DK2563122T3 - chemical compounds - Google Patents

Info

Publication number

DK2563122T3

DK2563122T3 DK11775513.2T DK11775513T DK2563122T3 DK 2563122 T3 DK2563122 T3 DK 2563122T3 DK 11775513 T DK11775513 T DK 11775513T DK 2563122 T3 DK2563122 T3 DK 2563122T3

Authority

DK

Denmark

Prior art keywords

mmol

phenyl

methyloxy

ethyl

tetrahydro

Prior art date

2010-04-27

Links

• Espacenet
• Global Dossier
• Discuss

• 150000001875 compounds Chemical class 0.000 title claims description 126
• 206010012601 diabetes mellitus Diseases 0.000 claims description 26
• 150000003839 salts Chemical class 0.000 claims description 23
• 239000003814 drug Substances 0.000 claims description 18
• 208000030159 metabolic disease Diseases 0.000 claims description 8
• 208000008589 Obesity Diseases 0.000 claims description 7
• 125000000217 alkyl group Chemical group 0.000 claims description 7
• 235000020824 obesity Nutrition 0.000 claims description 7
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
• 229910052757 nitrogen Inorganic materials 0.000 claims description 6
• 229910052794 bromium Inorganic materials 0.000 claims description 4
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
• 239000008194 pharmaceutical composition Substances 0.000 claims description 4
• 230000002265 prevention Effects 0.000 claims description 4
• 229910052739 hydrogen Inorganic materials 0.000 claims description 3
• 238000004519 manufacturing process Methods 0.000 claims description 3
• 229910052801 chlorine Inorganic materials 0.000 claims description 2
• 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
• 238000002560 therapeutic procedure Methods 0.000 claims 1
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 338
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 180
• 239000000243 solution Substances 0.000 description 164
• 229910001868 water Inorganic materials 0.000 description 162
• 239000011541 reaction mixture Substances 0.000 description 160
• 239000000203 mixture Substances 0.000 description 141
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 139
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 135
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 132
• 239000007787 solid Substances 0.000 description 132
• 238000005160 1H NMR spectroscopy Methods 0.000 description 116
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 108
• 238000006243 chemical reaction Methods 0.000 description 103
• 230000002829 reductive effect Effects 0.000 description 103
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 101
• 239000000543 intermediate Substances 0.000 description 100
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 87
• 238000000746 purification Methods 0.000 description 74
• QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 73
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 72
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 71
• 235000019439 ethyl acetate Nutrition 0.000 description 67
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 67
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 60
• WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 58
• 239000012044 organic layer Substances 0.000 description 56
• 239000010410 layer Substances 0.000 description 55
• 239000003921 oil Substances 0.000 description 54
• 235000019198 oils Nutrition 0.000 description 54
• 238000004007 reversed phase HPLC Methods 0.000 description 51
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 50
• 238000000524 positive electrospray ionisation mass spectrometry Methods 0.000 description 50
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 45
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 44
• 239000000741 silica gel Substances 0.000 description 44
• 229910002027 silica gel Inorganic materials 0.000 description 44
• 239000000047 product Substances 0.000 description 41
• IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 40
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 36
• 238000003756 stirring Methods 0.000 description 35
• 238000000034 method Methods 0.000 description 34
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 33
• 239000012267 brine Substances 0.000 description 30
• 239000012074 organic phase Substances 0.000 description 30
• PZYIRIHLNKVQKW-DHIUTWEWSA-N (3r,5r)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepine-8-carbaldehyde Chemical compound C1([C@@H]2C3=CC(OC)=C(C=O)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 PZYIRIHLNKVQKW-DHIUTWEWSA-N 0.000 description 26
• 229960000583 acetic acid Drugs 0.000 description 26
• 238000001914 filtration Methods 0.000 description 26
• 239000002002 slurry Substances 0.000 description 26
• WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 25
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 25
• VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 23
• 239000008346 aqueous phase Substances 0.000 description 22
• NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 22
• 235000011114 ammonium hydroxide Nutrition 0.000 description 21
• 239000003613 bile acid Substances 0.000 description 20
• 239000012071 phase Substances 0.000 description 20
• 208000001072 type 2 diabetes mellitus Diseases 0.000 description 20
• OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 19
• PMZXXNPJQYDFJX-UHFFFAOYSA-N acetonitrile;2,2,2-trifluoroacetic acid Chemical compound CC#N.OC(=O)C(F)(F)F PMZXXNPJQYDFJX-UHFFFAOYSA-N 0.000 description 19
• XXMFJKNOJSDQBM-UHFFFAOYSA-N 2,2,2-trifluoroacetic acid;hydrate Chemical compound [OH3+].[O-]C(=O)C(F)(F)F XXMFJKNOJSDQBM-UHFFFAOYSA-N 0.000 description 18
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
• WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 18
• 239000002253 acid Substances 0.000 description 18
• VFRSADQPWYCXDG-LEUCUCNGSA-N ethyl (2s,5s)-5-methylpyrrolidine-2-carboxylate;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.CCOC(=O)[C@@H]1CC[C@H](C)N1 VFRSADQPWYCXDG-LEUCUCNGSA-N 0.000 description 18
• 239000008103 glucose Substances 0.000 description 18
• DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical class C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 description 17
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 17
• 239000002904 solvent Substances 0.000 description 17
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 16
• BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 15
• IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 description 15
• 238000004587 chromatography analysis Methods 0.000 description 15
• 238000001816 cooling Methods 0.000 description 15
• 239000000706 filtrate Substances 0.000 description 15
• 101710198884 GATA-type zinc finger protein 1 Proteins 0.000 description 14
• 102400000322 Glucagon-like peptide 1 Human genes 0.000 description 14
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 14
• 229940079593 drug Drugs 0.000 description 14
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 13
• -1 diethanolamine salts Chemical class 0.000 description 13
• PXJFLUYRGQUUIN-UHFFFAOYSA-N dimethyl 3-aminopentanedioate Chemical compound COC(=O)CC(N)CC(=O)OC PXJFLUYRGQUUIN-UHFFFAOYSA-N 0.000 description 13
• 238000002360 preparation method Methods 0.000 description 13
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 12
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 12
• 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 12
• 210000004027 cell Anatomy 0.000 description 12
• 238000010992 reflux Methods 0.000 description 12
• 239000000377 silicon dioxide Substances 0.000 description 12
• WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 12
• NLCSQMQPMRVENI-FGZHOGPDSA-N (3r,5r)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepin-8-ol Chemical compound C1([C@@H]2C3=CC(OC)=C(O)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 NLCSQMQPMRVENI-FGZHOGPDSA-N 0.000 description 11
• 102000004877 Insulin Human genes 0.000 description 11
• 108090001061 Insulin Proteins 0.000 description 11
• 239000008280 blood Substances 0.000 description 11
• 210000004369 blood Anatomy 0.000 description 11
• 239000012230 colorless oil Substances 0.000 description 11
• 150000002148 esters Chemical class 0.000 description 11
• 238000004128 high performance liquid chromatography Methods 0.000 description 11
• 229940125396 insulin Drugs 0.000 description 11
• 239000000463 material Substances 0.000 description 11
• 239000008213 purified water Substances 0.000 description 11
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
• SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 10
• 238000005481 NMR spectroscopy Methods 0.000 description 10
• 150000001412 amines Chemical group 0.000 description 10
• JFCQEDHGNNZCLN-UHFFFAOYSA-N glutaric acid Chemical compound OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 10
• GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 10
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 10
• HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 description 9
• KBMAOLDNCSMGSE-DHIUTWEWSA-N (3r,5r)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepine-8-carbonitrile Chemical compound C1([C@@H]2C3=CC(OC)=C(C#N)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 KBMAOLDNCSMGSE-DHIUTWEWSA-N 0.000 description 9
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
• 239000007821 HATU Substances 0.000 description 9
• ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical compound OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 9
• VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 9
• 230000015572 biosynthetic process Effects 0.000 description 9
• KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
• RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 9
• 239000003960 organic solvent Substances 0.000 description 9
• NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 9
• 230000028327 secretion Effects 0.000 description 9
• ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 9
• PBIKLKFKYVHLRN-FYYLOGMGSA-N (3r,5r)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepine-8-carboxylic acid Chemical compound C1([C@@H]2C3=CC(OC)=C(C(O)=O)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 PBIKLKFKYVHLRN-FYYLOGMGSA-N 0.000 description 8
• TWOIQRCUTTZFTJ-FGZHOGPDSA-N (3r,5r)-3-butyl-3-ethyl-8-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepin-7-ol Chemical compound C1([C@@H]2C3=CC(O)=C(OC)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 TWOIQRCUTTZFTJ-FGZHOGPDSA-N 0.000 description 8
• 150000001299 aldehydes Chemical class 0.000 description 8
• 150000003863 ammonium salts Chemical class 0.000 description 8
• HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 8
• 239000000872 buffer Substances 0.000 description 8
• 239000003795 chemical substances by application Substances 0.000 description 8
• 238000010511 deprotection reaction Methods 0.000 description 8
• 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 8
• 150000002825 nitriles Chemical class 0.000 description 8
• 229910000027 potassium carbonate Inorganic materials 0.000 description 8
• XOAAWQZATWQOTB-UHFFFAOYSA-N taurine Chemical compound NCCS(O)(=O)=O XOAAWQZATWQOTB-UHFFFAOYSA-N 0.000 description 8
• RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 8
• 238000005406 washing Methods 0.000 description 8
• CKFWDLFFXXVSBJ-DHIUTWEWSA-N (3r,5r)-3-butyl-3-ethyl-7,8-dimethoxy-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepine 1,1-dioxide Chemical compound C1([C@@H]2C3=CC(OC)=C(OC)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 CKFWDLFFXXVSBJ-DHIUTWEWSA-N 0.000 description 7
