WO2009092324A1 - Oxazolidine derivatives as nmda antagonists - Google Patents
Oxazolidine derivatives as nmda antagonists Download PDFInfo
- Publication number
- WO2009092324A1 WO2009092324A1 PCT/CN2009/070178 CN2009070178W WO2009092324A1 WO 2009092324 A1 WO2009092324 A1 WO 2009092324A1 CN 2009070178 W CN2009070178 W CN 2009070178W WO 2009092324 A1 WO2009092324 A1 WO 2009092324A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- compound
- group
- nhr
- aryl
- Prior art date
Links
- 239000005557 antagonist Substances 0.000 title abstract description 18
- 229940053194 antiepileptics oxazolidine derivative Drugs 0.000 title abstract description 12
- 150000002917 oxazolidines Chemical class 0.000 title abstract description 11
- HOKKHZGPKSLGJE-GSVOUGTGSA-N N-Methyl-D-aspartic acid Chemical compound CN[C@@H](C(O)=O)CC(O)=O HOKKHZGPKSLGJE-GSVOUGTGSA-N 0.000 title abstract description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 347
- 238000000034 method Methods 0.000 claims abstract description 155
- 108090001041 N-Methyl-D-Aspartate Receptors Proteins 0.000 claims abstract description 55
- 239000000203 mixture Substances 0.000 claims abstract description 46
- 230000000694 effects Effects 0.000 claims abstract description 42
- 241000124008 Mammalia Species 0.000 claims abstract description 39
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 27
- 102000004868 N-Methyl-D-Aspartate Receptors Human genes 0.000 claims abstract description 22
- 210000004556 brain Anatomy 0.000 claims abstract description 22
- 230000004770 neurodegeneration Effects 0.000 claims abstract description 19
- 208000015122 neurodegenerative disease Diseases 0.000 claims abstract description 19
- 230000002981 neuropathic effect Effects 0.000 claims abstract description 16
- 230000003920 cognitive function Effects 0.000 claims abstract description 13
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 13
- 230000002708 enhancing effect Effects 0.000 claims abstract description 12
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims abstract description 11
- 208000015114 central nervous system disease Diseases 0.000 claims abstract description 10
- 229930195712 glutamate Natural products 0.000 claims abstract description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 153
- -1 /-Bu Chemical group 0.000 claims description 72
- 125000003118 aryl group Chemical group 0.000 claims description 70
- 150000003839 salts Chemical class 0.000 claims description 52
- 208000006011 Stroke Diseases 0.000 claims description 33
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 33
- 125000001424 substituent group Chemical group 0.000 claims description 33
- 125000004404 heteroalkyl group Chemical group 0.000 claims description 31
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 24
- 125000006239 protecting group Chemical group 0.000 claims description 23
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 21
- 229910052736 halogen Inorganic materials 0.000 claims description 19
- 239000008194 pharmaceutical composition Substances 0.000 claims description 19
- 229910006074 SO2NH2 Inorganic materials 0.000 claims description 18
- 125000005842 heteroatom Chemical group 0.000 claims description 18
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 17
- 208000030886 Traumatic Brain injury Diseases 0.000 claims description 16
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 16
- 150000002367 halogens Chemical class 0.000 claims description 16
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 16
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 14
- 201000010099 disease Diseases 0.000 claims description 14
- 206010015037 epilepsy Diseases 0.000 claims description 14
- 208000004296 neuralgia Diseases 0.000 claims description 14
- 208000021722 neuropathic pain Diseases 0.000 claims description 14
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 14
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 13
- 125000002947 alkylene group Chemical group 0.000 claims description 13
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims description 13
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 13
- 208000014674 injury Diseases 0.000 claims description 13
- 229910052760 oxygen Inorganic materials 0.000 claims description 13
- 208000024827 Alzheimer disease Diseases 0.000 claims description 12
- 208000023105 Huntington disease Diseases 0.000 claims description 12
- 208000018737 Parkinson disease Diseases 0.000 claims description 12
- 208000035475 disorder Diseases 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- 125000001072 heteroaryl group Chemical group 0.000 claims description 11
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 11
- 208000010496 Heart Arrest Diseases 0.000 claims description 10
- 210000003169 central nervous system Anatomy 0.000 claims description 10
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 9
- 125000004429 atom Chemical group 0.000 claims description 9
- 229910052799 carbon Inorganic materials 0.000 claims description 9
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 9
- 229910014033 C-OH Inorganic materials 0.000 claims description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 8
- 229910014570 C—OH Inorganic materials 0.000 claims description 8
- 206010019196 Head injury Diseases 0.000 claims description 8
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 8
- 229910052717 sulfur Inorganic materials 0.000 claims description 8
- 230000003961 neuronal insult Effects 0.000 claims description 7
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 6
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 239000006390 lc 2 Substances 0.000 claims description 5
- 230000008733 trauma Effects 0.000 claims description 5
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 4
- 229910017711 NHRa Inorganic materials 0.000 claims description 4
- 125000001931 aliphatic group Chemical group 0.000 claims description 4
- 125000000717 hydrazino group Chemical group [H]N([*])N([H])[H] 0.000 claims description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical group C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 125000006302 indol-3-yl methyl group Chemical group [H]N1C([H])=C(C2=C([H])C([H])=C([H])C([H])=C12)C([H])([H])* 0.000 claims description 3
- 125000004674 methylcarbonyl group Chemical group CC(=O)* 0.000 claims description 3
- 239000012453 solvate Substances 0.000 claims description 3
- 102000018899 Glutamate Receptors Human genes 0.000 claims description 2
- 108010027915 Glutamate Receptors Proteins 0.000 claims description 2
- 230000005540 biological transmission Effects 0.000 claims description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-L glutamate group Chemical group N[C@@H](CCC(=O)[O-])C(=O)[O-] WHUUTDBJXJRKMK-VKHMYHEASA-L 0.000 claims description 2
- 210000000225 synapse Anatomy 0.000 claims description 2
- 230000004112 neuroprotection Effects 0.000 abstract description 7
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 abstract description 3
- 239000011575 calcium Substances 0.000 abstract description 3
- 229910052791 calcium Inorganic materials 0.000 abstract description 3
- 230000003389 potentiating effect Effects 0.000 abstract description 3
- 206010029350 Neurotoxicity Diseases 0.000 abstract description 2
- 206010044221 Toxic encephalopathy Diseases 0.000 abstract description 2
- 230000007135 neurotoxicity Effects 0.000 abstract description 2
- 231100000228 neurotoxicity Toxicity 0.000 abstract description 2
- 231100000816 toxic dose Toxicity 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 194
- 229910052739 hydrogen Inorganic materials 0.000 description 103
- 241000699670 Mus sp. Species 0.000 description 74
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 63
- 241000700159 Rattus Species 0.000 description 59
- 238000003786 synthesis reaction Methods 0.000 description 51
- 230000015572 biosynthetic process Effects 0.000 description 50
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 49
- 229910002092 carbon dioxide Inorganic materials 0.000 description 44
- 238000005160 1H NMR spectroscopy Methods 0.000 description 42
- 210000003618 cortical neuron Anatomy 0.000 description 34
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 34
- 238000012360 testing method Methods 0.000 description 34
- 102000014649 NMDA glutamate receptor activity proteins Human genes 0.000 description 33
- 108020005497 Nuclear hormone receptor Proteins 0.000 description 30
- 102000007399 Nuclear hormone receptor Human genes 0.000 description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 29
- 230000004044 response Effects 0.000 description 29
- 210000004027 cell Anatomy 0.000 description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 28
- 239000000243 solution Substances 0.000 description 26
- 238000011282 treatment Methods 0.000 description 26
- 239000003814 drug Substances 0.000 description 23
- 210000004295 hippocampal neuron Anatomy 0.000 description 23
- 210000002569 neuron Anatomy 0.000 description 23
- 230000003492 excitotoxic effect Effects 0.000 description 22
- 231100000063 excitotoxicity Toxicity 0.000 description 22
- 238000012048 forced swim test Methods 0.000 description 22
- 125000004432 carbon atom Chemical group C* 0.000 description 21
- 229930000680 A04AD01 - Scopolamine Natural products 0.000 description 20
- STECJAGHUSJQJN-GAUPFVANSA-N Hyoscine Natural products C1([C@H](CO)C(=O)OC2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-GAUPFVANSA-N 0.000 description 20
- STECJAGHUSJQJN-UHFFFAOYSA-N N-Methyl-scopolamin Natural products C1C(C2C3O2)N(C)C3CC1OC(=O)C(CO)C1=CC=CC=C1 STECJAGHUSJQJN-UHFFFAOYSA-N 0.000 description 20
- STECJAGHUSJQJN-FWXGHANASA-N scopolamine Chemical compound C1([C@@H](CO)C(=O)O[C@H]2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-FWXGHANASA-N 0.000 description 20
- 229960002646 scopolamine Drugs 0.000 description 20
- 206010008089 Cerebral artery occlusion Diseases 0.000 description 19
- 201000007309 middle cerebral artery infarction Diseases 0.000 description 19
- 238000002360 preparation method Methods 0.000 description 19
- 239000003981 vehicle Substances 0.000 description 19
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 18
- 239000002904 solvent Substances 0.000 description 18
- 229940079593 drug Drugs 0.000 description 16
- 206010061216 Infarction Diseases 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 238000002474 experimental method Methods 0.000 description 15
- 230000007574 infarction Effects 0.000 description 15
- 229940002612 prodrug Drugs 0.000 description 15
- 239000000651 prodrug Substances 0.000 description 15
- 241001465754 Metazoa Species 0.000 description 14
- 238000012347 Morris Water Maze Methods 0.000 description 14
- 239000002253 acid Substances 0.000 description 14
- 239000011780 sodium chloride Substances 0.000 description 14
- 230000030833 cell death Effects 0.000 description 13
- 230000000302 ischemic effect Effects 0.000 description 13
- 125000003107 substituted aryl group Chemical group 0.000 description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 12
- 238000007912 intraperitoneal administration Methods 0.000 description 12
- 239000002609 medium Substances 0.000 description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 12
- 230000007423 decrease Effects 0.000 description 11
- 235000019439 ethyl acetate Nutrition 0.000 description 11
- 208000028867 ischemia Diseases 0.000 description 11
- 230000015654 memory Effects 0.000 description 11
- 230000002829 reductive effect Effects 0.000 description 11
- 230000035882 stress Effects 0.000 description 11
- 0 *[C@]1OC(*)(*)[C@](Cc2ccccc2)N1* Chemical compound *[C@]1OC(*)(*)[C@](Cc2ccccc2)N1* 0.000 description 10
- 208000026139 Memory disease Diseases 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 230000027455 binding Effects 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 10
- 230000006378 damage Effects 0.000 description 10
- 102000005962 receptors Human genes 0.000 description 10
- 108020003175 receptors Proteins 0.000 description 10
- 239000000725 suspension Substances 0.000 description 10
- 230000001225 therapeutic effect Effects 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 229960004801 imipramine Drugs 0.000 description 9
- 238000000338 in vitro Methods 0.000 description 9
- 206010027175 memory impairment Diseases 0.000 description 9
- 239000003703 n methyl dextro aspartic acid receptor blocking agent Substances 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- 208000024891 symptom Diseases 0.000 description 9
- 241000699666 Mus <mouse, genus> Species 0.000 description 8
- 229940099433 NMDA receptor antagonist Drugs 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 208000027418 Wounds and injury Diseases 0.000 description 8
- 239000004480 active ingredient Substances 0.000 description 8
- 230000003042 antagnostic effect Effects 0.000 description 8
- 230000001430 anti-depressive effect Effects 0.000 description 8
- 238000009472 formulation Methods 0.000 description 8
- 238000009650 gentamicin protection assay Methods 0.000 description 8
- BCGWQEUPMDMJNV-UHFFFAOYSA-N imipramine Chemical compound C1CC2=CC=CC=C2N(CCCN(C)C)C2=CC=CC=C21 BCGWQEUPMDMJNV-UHFFFAOYSA-N 0.000 description 8
- 238000011534 incubation Methods 0.000 description 8
- 230000036961 partial effect Effects 0.000 description 8
- 150000003254 radicals Chemical class 0.000 description 8
- 239000003826 tablet Substances 0.000 description 8
- 238000005481 NMR spectroscopy Methods 0.000 description 7
- 238000013459 approach Methods 0.000 description 7
- 238000003556 assay Methods 0.000 description 7
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 7
- 150000002148 esters Chemical class 0.000 description 7
- 230000001965 increasing effect Effects 0.000 description 7
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 7
- 238000012346 open field test Methods 0.000 description 7
- 229920000642 polymer Polymers 0.000 description 7
- 238000011084 recovery Methods 0.000 description 7
- 238000004809 thin layer chromatography Methods 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 6
- 206010012289 Dementia Diseases 0.000 description 6
- 239000004471 Glycine Substances 0.000 description 6
- 206010030113 Oedema Diseases 0.000 description 6
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 6
- 235000001014 amino acid Nutrition 0.000 description 6
- 229940024606 amino acid Drugs 0.000 description 6
- 150000001413 amino acids Chemical class 0.000 description 6
- 239000000935 antidepressant agent Substances 0.000 description 6
- 230000037396 body weight Effects 0.000 description 6
- 239000002775 capsule Substances 0.000 description 6
- 230000006735 deficit Effects 0.000 description 6
- 239000003480 eluent Substances 0.000 description 6
- 238000003818 flash chromatography Methods 0.000 description 6
- 239000000796 flavoring agent Substances 0.000 description 6
- 150000002500 ions Chemical class 0.000 description 6
- 230000013016 learning Effects 0.000 description 6
- 239000003446 ligand Substances 0.000 description 6
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 description 6
- 239000013642 negative control Substances 0.000 description 6
- 229920001223 polyethylene glycol Polymers 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- 239000003765 sweetening agent Substances 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 239000007832 Na2SO4 Substances 0.000 description 5
- 102100033810 RAC-alpha serine/threonine-protein kinase Human genes 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 150000007513 acids Chemical class 0.000 description 5
- 150000001414 amino alcohols Chemical class 0.000 description 5
- 230000006399 behavior Effects 0.000 description 5
- 210000005013 brain tissue Anatomy 0.000 description 5
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 5
- 239000000969 carrier Substances 0.000 description 5
- 239000007859 condensation product Substances 0.000 description 5
- 125000000753 cycloalkyl group Chemical group 0.000 description 5
- 230000003247 decreasing effect Effects 0.000 description 5
- 235000014113 dietary fatty acids Nutrition 0.000 description 5
- 239000003085 diluting agent Substances 0.000 description 5
- 231100000673 dose–response relationship Toxicity 0.000 description 5
- 239000000839 emulsion Substances 0.000 description 5
- 229930195729 fatty acid Natural products 0.000 description 5
- 239000000194 fatty acid Substances 0.000 description 5
- 150000004665 fatty acids Chemical class 0.000 description 5
- 235000003599 food sweetener Nutrition 0.000 description 5
- 125000000623 heterocyclic group Chemical group 0.000 description 5
- 238000001727 in vivo Methods 0.000 description 5
- 239000004615 ingredient Substances 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 231100000252 nontoxic Toxicity 0.000 description 5
- 230000003000 nontoxic effect Effects 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- 235000019198 oils Nutrition 0.000 description 5
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 5
- 230000026731 phosphorylation Effects 0.000 description 5
- 238000006366 phosphorylation reaction Methods 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 230000001681 protective effect Effects 0.000 description 5
- 125000006413 ring segment Chemical group 0.000 description 5
- 229910052938 sodium sulfate Inorganic materials 0.000 description 5
- 238000013268 sustained release Methods 0.000 description 5
- 239000012730 sustained-release form Substances 0.000 description 5
- 238000002560 therapeutic procedure Methods 0.000 description 5
- 238000001262 western blot Methods 0.000 description 5
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 4
- 208000000044 Amnesia Diseases 0.000 description 4
- 208000036864 Attention deficit/hyperactivity disease Diseases 0.000 description 4
- 206010048962 Brain oedema Diseases 0.000 description 4
- 102000005636 Cyclic AMP Response Element-Binding Protein Human genes 0.000 description 4
- 108010045171 Cyclic AMP Response Element-Binding Protein Proteins 0.000 description 4
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 4
- 239000007995 HEPES buffer Substances 0.000 description 4
- 241000282412 Homo Species 0.000 description 4
- 102000004310 Ion Channels Human genes 0.000 description 4
- 108090000862 Ion Channels Proteins 0.000 description 4
- 208000032382 Ischaemic stroke Diseases 0.000 description 4
- 208000002193 Pain Diseases 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 4
- 150000001299 aldehydes Chemical class 0.000 description 4
- 238000010171 animal model Methods 0.000 description 4
- 239000007900 aqueous suspension Substances 0.000 description 4
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 4
- 208000006752 brain edema Diseases 0.000 description 4
- 238000004113 cell culture Methods 0.000 description 4
- 239000003086 colorant Substances 0.000 description 4
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 4
- 239000002270 dispersing agent Substances 0.000 description 4
- QLTXKCWMEZIHBJ-PJGJYSAQSA-N dizocilpine maleate Chemical compound OC(=O)\C=C/C(O)=O.C12=CC=CC=C2[C@]2(C)C3=CC=CC=C3C[C@H]1N2 QLTXKCWMEZIHBJ-PJGJYSAQSA-N 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 235000013355 food flavoring agent Nutrition 0.000 description 4
- 239000000499 gel Substances 0.000 description 4
- 239000008103 glucose Substances 0.000 description 4
- 150000004795 grignard reagents Chemical class 0.000 description 4
- 230000003447 ipsilateral effect Effects 0.000 description 4
- 239000002502 liposome Substances 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 239000012528 membrane Substances 0.000 description 4
- 210000005036 nerve Anatomy 0.000 description 4
- 230000001537 neural effect Effects 0.000 description 4
- 230000007935 neutral effect Effects 0.000 description 4
- 230000036407 pain Effects 0.000 description 4
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 4
- 239000003755 preservative agent Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 230000011514 reflex Effects 0.000 description 4
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- 125000004434 sulfur atom Chemical group 0.000 description 4
- 239000000375 suspending agent Substances 0.000 description 4
- 230000009182 swimming Effects 0.000 description 4
- 230000000946 synaptic effect Effects 0.000 description 4
- 229940124597 therapeutic agent Drugs 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- 238000012549 training Methods 0.000 description 4
- 238000012384 transportation and delivery Methods 0.000 description 4
- 239000000080 wetting agent Substances 0.000 description 4
- VDXHEEWQCRXFES-NWDGAFQWSA-N (2r,4s)-2,5,5-triethyl-4-(2-methylpropyl)-1,3-oxazolidine Chemical compound CC[C@@H]1N[C@@H](CC(C)C)C(CC)(CC)O1 VDXHEEWQCRXFES-NWDGAFQWSA-N 0.000 description 3
- NKQDYROZBFHRJH-SAIIYOCFSA-N (2r,4s)-4-butan-2-yl-2,5,5-triethyl-1,3-oxazolidine Chemical compound CCC(C)[C@@H]1N[C@@H](CC)OC1(CC)CC NKQDYROZBFHRJH-SAIIYOCFSA-N 0.000 description 3
- QKHJTWAHLMVMHZ-HDYSRYHKSA-N (2r,4s)-4-butan-2-yl-5,5-diethyl-2-propyl-1,3-oxazolidine Chemical compound CCC[C@@H]1N[C@@H](C(C)CC)C(CC)(CC)O1 QKHJTWAHLMVMHZ-HDYSRYHKSA-N 0.000 description 3
- QUQDJZLKOSGPOC-QWHCGFSZSA-N (2r,4s)-5,5-diethyl-4-(2-methylpropyl)-2-propyl-1,3-oxazolidine Chemical compound CCC[C@@H]1N[C@@H](CC(C)C)C(CC)(CC)O1 QUQDJZLKOSGPOC-QWHCGFSZSA-N 0.000 description 3
- VDXHEEWQCRXFES-RYUDHWBXSA-N (2s,4s)-2,5,5-triethyl-4-(2-methylpropyl)-1,3-oxazolidine Chemical compound CC[C@H]1N[C@@H](CC(C)C)C(CC)(CC)O1 VDXHEEWQCRXFES-RYUDHWBXSA-N 0.000 description 3
- MXQLLTOYXFWRSF-IRXDYDNUSA-N (2s,4s)-4-benzyl-2-ethyl-5,5-dipropyl-1,3-oxazolidine Chemical compound CCCC1(CCC)O[C@@H](CC)N[C@H]1CC1=CC=CC=C1 MXQLLTOYXFWRSF-IRXDYDNUSA-N 0.000 description 3
- NKQDYROZBFHRJH-RAMGSTBQSA-N (2s,4s)-4-butan-2-yl-2,5,5-triethyl-1,3-oxazolidine Chemical compound CCC(C)[C@@H]1N[C@H](CC)OC1(CC)CC NKQDYROZBFHRJH-RAMGSTBQSA-N 0.000 description 3
- HUBNUGPJAUQGTR-BEEDKBRMSA-N (2s,4s)-4-butan-2-yl-2-phenyl-5,5-dipropyl-1,3-oxazolidine Chemical compound N1[C@@H](C(C)CC)C(CCC)(CCC)O[C@H]1C1=CC=CC=C1 HUBNUGPJAUQGTR-BEEDKBRMSA-N 0.000 description 3
- QKHJTWAHLMVMHZ-SPOOISQMSA-N (2s,4s)-4-butan-2-yl-5,5-diethyl-2-propyl-1,3-oxazolidine Chemical compound CCC[C@H]1N[C@@H](C(C)CC)C(CC)(CC)O1 QKHJTWAHLMVMHZ-SPOOISQMSA-N 0.000 description 3
- QUQDJZLKOSGPOC-STQMWFEESA-N (2s,4s)-5,5-diethyl-4-(2-methylpropyl)-2-propyl-1,3-oxazolidine Chemical compound CCC[C@H]1N[C@@H](CC(C)C)C(CC)(CC)O1 QUQDJZLKOSGPOC-STQMWFEESA-N 0.000 description 3
- OMBVEVHRIQULKW-DNQXCXABSA-M (3r,5r)-7-[3-(4-fluorophenyl)-8-oxo-7-phenyl-1-propan-2-yl-5,6-dihydro-4h-pyrrolo[2,3-c]azepin-2-yl]-3,5-dihydroxyheptanoate Chemical compound O=C1C=2N(C(C)C)C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)=C(C=3C=CC(F)=CC=3)C=2CCCN1C1=CC=CC=C1 OMBVEVHRIQULKW-DNQXCXABSA-M 0.000 description 3
- PKDBCJSWQUOKDO-UHFFFAOYSA-M 2,3,5-triphenyltetrazolium chloride Chemical compound [Cl-].C1=CC=CC=C1C(N=[N+]1C=2C=CC=CC=2)=NN1C1=CC=CC=C1 PKDBCJSWQUOKDO-UHFFFAOYSA-M 0.000 description 3
- 244000215068 Acacia senegal Species 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 3
- 241000283707 Capra Species 0.000 description 3
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 3
- 108010010803 Gelatin Proteins 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 239000007818 Grignard reagent Substances 0.000 description 3
- 229920000084 Gum arabic Polymers 0.000 description 3
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 3
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 150000001204 N-oxides Chemical class 0.000 description 3
