JP2021524498A - ピロリジン化合物 - Google Patents
ピロリジン化合物 Download PDFInfo
- Publication number
- JP2021524498A JP2021524498A JP2021505713A JP2021505713A JP2021524498A JP 2021524498 A JP2021524498 A JP 2021524498A JP 2021505713 A JP2021505713 A JP 2021505713A JP 2021505713 A JP2021505713 A JP 2021505713A JP 2021524498 A JP2021524498 A JP 2021524498A
- Authority
- JP
- Japan
- Prior art keywords
- tert
- oxo
- methyl
- mmol
- pyrrolidine
- 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.)
- Granted
Links
- -1 Pyrrolidine compound Chemical class 0.000 title description 42
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Natural products C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 171
- 150000003839 salts Chemical class 0.000 claims abstract description 67
- 238000011282 treatment Methods 0.000 claims abstract description 24
- 238000000034 method Methods 0.000 claims abstract description 22
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 7
- 239000000203 mixture Substances 0.000 claims description 89
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 36
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 16
- 230000036470 plasma concentration Effects 0.000 claims description 15
- 229940079593 drug Drugs 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000003085 diluting agent Substances 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 239000000126 substance Substances 0.000 abstract description 3
- 230000008569 process Effects 0.000 abstract description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 117
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 103
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 82
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 79
- 239000000243 solution Substances 0.000 description 76
- NYCVCXMSZNOGDH-UHFFFAOYSA-N pyrrolidine-1-carboxylic acid Chemical compound OC(=O)N1CCCC1 NYCVCXMSZNOGDH-UHFFFAOYSA-N 0.000 description 70
- 238000002360 preparation method Methods 0.000 description 67
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 62
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 60
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 47
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 43
- 239000007787 solid Substances 0.000 description 41
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 39
- 235000019439 ethyl acetate Nutrition 0.000 description 39
- 238000006243 chemical reaction Methods 0.000 description 34
- 239000002904 solvent Substances 0.000 description 33
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 28
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 27
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 26
- 229920006395 saturated elastomer Polymers 0.000 description 26
- 239000000543 intermediate Substances 0.000 description 25
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- 238000010898 silica gel chromatography Methods 0.000 description 24
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 23
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- 239000007864 aqueous solution Substances 0.000 description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 19
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 19
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 17
- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 description 16
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 16
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 15
