WO1999064009A1 - Use of an nk-1 receptor antagonist for treating cognitive disorders - Google Patents
Use of an nk-1 receptor antagonist for treating cognitive disorders Download PDFInfo
- Publication number
- WO1999064009A1 WO1999064009A1 PCT/GB1999/001818 GB9901818W WO9964009A1 WO 1999064009 A1 WO1999064009 A1 WO 1999064009A1 GB 9901818 W GB9901818 W GB 9901818W WO 9964009 A1 WO9964009 A1 WO 9964009A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- treatment
- disorders
- cognitive disorders
- triazol
- bis
- Prior art date
Links
- 208000010877 cognitive disease Diseases 0.000 title claims abstract description 40
- 108010040718 Neurokinin-1 Receptors Proteins 0.000 title abstract description 33
- 102000002002 Neurokinin-1 Receptors Human genes 0.000 title abstract description 33
- 239000002464 receptor antagonist Substances 0.000 title abstract description 28
- 229940044551 receptor antagonist Drugs 0.000 title abstract description 28
- 238000011282 treatment Methods 0.000 claims abstract description 33
- 238000000034 method Methods 0.000 claims abstract description 21
- 230000002265 prevention Effects 0.000 claims abstract description 16
- 239000003814 drug Substances 0.000 claims abstract description 11
- 238000004519 manufacturing process Methods 0.000 claims abstract description 7
- 150000003839 salts Chemical class 0.000 claims description 21
- 239000000203 mixture Substances 0.000 claims description 19
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 claims description 16
- 239000000935 antidepressant agent Substances 0.000 claims description 13
- 229940005513 antidepressants Drugs 0.000 claims description 12
- 239000000164 antipsychotic agent Substances 0.000 claims description 12
- 229940124834 selective serotonin reuptake inhibitor Drugs 0.000 claims description 12
- 239000000952 serotonin receptor agonist Substances 0.000 claims description 9
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 claims description 8
- -1 SSRIs Substances 0.000 claims description 8
- 239000003420 antiserotonin agent Substances 0.000 claims description 8
- 239000000221 dopamine uptake inhibitor Substances 0.000 claims description 8
- 239000003112 inhibitor Substances 0.000 claims description 8
- 229960002748 norepinephrine Drugs 0.000 claims description 8
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 claims description 8
- 229940076279 serotonin Drugs 0.000 claims description 8
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 7
- 208000031091 Amnestic disease Diseases 0.000 claims description 6
- 206010012289 Dementia Diseases 0.000 claims description 6
- 206010002660 Anoxia Diseases 0.000 claims description 5
- 241000976983 Anoxia Species 0.000 claims description 5
- 206010021143 Hypoxia Diseases 0.000 claims description 5
- 230000007953 anoxia Effects 0.000 claims description 5
- 230000003412 degenerative effect Effects 0.000 claims description 5
- 208000019553 vascular disease Diseases 0.000 claims description 5
- 208000028698 Cognitive impairment Diseases 0.000 claims description 3
- 208000017701 Endocrine disease Diseases 0.000 claims description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 3
- 208000015181 infectious disease Diseases 0.000 claims description 3
- 208000014674 injury Diseases 0.000 claims description 3
- 230000003902 lesion Effects 0.000 claims description 3
- 239000003053 toxin Substances 0.000 claims description 3
- 231100000765 toxin Toxicity 0.000 claims description 3
- 108700012359 toxins Proteins 0.000 claims description 3
- 230000008733 trauma Effects 0.000 claims description 3
- 206010010904 Convulsion Diseases 0.000 claims description 2
- 208000009889 Herpes Simplex Diseases 0.000 claims description 2
- 208000013016 Hypoglycemia Diseases 0.000 claims description 2
- 208000005428 Thiamine Deficiency Diseases 0.000 claims description 2
- 208000002894 beriberi Diseases 0.000 claims description 2
- 230000036461 convulsion Effects 0.000 claims description 2
- 230000006378 damage Effects 0.000 claims description 2
- 230000004770 neurodegeneration Effects 0.000 claims description 2
- 239000008203 oral pharmaceutical composition Substances 0.000 claims description 2
- 230000007170 pathology Effects 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 238000001356 surgical procedure Methods 0.000 claims description 2
- 210000003478 temporal lobe Anatomy 0.000 claims description 2
- 208000030401 vitamin deficiency disease Diseases 0.000 claims description 2
- 239000003762 serotonin receptor affecting agent Substances 0.000 claims 2
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 2
- 150000001875 compounds Chemical class 0.000 description 28
- 238000003556 assay Methods 0.000 description 15
- 238000010079 rubber tapping Methods 0.000 description 14
- 238000012360 testing method Methods 0.000 description 10
- 210000002683 foot Anatomy 0.000 description 9
- 230000000694 effects Effects 0.000 description 8
- 230000027455 binding Effects 0.000 description 7
- 241001465754 Metazoa Species 0.000 description 6
- 102100024304 Protachykinin-1 Human genes 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 206010002091 Anaesthesia Diseases 0.000 description 5
- 229920002261 Corn starch Polymers 0.000 description 5
- 101800003906 Substance P Proteins 0.000 description 5
- 229940123445 Tricyclic antidepressant Drugs 0.000 description 5
- 238000001949 anaesthesia Methods 0.000 description 5
- 230000037005 anaesthesia Effects 0.000 description 5
- 239000008120 corn starch Substances 0.000 description 5
- 208000035475 disorder Diseases 0.000 description 5
- 238000002955 isolation Methods 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- QDZOEBFLNHCSSF-PFFBOGFISA-N (2S)-2-[[(2R)-2-[[(2S)-1-[(2S)-6-amino-2-[[(2S)-1-[(2R)-2-amino-5-carbamimidamidopentanoyl]pyrrolidine-2-carbonyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-N-[(2R)-1-[[(2S)-1-[[(2R)-1-[[(2S)-1-[[(2S)-1-amino-4-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]pentanediamide Chemical compound C([C@@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](N)CCCNC(N)=N)C1=CC=CC=C1 QDZOEBFLNHCSSF-PFFBOGFISA-N 0.000 description 4
- 241000700199 Cavia porcellus Species 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 229930186949 TCA Natural products 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 230000009471 action Effects 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 239000012896 selective serotonin reuptake inhibitor Substances 0.000 description 4
- RENWFOYENNEQJW-HLAWJBBLSA-N (2s)-2-[3,5-bis(trifluoromethyl)phenyl]-2-[(2r,3s)-3-(4-fluorophenyl)-4-(1h-1,2,4-triazol-5-ylmethyl)morpholin-2-yl]oxyethanol Chemical compound O([C@@H]([C@@H]1C=2C=CC(F)=CC=2)O[C@H](CO)C=2C=C(C=C(C=2)C(F)(F)F)C(F)(F)F)CCN1CC=1N=CNN=1 RENWFOYENNEQJW-HLAWJBBLSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 206010061216 Infarction Diseases 0.000 description 3
- 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 3
- 241000282339 Mustela Species 0.000 description 3
- 206010047700 Vomiting Diseases 0.000 description 3
- 239000000556 agonist Substances 0.000 description 3
- 230000001430 anti-depressive effect Effects 0.000 description 3
- 230000002238 attenuated effect Effects 0.000 description 3
- 230000002146 bilateral effect Effects 0.000 description 3
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 3
- 229960004316 cisplatin Drugs 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
- 229940079593 drug Drugs 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 230000007574 infarction Effects 0.000 description 3
- 229940090044 injection Drugs 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 210000004731 jugular vein Anatomy 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 238000002203 pretreatment Methods 0.000 description 3
- 239000000018 receptor agonist Substances 0.000 description 3
- 229940044601 receptor agonist Drugs 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- 235000012431 wafers Nutrition 0.000 description 3
- 208000024827 Alzheimer disease Diseases 0.000 description 2
- 208000019901 Anxiety disease Diseases 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
- 101000600903 Homo sapiens Substance-P receptor Proteins 0.000 description 2
- 108091006905 Human Serum Albumin Proteins 0.000 description 2
- 102000008100 Human Serum Albumin Human genes 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 2
- 241000282341 Mustela putorius furo Species 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 108010079943 Pentagastrin Proteins 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 230000003444 anaesthetic effect Effects 0.000 description 2
- 230000036506 anxiety Effects 0.000 description 2
- 230000000338 anxiogenic effect Effects 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000019771 cognition Effects 0.000 description 2
- 230000006735 deficit Effects 0.000 description 2
- 239000012055 enteric layer Substances 0.000 description 2
- 230000000763 evoking effect Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 238000005469 granulation Methods 0.000 description 2
- 230000003179 granulation Effects 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 239000002742 neurokinin 1 receptor antagonist Substances 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 229960000444 pentagastrin Drugs 0.000 description 2
- ANRIQLNBZQLTFV-DZUOILHNSA-N pentagastrin Chemical compound C([C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1[C]2C=CC=CC2=NC=1)NC(=O)CCNC(=O)OC(C)(C)C)CCSC)C(N)=O)C1=CC=CC=C1 ANRIQLNBZQLTFV-DZUOILHNSA-N 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 210000004761 scalp Anatomy 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 230000035939 shock Effects 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000000126 substance Substances 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
- 239000003981 vehicle Substances 0.000 description 2
