ES2390052T3 - Agonistas del receptor opioide kappa que comprende un derivado de 2-fenilbenzotiazolina - Google Patents

Info

Publication number

ES2390052T3

ES2390052T3 ES03715569T ES03715569T ES2390052T3 ES 2390052 T3 ES2390052 T3 ES 2390052T3 ES 03715569 T ES03715569 T ES 03715569T ES 03715569 T ES03715569 T ES 03715569T ES 2390052 T3 ES2390052 T3 ES 2390052T3

Authority

ES

Spain

Prior art keywords

acetyl

compound

methoxyphenyl

benzothiazoline

propoxy

Prior art date

2002-03-29

Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

Expired - Lifetime

Links

• Espacenet
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• XBHOUXSGHYZCNH-UHFFFAOYSA-N 2-phenyl-1,3-benzothiazole Chemical class C1=CC=CC=C1C1=NC2=CC=CC=C2S1 XBHOUXSGHYZCNH-UHFFFAOYSA-N 0.000 title description 11
• 229940044601 receptor agonist Drugs 0.000 title description 8
• 239000000018 receptor agonist Substances 0.000 title description 8
• 102000048260 kappa Opioid Receptors Human genes 0.000 title 1
• 108020001588 κ-opioid receptors Proteins 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims abstract description 360
• 125000003545 alkoxy group Chemical group 0.000 claims abstract description 54
• 150000002148 esters Chemical class 0.000 claims abstract description 46
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 43
• 125000000217 alkyl group Chemical group 0.000 claims abstract description 42
• 229910052736 halogen Inorganic materials 0.000 claims abstract description 27
• 150000002367 halogens Chemical class 0.000 claims abstract description 27
• 150000003839 salts Chemical class 0.000 claims abstract description 27
• RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical group C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims abstract description 21
• 125000002252 acyl group Chemical group 0.000 claims abstract description 19
• 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 19
• 125000003118 aryl group Chemical group 0.000 claims abstract description 17
• 125000002947 alkylene group Chemical group 0.000 claims abstract description 14
• 239000001257 hydrogen Substances 0.000 claims abstract description 14
• 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 14
• 125000005083 alkoxyalkoxy group Chemical group 0.000 claims abstract description 9
• 125000004183 alkoxy alkyl group Chemical group 0.000 claims abstract description 8
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims abstract description 6
• 125000004414 alkyl thio group Chemical group 0.000 claims abstract description 5
• 150000002431 hydrogen Chemical class 0.000 claims abstract 5
• PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims abstract 2
• 239000003814 drug Substances 0.000 claims description 23
• 208000002193 Pain Diseases 0.000 claims description 13
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 9
• FZCPIIVQLXQADX-UHFFFAOYSA-N 1-[6-chloro-2-[2-[3-[2-hydroxyethyl(propan-2-yl)amino]propoxy]-5-methoxyphenyl]-2h-1,3-benzothiazol-3-yl]ethanone Chemical compound COC1=CC=C(OCCCN(CCO)C(C)C)C(C2N(C3=CC=C(Cl)C=C3S2)C(C)=O)=C1 FZCPIIVQLXQADX-UHFFFAOYSA-N 0.000 claims description 8
