AU729708B2 - Use of NK-1 receptor antagonists for treating severe anxiety disorders - Google Patents
Use of NK-1 receptor antagonists for treating severe anxiety disorders Download PDFInfo
- Publication number
- AU729708B2 AU729708B2 AU57527/98A AU5752798A AU729708B2 AU 729708 B2 AU729708 B2 AU 729708B2 AU 57527/98 A AU57527/98 A AU 57527/98A AU 5752798 A AU5752798 A AU 5752798A AU 729708 B2 AU729708 B2 AU 729708B2
- Authority
- AU
- Australia
- Prior art keywords
- phenyl
- methyl
- morpholine
- trifluoromethyl
- bis
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Ceased
Links
- 108010040718 Neurokinin-1 Receptors Proteins 0.000 title claims description 71
- 102000002002 Neurokinin-1 Receptors Human genes 0.000 title claims description 71
- 239000002464 receptor antagonist Substances 0.000 title claims description 68
- 229940044551 receptor antagonist Drugs 0.000 title claims description 68
- 208000019901 Anxiety disease Diseases 0.000 title description 39
- 239000000203 mixture Substances 0.000 claims description 84
- 150000001875 compounds Chemical class 0.000 claims description 73
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 66
- 238000000034 method Methods 0.000 claims description 34
- 239000002249 anxiolytic agent Substances 0.000 claims description 28
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 28
- 230000002265 prevention Effects 0.000 claims description 23
- -1 bis(trifluoromethyl)phenyl Chemical group 0.000 claims description 21
- 238000011970 concomitant therapy Methods 0.000 claims description 20
- 208000008811 Agoraphobia Diseases 0.000 claims description 19
- 206010034912 Phobia Diseases 0.000 claims description 19
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 19
- 229940124834 selective serotonin reuptake inhibitor Drugs 0.000 claims description 19
- 201000001716 specific phobia Diseases 0.000 claims description 19
- 206010041250 Social phobia Diseases 0.000 claims description 18
- 229940123445 Tricyclic antidepressant Drugs 0.000 claims description 17
- 239000003029 tricyclic antidepressant agent Substances 0.000 claims description 17
- 229940049706 benzodiazepine Drugs 0.000 claims description 15
- 239000003814 drug Substances 0.000 claims description 15
- 239000000952 serotonin receptor agonist Substances 0.000 claims description 15
- 150000001557 benzodiazepines Chemical class 0.000 claims description 14
- DIOQZVSQGTUSAI-UHFFFAOYSA-N decane Chemical compound CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 claims description 14
- 239000003420 antiserotonin agent Substances 0.000 claims description 13
- 150000003839 salts Chemical class 0.000 claims description 10
- 238000004519 manufacturing process Methods 0.000 claims description 8
- 239000003937 drug carrier Substances 0.000 claims description 5
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical class N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 claims description 2
- 125000001359 1,2,3-triazol-4-yl group Chemical group [H]N1N=NC([*])=C1[H] 0.000 claims 1
- 101100326677 Onchocerca volvulus crt-1 gene Proteins 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 112
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 68
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 54
- 239000000243 solution Substances 0.000 description 50
- 238000002360 preparation method Methods 0.000 description 45
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 38
- 235000019439 ethyl acetate Nutrition 0.000 description 38
- 239000002904 solvent Substances 0.000 description 34
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 29
- 239000000741 silica gel Substances 0.000 description 25
- 229910002027 silica gel Inorganic materials 0.000 description 25
- 238000005481 NMR spectroscopy Methods 0.000 description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 22
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 20
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- 230000001965 increasing effect Effects 0.000 description 18
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 238000003556 assay Methods 0.000 description 15
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 15
- 101150041968 CDC13 gene Proteins 0.000 description 14
- 238000003818 flash chromatography Methods 0.000 description 14
- 239000003921 oil Substances 0.000 description 13
- 235000019198 oils Nutrition 0.000 description 13
- 239000012896 selective serotonin reuptake inhibitor Substances 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 230000000694 effects Effects 0.000 description 11
- 238000010079 rubber tapping Methods 0.000 description 11
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 11
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- 230000036506 anxiety Effects 0.000 description 10
- 239000012267 brine Substances 0.000 description 10
- 235000019341 magnesium sulphate Nutrition 0.000 description 10
- 229910052757 nitrogen Inorganic materials 0.000 description 10
- 208000019906 panic disease Diseases 0.000 description 10
- 239000003826 tablet Substances 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- 241000699694 Gerbillinae Species 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- 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 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 241001465754 Metazoa Species 0.000 description 8
- 102100024304 Protachykinin-1 Human genes 0.000 description 8
- 210000002683 foot Anatomy 0.000 description 8
- 239000010410 layer Substances 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 7
- 101800003906 Substance P Proteins 0.000 description 7
- 230000009471 action Effects 0.000 description 7
- 230000027455 binding Effects 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 6
- 206010033664 Panic attack Diseases 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000004587 chromatography analysis Methods 0.000 description 6
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 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
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 5
- 206010002091 Anaesthesia Diseases 0.000 description 5
- 229920002261 Corn starch Polymers 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- 238000001949 anaesthesia Methods 0.000 description 5
- 230000037005 anaesthesia Effects 0.000 description 5
- 230000000949 anxiolytic effect Effects 0.000 description 5
- 239000008120 corn starch Substances 0.000 description 5
- 238000002955 isolation Methods 0.000 description 5
- GQNMAZUQZDEAFI-UHFFFAOYSA-N lithium;1h-naphthalen-1-ide Chemical compound [Li+].[C-]1=CC=CC2=CC=CC=C21 GQNMAZUQZDEAFI-UHFFFAOYSA-N 0.000 description 5
- 239000006187 pill Substances 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 241000700199 Cavia porcellus Species 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 206010047700 Vomiting Diseases 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 230000005587 bubbling Effects 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 229940090044 injection Drugs 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 239000000018 receptor agonist Substances 0.000 description 4
- 229940044601 receptor agonist Drugs 0.000 description 4
- 230000004044 response Effects 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- ZXSQEZNORDWBGZ-UHFFFAOYSA-N 1,3-dihydropyrrolo[2,3-b]pyridin-2-one Chemical compound C1=CN=C2NC(=O)CC2=C1 ZXSQEZNORDWBGZ-UHFFFAOYSA-N 0.000 description 3
- WDRJNKMAZMEYOF-UHFFFAOYSA-N 4-(trifluoromethoxy)phenol Chemical compound OC1=CC=C(OC(F)(F)F)C=C1 WDRJNKMAZMEYOF-UHFFFAOYSA-N 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
- 206010028813 Nausea Diseases 0.000 description 3
- 230000002411 adverse Effects 0.000 description 3
- 239000000556 agonist Substances 0.000 description 3
- 230000002238 attenuated effect Effects 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 210000003169 central nervous system Anatomy 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
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 208000035475 disorder Diseases 0.000 description 3
- 208000002173 dizziness Diseases 0.000 description 3
- 210000004731 jugular vein Anatomy 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 229910052744 lithium Inorganic materials 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 230000008693 nausea Effects 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 3
- 238000002203 pretreatment Methods 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
- 229910001958 silver carbonate Inorganic materials 0.000 description 3
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 description 3
- 235000012431 wafers Nutrition 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- AYRKHOMHAFKXFZ-UHFFFAOYSA-N (1-iodocyclopropyl)sulfanylbenzene Chemical compound C=1C=CC=CC=1SC1(I)CC1 AYRKHOMHAFKXFZ-UHFFFAOYSA-N 0.000 description 2
- YHSCBQZMCFSTGL-UHFFFAOYSA-N 2-bromo-4-(trifluoromethoxy)phenol Chemical compound OC1=CC=C(OC(F)(F)F)C=C1Br YHSCBQZMCFSTGL-UHFFFAOYSA-N 0.000 description 2
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 2
- 206010010219 Compulsions Diseases 0.000 description 2
- 206010013975 Dyspnoeas Diseases 0.000 description 2
- 208000010201 Exanthema Diseases 0.000 description 2
- 102000020897 Formins Human genes 0.000 description 2
- 108091022623 Formins Proteins 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
- 206010019233 Headaches Diseases 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
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- 208000008454 Hyperhidrosis Diseases 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-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
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- 206010029897 Obsessive thoughts Diseases 0.000 description 2
- 208000021384 Obsessive-Compulsive disease Diseases 0.000 description 2
- 108010079943 Pentagastrin Proteins 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 201000001880 Sexual dysfunction Diseases 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 208000001871 Tachycardia Diseases 0.000 description 2
- 206010044565 Tremor Diseases 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 208000021017 Weight Gain Diseases 0.000 description 2
- 208000027418 Wounds and injury Diseases 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 230000003444 anaesthetic effect Effects 0.000 description 2
- 230000001430 anti-depressive effect Effects 0.000 description 2
- 239000000935 antidepressant agent Substances 0.000 description 2
- 229940005513 antidepressants Drugs 0.000 description 2
- 230000000338 anxiogenic effect Effects 0.000 description 2
- 229940005530 anxiolytics Drugs 0.000 description 2
- 239000007900 aqueous suspension Substances 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 2
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 2
- 229910002091 carbon monoxide Inorganic materials 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- ZPUCINDJVBIVPJ-LJISPDSOSA-N cocaine Chemical compound O([C@H]1C[C@@H]2CC[C@@H](N2C)[C@H]1C(=O)OC)C(=O)C1=CC=CC=C1 ZPUCINDJVBIVPJ-LJISPDSOSA-N 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- 230000006735 deficit Effects 0.000 description 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 2
- 230000009429 distress Effects 0.000 description 2
- 206010013781 dry mouth Diseases 0.000 description 2
- 239000012055 enteric layer Substances 0.000 description 2
- 201000005884 exanthem Diseases 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
- 231100000869 headache Toxicity 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 208000014674 injury Diseases 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 239000002742 neurokinin 1 receptor antagonist Substances 0.000 description 2
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 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
- 229960000444 pentagastrin Drugs 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 2
- WFIZEGIEIOHZCP-UHFFFAOYSA-M potassium formate Chemical compound [K+].[O-]C=O WFIZEGIEIOHZCP-UHFFFAOYSA-M 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 206010037844 rash Diseases 0.000 description 2
- 230000000306 recurrent effect Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 210000004761 scalp Anatomy 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 231100000872 sexual dysfunction Toxicity 0.000 description 2
- 230000035939 shock Effects 0.000 description 2
- 231100000046 skin rash Toxicity 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 2
- 235000019345 sodium thiosulphate Nutrition 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 230000035900 sweating Effects 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 230000006794 tachycardia Effects 0.000 description 2
- GUERJXXMFLJFMZ-AWEZNQCLSA-N tert-butyl (2s)-3-oxo-2-phenylpiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCC(=O)[C@@H]1C1=CC=CC=C1 GUERJXXMFLJFMZ-AWEZNQCLSA-N 0.000 description 2
- ATJRDIDZQTXJLY-KBPBESRZSA-N tert-butyl (2s,3s)-3-hydroxy-2-phenylpiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC[C@H](O)[C@@H]1C1=CC=CC=C1 ATJRDIDZQTXJLY-KBPBESRZSA-N 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 238000002560 therapeutic procedure Methods 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
- 230000008673 vomiting Effects 0.000 description 2
- 230000004584 weight gain Effects 0.000 description 2
- 235000019786 weight gain Nutrition 0.000 description 2
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 2
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- 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
- UEXKTMCOJRYCCT-PDIWNELESA-N (3r,5r,10s)-3-[2-cyclopropyloxy-5-(trifluoromethoxy)phenyl]-10-phenyl-1-oxa-9-azaspiro[4.5]decane Chemical compound C1([C@H]2C[C@@]3(OC2)[C@@H](NCCC3)C=2C=CC=CC=2)=CC(OC(F)(F)F)=CC=C1OC1CC1 UEXKTMCOJRYCCT-PDIWNELESA-N 0.000 description 1
- UEXKTMCOJRYCCT-MQNAVGNWSA-N (3s,5r,10s)-3-[2-cyclopropyloxy-5-(trifluoromethoxy)phenyl]-10-phenyl-1-oxa-9-azaspiro[4.5]decane Chemical compound C1([C@@H]2C[C@@]3(OC2)[C@@H](NCCC3)C=2C=CC=CC=2)=CC(OC(F)(F)F)=CC=C1OC1CC1 UEXKTMCOJRYCCT-MQNAVGNWSA-N 0.000 description 1
