ZA200304311B - Excitatory amino acid receptor antagonists. - Google Patents
Excitatory amino acid receptor antagonists. Download PDFInfo
- Publication number
- ZA200304311B ZA200304311B ZA200304311A ZA200304311A ZA200304311B ZA 200304311 B ZA200304311 B ZA 200304311B ZA 200304311 A ZA200304311 A ZA 200304311A ZA 200304311 A ZA200304311 A ZA 200304311A ZA 200304311 B ZA200304311 B ZA 200304311B
- Authority
- ZA
- South Africa
- Prior art keywords
- pharmaceutically acceptable
- acceptable salt
- composition
- compound
- salt
- Prior art date
Links
- 229940123511 Excitatory amino acid receptor antagonist Drugs 0.000 title description 4
- 150000003839 salts Chemical class 0.000 claims description 61
- 150000001875 compounds Chemical class 0.000 claims description 48
- 238000000034 method Methods 0.000 claims description 28
- 125000000217 alkyl group Chemical group 0.000 claims description 26
- 239000000203 mixture Substances 0.000 claims description 23
- 208000012902 Nervous system disease Diseases 0.000 claims description 19
- 206010027599 migraine Diseases 0.000 claims description 17
- XTEGVFVZDVNBPF-UHFFFAOYSA-N naphthalene-1,5-disulfonic acid Chemical class C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1S(O)(=O)=O XTEGVFVZDVNBPF-UHFFFAOYSA-N 0.000 claims description 17
- 208000019695 Migraine disease Diseases 0.000 claims description 16
- 238000011282 treatment Methods 0.000 claims description 16
- IWYDHOAUDWTVEP-SSDOTTSWSA-N (R)-mandelic acid Chemical class OC(=O)[C@H](O)C1=CC=CC=C1 IWYDHOAUDWTVEP-SSDOTTSWSA-N 0.000 claims description 13
- 239000000651 prodrug Substances 0.000 claims description 13
- 229940002612 prodrug Drugs 0.000 claims description 13
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 11
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 11
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 230000004770 neurodegeneration Effects 0.000 claims description 8
- 125000005265 dialkylamine group Chemical group 0.000 claims description 7
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Natural products C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- 125000003342 alkenyl group Chemical group 0.000 claims description 6
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 230000008569 process Effects 0.000 claims description 5
- 239000003085 diluting agent Substances 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 3
- 230000026030 halogenation Effects 0.000 claims description 2
- 238000005658 halogenation reaction Methods 0.000 claims description 2
- 230000003647 oxidation Effects 0.000 claims description 2
- 238000007254 oxidation reaction Methods 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims 14
- AZNNFRBTUPHBIE-HWBDBZLXSA-N ethyl 6-[[(2s)-2-ethoxycarbonyl-4,4-difluoropyrrolidin-1-yl]methyl]-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate Chemical compound CCOC(=O)[C@@H]1CC(F)(F)CN1CC1CC2CC(C(=O)OCC)NCC2CC1 AZNNFRBTUPHBIE-HWBDBZLXSA-N 0.000 claims 6
- -1 decahydroisoquinoline derivative compounds Chemical class 0.000 description 61
- 125000001931 aliphatic group Chemical group 0.000 description 23
- 125000004432 carbon atom Chemical group C* 0.000 description 17
- 208000002193 Pain Diseases 0.000 description 13
- 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 12
- 102000018899 Glutamate Receptors Human genes 0.000 description 9
- 108010027915 Glutamate Receptors Proteins 0.000 description 9
- 102000005962 receptors Human genes 0.000 description 9
- 108020003175 receptors Proteins 0.000 description 9
- 208000025966 Neurological disease Diseases 0.000 description 7
- 125000003118 aryl group Chemical group 0.000 description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- 206010019233 Headaches Diseases 0.000 description 6
- 125000003545 alkoxy group Chemical group 0.000 description 6
- 208000035475 disorder Diseases 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 230000003492 excitotoxic effect Effects 0.000 description 6
- 231100000063 excitotoxicity Toxicity 0.000 description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 6
- 230000000626 neurodegenerative effect Effects 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 231100000869 headache Toxicity 0.000 description 5
- 210000002569 neuron Anatomy 0.000 description 5
- 229940098747 AMPA receptor antagonist Drugs 0.000 description 4
- 239000000775 AMPA receptor antagonist Substances 0.000 description 4
- 208000019901 Anxiety disease Diseases 0.000 description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 4
- 239000005557 antagonist Substances 0.000 description 4
- 230000036506 anxiety Effects 0.000 description 4
- 230000001684 chronic effect Effects 0.000 description 4
- 230000006378 damage Effects 0.000 description 4
- 230000002461 excitatory amino acid Effects 0.000 description 4
- 239000003257 excitatory amino acid Substances 0.000 description 4
- 125000000623 heterocyclic group Chemical group 0.000 description 4
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 4
- KQKPFRSPSRPDEB-UHFFFAOYSA-N sumatriptan Chemical compound CNS(=O)(=O)CC1=CC=C2NC=C(CCN(C)C)C2=C1 KQKPFRSPSRPDEB-UHFFFAOYSA-N 0.000 description 4
- 229960003708 sumatriptan Drugs 0.000 description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 208000000094 Chronic Pain Diseases 0.000 description 3
- 208000004404 Intractable Pain Diseases 0.000 description 3
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 3
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 3
- 210000004556 brain Anatomy 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 210000003169 central nervous system Anatomy 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 150000005690 diesters Chemical class 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 3
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 208000004296 neuralgia Diseases 0.000 description 3
- 208000021722 neuropathic pain Diseases 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 125000004430 oxygen atom Chemical group O* 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000010561 standard procedure Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- 208000030507 AIDS Diseases 0.000 description 2
- 206010003591 Ataxia Diseases 0.000 description 2
- 208000020925 Bipolar disease Diseases 0.000 description 2
- 201000006474 Brain Ischemia Diseases 0.000 description 2
- 206010048962 Brain oedema Diseases 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 206010008120 Cerebral ischaemia Diseases 0.000 description 2
- 208000006561 Cluster Headache Diseases 0.000 description 2
- 206010010904 Convulsion Diseases 0.000 description 2
- 206010012289 Dementia Diseases 0.000 description 2
- 206010052804 Drug tolerance Diseases 0.000 description 2
- 206010015866 Extravasation Diseases 0.000 description 2
- 208000010496 Heart Arrest Diseases 0.000 description 2
- 208000023105 Huntington disease Diseases 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- 206010026749 Mania Diseases 0.000 description 2
- 208000008238 Muscle Spasticity Diseases 0.000 description 2
- HOKKHZGPKSLGJE-GSVOUGTGSA-N N-Methyl-D-aspartic acid Chemical compound CN[C@@H](C(O)=O)CC(O)=O HOKKHZGPKSLGJE-GSVOUGTGSA-N 0.000 description 2
- 208000037212 Neonatal hypoxic and ischemic brain injury Diseases 0.000 description 2
- 208000007920 Neurogenic Inflammation Diseases 0.000 description 2
- 108090000189 Neuropeptides Proteins 0.000 description 2
- 208000018737 Parkinson disease Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 206010065016 Post-traumatic pain Diseases 0.000 description 2
- 208000028017 Psychotic disease Diseases 0.000 description 2
- 208000017442 Retinal disease Diseases 0.000 description 2
- 206010038923 Retinopathy Diseases 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 208000006011 Stroke Diseases 0.000 description 2
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 description 2
- 231100000643 Substance intoxication Toxicity 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 206010043118 Tardive Dyskinesia Diseases 0.000 description 2
- 208000008548 Tension-Type Headache Diseases 0.000 description 2
- 206010070863 Toxicity to various agents Diseases 0.000 description 2
- 206010044565 Tremor Diseases 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 208000005298 acute pain Diseases 0.000 description 2
- VLSMHEGGTFMBBZ-UHFFFAOYSA-N alpha-Kainic acid Natural products CC(=C)C1CNC(C(O)=O)C1CC(O)=O VLSMHEGGTFMBBZ-UHFFFAOYSA-N 0.000 description 2
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 208000006752 brain edema Diseases 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 230000000747 cardiac effect Effects 0.000 description 2
- 230000002490 cerebral effect Effects 0.000 description 2
- 206010008118 cerebral infarction Diseases 0.000 description 2
