JP2016504285A - ナトリウムグルコース共輸送体1の阻害剤 - Google Patents
ナトリウムグルコース共輸送体1の阻害剤 Download PDFInfo
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- JP2016504285A JP2016504285A JP2015542874A JP2015542874A JP2016504285A JP 2016504285 A JP2016504285 A JP 2016504285A JP 2015542874 A JP2015542874 A JP 2015542874A JP 2015542874 A JP2015542874 A JP 2015542874A JP 2016504285 A JP2016504285 A JP 2016504285A
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- 239000003112 inhibitor Substances 0.000 title abstract description 33
- 108091006277 SLC5A1 Proteins 0.000 title abstract description 29
- 102000058090 Sodium-Glucose Transporter 1 Human genes 0.000 title abstract description 28
- 150000001875 compounds Chemical class 0.000 claims abstract description 107
- 238000000034 method Methods 0.000 claims abstract description 41
- 239000000203 mixture Substances 0.000 claims abstract description 21
- -1 cyano, formyl Chemical group 0.000 claims description 114
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 37
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 32
- 150000001408 amides Chemical class 0.000 claims description 19
- 201000010099 disease Diseases 0.000 claims description 19
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 19
- 208000035475 disorder Diseases 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 18
- 125000003118 aryl group Chemical group 0.000 claims description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims description 17
- 239000001257 hydrogen Substances 0.000 claims description 17
- 238000006467 substitution reaction Methods 0.000 claims description 17
- 125000000623 heterocyclic group Chemical group 0.000 claims description 15
- 239000004202 carbamide Substances 0.000 claims description 13
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 12
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 10
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims description 10
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M Thiocyanate anion Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 claims description 8
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 8
- 150000002148 esters Chemical class 0.000 claims description 8
- 125000004404 heteroalkyl group Chemical group 0.000 claims description 8
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 claims description 8
- 150000003573 thiols Chemical class 0.000 claims description 8
- 125000000751 azo group Chemical group [*]N=N[*] 0.000 claims description 7
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 7
- 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 claims description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- 208000030159 metabolic disease Diseases 0.000 claims description 7
- 150000002825 nitriles Chemical class 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 7
- IPODYDRGWTWLKZ-UHFFFAOYSA-N (isothiocyanatohydrazinylidene)-sulfanylidenemethane Chemical compound S=C=NNN=C=S IPODYDRGWTWLKZ-UHFFFAOYSA-N 0.000 claims description 6
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 6
- 239000000539 dimer Substances 0.000 claims description 6
- 150000003949 imides Chemical class 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 6
- 239000013638 trimer Substances 0.000 claims description 6
- 241001061127 Thione Species 0.000 claims description 4
- 125000002252 acyl group Chemical group 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 230000002526 effect on cardiovascular system Effects 0.000 claims description 3
- 208000016097 disease of metabolism Diseases 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims 8
- 239000003085 diluting agent Substances 0.000 claims 1
- 238000011282 treatment Methods 0.000 abstract description 8
- 206010012601 diabetes mellitus Diseases 0.000 abstract description 5
- NQUVCRCCRXRJCK-UHFFFAOYSA-N 4-methylbenzoyl chloride Chemical compound CC1=CC=C(C(Cl)=O)C=C1 NQUVCRCCRXRJCK-UHFFFAOYSA-N 0.000 abstract 1
- 208000037765 diseases and disorders Diseases 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 156
- 238000006243 chemical reaction Methods 0.000 description 132
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 114
- 238000002360 preparation method Methods 0.000 description 65
- 238000005481 NMR spectroscopy Methods 0.000 description 59
- 235000019439 ethyl acetate Nutrition 0.000 description 57
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 51
- 239000012267 brine Substances 0.000 description 50
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 50
- 229920006395 saturated elastomer Polymers 0.000 description 43
- 239000000243 solution Substances 0.000 description 39
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 38
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 36
- 239000000047 product Substances 0.000 description 36
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 34