• CZGVOBIGEBDYTP-VSGBNLITSA-N 3-[[(3r,5r)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepin-8-yl]methylamino]pentanedioic acid Chemical compound C1([C@@H]2C3=CC(OC)=C(CNC(CC(O)=O)CC(O)=O)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 CZGVOBIGEBDYTP-VSGBNLITSA-N 0.000 description 7
• LHAYZDULSNURMY-FGZHOGPDSA-N [(3r,5r)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepin-8-yl] trifluoromethanesulfonate Chemical compound C1([C@@H]2C3=CC(OC)=C(OS(=O)(=O)C(F)(F)F)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 LHAYZDULSNURMY-FGZHOGPDSA-N 0.000 description 7
• HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 7
• 239000006260 foam Substances 0.000 description 7
• 210000001035 gastrointestinal tract Anatomy 0.000 description 7
• 150000002466 imines Chemical class 0.000 description 7
• 239000003112 inhibitor Substances 0.000 description 7
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 7
• 235000011181 potassium carbonates Nutrition 0.000 description 7
• 239000002244 precipitate Substances 0.000 description 7
• 125000001325 propanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 7
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 7
• 229910000029 sodium carbonate Inorganic materials 0.000 description 7
• BXZSTNOKQQGVMY-JWQCQUIFSA-N 3-[(3r,5r)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepin-8-yl]propanoic acid Chemical compound C1([C@@H]2C3=CC(OC)=C(CCC(O)=O)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 BXZSTNOKQQGVMY-JWQCQUIFSA-N 0.000 description 6
• ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 6
• XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 6
• 239000012043 crude product Substances 0.000 description 6
• NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 6
• LXCYSACZTOKNNS-UHFFFAOYSA-N diethoxy(oxo)phosphanium Chemical compound CCO[P+](=O)OCC LXCYSACZTOKNNS-UHFFFAOYSA-N 0.000 description 6
• 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 6
• 239000012065 filter cake Substances 0.000 description 6
• 239000012362 glacial acetic acid Substances 0.000 description 6
• 230000001404 mediated effect Effects 0.000 description 6
• 238000002483 medication Methods 0.000 description 6
• 229910052763 palladium Inorganic materials 0.000 description 6
• BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 description 6
• WXTMWNOWHQVFMB-DHIUTWEWSA-N (3r,5r)-8-(bromomethyl)-3-butyl-3-ethyl-7-methoxy-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepine 1,1-dioxide Chemical compound C1([C@@H]2C3=CC(OC)=C(CBr)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 WXTMWNOWHQVFMB-DHIUTWEWSA-N 0.000 description 5
• KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 5
• JVVRCYWZTJLJSG-UHFFFAOYSA-N 4-dimethylaminophenol Chemical compound CN(C)C1=CC=C(O)C=C1 JVVRCYWZTJLJSG-UHFFFAOYSA-N 0.000 description 5
• 229960000549 4-dimethylaminophenol Drugs 0.000 description 5
• VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-dimethylaminopyridine Substances CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 5
• YNXLOPYTAAFMTN-SBUIBGKBSA-N C([C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(N)=O)C1=CC=C(O)C=C1 Chemical compound C([C@H](N)C(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(N)=O)C1=CC=C(O)C=C1 YNXLOPYTAAFMTN-SBUIBGKBSA-N 0.000 description 5
• XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 5
• 102100025353 G-protein coupled bile acid receptor 1 Human genes 0.000 description 5
• 101000857733 Homo sapiens G-protein coupled bile acid receptor 1 Proteins 0.000 description 5
• MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 5
• 239000004472 Lysine Substances 0.000 description 5
• 108010088847 Peptide YY Proteins 0.000 description 5
• 102100029909 Peptide YY Human genes 0.000 description 5
• RCOCWDOJSUPGPF-DHIUTWEWSA-N [(3r,5r)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepin-8-yl]methanamine Chemical compound C1([C@@H]2C3=CC(OC)=C(CN)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 RCOCWDOJSUPGPF-DHIUTWEWSA-N 0.000 description 5
• 239000002585 base Substances 0.000 description 5
• SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 5
• 238000010168 coupling process Methods 0.000 description 5
• 238000005859 coupling reaction Methods 0.000 description 5
• 238000001035 drying Methods 0.000 description 5
• 230000003914 insulin secretion Effects 0.000 description 5
• 210000004185 liver Anatomy 0.000 description 5
• 230000009467 reduction Effects 0.000 description 5
• 238000006722 reduction reaction Methods 0.000 description 5
• 238000012552 review Methods 0.000 description 5
• 229920006395 saturated elastomer Polymers 0.000 description 5
• 235000010265 sodium sulphite Nutrition 0.000 description 5
• SJMDMGHPMLKLHQ-UHFFFAOYSA-N tert-butyl 2-aminoacetate Chemical compound CC(C)(C)OC(=O)CN SJMDMGHPMLKLHQ-UHFFFAOYSA-N 0.000 description 5
• 238000005292 vacuum distillation Methods 0.000 description 5
• SNKSVRWTOMEKGA-DHIUTWEWSA-N (3r,5r)-3-butyl-3-ethyl-4-hydroxy-7-methoxy-1,1-dioxo-5-phenyl-2,5-dihydro-1$l^{6},4-benzothiazepine-8-carbaldehyde Chemical compound C1([C@@H]2C3=CC(OC)=C(C=O)C=C3S(=O)(=O)C[C@@](N2O)(CC)CCCC)=CC=CC=C1 SNKSVRWTOMEKGA-DHIUTWEWSA-N 0.000 description 4
• ORQRVNOFESNJHT-DNQXCXABSA-N (3r,5r)-3-butyl-7-(dimethylamino)-3-ethyl-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepine-8-carbaldehyde Chemical compound C1([C@@H]2C3=CC(=C(C=O)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)N(C)C)=CC=CC=C1 ORQRVNOFESNJHT-DNQXCXABSA-N 0.000 description 4
• QQOCFESNFPMZHS-UHFFFAOYSA-N 3,3-dibutyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepine-8-carbaldehyde Chemical compound N1C(CCCC)(CCCC)CS(=O)(=O)C2=CC(C=O)=C(OC)C=C2C1C1=CC=CC=C1 QQOCFESNFPMZHS-UHFFFAOYSA-N 0.000 description 4
• IGRCWJPBLWGNPX-UHFFFAOYSA-N 3-(2-chlorophenyl)-n-(4-chlorophenyl)-n,5-dimethyl-1,2-oxazole-4-carboxamide Chemical compound C=1C=C(Cl)C=CC=1N(C)C(=O)C1=C(C)ON=C1C1=CC=CC=C1Cl IGRCWJPBLWGNPX-UHFFFAOYSA-N 0.000 description 4
• NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 4
• UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 4
• DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
• 206010022489 Insulin Resistance Diseases 0.000 description 4
• 229930040373 Paraformaldehyde Natural products 0.000 description 4
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
• 238000003556 assay Methods 0.000 description 4
• 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 description 4
• UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 4
• 229910052799 carbon Inorganic materials 0.000 description 4
• 229910002091 carbon monoxide Inorganic materials 0.000 description 4
• 210000001072 colon Anatomy 0.000 description 4
• 238000002425 crystallisation Methods 0.000 description 4
• 238000000354 decomposition reaction Methods 0.000 description 4
• 230000017858 demethylation Effects 0.000 description 4
• 238000010520 demethylation reaction Methods 0.000 description 4
• JYHWBQWYGJFGFO-LOYHVIPDSA-N dimethyl 3-[[(3r,5r)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepin-8-yl]methylamino]pentanedioate Chemical compound C1([C@@H]2C3=CC(OC)=C(CNC(CC(=O)OC)CC(=O)OC)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 JYHWBQWYGJFGFO-LOYHVIPDSA-N 0.000 description 4
• 230000000694 effects Effects 0.000 description 4
• 239000003480 eluent Substances 0.000 description 4
• 210000000232 gallbladder Anatomy 0.000 description 4
• QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 4
• 210000003405 ileum Anatomy 0.000 description 4
• JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropyl acetate Chemical compound CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 4
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 4
• 239000012452 mother liquor Substances 0.000 description 4
• 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 4
• 229920002866 paraformaldehyde Polymers 0.000 description 4
• TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical class [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 4
• 108090000765 processed proteins & peptides Proteins 0.000 description 4
• 235000019260 propionic acid Nutrition 0.000 description 4
• 125000006239 protecting group Chemical group 0.000 description 4
• 238000006268 reductive amination reaction Methods 0.000 description 4
• 239000007858 starting material Substances 0.000 description 4
• 239000012258 stirred mixture Substances 0.000 description 4
• 125000000446 sulfanediyl group Chemical group *S* 0.000 description 4
• 229960003080 taurine Drugs 0.000 description 4
• FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
• 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 4
• 239000002699 waste material Substances 0.000 description 4
• LQQFFUDSDQIUJL-UHFFFAOYSA-N (3,3-dibutyl-7-methoxy-5-phenyl-2h-1,4-benzothiazepin-8-yl)methanol Chemical compound N=1C(CCCC)(CCCC)CSC2=CC(CO)=C(OC)C=C2C=1C1=CC=CC=C1 LQQFFUDSDQIUJL-UHFFFAOYSA-N 0.000 description 3
• NQJVEUOSFUGUJG-DHIUTWEWSA-N (3r,5r)-3-butyl-7-(dimethylamino)-3-ethyl-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepin-8-ol Chemical compound C1([C@@H]2C3=CC(=C(O)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)N(C)C)=CC=CC=C1 NQJVEUOSFUGUJG-DHIUTWEWSA-N 0.000 description 3
• BRIGTXNYAXZUNT-DNQXCXABSA-N (3r,5r)-3-butyl-7-(dimethylamino)-3-ethyl-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepine-8-carbonitrile Chemical compound C1([C@@H]2C3=CC(=C(C#N)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)N(C)C)=CC=CC=C1 BRIGTXNYAXZUNT-DNQXCXABSA-N 0.000 description 3
• OAIRFXIPAGPFOJ-DHIUTWEWSA-N (3r,5r)-8-(bromomethyl)-3-butyl-3-ethyl-4-hydroxy-7-methoxy-5-phenyl-2,5-dihydro-1$l^{6},4-benzothiazepine 1,1-dioxide Chemical compound C1([C@@H]2C3=CC(OC)=C(CBr)C=C3S(=O)(=O)C[C@@](N2O)(CC)CCCC)=CC=CC=C1 OAIRFXIPAGPFOJ-DHIUTWEWSA-N 0.000 description 3
• PZYIRIHLNKVQKW-XZOQPEGZSA-N (3r,5s)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepine-8-carbaldehyde Chemical compound C1([C@H]2C3=CC(OC)=C(C=O)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 PZYIRIHLNKVQKW-XZOQPEGZSA-N 0.000 description 3
• SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 3
• DHQRAILUSHUBDQ-UHFFFAOYSA-N 3,3-dibutyl-8-(diethoxyphosphorylmethyl)-7-methoxy-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepine 1,1-dioxide Chemical compound N1C(CCCC)(CCCC)CS(=O)(=O)C2=CC(CP(=O)(OCC)OCC)=C(OC)C=C2C1C1=CC=CC=C1 DHQRAILUSHUBDQ-UHFFFAOYSA-N 0.000 description 3
• QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 3
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
• UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
• CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 3
• 239000004471 Glycine Substances 0.000 description 3
• AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
• 230000029936 alkylation Effects 0.000 description 3
• 238000005804 alkylation reaction Methods 0.000 description 3
• 150000001408 amides Chemical class 0.000 description 3
• DQPBABKTKYNPMH-UHFFFAOYSA-M amino sulfate Chemical compound NOS([O-])(=O)=O DQPBABKTKYNPMH-UHFFFAOYSA-M 0.000 description 3
• 239000007864 aqueous solution Substances 0.000 description 3
• 239000012131 assay buffer Substances 0.000 description 3
• 239000012298 atmosphere Substances 0.000 description 3
• WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
• 239000003858 bile acid conjugate Substances 0.000 description 3
• 239000003833 bile salt Substances 0.000 description 3
• UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 description 3
• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
• KVNRLNFWIYMESJ-UHFFFAOYSA-N butyronitrile Chemical compound CCCC#N KVNRLNFWIYMESJ-UHFFFAOYSA-N 0.000 description 3
• 150000001721 carbon Chemical group 0.000 description 3
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
• 239000003054 catalyst Substances 0.000 description 3
• 235000012000 cholesterol Nutrition 0.000 description 3
• 230000000112 colonic effect Effects 0.000 description 3
• 239000013058 crude material Substances 0.000 description 3
• 230000008025 crystallization Effects 0.000 description 3
• UAGGVDVXSRGPRP-UHFFFAOYSA-N diethylcarbamothioic s-acid Chemical compound CCN(CC)C(S)=O UAGGVDVXSRGPRP-UHFFFAOYSA-N 0.000 description 3
• COCJJUPDNGMKFE-LOYHVIPDSA-N dimethyl 3-[[(3r,5r)-3-butyl-3-ethyl-4-hydroxy-7-methoxy-1,1-dioxo-5-phenyl-2,5-dihydro-1$l^{6},4-benzothiazepin-8-yl]methylamino]pentanedioate Chemical compound C1([C@@H]2C3=CC(OC)=C(CNC(CC(=O)OC)CC(=O)OC)C=C3S(=O)(=O)C[C@@](N2O)(CC)CCCC)=CC=CC=C1 COCJJUPDNGMKFE-LOYHVIPDSA-N 0.000 description 3
• 229940090124 dipeptidyl peptidase 4 (dpp-4) inhibitors for blood glucose lowering Drugs 0.000 description 3
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
• 238000004090 dissolution Methods 0.000 description 3
• 210000003608 fece Anatomy 0.000 description 3
• 239000007789 gas Substances 0.000 description 3
• 239000011521 glass Substances 0.000 description 3
• JFCQEDHGNNZCLN-UHFFFAOYSA-L glutarate(2-) Chemical compound [O-]C(=O)CCCC([O-])=O JFCQEDHGNNZCLN-UHFFFAOYSA-L 0.000 description 3
• 238000010438 heat treatment Methods 0.000 description 3
• 238000005984 hydrogenation reaction Methods 0.000 description 3
• COQRGFWWJBEXRC-UHFFFAOYSA-N hydron;methyl 2-aminoacetate;chloride Chemical compound Cl.COC(=O)CN COQRGFWWJBEXRC-UHFFFAOYSA-N 0.000 description 3
• XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 3
• 230000005764 inhibitory process Effects 0.000 description 3
• 238000002347 injection Methods 0.000 description 3
• 239000007924 injection Substances 0.000 description 3
• 230000000968 intestinal effect Effects 0.000 description 3
• BBJIPMIXTXKYLZ-UHFFFAOYSA-N isoglutamic acid Chemical compound OC(=O)CC(N)CC(O)=O BBJIPMIXTXKYLZ-UHFFFAOYSA-N 0.000 description 3
• XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 3
• 229960003105 metformin Drugs 0.000 description 3
• XHLJWNZUVOEUHE-ISKFKSNPSA-N methyl (3r,5r)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepine-8-carboxylate Chemical compound C1([C@@H]2C3=CC(OC)=C(C(=O)OC)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 XHLJWNZUVOEUHE-ISKFKSNPSA-N 0.000 description 3
• WSYXJNIUKJDTFA-UHFFFAOYSA-N methyl 3,3-dibutyl-7-methoxy-5-phenyl-2h-1,4-benzothiazepine-8-carboxylate Chemical compound N=1C(CCCC)(CCCC)CSC2=CC(C(=O)OC)=C(OC)C=C2C=1C1=CC=CC=C1 WSYXJNIUKJDTFA-UHFFFAOYSA-N 0.000 description 3
• 125000000896 monocarboxylic acid group Chemical group 0.000 description 3
• 235000015097 nutrients Nutrition 0.000 description 3
• 210000000496 pancreas Anatomy 0.000 description 3
• UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 3
• 229960002429 proline Drugs 0.000 description 3
• DKORSYDQYFVQNS-UHFFFAOYSA-N propyl methanesulfonate Chemical compound CCCOS(C)(=O)=O DKORSYDQYFVQNS-UHFFFAOYSA-N 0.000 description 3
• 210000000813 small intestine Anatomy 0.000 description 3
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
• 229910000104 sodium hydride Inorganic materials 0.000 description 3
• 239000000126 substance Substances 0.000 description 3
• LSNNMFCWUKXFEE-UHFFFAOYSA-L sulfite Chemical compound [O-]S([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-L 0.000 description 3
• 238000003786 synthesis reaction Methods 0.000 description 3
• WBWWGRHZICKQGZ-HZAMXZRMSA-N taurocholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCS(O)(=O)=O)C)[C@@]2(C)[C@@H](O)C1 WBWWGRHZICKQGZ-HZAMXZRMSA-N 0.000 description 3
• 230000004580 weight loss Effects 0.000 description 3
• 239000011701 zinc Substances 0.000 description 3
• GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical compound [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 0.000 description 3
• CVPZAXFLSPHUAM-DANFDKMISA-N (2s)-2-[[(3r,5r)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepin-8-yl]methylamino]-4-methylsulfonylbutanoic acid Chemical compound C1([C@@H]2C3=CC(OC)=C(CN[C@@H](CCS(C)(=O)=O)C(O)=O)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 CVPZAXFLSPHUAM-DANFDKMISA-N 0.000 description 2
• GHWBKHYHXCSDGC-UHFFFAOYSA-N (3,3-dibutyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepin-8-yl)methanol Chemical compound N1C(CCCC)(CCCC)CS(=O)(=O)C2=CC(CO)=C(OC)C=C2C1C1=CC=CC=C1 GHWBKHYHXCSDGC-UHFFFAOYSA-N 0.000 description 2
• WCHIFTHQXPFCCC-UHFFFAOYSA-N (3,3-dibutyl-7-methoxy-5-phenyl-4,5-dihydro-2h-1,4-benzothiazepin-8-yl)methanol Chemical compound N1C(CCCC)(CCCC)CSC2=CC(CO)=C(OC)C=C2C1C1=CC=CC=C1 WCHIFTHQXPFCCC-UHFFFAOYSA-N 0.000 description 2
• ATQDSJVOOHSERZ-HSZRJFAPSA-N (3r)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-2h-1$l^{6},4-benzothiazepine-8-carbaldehyde Chemical compound C([C@@](N=1)(CC)CCCC)S(=O)(=O)C2=CC(C=O)=C(OC)C=C2C=1C1=CC=CC=C1 ATQDSJVOOHSERZ-HSZRJFAPSA-N 0.000 description 2
• PZGGMYJRDFOANI-DHIUTWEWSA-N (3r,5r)-3-butyl-3-ethyl-4-hydroxy-7-methoxy-1,1-dioxo-5-phenyl-2,5-dihydro-1$l^{6},4-benzothiazepine-8-carbonitrile Chemical compound C1([C@@H]2C3=CC(OC)=C(C#N)C=C3S(=O)(=O)C[C@@](N2O)(CC)CCCC)=CC=CC=C1 PZGGMYJRDFOANI-DHIUTWEWSA-N 0.000 description 2
• NJGBVIUDIFQUNF-FYYLOGMGSA-N (3r,5r)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepine-8-carboxamide Chemical compound C1([C@@H]2C3=CC(OC)=C(C(N)=O)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 NJGBVIUDIFQUNF-FYYLOGMGSA-N 0.000 description 2
• IQPBSABTUAEDBJ-ILBGXUMGSA-N (3r,5r)-3-butyl-3-ethyl-n,7-dimethoxy-n-methyl-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepine-8-carboxamide Chemical compound C1([C@@H]2C3=CC(OC)=C(C(=O)N(C)OC)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 IQPBSABTUAEDBJ-ILBGXUMGSA-N 0.000 description 2
• GHVBWYKPIRJOSL-FQLXRVMXSA-N (3r,5r)-3-butyl-8-(3-diethoxyphosphorylpropyl)-3-ethyl-7-methoxy-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepine 1,1-dioxide Chemical compound C1([C@@H]2C3=CC(OC)=C(CCCP(=O)(OCC)OCC)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 GHVBWYKPIRJOSL-FQLXRVMXSA-N 0.000 description 2
• CWBXCCQXSJLVIB-KAYWLYCHSA-N (3r,5r)-3-butyl-8-(diethoxyphosphorylmethyl)-3-ethyl-4-hydroxy-7-methoxy-5-phenyl-2,5-dihydro-1$l^{6},4-benzothiazepine 1,1-dioxide Chemical compound C1([C@@H]2C3=CC(OC)=C(CP(=O)(OCC)OCC)C=C3S(=O)(=O)C[C@@](N2O)(CC)CCCC)=CC=CC=C1 CWBXCCQXSJLVIB-KAYWLYCHSA-N 0.000 description 2
• KNKGOWLTKDTSAR-JWQCQUIFSA-N (3r,5r)-8-(3-bromopropyl)-3-butyl-3-ethyl-7-methoxy-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepine 1,1-dioxide Chemical compound C1([C@@H]2C3=CC(OC)=C(CCCBr)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 KNKGOWLTKDTSAR-JWQCQUIFSA-N 0.000 description 2
• GISFHTNTSMCXCF-RRPNLBNLSA-N (3r,5s)-3-butyl-8-(diethoxyphosphorylmethyl)-3-ethyl-7-methoxy-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepine 1,1-dioxide Chemical compound C1([C@H]2C3=CC(OC)=C(CP(=O)(OCC)OCC)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 GISFHTNTSMCXCF-RRPNLBNLSA-N 0.000 description 2
• WXTMWNOWHQVFMB-XZOQPEGZSA-N (3r,5s)-8-(bromomethyl)-3-butyl-3-ethyl-7-methoxy-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepine 1,1-dioxide Chemical compound C1([C@H]2C3=CC(OC)=C(CBr)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 WXTMWNOWHQVFMB-XZOQPEGZSA-N 0.000 description 2
• WOGAIDMSZKBXBZ-UHFFFAOYSA-N (4-bromo-2,5-dimethoxyphenyl)-phenylmethanone Chemical compound C1=C(Br)C(OC)=CC(C(=O)C=2C=CC=CC=2)=C1OC WOGAIDMSZKBXBZ-UHFFFAOYSA-N 0.000 description 2
• YVPDMSSKAJCLLY-UHFFFAOYSA-N (4-bromo-2-hydroxy-5-methoxyphenyl)-phenylmethanone Chemical compound C1=C(Br)C(OC)=CC(C(=O)C=2C=CC=CC=2)=C1O YVPDMSSKAJCLLY-UHFFFAOYSA-N 0.000 description 2
• WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 description 2
• UKVGMGJKMYZSBA-CZNDPXEESA-N 1-[(3r,5r)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepin-8-yl]-n,n-bis(diethoxyphosphorylmethyl)methanamine Chemical compound C1([C@@H]2C3=CC(OC)=C(CN(CP(=O)(OCC)OCC)CP(=O)(OCC)OCC)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 UKVGMGJKMYZSBA-CZNDPXEESA-N 0.000 description 2
• GUSDFYMNBLGHFL-VSGBNLITSA-N 1-[(3r,5r)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepin-8-yl]-n-(diethoxyphosphorylmethyl)methanamine Chemical compound C1([C@@H]2C3=CC(OC)=C(CNCP(=O)(OCC)OCC)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 GUSDFYMNBLGHFL-VSGBNLITSA-N 0.000 description 2
• LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 2
• JXFXKGILDJHHDM-DNQXCXABSA-N 2-[(3r,5r)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepin-8-yl]ethylphosphonic acid Chemical compound C1([C@@H]2C3=CC(OC)=C(CCP(O)(O)=O)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 JXFXKGILDJHHDM-DNQXCXABSA-N 0.000 description 2
• CAZSJDBYDDJGNV-ZHEQYFEDSA-N 2-[[(3r,5r)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepine-8-carbonyl]amino]ethanesulfonic acid;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.C1([C@@H]2C3=CC(OC)=C(C(=O)NCCS(O)(=O)=O)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 CAZSJDBYDDJGNV-ZHEQYFEDSA-N 0.000 description 2
• RDEFHGRTIKHVTK-UHFFFAOYSA-N 2-amino-2-butylhexan-1-ol Chemical compound CCCCC(N)(CO)CCCC RDEFHGRTIKHVTK-UHFFFAOYSA-N 0.000 description 2
• DWCGNRKFLRLWCJ-UHFFFAOYSA-N 2-bromo-1,4-dimethoxybenzene Chemical compound COC1=CC=C(OC)C(Br)=C1 DWCGNRKFLRLWCJ-UHFFFAOYSA-N 0.000 description 2
• JUAGHBASZWRMQH-UHFFFAOYSA-N 2-diethoxyphosphorylethanamine Chemical compound CCOP(=O)(CCN)OCC JUAGHBASZWRMQH-UHFFFAOYSA-N 0.000 description 2
• PSWZTHZAFPEYCC-JWQCQUIFSA-N 3-[(3r,5r)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepin-8-yl]propan-1-ol Chemical compound C1([C@@H]2C3=CC(OC)=C(CCCO)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 PSWZTHZAFPEYCC-JWQCQUIFSA-N 0.000 description 2
• WKJPADKIKWPORS-KAYWLYCHSA-N 4-[[(3r,5r)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepin-8-yl]methylamino]butanoic acid Chemical compound C1([C@@H]2C3=CC(OC)=C(CNCCCC(O)=O)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 WKJPADKIKWPORS-KAYWLYCHSA-N 0.000 description 2
• VLSUMBBYIPUKNY-UHFFFAOYSA-N 8-(bromomethyl)-3,3-dibutyl-7-methoxy-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepine 1,1-dioxide Chemical compound N1C(CCCC)(CCCC)CS(=O)(=O)C2=CC(CBr)=C(OC)C=C2C1C1=CC=CC=C1 VLSUMBBYIPUKNY-UHFFFAOYSA-N 0.000 description 2
• GVDSXNFDKIXJFD-UHFFFAOYSA-N 8-bromo-3,3-dibutyl-7-methoxy-5-phenyl-2h-1,4-benzothiazepine Chemical compound N=1C(CCCC)(CCCC)CSC2=CC(Br)=C(OC)C=C2C=1C1=CC=CC=C1 GVDSXNFDKIXJFD-UHFFFAOYSA-N 0.000 description 2
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
• 208000024172 Cardiovascular disease Diseases 0.000 description 2
• XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 2
• 208000032131 Diabetic Neuropathies Diseases 0.000 description 2
• 206010012689 Diabetic retinopathy Diseases 0.000 description 2
• ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
• 208000032928 Dyslipidaemia Diseases 0.000 description 2
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
• WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
• LRQKBLKVPFOOQJ-YFKPBYRVSA-N L-norleucine Chemical compound CCCC[C@H]([NH3+])C([O-])=O LRQKBLKVPFOOQJ-YFKPBYRVSA-N 0.000 description 2