- MRXDGVXSWIXTQL-HYHFHBMOSA-N (2s)-2-[[(1s)-1-(2-amino-1,4,5,6-tetrahydropyrimidin-6-yl)-2-[[(2s)-4-methyl-1-oxo-1-[[(2s)-1-oxo-3-phenylpropan-2-yl]amino]pentan-2-yl]amino]-2-oxoethyl]carbamoylamino]-3-phenylpropanoic acid Chemical compound C([C@H](NC(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C=O)C1NC(N)=NCC1)C(O)=O)C1=CC=CC=C1 MRXDGVXSWIXTQL-HYHFHBMOSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 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
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 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
- 235000017060 Arachis glabrata Nutrition 0.000 description 1
- 244000105624 Arachis hypogaea Species 0.000 description 1
- 235000010777 Arachis hypogaea Nutrition 0.000 description 1
- 235000018262 Arachis monticola Nutrition 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 208000000412 Avitaminosis Diseases 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 208000001408 Carbon monoxide poisoning Diseases 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- OLVPQBGMUGIKIW-UHFFFAOYSA-N Chymostatin Natural products C=1C=CC=CC=1CC(C=O)NC(=O)C(C(C)CC)NC(=O)C(C1NC(N)=NCC1)NC(=O)NC(C(O)=O)CC1=CC=CC=C1 OLVPQBGMUGIKIW-UHFFFAOYSA-N 0.000 description 1
- 244000060011 Cocos nucifera Species 0.000 description 1
- 235000013162 Cocos nucifera Nutrition 0.000 description 1
- 241000699802 Cricetulus griseus Species 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
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 201000011240 Frontotemporal dementia Diseases 0.000 description 1
- 102100021260 Galactosylgalactosylxylosylprotein 3-beta-glucuronosyltransferase 1 Human genes 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 241000699694 Gerbillinae Species 0.000 description 1
- 244000068988 Glycine max Species 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- 206010019196 Head injury Diseases 0.000 description 1
- 208000010496 Heart Arrest Diseases 0.000 description 1
- 101000894906 Homo sapiens Galactosylgalactosylxylosylprotein 3-beta-glucuronosyltransferase 1 Proteins 0.000 description 1
- 101000831616 Homo sapiens Protachykinin-1 Proteins 0.000 description 1
- 208000023105 Huntington disease 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
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 1
- 208000006264 Korsakoff syndrome Diseases 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- GDBQQVLCIARPGH-UHFFFAOYSA-N Leupeptin Natural products CC(C)CC(NC(C)=O)C(=O)NC(CC(C)C)C(=O)NC(C=O)CCCN=C(N)N GDBQQVLCIARPGH-UHFFFAOYSA-N 0.000 description 1
- 229910021380 Manganese Chloride Inorganic materials 0.000 description 1
- GLFNIEUTAYBVOC-UHFFFAOYSA-L Manganese chloride Chemical compound Cl[Mn]Cl GLFNIEUTAYBVOC-UHFFFAOYSA-L 0.000 description 1
- 201000009906 Meningitis Diseases 0.000 description 1
- 229940123685 Monoamine oxidase inhibitor Drugs 0.000 description 1
- 208000005314 Multi-Infarct Dementia Diseases 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 229920005439 Perspex® Polymers 0.000 description 1
- 208000000609 Pick Disease of the Brain Diseases 0.000 description 1
- 229920002873 Polyethylenimine Polymers 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 208000028017 Psychotic disease Diseases 0.000 description 1
- 244000000231 Sesamum indicum Species 0.000 description 1
- 235000003434 Sesamum indicum Nutrition 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 208000002667 Subdural Hematoma Diseases 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 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
- 229930006000 Sucrose Natural products 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 102000003141 Tachykinin Human genes 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
- 229920001615 Tragacanth Polymers 0.000 description 1
- 201000004810 Vascular dementia Diseases 0.000 description 1
- 229930003779 Vitamin B12 Natural products 0.000 description 1
- 206010047627 Vitamin deficiencies Diseases 0.000 description 1
- 201000008485 Wernicke-Korsakoff syndrome Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 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
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000003277 amino group Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000000561 anti-psychotic effect Effects 0.000 description 1
- 229940005529 antipsychotics Drugs 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
- 239000007900 aqueous suspension Substances 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- CREXVNNSNOKDHW-UHFFFAOYSA-N azaniumylideneazanide Chemical group N[N] CREXVNNSNOKDHW-UHFFFAOYSA-N 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 229940098773 bovine serum albumin Drugs 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
- 239000001506 calcium phosphate Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 210000004289 cerebral ventricle Anatomy 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 201000009950 chronic meningitis Diseases 0.000 description 1
- 108010086192 chymostatin Proteins 0.000 description 1
- 229940105442 cisplatin injection Drugs 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- AGVAZMGAQJOSFJ-WZHZPDAFSA-M cobalt(2+);[(2r,3s,4r,5s)-5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [(2r)-1-[3-[(1r,2r,3r,4z,7s,9z,12s,13s,14z,17s,18s,19r)-2,13,18-tris(2-amino-2-oxoethyl)-7,12,17-tris(3-amino-3-oxopropyl)-3,5,8,8,13,15,18,19-octamethyl-2 Chemical compound [Co+2].N#[C-].[N-]([C@@H]1[C@H](CC(N)=O)[C@@]2(C)CCC(=O)NC[C@@H](C)OP(O)(=O)O[C@H]3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)\C2=C(C)/C([C@H](C\2(C)C)CCC(N)=O)=N/C/2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O AGVAZMGAQJOSFJ-WZHZPDAFSA-M 0.000 description 1
- 230000001010 compromised effect Effects 0.000 description 1
- 238000011970 concomitant therapy Methods 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 230000003111 delayed effect Effects 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
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 230000009429 distress Effects 0.000 description 1
- 210000001198 duodenum Anatomy 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000020375 flavoured syrup Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 238000003304 gavage Methods 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
- 239000008187 granular material Substances 0.000 description 1
- 210000004326 gyrus cinguli Anatomy 0.000 description 1
- 229960003132 halothane Drugs 0.000 description 1
- BCQZXOMGPXTTIC-UHFFFAOYSA-N halothane Chemical compound FC(F)(F)C(Cl)Br BCQZXOMGPXTTIC-UHFFFAOYSA-N 0.000 description 1
- 210000000548 hind-foot Anatomy 0.000 description 1
- 230000000971 hippocampal effect Effects 0.000 description 1
- 239000008240 homogeneous mixture Substances 0.000 description 1
- 239000003326 hypnotic agent Substances 0.000 description 1
- 230000000147 hypnotic effect Effects 0.000 description 1
- 230000002989 hypothyroidism Effects 0.000 description 1
- 208000003532 hypothyroidism Diseases 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229960002725 isoflurane Drugs 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
- GDBQQVLCIARPGH-ULQDDVLXSA-N leupeptin Chemical compound CC(C)C[C@H](NC(C)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C=O)CCCN=C(N)N GDBQQVLCIARPGH-ULQDDVLXSA-N 0.000 description 1
- 108010052968 leupeptin Proteins 0.000 description 1
- 239000003446 ligand Substances 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
- 239000011565 manganese chloride Substances 0.000 description 1
- 230000008774 maternal effect Effects 0.000 description 1
- 206010027175 memory impairment Diseases 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000002899 monoamine oxidase inhibitor Substances 0.000 description 1
- 238000004264 monolayer culture Methods 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 229920001206 natural gum Polymers 0.000 description 1
- 208000000288 neurosarcoidosis Diseases 0.000 description 1
- 230000009871 nonspecific binding Effects 0.000 description 1
- 201000003077 normal pressure hydrocephalus Diseases 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
- 210000001672 ovary Anatomy 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 235000020232 peanut Nutrition 0.000 description 1
- 229950000964 pepstatin Drugs 0.000 description 1
- 108010091212 pepstatin Proteins 0.000 description 1
- FAXGPCHRFPCXOO-LXTPJMTPSA-N pepstatin A Chemical compound OC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](C(C)C)NC(=O)[C@H](C(C)C)NC(=O)CC(C)C FAXGPCHRFPCXOO-LXTPJMTPSA-N 0.000 description 1
- 239000002831 pharmacologic agent Substances 0.000 description 1
- 238000011458 pharmacological treatment Methods 0.000 description 1
- YBYRMVIVWMBXKQ-UHFFFAOYSA-N phenylmethanesulfonyl fluoride Chemical compound FS(=O)(=O)CC1=CC=CC=C1 YBYRMVIVWMBXKQ-UHFFFAOYSA-N 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000004926 polymethyl methacrylate Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000009117 preventive therapy Methods 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 238000001525 receptor binding assay Methods 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- ADNPLDHMAVUMIW-CUZNLEPHSA-N substance P Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(N)=O)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CCCN=C(N)N)C1=CC=CC=C1 ADNPLDHMAVUMIW-CUZNLEPHSA-N 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
- 239000000375 suspending agent Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 108060008037 tachykinin Proteins 0.000 description 1
- 239000002462 tachykinin receptor antagonist Substances 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
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 239000003029 tricyclic antidepressant agent Substances 0.000 description 1
- 239000011715 vitamin B12 Substances 0.000 description 1
- 235000019163 vitamin B12 Nutrition 0.000 description 1
- 210000004916 vomit Anatomy 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
Definitions
- This invention relates to the treatment or prevention of certain cognitive disorders by the administration of a NK-1 receptor antagonist, in particular, 2-(R)-(l-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)- 3-(S)-(4-fluorophenyl)-4-(l,2,4-triazol-3-yl)methylmorpholine, or a pharmaceutically acceptable salt thereof.