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 30
- 239000012044 organic layer Substances 0.000 description 29
- 239000007787 solid Substances 0.000 description 29
- 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 28
- 239000008103 glucose Substances 0.000 description 27
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 26
- 241000699670 Mus sp. Species 0.000 description 25
- 239000000460 chlorine Substances 0.000 description 25
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 24
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 24
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 23
- 229910052757 nitrogen Inorganic materials 0.000 description 23
- 238000002953 preparative HPLC Methods 0.000 description 22
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
- 239000002904 solvent Substances 0.000 description 20
- DNSISZSEWVHGLH-UHFFFAOYSA-N butanamide Chemical compound CCCC(N)=O DNSISZSEWVHGLH-UHFFFAOYSA-N 0.000 description 18
- 125000005843 halogen group Chemical group 0.000 description 18
- 238000000605 extraction Methods 0.000 description 17
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 16
- 210000004369 blood Anatomy 0.000 description 16
- 239000008280 blood Substances 0.000 description 16
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 150000001412 amines Chemical class 0.000 description 15
- 125000000217 alkyl group Chemical group 0.000 description 14
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 14
- 239000003814 drug Substances 0.000 description 13
- 230000000694 effects Effects 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 12
- 238000003818 flash chromatography Methods 0.000 description 12
- 239000000463 material Substances 0.000 description 12
- RXWNCPJZOCPEPQ-NVWDDTSBSA-N puromycin Chemical compound C1=CC(OC)=CC=C1C[C@H](N)C(=O)N[C@H]1[C@@H](O)[C@H](N2C3=NC=NC(=C3N=C2)N(C)C)O[C@@H]1CO RXWNCPJZOCPEPQ-NVWDDTSBSA-N 0.000 description 12
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 11
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 11
- 239000010410 layer Substances 0.000 description 11
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 11
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 10
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 10
- 230000005764 inhibitory process Effects 0.000 description 10
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- 241000282414 Homo sapiens Species 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000000556 agonist Substances 0.000 description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 9
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 9
- 238000000746 purification Methods 0.000 description 9
- 239000000741 silica gel Substances 0.000 description 9
- 229910002027 silica gel Inorganic materials 0.000 description 9
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 8
- 239000000872 buffer Substances 0.000 description 8
- XRLDSWLMHUQECH-UHFFFAOYSA-N cyclopentanecarboxamide Chemical compound NC(=O)C1CCCC1 XRLDSWLMHUQECH-UHFFFAOYSA-N 0.000 description 8
- 235000005911 diet Nutrition 0.000 description 8
- 230000037213 diet Effects 0.000 description 8
- 239000006260 foam Substances 0.000 description 8
- 238000004108 freeze drying Methods 0.000 description 8
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 7
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical compound 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 7
- 241000699666 Mus <mouse, genus> Species 0.000 description 7
- 239000002552 dosage form Substances 0.000 description 7
- 229940079593 drug Drugs 0.000 description 7
- 235000019253 formic acid Nutrition 0.000 description 7
- 239000011734 sodium Substances 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 239000007821 HATU Substances 0.000 description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 6
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 6
- 108091006269 SLC5A2 Proteins 0.000 description 6
- 102000058081 Sodium-Glucose Transporter 2 Human genes 0.000 description 6
- DNHNWFCEJXBXNL-HEXNFIEUSA-N [(2s,3s,4r,5s,6r)-3,5-diacetyloxy-2-[3-[(4-chlorophenyl)methyl]-4-methylphenyl]-6-methylsulfanyloxan-4-yl] acetate Chemical compound CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](SC)O[C@H]1C1=CC=C(C)C(CC=2C=CC(Cl)=CC=2)=C1 DNHNWFCEJXBXNL-HEXNFIEUSA-N 0.000 description 6
- 229960000583 acetic acid Drugs 0.000 description 6
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 6
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- 238000010898 silica gel chromatography Methods 0.000 description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
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- 230000009885 systemic effect Effects 0.000 description 6
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- 206010028980 Neoplasm Diseases 0.000 description 5