• UERWQKPXXLMLCD-UHFFFAOYSA-N 1-[6-chloro-2-[2-[3-[2-ethoxyethyl(propan-2-yl)amino]propoxy]-5-methoxyphenyl]-2h-1,3-benzothiazol-3-yl]ethanone Chemical compound CCOCCN(C(C)C)CCCOC1=CC=C(OC)C=C1C1N(C(C)=O)C2=CC=C(Cl)C=C2S1 UERWQKPXXLMLCD-UHFFFAOYSA-N 0.000 claims description 7
• XLPBLAYELDGZJK-UHFFFAOYSA-N 1-[6-chloro-2-[5-methoxy-2-[3-[2-methoxyethyl(propan-2-yl)amino]propoxy]phenyl]-2h-1,3-benzothiazol-3-yl]ethanone Chemical compound COCCN(C(C)C)CCCOC1=CC=C(OC)C=C1C1N(C(C)=O)C2=CC=C(Cl)C=C2S1 XLPBLAYELDGZJK-UHFFFAOYSA-N 0.000 claims description 7
• ZRBQEOVMKVUVPS-UHFFFAOYSA-N 1-[2-[2-[3-[2-ethoxyethyl(propan-2-yl)amino]propoxy]-5-methoxyphenyl]-2h-1,3-benzothiazol-3-yl]ethanone Chemical compound CCOCCN(C(C)C)CCCOC1=CC=C(OC)C=C1C1N(C(C)=O)C2=CC=CC=C2S1 ZRBQEOVMKVUVPS-UHFFFAOYSA-N 0.000 claims description 6
• ZCYZGWGJBAOGLL-UHFFFAOYSA-N 1-[6-chloro-2-[2-[3-[hydroxy(propan-2-yl)amino]propoxy]-5-methoxyphenyl]-2h-1,3-benzothiazol-3-yl]ethanone Chemical compound COC1=CC=C(OCCCN(O)C(C)C)C(C2N(C3=CC=C(Cl)C=C3S2)C(C)=O)=C1 ZCYZGWGJBAOGLL-UHFFFAOYSA-N 0.000 claims description 5
• 229940121954 Opioid receptor agonist Drugs 0.000 claims description 5
• 208000003251 Pruritus Diseases 0.000 claims description 5
• 239000003402 opiate agonist Substances 0.000 claims description 5
• MALQYAQZYNLLLE-UHFFFAOYSA-N 1-[6-chloro-2-[5-methoxy-2-[3-[2-(2-methoxyethoxymethoxy)ethyl-propan-2-ylamino]propoxy]phenyl]-2h-1,3-benzothiazol-3-yl]ethanone Chemical compound COCCOCOCCN(C(C)C)CCCOC1=CC=C(OC)C=C1C1N(C(C)=O)C2=CC=C(Cl)C=C2S1 MALQYAQZYNLLLE-UHFFFAOYSA-N 0.000 claims description 4
• SDSBUWUMPXICND-UHFFFAOYSA-N 1-[5-chloro-2-[2-[3-[2-hydroxyethyl(propan-2-yl)amino]propoxy]-5-methoxyphenyl]-2h-1,3-benzothiazol-3-yl]ethanone Chemical compound COC1=CC=C(OCCCN(CCO)C(C)C)C(C2N(C3=CC(Cl)=CC=C3S2)C(C)=O)=C1 SDSBUWUMPXICND-UHFFFAOYSA-N 0.000 claims description 3
• HXAPBSWEHMASPF-UHFFFAOYSA-N 1-[6-chloro-2-[2-[4-[2-hydroxyethyl(propan-2-yl)amino]butan-2-yloxy]-5-methoxyphenyl]-2h-1,3-benzothiazol-3-yl]ethanone Chemical compound COC1=CC=C(OC(C)CCN(CCO)C(C)C)C(C2N(C3=CC=C(Cl)C=C3S2)C(C)=O)=C1 HXAPBSWEHMASPF-UHFFFAOYSA-N 0.000 claims description 3
• RLXYTDORXJKXDZ-UHFFFAOYSA-N 1-[6-chloro-2-[5-methoxy-2-[3-[2-(methoxymethoxy)ethyl-propan-2-ylamino]propoxy]phenyl]-2h-1,3-benzothiazol-3-yl]ethanone Chemical compound COCOCCN(C(C)C)CCCOC1=CC=C(OC)C=C1C1N(C(C)=O)C2=CC=C(Cl)C=C2S1 RLXYTDORXJKXDZ-UHFFFAOYSA-N 0.000 claims description 3
• YLHIXANMKBCJOB-UHFFFAOYSA-N 2-[3-[2-(3-acetyl-6-chloro-2h-1,3-benzothiazol-2-yl)-4-methoxyphenoxy]propyl-propan-2-ylamino]ethyl acetate Chemical compound COC1=CC=C(OCCCN(CCOC(C)=O)C(C)C)C(C2N(C3=CC=C(Cl)C=C3S2)C(C)=O)=C1 YLHIXANMKBCJOB-UHFFFAOYSA-N 0.000 claims description 3
• SZOQMODWPLLMMC-UHFFFAOYSA-N 3-[3-[2-(3-acetyl-6-chloro-2h-1,3-benzothiazol-2-yl)-4-methoxyphenoxy]propyl-propan-2-ylamino]-2-phenylpropanoic acid Chemical compound S1C2=CC(Cl)=CC=C2N(C(C)=O)C1C1=CC(OC)=CC=C1OCCCN(C(C)C)CC(C(O)=O)C1=CC=CC=C1 SZOQMODWPLLMMC-UHFFFAOYSA-N 0.000 claims description 3
• 150000003235 pyrrolidines Chemical class 0.000 claims 1
• -1 alkoxy ester Chemical class 0.000 abstract description 43
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 222
• 239000000243 solution Substances 0.000 description 119
