NO314455B1 - Karboksamidotiazolderivater, fremgangsmåter for fremstilling derav og farmasöytiske blandinger - Google Patents

Info

Publication number

NO314455B1

NO314455B1 NO20001409A NO20001409A NO314455B1 NO 314455 B1 NO314455 B1 NO 314455B1 NO 20001409 A NO20001409 A NO 20001409A NO 20001409 A NO20001409 A NO 20001409A NO 314455 B1 NO314455 B1 NO 314455B1

Authority

NO

Norway

Prior art keywords

chloro

dimethoxyphenyl

cyclohexylethyl

thiazol

ylcarbamoyl

Prior art date

1997-09-19

Links

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• 238000000034 method Methods 0.000 title claims description 45
• 238000002360 preparation method Methods 0.000 title claims description 16
• 230000008569 process Effects 0.000 title claims description 10
• 239000008194 pharmaceutical composition Substances 0.000 title description 3
• 150000001875 compounds Chemical class 0.000 claims description 285
• 239000000203 mixture Substances 0.000 claims description 185
• 239000011734 sodium Substances 0.000 claims description 65
• -1 acetyloxy, methoxy, ethoxy, methylthio Chemical group 0.000 claims description 54
• 150000003839 salts Chemical class 0.000 claims description 35
• 239000001257 hydrogen Substances 0.000 claims description 32
• 229910052739 hydrogen Inorganic materials 0.000 claims description 32
• 239000002253 acid Substances 0.000 claims description 30
• 239000012453 solvate Substances 0.000 claims description 28
• QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 24
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 22
• 238000006243 chemical reaction Methods 0.000 claims description 21
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical class [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 19
• 125000001424 substituent group Chemical group 0.000 claims description 17
• 238000011282 treatment Methods 0.000 claims description 17
• 229910052736 halogen Inorganic materials 0.000 claims description 16
• 229910052708 sodium Inorganic materials 0.000 claims description 15
• 239000003814 drug Substances 0.000 claims description 14
• 229940079593 drug Drugs 0.000 claims description 13
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 13
• 150000002367 halogens Chemical class 0.000 claims description 13
• 150000002431 hydrogen Chemical class 0.000 claims description 12
• RAIPHJJURHTUIC-UHFFFAOYSA-N 1,3-thiazol-2-amine Chemical compound NC1=NC=CS1 RAIPHJJURHTUIC-UHFFFAOYSA-N 0.000 claims description 11
• 238000004519 manufacturing process Methods 0.000 claims description 10
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 9
• 239000000460 chlorine Substances 0.000 claims description 8
• 229910052801 chlorine Inorganic materials 0.000 claims description 8
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
• 230000008878 coupling Effects 0.000 claims description 6
• 238000010168 coupling process Methods 0.000 claims description 6
• 238000005859 coupling reaction Methods 0.000 claims description 6
• 208000035475 disorder Diseases 0.000 claims description 6
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
• NFDFTMICKVDYLQ-UHFFFAOYSA-N 2-[2-[[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-cyclohexylethyl)-1,3-thiazol-2-yl]carbamoyl]-5,7-dimethylindol-1-yl]acetic acid Chemical compound C1=C(Cl)C(OC)=CC(C2=C(SC(NC(=O)C=3N(C4=C(C)C=C(C)C=C4C=3)CC(O)=O)=N2)CCC2CCCCC2)=C1OC NFDFTMICKVDYLQ-UHFFFAOYSA-N 0.000 claims description 5
• ITSFURYNWBMEFN-UHFFFAOYSA-N 2-[2-[[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-cyclohexylethyl)-1,3-thiazol-2-yl]carbamoyl]-5-methylindol-1-yl]acetic acid Chemical compound C1=C(Cl)C(OC)=CC(C2=C(SC(NC(=O)C=3N(C4=CC=C(C)C=C4C=3)CC(O)=O)=N2)CCC2CCCCC2)=C1OC ITSFURYNWBMEFN-UHFFFAOYSA-N 0.000 claims description 5
• 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 claims description 5
• 229910052731 fluorine Inorganic materials 0.000 claims description 5
• 239000011737 fluorine Substances 0.000 claims description 5
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
• 208000008589 Obesity Diseases 0.000 claims description 4