- PNASXCQRRAKIOT-HEXNFIEUSA-N [(2s,3s,4r,5s,6r)-3,5-diacetyloxy-2-[3-[(4-hydroxyphenyl)methyl]-4-methylphenyl]-6-methylsulfanyloxan-4-yl] acetate Chemical compound CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](SC)O[C@H]1C1=CC=C(C)C(CC=2C=CC(O)=CC=2)=C1 PNASXCQRRAKIOT-HEXNFIEUSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 239000005557 antagonist Substances 0.000 description 5
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- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 5
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- QVQGTNFYPJQJNM-UHFFFAOYSA-N dicyclohexylmethanamine Chemical compound C1CCCCC1C(N)C1CCCCC1 QVQGTNFYPJQJNM-UHFFFAOYSA-N 0.000 description 5
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- 150000003457 sulfones Chemical class 0.000 description 5
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- YPUHUBGKKYQUCL-ZOROSQJXSA-N 1-(4-methylpiperazin-1-yl)-2-[5-[3-[4-[[2-methyl-5-[(2s,3r,4r,5s,6r)-3,4,5-trihydroxy-6-methylsulfanyloxan-2-yl]phenyl]methyl]phenyl]propyl]tetrazol-2-yl]ethanone Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](SC)O[C@H]1C1=CC=C(C)C(CC=2C=CC(CCCC3=NN(CC(=O)N4CCN(C)CC4)N=N3)=CC=2)=C1 YPUHUBGKKYQUCL-ZOROSQJXSA-N 0.000 description 4
- VMBNMMYBFZNCNN-UHFFFAOYSA-N 2-[4,5-bis(carboxymethyl)-2H-pyran-3-yl]acetic acid Chemical compound C1C(=C(C(=CO1)CC(=O)O)CC(=O)O)CC(=O)O VMBNMMYBFZNCNN-UHFFFAOYSA-N 0.000 description 4
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- 102000016622 Dipeptidyl Peptidase 4 Human genes 0.000 description 4
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- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
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- JYVXNLLUYHCIIH-ZCFIWIBFSA-N R-mevalonolactone, (-)- Chemical class C[C@@]1(O)CCOC(=O)C1 JYVXNLLUYHCIIH-ZCFIWIBFSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 102000000070 Sodium-Glucose Transport Proteins Human genes 0.000 description 4
- 108010080361 Sodium-Glucose Transport Proteins Proteins 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- CBTVGIZVANVGBH-UHFFFAOYSA-N aminomethyl propanol Chemical compound CC(C)(N)CO CBTVGIZVANVGBH-UHFFFAOYSA-N 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
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- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 229910002091 carbon monoxide Inorganic materials 0.000 description 4
- 230000003197 catalytic effect Effects 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 4
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 4
- 150000004675 formic acid derivatives Chemical class 0.000 description 4
- 125000001072 heteroaryl group Chemical group 0.000 description 4
- 125000005842 heteroatom Chemical group 0.000 description 4
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 208000028774 intestinal disease Diseases 0.000 description 4
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 4
- PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 description 4
- 235000015263 low fat diet Nutrition 0.000 description 4
- 238000007726 management method Methods 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- WSFSSNUMVMOOMR-BJUDXGSMSA-N methanone Chemical compound O=[11CH2] WSFSSNUMVMOOMR-BJUDXGSMSA-N 0.000 description 4
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Abstract
Description
本発明は、ナトリウムグルコース共輸送体1(SGLT1)の阻害に使用することができる化合物、それを含む組成物及びそれらを使用する方法に関する。
2型真性糖尿病は、肝臓でのグルコース産生、インスリン分泌不全及び/又は末梢インスリン抵抗性に起因する高血糖を特徴とする慢性疾患である。近年、相当な労力がこの疾患を治療する方法の発見に費やされている。比較的新しいアプローチの1つは、ナトリウムグルコース共輸送体(SGLT)の阻害であり、血流からグルコースを除去することによって血中グルコースレベルを低下させるものである。
本発明は、ナトリウムグルコース共輸送体1(SGLT1)の新規かつ強力な阻害剤の発見に基づく。特定の阻害剤はSGLT1の選択的阻害剤である。特定の阻害剤は全身曝露が低い。
の化合物及びその薬学的に許容される塩、二量体又は三量体を含む組成物及びそれを用いる方法に関する。
本発明の或る特定の態様は、図面を参照して理解できる。
本発明は、ナトリウムグルコース共輸送体1(SGLT1)の新規かつ強力な阻害剤の発見に基づく。
特に明示のない限り、「アルキル」という用語は、1〜20(例えば、1〜10又は1〜4)個の炭素原子を有する直鎖又は分岐鎖の炭化水素を意味する。1個〜4個の炭素を有するアルキル部分は「低級アルキル」と称される。アルキル基の例としては、メチル、エチル、プロピル、イソプロピル、n−ブチル、t−ブチル、イソブチル、ペンチル、ヘキシル、イソヘキシル、ヘプチル、4,4−ジメチルペンチル、2,2,4−トリメチルペンチル、ノニル、デシル、ウンデシル及びドデシルが挙げられるが、これらに限定されない。シクロアルキル部分は単環式又は多環式であってもよく、例としてはシクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル及びアダマンチルが挙げられる。アルキル部分の更なる例は直鎖部分、分岐鎖部分及び/又は環式部分(例えば、1−エチル−4−メチル−シクロヘキシル)を有する。「アルキル」という用語は飽和炭化水素、並びにアルケニル部分及びアルキニル部分を含む。
本発明は1つには、式:
の化合物及びその薬学的に許容される塩、二量体又は三量体を含む組成物及びそれを用いた方法に関する
本発明の化合物は当該技術分野で既知の方法、本明細書に記載の一般的及び具体的な方法、並びに当業者が容易に達成し得るこれらの方法の適合又は変更によって調製することができる。
本発明は心臓血管の疾患及び障害、代謝の疾患及び障害、腸の疾患及び障害、並びに或る特定のタイプの癌を治療又は管理する方法を包含する。
本発明は、5.4節で上述したもののような1つ又は複数の第2の有効成分と任意に組み合わせて、本発明の化合物を含む医薬組成物を包含する。
6.1. (2S,3S,4R,5S,6R)−2−(3−(4−クロロベンジル)−4−メチルフェニル)−6−(メチルチオ)テトラヒドロ−2H−ピラン−3,4,5−トリイルトリアセテート(7)の調製
2−メチル−4−ブロモ安息香酸(1、26.0g、121mmol)及び塩化オキサリル(13.2mL、152mmol)を520mLのCH2Cl2に懸濁した。触媒量のDMAP(0.5mL)を滴下し、反応物を室温で反応物が均質となるまで撹拌した。揮発性物質を真空で除去した。粗物質を200mLのCH2Cl2に溶解し、N,O−ジメチルヒドロキシルアミン塩酸塩(23.6g、242mmol)を添加した。反応物を0℃に冷却し、トリエチルアミン(55mL、399mmol)をゆっくりと添加した。トリエチルアミンの添加の終了後に、反応物を室温まで加温し、一晩撹拌した。反応物を50%飽和NaHSO4水溶液でクエンチした。水層をCH2Cl2で2回抽出した。合わせた有機層をブラインで洗浄し、Na2SO4で乾燥させ、濾過し、溶媒を真空で除去した。得られるワインレブアミド(31.3g、収率99%)を更に精製することなく次の工程に使用した。
