GB2288800A - Pyrazolo-quinoline derivatives as NMDA and AMPA antagonists - Google Patents
Pyrazolo-quinoline derivatives as NMDA and AMPA antagonists Download PDFInfo
- Publication number
- GB2288800A GB2288800A GB9507736A GB9507736A GB2288800A GB 2288800 A GB2288800 A GB 2288800A GB 9507736 A GB9507736 A GB 9507736A GB 9507736 A GB9507736 A GB 9507736A GB 2288800 A GB2288800 A GB 2288800A
- Authority
- GB
- United Kingdom
- Prior art keywords
- aryl
- compound
- hydrogen
- alkyl
- nitro
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 239000005557 antagonist Substances 0.000 title claims abstract description 17
- HOKKHZGPKSLGJE-GSVOUGTGSA-N N-Methyl-D-aspartic acid Chemical compound CN[C@@H](C(O)=O)CC(O)=O HOKKHZGPKSLGJE-GSVOUGTGSA-N 0.000 title abstract description 11
- MGRVRXRGTBOSHW-UHFFFAOYSA-N (aminomethyl)phosphonic acid Chemical compound NCP(O)(O)=O MGRVRXRGTBOSHW-UHFFFAOYSA-N 0.000 title abstract description 8
- UXYHZIYEDDINQH-UHFFFAOYSA-N C1=CNC2=C3C=NN=C3C=CC2=C1 Chemical class C1=CNC2=C3C=NN=C3C=CC2=C1 UXYHZIYEDDINQH-UHFFFAOYSA-N 0.000 title description 2
- 102000004868 N-Methyl-D-Aspartate Receptors Human genes 0.000 claims abstract description 9
- 108090001041 N-Methyl-D-Aspartate Receptors Proteins 0.000 claims abstract description 9
- 230000002265 prevention Effects 0.000 claims abstract description 9
- 102000003678 AMPA Receptors Human genes 0.000 claims abstract description 6
- 108090000078 AMPA Receptors Proteins 0.000 claims abstract description 6
- 230000036963 noncompetitive effect Effects 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 77
- -1 nitro, hydroxy, amino Chemical group 0.000 claims description 72
- 239000001257 hydrogen Substances 0.000 claims description 58
- 229910052739 hydrogen Inorganic materials 0.000 claims description 58
- 125000003118 aryl group Chemical group 0.000 claims description 50
- 150000002431 hydrogen Chemical class 0.000 claims description 36
- 229910052736 halogen Inorganic materials 0.000 claims description 33
- 150000002367 halogens Chemical class 0.000 claims description 33
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 33
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 29
- 125000000623 heterocyclic group Chemical group 0.000 claims description 29
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 28
- 125000000217 alkyl group Chemical group 0.000 claims description 25
- 150000003839 salts Chemical class 0.000 claims description 25
- 125000003545 alkoxy group Chemical group 0.000 claims description 21
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 20
- 239000000651 prodrug Substances 0.000 claims description 19
- 229940002612 prodrug Drugs 0.000 claims description 19
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 16
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 15
- 150000002430 hydrocarbons Chemical class 0.000 claims description 15
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 14
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 14
- 239000004215 Carbon black (E152) Substances 0.000 claims description 14
- 229930195733 hydrocarbon Natural products 0.000 claims description 14
- 125000003342 alkenyl group Chemical group 0.000 claims description 12
- 125000002837 carbocyclic group Chemical group 0.000 claims description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 12
- 125000001072 heteroaryl group Chemical group 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 12
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 12
- 125000004414 alkyl thio group Chemical group 0.000 claims description 11
- 125000000304 alkynyl group Chemical group 0.000 claims description 10
- 125000005129 aryl carbonyl group Chemical group 0.000 claims description 8
- 125000004104 aryloxy group Chemical group 0.000 claims description 8
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 7
- 125000001769 aryl amino group Chemical group 0.000 claims description 7
- 125000004658 aryl carbonyl amino group Chemical group 0.000 claims description 7
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 7
- 125000005110 aryl thio group Chemical group 0.000 claims description 7
- 125000005223 heteroarylcarbonyl group Chemical group 0.000 claims description 7
- 125000005553 heteroaryloxy group Chemical group 0.000 claims description 7
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 6
- 229910003827 NRaRb Inorganic materials 0.000 claims description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
- 239000004480 active ingredient Substances 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- PAHZJYVAKCMOHL-UHFFFAOYSA-N 2-phenyl-3,5-dihydropyrazolo[3,4-c]quinoline-1,4-dione Chemical compound N1C(C(NC2=CC=CC=C22)=O)=C2C(=O)N1C1=CC=CC=C1 PAHZJYVAKCMOHL-UHFFFAOYSA-N 0.000 claims description 4
- 125000003320 C2-C6 alkenyloxy group Chemical group 0.000 claims description 4
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 4
- 229910052705 radium Inorganic materials 0.000 claims description 4
- 229910052701 rubidium Inorganic materials 0.000 claims description 4
- MRHLTPHKARYESP-UHFFFAOYSA-N 2-(2-chlorophenyl)-3,5-dihydropyrazolo[3,4-c]quinoline-1,4-dione Chemical compound ClC1=CC=CC=C1N1C(=O)C(C=2C(=CC=CC=2)NC2=O)=C2N1 MRHLTPHKARYESP-UHFFFAOYSA-N 0.000 claims description 3
- ZMLJJKPTKVGPCF-UHFFFAOYSA-N 2-(4-chlorophenyl)-3,5-dihydropyrazolo[3,4-c]quinoline-1,4-dione Chemical compound C1=CC(Cl)=CC=C1N1C(=O)C(C=2C(=CC=CC=2)NC2=O)=C2N1 ZMLJJKPTKVGPCF-UHFFFAOYSA-N 0.000 claims description 3
- LFERNUMYBHHXAK-UHFFFAOYSA-N 7-chloro-2-(4-methoxyphenyl)-3,5-dihydropyrazolo[3,4-c]quinoline-1,4-dione Chemical compound C1=CC(OC)=CC=C1N1C(=O)C(C=2C(=CC(Cl)=CC=2)NC2=O)=C2N1 LFERNUMYBHHXAK-UHFFFAOYSA-N 0.000 claims description 3
- YTDGFBZNZQOLAO-UHFFFAOYSA-N 7-chloro-2-phenyl-3,5-dihydropyrazolo[3,4-c]quinoline-1,4-dione Chemical compound O=C1NC2=CC(Cl)=CC=C2C(C2=O)=C1NN2C1=CC=CC=C1 YTDGFBZNZQOLAO-UHFFFAOYSA-N 0.000 claims description 3
- 125000003302 alkenyloxy group Chemical group 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- MCNJCVRILYQVTA-UHFFFAOYSA-N 2-(4-methoxyphenyl)-3,5-dihydropyrazolo[3,4-c]quinoline-1,4-dione Chemical compound C1=CC(OC)=CC=C1N1C(=O)C(C=2C(=CC=CC=2)NC2=O)=C2N1 MCNJCVRILYQVTA-UHFFFAOYSA-N 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims 6
- 238000004519 manufacturing process Methods 0.000 claims 4
- 125000002346 iodo group Chemical group I* 0.000 claims 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 9
- VEYJJRADCABUQU-UHFFFAOYSA-N 3,5-dihydro-2h-pyrazolo[3,4-c]quinoline-1,4-dione Chemical class C12=CC=CC=C2NC(=O)C2=C1C(=O)NN2 VEYJJRADCABUQU-UHFFFAOYSA-N 0.000 abstract description 2
- 208000015122 neurodegenerative disease Diseases 0.000 abstract description 2
- 201000000980 schizophrenia Diseases 0.000 abstract description 2
- 206010010904 Convulsion Diseases 0.000 abstract 1
- 230000036461 convulsion Effects 0.000 abstract 1
- 239000000460 chlorine Substances 0.000 description 19
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 12
- 229910052801 chlorine Inorganic materials 0.000 description 12
- 125000004432 carbon atom Chemical group C* 0.000 description 10
- 238000000034 method Methods 0.000 description 10
- 125000001424 substituent group Chemical group 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- 239000002253 acid Substances 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 5
- 239000011630 iodine Substances 0.000 description 5
- 229910052740 iodine Inorganic materials 0.000 description 5
- 125000002757 morpholinyl group Chemical group 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
- 230000027455 binding Effects 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 125000006301 indolyl methyl group Chemical group 0.000 description 4
- 239000006187 pill Substances 0.000 description 4
- 125000005301 thienylmethyl group Chemical group [H]C1=C([H])C([H])=C(S1)C([H])([H])* 0.000 description 4
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 4
- 229920002554 vinyl polymer Polymers 0.000 description 4
- 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 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 229940127523 NMDA Receptor Antagonists Drugs 0.000 description 3
- 208000002193 Pain Diseases 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 3
- 125000003282 alkyl amino group Chemical group 0.000 description 3