- 208000018912 cluster headache syndrome Diseases 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- 230000006735 deficit Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 206010013663 drug dependence Diseases 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- 206010015037 epilepsy Diseases 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 230000036251 extravasation Effects 0.000 description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 2
- 229930195712 glutamate Natural products 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 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 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 2
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 2
- 230000002218 hypoglycaemic effect Effects 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 208000014674 injury Diseases 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 208000028867 ischemia Diseases 0.000 description 2
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 2
- VLSMHEGGTFMBBZ-OOZYFLPDSA-N kainic acid Chemical compound CC(=C)[C@H]1CN[C@H](C(O)=O)[C@H]1CC(O)=O VLSMHEGGTFMBBZ-OOZYFLPDSA-N 0.000 description 2
- 229950006874 kainic acid Drugs 0.000 description 2
- 230000003902 lesion Effects 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000003387 muscular Effects 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 230000001272 neurogenic effect Effects 0.000 description 2
- 230000003961 neuronal insult Effects 0.000 description 2
- 239000004090 neuroprotective agent Substances 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 150000002894 organic compounds Chemical class 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 2
- 208000033300 perinatal asphyxia Diseases 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 2
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 description 2
- 229940044551 receptor antagonist Drugs 0.000 description 2
- 239000002464 receptor antagonist Substances 0.000 description 2
- 201000000980 schizophrenia Diseases 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 208000018198 spasticity Diseases 0.000 description 2
- 210000000278 spinal cord Anatomy 0.000 description 2
- 208000011117 substance-related disease Diseases 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- 208000011580 syndromic disease Diseases 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 230000008733 trauma Effects 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- 210000000427 trigeminal ganglion Anatomy 0.000 description 2
- 210000005166 vasculature Anatomy 0.000 description 2
- 230000003639 vasoconstrictive effect Effects 0.000 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000006039 1-hexenyl group Chemical group 0.000 description 1
- 125000006018 1-methyl-ethenyl group Chemical group 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- UTQNKKSJPHTPBS-UHFFFAOYSA-N 2,2,2-trichloroethanone Chemical group ClC(Cl)(Cl)[C]=O UTQNKKSJPHTPBS-UHFFFAOYSA-N 0.000 description 1
- UQNAFPHGVPVTAL-UHFFFAOYSA-N 2,3-Dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline Chemical compound N1C(=O)C(=O)NC2=C1C=C([N+]([O-])=O)C1=C2C=CC=C1S(=O)(=O)N UQNAFPHGVPVTAL-UHFFFAOYSA-N 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000006022 2-methyl-2-propenyl group Chemical group 0.000 description 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
- 125000006024 2-pentenyl group Chemical group 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000005917 3-methylpentyl group Chemical group 0.000 description 1
- PXACTUVBBMDKRW-UHFFFAOYSA-N 4-bromobenzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=C(Br)C=C1 PXACTUVBBMDKRW-UHFFFAOYSA-N 0.000 description 1
- 125000002672 4-bromobenzoyl group Chemical group BrC1=CC=C(C(=O)*)C=C1 0.000 description 1
- 125000000242 4-chlorobenzoyl group Chemical group ClC1=CC=C(C(=O)*)C=C1 0.000 description 1
- OBKXEAXTFZPCHS-UHFFFAOYSA-N 4-phenylbutyric acid Chemical compound OC(=O)CCCC1=CC=CC=C1 OBKXEAXTFZPCHS-UHFFFAOYSA-N 0.000 description 1
- 108010005456 AMPA 4 glutamate receptor ionotropic Proteins 0.000 description 1
- 108090000078 AMPA Receptors Proteins 0.000 description 1
- 102000003678 AMPA Receptors Human genes 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 108091005462 Cation channels Proteins 0.000 description 1
- 108091006146 Channels Proteins 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 108091006027 G proteins Proteins 0.000 description 1
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- 102000030782 GTP binding Human genes 0.000 description 1
- 108091000058 GTP-Binding Proteins 0.000 description 1
- 102100030668 Glutamate receptor 4 Human genes 0.000 description 1
- 102100022767 Glutamate receptor ionotropic, kainate 3 Human genes 0.000 description 1
- 101710112357 Glutamate receptor ionotropic, kainate 3 Proteins 0.000 description 1
- AEMRFAOFKBGASW-UHFFFAOYSA-M Glycolate Chemical compound OCC([O-])=O AEMRFAOFKBGASW-UHFFFAOYSA-M 0.000 description 1
- 108090000862 Ion Channels Proteins 0.000 description 1
- 102000004310 Ion Channels Human genes 0.000 description 1
- 102000000079 Kainic Acid Receptors Human genes 0.000 description 1
- 108010069902 Kainic Acid Receptors Proteins 0.000 description 1
- 229930195714 L-glutamate Natural products 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 241000252067 Megalops atlanticus Species 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 description 1
- 102000011420 Phospholipase D Human genes 0.000 description 1
- 108090000553 Phospholipase D Proteins 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 1
- ZZXDRXVIRVJQBT-UHFFFAOYSA-M Xylenesulfonate Chemical compound CC1=CC=CC(S([O-])(=O)=O)=C1C ZZXDRXVIRVJQBT-UHFFFAOYSA-M 0.000 description 1
- IPBVNPXQWQGGJP-UHFFFAOYSA-N acetic acid phenyl ester Natural products CC(=O)OC1=CC=CC=C1 IPBVNPXQWQGGJP-UHFFFAOYSA-N 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 125000005076 adamantyloxycarbonyl group Chemical group C12(CC3CC(CC(C1)C3)C2)OC(=O)* 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000003194 amino acid receptor blocking agent Substances 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 210000003050 axon Anatomy 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 230000005779 cell damage Effects 0.000 description 1
- 208000037887 cell injury Diseases 0.000 description 1
- 230000006727 cell loss Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- KVSASDOGYIBWTA-UHFFFAOYSA-N chloro benzoate Chemical compound ClOC(=O)C1=CC=CC=C1 KVSASDOGYIBWTA-UHFFFAOYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000003412 degenerative effect Effects 0.000 description 1
- 230000002999 depolarising effect Effects 0.000 description 1
- VILAVOFMIJHSJA-UHFFFAOYSA-N dicarbon monoxide Chemical group [C]=C=O VILAVOFMIJHSJA-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical compound OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 description 1
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 1
- 235000011180 diphosphates Nutrition 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 230000002964 excitative effect Effects 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 238000010575 fractional recrystallization Methods 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000001030 gas--liquid chromatography Methods 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- KKLGDUSGQMHBPB-UHFFFAOYSA-N hex-2-ynedioic acid Chemical compound OC(=O)CCC#CC(O)=O KKLGDUSGQMHBPB-UHFFFAOYSA-N 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-M hexanoate Chemical compound CCCCCC([O-])=O FUZZWVXGSFPDMH-UHFFFAOYSA-M 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 230000001057 ionotropic effect Effects 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 description 1
- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 230000027928 long-term synaptic potentiation Effects 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 210000002418 meninge Anatomy 0.000 description 1
- 125000005341 metaphosphate group Chemical group 0.000 description 1
- IZYBEMGNIUSSAX-UHFFFAOYSA-N methyl benzenecarboperoxoate Chemical compound COOC(=O)C1=CC=CC=C1 IZYBEMGNIUSSAX-UHFFFAOYSA-N 0.000 description 1
- 229940095102 methyl benzoate Drugs 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- YZMHQCWXYHARLS-UHFFFAOYSA-N naphthalene-1,2-disulfonic acid Chemical compound C1=CC=CC2=C(S(O)(=O)=O)C(S(=O)(=O)O)=CC=C21 YZMHQCWXYHARLS-UHFFFAOYSA-N 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 230000007433 nerve pathway Effects 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 230000003705 neurological process Effects 0.000 description 1
- 230000000324 neuroprotective effect Effects 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 230000036963 noncompetitive effect Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical compound CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([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
- 150000007530 organic bases Chemical class 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 125000004043 oxo group Chemical group O=* 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 125000003232 p-nitrobenzoyl group Chemical group [N+](=O)([O-])C1=CC=C(C(=O)*)C=C1 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000007310 pathophysiology Effects 0.000 description 1