- 229930040373 Paraformaldehyde Natural products 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 235000010489 acacia gum Nutrition 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 230000001154 acute effect Effects 0.000 description 3
- 230000002411 adverse Effects 0.000 description 3
- 239000000443 aerosol Substances 0.000 description 3
- 239000000556 agonist Substances 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 235000008206 alpha-amino acids Nutrition 0.000 description 3
- 229940005513 antidepressants Drugs 0.000 description 3
- 230000006907 apoptotic process Effects 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 230000003542 behavioural effect Effects 0.000 description 3
- 229910000019 calcium carbonate Inorganic materials 0.000 description 3
- 239000001110 calcium chloride Substances 0.000 description 3
- 229910001628 calcium chloride Inorganic materials 0.000 description 3
- 239000001506 calcium phosphate Substances 0.000 description 3
- 229910000389 calcium phosphate Inorganic materials 0.000 description 3
- 235000011010 calcium phosphates Nutrition 0.000 description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
- 210000000269 carotid artery external Anatomy 0.000 description 3
- 239000001913 cellulose Substances 0.000 description 3
- 229920002678 cellulose Polymers 0.000 description 3
- 235000010980 cellulose Nutrition 0.000 description 3
- 206010008118 cerebral infarction Diseases 0.000 description 3
- 230000001684 chronic effect Effects 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
- 208000010877 cognitive disease Diseases 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- 229940126540 compound 41 Drugs 0.000 description 3
- 238000013270 controlled release Methods 0.000 description 3
- 231100000135 cytotoxicity Toxicity 0.000 description 3
- 230000003013 cytotoxicity Effects 0.000 description 3
- 230000001419 dependent effect Effects 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 235000005911 diet Nutrition 0.000 description 3
- 230000037213 diet Effects 0.000 description 3
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 3
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 3
- 239000008298 dragée Substances 0.000 description 3
- 230000029142 excretion Effects 0.000 description 3
- 235000013305 food Nutrition 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- 238000011990 functional testing Methods 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 239000008273 gelatin Substances 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- 235000011852 gelatine desserts Nutrition 0.000 description 3
- 230000014509 gene expression Effects 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- 125000001188 haloalkyl group Chemical group 0.000 description 3
- 230000036541 health Effects 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 102000048260 kappa Opioid Receptors Human genes 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 229940057995 liquid paraffin Drugs 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 230000001404 mediated effect Effects 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 239000002808 molecular sieve Substances 0.000 description 3
- 230000000926 neurological effect Effects 0.000 description 3
- 230000006576 neuronal survival Effects 0.000 description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 description 3
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 3
- 239000002674 ointment Substances 0.000 description 3
- 239000004006 olive oil Substances 0.000 description 3
- 235000008390 olive oil Nutrition 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 229920002866 paraformaldehyde Polymers 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 3
- 239000013641 positive control Substances 0.000 description 3
- 239000001103 potassium chloride Substances 0.000 description 3
- 235000011164 potassium chloride Nutrition 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- 235000018102 proteins Nutrition 0.000 description 3
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 238000006722 reduction reaction Methods 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 3
- 238000012453 sprague-dawley rat model Methods 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000000829 suppository Substances 0.000 description 3
- 238000001356 surgical procedure Methods 0.000 description 3
- 230000000699 topical effect Effects 0.000 description 3
- 231100000331 toxic Toxicity 0.000 description 3
- 230000002588 toxic effect Effects 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 3
- 108020001588 κ-opioid receptors Proteins 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- UQNATZJICTVVHV-KBPBESRZSA-N (2s,4s)-2,3,5,5-tetraethyl-4-(2-methylpropyl)-1,3-oxazolidine Chemical compound CC[C@@H]1OC(CC)(CC)[C@H](CC(C)C)N1CC UQNATZJICTVVHV-KBPBESRZSA-N 0.000 description 2
- OYJVTVZUXNMVGD-VXKWHMMOSA-N (2s,4s)-2,3-diethyl-4-(2-methylpropyl)-5,5-diphenyl-1,3-oxazolidine Chemical compound CC(C)C[C@@H]1N(CC)[C@H](CC)OC1(C=1C=CC=CC=1)C1=CC=CC=C1 OYJVTVZUXNMVGD-VXKWHMMOSA-N 0.000 description 2
- JBPRMFZTJLMPIR-KBPBESRZSA-N (2s,4s)-2-ethyl-4-(2-methylpropyl)-5,5-dipropyl-1,3-oxazolidine Chemical compound CCCC1(CCC)O[C@@H](CC)N[C@H]1CC(C)C JBPRMFZTJLMPIR-KBPBESRZSA-N 0.000 description 2
- JFHRHWGNGVIIMZ-GJZGRUSLSA-N (2s,4s)-3,5,5-triethyl-4-(2-methylpropyl)-2-propyl-1,3-oxazolidine Chemical compound CCC[C@@H]1OC(CC)(CC)[C@H](CC(C)C)N1CC JFHRHWGNGVIIMZ-GJZGRUSLSA-N 0.000 description 2
- OMWHSVQDJYUZRS-GOTSBHOMSA-N (2s,4s)-3-ethyl-4-(2-methylpropyl)-5,5-diphenyl-2-propyl-1,3-oxazolidine Chemical compound CC(C)C[C@@H]1N(CC)[C@H](CCC)OC1(C=1C=CC=CC=1)C1=CC=CC=C1 OMWHSVQDJYUZRS-GOTSBHOMSA-N 0.000 description 2
- AJQFMUIERNYKJS-GJZGRUSLSA-N (2s,4s)-4-(2-methylpropyl)-2,5,5-tripropyl-1,3-oxazolidine Chemical compound CCC[C@H]1N[C@@H](CC(C)C)C(CCC)(CCC)O1 AJQFMUIERNYKJS-GJZGRUSLSA-N 0.000 description 2
- FOEKTTZVDHQDCD-ROUUACIJSA-N (2s,4s)-4-(2-methylpropyl)-2-phenyl-5,5-dipropyl-1,3-oxazolidine Chemical compound N1[C@@H](CC(C)C)C(CCC)(CCC)O[C@H]1C1=CC=CC=C1 FOEKTTZVDHQDCD-ROUUACIJSA-N 0.000 description 2
- MKHFDKSJUKJNLT-ROUUACIJSA-N (2s,4s)-4-benzyl-2,5,5-tripropyl-1,3-oxazolidine Chemical compound CCCC1(CCC)O[C@@H](CCC)N[C@H]1CC1=CC=CC=C1 MKHFDKSJUKJNLT-ROUUACIJSA-N 0.000 description 2
- UYDNENFKUUGJMT-HOTGVXAUSA-N (2s,4s)-4-benzyl-5,5-diethyl-2-propyl-1,3-oxazolidine Chemical compound CCC1(CC)O[C@@H](CCC)N[C@H]1CC1=CC=CC=C1 UYDNENFKUUGJMT-HOTGVXAUSA-N 0.000 description 2
- NYRBSLMWHVGGFA-FGRDXJNISA-N (2s,4s)-4-butan-2-yl-2,5,5-tripropyl-1,3-oxazolidine Chemical compound CCC[C@H]1N[C@@H](C(C)CC)C(CCC)(CCC)O1 NYRBSLMWHVGGFA-FGRDXJNISA-N 0.000 description 2
- QIMJNMZDYJEJII-TTZKSVMKSA-N (2s,4s)-4-butan-2-yl-2-ethyl-5,5-dipropyl-1,3-oxazolidine Chemical compound CCCC1(CCC)O[C@@H](CC)N[C@H]1C(C)CC QIMJNMZDYJEJII-TTZKSVMKSA-N 0.000 description 2
- ACQOVYZXQYYPDB-OALUTQOASA-N (2s,4s)-5,5-dibutyl-2-ethyl-4-(2-methylpropyl)-3-propyl-1,3-oxazolidine Chemical compound CCCCC1(CCCC)O[C@@H](CC)N(CCC)[C@H]1CC(C)C ACQOVYZXQYYPDB-OALUTQOASA-N 0.000 description 2
- SKPWMSQSBBNATF-PMACEKPBSA-N (2s,4s)-5,5-dibutyl-4-(2-methylpropyl)-2,3-dipropyl-1,3-oxazolidine Chemical compound CCCCC1(CCCC)O[C@@H](CCC)N(CCC)[C@H]1CC(C)C SKPWMSQSBBNATF-PMACEKPBSA-N 0.000 description 2
- IDZBIRVAIUFFKP-HOTGVXAUSA-N (2s,4s)-5,5-diethyl-4-(2-methylpropyl)-2-phenyl-1,3-oxazolidine Chemical compound N1[C@@H](CC(C)C)C(CC)(CC)O[C@H]1C1=CC=CC=C1 IDZBIRVAIUFFKP-HOTGVXAUSA-N 0.000 description 2
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 2
- IZHVBANLECCAGF-UHFFFAOYSA-N 2-hydroxy-3-(octadecanoyloxy)propyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCCCCCCCCCCC IZHVBANLECCAGF-UHFFFAOYSA-N 0.000 description 2
- FWBHETKCLVMNFS-UHFFFAOYSA-N 4',6-Diamino-2-phenylindol Chemical compound C1=CC(C(=N)N)=CC=C1C1=CC2=CC=C(C(N)=N)C=C2N1 FWBHETKCLVMNFS-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 235000006491 Acacia senegal Nutrition 0.000 description 2
- 102000009346 Adenosine receptors Human genes 0.000 description 2
- 108050000203 Adenosine receptors Proteins 0.000 description 2
- 206010001497 Agitation Diseases 0.000 description 2
- 208000031091 Amnestic disease Diseases 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 2
- 208000019901 Anxiety disease Diseases 0.000 description 2
- 235000003911 Arachis Nutrition 0.000 description 2
- 244000105624 Arachis hypogaea Species 0.000 description 2
- 241000416162 Astragalus gummifer Species 0.000 description 2
- 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 description 2
- 208000020925 Bipolar disease Diseases 0.000 description 2
- 241000283690 Bos taurus Species 0.000 description 2
- 201000006474 Brain Ischemia Diseases 0.000 description 2
- 208000003174 Brain Neoplasms Diseases 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- 208000029812 Cerebral Small Vessel disease Diseases 0.000 description 2
- 206010008120 Cerebral ischaemia Diseases 0.000 description 2
- 206010067466 Cerebral microangiopathy Diseases 0.000 description 2
- 208000017667 Chronic Disease Diseases 0.000 description 2
- 208000035473 Communicable disease Diseases 0.000 description 2
- 208000011990 Corticobasal Degeneration Diseases 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- 201000010374 Down Syndrome Diseases 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 241000282326 Felis catus Species 0.000 description 2
- 206010016845 Foetal alcohol syndrome Diseases 0.000 description 2
- 208000001914 Fragile X syndrome Diseases 0.000 description 2
- 102100022630 Glutamate receptor ionotropic, NMDA 2B Human genes 0.000 description 2
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 2
- 208000016905 Hashimoto encephalopathy Diseases 0.000 description 2
- 208000026350 Inborn Genetic disease Diseases 0.000 description 2
- 150000008575 L-amino acids Chemical class 0.000 description 2
- 229930182816 L-glutamine Natural products 0.000 description 2
- STECJAGHUSJQJN-USLFZFAMSA-N LSM-4015 Chemical compound C1([C@@H](CO)C(=O)OC2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-USLFZFAMSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 208000020358 Learning disease Diseases 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 208000036626 Mental retardation Diseases 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 239000012901 Milli-Q water Substances 0.000 description 2
- 208000006079 Near drowning Diseases 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 102000003840 Opioid Receptors Human genes 0.000 description 2
- 108090000137 Opioid Receptors Proteins 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- WYNCHZVNFNFDNH-UHFFFAOYSA-N Oxazolidine Chemical compound C1COCN1 WYNCHZVNFNFDNH-UHFFFAOYSA-N 0.000 description 2
- 241001494479 Pecora Species 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 229920000954 Polyglycolide Polymers 0.000 description 2
- 241000288906 Primates Species 0.000 description 2
- 238000000692 Student's t-test Methods 0.000 description 2
- 208000032851 Subarachnoid Hemorrhage Diseases 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 102000003978 Tissue Plasminogen Activator Human genes 0.000 description 2
- 108090000373 Tissue Plasminogen Activator Proteins 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 229920001615 Tragacanth Polymers 0.000 description 2
- 229920004890 Triton X-100 Polymers 0.000 description 2
- 239000013504 Triton X-100 Substances 0.000 description 2
- 102000004243 Tubulin Human genes 0.000 description 2
- 108090000704 Tubulin Proteins 0.000 description 2
- 208000026928 Turner syndrome Diseases 0.000 description 2
- 206010054880 Vascular insufficiency Diseases 0.000 description 2
- 230000005856 abnormality Effects 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 229960005305 adenosine Drugs 0.000 description 2
- 125000003282 alkyl amino group Chemical group 0.000 description 2
- 125000004414 alkyl thio group Chemical group 0.000 description 2
- 230000006986 amnesia Effects 0.000 description 2
- 230000037005 anaesthesia Effects 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 230000036506 anxiety Effects 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical class OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 208000036815 beta tubulin Diseases 0.000 description 2
- 239000004305 biphenyl Chemical group 0.000 description 2
- 235000010290 biphenyl Nutrition 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 238000004364 calculation method Methods 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 239000013592 cell lysate Substances 0.000 description 2
- 210000004720 cerebrum Anatomy 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 239000002131 composite material Substances 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 229920001577 copolymer Polymers 0.000 description 2
- 230000001054 cortical effect Effects 0.000 description 2
- 230000007812 deficiency Effects 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 208000037765 diseases and disorders Diseases 0.000 description 2
- 239000000890 drug combination Substances 0.000 description 2
- 238000012377 drug delivery Methods 0.000 description 2
- 206010013932 dyslexia Diseases 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 230000021824 exploration behavior Effects 0.000 description 2
- 208000026934 fetal alcohol spectrum disease Diseases 0.000 description 2
- 201000007794 fetal alcohol syndrome Diseases 0.000 description 2
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 208000016361 genetic disease Diseases 0.000 description 2
- 239000004220 glutamic acid Substances 0.000 description 2
- 235000013922 glutamic acid Nutrition 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 229940093915 gynecological organic acid Drugs 0.000 description 2
- 125000005885 heterocycloalkylalkyl group Chemical group 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- 150000002430 hydrocarbons Chemical group 0.000 description 2
- 208000003906 hydrocephalus Diseases 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- 208000035231 inattentive type attention deficit hyperactivity disease Diseases 0.000 description 2
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 208000027866 inflammatory disease Diseases 0.000 description 2
- 230000000977 initiatory effect Effects 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 201000003723 learning disability Diseases 0.000 description 2
- 235000010445 lecithin Nutrition 0.000 description 2
- 239000000787 lecithin Substances 0.000 description 2
- 229940067606 lecithin Drugs 0.000 description 2
- 231100000518 lethal Toxicity 0.000 description 2
- 230000001665 lethal effect Effects 0.000 description 2
- 210000004558 lewy body Anatomy 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 230000006742 locomotor activity Effects 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
- BUGYDGFZZOZRHP-UHFFFAOYSA-N memantine Chemical compound C1C(C2)CC3(C)CC1(C)CC2(N)C3 BUGYDGFZZOZRHP-UHFFFAOYSA-N 0.000 description 2
- 229960004640 memantine Drugs 0.000 description 2
- 230000006984 memory degeneration Effects 0.000 description 2
- 208000023060 memory loss Diseases 0.000 description 2
- 208000030159 metabolic disease Diseases 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 208000027061 mild cognitive impairment Diseases 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 239000002480 mineral oil Substances 0.000 description 2
- 235000010446 mineral oil Nutrition 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 2
- 125000002757 morpholinyl group Chemical group 0.000 description 2
- 230000007659 motor function Effects 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 230000007658 neurological function Effects 0.000 description 2
- 230000016273 neuron death Effects 0.000 description 2
- 230000000324 neuroprotective effect Effects 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 239000000346 nonvolatile oil Substances 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 230000003204 osmotic effect Effects 0.000 description 2
- 230000036542 oxidative stress Effects 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229940124583 pain medication Drugs 0.000 description 2
- 230000007170 pathology Effects 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- 125000003386 piperidinyl group Chemical group 0.000 description 2
- 239000002798 polar solvent Substances 0.000 description 2
- 229920000747 poly(lactic acid) Polymers 0.000 description 2
- 239000004633 polyglycolic acid Substances 0.000 description 2
- 239000004626 polylactic acid Substances 0.000 description 2
- 208000001282 primary progressive aphasia Diseases 0.000 description 2
- 201000002212 progressive supranuclear palsy Diseases 0.000 description 2
- 238000000159 protein binding assay Methods 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 230000027425 release of sequestered calcium ion into cytosol Effects 0.000 description 2
- 230000010410 reperfusion Effects 0.000 description 2
- 201000000980 schizophrenia Diseases 0.000 description 2
- 230000037152 sensory function Effects 0.000 description 2
- 229910052710 silicon Inorganic materials 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 235000011069 sorbitan monooleate Nutrition 0.000 description 2
- 239000001593 sorbitan monooleate Substances 0.000 description 2
- 229940035049 sorbitan monooleate Drugs 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 230000006886 spatial memory Effects 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 230000005062 synaptic transmission Effects 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 229960000187 tissue plasminogen activator Drugs 0.000 description 2
- 238000011269 treatment regimen Methods 0.000 description 2
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- 208000023577 vascular insufficiency disease Diseases 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- 230000031836 visual learning Effects 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- SHAHPWSYJFYMRX-GDLCADMTSA-N (2S)-2-(4-{[(1R,2S)-2-hydroxycyclopentyl]methyl}phenyl)propanoic acid Chemical compound C1=CC([C@@H](C(O)=O)C)=CC=C1C[C@@H]1[C@@H](O)CCC1 SHAHPWSYJFYMRX-GDLCADMTSA-N 0.000 description 1
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 1
- YFRGJIVWBMOBIT-GTDPEVRFSA-N (2e,4e,8z,11z)-n-(2-methylpropyl)tetradeca-2,4,8,11-tetraenamide Chemical compound CC\C=C/C\C=C/CC\C=C\C=C\C(=O)NCC(C)C YFRGJIVWBMOBIT-GTDPEVRFSA-N 0.000 description 1
- DIXMBHMNEHPFCX-MCMMXHMISA-N (2r)-2-[5-[6-amino-5-[(1r)-1-[5-fluoro-2-(triazol-2-yl)phenyl]ethoxy]pyridin-3-yl]-4-methyl-1,3-thiazol-2-yl]propane-1,2-diol Chemical compound O([C@H](C)C=1C(=CC=C(F)C=1)N1N=CC=N1)C(C(=NC=1)N)=CC=1C=1SC([C@](C)(O)CO)=NC=1C DIXMBHMNEHPFCX-MCMMXHMISA-N 0.000 description 1
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- LJIOTBMDLVHTBO-CUYJMHBOSA-N (2s)-2-amino-n-[(1r,2r)-1-cyano-2-[4-[4-(4-methylpiperazin-1-yl)sulfonylphenyl]phenyl]cyclopropyl]butanamide Chemical compound CC[C@H](N)C(=O)N[C@]1(C#N)C[C@@H]1C1=CC=C(C=2C=CC(=CC=2)S(=O)(=O)N2CCN(C)CC2)C=C1 LJIOTBMDLVHTBO-CUYJMHBOSA-N 0.000 description 1
- KRIWIRSMQRQYJG-DLBZAZTESA-N (2s,3s)-3-[[7-(benzylamino)-3-propan-2-ylpyrazolo[1,5-a]pyrimidin-5-yl]amino]butane-1,2,4-triol Chemical compound C=1C(N[C@@H](CO)[C@H](O)CO)=NC2=C(C(C)C)C=NN2C=1NCC1=CC=CC=C1 KRIWIRSMQRQYJG-DLBZAZTESA-N 0.000 description 1
- LOGOEBMHHXYBID-WBKNRDRNSA-N (2s,3s,4r,5r)-5-[6-[(4-amino-3-iodanylphenyl)methylamino]purin-9-yl]-3,4-dihydroxy-n-methyloxolane-2-carboxamide Chemical compound O[C@@H]1[C@H](O)[C@@H](C(=O)NC)O[C@H]1N1C2=NC=NC(NCC=3C=C([125I])C(N)=CC=3)=C2N=C1 LOGOEBMHHXYBID-WBKNRDRNSA-N 0.000 description 1
- BQGZYYQWZXJRCS-KBPBESRZSA-N (2s,4s)-2-butyl-5,5-diethyl-4-(2-methylpropyl)-1,3-oxazolidine Chemical compound CCCC[C@H]1N[C@@H](CC(C)C)C(CC)(CC)O1 BQGZYYQWZXJRCS-KBPBESRZSA-N 0.000 description 1
- ABMYFPWZOAAEBP-ROUUACIJSA-N (2s,4s)-3,5,5-triethyl-4-(2-methylpropyl)-2-phenyl-1,3-oxazolidine Chemical compound O1C(CC)(CC)[C@H](CC(C)C)N(CC)[C@@H]1C1=CC=CC=C1 ABMYFPWZOAAEBP-ROUUACIJSA-N 0.000 description 1
- GIHFEAJBYUYYDV-GJZGRUSLSA-N (2s,4s)-4-benzyl-2,5,5-triethyl-1,3-oxazolidine Chemical compound CCC1(CC)O[C@@H](CC)N[C@H]1CC1=CC=CC=C1 GIHFEAJBYUYYDV-GJZGRUSLSA-N 0.000 description 1
- FCODYSZJZSCTRL-IRXDYDNUSA-N (2s,4s)-4-benzyl-2-butyl-5,5-diethyl-1,3-oxazolidine Chemical compound CCC1(CC)O[C@@H](CCCC)N[C@H]1CC1=CC=CC=C1 FCODYSZJZSCTRL-IRXDYDNUSA-N 0.000 description 1
- RVWAIUWAJDKTPB-OALUTQOASA-N (2s,4s)-4-benzyl-2-butyl-5,5-dipropyl-1,3-oxazolidine Chemical compound CCCC1(CCC)O[C@@H](CCCC)N[C@H]1CC1=CC=CC=C1 RVWAIUWAJDKTPB-OALUTQOASA-N 0.000 description 1
- TUMFLUKZJWVAQV-PMACEKPBSA-N (2s,4s)-4-benzyl-2-pentyl-5,5-dipropyl-1,3-oxazolidine Chemical compound CCCC1(CCC)O[C@@H](CCCCC)N[C@H]1CC1=CC=CC=C1 TUMFLUKZJWVAQV-PMACEKPBSA-N 0.000 description 1
- PFCUKQYBJOJTAJ-PMACEKPBSA-N (2s,4s)-4-benzyl-5,5-diethyl-2-(3-methylphenyl)-1,3-oxazolidine Chemical compound C([C@@H]1N[C@@H](OC1(CC)CC)C=1C=C(C)C=CC=1)C1=CC=CC=C1 PFCUKQYBJOJTAJ-PMACEKPBSA-N 0.000 description 1
- VEBITAQEJMXHTO-PMACEKPBSA-N (2s,4s)-4-benzyl-5,5-diethyl-2-(4-methylphenyl)-1,3-oxazolidine Chemical compound C([C@@H]1N[C@@H](OC1(CC)CC)C=1C=CC(C)=CC=1)C1=CC=CC=C1 VEBITAQEJMXHTO-PMACEKPBSA-N 0.000 description 1
- ZGMSBUMFGYWENA-ROUUACIJSA-N (2s,4s)-4-benzyl-5,5-diethyl-2-pentyl-1,3-oxazolidine Chemical compound CCC1(CC)O[C@@H](CCCCC)N[C@H]1CC1=CC=CC=C1 ZGMSBUMFGYWENA-ROUUACIJSA-N 0.000 description 1
- NYTNFICHFXWUBQ-OALUTQOASA-N (2s,4s)-4-benzyl-5,5-diethyl-2-phenyl-1,3-oxazolidine Chemical compound C([C@@H]1N[C@@H](OC1(CC)CC)C=1C=CC=CC=1)C1=CC=CC=C1 NYTNFICHFXWUBQ-OALUTQOASA-N 0.000 description 1
- OMXAULLPNIAOTQ-TTZKSVMKSA-N (2s,4s)-4-butan-2-yl-2-butyl-5,5-diethyl-1,3-oxazolidine Chemical compound CCCC[C@H]1N[C@@H](C(C)CC)C(CC)(CC)O1 OMXAULLPNIAOTQ-TTZKSVMKSA-N 0.000 description 1
- SODZEKXJEMBBBV-HGVHAKBWSA-N (2s,4s)-4-butan-2-yl-5,5-diethyl-2-(3-methylphenyl)-1,3-oxazolidine Chemical compound O1C(CC)(CC)[C@H](C(C)CC)N[C@@H]1C1=CC=CC(C)=C1 SODZEKXJEMBBBV-HGVHAKBWSA-N 0.000 description 1
- NAJHUUXCQMKEIT-HGVHAKBWSA-N (2s,4s)-4-butan-2-yl-5,5-diethyl-2-(4-methylphenyl)-1,3-oxazolidine Chemical compound O1C(CC)(CC)[C@H](C(C)CC)N[C@@H]1C1=CC=C(C)C=C1 NAJHUUXCQMKEIT-HGVHAKBWSA-N 0.000 description 1
- WVCGETCUEUKADB-FGRDXJNISA-N (2s,4s)-4-butan-2-yl-5,5-diethyl-2-pentyl-1,3-oxazolidine Chemical compound CCCCC[C@H]1N[C@@H](C(C)CC)C(CC)(CC)O1 WVCGETCUEUKADB-FGRDXJNISA-N 0.000 description 1
- ZNXCXMYHKUFEQU-FMYDAXTQSA-N (2s,4s)-4-butan-2-yl-5,5-diethyl-2-phenyl-1,3-oxazolidine Chemical compound O1C(CC)(CC)[C@H](C(C)CC)N[C@@H]1C1=CC=CC=C1 ZNXCXMYHKUFEQU-FMYDAXTQSA-N 0.000 description 1
- NUHMRJJTODDIFL-IRXDYDNUSA-N (2s,4s)-5,5-diethyl-2-(3-methylphenyl)-4-(2-methylpropyl)-1,3-oxazolidine Chemical compound N1[C@@H](CC(C)C)C(CC)(CC)O[C@H]1C1=CC=CC(C)=C1 NUHMRJJTODDIFL-IRXDYDNUSA-N 0.000 description 1
- QTNOXNHFSVYRAA-IRXDYDNUSA-N (2s,4s)-5,5-diethyl-2-(4-methylphenyl)-4-(2-methylpropyl)-1,3-oxazolidine Chemical compound N1[C@@H](CC(C)C)C(CC)(CC)O[C@H]1C1=CC=C(C)C=C1 QTNOXNHFSVYRAA-IRXDYDNUSA-N 0.000 description 1
- CCNNUCYXGWXFSO-GJZGRUSLSA-N (2s,4s)-5,5-diethyl-4-(2-methylpropyl)-2-pentyl-1,3-oxazolidine Chemical compound CCCCC[C@H]1N[C@@H](CC(C)C)C(CC)(CC)O1 CCNNUCYXGWXFSO-GJZGRUSLSA-N 0.000 description 1
- LPNRUMVKXCLEBE-JXVRESAISA-L (3r)-4-[[(e)-2-[5-ethyl-4-(4-fluorophenyl)-6-phenyl-2-propan-2-ylpyridin-3-yl]ethenyl]-oxidophosphoryl]-3-hydroxybutanoate Chemical compound CCC1=C(C=2C=CC=CC=2)N=C(C(C)C)C(\C=C\P([O-])(=O)C[C@H](O)CC([O-])=O)=C1C1=CC=C(F)C=C1 LPNRUMVKXCLEBE-JXVRESAISA-L 0.000 description 1