- WGFINUQQGVRTMJ-UHFFFAOYSA-N 1-hydroxy-3-[2-(phenoxymethyl)prop-2-enyl]-2-phenylpiperidine Chemical compound ON1C(C(CCC1)CC(COC1=CC=CC=C1)=C)C1=CC=CC=C1 WGFINUQQGVRTMJ-UHFFFAOYSA-N 0.000 description 1
- DLBIMYYCJAYTRS-UHFFFAOYSA-N 1-phenylmethoxy-4-(trifluoromethoxy)benzene Chemical compound C1=CC(OC(F)(F)F)=CC=C1OCC1=CC=CC=C1 DLBIMYYCJAYTRS-UHFFFAOYSA-N 0.000 description 1
- SGOQKRLQZLARAS-UHFFFAOYSA-N 2-(1-phenylsulfanylcyclopropyl)oxy-5-(trifluoromethoxy)benzaldehyde Chemical compound O=CC1=CC(OC(F)(F)F)=CC=C1OC1(SC=2C=CC=CC=2)CC1 SGOQKRLQZLARAS-UHFFFAOYSA-N 0.000 description 1
- FNRMMDCDHWCQTH-UHFFFAOYSA-N 2-chloropyridine;3-chloropyridine;4-chloropyridine Chemical compound ClC1=CC=NC=C1.ClC1=CC=CN=C1.ClC1=CC=CC=N1 FNRMMDCDHWCQTH-UHFFFAOYSA-N 0.000 description 1
- IADHRFAXAKFKJY-UHFFFAOYSA-N 2-iodo-1-phenylmethoxy-4-(trifluoromethoxy)benzene Chemical compound IC1=CC(OC(F)(F)F)=CC=C1OCC1=CC=CC=C1 IADHRFAXAKFKJY-UHFFFAOYSA-N 0.000 description 1
- ZCFQNFVODXNNOQ-UHFFFAOYSA-N 2-nitro-1-(1-phenylsulfanylcyclopropyl)oxy-4-(trifluoromethoxy)benzene Chemical compound [O-][N+](=O)C1=CC(OC(F)(F)F)=CC=C1OC1(SC=2C=CC=CC=2)CC1 ZCFQNFVODXNNOQ-UHFFFAOYSA-N 0.000 description 1
- WKQYNORESROFLZ-UHFFFAOYSA-N 2-phenylmethoxy-5-(trifluoromethoxy)phenol Chemical compound OC1=CC(OC(F)(F)F)=CC=C1OCC1=CC=CC=C1 WKQYNORESROFLZ-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
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 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
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 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
- RDHCTRIFDGGIAM-UHFFFAOYSA-M Cl[Mg]CC(=C)COC1=CC=CC=C1 Chemical compound Cl[Mg]CC(=C)COC1=CC=CC=C1 RDHCTRIFDGGIAM-UHFFFAOYSA-M 0.000 description 1
- 208000028698 Cognitive impairment Diseases 0.000 description 1
- 229940126062 Compound A Drugs 0.000 description 1
- 206010010774 Constipation Diseases 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
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 1
- 208000000059 Dyspnea Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 102100021260 Galactosylgalactosylxylosylprotein 3-beta-glucuronosyltransferase 1 Human genes 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 208000010412 Glaucoma Diseases 0.000 description 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 1
- 241000238631 Hexapoda Species 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
- 206010020400 Hostility 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
- 206010022998 Irritability Diseases 0.000 description 1
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 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
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 240000007472 Leucaena leucocephala Species 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
- 241000699684 Meriones unguiculatus Species 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 206010029216 Nervousness Diseases 0.000 description 1
- 108090000189 Neuropeptides Proteins 0.000 description 1
- 235000019502 Orange oil Nutrition 0.000 description 1
- 206010031127 Orthostatic hypotension Diseases 0.000 description 1
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 1
- 206010033557 Palpitations Diseases 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 229920005439 Perspex® Polymers 0.000 description 1
- 201000007100 Pharyngitis Diseases 0.000 description 1
- 229920002873 Polyethylenimine Polymers 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 102000056251 Prolyl Oligopeptidases Human genes 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
- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- 108091006629 SLC13A2 Proteins 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 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
- 206010046555 Urinary retention Diseases 0.000 description 1
- 208000012886 Vertigo Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 229940081735 acetylcellulose Drugs 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 208000012826 adjustment disease Diseases 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
- KRMDCWKBEZIMAB-UHFFFAOYSA-N amitriptyline Chemical compound C1CC2=CC=CC=C2C(=CCCN(C)C)C2=CC=CC=C21 KRMDCWKBEZIMAB-UHFFFAOYSA-N 0.000 description 1
- 229960000836 amitriptyline Drugs 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000000049 anti-anxiety effect Effects 0.000 description 1
- 230000001078 anti-cholinergic effect Effects 0.000 description 1
- 230000000561 anti-psychotic effect Effects 0.000 description 1
- 239000000164 antipsychotic agent Substances 0.000 description 1
- 230000036528 appetite Effects 0.000 description 1
- 235000019789 appetite Nutrition 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution 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
- 230000008901 benefit Effects 0.000 description 1
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 1
- 229960001948 caffeine Drugs 0.000 description 1
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 210000004289 cerebral ventricle Anatomy 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 210000004978 chinese hamster ovary cell Anatomy 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
- 229960003920 cocaine Drugs 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 208000010877 cognitive disease Diseases 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- 239000013058 crude material Substances 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- GVRWIAHBVAYKIZ-UHFFFAOYSA-N dec-3-ene Chemical compound CCCCCCC=CCC GVRWIAHBVAYKIZ-UHFFFAOYSA-N 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 230000001627 detrimental 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
- LTYMSROWYAPPGB-UHFFFAOYSA-N diphenyl sulfide Chemical compound C=1C=CC=CC=1SC1=CC=CC=C1 LTYMSROWYAPPGB-UHFFFAOYSA-N 0.000 description 1
- UZUODNWWWUQRIR-UHFFFAOYSA-L disodium;3-aminonaphthalene-1,5-disulfonate Chemical compound [Na+].[Na+].C1=CC=C(S([O-])(=O)=O)C2=CC(N)=CC(S([O-])(=O)=O)=C21 UZUODNWWWUQRIR-UHFFFAOYSA-L 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
- 238000004821 distillation Methods 0.000 description 1
- 210000001198 duodenum Anatomy 0.000 description 1
- 201000006549 dyspepsia Diseases 0.000 description 1
- 239000008157 edible vegetable oil Substances 0.000 description 1
- 230000008451 emotion Effects 0.000 description 1
- 230000002996 emotional effect Effects 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
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- FCZCIXQGZOUIDN-UHFFFAOYSA-N ethyl 2-diethoxyphosphinothioyloxyacetate Chemical compound CCOC(=O)COP(=S)(OCC)OCC FCZCIXQGZOUIDN-UHFFFAOYSA-N 0.000 description 1
- 230000000763 evoking effect Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000020375 flavoured syrup Nutrition 0.000 description 1
- 125000001207 fluorophenyl group Chemical group 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 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
- 239000000380 hallucinogen Substances 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
- 238000010438 heat treatment Methods 0.000 description 1
- 210000000548 hind-foot Anatomy 0.000 description 1
- 239000008240 homogeneous mixture Substances 0.000 description 1
- UJAICWUNNPDCPV-UHFFFAOYSA-N hydron;2,2,2-trifluoroacetic acid;chloride Chemical compound Cl.OC(=O)C(F)(F)F UJAICWUNNPDCPV-UHFFFAOYSA-N 0.000 description 1
- 239000003326 hypnotic agent Substances 0.000 description 1
- 230000000147 hypnotic effect Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 206010022437 insomnia Diseases 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052742 iron Inorganic materials 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
- 208000013433 lightheadedness Diseases 0.000 description 1
- 239000011981 lindlar catalyst Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 1
- 229910052808 lithium carbonate Inorganic materials 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
- 240000004308 marijuana Species 0.000 description 1
- 230000008774 maternal effect Effects 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- CWWARWOPSKGELM-SARDKLJWSA-N methyl (2s)-2-[[(2s)-2-[[2-[[(2s)-2-[[(2s)-2-[[(2s)-5-amino-2-[[(2s)-5-amino-2-[[(2s)-1-[(2s)-6-amino-2-[[(2s)-1-[(2s)-2-amino-5-(diaminomethylideneamino)pentanoyl]pyrrolidine-2-carbonyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-5 Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)OC)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 CWWARWOPSKGELM-SARDKLJWSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 238000004264 monolayer culture Methods 0.000 description 1
- 229920001206 natural gum Polymers 0.000 description 1
- MAJZZCVHPGUSPM-UHFFFAOYSA-N nitric acid nonahydrate Chemical compound O.O.O.O.O.O.O.O.O.O[N+]([O-])=O MAJZZCVHPGUSPM-UHFFFAOYSA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000012053 oil suspension Substances 0.000 description 1
- 239000008203 oral pharmaceutical composition Substances 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 1
- UQPUONNXJVWHRM-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 UQPUONNXJVWHRM-UHFFFAOYSA-N 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 239000000312 peanut oil Substances 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
- 230000002085 persistent effect Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000008024 pharmaceutical diluent Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- JTJMJGYZQZDUJJ-UHFFFAOYSA-N phencyclidine Chemical compound C1CCCCN1C1(C=2C=CC=CC=2)CCCCC1 JTJMJGYZQZDUJJ-UHFFFAOYSA-N 0.000 description 1
- 229950010883 phencyclidine Drugs 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
- 208000019899 phobic disease Diseases 0.000 description 1
- 239000004926 polymethyl methacrylate Substances 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000011698 potassium fluoride Substances 0.000 description 1
- 235000003270 potassium fluoride Nutrition 0.000 description 1
- 238000009117 preventive therapy Methods 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
- 230000000506 psychotropic effect Effects 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 239000002287 radioligand Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001525 receptor binding assay Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 229940125723 sedative agent Drugs 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 230000036299 sexual function Effects 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 238000005055 short column chromatography Methods 0.000 description 1
- 208000013220 shortness of breath Diseases 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- KZJPVUDYAMEDRM-UHFFFAOYSA-M silver;2,2,2-trifluoroacetate Chemical compound [Ag+].[O-]C(=O)C(F)(F)F KZJPVUDYAMEDRM-UHFFFAOYSA-M 0.000 description 1
- 210000003625 skull Anatomy 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 230000009870 specific binding Effects 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
- 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
- ARXGVDVGCGMLCC-BXGUEYFKSA-N tert-butyl (3S,5R,6S)-3-[2-cyclopropyloxy-5-(trifluoromethoxy)phenyl]-6-phenyl-1-oxa-2-azaspiro[4.5]decane-7-carboxylate Chemical compound C1(CC1)OC1=C(C=C(C=C1)OC(F)(F)F)[C@H]1NO[C@]2(C1)[C@@H](C(CCC2)C(=O)OC(C)(C)C)C1=CC=CC=C1 ARXGVDVGCGMLCC-BXGUEYFKSA-N 0.000 description 1
- RGBZNSHFKOQNCI-NBOJAAIQSA-N tert-butyl (3S,5R,6S)-3-[2-hydroxy-5-(trifluoromethoxy)phenyl]-6-phenyl-1-oxa-2-azaspiro[4.5]decane-7-carboxylate Chemical compound OC1=C(C=C(C=C1)OC(F)(F)F)[C@H]1NO[C@]2(C1)[C@@H](C(CCC2)C(=O)OC(C)(C)C)C1=CC=CC=C1 RGBZNSHFKOQNCI-NBOJAAIQSA-N 0.000 description 1
- MKACAKSUUOUFGX-HMEKMZBJSA-N tert-butyl (5R,6S)-3-methylidene-6-phenyl-1-oxa-2-azaspiro[4.5]decane-7-carboxylate Chemical compound C=C1NO[C@]2(C1)[C@@H](C(CCC2)C(=O)OC(C)(C)C)C1=CC=CC=C1 MKACAKSUUOUFGX-HMEKMZBJSA-N 0.000 description 1
- RUEDMIBYWRAPIB-JDQGPONISA-N tert-butyl (5R,6S)-3-oxo-6-phenyl-1-oxa-2-azaspiro[4.5]decane-7-carboxylate Chemical compound O=C1NO[C@]2(C1)[C@@H](C(CCC2)C(=O)OC(C)(C)C)C1=CC=CC=C1 RUEDMIBYWRAPIB-JDQGPONISA-N 0.000 description 1
- XPHRVHAQGUFKSQ-JTTKYZAMSA-N tert-butyl (5R,6S)-6-phenyl-3-trimethylstannyl-1-oxa-2-azaspiro[4.5]dec-3-ene-7-carboxylate Chemical compound C[Sn](C=1NO[C@@]2(C=1)[C@@H](C(CCC2)C(=O)OC(C)(C)C)C1=CC=CC=C1)(C)C XPHRVHAQGUFKSQ-JTTKYZAMSA-N 0.000 description 1
- GUERJXXMFLJFMZ-UHFFFAOYSA-N tert-butyl 3-oxo-2-phenylpiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCC(=O)C1C1=CC=CC=C1 GUERJXXMFLJFMZ-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- DBGVGMSCBYYSLD-UHFFFAOYSA-N tributylstannane Chemical compound CCCC[SnH](CCCC)CCCC DBGVGMSCBYYSLD-UHFFFAOYSA-N 0.000 description 1
- ZZRPJWCNCLSOLR-UHFFFAOYSA-N trimethyl(prop-2-ynoxy)silane Chemical compound C[Si](C)(C)OCC#C ZZRPJWCNCLSOLR-UHFFFAOYSA-N 0.000 description 1
- CCRMAATUKBYMPA-UHFFFAOYSA-N trimethyltin Chemical compound C[Sn](C)C.C[Sn](C)C CCRMAATUKBYMPA-UHFFFAOYSA-N 0.000 description 1
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 1
- 231100000889 vertigo Toxicity 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 210000004916 vomit Anatomy 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 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
-
- 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
- A61K31/66—Phosphorus compounds
- A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/438—The ring being spiro-condensed with carbocyclic or heterocyclic ring systems
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
-
- 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
-
- 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
-
- 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
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/56—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Description
1 I. 1 WO 98/24439 1 PCT/EP97/06683 USE OF NK-1 RECEPTOR ANTAGONISTS FOR TREATING SEVERE ANXIETY DISORDERS This invention relates to the treatment or prevention of certain anxiety disorders by the administration of a specific class of NK-1 receptor antagonists.