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 15
- 239000010410 layer Substances 0.000 description 15
- 229910052757 nitrogen Inorganic materials 0.000 description 14
- 239000011780 sodium chloride Substances 0.000 description 14
- 102100040214 Apolipoprotein(a) Human genes 0.000 description 13
- 239000012044 organic layer Substances 0.000 description 13
- 239000012074 organic phase Substances 0.000 description 13
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 12
- 101710115418 Apolipoprotein(a) Proteins 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 11
- 239000000706 filtrate Substances 0.000 description 11
- 239000000047 product Substances 0.000 description 11
- 235000019260 propionic acid Nutrition 0.000 description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 9
- 230000005764 inhibitory process Effects 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- 238000004007 reversed phase HPLC Methods 0.000 description 9
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 8
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 8
- 238000000338 in vitro Methods 0.000 description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 7
- 239000005416 organic matter Substances 0.000 description 7
- 239000002245 particle Substances 0.000 description 7
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 7
- 239000011734 sodium Substances 0.000 description 7
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 7
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 7
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 6
- 108010007622 LDL Lipoproteins Proteins 0.000 description 6
- 102000007330 LDL Lipoproteins Human genes 0.000 description 6
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 6
- 150000001299 aldehydes Chemical class 0.000 description 6
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 6
- 239000012230 colorless oil Substances 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 5
- 125000004208 3-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C([H])C(*)=C1[H] 0.000 description 5
- SLXKOJJOQWFEFD-UHFFFAOYSA-N 6-aminohexanoic acid Chemical compound NCCCCCC(O)=O SLXKOJJOQWFEFD-UHFFFAOYSA-N 0.000 description 5
- ADYNQDSPVWDXIH-ZFWWWQNUSA-N BrC=1C=C(C=CC=1)C[C@H](C(=O)O)[C@@H]1CN(CC1)C(=O)OC(C)(C)C Chemical compound BrC=1C=C(C=CC=1)C[C@H](C(=O)O)[C@@H]1CN(CC1)C(=O)OC(C)(C)C ADYNQDSPVWDXIH-ZFWWWQNUSA-N 0.000 description 5
- 101000889990 Homo sapiens Apolipoprotein(a) Proteins 0.000 description 5
- 239000005909 Kieselgur Substances 0.000 description 5
- 108010028554 LDL Cholesterol Proteins 0.000 description 5
- 230000027455 binding Effects 0.000 description 5
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 5
- 229910000024 caesium carbonate Inorganic materials 0.000 description 5
- 239000003636 conditioned culture medium Substances 0.000 description 5
- 238000010511 deprotection reaction Methods 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 238000004898 kneading Methods 0.000 description 5
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- 235000019198 oils Nutrition 0.000 description 5
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 238000006268 reductive amination reaction Methods 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- FESDUDPSRMWIDL-UHFFFAOYSA-N tert-butyl n,n'-di(propan-2-yl)carbamimidate Chemical compound CC(C)NC(OC(C)(C)C)=NC(C)C FESDUDPSRMWIDL-UHFFFAOYSA-N 0.000 description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- KAKZBPTYRLMSJV-UHFFFAOYSA-N Butadiene Chemical compound C=CC=C KAKZBPTYRLMSJV-UHFFFAOYSA-N 0.000 description 4