- 125000005336 allyloxy group Chemical group 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
- 230000001054 cortical effect Effects 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- 125000000753 cycloalkyl group Chemical group 0.000 description 3
- 125000001153 fluoro group Chemical group F* 0.000 description 3
- 125000006289 hydroxybenzyl group Chemical group 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 210000004129 prosencephalon Anatomy 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 208000019695 Migraine disease Diseases 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
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 239000005864 Sulphur Substances 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000007900 aqueous suspension Substances 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 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
- 239000002775 capsule Substances 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- MGNZXYYWBUKAII-UHFFFAOYSA-N cyclohexa-1,3-diene Chemical compound C1CC=CC=C1 MGNZXYYWBUKAII-UHFFFAOYSA-N 0.000 description 2
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 229960003638 dopamine Drugs 0.000 description 2
- 230000003291 dopaminomimetic effect Effects 0.000 description 2
- 239000012055 enteric layer Substances 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 125000002541 furyl group Chemical group 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 125000001041 indolyl group Chemical group 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 206010027599 migraine Diseases 0.000 description 2
- 239000002581 neurotoxin Substances 0.000 description 2
- 231100000618 neurotoxin Toxicity 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 210000001009 nucleus accumben Anatomy 0.000 description 2
- 125000001715 oxadiazolyl group Chemical group 0.000 description 2
- 150000005623 oxindoles Chemical class 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 229940067157 phenylhydrazine Drugs 0.000 description 2
- 238000000524 positive electrospray ionisation mass spectrometry Methods 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 125000000168 pyrrolyl group Chemical group 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000010561 standard procedure Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- UCKHICKHGAOGAP-UONOGXRCSA-N (2R,4S)-4-[[anilino(oxo)methyl]amino]-5,7-dichloro-1,2,3,4-tetrahydroquinoline-2-carboxylic acid Chemical compound N([C@H]1C[C@@H](NC2=CC(Cl)=CC(Cl)=C21)C(=O)O)C(=O)NC1=CC=CC=C1 UCKHICKHGAOGAP-UONOGXRCSA-N 0.000 description 1
- CMIBUZBMZCBCAT-HZPDHXFCSA-N (2r,3r)-2,3-bis[(4-methylbenzoyl)oxy]butanedioic acid Chemical compound C1=CC(C)=CC=C1C(=O)O[C@@H](C(O)=O)[C@H](C(O)=O)OC(=O)C1=CC=C(C)C=C1 CMIBUZBMZCBCAT-HZPDHXFCSA-N 0.000 description 1
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 description 1
- UGUHFDPGDQDVGX-UHFFFAOYSA-N 1,2,3-thiadiazole Chemical group C1=CSN=N1 UGUHFDPGDQDVGX-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- XUVKDAMSFVGWGX-UHFFFAOYSA-N 2-(3-chlorophenyl)-3,5-dihydropyrazolo[3,4-c]quinoline-1,4-dione Chemical compound ClC1=CC=CC(N2C(C3=C(C(NC4=CC=CC=C43)=O)N2)=O)=C1 XUVKDAMSFVGWGX-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- JSFLFNPZGIDUBV-UHFFFAOYSA-N 3-(2-amino-3-hydroxy-5-methyl-3h-1,2-oxazol-4-yl)propanoic acid Chemical compound CC1=C(CCC(O)=O)C(O)N(N)O1 JSFLFNPZGIDUBV-UHFFFAOYSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 206010002660 Anoxia Diseases 0.000 description 1
- 241000976983 Anoxia Species 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 206010008120 Cerebral ischaemia Diseases 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 229920002307 Dextran Polymers 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
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- 206010013647 Drowning Diseases 0.000 description 1
- 229940123511 Excitatory amino acid receptor antagonist Drugs 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 102000018899 Glutamate Receptors Human genes 0.000 description 1
- 108010027915 Glutamate Receptors Proteins 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 206010019196 Head injury Diseases 0.000 description 1
- 208000010496 Heart Arrest Diseases 0.000 description 1
- 208000023105 Huntington disease Diseases 0.000 description 1
- 208000013016 Hypoglycemia Diseases 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 229930194542 Keto Natural products 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 238000005684 Liebig rearrangement reaction Methods 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 201000005505 Measles Diseases 0.000 description 1
- 208000001089 Multiple system atrophy Diseases 0.000 description 1
- 229940099433 NMDA receptor antagonist Drugs 0.000 description 1
- 206010028923 Neonatal asphyxia Diseases 0.000 description 1
- 208000037212 Neonatal hypoxic and ischemic brain injury Diseases 0.000 description 1
- 206010029350 Neurotoxicity Diseases 0.000 description 1
- PCKPVGOLPKLUHR-UHFFFAOYSA-N OH-Indolxyl Chemical class C1=CC=C2C(O)=CNC2=C1 PCKPVGOLPKLUHR-UHFFFAOYSA-N 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 208000005374 Poisoning Diseases 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 206010037742 Rabies Diseases 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 206010043376 Tetanus Diseases 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 206010044221 Toxic encephalopathy Diseases 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 241001136075 Trulla Species 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 229940081735 acetylcellulose Drugs 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 description 1
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 description 1
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 1
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 description 1
- 125000004644 alkyl sulfinyl group Chemical group 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 125000005530 alkylenedioxy group Chemical group 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000007953 anoxia Effects 0.000 description 1
- 230000001773 anti-convulsant effect Effects 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 229940125681 anticonvulsant agent Drugs 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 239000002111 antiemetic agent Substances 0.000 description 1
- 229940125683 antiemetic agent Drugs 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 230000000949 anxiolytic effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000005199 aryl carbonyloxy group Chemical group 0.000 description 1
- 229940090047 auto-injector Drugs 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 125000005605 benzo group Chemical group 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 238000009395 breeding Methods 0.000 description 1
- 230000001488 breeding effect 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
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 230000003727 cerebral blood flow Effects 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 206010008129 cerebral palsy Diseases 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000002385 cottonseed oil Substances 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
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical class CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 210000001198 duodenum Anatomy 0.000 description 1
- 239000008157 edible vegetable oil Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- UXGCSFRJKPEYBN-UHFFFAOYSA-N ethyl 2-oxo-2-(2-oxo-1,3-dihydroindol-3-yl)acetate Chemical compound C1=CC=C2C(C(=O)C(=O)OCC)C(=O)NC2=C1 UXGCSFRJKPEYBN-UHFFFAOYSA-N 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 230000002461 excitatory amino acid Effects 0.000 description 1
- 239000003257 excitatory amino acid Substances 0.000 description 1
- 235000020375 flavoured syrup Nutrition 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000008240 homogeneous mixture Substances 0.000 description 1
- 208000013403 hyperactivity Diseases 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- JYGFTBXVXVMTGB-UHFFFAOYSA-N indolin-2-one Chemical class C1=CC=C2NC(=O)CC2=C1 JYGFTBXVXVMTGB-UHFFFAOYSA-N 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000003703 n methyl dextro aspartic acid receptor blocking agent Substances 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 239000004081 narcotic agent Substances 0.000 description 1