- 125000006678 phenoxycarbonyl group Chemical group 0.000 description 1
- DYUMLJSJISTVPV-UHFFFAOYSA-N phenyl propanoate Chemical compound CCC(=O)OC1=CC=CC=C1 DYUMLJSJISTVPV-UHFFFAOYSA-N 0.000 description 1
- 229940049953 phenylacetate Drugs 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- 229950009215 phenylbutanoic acid Drugs 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 150000003906 phosphoinositides Chemical class 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
- 125000001557 phthalyl group Chemical group C(=O)(O)C1=C(C(=O)*)C=CC=C1 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- KCXFHTAICRTXLI-UHFFFAOYSA-N propane-1-sulfonic acid Chemical compound CCCS(O)(=O)=O KCXFHTAICRTXLI-UHFFFAOYSA-N 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- UORVCLMRJXCDCP-UHFFFAOYSA-M propynoate Chemical compound [O-]C(=O)C#C UORVCLMRJXCDCP-UHFFFAOYSA-M 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 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
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 229940116351 sebacate Drugs 0.000 description 1
- CXMXRPHRNRROMY-UHFFFAOYSA-L sebacate(2-) Chemical compound [O-]C(=O)CCCCCCCCC([O-])=O CXMXRPHRNRROMY-UHFFFAOYSA-L 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- 230000021317 sensory perception Effects 0.000 description 1
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical group 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- TYFQFVWCELRYAO-UHFFFAOYSA-L suberate(2-) Chemical compound [O-]C(=O)CCCCCCC([O-])=O TYFQFVWCELRYAO-UHFFFAOYSA-L 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Chemical group 0.000 description 1
- 230000000946 synaptic effect Effects 0.000 description 1
- 230000003956 synaptic plasticity Effects 0.000 description 1
- 230000005062 synaptic transmission Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 230000018405 transmission of nerve impulse Effects 0.000 description 1
- 230000000472 traumatic effect Effects 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(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
- 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 1
- 230000002227 vasoactive effect Effects 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 229940071104 xylenesulfonate Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- 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
- A61P25/06—Antimigraine agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Description
In the mammalian central nervous system (CNS), the transmission of nerve impulses is controlled by the interaction between a neurotransmitter, that is released by a sending neuron, and a surface receptor on a receiving neuron, which causes excitation of this receiving neuron. L-Glutamate, which is the most abundant neurotransmiter in the
CNS, mediates the major excitatory pathways in mammals, and is referred to as an excitatory amino acid (EAA). The receptors that respond to glutamate are called excitatory amino acid receptors (EAA receptors). See Watkins & Evans, Ann. Rev.
Pharmacol. Toxicol., 21, 165 (1981); Monaghan, Bridges, and Cotman, Ann. Rev. :
Pharmacol. Toxicol., 29, 365 (1989); Watkins, Krogsgaard-Larsen, and Honore, Trans.
Pharm. Sci., 11, 25 (1990). The excitatory amino acids are of great physiological importance, playing a role in a variety of physiological processes, such as long-term potentiation (learning and memory), the development of synaptic plasticity, motor control, respiration, cardiovascular regulation, and sensory perception. :
Excitatory amino acid receptors are classified into two general types. Receptors that are directly coupled to the opening of cation channels in the cell membrane of the neurons are termed "ionotropic." This type of receptor has been subdivided into at least three subtypes, which are defined by the depolarizing actions of the selective agonists N- methyl-D-aspartate (NMDA), a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), and kainic acid (KA). Molecular biological studies have established that AMPA receptors are composed of subunits (GluR — GluR4), which can assemble to form functional ion channels. Five kainate receptors have been identified which are classified as either High Affinity (KA1 and KA2) or Low Affinity (composed of GluRs, GluRg, and/or GluR7 subunits). Bleakman et al., Molecular Pharmacology, 49, No.4, 581,(1996).
The second general type of receptor is the G-protein coupled or second messenger-linked "metabotropic” excitatory amino acid receptor. This second type is coupled to multiple ) second messenger systems that lead to enhanced phosphoinositide hydrolysis, activation : of phospholipase D, increases or decreases in cAMP formation, and changes in ion * channel function. Schoepp and Conn, Trends in Pharmacol. Sci., 14, 13 (1993). :
Both types of excitatory amino acid receptor appear not only to mediate normal synaptic transmission along éxcitatory pathways, but also to participate in the modification of synaptic connections during development and throughout life. Schoepp, Bockaert, and y
Sladeczek, Trends in Pharmacol. Sci., 11, 508 (1990); McDonald and Johnson, Brain
Research Reviews, 15,41 (1990). ,
The excessive or inappropriate stimulation of excitatory amino acid receptors leads to neuronal cell damage or loss by way of a mechanism known as excitotoxicity. }
This process has been suggested to mediate neuronal degeneration in a variety of neurological disorders and conditions. The medical consequences of such neuronal degeneration makes the abatement of these degenerative neurological processes an important therapeutic goal. For instance, excitatory amino acid receptor excitotoxicity has been implicated in the pathophysiology of numerous neurological disorders, including the etiology of cerebral deficits subsequent to cardiac bypass surgery and grafting, stroke, cerebral ischemia, spinal cord lesions resulting from trauma or inflammation, perinatal hypoxia, cardiac arrest, and hypoglycemic neuronal damage. In addition, excitotoxicity has been implicated in chronic neurodegenerative conditions including Alzheimer’s
Disease, Huntington’s Chorea, inherited ataxias, AIDS-induced dementia, amyotrophic lateral sclerosis, idiopathic and drug-induced Parkinson's Disease, as well as ocular damage and retinopathy. Other neurological disorders implicated with excitotoxicity and/or glutamate dysfunction include muscular spasticity including tremors, drug tolerance and withdrawal, brain edema, convulsive disorders including epilepsy, depression, anxiety and anxiety related disorders such as post-traumatic stress syndrome, tardive dyskinesia, , and psychosis related to depression, schizophrenia, bipolar disorder, mania, and drug intoxication or addiction. (see generally United States Patent No. 5,446,051 and 5,670,516) Excitatory amino acid receptor antagonists may also be useful as analgesic agents and for treating or preventing various forms of headache, including cluster headache, tension-type headache, and chronic daily headache. In addition, published European Patent application WO98/45720 reports that excitatory amino acid receptor excitotoxicity participates in the etiology of acute and chronic pain states including severe pain, intractable pain, neuropathic pain, post-traumatic pain.
It is also known that trigeminal ganglia, and their associated nerve pathways, are associated with painful sensations of the head and face such as headache and, in particular, migraine. Moskowitz (Cephalalgia, 12, 5-7, (1992) proposed that unknown triggers stimulate the trigeminal ganglia which in turn innervate vasculature within . cephalic tissue, giving rise to the release of vasoactive neuropeptides from axons innervating the vasculature. These neuropeptides initiate a series of events leading to . neurogenic inflammation of the meninges, a consequence of which is pain. This neurogenic inflammation is blocked by sumatriptan at doses similar to those required to treat acute migraine in humans. However, such doses of sumatriptan are associated with contraindications as a result of sumatriptan’s attendant vasoconstrictive properties.(see
Macintyre, P.D., et al., British Journal of Clinical Pharmacology, 34, 541-546 (1992); . Chester, A.H., et al., Cardiovascular Research, 24, 932-937 (1990); Conner, HE., et al.,
European Journal of Pharmacology, 161, 91-94 (1990)). Recently, it has been reported . that all five members of the kainate subtype of ionotropic glutamate receptors are expressed on rat trigeminal ganglion neurons, and in particular, high levels of GluR45 and
KA2 have been observed. (Sahara et al., The Journal of Neuroscience, 17(17), 6611 (1997). As such, migraine presents yet another neurological disorder which may be implicated with glutamate receptor excitotoxicity.