• 235000020824 obesity Nutrition 0.000 claims description 4
• 208000012661 Dyskinesia Diseases 0.000 claims description 3
• 125000003277 amino group Chemical group 0.000 claims description 3
• 210000003169 central nervous system Anatomy 0.000 claims description 3
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
• 159000000001 potassium salts Chemical class 0.000 claims description 3
• AGOJEFQTAMTJHV-UHFFFAOYSA-N 2-[2-[[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-cyclohexylethyl)-1,3-thiazol-2-yl]carbamoyl]-4,5-dimethylindol-1-yl]acetic acid Chemical compound C1=C(Cl)C(OC)=CC(C2=C(SC(NC(=O)C=3N(C4=CC=C(C)C(C)=C4C=3)CC(O)=O)=N2)CCC2CCCCC2)=C1OC AGOJEFQTAMTJHV-UHFFFAOYSA-N 0.000 claims description 2
• WYNBPYGACGYHSD-UHFFFAOYSA-N 2-[2-[[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-cyclohexylethyl)-1,3-thiazol-2-yl]carbamoyl]-4-methoxyindol-1-yl]acetic acid Chemical compound C1=C(Cl)C(OC)=CC(C2=C(SC(NC(=O)C=3N(C4=CC=CC(OC)=C4C=3)CC(O)=O)=N2)CCC2CCCCC2)=C1OC WYNBPYGACGYHSD-UHFFFAOYSA-N 0.000 claims description 2
• VZVMSBUIQNSYBC-UHFFFAOYSA-N 2-[2-[[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-cyclohexylethyl)-1,3-thiazol-2-yl]carbamoyl]-4-methylindol-1-yl]acetic acid Chemical compound C1=C(Cl)C(OC)=CC(C2=C(SC(NC(=O)C=3N(C4=CC=CC(C)=C4C=3)CC(O)=O)=N2)CCC2CCCCC2)=C1OC VZVMSBUIQNSYBC-UHFFFAOYSA-N 0.000 claims description 2
• HYGJUCCSZDXPRF-UHFFFAOYSA-N 2-[2-[[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-cyclohexylethyl)-1,3-thiazol-2-yl]carbamoyl]-5-methoxyindol-1-yl]acetic acid Chemical compound C=1C2=CC(OC)=CC=C2N(CC(O)=O)C=1C(=O)NC(S1)=NC(C=2C(=CC(Cl)=C(OC)C=2)OC)=C1CCC1CCCCC1 HYGJUCCSZDXPRF-UHFFFAOYSA-N 0.000 claims description 2
• MFWRPGPURWSDCK-UHFFFAOYSA-N 2-[2-[[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-cyclohexylethyl)-1,3-thiazol-2-yl]carbamoyl]-7-methylindol-1-yl]acetic acid Chemical compound C1=C(Cl)C(OC)=CC(C2=C(SC(NC(=O)C=3N(C4=C(C)C=CC=C4C=3)CC(O)=O)=N2)CCC2CCCCC2)=C1OC MFWRPGPURWSDCK-UHFFFAOYSA-N 0.000 claims description 2
• SXINCQCTZSUDRH-UHFFFAOYSA-N 2-[4,5-dichloro-2-[[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-cyclohexylethyl)-1,3-thiazol-2-yl]carbamoyl]indol-1-yl]acetic acid Chemical compound C1=C(Cl)C(OC)=CC(C2=C(SC(NC(=O)C=3N(C4=CC=C(Cl)C(Cl)=C4C=3)CC(O)=O)=N2)CCC2CCCCC2)=C1OC SXINCQCTZSUDRH-UHFFFAOYSA-N 0.000 claims description 2
• NZNSWXRZLJRSGW-UHFFFAOYSA-N 2-[5,7-dichloro-2-[[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-cyclohexylethyl)-1,3-thiazol-2-yl]carbamoyl]indol-1-yl]acetic acid Chemical compound C1=C(Cl)C(OC)=CC(C2=C(SC(NC(=O)C=3N(C4=C(Cl)C=C(Cl)C=C4C=3)CC(O)=O)=N2)CCC2CCCCC2)=C1OC NZNSWXRZLJRSGW-UHFFFAOYSA-N 0.000 claims description 2
• CUUMWIRAPXOFQO-UHFFFAOYSA-N 2-[5-chloro-2-[[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-cyclohexylethyl)-1,3-thiazol-2-yl]carbamoyl]-4-methylindol-1-yl]acetic acid Chemical compound C1=C(Cl)C(OC)=CC(C2=C(SC(NC(=O)C=3N(C4=CC=C(Cl)C(C)=C4C=3)CC(O)=O)=N2)CCC2CCCCC2)=C1OC CUUMWIRAPXOFQO-UHFFFAOYSA-N 0.000 claims description 2
• YJYRFYGFCXFFOQ-UHFFFAOYSA-N 2-[5-chloro-2-[[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-cyclohexylethyl)-1,3-thiazol-2-yl]carbamoyl]-7-(trifluoromethyl)indol-1-yl]acetic acid Chemical compound C1=C(Cl)C(OC)=CC(C2=C(SC(NC(=O)C=3N(C4=C(C=C(Cl)C=C4C=3)C(F)(F)F)CC(O)=O)=N2)CCC2CCCCC2)=C1OC YJYRFYGFCXFFOQ-UHFFFAOYSA-N 0.000 claims description 2
• VBRYWAAVGGWBTI-UHFFFAOYSA-N 2-[5-chloro-2-[[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-cyclohexylethyl)-1,3-thiazol-2-yl]carbamoyl]indol-1-yl]acetic acid Chemical compound C1=C(Cl)C(OC)=CC(C2=C(SC(NC(=O)C=3N(C4=CC=C(Cl)C=C4C=3)CC(O)=O)=N2)CCC2CCCCC2)=C1OC VBRYWAAVGGWBTI-UHFFFAOYSA-N 0.000 claims description 2
• ZGZDMSJKGUFBMR-UHFFFAOYSA-N 2-[7-chloro-2-[[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-cyclohexylethyl)-1,3-thiazol-2-yl]carbamoyl]-5-methylindol-1-yl]acetic acid Chemical compound C1=C(Cl)C(OC)=CC(C2=C(SC(NC(=O)C=3N(C4=C(Cl)C=C(C)C=C4C=3)CC(O)=O)=N2)CCC2CCCCC2)=C1OC ZGZDMSJKGUFBMR-UHFFFAOYSA-N 0.000 claims description 2
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
