EP1047685A1 - Beta,gamma-lactones substituees - Google Patents
Beta,gamma-lactones substitueesInfo
- Publication number
- EP1047685A1 EP1047685A1 EP99903604A EP99903604A EP1047685A1 EP 1047685 A1 EP1047685 A1 EP 1047685A1 EP 99903604 A EP99903604 A EP 99903604A EP 99903604 A EP99903604 A EP 99903604A EP 1047685 A1 EP1047685 A1 EP 1047685A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- compounds
- document
- general formula
- date
- formula
- Prior art date
- 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.)
- Ceased
Links
- 150000002596 lactones Chemical class 0.000 title abstract 3
- 238000000034 method Methods 0.000 claims abstract description 17
- 206010008120 Cerebral ischaemia Diseases 0.000 claims abstract description 5
- 201000010099 disease Diseases 0.000 claims abstract description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 5
- 208000007101 Muscle Cramp Diseases 0.000 claims abstract description 4
- 230000000848 glutamatergic effect Effects 0.000 claims abstract description 4
- 230000001404 mediated effect Effects 0.000 claims abstract description 4
- 230000036407 pain Effects 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 63
- 239000001257 hydrogen Substances 0.000 claims description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims description 15
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 13
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical group C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 11
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 8
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 8
- 229910052794 bromium Inorganic materials 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 8
- 230000002265 prevention Effects 0.000 claims description 7
- 125000004122 cyclic group Chemical group 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical group 0.000 claims description 6
- 125000000623 heterocyclic group Chemical group 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 5
- 241001465754 Metazoa Species 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 239000012442 inert solvent Substances 0.000 claims description 5
- 125000001624 naphthyl group Chemical group 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
- 125000006729 (C2-C5) alkenyl group Chemical group 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
- 125000003342 alkenyl group Chemical group 0.000 claims description 4
- 210000003169 central nervous system Anatomy 0.000 claims description 4
- 206010008118 cerebral infarction Diseases 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 230000006378 damage Effects 0.000 claims description 4
- 239000011737 fluorine Substances 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 201000006474 Brain Ischemia Diseases 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 2
- FSYOYGVXDPTVCA-UHFFFAOYSA-N 3-(naphthalen-2-ylmethyl)-3,3a,6,6a-tetrahydrocyclopenta[b]furan-2-one Chemical compound C1=CC=CC2=CC(CC3C4C=CCC4OC3=O)=CC=C21 FSYOYGVXDPTVCA-UHFFFAOYSA-N 0.000 claims description 2
- 208000030886 Traumatic Brain injury Diseases 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- 231100000252 nontoxic Toxicity 0.000 claims description 2
- 230000003000 nontoxic effect Effects 0.000 claims description 2
- UWGMZXGLUFIZKQ-UHFFFAOYSA-N 3-(naphthalen-2-ylmethyl)-3,3a,4,6a-tetrahydrocyclopenta[b]furan-2-one Chemical compound C1=CC=CC2=CC(CC3C4CC=CC4OC3=O)=CC=C21 UWGMZXGLUFIZKQ-UHFFFAOYSA-N 0.000 claims 1
- 229910000792 Monel Inorganic materials 0.000 claims 1
- 150000001768 cations Chemical class 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 238000006257 total synthesis reaction Methods 0.000 claims 1
- 230000001960 triggered effect Effects 0.000 claims 1
- 230000002490 cerebral effect Effects 0.000 abstract description 2
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- 230000008733 trauma Effects 0.000 abstract 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 54
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- 239000000243 solution Substances 0.000 description 26
- 239000000203 mixture Substances 0.000 description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 14
- -1 alkali metal salts Chemical class 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 8
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- RUHJZSZTSCSTCC-UHFFFAOYSA-N 2-(bromomethyl)naphthalene Chemical compound C1=CC=CC2=CC(CBr)=CC=C21 RUHJZSZTSCSTCC-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 210000004556 brain Anatomy 0.000 description 6
- 239000003921 oil Substances 0.000 description 6
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 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 description 5
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 239000012230 colorless oil Substances 0.000 description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 4
- 206010061216 Infarction Diseases 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 102000016193 Metabotropic glutamate receptors Human genes 0.000 description 4
- 108010010914 Metabotropic glutamate receptors Proteins 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 230000007574 infarction Effects 0.000 description 4
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 4
- 230000003961 neuronal insult Effects 0.000 description 4