- PNHBRYIAJCYNDA-VQCQRNETSA-N (4r)-6-[2-[2-ethyl-4-(4-fluorophenyl)-6-phenylpyridin-3-yl]ethyl]-4-hydroxyoxan-2-one Chemical compound C([C@H](O)C1)C(=O)OC1CCC=1C(CC)=NC(C=2C=CC=CC=2)=CC=1C1=CC=C(F)C=C1 PNHBRYIAJCYNDA-VQCQRNETSA-N 0.000 description 1
- QVBVQHTXLPNXEY-ZMFCMNQTSA-N (4r)-6-[2-[4-(4-fluorophenyl)-6-phenyl-2-propan-2-ylpyridin-3-yl]ethyl]-4-hydroxyoxan-2-one Chemical compound C([C@H](O)C1)C(=O)OC1CCC=1C(C(C)C)=NC(C=2C=CC=CC=2)=CC=1C1=CC=C(F)C=C1 QVBVQHTXLPNXEY-ZMFCMNQTSA-N 0.000 description 1
- FRJJJAKBRKABFA-TYFAACHXSA-N (4r,6s)-6-[(e)-2-[6-chloro-4-(4-fluorophenyl)-2-propan-2-ylquinolin-3-yl]ethenyl]-4-hydroxyoxan-2-one Chemical compound C(\[C@H]1OC(=O)C[C@H](O)C1)=C/C=1C(C(C)C)=NC2=CC=C(Cl)C=C2C=1C1=CC=C(F)C=C1 FRJJJAKBRKABFA-TYFAACHXSA-N 0.000 description 1
- HKJKCPKPSSVUHY-GRTNUQQKSA-M (6r)-6-[(5s)-6,6-dimethyl-7,8-dihydro-5h-[1,3]dioxolo[4,5-g]isoquinolin-6-ium-5-yl]-6h-furo[3,4-g][1,3]benzodioxol-8-one;iodide Chemical compound [I-].O([C@H]1[C@@H]2C3=CC=4OCOC=4C=C3CC[N+]2(C)C)C(=O)C2=C1C=CC1=C2OCO1 HKJKCPKPSSVUHY-GRTNUQQKSA-M 0.000 description 1
- QOLHWXNSCZGWHK-BWBORTOCSA-N (6r,7r)-1-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-4,7-dihydroxy-6-(11-phenoxyundecylcarbamoyloxy)-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid Chemical compound C([C@@H](C)[C@H](OC(C)=O)C(=C)CCC12[C@@H]([C@@H](OC(=O)NCCCCCCCCCCCOC=3C=CC=CC=3)C(O1)(C(O)=O)C(O)(C(O2)C(O)=O)C(O)=O)O)C1=CC=CC=C1 QOLHWXNSCZGWHK-BWBORTOCSA-N 0.000 description 1
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 description 1
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- DDMOUSALMHHKOS-UHFFFAOYSA-N 1,2-dichloro-1,1,2,2-tetrafluoroethane Chemical compound FC(F)(Cl)C(F)(F)Cl DDMOUSALMHHKOS-UHFFFAOYSA-N 0.000 description 1
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 1
- 125000005940 1,4-dioxanyl group Chemical group 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- UPMNYSLERSERFU-UHFFFAOYSA-N 2,4,6-tritert-butyl-n,n-dimethylbenzamide Chemical compound CN(C)C(=O)C1=C(C(C)(C)C)C=C(C(C)(C)C)C=C1C(C)(C)C UPMNYSLERSERFU-UHFFFAOYSA-N 0.000 description 1
- JGMXNNSYEFOBHQ-OWOJBTEDSA-N 2-[(e)-4-morpholin-4-ylbut-2-enyl]-1,1-dioxothieno[3,2-e]thiazine-6-sulfonamide Chemical compound O=S1(=O)C=2SC(S(=O)(=O)N)=CC=2C=CN1C\C=C\CN1CCOCC1 JGMXNNSYEFOBHQ-OWOJBTEDSA-N 0.000 description 1
- AKBHYCHPWZPGAH-UHFFFAOYSA-N 2-[3-[(3-chloro-4-methylphenyl)methoxy]azetidine-1-carbonyl]-7-oxa-5-azaspiro[3.4]octan-6-one Chemical compound CC1=C(Cl)C=C(COC2CN(C2)C(=O)C2CC3(C2)COC(=O)N3)C=C1 AKBHYCHPWZPGAH-UHFFFAOYSA-N 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- ZPSJGADGUYYRKE-UHFFFAOYSA-N 2H-pyran-2-one Chemical compound O=C1C=CC=CO1 ZPSJGADGUYYRKE-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- OVDGUTHABMXVMI-UHFFFAOYSA-N 3-nitro-4-(propylamino)benzoic acid Chemical compound CCCNC1=CC=C(C(O)=O)C=C1[N+]([O-])=O OVDGUTHABMXVMI-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-M 4-hydroxybenzoate Chemical compound OC1=CC=C(C([O-])=O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-M 0.000 description 1
- 125000004070 6 membered heterocyclic group Chemical group 0.000 description 1
- RRELDGDKULRRDM-UHFFFAOYSA-N 6-[2-chloro-4-nitro-5-(oxan-4-yloxy)anilino]-3,4-dihydro-1H-quinolin-2-one Chemical compound [O-][N+](=O)c1cc(Cl)c(Nc2ccc3NC(=O)CCc3c2)cc1OC1CCOCC1 RRELDGDKULRRDM-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical class CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 102000008161 Adenosine A3 Receptor Human genes 0.000 description 1
- 108010060261 Adenosine A3 Receptor Proteins 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Natural products OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 1
- 239000012583 B-27 Supplement Substances 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 206010057248 Cell death Diseases 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- 208000028698 Cognitive impairment Diseases 0.000 description 1
- 229940126559 Compound 4e Drugs 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- KDXKERNSBIXSRK-RXMQYKEDSA-N D-lysine Chemical compound NCCCC[C@@H](N)C(O)=O KDXKERNSBIXSRK-RXMQYKEDSA-N 0.000 description 1
- 239000004338 Dichlorodifluoromethane Substances 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 241000283073 Equus caballus Species 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical class [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- 102100029458 Glutamate receptor ionotropic, NMDA 2A Human genes 0.000 description 1
- 102100022631 Glutamate receptor ionotropic, NMDA 2C Human genes 0.000 description 1
- 102100022626 Glutamate receptor ionotropic, NMDA 2D Human genes 0.000 description 1
- 102100033495 Glycine dehydrogenase (decarboxylating), mitochondrial Human genes 0.000 description 1
- 244000068988 Glycine max Species 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 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 1
- 102000006541 Ionotropic Glutamate Receptors Human genes 0.000 description 1
- 108010008812 Ionotropic Glutamate Receptors Proteins 0.000 description 1
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- 102000003855 L-lactate dehydrogenase Human genes 0.000 description 1
- 108700023483 L-lactate dehydrogenases Proteins 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 1
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 102000004086 Ligand-Gated Ion Channels Human genes 0.000 description 1
- 108090000543 Ligand-Gated Ion Channels Proteins 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 208000019022 Mood disease Diseases 0.000 description 1
- TZYWCYJVHRLUCT-VABKMULXSA-N N-benzyloxycarbonyl-L-leucyl-L-leucyl-L-leucinal Chemical compound CC(C)C[C@@H](C=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)OCC1=CC=CC=C1 TZYWCYJVHRLUCT-VABKMULXSA-N 0.000 description 1
- HOKKHZGPKSLGJE-UHFFFAOYSA-N N-methyl-D-aspartic acid Natural products CNC(C(O)=O)CC(O)=O HOKKHZGPKSLGJE-UHFFFAOYSA-N 0.000 description 1
- TZCCKCLHNUSAMQ-DUGSHLAESA-N NC(=O)C[C@H](NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](Cc2ccc(F)cc2)NC(=O)[C@H](Cc3c[nH]c4ccccc34)NC(=O)Cc5cccs5)C(=O)N Chemical compound NC(=O)C[C@H](NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](Cc2ccc(F)cc2)NC(=O)[C@H](Cc3c[nH]c4ccccc34)NC(=O)Cc5cccs5)C(=O)N TZCCKCLHNUSAMQ-DUGSHLAESA-N 0.000 description 1
- 229940127523 NMDA Receptor Antagonists Drugs 0.000 description 1
- 108020002076 NR2 subfamily Proteins 0.000 description 1
- 102000038100 NR2 subfamily Human genes 0.000 description 1
- 108091008644 NR2D Proteins 0.000 description 1
- 229910003827 NRaRb Inorganic materials 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- 239000000020 Nitrocellulose Substances 0.000 description 1
- 208000035544 Nonketotic hyperglycinaemia Diseases 0.000 description 1
- 229910003849 O-Si Inorganic materials 0.000 description 1
- 229910004679 ONO2 Inorganic materials 0.000 description 1
- AKQOBHZKBDHWQI-BZEFIUHZSA-N O[C@H]1C[C@@H](CCC1)N1C(C2(C3=C1N=C(N=C3)NC1=CC=C(C=C1)S(=O)(=O)NC([2H])([2H])[2H])CC2)=O Chemical compound O[C@H]1C[C@@H](CCC1)N1C(C2(C3=C1N=C(N=C3)NC1=CC=C(C=C1)S(=O)(=O)NC([2H])([2H])[2H])CC2)=O AKQOBHZKBDHWQI-BZEFIUHZSA-N 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 229910003872 O—Si Inorganic materials 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 102000007982 Phosphoproteins Human genes 0.000 description 1
- 108010089430 Phosphoproteins Proteins 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920001710 Polyorthoester Polymers 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 102000004257 Potassium Channel Human genes 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 239000012083 RIPA buffer Substances 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 108010038912 Retinoid X Receptors Proteins 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 229940125907 SJ995973 Drugs 0.000 description 1
- 229910006124 SOCl2 Inorganic materials 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 229910007161 Si(CH3)3 Inorganic materials 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 241000282898 Sus scrofa Species 0.000 description 1
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 1
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 1
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 1
- 102000016913 Voltage-Gated Sodium Channels Human genes 0.000 description 1
- 108010053752 Voltage-Gated Sodium Channels Proteins 0.000 description 1
- WERKSKAQRVDLDW-ANOHMWSOSA-N [(2s,3r,4r,5r)-2,3,4,5,6-pentahydroxyhexyl] (z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO WERKSKAQRVDLDW-ANOHMWSOSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 150000001370 alpha-amino acid derivatives Chemical class 0.000 description 1
- 150000001371 alpha-amino acids Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 230000000338 anxiogenic effect Effects 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 235000009697 arginine Nutrition 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 235000009582 asparagine Nutrition 0.000 description 1
- 150000001508 asparagines Chemical class 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 210000003050 axon Anatomy 0.000 description 1
- 125000002393 azetidinyl group Chemical group 0.000 description 1
- 150000007514 bases Chemical class 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- 230000006736 behavioral deficit Effects 0.000 description 1
- 238000009227 behaviour therapy Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000004603 benzisoxazolyl group Chemical group O1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 238000002306 biochemical method Methods 0.000 description 1
- 229920002988 biodegradable polymer Polymers 0.000 description 1
- 239000004621 biodegradable polymer Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 229920001400 block copolymer Polymers 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 235000019437 butane-1,3-diol Nutrition 0.000 description 1
- AIYUHDOJVYHVIT-UHFFFAOYSA-M caesium chloride Chemical compound [Cl-].[Cs+] AIYUHDOJVYHVIT-UHFFFAOYSA-M 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 230000009460 calcium influx Effects 0.000 description 1
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229960004424 carbon dioxide Drugs 0.000 description 1
- 125000006243 carbonyl protecting group Chemical group 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 210000001168 carotid artery common Anatomy 0.000 description 1
- 210000005056 cell body Anatomy 0.000 description 1
- 230000005779 cell damage Effects 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 208000037887 cell injury Diseases 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 206010008129 cerebral palsy Diseases 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000007910 chewable tablet Substances 0.000 description 1
- 229940112822 chewing gum Drugs 0.000 description 1
- 235000015218 chewing gum Nutrition 0.000 description 1
- RNFNDJAIBTYOQL-UHFFFAOYSA-N chloral hydrate Chemical compound OC(O)C(Cl)(Cl)Cl RNFNDJAIBTYOQL-UHFFFAOYSA-N 0.000 description 1
- 229960002327 chloral hydrate Drugs 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 230000007278 cognition impairment Effects 0.000 description 1
- 230000003930 cognitive ability Effects 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229940125872 compound 4d Drugs 0.000 description 1
- 229940126115 compound 4f Drugs 0.000 description 1
- 229940125880 compound 4j Drugs 0.000 description 1
- 229940127108 compound 5g Drugs 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 230000001010 compromised effect Effects 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 210000004748 cultured cell Anatomy 0.000 description 1
- WZHCOOQXZCIUNC-UHFFFAOYSA-N cyclandelate Chemical compound C1C(C)(C)CC(C)CC1OC(=O)C(O)C1=CC=CC=C1 WZHCOOQXZCIUNC-UHFFFAOYSA-N 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 230000001351 cycling effect Effects 0.000 description 1
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 238000009795 derivation Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000000032 diagnostic agent Substances 0.000 description 1
- 229940039227 diagnostic agent Drugs 0.000 description 1
- 125000004663 dialkyl amino group Chemical group 0.000 description 1
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 1
- 235000019404 dichlorodifluoromethane Nutrition 0.000 description 1
- 229940042935 dichlorodifluoromethane Drugs 0.000 description 1
- 229940087091 dichlorotetrafluoroethane Drugs 0.000 description 1
- 230000003292 diminished effect Effects 0.000 description 1
- 230000003467 diminishing effect Effects 0.000 description 1
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 235000019800 disodium phosphate Nutrition 0.000 description 1
- 238000012137 double-staining Methods 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000007911 effervescent powder Substances 0.000 description 1
- 239000007938 effervescent tablet Substances 0.000 description 1
- 239000003974 emollient agent Substances 0.000 description 1
- 238000004945 emulsification Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 239000011982 enantioselective catalyst Substances 0.000 description 1
- 230000037149 energy metabolism Effects 0.000 description 1
- 210000004700 fetal blood Anatomy 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 229940074045 glyceryl distearate Drugs 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 201000011205 glycine encephalopathy Diseases 0.000 description 1
- 150000002357 guanidines Chemical class 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 108091008634 hepatocyte nuclear factors 4 Proteins 0.000 description 1
- 125000005343 heterocyclic alkyl group Chemical group 0.000 description 1
- FBPFZTCFMRRESA-UHFFFAOYSA-N hexane-1,2,3,4,5,6-hexol Chemical compound OCC(O)C(O)C(O)C(O)CO FBPFZTCFMRRESA-UHFFFAOYSA-N 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 210000001320 hippocampus Anatomy 0.000 description 1
- WJRBRSLFGCUECM-UHFFFAOYSA-N hydantoin Chemical compound O=C1CNC(=O)N1 WJRBRSLFGCUECM-UHFFFAOYSA-N 0.000 description 1
- 229940091173 hydantoin Drugs 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- 229920001600 hydrophobic polymer Polymers 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 208000013403 hyperactivity Diseases 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- YAMHXTCMCPHKLN-UHFFFAOYSA-N imidazolidin-2-one Chemical compound O=C1NCCN1 YAMHXTCMCPHKLN-UHFFFAOYSA-N 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 125000004857 imidazopyridinyl group Chemical class N1C(=NC2=C1C=CC=N2)* 0.000 description 1
- 238000012744 immunostaining Methods 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 229940102213 injectable suspension Drugs 0.000 description 1
- 150000002484 inorganic compounds Chemical class 0.000 description 1
- 229910010272 inorganic material Inorganic materials 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 230000004171 ischemic cascade Effects 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 235000015110 jellies Nutrition 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- TYQCGQRIZGCHNB-JLAZNSOCSA-N l-ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(O)=C(O)C1=O TYQCGQRIZGCHNB-JLAZNSOCSA-N 0.000 description 1
- 239000004922 lacquer Substances 0.000 description 1
- 238000000670 ligand binding assay Methods 0.000 description 1
- 235000015250 liver sausages Nutrition 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 230000027928 long-term synaptic potentiation Effects 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- 235000018977 lysine Nutrition 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 159000000003 magnesium salts Chemical class 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
- 239000011976 maleic acid Substances 0.000 description 1
- 238000007726 management method Methods 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000007334 memory performance Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- QVDXUKJJGUSGLS-LURJTMIESA-N methyl L-leucinate Chemical compound COC(=O)[C@@H](N)CC(C)C QVDXUKJJGUSGLS-LURJTMIESA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 210000001700 mitochondrial membrane Anatomy 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 125000006682 monohaloalkyl group Chemical group 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 230000001095 motoneuron effect Effects 0.000 description 1
- 229940126619 mouse monoclonal antibody Drugs 0.000 description 1
- 239000002324 mouth wash Substances 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- PHHRKRGXWSEXFZ-UHFFFAOYSA-N n-(pyridin-3-ylmethyl)-3-[[2-[(2,3,4-trifluorophenoxy)methyl]-1,3-benzoxazol-4-yl]oxy]propan-1-amine Chemical compound FC1=C(F)C(F)=CC=C1OCC(OC1=CC=C2)=NC1=C2OCCCNCC1=CC=CN=C1 PHHRKRGXWSEXFZ-UHFFFAOYSA-N 0.000 description 1
- XZMHJYWMCRQSSI-UHFFFAOYSA-N n-[5-[2-(3-acetylanilino)-1,3-thiazol-4-yl]-4-methyl-1,3-thiazol-2-yl]benzamide Chemical compound CC(=O)C1=CC=CC(NC=2SC=C(N=2)C2=C(N=C(NC(=O)C=3C=CC=CC=3)S2)C)=C1 XZMHJYWMCRQSSI-UHFFFAOYSA-N 0.000 description 1
- 239000006199 nebulizer Substances 0.000 description 1
- 230000032405 negative regulation of neuron apoptotic process Effects 0.000 description 1
- 210000000944 nerve tissue Anatomy 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 210000002241 neurite Anatomy 0.000 description 1
- 230000009223 neuronal apoptosis Effects 0.000 description 1
- 230000007604 neuronal communication Effects 0.000 description 1
- 230000007512 neuronal protection Effects 0.000 description 1
- 239000004090 neuroprotective agent Substances 0.000 description 1
- 230000002887 neurotoxic effect Effects 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 229920001220 nitrocellulos Polymers 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 231100000344 non-irritating Toxicity 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 230000001473 noxious effect Effects 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 229940041672 oral gel Drugs 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000003791 organic solvent mixture Substances 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 125000001312 palmitoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 201000005936 periventricular leukomalacia Diseases 0.000 description 1
- 239000002831 pharmacologic agent Substances 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 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
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical class OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 description 1
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical compound O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 229920003229 poly(methyl methacrylate) Polymers 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
- 229920001610 polycaprolactone Polymers 0.000 description 1
- 229920002721 polycyanoacrylate Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 125000006684 polyhaloalkyl group Polymers 0.000 description 1
- 229920000656 polylysine Polymers 0.000 description 1
- 239000004926 polymethyl methacrylate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 229920006324 polyoxymethylene Polymers 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 108020001213 potassium channel Proteins 0.000 description 1
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
- 235000008476 powdered milk Nutrition 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 238000011321 prophylaxis Methods 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
- 230000004224 protection Effects 0.000 description 1
- 230000001273 psychotogenic effect Effects 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 239000005297 pyrex Substances 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 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
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 description 1
- 239000007845 reactive nitrogen species Substances 0.000 description 1
- 239000003642 reactive oxygen metabolite Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 229940075993 receptor modulator Drugs 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 238000005464 sample preparation method Methods 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 229960004499 scopolamine hydrobromide Drugs 0.000 description 1
- WTGQALLALWYDJH-MOUKNHLCSA-N scopolamine hydrobromide (anhydrous) Chemical compound Br.C1([C@@H](CO)C(=O)O[C@H]2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 WTGQALLALWYDJH-MOUKNHLCSA-N 0.000 description 1
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 1
- 230000009155 sensory pathway Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 102000034285 signal transducing proteins Human genes 0.000 description 1
- 108091006024 signal transducing proteins Proteins 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 229910001467 sodium calcium phosphate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 235000011008 sodium phosphates Nutrition 0.000 description 1
- STZCRXQWRGQSJD-UHFFFAOYSA-M sodium;4-[[4-(dimethylamino)phenyl]diazenyl]benzenesulfonate Chemical compound [Na+].C1=CC(N(C)C)=CC=C1N=NC1=CC=C(S([O-])(=O)=O)C=C1 STZCRXQWRGQSJD-UHFFFAOYSA-M 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 208000020431 spinal cord injury Diseases 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 230000008293 synaptic mechanism Effects 0.000 description 1
- 230000003956 synaptic plasticity Effects 0.000 description 1
- WGRQANOPCQRCME-PMACEKPBSA-N teneligliptin Chemical compound O=C([C@H]1NC[C@H](C1)N1CCN(CC1)C1=CC(=NN1C=1C=CC=CC=1)C)N1CCSC1 WGRQANOPCQRCME-PMACEKPBSA-N 0.000 description 1
- 108091008646 testicular receptors Proteins 0.000 description 1
- YMBCJWGVCUEGHA-UHFFFAOYSA-M tetraethylammonium chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC YMBCJWGVCUEGHA-UHFFFAOYSA-M 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000003507 tetrahydrothiofenyl group Chemical group 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- CFMYXEVWODSLAX-QOZOJKKESA-N tetrodotoxin Chemical compound O([C@@]([C@H]1O)(O)O[C@H]2[C@@]3(O)CO)[C@H]3[C@@H](O)[C@]11[C@H]2[C@@H](O)N=C(N)N1 CFMYXEVWODSLAX-QOZOJKKESA-N 0.000 description 1
- 229950010357 tetrodotoxin Drugs 0.000 description 1
- CFMYXEVWODSLAX-UHFFFAOYSA-N tetrodotoxin Natural products C12C(O)NC(=N)NC2(C2O)C(O)C3C(CO)(O)C1OC2(O)O3 CFMYXEVWODSLAX-UHFFFAOYSA-N 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- AYEKOFBPNLCAJY-UHFFFAOYSA-O thiamine pyrophosphate Chemical compound CC1=C(CCOP(O)(=O)OP(O)(O)=O)SC=[N+]1CC1=CN=C(C)N=C1N AYEKOFBPNLCAJY-UHFFFAOYSA-O 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000005309 thioalkoxy group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
- 229940029284 trichlorofluoromethane Drugs 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 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
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 238000011179 visual inspection Methods 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/04—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
-
- 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
-
- 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
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Definitions
- iV-methyl-D-aspartate (NMDA) receptors are ligand-gated ion channels located primarily within the central nervous system (CNS). They belong to the family of ionotropic glutamate receptors and exist as multiple subtypes due to the different combinations of subunits - NRl, NR2 (NR2A, NR2B, NR2C, NR2D) and NR3 - that can be expressed. In addition to the agonist binding site, NMDA receptors have multiple distinct binding sites for various compounds that enhance, modulate and inhibit the activation of the receptors.