Anxiety is an emotional condition characterised by feelings such as apprehension and fear accompanied by physical symptoms such as tachycardia, increased respiration, sweating and tremor. It is a normal emotion but when it is severe and disabling it becomes pathological.
Anxiety disorders are generally treated using benzodiazepine sedative-antianxiety agents. Potent benzodiazepines should not be prescribed for more than 3 or 4 weeks, however, due to the risks associated with drug dependency. Tricyclic antidepressants (TCAs) such as amitriptyline which have both anxiolytic and antidepressant actions may also be used. 5-HTIA receptor agonists and antagonists may also have useful anxiolytic and other psychotropic activity (see R. J. Baldessarini in Goodman Gilman's The Pharmacological Basis of Therapeutics, 9th Edition, Chapter 18, McGraw-Hill, 1996 for a review). Selective serotonin reuptake inhibitors (SSRIs) are also widely prescribed for the treatment of anxiety.
Apart from the risks of drug dependency, benzodiazepines are also associated with a number of side-effects including increased hostility and irritability, vivid or disturbing dreams, weight gain, skin rash, nausea, headache, impairment of sexual function, vertigo, and lightheadedness.
Difficulties may also arise with the use of tricyclic antidepressants, in particular, due to their anticholinergic side-effects which are particularly troublesome in patients with prostatic enlargement or glaucoma. Other side-effects of tricyclic antidepressants include dry mouth, tachycardia, difficulty in visual accomodation, constipation, urinary retention, sexual dysfunction, cognitive impairment, postural hypotension, and weight gain.
I. Iw, (I WO 98/24439 PCT/EP97/06683 SSRIs are not without their own side-effects, including nausea, diarrhoea, dry mouth, reduced appetite, dyspepsia, vomiting, headache, nervousness, insomnia, anxiety, tremour, dizziness, fatigue, decreased libido, pharyngitis, dyspnoea, skin rash and sexual dysfunction.
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 implicated 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).
On the other hand, European Patent Specification No. 0 286 928 describes inhibitors of the enzyme prolyl-endopeptidase, which enzyme degrades neuropeptides such as substance P, the enzyme inhibitors having an antipsychotic, anxiolytic and antidepressant action. Thus, degrading substance P or reducing the action of substance P in some other way (e.g.
antagonism at its preferred NK-1 receptor) might be expected to be detrimental to the treatment of anxiety.
More recently, International (PCT) patent specification No. WO 96/24353 (published 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 a regimen would not be free of side-effects due to the serotonin agonist or SSRI.
NK-1 receptor antagonists are described in published European Patent Specification Nos. 0 360 390, 0 394 989, 0 429 366, 0 443 132, 0 482 539, 0 512 901, 0 512 902, 0 514 273, 0 514 275, 0 517 589, 0 520 555, 0 522 808, 0 528 495, 0 532 456, 0 533 280, 0 536 817, 0 545 478, 0 577 394, 0 590 152, 0 599 538, 0 610 793, 0 634 402, 0 686 629, 0 693 489, 0 694 535, 0 699 655, 0 699 674, 0 707 006, 0 708 101, 0 714 891, 0 723 959, 0 733 632 and 0 776 893; and in International Patent Specification Nos. 90/05525, 90/05729, 91/09844, 91/18899, 92/01688, 92/06079, 92/12151, 92/15585, 92/17449, 92/20661, 92/20676, 92/21677, 93/00330, 93/00331, 93/01159, 93/01165, 93/01169, 93/01170, 93/06099, 93/10073, 93/14113, 93/18023, 93/19064, 93/21155, 93/23380, 93/24465, 94/01402, 94/02461, 94/03429, 94/03445, 94/04494, 94/04496, 94/05625, 94/07843, 94/10165, 94/10167, 94/10168, 94/10170, 94/11368, 94/13639, 94/13663, 94/14767, 94/15903, 94/19320, 94/19323, 94/20500, 94/26735, 94/26740, 94/29309, 95/02595, 95/04040, 95/04042, 95/06645, 95/07886, 95/07908, 95/08549, 95/11880, 95/14017, 95/153 11, 95/16679, 95/17382, 95/18124, 95/18129, 95/19344, 95/20575, 95/21819, 96/22525, 95/23798, 95/26338, 95/28418, 95/30674, 95/30687, 96/05193, 96/05203, 96/06094, 96/07649, 96/10562, 96/16939, 96/18643, 96/20197, 96/21661, 96/29304, 96/29317, 96/29326, 96/29328, 96/31214, 96/32835, 96/37489, 97/01553, 97/01554, 97/03066, 97/08144, V. 97/14671, 97/17362, 97/18206, 97/19084, 97/19942 and 97/21702; and in British Patent Specifications Nos. 2 266 529, 2 268 931, 2 269 170, 2 269 590, 2 271 774, 2 292 144, 2 15 293 168, 2293 169, and 2302 689.
In view of the short-comings of existing anti-anxiety therapy, there is a need for new, safe and effective treatment of severe anxiety disorders.
The present invention provides the use of a CNS penetrant NK-1 receptor antagonist in an oral, once-a-day medicament for the treatment of severe anxiety disorder(s) selected from agoraphobia, specific phobia and social phobia ("severe anxiety disorders"). The compounds of this class advantageously exhibit a rapid onset of action and a reduced side-effect profile when compared against conventional anxiolytic agents.
In particular, the present invention provides a means for the identification of NK-1I receptor antagonists which would be effective in an oral once-a-day medicament for the treatment of severe anxiety disorders. The aforementioned patent specifications which describe NK-1 receptor antagonists provide no reliable method for the identification of such compounds.
[RA\UBAA]&435.doc:nixl WO 98/24439 PC'T/E P97/06683' WO 98/24439 4 1r The exceptional pharmacology of the class of NK-1 receptor antagonists of use in the present invention enables the treatment of severe anxiety disorders, without the need for concomitant therapy using benzodiazepines or tricyclic antidepressants or, in particular, without the need for concomitant use of a serotonin agonist or antagonist or an SSRI.
Furthermore, the exceptional pharmacology of the class of NK-1 receptor antagonists of use in the present invention results in a rapid onset of action.
The present invention accordingly provides the use of an orally active, long acting, CNS-penetrant NK-1 receptor antagonist (as hereinafter defined) for the manufacture of a medicament adapted for oral administration for the treatment or prevention of severe anxiety disorders without concomitant therapy with other anti-anxiety agents.
The present invention also provides a method for the treatment or prevention of severe anxiety disorders without concomitant therapy with other anti-anxiety agents, which method comprises the oral administration to a patient in need of such treatment of an effective amount of an orally active, long acting, CNS-penetrant NK-1 receptor antagonist (as hereinafter defined).
In a further aspect of the present invention, there is provided an oral pharmaceutical composition for the treatment of severe anxiety disorders which comprises essentially an orally active, long acting, CNSpenetrant NK-1 receptor antagonist (as hereinafter defined), together with a pharmaceutically acceptable carrier or excipient.
There exists a patient population in whom severe anxiety disorders are inadequately treated with benzodiazepines. Furthermore, some patients may be adversely affected by the side-effects of benzodiazepines.
The present invention accordingly provides the use of an orally active, long acting, CNS-penetrant NK-1 receptor antagonist for the manufacture of a medicament adapted for oral administration for the treatment or prevention of severe anxiety disorders, without concomitant
(I
WO 98/24439 PCT/EP97/06683 therapy with other anti-anxiety agents, in a patient who is non-responsive to benzodiazepines or for whom benzodiazepines are contraindicated.
The present invention also provides a method for the treatment or prevention of severe anxiety disorders, without concomitant therapy with other anti-anxiety agents, in a patient who is non-responsive to benzodiazepines or for whom benzodiazepines are contraindicated, which method comprises oral administration to the patient in need of such treatment of an effective amount of an orally active, long acting, CNSpenetrant NK-1 receptor antagonist.
Furthermore, there exists a patient population in whom severe anxiety disorders are inadequately treated with tricyclic antidepressants.
Furthermore, some patients may be adversely affected by the side-effects of tricyclic antidepressants.
The present invention accordingly provides the use of an orally active, long acting, CNS-penetrant NK-1 receptor antagonist for the manufacture of a medicament adapted for oral administration for the treatment or prevention of severe anxiety disorders, without concomitant therapy with other anti-anxiety agents, in a patient who is non-responsive to tricyclic antidepressants or for whom tricyclic antidepressants are contraindicated.