The use of a neuroprotective agent, such as an excitatory amino acid receptor antagonist, is believed to be useful in treating or preventing all of the aforementioned disorders and/or reducing the amount of neurological damage associated with these disorders. For example, studies have shown that AMPA receptor antagonists are neuroprotective in focal and global ischemia models. The competitive AMPA receptor antagonist NBQX (2,3-dihydroxy-6-nitro-7-sulfamoylbenzo[flquinoxaline) has been reported effective in preventing global and focal ischemic damage. Sheardown et al., - Science, 247, 571 (1900); Buchan et al., Neuroreport, 2, 473 (1991); LePeillet et al.,
Brain Research, 571, 115 (1992). The noncompetitive AMPA receptor antagonists GK'YT 52466 has been shown to be an effective neuroprotective agent in rat global ischemia models. LaPeillet et al., Brain Research, 571, 115 (1992). European Patent Application
Publication No. 590789A1 and United States Patents No. 5,446,051 and 5,670,516 disclose that certain decahydroisoquinoline derivative compounds are AMPA receptor antagonists and, as such, are useful in the treatment of a multitude of disorders conditions, including pain and migraine headache. W098/45270 discloses that certain decahydroisoquinoline derivative compounds are selective antagonists of the iGluR5 receptor and are useful for the treatment of various types of pain, including; severe, chronic, intractable, and neuropathic pain
In accordance with the present invention, Applicants have discovered novel compounds that are selective antagonists of the iGluR4 receptor subtype and, thus, could be useful in treating the multitude of neurological disorders or neurodegenerative diseases, as discussed above. Such selective antagonists could address a long feltneed ) for safe and effective treatments for neruological disorders, without attending side effects.
The treatment of neurological disorders and neurodegenerative diseases is hereby : furthered.
n
The present invention provides a compound of Formula I
H 0
H H H : , py A ,, z
N OH
NH
F™
F H
Formula I or a pharmaceutically acceptable salt or prodrug thereof.
In a preferred embodiment, the present invention provides a compound of Formula
Ia
RO 0 ~~ N " OR?
F™ : :
F H
Formula Ia wherein
R1 and R2 each independently represent hydrogen, (Ci-Cag)alkyl, (C-Cg)alkenyl, (C;-Cg)alkylaryl, (C1-Ce)alkyl(Cs-Cyp)cycloalkyl, (C1-Cg)alkyl-N ,N-C;-Cg dialkylamine, (C;-Cg)alkyl-pyrrolidine, (C;-Cg)alkyl-piperidine, or (C,-Cg)alkyl- morpholine, with the proviso that at least one of RY and R2 are other than hydrogen, or a pharmaceutically acceptable salt thereof.
In a particularly preferred embodiment, the present invention provides the . D- (-) -mandelic acid salt of Formula I or Formula Ja, wherein Formula I and Formula Ia are as defined hereinabove. . In another embodiment, the present invention provides a method of treating or preventing a neurological disorder, or neurodegenerative condition, comprising administering to a patient in need thereof an effective amount of a compound of Formula I or Formula Ia, or a pharmaceutically acceptable salt thereof. Examples of such neurological disorders, or neurodegenerative conditions, include: cerebral deficits subsequent to cardiac bypass surgery and grafting; stroke; cerebral ischemia; spinal cord lesions resulting from trauma or inflammation; perinatal hypoxia; cardiac arrest; hypoglycemic neuronal damage; Alzheimer’s Disease; Huntington's Chorea; inherited ataxias; AIDS-induced dementia; amyotrophic lateral sclerosis; idiopathic and drug- induced Parkinson’s Disease; ocular damage and retinopathy; muscular spasticity including tremors; drug tolerance and withdrawal; brain edema; convulsive disorders including epilepsy; depression; anxiety and anxiety related disorders such as post- traumatic stress syndrome; tardive dyskinesia; psychosis related to depression, schizophrenia, bipolar disorder, mania, and drug intoxication or addiction; headache, including cluster headache, tension-type headache, and chronic daily headache; migraine; and acute and chronic pain states including severe pain, intractable pain, neuropathic pain, and post-traumatic pain. :
Specifically, the present invention provides a method of treating or preventing migraine comprising administering to a patient in need thereof an effective amount of a compound of Formula I or Formula Ia, or a pharmaceutically acceptable salt thereof.
More specifically, the present invention provides a method of treating or preventing migraine comprising administering to a patient in need thereof an effective amount of the D- (-) —mandelic acid salt of Formula I or Formula Ia.
The present invention also provides a process for making a compound of Formula
Ia, comprising combining a compound of structure (2)
H H H
. Lod” ; OR?
N ro : H @) :
wherein R2 is as defined herein, Pg is a suitable nitrogen protecting group, and LgO is a suitable leaving group, with a suitable base in a suitable solvent, followed by addition ofa . compound of structure (3)
RO
NH
:@
EC) wherein Rl is as defined herein, followed by oxidation to a compound of structure (5) 0
R'O H H H
I OR?
N pg
H oO (5) followed by halogenation and removal of the nitrogen protecting group.
In addition, the present invention provides pharmaceutical compositions of compounds of Formula I and Formula Ia, including the pharmaceutically acceptable salts, and hydrates thereof, useful for treating neurological disorders or neurodegenerative conditions, comprising, as an active ingredient, a compound of Formula I or Formula Ia in combination with a pharmaceutically acceptable carrier, diluent or excipient. This invention also encompasses novel intermediates, and processes for the synthesis of the compounds of Formula I and Formula Ia.
More specifically, the present invention provides pharmaceutical compositions useful for treating or preventing migraine comprising, as an active ingredient, the D- -)- mandelic acid salt of Formula I or Formula Ia, in combination with one or more pharmaceutically acceptable carriers, diluents, or excipients. .
The present invention also provides the use of a compound of Formula I or
Formula Ia for the manufacture of a medicament for treating or preventing a neurological disorder, or neurodegenerative condition.
More specifically, the present invention provides the use of a compound of
Formula I or Formula Ia for the manufacture of a medicament for treating or preventing migraine.
The present invention provides compounds functional as selective iGluR 5 receptor antagonists as well as pharmaceutically acceptable salts, prodrugs, and compositions thereof.
In addition, the present invention provides a method for the treatment of a neurological disorder, or neurodegenerative condition. Particularly, the present invention provides a method for the treatment of migraine which can be demonstrated by a particular mechanism of action, inhibition of neurogenic dural protein extravasation. By treating a migraineur with a compound or composition which is a selective antagonist of the iGluR 5 receptor relative to other excitatory amino acid receptors, the neurogenic extravasation which mediates migraine is inhibited without the attending side effects of agents designed to optimize the 5-HT]-like mediated vasoconstrictive activity of sumatriptan.
It should be understood by the skilled artisan that all of the compounds useful for the methods of the present invention are available for prodrug formualtion. As used herein, the term “prodrug” refers to a compound of Formula I or which has been structurally modified such that in vivo the prodrug is converted, for example, by hydrolytic, oxidative, reductive, or enzymatic cleavage into the parent compound (e.g. the carboxylic acid (drug), or as the case may be the parent dicarboxylic acid ) as given by
Formula I. Such prodrugs may be, for example, metabolically labile ester or diester derivatives of the parent compounds having a carboxylic acid group. Itis to be understood that the present invention includes any such prodrugs, such as metabolically labile ester or diester derivatives of compounds of the Formula I. In all cases, the use of the compounds described herein as prodrugs is contemplated, and often is preferred, and thus, the prodrugs of all of the compounds employed are encompassed in the names of the compounds herein. Preferred prodrugs include the diester derivatives of Formula I.