- 150000003254 radicals Chemical class 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 102000018899 Glutamate Receptors Human genes 0.000 description 3
- 108010027915 Glutamate Receptors Proteins 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000011097 chromatography purification Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
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- 102000005962 receptors Human genes 0.000 description 3
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- 229910052708 sodium Inorganic materials 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- DICZUTMNXOMHQD-UHFFFAOYSA-N 3,3a,4,5,6,6a-hexahydrocyclopenta[b]furan-2-one Chemical compound C1CCC2OC(=O)CC21 DICZUTMNXOMHQD-UHFFFAOYSA-N 0.000 description 2
- AQKZNTBBGPQPBG-UHFFFAOYSA-N 3a,4,5,6,7,7a-hexahydro-3h-1-benzofuran-2-one Chemical compound C1CCCC2OC(=O)CC21 AQKZNTBBGPQPBG-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
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- 208000002667 Subdural Hematoma Diseases 0.000 description 1
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- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 201000004810 Vascular dementia Diseases 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000003929 acidic solution Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 1
- 230000003444 anaesthetic effect Effects 0.000 description 1
- 230000007953 anoxia Effects 0.000 description 1
- 230000003556 anti-epileptic effect Effects 0.000 description 1
- 230000002253 anti-ischaemic effect Effects 0.000 description 1
- 150000005840 aryl radicals Chemical class 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- 208000006752 brain edema Diseases 0.000 description 1
- 125000005997 bromomethyl group Chemical group 0.000 description 1
- RHDGNLCLDBVESU-UHFFFAOYSA-N but-3-en-4-olide Chemical compound O=C1CC=CO1 RHDGNLCLDBVESU-UHFFFAOYSA-N 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 210000001638 cerebellum Anatomy 0.000 description 1
- 210000001627 cerebral artery Anatomy 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- JMRYOSQOYJBDOI-UHFFFAOYSA-N dilithium;di(propan-2-yl)azanide Chemical compound [Li+].CC(C)[N-]C(C)C.CC(C)N([Li])C(C)C JMRYOSQOYJBDOI-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- UZZWBUYVTBPQIV-UHFFFAOYSA-N dme dimethoxyethane Chemical compound COCCOC.COCCOC UZZWBUYVTBPQIV-UHFFFAOYSA-N 0.000 description 1
- 238000009297 electrocoagulation Methods 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 208000020658 intracerebral hemorrhage Diseases 0.000 description 1
- 208000001286 intracranial vasospasm Diseases 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 229960002725 isoflurane Drugs 0.000 description 1
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 159000000003 magnesium salts Chemical class 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
- 239000011976 maleic acid Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229940126601 medicinal product Drugs 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 230000000897 modulatory effect Effects 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 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 1
- YZMHQCWXYHARLS-UHFFFAOYSA-N naphthalene-1,2-disulfonic acid Chemical compound C1=CC=CC2=C(S(O)(=O)=O)C(S(=O)(=O)O)=CC=C21 YZMHQCWXYHARLS-UHFFFAOYSA-N 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 230000009689 neuronal regeneration Effects 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 150000002902 organometallic compounds Chemical class 0.000 description 1
- 229910000489 osmium tetroxide Inorganic materials 0.000 description 1
- 239000012285 osmium tetroxide Substances 0.000 description 1
- 230000004963 pathophysiological condition Effects 0.000 description 1
- 208000033300 perinatal asphyxia Diseases 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 210000001428 peripheral nervous system Anatomy 0.000 description 1
- NHKJPPKXDNZFBJ-UHFFFAOYSA-N phenyllithium Chemical compound [Li]C1=CC=CC=C1 NHKJPPKXDNZFBJ-UHFFFAOYSA-N 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 description 1
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000036280 sedation Effects 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 208000020431 spinal cord injury Diseases 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 238000011477 surgical intervention Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 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
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered
- C07D307/935—Not further condensed cyclopenta [b] furans or hydrogenated cyclopenta [b] furans
-
- 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
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Definitions
- R 3 represents hydrogen, (C, -C 6 ) alkyl or (C 2 -C 6 ) alkenyl
- R 4 represents a radical of the formula -CH -R 5 ,
- R 5 is aryl having 6 to 10 carbon atoms or benzothiophene bonded via the heterocycle, the ring systems optionally being substituted one to more times, identically or differently, by halogen or (C, -C 6 ) -alkyl,
- R 3 represents (C 2 -C 6 ) alkenyl
- R 4 represents hydrogen
- the compounds according to the invention can exist in stereoisomeric forms which either behave like image and mirror image (enantiomers) or do not behave like image and mirror image (diastereomers).