• 208000017170 Lipid metabolism disease Diseases 0.000 description 2
• 229910017974 NH40H Inorganic materials 0.000 description 2
• NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
• ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
• YASAKCUCGLMORW-UHFFFAOYSA-N Rosiglitazone Chemical compound C=1C=CC=NC=1N(C)CCOC(C=C1)=CC=C1CC1SC(=O)NC1=O YASAKCUCGLMORW-UHFFFAOYSA-N 0.000 description 2
• QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
• 239000004473 Threonine Substances 0.000 description 2
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
• 239000007983 Tris buffer Substances 0.000 description 2
• HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
• BHTYNULXKZYRSV-DHIUTWEWSA-N [(3r,5r)-3-butyl-3-ethyl-4-hydroxy-7-methoxy-1,1-dioxo-5-phenyl-2,5-dihydro-1$l^{6},4-benzothiazepin-8-yl]methylphosphonic acid Chemical compound C1([C@@H]2C3=CC(OC)=C(CP(O)(O)=O)C=C3S(=O)(=O)C[C@@](N2O)(CC)CCCC)=CC=CC=C1 BHTYNULXKZYRSV-DHIUTWEWSA-N 0.000 description 2
• IWCHBCXPJGQUOG-FGZHOGPDSA-N [(3r,5r)-3-butyl-3-ethyl-8-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepin-7-yl] trifluoromethanesulfonate Chemical compound C1([C@@H]2C3=CC(OS(=O)(=O)C(F)(F)F)=C(OC)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 IWCHBCXPJGQUOG-FGZHOGPDSA-N 0.000 description 2
• JWDUAONWYVJAMY-DHIUTWEWSA-N [(3r,5r)-3-butyl-7-(dimethylamino)-3-ethyl-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepin-8-yl] trifluoromethanesulfonate Chemical compound C1([C@@H]2C3=CC(=C(OS(=O)(=O)C(F)(F)F)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)N(C)C)=CC=CC=C1 JWDUAONWYVJAMY-DHIUTWEWSA-N 0.000 description 2
• XKPRRKCIBNCOBV-JWQCQUIFSA-N [[(3r,5r)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepin-8-yl]methyl-(phosphonomethyl)amino]methylphosphonic acid Chemical compound C1([C@@H]2C3=CC(OC)=C(CN(CP(O)(O)=O)CP(O)(O)=O)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 XKPRRKCIBNCOBV-JWQCQUIFSA-N 0.000 description 2
• 230000009102 absorption Effects 0.000 description 2
• 238000010521 absorption reaction Methods 0.000 description 2
• 238000009825 accumulation Methods 0.000 description 2
• 150000001242 acetic acid derivatives Chemical class 0.000 description 2
• JCFADYTWTKDWKU-UHFFFAOYSA-N acetic acid;hydrochloride Chemical compound Cl.CC(O)=O.CC(O)=O JCFADYTWTKDWKU-UHFFFAOYSA-N 0.000 description 2
• 230000002378 acidificating effect Effects 0.000 description 2
• 230000010933 acylation Effects 0.000 description 2
• 238000005917 acylation reaction Methods 0.000 description 2
• 229910052782 aluminium Inorganic materials 0.000 description 2
• XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
• 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 2
• 239000000908 ammonium hydroxide Substances 0.000 description 2
• 238000013459 approach Methods 0.000 description 2
• APSMVGSSXZDZCH-DLUKRPPHSA-N azanium;(2r)-1-[[(3r,5r)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepin-8-yl]methyl]pyrrolidine-2-carboxylate Chemical compound [NH4+].C([C@@](N[C@@H](C1=CC=2OC)C=3C=CC=CC=3)(CC)CCCC)S(=O)(=O)C1=CC=2CN1CCC[C@@H]1C([O-])=O APSMVGSSXZDZCH-DLUKRPPHSA-N 0.000 description 2
• PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 2
• 229910000085 borane Inorganic materials 0.000 description 2
• 230000005587 bubbling Effects 0.000 description 2
• KMGBZBJJOKUPIA-UHFFFAOYSA-N butyl iodide Chemical compound CCCCI KMGBZBJJOKUPIA-UHFFFAOYSA-N 0.000 description 2
• 239000006227 byproduct Substances 0.000 description 2
• 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
• 230000001413 cellular effect Effects 0.000 description 2
• 230000019522 cellular metabolic process Effects 0.000 description 2
• 238000004891 communication Methods 0.000 description 2
• 230000008878 coupling Effects 0.000 description 2
• 239000013078 crystal Substances 0.000 description 2
• 238000007872 degassing Methods 0.000 description 2
• JFWILMGMIVZYOP-HXFSWNFUSA-N diazanium 3-[[(3R,5R)-3-butyl-7-(dimethylamino)-3-ethyl-1,1-dioxo-5-phenyl-4,5-dihydro-2H-1lambda6,4-benzothiazepin-8-yl]methylamino]pentanedioate Chemical compound [NH4+].[NH4+].CCCC[C@]1(CC)CS(=O)(=O)c2cc(CNC(CC([O-])=O)CC([O-])=O)c(cc2[C@H](N1)c1ccccc1)N(C)C JFWILMGMIVZYOP-HXFSWNFUSA-N 0.000 description 2
• HHAVCSRKPXOHIJ-POURPWNDSA-N diethyl 2-[[(3r,5r)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepin-8-yl]methylidene]propanedioate Chemical compound C1([C@@H]2C3=CC(OC)=C(C=C(C(=O)OCC)C(=O)OCC)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 HHAVCSRKPXOHIJ-POURPWNDSA-N 0.000 description 2
• XLKAVGMBLPDKSQ-KKLWWLSJSA-N diethyl 3-[[2-[[(3r,5r)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepin-8-yl]methylamino]-2-oxoethyl]amino]pentanedioate Chemical compound C1([C@@H]2C3=CC(OC)=C(CNC(=O)CNC(CC(=O)OCC)CC(=O)OCC)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 XLKAVGMBLPDKSQ-KKLWWLSJSA-N 0.000 description 2
• BERJDKNLNWRJSZ-UHFFFAOYSA-N diethyl 3-aminopentanedioate Chemical compound CCOC(=O)CC(N)CC(=O)OCC BERJDKNLNWRJSZ-UHFFFAOYSA-N 0.000 description 2
• JVBOQKKOCMLFGZ-STJVVJFLSA-N dimethyl (2r)-2-[[(3r,5r)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepin-8-yl]methylamino]butanedioate Chemical compound C1([C@@H]2C3=CC(OC)=C(CN[C@H](CC(=O)OC)C(=O)OC)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 JVBOQKKOCMLFGZ-STJVVJFLSA-N 0.000 description 2
• SEMQYRDTDOGKDQ-UHFFFAOYSA-N dimethyl 3-[(3,3-dibutyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepin-8-yl)methylamino]pentanedioate Chemical compound N1C(CCCC)(CCCC)CS(=O)(=O)C2=CC(CNC(CC(=O)OC)CC(=O)OC)=C(OC)C=C2C1C1=CC=CC=C1 SEMQYRDTDOGKDQ-UHFFFAOYSA-N 0.000 description 2
• JYHWBQWYGJFGFO-XZWHSSHBSA-N dimethyl 3-[[(3r,5s)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepin-8-yl]methylamino]pentanedioate Chemical compound C1([C@H]2C3=CC(OC)=C(CNC(CC(=O)OC)CC(=O)OC)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 JYHWBQWYGJFGFO-XZWHSSHBSA-N 0.000 description 2
• USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 description 2
• 208000035475 disorder Diseases 0.000 description 2
• 238000004821 distillation Methods 0.000 description 2
• 231100000673 dose–response relationship Toxicity 0.000 description 2
• 238000007876 drug discovery Methods 0.000 description 2
• 239000003623 enhancer Substances 0.000 description 2
• CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 2
• FGZQVNGDKVXVBW-FDFRSNTISA-N ethyl (e)-3-[(3r,5r)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepin-8-yl]prop-2-enoate Chemical compound C1([C@@H]2C3=CC(OC)=C(\C=C\C(=O)OCC)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 FGZQVNGDKVXVBW-FDFRSNTISA-N 0.000 description 2
• FZEMJLFRGFKZGB-UHFFFAOYSA-N ethyl 2-amino-2-butylhexanoate Chemical compound CCCCC(N)(CCCC)C(=O)OCC FZEMJLFRGFKZGB-UHFFFAOYSA-N 0.000 description 2
• PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 2
• 238000002474 experimental method Methods 0.000 description 2
• 239000000284 extract Substances 0.000 description 2
• 208000019622 heart disease Diseases 0.000 description 2
• 230000002440 hepatic effect Effects 0.000 description 2
• 229940088597 hormone Drugs 0.000 description 2
• 239000005556 hormone Substances 0.000 description 2
• 239000012535 impurity Substances 0.000 description 2
• 239000000859 incretin Substances 0.000 description 2
• UEXQBEVWFZKHNB-UHFFFAOYSA-N intermediate 29 Natural products C1=CC(N)=CC=C1NC1=NC=CC=N1 UEXQBEVWFZKHNB-UHFFFAOYSA-N 0.000 description 2
• 208000002551 irritable bowel syndrome Diseases 0.000 description 2
• 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 2
• GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 2
• 235000012054 meals Nutrition 0.000 description 2
• 230000004060 metabolic process Effects 0.000 description 2
• XYTLYINPZMCMEJ-VSGBNLITSA-N methyl 2-[[2-[[(3r,5r)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepin-8-yl]methylamino]-2-oxoethyl]amino]acetate Chemical compound C1([C@@H]2C3=CC(OC)=C(CNC(=O)CNCC(=O)OC)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 XYTLYINPZMCMEJ-VSGBNLITSA-N 0.000 description 2
• CPKQVDORZWRHLQ-FIRIVFDPSA-N n-[[(3r,5r)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepin-8-yl]methyl]-2-(2-diethoxyphosphorylethylamino)acetamide Chemical compound C1([C@@H]2C3=CC(OC)=C(CNC(=O)CNCCP(=O)(OCC)OCC)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 CPKQVDORZWRHLQ-FIRIVFDPSA-N 0.000 description 2
• YTJHQPBQBQLCJX-JWQCQUIFSA-N n-[[(3r,5r)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepin-8-yl]methyl]-2-chloroacetamide Chemical compound C1([C@@H]2C3=CC(OC)=C(CNC(=O)CCl)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 YTJHQPBQBQLCJX-JWQCQUIFSA-N 0.000 description 2
• JRPYVALJPUBDNI-FQLXRVMXSA-N n-[[(3r,5r)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepin-8-yl]methyl]-2-diethoxyphosphorylacetamide Chemical compound C1([C@@H]2C3=CC(OC)=C(CNC(=O)CP(=O)(OCC)OCC)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 JRPYVALJPUBDNI-FQLXRVMXSA-N 0.000 description 2
• DVTXCLKENJZTES-FQLXRVMXSA-N n-[[(3r,5r)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepin-8-yl]methyl]-2-diethoxyphosphorylethanamine Chemical compound C1([C@@H]2C3=CC(OC)=C(CNCCP(=O)(OCC)OCC)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 DVTXCLKENJZTES-FQLXRVMXSA-N 0.000 description 2
• OLAUPQVXYZMGOZ-CLJLJLNGSA-N n-[[(3r,5r)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepin-8-yl]methyl]-3-chloropropanamide Chemical compound C1([C@@H]2C3=CC(OC)=C(CNC(=O)CCCl)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 OLAUPQVXYZMGOZ-CLJLJLNGSA-N 0.000 description 2
• 239000012038 nucleophile Substances 0.000 description 2
• 235000016709 nutrition Nutrition 0.000 description 2
• 230000035764 nutrition Effects 0.000 description 2
• CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
• 230000003647 oxidation Effects 0.000 description 2
• 238000007254 oxidation reaction Methods 0.000 description 2
• YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 2
• QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 2
• 150000003009 phosphonic acids Chemical class 0.000 description 2
• 230000037081 physical activity Effects 0.000 description 2
• HYAFETHFCAUJAY-UHFFFAOYSA-N pioglitazone Chemical compound N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 HYAFETHFCAUJAY-UHFFFAOYSA-N 0.000 description 2
• BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
• 229920001843 polymethylhydrosiloxane Polymers 0.000 description 2
• 229910052700 potassium Inorganic materials 0.000 description 2
• 239000011591 potassium Substances 0.000 description 2
• 238000000634 powder X-ray diffraction Methods 0.000 description 2
• 230000008569 process Effects 0.000 description 2
• 102000004196 processed proteins & peptides Human genes 0.000 description 2
• 238000010926 purge Methods 0.000 description 2
• 238000011160 research Methods 0.000 description 2
• 239000011347 resin Substances 0.000 description 2
• 229920005989 resin Polymers 0.000 description 2
• CBAGWGHRMFYULK-UHFFFAOYSA-N s-(2-benzoyl-5-bromo-4-methoxyphenyl) n,n-diethylcarbamothioate Chemical compound CCN(CC)C(=O)SC1=CC(Br)=C(OC)C=C1C(=O)C1=CC=CC=C1 CBAGWGHRMFYULK-UHFFFAOYSA-N 0.000 description 2
• 235000017557 sodium bicarbonate Nutrition 0.000 description 2
• 239000012321 sodium triacetoxyborohydride Substances 0.000 description 2
• UGJCNRLBGKEGEH-UHFFFAOYSA-N sodium-binding benzofuran isophthalate Chemical compound COC1=CC=2C=C(C=3C(=CC(=CC=3)C(O)=O)C(O)=O)OC=2C=C1N(CCOCC1)CCOCCOCCN1C(C(=CC=1C=2)OC)=CC=1OC=2C1=CC=C(C(O)=O)C=C1C(O)=O UGJCNRLBGKEGEH-UHFFFAOYSA-N 0.000 description 2