1H NMR(400MHz,クロロホルム−d) δ ppm 7.74(d,J=8.3Hz,2H)、7.53(dd,J=8.1、2.0Hz,1H)、7.46(d,J=8.3Hz,2H)、7.42(d,J=2.0Hz,1H)、7.18(d,J=8.1Hz,1H)、2.26(s,3H)。GCMS(CH4−Cl)[M+H]+=309。
(5−ブロモ−2−メチルフェニル)(4−クロロフェニル)メタノン(2、37.0g、121mmol)及びトリエチルシラン(77.3mL、484mmol)を300mLのCH3CNに溶解し、0℃に冷却した。BF3OEt2(91mL、726mmol)を添加し、反応物を60℃に2時間加熱した。GCMSを用いて反応をモニタリングした。完了後、反応物を0℃に冷却し、500mLの飽和NaHCO3水溶液でクエンチした。水相をEtOAcで2回抽出した。合わせた有機層をH2O及びブラインで洗浄し、Na2SO4で乾燥させ、濾過し、溶媒を真空で除去した。粗固体を20%EtOAc/ヘキサンでスラリー化し、シリカプラグに通して残留塩を除去した。濾液の濃縮により標題の化合物を白色の固体として得た(22.0g、収率62%)。1H NMR(400MHz,クロロホルム−d) δ ppm 7.22(d,J=2.0Hz,1H)、7.21〜7.31(m,3H)、7.04(d,J=8.3Hz,2H)、7.04(d,J=8.1Hz,2H)、3.91(s,2H)、2.17(s,3H)。GCMS(CH4−Cl)[M+H]+=295。
THF(200mL)中の((3aS,5R,6S,6aS)−6−ヒドロキシ−2,2−ジメチルテトラヒドロフロ[2,3−d][1,3]ジオキソール−5−イル)(モルホリノ)メタノン(25.3g、92.6mmol)の溶液に窒素下、0℃でtert−ブチルマグネシウムクロリド(THF中1M、100mL、100mmol)を添加した。この溶液を0℃で30分間撹拌した。一方で、THF(330mL)中の4−ブロモ−2−(4−クロロベンジル)−1−メチルベンゼン(3、32.9g、111.1mmol)の溶液を窒素下で−78℃に冷却した。n−ブチルリチウム(ヘキサン中2.5M、48mL、120mmol)をシリンジで滴下し、10分間撹拌した。マグネシウムアルコキシド溶液をカニューレによりアリールリチウム溶液に−78℃で移した。反応物を−78℃で30分間撹拌し、室温まで加温し、60分間撹拌し、500mLの飽和NH4Cl水溶液/ブラインの1:1(v:v)溶液でクエンチした。水層を300mLのEtOAcで2回抽出した。合わせた有機層をブラインで洗浄し、MgSO4で乾燥させ、濾過し、真空下で濃縮した。粗残渣を100mLのEtOAcに取り、固体の大部分が溶解するまで加熱した。250mLのヘキサンを添加し、フラスコを氷浴内で2時間冷却した。白色の沈殿物を濾別し、20%EtOAc/ヘキサンで洗浄し、標題の化合物を白色の固体として得た(26.09g、収率70%)。1H NMR(400MHz,クロロホルム−d) δ ppm 7.88(dd,J=7.8、1.8Hz,1H)、7.76(d,J=1.5Hz,1H)、7.29(d,J=8.1Hz,1H)、7.26(d,J=8.3Hz,2H)、7.05(d,J=8.3Hz,2H)、6.08(d,J=3.8Hz,1H)、5.28(d,J=2.8Hz,1H)、4.59(d,J=3.5Hz,1H)、4.57(t,J=3.2Hz,1H)、4.01(s,2H)、3.06(d,J=4.0Hz,1H)、2.30(s,3H)、1.37(s,3H)。MS(ES+)[M+H]+=403。
(3−(4−クロロベンジル)−4−メチルフェニル)((3aS,5R,6S,6aS)−6−ヒドロキシ−2,2−ジメチルテトラヒドロフロ[2,3−d][1,3]ジオキソール−5−イル)メタノン(4、26.1g、64.9mmol)及びCeCl3・7H2O(29.0g、77.9mmol)を520mLのMeOHに懸濁した。水素化ホウ素ナトリウム(982mg、26.0mmol、10mLの1N NaOH水溶液に溶解した)を添加し、反応物を約5分間かけてゆっくりと溶液に溶かした。更に100mg(2.6mmol)の水素化ホウ素ナトリウムを添加して、反応を完了させた。反応物を10分間撹拌し、500mLの飽和NH4Cl水溶液でクエンチした。MeOHの大部分を真空で除去し、残留溶媒を飽和NH4Cl水溶液:ブラインの1:1(v:v)溶液で希釈した。水層を500mLのEtOAcで3回抽出した。合わせた有機層をブラインで洗浄し、MgSO4で乾燥させ、濾過し、真空下で濃縮した。粗生成物を更に精製することなく次の工程に使用した(26.2g、収率99%、>10:1 d.r.)。1H NMR(400MHz,クロロホルム−d) δ ppm 7.14〜7.31(m,5H)、7.04(d,J=8.3Hz,2H)、6.04(d,J=3.8Hz,1H)、5.24(t,J=3.4Hz,1H)、4.51(d,J=3.8Hz,1H)、4.14〜4.21(m,2H)、4.04(d,J=1.5Hz,1H)、3.97(s,2H)、2.77(d,J=3.0Hz,1H)、2.20〜2.27(m,3H)、1.46(s,3H)、1.33(s,3H)。MS(ES+)[M+NH4]+=422。
(3aS,5S,6R,6aS)−5−((S)−(3−(4−クロロベンジル)−4−メチルフェニル)(ヒドロキシ)−メチル)−2,2−ジメチルテトラヒドロフロ[2,3−d][1,3]ジオキソール−6−オール(5、26.2g、64.8mmol)を150mLのH2O及び150mLの氷酢酸に懸濁した。反応物を100℃に7時間加熱した。溶媒を真空で除去し、粗残渣をトルエンから3回共沸した。粗物質を高真空下に一晩置き、更に精製することなく次の工程に使用した。
1H NMR(400MHz,クロロホルム−d) δ ppm 7.24(d,J=8.3Hz,2H)、7.13〜7.21(m,2H)、7.09(s,1H)、7.01(d,J=8.3Hz,2H)、6.47(d,J=3.5Hz,1Hα)、5.89(d,J=8.3Hz,1Hβ)、5.59(t,J=9.8Hz,1Hα)、5.37(t,J=9.6Hz,1Hβ)、5.23〜5.31(m,1Hα+1Hβ)、5.19(t,J=9.6Hz,1Hβ)、5.14(t,J=9.7Hz,1Hα)、4.82(d,J=10.1Hz,1Hα)、4.51(d,J=9.9Hz,1Hβ)、3.94(s,2H)、2.21(s,3Hα)、2.20(s,3Hα)、2.19(s,3Hβ)、2.11(s,3Hβ)、2.07(s,3Hβ)、2.06(s,3Hα)、2.04(s,3Hα)、2.03(s,3Hβ)、1.79(s,3Hα)、1.77(s,3Hβ)。MS(ES+)[M+NH4]+=550。
トリメチルシリルトリフルオロメタンスルホネート(19.7mL、108.5mmol)を、340mLのジオキサン中の(3S,4R,5S,6S)−6−(3−(4−クロロベンジル)−4−メチルフェニル)テトラヒドロ−2H−ピラン−2,3,4,5−テトライルテトラアセテート(6、33.9g、63.8mmol)及びチオ尿素(9.71g、128mmol)の溶液に添加した。反応物を80℃に2時間加熱すると、その時点でLCMS分析により反応が失速していることが明らかとなった。更なるTMSOTfを添加し(2mL、10.8mmol)、反応物を80℃で1時間撹拌した。反応物を室温まで冷却した。ヨウ化メチル(11.9mL、191mmol)に続くDIPEA(55.6mL、319mmol)の連続添加を行い、反応物を18時間撹拌した。500mLのH2Oをゆっくりと添加し、反応物をクエンチした。水層を300mLのEtOAcで2回抽出した。合わせた有機層を飽和NaHSO4水溶液及びブラインで洗浄し、MgSO4で乾燥させ、濾過し、真空下で濃縮した。粗固体を300mLのMeOHでスラリー化した。超音波処理により淡いベージュ色の沈殿物が生じ、これを濾過し、冷MeOHで洗浄した。濾液を濃縮し、スラリー手順を再度繰り返して生成物を得て、最初のバッチと合わせた。生成物を淡いベージュ色の固体である純粋なβアノマーとして単離した(20.4g、収率60%)。1H NMR(400MHz,クロロホルム−d) δ ppm 7.24(d,J=8.6Hz,2H)、7.10〜7.18(m,2H)、7.05(s,1H)、7.00(d,J=8.6Hz,2H)、5.34(dd,J=9.6Hz,1H)、5.21(dd,J=9.6Hz,1H)、5.12(dd,J=9.6Hz,1H)、4.53(d,J=9.9Hz,1H)、4.39(d,J=9.9Hz,1H)、3.86〜4.00(m,2H)、2.19(s,3H)、2.17(s,3H)、2.10(s,3H)、2.01(s,3H)、1.76(s,3H)。MS(ES+)[M+NH4]+=538。
マイクロ波バイアルに(2S,3S,4R,5S,6R)−2−(3−(4−クロロベンジル)−4−メチルフェニル)−6−(メチルチオ)テトラヒドロ−2H−ピラン−3,4,5−トリイルトリアセテート(7、1.04g、2.0mmol)、メチルブタ−5−エノエート(600mg、6.0mmol)、Pd2dba3(183mg、0.20mmol)、トリ(tert−ブチル)ホスホニウムテトラフルオロボレート(235mg、0.80mmol)、ジシクロヘキシルメチルアミン(1.27mL、6.0mmol)及びN−メチルピロリジノン(10mL)を投入した。反応物をマイクロ波バイアル内、160℃で20分間加熱した。反応物を過剰なEtOAcによりセライトで濾過した。有機層をH2O、飽和NaHSO4水溶液及びブラインで洗浄した。これをMgSO4で乾燥させ、真空で濃縮した。シリカゲルフラッシュクロマトグラフィー(勾配10%→50%のEtOAc/ヘキサン)によりヘック付加物8が淡黄色の固体として得られた(700mg、収率60%)。少量の異性化オレフィンが1H NMRで観察された。1H NMR(400MHz,クロロホルム−d) δ ppm 7.28〜7.31(m,2H)、6.97〜7.19(m,5H)、6.46(d,J=15.9Hz,1H)、6.25(dt,J=15.9、7.1Hz,1H)、5.33(dd,J=9.6Hz,1H)、5.21(dd,J=9.6Hz,1H)、5.12(dd,J=9.6Hz,1H)、4.52(d,J=9.6Hz,1H)、4.39(d,J=9.6Hz,1H)、3.87〜4.01(m,2H)、3.72(s,2H)、3.24(dd,J=7.1、1.3Hz,2H)、2.21(s,3H)、2.17(s,3H)、2.10(s,3H)、2.01(s,3H)、1.75(s,3H)。MS(ES+)[M+NH4]+=602。