- a NK-1 receptor antagonist in particular, 2-(R)-(l-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)- 3-(S)-(4-fluorophenyl)-4-(l,2,4-triazol-3-yl)methylmorpholine, or a pharmaceutically acceptable salt thereof.
- Cognitive disorders include dementia, amnestic disorders and cognitive disorders not otherwise specified.
- the prominent disturbance associated with these conditions is a clinically significant deficit in cognition or memory that represents a significant change from a previous level of functioning.
- dementia is now defined as a syndrome consisting of progressive impairment in two or more areas of cognition (i.e. memory, language, visuospatial and perceptual ability, thinking and problem solving, and personality) sufficient to interfere with work, social function or relationships.
- areas of cognition i.e. memory, language, visuospatial and perceptual ability, thinking and problem solving, and personality
- An amnestic disorder is characterised by memory impairment in the absence of other significant cognitive impairments.
- Neurokinin 1 (NK-1; substance P) receptor antagonists are being developed for the treatment of a number of physiological disorders associated with an excess or imbalance of tachykinins, and in particular substance P.
- Examples of conditions in which substance P has been imphcated include disorders of the central nervous system such as anxiety, depression and psychosis (see, for instance, International (PCT) patent specification Nos. WO 95/16679, WO 95/18124 and WO 95/23798). More recently, International (PCT) patent specification No.
- WO 96/24353 suggests that a more efficacious and safe treatment of psychiatric disorders would be achieved using a combination of a tachykinin antagonist and a serotonin agonist or selective serotonin reuptake inhibitor (SSRI).
- SSRI serotonin agonist or selective serotonin reuptake inhibitor
- the present invention provides the use of 2-(R)-(l-(S)-(3,5- bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)-4- (l,2,4-triazol-3-yl)methylmorpholine, or a pharmaceutically acceptable salt thereof in an oral, once-a-day medicament for the treatment of cognitive disorders.
- the compounds of this class advantageously exhibit a rapid onset of action and a reduced side-effect profile when compared against conventional antidepressant or antipsychotic agents.
- the exceptional pharmacology of the NK- 1 receptor antagonist of use in the present invention enables the treatment of cognitive disorders, without the need for concomitant therapy using tricyclic antidepr ess ants or monoamine oxidase inhibitors, or antipsychotic agents, or in particular, without the need for concomitant use of a serotonin agonist or an SSRI. Furthermore, the exceptional pharmacology of the NK- 1 receptor antagonist of use in the present invention results in a rapid onset of action.
- the present invention accordingly provides the use of 2-(R)-(l-(S)- (3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)- 4-(l,2,4-triazol-3-yl)methylmorphohne, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament adapted for oral administration for the treatment or prevention of cognitive disorders.
- the present invention also provides a method for the treatment or prevention of cognitive disorders, which method comprises the oral administration to a patient in need of such treatment of an effective amount of 2-(R)-(l-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)- 3-(S)-(4-fluorophenyl)-4-(l,2,4-triazol-3-yl)methylmorphohne, or a pharmaceutically acceptable salt thereof.
- an oral pharmaceutical composition for the treatment of cognitive disorders which comprises 2-(R)-(l-(S)-(3,5-bis(trifluoromethyl)phenyl)-2- hydroxyethoxy)-3-(S)-(4-fluorophenyl)-4-(l,2,4-triazol-3- yl)methylmorpholine, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or excipient.
- the present invention accordingly provides the use of 2-(R)-(l-(S)- (3 , 5 -bis(trifluoromethyl)phenyl) -2 -hy droxy ethoxy)- 3 - (S) - (4-fl.uorophenyl) - 4-(l,2,4-triazol-3-yl)methylmorpholine, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament adapted for oral administration for the treatment or prevention of cognitive disorders in a patient who is non-responsive to heterocycHc antidepressants (TCAs, tetracyclics, and the like), SSRIs, serotonin agonists or antagonists, mixed serotonin and norepinephrine selective reuptake inhibitors, dopamine reuptake inhibitors or MAOIs, or for whom heterocycHc antidepressants (TCAs, tetracycHcs, and the Hke), SSRIs, serot
- the present invention also provides a method for the treatment or prevention of cognitive disorders in a patient who is non-responsive to heterocycHc antidepressants (TCAs, tetracycHcs, and the Hke), SSRIs, serotonin agonists or antagonists, mixed serotonin and norepinephrine selective reuptake inhibitors, dopamine reuptake inhibitors or MAOIs, or for whom heterocycHc antidepressants (TCAs, tetracycHcs, and the Hke), SSRIs, serotonin agonists or antagonists, mixed serotonin and norepinephrine selective reuptake inhibitors, dopamine reuptake inhibitors or MAOIs are contraindicated, which method comprises oral administration to the patient in need of such treatment of an effective amount of 2 - (R) - ( 1 - (S) - (3 , 5 -bis(trifluoromethyl)phenyl) - 2
- the present invention also provides a method for the treatment or prevention of cognitive disorders in the patient who is non-responsive to antipsychotic agents, or for whom antipsychotic agents are contraindicated, which method comprises oral administration to the patient in need of such treatment of an effective amount of 2-(R)-(l-(S)- (3 , 5 -bis(trifluoromethyl)phenyl) -2 -hy droxyethoxy)- 3 - (S)- (4-fluorophenyl) - 4-(l,2,4-triazol-3-yl)methylmorphoHne, or a pharmaceuticaUy acceptable salt thereof.
- the term "cognitive disorders” includes dementia, amnestic disorders and cognitive disorders not otherwise specified.
- the term "cognitive disorders” includes dementia caused by degenerative disorders, lesions, trauma, infections, vascular disorders, toxins, anoxia, vitamin deficiency and endocrine disorders.
- specific examples of these causes include degenerative disorders such as Alzheimer's disease, multiple sclerosis, Parkinson's disease, normal pressure hydrocephalus and Huntington's chorea; space occupying lesions including tumors and chronic subdural haematoma; trauma including severe head injury; infections including postencephaHtis and syphiHs; vascular disorders including multi-infarct dementia; toxins including alcohol; anoxia caused by cardiac arrest and carbon monoxide poisoning, vitamin deficiencies including lack of vitamin B12; and endocrine disorders including hypothyroidism.
- cognitive disorders includes amnestic disorders caused by alcohol (Korsakoff psychosis) and other causes of thiamine deficiency; bilateral temporal lobe damage due to herpes simplex encephafitis and other Hmbic encephahtis, neuronal loss secondary to anoxia/hypoglycaemia/severe convulsions, and surgery; degenerative disorders including Alzheimer's and Pick's diseases; vascular disorders including bilateral infarction, hippocampal infarction and bilateral cingulate cortex infarction; and pathology around ventricle III including tumors, chronic meningitis and neurosarcoidosis.
- cognitive disorders includes cognitive impairment resulting from other medical conditions, most especiaUy resulting from depression and/or anxiety.
- treatment refers both to the treatment and to the prevention or prophylactic therapy of the aforementioned conditions.
- Suitable pharmaceuticaUy acceptable salts of the NK-1 receptor antagonist of use in the present invention include acid addition salts which may, for example, be formed by mixing a solution of the compound with a solution of a pharmaceuticaUy acceptable non-toxic acid such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid or sulphuric acid.
- Salts of amine groups may also comprise the quaternary ammonium salts in which the amino nitrogen atom carries an alkyl, alkenyl, alkynyl or aralkyl group.
- compositions containing the NK-1 receptor antagonist of use according to the present invention are in unit dosage forms such as tablets, piUs, capsules, wafers and the Hke.
- the NK- 1 receptor antagonist of use according to the present invention may be presented as granules or powders for extemporaneous formulation as volume defined solutions or suspensions.
- the NK-1 receptor antagonist of use according to the present invention may be presented in ready-prepared volume defined solutions or suspensions.
- Preferred forms are tablets and capsules.
- soHd 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 dUuents, e.g. water, to form a soHd preformulation composition containing a homogeneous mixture of a compound of the present invention, or a non-toxic pharmaceuticaUy acceptable salt thereof.
- 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 dUuents, e.g. water
- preformulation compositions 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 reacUly subdivided into equaUy effective unit dosage forms such as tablets, piUs and capsules.
- This soHd 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.
- the tablet or piU 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.
- enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as sheUac, cetyl alcohol and ceUulose acetate.
- compositions of the present invention may be incorporated for administration oraUy
- aqueous solutions suitably flavoured syrups, aqueous or oU suspensions, and flavoured emulsions with edible oUs such as cottonseed oU, sesame oU, coconut oU, peanut oU or soybean oU, as weU as ehxirs and similar pharmaceutical vehicles.
- Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylceUulose, methylceUulose, polyvinyl-pyrroHdone or gelatin.
- Compositions of the present invention may also be administered via the buccal cavity using conventional technology, for example, absorption wafers.
- compositions in the form of tablets, piUs, capsules or wafers for oral administration are particularly preferred.
- a minimum dosage level for the NK- 1 receptor antagonist is about lmg per day, preferably about 5mg per day and especiaUy about lOmg per day.
- a maximum dosage level for the NK-1 receptor antagonist is about 1500mg per day, preferably about lOOOmg per day and especiaUy about 500mg per day. The compounds are administered once a day.
- the amount of the NK- 1 receptor antagonist required for use in the treatment or prevention of cognitive disorders wiU vary not only with the particular compounds or compositions selected but also with the route of administration, the nature of the condition being treated, and the age and condition of the patient, and wiU ultimately be at the discretion of the patient's physician or pharmacist.