- the invention relates to both the enantiomers or diastereomers or their respective mixtures. Like the diastereomers, the racemic forms can be separated into the stereoisomerically uniform constituents in a known manner.
- Physiologically acceptable salts of the compounds according to the invention can be salts of the substances according to the invention with mineral acids, carboxylic acids or sulfonic acids.
- Propionic acid lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.
- Salts which can be mentioned are salts with customary bases, such as, for example, alkali metal salts (e.g. sodium or potassium salts), alkaline earth metal salts (e.g. calcium or
- Amines such as, for example, diethylamine, triethylamine, ethyldiisopropylamine, procaine,
- Aryl generally represents an aromatic radical having 6 to 10 carbon atoms.
- Preferred aryl radicals are phenyl and naphthyl.
- (CC f i) -alkyl in the context of the invention represents a straight-chain or branched alkyl radical having 1 to 6 carbon atoms.
- a straight-chain or branched alkyl radical having 1 to 4 carbon atoms is preferred. Examples include: methyl, ethyl, propyl, isopropyl, tert-butyl, n-pentyl and n-hexyl.
- (C 2 -C 6 ) alkenyl represents a straight-chain or branched alkenyl radical having 2 to 6 carbon atoms.
- a straight-chain or branched alkenyl radical having 3 to 5 carbon atoms is preferred. Examples include: vinyl, allyl, isopropenyl, but-3-en-1-yl, n-pent-3-en-1-yl and n-hex-3-en-1-yi.
- R 3 represents hydrogen or (C 2 -C 5 ) alkenyl
- R 4 represents a radical of the formula -CH 2 -R 5 ,
- R 5 denotes phenyl, naphthyl or benzothiophene bonded via the heterocycle, the ring systems optionally being substituted one to more times, identically or differently, by fluorine, chlorine, bromine or (C 1 -C 4 ) -alkyl,
- R 3 represents (C 2 -C 5 ) alkenyl
- R 4 represents hydrogen
- R 3 represents hydrogen or (C 3 -C 5 ) alkenyl
- R 4 represents a radical of the formula -CH 2 -R 5 ,
- R 5 is phenyl, naphthyl or benzothiophene bonded via the heterocycle, the ring systems optionally being one to two times, identical or different, by fluorine, chlorine, bromine or (C, -
- R 3 represents (C 3 -C 5 ) alkenyl
- R 4 represents hydrogen -
- the compounds of the general formula (I) according to the invention can be prepared by:
- R 4 has the meaning given above
- A represents halogen, preferably bromine
- R, R and R have the meaning given above, - -
- R 3 has the meaning of R 3 given above, but does not represent hydrogen
- D represents halogen, preferably bromine
- Suitable solvents are all inert solvents that do not change under the reaction conditions. These preferably include ethers such as diethyl ether,
- Tetrahydrofuran is particularly preferred.
- bases are suitable as bases. These preferably include alkali metal hydroxides such as sodium or potassium hydroxide, or alkali metal carbonates such as sodium or potassium carbonate, or sodium or potassium methoxide, or sodium or potassium ethanolate or potassium tert-butoxide, or amides such as sodium amide, lithium bis (trimethylsilyl) amide, lithium diisopropylamide , or organometallic compounds such as butyllithium or phenyllithium. Lithium diisopropylamide and lithium bis (trimethylsilyl) amide are preferred.
- the base is used in an amount of 1 to 5, preferably 1 to 2, mol, based on 1 mol of the compounds of the general formulas (III) and (IV).
- the reaction generally takes place in a temperature range from -78 ° C to
- Reflux temperature preferably from -78 ° C to + 20 ° C.
