NZ337830A - Combination therapy employing ileal bile acid transport inhibiting benzothiepines and HMG Co-A reductase inhibitors - Google Patents

Info

Publication number

NZ337830A

NZ337830A NZ337830A NZ33783098A NZ337830A NZ 337830 A NZ337830 A NZ 337830A NZ 337830 A NZ337830 A NZ 337830A NZ 33783098 A NZ33783098 A NZ 33783098A NZ 337830 A NZ337830 A NZ 337830A

Authority

NZ

New Zealand

Prior art keywords

heterocycle

heteroaryl

quaternary

alkyl

alkynyl

Prior art date

1997-03-11

Links

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• 239000003112 inhibitor Substances 0.000 title claims abstract description 43
• 238000002648 combination therapy Methods 0.000 title claims abstract description 18
• 239000003613 bile acid Substances 0.000 title claims description 31
• 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 title claims description 22
• 230000002401 inhibitory effect Effects 0.000 title claims description 8
• NIGNBCLEMMGDQP-UHFFFAOYSA-N 1-benzothiepine Chemical class S1C=CC=CC2=CC=CC=C12 NIGNBCLEMMGDQP-UHFFFAOYSA-N 0.000 title abstract description 23
• 239000000203 mixture Substances 0.000 claims abstract description 133
• 229940077672 Ileal bile acid transport inhibitor Drugs 0.000 claims abstract description 19
• 238000011282 treatment Methods 0.000 claims abstract description 19
• 201000001320 Atherosclerosis Diseases 0.000 claims abstract description 12
• 238000011321 prophylaxis Methods 0.000 claims abstract description 9
• 241000124008 Mammalia Species 0.000 claims abstract description 8
• 208000035150 Hypercholesterolemia Diseases 0.000 claims abstract description 6
• 125000000623 heterocyclic group Chemical group 0.000 claims description 180
• 150000001875 compounds Chemical class 0.000 claims description 168
• 125000001072 heteroaryl group Chemical group 0.000 claims description 165
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 151
• -1 carboalkoxyalkyl Chemical group 0.000 claims description 133
• 125000000217 alkyl group Chemical group 0.000 claims description 125
• 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 122
• 125000003118 aryl group Chemical group 0.000 claims description 110
• 125000003342 alkenyl group Chemical group 0.000 claims description 103
• 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 103
• 125000000304 alkynyl group Chemical group 0.000 claims description 102
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 94
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 79
• 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 72
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 71
• 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 64
• 239000004721 Polyphenylene oxide Substances 0.000 claims description 59
• 229920000570 polyether Polymers 0.000 claims description 59
• 229910052739 hydrogen Inorganic materials 0.000 claims description 58
• 125000001424 substituent group Chemical group 0.000 claims description 56
• 108090000765 processed proteins & peptides Proteins 0.000 claims description 54
• 125000001188 haloalkyl group Chemical group 0.000 claims description 53
• 125000004043 oxo group Chemical group O=* 0.000 claims description 50
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 48
• 229910052736 halogen Inorganic materials 0.000 claims description 46
• 150000002367 halogens Chemical class 0.000 claims description 45
• 229940123934 Reductase inhibitor Drugs 0.000 claims description 39
• 229910052757 nitrogen Inorganic materials 0.000 claims description 37
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 35
• 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims description 32
• 150000001413 amino acids Chemical class 0.000 claims description 30
• 150000001720 carbohydrates Chemical class 0.000 claims description 29
• 239000001257 hydrogen Substances 0.000 claims description 28
• 229910052799 carbon Inorganic materials 0.000 claims description 27
• 229920001184 polypeptide Polymers 0.000 claims description 26
• 102000004196 processed proteins & peptides Human genes 0.000 claims description 26
• 239000008194 pharmaceutical composition Substances 0.000 claims description 24
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 22
• 150000003839 salts Chemical class 0.000 claims description 21
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 20
• 125000003545 alkoxy group Chemical group 0.000 claims description 18
• 125000004122 cyclic group Chemical group 0.000 claims description 16
• 125000002252 acyl group Chemical group 0.000 claims description 15
• 239000003814 drug Substances 0.000 claims description 13
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
• YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 12
• 239000002253 acid Substances 0.000 claims description 12
• 125000004423 acyloxy group Chemical group 0.000 claims description 12
• 229910052760 oxygen Inorganic materials 0.000 claims description 12
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 11
• 125000002877 alkyl aryl group Chemical group 0.000 claims description 11
• 150000001450 anions Chemical class 0.000 claims description 11
• 102000004316 Oxidoreductases Human genes 0.000 claims description 10
• 108090000854 Oxidoreductases Proteins 0.000 claims description 10
• 125000005098 aryl alkoxy carbonyl group Chemical group 0.000 claims description 10
• 239000003643 water by type Substances 0.000 claims description 10
• 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 9
• VMWNQDUVQKEIOC-CYBMUJFWSA-N apomorphine Chemical compound C([C@H]1N(C)CC2)C3=CC=C(O)C(O)=C3C3=C1C2=CC=C3 VMWNQDUVQKEIOC-CYBMUJFWSA-N 0.000 claims description 9
• 150000002431 hydrogen Chemical class 0.000 claims description 9