• HNFOAHXBHLWKNF-UHFFFAOYSA-M sodium;2-bromoethanesulfonate Chemical compound [Na+].[O-]S(=O)(=O)CCBr HNFOAHXBHLWKNF-UHFFFAOYSA-M 0.000 description 2
• 239000006228 supernatant Substances 0.000 description 2
• 239000000725 suspension Substances 0.000 description 2
• 208000024891 symptom Diseases 0.000 description 2
• 238000010189 synthetic method Methods 0.000 description 2
• XJJBXZIKXFOMLP-ZETCQYMHSA-N tert-butyl (2s)-pyrrolidine-2-carboxylate Chemical compound CC(C)(C)OC(=O)[C@@H]1CCCN1 XJJBXZIKXFOMLP-ZETCQYMHSA-N 0.000 description 2
• SKFMNRXTUSCISF-UHFFFAOYSA-N tert-butyl 2-[(3,3-dibutyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepin-8-yl)methylamino]acetate Chemical compound N1C(CCCC)(CCCC)CS(=O)(=O)C2=CC(CNCC(=O)OC(C)(C)C)=C(OC)C=C2C1C1=CC=CC=C1 SKFMNRXTUSCISF-UHFFFAOYSA-N 0.000 description 2
• WHSBWNOUFOVYHX-XRKRLSELSA-N tert-butyl 2-[[(3r,5r)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepin-8-yl]methylamino]acetate Chemical compound C1([C@@H]2C3=CC(OC)=C(CNCC(=O)OC(C)(C)C)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 WHSBWNOUFOVYHX-XRKRLSELSA-N 0.000 description 2
• WHSBWNOUFOVYHX-LMSSTIIKSA-N tert-butyl 2-[[(3r,5s)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepin-8-yl]methylamino]acetate Chemical compound C1([C@H]2C3=CC(OC)=C(CNCC(=O)OC(C)(C)C)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 WHSBWNOUFOVYHX-LMSSTIIKSA-N 0.000 description 2
• 238000012360 testing method Methods 0.000 description 2
• HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 2
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
• 230000001225 therapeutic effect Effects 0.000 description 2
• 229960002898 threonine Drugs 0.000 description 2
• JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
• VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
• LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
• 229910000404 tripotassium phosphate Inorganic materials 0.000 description 2
• 235000019798 tripotassium phosphate Nutrition 0.000 description 2
• 208000035408 type 1 diabetes mellitus 1 Diseases 0.000 description 2
• 235000013343 vitamin Nutrition 0.000 description 2
• 239000011782 vitamin Substances 0.000 description 2
• 229940088594 vitamin Drugs 0.000 description 2
• 229930003231 vitamin Natural products 0.000 description 2
• 239000011534 wash buffer Substances 0.000 description 2
• 230000004584 weight gain Effects 0.000 description 2
• 235000019786 weight gain Nutrition 0.000 description 2
• ZKLDRHAMGXNWQJ-NQYPTXOGSA-N (2r)-2-amino-3-[[(2r)-2-[[(3r,5r)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepin-8-yl]methylamino]-2-carboxyethyl]disulfanyl]propanoic acid Chemical compound C1([C@@H]2C3=CC(OC)=C(CN[C@@H](CSSC[C@H](N)C(O)=O)C(O)=O)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 ZKLDRHAMGXNWQJ-NQYPTXOGSA-N 0.000 description 1
• AJYFZOBQWMLBBJ-BBVWWWHTSA-N (2s)-2-[[(3r,5r)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepin-8-yl]methylamino]-3-hydroxypropanoic acid Chemical compound C1([C@@H]2C3=CC(OC)=C(CN[C@@H](CO)C(O)=O)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 AJYFZOBQWMLBBJ-BBVWWWHTSA-N 0.000 description 1
• NPBCMXATLRCCLF-IRRLEISYSA-N (2s,4r)-4-[(3r,5s,6r,7r,8r,9s,10s,12s,13r,14s,17r)-6-ethyl-3,7,12-trihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2C[C@H](O)[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 NPBCMXATLRCCLF-IRRLEISYSA-N 0.000 description 1
• PGZJWCFWLZZHIJ-UHFFFAOYSA-N (3,3-dibutyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepin-8-yl)methylphosphonic acid Chemical compound N1C(CCCC)(CCCC)CS(=O)(=O)C2=CC(CP(O)(O)=O)=C(OC)C=C2C1C1=CC=CC=C1 PGZJWCFWLZZHIJ-UHFFFAOYSA-N 0.000 description 1
• HXIKKZHNPRYUOQ-UHFFFAOYSA-N (3,3-dibutyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepin-8-yl)methylphosphonic acid;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.N1C(CCCC)(CCCC)CS(=O)(=O)C2=CC(CP(O)(O)=O)=C(OC)C=C2C1C1=CC=CC=C1 HXIKKZHNPRYUOQ-UHFFFAOYSA-N 0.000 description 1
• KBRZBBOTZJFKFH-UHFFFAOYSA-N (3,5-dichlorophenyl) carbamate Chemical compound NC(=O)OC1=CC(Cl)=CC(Cl)=C1 KBRZBBOTZJFKFH-UHFFFAOYSA-N 0.000 description 1
• MXFIDIKKJFOBRK-HSZRJFAPSA-N (3r)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-2h-1$l^{6},4-benzothiazepine-8-carbonitrile Chemical compound C([C@@](N=1)(CC)CCCC)S(=O)(=O)C2=CC(C#N)=C(OC)C=C2C=1C1=CC=CC=C1 MXFIDIKKJFOBRK-HSZRJFAPSA-N 0.000 description 1
• ALZAJJBAMIBCCN-ZRKZVOQISA-N (3r,5r)-3-butyl-8-[(e)-2-diethoxyphosphorylethenyl]-3-ethyl-7-methoxy-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepine 1,1-dioxide Chemical compound C1([C@@H]2C3=CC(OC)=C(\C=C\P(=O)(OCC)OCC)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 ALZAJJBAMIBCCN-ZRKZVOQISA-N 0.000 description 1
• LVEYOSJUKRVCCF-UHFFFAOYSA-N 1,3-Bis(diphenylphosphino)propane Substances C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCP(C=1C=CC=CC=1)C1=CC=CC=C1 LVEYOSJUKRVCCF-UHFFFAOYSA-N 0.000 description 1
• KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 description 1
• 150000004915 1,4-thiazepines Chemical class 0.000 description 1
• ORQGKRJTFLGHMF-DNQXCXABSA-N 1-[(3r,5r)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepin-8-yl]ethanone Chemical compound C1([C@@H]2C3=CC(OC)=C(C(C)=O)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 ORQGKRJTFLGHMF-DNQXCXABSA-N 0.000 description 1
• HSEGPEWZGNIXRH-CNZCJKERSA-N 1-[[(3r,5r)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepin-8-yl]methyl]pyrrolidin-2-one;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.C([C@@](N[C@@H](C1=CC=2OC)C=3C=CC=CC=3)(CC)CCCC)S(=O)(=O)C1=CC=2CN1CCCC1=O HSEGPEWZGNIXRH-CNZCJKERSA-N 0.000 description 1
• STJWVOQLJPNAQL-UHFFFAOYSA-N 1-[diethoxyphosphorylmethyl(ethoxy)phosphoryl]oxyethane Chemical compound CCOP(=O)(OCC)CP(=O)(OCC)OCC STJWVOQLJPNAQL-UHFFFAOYSA-N 0.000 description 1
• PINITSMLVXAASM-UHFFFAOYSA-N 1-bromo-2-diethoxyphosphorylethane Chemical compound CCOP(=O)(CCBr)OCC PINITSMLVXAASM-UHFFFAOYSA-N 0.000 description 1
• BDERNNFJNOPAEC-UHFFFAOYSA-N 1-propanol Substances CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
• QRUWNLWDXIBBCK-UHFFFAOYSA-N 2-(1-carboxypropylamino)butanoic acid Chemical compound CCC(C(O)=O)NC(CC)C(O)=O QRUWNLWDXIBBCK-UHFFFAOYSA-N 0.000 description 1
• KBZOLELTOAPIRR-UHFFFAOYSA-N 2-[(3,3-dibutyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepin-8-yl)methylamino]acetic acid Chemical compound N1C(CCCC)(CCCC)CS(=O)(=O)C2=CC(CNCC(O)=O)=C(OC)C=C2C1C1=CC=CC=C1 KBZOLELTOAPIRR-UHFFFAOYSA-N 0.000 description 1
• HAAASQBXABIHAU-FQLXRVMXSA-N 2-[3-[(3r,5r)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepin-8-yl]propanoyl-(carboxymethyl)amino]acetic acid Chemical compound C1([C@@H]2C3=CC(OC)=C(CCC(=O)N(CC(O)=O)CC(O)=O)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 HAAASQBXABIHAU-FQLXRVMXSA-N 0.000 description 1
• VSUWLPYLNRWCFN-GGXMVOPNSA-N 2-[3-[(3r,5r)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepin-8-yl]propanoylamino]-2-methylpropanoic acid Chemical compound C1([C@@H]2C3=CC(OC)=C(CCC(=O)NC(C)(C)C(O)=O)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 VSUWLPYLNRWCFN-GGXMVOPNSA-N 0.000 description 1
• DCIQRNLDCSLTEC-CNZCJKERSA-N 2-[3-[(3r,5r)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepin-8-yl]propylamino]ethanesulfonic acid;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.C1([C@@H]2C3=CC(OC)=C(CCCNCCS(O)(=O)=O)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 DCIQRNLDCSLTEC-CNZCJKERSA-N 0.000 description 1
• PCMCCYYBJIOGNP-JWQCQUIFSA-N 2-[[(3r,5r)-3-butyl-3-ethyl-4-hydroxy-7-methoxy-1,1-dioxo-5-phenyl-2,5-dihydro-1$l^{6},4-benzothiazepin-8-yl]methylamino]acetic acid Chemical compound C1([C@@H]2C3=CC(OC)=C(CNCC(O)=O)C=C3S(=O)(=O)C[C@@](N2O)(CC)CCCC)=CC=CC=C1 PCMCCYYBJIOGNP-JWQCQUIFSA-N 0.000 description 1
• OFVNNXAAXDPUOD-JWQCQUIFSA-N 2-[[(3r,5r)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepin-8-yl]methyl-hydroxyamino]acetic acid Chemical compound C1([C@@H]2C3=CC(OC)=C(CN(O)CC(O)=O)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 OFVNNXAAXDPUOD-JWQCQUIFSA-N 0.000 description 1
• YTNFDGWRKQEREI-CLJLJLNGSA-N 2-[[(3r,5r)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepin-8-yl]methyl-methylamino]acetic acid Chemical compound C1([C@@H]2C3=CC(OC)=C(CN(C)CC(O)=O)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 YTNFDGWRKQEREI-CLJLJLNGSA-N 0.000 description 1
• KUZXMNYNPRMUEY-RCZVLFRGSA-N 2-[[(3r,5r)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepin-8-yl]methylamino]-2-oxoacetic acid Chemical compound C1([C@@H]2C3=CC(OC)=C(CNC(=O)C(O)=O)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 KUZXMNYNPRMUEY-RCZVLFRGSA-N 0.000 description 1
• YZNJXTBHSBTOBC-JWQCQUIFSA-N 2-[[(3r,5r)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepin-8-yl]methylamino]-2-oxoethanesulfonic acid Chemical compound C1([C@@H]2C3=CC(OC)=C(CNC(=O)CS(O)(=O)=O)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 YZNJXTBHSBTOBC-JWQCQUIFSA-N 0.000 description 1
• RFSXTWRAEJMNPX-JWQCQUIFSA-N 2-[[(3r,5r)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepin-8-yl]methylamino]acetic acid Chemical compound C1([C@@H]2C3=CC(OC)=C(CNCC(O)=O)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 RFSXTWRAEJMNPX-JWQCQUIFSA-N 0.000 description 1
• VYQNHNKZOOHGOK-CNZCJKERSA-N 2-[[(3r,5r)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepin-8-yl]methylamino]ethyl-ethoxyphosphinic acid;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.C1([C@@H]2C3=CC(OC)=C(CNCCP(O)(=O)OCC)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 VYQNHNKZOOHGOK-CNZCJKERSA-N 0.000 description 1
• CPSKBEWIYDLGCB-JIMLSGQQSA-N 2-[[(3r,5r)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepin-8-yl]methylamino]ethylphosphonic acid;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.C1([C@@H]2C3=CC(OC)=C(CNCCP(O)(O)=O)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 CPSKBEWIYDLGCB-JIMLSGQQSA-N 0.000 description 1
• YRAFYXWUQIXOQR-ILBGXUMGSA-N 2-[[(3r,5r)-3-butyl-3-ethyl-7-methoxy-5-phenyl-4,5-dihydro-2h-1,4-benzothiazepine-8-carbonyl]amino]acetic acid Chemical compound C1([C@@H]2C3=CC(OC)=C(C(=O)NCC(O)=O)C=C3SC[C@@](N2)(CC)CCCC)=CC=CC=C1 YRAFYXWUQIXOQR-ILBGXUMGSA-N 0.000 description 1
• YDNUWKMVHCGZIC-JUJAXGASSA-N 2-[[(3r,5r)-3-butyl-7-(dimethylamino)-3-ethyl-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepin-8-yl]methylamino]acetic acid;2,2,2-trifluoroacetic acid Chemical class OC(=O)C(F)(F)F.C1([C@@H]2C3=CC(=C(CNCC(O)=O)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)N(C)C)=CC=CC=C1 YDNUWKMVHCGZIC-JUJAXGASSA-N 0.000 description 1
• GCVKJIQRRSZWDV-CNZCJKERSA-N 2-[[2-[[(3r,5r)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepin-8-yl]methylamino]-2-oxoethyl]amino]ethylphosphonic acid;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.C1([C@@H]2C3=CC(OC)=C(CNC(=O)CNCCP(O)(O)=O)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 GCVKJIQRRSZWDV-CNZCJKERSA-N 0.000 description 1
• YSWCBAKPAOEYGF-UHFFFAOYSA-N 2-aminoacetic acid;2,2,2-trifluoroacetic acid Chemical class NCC(O)=O.OC(=O)C(F)(F)F YSWCBAKPAOEYGF-UHFFFAOYSA-N 0.000 description 1
• NWQMRLFYJYLMGL-UHFFFAOYSA-N 3-[(3,3-dibutyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepin-8-yl)methylamino]pentanedioic acid Chemical compound N1C(CCCC)(CCCC)CS(=O)(=O)C2=CC(CNC(CC(O)=O)CC(O)=O)=C(OC)C=C2C1C1=CC=CC=C1 NWQMRLFYJYLMGL-UHFFFAOYSA-N 0.000 description 1