- the reaction can be carried out at normal, elevated or reduced pressure (e.g. from 0.5 to 5 bar). Generally one works at normal pressure.
- the compounds of the general formula (I) according to the invention are suitable for use as medicaments in the treatment of humans and animals.
- the compounds of the general formula (I) according to the invention are suitable for modulating metabotropic glutamate receptors and therefore influence the glutamatergic neurotransmitter system.
- a modulator of the metabotropic glutamate receptor in the sense of the invention is an agonist or antagonist of this receptor.
- the compounds according to the invention are particularly suitable as modulators of the metabotropic glutamate receptor of subtype 1, very particularly as antagonists of this receptor subtype.
- the compounds of the invention can be based on their pharmacological
- the compounds according to the invention are also suitable for the therapy of primary and / or secondary pathological conditions in the brain, for example during or after cerebral vasospasm, hypoxia and / or anoxia of a genesis not mentioned above, perinatal asphyxia, autoimmune diseases, metabolic and organ diseases associated with Damage to the brain can go hand in hand as well as damage to the brain due to primary brain diseases, for example
- Seizures and atherosclerotic and / or atherosclerotic changes For the treatment of chronic or psychiatric conditions such as depression, neurodegenerative diseases such as Alzheimer's, Parkinson's or Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, neurodegeneration due to acute and / or chronic viral or bacterial infections and multi-infarct dementia.
- chronic or psychiatric conditions such as depression
- neurodegenerative diseases such as Alzheimer's, Parkinson's or Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis, neurodegeneration due to acute and / or chronic viral or bacterial infections and multi-infarct dementia.
- the compounds can be used as medicines for the prevention and / or treatment of dementias of different origins, brain disorders in old age, memory disorders, spinal cord injuries, painful conditions, anxiety states of different origins, drug-related Parkinson's syndrome, psychoses (such as schizophrenia), cerebral edema, neuronal damage after hypoglycemia, vomiting, nausea, obesity, addiction and withdrawal symptoms, CNS-mediated cramps, sedation and movement disorders.
- the compounds can also be used to promote neuronal regeneration in the post-acute phase of cerebral injuries or chronic diseases of the nervous system.
- They are preferably used as medicinal products for the prevention and / or treatment of cerebral ischaemia, skull / brain trauma, pain or CNS-mediated cramps (such as epilepsy).
- the modulation of substances on the metabotropic glutamate receptor can be checked on primary cerebellar cell cultures from the cerebellum. Electrophysiological measurements on these cell cultures in the "cell attached" mode show that L-type Ca 2+ channels in this preparation are activated by mGluRl glutamate receptors (J. Neurosci. 1995, 15, 135), whereas they by group II receptors can be blocked (J. Neurosci. 1994, 14, 7067).
- the experimental arrangement can be used to control the modulatory effect of pharmacological test substances on glutamate receptors Subtype DNA take place (WO 92/10583).
- test models can be used to demonstrate the anti-ischemic activity of the compounds in vivo.
- the cerebral artery is unilaterally dissected using electrocoagulation and this and its secondary branches are irreversibly closed.
- a cerebral infarction develops.
- the animal's body temperature is kept at 37 ° C.
- the anesthetic has subsided, the animals are released back into their cages.
- the substance- Application takes place according to different time schedules and via different application routes (ivip) after the occlusion.
- the infarct size is determined after 7 days. For this purpose, the brain is removed, histologically processed and the infarct volume determined using a computer-aided evaluation system.
- the animals are injected with subdural autologous blood under anesthesia.
- An infarction forms under the hematoma.
- the substance is administered according to different time schedules and via different application routes (i.v. i.p.).
- the infarct size is determined as described in the model of permanent focal ischemia in the rat (MCA-O).
- the anti-epileptic effect can be tested according to the method described in NeuroReport 1996, 7, 1469-1474.
- the suitability of the compounds according to the invention for the treatment of schizophrenia can be determined according to the methods described in Science 1998, 281, 1349-1352 and Eur. J. Pharmacol. 1996, 316, 129-136 methods can be determined.
- the present invention also includes pharmaceutical preparations which, in addition to inert, non-toxic, pharmaceutically suitable auxiliaries and excipients, contain one or more compounds of the general formulas (I), (Ia) and (Ib), or which consist of one or more active ingredients of the Formulas (I), (Ia) and (Ib) exist, and processes for the preparation of these preparations.