The present invention also provides a method for the treatment or prevention of severe anxiety disorders, without concomitant therapy with other anti-anxiety agents, in a patient who is non-responsive to tricyclic antidepressants or for whom tricyclic antidepressants are contraindicated, which method comprises oral administration to the patient in need of such treatment of an effective amount of an orally active, long acting, CNSpenetrant NK-1 receptor antagonist.
Furthermore, there exists a patient population in whom severe anxiety disorders are inadequately treated with SSRIs or serotonin agonists or antagonists. Furthermore, some patients may be adversely affected by the side-effects of SSRIs or serotonin agonists or antagonists.
t D WO 98/24439 PCT/IEP97/06683 The present invention accordingly provides the use of an orally active, long acting, CNS-penetrant NK-1 receptor antagonist for the manufacture of a medicament adapted for oral administration for the treatment or prevention of severe anxiety disorders, without concomitant therapy with other anti-anxiety agents, in a patient who is non-responsive to SSRIs or serotonin agonists or antagonists or for whom SSRIs or serotonin agonists or antagonists are contraindicated.
The present invention also provides a method for the treatment or prevention of severe anxiety disorders, without concomitant therapy with other anti-anxiety agents, in the patient who is non-responsive to SSRIs or serotonin agonists or antagonists or for whom SSRIs or serotonin agonists or antagonists are contraindicated, which method comprises oral administration to the patient in need of such treatment of an effective amount of an orally active, long acting, CNS-penetrant NK-1 receptor antagonist.
As used herein, the term "non-responsive" in relation to severe anxiety disorders means patients who have not had a reasonable clinical response a 50% reduction in Hamilton Anxiety Scale (HAM-A) from a patient's baseline score after treatment with one or more clinical courses of conventional anxiolytics).
As used herein, the term "severe anxiety disorders" includes panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, specific phobias, social phobias and obsessive-compulsive disorder.
"Panic disorder" is defined as the presence of recurrent panic attacks followed by at least one month of persistent concern about having another panic attack. A "panic attack" is a discrete period in which there is a sudden onset of intense apprehension, fearfulness or terror. During a panic attack, the individual may experience a variety of symptoms including palpitations, sweating, trembling, shortness of breath, chest WO 98/24439 PCTIEP97/016683 WO 9824439PCT/EP97/06683 -7pain, nausea and dizziness. Panic disorder may occur with or without agoraphobia.
"Phobias" includes agoraphobia, specific phobias and social phobias.
"Agoraphobia" is characterised by an anxiety about being in places or situations from which escape might be difficult or embarrassing or in which help may not be available in the event of a panic attack.
Agoraphobia may occur without history of a panic attack. A "specific phobia" is characterised by clinically significant anxiety provoked by exposure to a specific feared object or situation. Specific phobias include the following subtypes: animal type, cued by animals or insects; natural environment type, cued by objects in the natural environment, for example storms, heights or water; blood-injection-injury type, cued by the sight of blood or an injury or by seeing or receiving an injection or other invasive medical procedure; situational type, cued by a specific situation such as public transportation, tunnels, bridges, elevators, flying, driving or enclosed spaces; and other type where fear is cued by other stimuli.
Specific phobias may also be referred to as simple phobias. A "social phobia" is characterised by clinically significant anxiety provoked by exposure to certain types of social or performance circumstances. Social phobia may also be referred to as social anxiety disorder.
"Obsessive-compulsive disorder is characterised by recurrent obsessions or compulsions that are severe enough to be time consuming they take at least one hour a day) or cause marked distress or significant impairment. At some point during the course of the disorder, the patient should recognise that the obsessions or compulsions are excessive or unreasonable.
Other anxiety disorders encompassed within the term "severe anxiety disorders" include anxiety disorders induced by alcohol, amphetamines, caffeine, cannabis, cocaine, hallucinogens, inhalants, phencyclidine, sedatives, hypnotics, anxiolytics and other substances, and adjustment disorders with anxiety.
WA QRI2dd~O -8- As used herein, the term "treatment" refers both to the treatment and to the prevention or prophylactic therapy of the aforementioned conditions.
Preferred NK-1 receptor antagonists for use in the present invention are selected from the classes of compounds described in European Patent Specification No. 0 577 394, and International Patent Specification Nos. 95/08549, 95/18124, 95/23798 and 96/05181, and International Patent Application No. P CT/GB97/0 1630. The preparation of such compounds is fully described in the aforementioned publications.
Particularly preferred NK-1 receptor antagonists of use in the present invention include: 5-bis(trifluoromethyl)benzyloxy)-3(S)-(4-fluorophenyl) 1H,4H- 1,2, 4-triazolo)methyl)morpholine; 5-bis(trifluoromethyl)phenyl)ethoxy)-4-(3-(5-oxo- 1H, 4H- 1,2,4-triazolo)methyl)-3-(S)-phenyl-morpholine; 5-bis(trifluoromethyl)benzyloxy)-4-(3-(5-oxo- 1H, 4H- 1,2,4triazolo)methyl) (S)-phenyl-morpholine; 2- 5-bis(trifluoromethyl)phenyl)ethoxy)-3- (4-fluorophenyl).
4-(3-(5-oxo- 1H, 4H- 1, 2,4-triazolo)methyl)morpholine; 5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(N,
N-
dimethylamino)methyl- 1,2, 3-triazol-4-yl)methyl- henylmorpholine; ,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(N,N.
dimethylamino)methyl- 1,2, 3-triazol-4-yl)methyl-3-(S)- (4fluorophenyl)morpholine; 2- 5-bis (trifluoromethyl)phenyl)ethoxy)- 3- -(4-fluorophenyl) 4- (3-(4-monophosphoryl. 5-oxo-l1H- 1,2, 4-triazolo)methyl)morpholine; 5-bis(trifluoromethyl)phenyl)ethoxy)- 3 -(S)-(4-fluorophenyl) -monophosphoryl-5-oxo- 1H- 1,2, 4-triazolO)methyl)morpholine; 5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4.fluorophenyl).
4-(3-(2-monophosphoryl-5-oxo- 1H- 1,2, 4-triazolo)methyl)morpholine; WO 98/24439 PCT/l.PO'7/n683 -9- (1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)- 4-(3-(5-oxyphosphoryl- 1H- 1,2,4-triazolo)methyl)morpholine; 2-(S)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)- 4-(3-(1-monophosphoryl-5-oxo-4H-1,2,4-triazolo)methyl)morpholine; 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-N,Ndimethylaminobut-2-yn-yl)-3-(S)-(4-fluorophenyl)morpholine; (3S,5R,6S)-3- [2-cyclopropoxy-5-(trifluoromethoxy)phenyl]-6-phenyl- 1-oxa- 7-aza-spiro[4.5]decane; (3R,5R,6S)-3-[2-cyclopropoxy-5-(trifluoromethoxy)phenyl]-6-phenyl- 1-oxa- 7-aza-spiro[4.5]decane; or a pharmaceutically acceptable salt thereof.
Full descriptions of the preparation of the NK-1 receptor antagonists which may be employed in the present invention may be found in the references cited herein.
Suitable pharmaceutically acceptable salts of the NK-1 receptor antagonists 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 pharmaceutically 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. Where the compound carries an acidic group, for example a carboxylic acid group, the present invention also contemplates salts thereof, preferably non-toxic pharmaceutically acceptable salts thereof, such as the sodium, potassium and calcium salts thereof.
Preferably the compositions containing an NK-1 receptor antagonist of use according to the present invention are in unit dosage forms such as tablets, pills, capsules, wafers and the like. Additionally, the NK-1 receptor antagonists of use according to the present invention may be presented as granules or powders for extemporaneous formulation as WO 98/24439 PCT/EPQ7/l6K83 10- volume defined solutions or suspensions. Alternatively, the NK-1 receptor antagonists 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 solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a non-toxic pharmaceutically acceptable salt thereof.
When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may bereadily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and Wr O9/24439 PCT/E P97/06683 1 1 flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, peanut oil or soybean oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone 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, pills, capsules or wafers for oral administration are particularly preferred.
A minimum dosage level for the NK-1 receptor antagonist is about 1mg per day, preferably about 5mg per day and especially about 10mg per day. A maximum dosage level for the NK-1 receptor antagonist is about 1500mg per day, preferably about 1000mg per day and especially 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 severe anxiety disorders will 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 will ultimately be at the discretion of the patient's physician or pharmacist.
Two compounds of use in the present invention which are described in International Patent Application No. PCT/GB97/01630 may be prepared according to the following methods: PREPARATION 1 l-tert-Butoxvcarbonvl-2-phenylpiperidin-3-one Dimethyl sulfoxide (20.80ml, 22.90g, 29.3mmol) in dichloromethane was added dropwise to a cooled (-70 0 C) solution of oxalyl chloride WO 98/24439 PCT/E.P07/06683 12- (13.95ml, 2 0.30g, 160mmol) in dichloromethane (350ml). The mixture was stirred at -70 0 C for 15 minutes, then (2S,3S)-l-tert-butoxycarbonyl-3hydroxy-2-phenylpiperidine (prepared by the method described in European Patent Specification number 0 528 495-A; 36.91g, 1 3 3 mmol) in dichloromethane (150ml) was added dropwise. The mixture was stirred at °C for 20 minutes, then allowed to warm to -30°C. The mixture was cooled to -50 °C and triethylamine (55.95ml, 40.45g, 400mmol) was added slowly. The mixture was allowed to warm to 0 C and diluted with icecooled dichloromethane (250ml). The mixture was washed with ice cold aqueous citric acid solution 2x300ml) and water (300ml), dried (MgSO4), and the solvent was evaporated under reduced pressure to give the title compound as a yellow oil (42.3g), which was used immediately without further purification. 'H NMR (250MHz, CDC13) 8 7.5-7.3 (5H, m), 5.8 (1H, br 4.2 (1H, br 3.4 (1H, 2.6 (2H, 2.0 (2H, and 1.54 (9H, s).
PREPARATION 2 (2S,3R)-1-tert-Butoxvcarbonvl-3-hydroxv-3-(2-methylene-3phenoxyvpropvl)-2-phenylpiperidine A solution of 3-(chloromagnesio)-2-(phenoxymethyl)-1-propene in THF (0.91M, 3ml) (Louw et. al., Tetrahedron, 48, 6087-6104, 1992, prepared from 2.74mmol of 3-chloro-2-(phenoxymethyl)-l1-propene) was slowly added to a solution of (2S)-l-tert-butoxycarbonyl-2-phenylpiperidin- 3-one (Preparation 1) in THF (3ml). The mixture was stirred at room temperature for 1 hours, then saturated aqueous ammonium chloride was added and the mixture was extracted with ethyl acetate The organic phase was washed with brine, dried (MgSO4) and the solvent was evaporated under reduced pressure The residue was purified by column chromatography on silica gel, eluting with hexane/ethyl acetate (100:0 increasing to 80:20) to give the title compound. 'H NMR (360MHz, CDC13) 8 7.48 (2H, d, J=6.9 Hz), 7.35-7.2 (6H, 6.9-6.88 (3H, 5.4 WO 98/24439 PCTIVVQ-I/n'<JCQ-1 (1H, 5.15 (2H, d, J=13.7 Hz), 4.61 (2H, 4.11 (2H, in), 3.17 (11H, in), 2.66 and 2.59 (2H, AB d, J=14.0 Hz), 1.95 (2H, in), 1.79 (2H, in), and 1.36 (9H, m/z 424 PREPARATION 3 6S)- 3-Methylene-6-p~henyl-l1-oxa-7- (tert-butoxvcarbonvl)aza.