Conventional procedures for the selection and preparation of suitable prodrugs are well known to one of ordinary skill in the art. . More specifically, examples of prodrugs of Formula I which are understood to be included within the scope of the present invention, are represented by Formula Ia below:
Yr 0
H H H
7 TN ~~ 160% pu NH
F
F - H
Formula Ia wherein
R! and R2 each independently represent hydrogen, (C;-Cyp)alkyl, (C,-Ce)alkenyl, (C:-Cg)alkylaryl, (C;-Ce)alkyl(Cs-Cio)cycloalkyl, (C;-Ce)alkyl-N,N-C;-Ce dialkylamine, (C;-Cs)alkyl-pyrrolidine, (C,-Ce)alkyl-piperidine, or (C;-Cs)alkyl- morpholine, with the proviso that at least one of RI and R2 are other than hydrogen, or a pharmaceutically acceptable salt thereof.
It is understood that the selective iGluR 5 receptor antagonists of the present invention may exist as pharmaceutically acceptable salts and, as such, salts are therefore included within the scope of the present invention. The term "pharmaceutically acceptable salt" as used herein, refers to salts of the compounds provided by, or employed in the present invention which are substantially non-toxic to living organisms. Typical pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a pharmaceutically acceptable mineral or organic acid or an organic or inorganic base. Such salts are known as acid addition and base addition salts.
It will be understood by the skilled reader that most or all of the compounds used in the present invention are capable of forming salts, and that the salt forms of pharmaceuticals are commonly used, often because they are more readily crystallized and purified than are the free bases. In all cases, the use of the pharmaceuticals described herein as salts is contemplated in the description herein, and often is preferred, and the pharmaceutically acceptable salts of all of the compounds are included in the names of them.
Acids commonly employed to form acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as p-toluenesulfonic acid, mandelic acid, 1,5- , naphthalenedisulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.
Examples of such pharmaceutically acceptable salts are the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate,
metaphosphate, pyrophosphate, bromide, iodide, acetate, propionate, decanoate, caprylate, } acrylate, formate, hydrochloride, dihydrochloride, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne- ) 1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate, phthalate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, o-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, napththalene-2-sulfonate, mandelate, napadysilate and the like. Preferred pharmaceutically acceptable acid addition salts are those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as D- (-) — mandelic acid, 1,5- naphthalenedisulfonic acid , maleic acid, and methanesulfonic acid.
Base addition salts include those derived from inorganic bases, such as ammonium or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, and the like. Such bases useful in preparing the salts of this invention thus include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the like. The potassium and sodium salt forms are particularly preferred. It should be recognized that the particular counterion forming a part of any salt of this invention is ] usually not of a critical nature, so long as the salt as a whole is pharmacologically acceptable and as long as the counterion does not contribute undesired qualities to the salt as a whole. It is further understood that such salts may exist as a hydrate.
As used herein, the term "stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures which are not interchangeable. The three-dimensional structures are called configurations. As used herein, the term "enantiomer" refers to two stereoisomers whose molecules are nonsuperimposable mirror images of one another. The term "chiral center" refers to a carbon atom to which four different groups are attached. As used herein, the term "diastereomers" refers to stereoisomers which are not enantiomers. In addition, two diastereomers which have a different configuration at only one chiral center are referred to herein as "epimers". The terms "racemate”, "racemic mixture" or "racemic modification" . refer to a mixture of equal parts of enantiomers.
The term "enantiomeric enrichment" as used herein refers to the increase in the . amount of one enantiomer as compared to the other. A convenient method of expressing the enantiomeric enrichment achieved is the concept of enantiomeric excess, or "ee", which is found using the following equation:
ee = E'-E* X100
E' +E wherein E' is the amount of the first enantiomer and E is the amount of the second enantiomer. Thus, if the initial ratio of the two enantiomers is 50:50, such as is present in a racemic mixture, and an enantiomeric enrichment sufficient to produce a final ratio of 50:30 is achieved, the ee with respect to the first enantiomer is 25%. However, if the final ratio is 90:10, the ee with respect to the first enantiomer is 80%. An ee of greater than 90% is preferred, an ee of greater than 95% is most preferred and an ee of greater than 99% is most especially preferred. Enantiomeric enrichment is readily determined by one of ordinary skill in the art using standard techniques and procedures, such as gas or high performance liquid chromatography with a chiral column. Choice of the appropriate chiral column, eluent and conditions necessary to effect separation of the enantiomeric pair is well within the knowledge of one of ordinary skill in the art. In addition, the enantiomers of compounds of Formula I or Formula Ia can be resolved by one of ordinary skill in the art using standard techniques well known in the art, such as those described by
J. Jacques, et al., "Enantiomers, Racemates, and Resolutions”, John Wiley and Sons, Inc., : 1981.
The compounds of the present invention have one or more chiral centers and may exist in a variety of stereoisomeric configurations. As a consequence of these chiral centers, the compounds of the present invention occur as racemates, mixtures of enantiomers and as individual enantiomers, as well as diastereomers and mixtures of diastereomers. All such racemates, enantiomers, and diastereomers are within the scope of the present invention.
The terms "R" and "S" are used herein as commonly used in organic chemistry to denote specific configuration of a chiral center. The term "R" (rectus) refers to that configuration of a chiral center with a clockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group. The term "S" (sinister) refers to that configuration of a chiral center with a counterclockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group. The priority of groups is based upon their atomic ’ number (in order of decreasing atomic number). A partial list of priorities and a discussion of stereochemistry is contained in "Nomenclature of Organic Compounds: ’
Principles and Practice”, (J.H. Fletcher, et al, eds., 1974) at pages 103-120.
The specific stereoisomers and enantiomers of compounds of Formula I and
Formula Ia can be prepared by one of ordinary skill in the art utilizing well known techniques and processes, such as those disclosed by Eliel and Wilen, “Stereochemistry of
Organic Compounds”, John Wiley & Sons, Inc., 1994, Chapter 7, Separation of . Stereoisomers. Resolution. Racemization, and by Collet and Wilen, “Enantiomers,
Racemates, and Resolutions”, John Wiley & Sons, Inc., 1981. For example, the specific . stereoisomers and enantiomers can be prepared by stereospecific syntheses using enantiomerically and geometrically pure, or enantiomerically or geometrically enriched starting materials. In addition, the specific stereoisomers and enantiomers can be resolved and recovered by techniques such as chromatography on chiral stationary phases, enzymatic resolution or fractional recrystallization of addition salts formed by reagents used for that purpose.
As used herein the term "Pg" refers to a suitable nitrogen protecting group.
Examples of a suitable nitrogen protecting group as used herein refers to those groups intended to protect or block the nitrogen group against undesirable reactions during synthetic procedures. Choice of the suitable nitrogen protecting group used will depend upon the conditions that will be employed in subsequent reaction steps wherein protection is required, and is well within the knowledge of one of ordinary skill in the art.
Commonly used nitrogen protecting groups are disclosed in Greene, "Protective Groups
In Organic Synthesis," (John Wiley & Sons, New York (1981)). Suitable nitrogen protecting groups comprise acyl groups such as formyl, acetyl, propionyl, pivaloyl, t- butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o- nitrophenoxyacetyl, .alpha.-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4- nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; carbamate forming groups such as benzyloxycarbonyl, p- chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2- nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyi, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4- methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5- trimethoxybenzyloxycarbonyl, 1-(p-biphenylyl)-1-methylethoxycarbonyl, .alpha.,.alpha.- dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4- : nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and the like; alkyl - groups such as benzyl, triphenylmethyl, benzyloxymethyl and the like; and silyl groups such as trimethylsilyl and the like. Preferred suitable nitrogen protecting groups are formyl, acetyl, methoxycarbonyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).
As used herein the term "(Ci-Cqg)alkyl” refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 4 carbon atoms and includes, but is not . limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and the like.
As used herein the term "(C;-Ce)alkyl" refers to a straight or branched, . monovalent, saturated aliphatic chain of 1 to 6 carbon atoms and includes, but is not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, n-hexyl, and the like.
As used herein the term "(C;-Cyp)alkyl” refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 10 carbon atoms and includes, but is not limited to methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tertiary butyl, pentyl, isopentyl, hexyl, 2,3-dimethyl-2-butyl, heptyl, 2,2-dimethyl-3-pentyl, 2-methyl-2-hexyl, octyl, 4-methyl-3-heptyl and the like.