- the active compounds of the formulas (I), (Ia) and (Ib) should be present in these preparations in a concentration of 0.1 to 99.5% by weight, preferably 0.5 to 95% by weight, of the total mixture . - -
- the pharmaceutical preparations can also contain other active pharmaceutical ingredients.
- the pharmaceutical preparations listed above can be prepared in a customary manner by known methods, for example using the excipient or excipients.
- the active compound or formulas (I), (Ia) and (Ib) in total amounts from about 0.01 to about 100 mg / kg, preferably in total amounts from about 1 mg / kg to 50 mg / kg body weight per 24
- Example 2 fraction 1, diastereomer A
- example 3 fraction 2, diasteromer B
- Example 4 In analogy to the procedure of Example 4, the title compound is made from 0.55 g (3.3 mmol) of the compound from Example 3, 4 ml of 1 molar lithium bis (trimethylsilyl) amide solution in THF and 0.73 g (3.3 mmol) of 2- ( Bromomethyl) -naphthalene prepared in 15 ml THF. Yield: 823 mg (81.2%) of a colorless oil. - -
- Example 9 (Fraction 2)
- Example 10 (Fraction 3)
- Example 11 (Fraction 4)
- the compounds listed in Table 1 below were prepared in analogy to the instructions of Examples 1-7.
- Example 3 In analogy to the procedure of Example 3, the title compound was obtained from 0.79 g (3 mmol) of the compound from Example 7, 3 ml of 1 molar lithium bis (trimethylsilyl) amide solution in THF and 0.36 g (3 mmol) Allyl bromide made in 10 ml THF.
- the chromatographic purification was carried out with a mixture of dichloromethane and petroleum ether (40-60) in a ratio of 100: 4. Yield: 684 mg (74.8%) of a pale yellow oil; Diastereomeric purity:> 99% de (HPLC).
- HPLC Examples 22, 23, 24 and 25.
- Example 4 In analogy to the procedure of Example 4, the title compound was made from 0.23 g (1.38 mmol) of the compound from Example 16, 1.4 ml of 1 molar lithium bis (trimethylsilyl) amide solution in THF and 0.3 g (1.38 mmol) 2 -Bromomethylnaphthalene made in 5 ml THF.
- R 3 represents hydrogen, (C, -C 6 ) alkyl or (C 2 -C 6 ) alkenyl
- R 4 represents a radical of the formula -CH 2 -R 5 ,
- R 5 denotes aryl having 6 to 10 carbon atoms or benzothiophene bonded via the heterocycle, the ring systems optionally being substituted one to more times, identically or differently, by halogen or (C, -C 6 ) alkyl,
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pain & Pain Management (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Furan Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
L'invention concerne de nouvelles beta , gamma -lactones annelées substituées, leurs procédés de production et leur utilisation pour prévenir et/ou traiter des maladies provoquées par une hyperfonction ou une hypofonction du système glutamatergène, notamment les ischémies cérébrales, les traumatismes crâniens/cérébraux, les douleurs ou les crampes induites par le SNC.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19801647A DE19801647A1 (de) | 1998-01-17 | 1998-01-17 | Substituierte beta,gamma-annellierte Lactone |
DE19801647 | 1998-01-17 | ||
PCT/EP1999/000022 WO1999036417A1 (fr) | 1998-01-17 | 1999-01-05 | β,η-LACTONES SUBSTITUEES |
Publications (1)
Publication Number | Publication Date |
---|---|
EP1047685A1 true EP1047685A1 (fr) | 2000-11-02 |
Family
ID=7854913
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP99903604A Ceased EP1047685A1 (fr) | 1998-01-17 | 1999-01-05 | Beta,gamma-lactones substituees |
Country Status (6)
Country | Link |
---|---|
US (1) | US6433004B1 (fr) |
EP (1) | EP1047685A1 (fr) |