To a cooled(-80 0 C) solution of (2S,3R)-1-tert-butoxycarbonyl3.
hydroxy- 3-(2-methylene- 3 -phenoxypropyl)-2-phenylpiperidine (Preparation 2, 1.53g, 3.62mmol) in THF (2Oml) was added n-butyl lithium (2.5M in hexanes, 1.45m1, 3.62inmol) followed by a solution of zinc chloride (0.5M in THF, 7.24m1, 3.62minol). The solution was allowed to warm to room temperature and tetrakis (trip he nylphosphine)p alla dium 23g, 0.2mmol) was added. The mixture was degassed with bubbling nitrogen and heated under reflux for 16 hours. The mixture was cooled and the solvent was evaporated under reduced pressure.The residue was partitioned between ethyl acetate and 2M sodium hydroxide. The organic phase was washed with saturated brine, dried (MgSO 4 and purified. by chromatography on a column containing silica gel (eluting with hexane containing increasing proportions of ethyl acetate between 0% to Evaporation of the fractions gave (6S,5R)-3-methyle7ne-6-phenyl-1-oxa-.7- (tert- butoxycarbonyl)aza-spiro[4. 5]decanie. 'H NMR (360MHz, CD Cl 3 6 7.58 (2H, d, J=8.4 Hz), 7.32-7.21 (3H, in), 5.23 (1H, 5.06 (1H, in), 4.97 (1H, in), 4.39 (2H, AB d, J=13.3 Hz), 3.99 (1H, dd, J=13.3, 4.48 Hz), 2. 83 (1H, ABd J=15.5 Hz), 2.7 (1H,td J=12.5, 3.93 Hz), 2.5 (1H, ABd, J=15.4 Hz), 2.15 (2H, td, J=12., .4 Hz), 1.69 (2H, in), and 1.46 mlz (ES+) 329 (M+2H-tBuOCO).
WO 98/24439 PCT/EI'P906683 -14- PREPARATION 4 (5R,6S)-3-Keto-6-phenvl-1-oxa-7-(tert-butoxvcarbonvl)aza-spiro[4.51 decane Through a cooled (-80 solution of (5R, 6 S)-3-methylene-6-phenyl- 1-oxa-7-(tert-butoxycarbonyl)aza-spiro[4.5]decane (Preparation 3; 0.665g) in dichloromethane (5ml) and methanol (5ml) was bubbled a mixture of ozone and oxygen for 45 minutes. After the solution had been purged with nitrogen, dimethyl sulphide (0.5ml) was added and then stirred under nitrogen at room temperature for 16 hours. The solvent was removed in vacuo and the residue partitioned between ethyl acetate and water. The organic phase was dried (MgSO4), evaporated and the residue purified by chromatography on a column containing silica gel (eluting with hexane containing increasing proportions of ethyl acetate between 0% to Evaporation of the fractions gave the title compound. 'H NMR (250MHz, CDC13) 8 7.58 (2H, d, J=6.2 Hz), 7.37-7.26 (3H, 5.3 (1H, 4.15 and 4.09 (2H, AB d, J=17.4 Hz), 3.97 (1H, 2.80. (1H, td, J=12.9, 4.0 Hz), 2.74 and 2.48 (2H, ABd, J=18.1 Hz), 2.29 (2H, 1.88-1.63 (2H, and 1.44 (9H, m/z 332 PREPARATION (5R,6S)-3-Trifluoromethylsulfonyloxy-6-phenyl-l-oxa-7-(tertbutoxvcarbonyl)aza-spiro[4.5]dec-3-ene To a cooled (-80 solution of 1M sodium hexamethyldisilazide (0.38ml, 0.38mmol) in THF was added a solution of (5R,6S)-3-keto-6phenyl-l-oxa-7-(tert-butoxycarbonyl)aza-spiro[4.5]decane (Preparation 4; 0.105mg, 0.319mmol) in THF (3ml). The solution was stirred for 1 hours at -80*C then a solution of chloropyridine (0.163g, 0.415mmol) in THF (3ml) was added. The solution was stirred at -80°C for 30 minutes then at room temperature for minutes before being quenched by addition of saturated ammonium chloride solution and ethyl acetate. The dried (MgSO 4 organic phase was purified by chromatography on a column containing silica gel (eluting with Wn~f hexane containing increasing proportions of ethyl acetate between 0% to Evaporation of the fractions gave the title compound. 'H NMR (360MHz, CDCl 3 5 7.4 (2H, d, J=7.3 Hz), 7.3-7.22 (3H, in), 6.01 (1H, t, J=2.13 Hz), 5.13 (1H, 4.56 and 4.26 (2H, ABdd, J=12.4, 1.97 Hz),4. (1H, dt, J=12.6, 4.22 Hz), 3.00 (1H, in), 2.28-2.04 (2H, in), 1.88-1.76 (2H, in), and 1.37 (9H, inlz 464 PREPARATION 6 6S)-3-Trimethylstannvl-6-phenyl- l-oxa- 7 -(tert-butoxvcarbonyl)azaspiro,4.51dec-3-ene To a de gassed solution of (5R, 68)- 3-trifluoromethylsulfonyloxy-6phenyl- 1-oxa-7-(tert-butoxycarbonyl)aza-spiro 5jdec- 3-ene (Preparation 0.482g, 1.O4mmol), lithium chloride (0.264g, 6.25minol), lithium carbonate (0.076g) and hexamethyl distannane(0.96g, 2.9minol) in THF (l0mi) was added triphenyiphosphine palladium (0.06g). The solution was degassed and then heated at 60'C for 5 hours under nitrogen. Water (20m1) and ethyl acetate (20in1) were added and the dried organic phase was purified by chromatography. on a column containing silica gel (eluting with hexane containing increasing proportions of ethyl acetate between 0% to Evaporation of the fractions gave the title compound as a crystalline solid. 'H NMR (360MHz, CDC1 3 8 7.25 (2H, d, J=7.3 Hz), 7.1- (3H, in), 5.83 (1H, t, J=2.5 Hz), 4.78 (1H, 4.48 and4.02 (2H, dd, J=12.9, 2.3 Hz), 3.96 (1H, dd, J6.16, 13.4 Hz), 2.95 (1H, td, J=13.3, Hz), 1.84 (1H, mn), 1.68 (1H, in), 1.60 (2H, in), 1.19 (9H, and 0.0 (6H, s).
PREPARATION 7 (2831?) tert- Butoxycarbonyl- 3-(3-hydrox-vprop~yn-l 1 l-2-phenylpiperidin- 3-ol O-Trimethylsilylpropargyl alcohol (24.51ml, 20. 47g, 160m1) was added slowly to a cooled solution of ethylinagnesium bromide (IM in tetra hydrofuran, 160in1, l6Oinmol). The mixture was stirred at 0 0 C for
I,;
WO 98/24439 -16- PCT/EP97/06683 minutes, then at room temperature for 2 hours. The mixture was cooled to -10°C and a solution of (2S)-l-tert-butoxycarbonyl-2phenylpiperidin-3-one (Preparation 1; 42.3g) in tetrahydrofuran (200ml) was added dropwise over 30 minutes. (Internal temperature below -5 0
C).
The mixture was stirred at room temperature for 14 hours, poured into water (300ml) and saturated aqueous ammonium chloride (300ml) and extracted with ethyl acetate (2x300ml). The combined organic fractions were washed with brine (300ml), dried (MgSO 4 and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (500ml) and a solution of tetrabutylammonium fluoride (1M in THF, 160ml, 160mmol) was added dropwise. The mixture was stirred at room temperature for 30 minutes, water (300ml) was added, and the layers were separated. The aqueous layer was extracted with ethyl acetate (2x300ml) and the combined organic fractidns were washed with water (300ml) and brine (300ml), dried (MgS04) and the solvent was evaporated under reduced pressure to give the crude title compound as an orange oil (45g). The crude material was purified by flash column chromatography on silica gel, eluting with hexane/ethyl acetate (90:10 increasing to 25:75) to give the title compound as an amber oil (32.2g). 1H NMR (CDC13) 5 7.53-7.55 (2H, 7.19-7.35 (3H, 5.56 (1H, 4.27 (2H, 3.99-4.03 (1H, 3.25 (1H, br 2.77-2.81 (1H, 2.77 (1H, br s), 2.12-2.20 (1H, 1.91-1.99 (2H, 1.77-1.83 (1H, and 1.39 (9H, s).
PREPARATION 8 2-Bromo-4-(trifluoromethoxv)phenol To a cooled (0 solution of 4-trifluoromethoxyphenol (35.6g, 0.2mol) in chloroform (280ml) was added dropwise a solution of bromine (32g, 0.2mol) in chloroform (50ml). The solution was stirred at 0°C for 1 hour and at room temperature for 2 hours. Dichloromethane (200ml) and water (400ml) ware added and the organic phase was washed further with water(400ml), brine (200ml) and dried (MgSO4). The solvent was removed U'9 /I'4AA20 lr r Wl rr lr a f f C- OQu/AA- 17C r IPy/I/uoo663 and the residue was purified by distillation at reduced pressure to give the title compound. 1H NMR (250MHz, CDCl 3 8 7.38 (1H, d, J=2.1 Hz), 7.13 (1H, dd, J=9.1, 2.1 Hz), 7.03 (1H, d, J=9.1 Hz), and 5.53 (1H, s).
PREPARATION 9 2-Bromo-4-(trifluoromethoxy)phenol (Preparation 8; 5g, 2 0mmol) was dissolved in N,N-dimethylformamide (60ml), and potassium carbonate (5.4g, 40mmol) was added, followed by benzyl bromide (3.5ml, and the reaction was stirred at ambient temperature for 15 hours. The reaction was diluted with water (150ml) and extracted into ethyl acetate (3x60ml). The combined organic fractions were washed with water (100ml), brine (100ml), dried (MgS04) and evaporated in vacuo.
Purification on silica, eluting with 2% and 5% ethyl, acetate in hexane gave the title compound as a clear oil (6.7g, IH NMR (250MHz, CDCl 3 8 5.47,(2H, 7.23 (1H, d, J=9 Hz), 7.43 (1H, dd J=8.2, 2.9 Hz), and 7.75 (6H, m).
PREPARATION Z-(2S, 3R)-1-tert-Butoxvcarbonvl-3-(3-hvdroxvprop-1-en-1-vl)-2phenylpiperidin-3-ol Palladium on calcium carbonate, poisoned with lead (Lindlar catalyst, 2g) was added to a solution of (2S,3R)-l-tert-butoxycarbonyl-3-(3hydroxypropyn-lyl)-2-phenylpiperidin-3-ol (Preparation 7; 32g, 96.6mmol) in ethyl acetate (300ml) and the mixture was stirred under hydrogen (1 atmosphere) for 4 hours. The mixture was filtered and the solvent was evaporated under reduced pressure to give the title compound as an oil (32g, 100%). IH NMR (360MHz, CDC13) 8 7.42 (2H, d, J=7.6 Hz), 7.35-7.25 (3H, 5.83 (1H, d, J12.3 Hz), 5.68 (1H, dt, J=12.3, 6.0 Hz), 5.06 (1H, s), WO OR/24439 PC^TIEPn^A'- 18
UO
4.27 (1H, 4.12 (2H, 3.32 (1H, 3.13 (1H, 2.28 (1H, t, J=5.9 Hz), 2.02 (1H, 1.92-1.78 (3H, and 1.32 (9H, m/z 334 PREPARATION 11 (5R,6S)-6-Phenyl-1-oxa-7-(tert-butoxvcarbonvl)aza-spiro[4.5]dec-3-ene Diethylazodicarboxylate (18.2ml, 115mmol) in THF (100ml) was added dropwise to a solution of Z-(2S,3R)-l-tert-butoxycarbonyl-3-(3hydroxyprop-1-en-1-yl)-2-phenylpiperidin-3-ol (Preparation 10; 32g, 96mmol) and triphenylphosphine (30.2g, 115mmol) in THF 7 00ml). The mixture was stirred at 0°C for 30 minutes then at room temperature for hours. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel, eluting with hexane/ethyl acetate (95:5 increasing to 80:20) to give the title compound as a colorless solid (23.4g, IH NMR (CDCla) 8 7.45 (2H, d, J=7.4 Hz), 7.27 (2H, t, J=7.4 Hz), 7.20 (1H, t, J=7.4 Hz), 6.03 (1H, dt, J=6.1, 2.0 Hz), 5.68 (1H, dt, J=6.1, 2.0 Hz), 5.06 (1H, 4.61 (1H, dt, J=13.1, 2.0 Hz), 4.32 (1H, dt, J=13.1, 2.0 Hz), 4.08 (1H, 3.05 (1H, m), 2.05 (1H, 1.75 (3H, and 1.37 (9H, m/z 316 PREPARATION 12 Benzyl bromide (66.17ml, 95.35g, 0.56mol) was added to a mixture of 4-(trifluoromethoxy)phenol (90.26g, 0.51mol) and potassium carbonate (140.97g, 1.2mol) in dimethylformamide (160ml) and the mixture was stirred at room temperature for 72 hours. The mixture was poured into water (1.5 1) and extracted with ethyl acetate (3x500ml). The combined organic fractions were washed with aqueous sodium carbonate (saturated, 500ml), dried (MgSO 4 and the solvent was evaporated under reduced pressure to give the title compound as a colorless solid 1 33.5g, IH NMR (360MHz, CDCl 3 8 7.39 (5H, 7.14 (2H, d, J=9.0 Hz), 6.95 (2H, d, Hz), and 5.05 (2H, s).