- the activity of the NK- 1 receptor antagonist of use in the present invention may be measured using the foUowing assays:
- NK-1 Receptor binding NK-1 receptor binding assays are performed in intact Chinese hamster ovary (CHO) ceUs expressing the human NK- 1 receptor using a modification of the assay conditions described by Cascieri et al, J. Pharmacol. Exp. Ther.. 1992, 42, 458.
- TypicaUy the receptor is expressed at a level of 3xl0 5 receptors per ceU.
- CeUs are grown in monolayer culture, detached from the plate with enzyme-free dissociation solution (SpeciaHty Media Inc.), and washed prior to use in the assay.
- I-Tyr 8 - substance P (O.lnM, 2000Ci/mmol; New England Nuclear) is incubated in the presence or absence of test compounds (dissolved in 5 ⁇ l dimethylsulphoxide, DMSO) with 5xl0 4 CHO ceUs. Ligand binding is performed in 0.25ml of 50mM Tris-HCl, pH7.5, containing 5mM MnCl 2>
- GerbU Foot-Tapping CNS-penetrant NK-1 receptor antagonists for use in the present invention can be identified by their abiHty to inhibit foot tapping in gerbUs induced by anxiogenic agents (such as pentagastrin) or central infusion of NK-1 receptor agonists such as GR73632, or caused by aversive stimulation such as foot shock or single housing, based on the method of Rupniak & WiUiams, Eur. J. Pharmacol., 1994, 265, 179.
- Male or female MongoHan gerbUs (35-70g) are anaesthetised by inhalation of an isoflurane/oxygen mixture to permit exposure of the jugular vein in order to permit administration of test compounds or vehicle in an injection volume of 5ml/kg i.v.
- test compounds may be administered oraUy or by subcutaneous or intraperitoneal routes. A skin incision is then made in the midHne of the scalp to expose the skuU.
- An anxiogenic agent e.g. pentagastrin
- a selective NK-1 receptor agonist e.g.
- GR73632 (d Ala[L-Pro 9 ,Me-Leu 10 ] -substance P-(7-l l)) is infused directly into the cerebral ventricles (e.g. 3pmol in 5 ⁇ l i.c.v., depending on test substance) by vertical insertion of a cuffed 27 gauge needle to a depth of 4.5mm below bregma. The scalp incision is closed and the animal aUowed to recover from anaesthesia in a clear perspex observation box (25cm x 20cm x 20cm). The duration and/or intensity of hind foot tapping is then recorded continuously for approximately 5 minutes. Alternatively, the ability of test compounds to inhibit foot tapping evoked by aversive stimulation, such as foot shock or single housing, may be studied using a similar method of quantification.
- ASSAY 3 Ferret Emesis IndividuaUy housed male ferrets (1.0 -2.5 kg) are dosed oraUy by gavage with test compound. Ten minutes later they are fed with approximately lOOg of tinned cat food. At 60 minutes foUowing oral dosing, cisplatin (lOmg/kg) is given i.v. via a jugular vein catheter inserted under a brief period of halothane anaesthesia. The catheter is then removed, the jugular vein Hgated and the skin incision closed. The ferrets recover rapidly from the anaesthetic and are mobUe within 10-20 minutes.
- the animals are observed continuously during recovery from the anaesthetic and for 4 hours foUowing the cisplatin injection, after which time the animals are kiUed humanely.
- the numbers of retches and vomits occurring during the 4 hours after cisplatin administration are recorded by trained observers.
- mice Male and female guinea-pigs pups are housed in family groups with their mothers and Httermates throughout the study. Experiments are commenced after weaning when the pups are 2 weeks old. Before entering an experiment, the pups are screened to ensure that a vigorous vocaHsation response is reproducibly eHcited foUowing maternal separation. The pups are placed individuaUy in an observation cage (55cm x 39cm x 19cm) in a room physically isolated from the home cage for 15 minutes and the duration of vocaHsation during this baseHne period is recorded.
- CNS-penetrant refers to NK-1 receptor antagonists which are able to inhibit NK-1 receptor antagonist-induced foot-tapping in the gerbU as hereinafter defined.
- the NK- 1 receptor antagonist is administered oraUy, 1 hour prior to GR73632 chaUenge, wherein the foot- tapping over a period of five minutes foUowing recovery from anaesthesia is inhibited with an IDso ⁇ 30mg/kg, and preferably with an IDso ⁇ lOmg/kg.
- CNS-penetrant NK-1 receptor antagonists of use in the present invention are also effective in the attenuation of separation-induced vocaHsations by guinea-pig pups as hereinafter defined.
- a vocaHsation response in guinea-pig pups is induced by isolation from their mothers and Httermates, which response is attenuated when a CNS-penetrant NK-1 receptor antagonist is administered subcutaneously 30 minutes prior to isolation, wherein vocaHsations during the first 15 minutes of isolation are attenuated with an ID5o ⁇ 20mg/kg, preferably with an ID ⁇ o ⁇ lOmg/kg, and especiaUy with an IDso ⁇ mg/kg.
- the NK-1 receptor antagonist is administered oraUy, 4 hours prior to isolation, wherein vocaHsations during the first 15 minutes of isolation are attenuated with an IDso ⁇ 20mg/kg, preferably with an IDso ⁇ lOmg/kg, and especially with an IDso ⁇ mg/kg.
- a suitable selection cascade for NKi antagonists of use according to the present invention is as foUows: (i) Determine affinity for human NKi receptor in radioHgand binding studies (Assay 1); select compounds with IC ⁇ o ⁇ lOnM, preferably IC50 ⁇ 2nM, especiaUy ICso ⁇ InM.
- step (iv) Determine oral bioavaUabiHty of compounds by pharmacokinetic analysis, activity in gerbU foot tapping assay foUowing oral administration and/or by abiHty to inhibit cisplatin-induced emesis in ferrets (Assay 3); select compounds with ID90 ⁇ 3mg/kg p.o., and preferably Particularly preferred compounds of use in the present invention are identified using steps (i) to (iv) foUowed by step (v):
- step (v) Determine activity of compounds in assays sensitive to conventional antidepressant/anxiolytic drugs (inhibition of pharmacologicaUy evoked foot tapping in gerbUs and/or inhibition of distress vocaHsations in guinea-pig pups (Assay 4)).
- Yet further preferred compounds of use in the present invention may be selected from those compounds which satisfy the NK-1 receptor binding criteria of step (i) which, in addition, have ⁇ 5-fold shift in affinity when incubated in the presence of human serum albumin (HSA) to show non-specific protein binding.
- HSA human serum albumin
- the NK- 1 receptor antagonist of use in the present invention is the compound 2-(R)-(l-(S)-(3,5-bis(trifl.uoromethyl)phenyl)-2-hydroxyethoxy)- 3-(S)-(4-fluorophenyl)-4-(l,2,4-triazol-3-yl)methylmorphoHne, the preparation of which is described in International Patent Specification No. WO 95/18124 and US Patent No. 5,612,337. In the aforementioned assays, this compound has the foUowing activity:
- the foUowing example illustrates pharmaceutical compositions according to the invention.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention provides the use of an NK-1 receptor antagonist for the manufacture of a medicament adapted for oral administration for the treatment or prevention of cognitive disorders, methods of medical treatment using such an NK-1 receptor antagonist and pharmaceutical compositions comprising it.
Description
USE OF A NK-1 RECEPTOR ANTAGONIST FOR TREATING COGNITIVE DISORDERS
This invention relates to the treatment or prevention of certain cognitive disorders by the administration of a NK-1 receptor antagonist, in particular, 2-(R)-(l-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)- 3-(S)-(4-fluorophenyl)-4-(l,2,4-triazol-3-yl)methylmorpholine, or a pharmaceutically acceptable salt thereof.
Cognitive disorders include dementia, amnestic disorders and cognitive disorders not otherwise specified. The prominent disturbance associated with these conditions is a clinically significant deficit in cognition or memory that represents a significant change from a previous level of functioning.
For instance, dementia is now defined as a syndrome consisting of progressive impairment in two or more areas of cognition (i.e. memory, language, visuospatial and perceptual ability, thinking and problem solving, and personality) sufficient to interfere with work, social function or relationships.
An amnestic disorder is characterised by memory impairment in the absence of other significant cognitive impairments.
Pharmacological treatment of such cognitive disorders is poorly developed. In some instances, antidepressants, hypnotics or antipsychotics may be used in order to manage specific behavioural disturbances associated with the cognitive disorder. Such treatments, however, may be compromised by the side effects associated with these classes of pharmacological agent and, as such, are far from ideal means for treating cognitive disorders.
Neurokinin 1 (NK-1; substance P) receptor antagonists are being developed for the treatment of a number of physiological disorders associated with an excess or imbalance of tachykinins, and in particular substance P. Examples of conditions in which substance P has been
imphcated include disorders of the central nervous system such as anxiety, depression and psychosis (see, for instance, International (PCT) patent specification Nos. WO 95/16679, WO 95/18124 and WO 95/23798). More recently, International (PCT) patent specification No. WO 96/24353 (pubhshed 15th August 1996) suggests that a more efficacious and safe treatment of psychiatric disorders would be achieved using a combination of a tachykinin antagonist and a serotonin agonist or selective serotonin reuptake inhibitor (SSRI). However, such as regimen would not be free of side-effects due to the serotonin agonist or SSRI. In view of the short-comings of existing therapy, there is a need for new, safe and effective treatment for cognitive disorders.