- NMDA receptors are involved in neuronal communication and play important roles in synaptic plasticity and mechanisms that underlie learning and memory.
- NMDA receptors engage in synaptic transmission via the neurotransmitter glutamate, which regulates and refines synaptic growth and plasticity.
- glutamate i.e. under pathological conditions
- NMDA receptors become over-activated, resulting in an excess of Ca 2+ influx into neuronal cells, which in turn leads to excitotoxicity and the activation of several signaling pathways that trigger neuronal apoptosis.
- Glutamate-induced apoptosis in brain tissue also accompanies oxidative stress resulting in loss of ATP, loss of mitochondrial membrane potential, and the release of reactive oxygen species and reactive nitrogen species (e.g. H 2 O 2 , NO, OONO “ , O 2 " ) causing associated cell damage and death. Decreased nerve cell function and neuronal cell death eventually occur. Excitotoxicity also occurs if the cell's energy metabolism is compromised.
- NMDA receptors Over-activation of the NMDA receptors is implicated in neurodegenerative diseases and other neuro-related conditions as it causes neuronal loss and cognitive impairment, and also plays a part in the final common pathway leading to neuronal injury in a variety of neurodegenerative disorders such as amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease and Huntington's disease, as well as conditions such as stroke. Recent findings have implicated NMDA receptors in many other neurological disorders, such as multiple sclerosis, cerebral palsy (periventricular leukomalacia), and spinal cord injury, as well as in chronic and severe mood disorders (Mathew SJ et al, Rev Bras Psiquiatr, 27:243- 248 (2005)).
- NMDA receptors play crucial roles in both regulating and promoting normal nervous system functions as well as in causing cell-death, which leads to lethal conditions.
- type of signal given to a cell depends on the location of the activated NMDA receptor. Growth and survival-promoting signals result from the activated synaptic NMDA receptors, while cell death causing signals result from the extrasynaptic NMDA receptors.
- Recent studies also indicate that the activated synaptic NMDA receptors lead to robust phosphorylation of the transcription factor CREB on the transcriptional regulatory residue Serl33 and promote CREB-dependent gene expression and neuronal survival.
- the activated extrasynaptic NMDA receptors transiently phosphorylate CREB and do not activate CREB-dependent gene expression, resulting in neuronal cell death (Hardingham GE et al., NatNeurosci, 5: 405-414 (2002)).
- NMDA antagonists as neurotherapeutic drugs is that many NMDA antagonists also exhibit psychotogenic and neurotoxic properties.
- MK-801 dizocilpine maleate
- MK-801 is capable of providing certain degree of neuroprotection in ischemic stroke, but is associated with pyschotropic and adverse motor effects.
- NMDA antagonists that are capable of (i) preventing and/or treating CNS disorders, such as excitotoxicity, neurodegenerative diseases and neuropathological conditions; (ii) providing neuroprotection under stress conditions, such as a stroke; and (iii) enhancing the brain's cognitive functions.
- CNS disorders such as excitotoxicity, neurodegenerative diseases and neuropathological conditions
- neuroprotection under stress conditions such as a stroke
- enhancing the brain's cognitive functions satisfies this and other needs.
- the present invention provides a compound of formula (I):
- R 1 is selected from the group consisting of (Ci-C 8 )alkyl, (Ci-C 8 )heteroalkyl, arylalkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-(Ci-
- R 2 and R 3 are each independently selected from the group consisting of -H,
- R 4 is selected from the group consisting of -H, (Ci-C8)alkyl, (C 1 -
- R" is (Ci-C8)alkyl or aryl and each X 1 is independently a bond or an (Ci-C 4 )alkylene; the wavy line denoted by ⁇ , indicates the carbon to which the wavy line is attached has a stereoconfiguration of R, S or a mixture (racemic) thereof; optionally, R 1 and R 4 together with the atoms to which they are attached form a 5-membered heterocyclic ring containing 0-1 additional ring heteroatom selected from O or
- each of R 1 -R 4 groups is optionally substituted with from 1-3 R b substituents independently selected from the group consisting of halogen, -OH, -OR C , -OSi(R c ) 3 , -
- each R c is independently an alkyl or aryl, wherein R c is optionally further substituted with from 1-3 substituents selected from the group consisting of halogen, -OH, -0R d , -SH, -SR d , -S(O) 2 R d , -SO 2 NH 2 , -C(O)NH 2 , -C(0)NHR d , -C(0)N(R d ) 2 , -
- the present invention provides a method of inhibiting the activities of an NMDA receptor.
- the method includes contacting compounds of formula I or any of the compounds as described herein with the NMDA receptor.
- the present invention provides methods of preventing and/or treating central nervous system disorders in a mammal.
- the present invention provides methods for preventing and/or treating a neurodegenerative disease and neuropathological conditions in a mammal.
- the present invention provides a method for enhancing the brain's cognitive function in a mammal.
- the present invention provides a method of preventing neuronal damage under a stress condition, such as a stroke in a mammal.
- the methods for treating and/or preventing CNS disorders in the above embodiments include administering to the mammal a therapeutically effective amount of compounds of formula I or any of the compounds as described herein.
- Figure 1 illustrates that compound LC-02 decreases NMDA induced current in hippocampal neurons.
- DIV10-14 rat hippocampal neurons were treated with NMDA (50 ⁇ M) in the absence or presence of the compound LC-02 (10 ⁇ g/mL). Data is presented as % of NMDA-induced current.
- B NMDA antagonistic effect of LC-02 on current responses of a single hippocampal neuron.
- C Effects of LC-02 on pooled NMDA current responses.
- Figure 2 illustrates the effect of NMDA insults on cortical neurons in the absence (DMSO) and presence of these novel compounds.
- Oxazolidine derivatives protect against NMDA excitotoxicity in rat cortical neurons.
- Figure 3 shows that cell death was markedly reduced in the presence of either LC-Ol or LC-02 (10 ⁇ g/ mL) in comparison to the negative control (DMSO).
- LC-Ol and LC-02 protect against NMDA excitotoxicity in rat cortical neurons at various concentrations.
- Figure 4 shows that cell death was markedly reduced in the presence of LC-06 (10 ⁇ g/ mL) in comparison to the negative control (DMSO).
- Compound LC-06 protects against NMDA excitotoxicity in rat cortical neurons.
- Figure 5 shows that cell death was markedly reduced in the presence of either LC-24 or LC-25 (10 ⁇ g/ mL) in comparison to the negative control (DMSO).
- Compounds LC-24 and LC-25 protect against NMDA excitotoxicity in rat cortical neurons.
- Figure 6 illustrates that NMDA insults clearly led to cell death while the addition of compound LC-02 (10 ⁇ g/ml) protected the cells from excitotoxicity and the resulting apoptosis at a level similar to control cells (no NMDA insults).
- Compound LC-02 protects embryonic rat primary cortical neurons against NMDA excitotoxicity.
- Figure 7 shows that compound LC-02 decreases escape latencies in scopolamine- induced memory deficit mice.
- Figure 8 illustrates that compound LC-06 decreases NMDA induced current in hippocampal neurons, (a) NMDA antagonistic effect of LC-06 on current responses of a single hippocampal neuron, (b) Effects of LC-06 on pooled NMDA current responses.
- Figure 9 illustrates that compound LC-24 decreases NMDA induced current in hippocampal neurons, (a) NMDA antagonistic effect of LC-24 on current responses of a single hippocampal neuron, (b) Effects of LC-24 on pooled NMDA current responses.
- Figure 10 illustrates that compound LC-25 decreases NMDA induced current in hippocampal neurons, (a) NMDA antagonistic effect of LC-25 on current responses of a single hippocampal neuron, (b) Effects of LC-25 on pooled NMDA current responses.
- Figure 11 shows LC-02 improves behavioral test scores in MCAO rats. Behavioral functional tests were performed in rats after MCAO.
- Group II: LC-02 (L, 35 mg/kg) n 8, grey bars;
- Group III: LC-02 (H, 70 mg/kg) n 9, solid bars.
- Figure 12 Illustrative coronal sections (2-mm thick) of ischemic or sham rats. The infarct area in the ischemic cerebral hemisphere were represented as distinct pale-stained area in rats with 2 hours MCAO treated with 1.5% DMSO/ saline (vehicle) or LC-02 of 35 and 70 mg/kg at 6, 24 and 48 hours following the onset of ischemia, (b) Infarct area of ischemic rats was measured in 2-mm-think coronal brain sections treated with 1.5% DMSO/saline or LC-02 (35 mg/kg (L) and 70 mg/kg (H)) at 6, 24 and 48 hours following the onset of ischemia.
- FIG 13 illustrates that compound LC-24 reverses scopolamine-induced performance deficits in Morris Water Maze test Mice were first orally administered LC-24 (30 mg/kg), scopolamine (4 mg/kg) was i.p. administered to mice 15 min to impair their memories. Treated mice were subjected to the Morris Water Maze 30 min after scopolamine injection and the procedures were repeated over a period of 4 days. On each day, the time taken for the mice to detect the hidden platform in the water maze was measured, in seconds.
- FIG 14 illustrates that compound LC-06 reverses scopolamine-induced performance deficits in Morris Water Maze test.
- Mice were first orally administered LC-06 (100 mg/kg), scopolamine (4 mg/kg) was i.p. administered to mice 15 min to impair their memories.
- Treated mice were subjected to the Morris Water Maze 30 min after scopolamine injection and the procedures were repeated over a period of 4 days. On each day, the time taken for the mice to detect the hidden platform in the water maze was measured, in seconds.
- Figure 15 illustrates that compound LC-02 significantly reduces the duration of immobility time of mice in the Forced Swim Test.
- Figure 16 shows that compound LC-02- treated mice do not result in increased excitable behavior.
- Figure 17 illustrates that compound LC-06 reduces the duration of immobility of mice in the Forced Swim Test.
- FIG. 18 illustrates that compounds LC-24 and LC-25 significantly reduce the duration of immobility of mice in the Forced Swim Test.
- Figure 19 illustrates that compound LC-02 induces the phosphorylation of ERK and AKT protein in rat cortical neurons.
- the present invention is directed to therapeutically active compounds and pharmaceutical compositions as NMDA antagonists, methods of inhibiting over-activation of NMDA receptors, methods of treating and/or preventing neurodegenerative diseases and neuropathological disorders, methods of providing neuroprotection under stress conditions, such as a stroke, and methods of enhancing the brain's cognitive functions in mammals and humans.
- the present invention provides therapeutic agents and methods for prevention and/or treatment of acute and chronic disorders of the CNS, ranging from neuropathological conditions, such as neuropathic pain, stroke, brain trauma, and epilepsy to neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Parkinson's disease and Huntington's disease.
- neuropathological conditions such as neuropathic pain, stroke, brain trauma, and epilepsy
- neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Parkinson's disease and Huntington's disease.
- the present invention provides NMDA antagonists that may be useful in the treatment of nonketotic hyperglycinemia, an autosomal recessive disorder associated with absent or diminished glycine cleavage enzyme activity. Furthermore, the present invention provides neuronal protection against glutamate- induced neurodegeneration and toxicity, and enhances the brain's cognitive functions, such as learning and memory.
- compounds (S)-4-(substituted)-5,5-(disubstituted or unsubstituted)-3-(substituted or unsubstituted)-2-(substituted) oxazolidine derivatives are capable of protecting nerve cells and tissues subjected to glutamate-induced stress from damage by blocking the toxic effects of over-activated NMDA receptors.
- the present invention provides NMDA antagonists that exhibit reduced side effects.
- the present invention provides NMDA antagonists that have unique functionality, for example, the compounds can (i) inhibit NMDA receptor- mediated excitotoxicity; (ii) prevent and/or treat neurodegenerative diseases including amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease and Huntington's disease, and neuropathological conditions; (iii) improve learning and memory in mammals or humans by enhancing long-term potentiation; and (iv) confer neuroprotection under oxidative stress and in stroke-like conditions.
- the compounds are therapeutically potent over a range of disorders including dementia, neurodegeneration, brain trauma and stroke.
- a or "an” entity as used herein refers to one or more of that entity; for example, a compound refers to one or more compounds or at least one compound.
- a compound refers to one or more compounds or at least one compound.
- the terms “a” (or “an”), “one or more”, and “at least one” can be used interchangeably herein.
- alkyl refers to a straight or branched, saturated, aliphatic radical having the number of carbon atoms indicated (i.e. C 1 -S or C 1 -Cs means one to eight carbons.
- C 1 -C 6 alkyl includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl, etc.
- C 1 8 alkyl refers to a hydrocarbon radical straight or branched having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms and includes, but are not limited to, C 1 2 alkyl, C 1 4 alkyl, C 2 6 alkyl, C 2 4 alkyl, C 1 6 alkyl, C 2 8 alkyl, C 1 y alkyl, C 2 y alkyl and C 3 8 alkyl.
- alkylene by itself or as part of another substituent means a divalent radical derived from an alkane, as exemplified by -CH 2 CH 2 CH 2 CH 2 -.
- an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the present invention.
- alkoxy As used herein, the terms “alkoxy,” “alkylamino” and “alkylthio” (or thioalkoxy) are used in their conventional sense, and refer to those alkyl groups attached to the remainder of the molecule via an oxygen atom, an amino group, or a sulfur atom, respectively.
- the alkyl portions can be the same or different and can also be combined to form a 3-7 membered ring with the nitrogen atom to which each is attached.
- a group represented as -NR a R b is meant to include piperidinyl, pyrrolidinyl, morpholinyl, azetidinyl and the like.
- cycloalkyl refers to hydrocarbon rings having the indicated number of ring atoms (e.g., C 3 _ 6 Cycloalkyl) and being fully saturated or having no more than one double bond between ring vertices. One or two C atoms may optionally be replaced by a carbonyl.
- cycloalkyl-alkyl refers to a radical -R'R", where R' is an alkylene group (having the indicated number of carbon atoms, or if unspecified having six or fewer main chain carbon atoms) and R" is a cycloalkyl group as defined herein.
- R' is an alkylene group (having the indicated number of carbon atoms, or if unspecified having six or fewer main chain carbon atoms) and R" is a cycloalkyl group as defined herein.
- Examples of cycloalkylalkyl include cyclohexylmethyl, pentylethyl and the like.
- aryl refers to, unless otherwise stated, a polyunsaturated, typically aromatic, hydrocarbon group which can be a single ring or multiple rings (up to three rings, one or more of which is optionally a cycloalkyl or heterocycloalkyl) which are fused together or linked covalently.
- aryl groups include phenyl, naphthyl and biphenyl.
- arylalkyl refers to a radical -R'R", where R is an alkylene group (having the indicated number of carbon atoms, or if unspecified having six or fewer main chain carbon atoms) and R" is an aryl group as defined herein.
- R is an alkylene group (having the indicated number of carbon atoms, or if unspecified having six or fewer main chain carbon atoms) and R" is an aryl group as defined herein.
- arylalkyl include benzyl, phenethyl and the like.
- the heteroatom(s) O, N and S may be placed at any interior position of the heteroalkyl group.
- the heteroatom Si may be placed at any position of the heteroalkyl group, including the position at which the alkyl group is attached to the remainder of the molecule.
- Up to two heteroatoms may be consecutive, such as, for example, -CH 2 -NH-OCH 3 and -CH 2 - O-Si(CH 3 ) 3 .
- heterocycloalkyl refers to a cycloalkyl group that contain from one to five heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized, the remaining ring atoms being C, where one or two C atoms may optionally be replaced by a carbonyl.
- the heterocycloalkyl may be a monocyclic, a bicyclic or a polycylic ring system.
- the heterocycloalkyl can also be a heterocyclic alkyl ring fused with an aryl or a heteroaryl ring.
- heterocycloalkyl groups include pyrrolidinyl, piperidinyl, imidazolidinyl, pyrazolidinyl, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolane, phthalimide, piperidine, 1,4-dioxanyl, morpholinyl, thiomorpholinyl, thiomorpholinyl-S-oxide, piperazinyl, pyranyl, thiopyranyl, pyrone, tetrahydrofuranyl, tetrahydrothiophenyl, quinuclidinyl, and the like.
- a heterocycloalkyl group can be attached to the remainder of the molecule through a ring carbon or a heteroatom.
- heterocycloalkylalkyl refers to a radical -R'R", where R' is an alkylene group (having the indicated number of carbon atoms, or if unspecified having six or fewer main chain carbon atoms) and R" is a heterocycloalkyl group as defined herein.
- R' is an alkylene group (having the indicated number of carbon atoms, or if unspecified having six or fewer main chain carbon atoms) and R" is a heterocycloalkyl group as defined herein.
- heterocycloalkylalkyl include piperidinylmethyl, tetrahydrofuranylethyl and the like.
- heterocyclic or “heterocyclyl” refers to a saturated or unsaturated non-aromatic cyclic radical of 3 to 8 ring atoms in which one or two ring atoms are heteroatoms selected from O, NR (where R is independently hydrogen or alkyl) or S(O) n (where n is an integer from 0 to 2), the remaining ring atoms being C, where one or two C atoms may optionally be replaced by a carbonyl group.
- heterocyclyl examples include, but is not limited to, tetrahydropyranyl, piperidino, N-methylpiperidin-3-yl, piperazino, N- methylpyrrolidin-3-yl, 3-pyrrolidino, 3-pyrrolinyl, 2-pyrrolidon-l-yl, morpholino, thiomorpholino, thiomorpholino-1 -oxide, thiomorpholino- 1,1 -dioxide, pyrrolidinyl, and the like.
- heterocyclylalkyl refers to a radical -R'R", where R is an alkylene group (having the indicated number of carbon atoms, or if unspecified having six or fewer main chain carbon atoms) and R" is a heterocyclyl group as defined herein.
- R is an alkylene group (having the indicated number of carbon atoms, or if unspecified having six or fewer main chain carbon atoms) and R" is a heterocyclyl group as defined herein.