As used herein the term "(C;-Cqg)alkyl” refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 20 carbon atoms and includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl, 3-methylpentyl, 2-ethylbutyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n- dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-nonadecyl, n- eicosyl and the like. It is understood that the terms "(C;-Cg)alkyl", "(C1-Cg)alkyl", and "(C1-Cio)alkyl" are included within the definition of "(C;-Cyg)alkyl".
As used herein, the terms "Me", "Et", "Pr", "iPr", "Bu" and "t-Bu" refer to methyl, ethyl, propyl, isopropyl, butyl and tert-butyl respectively.
As used herein, the term "(C;-C4)alkoxy” refers to an oxygen atom bearing a straight or branched, monovalent, saturated aliphatic chain of 1 to 4 carbon atoms and includes, but is not limited to methyoxy, ethyoxy, n-propoxy, isopropoxy, n-butoxy, and the like.
As used herein the term “(C,-Cg)alkoxy” refers to an oxygen atom bearing a straight or branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms and includes, but is not limited to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, n- pentoxy, n-hexoxy, and the like.
As used herein, the term "(C-Ce)alkyl(C;-Cg)alkoxy” refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms which has a (C;- ’
Cs)alkoxy group attached to the aliphatic chain.
As used herein, the terms "Halo", "Halide" or "Hal" refer to a chlorine, bromine, : iodine or fluorine atom, unless otherwise specified herein.
As used herein the term "(C,-Ce)alkenyl” refers to a straight or branched, monovalent, unsaturated aliphatic chain having from two to six carbon atoms. Typical
C»-Cs alkenyl groups include ethenyl (also known as vinyl), 1-methylethenyl, 1-methy}-1-
propenyl, 1-butenyl, 1-hexenyl, 2-methyl-2-propenyl, 1-propenyl, 2-propenyl, 2-butenyl, : 2-pentenyl, and the like.
As used herein, the term “aryl” refers to a monovalent carbocyclic group containing one or more fused or non-fused phenyl rings and includes, for example, phenyl, 1- or 2-naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, and the like.
The term “substituted aryl” refers to an aryl group substituted with one or two moieties chosen from the group consisting of halogen, hydroxy, cyano, nitro, (C;-Cg)alkyl, (C1-
Cy)alkoxy, (C;-Ce)alkyl(Cs-Co)cycloalkyl, (C;-Ce)alkylaryl, (C;-Cg)alkoxycarbonyl, protected carboxy, carboxymethyl, hydroxymethyl, amino, aminomethyl, or trifluoromethyl.
As used herein, the term “(C,-Cg)alkylaryl™ refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms which has an aryl group attached to the aliphatic chain. Included within the term “C;-Cg alkylaryl” are the following: . 0 oho and.the like.
As used herein, the term “aryl(C,-Cs )alkyl” refers to an aryl group which has a straight or branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms attached to the aryl group. Included within the term “aryl(C,-Cs )alkyl” are the following: and the like.
As used herein the term "(Cs-C;p)cycloalkyl” refers to a saturated hydrocarbon ring structure composed of one or more fused or unfused rings containing from three to ten carbon atoms. Typical C3-C;o cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantanyl, and the like.
As used herein, the term “C;-Cs alkyl(C3-Cjo)cycloalkyl” refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms which has a (Cs- .
Cio)cycloalkyl attached to the aliphatic chain. Included within the term “C;-C¢ alkyl(Cs-
Cio)cycloalkyl” are the following: ’
BOT oR oRiave and the like.
As used herein, the term *“(C;-Cs) alkoxycarbonyl” refers to a carbonyl group having a (C1-Cg)alkyl group attached to the carbonyl carbon through an oxygen atom. ,
Examples of this group include t-buoxycarbonyl, methoxycarbonyl, and the like.
As used herein the term “heterocycle” refers to a five- or six-membered ring, . which contains one to four heteroatoms selected from the group consisting of oxygen, sulfur, and nitorgen. The remaining atoms of the ring are recognized as carbon by those of skill in the art. Rings may be saturated or unsaturated. Examples of heterocycle groups include thiophenyl, furyl, pyrrolyl, imidazolyl, pyrrazolyl, thiazolyl, thiazolidinyl, . isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridiazinyl, triazinyl, imidazolyl, dihydropyrimidyl, . tetrahydropyrimdyl, pyrrolidinyl, piperidinyl, piperazinyl, pyrazolidinyl, pyrimidinyl, imidazolidimyl, morpholinyl, pyranyl, thiomorpholinyl, and the like. The term “substituted heterocycle” represents a heterocycle group substituted with one or two moieties chosen from the group consisting of halogen, hydroxy, cyano, nitro, oxo, (C;-
Cealkyl, (C1-Cg)alkoxy, C;-Cq alkyl(C3-Cjo)cycloalkyl, (C1-Ce)alkylaryl, (C,;-
Ce)alkoxycarbonyl, protected carboxy, carboxymethyl, hydroxymethyl, amino, aminomethyl, or trifluoromethyl.
As used herein the term “N,N-C;-C; dialkylamine™ refers to a nitrogen atom substituted with two straight or branched, monovalent, saturated aliphatic chains of 1 to 6 carbon atoms. Included within the term “N,N-C;-Cg dialkylamine” are —N(CHs),, -
N(CH2CH3),, -N(CH2CH;CH3),, -N(CH,CH,CH,CH3),, and the like.
As used herein the term “C,;-Cgalkyl-N,N-C;-Cgdialkylamine” refers to straight or branched, monovalent, saturated aliphatic chain of 1to 6 carbon atoms which has an N,N-
C1-Cs dialkylamine attached to the aliphatic chain. Included within the term “C;-Cg alkyl-N,N-C,;-C¢ dialkylamine” are the following:
ONT SN shad PR , dd
XN > XN eh ] 20 and the like.
As used herein the term “(C;-Ce)alkyl-pyrrolidine” refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms which has a pyrrolidine attached to the aliphatic chain. Included within the scope of the term “(C,;-Cg)alkyl- pyrrolidine” are the following: : ny Dee ’ dN ' ’ ; WL) NSS y NY
INN ’ . N y . ] and the like.
As used herein the term “(C,-Cg)alkyl-piperidine” refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms which has a piperidine attached to the aliphatic chain. Included within the scope of the term *“(C;-Cg)alkyl- piperidine” are the following: » SN * E]
NTN ’ . , \ ) and the like.
As used herein the term “(C;-Cg)alkyl-morpholine” refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms which has a morpholine attached to the aliphatic chain. Included within the scope of the term “C;-Cg alkyl-morpholine” are the following: . 0
ZN a HON
YL seh oy : _o 9 (3 0) and the like.
Claims (40)
1. A pharmaceutically acceptable salt of a compound of the formula: } H 0) 0 } H H H yd N z OH pu NH F™ F H or a prodrug thereof, wherein the pharmaceutically acceptable salt is selected from the group consisting of the D-(-)-mandelic acid salt or the 1,5-naphthalene disulfonic acid salt.
2. The pharmaceutically acceptable salt according to Claim 1, wherein the salt is the D-(-)-mandelic acid salt.
3. The pharmaceutically acceptable salt according to Claim 1, wherein the salt is the 1,5-naphthalene disulfonic acid salt. :
4. A compound which is 3S, 4aR, 6S, 8aR 6-(((2S)-2-(carboxylic acid)-4,4- difluoropyrrolidinyDmethyl)-1, 2, 3, 4, 4a, 5, 6, 7, 8, 8a-decahydroisoquinoline-3- carboxylic acid ® D-(-)-mandelic acid.
5. A compound which is 3S, 4aR, 6S, 8aR 6-(((2S)-2-(carboxylic acid)-4,4- difluoropyrrolidinyl)methyl)-1, 2, 3, 4, 4a, 5, 6, 7, 8, 8a-decahydroisoquinoline-3- carboxylic acid e 1,5-naphthalene disulfonic acid.
