WO1998003469A1 - Derives d'esters d'acide benzoylpropionique - Google Patents
Derives d'esters d'acide benzoylpropionique Download PDFInfo
- Publication number
- WO1998003469A1 WO1998003469A1 PCT/EP1997/003588 EP9703588W WO9803469A1 WO 1998003469 A1 WO1998003469 A1 WO 1998003469A1 EP 9703588 W EP9703588 W EP 9703588W WO 9803469 A1 WO9803469 A1 WO 9803469A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- formula
- oxo
- dichlorophenyl
- amino
- Prior art date
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- -1 Benzoylpropionic acid ester Chemical class 0.000 title claims abstract description 16
- 150000001875 compounds Chemical class 0.000 claims abstract description 74
- 150000003839 salts Chemical class 0.000 claims abstract description 15
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 5
- 239000002532 enzyme inhibitor Substances 0.000 claims abstract description 4
- 238000004519 manufacturing process Methods 0.000 claims abstract description 4
- 230000004770 neurodegeneration Effects 0.000 claims abstract 3
- 208000015122 neurodegenerative disease Diseases 0.000 claims abstract 3
- 238000000034 method Methods 0.000 claims description 19
- 239000000203 mixture Substances 0.000 claims description 16
- 239000002253 acid Substances 0.000 claims description 7
- 208000030507 AIDS Diseases 0.000 claims description 6
- 206010012289 Dementia Diseases 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 208000012902 Nervous system disease Diseases 0.000 claims description 4
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 208000024827 Alzheimer disease Diseases 0.000 claims description 3
- 208000002381 Brain Hypoxia Diseases 0.000 claims description 3
- 201000006474 Brain Ischemia Diseases 0.000 claims description 3
- 206010008120 Cerebral ischaemia Diseases 0.000 claims description 3
- 206010008748 Chorea Diseases 0.000 claims description 3
- 241000124008 Mammalia Species 0.000 claims description 3
- 208000018737 Parkinson disease Diseases 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 206010008118 cerebral infarction Diseases 0.000 claims description 3
- 208000012601 choreatic disease Diseases 0.000 claims description 3
- 206010015037 epilepsy Diseases 0.000 claims description 3
- 241001465754 Metazoa Species 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims 1
- 229940122439 Hydroxylase inhibitor Drugs 0.000 claims 1
- BZOWACODROCYIR-UHFFFAOYSA-N NC(CC(=O)c1ccc(Cl)c(Cl)c1)C(=O)OCc1ccccc1 Chemical compound NC(CC(=O)c1ccc(Cl)c(Cl)c1)C(=O)OCc1ccccc1 BZOWACODROCYIR-UHFFFAOYSA-N 0.000 claims 1
- 239000004480 active ingredient Substances 0.000 claims 1
- 229940125532 enzyme inhibitor Drugs 0.000 claims 1
- KZNXAEIPUOFSLW-UHFFFAOYSA-N ethyl 2-amino-4-(3,4-dichlorophenyl)-4-oxobutanoate Chemical compound CCOC(=O)C(N)CC(=O)C1=CC=C(Cl)C(Cl)=C1 KZNXAEIPUOFSLW-UHFFFAOYSA-N 0.000 claims 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- YTPAAFAUNSLSJY-UHFFFAOYSA-N methyl 2-amino-4-(3,4-dichlorophenyl)-4-oxobutanoate Chemical compound COC(=O)C(N)CC(=O)C1=CC=C(Cl)C(Cl)=C1 YTPAAFAUNSLSJY-UHFFFAOYSA-N 0.000 claims 1
- ZUFWYFGCWGDNFP-UHFFFAOYSA-N propan-2-yl 2-amino-4-(3,4-dichlorophenyl)-4-oxobutanoate Chemical compound CC(C)OC(=O)C(N)CC(=O)C1=CC=C(Cl)C(Cl)=C1 ZUFWYFGCWGDNFP-UHFFFAOYSA-N 0.000 claims 1
- DRVYYIZIWMGMDC-UHFFFAOYSA-N tert-butyl 2-amino-4-(3,4-dichlorophenyl)-4-oxobutanoate Chemical compound CC(C)(C)OC(=O)C(N)CC(=O)C1=CC=C(Cl)C(Cl)=C1 DRVYYIZIWMGMDC-UHFFFAOYSA-N 0.000 claims 1
- 238000002560 therapeutic procedure Methods 0.000 claims 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 1
- 102100037652 Kynurenine 3-monooxygenase Human genes 0.000 abstract 1
- 108010033242 Kynurenine 3-monooxygenase Proteins 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 21
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- 239000000460 chlorine Substances 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 description 6
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- PIJXRNNCIJAUOX-UHFFFAOYSA-N butanoic acid;hydrochloride Chemical compound Cl.CCCC(O)=O PIJXRNNCIJAUOX-UHFFFAOYSA-N 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 4
- 235000001014 amino acid Nutrition 0.000 description 4
- 238000003556 assay Methods 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 238000001802 infusion Methods 0.000 description 4
- 238000004452 microanalysis Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- VNCQTTDYACAVDT-UHFFFAOYSA-N 2-methyl-3-oxo-3-phenylpropanoic acid Chemical class OC(=O)C(C)C(=O)C1=CC=CC=C1 VNCQTTDYACAVDT-UHFFFAOYSA-N 0.000 description 3
- 102000008109 Mixed Function Oxygenases Human genes 0.000 description 3
- 108010074633 Mixed Function Oxygenases Proteins 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000005886 esterification reaction Methods 0.000 description 3