The present invention provides the use of 2-(R)-(l-(S)-(3,5- bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)-4- (l,2,4-triazol-3-yl)methylmorpholine, or a pharmaceutically acceptable salt thereof in an oral, once-a-day medicament for the treatment of cognitive disorders. The compounds of this class advantageously exhibit a rapid onset of action and a reduced side-effect profile when compared against conventional antidepressant or antipsychotic agents.
The exceptional pharmacology of the NK- 1 receptor antagonist of use in the present invention enables the treatment of cognitive disorders, without the need for concomitant therapy using tricyclic antidepr ess ants or monoamine oxidase inhibitors, or antipsychotic agents, or in particular, without the need for concomitant use of a serotonin agonist or an SSRI. Furthermore, the exceptional pharmacology of the NK- 1 receptor antagonist of use in the present invention results in a rapid onset of action.
The present invention accordingly provides the use of 2-(R)-(l-(S)- (3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)- 4-(l,2,4-triazol-3-yl)methylmorphohne, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament adapted for oral administration for the treatment or prevention of cognitive disorders.
The present invention also provides a method for the treatment or prevention of cognitive disorders, which method comprises the oral administration to a patient in need of such treatment of an effective amount of 2-(R)-(l-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)- 3-(S)-(4-fluorophenyl)-4-(l,2,4-triazol-3-yl)methylmorphohne, or a pharmaceutically acceptable salt thereof.
In a further aspect of the present invention, there is provided an oral pharmaceutical composition for the treatment of cognitive disorders which comprises 2-(R)-(l-(S)-(3,5-bis(trifluoromethyl)phenyl)-2- hydroxyethoxy)-3-(S)-(4-fluorophenyl)-4-(l,2,4-triazol-3- yl)methylmorpholine, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or excipient.
There exists a patient population in whom cognitive disorders are inadequately treated with existing antidepressant therapy. Furthermore, some patients may be adversely affected by the side-effects of existing antidepressant drugs.
The present invention accordingly provides the use of 2-(R)-(l-(S)- (3 , 5 -bis(trifluoromethyl)phenyl) -2 -hy droxy ethoxy)- 3 - (S) - (4-fl.uorophenyl) - 4-(l,2,4-triazol-3-yl)methylmorpholine, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament adapted for oral administration for the treatment or prevention of cognitive disorders in a patient who is non-responsive to heterocycHc antidepressants (TCAs, tetracyclics, and the like), SSRIs, serotonin agonists or antagonists, mixed serotonin and norepinephrine selective reuptake inhibitors, dopamine reuptake inhibitors or MAOIs, or for whom heterocycHc antidepressants (TCAs, tetracycHcs, and the Hke), SSRIs, serotonin agonists or antagonists, mixed serotonin and norepinephrine selective reuptake inhibitors, dopamine reuptake inhibitors or MAOIs are contraindicated. The present invention also provides a method for the treatment or prevention of cognitive disorders in a patient who is non-responsive to heterocycHc antidepressants (TCAs, tetracycHcs, and the Hke), SSRIs,
serotonin agonists or antagonists, mixed serotonin and norepinephrine selective reuptake inhibitors, dopamine reuptake inhibitors or MAOIs, or for whom heterocycHc antidepressants (TCAs, tetracycHcs, and the Hke), SSRIs, serotonin agonists or antagonists, mixed serotonin and norepinephrine selective reuptake inhibitors, dopamine reuptake inhibitors or MAOIs are contraindicated, which method comprises oral administration to the patient in need of such treatment of an effective amount of 2 - (R) - ( 1 - (S) - (3 , 5 -bis(trifluoromethyl)phenyl) - 2 -hy droxy ethoxy ) - 3-(S)-(4-fluorophenyl)-4-(l,2,4-triazol-3-yl)methylmorphoHne, or a pharmaceuticaUy acceptable salt thereof.
Furthermore, there exists a patient population in whom cognitive disorders are inadequately treated with existing antipsychotic therapy. Furthermore, some patients may be adversely affected by the side-effects of antipsychotic drugs. The present invention accordingly provides the use of 2-(R)-(l-(S)-
(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)- 4-(l,2,4-triazol-3-yl)methylmorphoHne, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament adapted for oral administration for the treatment or prevention of cognitive disorders in a patient who is non-responsive to antipsychotic agents, or for whom antipsychotic agents are contraindicated.
The present invention also provides a method for the treatment or prevention of cognitive disorders in the patient who is non-responsive to antipsychotic agents, or for whom antipsychotic agents are contraindicated, which method comprises oral administration to the patient in need of such treatment of an effective amount of 2-(R)-(l-(S)- (3 , 5 -bis(trifluoromethyl)phenyl) -2 -hy droxyethoxy)- 3 - (S)- (4-fluorophenyl) - 4-(l,2,4-triazol-3-yl)methylmorphoHne, or a pharmaceuticaUy acceptable salt thereof. As used herein, the term "cognitive disorders" includes dementia, amnestic disorders and cognitive disorders not otherwise specified.
In particular, the term "cognitive disorders" includes dementia caused by degenerative disorders, lesions, trauma, infections, vascular disorders, toxins, anoxia, vitamin deficiency and endocrine disorders. Specific examples of these causes include degenerative disorders such as Alzheimer's disease, multiple sclerosis, Parkinson's disease, normal pressure hydrocephalus and Huntington's chorea; space occupying lesions including tumors and chronic subdural haematoma; trauma including severe head injury; infections including postencephaHtis and syphiHs; vascular disorders including multi-infarct dementia; toxins including alcohol; anoxia caused by cardiac arrest and carbon monoxide poisoning, vitamin deficiencies including lack of vitamin B12; and endocrine disorders including hypothyroidism.
Furthermore, the term "cognitive disorders" includes amnestic disorders caused by alcohol (Korsakoff psychosis) and other causes of thiamine deficiency; bilateral temporal lobe damage due to herpes simplex encephafitis and other Hmbic encephahtis, neuronal loss secondary to anoxia/hypoglycaemia/severe convulsions, and surgery; degenerative disorders including Alzheimer's and Pick's diseases; vascular disorders including bilateral infarction, hippocampal infarction and bilateral cingulate cortex infarction; and pathology around ventricle III including tumors, chronic meningitis and neurosarcoidosis.
Also, as used herein, the term "cognitive disorders" includes cognitive impairment resulting from other medical conditions, most especiaUy resulting from depression and/or anxiety. As used herein, the term "treatment" refers both to the treatment and to the prevention or prophylactic therapy of the aforementioned conditions.
In particular, the NK-1 receptor antagonist of use in the present invention is the compound 2-(R)-(l-(S)-(3,5-bis(trifluoromethyl)phenyl)-2- hydxoxyethoxy)-3-(S)-(4-fluorophenyl)-4-(l,2,4-triazol-3- yl)methylmorphohne, or a pharmaceuticaUy acceptable salt thereof.
FuU descriptions of the preparation of the NK-1 receptor antagonist which may be employed in the present invention may be found in International Patent Specification No. WO 95/18124 and US Patent No. 5,612,337. Suitable pharmaceuticaUy acceptable salts of the NK-1 receptor antagonist of use in the present invention include acid addition salts which may, for example, be formed by mixing a solution of the compound with a solution of a pharmaceuticaUy acceptable non-toxic acid such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid or sulphuric acid. Salts of amine groups may also comprise the quaternary ammonium salts in which the amino nitrogen atom carries an alkyl, alkenyl, alkynyl or aralkyl group.
Preferably the compositions containing the NK-1 receptor antagonist of use according to the present invention are in unit dosage forms such as tablets, piUs, capsules, wafers and the Hke. AdditionaUy, the NK- 1 receptor antagonist of use according to the present invention may be presented as granules or powders for extemporaneous formulation as volume defined solutions or suspensions. Alternatively, the NK-1 receptor antagonist of use according to the present invention may be presented in ready-prepared volume defined solutions or suspensions. Preferred forms are tablets and capsules.
For preparing soHd 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 dUuents, e.g. water, to form a soHd preformulation composition containing a homogeneous mixture of a compound of the present invention, or a non-toxic pharmaceuticaUy 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 reacUly subdivided into equaUy effective unit dosage forms such as tablets, piUs and capsules. This soHd 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 piU 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 sheUac, cetyl alcohol and ceUulose acetate.
The Hquid forms in which the novel compositions of the present invention may be incorporated for administration oraUy include aqueous solutions, suitably flavoured syrups, aqueous or oU suspensions, and flavoured emulsions with edible oUs such as cottonseed oU, sesame oU, coconut oU, peanut oU or soybean oU, as weU as ehxirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylceUulose, methylceUulose, polyvinyl-pyrroHdone or gelatin. Compositions of the present invention may also be administered via the buccal cavity using conventional technology, for example, absorption wafers.
Compositions in the form of tablets, piUs, capsules or wafers for oral administration are particularly preferred. A minimum dosage level for the NK- 1 receptor antagonist is about lmg per day, preferably about 5mg per day and especiaUy about lOmg per
day. A maximum dosage level for the NK-1 receptor antagonist is about 1500mg per day, preferably about lOOOmg per day and especiaUy about 500mg per day. The compounds are administered once a day.