- 229920001206 natural gum Polymers 0.000 description 1
- 210000001577 neostriatum Anatomy 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 239000003176 neuroleptic agent Substances 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 210000000607 neurosecretory system Anatomy 0.000 description 1
- 230000007135 neurotoxicity Effects 0.000 description 1
- 231100000228 neurotoxicity Toxicity 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000012053 oil suspension Substances 0.000 description 1
- 208000031237 olivopontocerebellar atrophy Diseases 0.000 description 1
- 239000013110 organic ligand Substances 0.000 description 1
- 239000003182 parenteral nutrition solution Substances 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 208000033300 perinatal asphyxia Diseases 0.000 description 1
- 239000008024 pharmaceutical diluent Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- HKOOXMFOFWEVGF-UHFFFAOYSA-N phenylhydrazine Chemical compound NNC1=CC=CC=C1 HKOOXMFOFWEVGF-UHFFFAOYSA-N 0.000 description 1
- 150000004031 phenylhydrazines Chemical class 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 231100000572 poisoning Toxicity 0.000 description 1
- 230000000607 poisoning effect Effects 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 210000002442 prefrontal cortex Anatomy 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 238000004237 preparative chromatography Methods 0.000 description 1
- 230000003518 presynaptic effect Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 230000002685 pulmonary effect Effects 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
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000001932 seasonal effect Effects 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 208000020431 spinal cord injury Diseases 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 230000007480 spreading Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000005062 synaptic transmission Effects 0.000 description 1
- 230000015883 synaptic transmission, dopaminergic Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
A class of 3,5-dihydro-1H-pyrazolo[3,4-c]quinoline-1,4(2H)-dione derivatives, substituted in the 2-position by an optionally substituted phenyl moiety, (formula IA; R<1> - R<6> are H or organic residues as defined in claim 1) are selective non-competitive antagonists of NMDA receptors and/or are antagonists of AMPA receptors, and are therefore of utility in the treatment and/or prevention of a wide range of conditions (including neurodegenerative disorders, convulsions or schizophrenia) which require the administration of an NMDA and/or AMPA antagonist. <IMAGE>
Description
PYRAZOLO-QUINOLINE DERIVATIVES
This invention relates to a class of 3,5-dihydro-lH- pyrazolo[3,4-c]quinoline- 1,4(2H)-dione derivatives which are substituted in the 2-position by an optionally substituted phenyl moiety. These compounds are selective non-competitive antagonists of N-methyl-Daspartate (NMDA) receptors. More particularly, the class of compounds provided by the present invention are ligands for the strychnineinsensitive glycine modulatory site of the NMDA receptor and are therefore useful in the treatment and/or prevention of neurodegenerative disorders arising as a consequence of such pathological conditions as stroke, hypoglycaemia, cerebral palsy, transient cerebral ischaemic attack, cerebral ischaemia during cardiac pulmonary surgery or cardiac arrest, perinatal asphyxia, epilepsy, Huntington's chorea, Alzheimer's disease,
Amyotrophic Lateral Sclerosis, Parkinson's disease, Olivo-ponto-cerebellar atrophy, anoxia such as from drowning, spinal cord and head injury, and poisoning by exogenous and endogenous NMDA receptor agonists and neurotoxins, including environmental neurotoxins.
By virtue of their NMDA receptor antagonist properties, the compounds according to the present invention are also useful as anticonvulsant and antiemetic agents, as well as being of value in the prevention or reduction of dependence on dependence-inducing agents such as narcotics.
NMDA receptor antagonists have recently been shown to possess analgesic (see, for example, Dickenson and Aydar, Neuroscience
Lett., 1991, 121, 263; Murray et al Pain, 1991, 44, 179; and Woolf and
Thompson, Pain, 1991, 44, 293), antidepressant (see, for example, Trullas and Skolnick, Eur. J. Pharmacol., 1990, 185, 1) and anxiolytic (see, for example, Rehne et al., Eur. J. Pharmacol., 1991, 193, 283) effects, and the compounds of the present invention may accordingly be useful in the management of pain, depression and anxiety.
The association of NMDA receptor antagonists with regulation of the nigrostriatal dopaminergic system has recently been reported (see, for example, Werling et al., J. Pharmacol. Exo. Ther., 1990, 255, 40; Graham et al., Life Sciences, 1990, 47, PL-41; and Turski et al., Nature (London), 1991, 349, 414). This suggests that the compounds of the present invention may thus be of assistance in the prevention and/or treatment of disorders of the dopaminergic system such as schizophrenia and Parkinson's disease.
It has also been reported recently (see Lauritzen et al.,
Journal of Cerebral Blood Flow and Metabolism, 1991, vol. 11, suppl. 2,
Abstract XV-4) that NMDA receptor antagonists block cortical spreading depression (CSD), which may thus be of clinical importance since CSD is a possible mechanism of migraine. The class of substituted 2-amino-4phosphonomethylalk-3-ene carboxylic acids and esters described in EP-A0420806, which are stated to be selective NMDA antagonists, are alleged thereby to be of potential utility in the treatment of inter alia migraine.
Excitatory amino acid receptor antagonists, including inter alia antagonists of NMDA receptors, are alleged in EP-A-0432994 to be of use in suppressing emesis.
Recent reports in the literature have also suggested a link between the neurotoxicity of certain viruses and the deleterious effects of these viruses on an organism caused by the potentiation of neurotransmission via excitatory amino acid receptors. By virtue of their activity as antagonists of NMDA receptors, therefore, the compounds of the present invention may be effective in controlling the manifestations of neuroviral diseases such as measles, rabies, tetanus (cf. Bagetta et al Br.
J. Pharmacol., 1990, 101, 776) and AIDS (cf. Lipton et al., Societv for
Neuroscience Abstracts, 1990, 1G, 128.11).
NMDA antagonists have, moreover, been shown to have an effect on the neuroendocrine system (see, for example, van den Pol et al Science, 1990, 250, 1276; and Urbanski, Endocrinology, 1990, 127, 2223), and the compounds of this invention may therefore also be effective in the control of seasonal breeding in mammals.
In addition, certain compounds of the invention are antagonists of 2 -amino-3 -hydroxy- 5 -methyl-4-isoxazolepropionic acid (AMPA) receptors, also known as quisqualate receptors. An excitatory amino acid projection from the prefrontal cortex to the nucleus accumbens (a particular region of the forebrain possessing dopamine-sensitive neurones) is well known to exist (see, for example, J. Neurochem., 1985, 45 477). It is also well known that dopaminergic transmission in the striatum is modulated by glutamate (see, for example, Neurochem. Int., 1983, 5, 479), as also is the hyperactivity associated with presynaptic stimulation of the dopamine system by AMPA in the nucleus accumbens (cf. Life Sci., 1981, 28, 1597). Compounds which are antagonists of AMPA receptors are therefore of value as neuroleptic agents.
The preparation of the specific compound 3,5-dihydro-2 phenyl- 1H-pyrazolo[3,4-c]quinoline- 1,4(2H)-dione is described both in
Helv. Chim. Acta, 1928, 11, 242; and in Ind. J. Chem., 1992, 31B, 316. In neither of these publications, however, is any pharmaceutical utility ascribed to this compound. Moreover, in neither of these publications is there any suggestion that the compounds described therein would be of assistance in solving the problem of providing an effective agent for the treatment and/or prevention of conditions requiring the administration of an antagonist of NMDA and/or AMPA receptors.