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 4
- 229910021529 ammonia Inorganic materials 0.000 description 4
- 238000003556 assay Methods 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 239000012141 concentrate Substances 0.000 description 4
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 4
- 208000035475 disorder Diseases 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 4
- 239000012299 nitrogen atmosphere Substances 0.000 description 4
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 4
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- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 3
- KPZGRMZPZLOPBS-UHFFFAOYSA-N 1,3-dichloro-2,2-bis(chloromethyl)propane Chemical compound ClCC(CCl)(CCl)CCl KPZGRMZPZLOPBS-UHFFFAOYSA-N 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 3
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- 101000889953 Homo sapiens Apolipoprotein B-100 Proteins 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 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 1
- 108010033266 Lipoprotein(a) Proteins 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 238000006751 Mitsunobu reaction Methods 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- 101710163270 Nuclease Proteins 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 229910052770 Uranium Inorganic materials 0.000 description 1
- 235000000760 Wasabia japonica Nutrition 0.000 description 1
- 108010046516 Wheat Germ Agglutinins Proteins 0.000 description 1
- 239000012391 XPhos Pd G2 Substances 0.000 description 1
- WDRJIRIMKOQABQ-UHFFFAOYSA-N [2-chloro-6-(2,4,6-tripropylphenyl)phenyl]-dicyclohexylphosphane Chemical group ClC=1C(=C(C=CC=1)C1=C(C=C(C=C1CCC)CCC)CCC)P(C1CCCCC1)C1CCCCC1 WDRJIRIMKOQABQ-UHFFFAOYSA-N 0.000 description 1
- UJQAHAANAPEYLR-UHFFFAOYSA-N [2-chloro-6-[2,4,6-tri(propan-2-yl)phenyl]phenyl]-dicyclohexylphosphane Chemical group CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC(Cl)=C1P(C1CCCCC1)C1CCCCC1 UJQAHAANAPEYLR-UHFFFAOYSA-N 0.000 description 1
- CSKBKBXBXCCPSO-UWJYYQICSA-N [C@H]([C@H]1CCNC1)(C(=O)O)CC1=CC(N2CCN(C2=O)C2=CC(=CC=C2)OC)=CC=C1 Chemical compound [C@H]([C@H]1CCNC1)(C(=O)O)CC1=CC(N2CCN(C2=O)C2=CC(=CC=C2)OC)=CC=C1 CSKBKBXBXCCPSO-UWJYYQICSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 230000002785 anti-thrombosis Effects 0.000 description 1
- 239000002518 antifoaming agent Substances 0.000 description 1
- 238000002617 apheresis Methods 0.000 description 1
- 239000006286 aqueous extract Substances 0.000 description 1
- 239000012131 assay buffer Substances 0.000 description 1
- 230000003143 atherosclerotic effect Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- ISYGJZCYFUUIRO-UHFFFAOYSA-N azane;pyrrolidine-1-carboxylic acid Chemical compound N.OC(=O)N1CCCC1 ISYGJZCYFUUIRO-UHFFFAOYSA-N 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- ZCILODAAHLISPY-UHFFFAOYSA-N biphenyl ether Natural products C1=C(CC=C)C(O)=CC(OC=2C(=CC(CC=C)=CC=2)O)=C1 ZCILODAAHLISPY-UHFFFAOYSA-N 0.000 description 1
- 125000006267 biphenyl group Chemical group 0.000 description 1