(2S,3S,4R,5S,6R)−2−(3−(4−((E)−4−メトキシ−4−オキソブタ−1−エン−1−イル)ベンジル)−4−メチルフェニル)−6−(メチルチオ)テトラヒドロ−2H−ピラン−3,4,5−トリイルトリアセテート(8、1.74g、3.0mmol)を1:1(v:v)のTHF/MeOH溶液に溶解した。Pd/C(10%ウェット、174mg)を添加し、反応物を40psiで3時間水素化した。反応物を1H NMRによってモニタリングした。完了後、反応物を過剰なMeOHによりセライトで濾過した。真空で溶媒を除去することにより、生成物が淡黄色の固体として得られた(1.65g、収率94%)。1H NMR(400MHz,クロロホルム−d) δ ppm 7.11〜7.20(m,2H)、7.07(t,J=7.8Hz,3H)、6.99(d,J=8.1Hz,2H)、5.33(dd,J=9.6Hz,1H)、5.21(dd,J=9.6Hz,1H)、5.12(dd,J=9.6Hz,1H)、4.52(d,J=9.9Hz,1H)、4.39(d,J=9.9Hz,1H)、3.85〜4.00(m,2H)、3.67(s,3H)、2.61(t,J=7.6Hz,2H)、2.33(t,J=7.5Hz,2H)、2.21(s,3H)、2.18(s,3H)、2.10(s,3H)、2.01(s,3H)、1.93(quin,J=7.6Hz,2H)、1.75(s,3H)。MS(ES+)[M+NH4]+=604。
(2S,3S,4R,5S,6R)−2−(3−(4−(4−メトキシ−4−オキソブチル)ベンジル)−4−メチルフェニル)−6−(メチルチオ)テトラヒドロ−2H−ピラン−3,4,5−トリイルトリアセテート(9、1.65g、2.81mmol)をMeOH/THF/H2O溶液(25mL、2:1:2の体積比)に溶解した。水酸化リチウム(674mg、28.1mmol)を添加し、反応物を室温で1時間撹拌した。反応物を、飽和NaHSO4水溶液を用いてpH=1〜2まで酸性化した。酸性水層をEtOAcで3回抽出した。合わせた有機層をブラインで洗浄し、MgSO4で乾燥させ、濾過し、真空で濃縮した。粗生成物をヘキサンからロータリーエバポレーターで1回蒸発させ(rotovapped down)、生成物を白色の変換可能な固体として得た(1.27g、収率99%)。1H NMR(400MHz,DMSO−d6) δ ppm 11.99(s,1H)、6.96〜7.16(m,7H)、5.16(d,J=5.8Hz,1H)、5.06(d,J=4.3Hz,1H)、4.82(d,J=5.6Hz,1H)、4.32(d,J=9.6Hz,1H)、4.04(d,J=9.1Hz,1H)、3.90(s,2H)、2.53(t,J=7.3Hz,2H)、2.19(t,J=7.3Hz,2H)、2.17(s,3H)、2.03(s,3H)、1.76(quin,J=7.6Hz,2H)。MS(ES+)[M+NH4]+=464。
4−(4−(2−メチル−5−((2S,3R,4R,5S,6R)−3,4,5−トリヒドロキシ−6−(メチルチオ)テトラヒドロ−2H−ピラン−2−イル)ベンジル)フェニル)ブタン酸(10、157mg、0.35mmol)、2−アミノ−2−メチルプロパンアミドヒドロクロリド(73mg、0.53mmol)、HATU(161mg、0.42mmol)及びDIPEA(0.15mL、1.06mmol)をDMF(2mL)中で合わせ、室温で2時間撹拌した。反応物を飽和NaHCO3水溶液でクエンチし、EtOAcで2回抽出した。合わせた有機層をブラインで洗浄し、MgSO4で乾燥させ、濾過し、真空下で濃縮した。残渣を分取HPLC(C18 30×100mmカラム、5%→100%のCH3CN/10mMギ酸アンモニウム水溶液、45mL/分)で精製し、凍結乾燥後に標題の化合物11を得た(75mg、収率40%)。1H NMR(400MHz,MeOH−d4) δ ppm 6.96〜7.23(m,7H)、4.39(d,J=9.6Hz,1H)、4.12(d,J=9.1Hz,1H)、3.96(s,2H)、3.33〜3.51(m,3H)、2.59(t,J=7.6Hz,2H)、2.20(t,J=7.6Hz,2H)、2.20(s,3H)、2.14(s,3H)、1.87(quin,J=7.6Hz,2H)、1.45(s,6H)。MS(ES+)[M+H]+=531。
(2S,3S,4R,5S,6R)−2−(3−(4−(5−アミノペンチル)ベンジル)−4−メチルフェニル)−6−(メチルチオ)テトラヒドロ−2H−ピラン−3,4,5−トリイルトリアセテート(16)の合成に用いたものと同じ手順を用い、tert−ブチルブタ−3−エン−1−イルカルバメートをヘック反応の試薬として使用した。
CH3CN中の(2S,3S,4R,5S,6R)−2−(3−(4−(4−アミノブチル)ベンジル)−4−メチルフェニル)−6−(メチルチオ)テトラヒドロ−2H−ピラン−3,4,5−トリイルトリアセテート(19、50mg、0.090mmol)及び3,5−ジメチル−1H−ピラゾール−1−カルボキシイミドアミドニトレート(66mg、0.33mmol)の溶液にDIPEA(62μL、0.35mmol)を添加した。反応物を70℃で2時間加熱した後、室温に冷却し、真空下で濃縮した。残渣をMeOHに溶解し、数滴のNaOMe(MeOH中25wt%)で1時間処理した。反応物を真空下で濃縮し、残渣を分取HPLC(C18 30×100mmカラム、5%→40%のCH3CN/10mMギ酸アンモニウム水溶液、45mL/分)によって精製し、標題の化合物20をギ酸塩として得た(22mg、収率43%)。1H NMR(400MHz,MeOH−d4) δ ppm 8.55(s,1H)、7.00〜7.24(m,7H)、4.39(d,J=9.6Hz,1H)、4.12(d,J=9.1Hz,1H)、3.92〜4.02(m,2H)、3.34〜3.51(m,3H)、3.17(t,J=6.8Hz,2H)、2.62(t,J=7.3Hz,2H)、2.21(s,3H)、2.14(s,3H)、1.63〜1.73(m,2H)、1.59(s,2H)。MS(ES+)[M+H]+=474。
20mL容のマイクロ波バイアルに(2S,3S,4R,5S,6R)−2−(3−(4−クロロベンジル)−4−メチルフェニル)−6−(メチルチオ)テトラヒドロ−2H−ピラン−3,4,5−トリイルトリアセテート(7、520mg、1.0mmol)、3−ブテノール(0.26mL、3.0mmol)、Pd2dba3(183mg、0.20mmol)、トリ(tert−ブチル)ホスホニウムテトラフルオロボレート(232mg、0.80mmol)、ジシクロヘキシルメチルアミン(0.64mL、3.0mmol)及び10mLのN−メチルピロリジノンを投入した。反応物をマイクロ波バイアル内、160℃で20分間加熱した。反応物を過剰なEtOAcによりセライトで濾過した。有機層をH2O、飽和NaHSO4水溶液及びブラインで洗浄した。これをMgSO4で乾燥させ、真空で濃縮した。フラッシュクロマトグラフィー(勾配10%→80%のEtOAc/ヘキサン)によりヘック付加物(257mg)が得られた。この精製生成物を5mLのMeOH/THFの1:1(v:v)混合物に溶解した。Pd/C(10%ウェット、26mg)を添加し、40psiの水素圧に5時間供した。反応物を過剰なMeOHによりセライトで濾過し、真空で濃縮して標題の化合物22を得た(247mg、収率44%)。1H NMR(400MHz,クロロホルム−d) δ ppm 7.11〜7.18(m,2H)、7.09(d,J=8.1Hz,2H)、6.95〜7.06(m,3H)、5.33(dd,J=9.6Hz,1H)、5.20(dd,J=9.6Hz,1H)、5.10(dd,J=9.7Hz,1H)、4.52(d,J=9.9Hz,1H)、4.38(d,J=9.9Hz,1H)、3.93(d,J=4.5Hz,2H)、3.66(t,J=5.9Hz,2H)、2.61(t,J=7.3Hz,2H)、2.22(s,3H)、2.17(s,3H)、2.10(s,3H)、2.01(s,3H)、1.74(s,3H)、1.64〜1.73(m,2H)、1.56〜1.64(m,2H)。MS(ES+)[M+NH4]+=576。
塩化メタンスルホニル(41μL、0.53mmol)及びトリエチルアミン(80μL、0.58mmol)を、5mLのCH2Cl2中の(2S,3S,4R,5S,6R)−2−(3−(4−(4−ヒドロキシブチル)ベンジル)−4−メチルフェニル)−6−(メチルチオ)テトラヒドロ−2H−ピラン−3,4,5−トリイルトリアセテート(22、247mg、0.44mmol)の溶液に添加し、室温で2時間撹拌した。反応物を1N HCl水溶液でクエンチした。水層をEtOAcで2回抽出した。合わせた有機層をH2O及びブラインで洗浄し、MgSO4で乾燥させ、濾過し、真空で濃縮して生成物23(279mg、収率99%)を得て、これを更に精製することなく次の工程に使用した。1H NMR(400MHz,クロロホルム−d) δ ppm 7.14(s,2H)、7.02〜7.11(m,3H)、7.00(d,J=7.8Hz,2H)、5.33(dd,J=9.6Hz,1H)、5.21(dd,J=9.6Hz,1H)、5.12(dd,J=9.6Hz,1H)、4.48〜4.56(m,1H)、4.39(d,J=9.9Hz,1H)、4.24(t,J=6.1Hz,1H)、3.93(d,J=3.8Hz,2H)、2.99(s,3H)、2.62(t,J=7.2Hz,2H)、2.22(s,3H)、2.15〜2.20(m,3H)、2.10(s,3H)、2.01(s,3H)、1.70〜1.81(m,4H)。MS(ES+)[M+NH4]+=654。
2−アミノ−2−メチルプロパン−1−オール(23mg、0.25mmol)、触媒ヨウ化ナトリウム及び(2S,3S,4R,5S,6R)−2−(4−メチル−3−(4−(4−((メチルスルホニル)オキシ)ブチル)ベンジル)フェニル)−6−(メチルチオ)テトラヒドロ−2H−ピラン−3,4,5−トリイルトリアセテート(65mg、0.10mmol)を0.5mLのイソプロパノール/CH3CN(1:1(v:v))中、80℃で64時間加熱した。反応物を室温に冷却し、2mLのMeOHで希釈し、NaOMe(MeOH中25wt%、0.5mL)を添加した。酢酸脱保護が30分以内に完了した。揮発性物質を真空で除去し、粗残渣を分取HPLC(C18 30×100mmカラム、5%→100%CH3CN/10mMギ酸アンモニウム水溶液、45mL/分)によって精製し、凍結乾燥後に生成物をビスホルメート塩として得た(17mg、収率34%)。1H NMR(400MHz,MeOH−d4) δ ppm 8.53(s,2H)、7.01〜7.25(m,7H)、4.39(d,J=9.6Hz,1H)、4.13(d,J=9.1Hz,1H)、3.90〜4.02(m,2H)、3.50(s,2H)、3.35〜3.48(m,3H)、2.87〜2.97(m,2H)、2.65(t,J=6.9Hz,2H)、2.20(s,3H)、2.15(s,3H)、1.59〜1.78(m,4H)、1.27(s,6H)。MS(ES+)[M+H]+=504。