The present invention accordingly provides a pharmaceutical composition comprising a compound of formula IA or a pharmaceutically acceptable salt thereof or a prodrug thereof:
wherein
R1 and R2 independently represent hydrogen, hydrocarbon, a heterocyclic group, halogen, cyano, trifluoromethyl, nitro, -ORa, -SRn, -SORa, -SO2Ra, -SO2NRaRb, -NRaRb, -NRaCORb, -NRaCO2Rb, -CORa, -CO2Ra or -CONRaRb; or R1 and R2 together represent the residue of a carbocyclic or heterocyclic ring;
R3, R4, R5 and R6 independently represent hydrogen, hydrocarbon, a heterocyclic group, halogen, cyano, trifluoromethyl, nitro, -ORa, -SRa, -SORa, -SO2Ra, -SO2NRaRb, -NRaRb, -NRaCORb, -NRaCO2Rb, -CORa, -C02Ra or -CONRaRb; and
Ra and Rb independently represent hydrogen, hydrocarbon or a heterocyclic group; in association with one or more pharmaceutically acceptable carriers and/or excipients.
The invention also provides a compound of formula IA as defined above or a pharmaceutically acceptable salt thereof or a prodrug thereof for use in therapy.
The term "hydrocarbon" as used herein includes straightchained, branched and cyclic groups containing up to 18 carbon atoms, suitably up to 15 carbon atoms, and conveniently up to 12 carbon atoms.
Suitable hydrocarbon groups include Cl.6 alkyl, C2-6 alkenyl, C2.6 alkynyl,
C3-7 cycloalkyl, C3.7 cyclo alkyl(C i.e) alkyl, aryl, aryl(C i.e) alkyl, aryl(C2.6)alkenyl and aryl(C2.6)alkynyl.
The expression "a heterocyclic group" as used herein includes cyclic groups containing up to 18 carbon atoms and at least one heteroatom preferably selected from oxygen, nitrogen and sulphur. The heterocyclic group suitably contains up to 15 carbon atoms and conveniently up to 12 carbon atoms, and is preferably linked through carbon. Examples of suitable heterocyclic groups include C3.7 heterocycloalkyl, C3.7 heterocyclo alkyl(C 1.6) alkyl, heteroaryl and heteroaryl(C1-6)alkyl groups.
Suitable alkyl groups include straight-chained and branched alkyl groups containing from 1 to 6 carbon atoms. Typical examples include methyl and ethyl groups, and straight-chained or branched propyl and butyl groups. Particular alkyl groups are methyl, ethyl, n-propyl, isopropyl and t-butyl.
Suitable alkenyl groups include straight-chained and branched alkenyl groups containing from 2 to 6 carbon atoms. Typical examples include vinyl and allyl groups.
Suitable alkynyl groups include straight-chained and branched alkynyl groups containing from 2 to 6 carbon atoms. Typical examples include ethynyl and propargyl groups.
Suitable cycloalkyl groups include groups containing from 3 to 7 carbon atoms. Particular cycloalkyl groups are cyclopropyl and cyclohexyl.
Suitable aryl groups include phenyl and naphthyl groups.
A particular aryl(Ci.e)alkyl group is benzyl.
A particular aryl(C2-6)alkenyl group is phenylethenyl.
A particular aryl(C2.6)alkynyl group is phenylethynyl.
Suitable heterocycloalkyl groups include piperidyl, piperazinyl and morpholinyl groups.
A particular heterocycloalkyl(Cl.6)alkyl group is morpholinylethyl.
Suitable heteroaryl groups include pyridyl, quinolyl, isoquinolyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, indolyl, pyranyl, furyl, benzofuryl, thienyl, benzthienyl, imidazolyl, oxadiazolyl and thiadiazolyl groups. Particular heteroaryl groups are pyridyl, pyrrolyl, indolyl, furyl, benzofuryl, thienyl, benzthienyl and oxadiazolyl.
Particular heteroaryl(Cl.6)alkyl groups include pyridylmethyl, pyrrolylmethyl, indolylmethyl, furylmethyl and thienylmethyl.
Where Rl and R2 together represent the residue of a carbocyclic or heterocyclic ring, the ring may be saturated or unsaturated.
The ring may suitably be a 4- to 9-membered ring, but will preferably be a 5- or 6-membered ring. Where R' and R2 together represent the residue of a heterocyclic ring, this ring may contain up to four heteroatoms selected from oxygen, nitrogen and sulphur. Suitable carbocyclic rings of which Rl and R2 together represent the residue include cyclohexane, cyclohexene, cyclohexadiene and benzene rings. Suitable heterocyclic rings of which R' and R2 together represent the residue include dioxolane, dioxane, pyridine, furan, thiophene, pyrrole, thiazole and thiadiazole rings.
The hydrocarbon and heterocyclic groups, as well as the carbocyclic or heterocyclic ring completed by R1 and R2, may in turn be optionally substituted by one or more groups selected from C1.6 alkyl, adamantyl, phenyl, halogen, C i.e haloalkyl, morpholinyl(C i.e)alkyl, trifluoromethyl, hydroxy, C1-6 alkoxy, C1-6 alkoxy(C1-6)alkyl, C1-6 alkoxy(Ci-e)alkoxy, aryloxy, keto, C1.3 alkylenedioxy, nitro, cyano, carboxy, C2.e alkoxycarbonyl, C.e alkoxycarbonyl(Ci.6)alkyl, C2-6 alkylcarbonyloxy, arylcarbonyloxy, C2.6 alkylcarbonyl, arylcarb onyl, C1-6 alkylthio, C1.6 alkylsulphinyl, Cl.6 alkylsulphonyl, amino, mono- or di(C1-6)alkylamino, C2.6 alkylcarbonylamino and C2.6 alkoxycarbonylamino.
The term "halogen" as used herein includes fluorine, chlorine, bromine and iodine, especially chlorine.
Suitable values for the substituents R1 and R2 include C1-6 alkyl, aryl, aryl(C1-6)alkyl, aryl(C2.6)alkenyl, aryl(C2.6)alkynyl, heteroaryl(C1-6)alkyl, C1-6 alkoxy, C2-6 alkenyloxy, aryloxy, aryl(C1-6)alkoxy, heteroaryloxy, arylthio, arylsulphonyl, arylamino, aryl(C i.e)alkylamino, di(C1-6)alkylamino, arylcarbonylamino, arylcarbonyl or heteroarylcarbonyl, any of which groups may be optionally substituted; and hydrogen, halogen, trifluoromethyl or nitro. Examples of optional substituents on the groups Rl and/or R2 include C1-6 alkyl, morpholinyl(Ci.e)alkyl, hydroxy, Cl.6 alkoxy, Ci.e alkoxy(Ci.e)alkyl, C1-6 alkoxy(C i.e) alkoxy, C i.e alkylthio and di(C i.e)alkylamino.
Particular values for the substituents R1 and R2 include hydrogen, methyl, phenyl, benzyl, methoxymethyl-benzyl, morpholinylethyl-benzyl, hydroxybenzyl, methoxybenzyl, methoxymethoxy-benzyl, methylthio-benzyl, phenylethenyl, phenylethynyl, thienylmethyl, pyrrolylmethyl, indolylmethyl, fluoro, chloro, bromo, iodo, trifluoromethyl, nitro, methoxy, ethoxy, allyloxy, methyl-allyloxy, phenoxy, methyl-phenoxy, methoxy-phenoxy, dimethylamino-phenoxy, benzyloxy, furyloxy, thienyloxy, pyridyloxy, phenylthio, phenylsulphonyl, phenylamino, benzylamino, dimethylamino, phenylcarbonylamino, phenylcarbonyl, furylcarb onyl and thienylcarb onyl.
Suitably, one or both of R1 and R2 represent hydrogen.
Where Rl and R2 together represent the residue of a carbocyclic or heterocyclic ring, this may be, in particular, a dioxolane or optionally substituted benzene ring.