- 125000006269 biphenyl-2-yl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C1=C(*)C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 150000001649 bromium compounds Chemical group 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 210000002421 cell wall Anatomy 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- RSLSVURFMXHEEU-UHFFFAOYSA-M chloropalladium(1+);dicyclohexyl-[3-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphane;2-phenylaniline Chemical compound [Pd+]Cl.NC1=CC=CC=C1C1=CC=CC=[C-]1.CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC(P(C2CCCCC2)C2CCCCC2)=C1 RSLSVURFMXHEEU-UHFFFAOYSA-M 0.000 description 1
- 238000012875 competitive assay Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 1
- DMBHHRLKUKUOEG-UHFFFAOYSA-N diphenylamine Chemical class C=1C=CC=CC=1NC1=CC=CC=C1 DMBHHRLKUKUOEG-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- SACNIGZYDTUHKB-UHFFFAOYSA-N ditert-butyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphane Chemical group CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC=C1P(C(C)(C)C)C(C)(C)C SACNIGZYDTUHKB-UHFFFAOYSA-N 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 238000003821 enantio-separation Methods 0.000 description 1
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 1
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229940125753 fibrate Drugs 0.000 description 1
- 230000020764 fibrinolysis Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 238000005111 flow chemistry technique Methods 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- FATAVLOOLIRUNA-UHFFFAOYSA-N formylmethyl Chemical group [CH2]C=O FATAVLOOLIRUNA-UHFFFAOYSA-N 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- ZTQSADJAYQOCDD-UHFFFAOYSA-N ginsenoside-Rd2 Natural products C1CC(C2(CCC3C(C)(C)C(OC4C(C(O)C(O)C(CO)O4)O)CCC3(C)C2CC2O)C)(C)C2C1C(C)(CCC=C(C)C)OC(C(C(O)C1O)O)OC1COC1OCC(O)C(O)C1O ZTQSADJAYQOCDD-UHFFFAOYSA-N 0.000 description 1
- 239000003365 glass fiber Substances 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- YAMHXTCMCPHKLN-UHFFFAOYSA-N imidazolidin-2-one Chemical compound O=C1NCCN1 YAMHXTCMCPHKLN-UHFFFAOYSA-N 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 1
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- RMNJNEUWTBBZPT-UHFFFAOYSA-N methyl 4-nitrobenzenesulfonate Chemical compound COS(=O)(=O)C1=CC=C([N+]([O-])=O)C=C1 RMNJNEUWTBBZPT-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- DBNQIOANXZVWIP-UHFFFAOYSA-N n,n-dimethyl-1,1-bis[(2-methylpropan-2-yl)oxy]methanamine Chemical compound CC(C)(C)OC(N(C)C)OC(C)(C)C DBNQIOANXZVWIP-UHFFFAOYSA-N 0.000 description 1
- DAZXVJBJRMWXJP-UHFFFAOYSA-N n,n-dimethylethylamine Chemical compound CCN(C)C DAZXVJBJRMWXJP-UHFFFAOYSA-N 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 230000009871 nonspecific binding Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 102000013415 peroxidase activity proteins Human genes 0.000 description 1
- 108040007629 peroxidase activity proteins Proteins 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229920002102 polyvinyl toluene Polymers 0.000 description 1
- 238000007867 post-reaction treatment Methods 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 239000013014 purified material Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 150000003235 pyrrolidines Chemical class 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000002287 radioligand Substances 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000009287 sand filtration Methods 0.000 description 1