6. A pharmaceutically acceptable salt of a compound of the formula: 1 R'O Oo 0 H H H ~ ON 7 OR? A NH F™ : F H : wherein R! and RZ each independently represent hydrogen, (C1-Cyo)alkyl, (C,-Cg)alkenyl, (C;-Cg)alkylaryl, (C;-Cg)alkyl(Cs-Cjo)cycloalkyl, (C1-Ce)alkyl-N,N-C;-Cg dialkylamine, (C;-Ce)alkyl-pyrrolidine, (C;-Cg)alkyl-piperidine, or (C;-Ce)alkyl- morpholine, with the proviso that at least one of R1 and R? are other than hydrogen;
-47- PCT/US01/44715 wherein the pharmaceutically acceptable salt is selected from the group consisting of the D-(-)-mandelic acid salt or the 1,5-naphthalene disuifonic acid salt.
7. The pharmaceutically acceptable salt according to Claim 6, wherein R! and R? are each independently (C,;-C,)alkyl.
8. The pharmaceutically acceptable salt according to Claim 7, wherein R! and R2 are each independently (C,-Cg)alkyl.
9. The pharmaceutically acceptable salt according to Claim 8, wherein the salt is the D-(-)-mandelic acid salt.
10. The pharmaceutically acceptable salt according to Claim 8, wherein the salt is the 1,5-naphthalene disulfonic acid salt.
11. A compound which is 3S, 4aR, 6S, 8aR Ethyl 6-(((2S)-2-(Ethoxycarbonyl)-4,4- difluoropyrrolidinyl)methyl)-1, 2, 3, 4, 4a, 5, 6, 7, 8, 8a-decahydroisoquinoline-3- carboxylate ® D-(-)-mandelic acid.
12. A compound which is 3S, 4aR, 6S, 8aR Ethyl 6-(((2S)-2-(Ethoxycarbonyl)-4,4- difluoropyrrolidinyl)methyl)-1, 2,3,4,4a,5, 6, 7, 8, 8a-decahydroisoquinoline-3- carboxylate ® 1,5-naphthalene disulfonic acid.
13. Use of a pharmaceutically acceptable salt according to Claim 1 in the manufacture of a medicament for treating a neurological disorder or neurodegenerative disease.
14. Use according to Claim 13, wherein the neurological disorder is migraine.
15. Use according to Claim 14, wherein the pharmaceutically acceptable salt is 3S, : 4aR, 6S, 8aR 6-(((2S)-2-(carboxylic acid)-4,4-difluoropyrrolidinyl)methyl)-1, 2, 3, 4, 4a, 5, 6, 7, 8, 8a-decahydroisoquinoline-3-carboxylic acid ® D-(-)-mandelic acid.
16. Use according to Claim 14, wherein the pharmaceutically acceptable salt is 3S, 4aR, 6S, 8aR 6-(((2S)-2-(carboxylic acid)-4,4-difluoropyrrolidinyl)methyl)-1, 2, 3, 4, 4a, 5, 6, 7, 8, 8a-decahydroisoquinoline-3-carboxylic acid ® 1,5-naphthalene disulfonic acid.
17. Use of a pharmaceutically acceptable salt according to Claim 6 in the manufacture of a medicament for treating a neurological disorder or neurodegenerative disease.
18. Use according to Claim 17, wherein the neurological disorder is migraine.
19. Use according to Claim 17, wherein the pharmaceutically acceptable salt is 3S, 4aR, 6S, 8aR Ethyl 6-(((2S)-2-(Ethoxycarbonyl)-4,4-difluoropyrrolidinyl)methyl)-1, 2, 3, 4, 4a, 5, 6, 7, 8, 8a-decahydroisoquinoline-3-carboxylate ® D-(-)-mandelic acid.
20. Use according to Claim 17, wherein the pharmaceutically acceptable salt is 3S, + MENDED SHEET N
: -48- PCT/US01/44715 ’ 4aR, 6S, 8aR Ethyl 6-(((2S)-2-(Ethoxycarbonyl)-4,4-difluoropyrrolidinyl)methyl)-1, 2, 3, 4, 4a, 5, 6, 7, 8, 8a-decahydroisoquinoline-3-carboxylate ® 1,5-naphthalene disulfonic acid.
21. A pharmaceutical composition comprising an effective amount of the pharmaceutically acceptable salt according to Claim 1, in combination with a pharmaceutically acceptable carrier, diluent, or excipient.
22. A pharmaceutical composition comprising an effective amount of the pharmaceutically acceptable salt according to Claim 6, in combination with a pharmaceutically acceptable carrier, diluent, or excipient. .
23. The use of a compound according to Claim 1 for the treatment of migraine.
24. The use of a compound according to Claim 6 for the treatment of migraine.
25. A process for preparing a compound of the formula: R? 0) YT WH <7 ~ ~~ OR? 0 ET NH F H : wherein R! and R? each independently represent hydrogen, (C;-Cyalkyl, (C,-Cg)alkenyl, (C,-Cgalkylaryl, (C,-Cgalkyl(C;-C,g)cycloalkyl, (C,-Cgalkyl-N,N-C;-Cq dialkylamine, (C;-Cy)alkyl-pyrrolidine, (C,-Cy)alkyl-piperidine, or (C,-Cyalkyl- morpholine, with the proviso that at least one of R! and R? are other than hydrogen, comprising combining a compound of structure 2) {ENDED SHEET BN
0] H H H
Ld . = OR? . N pg H 2) wherein R2 is as defined above, Pg is a suitable nitrogen protecting group, and LgO is a suitable leaving group, with a suitable base in a suitable solvent, followed by addition of a compound of structure (3) : R'O : NH i: @ HO ( ) wherein R1 is as defined above, followed by oxidation to a compound of structure (5) RIO™X H HH I OR? ) N ~N Pg H 0] 6) followed by halogenation and removal of the nitrogen protecting group.
. -50- PCT/US01/44715 )
26. A substance or composition for use in a method of treating a neurological disorder or neurodegenerative disease, said substance or composition comprising a pharmaceutically acceptable salt according to Claim 1, and said method comprising administering an effective amount of said substance or composition to a patient in need thereof.
27. A substance or composition for use in a method of treatment according to Claim 26, wherein the neurological disorder is migraine.
28. A substance or composition for use in a method of treatment according to Claim 26, wherein the pharmaceutically acceptable salt is 3S, 4aR, 6S, 8aR 6-(((2S)-2- (carboxylic acid)-4,4-difluoropyrrolidinyl)methyl)-1, 2, 3, 4, 4a, 5, 6, 7, 8, 8a- decahydroisoquinoline-3-carboxylic acid ® D-(-)-mandelic acid.
29. A substance or composition for use in a method of treatment according to Claim 26, wherein the pharmaceutically acceptable salt is 3S, 4aR, 6S, 8aR 6-(((2S)-2- (carboxylic acid)-4,4-difluoropyrrolidinyl)methyl)-1, 2, 3, 4, 4a, 5, 6, 7, 8, 8a- decahydroisoquinoline-3-carboxylic acid ® 1,5-naphthalene disulfonic acid.
30. A substance or composition for use in a method of treating a neurological disorder or neurodegenerative disease, said substance or composition comprising a pharmaceutically acceptable salt according to Claim 6, and said method comprising administering an effective amount of said substance or composition to a patient in need thereof.
31. A substance or composition for use in a method of treatment according to Claim 30, wherein the neurological disorder is migraine.
32. A substance or composition for use in a method of treatment according to Claim 30, wherein the pharmaceutically acceptable salt is 3S, 4aR, 6S, 8aR Ethyl 6- (((2S)-2-(Ethoxycarbonyl)-4,4-difluoropyrrolidinyl)methyl)-1, 2, 3, 4, 4a, 5,6, 7, 8, 8a- decahydroisoquinoline-3-carboxylate ® D-(-)-mandelic acid.