• 125000004414 alkyl thio group Chemical group 0.000 claims description 7
• 150000001768 cations Chemical class 0.000 claims description 6
• 125000004663 dialkyl amino group Chemical group 0.000 claims description 6
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
• 239000000651 prodrug Substances 0.000 claims description 6
• 229940002612 prodrug Drugs 0.000 claims description 6
• 125000000168 pyrrolyl group Chemical group 0.000 claims description 6
• 239000012453 solvate Substances 0.000 claims description 6
• GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 6
• 102220465932 Beta-1,3-glucuronyltransferase LARGE2_R13A_mutation Human genes 0.000 claims description 5
• 101150020251 NR13 gene Proteins 0.000 claims description 5
• 125000004946 alkenylalkyl group Chemical group 0.000 claims description 5
• 125000005038 alkynylalkyl group Chemical group 0.000 claims description 5
• 125000004966 cyanoalkyl group Chemical group 0.000 claims description 5
• 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 5
• 125000004964 sulfoalkyl group Chemical group 0.000 claims description 5
• 229930192474 thiophene Natural products 0.000 claims description 5
• 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 claims description 4
• 150000001721 carbon Chemical group 0.000 claims description 4
• 239000003937 drug carrier Substances 0.000 claims description 4
• 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
• 125000001624 naphthyl group Chemical group 0.000 claims description 4
• 229960005235 piperonyl butoxide Drugs 0.000 claims description 4
• 125000001425 triazolyl group Chemical group 0.000 claims description 4
• KBXILIYZUWEKCM-UHFFFAOYSA-N N-amino-N-ethylsulfanylhydroxylamine Chemical compound CCSN(N)O KBXILIYZUWEKCM-UHFFFAOYSA-N 0.000 claims description 3
• 125000003705 anilinocarbonyl group Chemical group O=C([*])N([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
• 125000004429 atom Chemical group 0.000 claims description 3
• 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 3
• 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 3
• 125000002541 furyl group Chemical group 0.000 claims description 3
• 125000002883 imidazolyl group Chemical group 0.000 claims description 3
• 125000001041 indolyl group Chemical group 0.000 claims description 3
• 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 3
• 125000001786 isothiazolyl group Chemical group 0.000 claims description 3
• 125000000842 isoxazolyl group Chemical group 0.000 claims description 3
• 238000004519 manufacturing process Methods 0.000 claims description 3
• 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 3
• 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 3
• 125000002971 oxazolyl group Chemical group 0.000 claims description 3
• 125000004591 piperonyl group Chemical group C(C1=CC=2OCOC2C=C1)* 0.000 claims description 3
• 125000003226 pyrazolyl group Chemical group 0.000 claims description 3
• 125000004076 pyridyl group Chemical group 0.000 claims description 3
• 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 3
• 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 claims description 3
• 125000005504 styryl group Chemical group 0.000 claims description 3
• 125000000335 thiazolyl group Chemical group 0.000 claims description 3
• 125000001544 thienyl group Chemical group 0.000 claims description 3
• 125000004193 piperazinyl group Chemical group 0.000 claims description 2
• PCZOHLXUXFIOCF-UHFFFAOYSA-N Monacolin X Natural products C12C(OC(=O)C(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 PCZOHLXUXFIOCF-UHFFFAOYSA-N 0.000 claims 13
• TUZYXOIXSAXUGO-UHFFFAOYSA-N Pravastatin Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(O)C=C21 TUZYXOIXSAXUGO-UHFFFAOYSA-N 0.000 claims 13
• RYMZZMVNJRMUDD-UHFFFAOYSA-N SJ000286063 Natural products C12C(OC(=O)C(C)(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 RYMZZMVNJRMUDD-UHFFFAOYSA-N 0.000 claims 13
• 229960004844 lovastatin Drugs 0.000 claims 13
• PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical group 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 claims 13
• QLJODMDSTUBWDW-UHFFFAOYSA-N lovastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(C)C=C21 QLJODMDSTUBWDW-UHFFFAOYSA-N 0.000 claims 13
• 229960002965 pravastatin Drugs 0.000 claims 13
• TUZYXOIXSAXUGO-PZAWKZKUSA-N pravastatin Chemical compound C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(O)=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)C[C@H](O)C=C21 TUZYXOIXSAXUGO-PZAWKZKUSA-N 0.000 claims 13
• 229960002855 simvastatin Drugs 0.000 claims 13
• RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 claims 13
• XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 claims 7
• XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 claims 7
• 229960005370 atorvastatin Drugs 0.000 claims 7
• ZGGHKIMDNBDHJB-NRFPMOEYSA-M (3R,5S)-fluvastatin sodium Chemical compound [Na+].C12=CC=CC=C2N(C(C)C)C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)=C1C1=CC=C(F)C=C1 ZGGHKIMDNBDHJB-NRFPMOEYSA-M 0.000 claims 5
• 229960003765 fluvastatin Drugs 0.000 claims 5
• 230000001315 anti-hyperlipaemic effect Effects 0.000 claims 4
• 125000004181 carboxyalkyl group Chemical group 0.000 claims 4
• 240000005020 Acaciella glauca Species 0.000 claims 1
• 238000000034 method Methods 0.000 abstract description 80
• 235000011468 Albizia julibrissin Nutrition 0.000 description 268
• 241001070944 Mimosa Species 0.000 description 268
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 226
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 149
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 144
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 131
