl and aryl-substituted lower alkyl;
R6, R7 and R8 are independently selected from the group consisting of hydrogen, lower alkyl, aryl and aryl-substituted lower alkyl;
R9 is lower alkyl, aryl or aryl-substituted lower alkyl; and R10 is hydrogen, lower alkyl, aryl lower alkyl or -C(O)R6.
Ar1 is aryl or R3-substituted aryl;
Ar2 is aryl or R4-subtituted aryl;
R1 is selected from the group consisting of -(CH2)q-, wherein q is 2, 3, 4, 5 or 6;
-(CH2)e-Z-(CH2)r, wherein Z is -O-, -C(O)-, phenylene, -NR10- or -S(O)0-2-, e is 0-5 and r is 0-5, provided that the sum of e and r is 1-6;
-(C2-C6 alkenylene)-; and -(CH2)t-V-(CH2)?-, wherein V is C3-C6 cycloalkylene, f is 1-5 and g is 0-5, provided that the sum of f and 9 is 1-6;
R2 is -(lower alkylene)-COR5 or -(CH=CH)-COR5;
R3 and R4 are independently selected from the group consisting of 1-3 substituents independently selected from the group consisting of lower alkyl, -OR6, -O(CO) R6, -O(CO)OR9, -O(CH2)1-5OR6, -O(CO)NR6R7, -NR6R7, -NR6(CO)R7, -NR6(CO)OR9, -NR6(CO)NR7R8, -NR6SO2R9, -COOR6, -CONR6R7, -COR6, -SO2NR6R7, S(O)0-2R9, -O(CH2)1-10-COOR6,-O(CH2)1-10CONR6R7,-(lower alkylene)-COOR6, -CH=CH-COOR6, -CF3, -CN, -NO2 and halogen;
R5 is -OR or -NRR12, wherein R and R12 are independently selected from the group consisting of hydrogen, lower alkyl, aryl and aryl-substituted lower alkyl;
R6, R7 and R8 are independently selected from the group consisting of hydrogen, lower alkyl, aryl and aryl-substituted lower alkyl;
R9 is lower alkyl, aryl or aryl-substituted lower alkyl; and R10 is hydrogen, lower alkyl, aryl lower alkyl or -C(O)R6.
2. A compound of claim 1 wherein Ar1 is phenyl and Ar2 is phenyl or R4-substituted phenyl, wherein R4 is halogeno or -OR6, and wherein R6 is hydrogen or lower alkyl.
3. A compound of claim 1 or 2 wherein R1 is -(CH2)q- or -(CH2)e-Z-(CH2)r-wherein q is 2 or 3; Z is -O-; e is 0; and r is 2.
4. A compound of any of claims 1,2 or 3 wherein R5 is -OR, wherein R
is hydrogen or lower alkyl.
is hydrogen or lower alkyl.