• 208000030499 combat disease Diseases 0.000 claims description 2
• 238000010511 deprotection reaction Methods 0.000 claims description 2
• 210000005095 gastrointestinal system Anatomy 0.000 claims description 2
• 150000004677 hydrates Chemical class 0.000 claims description 2
• 208000002551 irritable bowel syndrome Diseases 0.000 claims description 2
• UCFFGYASXIPWPD-UHFFFAOYSA-N methyl hypochlorite Chemical compound COCl UCFFGYASXIPWPD-UHFFFAOYSA-N 0.000 claims description 2
• 230000000638 stimulation Effects 0.000 claims description 2
• KNMAHODWYDYBNW-UHFFFAOYSA-N 2-[2-[[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-cyclohexylethyl)-1,3-thiazol-2-yl]carbamoyl]-4,5-dimethoxyindol-1-yl]acetic acid Chemical compound C1=C(Cl)C(OC)=CC(C2=C(SC(NC(=O)C=3N(C4=CC=C(OC)C(OC)=C4C=3)CC(O)=O)=N2)CCC2CCCCC2)=C1OC KNMAHODWYDYBNW-UHFFFAOYSA-N 0.000 claims 1
• JBGFIZSFYCETDI-UHFFFAOYSA-N 2-[2-[[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-cyclohexylethyl)-1,3-thiazol-2-yl]carbamoyl]-4,7-dimethoxyindol-1-yl]acetic acid Chemical compound C1=C(Cl)C(OC)=CC(C2=C(SC(NC(=O)C=3N(C4=C(OC)C=CC(OC)=C4C=3)CC(O)=O)=N2)CCC2CCCCC2)=C1OC JBGFIZSFYCETDI-UHFFFAOYSA-N 0.000 claims 1
• PQAPEXJKQQHFKZ-UHFFFAOYSA-N 2-[2-[[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-cyclohexylethyl)-1,3-thiazol-2-yl]carbamoyl]-4,7-dimethylindol-1-yl]acetic acid Chemical compound C1=C(Cl)C(OC)=CC(C2=C(SC(NC(=O)C=3N(C4=C(C)C=CC(C)=C4C=3)CC(O)=O)=N2)CCC2CCCCC2)=C1OC PQAPEXJKQQHFKZ-UHFFFAOYSA-N 0.000 claims 1
• IXSKIUYWZMHWPS-UHFFFAOYSA-N 2-[2-[[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-cyclohexylethyl)-1,3-thiazol-2-yl]carbamoyl]-4-methoxy-7-methylindol-1-yl]acetic acid Chemical compound C1=C(Cl)C(OC)=CC(C2=C(SC(NC(=O)C=3N(C4=C(C)C=CC(OC)=C4C=3)CC(O)=O)=N2)CCC2CCCCC2)=C1OC IXSKIUYWZMHWPS-UHFFFAOYSA-N 0.000 claims 1
• AXDWNJKERZGTNC-UHFFFAOYSA-N 2-[2-[[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-cyclohexylethyl)-1,3-thiazol-2-yl]carbamoyl]-7-methoxyindol-1-yl]acetic acid Chemical compound C1=C(Cl)C(OC)=CC(C2=C(SC(NC(=O)C=3N(C4=C(OC)C=CC=C4C=3)CC(O)=O)=N2)CCC2CCCCC2)=C1OC AXDWNJKERZGTNC-UHFFFAOYSA-N 0.000 claims 1
• 125000001309 chloro group Chemical group Cl* 0.000 claims 1
• 238000002955 isolation Methods 0.000 claims 1
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 174
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 142
• 239000000243 solution Substances 0.000 description 132
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 115
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 113
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 112
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• 206010012812 Diffuse cutaneous mastocytosis Diseases 0.000 description 81
• 239000000047 product Substances 0.000 description 76
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• 235000019439 ethyl acetate Nutrition 0.000 description 68
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 58
• IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 58
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 58
• 239000000377 silicon dioxide Substances 0.000 description 55
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 48
• 238000003756 stirring Methods 0.000 description 46
• OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 44
• 239000002244 precipitate Substances 0.000 description 44
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• 239000013067 intermediate product Substances 0.000 description 37
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• ZUTGOBZDHFXKHW-UHFFFAOYSA-N tert-butyl n-(6-methoxy-4-methylpyridin-3-yl)carbamate Chemical compound COC1=CC(C)=C(NC(=O)OC(C)(C)C)C=N1 ZUTGOBZDHFXKHW-UHFFFAOYSA-N 0.000 description 1
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• 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
• 238000012360 testing method Methods 0.000 description 1
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• 150000004684 trihydrates Chemical class 0.000 description 1
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