• RWTSVECPZSMPPS-UHFFFAOYSA-N 3-[(3,3-dibutyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepin-8-yl)methylamino]pentanedioic acid;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.N1C(CCCC)(CCCC)CS(=O)(=O)C2=CC(CNC(CC(O)=O)CC(O)=O)=C(OC)C=C2C1C1=CC=CC=C1 RWTSVECPZSMPPS-UHFFFAOYSA-N 0.000 description 1
• DCFLMHOOIZCSCK-CLJLJLNGSA-N 3-[(3r,5r)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepin-8-yl]propyl methanesulfonate Chemical compound C1([C@@H]2C3=CC(OC)=C(CCCOS(C)(=O)=O)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 DCFLMHOOIZCSCK-CLJLJLNGSA-N 0.000 description 1
• CXJYCOXIHSSRGX-JIMLSGQQSA-N 3-[(3r,5r)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepin-8-yl]propylphosphonic acid;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.C1([C@@H]2C3=CC(OC)=C(CCCP(O)(O)=O)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 CXJYCOXIHSSRGX-JIMLSGQQSA-N 0.000 description 1
• FSTNPGUOKJUMKQ-VSGBNLITSA-N 3-[[(3r,5r)-3-butyl-3-ethyl-4-hydroxy-7-methoxy-1,1-dioxo-5-phenyl-2,5-dihydro-1$l^{6},4-benzothiazepin-8-yl]methylamino]pentanedioic acid Chemical compound C1([C@@H]2C3=CC(OC)=C(CNC(CC(O)=O)CC(O)=O)C=C3S(=O)(=O)C[C@@](N2O)(CC)CCCC)=CC=CC=C1 FSTNPGUOKJUMKQ-VSGBNLITSA-N 0.000 description 1
• FZCHBAUNVJSRDM-LTRMXRMOSA-N 3-[[(3r,5r)-3-butyl-3-ethyl-4-hydroxy-7-methoxy-1,1-dioxo-5-phenyl-2,5-dihydro-1$l^{6},4-benzothiazepin-8-yl]methylamino]pentanedioic acid;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.C1([C@@H]2C3=CC(OC)=C(CNC(CC(O)=O)CC(O)=O)C=C3S(=O)(=O)C[C@@](N2O)(CC)CCCC)=CC=CC=C1 FZCHBAUNVJSRDM-LTRMXRMOSA-N 0.000 description 1
• WAALSHILIAIMSO-UFHPHHKVSA-N 3-[[(3r,5r)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepine-8-carbonyl]amino]-2,2-dimethylpropanoic acid Chemical compound C1([C@@H]2C3=CC(OC)=C(C(=O)NCC(C)(C)C(O)=O)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 WAALSHILIAIMSO-UFHPHHKVSA-N 0.000 description 1
• JZUYZUVJGTTXPA-IXCJQBJRSA-N 3-[[(3r,5r)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepine-8-carbonyl]amino]pentanedioic acid Chemical compound C1([C@@H]2C3=CC(OC)=C(C(=O)NC(CC(O)=O)CC(O)=O)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 JZUYZUVJGTTXPA-IXCJQBJRSA-N 0.000 description 1
• CZGVOBIGEBDYTP-WUFINQPMSA-N 3-[[(3r,5s)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepin-8-yl]methylamino]pentanedioic acid Chemical compound C1([C@H]2C3=CC(OC)=C(CNC(CC(O)=O)CC(O)=O)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 CZGVOBIGEBDYTP-WUFINQPMSA-N 0.000 description 1
• PCFHUOIZSQIUBU-GAQUOPITSA-N 3-[[2-[[(3r,5r)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepin-8-yl]methylamino]-2-oxoethyl]amino]pentanedioic acid;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.C1([C@@H]2C3=CC(OC)=C(CNC(=O)CNC(CC(O)=O)CC(O)=O)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 PCFHUOIZSQIUBU-GAQUOPITSA-N 0.000 description 1
• INUNLMUAPJVRME-UHFFFAOYSA-N 3-chloropropanoyl chloride Chemical compound ClCCC(Cl)=O INUNLMUAPJVRME-UHFFFAOYSA-N 0.000 description 1
• RQFHYZOQHZMKQQ-JUJAXGASSA-N 4-[(3r,5r)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepin-8-yl]butanamide;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.C1([C@@H]2C3=CC(OC)=C(CCCC(N)=O)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 RQFHYZOQHZMKQQ-JUJAXGASSA-N 0.000 description 1
• MIPDNDHNDUHCGU-JUJAXGASSA-N 4-[(3r,5r)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepin-8-yl]butanoic acid;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.C1([C@@H]2C3=CC(OC)=C(CCCC(O)=O)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 MIPDNDHNDUHCGU-JUJAXGASSA-N 0.000 description 1
• ZOUMGGZKWOCOOY-CNZCJKERSA-N 4-[[(3r,5r)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepin-8-yl]methylamino]butanoic acid;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.C1([C@@H]2C3=CC(OC)=C(CNCCCC(O)=O)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 ZOUMGGZKWOCOOY-CNZCJKERSA-N 0.000 description 1
• HFGHRUCCKVYFKL-UHFFFAOYSA-N 4-ethoxy-2-piperazin-1-yl-7-pyridin-4-yl-5h-pyrimido[5,4-b]indole Chemical compound C1=C2NC=3C(OCC)=NC(N4CCNCC4)=NC=3C2=CC=C1C1=CC=NC=C1 HFGHRUCCKVYFKL-UHFFFAOYSA-N 0.000 description 1
• YZSCPLGKKMSBMV-UHFFFAOYSA-N 5-fluoro-4-(8-fluoro-4-propan-2-yl-2,3-dihydro-1,4-benzoxazin-6-yl)-N-[5-(1-methylpiperidin-4-yl)pyridin-2-yl]pyrimidin-2-amine Chemical compound FC=1C(=NC(=NC=1)NC1=NC=C(C=C1)C1CCN(CC1)C)C1=CC2=C(OCCN2C(C)C)C(=C1)F YZSCPLGKKMSBMV-UHFFFAOYSA-N 0.000 description 1
• QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
• 229940077274 Alpha glucosidase inhibitor Drugs 0.000 description 1
• NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
• 210000002237 B-cell of pancreatic islet Anatomy 0.000 description 1
• 241000894006 Bacteria Species 0.000 description 1
• 239000005711 Benzoic acid Substances 0.000 description 1
• 201000004569 Blindness Diseases 0.000 description 1
• 208000010392 Bone Fractures Diseases 0.000 description 1
• OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
• 206010007559 Cardiac failure congestive Diseases 0.000 description 1
• 108010078791 Carrier Proteins Proteins 0.000 description 1
• VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
• VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 1
• KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
• 206010010774 Constipation Diseases 0.000 description 1
• RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
• 108020003264 Cotransporters Proteins 0.000 description 1
• 102000034534 Cotransporters Human genes 0.000 description 1
• 208000011231 Crohn disease Diseases 0.000 description 1
• DSLZVSRJTYRBFB-LLEIAEIESA-N D-glucaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O DSLZVSRJTYRBFB-LLEIAEIESA-N 0.000 description 1
• RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
• KDXKERNSBIXSRK-RXMQYKEDSA-N D-lysine group Chemical group N[C@H](CCCCN)C(=O)O KDXKERNSBIXSRK-RXMQYKEDSA-N 0.000 description 1
• FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
• 208000007342 Diabetic Nephropathies Diseases 0.000 description 1
• 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
• JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 description 1
• HTQBXNHDCUEHJF-XWLPCZSASA-N Exenatide Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)NCC(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 HTQBXNHDCUEHJF-XWLPCZSASA-N 0.000 description 1
• 108010011459 Exenatide Proteins 0.000 description 1
• VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
• 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 1
• 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 1
• 230000005526 G1 to G0 transition Effects 0.000 description 1
• 108010088406 Glucagon-Like Peptides Proteins 0.000 description 1
• 102400000326 Glucagon-like peptide 2 Human genes 0.000 description 1
• 101800000221 Glucagon-like peptide 2 Proteins 0.000 description 1
• 229910004373 HOAc Inorganic materials 0.000 description 1
• 206010019280 Heart failures Diseases 0.000 description 1
• 238000007341 Heck reaction Methods 0.000 description 1
• 241000282412 Homo Species 0.000 description 1
• CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
• 208000035150 Hypercholesterolemia Diseases 0.000 description 1
• 208000013016 Hypoglycemia Diseases 0.000 description 1
• 102100021711 Ileal sodium/bile acid cotransporter Human genes 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
• 102000036770 Islet Amyloid Polypeptide Human genes 0.000 description 1
• 108010041872 Islet Amyloid Polypeptide Proteins 0.000 description 1
• 239000005909 Kieselgur Substances 0.000 description 1
• 239000004158 L-cystine Substances 0.000 description 1
• JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
• 239000002841 Lewis acid Substances 0.000 description 1
• YSDQQAXHVYUZIW-QCIJIYAXSA-N Liraglutide Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)CC[C@H](NC(=O)CCCCCCCCCCCCCCC)C(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=C(O)C=C1 YSDQQAXHVYUZIW-QCIJIYAXSA-N 0.000 description 1
• 108010019598 Liraglutide Proteins 0.000 description 1
• FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
• 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
• 241000699670 Mus sp. Species 0.000 description 1
• 229910002651 NO3 Inorganic materials 0.000 description 1
• 229920002274 Nalgene Polymers 0.000 description 1
• 206010028813 Nausea Diseases 0.000 description 1
• 208000028389 Nerve injury Diseases 0.000 description 1
• 102400001103 Neurotensin Human genes 0.000 description 1
• 101800001814 Neurotensin Proteins 0.000 description 1
• 238000006174 Newman-Kwart rearrangement reaction Methods 0.000 description 1
• NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
• 108020005497 Nuclear hormone receptor Proteins 0.000 description 1
• 206010030113 Oedema Diseases 0.000 description 1
• 235000019502 Orange oil Nutrition 0.000 description 1
• 229910019142 PO4 Inorganic materials 0.000 description 1
• 108091005804 Peptidases Proteins 0.000 description 1
• NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 description 1
• 208000004880 Polyuria Diseases 0.000 description 1
• 102000004257 Potassium Channel Human genes 0.000 description 1
• 239000004365 Protease Substances 0.000 description 1
• 208000001647 Renal Insufficiency Diseases 0.000 description 1
• 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
• 108091006614 SLC10A2 Proteins 0.000 description 1
• 206010049416 Short-bowel syndrome Diseases 0.000 description 1
• XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
• KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
• 102100030511 Stanniocalcin-1 Human genes 0.000 description 1
• 101710142157 Stanniocalcin-1 Proteins 0.000 description 1
• 229940100389 Sulfonylurea Drugs 0.000 description 1
• UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 1
• 229940123464 Thiazolidinedione Drugs 0.000 description 1
• 241000700605 Viruses Species 0.000 description 1
• 208000021017 Weight Gain Diseases 0.000 description 1
• XNYCXGUIIWUJHY-OHIDFYLOSA-N [(3r,5r)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepin-8-yl]methanesulfonic acid;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.C1([C@@H]2C3=CC(OC)=C(CS(O)(=O)=O)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 XNYCXGUIIWUJHY-OHIDFYLOSA-N 0.000 description 1
• DRLUWKBEMYFOIB-DHIUTWEWSA-N [(3r,5r)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepin-8-yl]methanol Chemical compound C1([C@@H]2C3=CC(OC)=C(CO)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 DRLUWKBEMYFOIB-DHIUTWEWSA-N 0.000 description 1
• DRLUWKBEMYFOIB-XZOQPEGZSA-N [(3r,5s)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepin-8-yl]methanol Chemical compound C1([C@H]2C3=CC(OC)=C(CO)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 DRLUWKBEMYFOIB-XZOQPEGZSA-N 0.000 description 1
• FLCQZSAXNIWESK-PEADMDKFSA-N [(3r,5s)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepin-8-yl]methylphosphonic acid;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.C1([C@H]2C3=CC(OC)=C(CP(O)(O)=O)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 FLCQZSAXNIWESK-PEADMDKFSA-N 0.000 description 1
• NXFMLDQQDMMGSN-DVZRSZBPSA-N [(e)-2-[(3r,5r)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepin-8-yl]ethenyl]phosphonic acid Chemical compound C1([C@@H]2C3=CC(OC)=C(\C=C\P(O)(O)=O)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 NXFMLDQQDMMGSN-DVZRSZBPSA-N 0.000 description 1
• QDZMDWRIPSMULW-JIMLSGQQSA-N [2-[[(3r,5r)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepin-8-yl]methylamino]-2-oxoethyl]phosphonic acid;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.C1([C@@H]2C3=CC(OC)=C(CNC(=O)CP(O)(O)=O)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 QDZMDWRIPSMULW-JIMLSGQQSA-N 0.000 description 1