It will be appreciated that the amount of the NK- 1 receptor antagonist required for use in the treatment or prevention of cognitive disorders wiU vary not only with the particular compounds or compositions selected but also with the route of administration, the nature of the condition being treated, and the age and condition of the patient, and wiU ultimately be at the discretion of the patient's physician or pharmacist.
The activity of the NK- 1 receptor antagonist of use in the present invention may be measured using the foUowing assays:
ASSAY 1: NK-1 Receptor binding NK-1 receptor binding assays are performed in intact Chinese hamster ovary (CHO) ceUs expressing the human NK- 1 receptor using a modification of the assay conditions described by Cascieri et al, J. Pharmacol. Exp. Ther.. 1992, 42, 458. TypicaUy the receptor is expressed at a level of 3xl05 receptors per ceU. CeUs are grown in monolayer culture, detached from the plate with enzyme-free dissociation solution (SpeciaHty Media Inc.), and washed prior to use in the assay. i25I-Tyr8- substance P (O.lnM, 2000Ci/mmol; New England Nuclear) is incubated in the presence or absence of test compounds (dissolved in 5μl dimethylsulphoxide, DMSO) with 5xl04 CHO ceUs. Ligand binding is performed in 0.25ml of 50mM Tris-HCl, pH7.5, containing 5mM MnCl2>
150mM NaCl, 0.02% bovine serum albumin (Sigma), 50μg/ml chymostatin (Peninsula), O. lnM phenylmethylsulphonyl fluoride, 2μg/ml pepstatin, 2μg/ml leupeptin and 2.8μg/ml furoyl saccharine. The incubation proceeds at room temperature untU equihbrium is achieved (>40 minutes) and the receptor-Hgand complex is harvested by filtration over GF/C filters pre- soaked in 0.1% polyethylenimine using a Tomtek 96-weU harvester. Non-
specific binding is determined using excess substance P (lμM) and represents <10% of total binding.
ASSAY 2: GerbU Foot-Tapping CNS-penetrant NK-1 receptor antagonists for use in the present invention can be identified by their abiHty to inhibit foot tapping in gerbUs induced by anxiogenic agents (such as pentagastrin) or central infusion of NK-1 receptor agonists such as GR73632, or caused by aversive stimulation such as foot shock or single housing, based on the method of Rupniak & WiUiams, Eur. J. Pharmacol., 1994, 265, 179.
Male or female MongoHan gerbUs (35-70g) are anaesthetised by inhalation of an isoflurane/oxygen mixture to permit exposure of the jugular vein in order to permit administration of test compounds or vehicle in an injection volume of 5ml/kg i.v. Alternatively, test compounds may be administered oraUy or by subcutaneous or intraperitoneal routes. A skin incision is then made in the midHne of the scalp to expose the skuU. An anxiogenic agent (e.g. pentagastrin) or a selective NK-1 receptor agonist (e.g. GR73632 (d Ala[L-Pro9,Me-Leu10] -substance P-(7-l l)) is infused directly into the cerebral ventricles (e.g. 3pmol in 5μl i.c.v., depending on test substance) by vertical insertion of a cuffed 27 gauge needle to a depth of 4.5mm below bregma. The scalp incision is closed and the animal aUowed to recover from anaesthesia in a clear perspex observation box (25cm x 20cm x 20cm). The duration and/or intensity of hind foot tapping is then recorded continuously for approximately 5 minutes. Alternatively, the ability of test compounds to inhibit foot tapping evoked by aversive stimulation, such as foot shock or single housing, may be studied using a similar method of quantification.
ASSAY 3: Ferret Emesis IndividuaUy housed male ferrets (1.0 -2.5 kg) are dosed oraUy by gavage with test compound. Ten minutes later they are fed with
approximately lOOg of tinned cat food. At 60 minutes foUowing oral dosing, cisplatin (lOmg/kg) is given i.v. via a jugular vein catheter inserted under a brief period of halothane anaesthesia. The catheter is then removed, the jugular vein Hgated and the skin incision closed. The ferrets recover rapidly from the anaesthetic and are mobUe within 10-20 minutes. The animals are observed continuously during recovery from the anaesthetic and for 4 hours foUowing the cisplatin injection, after which time the animals are kiUed humanely. The numbers of retches and vomits occurring during the 4 hours after cisplatin administration are recorded by trained observers.
ASSAY 4: Separation-Induced VocaHsation
Male and female guinea-pigs pups are housed in family groups with their mothers and Httermates throughout the study. Experiments are commenced after weaning when the pups are 2 weeks old. Before entering an experiment, the pups are screened to ensure that a vigorous vocaHsation response is reproducibly eHcited foUowing maternal separation. The pups are placed individuaUy in an observation cage (55cm x 39cm x 19cm) in a room physically isolated from the home cage for 15 minutes and the duration of vocaHsation during this baseHne period is recorded. Only animals which vocaHse for longer than 5 minutes are employed for drug chaUenge studies (approximately 50% of available pups may faU to reach this criterion). On test days each pup receives an oral dose or an s.c. or i.p. injection of test compound or vehicle and is then immediately returned to the home cage with its mother and sibHngs for 30 to 60 minutes (or for up to 4 hours foUowing an oral dose, dependant upon the oral pharmacokinetics of the test compound) before social isolation for 15 minutes as described above. The duration of vocaHsation on drug treatment days is expressed as a percentage of the pre-treatment baseHne value for each animal. The same subjects are retested once weekly for up
to 6 weeks. Between 6 and 8 animals receive each test compound at each dose tested.
As used herein, the term "CNS-penetrant" refers to NK-1 receptor antagonists which are able to inhibit NK-1 receptor antagonist-induced foot-tapping in the gerbU as hereinafter defined.
EssentiaUy, hind foot-tapping in the gerbil induced by infusion of the NK-1 receptor agonist, GR73632 (d Ala[L-Pro9,Me-Leu10]-substance P- (7-11)), under anaesthesia, directly into the central ventricles is inhibited when a CNS-penetrant NK-1 receptor antagonist is administered intravenously immediately prior to GR73632 chaUenge, wherein hind foot- tapping over a period of five minutes foUowing recovery from the anaesthesia is inhibited with an IDso<3mg/kg, and preferably with an
In an alternative method, the NK- 1 receptor antagonist is administered oraUy, 1 hour prior to GR73632 chaUenge, wherein the foot- tapping over a period of five minutes foUowing recovery from anaesthesia is inhibited with an IDso<30mg/kg, and preferably with an IDso≤lOmg/kg.
CNS-penetrant NK-1 receptor antagonists of use in the present invention are also effective in the attenuation of separation-induced vocaHsations by guinea-pig pups as hereinafter defined.
EssentiaUy, a vocaHsation response in guinea-pig pups is induced by isolation from their mothers and Httermates, which response is attenuated when a CNS-penetrant NK-1 receptor antagonist is administered subcutaneously 30 minutes prior to isolation, wherein vocaHsations during the first 15 minutes of isolation are attenuated with an ID5o<20mg/kg, preferably with an IDδo≤lOmg/kg, and especiaUy with an IDso≤δmg/kg.
In an alternative method, the NK-1 receptor antagonist is administered oraUy, 4 hours prior to isolation, wherein vocaHsations during the first 15 minutes of isolation are attenuated with an
IDso<20mg/kg, preferably with an IDso≤lOmg/kg, and especially with an IDso≤δmg/kg.
A suitable selection cascade for NKi antagonists of use according to the present invention is as foUows: (i) Determine affinity for human NKi receptor in radioHgand binding studies (Assay 1); select compounds with ICεo < lOnM, preferably IC50 < 2nM, especiaUy ICso < InM.
(fi) Determine abihty of compounds to penetrate CNS by their abiHty to inhibit foot tapping in gerbUs induced by central injection of an NKi agonist (Assay 2); select compounds that inhibit foot tapping with IDso < 3mg/kg i.v., and preferably IDso < lmg/kg i.v. when administered immediately prior to central NKi agonist chaUenge, or IDso < 30mg/kg p.o., and preferably IDso < lOmg/kg p.o. 1 hour prior to chaUenge.
(Hi) Determine central duration of action of compounds in gerbU foot tapping assay foUowing intravenous administration 24 hours prior to central NKi agonist chaUenge; select compounds showing < 25-fold loss of potency compared with IDso determined in step (n) above with the proviso that IDso ≤ lOmg/kg i.v., and preferably < 5mg/kg i.v. after 24 hour pre-treatment. (iv) Determine oral bioavaUabiHty of compounds by pharmacokinetic analysis, activity in gerbU foot tapping assay foUowing oral administration and/or by abiHty to inhibit cisplatin-induced emesis in ferrets (Assay 3); select compounds with ID90 < 3mg/kg p.o., and preferably
Particularly preferred compounds of use in the present invention are identified using steps (i) to (iv) foUowed by step (v):
(v) Determine activity of compounds in assays sensitive to conventional antidepressant/anxiolytic drugs (inhibition of pharmacologicaUy evoked foot tapping in gerbUs and/or inhibition of distress vocaHsations in guinea-pig pups (Assay 4)). Select compounds with IDso < 20mg kg, and preferably IDso < lOmg/kg.
Yet further preferred compounds of use in the present invention may be selected from those compounds which satisfy the NK-1 receptor binding criteria of step (i) which, in addition, have < 5-fold shift in affinity when incubated in the presence of human serum albumin (HSA) to show non-specific protein binding.