- heterocyclylalkyl include piperidinylmethyl, tetrahydrofuranylethyl, pyronylmethyl, 3- pyrrolinylmethyl and the like.
- heteroaryl refers to aryl groups (or rings) that contain from one to five heteroatoms delected from N, O, or S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized.
- a heteroaryl group can be attached to the remainder of the molecule through a heteroatom.
- Non-limiting examples of aryl groups include phenyl, naphthyl and biphenyl, while non-limiting examples of heteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, pyrimindinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalaziniyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuryl, isoindolyl, indolizinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridines, benzothiaxolyl, benzofuranyl, benzothienyl, indolyl, quinoly
- heteroarylalkyl refers to a radical -R'R", where R' is an alkylene group (having the indicated number of carbon atoms, or if unspecified having six or fewer main chain carbon atoms) and R" is a heteroaryl group as defined herein.
- heteroarylalkyl include pyridylmethyl, pyrazolyethyl, benzoimidazolylmethyl and the like.
- halo or halogen, by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.
- haloalkyl refers to monohaloalkyl and polyhaloalkyl.
- C 1-4 haloalkyl is meant to include trifluoromethyl, 2,2,2-trifluoroethyl, 4- chlorobutyl, 3-bromopropyl, and the like.
- protecting group refers to a grouping of atoms that when attached to a reactive group in a molecule masks, reduces or prevents that reactivity.
- protecting groups can be found in T. W. Greene and P. G. Wuts, PROTECTIVE GROUPS IN ORGANIC CHEMISTRY, (Wiley, 4th ed. 2006), Beaucage and Iyer, Tetrahedron 48:2223-2311 (1992), and Harrison and Harrison et al, COMPENDIUM OF SYNTHETIC ORGANIC METHODS, VOIS. 1-8 (John Wiley and Sons.
- Representative amino protecting groups include formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (CBZ), fert-butoxycarbonyl (Boc), trimethyl silyl (TMS), 2-trimethylsilyl-ethanesulfonyl (SES), trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (FMOC), nitro-veratryloxycarbonyl (NVOC) and the like (see also, Boyle, A. L. (Editor), CURRENT PROTOCOLS IN NUCLEIC ACID CHEMISTRY, John Wiley and Sons, New York, Volume 1, 2000).
- labile protecting group refers to those protecting groups that are removeable under mild conditions that do not significantly impact the remainder of the molecule.
- composition as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
- prodrugs means any compound which releases an active parent drug according to Formula I in vivo when such prodrug is administered to a mammalian subject.
- Prodrugs of a compound of Formula I are prepared by modifying functional groups present in the compound of Formula I in such a way that the modifications may be cleaved in vivo to release the parent compound.
- Prodrugs include compounds of Formula I wherein a hydroxy, amino, or sulfhydryl group in a compound of Formula I is bonded to any group that may be cleaved in vivo to regenerate the free hydroxyl, amino, or sulfhydryl group, respectively.
- prodrugs include, but are not limited to esters ⁇ e.g., acetate, formate, and benzoate derivatives), amides, guanidines, carbamates ⁇ e.g., N,N-dimethylaminocarbonyl) of hydroxy functional groups in compounds of Formula I, and the like.
- Other examples of prodrugs include compounds that comprise -NO, -NO 2 , --ONO, or -ONO 2 moieties.
- Disease states that can be treated using the compounds of the invention to inhibit glutamate induced neurotoxicity include, but are not limited to, neurodegenerative disorders, head and brain trauma, genetic disorders, infectious disease, inflammatory disease, medication, drug and alcohol disorders, neuropathic pain, cancer, metabolic disorders, mental retardation, and learning and memory disorders, such as age related memory loss, Alzheimer's disease, mild cognitive impairment, amyotrophic lateral sclerosis, Huntington's chorea, amnesia, Bl deficiency, schizophrenia, depression and bipolar disorder, stroke, hydrocephalus, subarachnoid hemorrhage, vascular insufficiency, brain tumor, epilepsy, Parkinson's disease, cerebral microangiopathy, pain medication, chemotherapy, oxygen deprivation, e.g, caused by a heart-lung machine, anesthesia, or near drowning, dementia (vascular, frontotemporal, Lewy-body, semantic, primary progressive aphasia, Pick's), progressive supranucle
- dementia vascular, frontotemporal,
- neuroopathic pain refers to pain resulting from injury to or chronic changes in peripheral and/or central sensory pathways, where the pain often occurs or persists without an obvious noxious input.
- administering refers to oral administration, administration as a suppository, topical contact, parenteral, intravenous, intraperitoneal, intramuscular, intralesional, intranasal or subcutaneous administration, intrathecal administration, or the implantation of a slow-release device e.g., a mini-osmotic pump, to the subject.
- a slow-release device e.g., a mini-osmotic pump
- hydrate refers to a compound that is complexed to at least one water molecule.
- the compounds of the present invention can be complexed with from 1 to 10 water molecules.
- inhibiting refers to a compound that partially or fully prohibits or a method of partially or fully prohibiting a specific action or function.
- the term "patient in need” refers to a patient suffering from the central nervous disorders including neurodegenerative diseases and neuropathological conditions.
- Non-limiting examples include amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, neuropathic pain, stroke, brain trauma, epilepsy stroke, and dementia.
- Patients suffering from other conditions treatable with the NMDA antagonists are also treatable with the methods of the present invention.
- Patients treatable using the methods of the present invention are animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like.
- the patient is a human.
- salt refers to acid or base salts of the compounds used in the methods of the present invention.
- pharmaceutically acceptable salts are mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid, and the like) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid and the like) salts, quaternary ammonium (methyl iodide, ethyl iodide, and the like) salts. It is understood that the pharmaceutically acceptable salts are non-toxic.
- salt(s) includes salts of the compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein.
- base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt.
- acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
- acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, butyric, maleic, malic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like.
- salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge et ah, Journal of Pharmaceutical Science , 66: 1-19 (1977)).
- Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
- the salt is preferably a pharmaceutically acceptable salt.
- pharmaceutically acceptable salts are presented hereinabove, and are generally known in the art. See, for example, Wermuth, C, PHARMACEUTICAL SALTS: PROPERTIES, SELECTION AND USE- A HANDBOOK, Verlag Helvetica Chimica Acta (2002) [0063]
- the neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
- the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.
- the present invention provides compounds that are in a prodrug form.
- Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention.
- prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.
- salts of the basic compounds of the present invention are salts formed with acids, such as of mineral acids, organic carboxylic and organic sulfonic acids, e.g., hydrochloric acid, methanesulfonic acid, maleic acid, are also possible provided a basic group, such as pyridyl, constitutes part of the structure.
- pharmaceutically acceptable is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
- the neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
- the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.
- terapéuticaally sufficient amount or dose or “effective or sufficient amount or dose” refer to a dose that produces therapeutic effects for which it is administered. The exact dose will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques ⁇ see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999);
- the therapeutically effective dose can often be lower than the conventional therapeutically effective dose for non-sensitized cells.
- the terms “treat”, “treating” and “treatment” refers to any indicia of success in the treatment or amelioration of an injury, pathology, condition, or symptom (e.g., pain), including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the symptom, injury, pathology or condition more tolerable to the patient; decreasing the frequency or duration of the symptom or condition; or, in some situations, preventing the onset of the symptom or condition.
- the treatment or amelioration of symptoms can be based on any objective or subjective parameter; including, e.g., the result of a physical examination.
- Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms.
- “Solvate” refers to a complex formed by combination of solvent molecules with molecules or ions of the solute.
- the solvent can be an organic compound, an inorganic compound, or a mixture of both.
- Some examples of solvents include, but are not limited to, methanol, N,N-dimethylformamide, tetrahydrofuran, dimethylsulfoxide, and water.
- the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present invention.
- Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.
- Certain compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers and individual isomers are encompassed within the scope of the present invention. These isomers can be resolved or asymmetrically synthesized using conventional methods to render the isomers "optically pure", i.e., substantially free of its other isomers. If, for instance, a particular enantiomer of a compound of the present invention is desired, it may be prepared by asymmetric synthesis, or by derivation with a chrial auxilliary, where the resulting diastereomeric mixture is separated and the auxilliary group cleaved to provide the pure desired enantiomers.
- diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diasteromers thus formed by fractional crystallization or chromatagraphic means well known in the art, and subsequent recovery of the pure enantiomers.
- the present invention provides a compound of formula (I):
- R 1 is selected from the group consisting of (Ci-C 8 )alkyl, (C 1 - C 8 )heteroalkyl, arylalkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl-alkyl, (Ci-C 8 )haloalkyl, heterocycloalkyl, heterocycloalkyl-(Ci-C 6 )alkyl, heteroaryl-(Ci-C 6 )alkyl, heterocyclyl-alkyl and aryl.
- R 1 is selected from the group consisting of (Ci-C 8 )alkyl, (Ci-C 8 )heteroalkyl, aryl-(Ci-C 6 )alkyl and heteroaryl-Ci. ⁇ alkyl, each of which is optionally substituted with from 1-3 R b substituents independently selected from the group consisting of halogen, -OH, -OR C , -OSi(R c ) 3 , -OC(O)O-R C , -
- each R c is independently an alkyl or aryl, wherein R c is optionally further substituted with from 1-3 substituents selected from the group consisting of halogen, -OH, -0R d , -SH, -SR d , -S(O) 2 R d , -SO 2 NH 2 , -C(O)NH 2 , -C(0)NHR d , -C(0)N(R d ) 2 , - C(0)R d , -C(O)H, -NHC(0)R d , -NR d C(0)R d , -CO 2 H, -C0 2 R d , -
- R 1 is selected from (Ci-C 8 )alkyl, phenyl-(Ci-C 6 )alkyl and 5- or 6-membered heteroaryl-Ci.
- R 1 is selected from the group consisting phenyl-(Ci-C 6 )alkyl and 5-membered heteroaryl-Ci- ⁇ alkyl, wherein the heteroaryl is optionally fused with a 5- or 6-membered aromatic ring having from 0-2 additional heteroatoms selected from N, O or S.
- R 1 is selected from (Ci-C 8 )alkyl, phenyl-(Ci-C 6 )alkyl, imidazoly-Cr C ⁇ alkyl, pyrazolyl-(Ci-C 6 )alkyl, oxazoly-(Ci-C 6 )alkyl, isoxazoyl-(Ci-C 6 )alkyl, thiazolyl-(Ci- Ce)alkyl, isothiazoly-(Ci-C 6 )alkyl, furanyl-(Ci-C 6 )alkyl, indolyl-(Ci-C 6 )alkyl and thiophenyl- (Ci-C6)alkyl.
- substitutions for R 1 to R 4 groups by R b are on the aromatic porion of the R 1 - R 4 groups, wherein the aromatic portion of each of R ! -R 4 groups is optionally substituted with from 1-3 R b groups.
- R 1 is selected from the group consisting of -Me, - CH 2 (Me) 2 , -CH 2 CH(Me) 2 , -CHMe(Et), -CH 2 CH 2 CH 3 , -CH 2 Ph, -CH 2 PhOH, - CH 2 CH 2 CH 2 CH 2 NH 2 , -CH 2 CH 2 CONH 2 , -Ph, -MePh, -PhNO 2 , -PhOCH 3 , -PhNH 2 , -PhF, - PhBr, -PhI, PhCN, -Ph-COOR C , -Ph-OCOR C , -PhNHC0R c , -Ph-COOH, -CH 2 CO 2 H, - CH 2 CH 2 COOH, -CH 2 CONH 2 , -CH 2 OH, -CH(OH)CH 3 , indolyl-CH
- R 1 is a side chain of a naturally occurring amino acid. In certain other instances, R 1 is selected from the group consisting Of -CH 2 CH(Me) 2 , CH 3 CH 2 (CH 3 )CH-, benzyl, imidazoly-CH 2 - or imidazol-5-yl- CH 2 -. In some embodiments, R 1 is isobutyl, benzyl or 2-butyl.
- R 2 is selected from the group consisting of -H, C 8 )heteroalkyl, heteroaryl-alkyl and aryl, wherein the heteroaryl-alkyl and aryl groups are each optionally substituted with from 1-3 R b substituents. In certain instances, the aromatic portion of R 2 is optionally substituted with from 1-3 R b substituents.
- R 2 is selected from the group consisting of -H, and aryl, wherein the alkyl and aryl are optionally substituted with from 1-3 R .
- R is selected from the group consisting of -H, (Ci-C 8 )alkyl and phenyl, wherein the alkyl and/or phenyl are optionally substituted with from 1-3 R b substituents selected from the group consisting of -OH, -OR C , -OSi(R c )3, - OC(O)O-R C , - OC(O)R C , -0C(0)NHR c , -0C(0)N(R c ) 2 , -SH, -SR C , -S(O)R C , -S(O) 2 R C , -C(O)N(R C ) 2 , -C(O)R c ,
- R b is selected from the group consisting of halogen, -OH, -OR C , - R c , -CN, -NO 2 , -NH 2 , -NHR C and -N(R C ) 2 .
- R 2 is selected from the group consisting of -H, -Me, -Et, -Pr, -Bu, -/-Pr, -t-Bu, -/-Bu, -CH 2 CH 2 CH 2 CH 2 CH 3 , -Ph, -PhMe, 4-methylphenyl, 3-methylphenyl, 2-methylphenyl, - PhNO 2 , -PhOMe, -PhNH 2 , -Ph-F, -Ph-Br, -Ph-Cl, -Ph-I, -PhCN, -Ph- C00R c , -Ph-OCOR c , -PhNHC0R c and -Ph-COOH.
- R 2 is -H, ethyl, n- propyl or Bu. In some instances, R 2 is ethyl or n-propyl.
- R 3 is selected from the group consisting of - - C 8 )heteroalkyl, heteroaryl-alkyl and aryl, where the heteroaryl-alkyl and aryl groups are each optionally substituted with from 1-3 R b substituents. In certain instances, the aromatic portions of R 3 are optionally substituted with from 1-3 R b substituents.
- R 3 is selected from the group consisting of -H, (Ci-C 8 )alkyl and aryl, wherein the alkyl and/or aryl are optionally substituted with from 1-3 R b .
- R 3 is selected from the group consisting of -H, (Ci-C 8 )alkyl and phenyl, wherein the alkyl and phenyl are optionally substituted with from 1-3 R b substituents selected from the group consisting of -OH, -OR C , -OSi(R c ) 3 , - 0C(0)0-R c , -
- R b is selected from the group consisting of halogen, -OH, -OR C , - R c , -CN, -NO 2 , -NH 2 , -NHR C and -N(R C ) 2 .
- R 3 is selected from the group consisting of -H, -Me, -Et, -Pr, -Bu, -/Pr, -tBu, -/Bu, -CH 2 CH 2 CH 2 CH 2 CH 3 , -Ph, -PhMe, 4-methylphenyl, 3-methylphenyl, 2- methylphenyl, - PhNO 2 , -PhOMe, -PhNH 2 , -Ph-F, -Ph-Br, -Ph-Cl, -Ph-I, -PhCN, -Ph-COOR C , -Ph-OCOR C , -PhNHCOR c and -Ph-COOH.
- R 3 is ethyl, n-propyl, butyl or -phenyl.
- R 3 is butyl, pentyl, 3 -methylphenyl or
- R 3 is -H.
- R 4 is selected from the group consisting of -H, (Ci-C 8 )alkyl, (C 1 - C 8 )heteroalkyl, arylalkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl- alkyl, -X 1 S(O)R", - X 1 S(O) 2 R", - X 1 SO 2 NH 2 , - X 1 S(O) 2 NHR", - X 1 S(O) 2 N(R ⁇ 2 , - X 1 C(O)NH 2 , - X 1 C(O)NHR", - X 1 C(O)N(R ⁇ 2 , - X 1 C(O)R", - X 1 C(O)H, -
- X 1 Q S)R", - X 1 CO 2 H, - X 1 CO 2 R", - X 1 P(O)(OR ⁇ 2 and an amino protecting group; wherein R" is (Ci-C 8 )alkyl or aryl and each X 1 is independently a bond or an (Ci-C 4 )alkylene, where the aliphatic and/or aromatic portions of R 4 group is further substituted with from 1-3 R b substituents.
- R 4 is selected from the group consisting of -H, -CHO, PhCO-, PhNHCO-, PhOCO-, CH 3 NHCO-, CH 3 OCO-, CH 3 CO-, EtCO-, -Me, -Et, -Pr, -Bu, /Pr, /Bu, -fflu, -CH 2 CH 2 CH 2 CH 3 and t-BuO-CO-.
- R 4 is -H, ethyl, n-propyl, -C(O)Ph, -C(O)CH 3 , -C(O)CH 2 CH 3 or Boc. In one embodiment, R 4 is -H.
- R 1 and R 4 together with the atoms to which they are attached form a 5- or 6-membered heterocyclic ring having from 0-2 additional heteroatoms as ring members selected from O or N, optionally the heterocyclic ring is substituted with from 1-3 Ci-6alkyl substituents.
- R 1 and R 4 together with the atoms to which they are attached for a 5-membered heterocyclic ring having from 0-2 additional heteroatoms as ring members selected from O or N, optionally substituted with from 1-3 C ⁇ alkyl substituents.
- R 1 and R 4 together with the atoms to which they are attached for a 5-membered pyrrolidine ring containing 0-1 additional heteroatom selected from N or O, optionally substituted with from 1-3 substituents.
- the wavy line denoted by ⁇ indicates the carbon to which the wavy line is attached has a stereoconfiguration of R, S or a mixture (racemic) thereof.
- the carbon attached to the wavy line has a stereoconfiguration of R.
- the carbon attached to the wavy line has a stereoconfiguration of S.
- the carbon attached to the wavy line has a racemic stereoconfiguration, i.e. 50% R and 50% S.
- R 3 is selected from the group heteroaryl-alkyl and aryl.
- R 1 , R 2 , R 3 and R 4 are as defined in any of the above formulas and embodiments.
- R 1 is (CH 3 ) 2 CHCH 2 -.
- R 1 is isobutyl.
- R 1 is benzyl.
- R 4 is -H;
- R 1 is 2-butyl, isobutyl or benzyl;
- R 2 is ethyl or n-propyl;
- R 3 is butyl, pentyl, 2-methylphenyl, 3- methylphenyl, 4-methylphenyl.
- R 3 is selected from the group consisting of (Ci-C 8 )alkyl, (Ci-C 8 )heteroalkyl, heteroaryl-alkyl and aryl.
- R 1 , R 2 , R 3 and R 4 are as defined in any of the above formulas and embodiments.
- R 1 is (CH 3 ) 2 CHCH 2 -.
- R 1 is isobutyl.
- R 1 is benzyl.
- compounds of formula I have subformula Ic:
- R 3 is selected from the group consisting of (Ci-C 8 )alkyl, (Ci-C 8 )heteroalkyl, heteroaryl-alkyl and aryl and the carbon center to which R 3 is attached has a racemic stereoconfiguration.
- R 1 , R 2 , R 3 and R 4 are as defined in any of the above formulas and embodiments. In one instance, R 1 is (CHs) 2 CHCH 2 -. In another instance, R 1 is isobutyl. In yet another instance, R 1 is benzyl.
- R 5 is selected from the group consisting of -H, (Ci-C 8 )alkyl, (Ci-C 8 )heteroalkyl, arylalkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl- alkyl, -X 1 S(O)R", - X 1 S(O) 2 R", - X 1 SO 2 NH 2 , - X 1 S(O) 2 NHR", - X 1 S(O) 2 N(R ⁇ 2 , - X 1 C(O)NH 2
- R 4 is -H. -C(0)Ci.6alkyl or -C(O)-aryl. In one occurrence, R 4 is -
- R 2 and R 3 are each independently a Ci.galkyl.
- the substituents R 1 , R 2 , R 3 , R 4 , X 1 , R" and R c are as defined in any of the above formulas and embodiments.
- compounds of formula I is selected from the group consisting of:
- R 5 is selected from the group consisting of -H, (Ci-C 8 )alkyl, (Ci-C 8 )heteroalkyl, arylalkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl- alkyl, -X 1 S(O)R", - X 1 S(O) 2 R", - X 1 SO 2 NH 2 , - X 1 S(O) 2 NHR", - X 1 S(O) 2 N(R ⁇ 2 , - X 1 C(O)NH 2 , - X 1 C(O)NHR", - X 1 C(O)N(R ⁇ 2 , - X 1 C(O)R", - X 1 C(O)H, -
- R 4 is -H. -C(0)Ci-6alkyl or -C(O)-aryl.
- R 4 is - C(O)Ph, optionally substituted with from 1-3 R c .
- R 2 and R 3 are each independently a C 1-8 alkyl.
- the substituents R 1 , R 2 , R 3 , R 4 , X 1 , R" and R c are as defined in any of the above formulas and embodiments.
- R 2 is (Ci-C 8 )alkyl
- R 3 is (Ci-C 8 )alkyl or optionally substituted aryl
- R 4 is -H or -COR".
- R 3 is (Ci-C 8 )alkyl.
- R 3 is optionally substituted aryl, such as optionally substituted phenyl.
- R 4 is -H or -COR".
- R" is optionally substituted phenyl, - CH 3 , -CH 2 CH 3 or -Ph.
- R 4 is (Ci-C 8 )alkyl
- R 2 is (Ci-C 8 )alkyl or optionally substituted aryl
- R 3 is (Ci-C 8 )alkyl or optionally substituted aryl.
- R 4 is (Ci-C 8 )alkyl
- R 2 is (Ci-C 8 )alkyl
- R 3 is (Ci-C 8 )alkyl or optionally substituted aryl, such as optionally substituted phenyl.
- R 4 is (C 1 - C 8 )alkyl and R 2 and R 3 are each independently optionally substituted aryl, such as substituted phenyl.
- R 4 is -H.
- R 2 is ethyl or n-propyl.
- R 3 is C 1 -C 6 alkyl, butyl, pentyl, 3-methylphenyl, 3- methylphenyl or 4-methylphenyl.
- R 1 is Ci-C ⁇ alkyl, 2-butyl, isobutyl or benzyl.
- a family of specific compounds of particular interest having formula I includes compounds, pharmaceutically acceptable salts, prodrugs, hydrates, solvates and isomers thereof are set forth in Tables 1, 2 and 3.
- Table 2 lists some selected compounds according to an embodiment of the present invention.
- Table 3 lists some selected chiral oxazolidine compounds according to an embodiment of the present invention.