WO 9R8/24430 o~TnPC T 19 l I 7 UOO B PREPARATION 13 Iodine (71.96g, 0.28mol) in chloroform was added dropwise to a mixture of 2 -benzyloxy-5-(trifluoromethoxy)benzene (Preparation 12, 73.06g, 0.27mol) and silver trifluoroacetate (71.57g, 0.32mol) in dichloromethane and the mixture was stirred at room temperature for 18 hours. The mixture was filtered through celite, washed with aqueous sodium thiosulfate 2x2 dried (MgS04) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane/ethyl acetate, to give the title compound as a colorless oil (108.03g), containing 11% unreacted 2-benzyloxy-5-(trifluoromethoxy)iodobenzene. 1H NMR (360MHz, CDCla) 5 7.67 (1H, d, J=2.8 Hz), 7.40 (5H, 7.16 (1H, dd, J=8.9, 2.8 Hz), 6.82 (1H, d, J=8.9 Hz), and 5.14 (2H, s).
PREPARATION 14 (5R,.6S)-3-(2-Benzvloxv-5-(trifluoromethoxy)phenvl)-6-phenyl-1-oxa-7-(tertbutoxvcarbonvl)aza-spiro[4.51dec-3-ene (5R,6S)-3-Trimethylstannyl-6-phenyl-l-oxa-7-(tertbutoxycarbonyl)aza-spiro[4.5]dec-3-ene (Preparation 6; 6.43mmol), lithium chloride (0.163g), benzyloxy-5-(trifluoromethoxy)phenol (Preparation 9; 7.7mmol) in toluene (25ml) was degassed before addition of triphenylphosphine palladium (0.37g). The solution was degassed thoroughly before heating to 110 0 C for 14 hours. The solution was partitioned between water and ethyl acetate and the dried organic phase was purified by chromatography on a column containing silica gel (eluting with hexane containing increasing proportions of ethyl acetate between 0% to to give the title compound. 1H NMR (360MHz, CDC13) 8 1.33 (9H, 1.65 (1H, 1.76 (2H, 2.08 (1H, 3.11 (1H, 4.08 (1H, m), 4.60 (1H, dd, J=12.2 Hz, J=2 Hz), 4.92 (1H, dd, J=12.1 Hz, J=1.8 Hz), 5.08 WO) 98/24439 1D9CTIIfVDfr7, l -20 IA IUO (1H, 5.1 (2H, q, Jill.5 Hz), 6.65 (lH, 6.94 (2H, d, J=8.9 Hz), 7.08 (1H, d, J=9 Hz), 7.18 (2H, t, J=8.1 Hz), 7.25 (3H, in), 7.38 (5H, mn).
PREPARATION (3S. SR.6S)-3-(2-Hydroxy-5-(trifluoromethoxv~ihhenvl)-6-phenvl-. -oxa-7- (tert-butoxycarbonvl) aza-spiro [4.51 decane 6S)-3- (2-Benzyloxy-5-(trifluoromethoxy)phenyl)-6-phenyp 1 -oxa 7-(tert-butoxycarbonyl)aza-spiro dec-3-ene (Preparation 14) (3 .88g) was dissolved in ethyl acetate (i1ini) and methanol (i1ini). Palladium hydroxide on carbon (1.00g) was added and the suspension was shaken under a hydrogen atmosphere (50 psi) for 72 hours. The mixture was filtered and the solvent was evaporated under reduced pressure. The residue was purified by medium pressure chromatography on silica gel, eluting with hexane/ethyl acetate (75:25) to give (3R, 5R, 6S)-3-(2-hydroxy- 5-(trifluoromethoxy)phentyl)- 6-p henyl- 1-oxa- 7-tert -butoxycarbonyl)aza- (191mg), 'H NMR (250MHz, CDCl3) 8 7.70 (2H, d, J=7.3 Hz), 7.33 (2H, t, J=7.3 Hz), 7.26 (1H, d, J=7.3 Hz), 7.05 (1H, br 6.96 (2H, in), 6.82 (1H, d, J=9.4 Hz), 5.43 (1H, 4.27 (1H, in), 4.01 (1H, mn), 3.95 (1H, mn), 3.73 (1H, mn), 2.73 (2H, in), 2.33 (1H, mn), 1.87-1.58 (4H, in); and 1.50 (9H, s).and (38,5R,6S)-3-(2-hydroxy-5-(trifluoromnethoxy)phenyl).
6-phenyl-l1-oxa- 7-(tert- butoxycarbonyl)aza-spiro[4. 5]decane (2.3 'H NMR (360MHz, CDCl 3 6 1.38 (9H, 1.73 (2H, in), 1.81 (1H, in), 2.18 (2H, mn), 2.50 (1H, in), 2.81 (1H, in), 3.62 (1H, t, J=7.2 Hz), 3.92 (1H, mn), 3.98 (1H, d, J=13.2 Hz), 4.23 (1H, mn), 5.33 (1H, 6.75 (1H, d, J=8-5 Hz), 6.94 (2H, in), 7.25 (1H, in), 7.31 (2H, in), and 7.55 (2H, d, J=7.8 Hz).
PREPARATION 16 (3R. SR.6S)-3- (2-Benzvloxv-5-(trifluoromethoxv)phenvl-6-phenl. 1-oxa-7 (tert -b utoxvcarb o nl) aza -sipiro r4.51 decane A mixture of (Preparation 13, 55.2inmol), (5R,6S)-6-phenyl- 1-oxa-7-(tert- WO 98/2>4430 PT/-iEP9/oi -21 butoxycarbonyl)aza-spiro[4.5]dec-3-ene (Preparation 11, 7.0g, 22.1mmol), tetra-n-butylammonium chloride (6.18g, 22.2mmol), lithium chloride (9.35g, 0.22mol) and potassium formate (5.64g, 67.0mmol) in dimethylformamide (100ml) was degassed with a firestone valve (5 x).
Palladium acetate (491mg, 2.2mmol) was added and the mixture was degassed with a firestone valve (5 The mixture was stirred at 60 0 C for hours, then further (Preparation 13, 4.32g, ll.0mmol), potassium formate (2.78g, 3 and palladium acetate (260mg, 1.1mmol) were added. The mixture was stirred at 60°C for 22 hours, cooled and filtered. The solvent was evaporated under reduced pressure, water (600ml) was added and the mixture was extracted with ethyl acetate (2x300ml). The combined organic fractions were washed with brine (300ml), dried (MgS0 4 and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane/dichloromethane (75:25 increasing to 0:100) then dichloromethane/ethyl acetate to give the title compound (9.42g, 1H NMR (360MHz, CDCl 3 8 7.56 (2H, d, J=7.7 Hz), 7.40-7.20 (8H, 7.14 (1H, d, J=2.0 Hz), 7.00 (1H, dd, J=8.9, 2.0 Hz), 6.88 (1H, d, J=8.9 Hz), 5.30 (1H, 5.08 (2H, 4.27 (1H, 3.97 (1H, 3.87 (2H, m), 2.78 (1H, 2.56 (1H, 2.15 (1H, 1.96 (1H, 1.67 (3H, and 1.42 (9H, s).
PREPARATION 17 (3R,5R,6S)-3-(2-Hydroxy-5-(trifluoromethoxv)phenvl)-6-phenvl-l-oxa-7- (tert-butoxvcarbonvl)aza-spiro [4.51 decane Palladium on carbon 0.59g) was added to a solution of (3R,5R,6S)-3-(2-benzyloxy-5-(trifluoromethoxy)phenyl)-6-phenyl-l-oxa-7- (Preparation 16, 6.10g, 10.5mmol) in methanol-water (99:1, 200ml) and the mixture was stirred under hydrogen (50 psi.) for 72 hours. The mixture was filtered, washing WO 98/24439 PCT/EP97/i6683 22 with ethanol, and the solvent was evaporated under reduced pressure.
The residue was purified by flash column chromatography on silica gel, eluting with dichloromethane/ethyl acetate (99:1 increasing to 90:10) to give the title compound. 1 H NMR (360MHz, CDCl 3 5 7.70 (2H, d, J=7.3 Hz), 7.33 (2H, t, J=7.3 Hz), 7.26 (1H, d, J=7.3 Hz), 7.05 (1H, br 6.96 (2H, 6.82 (1H, d, J=9.4 Hz), 5.43 (1H, 4.27 (1H, 4.01 (1H, m), 3.95 (1H, 3.73 (1H, 2.73 (2H, 2.33 (1H, 1.87-1.58 (4H, m), and 1.50 (9H, s).
PREPARATION 18 (3S,5R,6S)-3-[2-(1-Phenvlthiocvcloprop-1-yl)oxy-5- (trifluoromethoxv)phenyll-6-phenyl-l-oxa-7-(tert-butoxvcarbonvl)azaspiro[4.51decane (3S, 5R,6S)-3-(2-Hydroxy-5-(trifluoromethoxy)phenyl)-6-phenyl-1oxa-7-(tert-butoxycarbonyl)aza-spiro[4.5]decane (Preparation 15) (290mg, 0.59mmol) was dissolved in toluene (5ml) and silver carbonate (179mg, 0.65mmol) was added in one portion. (1-Iodocycloprop-1-yl)phenylsulfide (Cohen T. and Matz J. J. Am. Chem. Soc. 1980, 102, 6902) (180mg, 0.65mmol) was then added over one minute at room temperature. The mixture was stirred at 55 0 C for 4 hours, then further portions of silver carbonate (179mg, 0.65mmol) and (1-iodocycloprop-l1-yl)phenylsulfide (180mg, 0.65mmol) were added. The mixture was stirred at 55*C for a further 3 hours, cooled, filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with hexane/ethyl acetate (90:10 increasing to 80:20) to give the title compound as a colourless oil (120mg, 1 H NMR (250MHz, CDC13) 5 7.55-7.44 (4H, 7.36-7.23 (7H, 7.13-7.02 (2H, m), 5.16 (1H, br 4.09 (1H, t, J=6 Hz), 4.03-3.92 (1H, 3.67-3.49 (2H, m), 2.94-2.79 (1H, 2.26 (1H, dd, J=7.9, 12.9 Hz), 2.15-2.01 (2H, 1.76- 1.59 (3H, 1.53-1.45 (4H, and 1.36 (9H, m/z 642
I-.