5mL容のマイクロ波バイアルに(2S,3S,4R,5S,6R)−2−(3−(4−クロロベンジル)−4−メチルフェニル)−6−(メチルチオ)テトラヒドロ−2H−ピラン−3,4,5−トリイルトリアセテート(7、208mg、0.40mmol)、ブタ−3−エンニトリル(0.10mL、1.2mmol)、Pd2dba3(37mg、0.040mmol)、トリ(tert−ブチル)ホスホニウムテトラフルオロボレート(46mg、0.16mmol)、ジシクロヘキシルメチルアミン(0.25mL、1.2mmol)及び2mLのN−メチルピロリジノンを投入した。反応物をマイクロ波バイアル内、160℃で20分間加熱した。反応物を過剰なEtOAcによりセライトで濾過した。有機層をH2O、飽和NaHSO4水溶液及びブラインで洗浄した。これをMgSO4で乾燥させ、真空で濃縮した。フラッシュクロマトグラフィー(勾配10%→80%のEtOAc/ヘキサン)によりヘック付加物28を得た(140mg、収率64%)。1H NMR(400MHz,クロロホルム−d) δ ppm 7.24〜7.31(m,2H)、7.11〜7.20(m,2H)、7.02〜7.09(m,3H)、6.70(dt,J=15.9、1.6Hz,1H)、6.01(dt,J=15.8、5.7Hz,1H)、5.33(t,J=9.3Hz,1H)、5.21(t,J=9.7Hz,1H)、5.12(t,J=9.6Hz,1H)、4.52(d,J=9.9Hz,1H)、4.39(d,J=9.9Hz,1H)、3.95(d,J=3.5Hz,2H)、3.28(dd,J=5.8、1.8Hz,2H)、2.20(s,3H)、2.16(s,3H)、2.09(s,3H)、2.01(s,3H)、1.75(s,3H)。MS(ES+)[M+NH4]+=567。
(2S,3S,4R,5S,6R)−2−(3−(4−((E)−3−シアノプロパ−1−エン−1−イル)ベンジル)−4−メチルフェニル)−6−(メチルチオ)テトラヒドロ−2H−ピラン−3,4,5−トリイルトリアセテート(28、140mg、0.25mmol)を6mLのMeOHに溶解した。Pd/C(10%ウェット、14mg)を添加し、40psiの水素圧に5時間供した。反応物を過剰なMeOHによりセライトで濾過し、真空で濃縮した。粗生成物を更に精製することなく使用した(120mg、収率87%)。MS(ES+)[M+NH4]+=569。
(2S,3S,4R,5S,6R)−2−(3−(4−(3−(2H−テトラゾール−5−イル)プロピル)ベンジル)−4−メチルフェニル)−6−(メチルチオ)テトラヒドロ−2H−ピラン−3,4,5−トリイルトリアセテート(29、32mg、0.0537mmol)を、0.5mLのCH3CN中の2−クロロ−1−(4−メチルピペラジン−1−イル)エタノン(14mg、0.0644mmol)及びトリエチルアミン(22μL、0.161mmol)と合わせた。反応物を60℃で18時間撹拌し、2つの位置異性体の混合物を得た。反応物をH2Oで希釈し、濾過し、分取HPLC(C18 30×100mmカラム、5%→100%のCH3CN/10mMギ酸アンモニウム水溶液、45mL/分)によって精製した。位置異性体がはっきりと分離した。それぞれの生成物残渣を、MeOH(2mL)中のナトリウムメトキシド(0.10mL、MeOH中25wt%)により窒素下で30分間処理した。反応物を真空下で濃縮し、反応物を分取HPLC(C18 30×100mmカラム、5%→100%のCH3CN/10mMギ酸アンモニウム水溶液、45mL/分)によって精製し、凍結乾燥して、アルキル化テトラゾール位置異性体30及び31を得た(ビスホルメート塩としてそれぞれ4.3mg及び3.1mg)。位置化学をNOESY相関によって確認した。
1,2−二置換テトラゾール30:1H NMR(400MHz,MeOH−d4) δ ppm 8.39(s,2H,ホルメート)、7.01〜7.21(m,8H)、5.45(s,2H)、4.39(d,J=9.6Hz,1H)、4.13(d,J=9.1Hz,1H)、3.97(s,2H)、3.60(q,J=4.8Hz,4H)、3.33〜3.50(m,3H)、2.79(t,J=7.5Hz,2H)、2.68(t,J=7.5Hz,2H)、2.62(t,J=5.1Hz,2H)、2.53(t,J=5.1Hz,2H)、2.41(s,3H)、2.21(s,3H)、2.14(s,3H)、2.09(quin,J=7.6Hz,2H)。MS(ES+)[M+H]+=611。
1,3−二置換テトラゾール31:1H NMR(400MHz,MeOH−d4) δ ppm 8.38(s,2H)、6.99〜7.20(m,7H)、5.74(s,2H)、4.38(d,J=9.3Hz,1H)、4.12(d,J=9.1Hz,1H)、3.96(s,2H)、3.65(t,J=5.3Hz,4H)、3.33〜3.49(m,3H)、2.88(t,J=7.5Hz,2H)、2.60〜2.69(m,4H)、2.57(t,J=5.1Hz,2H)、2.41(s,3H)、2.21(s,3H)、2.10〜2.14(m,3H)、2.07(quin,J=7.3Hz,2H)。MS(ES+)[M+H]+=611。
THF(50mL)中の4−ベンジルオキシブロモベンゼン(2.63g、10mmol)の溶液に−78℃、窒素下でn−ブチルリチウム(ヘキサン中2.5M、4.4mL、11mmol)をゆっくりと添加した。反応物を30分間撹拌した。THF(4mL+1mLリンス)中の5−ブロモ−2−メチルベンズアルデヒド(32、1.99g、10mmol)をゆっくりと添加した。反応物を約0℃まで2時間かけてゆっくりと加温した後、飽和NH4Cl水溶液でクエンチし、エーテルで希釈し、H2O及びブラインで洗浄し、MgSO4で乾燥させ、濾過し、真空下で濃縮した。残渣をシリカゲルフラッシュクロマトグラフィー(勾配0%→25%のEtOAc/ヘキサン)によって精製し、3.12g(収率82%)の標題の化合物33を透明な油として得た。1H NMR(400MHz,クロロホルム−d) δ ppm 7.80(d,J=2.3Hz,1H)、7.36〜7.47(m,4H)、7.29〜7.36(m,2H)、7.18〜7.24(m,2H)、6.99(d,J=8.1Hz,1H)、6.88〜6.97(m,2H)、5.89(d,J=3.5Hz,1H)、5.06(s,2H)、2.12(s,3H)、2.06(d,J=3.5Hz,1H);MS(ES+)[M−OH]+=365、367。
CH2Cl2(40mL)中の(4−(ベンジルオキシ)フェニル)(5−ブロモ−2−メチルフェニル)メタノール(33、3.12g、8.2mmol)及びトリエチルシラン(1.6mL、9.8mmol)の溶液に0℃、窒素下でBF3OEt2(1.4mL、11.4mmol)をゆっくりと添加した。反応物を室温で一晩撹拌した後、飽和NaHCO3水溶液でクエンチし、30分間撹拌した。反応物をエーテルで希釈し、更なる飽和NaHCO3水溶液及びブラインで(逆抽出により)洗浄し、MgSO4で乾燥させ、濾過し、真空下で濃縮した。残渣をシリカゲルフラッシュクロマトグラフィー(勾配0%→10%のEtOAc:ヘキサン)によって精製し、2.71g(収率91%)の生成物34を白色の固体として得た。1H NMR(400MHz,クロロホルム−d) δ ppm 7.30〜7.49(m,5H)、7.27(dd,J=8.0、2.1Hz,1H)、7.22(d,J=2.0Hz,1H)、6.98〜7.09(m,3H)、6.86〜6.97(m,2H)、5.05(s,2H)、3.88(s,2H)、2.19(s,3H);MS(ES+)[M+NH4]+=384、386。
THF(37mL)中の2−(4−(ベンジルオキシ)ベンジル)−4−ブロモ−1−メチルベンゼン(34、2.71g、7.4mmol)の溶液に窒素下、−78℃でn−ブチルリチウム(ヘキサン中3.3mLの2.5M溶液、8.1mmol)をゆっくりと添加し、反応物を30分間撹拌した。一方で、THF(37mL)中の((3aS,5R,6S,6aS)−6−ヒドロキシ−2,2−ジメチルテトラヒドロフロ[2,3−d][1,3]ジオキソール−5−イル)(モルホリノ)メタノン(2.02g、7.4mmol)の溶液に窒素下、0℃でtert−ブチルマグネシウムクロリド(THF中8.1mLの1M溶液、8.1mmol)を添加した。反応物を20分間撹拌した後、カニューレによりアリールリチウム溶液に−78℃でゆっくりと添加した。反応物を3時間かけて徐々に室温まで加温した後、飽和NH4Cl水溶液でクエンチし、EtOAcで希釈し、H2O及びブラインで(逆抽出により)洗浄し、MgSO4で乾燥させ、濾過し、真空下で濃縮した。残渣をシリカゲルフラッシュクロマトグラフィー(勾配0%→50%のEtOAc/ヘキサン)によって精製し、2.44g(収率70%)の生成物35を白色の発泡体として得た。1H NMR(400MHz,クロロホルム−d) δ ppm 7.86(dd,J=7.8、1.8Hz,1H)、7.75〜7.80(m,1H)、7.27〜7.49(m,6H)、7.04(d,J=8.6Hz,2H)、6.86〜6.96(m,2H)、6.09(d,J=3.5Hz,1H)、5.32(d,J=2.8Hz,1H)、5.04(s,2H)、4.60(d,J=3.5Hz,1H)、4.53〜4.58(m,1H)、3.98(s,2H)、3.03(d,J=4.3Hz,1H)、2.31(s,3H)、1.56(s,3H)、1.36(s,3H);MS(ES+)[M+H]+=475。
MeOH中の(3−(4−(ベンジルオキシ)ベンジル)−4−メチルフェニル)((3aS,5R,6S,6aS)−6−ヒドロキシ−2,2−ジメチルテトラヒドロフロ[2,3−d][1,3]ジオキソール−5−イル)メタノン(35、2.44g、5.1mmol)及びCeCl3・7H2O(2.30g、6.2mmol)の溶液に、水素化ホウ素ナトリウム(78mg、1mLの1M NaOH水溶液中2.1mmol)を0℃でゆっくりと添加した。反応物を0℃で15分間、室温で15分間撹拌した後、飽和NH4Cl水溶液でクエンチした。反応物を真空下で部分的に濃縮し、EtOAcで希釈し、H2O、更にブラインで2回(逆抽出により)洗浄し、Na2SO4で乾燥させ、真空下で濃縮して、2.4gのジオールを白色の固体として得た。
(3S,4R,5S,6S)−6−(3−(4−(ベンジルオキシ)ベンジル)−4−メチルフェニル)テトラヒドロ−2H−ピラン−2,3,4,5−テトライルテトラアセテート(36、5.29g、8.8mmol)をTHF(44mL)中の10%Pd/C(50%ウェット)(0.93g、0.44mmol)で水素下、大気圧で1時間水素化した。反応物をセライトで濾過し、真空下で濃縮し、トルエンで2回共沸し、高真空下に置いて完全に乾燥させた。得られたフェノールを更に精製することなく次の工程に移した。これをチオ尿素(2.01g、26mmol)と合わせ、ジオキサン(44mL)に溶解した。TMSOTf(4.8mL、26mmol)を添加した。反応物を80℃で3時間加熱した後、室温まで冷却した。ヨウ化メチル(2.2mL、35mmol)、続いてDIPEA(12mL、70mmol)を添加した。反応物を一晩撹拌した後、飽和NaHSO4水溶液(150mL)でクエンチし、2時間激しく撹拌し、EtOAcで希釈し、H2O及びブラインで(逆抽出により)洗浄し、MgSO4で乾燥させ、濾過し、真空下で濃縮した。残渣をシリカゲルクロマトグラフィー(勾配0%→50%のEtOAc/ヘキサン)によって精製し、3.88g(収率88%)の生成物37を白色の発泡体として得た。1H NMR(400MHz,クロロホルム−d) δ ppm 7.10〜7.19(m,2H)、7.03(s,1H)、6.94(d,J=8.6Hz,2H)、6.68〜6.77(m,2H)、5.33(t,J=9.3Hz,1H)、5.21(t,J=9.6Hz,1H)、5.12(t,J=9.6Hz,1H)、4.59(s,1H)、4.52(d,J=9.9Hz,1H)、4.38(d,J=9.9Hz,1H)、3.82〜3.96(m,2H)、2.21(s,3H)、2.18(s,3H)、2.10(s,3H)、2.01(s,3H)、1.75(s,3H);MS(ES+)[M+NH4]+=520。