- the invention provides a compound of formula (I):
- R 1 is selected from the group consisting of (Ci-C 8 )alkyl, (Ci-C 8 )heteroalkyl, arylalkyl, (C 3 -
- C 8 cycloalkyl, (C 3 -C 8 )cycloalkyl-alkyl, heterocycloalkyl, heterocycloalkyl-(Ci-C 6 )alkyl, heteroaryl-(Ci-C 6 )alkyl, heterocyclyl-alkyl and aryl;
- R 2 and R 3 are each independently selected from the group consisting of -H, (Ci-C8)alkyl, (C 1 - C 8 )heteroalkyl, heteroaryl-alkyl and aryl;
- R 4 is selected from the group consisting of -H, (Ci-C 8 )alkyl, (Ci-C 8 )heteroalkyl, arylalkyl,
- R" is (Ci-C8)alkyl or aryl and each X 1 is independently a bond or an (Ci-C 4 )alkylene; the wavy line denoted by ⁇ , indicates the carbon to which the wavy line is attached has a stereoconfiguration of R, S or a mixture thereof; optionally, R 1 and R 4 together with the atoms to which they are attached form a 5-membered heterocyclic ring containing 0-1 additional ring heteroatom selected from O or N; and wherein each of R ! -R 4 groups is optionally substituted with from 1-3 R b substituents independently selected from the group consisting of halogen, -OH, -OR C , -OSi(R c ) 3 , -
- each R c is independently an alkyl or aryl, wherein R c is optionally further substituted with from 1-3 substituents selected from the group consisting of halogen, -OH, -0R d , -SH, -SR d , -S(O) 2 R d , -SO 2 NH 2 , -C(O)NH 2 , -C(0)NHR d , -C(0)N(R d ) 2 , - C(0)R d , -C(O)H, -NHC(0)R d , -NR d C(0)R d , -CO 2 H, -C0 2 R d , -
- the invention provides a compound of formula Ia:
- R 3 is selected from the group consisting of (Ci-C 8 )alkyl, (Ci-C 8 )heteroalkyl, heteroaryl-alkyl and aryl; and the substitutuents R 1 , R 2 and R 4 are as defined in the compounds of the first set.
- the invention provides a compound of formula Ib:
- R 3 is selected from the group consisting of (Ci-C 8 )alkyl, (Ci-C 8 )heteroalkyl, heteroaryl-alkyl and aryl; and the substitutuents R 1 , R 2 and R 4 are as defined in the compounds of the first set.
- the invention provides a compound of any of the first, second and third sets, wherein R 3 is -H.
- the invention provides a compound of any of the first, second, third and fourth sets, wherein R 1 is selected from the group consisting of (Ci-C 8 )alkyl, (Ci-C 8 )heteroalkyl, aryl-(Ci-C 6 )alkyl and heteroaryl-Ci-oalkyl, each of which is optionally substituted with from 1-3 R b .
- the invention provides a compound of any of the first, second, third and fourth sets, wherein R 1 is selected from (Ci-C 8 )alkyl, phenyl-(Ci-C 6 )alkyl and 5- or 6-membered heteroaryl-Ci. 6 alkyl, each of which is optionally substituted with from 1-3 R b .
- the invention provides a compound of any of the first, second, third, fourth, fifth, sixth and seventh sets, wherein R 1 is selected from the group consisting of (Ci-C 8 )alkyl, phenyl-(Ci-C 6 )alkyl and 5-membered heteroaryl-Ci. 6 alkyl, wherein the heteroaryl is optionally fused with a 5- or 6-membered aromatic ring having from 0-2 additional heteroatoms selected from N, O or S.
- R 1 is selected from the group consisting of (Ci-C 8 )alkyl, phenyl-(Ci-C 6 )alkyl and 5-membered heteroaryl-Ci. 6 alkyl, wherein the heteroaryl is optionally fused with a 5- or 6-membered aromatic ring having from 0-2 additional heteroatoms selected from N, O or S.
- the invention provides a compound of any of the first, second, third, fourth, fifth, sixth, seventh and eighth sets, wherein R 1 is selected from (C 1 - Cs)alkyl, phenyl-(Ci-C 6 )alkyl, imidazoly-Ci-C ⁇ alkyl, pyrazolyl-(Ci-C 6 )alkyl, oxazoly-(Ci- Ce)alkyl, isoxazoyl-(Ci-C 6 )alkyl, thiazolyl-(Ci-C 6 )alkyl, isothiazoly-(Ci-C 6 )alkyl, furanyl- (Ci-C 6 )alkyl, indolyl-(Ci-C 6 )alkyl and thiophenyl-(Ci-C 6 )alkyl.
- R 1 is selected from (C 1 - Cs)alkyl, phenyl-(Ci-C 6 )alky
- the invention provides a compound of any of the first, second, third, fourth, fifth, sixth, seventh, eighth and ninth sets, wherein R 1 is selected from the group consisting of -Me, -CH 2 (Me) 2 , -CH 2 CH(Me) 2 , -CHMe(Et), -CH 2 CH 2 CH 3 , -CH 2 Ph, -CH 2 PhOH, -CH 2 CH 2 CH 2 CH 2 NH 2 , -CH 2 CH 2 CONH 2 , -Ph, -PhMe, -PhNO 2 , -PhOCH 3 , - PhNH 2 , -PhF, -PhBr, -PhI, PhCN, -Ph-COOR C , -Ph-OCOR C , -PhNHCOR c , -Ph-COOH, - CH 2 CO 2 H, -CH 2 CH 2 COOH
- the invention provides a compound of any of the first, second, third, fourth, fifth, sixth, seventh, eighth and ninth and tenth sets, wherein R 1 is selected from the group consisting Of -CH 2 CH(Me) 2 , CH 3 CH 2 (CH 3 )CH-, benzyl or imidazoly-CH 2 -.
- the invention provides a compound of any one of sets 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 and 11, wherein R 2 is selected from the group consisting of -H, (Ci-C 8 )alkyl and aryl, wherein the alkyl and aryl are optionally substituted with from 1-3 R b .
- the invention provides a compound of any one of sets 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12, wherein R 2 is selected from the group consisting of -H, (Ci-C 8 )alkyl and phenyl, wherein the alkyl and phenyl are optionally substituted with from 1-3 R b substituents selected from the group consisting of -OH, -OR C , -OSi(R c ) 3 , - OC(O)O-R C , -
- the invention provides a compound of any one of sets 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 and 13, wherein R b is selected from the group consisting of halogen, -OH, -OR C , -R c , -CN, -NO 2 , -NH 2 , -NHR C and -N(R C ) 2 .
- the invention provides a compound of any one of sets 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 and 11, wherein R 2 is selected from the group consisting of -H, -Me, -Et, -Pr, -Bu, -/Pr, -tBu, -/Bu, -CH 2 CH 2 CH 2 CH 2 CH 3 , -Ph, -PhMe, - PhNO 2 , -PhOMe, - PhNH 2 , -Ph-F, -Ph-Br, -Ph-Cl, -Ph-I, -PhCN, -Ph-COOR C , -Ph-OCOR C , -PhNHCOR c and - Ph-COOH.
- R 2 is selected from the group consisting of -H, -Me, -Et, -Pr, -Bu, -/Pr, -tBu, -/Bu, -CH 2 CH 2 CH 2 CH
- the invention provides a compound of the any one of sets the 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15, wherein R 3 is selected from the group consisting of -H, and aryl, wherein the alkyl and aryl are optionally substituted with from 1-3 R b .
- the invention provide a compound of any one of sets 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15, wherein R 3 is selected from the group consisting of -H, and phenyl, wherein the alkyl and phenyl are optionally substituted with from 1-3 R b substituents selected from the group consisting of -OH, -OR C , - OSi(R c ) 3 , -OC(O)O-R C , -
- R c -CN, -NO 2 , -NH 2 , -NHR C , -N(R C ) 2 , -N 3 , -NH-OH, -NR C -OH and -NR C -OR C .
- the invention provides a compound of any one of sets 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 and 17, wherein R b is selected from the group consisting of halogen, -OH, -OR C , -R c , -CN, -NO 2 , -NH 2 , -NHR C and -N(R C ) 2 .
- the invention provides a compound of any one of sets 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15, wherein R 3 is selected from the group consisting of -H, -Me, -Et, -Pr, -Bu, -/Pr, -fflu, -/Bu, -CH 2 CH 2 CH 2 CH 2 CH 3 , -Ph, -PhMe, - PhNO 2 , -PhOMe, -PhNH 2 , -Ph-F, -Ph-Br, -Ph-Cl, -Ph-I, -PhCN, -Ph-COOR C , -Ph-OCOR C , - PhNHCOR c and -Ph-COOH.
- R 3 is selected from the group consisting of -H, -Me, -Et, -Pr, -Bu, -/Pr, -fflu, -/Bu, -CH 2
- R 4 is selected from the group consisting of -H, aryl-(Ci-C 6 )alky
- the invention provides a compound of any one of sets 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 and 19, wherein R 4 is selected from the group consisting of -H, phenyl-(Ci-C 6 )alkyl, (C 1 -
- the invention provides a compound of any one of sets 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 and 19, wherein R 4 is selected from the group consisting of -H, -CHO, PhCO-, PhNHCO-, PhOCO-, CH 3 NHCO-, CH 3 OCO-, CH 3 CO-, EtCO-, -Me, -Et, -Pr, -Bu, /Pr, /Bu, -tBu, -CH 2 CH 2 CH 2 CH 2 CH 3 and t-BuO-CO-.
- the invention provides a compound of any one of sets 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 and 22, wherein R 1 and R 4 together with the atoms to which they are attached form a pyrrolidine ring, optionally substituted with from 1-3 R d .
- the invention provides a compound of any one of sets 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 and 22, wherein the compound is selected from the group consisting of:
- R 5 is selected from the group consisting of -H, arylalkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl- alkyl, -X 1 S(O)R", - X 1 S(O) 2 R", - X 1 SO 2 NH 2 , - X 1 S(O) 2 NHR", - X 1 S(O) 2 N(R ⁇ 2 , - X 1 C(O)NH 2
- the invention provides a compound of any one of sets 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 and 22, wherein the compound is selected from the group consisting of:
- R 5 is selected from the group consisting of -H, arylalkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl- alkyl, -X 1 S(O)R", - X 1 S(O) 2 R", - X 1 SO 2 NH 2 , - X 1 S(O) 2 NHR", - X 1 S(O) 2 N(R ⁇ 2 , - X 1 C(O)NH 2
- the invention provides a compound of any of sets 1, 2,
- R 2 is (Ci-C 8 )alkyl
- R 3 is (Ci-C 8 )alkyl or optionally substituted aryl
- R 4 is -H or -COR".
- the invention provides a compound of any of sets 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 and 26, wherein R 3 is (C 1 -C 8 ) ⁇ yI.
- the invention provides a compound of any of sets 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 and 26, wherein R 3 is an optionally substituted aryl.
- the invention provides a compound of any of sets 1, 2,
- R 4 is -H.
- the invention provides a compound of any of sets 1, 2,
- R 4 is -COR a .
- the invention provides a compound of any of sets 1, 2,
- R a is optionally substituted phenyl
- the invention provides a compound of any of sets 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 and 28, wherein R 4 is (Ci-C 8 )alkyl, R 2 is (Ci-C 8 )alkyl or optionally substituted aryl and R 3 is (C 1 - C8)alkyl or optionally substituted aryl.
- the invention provides a compound of any of sets 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 and 28, wherein R 4 is (C 1 -C 8 )alkyl, R 2 is (Ci-C 8 )alkyl and R 3 is (Ci-C 8 )alkyl or optionally substituted aryl.
- the invention provides a compound of any of sets 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 and 28, wherein R 4 is (Ci-C 8 )alkyl and each of R 2 and R 3 is independently optionally substituted aryl.
- the invention provides a compound of any of sets 1, 2,
- the invention provides a pharmaceutical composition comprising a compound of any one of sets 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33 and 34 wherein the optionally substituted aryl is an optionally substituted phenyl.
- the invention provides a pharmaceutical composition comprising a compound of any one of sets 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34 and 35, and a pharmaceutically acceptable carrier or excipient.
- the invention provides a method of inhibiting the activities of an NMDA receptor, the method comprising: contacting a compound of any one of sets 1-35 or a composition of set 36 with the NMDA receptor.
- the invention provides a a method of set 37, wherein the NMDA receptor is an activated glutamate receptor.
- the invention provides a method of inhibiting the synapse transmission by glutamate, the method comprising: contacting a compound of any one of sets 1-35 or a composition of set 36 with an activated extrasynaptic NMDA receptor.
- the invention provides a method of treating central nervous system disorders in a mammal, the method comprising: contacting a compound of any one of sets 1-35 or a composition of set 36 with the NMDA receptor.
- the invention provides a method of treating or preventing a neurodegenerative disease or neuropathological conditions in a mammal, the method comprising: administering to said mammal a therapeutically effective amount of a compound of any one of sets 1-35 or a composition of set 36.
- the invention provides a method of set 41, wherein the disease is selected from the group consisting of amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, neuropathic pain, stroke, epilepsy, CNS trauma, brain trauma, and cardiac arrest.
- the disease is selected from the group consisting of amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, neuropathic pain, stroke, epilepsy, CNS trauma, brain trauma, and cardiac arrest.
- the invention provides a method of set 42, wherein the condition is selected from the group consisting of neuropathic pain, stroke, brain trauma and epilepsy.
- the invention provides a method of enhancing the brain's cognitive function in a mammal, the method comprising: administering to said mammal a therapeutically effective amount of a compound of any one of sets 1-35 or a composition of set 36.
- the invention provides a method of preventing neuronal damage under a stress condition in a mammal, the method comprising: administering to said mammal a therapeutically effective amount of a compound of any one of sets 1-35 or a composition of set 36.
- the invention provides a method of set 45, wherein said stress condition is a stroke, head trauma or cardiac arrest.
- the invention provides a method of inhibiting the activities of an NMDA receptor, the method comprising: contacting any of compounds LC- 01 to LC-46, 4a to 4p, 5a to 5g, 8a to 8g and LC-02-dOl to LC-02-dl5 as set forth in Tables 1 to 3 and Examples.
- the invention provides a method of treating or preventing neurodegenerative diseases and neuropathological disorders or enhancing the brain's cognitive function in a mammal, said method comprising: administering to said mammal a therapeutically effective amount of any of compounds LC-Ol to LC-46, 4a to 4p, 5a to 5g, 8a to 8g and LC-02-dOl to LC-02-dl5 as set forth in Tables 1 to 3 and Examples.
- Compounds of the present invention can be prepared using readily available starting materials or known intermediates.
- starting materials available from commercial suppliers include, but are not limited to, naturally occurring L-amino acids, such as glycine, alanine, valine, lucine, isolucine, phenylalanine, proline, serine, threonine, tyrosine, cysteine, methionine, asparagines, glutamine, tryptophan, aspartic acid, glutamic acid, lysine, arginine, histidien and the like.
- the amino acids can be either optically active or racemic.
- Non commercially available amino acids with various side chains can be prepared using Strecker amino acid synthetic approach by condensing an aldehyde or ketone with ammonium chloride in the presence of potassium cyanide to form an ⁇ -aminonitrile, which is subsequently hydrolyzed to give the desired amino-acid (see, Kendall, et al. Organic Syntheses, Coll. Vol. 1, 1941, p.21; Vol. 9, 1929, p.4; and Clarke, et al. Organic Syntheses, Coll. Vol. 2, 1943, p.29; Vol. 11, 1931, p.4). All the compounds can be prepared by the methods described in the synthetic schemes and Examples 1 and 2. For example, the compounds set forth in Tables 1-3 can be prepared by the methods described in Schemes 1 to 3 described hereinbelow. Scheme 1 illustrates a Strecker synthetic process.
- Optically active ⁇ -amino acids can be readily prepared by using chiral auxiliaries or asymmetric catalysts (see, Ishitani, et al. J. Am. Chem. Soc. 2000, 122, 762-766; Huang, et al. Org, Lett. 2004, 6, 5027-5029; and Duthaler Tetrahedron 1994, 50, 1539-1650). The choice of appropriate reaction conditions are within those of skill in the art.
- Scheme 2 shows one synthetic approach to oxazolidine derivatives.
- ⁇ - amino acid compound 1 is converted to ⁇ -amino acid ester compound 2, which is reacted with a Grignard reagent to generate amino alcohol 3.
- Compound 4 obtained can be a single isomer or a mixture of two diastereomers.
- optically active single isomer of compound 4 can be obtained from the diastereomers mixture using standard chiral separation techniques, such as recrystallizations or column chromatographies, which are well known to those of skill in the art.
- Compound 5 can be synthesized by reacting the secondary amino group with an acyl chloride.
- Scheme 3 shows another approach for the synthesis of oxazolidine derivatives.
- the ⁇ -amino group in compound 2 is alkylated through a reductive amination process before compound 2 is converted to amino alcohol 7.
- the processes for formation of oxazolidine 8 are similar to those shown in Scheme 2.
- a therapeutically effective amount of a compound of any of Formulas I, Ia, Ib, Ic, Ia-I, Ia-2, Ia-3, Ia-4, Ib-I, Ib-2, Ib-3, Ib-4, Ic-I, Ic- 2, Ic-3, Ic-4, Ia-3', Ib-3', Ic-3', LC-Ol to LC-46, 4a to 4p, 5a to 5g, 8a to 8g, and LC-02-dOl to LC-02-dl5 and a compound as defined in any one of claims 1 to 35 can be used for the preparation of a pharmaceutical composition useful for treating and/or preventing amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, neuropathic pain, stroke, epilepsy, CNS trauma, head trauma, brain trauma, cardiac arrest and other diseases and disorders of the central nervous system.
- compositions of the invention can include compounds of any of Formulas (I), I, Ia, Ib, Ic, Ia-I, Ia-2, Ia-3, Ia-4, Ib-I, Ib-2, Ib-3, Ib-4, Ic-I, Ic-2, Ic-3, Ic-4, Ia-3', Ib-3', Ic-3', LC-Ol to LC-46, 4a to 4p, 5a to 5g, 8a to 8g, and LC-02-dOl to LC-02-dl5, and a compound as defined in any one of claims 1 to 35, pharmaceutically acceptable salts thereof, a hydrate thereof or a hydrolysable precursor thereof.
- the compound is mixed with suitable carriers or excipient(s) in a therapeutically effective amount.
- a therapeutically effective dose By a “therapeutically effective dose”, “therapeutically effective amount” or, interchangeably, “pharmacologically acceptable dose” or “pharmacologically acceptable amount”, it is meant that a sufficient amount of the compound of the present invention and a pharmaceutically acceptable carrier, will be present in order to achieve a desired result, e.g., alleviating a symptom or complication of central nervous system diseases or disorders.
- the compounds of any of Formulas I, Ia, Ib, Ic, Ia-I, Ia-2, Ia-3, Ia-4, Ib-I, Ib-2, Ib-3, Ib-4, Ic-I, Ic-2, Ic-3, Ic-4, Ia-3', Ib-3', Ic-3', LC-Ol to LC-46, 4a to 4p, 5a to 5g, 8a to 8g and LC-02- d01 to LC-02-dl5 or a pharmaceutically acceptable salt thereof, as defined in any one of claims 1 to 36 can be formulated into pharmaceutical compositions by combination with appropriate, pharmaceutically acceptable carriers or diluents and can be formulated into preparations in solid, semi-solid, liquid or gaseous forms, such as tablets, capsules, pills, powders, granules, dragees, suspensions, gels, slurries, ointments, solutions, suppositories, injections, inhalants and
- administration of the compounds can be achieved in various ways, including oral, buccal, rectal, parenteral, intraperitoneal, intradermal, transdermal, intratracheal administration.
- the compound can be administered in a local manner, in a depot or sustained release formulation.
- the compounds can be administered in a liposome.
- the compounds of any of Formulas I, Ia, Ib, Ic, Ia-I, Ia-2, Ia-3, Ia-4, Ib-I, Ib-2, Ib-3, Ib-4, Ic-I, Ic-2, Ic-3, Ic-4, Ia-3', Ib-3', Ic-3', LC-Ol to LC-46, 4a to 4p, 5a to 5g, 8a to 8g and LC-02-dOl to LC-02-dl5 or a pharmaceutically acceptable salt thereof, as defined in any one of claims 1 to 36 can be formulated with common excipients, diluents or carriers and compressed into tablets or formulated as elixirs or solutions for convenient oral administration or administered by intramuscular or intravenous routes.
- the compounds can be administered transdermally and can be formulated as sustained release dosage forms and the like.
- Compounds of Formula (I) can be administered alone, in combination with each other or they can be used in combination with other known
- Suitable formulations for use in the present invention are found in Remington: The Science and Practice of Pharmacy, 21st ed., Lippincott Williams & Wilkins, Philadelphia, PA, 2005, which is incorporated herein by reference. Moreover, for a brief review of methods for drug delivery, see, Langer, Science (1990) 249: 1527-1533, which is incorporated herein by reference.
- the pharmaceutical compositions described herein can be manufactured in a manner that is known to those of skill in the art, i.e., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes. The following methods and excipients are merely exemplary and are in no way limiting.
- compositions for the administration of the compounds of this invention may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy and drug delivery. All methods include the step of bringing the active ingredient into association with the carrier, which constitutes one or more accessory ingredients.
- the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.
- the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases.
- compositions containing a compound of any of formulas I, Ia, Ib, Ic, Ia- 1 , Ia-2, Ia-3 , Ia-4, Ib- 1 , Ib-2, Ib-3 , Ib-4, Ic- 1 , Ic-2, Ic-3 , Ic-4, Ia-3 ', Ib-3 ', Ic-3 ', LC-01 to LC-46, 4a to 4p, 5a to 5g, 8a to 8g and LC-02-dOl to LC-02-dl5 or a pharmaceutically acceptable salt thereof, as defined in any one of claims 1 to 36 may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions and self emulsifications as described in U.S.
- compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents, antioxidants and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients, which are suitable for the manufacture of tablets.
- excipients may be for example, inert diluents, such as cellulose, silicon dioxide, aluminum oxide, calcium carbonate, sodium carbonate, glucose, mannitol, sorbitol, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example PVP, cellulose, PEG, starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
- the tablets may be uncoated or they may be coated, enterically or otherwise, by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
- a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in the U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for control release.
- Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
- emulsions can be prepared with a non-water miscible ingredient such as oils and stabilized with surfactants such as mono-diglycerides, PEG esters and the like.
- Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
- excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy- propylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxy- ethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbito
- the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n- propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
- preservatives for example ethyl, or n- propyl, p-hydroxybenzoate
- coloring agents for example ethyl, or n- propyl, p-hydroxybenzoate
- coloring agents for example ethyl, or n- propyl, p-hydroxybenzoate
- flavoring agents such as sucrose or saccharin.
- sweetening agents such as sucrose or saccharin.
- Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
- the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
- Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
- a dispersing or wetting agent e.g., sodium EDTA
- suspending agent e.g., sodium EDTA
- preservatives e.g., sodium EDTA, sodium bicarbonate, sodium bicarbonate
- the pharmaceutical compositions of the invention may also be in the form of oil-in- water emulsions.
- the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
- Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally- occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
- the emulsions may also contain sweetening and flavoring agents.
- Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. Oral solutions can be prepared in combination with, for example, cyclodextrin, PEG and surfactants.
- the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
- the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butane diol.
- a non-toxic parenterally-acceptable diluent or solvent for example as a solution in 1,3-butane diol.
- acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
- sterile, fixed oils are conventionally employed as a solvent or suspending medium.