- 238000010956 selective crystallization Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 238000011301 standard therapy Methods 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- NVBFHJWHLNUMCV-UHFFFAOYSA-N sulfamide Chemical compound NS(N)(=O)=O NVBFHJWHLNUMCV-UHFFFAOYSA-N 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- RUPAXCPQAAOIPB-UHFFFAOYSA-N tert-butyl formate Chemical compound CC(C)(C)OC=O RUPAXCPQAAOIPB-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000011285 therapeutic regimen Methods 0.000 description 1
- 230000002885 thrombogenetic effect Effects 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 1
- 235000019798 tripotassium phosphate Nutrition 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 229910052720 vanadium Inorganic materials 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- 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
- C07D401/12—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 linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- 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
-
- 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
- C07D401/14—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 three or more hetero rings
-
- 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
- C07D403/14—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 three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Obesity (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Epidemiology (AREA)
- Pyrrole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Description
Lは、−CH2NHCH2−、−CH2NH−、−NH−、−S−、−S(O)−、−S(O)2−、−O−、−OCH2−、−OCH2CH2O−、−NHSO2NH−、
R1、R2、R3、R4、R5、およびR6は、それぞれ独立して、HおよびCH3からなる群から選択される、式I’の化合物、または
その薬学的に許容される塩が提供される。
tert−ブチル(3R)−3−[2−[(4S)−4−ベンジル−2−オキソ−オキサゾリジン−3−イル]−2−オキソ−エチル]ピロリジン−1−カルボキシレート
tert−ブチル(3S)−3−[2−[(4R)−4−ベンジル−2−オキソ−オキサゾリジン−3−イル]−2−オキソ−エチル]ピロリジン−1−カルボキシレート
tert−ブチル(3R)−3−(2−メトキシ−2−オキソ−エチル)ピロリジン−1−カルボキシレート
tert−ブチル(3R)−3−[1−[(3−ブロモフェニル)メチル]−2−メトキシ−2−オキソ−エチル]ピロリジン−1−カルボキシレート
3−(3−ブロモフェニル)−2−[(3R)−1−tert−ブトキシカルボニルピロリジン−3−イル]−2−メチル−プロパン酸
tert−ブチル(3R)−3−[(1S)−2−[(4S)−4−ベンジル−2−オキソ−オキサゾリジン−3−イル]−1−[(3−ブロモフェニル)メチル]−2−オキソ−エチル]ピロリジン−1−カルボキシレート
tert−ブチル(3S)−3−[(1R)−2−[(4R)−4−ベンジル−2−オキソ−オキサゾリジン−3−イル]−1−[(3−ブロモフェニル)メチル]−2−オキソ−エチル]ピロリジン−1−カルボキシレート
tert−ブチル(3R)−3−[(1S)−2−[(4S)−4−ベンジル−2−オキソ−オキサゾリジン−3−イル]−1−[(3−ニトロフェニル)メチル]−2−オキソ−エチル]ピロリジン−1−カルボキシレート
tert−ブチル(3R)−3−[(1S)−1−ベンジル−2−[(4S)−4−ベンジル−2−オキソ−オキサゾリジン−3−イル]−2−オキソ−エチル]ピロリジン−1−カルボキシレート
(2S)−3−(3−ブロモフェニル)−2−[(3R)−1−tert−ブトキシカルボニルピロリジン−3−イル]プロパン酸
アンモニウム;(2S)−3−(3−ブロモフェニル)−2−[(3R)−1−tert−ブトキシカルボニルピロリジン−3−イル]プロパノエート
アンモニウム;(2R)−3−(3−ブロモフェニル)−2−[(3S)−1−tert−ブトキシカルボニルピロリジン−3−イル]プロパノエート
(2S)−2−[(3R)−1−tert−ブトキシカルボニルピロリジン−3−イル]−3−(3−ニトロフェニル)プロパン酸
(2S)−2−[(3R)−1−tert−ブトキシカルボニルピロリジン−3−イル]−3−フェニル−プロパン酸
(2R)−2−[(3S)−1−tert−ブトキシカルボニルピロリジン−3−イル]−3−フェニル−プロパン酸
tert−ブチル(3R)−3−[(1S)−1−[(3−ブロモフェニル)メチル]−2−tert−ブトキシ−2−オキソ−エチル]ピロリジン−1−カルボキシレート
tert−ブチル(3R)−3−[1−[(3−ブロモフェニル)メチル]−2−tert−ブトキシ−1−メチル−2−オキソ−エチル]ピロリジン−1−カルボキシレート
tert−ブチル(3R)−3−[(1S)−2−tert−ブトキシ−1−[(3−ニトロフェニル)メチル]−2−オキソ−エチル]ピロリジン−1−カルボキシレート
tert−ブチル(3R)−3−[(1S)−2−tert−ブトキシ−1−[(3−ホルミルフェニル)メチル]−2−オキソ−エチル]ピロリジン−1−カルボキシレート
tert−ブチル(3R)−3−[2−tert−ブトキシ−1−[(3−ホルミルフェニル)メチル]−1−メチル−2−オキソ−エチル]ピロリジン−1−カルボキシレート
tert−ブチル(3R)−3−[(1S)−2−tert−ブトキシ−1−[[3−[ヒドロキシイミノメチル]フェニル]メチル]−2−オキソ−エチル]ピロリジン−1−カルボキシレート
tert−ブチル(3R)−3−[(1S)−1−[[3−(アミノメチル)フェニル]メチル]−2−tert−ブトキシ−2−オキソ−エチル]ピロリジン−1−カルボキシレート
tert−ブチル(3R)−3−[(1S)−1−[(3−アミノフェニル)メチル]−2−tert−ブトキシ−2−オキソ−エチル]ピロリジン−1−カルボキシレート
tert−ブチル(3R)−3−[(1S)−2−tert−ブトキシ−1−[[3−(ヒドロキシメチル)フェニル]メチル]−2−オキソ−エチル]ピロリジン−1−カルボキシレート
[3−[(2S)−3−tert−ブトキシ−2−[(3R)−1−tert−ブトキシカルボニルピロリジン−3−イル]−3−オキソ−プロピル]フェニル]ボロン酸
