IL109111A - HISTORY OF MORPOLIN AND THOMORPOLIN-2 Transformed as GABA-B Antagonists, Preparation and Pharmaceutical Preparations Containing Them - Google Patents
HISTORY OF MORPOLIN AND THOMORPOLIN-2 Transformed as GABA-B Antagonists, Preparation and Pharmaceutical Preparations Containing ThemInfo
- Publication number
- IL109111A IL109111A IL10911194A IL10911194A IL109111A IL 109111 A IL109111 A IL 109111A IL 10911194 A IL10911194 A IL 10911194A IL 10911194 A IL10911194 A IL 10911194A IL 109111 A IL109111 A IL 109111A
- Authority
- IL
- Israel
- Prior art keywords
- compound
- formula
- alkyl
- group
- compounds
- Prior art date
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 17
- 238000002360 preparation method Methods 0.000 title claims description 13
- -1 2-substituted morpholine Chemical class 0.000 title claims description 11
- 150000004886 thiomorpholines Chemical class 0.000 title description 3
- 239000003412 4 aminobutyric acid B receptor blocking agent Substances 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 276
- 238000000034 method Methods 0.000 claims abstract description 34
- 150000003839 salts Chemical class 0.000 claims abstract description 19
- 206010010904 Convulsion Diseases 0.000 claims abstract description 17
- 208000004756 Respiratory Insufficiency Diseases 0.000 claims abstract description 9
- 206010038678 Respiratory depression Diseases 0.000 claims abstract description 9
- 229910006069 SO3H Inorganic materials 0.000 claims abstract description 8
- 101100516568 Caenorhabditis elegans nhr-7 gene Proteins 0.000 claims abstract description 7
- 230000003931 cognitive performance Effects 0.000 claims abstract description 7
- 239000012453 solvate Substances 0.000 claims abstract description 7
- 208000015114 central nervous system disease Diseases 0.000 claims abstract description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 5
- 230000002708 enhancing effect Effects 0.000 claims abstract 5
- 239000000203 mixture Substances 0.000 claims description 38
- 125000000217 alkyl group Chemical group 0.000 claims description 37
- 239000002904 solvent Substances 0.000 claims description 22
- 239000002585 base Substances 0.000 claims description 21
- 229910052727 yttrium Inorganic materials 0.000 claims description 20
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 14
- 229910052760 oxygen Inorganic materials 0.000 claims description 14
- 125000000623 heterocyclic group Chemical group 0.000 claims description 11
- 229910052717 sulfur Inorganic materials 0.000 claims description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- 150000007522 mineralic acids Chemical class 0.000 claims description 10
- 230000000638 stimulation Effects 0.000 claims description 10
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 10
- 238000010438 heat treatment Methods 0.000 claims description 9
- 206010034759 Petit mal epilepsy Diseases 0.000 claims description 8
- 229910052794 bromium Inorganic materials 0.000 claims description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 7
- 125000001589 carboacyl group Chemical group 0.000 claims description 7
- 229910052740 iodine Inorganic materials 0.000 claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- 241000124008 Mammalia Species 0.000 claims description 6
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- 238000005859 coupling reaction Methods 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 150000001768 cations Chemical class 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 3
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 3
- 150000001412 amines Chemical class 0.000 claims description 3
- 238000009835 boiling Methods 0.000 claims description 3
- 230000008878 coupling Effects 0.000 claims description 3
- 238000010168 coupling process Methods 0.000 claims description 3
- 150000007530 organic bases Chemical class 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- 125000006239 protecting group Chemical group 0.000 claims description 3
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- 125000002837 carbocyclic group Chemical group 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 208000010877 cognitive disease Diseases 0.000 claims description 2
- 239000007822 coupling agent Substances 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 239000012038 nucleophile Substances 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000006413 ring segment Chemical group 0.000 claims description 2
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 230000003301 hydrolyzing effect Effects 0.000 claims 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 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 2