- any bland fixed oil may be employed including synthetic mono- or diglycerides.
- fatty acids such as oleic acid find use in the preparation of injectables.
- the compounds of the present invention may also be administered in the form of suppositories for rectal administration of the drug.
- These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
- a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
- Such materials include cocoa butter and polyethylene glycols.
- the compounds can be administered via ocular delivery by means of solutions or ointments.
- transdermal delivery of the subject compounds can be accomplished by means of iontophoretic patches and the like.
- creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of the present invention are employed.
- topical application is also meant to include the use of mouth washes and gargles.
- Dragee cores are provided with suitable coatings.
- suitable coatings can be used, which can optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures.
- Dyestuffs or pigments can be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
- the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or from propellant-free, dry-powder inhalers.
- a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or from propellant-free, dry-powder inhalers.
- a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or from propellant-free, dry-powder inhalers.
- the dosage unit can
- hydrophobic pharmaceutical compounds can be employed.
- Liposomes and emulsions are well known examples of delivery vehicles or carriers for hydrophobic drugs.
- long-circulating, i.e., stealth liposomes can be employed.
- liposomes are generally described in Woodle, et ah, U.S. Patent No. 5,013,556.
- the compounds of the present invention can also be administered by controlled release means and/or delivery devices such as those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719.
- the compounds of this invention may also be coupled with a carrier that is a suitable polymer as targetable drug carriers.
- a carrier that is a suitable polymer as targetable drug carriers.
- suitable polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxy-propyl-methacrylamide-phenol, polyhydroxyethyl-aspartamide- phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues.
- the compounds of the invention may be coupled to a carrier that is a class of biodegradable polymers useful in achieving controlled release of a drug, for example polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross linked or amphipathic block copolymers of hydrogels.
- Polymers and semipermeable polymer matrices may be formed into shaped articles, such as valves, stents, tubing, prostheses and the like.
- the compound of the invention is coupled to a polymer or semipermeable polymer matrix that is formed as a stent or stent-graft device.
- DMSO dimethylsulfoxide
- the compounds can be delivered using a sustained-release , such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent.
- sustained-release materials have been established and are well known by those skilled in the art. Sustained-release capsules can, depending on their chemical nature, release the compounds for a few hours up to over 100 days.
- compositions also can comprise suitable solid or gel phase carriers or excipients.
- suitable solid or gel phase carriers or excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin and polymers such as polyethylene glycols.
- compositions suitable for use in the present invention include compositions wherein the active ingredients are contained in a therapeutically effective amount.
- the amount of composition administered will, of course, be dependent on the subject being treated, on the subject's weight, the severity of the affliction, the manner of administration and the judgment of the prescribing physician. Determination of an effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.
- a therapeutically effective dose can be estimated initially from cell culture assays or animal models.
- toxicity and therapeutic efficacy of the compounds described herein can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., by determining the LD50, (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population).
- the dose ratio between toxic and therapeutic effect is the therapeutic index and can be expressed as the ratio between LD 50 and ED 50 .
- Compounds which exhibit high therapeutic indices are preferred.
- the data obtained from these cell culture assays and animal studies can be used in formulating a dosage range that is not toxic for use in human.
- the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED 50 with little or no toxicity.
- the dosage can vary within this range depending upon the dosage form employed and the route of administration utilized.
- the exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition. (See, e.g., Fingl et al. 1975 In: The Pharmacological Basis of Therapeutics, Ch. 1).
- the present invention provides a method of inhibiting the activities of an NMDA receptor.
- the method includes/comprises contacting a compound of any of formulas I, Ia, Ib, Ic, Ia-I, Ia-2, Ia-3, Ia-4, Ib-I, Ib-2, Ib-3, Ib-4, Ic-I, Ic-2, Ic-3, Ic-4, Ia-3', Ib-3', Ic-3', LC-Ol to LC-46, 4a to 4p, 5a to 5g, 8a to 8g and LC-02-dOl to LC-02-dl5 or a pharmaceutically acceptable salt thereof, as defined in any one of claims 1 to 36 or a pharmaceutical composition thereof with the NMDA receptor.
- the NMDA receptor is an activated NMDA receptor.
- the compounds of the present invention are NMDA antagonists that can be used to inhibit the binding of NMDA receptor ligand (e.g., glutamate) to NMDA receptor in vitro or in vivo.
- NMDA receptor ligand e.g., glutamate
- such methods comprise the step of contacting an NMDA receptor with a sufficient amount of one or more NMDA receptor antagonist as provided herein, in the presence of NMDA receptor ligand in aqueous solution and under conditions otherwise suitable for binding of the ligand to NMDA receptor.
- the NMDA receptor may be present in suspension (e.g., in an isolated membrane or cell preparation), or in a cultured or isolated neuron cell.
- the amount of NMDA receptor modulator contacted with the receptor should be sufficient to inhibit NMDA binding to NMDA receptor in vitro as measured, for example, using whole-cell patch clamp studies, calcium mobilization assay, fluormetric imaging plate reader (FLIPR) assey, or neuronal survival assay.
- FLIPR fluormetric imaging plate reader
- the NMDA antagonists of the invention are used to modulate, preferably inhibit, the activity of a NMDA receptor, for example, by contacting one or more compound(s) of the invention with a NMDA receptor (either in vitro or in vivo) under conditions suitable for binding of the modulator(s) to the receptor.
- the receptor may be present in solution or suspension, in a cultured or isolated cell preparation or within a patient. Any modulation of the activity may be assessed using patch clamp, FLIPR, or calcium assay techniques by detecting the ion current across the surface of neurons, or by survival assay, or immunocytochemical analysis.
- an effective amount of NMDA antagonist(s) in an amount sufficient to modulate NMDA receptor activity in vitro within patch clamp studies and calcium mobilization assays, followed by neuronal survival assays.
- comparative studies are conducted to determine its efficacy in comparison to the known antagonist memantine.
- the effect of the compound on cognitive functions, such as in treating dementia, improving memory in test subjects is evaluated in animal models using Morris Water Maze task.
- the present invention provides methods and use of the compounds of any of formulas I, Ia, Ib, Ic, Ia-I, Ia-2, Ia-3, Ia-4, Ib-I, Ib-2, Ib-3, Ib-4, Ic-I, Ic- 2, Ic-3, Ic-4, Ia-3', Ib-3', Ic-3', LC-Ol to LC-46, 4a to 4p, 5a to 5g, 8a to 8g and LC-02-dOl to LC-02-dl5 or a pharmaceutically acceptable salt thereof, as defined in any one of claims 1 to 36 for preventing and/or treating a neurodegenerative diseases or neuropathological conditions in a mammal or human.
- the methods include administering to the mammal or human a therapeutically effective amount of the compounds of the present invention.
- the present invention provides methods and uses of compounds of any of formulas I, Ia, Ib, Ic, Ia-I, Ia-2, Ia-3, Ia-4, Ib-I, Ib-2, Ib-3, Ib-4, Ic-I, Ic-2, Ic-3, Ic-4, Ia-3', Ib-3', Ic-3', LC-Ol to LC-46, 4a to 4p, 5a to 5g, 8a to 8g and LC-02-dOl to LC-02-dl5 or a pharmaceutically acceptable salt thereof, as defined in any one of claims 1 to 36 for enhancing the brain's cognitive function in a mammal or human.
- the methods include administering to the subject a therapeutically effective amount of the compounds of the present invention.
- the present invention provides neuroprotection as well as improves cognitive deficits.
- NMDA receptor antagonists the compounds of the present invention are useful in the treatment of acute and chronic disorders of CNS, ranging from neuropathological conditions to neurodegenerative diseases and conditions related to excitotoxicity.
- Disease states that can be treated using the compounds of the present invention include, but are not limited to, neurodegenerative disorders, head and brain trauma, genetic disorders, infectious disease, inflammatory disease, medication, drug and alcohol disorders, neuropathic pain, cancer, metabolic disorders, mental retardation, and learning and memory disorders, such as age related memory loss, Alzheimer's disease, mild cognitive impairment, amyotrophic lateral sclerosis, Huntington's chorea, amnesia, Bl deficiency, schizophrenia, depression and bipolar disorder, stroke, hydrocephalus, subarachnoid hemorrhage, vascular insufficiency, brain tumor, head trauma, brain trauma, epilepsy, Parkinson's disease, cerebral microangiopathy, cardiac arrest, pain medication, chemotherapy, oxygen deprivation, e.g, caused by a heart- lung machine, anesthesia, or near drowning, dementia (vascular, frontotemporal, Lewy-body, semantic, primary progressive aphasia, Pick's), progressive supranuclear palsy, corticobasal
- the present invention also represents a new paradigm for ischemic stroke treatment.
- Current treatments are severely limited.
- Traditionally, acute ischemic stroke is treated using a tissue plasminogen activator (tPA).
- tPA tissue plasminogen activator
- This drug can prevent some of the adverse impacts associated with stroke but only if it is administered intravenously within the first three hours of the event and only if there is no bleeding in the brain. With such a small therapeutic window, only a small percentage of stroke patients (-3%) receive effective treatment.
- stroke research has focused on developing neuroprotective agents, compounds that may make the brain more resistant to damage from stroke.
- the compounds of the present invention have the ability to halt the ischemic cascade.
- the compounds of the present invention exhibit neuroprotective properties. Moreover, they have demonstrated the abilities to prevent neuronal damage under conditions of stress. They confer protection to neuronal tissue when exposed to stroke-related conditions, and have immense potential as therapeutic drugs in the prevention and management of ischemic stroke.
- the compounds of the invention can be used for the treatment of diseases selected from the group consisting of amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease and Huntington's disease, acute or chronic neuropathic pain, stroke, brain trauma, epilepsy stroke and dementia.
- diseases selected from the group consisting of amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease and Huntington's disease, acute or chronic neuropathic pain, stroke, brain trauma, epilepsy stroke and dementia.
- Treatment methods provided herein include, in general, administration to a patient an effective amount of one or more compounds provided herein, e.g., orally, nasally or parenterally.
- Suitable patients include those patients suffering from or susceptible to (i.e., prophylactic treatment) a disorder or disease identified herein.
- Typical patients for treatment as described herein include mammals, particularly primates, especially humans.
- Other suitable patients include domesticated companion animals such as a dog, cat, horse, and the like, or a livestock animal such as cattle, pig, sheep and the like.
- treatment methods provided herein comprise administering to a patient an effective amount of a compound one or more compounds provided herein, for example, compounds of formula I.
- the compound(s) of the invention are preferably administered to a patient (e.g., a human) orally.
- the effective amount may be an amount sufficient to modulate the NMDA receptor activity and/or an amount sufficient to reduce or alleviate the symptoms presented by the patient.
- the amount administered is sufficient to yield a plasma concentration of the compound (or its active metabolite, if the compound is a pro-drug) high enough to detectably inhibit the NMDA receptor in vitro.
- Treatment regimens may vary depending on the compound used and the particular condition to be treated; for treatment of most disorders, a frequency of administration of 4 times daily or less is preferred. In general, a dosage regimen of 2 times daily is more preferred, with once a day dosing particularly preferred. It will be understood, however, that the specific dose level and treatment regimen for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination (i.e., other drugs being administered to the patient) and the severity of the particular disease undergoing therapy, as well as the judgment of the prescribing medical practitioner. In general, the use of the minimum dose sufficient to provide effective therapy is preferred. Patients may generally be monitored for therapeutic effectiveness using medical or veterinary criteria suitable for the condition being treated or prevented.
- the compounds of the present invention can be administered as frequently as necessary, including hourly, daily, weekly or monthly. Frequency of dosage may also vary depending on the compound used and the particular disease treated. However, for treatment of most disorders, a dosage regimen of 4 times daily, three times daily, or less is preferred, with a dosage regimen of once daily or 2 times daily being particularly preferred.
- the compounds utilized in the pharmaceutical method of the invention are administered at the initial dosage of about 0.0001 mg/kg to about 3000 mg/kg daily.
- dosages may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being employed. For example, dosages can be empirically determined considering the type and stage of disease diagnosed in a particular patient.
- the dose administered to a patient, in the context of the present invention should be sufficient to effect a beneficial therapeutic response in the patient over time.
- the size of the dose also will be determined by the existence, nature, and extent of any adverse side-effects that accompany the administration of a particular compound in a particular patient.
- the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination (i.e., other drugs being administered to the patient), the severity of the particular disease undergoing therapy, and other factors, including the judgment of the prescribing medical practitioner. Determination of the proper dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day, if desired.
- Doses can be given daily, or on alternate days, as determined by the treating physician. Doses can also be given on a regular or continuous basis over longer periods of time (weeks, months or years), such as through the use of a subdermal capsule, sachet or depot, or via a patch. It will be understood, however, that the specific dose level for any particular patient will depend on a variety of factors including the activity of the specific compound employed; the age, body weight, general health, sex and diet of the individual being treated; the time and route of administration; the rate of excretion; other drugs which have previously been administered; and the severity of the particular disease undergoing therapy, as is well understood by those of skill in the area.
- the time-release effect can be obtained by capsule materials that dissolve at different pH values, by capsules that release slowly by osmotic pressure or by any other known means of controlled release.
- compositions can be administered to the patient in a variety of ways, including topically, parenterally, intravenously, intradermally, intramuscularly, colonically, rectally or intraperitoneally.
- pharmaceutical compositions are administered parenterally, topically, intravenously, intramuscularly or orally.
- the present invention provides a compound of any of formulas I, Ia, Ib, Ic, Ia-I, Ia-2, Ia-3, Ia-4, Ib-I, Ib-2, Ib-3, Ib-4, Ic-I, Ic-2, Ic-3, Ic-4, Ia-3', Ib-3', Ic-3', LC-Ol to LC-46, 4a to 4p, 5a to 5g, 8a to 8g and LC-02-dOl to LC-02-dl5 or a pharmaceutically acceptable salt thereof, as defined in any one of claims 1 to 36, for use as a medicament.
- the present invention provides a compound of any of formulas I, Ia, Ib, Ic, Ia-I, Ia-2, Ia-3, Ia-4, Ib-I, Ib-2, Ib-3, Ib-4, Ic-I, Ic-2, Ic-3, Ic-4, Ia-3', Ib-3', Ic-3', LC-Ol to LC-46, 4a to 4p, 5a to 5g, 8a to 8g and LC-02-dOl to LC-02-dl5 or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 36, for use in treating central nervous system disorders in a mammal, for treating or preventing a neurodegenerative disease or neuropathological conditions in a mammal, for enhancing the brain's cognitive function in a mammal, and for preventing neuronal damage under a stress condition in a mammal.
- the treatable diseases include, but are not limited to, amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, neuropathic pain, stroke, epilepsy, CNS trauma, brain trauma, and cardiac arrest.
- the treatable and/or preventable conditions include neuropathic pain, stroke, brain trauma and epilepsy.
- the preventable stress condition includes a stroke, head trauma or cardiac arrest.
- the present invention provides use of a compound of of any of formulas I, Ia, Ib, Ic, Ia-I, Ia-2, Ia-3, Ia-4, Ib-I, Ib-2, Ib-3, Ib-4, Ic-I, Ic-2, Ic-3, Ic-4, Ia-3', Ib-3', Ic-3', LC-Ol to LC-46, 4a to 4p, 5a to 5g, 8a to 8g and LC-02-dOl to LC-02-dl5 or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 36, in the manufacture of a medicament for the prevention and/or treatment of central nervous system disorders and neurodegenerative disease or neuropathological conditions, for enhancing the brain's cognitive function in a mammal, and for preventing neuronal damage under a stress condition in a mammal.
- the treatable diseases include, but are not limited to, amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, neuropathic pain, stroke, epilepsy, CNS trauma, brain trauma, and cardiac arrest.
- the treatable and/or preventable conditions include neuropathic pain, stroke, brain trauma and epilepsy.
- the preventable stress condition includes a stroke, head trauma or cardiac arrest.
- NMDA N-methyl-D-aspartic acid
- M.S. molecular sieves
- DMSO dimethyl sufoxide
- EtOAc ethyl acetate
- Example 1 [0202] This example illustrates a general synthetic approach for the preparation of 1,3-N,O- oxazolidine derivatives.
- Example 2 [0207] This example illustrates another general synthetic approach for the preparation of 1,3- N,O-oxazolidine derivatives.
- Hippocampal neurons were prepared from embryonic day 18 Sprague-Dawley rats. After the hippocampus had been removed from the brain, isolated cells were plated onto Poly d-Lysine (PDL) (P0899, Sigma)-coated 35 mm dishes (153066, NUNC) at a density of 3xlO 5 cell per plate using Neurobasal Medium (NB) (21103-049, Gibco) with B27 supplement (17504-044, Gibco), penicillin/streptomycin (15140, Gibco) and 1 mM L-glutamine (25030, Gibco). The cell culture was incubated at 37 0 C in a humidified atmosphere of 5% CO 2 in air.
- PDL Poly d-Lysine
- the internal solution contained 120 mM cesium chloride, 20 mM tetraethylammonium chloride, 2 mM magnesium chloride, 1 mM calcium chloride and 10 mM HEPES (pH 7.2).
- the external solution contained 137 mM sodium chloride, 1 mM sodium bicarbonate, 0.34 mM sodium phosphate dibasic, 5.37 mM potassium chloride, 0.44 mM potassium phosphate monobasic, 2.5 mM HEPES (pH 7.4) and 22.2 mM glucose.
- Tetrodotoxin (5 ⁇ M) and bicuculline methiodide (20 ⁇ M) (0109, Tocris) were present in the bath solution to block synaptic transmission mediated by voltage-gated sodium channels and Ca 2+ -activated potassium channels, respectively.
- the neurons were rinsed with Locke's solution (5 mM potassium chloride, 128 mM sodium chloride, 2.7 mM calcium chloride, 1 mM di-sodium hydrogen orthophosphate, 5 mM HEPES and 10 mM glucose in Milli-Q water) without Mg 2+ , and incubated with addition of glycine (10 ⁇ M) for 15 minutes. After the incubation, the neurons were co-treated with the test compound (dissolved in Locke's plus glycine solution) and NMDA (20 ⁇ M; Sigma) for 20 minutes. Neurons were rinsed with Locke's plus Mg 2+ and replaced with fresh growth medium. The cell death was assayed and quantified using the lactate dehydrogenase release assay (Roche) after 24 hours.
- Locke's solution 5 mM potassium chloride, 128 mM sodium chloride, 2.7 mM calcium chloride, 1 mM di-sodium hydrogen orthophosphate, 5 mM HEPES and 10
- the neurons were rinsed with Locke's solution (5 mM potassium chloride, 128 mM sodium chloride, 2.7 mM calcium chloride, 1 mM di-sodium hydrogen orthophosphate, 5 mM HEPES and 10 mM glucose in Milli-Q water) without Mg 2+ , and incubated with addition of glycine (10 ⁇ M) for 15 minutes. After the incubation, the neurons were co-treated with the test compound (dissolved in Locke's plus glycine solution) and NMDA (20 ⁇ M; Sigma) for 20 minutes. Neurons were rinsed with Locke's plus Mg 2+ and replaced with fresh growth medium.
- Locke's solution 5 mM potassium chloride, 128 mM sodium chloride, 2.7 mM calcium chloride, 1 mM di-sodium hydrogen orthophosphate, 5 mM HEPES and 10 mM glucose in Milli-Q water
- glycine 10 mM glucose in Milli-Q water
- the neurons were
- mice were fixed with 4% paraformaldehyde for 20 minutes at room temperature, permeabilized and blocked with 4% goat serum and 0.4% Triton X-100. Double staining was performed by incubating the neurons with mouse monoclonal antibody specific for ⁇ tubulin isotype III (1 : 1000; Sigma) at 4 0 C overnight followed by FITC-conjugated goat anti-mouse antibody (1 : 1000; Invitrogen). Neurons were counter- stained with DAPI (1 :5000) to visualize nuclei before mounting. Neurons were then analyzed by a fluorescence microscope using a 4OX objective (DMRA; Leica). Immunofluorescent images were acquired with a RT Slider digital camera (#2.3.1, Diagnostics Instruments), collected with SPOT software (Diagnostics Instruments) and prepared for presentation with Adobe Photoshop®.
- mNSS Neurological Severity Score
- the mNSS system is a composite evaluation of motor and sensory function, balance impairment and reflex abnormality of ischemic animals (Chen et al, 2001 Intravenous administration of human umbilical cord blood reduces behavioral deficits after stroke in rats. Stroke 32:2682-8.).
- 1 score point is awarded for the inability to perform the test or for the lack of a tested reflex; thus, the higher the score, the more severe is the injury.
- the infarct area in each slice was calculated by subtracting the normal ipsilateral (ischemic) area from that of the contralateral (non-ischemic) hemisphere to reduce errors due to cerebral edema and was presented as a percentage relative to the area of the contralateral hemisphere.
- the contralateral hemispheric volume was used as a control for calculation of ischemia-induced brain edema in the ipsilateral hemisphere.
- a net difference in hemispheric volumes was gained by subtracting the volume of the hemisphere from that of the infracted hemisphere.
- Brain swelling was expressed as a percentage of the net difference in ischemic hemispheric volume over the contralateral hemispheric volume.
- mice 6-8 week old outbred male I. CR. mice, weighing 25-35 g were housed two per cage in a climatically controlled animal room (23-25 0 C) under 12 hours light/dark cycling. The animals were allowed access to water and food ad lib. The mice used for the experiment were brought to particular laboratory conditions for two days. All the experiments were conducted between 14:00 and 18:00. Scopolamine hydrobromide (Sigma, USA) was dissolved in saline in 4 mg/kg and administered in a volume of 10 ml/kg body weight. The experimental mice were randomly assigned into 3 groups, each consisting of 12 mice with similar mean body weights and age. Test sample was dissolved in physiological saline before the experiments each day.
- Scopolamine was administered through intraperitoneal injection (i.p.) at 30 minutes before the swimming tasks to induce memory deficit.
- Oral administrations (p.o.) of the test compound, or saline (0.9%) was started at the first day of the task and administrated according to a volume of 10 ml/kg body weight.
- Oral drug administrations were 45 minutes before the swimming tasks and conducted daily for 4 consecutive days until the end of the task.
- mice of -3-4 weeks old weighing 20-22 g were used. The mice had free access to food (rodent chow #2053, 5 g/mouse/day) and water. The cage floors were covered with wood shavings and the mice were handled once per week while the cages were cleaned. Mice were randomly assigned into groups: group 1 - test group; group 2 - Vehicle; group 3 - imipramine. Number of mice per group was -10-15. To facilitate adaptation to novel surroundings, mice were transported to the testing area from the core animal facility at least one week prior to testing. All experimental sessions were conducted between 0900 and 1200 hours.