tert−ブチル(3R)−3−[(1S)−2−tert−ブトキシ−1−[(3−ヒドロキシフェニル)メチル]−2−オキソ−エチル]ピロリジン−1−カルボキシレート
tert−ブチル(3R)−3−[(1S)−2−tert−ブトキシ−1−[[3−[[[[3−[(2S)−3−tert−ブトキシ−2−[(3R)−1−tert−ブトキシカルボニルピロリジン−3−イル]−3−オキソ−プロピル]フェニル]メチル]アミノ]メチル]フェニル]メチル]−2−オキソ−エチル]ピロリジン−1−カルボキシレート
tert−ブチル(3R)−3−[(1S)−1−[[3−[[ビス[[3−[(2S)−3−tert−ブトキシ−2−[(3R)−1−tert−ブトキシカルボニルピロリジン−3−イル]−3−オキソ−プロピル]フェニル]メチル]アミノ]メチル]フェニル]メチル]−2−tert−ブトキシ−2−オキソ−エチル]ピロリジン−1−カルボキシレートおよびtert−ブチル(3R)−3−[(1S)−2−tert−ブトキシ−1−[[3−[[[[3−[(2S)−3−tert−ブトキシ−2−[(3R)−1−tert−ブトキシカルボニルピロリジン−3−イル]−3−オキソ−プロピル]フェニル]メチル]アミノ]メチル]フェニル]メチル]−2−オキソ−エチル]ピロリジン−1−カルボキシレート
丸底フラスコに、tert−ブチル(3R)−3−[(1S)−2−tert−ブトキシ−1−[(3−ホルミルフェニル)メチル]−2−オキソ−エチル]ピロリジン−1−カルボキシレート(222g、550mmol)、2−プロパノール(888mL)およびアンモニア溶液(2−プロパノール中2M、302.6mL、605.2mmol、1.1当量)を入れる。氷水浴で混合物を0〜5℃に冷却する。トリアセトキシ水素化ホウ素ナトリウム(116.6g、550.2mmol、1当量)を4回に分けて添加し、各部分を添加する間隔を40分にする。この混合物を室温で一晩撹拌する。溶媒を蒸発乾固させる。残渣に水(200mL)、K2HPO4水溶液(300mL)を添加し、MTBE(2×500mL)で水層を抽出する。有機層をMgSO4で乾燥させ、濾過し、濃縮乾固させる。ヘキサン中の20〜80%のEtOAcの勾配を使用するシリカゲルクロマトグラフィーにより残渣を精製して、tert−ブチル(3R)−3−[(1S)−1−[[3−[[biS[[3−[(2S)−3−tert−ブトキシ−2−[(3R)−1−tert−ブトキシカルボニルピロリジン−3−イル]−3−オキソ−プロピル]フェニル]メチル]アミノ]メチル]フェニル]メチル]−2−tert−ブトキシ−2−オキソ−エチル]ピロリジン−1−カルボキシレート(57.8g、27%)を白色固形物として得る。1H−NMR(400MHz、CDCl3)δ7.30−7.24(m、6H)、7.12(S、3H)、7.04(S、3H)、3.75−3.43(m、12H)、3.30−3.21(m、3H)、3.10−2.96(m、3H)、2.89−2.76(m、6H)、2.49(d、J=4.7Hz、3H)、2.37(dd、J=7.2、14.4Hz、3H)、1.98−1.90(m、3H)、1.74−1.61(m、3H)、1.48(S、27H)、1.22(S、27H)。
丸底フラスコにtert−ブチル(3R)−3−[(1S)−2−tert−ブトキシ−1−[[3−[[[[3−[(2S)−3−tert−ブトキシ−2−[(3R)−1−tert−ブトキシカルボニルピロリジン−3−イル]−3−オキソ−プロピル]フェニル]メチル]アミノ]メチル]フェニル]メチル]−2−オキソ−エチル]ピロリジン−1−カルボキシレート(90重量%の純度、81.5g、92.6mmol)、tert−ブチル(3R)−3−[(1S)−2−tert−ブトキシ−1−[(3−ホルミルフェニル)メチル]−2−オキソ−エチル]ピロリジン−1−カルボキシレート(純度85重量%、50.6g、106mmol、1.15当量)、2−プロパノール(652mL)および酢酸(5.31mL、92.6mmol、1当量)に入れ、混合物を30分間撹拌する。トリアセトキシ水素化ホウ素ナトリウム(2当量、185mmol、39.3g)を混合物に添加し、室温で2時間撹拌し、次いで反応混合物を真空中で濃縮する。残渣に水(200mL)およびMTBE(300mL)を添加し、次いで濃水酸化アンモニウム水溶液を添加して、pH9〜10に調整する。有機相を分離し、MgSO4上で乾燥させ、濾過し、濃縮乾固させる。ヘキサン中の20〜40%のEtOAcの勾配を使用するシリカゲルクロマトグラフィーにより残渣を精製して、tert−ブチル(3R)−3−[(1S)−1−[[3−[[biS[[3−[(2S)−3−tert−ブトキシ−2−[(3R)−1−tert−ブトキシカルボニルピロリジン−3−イル]−3−オキソ−プロピル]フェニル]メチル]アミノ]メチル]フェニル]メチル]−2−tert−ブトキシ−2−オキソ−エチル]ピロリジン−1−カルボキシレート(89g、82%)を白色固形物として得る。
tert−ブチル(3R)−3−[(1S)−2−tert−ブトキシ−1−[[3−[[[3−[(2S)−3−tert−ブトキシ−2−[(3R)−1−tert−ブトキシカルボニルピロリジン−3−イル]−3−オキソ−プロピル]フェニル]メチル−[(3−フルオロ−5−メトキシ−フェニル)メチル]アミノ]メチル]フェニル]メチル]−2−オキソ−エチル]ピロリジン−1−カルボキシレート
tert−ブチル(3R)−3−[1−[[3−[[ビス[[3−[3−tert−ブトキシ−2−[(3R)−1−tert−ブトキシカルボニルピロリジン−3−イル]−2−メチル−3−オキソ−プロピル]フェニル]メチル]アミノ]メチル]フェニル]メチル]−2−tert−ブトキシ−1−メチル−2−オキソ−エチル]ピロリジン−1−カルボキシレート
tert−ブチル(3R)−3−[(1S)−2−tert−ブトキシ−1−[[3−[3−[(2S)−3−tert−ブトキシ−2−[(3R)−1−tert−ブトキシカルボニルピロリジン−3−イル]−3−オキソ−プロピル]フェノキシ]フェニル]メチル]−2−オキソ−エチル]ピロリジン−1−カルボキシレート
tert−ブチル(3R)−3−[(1S)−2−tert−ブトキシ−1−[[3−[2−[3−[(2S)−3−tert−ブトキシ−2−[(3R)−1−tert−ブトキシカルボニルピロリジン−3−イル]−3−オキソ−プロピル]フェノキシ]エトキシ]フェニル]メチル]−2−オキソ−エチル]ピロリジン−1−カルボキシレート
tert−ブチル(3R)−3−[(1S)−2−tert−ブトキシ−1−[[3−[[3−[(2S)−3−tert−ブトキシ−2−[(3R)−1−tert−ブトキシカルボニルピロリジン−3−イル]−3−オキソ−プロピル]フェノキシ]メチル]フェニル]メチル]−2−オキソ−エチル]ピロリジン−1−カルボキシレート
tert−ブチル(3R)−3−[(1S)−2−tert−ブトキシ−1−[[3−[3−[(2S)−3−tert−ブトキシ−2−[(3R)−1−tert−ブトキシカルボニルピロリジン−3−イル]−3−オキソ−プロピル]フェニル]スルファニルフェニル]メチル]−2−オキソ−エチル]ピロリジン−1−カルボキシレート
tert−ブチル(3R)−3−[(1S)−2−tert−ブトキシ−1−[[3−[3−[(2S)−3−tert−ブトキシ−2−[(3R)−1−tert−ブトキシカルボニルピロリジン−3−イル]−3−オキソ−プロピル]フェニル]スルフィニルフェニル]メチル]−2−オキソ−エチル]ピロリジン−1−カルボキシレート
tert−ブチル(3R)−3−[(1S)−2−tert−ブトキシ−1−[[3−[3−[(2S)−3−tert−ブトキシ−2−[(3R)−1−tert−ブトキシカルボニルピロリジン−3−イル]−3−オキソ−プロピル]フェニル]スルホニルフェニル]メチル]−2−オキソ−エチル]ピロリジン−1−カルボキシレート