WO 98/24439 -23- PCT/EP97/06683 PREPARATION 19 (3R,5R,6S)-3-[2-(1-Phenvlthiocycloprop-1-vl)oxy-5- (trifluoromethoxy)p henvyl-6-phenyl-1-oxa-7-(tert-butoxvcarbonyl)aza- Prepared from (3R,5R,6S)-3-(2-hydroxy-5- (trifluoromethoxy)phenyl)-6-phenyl-l-oxa-7-(tert-butoxycarbonyl)aza- (Preparation 17) according to the method of Preparation 18. 1 H NMR (360MHz, CDC13) 8 7.57 (2H, app. d, J=7.6 Hz), 7.45 (2H, app. d, J=7.7 Hz), 7.36-7.19 (7H, 7.16-7.06 (2H, 5.28 (1H, br s), 4.13 (1H, app. t, J=7.8 Hz), 3.96 (1H, br. d, J=13 Hz), 3.80-3.60 (2H, m), 2.79 (1H, br. t, J=13 Hz), 2.50 (1H, dd, J=13, 7.9 Hz), 2.17 (1H, dt, J=13, 4.6 Hz), 1.80 (1H, dd, J=12, 9.8 Hz), 1.75-1.38 (7H, and 1.44 (9H, s).
m/z 642 PREPARATION (3S,5R,6S)-3-[2-Cyclopropoxy-5-(trifluoromethoxv)phenvyl-6-phenyl-1-oxa- 7-(tert-butoxvcarbonyl)aza-spiroF4.51decane Naphthalene (120mg, 0.936mmol) was dissolved.in THF under nitrogen and freshly cut lithium metal (7.0mg, 0.94mmol) was added. The mixture was then sonicated at room temperature for minutes to produce a dark green solution of lithium naphthalenide. This solution was cooled to -78 then (3S,5R,6S)-3-[2-(1-phenylthiocycloprop- 1-yl)oxy-5-(trifluoromethoxy)phenyl]-6-phenyl-l-oxa-7-(tert- (Preparation 18) (120mg, 0.187mmol) in THF (0.5ml) was added over 1 minute. The reaction mixture was stirred for 30 minutes, then water (5ml) and ether (10ml) were added. The layers were separated and the aqueous layer was extracted with ether The combined organic fractions were dried (MgSO 4 and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with hexane/ethyl acetate (90:10 increasing to 80:20) to give the title compound as a colourless oil WO 98/24439 PCT/EP97/06683 24 (58.6mg, IH NMR (250MHz, CDCl 3 8 7.58-7.52 (2H, 7.36-7.17 (4H, 7.10-7.01 (2H, 5.18 (1H, br 4.20 (1H, t, J=6.7 Hz), 4.05-3.95 (1H, 3.76-3.55 (3H, 2.92-2.79 (1H, 2.37 (1H, dd, J=12.9, 7.8 Hz), 2.18-2.06 (2H, 1.80-1.67 (3H, 1.38 (9H, and 0.86-0.73 (4H, m/z 534 PREPARATION 21 (3R,5R,6S)-3-[2-Cyclopropoxy-5-(trifluoromethoxv)phenvll-6-phenvl-1-oxa- 7-(tert-butoxvcarbonvl)aza-spiro[4.51decane Naphthalene (120mg, 0.936mmol) was dissolved in THF under nitrogen and freshly cut lithium metal (7.0mg, 0.94mmol) was added. The mixture was then sonicated at room temperature for minutes to produce a dark green solution of lithium naphthalenide. A solution of (3R, 5R,6S)-3-[2-(1-phenylthiocycloprop-1-yl)oxy-5- (trifluoromethoxy)phenyl]-6-phenyl-l-oxa-7-(tert-butoxycarbonyl)aza- (Preparation 19, 135mg, 0.21mmol) in THF (2ml) under nitrogen was cooled to -78*C and the solution of lithium naphthalenide in THF was added dropwise until the intense green colour persisted. The reaction was then stirred for one minute, water (5ml) was added and the mixture was warmed to room temperature. Ether (10ml) was added and the layers were separated. The aqueous phase was extracted with a further portion of ether (10ml) and the combined organic phases were dried (MgSO 4 and the solvent was evaporated under reduced pressure.
The residue was purified by column chromatography on silica gel, eluting with hexane/ethyl acetate (50:50) to give the title compound as a colourless oil (87mg, 1H NMR (360MHz, CDCla) 5 7.59 (2H, app. d, J=7.6 Hz), 7.32 (2H, app. t, J=7.6 Hz), 7.27-7.18 (2H, 7.11-7.03 (2H, 5.32 (1H, br 4.29-4.21 (1H, 3.97 (1H, br. d, J=13 Hz), 3.83-3.68 (3H, 2.76 (1H, dt, J=13, 4.1 Hz), 2.55 (1H, dd, J=13, 7.2 Hz), 2.22 (1H, dt, J=12, 5.2 Hz), 1.85 (1H, dd, J=13, 9.9 Hz), 1.80-1.63 (3H, 1.46 (9H, and 0.82- 0.76 (4H, m/z 534 WO 98/24439 -25- PCT/EP97/06683 COMPOUND A (3S. 5R, 6S)-3-[2-Cyclopropoxy-5-(trifluoromethoxv)phenvyl-6-phenyl- 1-oxa- 7-aza-spiro[4.51decane Hydrochloride Trifluoroacetic acid (2.5ml) was added dropwise to a stirred, cooled 0°C) solution of (3S,5R,6S)-3-[2-cyclopropoxy-5-(trifluoromethoxy)phenyl]- 6-phenyl-l-oxa-7-(tert-butoxycarbonyl)aza-spiro[4.5]decane (Preparation 492mg, 0.92mmol) in dichloromethane (25ml) and the mixture was stirred at room temperature for 3 hours. The mixture was poured into water (50ml), the pH was adjusted to 10.0 with aqueous sodium hydroxide (4M) and the mixture was extracted with dichloromethane (3x50ml). The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with dichloromethane/methanollammonia (96:4:0.4 increasing to 94:6:0.6).
The residue was dissolved in ethanol (20ml), cooled in ice and ethereal hydrogen chloride (1M, 1.8ml, 1.8mmol) was added dropwise. The mixture was stirred at 0 C for 5 minutes, then the solvent was evaporated under reduced pressure. The residue was crystallized from ether (0.5ml) and the solid was collected and dried in vacuo to give the title compound as a colorless solid (354mg, m.p. 214-216 IH NMR (500MHz, CD 3 OD) 8 7.59 (2H, 7.52 (3H, 7.26 (1H, d, J=8.9 Hz), 7.03 (1H, dd, J=8.9, 2.2 Hz), 6.20 (1H, d, J=2.2 Hz), 4.85 (2H, br 4.43 (1H, 4.19 (1H, t, J=8.0 Hz), 3.87 (1H, quin, J=8.0 Hz), 3.76 (1H, m), 3.44 (1H, 3.25 (2H, m) 2.29-1.78 (6H, 0.80 (2H, and 0.66 (2H, m/z 434 Found: C, 61.41; H, 5.51; N, 3.08.
C
24
H
26
F
3 N0 3 .HC1 requires: C, 61.34; H, 5.79; N, 2.98%.
WO 98/24439 PC("T/E'P97/06683c" 26 u u' COMPOUND B (3R, 5R,.6S)-3-[2-Cvclopropoxy-5-(trifluoromethoxy)phenyll-6-phenvl- -oxa- 7-aza-spiro[4.5]decane Prepared from the compound of Preparation 21 according to the method used for Compound A. 1H NMR (360MHz, CDC13) 8 7.50-7.42 (2H, 7.36-7.26 (3H, 7.03 (1H, d, J=8.9 Hz), 6.95 (1H, br. d, J=8.9 Hz), 6.81 (1H, br 3.92 (1H, t, J=7.4 Hz), 3.62-3.53 (2H, 3.50 (1H, 3.20 (1H, dd, J=12, 4.2 Hz), 2.77 (1H, dt, J=12, 2.8 Hz), 2.30-1.93 (4H, 1.87 (1H, br 1.71-1.49 (3H, 0.76-0.65 (2H, and 0.65-0.54 (2H, m/z (ES 434 A further compound and diastereomers thereof of use in the present invention may be prepared according to the following method: DESCRIPTION 1 2-(1-Phenvlthiocycloprop-1-vl)oxy-5-(trifluoromethoxv)benzaldehvde Silver carbonate (1.2 g, 4.34 mmol) was added to a solution of (0.5 g, 2.43 mmol) and (1-iodocycloprop-1-yl)phenylsulfide (Cohen T. and Matz J. J. Am.
Chem. Soc. 1980, 102, 6902) (1.2 g, 4.34 mmol) in toluene (30 mL) and the mixture was stirred at 40 °C overnight. The mixture was cooled, diluted with ethyl acetate and filtered, washing well with ethyl acetate. The mixture was washed with aqueous sodium hydroxide, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane/Et20 to give the title compound as a yellow oil (191 mg, IH NMR (360MHz, CDC13) 8 1.51-1.56 (2H, 1.44-1.48 (2H, m), 7.25-7.35 (7H, 7.69 (1H, d, J 2.0 Hz), and 10.26 (1H, s).
WO 98/24439 27 PCT/EP97/06683 DESCRIPTION 2 Freshly cut lithium metal (97 mg, 13.9 mmol) was added to a solution of naphthalene (1.77 g, 13.9 mmol) in THF (20 mL) and the mixture was sonicated at room temperature for 30 min. to produce a dark green solution of lithium naphthalenide. A solution of 2-(1-phenylthiocycloprop-1-yl)oxy-5-(trifluoromethoxy)benzaldehyde (Description 1, 96 mg, 0.27 mmol) in THF (2 mL) was cooled to -78 oC and the solution of lithium naphthalenide in THF (2 mL) was added dropwise until the intense green colour persisted. The reaction was then stirred for min., water (6 mL) was added and the mixture was warmed to room temperature. The mixture was extracted with ethyl acetate, the combined organic fractions were dried (MgSO 4 and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane/Et 2 0 (80:20), to give to give the title compound as a colourless oil (4 mg, 'H NMR (360MHz, CDC13) 8 0.86 (4H, 3.82-3.9 (1H, 7.42 (2H, 7.62 (1H, d, J Hz), and 10.36 (1H, s).
DESCRIPTION 3 2-Nitro-4-(trifluoromethoxyv)phenol Iron(111)nitrate nonahydrate (1.97 g, 4.87 mmol) was added to a solution of 4-(trifluoromethoxy)phenol (2 g, 11.24 mmol) in ethanol mL) and the mixture was heated under reflux overnight. The mixture was allowed to cool to room temperature, acidified to pH 1 with aqueous hydrochloric acid (IM) and extracted with ethyl acetate. The combined organic fractions were dried (MgSO4), and the solvent was evaporated under reduced pressure. The residue was purified by short column chromatography on silica gel, eluting with hexane/EtOAc (70:30), to give the title compound as a yellow oil (2.25 g, 1 H NMR (360MHz, CDC1 3 d WO 98/24439 28 PCT/EP97/06683 8 10.53 (1H, 8.01 (1H, d, J 3.0 Hz), 7.49 (1H, dd, J9.1, 3.0 Hz), and 7.23 (1H, d, J 9.1 Hz).
DESCRIPTION 4 2-(1-Phenyvlthiocvcloprop-l-vl)oxv-5-(trifluoromethoxy)nitrobenzene Prepared from the compound of Description 3 according to the method of Description 1. 1H NMR (360MHz, CDC1 3 8 7.73 (1H, d, J2.7 Hz), 7.58 (1H, d, J 9.2 Hz), 7.50-7.24 (6H, 1.57-1.53 (2H, and 1.44-1.40 (2H, m).