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 69
• 239000000203 mixture Substances 0.000 description 55
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 45
• 238000000034 method Methods 0.000 description 40
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 39
• 238000001816 cooling Methods 0.000 description 37
• 239000000126 substance Substances 0.000 description 37
• 239000011541 reaction mixture Substances 0.000 description 36
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 33
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 31
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 30
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 30
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 29
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 28
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 27
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 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 21
• KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 21
• 238000002360 preparation method Methods 0.000 description 21
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
• 239000013078 crystal Substances 0.000 description 18
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 18
• WOHLSTOWRAOMSG-UHFFFAOYSA-N 2,3-dihydro-1,3-benzothiazole Chemical compound C1=CC=C2SCNC2=C1 WOHLSTOWRAOMSG-UHFFFAOYSA-N 0.000 description 17
• 102000003840 Opioid Receptors Human genes 0.000 description 17
• 108090000137 Opioid Receptors Proteins 0.000 description 17
• 239000000872 buffer Substances 0.000 description 17
• 229940079593 drug Drugs 0.000 description 17
• 238000010898 silica gel chromatography Methods 0.000 description 16
• WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 15
• XKMLYUALXHKNFT-UUOKFMHZSA-N Guanosine-5'-triphosphate Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O XKMLYUALXHKNFT-UUOKFMHZSA-N 0.000 description 15
• 239000000556 agonist Substances 0.000 description 15
• XKMLYUALXHKNFT-UHFFFAOYSA-N rGTP Natural products C1=2NC(N)=NC(=O)C=2N=CN1C1OC(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)C(O)C1O XKMLYUALXHKNFT-UHFFFAOYSA-N 0.000 description 15
• PUMTTZYYKPFOTK-UHFFFAOYSA-N 1-[6-chloro-2-(2-hydroxy-5-methoxyphenyl)-2h-1,3-benzothiazol-3-yl]ethanone Chemical compound COC1=CC=C(O)C(C2N(C3=CC=C(Cl)C=C3S2)C(C)=O)=C1 PUMTTZYYKPFOTK-UHFFFAOYSA-N 0.000 description 14
• 239000003960 organic solvent Substances 0.000 description 14
• 238000011534 incubation Methods 0.000 description 13
• 102000005962 receptors Human genes 0.000 description 13
• 108020003175 receptors Proteins 0.000 description 13
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
• 230000027455 binding Effects 0.000 description 12
• 230000000694 effects Effects 0.000 description 12
• 239000012044 organic layer Substances 0.000 description 12
• 230000000202 analgesic effect Effects 0.000 description 11
• 239000007864 aqueous solution Substances 0.000 description 11
• 125000004104 aryloxy group Chemical group 0.000 description 11
• IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 11
• 229910000041 hydrogen chloride Inorganic materials 0.000 description 11
• 239000010410 layer Substances 0.000 description 11