5. A compound of claim 1 selected from the group consisting of trans methyl 3-[4-[1-(4-methoxyphenyl)-4-oxo-3-(3-phenylpropyl)-2-azetidinyl]phenyl]-2-propenoate;
trans methyl 3-[4-[1-(4-methoxyphenyl)-4-oxo-3-(3-phenylpropyl)-2-azatidinyl]phenyl]-propanoate;
trans methyl 3-[(3S 2R)-4-[1-(4-methoxyphenyl)-4-oxo-3-(3-phenylpropyl)-2-azetidinyl]phenyl]propanoate;
trans methyl 2-[4-[1-(4-methoxyphenyl)-4-oxo-3-(3-phenylpropyl)-2 azetidinyl]phenyl]ethanoate;
trans methyl 3-[3-[1-phenyl-4-oxo-3-(3-phenylpropyl)-2-azetidinyl]phenyl]propanoate;
trans (3R,4S)-methyl 3-[4-[1-(4-methoxyphenyl)-4-oxo-3-(3-phenyl-propyl)-2-azetidinyl]phenyl]-2-propenoate;
(3S,2R) trans methyl 4-[1-(4-chlorophenyl)-4-oxo-3-(2-(4-fluoro-phenoxy)ethyl)-2-azetidinyl]phenyl-2-prppenoate;
(3R,2S) trans methyl 4-[1-(4-chlorophenyl)-4-oxo-3-(2-(4-fluoro-phenoxy)ethyl)-2-azetidinyl]phenyl-2-propenoate;
trans 3-[4-[1-(4-methoxyphenyl)-4-oxo-3-(3-phenylpropyl)-2-azetidinyl]phenyl]propanoic acid;
trans methyl 3-[4-[1-(4-fluorophenyl)-4-oxo-3-(3-phenylpropyl)-2-azetidinyl]phenyl]propenoate;
trans (3R,2S)-4-[1-(4-fluorophenyl)-4-oxo-3-(3-phenylpropyl)-2-azetidinyl]benzeneacetic acid;
trans methyl (3R,2S)-4-[1-(4-fluorophenyl)-4-oxo-3-(3-phenyl-propyl)-2-azetidinyl]benzenepropanoate;
trans (3R,2S)-4-[1-(4-fluorophenyl)-4-oxo-3-(3-phenylpropyl)-2-azetidiny]benzenepropanoic acid;
trans methyl (3R,2S)-4-[1-(4-fluorophenyl)-4-oxo-3-(3-phenyl-propyl)-2-azetidinyl]benzenepropanoate;
trans ethyl (3R,2S)-4-[1-(4-fluorophenyl)-4-oxo-3-(3-phenylpropyl)-2-azetidinyl]benzene acetate;
trans (3R,2S)-3-[4-[1-(4-fluorophenyl)-4-oxo-3-(3-phenylproppyl)-2-azetidinyl]phenyl]-E-2-propenoic acid; and trans N,N-diethyl-(3R,2S)-4-[1-(4-fluorophenyl)-4-oxo-3-(3-phenyl-propyl)-2-azetidinyl]benzenepropanamide.
trans methyl 3-[4-[1-(4-methoxyphenyl)-4-oxo-3-(3-phenylpropyl)-2-azatidinyl]phenyl]-propanoate;
trans methyl 3-[(3S 2R)-4-[1-(4-methoxyphenyl)-4-oxo-3-(3-phenylpropyl)-2-azetidinyl]phenyl]propanoate;
trans methyl 2-[4-[1-(4-methoxyphenyl)-4-oxo-3-(3-phenylpropyl)-2 azetidinyl]phenyl]ethanoate;
trans methyl 3-[3-[1-phenyl-4-oxo-3-(3-phenylpropyl)-2-azetidinyl]phenyl]propanoate;
trans (3R,4S)-methyl 3-[4-[1-(4-methoxyphenyl)-4-oxo-3-(3-phenyl-propyl)-2-azetidinyl]phenyl]-2-propenoate;
(3S,2R) trans methyl 4-[1-(4-chlorophenyl)-4-oxo-3-(2-(4-fluoro-phenoxy)ethyl)-2-azetidinyl]phenyl-2-prppenoate;
(3R,2S) trans methyl 4-[1-(4-chlorophenyl)-4-oxo-3-(2-(4-fluoro-phenoxy)ethyl)-2-azetidinyl]phenyl-2-propenoate;
trans 3-[4-[1-(4-methoxyphenyl)-4-oxo-3-(3-phenylpropyl)-2-azetidinyl]phenyl]propanoic acid;
trans methyl 3-[4-[1-(4-fluorophenyl)-4-oxo-3-(3-phenylpropyl)-2-azetidinyl]phenyl]propenoate;
trans (3R,2S)-4-[1-(4-fluorophenyl)-4-oxo-3-(3-phenylpropyl)-2-azetidinyl]benzeneacetic acid;
trans methyl (3R,2S)-4-[1-(4-fluorophenyl)-4-oxo-3-(3-phenyl-propyl)-2-azetidinyl]benzenepropanoate;
trans (3R,2S)-4-[1-(4-fluorophenyl)-4-oxo-3-(3-phenylpropyl)-2-azetidiny]benzenepropanoic acid;
trans methyl (3R,2S)-4-[1-(4-fluorophenyl)-4-oxo-3-(3-phenyl-propyl)-2-azetidinyl]benzenepropanoate;
trans ethyl (3R,2S)-4-[1-(4-fluorophenyl)-4-oxo-3-(3-phenylpropyl)-2-azetidinyl]benzene acetate;
trans (3R,2S)-3-[4-[1-(4-fluorophenyl)-4-oxo-3-(3-phenylproppyl)-2-azetidinyl]phenyl]-E-2-propenoic acid; and trans N,N-diethyl-(3R,2S)-4-[1-(4-fluorophenyl)-4-oxo-3-(3-phenyl-propyl)-2-azetidinyl]benzenepropanamide.