- 150000002431 hydrogen Chemical class 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- GWKOSRIHVSBBIA-REOHCLBHSA-N (3s)-3-aminooxolane-2,5-dione Chemical compound N[C@H]1CC(=O)OC1=O GWKOSRIHVSBBIA-REOHCLBHSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- WADSJYLPJPTMLN-UHFFFAOYSA-N 3-(cycloundecen-1-yl)-1,2-diazacycloundec-2-ene Chemical compound C1CCCCCCCCC=C1C1=NNCCCCCCCC1 WADSJYLPJPTMLN-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- UUIQMZJEGPQKFD-UHFFFAOYSA-N Methyl butyrate Chemical compound CCCC(=O)OC UUIQMZJEGPQKFD-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- HOKKHZGPKSLGJE-GSVOUGTGSA-N N-Methyl-D-aspartic acid Chemical compound CN[C@@H](C(O)=O)CC(O)=O HOKKHZGPKSLGJE-GSVOUGTGSA-N 0.000 description 2
- HOKKHZGPKSLGJE-UHFFFAOYSA-N N-methyl-D-aspartic acid Natural products CNC(C(O)=O)CC(O)=O HOKKHZGPKSLGJE-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 238000005903 acid hydrolysis reaction Methods 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 2
- 150000003840 hydrochlorides Chemical class 0.000 description 2
- 238000005805 hydroxylation reaction Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- WMFOQBRAJBCJND-UHFFFAOYSA-M lithium hydroxide Inorganic materials [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000463 material Substances 0.000 description 2
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- 230000008018 melting Effects 0.000 description 2
- 230000037353 metabolic pathway Effects 0.000 description 2
- 239000002207 metabolite Substances 0.000 description 2
- RUZLIIJDZBWWSA-INIZCTEOSA-N methyl 2-[[(1s)-1-(7-methyl-2-morpholin-4-yl-4-oxopyrido[1,2-a]pyrimidin-9-yl)ethyl]amino]benzoate Chemical group COC(=O)C1=CC=CC=C1N[C@@H](C)C1=CC(C)=CN2C(=O)C=C(N3CCOCC3)N=C12 RUZLIIJDZBWWSA-INIZCTEOSA-N 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 230000002438 mitochondrial effect Effects 0.000 description 2
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 2
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 230000007170 pathology Effects 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 239000012048 reactive intermediate Substances 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 230000005062 synaptic transmission Effects 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
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- QISOBCMNUJQOJU-UHFFFAOYSA-N 4-bromo-1h-pyrazole-5-carboxylic acid Chemical compound OC(=O)C=1NN=CC=1Br QISOBCMNUJQOJU-UHFFFAOYSA-N 0.000 description 1
- PXRKCOCTEMYUEG-UHFFFAOYSA-N 5-aminoisoindole-1,3-dione Chemical compound NC1=CC=C2C(=O)NC(=O)C2=C1 PXRKCOCTEMYUEG-UHFFFAOYSA-N 0.000 description 1
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- 125000000041 C6-C10 aryl group Chemical group 0.000 description 1
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- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
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- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
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- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000002964 excitative effect Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 230000033444 hydroxylation Effects 0.000 description 1
- QWPPOHNGKGFGJK-UHFFFAOYSA-N hypochlorous acid Chemical compound ClO QWPPOHNGKGFGJK-UHFFFAOYSA-N 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 230000000155 isotopic effect Effects 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000011968 lewis acid catalyst Substances 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 101150067960 mmoD gene Proteins 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 230000000626 neurodegenerative effect Effects 0.000 description 1
- 239000004090 neuroprotective agent Substances 0.000 description 1
- 230000000324 neuroprotective effect Effects 0.000 description 1
- 231100000189 neurotoxic Toxicity 0.000 description 1
- 230000002887 neurotoxic effect Effects 0.000 description 1
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 238000011422 pharmacological therapy Methods 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 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
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
- C07C229/36—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Definitions
- the present invention relates to benzoylpropionic acid esters derivatives, to their pharmaceutically acceptable salts, to a process for their preparation and to pharmaceutical compositions comprising them
- each of the groups X and Y is, independently, hydrogen, halogen, trifluoromethyl , hydroxy, C- L -Cg alkyl, benzyl, C 6 -C 10 aryl, -OR', -SR' , -SOR' , -S0 2 R' in which R' is -C 5 alkyl or benzyl , and
- R is hydroxy, ammo, hydroxylamme , -OR', -NHR' , -N(R') 2 or
- the compounds of formula (IA) are, in general, soluble in aqueous vehicles suitable for parenteral administration
- R is C- L -C, alkyl or benzyl, and the pharmaceutically acceptable salts thereof.