The benzo moiety of the fused tricyclic ring system shown in formula IA above may be substituted or unsubstituted. Particular substituents include halogen, cyano, trifluoromethyl, nitro, hydroxy, amino, carboxy, C1-6 alkyl, C2-6 alkenyl, C1.6 alkoxy, C1.6 alkylthio and C2-7 alkoxycarbonyl. Suitably R6 is hydrogen and R3, R4 and R5 independently represent hydrogen, halogen, cyano, trifluoromethyl, nitro, Ci.e alkyl or C2.e alkenyl, at least one of R3, R4 and R5 desirably being other than hydrogen. Preferably, R4 and R6 each represents hydrogen and R3 and R" independently represent hydrogen, cyano, trifluoromethyl, nitro, methyl, ethyl, vinyl or halogen, especially chlorine or iodine. In a particular embodiment, R5 represents hydrogen, cyano, trifluoromethyl, nitro or halogen, especially chlorine; and R3 is hydrogen or ethyl.
Particular pharmaceutical compositions according to the invention contain, as the active ingredient, at least one of the following compounds: 3,5-dihydro-2-phenyl- 1H-pyrazolo[3,4-c] quinoline- 1,4(2H)-dione; and pharmaceutically acceptable salts thereof and pro drugs thereof.
Certain compounds falling within the definition of formula
IA above are novel. Accordingly, in a still further aspect the present invention provides a compound of formula IB or a salt or prodrug thereof:
wherein Ril and Rl2 independently represent hydrogen, hydrocarbon, a heterocyclic group, halogen, cyano, trifluoromethyl, nitro, -ORa, -SRa, -SORn, -SO2Ra, -SO2NRaRb, -NRaRs, -NRnCORb, -NRaCO2Rb, -CORa, -CO2Ra or -CONRaRb; or R11 and R2 together represent the residue of a carbocyclic or heterocyclic ring; Rl3, R14, R15 and Rie independently represent hydrogen, hydrocarbon, a heterocyclic group, halogen, cyano, trifluoromethyl, nitro, -ORa, -SRB, -SORa, -SO2Ra, -SO2NRaRb, -NRBRb, -NRaCORb, -NRaCO2Rb, -CORB, -CO2Ra or -CONRaRb; and
Ra and Rb independently represent hydrogen, hydrocarbon or a heterocyclic group;
provided that R, R12, R13, R14 R15 and R16 are not all simultaneously hydrogen.
Subject to the above proviso, the substituents Rii to Rie in the compounds of formula IB correspond to the substituents R' to R6 respectively as defined with reference to the compounds of formula IA.
For use in medicine, the salts of the compounds of formula IB will be pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds according to the invention or of their pharmaceutically acceptable salts.
Suitable pharmaceutically acceptable salts of the compounds of formulae IA and IB above include alkali metal salts, e.g. lithium, sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; and salts formed with suitable organic ligands, e.g. quaternary ammonium salts. Where appropriate, acid addition salts may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
The present invention includes within its scope prodrugs of the compounds of formulae IA and IB above. In general, such prodrugs will be functional derivatives of the compounds of formulae IA and IB which are readily convertible in vivo into the required compound.
Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
Where the compounds according to the invention have at least one asymmetric centre, they may accordingly exist as enantiomers.
Where the compounds according to the invention possess two or more asymmetric centres, they may additionally exist as diastereoisomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention.
One sub-class of compounds according to the invention is represented by the compounds of formula IIA and salts and pro drugs thereof:
wherein R2i and R22 independently represent C1-6 alkyl, C2.e alkenyl,
C2-6 alkynyl, aryl, aryl(Cl.6)alkyl, aryl(C2.6)alkenyl, aryl(C2.6)alkynyl, heteroaryl(C1-6)alkyl, C1-6 alkoxy, C2-6 alkenyloxy, aryloxy, aryl(C1-6)alkoxy, heteroaryloxy, C1-6 alkylthio, arylthio, arylsulphonyl, arylamino, aryl(C1-6)alkylamino, di(C1-6)alkylamino, arylcarbonylamino, arylcarbonyl, heteroarylcarbonyl or C2.7 alkoxycarbonyl, any of which groups may be optionally substituted; or hydrogen, halogen, cyano, trifluoromethyl, nitro, hydroxy, amino or carboxy; or
R21 and R22 together represent the residue of a carbocyclic or heterocyclic ring;
R23 and R24 independently represent hydrogen, halogen, cyano, trifluoromethyl, nitro, hydroxy, amino, carboxy, C1-6 alkyl, C2.6 alkenyl, C1-6 alkoxy, Ci.e alkylthio or C2.7 alkoxycarbonyl; and
R25 represents halogen, cyano, trifluoromethyl, nitro, hydroxy, amino, carboxy, Ci.e alkyl, C2-6 alkenyl, Ci.e alkoxy, C1-6 alkylthio or C2.7 alkoxycarbonyl.
Examples of optional substituents on the groups R21 and/or
R22 include Ci.e alkyl, morpholinyl(C1-6)alkyl, hydroxy, Ci.e alkoxy, Ci.e alkoxy(Ci.e)alkyl, Ci.e alkoxy(Ci.e)alkoxy, Ci.6 alkylthio and di(C1-6)alkylamino.
Particular values of R21 and/or R22 with respect to formula IIA include hydrogen, methyl, phenyl, benzyl, methoxymethyl-benzyl, morpholinylethyl-benzyl, hydroxybenzyl, methoxybenzyl, methoxymethoxy-benzyl, methylthio-b enzyl, phenylethenyl, phenylethynyl, thienylmethyl, pyrrolylmethyl, indolylmethyl, fluoro, chloro, bromo, iodo, trifluoromethyl, nitro, methoxy, ethoxy, allyloxy, methyl-allyloxy, phenoxy, methyl-phenoxy, methoxy-phenoxy, dimethylamino-phenoxy, benzyloxy, furyloxy, thienyloxy, pyridyloxy, phenylthio, phenylsulphonyl, phenylamino, benzylamino, dimethylamino, phenylcarbonylamino, phenylcarb onyl, furylcarbonyl and thienylcarbonyl.
Suitably, at least one of R2l and R22 represents hydrogen. In a particular embodiment, one of R21 and R22 is hydrogen and the other is hydrogen, chloro, methoxy or phenoxy.
Suitably, R23 represents hydrogen, nitro, methyl, ethyl, vinyl or halogen, especially chlorine or iodine. Preferably, R23 is hydrogen, ethyl, chlorine or iodine.
Suitably, R24 represents hydrogen or chlorine, preferably hydrogen.
Suitably, R25 represents cyano, trifluoromethyl, nitro, methyl or halogen, preferably chlorine.
Another sub-class of compounds according to the invention is represented by the compounds of formula IIB and salts and prodrugs thereof:
wherein
R31 represents Ci.e alkyl, C.e alkenyl, C2-6 alkynyl, aryl, aryl(C1-6)alkyl, aryl(C2-6)alkenyl, aryl(C2-6alkynyl, heteroaryl(C1-6)alkyl,
C1-6 alkoxy, C2-6 alkenyloxy, aryloxy, aryl(Ci.e)alkoxy, heteroaryloxy, Ci.e alkylthio, arylthio, arylsulphonyl, arylamino, aryl(C1-6)alkylamino, di(C1-6)alkylaminbo, arylcarb onylamino, arylcarb onyl, heteroarylcarbonyl or C2.7 alkoxycarbonyl, any of which groups may be optionally substituted; or hydrogen, halogen, cyano, trifluoromethyl, nitro, hydroxy, amino or carboxy; and
R32 represents C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, aryl(C1-6)alkyl, aryl(C2-6)alkenyl, aryl(C2-6)alkylnyl, heteroaryl(C1-6)alkyl, Ci-6 alkoxy, C2.6 alkenyloxy, aryloxy, aryl(Ci.e)alkoxy, heteroaryloxy, Ci.6 alkylthio, arylthio, arylsulphonyl, arylamino, aryl(C1-6)alkylamino, di(C1-6)alkylamino, arylcarbonylamino, arylcarb onyl, hetero arylcarb onyl or C2.7 alkoxycarbonyl, any of which groups may be optionally substituted; or halogen, cyano, trifluoromethyl, nitro, hydroxy, amino or carboxy; or R3l and R32 together represent the residue of a carbocyclic or heterocyclic ring; and
R33, R34 and R95 independently represent hydrogen, halogen, cyano, trifluoromethyl, nitro, hydroxy, amino, carboxy, C1-6 alkyl, C.e alkenyl, C1-6 alkoxy, Ci.e alkylthio or C2.7 alkoxycarbonyl.
