NO323699B1 - Substituerte oksazolidinoner, fremgangsmate for fremstilling derav og deres anvendelse innenfor feltet blodkoagulasjon - Google Patents

Info

Publication number

NO323699B1

NO323699B1 NO20023043A NO20023043A NO323699B1 NO 323699 B1 NO323699 B1 NO 323699B1 NO 20023043 A NO20023043 A NO 20023043A NO 20023043 A NO20023043 A NO 20023043A NO 323699 B1 NO323699 B1 NO 323699B1

Authority

NO

Norway

Prior art keywords

chloro

oxo

methyl

hplc

thiophenecarboxamide

Prior art date

1999-12-24

Links

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• 238000000034 method Methods 0.000 title claims description 190
• 238000002360 preparation method Methods 0.000 title claims description 36
• IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical class O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 title claims description 16
• 230000023555 blood coagulation Effects 0.000 title description 5
• 150000001875 compounds Chemical class 0.000 claims description 91
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 36
• 239000000460 chlorine Substances 0.000 claims description 28
• 238000006243 chemical reaction Methods 0.000 claims description 27
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 27
• 208000035475 disorder Diseases 0.000 claims description 27
• -1 nitro, amino Chemical group 0.000 claims description 27
• 108010074860 Factor Xa Proteins 0.000 claims description 23
• YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 22
• 229940079593 drug Drugs 0.000 claims description 21
• 239000003814 drug Substances 0.000 claims description 21
• 238000011282 treatment Methods 0.000 claims description 19
• 150000001412 amines Chemical class 0.000 claims description 15
• 150000003839 salts Chemical class 0.000 claims description 15
• 230000015271 coagulation Effects 0.000 claims description 14
• 238000005345 coagulation Methods 0.000 claims description 14
• 238000011321 prophylaxis Methods 0.000 claims description 14
• 230000009424 thromboembolic effect Effects 0.000 claims description 14
• 239000008280 blood Substances 0.000 claims description 13
• 210000004369 blood Anatomy 0.000 claims description 13
• 150000004677 hydrates Chemical class 0.000 claims description 13
• 238000004519 manufacturing process Methods 0.000 claims description 13
• 239000008194 pharmaceutical composition Substances 0.000 claims description 12
• 230000005764 inhibitory process Effects 0.000 claims description 11
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 10
• YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical class ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims description 9
• 229910052739 hydrogen Inorganic materials 0.000 claims description 8
• 239000012442 inert solvent Substances 0.000 claims description 8
• 206010047249 Venous thrombosis Diseases 0.000 claims description 7
• PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims description 7
• 229910052801 chlorine Inorganic materials 0.000 claims description 7
• 239000001257 hydrogen Substances 0.000 claims description 7
• 150000001735 carboxylic acids Chemical class 0.000 claims description 6
• 229910052757 nitrogen Inorganic materials 0.000 claims description 6
• 206010002383 Angina Pectoris Diseases 0.000 claims description 5
• 206010002388 Angina unstable Diseases 0.000 claims description 5
• 206010051055 Deep vein thrombosis Diseases 0.000 claims description 5
• 208000010378 Pulmonary Embolism Diseases 0.000 claims description 5
• 208000006011 Stroke Diseases 0.000 claims description 5
• 208000007814 Unstable Angina Diseases 0.000 claims description 5
• 238000002399 angioplasty Methods 0.000 claims description 5
• 239000012472 biological sample Substances 0.000 claims description 5
• 201000004332 intermediate coronary syndrome Diseases 0.000 claims description 5
• 208000010125 myocardial infarction Diseases 0.000 claims description 5
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 5
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
• 230000008569 process Effects 0.000 claims description 5
• 229940002612 prodrug Drugs 0.000 claims description 5
• 239000000651 prodrug Substances 0.000 claims description 5
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
• 206010038563 Reocclusion Diseases 0.000 claims description 4
• 208000032109 Transient ischaemic attack Diseases 0.000 claims description 4
• 239000003054 catalyst Substances 0.000 claims description 4
• 208000009190 disseminated intravascular coagulation Diseases 0.000 claims description 4
• 238000000338 in vitro Methods 0.000 claims description 4
• 230000002401 inhibitory effect Effects 0.000 claims description 4
• 201000010875 transient cerebral ischemia Diseases 0.000 claims description 4
• 208000024827 Alzheimer disease Diseases 0.000 claims description 3
• 201000001320 Atherosclerosis Diseases 0.000 claims description 3
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 3
• 206010028980 Neoplasm Diseases 0.000 claims description 3
• 230000003213 activating effect Effects 0.000 claims description 3
• 206010003246 arthritis Diseases 0.000 claims description 3
• 201000011510 cancer Diseases 0.000 claims description 3
• 125000000623 heterocyclic group Chemical group 0.000 claims description 3
• 239000007800 oxidant agent Substances 0.000 claims description 3
• 229920006395 saturated elastomer Polymers 0.000 claims description 3
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
• 208000030831 Peripheral arterial occlusive disease Diseases 0.000 claims description 2
• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
• 229910052794 bromium Inorganic materials 0.000 claims description 2
• 150000001244 carboxylic acid anhydrides Chemical class 0.000 claims description 2
• 239000007822 coupling agent Substances 0.000 claims description 2
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
• 239000011737 fluorine Substances 0.000 claims description 2
• 229910052731 fluorine Inorganic materials 0.000 claims description 2
• 125000005842 heteroatom Chemical group 0.000 claims description 2
• 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims description 2
• 229910052717 sulfur Inorganic materials 0.000 claims description 2
• 150000002118 epoxides Chemical class 0.000 claims 1
• 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 187
• 238000004128 high performance liquid chromatography Methods 0.000 description 142
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 114
• 239000000203 mixture Substances 0.000 description 94
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 81
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 77
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 65
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 63
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 58
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 57
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 50
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 48
• 239000000243 solution Substances 0.000 description 48
• 239000000047 product Substances 0.000 description 41
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 39
• 235000019439 ethyl acetate Nutrition 0.000 description 38
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
• 230000002829 reductive effect Effects 0.000 description 27
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 26
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 26
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 22
• 239000011347 resin Substances 0.000 description 20
• 229920005989 resin Polymers 0.000 description 20
• 239000000126 substance Substances 0.000 description 20
• 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 19
• 239000012074 organic phase Substances 0.000 description 19
• 238000012360 testing method Methods 0.000 description 19
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 17
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 16
• BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 16
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 15
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
• 230000015572 biosynthetic process Effects 0.000 description 15
• 239000000741 silica gel Substances 0.000 description 15
• 229910002027 silica gel Inorganic materials 0.000 description 15
• XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 14
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 14
• 239000011541 reaction mixture Substances 0.000 description 14
• 150000003254 radicals Chemical class 0.000 description 13
• 238000004007 reversed phase HPLC Methods 0.000 description 13
• PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 12
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• 239000002904 solvent Substances 0.000 description 11
• 239000007858 starting material Substances 0.000 description 11
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
• 239000003480 eluent Substances 0.000 description 10
• 239000011734 sodium Substances 0.000 description 10
• 238000003786 synthesis reaction Methods 0.000 description 10
• 229930192474 thiophene Natural products 0.000 description 10
• ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 9
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• 235000019253 formic acid Nutrition 0.000 description 8
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 8
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• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 7
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• RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 7
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