- 239000007864 aqueous solution Substances 0.000 claims 2
- 230000003287 optical effect Effects 0.000 claims 2
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims 1
- 125000004093 cyano group Chemical group *C#N 0.000 claims 1
- 238000002955 isolation Methods 0.000 claims 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims 1
- 230000001590 oxidative effect Effects 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 81
- 239000000047 product Substances 0.000 description 48
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 47
- 239000012141 concentrate Substances 0.000 description 41
- 238000006243 chemical reaction Methods 0.000 description 40
- 239000000243 solution Substances 0.000 description 32
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 26
- 238000003756 stirring Methods 0.000 description 25
- 235000019439 ethyl acetate Nutrition 0.000 description 23
- 229910001868 water Inorganic materials 0.000 description 23
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 22
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- 239000000741 silica gel Substances 0.000 description 21
- 229910002027 silica gel Inorganic materials 0.000 description 21
- 239000012043 crude product Substances 0.000 description 19
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 17
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 238000000921 elemental analysis Methods 0.000 description 13
- 238000003818 flash chromatography Methods 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- 238000010992 reflux Methods 0.000 description 12
- 239000012267 brine Substances 0.000 description 11
- 239000000706 filtrate Substances 0.000 description 11
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 10
- KPYSYYIEGFHWSV-UHFFFAOYSA-N Baclofen Chemical compound OC(=O)CC(CN)C1=CC=C(Cl)C=C1 KPYSYYIEGFHWSV-UHFFFAOYSA-N 0.000 description 9
- 229960000794 baclofen Drugs 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- 102000005962 receptors Human genes 0.000 description 9
- 108020003175 receptors Proteins 0.000 description 9
- RULDHHMNJXAYGW-UHFFFAOYSA-N 2-[4-(2-aminoethyl)phenoxy]-n,n-diethylacetamide Chemical compound CCN(CC)C(=O)COC1=CC=C(CCN)C=C1 RULDHHMNJXAYGW-UHFFFAOYSA-N 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 8
- 239000000284 extract Substances 0.000 description 8
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 7
- 239000005557 antagonist Substances 0.000 description 7
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 6
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 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 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 6
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- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- CWRVKFFCRWGWCS-UHFFFAOYSA-N Pentrazole Chemical compound C1CCCCC2=NN=NN21 CWRVKFFCRWGWCS-UHFFFAOYSA-N 0.000 description 4
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- 125000006242 amine protecting group Chemical group 0.000 description 4
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- 238000001727 in vivo Methods 0.000 description 4
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 230000002265 prevention Effects 0.000 description 4
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- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 3
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 3
- DLNWZIVYKQXLTN-UMJYHBPBSA-N [(1r,8s)-4-oxido-2,3,5,6,7,8-hexahydro-1h-pyrrolizin-4-ium-1-yl]methyl (2s)-2-hydroxy-2-[(1s)-1-hydroxyethyl]-3-methylbutanoate Chemical compound C1CC[C@H]2[C@H](COC(=O)[C@@](O)([C@H](C)O)C(C)C)CC[N+]21[O-] DLNWZIVYKQXLTN-UMJYHBPBSA-N 0.000 description 3
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- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
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- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical group C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 3
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- YXIWHUQXZSMYRE-UHFFFAOYSA-N 1,3-benzothiazole-2-thiol Chemical compound C1=CC=C2SC(S)=NC2=C1 YXIWHUQXZSMYRE-UHFFFAOYSA-N 0.000 description 2
- OGYGFUAIIOPWQD-UHFFFAOYSA-N 1,3-thiazolidine Chemical compound C1CSCN1 OGYGFUAIIOPWQD-UHFFFAOYSA-N 0.000 description 2
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- WBSMZVIMANOCNX-UHFFFAOYSA-N 3-amino-2-(4-chlorophenyl)-2-hydroxy-1-propanesulfonic acid Chemical compound OS(=O)(=O)CC(O)(CN)C1=CC=C(Cl)C=C1 WBSMZVIMANOCNX-UHFFFAOYSA-N 0.000 description 2
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