- a C-,-C 4 alkyl group may be a branched oi straight chain group, typically methyl, ethyl, isopropyl 01 preferably tert butyl .
- Preferred salts according to the invention are hydrochlorides .
- R x is preferably trifluoromethyl or C ⁇ C ⁇ alkoxy, in particular methoxy, ethoxy or tert-butoxy.
- reaction of a compound of formula (II) with a compound of formula (III) as described under step a) may be carried out according to known methods (see, for example, J.E. Nordlander, J. Org. Chem., 5_Q, 3619-22, 1985 and D.G. Melillo, J. Org. Chem.
- reaction may be performed in the presence of a suitable Lewis acid catalyst, in an inert solvent such as, e.g., dichloromethane or dichloroethane , nitromethane , cyclohexane or heptane, or using an excess of 1 , 2-dichlorobenzene , used in this case as reagent and as solvent; at a temperature ranging from about -5°C to about 60°C; optionally in the presence of a cosolvent such as, for example, nitromethane .
- a suitable Lewis acid may be, e.g., anhydrous aluminium trichoride, anhydrous tin dichloride, titanium tetrachloride or zinc dichloride, typically aluminium trichloride.
- the conversion of a compound of formula (IV) into the compound of formula (V) as described under step b) may be carried out according to known procedures under either acidic or alkaline hydrolytic conditions.
- Alkaline hydrolysis may be performed by an alkali metal hydroxide such as, e.g., lithium, sodium or potassium hydroxide or sodium carbonate, in a suitable solvent such as, e.g., aqueous methanol or ethanol, at a temperature ranging from about 0°C to about 50°C.
- Acidic hydrolysis may be catalysed by an inorganic acid such as, e.g., hydrochloric acid, at a temperature ranging from about 60°C to about 110°C, for a time which may vary from about 4 hours to about 12 hours.
- step c) The conversion of a compound of formula (V) into a compound of formula (I) as described under step c) may be carried out following known procedures.
- a compound of formula (V) can be converted into a compound of formula (I) by heating a compound of formula (V) either as free amino acid or as its inorganic salt, e.g. the hydrochloride, with the corresponding alcohol, e.g. methanol or ethanol, at the presence of a suitable catalyst, e.g. anhydrous hydrochloric acid.
- a compound of formula (V) either as free amino acid or as its inorganic salt, e.g. the hydrochloride
- the corresponding alcohol e.g. methanol or ethanol
- a suitable catalyst e.g. anhydrous hydrochloric acid
- the esterification reaction may be also cai ⁇ ed out by treatment of a compound of formula (IV) with a suitable alkylatmg agent of formula R-X in which R is as defined above, and X is an suitable leaving group such as, e.g a halogen atom, preferably iodine or bromine, or a sul ate ester, m the presence of an inorganic base, e g potassium carbonate or bicarbonate, or in the presence of an organic base, e.g. diazabicycloundecene (DBU) , in a suitable solvent, e.g. dimethylformamide , at a reaction temperature that may range from about 0°C to about 60°C.
- a compound of formula (IV) wherein R_ is tert-butoxy or benzyloxy may preferably be obtained from a compoun ⁇ of formula (V) wherein R_ is different from tert-butoxy or benzyloxy by usual and well known methods of nitrogen protection of amino acids; this compound of formula (IV) may be converted into a compound of formula (VI) as above described .
- a compound of formula (VI) may be converted into a compound of formula (I), for example, by mild basic hydrolysis of the nitrogen protecting group when it is a t ⁇ fluoro- acetyl group, mild acid hydrolysis when it is a tert- butoxycarbonyl group or hydrogenolysis when it is a benzyloxycarbonyl protecting group.
- the compounds of formula (II) and (III) are known compounds or may be obtained by known procedures .
- the compounds of formula (I) are active as kynurenme- 3 - hydroxylase enzyme inhibitors exhibiting a broad spectrum of CNS related activities pertaining to the metabolic pathway of kynurenines leading to the formation of quinolmic acid
- the assay for kynurenme 3 -hydroxylase was based on the enzymatic synthesis of tritiated water during the hydroxylation reaction. Radiolabeled water was quantified following selective adsorption of the isotopic substrate and its metabolite with activated charcoal .