Examples of optional substituents on the groups R3l and/or
R32 include C1-6 alkyl, morpholinyl(C1-6)alkyl, hydroxy, Ci.e alkoxy, Ci.e alkoxy(C1-6)alkyl, C1-6alkoxy(C1-6)alkoxy, C1-6 alkylthio and di(Cl.6)alkylamino.
Particular values of R31 and/or R82 with respect to formula IIB include methyl, phenyl, benzyl, methoxymethyl-benzyl, morpholinylethylbenzyl, hydroxyb enzyl, methoxybenzyl, methoxymethoxy-benzyl, methylthio-benzyl, phenylethenyl, phenylethynyl, thienylmethyl, pyrrolylmethyl, indolylmethyl, fluoro, chloro, bromo, iodo, trifluoromethyl, nitro, methoxy, ethoxy, allyloxy, methyl-allyloxy, phenoxy, methylphenoxy, methoxy-phenoxy, dimethylamino-phenoxy, benzyloxy, furyloxy, thienyloxy, pyridyloxy, phenylthio, phenylsulphonyl, phenylamino, benzylamino, dimethylamino, phenylcarb onylamino, phenylcarbonyl, furylcarbonyl and thienylcarbonyl. In addition, R3l may represent hydrogen.
Suitably, R3l is hydrogen. In a particular embodiment, R31 is hydrogen and R32 is chloro, methoxy or phenoxy.
Suitably, R33 represents hydrogen, nitro, methyl, ethyl, vinyl or halogen, especially chlorine or iodine. Preferably, R33 is hydrogen, ethyl, chlorine or iodine.
Suitably, R34 represents hydrogen or chlorine, preferably hydrogen.
Suitably, R35 represents hydrogen, cyano, trifluoromethyl, nitro, methyl or halogen, preferably hydrogen or chlorine.
Specific compounds within the scope of the present invention include: 7-chloro-3,5-dihydro-2-phenyl- 1H-pyrazolo [3,4-c] quinoline- 1,4(2H)-dione; 2-(2-chlorophenyl)-3,5-dihydro- lH-pyrazolo[3,4-c] quinoline- 1,4(2H)-dione; 2-(3-chlorophenyl)-3,5-dihydro- 1H-pyrazolo[3,4-c]quinoline- 1,4(2H)-dione; 2-(4-chlorophenyl)-3,5-dihydro- lH-pyrazolo[3,4-c] quinoline- 1,4(2H)-dione; 3,5-dihydro-2-(4-methoxyphenyl)- 1H-pyrazolo[3,4-c] quinoline-1,4(2H)- dione; 7-chloro-3, 5-dihydro-2-(4-methoxyphenyl)- lH-pyrazolo[3,4-c] quinoline1,4(2H)-dione; and salts and prodrugs thereof.
The pharmaceutical compositions according to the invention are preferably in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, auto-injector devices or suppositories; for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation.
Alternatively, the compositions may be presented in a form suitable for once-weekly or once-monthly administration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection. For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, p olyvinyl-pyrrolidone or gelatin.
In the treatment of neurodegeneration, a suitable dosage level is about 0.01 to 250 mg/kgper day, preferably about 0.05 to 100 mg/kg per day, and especially about 0.05 to 5 mg/kg per day. The compounds may be administered on a regimen of 1 to 4 times per day. In a particular embodiment, the compounds may be conveniently administered by intravenous infusion.
The compounds of formula IA above, including the novel compounds according to the present invention, may be prepared by a process which comprises reacting a compound of formula III with a compound of formula IV:
wherein R1, R2, R3, R4, R5 and Re are as defined above, and R represents C1.4 alkyl; in the presence of an acid.
Suitable values for the substituent R include methyl and ethyl, especially ethyl.
The reaction is conveniently effected by heating compounds
III and IV together at reflux in acetic acid, which also acts as the solvent.
The starting materials of formula III may conveniently be prepared from a substituted oxindole derivative by a method analogous to that described in Justus Liebigs Ann. Chem., 1924, 436, 113. A general procedure for preparing substituted oxindoles is described in Svnthesis, 1993, 51.
Where they are not commercially available, the reagents of formula IV may suitably be prepared by standard methods well known from the art.
It will be appreciated that any compound of formula IA initially obtained from the above process may, where appropriate, subsequently be elaborated into a further desired compound of formula IA using techniques known from the art.
Where the above-described process for the preparation of compounds of use in the invention gives rise to mixtures of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The compounds may, for example, be resolved into their component enantiomers by standard techniques such as preparative HPLC, or the formation of diastereomeric pairs by salt formation with an optically active acid, such as (-)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid, followed by fractional crystallization and regeneration of the free base. The compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary.
During any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Grounds in Organic
Chemistrv, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene &
P.G.M. Wuts, Protective Groups in Organic Svnthesis, John Wiley & Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.
The following Examples illustrate the preparation of compounds of use in the invention.
The compounds useful in this invention potently and selectively block responses to NMDA and/or AMPA in a brain slice from rat cortex, and inhibit the binding of agonists and antagonists to the strychnine-insensitive site present on the NMDA receptor and/or AMPA binding to rat forebrain membranes.
Cortical Slice Studies
The effects of compounds of use in the invention on responses to NMDA and AMPA can be assessed using the rat cortical slice as described by Wong et al., Proc. Natl. Acad. Sci. USA, 1986, 83, 7104. The apparent equilibrium constant (Kb) iS calculated from the righthand shift in the NMDA or AMPA concentration-response curves produced by the compound under test. The compounds of the accompanying Examples were tested and were found to possess Kb values in response to NMDA of below 150 ,eM in each case.
Binding Studies
The ability of test compounds to displace 3H-L-689,560 (trans-2-carboxy-5, 7-dichloro-4-phenyl-aminocarbonylamino- 1,2,3,4- tetrahydroquinoline) binding to the strychnine-insensitive site present on the NMDA receptor of rat forebrain membranes can be determined by the method of Grimwood et al., Proceedings of The British Pharmacological
Societv, July 1991, Abstract C78. The concentration of the compounds of the accompanying Examples required to displace 50% of the specific binding (IC50) iS below 50 RM in each case.
EXAMPLE 1 3,5-dihydro-2-phenyl-1H-pyrazolo[3,4-c]quinoline-1,4(2H)-dione
Ethyl oxindole-3-glyoxylate (220 mg) in glacial acetic acid (2 ml) was heated under reflux for 10 minutes with phenylhydrazine (0.1 ml). The reaction was cooled and the resulting precipitate filtered and crystallised from methanol to give the title compound, mp > 260"C; 1H nmr (250MHz, de-DMSO) 6 11.86 (1H, broad s), 8.25 (1H, broad d), 7.86 (2H, d, J=8Hz), 7.56 (2H, t, J=8Hz) and 7.22-7.42 (4H, m).
The following examples were prepared by the method of
Example 1 using the appropriately substituted phenylhydrazine and oxindole reagents.
EXAMPLE 2 7-Chloro-3,5-dihydro-2-phenyl-1H-pyrazolo[3,4-c]quinoline-1,4(2H)-dione lH nmr (250MHz, d6-DMSO) 7.30 (1H, dd, J=3Hz and 12.2Hz), 7.37-7.43 (2H, m), 7.56 (2H, t, J=8Hz), 7.84 (2H, d, J=8Hz) and 8.20 (1H, d, J=8Hz).