JP (1) | JP2002509145A (fr) |
AU (1) | AU2419899A (fr) |
DE (1) | DE19801647A1 (fr) |
WO (1) | WO1999036417A1 (fr) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1408959A1 (fr) * | 2000-07-03 | 2004-04-21 | Institut für Biotechnologie und Wirkstoff-Forschung e.V. | Utilisation de lactone de galielle |
TWI375121B (en) * | 2004-06-28 | 2012-10-21 | Fujifilm Corp | Photosensitive composition and method for forming pattern using the same |
HU226863B1 (en) * | 2005-12-09 | 2009-12-28 | Chinoin Gyogyszer Es Vegyeszet | Process for separation of optical isomers of "corey-lactone" by liquid chromatography |
Family Cites Families (17)
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JPS49110659A (fr) * | 1973-03-06 | 1974-10-22 | ||
NZ240921A (en) | 1990-12-12 | 1994-06-27 | Zymogenetics Inc | G protein coupled glutamate receptor (neurotransmitters), recombinant production |
GB9324872D0 (en) | 1993-12-03 | 1994-01-19 | Univ Pasteur | Pharmaceutical compounds |
US5576323A (en) | 1993-12-03 | 1996-11-19 | Eli Lilly And Company | Excitatory amino acid receptor antagonists |
GB9325360D0 (en) | 1993-12-10 | 1994-02-16 | Univ Bristol | Organic compounds |
GB9325368D0 (en) | 1993-12-10 | 1994-02-16 | Univ Bristol | Organic compounds |
BR9507073A (pt) | 1994-03-14 | 1997-09-09 | Novo Nordisk As | Composto processos para preparar o mesmo e para tratar uma doença no sistema nervoso central composiçao farmacêutica e uso do composto |
AU3414295A (en) | 1994-08-19 | 1996-03-14 | Nps Pharmaceuticals, Inc. | Methods and compounds active at metabotropic glutamate receptors useful for treatment of neurological disorders and diseases |
DE69513832T2 (de) * | 1994-09-08 | 2000-04-13 | Eli Lilly And Co., Indianapolis | Exzitatorische aminosäure-rezeptor-antagonisten |
JP3993651B2 (ja) | 1994-10-21 | 2007-10-17 | アスビオファーマ株式会社 | シクロプロパクロメンカルボン酸誘導体 |
WO1996015099A1 (fr) | 1994-11-09 | 1996-05-23 | Novo Nordisk A/S | Composes heterocycliques, preparation et utilisation de ces composes |
US5701168A (en) | 1995-06-29 | 1997-12-23 | Bell Communications Research, Inc. | Inverse twisted and super-twisted nematic liquid crystal device |
US5945417A (en) | 1995-07-31 | 1999-08-31 | Novo Nordisk | Heterocyclic compounds, their preparation and use |
AU6514296A (en) | 1995-07-31 | 1997-02-26 | Novo Nordisk A/S | Heterocyclic compounds, their preparation and use |
US5688826A (en) | 1995-11-16 | 1997-11-18 | Eli Lilly And Company | Excitatory amino acid derivatives |
GB9605429D0 (en) | 1995-11-16 | 1996-05-15 | Lilly Co Eli | Excitatory amino acid receptor antagonists |
TR199800877T2 (xx) * | 1995-11-16 | 1998-09-21 | Eli Lilly And Company | Uyar�c� amino asit t�revleri. |
-
1998
- 1998-01-17 DE DE19801647A patent/DE19801647A1/de not_active Withdrawn
-
1999
- 1999-01-05 EP EP99903604A patent/EP1047685A1/fr not_active Ceased
- 1999-01-05 US US09/600,430 patent/US6433004B1/en not_active Expired - Fee Related
- 1999-01-05 JP JP2000540133A patent/JP2002509145A/ja active Pending
- 1999-01-05 AU AU24198/99A patent/AU2419899A/en not_active Abandoned
- 1999-01-05 WO PCT/EP1999/000022 patent/WO1999036417A1/fr not_active Application Discontinuation
Non-Patent Citations (1)
Title |
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See references of WO9936417A1 * |
Also Published As
Publication number | Publication date |
---|---|
AU2419899A (en) | 1999-08-02 |
US6433004B1 (en) | 2002-08-13 |
WO1999036417A1 (fr) | 1999-07-22 |
JP2002509145A (ja) | 2002-03-26 |
DE19801647A1 (de) | 1999-07-22 |
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