33. A substance or composition for use in a method of treatment according to Claim 30, wherein the pharmaceutically acceptable salt is 3S, 4aR, 6S, 8aR Ethyl 6- (((2S)-2-(Ethoxycarbonyl)-4,4-difluoropyrrolidinyl)methyl)-1, 2, 3, 4, 4a, 5, 6, 7, 8, 8a- decahydroisoquinoline-3-carboxylate ® 1,5-naphthalene disulfonic acid.
34. A salt according to any one of claims 1 or 6, substantially as herein described and illustrated.
35. A compound according to any one of claims 4, 5, 11, or 12, substantially as herein described and illustrated.
36. Use according to any one of claims 13 to 20, or 23, or 24, substantially as * VIENDED SHEET BN
. -51- PCT/US01/44715 ) herein described and illustrated.
37. A composition according to claim 21 or claim 22, substantially as herein described and illustrated.
38. A process according to claim 25, substantially as herein described and illustrated.
39. A substance or composition for use in a method of treatment according to any one of claims 26 to 33, substantially as herein described and illustrated.
40. A pew salt; a new compound; a new use of a salt as claimed in claim 1, or claim 6; a new composition; a new process for preparing a compound; or a substance or composition for a new use in a method of treatment; substantially as herein described. * MENDED SHEET
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US26001401P | 2001-01-05 | 2001-01-05 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ZA200304311B true ZA200304311B (en) | 2004-09-02 |
Family
ID=22987455
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ZA200304311A ZA200304311B (en) | 2001-01-05 | 2003-06-02 | Excitatory amino acid receptor antagonists. |
Country Status (23)
| Country | Link |
|---|---|
| EP (1) | EP1351955A1 (en) |
| JP (1) | JP2004520335A (en) |
| KR (1) | KR20030066797A (en) |
| CN (1) | CN1484642A (en) |
| AR (1) | AR035679A1 (en) |
| BR (1) | BR0116672A (en) |
| CA (1) | CA2431545A1 (en) |
| CZ (1) | CZ20031856A3 (en) |
| DZ (1) | DZ3460A1 (en) |
| EA (1) | EA200300770A1 (en) |
| EC (1) | ECSP034682A (en) |
| HR (1) | HRP20030544A2 (en) |
| HU (1) | HUP0302528A2 (en) |
| IL (1) | IL156138A0 (en) |
| MX (1) | MXPA03005981A (en) |
| NO (1) | NO20032973L (en) |
| NZ (1) | NZ525821A (en) |
| PE (1) | PE20020792A1 (en) |
| PL (1) | PL361934A1 (en) |
| SK (1) | SK8242003A3 (en) |
| TW (1) | TW591023B (en) |
| WO (1) | WO2002053561A1 (en) |
| ZA (1) | ZA200304311B (en) |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5284957A (en) * | 1992-09-03 | 1994-02-08 | Eli Lilly And Company | Excitatory amino acid receptor antagonists |
| EP1053234A1 (en) * | 1998-02-06 | 2000-11-22 | Smithkline Beecham Plc | Salts of paroxetine |
| GB9908175D0 (en) * | 1999-04-09 | 1999-06-02 | Lilly Co Eli | Method of treating neurological disorders |
| TR200200066T2 (en) * | 1999-07-06 | 2002-04-22 | Eli Lilly And Company | Selective iGluR5 receptor antagonists for the treatment of migraine |
-
2001
- 2001-12-20 PL PL01361934A patent/PL361934A1/en not_active Application Discontinuation
- 2001-12-20 MX MXPA03005981A patent/MXPA03005981A/en unknown
- 2001-12-20 CN CNA018217508A patent/CN1484642A/en active Pending
- 2001-12-20 BR BR0116672-7A patent/BR0116672A/en not_active IP Right Cessation
- 2001-12-20 WO PCT/US2001/044715 patent/WO2002053561A1/en not_active Application Discontinuation
- 2001-12-20 NZ NZ525821A patent/NZ525821A/en unknown
- 2001-12-20 IL IL15613801A patent/IL156138A0/en unknown
- 2001-12-20 HU HU0302528A patent/HUP0302528A2/en unknown
- 2001-12-20 CA CA002431545A patent/CA2431545A1/en not_active Abandoned
- 2001-12-20 EP EP01995980A patent/EP1351955A1/en not_active Withdrawn
- 2001-12-20 KR KR10-2003-7008977A patent/KR20030066797A/en not_active Application Discontinuation
- 2001-12-20 DZ DZ013460A patent/DZ3460A1/en active
- 2001-12-20 CZ CZ20031856A patent/CZ20031856A3/en unknown
- 2001-12-20 EA EA200300770A patent/EA200300770A1/en unknown
- 2001-12-20 JP JP2002554680A patent/JP2004520335A/en active Pending
- 2001-12-20 SK SK824-2003A patent/SK8242003A3/en unknown
-
2002
- 2002-01-04 AR ARP020100030A patent/AR035679A1/en not_active Application Discontinuation
- 2002-01-04 PE PE2002000003A patent/PE20020792A1/en not_active Application Discontinuation
- 2002-01-04 TW TW091100071A patent/TW591023B/en not_active IP Right Cessation
-
2003
- 2003-06-02 ZA ZA200304311A patent/ZA200304311B/en unknown
- 2003-06-27 NO NO20032973A patent/NO20032973L/en not_active Application Discontinuation
- 2003-07-03 HR HR20030544A patent/HRP20030544A2/en not_active Application Discontinuation
- 2003-07-03 EC EC2003004682A patent/ECSP034682A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| JP2004520335A (en) | 2004-07-08 |
| IL156138A0 (en) | 2003-12-23 |
| KR20030066797A (en) | 2003-08-09 |
| TW591023B (en) | 2004-06-11 |
| CA2431545A1 (en) | 2002-07-11 |
| MXPA03005981A (en) | 2003-09-10 |
| EA200300770A1 (en) | 2003-10-30 |
| HRP20030544A2 (en) | 2004-08-31 |
| PE20020792A1 (en) | 2002-09-06 |
| DZ3460A1 (en) | 2002-07-11 |
| PL361934A1 (en) | 2004-10-18 |
| EP1351955A1 (en) | 2003-10-15 |
| SK8242003A3 (en) | 2004-01-08 |
| NO20032973D0 (en) | 2003-06-27 |
| NZ525821A (en) | 2004-07-30 |
| CN1484642A (en) | 2004-03-24 |
| CZ20031856A3 (en) | 2003-09-17 |
| ECSP034682A (en) | 2003-08-29 |
| NO20032973L (en) | 2003-06-27 |
| BR0116672A (en) | 2003-09-23 |
| HUP0302528A2 (en) | 2003-11-28 |
| WO2002053561A1 (en) | 2002-07-11 |
| AR035679A1 (en) | 2004-06-23 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US7157582B2 (en) | Selective iGluR5 receptor antagonists | |
| US6579886B2 (en) | Selective iglur5 receptor antagonists | |
| ZA200304311B (en) | Excitatory amino acid receptor antagonists. | |
| JP2008179650A (en) | Medicine composition containing excitatory amino acid receptor antagonists | |
| US7205313B2 (en) | Excitatory amino acid receptor antagonists | |
| US6924294B2 (en) | Excitatory amino acid receptor antagonists | |
| US20040082606A1 (en) | Excitatory amino acid receptor antagonists | |
| US6855725B2 (en) | Excitatory amino acid receptor antagonists | |
| WO2003024934A2 (en) | Derivatives of the (3s, 4ar, 6s, 8ar) 6-phenylamino-1, 2, 3, 4, 4a, 5, 6, 7, 8, 8a-decahydro isoquinoline-3-carboxylic acid as excitatory amino acid receptor antagonists for the treatment of neurological disorders and neurodegenerative diseases | |
| JP2004522804A5 (en) | ||
| WO2003082856A1 (en) | Isoquinoline-3-carboxylic acid derivatives as excitatory amino acid receptor antagonists | |
| AU2002227021A1 (en) | Excitatory amino acid receptor antagonists | |
| ZA200109747B (en) | Selective iGluR5 receptor antagonists for the treatment of migraine. | |
| JP2004520335A5 (en) |