EXAMPLE 3 3,5-Dihydro-2-(2-chlorophenyl)-1H-pyrazolo[3,4-c]quinoline-1,4(2H)-dione
1H nmr (250MHz, d6-DMSO) 7.29-7.41 (3H, m), 7.52-7.77 (4H, m) and 8.16 (1H, bs).
EXAMPLE 4 3,5-Dihydor-2-(3-chlorophenyl)-1H-pyrazolo[3,4-c]quinoline-1,4(2H)-dione lH nmr (360MHz, d6-DMSO) 7.20-7.44 (4H, m), 7.58 (1H, t,
J=8Hz), 7.86 (1H, d, J=8Hz), 8.02 (1H, s) and 8.37 (1H, d, J=8Hz).
EXAMPLE 5 3,5-Dihydro-2-(4-chlorophenyl)-1H-pyrazolo[3,4-c]quinoline-1,4(2H)-dione 1H nmr (250MHz, dG-DMSO) 7.20-7.38 (3H, m), 7.62 (2H, d,
J=12.6Hz), 7.91 (2H, d, J=12.6Hz) and 8.25 (1H, d, J=10.9Hz).
EXAMPLE 6 3.5-Dihydro-2-(4-methoxyphenyl)-1H-pyrazolo[3,4-c]quinoline-1,4(2H0dione
1H nmr (250MHz, d6-DMSO) 6 8.21 (1H, broad s,), 7.73 (2H, d, J=9Hz), 7.31-7.35 (2H, m), 7.12-7.25 (1H, m), 7.11 (2H, d, J=9Hz), 3.82 (3H, s); MS (ES+) 308 [M+H]+.
EXAMPLE 7 7-Chloro-3,5-dihydro-2-(4-methoxyphenyl)-1H-pyrazolo[3,4-c]quinoline1,4(2H)-dione
1H nmr (250MHz, de-DMSO) 6 11.46 (1H, broad s), 7.85 (1H, d, J=8.4Hz), 7.40 (2H, d, J=9.0Hz), 7.07 (1H, d, J=2Hz), 6.98 (1H, dd,
J=2Hz and 8.4Hz), 6.81 (2H, d, J=9.0Hz), 3.52 (3H, s); MS (ES+) 342/344 [M+H]+.
Claims (21)
1. A pharmaceutical composition comprising a compound of formula IA or a pharmaceutically acceptable salt thereof or a pro drug thereof:
wherein
R1 and R2 independently represent hydrogen, hydrocarbon, a heterocyclic group, halogen, cyano, trifluoromethyl, nitro, -ORa, -SRa, -SORa, -S02Ra, -SO2NRaRb, -NRaRb, -NRaCORb, -NRaCO2Rb, -CORa, -CO2Ra or -CONRaRb; or R1 and R2 together represent the residue of a carbocyclic or heterocyclic ring;
R3, R4, R5 and R6 independently represent hydrogen, hydrocarbon, a heterocyclic group, halogen, cyano, trifluoromethyl, nitro, -ORa, -SRa, -SORa, -SO2Ra, -SO2NRaRb, -NRaRb, -NRaCORb, -NRaCO2Rb, -CORa, -CO2Ra or -CONRaRb; and
Ra and Rb independently represent hydrogen, hydrocarbon or a heterocyclic group; in association with one or more pharmaceutically acceptable carriers and/or excipients.
2. A composition as claimed in claim 1 containing, as the active ingredient, at least one of the following compounds: 3,5-dihydro-2-phenyl- lH-pyrazolo[3,4-c]quinoline- 1,4(2H)-dione; and pharmaceutically acceptable salts thereof and prodrugs thereof.
3. The use of a compound of formula IA as defined in claim 1, or a pharmaceutically acceptable salt thereof or a prodrug thereof, for the manufacture of a medicament for the treatment and/or prevention of conditions which require the administration of a selective noncompetitive antagonist of NMDA receptors.
4. The use of a compound of formula IA as defined in claim 1, or a pharmaceutically acceptable salt thereof or a prodrug thereof, for the manufacture of a medicament for the treatment and/or prevention of conditions which require the administration of an antagonist of AMPA receptors.
5. A compound of formula IB or a salt or prodrug thereof:
wherein Ril and R12 independently represent hydrogen, hydrocarbon, a heterocyclic group, halogen, cyano, trifluoromethyl, nitro, -ORa, -SRa, -SORa, -SO2Ra, -SO2NRaRb, -NRaRb, -NRaCORb, -NRaCO2Rb, -CORa, -CO2Ra or -CONRaRb; or R11 and R12 together represent the residue of a carbocyclic or heterocyclic ring; Rl3, R14, R15 and R16 independently represent hydrogen, hydrocarbon, a heterocyclic group, halogen, cyano, trifluoromethyl, nitro, -ORa, -SRA, -SORa, -S02Ra, -SO2NRaRb, -NRaRb, -NRaCORb, -NRaCO2Rb, -CORa, -CO2Ra or -CONRaRb; and
Ra and Rb independently represent hydrogen, hydrocarbon or a heterocyclic group;
provided that R11, R12, R13, R14, R15 and R16 are not all simultaneously hydrogen.
6. A compound as claimed in claim 5 represented by formula IIA and salts and pro drugs thereof:
wherein R21 and R22 independently represent C1-6 alkyl, C2-6 alkenyl,
C2-6 alkynyl, aryl, aryl(C1-6)alkyl, aryl(C2-6)alkenyl, aryl(C2-6)alkynyl, heteroaryl(C1-6)alkyl, C1.6 alkoxy, C2.6 alkenyloxy, aryloxy, aryl(Cl.6)alkoxy, heteroaryloxy, Ci.e alkylthio, arylthio, arylsulphonyl, arylamino, aryl(C1-6)alkylamino, di(C1-6)alkylamino, arylcarbonylamino, arylcarbonyl, heteroarylcarbonyl or C2-7 alkoxycarbonyl, any of which groups may be optionally substituted; or hydrogen, halogen, cyano, trifluoromethyl, nitro, hydroxy, amino or carboxy; or
R21 and R22 together represent the residue of a carbocyclic or heterocyclic ring;
R23 and R24 independently represent hydrogen, halogen, cyano, trifluoromethyl, nitro, hydroxy, amino, carboxy, C1-6 alkyl, C2-6 alkenyl, Ci.e alkoxy, Ci.e alkylthio or C2.7 alkoxycarbonyl; and
R25 represents halogen, cyano, trifluoromethyl, nitro, hydroxy, amino, carboxy, Ci.e alkyl, C.e alkenyl, Ci.e alkoxy, Cie alkylthio or C2.7 alkoxycarbonyl.
7. A compound as claimed in claim 6 wherein one of R21 and R22 is hydrogen and the other is hydrogen, chloro, methoxy or phenoxy.
8. A compound as claimed in claim 6 or claim 7 wherein
R23 is hydrogen, ethyl, chloro or iodo.
9. A compound as claimed in any one of claims 6 to 8 wherein R24 is hydrogen or chloro.
10. A compound as claimed in any one of claims 6 to 9 wherein R25 represents cyano, trifluoromethyl, nitro, methyl or halogen.