• 239000000243 solution Substances 0.000 description 129
• 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 102
• 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 101
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 98
• 238000006243 chemical reaction Methods 0.000 description 88
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 84
• 239000000047 product Substances 0.000 description 84
• 229910001868 water Inorganic materials 0.000 description 82
• FKNQCJSGGFJEIZ-UHFFFAOYSA-N gamma-methylpyridine Natural products CC1=CC=NC=C1 FKNQCJSGGFJEIZ-UHFFFAOYSA-N 0.000 description 78
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 73
• 239000011541 reaction mixture Substances 0.000 description 68
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 66
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 63
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 60
• 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 53
• 239000007787 solid Substances 0.000 description 49
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 48
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 46
• 235000019439 ethyl acetate Nutrition 0.000 description 46
• 238000005481 NMR spectroscopy Methods 0.000 description 44
• 238000002360 preparation method Methods 0.000 description 44
• 239000003921 oil Substances 0.000 description 43
• 235000019198 oils Nutrition 0.000 description 43
• 238000003756 stirring Methods 0.000 description 43
• RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 43
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 42
• 238000001819 mass spectrum Methods 0.000 description 39
• 239000012044 organic layer Substances 0.000 description 37
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 37
• 238000004128 high performance liquid chromatography Methods 0.000 description 36
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 34
• 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 33
• 239000012267 brine Substances 0.000 description 33
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 33
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 32
• 238000010992 reflux Methods 0.000 description 32
• 239000010410 layer Substances 0.000 description 30
• 238000007792 addition Methods 0.000 description 29
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 27
• KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 27
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 26
• 239000000284 extract Substances 0.000 description 26
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 26
• NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 25
• OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 24
• RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 24
• 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 23
• 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 22
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 20
• 125000004705 ethylthio group Chemical group C(C)S* 0.000 description 20
• 239000000463 material Substances 0.000 description 19
• LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 19
• 238000000746 purification Methods 0.000 description 19
• AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 18
• TZSDMELQUACXIN-UHFFFAOYSA-N 2,3,4,5-tetrahydro-1$l^{6}-benzothiepine 1,1-dioxide Chemical class O=S1(=O)CCCCC2=CC=CC=C12 TZSDMELQUACXIN-UHFFFAOYSA-N 0.000 description 17
• 238000010898 silica gel chromatography Methods 0.000 description 17
• 239000007858 starting material Substances 0.000 description 17
• AOJDZKCUAATBGE-UHFFFAOYSA-N bromomethane Chemical compound Br[CH2] AOJDZKCUAATBGE-UHFFFAOYSA-N 0.000 description 16
• XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 15
• ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 15
• 239000000706 filtrate Substances 0.000 description 14
• 238000010926 purge Methods 0.000 description 14
• 238000004809 thin layer chromatography Methods 0.000 description 14
• 229940086542 triethylamine Drugs 0.000 description 14
• WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 13
• 235000014633 carbohydrates Nutrition 0.000 description 13
• 229920000642 polymer Polymers 0.000 description 13
• 229910000027 potassium carbonate Inorganic materials 0.000 description 13
• 235000011181 potassium carbonates Nutrition 0.000 description 13
• 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 13
• 229910000104 sodium hydride Inorganic materials 0.000 description 13
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 12
• 150000001412 amines Chemical class 0.000 description 12
• ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 12
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 12
• 238000003786 synthesis reaction Methods 0.000 description 12
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• 230000029936 alkylation Effects 0.000 description 11
• 238000005804 alkylation reaction Methods 0.000 description 11
• 229940024606 amino acid Drugs 0.000 description 11
• 235000001014 amino acid Nutrition 0.000 description 11
• 230000015572 biosynthetic process Effects 0.000 description 11
• 230000037396 body weight Effects 0.000 description 11
• 201000010099 disease Diseases 0.000 description 11
• 238000009472 formulation Methods 0.000 description 11
• 238000004949 mass spectrometry Methods 0.000 description 11
• 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 11
• 239000000741 silica gel Substances 0.000 description 11
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• 229960001866 silicon dioxide Drugs 0.000 description 11
• 239000003826 tablet Substances 0.000 description 11
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