- mice were put into a pyrex cylinder of 30 cm in height and 11.5 cm in diameter with water (10 cm) to a level that they would not be able to touch the bottom. Mice were put into the cylinder for twice, first day 15 min and second day 6 min. The duration of immobility (within the last 4 min in the 6-min time frame) of mice in FST were recorded using Etho- Vision® XT Mobility (Noldus software). The parameters to score the behavior of animals in the FST were fine-tuned by visual inspection. The threshold settings in Etho Vision to distinguish between immobility, mobility and strong mobility were established. The mean score resulting from this inspection was used as threshold setting during the entire experiment. The test compound was orally administered at 24 hour (right after the 15-min swim) and 45 min before the swimming session (6-min swim). Mice were fasted for 12 hours before testing.
- Embryonic day 18 Sprague Dawley rat pups were decapitated, their brains removed, and the cortices were isolated. Tissues were triturated and isolated neurons were plated onto 60 mm plate and cultured with Neurobasal medium supplemented with 2% B27 (Invitrogen). Experiments were performed after 10-12 days in vitro (DIV). Cultured cells were stimulated with a test compound or vehicle control (DMSO) for different time intervals and then lysed with RIPA buffer including protease inhibitors. Cell lysates were stored at -80 0 C before use.
- DMSO test compound or vehicle control
- the lysates were heated to 95°C for 10 min, vortexed and centrifuged for 7 min at 15,000 x g.
- Supernatants were electrophoresed on 10% SDS-polyacrylamide gel and transblotted to nitrocellulose membrane.
- the membranes were washed with 5% (w/v) powdered milk dissolved in PBS with 0.1% Triton X-100, followed by incubation at 4°C overnight with rabbit polyclonal against phospho-ERK or phosphor-AKT (1 : 1000, Cell Signaling Technology).
- HRP horseradish peroxidase
- Compound LC-02 exhibits NMDA receptor antagonist activity via whole cell patch clamp
- NMDA receptor is a gated ion channel, which allows inflow of current during a nerve impulse. Antagonists to the receptor would prevent the inflow of current.
- co-application of LC-02 resulted in a decreases in NMDA induced current in hippocampal neurons.
- FIG. IA hippocampal neurons from embryonic day 18 rats were isolated, trypsinized, plated onto 35-mm plates at a density of 3x10 4 cells/plate and cultured in Neurobasal medium (NB) supplemented with B27 nutrient.
- Rat hippocampal neurons (10-14 DIV) were treated with NMDA (50 ⁇ M) in the absence or presence of the compound LC-02 (10 ⁇ g/mL). Data is presented as % of NMDA-induced current.
- DMSO is the solvent control.
- NMDA antagonistic effect of LC-02 on current responses of a single hippocampal neuron was applied for 2.5 sec every 30 sec but these inter- response intervals have been deleted from the above figure for a better resolution of the kinetics of individual responses (blank space in trace).
- LC-02 500 uM was co-applied with NMDA. Partial recovery of NMDA-induced current was readily observed after LC-02 was washed out.
- LC oxazolidine derivative compounds protect rat primary cortical neurons against NMDA excitotoxicity
- Novel compounds (LC-O l-LC-46) were subjected to NMDA survival assays to evaluate their ability to reduce NMDA receptor-mediated excitotoxicity in primary cortical neuronal cells.
- Figure 2 shows the effect of NMDA insults on cortical neurons in the absence (DMSO) and presence of these novel compounds. Cell death was reduced by more than 60% in some instances, compared to the DMSO control. The LC series of compounds protect against NMDA excitotoxicity in rat cortical neurons.
- Embryonic rat cortical neurons (1 IDIV) were treated with NMDA (20 ⁇ M) in the absence or presence of the LC series of compounds (10-30 ⁇ g/ml).
- LC-Ol, LC-02, LC-06, LC-24 and LC-25 significantly protected rat primary cortical neurons from NMDA insults while LC-09, LC-10, LC-I l, LC-12, LC-14, LC-15, LC-16 indicated weaker neuroprotective effects.
- LDH release in the medium after overnight incubation was measured and fold change was calculated when compared to the solvent control, DMSO.
- Example 55 Dose-dependent protective effect of compounds LC-Ol and LC-02 on rat primary cortical neurons upon NMDA insult
- Embryonic rat cortical neurons were treated with NMDA (20 ⁇ M) in the absence or presence of LC-Ol or LC-02 ( ⁇ g/mL). LDH release in the medium after overnight incubation was measured and cell cytotoxicity was calculated in percentage when compared to the solvent control, DMSO.
- NMDA survival assays were conducted on the compound LC-06. Rat primary cortical neurons were subjected to NMDA (20 ⁇ M) in the absence and presence of varying concentrations of the compound. Figure 4 shows that cell death was markedly reduced in the presence of LC-06 (10 ⁇ g/ mL) in comparison to the negative control (DMSO). LC-06 protects against NMDA excitotoxicity in rat cortical neurons.
- Embryonic rat cortical neurons were treated with NMDA (20 ⁇ M) in the absence or presence of LC-06 ( ⁇ g/mL). LDH release in the medium after overnight incubation was measured and cell cytotoxicity was calculated in percentage when compared to the solvent control, DMSO.
- NMDA survival assays were conducted on the compounds LC-24 and LC-25. Rat primary cortical neurons were subjected to NMDA (20 ⁇ M) in the absence and presence of varying concentrations of these compounds. Figure 5 shows that cell death was markedly reduced in the presence of either LC-24 or LC-25 (10 ⁇ g/ mL) in comparison to the negative control (DMSO). LC-24 and LC-25 protect against NMDA excitotoxicity in rat cortical neurons.
- Embryonic rat cortical neurons (1 IDIV) were treated with NMDA (20 ⁇ M) in the absence or presence of LC-24 or LC-25 ( ⁇ g/mL). LDH release in the medium after overnight incubation was measured and cell cytotoxicity was calculated in percentage when compared to solvent control (DMSO).
- Compound LC-02 prevents NMDA-induced excitotoxicity in rat primary cortical neurons
- LC-02 (10 ⁇ g/mL) protects embryonic rat primary cortical neurons against NMDA excitotoxicity. Neurites were immunostained with beta-tubulin type III antibody and detected with FITC-conjugated antibody. Cell bodies were highlighted with DAPI stain. DMSO was used as the solvent control (CTL).
- Compound LC-02 decreases escape latencies in scopolamine-induced memory deficit mice
- Compound LC-06 exhibits NMDA receptor antagonist activity via whole cell patch clamp
- the NMDA receptor is a gated ion channel, which allows inflow of current during a nerve impulse.
- Whole cell patch clamp studies were conducted to measure the ion current across the surface of hippocampal neurons in the presence and absence of LC-06 to demonstrate NMDA receptor antagonist activity since antagonists to the receptor would prevent the inflow of current.
- co-application of LC-06 with NMDA resulted in a decrease in NMDA -induced current.
- Compound LC-24 exhibits NMDA receptor antagonist activity via whole cell patch clamp
- the NMDA receptor is a gated ion channel, which allows inflow of current during a nerve impulse.
- Whole cell patch clamp studies were conducted to measure the ion current across the surface of hippocampal neurons in the presence and absence of LC-24 to demonstrate NMDA receptor antagonist activity since antagonists to the receptor would prevent the inflow of current.
- co-application of LC-24 with NMDA resulted in a decrease in NMDA -induced current.
- NMDA 200 uM
- LC-24 500 uM
- NMDA NMDA
- Partial recovery of NMDA-induced current was readily observed after LC-24 was washed out.
- Compound LC-25 exhibits NMDA receptor antagonist activity via whole cell patch clamp
- the NMDA receptor is a gated ion channel, which allows inflow of current during a nerve impulse.
- Whole cell patch clamp studies were conducted to measure the ion current across the surface of hippocampal neurons in the presence and absence of LC-25 to demonstrate NMDA receptor antagonist activity since antagonists to the receptor would prevent the inflow of current.
- co-application of LC-25 with NMDA resulted in a decrease in NMDA -induced current.
- Compound LC-02 improves neurological scores in rats subjected to MCAO
- Rats were subjected to middle cerebral artery occlusion (MCAO) to induce focal cerebral ischemia.
- Neurological functions of these ischemic rats were then graded on a modified Neurological Severity Score (mNSS) system from a range of 0 to 18 (normal score, 0; maximal deficit score, 18).
- mNSS Neurological Severity Score
- the mNSS system is a composite evaluation of motor and sensory function, balance impairment and reflex abnormality of ischemic animals.
- 1 score point is awarded for the inability to perform the test or for the lack of a tested reflex; thus, the higher the score, the more severe the injury.
- oral treatment of LC-02 (70 mg/kg, H) at 24, 48 and 72 hours after MCAO significantly improved functional recovery, as evidenced by mNSS scores compared with vehicle-treated control.
- LC-02 decreased cerebral infarction and edema in MCAO-induced cerebral ischemia
- FIG. 12 Illustrative coronal sections (2-mm thick) of ischemic or sham rats. The infarct area in the ischemic cerebral hemisphere were represented as distinct pale-stained area in rats with 2 hours MCAO treated with 1.5% DMSO/ saline (vehicle) or LC-02 of 35 and 70 mg/kg at 6, 24 and 48 hours following the onset of ischemia, (b) Infarct area of ischemic rats was measured in 2-mm-think coronal brain sections treated with 1.5% DMSO/saline or LC-02 (35 mg/kg (L) and 70 mg/kg (H)) at 6, 24 and 48 hours following the onset of ischemia.
- LC-24 shortens the escape latencies of memory-deficit mice in Morris Water Maze test [0298] As shown in Figure 13, the therapeutic effect of LC-24 on spatial learning and memory in mice was demonstrated using the Morris Water Maze task, the favoured test to study hippocampal-dependant learning and memory.
- the Morris Water Maze consists of a water pool with a hidden, submerged escape platform. The rats must learn, over a period of consecutive days, the location of the platform using either contextual or local cues. The time taken to locate the hidden platform (escape latency) is a measure of the animal's cognitive abilities.
- LC-24 For the compound designated LC-24, the test subjects in the control group (saline) took -20 seconds to detect the platform after 4 days of training. In contrast, the scopolamine- induced memory-impaired group required more than three times the amount of time to locate the platform after an identical training period. LC-24 reduced the increased escape latency induced by scopolamine at a concentration of 30 mg/kg.
- mice were first orally administered LC-24 (30 mg/kg), scopolamine (4 mg/kg) was i.p. administered to mice 15 min to impair their memories. Treated mice were subjected to the Morris Water Maze 30 min after scopolamine injection and the procedures were repeated over a period of 4 days. On each day, the time taken for the mice to detect the hidden platform in the water maze was measured, in seconds.
- mice were first orally administered LC-06 (100 mg/kg), scopolamine (4 mg/kg) was i.p. administered to mice 15 min to impair their memories. Treated mice were subjected to the Morris Water Maze 30 min after scopolamine injection and the procedures were repeated over a period of 4 days. On each day, the time taken for the mice to detect the hidden platform in the water maze was measured, in seconds.
- the Forced Swim Test is a popular animal model for assessing depression. Animals are subjected to two trials during which they are forced to swim in an acrylic glass cylinder filled with water from which they cannot escape. The time that the test animal spends in an immobile state in the second trial is measured (immobility time). This immobility time is decreased by antidepressants.
- LC-02 100 mg/kg, p.o. or a known anti-depressant, imipramine, (15 mg/kg, i.p.) or water control was administered 7 times, once per day for 6 days and 45 min before the task. The task was then performed twice and the duration of time the mice spent in an immobile state during the second trial was measured. As indicated in Figure 15, a significant reduction in mobility was observed for mice treated with LC-02, similar to that observed with the anti- depressant imipramine.
- mice were transferred to the experimental room 40 min prior to initiating the test to acclimate and habituate the mice to the field.
- the total distance traveled during the last five minutes in the open field was recorded by a videocamera
- mice (mounted over the open field 2 metres above the floor) and scored by the Noldus Etho Vision XT software package.
- LC-02 100 mg/kg, p.o.
- imipramine 15 mg/kg, i.p.
- water control was administered 7 times, once per day for 6 days and 45 min before the task.
- LC-06 100 mg/kg, p.o.
- imipramine 15 mg/kg, i.p.
- water control was administered 7 times, once per day for 6 days and 45 min before the task. The task was then performed twice and the duration of time the mice spent in an immobile state during the second trial was measured. As indicated in Figure 17, a significant reduction in mobility was observed for mice treated with LC-02, similar to that observed with the antidepressant imipramine.
- LC-24 100 mg/kg, p.o.
- LC-25 100 mg/kg, p.o.
- imipramine 15 mg/kg, i.p.
- water control was administered 7 times, once per day for 6 days and 45 min before the task. The task was then performed twice and the duration of time the mice spent in an immobile state during the second trial was measured. As indicated in Figure 18, a significant reduction in mobility was observed for mice treated with LC-24 and LC-25, similar to that observed with the anti-depressant imipramine.
- LC-02 induces the phosphorylation of ERK and AKT protein in rat cortical neurons
- LC-02 induced phosphorylation of ERK after a 15-min treatment period and persisted to 60 min when compared to D5 (DMSO control).
- AKT protein was phosphorylated within 5-15 min after initiation of the treatment.
- rat cortical neurons of 11 DIV were treated with LC-02 (500 ⁇ M) for various time intervals.
- Western blot analysis was performed on the total cell lysates.
- Antibodies against phospho-ERKl/2 and phospho-AKT were used and detected with HRP conjugated secondary antibodies. Protein bands were visualized using ECL Western blot detection kit. 30 ⁇ g of proteins were loaded and equal loading of proteins were compared by probing with antibodies against total protein of ERK and AKT.
- Example 72 LC-02 inhibits the ligand binding of adenosine and opioid receptors
- LC-02 was evaluated at a single concentration in these specific binding assays. As shown in Table 4, LC-02 showed a moderate inhibitory effect on ligand binding to the adenosine A3 receptor and the opioid kappa receptor. A cutoff of 25% is considered as a moderate effect. LC-02 showed a 30% inhibition on [ 125 I]AB-MECA binding to the A3 receptor and [ 3 H]U 69593 to the kappa receptor.
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Biomedical Technology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- Psychology (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Pain & Pain Management (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB1011914.7A GB2470495B (en) | 2008-01-16 | 2009-01-16 | Oxazolidine derivatives as NMDA antagonists |
CN2009801093138A CN102066345B (en) | 2008-01-16 | 2009-01-16 | Oxazolidine derivatives as NMDA antagonists |
US12/812,940 US8722714B2 (en) | 2008-01-16 | 2009-01-16 | Oxazolidine derivatives as NMDA antagonists |
HK11105141.4A HK1151025A1 (en) | 2008-01-16 | 2011-05-24 | Oxazolidine derivatives as nmda antagonists |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US2160808P | 2008-01-16 | 2008-01-16 | |
US61/021,608 | 2008-01-16 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2009092324A1 true WO2009092324A1 (en) | 2009-07-30 |
Family
ID=40900773
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2009/070178 WO2009092324A1 (en) | 2008-01-16 | 2009-01-16 | Oxazolidine derivatives as nmda antagonists |
Country Status (5)
Country | Link |
---|---|
US (1) | US8722714B2 (en) |
CN (1) | CN102066345B (en) |
GB (1) | GB2470495B (en) |
HK (1) | HK1151025A1 (en) |
WO (1) | WO2009092324A1 (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011101774A1 (en) | 2010-02-16 | 2011-08-25 | Pfizer Inc. | (r)-4-((4-((4-(tetrahydrofuran-3-yloxy)benzo[d]isoxazol-3-yloxy)methyl)piperidin-1-yl)methyl)tetrahydro-2h-pyran-4-ol, a partial agonist of 5-ht4 receptors |
US9469601B2 (en) | 2012-12-04 | 2016-10-18 | Pierre Fabre Medicament | Aminocyclobutane derivatives, method for preparing same and the use thereof as drugs |
WO2017093354A1 (en) | 2015-11-30 | 2017-06-08 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Nmdar antagonists for the treatment of diseases associated with angiogenesis |
WO2018144551A3 (en) * | 2017-01-31 | 2018-09-07 | Manfredi Paolo L | D-methadone and its derivatives for use in the treatment of disorders of the nervous system |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
RU2496495C2 (en) * | 2011-12-05 | 2013-10-27 | Учреждение Российской академии медицинских наук Научно-исследовательский институт нормальной физиологии имени П.К. Анохина РАМН | USING SELECTIVE ANTAGONIST OF GLUAMATE RECEPTOR Ro-256981 FOR TARGETED EFFECT ON COGNITIVE FUNCTIONS |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998015542A1 (en) * | 1996-10-04 | 1998-04-16 | H. Lundbeck A/S | 3-alkoxyisoxazol-4-yl-substituted 2-amino carboxylic acid compounds |
CN1539837A (en) * | 2003-09-03 | 2004-10-27 | 中国科学院昆明植物研究所 | Analog of nerve growth factor (2S, 4S)-2-(2'substituent)-4-(indole-3-methine) |
WO2006046595A1 (en) * | 2004-10-28 | 2006-05-04 | Sankyo Company, Limited | Optically active 4,4-disubstituted oxazolidine derivative and method for producing same |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB0612423D0 (en) * | 2006-06-23 | 2006-08-02 | Angeletti P Ist Richerche Bio | Therapeutic agents |
-
2009
- 2009-01-16 GB GB1011914.7A patent/GB2470495B/en active Active
- 2009-01-16 US US12/812,940 patent/US8722714B2/en active Active
- 2009-01-16 WO PCT/CN2009/070178 patent/WO2009092324A1/en active Application Filing
- 2009-01-16 CN CN2009801093138A patent/CN102066345B/en active Active
-
2011
- 2011-05-24 HK HK11105141.4A patent/HK1151025A1/en unknown
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998015542A1 (en) * | 1996-10-04 | 1998-04-16 | H. Lundbeck A/S | 3-alkoxyisoxazol-4-yl-substituted 2-amino carboxylic acid compounds |
CN1539837A (en) * | 2003-09-03 | 2004-10-27 | 中国科学院昆明植物研究所 | Analog of nerve growth factor (2S, 4S)-2-(2'substituent)-4-(indole-3-methine) |
WO2006046595A1 (en) * | 2004-10-28 | 2006-05-04 | Sankyo Company, Limited | Optically active 4,4-disubstituted oxazolidine derivative and method for producing same |
Non-Patent Citations (1)
Title |
---|
DAI, W. ET AL.: "Chiral ligands derived from Abrine.2. oxazolidines as promoters for enantioselective addition of diethylzinc toward aromatic aldehydes.", TETRAHEDRON: ASYMMETRY, vol. 7, no. 5, 1996, pages 1245 - 1248 * |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011101774A1 (en) | 2010-02-16 | 2011-08-25 | Pfizer Inc. | (r)-4-((4-((4-(tetrahydrofuran-3-yloxy)benzo[d]isoxazol-3-yloxy)methyl)piperidin-1-yl)methyl)tetrahydro-2h-pyran-4-ol, a partial agonist of 5-ht4 receptors |
US9469601B2 (en) | 2012-12-04 | 2016-10-18 | Pierre Fabre Medicament | Aminocyclobutane derivatives, method for preparing same and the use thereof as drugs |
US9687459B2 (en) | 2012-12-04 | 2017-06-27 | Pierre Fabre Medicament | Aminocyclobutane derivatives, method for preparing same and the use thereof as drugs |
WO2017093354A1 (en) | 2015-11-30 | 2017-06-08 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Nmdar antagonists for the treatment of diseases associated with angiogenesis |
WO2018144551A3 (en) * | 2017-01-31 | 2018-09-07 | Manfredi Paolo L | D-methadone and its derivatives for use in the treatment of disorders of the nervous system |
JP2020506231A (en) * | 2017-01-31 | 2020-02-27 | パオロ エル マンフレディ | Compounds for treating or preventing disorders of the nervous system and their symptoms and signs, and for protecting cells against diseases and aging of the cells and their symptoms and signs |
Also Published As
Publication number | Publication date |
---|---|
US20110144168A1 (en) | 2011-06-16 |
GB2470495A (en) | 2010-11-24 |
GB2470495B (en) | 2012-12-26 |
CN102066345A (en) | 2011-05-18 |
CN102066345B (en) | 2013-07-17 |
GB201011914D0 (en) | 2010-09-01 |
US8722714B2 (en) | 2014-05-13 |
HK1151025A1 (en) | 2012-01-20 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA2986930C (en) | Chemical modulators of signaling pathways and therapeutic use | |
US10065951B2 (en) | Small molecule transcription modulators of bromodomains | |
EP3148974A1 (en) | Cyclopropylamine compounds as histone demethylase inhibitors | |
KR20190077544A (en) | MAGL inhibitor | |
EP2560008A2 (en) | Pharmaceutical compositions for preventing or treating degenerative brain disease and method of screening the same | |
EP2809318B1 (en) | Ammonium-containing sulfonic acid, phosphonic acid and carboxylic acid derivatives and their medical use | |
JP2016506961A (en) | Spirolactam NMDA receptor modulator and use thereof | |
JP5775094B2 (en) | Tetrahydrotriazolopyridine compounds as selective mGlu5 receptor potentiators useful in the treatment of schizophrenia | |
JP2020502047A (en) | MAGL inhibitor | |
BR112019009880A2 (en) | magl inhibitors | |
JP6302929B2 (en) | Hydroxy aliphatic substituted phenylaminoalkyl ether derivatives | |
US8722714B2 (en) | Oxazolidine derivatives as NMDA antagonists | |
DK2739606T3 (en) | Hydroxy-substituted amino and ammonium derivatives and their medical use | |
EP2809648B1 (en) | Oxygenated amino- or ammonium-containing sulfonic acid derivatives and their medical use | |
JP2022532810A (en) | Condensed heterocyclic derivative with selective BACE1 inhibitory activity | |
EP2874987B1 (en) | alpha-AND gamma-TRUXILLIC ACID DERIVATIVES AND PHARMACEUTICAL COMPOSITIONS THEREOF | |
WO2022197690A1 (en) | Non-hydroxamate hdac6 inhibitors and related methods of use | |
JP7228897B2 (en) | Adamantylmethylamine derivatives and their use as pharmaceuticals | |
JP5755821B2 (en) | MGLU2 / 3 agonist | |
WO2020059841A1 (en) | Therapeutic agent for prion diseases | |
WO2024123700A1 (en) | Histone deacetylase inhibitors | |
TW202340207A (en) | Inducers of klf2 and methods of use thereof | |
CN112313238A (en) | Tetrahydropyrano-oxazine derivatives having selective BACE1 inhibitory activity | |
JP2020526533A (en) | 2-oxo-1-imidazolidinyl imidazole thiadiazole derivative | |
JP2020526532A (en) | 2-Oxo-1,3-oxazolidinyl imidazole thiadiazole derivative |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WWE | Wipo information: entry into national phase |
Ref document number: 200980109313.8 Country of ref document: CN |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 09703172 Country of ref document: EP Kind code of ref document: A1 |
|
ENP | Entry into the national phase |
Ref document number: 1011914 Country of ref document: GB Kind code of ref document: A Free format text: PCT FILING DATE = 20090116 |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1011914.7 Country of ref document: GB |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 12812940 Country of ref document: US |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 09703172 Country of ref document: EP Kind code of ref document: A1 |