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- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 2
- OGNSCSPNOLGXSM-UHFFFAOYSA-N (+/-)-DABA Natural products NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 description 1
- PDNZJLMPXLQDPL-UHFFFAOYSA-N (1-aminocyclopentyl)methanol Chemical compound OCC1(N)CCCC1 PDNZJLMPXLQDPL-UHFFFAOYSA-N 0.000 description 1
- JCBPETKZIGVZRE-SCSAIBSYSA-N (2r)-2-aminobutan-1-ol Chemical compound CC[C@@H](N)CO JCBPETKZIGVZRE-SCSAIBSYSA-N 0.000 description 1
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 1
- JWQMKMSVOYQICF-UPHRSURJSA-N (z)-1,3-dibromoprop-1-ene Chemical compound BrC\C=C/Br JWQMKMSVOYQICF-UPHRSURJSA-N 0.000 description 1
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- LDHQCZJRKDOVOX-NSCUHMNNSA-N crotonic acid Chemical class C\C=C\C(O)=O LDHQCZJRKDOVOX-NSCUHMNNSA-N 0.000 description 1
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- VLFHLSNQRYRPOC-SNAWJCMRSA-N ethyl (e)-4-(2-methylaziridin-1-yl)but-2-enoate Chemical compound CCOC(=O)\C=C\CN1CC1C VLFHLSNQRYRPOC-SNAWJCMRSA-N 0.000 description 1
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- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
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- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 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
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- 239000002244 precipitate Substances 0.000 description 1
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- ALDITMKAAPLVJK-UHFFFAOYSA-N prop-1-ene;hydrate Chemical group O.CC=C ALDITMKAAPLVJK-UHFFFAOYSA-N 0.000 description 1
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- 239000012264 purified product Substances 0.000 description 1
- KOUKXHPPRFNWPP-UHFFFAOYSA-N pyrazine-2,5-dicarboxylic acid;hydrate Chemical compound O.OC(=O)C1=CN=C(C(O)=O)C=N1 KOUKXHPPRFNWPP-UHFFFAOYSA-N 0.000 description 1
- 238000001525 receptor binding assay Methods 0.000 description 1
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- 229910052708 sodium Inorganic materials 0.000 description 1
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- 239000011780 sodium chloride Substances 0.000 description 1
- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 description 1
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- 229910052623 talc Inorganic materials 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
- 150000003536 tetrazoles Chemical class 0.000 description 1
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- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
- C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/16—Central respiratory analeptics
-
- 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
- A61P25/28—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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
- C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
- C07D279/12—1,4-Thiazines; Hydrogenated 1,4-thiazines not condensed with other rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6527—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and oxygen atoms as the only ring hetero atoms
- C07F9/6533—Six-membered rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6527—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and oxygen atoms as the only ring hetero atoms
- C07F9/6533—Six-membered rings
- C07F9/65335—Six-membered rings condensed with carbocyclic rings or carbocyclic ring systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Psychiatry (AREA)
- Pain & Pain Management (AREA)
- Hospice & Palliative Care (AREA)
- Pulmonology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
- Plural Heterocyclic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Hydrogenated Pyridines (AREA)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US3858493A | 1993-03-26 | 1993-03-26 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IL109111A0 IL109111A0 (en) | 1994-06-24 |
| IL109111A true IL109111A (en) | 1999-07-14 |
Family
ID=21900746
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IL10911194A IL109111A (en) | 1993-03-26 | 1994-03-24 | HISTORY OF MORPOLIN AND THOMORPOLIN-2 Transformed as GABA-B Antagonists, Preparation and Pharmaceutical Preparations Containing Them |
Country Status (14)
| Country | Link |
|---|---|
| US (1) | US5929236A (enExample) |
| EP (1) | EP0690850B1 (enExample) |
| JP (1) | JP2778832B2 (enExample) |
| AT (1) | ATE160143T1 (enExample) |
| AU (1) | AU6408894A (enExample) |
| CA (1) | CA2158952C (enExample) |
| DE (1) | DE69406779T2 (enExample) |
| DK (1) | DK0690850T3 (enExample) |