DMF(8mL)中の(2S,3S,4R,5S,6R)−2−(3−(4−ヒドロキシベンジル)−4−メチルフェニル)−6−(メチルチオ)テトラヒドロ−2H−ピラン−3,4,5−トリイルトリアセテート(37、2.01g、4.0mmol)及びK2CO3(2.76g、20mmol)の混合物に、窒素下で4−ヨードブタン酸メチル(0.81mL、6.0mmol)を添加した。反応物を室温で一晩撹拌した後、Et2Oで希釈した。有機層を飽和NaHCO3水溶液及びブラインで(逆抽出により)洗浄し、MgSO4で乾燥させ、濾過し、真空下で濃縮した。残渣をシリカゲルフラッシュクロマトグラフィー(勾配0%→50%のEtOAc/ヘキサン)によって精製し、2.18g(収率90%)のエステルを白色の発泡体として得た。
4−(4−(2−メチル−5−((2S,3R,4R,5S,6R)−3,4,5−トリヒドロキシ−6−(メチルチオ)テトラヒドロ−2H−ピラン−2−イル)ベンジル)フェノキシ)ブタン酸(39、1.47g、3.2mmol)、2−アミノ−2−メチル−1−(4−メチルピペラジン−1−イル)プロパン−1−オン(1.07g、2HCl塩、4.1mmol)、HATU(1.45g、3.8mmol)及びDIPEA(2.2mL、13mmol)をCH3CN(32mL)中で合わせ、室温で一晩撹拌した。反応物にDMAP(39mg、0.32mmol)、DIPEA(3.3mL、19mmol)及び無水酢酸(1.5mL、16mmol)を添加した。反応物を1時間撹拌した後、飽和NaHCO3水溶液でクエンチし、1時間撹拌し、EtOAcで2回抽出した。合わせた有機相をブラインで洗浄し、MgSO4で乾燥させ、濾過し、真空下で濃縮した。残渣をシリカゲルクロマトグラフィー(勾配2%→10%のMeOH/CH2Cl2)によって精製し、2.27g(収率94%)のトリアセテートを黄色の発泡体として得た。
(2S,3S,4R,5S,6R)−2−(3−(4−ヒドロキシベンジル)−4−メチルフェニル)−6−(メチルチオ)テトラヒドロ−2H−ピラン−3,4,5−トリイルトリアセテート(37、0.50g、1.0mmol)、tert−ブチル(2−ブロモエチル)カルバメート(0.62g、3.0mmol)及びK2CO3(0.64g、5.0mmol)をDMF(2mL)中、窒素下で合わせ、室温で一晩撹拌した。更なるtert−ブチル(2−ブロモエチル)カルバメート(0.62g、3.0mmol)を添加し、反応物を更に3日間撹拌した。反応物をEt2Oで希釈し、飽和NaHCO3水溶液及びブラインで(逆抽出により)洗浄し、MgSO4で乾燥させ、濾過し、真空下で濃縮した。残渣をシリカゲルクロマトグラフィー(勾配0%→50%のEtOAc/ヘキサン)によって精製し、0.37g(収率58%)のアルキル化生成物を白色の発泡体として得た。
CH2Cl2(1mL)中の(2S,3S,4R,5S,6R)−2−(3−(4−(2−アミノエトキシ)ベンジル)−4−メチルフェニル)−6−(メチルチオ)テトラヒドロ−2H−ピラン−3,4,5−トリイルトリアセテート(44、55mg、0.10mmol)及び4−ニトロフェニルクロロホルメート(24mg、0.12mmol)の溶液にトリエチルアミン(19μL、0.14mmol)を添加した。反応物を4時間撹拌した後、2−アミノ−2−メチルプロパン−1−オール(19μL、0.20mmol)を添加した。反応物を90分間撹拌した後、EtOAcで希釈し、飽和NaHCO3水溶液及びブラインで(逆抽出により)洗浄し、MgSO4で乾燥させ、濾過し、真空下で濃縮した。
(2S,3S,4R,5S,6R)−2−(3−(4−ヒドロキシベンジル)−4−メチルフェニル)−6−(メチルチオ)テトラヒドロ−2H−ピラン−3,4,5−トリイルトリアセテート(37、2.01g、4.0mmol)、((3−ブロモプロポキシ)メチル)ベンゼン(1.41mL、8.0mmol)、Bu4NI(148mg、0.40mmol)及びK2CO3(2.76g、20mmol)をDMF(8mL)中、窒素下で合わせ、室温で一晩撹拌した。反応物をEt2Oで希釈し、飽和NaHCO3水溶液及びブラインで(逆抽出により)洗浄し、MgSO4で乾燥させ、濾過し、真空下で濃縮した。残渣をシリカゲルクロマトグラフィー(勾配0%→50%のEtOAc/ヘキサン)によって精製し、アルキル化生成物47をガラス状固体として得た(2.36g、収率91%)。1H NMR(400MHz,クロロホルム−d) δ ppm 7.28〜7.36(m,5H)、7.10〜7.18(m,2H)、7.03(s,1H)、6.97(d,J=8.6Hz,2H)、6.77〜6.84(m,2H)、5.33(t,J=9.6Hz,1H)、5.21(t,J=9.6Hz,1H)、5.12(t,J=9.6Hz,1H)、4.48〜4.54(m,3H)、4.38(d,J=9.9Hz,1H)、4.06(t,J=6.3Hz,2H)、3.83〜3.96(m,2H)、3.66(t,J=6.2Hz,2H)、2.21(s,3H)、2.17(s,3H)、2.10(s,3H)、2.04〜2.12(m,2H)、2.01(s,3H)、1.75(s,3H);MS(ES+)[M+NH4]+=668。
(2S,3S,4R,5S,6R)−2−(3−(4−(3−(ベンジルオキシ)プロポキシ)ベンジル)−4−メチルフェニル)−6−(メチルチオ)テトラヒドロ−2H−ピラン−3,4,5−トリイルトリアセテート(47、2.36g、3.6mmol)をTHF(36mL)中の10%Pd/C(50%ウェット、0.38g、0.18mmol)により水素下、大気圧で18時間水素化した。反応物をセライトで濾過し、真空下で濃縮した。残渣をシリカゲルクロマトグラフィー(勾配0%→70%のEtOAc/ヘキサン)によって精製し、対応するアルコールを白色の固体として得た(1.90g、収率93%)。
(2S,3S,4R,5S,6R)−2−(4−メチル−3−(4−(3−((メチルスルホニル)オキシ)プロポキシ)ベンジル)フェニル)−6−(メチルチオ)テトラヒドロ−2H−ピラン−3,4,5−トリイルトリアセテート(48、1.23g、1.9mmol)及び2−アミノ−2−メチルプロパン−1−オール(0.52g、5.8mmol)を、イソプロピルアルコール(3.9mL)及びCH3CN(3.9mL)に窒素下で溶解した。反応物を90℃で一晩加熱した後、室温まで冷却した。これをEtOAcで希釈し、飽和NaHCO3水溶液及びブラインで(逆抽出により)洗浄し、MgSO4で乾燥させ、濾過し、真空下で濃縮した。残渣をシリカゲルクロマトグラフィー(勾配0%→10%[10%のNH4OH/MeOH]CH2Cl2)によって精製し、1.04gの保護糖を白色の固体として得た。
過酢酸(希HOAc中32%、0.12mL、0.512mmol)を、1mLのHOAc及び2mLのCH3CN中の(2S,3S,4R,5S,6R)−2−(3−(4−(4−メトキシ−4−オキソブチル)ベンジル)−4−メチルフェニル)−6−(メチルチオ)テトラヒドロ−2H−ピラン−3,4,5−トリイルトリアセテート(9、100mg、0.170mmol)の溶液に0℃で添加した。反応物を0℃で20分間撹拌した。反応物を1N NaOH水溶液でクエンチした後、EtOAcで2回抽出した。合わせた有機層をブラインで洗浄し、MgSO4で乾燥させ、濾過し、溶媒を真空で除去して、スルホキシド60の2:1ジアステレオマー混合物(60mg、収率58%)を得て、これを更に精製することなく次の工程に移した。1H NMR(400MHz,クロロホルム−d、Sジアステレオマーの2:1混合物、主要Ha及び微量Hbと表される) δ ppm 7.11〜7.17(m,2H)、7.05〜7.09(m,2H)、6.97〜7.02(m,3H)、5.59(t,J=9.3Hz,1Hb)、5.46(t,J=9.3Hz,1Hb)、5.41(t,J=9.6Hz,1Ha)、5.21(t,J=9.9Hz,1Ha)、5.17(t,J=9.3Hz,1Hb)、5.13(t,J=9.9Hz,1Ha)、4.50(t,J=10.4Hz,1Ha)、4.48(d,J=9.9Hz,1Ha)、4.46(d,J=10.1Hz,1Hb)、4.31(d,J=10.1Hz,1Hb)、3.93(m,2Hb)、3.92(m,2Ha)、3.66(s,3H)、2.67(s,3Ha)、2.64(s,3Hb)、2.61(t,J=7.8Hz,2H)、2.33(t,J=7.3Hz,2H)、2.23(s,3H)、2.09(s,3Ha)、2.08(s,3Hb)、2.02(s,3Hb)、2.01(s,3Ha)、1.93(quin,J=7.3Hz,2H)、1.75(s,3Ha)、1.74(s,3Hb)。MS(ES+)[M+H]+=603。
スルホキシド60(60mg、0.10mmol)を2.5mLのMeOH/H2O/THFの2:2:1混合物に懸濁した。LiOH(24mg、1.0mmol)を添加した。反応物を室温で4時間撹拌すると、その時点で出発物質が溶液に溶けた。反応物を飽和NaHSO4水溶液でクエンチした。この酸性層をEtOAcで3回抽出した。合わせた有機層をブラインで洗浄し、MgSO4で乾燥させ、濾過し、溶媒を真空で除去した。この粗残渣を1mLのCH3CNで溶解した。EDC・HCl(31mg、0.16mmol)、HOBt(31mg、0.16mmol)及びDIPEA(50μL、0.30mmol)を添加し、10分間撹拌した。0.5mLのCH3CN中の2−アミノ−N−(2−(ジメチルアミノ)エチル)−2−メチル−プロパンアミド(30mg、0.17mmol)を添加した。反応物を室温で一晩撹拌した。反応が完了した後、溶媒を真空で除去した。残渣を分取HPLC(C18 30×100mmカラム、5%→95%のMeOH/10mMギ酸水溶液、45mL/分)によって精製し、スルホキシド61のギ酸塩(23mg、収率35%)をスルホキシドの2:1ジアステレオマー混合物として得た。1H NMR(400MHz,MeOH−d4、Sジアステレオマーの2:1混合物、主要Ha及び微量Hbと表される) δ ppm 8.54(br.s,1H,ホルメート)、7.14〜7.19(m,3H)、7.04〜7.10(m,4H)、4.47(d,J=9.6Hz,1Ha)、4.28(d,J=9.1Hz,1Hb)、4.26(d,J=9.3Hz,1Ha)、4.12(d,J=9.9Hz,1Hb)、3.97(s,3Hb)、3.96(s,3Ha)、3.82(t,J=9.6Hz,1Hb)、3.68(t,J=9.1Hz,1Ha)、3.60(t,J=9.0Hz,1Hb)、3.58(t,J=8.8Hz,1Ha)、3.45(t,J=5.6Hz,2H)、3.39〜3.47(m,1Ha+1Hb)、2.91(t,J=5.1Hz,2H)、2.73(s,3Ha)、2.64(s,6H)、2.61(s,3Hb)、2.60(t,J=7.6Hz,2H)、2.22(s,3Ha)、2.21(s,3Hb)、2.21(t,J=7.6Hz,2H)、1.87(quin,J=7.3Hz,2H)、1.41(s,6H)。MS(ES+)[M+H]+=618。