• DMZZOWRLYKBJBA-DNQXCXABSA-N [[(3r,5r)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepin-8-yl]methylamino]methylphosphonic acid Chemical compound C1([C@@H]2C3=CC(OC)=C(CNCP(O)(O)=O)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 DMZZOWRLYKBJBA-DNQXCXABSA-N 0.000 description 1
• ZAUYJKJJVMIDDO-ISKFKSNPSA-N [[(3r,5r)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepine-8-carbonyl]amino]methanesulfonic acid Chemical compound C1([C@@H]2C3=CC(OC)=C(C(=O)NCS(O)(=O)=O)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 ZAUYJKJJVMIDDO-ISKFKSNPSA-N 0.000 description 1
• WDJHALXBUFZDSR-UHFFFAOYSA-N acetoacetic acid Chemical compound CC(=O)CC(O)=O WDJHALXBUFZDSR-UHFFFAOYSA-N 0.000 description 1
• 150000007513 acids Chemical class 0.000 description 1
• 230000009471 action Effects 0.000 description 1
• 239000012190 activator Substances 0.000 description 1
• 210000000577 adipose tissue Anatomy 0.000 description 1
• 230000002411 adverse Effects 0.000 description 1
• 239000000556 agonist Substances 0.000 description 1
• 239000003888 alpha glucosidase inhibitor Substances 0.000 description 1
• 239000004411 aluminium Substances 0.000 description 1
• 238000010640 amide synthesis reaction Methods 0.000 description 1
• 238000005576 amination reaction Methods 0.000 description 1
• OBESRABRARNZJB-UHFFFAOYSA-N aminomethanesulfonic acid Chemical compound NCS(O)(=O)=O OBESRABRARNZJB-UHFFFAOYSA-N 0.000 description 1
• 238000004458 analytical method Methods 0.000 description 1
• 206010003246 arthritis Diseases 0.000 description 1
• 229960005261 aspartic acid Drugs 0.000 description 1
• 230000001363 autoimmune Effects 0.000 description 1
• FISUYHWSFLPVMT-QJVAZPMTSA-N azane;(e)-3-[(3r,5r)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepin-8-yl]prop-2-enoic acid Chemical compound [NH4+].C1([C@@H]2C3=CC(OC)=C(\C=C\C([O-])=O)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 FISUYHWSFLPVMT-QJVAZPMTSA-N 0.000 description 1
• BYQIPTSLGIQWNN-JIMLSGQQSA-N azanium;2-[[(3r,5r)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepin-8-yl]methylamino]ethanesulfonate Chemical compound N.C1([C@@H]2C3=CC(OC)=C(CNCCS(O)(=O)=O)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 BYQIPTSLGIQWNN-JIMLSGQQSA-N 0.000 description 1
• UZTKHMVVSPRQNF-JUJAXGASSA-N azanium;3-[[(3r,5r)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepin-8-yl]methylamino]-3-oxopropane-1-sulfonate Chemical compound N.C1([C@@H]2C3=CC(OC)=C(CNC(=O)CCS(O)(=O)=O)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 UZTKHMVVSPRQNF-JUJAXGASSA-N 0.000 description 1
• 239000003855 balanced salt solution Substances 0.000 description 1
• 229940077388 benzenesulfonate Drugs 0.000 description 1
• SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
• 229940053197 benzodiazepine derivative antiepileptics Drugs 0.000 description 1
• 125000003310 benzodiazepinyl group Chemical class N1N=C(C=CC2=C1C=CC=C2)* 0.000 description 1
• 235000010233 benzoic acid Nutrition 0.000 description 1
• 229940093761 bile salts Drugs 0.000 description 1
• 239000012455 biphasic mixture Substances 0.000 description 1
• 150000001649 bromium compounds Chemical class 0.000 description 1
• 239000011575 calcium Substances 0.000 description 1
• 229910052791 calcium Inorganic materials 0.000 description 1
• MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
• 230000006315 carbonylation Effects 0.000 description 1
• 238000005810 carbonylation reaction Methods 0.000 description 1
• 230000007211 cardiovascular event Effects 0.000 description 1
• 230000015556 catabolic process Effects 0.000 description 1
• 230000003197 catalytic effect Effects 0.000 description 1
• 239000013592 cell lysate Substances 0.000 description 1
• 239000001913 cellulose Substances 0.000 description 1
• 229920002678 cellulose Polymers 0.000 description 1
• 210000003169 central nervous system Anatomy 0.000 description 1
• KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 1
• 150000001805 chlorine compounds Chemical class 0.000 description 1
• 125000004965 chloroalkyl group Chemical group 0.000 description 1
• XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 1
• 230000031154 cholesterol homeostasis Effects 0.000 description 1
• 230000001684 chronic effect Effects 0.000 description 1
• 229940001468 citrate Drugs 0.000 description 1
• ONCCWDRMOZMNSM-FBCQKBJTSA-N compound Z Chemical compound N1=C2C(=O)NC(N)=NC2=NC=C1C(=O)[C@H]1OP(O)(=O)OC[C@H]1O ONCCWDRMOZMNSM-FBCQKBJTSA-N 0.000 description 1
• 230000021615 conjugation Effects 0.000 description 1
• 229910052802 copper Inorganic materials 0.000 description 1
• 239000010949 copper Substances 0.000 description 1
• 238000002447 crystallographic data Methods 0.000 description 1
• 238000007333 cyanation reaction Methods 0.000 description 1
• 229960003067 cystine Drugs 0.000 description 1
• 230000006378 damage Effects 0.000 description 1
• DEZRYPDIMOWBDS-UHFFFAOYSA-N dcm dichloromethane Chemical compound ClCCl.ClCCl DEZRYPDIMOWBDS-UHFFFAOYSA-N 0.000 description 1
• 230000034994 death Effects 0.000 description 1
• 231100000517 death Toxicity 0.000 description 1
• 238000010908 decantation Methods 0.000 description 1
• 230000003247 decreasing effect Effects 0.000 description 1
• 230000007547 defect Effects 0.000 description 1
• 238000006731 degradation reaction Methods 0.000 description 1
• 229940009976 deoxycholate Drugs 0.000 description 1
• KXGVEGMKQFWNSR-LLQZFEROSA-N deoxycholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 KXGVEGMKQFWNSR-LLQZFEROSA-N 0.000 description 1
• 208000033679 diabetic kidney disease Diseases 0.000 description 1
• NKTADINVBDSUAN-KKLWWLSJSA-N diethyl 3-[3-[(3r,5r)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepin-8-yl]propanoylamino]pentanedioate Chemical compound C1([C@@H]2C3=CC(OC)=C(CCC(=O)NC(CC(=O)OCC)CC(=O)OCC)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 NKTADINVBDSUAN-KKLWWLSJSA-N 0.000 description 1
• OZEUGGINPPGZQQ-ROJLCIKYSA-N diethyl 3-[[(3r,5r)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepin-8-yl]methylamino]pentanedioate Chemical compound C1([C@@H]2C3=CC(OC)=C(CNC(CC(=O)OCC)CC(=O)OCC)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 OZEUGGINPPGZQQ-ROJLCIKYSA-N 0.000 description 1
• HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
• 238000000113 differential scanning calorimetry Methods 0.000 description 1
• 230000029087 digestion Effects 0.000 description 1
• 238000010790 dilution Methods 0.000 description 1
• 239000012895 dilution Substances 0.000 description 1
• BYHXBBOSJKPUJL-SCSAIBSYSA-N dimethyl (2r)-2-aminobutanedioate Chemical compound COC(=O)C[C@@H](N)C(=O)OC BYHXBBOSJKPUJL-SCSAIBSYSA-N 0.000 description 1
• BYHXBBOSJKPUJL-BYPYZUCNSA-N dimethyl (2s)-2-aminobutanedioate Chemical compound COC(=O)C[C@H](N)C(=O)OC BYHXBBOSJKPUJL-BYPYZUCNSA-N 0.000 description 1
• CIDSYVVJNVVERM-HYXAFXHYSA-N dimethyl (z)-3-aminopent-2-enedioate Chemical compound COC(=O)C\C(N)=C\C(=O)OC CIDSYVVJNVVERM-HYXAFXHYSA-N 0.000 description 1
• DARAAHVRAMNFLY-PQHLKRTFSA-N dimethyl 3-[[(3r,5r)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepine-8-carbonyl]amino]pentanedioate Chemical compound C1([C@@H]2C3=CC(OC)=C(C(=O)NC(CC(=O)OC)CC(=O)OC)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 DARAAHVRAMNFLY-PQHLKRTFSA-N 0.000 description 1
• LDCRTTXIJACKKU-ONEGZZNKSA-N dimethyl fumarate Chemical compound COC(=O)\C=C\C(=O)OC LDCRTTXIJACKKU-ONEGZZNKSA-N 0.000 description 1
• 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
• 201000010099 disease Diseases 0.000 description 1
• 239000006185 dispersion Substances 0.000 description 1
• CNXMDTWQWLGCPE-UHFFFAOYSA-N ditert-butyl-(2-phenylphenyl)phosphane Chemical compound CC(C)(C)P(C(C)(C)C)C1=CC=CC=C1C1=CC=CC=C1 CNXMDTWQWLGCPE-UHFFFAOYSA-N 0.000 description 1
• CETRZFQIITUQQL-UHFFFAOYSA-N dmso dimethylsulfoxide Chemical compound CS(C)=O.CS(C)=O CETRZFQIITUQQL-UHFFFAOYSA-N 0.000 description 1
• 210000001198 duodenum Anatomy 0.000 description 1
• 238000003821 enantio-separation Methods 0.000 description 1
• 230000019439 energy homeostasis Effects 0.000 description 1
• 210000001842 enterocyte Anatomy 0.000 description 1
• OCLXJTCGWSSVOE-UHFFFAOYSA-N ethanol etoh Chemical compound CCO.CCO OCLXJTCGWSSVOE-UHFFFAOYSA-N 0.000 description 1
• CZPSEFMLFUPGIM-AWEZNQCLSA-N ethyl (2s)-2-(benzylideneamino)hexanoate Chemical compound CCCC[C@@H](C(=O)OCC)N=CC1=CC=CC=C1 CZPSEFMLFUPGIM-AWEZNQCLSA-N 0.000 description 1
• SHKMMWRRLVGMOV-FJXQXJEOSA-N ethyl (2s)-2-aminohexanoate;hydrochloride Chemical compound Cl.CCCC[C@H](N)C(=O)OCC SHKMMWRRLVGMOV-FJXQXJEOSA-N 0.000 description 1
• MNZHWCBTRWBJLM-UHFFFAOYSA-N ethyl 2-(benzylideneamino)-2-butylhexanoate Chemical compound CCCCC(CCCC)(C(=O)OCC)N=CC1=CC=CC=C1 MNZHWCBTRWBJLM-UHFFFAOYSA-N 0.000 description 1
• LJDNMOCAQVXVKY-UHFFFAOYSA-N ethyl 2-[(2-ethoxy-2-oxoethyl)amino]acetate Chemical compound CCOC(=O)CNCC(=O)OCC LJDNMOCAQVXVKY-UHFFFAOYSA-N 0.000 description 1
• VOOSREZGNYADBY-CZNDPXEESA-N ethyl 2-[3-[(3r,5r)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepin-8-yl]propanoyl-(2-ethoxy-2-oxoethyl)amino]acetate Chemical compound C1([C@@H]2C3=CC(OC)=C(CCC(=O)N(CC(=O)OCC)CC(=O)OCC)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 VOOSREZGNYADBY-CZNDPXEESA-N 0.000 description 1
• UIKOVWUYANJUPR-UHFFFAOYSA-N ethyl 2-iminobutanoate Chemical compound CCOC(=O)C(=N)CC UIKOVWUYANJUPR-UHFFFAOYSA-N 0.000 description 1
• RYKWAKCJLTYPCV-UHFFFAOYSA-N ethyl 3-amino-2,2-dimethylpropanoate Chemical compound CCOC(=O)C(C)(C)CN RYKWAKCJLTYPCV-UHFFFAOYSA-N 0.000 description 1
• 125000004494 ethyl ester group Chemical group 0.000 description 1
• OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 1
• 230000005713 exacerbation Effects 0.000 description 1
• 229960001519 exenatide Drugs 0.000 description 1
• 230000002550 fecal effect Effects 0.000 description 1
• 239000012527 feed solution Substances 0.000 description 1
• 238000011049 filling Methods 0.000 description 1
• 230000037406 food intake Effects 0.000 description 1
• 238000007306 functionalization reaction Methods 0.000 description 1
• 230000002496 gastric effect Effects 0.000 description 1
• 208000004104 gestational diabetes Diseases 0.000 description 1
• TWSALRJGPBVBQU-PKQQPRCHSA-N glucagon-like peptide 2 Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(O)=O)[C@@H](C)CC)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)CC)C1=CC=CC=C1 TWSALRJGPBVBQU-PKQQPRCHSA-N 0.000 description 1
• 229940050410 gluconate Drugs 0.000 description 1
• 230000009229 glucose formation Effects 0.000 description 1
• 230000014101 glucose homeostasis Effects 0.000 description 1
• 230000004190 glucose uptake Effects 0.000 description 1
• 230000002641 glycemic effect Effects 0.000 description 1
• HHLFWLYXYJOTON-UHFFFAOYSA-N glyoxylic acid Chemical compound OC(=O)C=O HHLFWLYXYJOTON-UHFFFAOYSA-N 0.000 description 1
• 230000036541 health Effects 0.000 description 1
• 229910001385 heavy metal Inorganic materials 0.000 description 1
• 235000003642 hunger Nutrition 0.000 description 1
• 239000001257 hydrogen Substances 0.000 description 1
• IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
• 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
• XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
• 230000007062 hydrolysis Effects 0.000 description 1
• 238000006460 hydrolysis reaction Methods 0.000 description 1