tert−ブチル(3R)−3−[(1S)−2−tert−ブトキシ−1−[[3−[[3−[(2S)−3−tert−ブトキシ−2−[(3R)−1−tert−ブトキシカルボニルピロリジン−3−イル]−3−オキソ−プロピル]アニリノ]メチル]フェニル]メチル]−2−オキソ−エチル]ピロリジン−1−カルボキシレート
(2S)−3−[3−[3−[(2S)−3−tert−ブトキシ−2−[(3R)−1−tert−ブトキシカルボニルピロリジン−3−イル]−3−オキソ−プロピル]アニリノ]フェニル]−2−[(3R)−1−tert−ブトキシカルボニルピロリジン−3−イル]プロパン酸
ジ−tert−ブチル3,3’−((2S,2’S)−((スルホニルビス(アザネジイル))ビス(3,1−フェニレン))ビス(3−(tert−ブトキシ)−3−オキソプロパン−1,2−ジイル))(3R,3’R)−ビス(ピロリジン−1−カルボキシレート)
(2S)−3−[3−[[ビス[[3−[(2S)−2−カルボキシ−2−[(3R)−ピロリジン−3−イル]エチル]フェニル]メチル]アミノ]メチル]フェニル]−2−[(3R)−ピロリジン−3−イル]プロパン酸、四塩酸塩
(2S)−3−[3−[[ビス[[3−[(2S)−2−カルボキシ−2−[(3R)−ピロリジン−3−イル]エチル]フェニル]メチル]アミノ]メチル]フェニル]−2−[(3R)−ピロリジン−3−イル]プロパン酸
(2S)−3−[3−[[[3−[(2S)−2−カルボキシ−2−[(3R)−ピロリジン−3−イル]エチル]フェニル]メチルアミノ]メチル]フェニル]−2−[(3R)−ピロリジン−3−イル]プロパン酸、三塩酸塩
(2S)−3−[3−[[[3−[(2S)−2−カルボキシ−2−[(3R)−ピロリジン−3−イル]エチル]フェニル]メチル−[(3−フルオロ−5−メトキシ−フェニル)メチル]アミノ]メチル]フェニル]−2−[(3R)−ピロリジン−3−イル]プロパン酸
(2S)−3−[3−[[[3−[(2S)−2−カルボキシ−2−[(3R)−ピロリジン−3−イル]エチル]フェニル]メチル−[(3−フルオロ−5−メトキシ−フェニル)メチル]アミノ]メチル]フェニル]−2−[(3R)−ピロリジン−3−イル]プロパン酸、三塩酸塩
3−[3−[[ビス[[3−[2−カルボキシ−2−[(3R)−ピロリジン−3−イル]プロピル]フェニル]メチル]アミノ]メチル]フェニル]−2−メチル−2−[(3R)−ピロリジン−3−イル]プロパン酸、四塩酸塩
(2S)−3−[3−[3−[(2S)−2−カルボキシ−2−[(3R)−ピロリジン−3−イル]エチル]フェノキシ]フェニル]−2−[(3R)−ピロリジン−3−イル]プロパン酸、二塩酸塩
(2S)−3−[3−[2−[3−[(2S)−2−カルボキシ−2−[(3R)−ピロリジン−3−イル]エチル]フェノキシ]エトキシ]フェニル]−2−[(3R)−ピロリジン−3−イル]プロパン酸、二塩酸塩
(2S)−3−[3−[[3−[(2S)−2−カルボキシ−2−[(3R)−ピロリジン−3−イル]エチル]フェノキシ]メチル]フェニル]−2−[(3R)−ピロリジン−3−イル]プロパン酸、二塩酸塩
(2S)−3−[3−[3−[(2S)−2−カルボキシ−2−[(3R)−ピロリジン−3−イル]エチル]フェニル]スルファニルフェニル]−2−[(3R)−ピロリジン−3−イル]プロパン酸、二塩酸塩
(2S)−3−[3−[3−[(2S)−2−カルボキシ−2−[(3R)−ピロリジン−3−イル]エチル]フェニル]スルフィニルフェニル]−2−[(3R)−ピロリジン−3−イル]プロパン酸、二塩酸塩
(2S)−3−[3−[3−[(2S)−2−カルボキシ−2−[(3R)−ピロリジン−3−イル]エチル]フェニル]スルホニルフェニル]−2−[(3R)−ピロリジン−3−イル]プロパン酸、二塩酸塩
(2S)−3−[3−[[3−[(2S)−2−カルボキシ−2−[(3R)−ピロリジン−3−イル]エチル]アニリノ]メチル]フェニル]−2−[(3R)−ピロリジン−3−イル]プロパン酸、三塩酸塩
(2S)−3−[3−[[3−[(2S)−2−カルボキシ−2−[(3R)−ピロリジン−3−イル]エチル]アニリノ]フェニル]−2−[(3R)−ピロリジン−3−イル]プロパン酸、二塩酸塩
(2S)−3−[3−[[3−[(2S)−2−カルボキシ−2−[(3R)−1−メチルピロリジン−3−イル]エチル]アニリノ]フェニル]−2−[(3R)−1−メチルピロリジン−3−イル]プロパン酸、二塩酸塩
(2S,2’S)−3,3’−[スルホニルビス(アザンジイル−3,1−フェニレン)]ビス{2−[(3R)−ピロリジン−3−イル]プロパン酸}、二塩酸塩
(2S)−3−フェニル−2−[(3R)−ピロリジン−3−イル]プロパン酸、塩酸塩
(2R)−3−フェニル−2−[(3S)−ピロリジン−3−イル]プロパン酸、塩酸塩
調製物40
1−(3−ベンジルオキシフェニル)イミダゾリジン−2−オン
(2S)−3−[3−[3−(3−ベンジルオキシフェニル)−2−オキソ−イミダゾリジン−1−イル]フェニル]−2−[(3R)−1−tert−ブトキシカルボニルピロリジン−3−イル]プロパン酸
tert−ブチル(3R)−3−[(1S)−1−[[3−[3−(3−ベンジルオキシフェニル)−2−オキソ−イミダゾリジン−1−イル]フェニル]メチル]−2−tert−ブトキシ−2−オキソ−エチル]ピロリジン−1−カルボキシレート
tert−ブチル(3R)−3−[(1S)−2−tert−ブトキシ−1−[[3−[3−(3−ヒドロキシフェニル)−2−オキソ−イミダゾリジン−1−イル]フェニル]メチル]−2−オキソ−エチル]ピロリジン−1−カルボキシレート
tert−ブチル(3R)−3−[(1S)−2−tert−ブトキシ−2−オキソ−1−[[3−[2−オキソ−3−[3−(トリトリチオメトキシ)フェニル]イミダゾリジン−1−イル]フェニル]メチル]エチル]ピロリジン−1−カルボキシレート
(2S)−3−[3−[2−オキソ−3−[3−(トリトリチオメトキシ)フェニル]イミダゾリジン−1−イル]フェニル]−2−[(3R)−ピロリジン−3−イル]プロパン酸、塩酸塩
1−(3−メトキシフェニル)イミダゾリジン−2−オン
(2S)−2−[(3R)−1−tert−ブトキシカルボニルピロリジン−3−イル]−3−[3−[3−(3−メトキシフェニル)−2−オキソ−イミダゾリジン−1−イル]フェニル]プロパン酸
(2S)−3−[3−[2−オキソ−3−[3−(メトキシ)フェニル]イミダゾリジン−1−イル]フェニル]−2−[(3R)−ピロリジン−3−イル]プロパン酸、塩酸塩
インビトロApo(a)結合アッセイ
目的の標的ヒトApo(a)タンパク質に対する化合物のインビトロ結合親和性を、競合結合アッセイで試験する。17個のクリングルリピートを含有するヒトApo(a)タンパク質を、一過性にトランスフェクトされたHEK−293F細胞の馴化培地から親和性精製する。すべての試薬は、50mMのTris−HCl pH7.4、0.1%のBSAを含有するアッセイ緩衝液中で調製する。結合アッセイは、透明底プレートの各ウェルに、(1)希釈系列の試験化合物(最終濃度0.32〜10000nM)、(2)Apo(a)タンパク質(6ng/ウェル)、(3)再懸濁した小麦胚芽凝集素ポリビニルトルエンSPAビーズ(20mg/mL)、および(4)放射性リガンド、トリチウム標識(2S)−3−[3−[2−オキソ−3−[3−(トリトリチオメトキシ)フェニル]イミダゾリジン−1−イル]フェニル]−2−[(3R)−ピロリジン−3−イル]プロパン酸;、塩酸塩(最終濃度0.52nM)のそれぞれ50μlを添加することによって行う。プレートを室温で60分間インキュベートし、TRILUX LSCでカウントする。非特異的結合、10μMの低温(すなわち、非放射性標識)リガンドの存在下での結合として定義され、(2S)−3−[3−[2−オキソ−3−[3−(メトキシ)フェニル]イミダゾリジン−1−イル]フェニル]−2−[(3R)−ピロリジン−3−イル]プロパン酸、塩酸塩を差し引いて、特異的結合を決定する。標準的な単一部位結合モデルに適合させることによってデータを分析し、例示的試験化合物のIC50を決定する。これらの結果は表1に要約されており、試験化合物の例がヒトApo(a)タンパク質に結合することを示している。Apo(a)タンパク質への結合を介したapo(a)によるLDL粒子の集合体の阻害は、Lp(a)レベルの低下を支持する。