尿素過酸化水素(UHP、48mg、0.512mmol)及び無水フタル酸(151mg、1.02mmol)を、1.5mLのCH3CN及び0.3mLのMeOHに溶解した。2mLのCH3CNに溶解した(2S,3S,4R,5S,6R)−2−(3−(4−(4−メトキシ−4−オキソブチル)ベンジル)−4−メチルフェニル)−6−(メチルチオ)テトラヒドロ−2H−ピラン−3,4,5−トリイルトリアセテート(9、100mg、0.170mmol)を添加した。反応物を室温で16時間撹拌した。反応物に更なるUHP(12mg、0.128mmol)及び無水フタル酸(38mg、0.255mmol)を投入し、1時間撹拌した。スルホンへと完全に変換された後、反応物を飽和NaHCO3水溶液でクエンチした。この水層をEtOAcで3回抽出した。合わせた有機層をブラインで洗浄し、MgSO4で乾燥させ、濾過し、溶媒を真空で除去してスルホン62(95mg、収率92%)を得て、これを更に精製することなく次の工程に移した。1H NMR(400MHz,クロロホルム−d) δ ppm 7.11〜7.20(m,2H)、7.08(d,J=8.1Hz,2H)、6.93〜7.04(m,3H)、5.57(t,J=9.7Hz,1H)、5.41(t,J=9.3Hz,1H)、5.17(t,J=9.7Hz,1H)、4.49(d,J=9.7Hz,1H)、4.52(d,J=9.7Hz,1H)、3.93(m,2H)、3.67(s,3H)、2.92(s,3H)、2.62(t,J=7.5Hz,2H)、2.33(t,J=7.5Hz,2H)、2.24(s,3H)、2.09(s,3H)、2.02(s,3H)、1.94(quin,J=7.5Hz,2H)、1.75(s,3H)。MS(ES+)[M+H]+=619。
スルホン62(95mg、0.15mmol)を5mLのMeOH/H2O/THFの2:2:1混合物に懸濁した。LiOH(37mg、1.53mmol)を添加した。反応物を室温で4時間撹拌すると、その時点で出発物質が溶液に溶けた。反応物を飽和NaHSO4水溶液でクエンチした。この酸性層をEtOAcで3回抽出した。合わせた有機層をブラインで洗浄し、MgSO4で乾燥させ、濾過し、溶媒を真空で除去した。この粗残渣を1.5mLのCH3CNに溶解した。EDC・HCl(43mg、0.22mmol)、HOBt(43mg、0.22mmol)及びDIPEA(75μL、0.30mmol)を添加し、10分間撹拌した。0.5mLのCH3CN中の2−アミノ−N−(2−(ジメチルアミノ)エチル)−2−メチルプロパンアミド(30mg、0.45mmol)を添加した。反応物を室温で一晩撹拌した。反応が完了した後、溶媒を真空で除去した。残渣を分取HPLC(C18 30×100mmカラム、5%→95%のMeOH/10mMギ酸水溶液、45mL/分)によって精製し、標題の化合物63をギ酸塩として得た(30mg、収率30%)。1H NMR(400MHz,MeOH−d4) δ ppm 8.54(br.s,1H,ホルメート)、7.12〜7.22(m,3H)、7.10(d,J=8.0Hz,2H)、7.06(d,J=8.0Hz,2H)、4.52(d,J=9.5Hz,1H)、4.28(d,J=9.5Hz,1H)、3.96(s,2H)、3.88(t,J=9.2Hz,1H)、3.56(t,J=8.9Hz,1H)、3.45(t,J=5.3Hz,2H)、3.41(t,J=9.3Hz,1H)、2.93(s,3H)、2.89(t,J=5.3Hz,2H)、2.64(s,6H)、2.61(t,J=7.8Hz,2H)、2.21(t,J=8.0Hz,5H)、2.14〜2.29(m,3H)、1.88(quin,J=7.5Hz,2H)、1.41(s,6H)。MS(ES+)[M+H]+=634。
本発明の多数の付加的な化合物を上記と同様の手順を用いて調製した。これらの化合物は表1に挙げられる。「SGLT1」及び「SGLT2」の欄は、下記のように得られるヒトのSGLT1 IC50及びSGLT1 IC50の測定値を示す。ここで、***は0.01μM未満の値を表し、**は0.1μM未満の値を表し、*は1μM未満の値を表し、−−は測定されなかった又はμM単位を超える値を表す。
ヒトナトリウム/グルコース共輸送体1型(SGLT1;アクセッション番号NP_000334、GI:4507031)を、哺乳動物発現用のpIRESpuro2ベクターへクローニングした(構築物:HA−SGLT1−pIRESpuro2)。
ヒトナトリウム/グルコース共輸送体2型(SGLT2;アクセッション番号P31639、GI:400337)を、哺乳動物発現用のpIRESpuro2ベクターへクローニングした(構築物:HA−SGLT2−pIRESpuro2)。
本発明の化合物のin vivo耐容性及び薬理を、18週齢の雄性C57/Blk6マウスを用いて決定した。研究前の1週間はマウスを標準食から10%低脂肪食(LFD、D12450Bi)に切り替え、個別に飼育した。次いで、マウスをその体重によって無作為に以下の群に分けた。
12週齢の雄性KKayマウスをThe Jackson Laboratory(Bar Harbor,ME)から購入した。研究前の1週間はマウスを45%高脂肪食(HFD;食餌D12451i、Research Diets)に切り替え、個別に飼育した。マウスをそのHbA1cレベル及び体重によって無作為に以下の群に分けた。
Claims (20)
- 式:
R1は、水素又は任意に置換されたC1〜10−アルキル、C1〜5−シクロアルキル、若しくは5員複素環であり、任意の置換が1つ又は複数のR1Aによるものであり、
R1Aはそれぞれ独立してアミノ、エステル、アミド、チオール、カルボン酸、シアノ、ハロ、ヒドロキシル、又は任意に置換されたC1〜4−アルコキシ、C1〜5−シクロアルキル、若しくは5員複素環であり、任意の置換が1つ又は複数のR1Bによるものであり、
R1Bはそれぞれ独立してC1〜4−アルキル、ハロ、又はヒドロキシルであり、
nは0、1、又は2であり、
R2はそれぞれ独立してF又はOR2Aであり、R2Aはそれぞれ独立して水素、C1〜4−アルキル、又はアシルであり、
R3はそれぞれ独立してハロ、ヒドロキシル、又は任意に置換されたC1〜10−アルキル若しくはC1〜10−アルコキシであり、任意の置換が1つ又は複数のR3Aによるものであり、
R3Aはそれぞれ独立してアミノ、エステル、アミド、チオール、カルボン酸、シアノ、ハロ、ヒドロキシル、又は任意に置換されたC1〜4−アルコキシ、C1〜5−シクロアルキル、若しくは5員複素環であり、任意の置換が1つ又は複数のR3Bによるものであり、
R3Bはそれぞれ独立してC1〜4−アルキル、アミノ、シアノ、ハロ、又はヒドロキシルであり、
pは0、1、又は2であり、
R4はそれぞれ独立してR4A、−N(R4A)(R4B)、−OR4A、−SR4A、−S(O)R4A、又は−S(O)2R4Aであり、
R4Aは任意の置換が1つ又は複数のR4Cによるものであり、かつ別のR4A部分に任意に結合して二量体又は三量体が得られる、任意に置換されたC4〜20−アルキル又は4員〜20員ヘテロアルキルであり、
R4Bは水素又はR4Aであり、
R4Cはそれぞれ独立してアミノ、アミド、アゾ、カルボニル、カルボキシル、シアノ、ホルミル、グアニジノ、ハロ、ヒドロキシル、イミド、イミノ、イソチオシアネート、ニトリル、ニトロ、ニトロソ、ニトロキシ、オキソ、スルファニル、スルフィニル、スルホニル、チアール、チオシアネート、チオン、チオ尿素、尿素、又はX1、X1−L1−X2、若しくはX1−L1−X2−L2−X3であり、X1、X2及びX3はそれぞれ独立して、任意の置換が1つ又は複数のR4Dによるものである、任意に置換されたC1〜4−アルキル、C1〜6−シクロアルキル、5員若しくは6員複素環、又はアリールであり、かつL1及びL2はそれぞれ独立して、任意の置換が1つ又は複数のR4Eによるものである、任意に置換されたC1〜6−アルキル又は1員〜10員ヘテロアルキルであり、
R4Dはそれぞれ独立してR4E又は1つ若しくは複数のR4Eにより任意に置換されたC1〜6−アルキルであり、
R4Eはそれぞれ独立してアミノ、アミド、アゾ、カルボニル、カルボキシル、シアノ、ホルミル、グアニジノ、ハロ、ヒドロキシル、イミド、イミノ、イソチオシアネート、ニトリル、ニトロ、ニトロソ、ニトロキシ、オキソ、スルファニル、スルフィニル、スルホニル、チアール、チオシアネート、チオン、又は尿素であり、
mは1、2又は3である)
の化合物、又はその薬学的に許容される塩、二量体若しくは三量体。 - R1は任意に置換されたC1〜4−アルキルである、請求項1に記載の化合物。
- nは0である、請求項1に記載の化合物。
- R2はOR2Aである、請求項1に記載の化合物。
- 少なくとも1つのR2Aは水素である、請求項4に記載の化合物。
- R3は任意に置換されたC1〜4−アルキルである、請求項1に記載の化合物。
- R3はハロである、請求項1に記載の化合物。
- R3は任意に置換されたC1〜4−アルコキシである、請求項1に記載の化合物。
- pは1である、請求項1に記載の化合物。
- R4はR4Aである、請求項1に記載の化合物。
- R4は−OR4Aである、請求項1に記載の化合物。
- R1はC1〜4−アルキルである、請求項13に記載の化合物。
- R3はメチルである、請求項13に記載の化合物。
- R4はR4Aである、請求項13に記載の化合物。
- R4は−OR4Aである、請求項13に記載の化合物。
- R4Aは、
−C1〜10−アルキル−N(R4C)2、
−C1〜10−アルキル−N(R4C)C(O)R4C、
−C1〜10−アルキル−C(O)N(R4C)2、
−C1〜10−アルキル−C(O)N(R4C)−C0〜6−アルキル−C(O)R4C、
−C1〜10−アルキル−C(O)N(R4C)−C0〜6−アルキル−C(O)N(R4C)2、
−C1〜10−アルキル−N(R4C)C(O)−C0〜6−アルキル−N(R4C)2、又は、
−C1〜10−アルキル−N(R4C)C(O)−C0〜6−アルキル−N(R4C)C(O)R4C、
である、請求項16又は17に記載の化合物。 - 請求項1〜18のいずれか一項に記載の化合物と、薬学的に許容される賦形剤又は希釈剤とを含む医薬組成物。
- 疾患又は障害を治療又は管理する方法であって、それを必要とする患者に治療的に有効な量の請求項1〜19のいずれか一項に記載の化合物又は組成物を投与することを含み、前記疾患又は障害が心臓血管又は代謝の疾患又は障害である、方法。
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