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 11
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
• 150000001412 amines Chemical class 0.000 description 10
• 230000003502 anti-nociceptive effect Effects 0.000 description 9
• 229910000027 potassium carbonate Inorganic materials 0.000 description 9
• FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 9
• 239000002904 solvent Substances 0.000 description 9
• QVVAWONRFLJUBP-UHFFFAOYSA-N 1,3-benzothiazol-3-ium;chloride Chemical compound Cl.C1=CC=C2SC=NC2=C1 QVVAWONRFLJUBP-UHFFFAOYSA-N 0.000 description 8
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
• 239000002253 acid Substances 0.000 description 8
• 239000002585 base Substances 0.000 description 8
• 229910052757 nitrogen Inorganic materials 0.000 description 8
• 239000013641 positive control Substances 0.000 description 8
• QGWNDRXFNXRZMB-UUOKFMHZSA-K GDP(3-) Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](COP([O-])(=O)OP([O-])([O-])=O)[C@@H](O)[C@H]1O QGWNDRXFNXRZMB-UUOKFMHZSA-K 0.000 description 7
• 239000013543 active substance Substances 0.000 description 7
• 235000015165 citric acid Nutrition 0.000 description 7
• QGWNDRXFNXRZMB-UHFFFAOYSA-N guanidine diphosphate Natural products C1=2NC(N)=NC(=O)C=2N=CN1C1OC(COP(O)(=O)OP(O)(O)=O)C(O)C1O QGWNDRXFNXRZMB-UHFFFAOYSA-N 0.000 description 7
• 239000012452 mother liquor Substances 0.000 description 7
• 238000003756 stirring Methods 0.000 description 7
• ROSJMNJJOXFJGH-UHFFFAOYSA-N 1-[2-(2-hydroxy-5-methoxyphenyl)-2h-1,3-benzothiazol-3-yl]ethanone Chemical compound COC1=CC=C(O)C(C2N(C3=CC=CC=C3S2)C(C)=O)=C1 ROSJMNJJOXFJGH-UHFFFAOYSA-N 0.000 description 6
• KHVVCKGCWWQHHX-UHFFFAOYSA-N 1-[6-chloro-2-[2-(3-chloropropoxy)-5-methoxyphenyl]-2h-1,3-benzothiazol-3-yl]ethanone Chemical compound COC1=CC=C(OCCCCl)C(C2N(C3=CC=C(Cl)C=C3S2)C(C)=O)=C1 KHVVCKGCWWQHHX-UHFFFAOYSA-N 0.000 description 6
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
• UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
• SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
• 125000004448 alkyl carbonyl group Chemical group 0.000 description 6
• 125000005129 aryl carbonyl group Chemical group 0.000 description 6
• HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 6
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 6
• 238000009472 formulation Methods 0.000 description 6
• 125000000623 heterocyclic group Chemical group 0.000 description 6
• 230000000144 pharmacologic effect Effects 0.000 description 6
• 229920006395 saturated elastomer Polymers 0.000 description 6
• 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 6
• KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 5
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
• GFOWYEIMOUPRRY-ZLBDCPSSSA-N [2-(3-acetyl-6-chloro-2h-1,3-benzothiazol-2-yl)-4-methoxyphenyl] (2s,4s)-3-acetyl-5,5-dimethyl-2-phenyl-1,3-thiazolidine-4-carboxylate Chemical compound C1([C@H]2N([C@H](C(S2)(C)C)C(=O)OC2=CC=C(C=C2C2N(C3=CC=C(Cl)C=C3S2)C(C)=O)OC)C(C)=O)=CC=CC=C1 GFOWYEIMOUPRRY-ZLBDCPSSSA-N 0.000 description 5
• 125000003282 alkyl amino group Chemical group 0.000 description 5
• 239000000730 antalgic agent Substances 0.000 description 5
• 125000001769 aryl amino group Chemical group 0.000 description 5