化合物がインビトロでLp(a)粒子の形成を阻害する能力は、無細胞集合アッセイによって評価される。馴化培地(10%のFBS、20mMのHEPES、および1xペニシリン/ストレプトマイシンを添加したDMEM)は、37℃および5%のCO2で24時間培養した後、コンフルエントな野生型HepG2細胞(内因的に発現するApoBの供給源)から、および17個のクリングルリピートを含有するヒトApo(a)を発現するHEK293安定細胞株(1mg/mlのジェネティシンで選択された)から回収される。等量のHepG2およびHEK293馴化培地を希釈系列(最終濃度0.01〜100nM)で添加した試験化合物と組み合わせることにより、インビトロ集合アッセイを実施する。反応を37℃で2時間インキュベートし、次いで6−アミノカプロン酸(EACA)を最終濃度150mMまで添加して停止させる。Lp(a)は、抗Lp(a)捕捉抗体とHRP結合抗ApoB検出抗体を用いたサンドイッチELISAを使用して検出される。ELISAはTMBを使用して発色され、1Nの硫酸を使用して停止され、シグナルはMolecular Devicesプレートリーダーで450nmで読み取られる。各試験条件で形成されたLp(a)の阻害%は、阻害剤が存在しない(DMSO濃度が1%に一致する)集合反応を0%の阻害に設定し、存在する最小量のHepG2馴化培地(50倍希釈)を100%阻害に設定する。表2に要約されているIC50値を決定するために、データは4パラメータ曲線に適合される。表2に要約されているように、ApoBおよびApo(a)を含有する馴化培地への例示的な試験化合物の添加は、インビトロでのLp(a)形成の濃度依存性阻害をもたらす。結果は、これらの化合物がApo(a)およびLDL粒子からのLp(a)の集合体を阻害することを示している。
インビボで定常状態のLp(a)レベルを低下させる化合物の能力は、ヒト化Lp(a)粒子を産生することができるトランスジェニックマウスモデルで評価する。Lp(a)ディスラプター化合物のインビボ効果は、ヒトapoB−100および17個のクリングルリピートを含有するヒトapo(a)を発現する7〜17か月齢の雌ダブルトランスジェニックマウスで試験する:B6.SJL−Tg(APOB)1102Sgy Tg(Alb−LPA)32Arte。マウスは、標準的な光サイクル(12時間明期/12時間暗期)、室温72±8°F、相対湿度30〜70%で飼育され、水と通常の固形飼料を自由に摂取できる状態にする(Harlan Tecklad diet 2014)。マウスは、研究のためにBRAT(ブロックランダム割付けツール)を使用して、体重およびベースライン血漿Lp(a)濃度によって、研究の3〜5日前に処置群(n=5/群)にランダム化される。マウスにビヒクル(経口投与ビヒクル:10mL/kg、1%のHEC、0.25%のTween80、0.01%の消泡剤、皮下投与ビヒクル:5mL/kgの生理食塩水)または試験化合物を様々な用量で、1日2回(6:30amおよび3:30pm)5日間経口投与(または記載されている場合は皮下投与)する。血液は、尾出血を介してヘパリンでコーティングされたキャピラリーチューブに回収する。各血液サンプルの20μLを、薬物曝露分析のためにDBSカード(Whatmanカタログ番号:WB12 9243)に付着させる。残りの血液サンプルは、血漿を分離するために遠心分離する。血漿中のLp(a)濃度は、インビトロLp(a)集合アッセイで説明したサンドイッチELISAを使用して測定する。各用量群の阻害%は、ビヒクル対照群の平均Lp(a)レベルを0%の阻害に設定して決定する。表3は、3日目の朝の経口投与の8時間後に尾出血サンプルを採取した用量反応試験の結果を示している。Ed50(50%のLp(a)を阻害するための有効量)の計算値は、閾値最小有効量の分析によって決定される。表4は、3日目の朝の経口投与(または記載されている場合は皮下投与)の4時間後(または記載されている場合は8時間)に尾出血サンプルを採取した単回投与試験の結果を示している。表3および4に示されるこれらの結果は、化合物がインビボで血漿Lp(a)レベルを低下させるのに有効であることを示し、化合物がLp(a)血漿濃度を低下させるために使用できるという命題を支持する。
Claims (25)
- R1がHであり、R3がHである、請求項1に記載の化合物、またはその薬学的に許容される塩。
- R5がHである、請求項1または2のいずれか一項に記載の化合物、またはその薬学的に許容される塩。
- R2がHであり、R4がHである、請求項1〜3のいずれか一項に記載の化合物、またはその薬学的に許容される塩。
- R6がHである、請求項1〜4のいずれか一項に記載の化合物、またはその薬学的に許容される塩。
- R2がCH3であり、R4がCH3である、請求項1〜3のいずれか一項に記載の化合物、またはその薬学的に許容される塩。
- R2がCH3であり、R4がCH3であり、R6がCH3である、請求項1〜3のいずれか一項に記載の化合物、またはその薬学的に許容される塩。
- Lが、−CH2NHCH2−、−CH2NH−、−NH−、−S−、−S(O)−、−S(O)2−、−O−、−OCH2−、−OCH2CH2O−、および−NHSO2NH−からなる群から選択される、請求項1、2、4または6のいずれか一項に記載の化合物、またはその薬学的に許容される塩。
- 前記化合物が塩酸塩である、請求項11に記載の化合物。
- 前記化合物が四塩酸塩である、請求項12に記載の化合物。
- 請求項1〜13のいずれか一項に記載の化合物、またはその薬学的に許容される塩と、少なくとも1つの薬学的に許容される担体、希釈剤、もしくは賦形剤とを含む、薬学的組成物。
- 心血管疾患の治療に使用するための、請求項14に記載の組成物。
- Lp(a)血漿レベルの上昇の治療に使用するための、請求項14に記載の組成物。
- 心血管疾患の治療を、それを必要とする患者において行うための方法であって、有効量の請求項1〜13のいずれか一項に記載の化合物、もしくはその薬学的に許容される塩、または請求項14に記載の組成物、もしくはその薬学的に許容される塩を投与することを含む、方法。
- Lp(a)血漿レベルの上昇を治療するための方法であって、有効量の請求項1〜13のいずれか一項に記載の化合物、もしくはその薬学的に許容される塩、または請求項14に記載の組成物、もしくはその薬学的に許容される塩を投与することを含む、方法。
- 治療に使用するための、請求項1〜13のいずれか一項に記載の化合物、またはその薬学的に許容される塩。
- 心血管疾患の治療に使用するための、請求項1〜13のいずれか一項に記載の化合物、またはその薬学的に許容される塩。
- Lp(a)血漿レベルの上昇の治療に使用するための、請求項1〜13のいずれか一項に記載の化合物、またはその薬学的に許容される塩。
- 心血管疾患を治療するための薬剤の製造に使用するための、請求項1〜13のいずれか一項に記載の化合物、またはその薬学的に許容可能な塩の使用。
- 請求項1〜13のいずれか一項に記載の化合物、またはその薬学的に許容される塩の使用であって、薬剤が、Lp(a)血漿レベルの上昇の治療において有用である、使用。
- 請求項24に記載の化合物、またはその薬学的に許容される塩と、少なくとも1つの薬学的に許容される担体、希釈剤、もしくは賦形剤とを含む、薬学的組成物。
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