• 230000002218 hypoglycaemic effect Effects 0.000 description 1
• 238000001727 in vivo Methods 0.000 description 1
• MGXWVYUBJRZYPE-YUGYIWNOSA-N incretin Chemical class C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(N)=O)C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)[C@@H](C)O)[C@@H](C)CC)C1=CC=C(O)C=C1 MGXWVYUBJRZYPE-YUGYIWNOSA-N 0.000 description 1
• 201000006747 infectious mononucleosis Diseases 0.000 description 1
• 238000001802 infusion Methods 0.000 description 1
• 210000000936 intestine Anatomy 0.000 description 1
• 238000003402 intramolecular cyclocondensation reaction Methods 0.000 description 1
• INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
• 230000000302 ischemic effect Effects 0.000 description 1
• JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
• 230000000366 juvenile effect Effects 0.000 description 1
• 208000017169 kidney disease Diseases 0.000 description 1
• 201000006370 kidney failure Diseases 0.000 description 1
• 229940001447 lactate Drugs 0.000 description 1
• 208000006443 lactic acidosis Diseases 0.000 description 1
• 150000007517 lewis acids Chemical class 0.000 description 1
• 150000002632 lipids Chemical class 0.000 description 1
• 239000007788 liquid Substances 0.000 description 1
• 229960002701 liraglutide Drugs 0.000 description 1
• 150000002643 lithocholic acids Chemical class 0.000 description 1
• 230000007774 longterm Effects 0.000 description 1
• 239000011777 magnesium Substances 0.000 description 1
• 229910052749 magnesium Inorganic materials 0.000 description 1
• NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 1
• 238000012423 maintenance Methods 0.000 description 1
• VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
• 238000005259 measurement Methods 0.000 description 1
• 230000007246 mechanism Effects 0.000 description 1
• BCVXHSPFUWZLGQ-UHFFFAOYSA-N mecn acetonitrile Chemical compound CC#N.CC#N BCVXHSPFUWZLGQ-UHFFFAOYSA-N 0.000 description 1
• 239000002609 medium Substances 0.000 description 1
• COTNUBDHGSIOTA-UHFFFAOYSA-N meoh methanol Chemical compound OC.OC COTNUBDHGSIOTA-UHFFFAOYSA-N 0.000 description 1
• 238000003328 mesylation reaction Methods 0.000 description 1
• 229910052751 metal Inorganic materials 0.000 description 1
• 239000002184 metal Substances 0.000 description 1
• 229940098779 methanesulfonic acid Drugs 0.000 description 1
• HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 description 1
• QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
• NXPNPYNCKSWEHA-WDSKDSINSA-N methyl (2r)-2-amino-3-[[(2r)-2-amino-3-methoxy-3-oxopropyl]disulfanyl]propanoate Chemical compound COC(=O)[C@@H](N)CSSC[C@H](N)C(=O)OC NXPNPYNCKSWEHA-WDSKDSINSA-N 0.000 description 1
• BYZSYVVCZKASDQ-POURPWNDSA-N methyl 2-[3-[(3r,5r)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepin-8-yl]propanoylamino]-2-methylpropanoate Chemical compound C1([C@@H]2C3=CC(OC)=C(CCC(=O)NC(C)(C)C(=O)OC)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 BYZSYVVCZKASDQ-POURPWNDSA-N 0.000 description 1
• JIWQROJBWSUWOT-VSGBNLITSA-N methyl 2-[3-[(3r,5r)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepin-8-yl]propanoylamino]acetate Chemical compound C1([C@@H]2C3=CC(OC)=C(CCC(=O)NCC(=O)OC)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 JIWQROJBWSUWOT-VSGBNLITSA-N 0.000 description 1
• HMZHEECHJWHZJX-UHFFFAOYSA-N methyl 2-amino-2-methylpropanoate Chemical compound COC(=O)C(C)(C)N HMZHEECHJWHZJX-UHFFFAOYSA-N 0.000 description 1
• NVWZNEDLYYLQJC-UHFFFAOYSA-N methyl 2-amino-2-methylpropanoate;hydrochloride Chemical compound Cl.COC(=O)C(C)(C)N NVWZNEDLYYLQJC-UHFFFAOYSA-N 0.000 description 1
• KVQGGLZHHFGHPU-UHFFFAOYSA-N methyl 4-aminobutanoate Chemical compound COC(=O)CCCN KVQGGLZHHFGHPU-UHFFFAOYSA-N 0.000 description 1
• 150000004702 methyl esters Chemical class 0.000 description 1
• 230000027939 micturition Effects 0.000 description 1
• 230000004048 modification Effects 0.000 description 1
• 238000012986 modification Methods 0.000 description 1
• 108091005601 modified peptides Proteins 0.000 description 1
• 210000003205 muscle Anatomy 0.000 description 1
• WOOWBQQQJXZGIE-UHFFFAOYSA-N n-ethyl-n-propan-2-ylpropan-2-amine Chemical compound CCN(C(C)C)C(C)C.CCN(C(C)C)C(C)C WOOWBQQQJXZGIE-UHFFFAOYSA-N 0.000 description 1
• 230000008693 nausea Effects 0.000 description 1
• 230000008764 nerve damage Effects 0.000 description 1
• PCJGZPGTCUMMOT-ISULXFBGSA-N neurotensin Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 PCJGZPGTCUMMOT-ISULXFBGSA-N 0.000 description 1
• 239000012299 nitrogen atmosphere Substances 0.000 description 1
• 102000006255 nuclear receptors Human genes 0.000 description 1
• 108020004017 nuclear receptors Proteins 0.000 description 1
• 238000010899 nucleation Methods 0.000 description 1
• XULSCZPZVQIMFM-IPZQJPLYSA-N odevixibat Chemical compound C12=CC(SC)=C(OCC(=O)N[C@@H](C(=O)N[C@@H](CC)C(O)=O)C=3C=CC(O)=CC=3)C=C2S(=O)(=O)NC(CCCC)(CCCC)CN1C1=CC=CC=C1 XULSCZPZVQIMFM-IPZQJPLYSA-N 0.000 description 1
• 238000005580 one pot reaction Methods 0.000 description 1
• 229940126701 oral medication Drugs 0.000 description 1
• 239000010502 orange oil Substances 0.000 description 1
• 210000000056 organ Anatomy 0.000 description 1
• 230000008520 organization Effects 0.000 description 1
• 150000003891 oxalate salts Chemical class 0.000 description 1
• 238000012856 packing Methods 0.000 description 1
• QJPQVXSHYBGQGM-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 QJPQVXSHYBGQGM-UHFFFAOYSA-N 0.000 description 1
• PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 description 1
• 239000000813 peptide hormone Substances 0.000 description 1
• 230000002093 peripheral effect Effects 0.000 description 1
• 230000000144 pharmacologic effect Effects 0.000 description 1
• 239000010452 phosphate Substances 0.000 description 1
• NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
• 230000000704 physical effect Effects 0.000 description 1
• 230000006461 physiological response Effects 0.000 description 1
• 229960005095 pioglitazone Drugs 0.000 description 1
• 229960005235 piperonyl butoxide Drugs 0.000 description 1
• 229910052697 platinum Inorganic materials 0.000 description 1
• 238000005498 polishing Methods 0.000 description 1
• 206010036067 polydipsia Diseases 0.000 description 1
• 229920000642 polymer Polymers 0.000 description 1
• 210000003240 portal vein Anatomy 0.000 description 1
• 230000000291 postprandial effect Effects 0.000 description 1
• 235000015320 potassium carbonate Nutrition 0.000 description 1
• 108020001213 potassium channel Proteins 0.000 description 1
• 230000003389 potentiating effect Effects 0.000 description 1
• 238000001144 powder X-ray diffraction data Methods 0.000 description 1
• 238000001556 precipitation Methods 0.000 description 1
• 238000002953 preparative HPLC Methods 0.000 description 1
• 238000004237 preparative chromatography Methods 0.000 description 1
• 230000001737 promoting effect Effects 0.000 description 1
• QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 1
• 230000009103 reabsorption Effects 0.000 description 1
• 238000004064 recycling Methods 0.000 description 1
• 230000001105 regulatory effect Effects 0.000 description 1
• 239000011369 resultant mixture Substances 0.000 description 1
• 229960004586 rosiglitazone Drugs 0.000 description 1
• 238000007127 saponification reaction Methods 0.000 description 1
• QGJUIPDUBHWZPV-SGTAVMJGSA-N saxagliptin Chemical compound C1C(C2)CC(C3)CC2(O)CC13[C@H](N)C(=O)N1[C@H](C#N)C[C@@H]2C[C@@H]21 QGJUIPDUBHWZPV-SGTAVMJGSA-N 0.000 description 1
• 229960004937 saxagliptin Drugs 0.000 description 1
• 108010033693 saxagliptin Proteins 0.000 description 1
• 229960001153 serine Drugs 0.000 description 1
• 210000001599 sigmoid colon Anatomy 0.000 description 1
• 230000007727 signaling mechanism Effects 0.000 description 1
• 239000011863 silicon-based powder Substances 0.000 description 1
• 238000009097 single-agent therapy Methods 0.000 description 1
• 229960004034 sitagliptin Drugs 0.000 description 1
• MFFMDFFZMYYVKS-SECBINFHSA-N sitagliptin Chemical compound C([C@H](CC(=O)N1CC=2N(C(=NN=2)C(F)(F)F)CC1)N)C1=CC(F)=C(F)C=C1F MFFMDFFZMYYVKS-SECBINFHSA-N 0.000 description 1
• 229910052708 sodium Inorganic materials 0.000 description 1
• 239000011734 sodium Substances 0.000 description 1
• 239000011780 sodium chloride Substances 0.000 description 1
• QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
• 239000012312 sodium hydride Substances 0.000 description 1
• 239000011343 solid material Substances 0.000 description 1
• 238000010561 standard procedure Methods 0.000 description 1
• KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
• 150000003462 sulfoxides Chemical class 0.000 description 1
• 229910021653 sulphate ion Inorganic materials 0.000 description 1
• 229940095064 tartrate Drugs 0.000 description 1
• XJJBXZIKXFOMLP-SSDOTTSWSA-N tert-butyl (2r)-pyrrolidine-2-carboxylate Chemical compound CC(C)(C)OC(=O)[C@H]1CCCN1 XJJBXZIKXFOMLP-SSDOTTSWSA-N 0.000 description 1
• XUXSWLABAXJRBY-MRPJDYLLSA-N tert-butyl (2s)-2-[[(3r,5r)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepin-8-yl]methylamino]-4-methylsulfanylbutanoate Chemical compound C1([C@@H]2C3=CC(OC)=C(CN[C@@H](CCSC)C(=O)OC(C)(C)C)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 XUXSWLABAXJRBY-MRPJDYLLSA-N 0.000 description 1
• XHWXHVOIWMNRLH-YFKPBYRVSA-N tert-butyl (2s)-2-amino-3-hydroxypropanoate Chemical compound CC(C)(C)OC(=O)[C@@H](N)CO XHWXHVOIWMNRLH-YFKPBYRVSA-N 0.000 description 1
• MOJADIHIJINDQF-ZETCQYMHSA-N tert-butyl (2s)-2-amino-4-methylsulfanylbutanoate Chemical compound CSCC[C@H](N)C(=O)OC(C)(C)C MOJADIHIJINDQF-ZETCQYMHSA-N 0.000 description 1
• XASPGLPXANLVTJ-RITPCOANSA-N tert-butyl (2s,3r)-2-amino-3-hydroxybutanoate Chemical compound C[C@@H](O)[C@H](N)C(=O)OC(C)(C)C XASPGLPXANLVTJ-RITPCOANSA-N 0.000 description 1
• MYKMOIQAHCMLIR-UHFFFAOYSA-N tert-butyl 2-(methylamino)acetate Chemical compound CNCC(=O)OC(C)(C)C MYKMOIQAHCMLIR-UHFFFAOYSA-N 0.000 description 1
• ZJXHVYSDMUKUCA-UHFFFAOYSA-N tert-butyl 3-aminopropanoate Chemical compound CC(C)(C)OC(=O)CCN ZJXHVYSDMUKUCA-UHFFFAOYSA-N 0.000 description 1
• GLSNUAKOIFDJLR-WECIHKQLSA-N tetraethyl 2-[(3r,5r)-3-butyl-3-ethyl-7-methoxy-1,1-dioxo-5-phenyl-4,5-dihydro-2h-1$l^{6},4-benzothiazepin-8-yl]propane-1,1,3,3-tetracarboxylate Chemical compound C1([C@@H]2C3=CC(OC)=C(C(C(C(=O)OCC)C(=O)OCC)C(C(=O)OCC)C(=O)OCC)C=C3S(=O)(=O)C[C@@](N2)(CC)CCCC)=CC=CC=C1 GLSNUAKOIFDJLR-WECIHKQLSA-N 0.000 description 1
• WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
• 229940124597 therapeutic agent Drugs 0.000 description 1
• 238000002411 thermogravimetry Methods 0.000 description 1
• 150000001467 thiazolidinediones Chemical class 0.000 description 1
• 230000035922 thirst Effects 0.000 description 1
• 210000001519 tissue Anatomy 0.000 description 1
• 238000012546 transfer Methods 0.000 description 1
• 230000032258 transport Effects 0.000 description 1
• DQWPFSLDHJDLRL-UHFFFAOYSA-N triethyl phosphate Chemical compound CCOP(=O)(OCC)OCC DQWPFSLDHJDLRL-UHFFFAOYSA-N 0.000 description 1
• ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
• 238000003828 vacuum filtration Methods 0.000 description 1
• SYOKIDBDQMKNDQ-XWTIBIIYSA-N vildagliptin Chemical compound C1C(O)(C2)CC(C3)CC1CC32NCC(=O)N1CCC[C@H]1C#N SYOKIDBDQMKNDQ-XWTIBIIYSA-N 0.000 description 1
• 229960001254 vildagliptin Drugs 0.000 description 1
• 238000010792 warming Methods 0.000 description 1
• 229910052725 zinc Inorganic materials 0.000 description 1