6. A pharmaceutical composition comprising a cholesterol-lowering effective amount of a compound of any of claims 1, 2, 3, 4 or 5, alone or in combination with a cholesterol biosynthesis inhibitor, in a pharmaceutically acceptable carrier,
7. The use of a compound of any of claims 1, 2, 3, 4 or 5 for the preparation of a medicament for the treatment or prevention of atherosclerosis, or for the reduction of plasma cholesterol levels, comprising a compound as defined in any of claims 1, 2, 3, 4 or 5, alone or in combination with a cholesterol biosynthesis inhibitor, and a pharmaceutically acceptable carrier.
8. A kit comprising in separate containers in a single package pharmaceutical compositions for use in combination to treat or prevent atherosclerosis or to reduce plasma cholesterol levels which comprises in one container an effective amount of a cholesterol biosynthesis inhibitor in a pharmaceutically acceptable carrier, and in a second container, an effective amount of a compound of any of claims 1, 2, 3, 4 or 5 in a pharmaceutically acceptable carrier.
9. A method of treating or preventing atherosclerosis or reducing plasma cholesterol levels comprising administering to a mammal in need of such treatment an effective amount of a compound of any of claims 1, 2, 3, 4 or 5, alone or in combination with a cholesterol biosynthesis inhibitor.
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JP2004516289A (en) * | 2000-12-21 | 2004-06-03 | アベンティス・ファーマ・ドイチユラント・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング | Diphenylazetidinone derivatives, methods for their preparation, drugs containing the compounds and uses thereof |
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 |
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Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0596015B1 (en) * | 1991-07-23 | 1997-10-01 | Schering Corporation | Substituted beta-lactam compounds useful as hypocholesterolemic agents and processes for the preparation thereof |
US5631365A (en) * | 1993-09-21 | 1997-05-20 | Schering Corporation | Hydroxy-substituted azetidinone compounds useful as hypocholesterolemic agents |
-
1995
- 1995-06-15 WO PCT/US1995/007117 patent/WO1995035277A1/en not_active Application Discontinuation
- 1995-06-15 EP EP95925237A patent/EP0766667A1/en not_active Withdrawn
- 1995-06-15 CA CA002191455A patent/CA2191455A1/en not_active Abandoned
- 1995-06-15 MX MX9606319A patent/MX9606319A/en unknown
- 1995-06-15 JP JP8502289A patent/JPH10501811A/en active Pending
- 1995-06-15 AU AU29430/95A patent/AU2943095A/en not_active Abandoned
Also Published As
Publication number | Publication date |
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AU2943095A (en) | 1996-01-15 |
EP0766667A1 (en) | 1997-04-09 |
WO1995035277A1 (en) | 1995-12-28 |
JPH10501811A (en) | 1998-02-17 |
MX9606319A (en) | 1997-05-31 |
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