The NK- 1 receptor antagonist of use in the present invention is the compound 2-(R)-(l-(S)-(3,5-bis(trifl.uoromethyl)phenyl)-2-hydroxyethoxy)- 3-(S)-(4-fluorophenyl)-4-(l,2,4-triazol-3-yl)methylmorphoHne, the preparation of which is described in International Patent Specification No. WO 95/18124 and US Patent No. 5,612,337. In the aforementioned assays, this compound has the foUowing activity:
human NK- 1 receptor binding: ICso = 0.12 nM gerbU foot-tapping (5 mins.): IDso = 0.38 mg/kg i.v. gerbU foot-tapping (24 hrs.): IDso = 2.2 mg/kg i.v. ferret emesis: ID90 = 1 mg/kg p.o. guinea-pig vocaHsation
(4 hr. pre-treatment): IDso = 0.91 mg/kg p.o.
The foUowing example illustrates pharmaceutical compositions according to the invention.
EXAMPLE 1 Tablets containing 50-300mg of NK-1 antagonist
Amount mg NK-1 antagonist 50.0 100.0 300.0
MicrocrystaUine ceUulose 80.0 80.0 80.0
Modified food corn starch 80.0 80.0 80.0
Lactose 189.5 139.5 139.5
Magnesium Stearate 0.5 0.5 0.5
The active ingredient, ceUulose, lactose and a portion of the corn starch are mixed and granulated with 10% corn starch paste. The resulting granulation is sieved, dried and blended with the remainder of the corn starch and the magnesium stearate. The resulting granulation is then compressed into tablets containing 50mg, lOOmg and 300mg of the NK-1 receptor antagonist per tablet.
Claims
1. Use of 2-(R)-(l-(S)-(3,5-bis(trifluoromethyl)phenyl)-2- hydroxyethoxy)-3-(S)-(4-fluorophenyl)-4-(l,2,4-triazol-3- yl)methyhnorphoHne, or a pharmaceuticaUy acceptable salt thereof, for the manufacture of a medicament adapted for oral administration for the treatment or prevention of cognitive disorders.
2. Use of 2-(R)-(l-(S)-(3,5-bis(trifluoromethyl)phenyl)-2- hydroxyethoxy)-3-(S)-(4-fluorophenyl)-4-(l,2,4-triazol-3- yl)methylmorphoHne, or a pharmaceuticaUy acceptable salt thereof, for the manufacture of a medicament adapted for oral administration for the treatment or prevention of cognitive disorders in a patient who is non- responsive to heterocycHc antidepressants, SSRIs, serotonin agonists or antagonists, mixed serotonin and norepinephrine selective reuptake inhibitors, dopamine reuptake inhibitors or MAOIs, or for whom heterocycHc antidepressants, SSRIs, serotonin agonists or antagonists, mixed serotonin and norepinephrine selective reuptake inhibitors, dopamine reuptake inhibitors or MAOIs are contraindicated.
3. Use of 2-(R)-(l-(S)-(3,5-bis(trifluoromethyl)phenyl)-2- hydroxyethoxy)-3-(S)-(4-fluorophenyl)-4-(l,2,4-triazol-3- yl)methylmorphoHne, or a pharmaceuticaUy acceptable salt thereof, for the manufacture of a medicament adapted for oral administration for the treatment or prevention of cognitive disorders in a patient who is non- responsive to antipsychotic agents, or for whom antipsychotic agents are contraindicated.
4. An oral pharmaceutical composition for the treatment of cognitive disorders which comprises 2-(R)-(l-(S)-(3,5- bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)-4- (l,2,4-triazol-3-yl)methylmorphoHne, or a pharmaceuticaUy acceptable salt thereof, together with a pharmaceuticaUy acceptable carrier or excipient.
5. A method for the treatment or prevention of cognitive disorders, which method comprises the oral administration to a patient in need of such treatment of an effective amount of 2-(R)-(l-(S)-(3,5- bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)-4- (l,2,4-triazol-3-yl)methylmorphoHne, or a pharmaceuticaUy acceptable salt thereof.
6. A method for the treatment or prevention of cognitive disorders in a patient who is non-responsive to heterocycHc antidepressants, SSRIs, serotonin agents or antagonists, mixed serotonin and norepinephrine selective reuptake inhibitors, dopamine reuptake inhibitors or MAOIs, or for whom heterocycHc antidepressants, SSRIs, serotonin agents or antagonists, mixed serotonin and norepinephrine selective reuptake inhibitors, dopamine reuptake inhibitors or MAOIs are contraindicated, which method comprises oral administration to the patient in need of such treatment of an effective amount of 2-(R)-(l-(S)- (3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)-3-(S)-(4-fluorophenyl)- 4-(l,2,4-triazol-3-yl)methylmorphoHne, or a pharmaceuticaUy acceptable salt thereof.
7. A method for the treatment or prevention of cognitive disorders in a patient who is non-responsive to antipsychotic agents, or for whom antipsychotic agents are contraindicated, which method comprises oral administration to the patient in need of such treatment of an effective amount of 2-(R)-(l-(S)-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxyethoxy)- 3-(S)-(4-fluorophenyl)-4-(l,2,4-triazol-3-yl)methylmorphoHne, or a pharmaceuticaUy acceptable salt thereof.
8. A use according to claim 1, 2 or 3, or a composition according to claim 4 or a method according to claim 5, 6 or 7 wherein the cognitive disorders are selected from dementia, amnestic disorders and cognitive disorders not otherwise specified.
9. A use, composition or method according to claim 10 wherein the dementia is caused by degenerative disorders, lesions, trauma, infections, vascular disorders, toxins, anoxia, vitamin deficiency or endocrine disorders.
10. A use, composition or method according to claim 8 wherein the amnestic disorders are caused by: alcohol and other causes of thiamine deficiency; bUateral temporal lobe damage due to herpes simplex encephaHtis and other Hmbic encephaHtis, neuronal loss secondary to anoxia/hyp oglycaemia/severe convulsions, and surgery; degenerative disorders; vascular disorders; or pathology around ventricle III.
11. A use according to claim 1, 2 or 3, or a composition according to claim 4 or a method according to claim 5, 6 or 7 wherein the cognitive disorders are due to cognitive impairment resulting from other medical conditions.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA002334606A CA2334606A1 (en) | 1998-06-11 | 1999-06-08 | Use of an nk-1 receptor antagonist for treating cognitive disorders |
| EP99955426A EP1119358A1 (en) | 1998-06-11 | 1999-06-08 | Use of an nk-1 receptor antagonist for treating cognitive disorders |
| AU42795/99A AU4279599A (en) | 1998-06-11 | 1999-06-08 | Use of an nk-1 receptor antagonist for treating cognitive disorders |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9812662.6 | 1998-06-11 | ||
| GBGB9812662.6A GB9812662D0 (en) | 1998-06-11 | 1998-06-11 | Therapeutic use |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1999064009A1 true WO1999064009A1 (en) | 1999-12-16 |
Family
ID=10833616
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/GB1999/001818 WO1999064009A1 (en) | 1998-06-11 | 1999-06-08 | Use of an nk-1 receptor antagonist for treating cognitive disorders |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP1119358A1 (en) |
| AU (1) | AU4279599A (en) |
| CA (1) | CA2334606A1 (en) |
| GB (1) | GB9812662D0 (en) |
| WO (1) | WO1999064009A1 (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001052844A1 (en) * | 2000-01-18 | 2001-07-26 | F. Hoffmann-La Roche Ag | Brain, spinal and nerve injury treatment |
| WO2002016343A1 (en) * | 2000-08-22 | 2002-02-28 | Merck Sharp & Dohme Limited | Tetrahydropyran derivatives as nk-1 receptor antagonists |
| WO2004018441A1 (en) * | 2002-08-23 | 2004-03-04 | Eli Lilly And Company | Aryl and heteroaryl morpholine derivatives |
| US7384941B2 (en) | 2002-08-23 | 2008-06-10 | Eli Lilly And Company | 2-(phenoxymethyl)-and 2-(phenylthiomethyl)-morpholine derivatives for use as selective norepinephrine reuptake inhibitors |
Citations (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0533280A1 (en) * | 1991-09-20 | 1993-03-24 | Glaxo Group Limited | Novel medical use for tachykinin antagonists |
| WO1995018124A1 (en) * | 1993-12-29 | 1995-07-06 | Merck Sharp & Dohme Limited | Substituted morpholine derivatives and their use as therapeutic agents |
| WO1996024353A1 (en) * | 1995-02-10 | 1996-08-15 | Eli Lilly And Company | Methods of treating or preventing psychiatric disorders |
| WO1996029328A1 (en) * | 1995-03-18 | 1996-09-26 | Merck Sharp & Dohme Limited | Morpholine derivatives, compositions containing them and their use as therapeutic agents |
| WO1996029326A1 (en) * | 1995-03-21 | 1996-09-26 | Glaxo Group Limited | 3-benzylamino-2-phenylpiperidines as neurokinin antagonists |
| WO1997049710A1 (en) * | 1996-06-21 | 1997-12-31 | Merck Sharp & Dohme Limited | Spiro-piperidine derivatives and their use as therapeutic agents |