- Capsule each weighing 0.230 g and containing 50 mg of the active substance can be prepared as follows: Composition for 500 capsules:
- a pharmaceutical injectable composition can be manufactured dissolving 50 g of (R,S) -Methyl 2-amino-4 -oxo-4 - (3 ' , 4 ' - dichlorophenyl) butanoate hydrochloride in sterile water (1000 ml) and sealed in 1-5 ml ampoules.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- General Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Psychology (AREA)
- Pain & Pain Management (AREA)
- Heart & Thoracic Surgery (AREA)
- Urology & Nephrology (AREA)
- Cardiology (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Vascular Medicine (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU40096/97A AU4009697A (en) | 1996-07-23 | 1997-07-03 | Benzoylpropionic acid ester derivatives |
EP97937467A EP0915830A1 (fr) | 1996-07-23 | 1997-07-03 | Derives d'esters d'acide benzoylpropionique |
JP10506490A JP2000515143A (ja) | 1996-07-23 | 1997-07-03 | ベンゾイルプロピオン酸エステル誘導体 |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB9615441.4A GB9615441D0 (en) | 1996-07-23 | 1996-07-23 | Benzoylpropionic acid ester derivatives |
GB9615441.4 | 1996-07-23 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1998003469A1 true WO1998003469A1 (fr) | 1998-01-29 |
Family
ID=10797362
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP1997/003588 WO1998003469A1 (fr) | 1996-07-23 | 1997-07-03 | Derives d'esters d'acide benzoylpropionique |
Country Status (8)
Country | Link |
---|---|
EP (1) | EP0915830A1 (fr) |
JP (1) | JP2000515143A (fr) |
AR (1) | AR007946A1 (fr) |
AU (1) | AU4009697A (fr) |
CA (1) | CA2258074A1 (fr) |
GB (1) | GB9615441D0 (fr) |
WO (1) | WO1998003469A1 (fr) |
ZA (1) | ZA976429B (fr) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103554006A (zh) * | 2009-09-11 | 2014-02-05 | 伊文蒂瓦公司 | 吲哚衍生物作为nurr-1激活剂用作治疗帕金森病的药剂的用途 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1995003271A1 (fr) * | 1993-07-23 | 1995-02-02 | Pharmacia S.P.A. | Derives de l'acide 2-amino-4-phenyl-4-oxobutyrique, ayant une activite inhibitrice de la cynureninase et/ou de la cynurenine-3-hydroxylase |
-
1996
- 1996-07-23 GB GBGB9615441.4A patent/GB9615441D0/en active Pending
-
1997
- 1997-07-03 CA CA002258074A patent/CA2258074A1/fr not_active Abandoned
- 1997-07-03 WO PCT/EP1997/003588 patent/WO1998003469A1/fr not_active Application Discontinuation
- 1997-07-03 AU AU40096/97A patent/AU4009697A/en not_active Abandoned
- 1997-07-03 EP EP97937467A patent/EP0915830A1/fr not_active Ceased
- 1997-07-03 JP JP10506490A patent/JP2000515143A/ja not_active Withdrawn
- 1997-07-21 ZA ZA9706429A patent/ZA976429B/xx unknown
- 1997-07-22 AR ARP970103274A patent/AR007946A1/es unknown
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1995003271A1 (fr) * | 1993-07-23 | 1995-02-02 | Pharmacia S.P.A. | Derives de l'acide 2-amino-4-phenyl-4-oxobutyrique, ayant une activite inhibitrice de la cynureninase et/ou de la cynurenine-3-hydroxylase |
Non-Patent Citations (1)
Title |
---|
SPECIALE, CARMELA ET AL: "(R,S)-3,4-dichlorobenzoylalanine (FCE 28833A) causes a large and persistent increase in brain kynurenic acid levels in rats", EUR. J. PHARMACOL. (1996), 315(3), 263-267 CODEN: EJPHAZ;ISSN: 0014-2999, 1996, XP002043986 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103554006A (zh) * | 2009-09-11 | 2014-02-05 | 伊文蒂瓦公司 | 吲哚衍生物作为nurr-1激活剂用作治疗帕金森病的药剂的用途 |
Also Published As
Publication number | Publication date |
---|---|
ZA976429B (en) | 1998-02-18 |
CA2258074A1 (fr) | 1998-01-29 |
GB9615441D0 (en) | 1996-09-04 |
AR007946A1 (es) | 1999-11-24 |
JP2000515143A (ja) | 2000-11-14 |
EP0915830A1 (fr) | 1999-05-19 |
AU4009697A (en) | 1998-02-10 |
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