• 238000003556 assay Methods 0.000 description 5
• 125000004432 carbon atom Chemical group C* 0.000 description 5
• 239000000706 filtrate Substances 0.000 description 5
• 238000010438 heat treatment Methods 0.000 description 5
• 230000005764 inhibitory process Effects 0.000 description 5
• 239000012528 membrane Substances 0.000 description 5
• PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 5
• 125000006239 protecting group Chemical group 0.000 description 5
• 235000017557 sodium bicarbonate Nutrition 0.000 description 5
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
• 239000012312 sodium hydride Substances 0.000 description 5
• 229910000104 sodium hydride Inorganic materials 0.000 description 5
• 125000001424 substituent group Chemical group 0.000 description 5
• 229940124597 therapeutic agent Drugs 0.000 description 5
• KTQBGMMWEAVGEQ-RYUDHWBXSA-N (2s,4s)-3-acetyl-5,5-dimethyl-2-phenyl-1,3-thiazolidine-4-carboxylic acid Chemical compound S1C(C)(C)[C@H](C(O)=O)N(C(=O)C)[C@@H]1C1=CC=CC=C1 KTQBGMMWEAVGEQ-RYUDHWBXSA-N 0.000 description 4
• QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 4
• FZHSPPYCNDYIKD-UHFFFAOYSA-N 5-methoxysalicylaldehyde Chemical compound COC1=CC=C(O)C(C=O)=C1 FZHSPPYCNDYIKD-UHFFFAOYSA-N 0.000 description 4
• GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 4
• 150000001350 alkyl halides Chemical class 0.000 description 4
• 125000003277 amino group Chemical group 0.000 description 4
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• 239000002775 capsule Substances 0.000 description 4
• 239000003153 chemical reaction reagent Substances 0.000 description 4
• 239000008101 lactose Substances 0.000 description 4
• HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
• BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 4
• 239000012299 nitrogen atmosphere Substances 0.000 description 4
• 230000003287 optical effect Effects 0.000 description 4
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
• 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 4
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
• 229910021642 ultra pure water Inorganic materials 0.000 description 4
• 239000012498 ultrapure water Substances 0.000 description 4
• NEDALSUIDQEZPT-UHFFFAOYSA-N 1-[6-chloro-2-[2-[3-[2-ethoxyethyl(propan-2-yl)amino]propoxy]-5-methoxyphenyl]-2h-1,3-benzothiazol-3-yl]ethanone;hydrochloride Chemical compound Cl.CCOCCN(C(C)C)CCCOC1=CC=C(OC)C=C1C1N(C(C)=O)C2=CC=C(Cl)C=C2S1 NEDALSUIDQEZPT-UHFFFAOYSA-N 0.000 description 3
• VHNVTJXVGIDJOD-UHFFFAOYSA-N 1-[6-chloro-2-[5-methoxy-2-[3-[2-methoxyethyl(propan-2-yl)amino]propoxy]phenyl]-2h-1,3-benzothiazol-3-yl]ethanone;hydrochloride Chemical compound Cl.COCCN(C(C)C)CCCOC1=CC=C(OC)C=C1C1N(C(C)=O)C2=CC=C(Cl)C=C2S1 VHNVTJXVGIDJOD-UHFFFAOYSA-N 0.000 description 3
• HOHZSVHEGJFWGN-UHFFFAOYSA-N 3-[2-(3-acetyl-6-chloro-2h-1,3-benzothiazol-2-yl)-4-methoxyphenoxy]butyl 4-methylbenzenesulfonate Chemical compound S1C2=CC(Cl)=CC=C2N(C(C)=O)C1C1=CC(OC)=CC=C1OC(C)CCOS(=O)(=O)C1=CC=C(C)C=C1 HOHZSVHEGJFWGN-UHFFFAOYSA-N 0.000 description 3
• WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
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