| US5719147A (en) * | 1992-06-29 | 1998-02-17 | Merck & Co., Inc. | Morpholine and thiomorpholine tachykinin receptor antagonists |
| WO1998013369A1 (en) * | 1996-09-25 | 1998-04-02 | Merck Sharp & Dohme Limited | Spiro-azacyclic derivatives, their preparation and their use as tachykinin antagonists |
| WO1998054187A1 (en) * | 1997-05-29 | 1998-12-03 | Merck Sharp & Dohme Limited | Spiro-azacyclic derivatives and their use as therapeutic agents |
| WO1999007375A1 (en) * | 1997-08-04 | 1999-02-18 | Merck Sharp & Dohme Limited | Use of nk-1 receptor antagonists for treating aggressive behaviour disorders |
| WO1999025714A1 (en) * | 1997-11-19 | 1999-05-27 | Pfizer Pharmaceuticals Inc. | Piperidinylaminomethyl trifluoromethyl cyclic ether compounds as substance p antagonists |
-
1998
- 1998-06-11 GB GBGB9812662.6A patent/GB9812662D0/en not_active Ceased
-
1999
- 1999-06-08 EP EP99955426A patent/EP1119358A1/en not_active Withdrawn
- 1999-06-08 AU AU42795/99A patent/AU4279599A/en not_active Abandoned
- 1999-06-08 WO PCT/GB1999/001818 patent/WO1999064009A1/en not_active Application Discontinuation
- 1999-06-08 CA CA002334606A patent/CA2334606A1/en not_active Abandoned
Patent Citations (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0533280A1 (en) * | 1991-09-20 | 1993-03-24 | Glaxo Group Limited | Novel medical use for tachykinin antagonists |
| US5719147A (en) * | 1992-06-29 | 1998-02-17 | Merck & Co., Inc. | Morpholine and thiomorpholine tachykinin receptor antagonists |
| WO1995018124A1 (en) * | 1993-12-29 | 1995-07-06 | Merck Sharp & Dohme Limited | Substituted morpholine derivatives and their use as therapeutic agents |
| WO1996024353A1 (en) * | 1995-02-10 | 1996-08-15 | Eli Lilly And Company | Methods of treating or preventing psychiatric disorders |
| WO1996029328A1 (en) * | 1995-03-18 | 1996-09-26 | Merck Sharp & Dohme Limited | Morpholine derivatives, compositions containing them and their use as therapeutic agents |
| WO1996029326A1 (en) * | 1995-03-21 | 1996-09-26 | Glaxo Group Limited | 3-benzylamino-2-phenylpiperidines as neurokinin antagonists |
| WO1997049710A1 (en) * | 1996-06-21 | 1997-12-31 | Merck Sharp & Dohme Limited | Spiro-piperidine derivatives and their use as therapeutic agents |
| WO1998013369A1 (en) * | 1996-09-25 | 1998-04-02 | Merck Sharp & Dohme Limited | Spiro-azacyclic derivatives, their preparation and their use as tachykinin antagonists |
| WO1998054187A1 (en) * | 1997-05-29 | 1998-12-03 | Merck Sharp & Dohme Limited | Spiro-azacyclic derivatives and their use as therapeutic agents |
| WO1999007375A1 (en) * | 1997-08-04 | 1999-02-18 | Merck Sharp & Dohme Limited | Use of nk-1 receptor antagonists for treating aggressive behaviour disorders |
| WO1999025714A1 (en) * | 1997-11-19 | 1999-05-27 | Pfizer Pharmaceuticals Inc. | Piperidinylaminomethyl trifluoromethyl cyclic ether compounds as substance p antagonists |
Cited By (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6841551B2 (en) | 2000-01-18 | 2005-01-11 | Hoffmann-La Roche Inc. | Brain, spinal, and nerve injury treatment |
| JP4794794B2 (en) * | 2000-01-18 | 2011-10-19 | エフ．ホフマン−ラ ロシュ アーゲー | Treatment of brain, spinal cord and nerve damage |
| JP2003520232A (en) * | 2000-01-18 | 2003-07-02 | エフ．ホフマン−ラ ロシュ アーゲー | Treatment of brain, spinal cord and nerve damage |
| KR100780119B1 (en) * | 2000-01-18 | 2007-11-27 | 에프. 호프만-라 로슈 아게 | Brain, spinal cord and nerve damage treatment |
| EP1261335A4 (en) * | 2000-01-18 | 2004-09-22 | Hoffmann La Roche | METHOD OF TREATING CEREBRAL AND SPINAL LESION AND NEUROLOGICAL DEFICIT |
| US10201568B2 (en) | 2000-01-18 | 2019-02-12 | Eustralis Pharmaceuticals Limited | Brain, spinal, and nerve injury treatment |
| WO2001052844A1 (en) * | 2000-01-18 | 2001-07-26 | F. Hoffmann-La Roche Ag | Brain, spinal and nerve injury treatment |
| US9186404B2 (en) | 2000-01-18 | 2015-11-17 | Eustralis Pharmaceuticals Limited | Brain, spinal and nerve injury treatment |
| RU2276996C2 (en) * | 2000-01-18 | 2006-05-27 | Ф.Хоффманн-Ля Рош Аг | Method for treating the cases of brain, spinal cord and nerve injuries |
| HRP20020593B1 (en) * | 2000-01-18 | 2011-03-31 | F. Hoffmann - La Roche Ag | Brain, spinal and nerve injury treatment |
| WO2002016344A1 (en) * | 2000-08-22 | 2002-02-28 | Merck Sharp & Dohme Limited | Tetrahydropyran derivatives as nk-1 receptor antagonists |
| WO2002016343A1 (en) * | 2000-08-22 | 2002-02-28 | Merck Sharp & Dohme Limited | Tetrahydropyran derivatives as nk-1 receptor antagonists |
| WO2004018441A1 (en) * | 2002-08-23 | 2004-03-04 | Eli Lilly And Company | Aryl and heteroaryl morpholine derivatives |
| US7354920B2 (en) | 2002-08-23 | 2008-04-08 | Eli Lilly And Company | Aryl and heteroaryl morpholine derivatives |
| US7384941B2 (en) | 2002-08-23 | 2008-06-10 | Eli Lilly And Company | 2-(phenoxymethyl)-and 2-(phenylthiomethyl)-morpholine derivatives for use as selective norepinephrine reuptake inhibitors |
Also Published As
| Publication number | Publication date |
|---|---|
| AU4279599A (en) | 1999-12-30 |
| EP1119358A1 (en) | 2001-08-01 |
| GB9812662D0 (en) | 1998-08-12 |
| CA2334606A1 (en) | 1999-12-16 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US5929054A (en) | Use of NK-1 receptor antagonists for treating sexual dysfunctions | |
| EP0977573A1 (en) | Use of an nk-1 receptor antagonist and an ssri for treating obesity | |
| US5952315A (en) | Use of NK-1 receptor antagonists for treating bipolar disorders | |
| JP2001513496A (en) | Use of cholinesterase inhibitors to treat attention deficit disorder | |
| US5977104A (en) | Use of NK-1 receptor antagonists for treating bipolar disorders | |
| WO1999064009A1 (en) | Use of an nk-1 receptor antagonist for treating cognitive disorders | |
| US6114315A (en) | Use of NK-1 receptor antagonists for treating major depressive disorders with anxiety | |
| EP0942731B1 (en) | Use of nk-1 receptor antagonists for treating substance use disorders | |
| EP0942729B1 (en) | Use of nk-1 receptor antagonists for treating stress disorders | |
| EP0941092B1 (en) | Use of nk-1 receptor antagonists for treating major depressive disorders | |
| AU729708B2 (en) | Use of NK-1 receptor antagonists for treating severe anxiety disorders | |
| EP1099446B1 (en) | Combination for treating depression and anxiety containing a CNS-penetrant NK-1 receptor antagonist and an antidepressant or anxiolytic agent | |
| EP1085875A1 (en) | Use of a nk-1 receptor antagonist for treating psychiatric disorders | |
| AU744261B2 (en) | Use of NK-1 receptor antagonists for treating eating disorders | |
| WO1999064006A1 (en) | Use of a nk-1 receptor antagonist for treating psychiatric disorders | |
| US6096729A (en) | Use of NK-1 receptor antagonists for treating amnestic disorders | |
| AU736042B2 (en) | Use of NK-1 receptor antagonists for treating major depressive disorders with anxiety | |
| WO1999064007A1 (en) | Use of a nk-1 receptor antagonist for treating bipolar disorders | |
| WO1999064008A1 (en) | Use of a nk-1 receptor antagonist for treating sexual dysfunctions | |
| US6271230B1 (en) | Use of NK-1 receptor antagonists for treating cognitive disorders | |
| AU745524B2 (en) | Method for treating attention deficit disorder | |
| AU738047B2 (en) | Use of NK-1 receptor antagonists for treating mania | |
| US6613765B1 (en) | Use of NK-1 receptor antagonists for treating major depressive disorders |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| AK | Designated states |
Kind code of ref document: A1 Designated state(s): AE AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG US UZ VN YU ZA ZW |
|
| AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): GH GM KE LS MW SD SL SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG |
|
| DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
| WWE | Wipo information: entry into national phase |
Ref document number: 1999955426 Country of ref document: EP |
|
| ENP | Entry into the national phase |
Ref document number: 2334606 Country of ref document: CA |
|
| WWE | Wipo information: entry into national phase |
Ref document number: 42795/99 Country of ref document: AU |
|
| WWE | Wipo information: entry into national phase |
Ref document number: 09719181 Country of ref document: US |
|
| REG | Reference to national code |
Ref country code: DE Ref legal event code: 8642 |
|
| WWP | Wipo information: published in national office |
Ref document number: 1999955426 Country of ref document: EP |
|
| WWW | Wipo information: withdrawn in national office |
Ref document number: 1999955426 Country of ref document: EP |