11. A compound as claimed in claim 10 wherein R25 is chloro.
12. A compound as claimed in claim 5 represented by formula IIB and salts and prodrugs thereof:
wherein
R31 represents Ci.e alkyl, C.e alkenyl, C2-6 alkynyl, aryl, aryl(C1-6)alkyl, aryl(C2-6)alkenyl, aryl(C2-6)alkynyl, heteroaryl(C1-6)alkyl,
C1-6 alkoxy, C2.e alkenyloxy, aryloxy, aryl(Ci.e)alkoxy, heteroaryloxy, Ci.e alkylthio, arylthio, arylsulphonyl, arylamino, aryl(C1-6)alkylamino, di(C1-6)alkylamino, arylcarbonylamino, arylcarbonyl, heteroarylcarbonyl or C2.7 alkoxycarbonyl, any of which groups may be optionally substituted; or hydrogen, halogen, cyano, trifluoromethyl, nitro, hydroxy, amino or carboxy; and
R32 represents C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, aryl(C1-6)alkyl, aryl(C2-6)alkenyl, aryl(C2-6)alkynyl, heteroaryl(C1-6)alkyl,
C1-6 alkoxy, C2-6 alkenyloxy, aryloxy, aryl(C1-6)alkoxy, heteroaryloxy, C1-6 alkylthio, arylthio, arylsulphonyl, arylamino, aryl(C1-6)alkylamino, di(C1-6)alkylamino, arylcarbonylamino, arylcarbonyl, heteroarylcarbonyl or C2.7 alkoxycarbonyl, any of which groups may be optionally substituted; or halogen, cyano, trifluoromethyl, nitro, hydroxy, amino or carboxy; or
R31 and R32 together represent the residue of a carbocyclic or heterocyclic ring; and
R33, R34 and R35 independently represent hydrogen, halogen, cyano, trifluoromethyl, nitro, hydroxy, amino, carboxy, Ci.6 alkyl, C2-6 alkenyl, Ci.e alkoxy, C1-6 alkylthio or C2.7 alkoxycarbonyl.
13. A compound as claimed in claim 12 wherein R3l is hydrogen and R92 is chloro, methoxy or phenoxy.
14. A compound as claimed in claim 12 or claim 13 wherein R93 is hydrogen, ethyl, chloro or iodo.
15. A compound as claimed in any one of claims 12 to 14 wherein R34 is hydrogen or chloro.
16. A compound as claimed in any one of claims 12 to 15 wherein R35 represents hydrogen, cyano, trifluoromethyl, nitro, methyl or halogen.
17. A compound as claimed in claim 16 wherein R35 is hydrogen or chloro.
18. A compound as claimed in claim 5 selected from: 7-chloro-3 ,5-dihydro-2-phenyl- lH-pyrazolo[3,4-c]quinoline- 1,4(2H)-dione; 2-(2-chlorophenyl)-3,5-dihydro-1H-pyrazolo[3,4-c]quinoline-1,4(2H)-dione; 2-(3-chlorophenyl)-3,5-dihydor-1H-pyrazolo[3,4-c]quinoline-1,4(2H0-dione; 2-(4-chlorophenyl)-3,5-dihydro- 1H-pyrazolo [3,4-c] quinoline- 1 ,4(2H)-dione; 3,5-dihydro-2-(4-methoxyphenyl) - 1H-pyrazolo[3,4-c] quinoline- 1,4(2H)- dione; 7-chloro-3,5-dihydro-2-(4-methoxyphenyl)-1H-pyrazolo[3,4-c]quinoline1,4(2H)-dione; and salts and prodrugs thereof.
19. A pharmaceutical composition comprising a compound as claimed in any one of claims 5 to 18 in association with one or more pharmaceutically acceptable carriers and/or excipients.
20. The use of a compound as claimed in any one of claims 5 to 18 for the manufacture of a medicament for the treatment and/or prevention of conditions which require the administration of a selective non-competitive antagonist of NMDA receptors.
21. The use of a compound as claimed in any one of claims 5 to 18 for the manufacture of a medicament for the treatment and/or prevention of conditions which require the administration of an antagonist of AMPA receptors.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB9507736A GB2288800A (en) | 1994-04-25 | 1995-04-13 | Pyrazolo-quinoline derivatives as NMDA and AMPA antagonists |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB9408160A GB9408160D0 (en) | 1994-04-25 | 1994-04-25 | Therapeutic agents |
GB9411953A GB9411953D0 (en) | 1994-06-15 | 1994-06-15 | Therapeutic agents |
GBGB9425035.4A GB9425035D0 (en) | 1994-12-09 | 1994-12-09 | Therapeutic agents |
GB9507736A GB2288800A (en) | 1994-04-25 | 1995-04-13 | Pyrazolo-quinoline derivatives as NMDA and AMPA antagonists |
Publications (2)
Publication Number | Publication Date |
---|---|
GB9507736D0 GB9507736D0 (en) | 1995-05-31 |
GB2288800A true GB2288800A (en) | 1995-11-01 |
Family
ID=27451149
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB9507736A Withdrawn GB2288800A (en) | 1994-04-25 | 1995-04-13 | Pyrazolo-quinoline derivatives as NMDA and AMPA antagonists |
Country Status (1)
Country | Link |
---|---|
GB (1) | GB2288800A (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001046190A1 (en) * | 1999-12-22 | 2001-06-28 | Kyorin Pharmaceutical Co., Ltd. | Tricyclic compounds and addition salts thereof |
US7812038B2 (en) | 1999-05-07 | 2010-10-12 | Encysive Pharmaceuticals, Inc. | Carboxylic acid derivatives that inhibit the binding of integrins to their receptors |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1551653A (en) * | 1976-05-10 | 1979-08-30 | Fuji Photo Film Co Ltd | Pyrazolopyridine methine dyes and photographic materials containing these dyes |
-
1995
- 1995-04-13 GB GB9507736A patent/GB2288800A/en not_active Withdrawn
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1551653A (en) * | 1976-05-10 | 1979-08-30 | Fuji Photo Film Co Ltd | Pyrazolopyridine methine dyes and photographic materials containing these dyes |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7812038B2 (en) | 1999-05-07 | 2010-10-12 | Encysive Pharmaceuticals, Inc. | Carboxylic acid derivatives that inhibit the binding of integrins to their receptors |
WO2001046190A1 (en) * | 1999-12-22 | 2001-06-28 | Kyorin Pharmaceutical Co., Ltd. | Tricyclic compounds and addition salts thereof |
Also Published As
Publication number | Publication date |
---|---|
GB9507736D0 (en) | 1995-05-31 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US5420155A (en) | Tetramic acid derivatives | |
US5475008A (en) | Quinolone derivatives | |
US5426106A (en) | Pyrrolo-pyridazinone derivatives | |
JP4347125B2 (en) | Intermediates of tetracyclic derivatives | |
EP0489458B1 (en) | Hydroxyquinolone derivatives | |
TW201506028A (en) | 1,2-disubstituted heterocyclic compounds | |
CN101534824A (en) | Aminopyrrolidines as chemokine receptor antagonists | |
EP0620812A1 (en) | Quinolone derivatives | |
CN103619841A (en) | Heteroaryl compounds and methods of use thereof | |
CN103582478A (en) | Methods and compositions for treating neurodegenerative diseases | |
JP5856086B2 (en) | Use of isoquinolones for drug manufacture, novel isoquinolones and methods for their synthesis | |
JPH09505030A (en) | Hydroisoquinoline derivative | |
JPH08510221A (en) | AMPA antagonist and treatment method using the same | |
JPH0311067A (en) | Excitatory amino acid antagonist | |
US5652239A (en) | Pyridazinedione derivatives useful in treatment of neurological disorders | |
CA2544213A1 (en) | Imidazo[1,2-a]pyridine anxiolytics | |
US5693640A (en) | Pyridazino-indole derivatives | |
US5580877A (en) | Pyrazolo-quinoline derivatives for treating cerebral ischemia | |
WO2016200339A1 (en) | Selective anti-cancer compounds | |
JP2010229034A (en) | Bicyclic pyrrole derivative | |
SK61793A3 (en) | New 3,4-dihydroisoquinoline derivatives and new pharmaceutical use of carbocyclically and heterocyclically annulated dihydropyridines | |
GB2288800A (en) | Pyrazolo-quinoline derivatives as NMDA and AMPA antagonists | |
JPH0555511B2 (en) | ||
WO2022197789A1 (en) | Polycyclic inhibitors of plasma kallikrein | |
US5376748A (en) | Nitroquinolone derivatives |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WAP | Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1) |