| ES (1) | ES2109683T3 (enExample) |
| GR (1) | GR3025950T3 (enExample) |
| IL (1) | IL109111A (enExample) |
| TW (1) | TW280817B (enExample) |
| WO (1) | WO1994022843A1 (enExample) |
| ZA (1) | ZA942090B (enExample) |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PL324987A1 (en) * | 1995-09-07 | 1998-07-06 | Ciba Geigy Ag | Substituted phosphonic compounds and their application as pharmaceutic agents |
| AU5859598A (en) * | 1996-12-24 | 1998-07-17 | Novartis Ag | (thio)morpholine-substituted carboxylic and phosphinic acids |
| EP2258359A3 (en) | 2005-08-26 | 2011-04-06 | Braincells, Inc. | Neurogenesis by muscarinic receptor modulation with sabcomelin |
| US7678363B2 (en) | 2005-08-26 | 2010-03-16 | Braincells Inc | Methods of treating psychiatric conditions comprising administration of muscarinic agents in combination with SSRIs |
| EP1940389A2 (en) | 2005-10-21 | 2008-07-09 | Braincells, Inc. | Modulation of neurogenesis by pde inhibition |
| US20070112017A1 (en) * | 2005-10-31 | 2007-05-17 | Braincells, Inc. | Gaba receptor mediated modulation of neurogenesis |
| US20100216734A1 (en) | 2006-03-08 | 2010-08-26 | Braincells, Inc. | Modulation of neurogenesis by nootropic agents |
| JP2009536667A (ja) | 2006-05-09 | 2009-10-15 | ブレインセルス，インコーポレイティド | ５ｈｔ受容体介在性の神経新生 |
| EP2382975A3 (en) | 2006-05-09 | 2012-02-29 | Braincells, Inc. | Neurogenesis by modulating angiotensin |
| WO2008030651A1 (en) | 2006-09-08 | 2008-03-13 | Braincells, Inc. | Combinations containing a 4-acylaminopyridine derivative |
| US20100216805A1 (en) | 2009-02-25 | 2010-08-26 | Braincells, Inc. | Modulation of neurogenesis using d-cycloserine combinations |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4889857A (en) * | 1987-10-12 | 1989-12-26 | Yoshitomi Pharmaceutical Industries, Ltd. | Quinolonecarboxylic acid compounds and pharmaceutical use thereof |
| NZ233503A (en) * | 1989-05-15 | 1991-06-25 | Janssen Pharmaceutica Nv | Substituted (thio)morpholinyl and piperazinyl alkylphenol ethers |
| JPH04270272A (ja) * | 1991-02-25 | 1992-09-25 | Yoshitomi Pharmaceut Ind Ltd | アミノアルキルモルホリン誘導体の製造法 |
-
1994
- 1994-03-23 DE DE69406779T patent/DE69406779T2/de not_active Expired - Lifetime
- 1994-03-23 WO PCT/US1994/002803 patent/WO1994022843A1/en not_active Ceased
- 1994-03-23 DK DK94911608.1T patent/DK0690850T3/da active
- 1994-03-23 JP JP6522103A patent/JP2778832B2/ja not_active Expired - Fee Related
- 1994-03-23 EP EP94911608A patent/EP0690850B1/en not_active Expired - Lifetime
- 1994-03-23 ES ES94911608T patent/ES2109683T3/es not_active Expired - Lifetime
- 1994-03-23 US US08/525,795 patent/US5929236A/en not_active Expired - Fee Related
- 1994-03-23 AT AT94911608T patent/ATE160143T1/de not_active IP Right Cessation
- 1994-03-23 AU AU64088/94A patent/AU6408894A/en not_active Abandoned
- 1994-03-23 CA CA002158952A patent/CA2158952C/en not_active Expired - Fee Related
- 1994-03-24 TW TW083102586A patent/TW280817B/zh active
- 1994-03-24 IL IL10911194A patent/IL109111A/en not_active IP Right Cessation
- 1994-03-24 ZA ZA942090A patent/ZA942090B/xx unknown
-
1998
- 1998-01-20 GR GR980400120T patent/GR3025950T3/el unknown
Also Published As
| Publication number | Publication date |
|---|---|
| JP2778832B2 (ja) | 1998-07-23 |
| CA2158952C (en) | 1999-05-18 |
| ES2109683T3 (es) | 1998-01-16 |
| JPH08503229A (ja) | 1996-04-09 |
| DE69406779T2 (de) | 1998-03-12 |
| ZA942090B (en) | 1994-09-26 |
| DE69406779D1 (en) | 1997-12-18 |
| US5929236A (en) | 1999-07-27 |
| EP0690850A1 (en) | 1996-01-10 |
| DK0690850T3 (da) | 1998-02-09 |
| IL109111A0 (en) | 1994-06-24 |
| GR3025950T3 (en) | 1998-04-30 |
| CA2158952A1 (en) | 1994-10-13 |
| TW280817B (enExample) | 1996-07-11 |
| WO1994022843A1 (en) | 1994-10-13 |
| EP0690850B1 (en) | 1997-11-12 |
| ATE160143T1 (de) | 1997-11-15 |
| AU6408894A (en) | 1994-10-24 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FF | Patent granted | ||
| HK | Corrigendum |
Free format text: JOURNAL 2/99 P. 263 PATENT APPLICATION NO. 109111 CORRECT ADDRESS FOR SERVICE TO - EITAN, PEARL, ATZER AND COHEN ZEDEK 7 SHENKAR ST., HERZLIYA |
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| NP | Permission for amending the patent specification granted (section 66, patents law 1967) | ||
| HK | Corrigendum |
Free format text: CORRECT ADDRESS FOR SERVICE TO- EITAN, PEARL, LATZER AND COHEN ZEDEK 7 SHENKAR ST., HERZLIYA |
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| RH | Patent void | ||
| NE | Application for restoration - patent lapsed through non-payment of renewal fees (section 60, patents law, 5727-1967) | ||
| MM9K | Patent not in force due to non-payment of renewal fees |