DESCRIPTION 2- Cycloprop oxy- Prepared from the compound of Description 4 according to the method of Description 2. 'H NMR (360MHz, CDC13) 8 7.06 (1H, dd, J 2.8, 6.7 Hz), 6.56 (2H, 3.83 (2H, br 3.74 (1H, and 0.79 (4H, m/z (ES 234 DESCRIPTION 6 2-(l-Phenvylthiocvcloprop-1-yl)oxy-5- (trifluoromethoxy)benzeneamine Iron powder (13.5 g, 241 mmol) was added to a suspension of 2-(1-phenylthiocycloprop-1-yl)oxy-5-(trifluoromethoxy)nitrobenzene (Description 4, 11.27 g, 30.1 mmol) in water (300 mL) and acetic acid mL) and the mixture was stirred at 80 °C overnight. The mixture was cooled and filtered through celite, washing with ether. The filtrate was extracted with ether, the combined organic fractions were washed with aqueous sodium hydroxide dried (MgS04), and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane/Et 2 0 (90:10 increasing to 80:20), to give the title compound as a yellow solid (8 g, 78%).
IH NMR (360MHz, CDCl 3 8 7.48 (2H, 7.34-7.23 (3H, 7.15 (1H, d, J 1 WO 98/24439 29 PCT/EP97/06683 8.74 Hz), 6.60-6.56 (2H, 3.78 (2H, br 1.49-1.46 (2H, and 1.39-1.35 (2H, m).
DESCRIPTION 7 Prepared from the compound of Description 6 according to the method of Description 2. 1 H NMR (360MHz, CDC13) 8 7.06 (1H, dd, J 2.8, 6.7 Hz), 6.56 (2H, 3.83 (2H, br 3.74 (1H, and 0.79 (4H, m/z 234 DESCRIPTION 8 An ice-cooled solution of sodium nitrite (3.55 g, 51 mmol) in water mL) was added dropwise to a stirred, cooled (0 oC) solution of 2-cyclopropoxy-5-(trifluoromethoxy)benzeneamine (Description 7, 4.8 g, 20.6 mmol) in aqueous hydrochloric acid (5M, 300 mL), maintaining the internal temperature at 0 The mixture was stirred at 0 °C for 30 min., then potassium iodide (8.55 g, 51.5 mmol) in water (10 mL) was added dropwise, maintaining the internal temperature at 0 The mixture was stirred at 0 °C for 30 min., then allowed to warm up to room temperature and stirred until nitrogen evolution ceased. The mixture was extracted with ether, the organic fraction was washed with aqueous sodium thiosulfate dried (MgSO4), and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane/Et20 (98:2 increasing to 95:5), to give the title compound as a colourless oil (6.23 g, 1 H NMR (360MHz, CDC13) 8 7.62 (1H, d, J 2.4 Hz), 7.20 (1H, dd, J 9.1, 2.4 Hz), 7.15 (1H, d, J9.1 Hz), 3.80 (1H, and 0.83 (4H, m).
WO 98/24439 PCT/'po7/068;3 30 DESCRIPTION 9 A solution of (Description 8, 0.344 g, 1 mmol) in toluene (2.5 mL) was degassed with bubbling nitrogen for 10 min. Tetrakis(triphenylphosphine)palladium (0) mg) was added, the mixture was degassed with bubbling nitrogen for a further 5 min., then carbon monoxide was bubbled through the mixture for min. The mixture was warmed to 50 °C and a solution of tributyl tin hydride (0.3 mL, 1.1 mmol) in toluene (5 mL) was added at a rate of 2 mL/h. via a syringe pump, maintaining carbon monoxide bubbling throughout. The mixture was cooled, diluted with ether (20 mL) and aqueous potassium fluoride solution was added. The mixture was stirred at room temperature overnight, filtered and the layers were separated. The organic layer was dried (MgS04), and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane/Et 2 0 (80:20), to give the title compound as a colourless oil. 1H NMR (360MHz, CDC1 3 6 0.86 (4H, 3.82-3.9 (1H, 7.42 (2H, 7.62 (1H, d, J 2.5 Hz), and 10.36 (1H, s).
DESCRIPTION (2RS)- 1-tert-Butoxvcarbonyl-2-phenvlpiperidin- 3-one Dimethyl sulfoxide (32.0 mL, 35.3 g, 0.45 mol) in dichloromethane (100 mL) was added dropwise to a cooled (-70 solution of oxalyl chloride (18.7 mL, 27.5 g, 0.22 mol) in dichloromethane (1000 mL). The mixture was stirred at -70 °C for 15 min., then (2S,3S)-l-tert-butoxycarbonyl-3-hydroxy-2-phenylpiperidine (prepared by the method described in European Patent Specification number 0 528 495-A; 50 g, 0.18 mol) in dichloromethane (150 mL) was added dropwise.
The mixture was stirred at -70 °C for 1 then triethylamine (125.8 mL, 91.3 g, 0.9 mol) was added slowly. The mixture was stirred at room WO 98/24439 PCT/E.P97/06683a -31 temperature for 1 water (250 mL) and aqueous sodium hydrogen carbonate (saturated, 250 mL) were added and the mixture was stirred at room temperature overnight. The layers were separated and the aqueous layer was extracted with dichloromethane (2 x 300 mL). The combined organic fractions were washed with brine, dried (MgS0 4 and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane/EtOAc (90:10), to give the title compound as a yellow oil (45.0 g, 1H NMR (250MHz, CDC13) 8 7.5-7.3 (5H, 5.8 (1H, br 4.2 (1H, br 3.4 (1H, 2.6 (2H, 2.0 (2H, and 1.54 (9H, s).
DESCRIPTION 11 (±)-(2R3R.2S3S)- -(tert-Butoxvcarbonvyl)-2-phenvlpiperidin-3-amine A solution of hydroxylamine hydrochloride (17 g, 0.24 mol) and sodium acetate (55.67 g, 0.41 mol) in water (150 mL) was added to a solution of (±)-(2RS)-1-tert-butoxycarbonyl-2-phenylpiperidin-3-one (Description 10, 45 g, 0.16 mol) in ethanol (300 mL) and the mixture was stirred at room temperature for 1 h. The solvent was evaporated under reduced pressure, water was added and the mixture was extracted with ethyl acetate. The organic fraction was washed with brine, dried (MgSO 4 and the solvent was evaporated under reduced pressure. The residue was dissolved in ethanol (400 mL) and Raney nickel (50 g) was added. The mixture was shaken under hydrogen (40 psi) overnight, filtered and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with CH 2 Cl 2 /MeOH (100:0 increasing to 85:15), to give the title compound as a colorless oil (10.9 g, 1 H NMR (360MHz, CDC13) 8 7.43 (2H, d, J 7.0 Hz), 7.30 (3H, 5.19 (1H, d, J6.2 Hz), 4.00 (1H, 3.17 (2H, 1.90-1.64 (4H, m), 1.36 (9H, and 1.26 (2H, br s).
WO 98/24439 32 PCT/EP97/06683 COMPOUND C (±)-(2R3R,2S3S)-N-{[2-Cyclopropoxy-5-(trifluoromethoxy)phenvlmethyll-2 -phenylpiperidin-3-amine Dihydrochloride (Description 9, mg, 0.21 mmol) was added to (±)-(2R3R,2S3S)-l-(tert-butoxycarbonyl)-2phenylpiperidin-3-amine (Description 11, 58 mg, 0.21 mmol), citric acid (89 mg, 0.42 mmol) and 3A molecular sieves in dry methanol (5 mL) and the mixture was stirred at room temperature for 1.5 h. Sodium borohydride (30 mg) was added and the mixture was stirred at room temperature for 2 h. Ethyl acetate was added and the mixture was washed with aqueous hydrochloric acid (0.1M, 2 x 25 mL) and brine (25 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was dissolved in dichloromethane (3 mL), cooled to 0 °C and trifluoroacetic acid (2 mL) was added slowly. The mixture was stirred at room temperature for 1 the solvent was evaporated under reduced pressure and ethyl acetate was added. The mixture was washed with aqueous sodium hydrogen carbonate (saturated, 2 x 25 mL) and brine mL), dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with CH 2 Cl2/MeOH/NH3(Aq.) The residue was dissolved in ethanol (2 mL), cooled in ice and ethereal hydrogen chloride (1M, 0.24 mL, 0.24 mmol) was added. The solvent was evaporated under reduced pressure and the residue was recrystallised from ethanol to give the title compound as a colorless solid (20 mg, m.p. 169-171 IH NMR (400MHz, CD 3 OD) 8 0.64 (1H, 0.80 (3H, 1.99 (1H, 2.24 (1H, 2.46 (2H, 3.30 (1H, 3.64 (1H, 3.75 (2H, 3.96 (1H, br 4.08 (1H, 4.95 (1H, 7.23 (1H, 7.31 (1H, d, J 9.0 Hz), 7.37 (1H, d, J 9.0 Hz), 7.54 (3H, and 7.67 (2H, m/z 407 Particularly preferred NK-1 receptor antagonists of use in the present invention are compounds which are potent NK-1 receptor WO 98/24430 PC^TIEP9^-o 33 i1 J. IUU33OOJantagonists, i.e. compounds with an NK-1 receptor affinity (IC 50 of less than 10nM, favourably less than 2nM and preferably less than InM.
The class of orally active, long acting, CNS-penetrant NK-1 receptor antagonists of use in the present invention is identified using a combination of the following assays: ASSAY 1: NK-1 Receptor binding NK-1 receptor binding assays are performed in intact Chinese hamster ovary (CHO) cells 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. Typically, the receptor is expressed at a level of 3x10 5 receptors per cell. Cells are grown in monolayer culture, detached from the plate with enzyme-free dissociation solution (Speciality Media Inc.), and washed prior to use in the assay. 1 25 1-Tyr 8 substance P (0.lnM, 2000Ci/mmol; New England Nuclear) is incubated in the presence or absence of test compounds (dissolved in dimethylsulphoxide, DMSO) with 5x10 4 CHO cells. Ligand binding is performed in 0.25ml of 50mM Tris-HC1, pH7.5, containing 5mM MnC1 2 150mM NaC1, 0.02% bovine serum albumin (Sigma), 50[.g/ml chymostatin (Peninsula), 0.lnM phenylmethylsulphonyl fluoride, 2tg/ml pepstatin, 2 ig/ml leupeptin and 2.8pg/ml furoyl saccharine. The incubation proceeds at room temperature until equilibrium is achieved (>40 minutes) and the receptor-ligand complex is harvested by filtration over GF/C filters presoaked in 0.1% polyethylenimine using a Tomtek 96-well harvester. Non-! specific binding is determined using excess substance P (1iM) and represents <10% of total binding.
ASSAY 2: Gerbil Foot-Tapping CNS-penetrant NK-1 receptor antagonists for use in the present invention can be identified by their ability to inhibit foot tapping in gerbils WO 98/24439 34- PCT/EP97/06683 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 Williams, Eur. J. Pharmacol., 1994, 265, 179.
Male or female Mongolian gerbils (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 orally or by subcutaneous or intraperitoneal routes. A skin incision is then made in the midline of the scalp to expose the skull. An anxiogenic agent pentagastrin) or a selective NK-1 receptor agonist GR73632 (d Ala[L-Pro 9 ,Me-Leul]-substance is infused directly into the cerebral ventricles 3pmol in 5pl 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 allowed to recover from anaesthesia in a clear perspex observation box 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 Individually housed male ferrets (1.0 -2.5 kg) are dosed orally by gavage with test compound. Ten minutes later they are fed with approximately 100g of tinned cat food. At 60 minutes following oral dosing, cisplatin (10mg/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 ligated and the skin incision closed. The ferrets recover rapidly from the anaesthetic and are mobile within 10-20 minutes. The animals are observed continuously during recovery from the Wn 98/2443o PCT/EP97/06683 35 anaesthetic and for 4 hours following the cisplatin injection, after which time the animals are killed humanely. The numbers of retches and vomits occurring during the 4 hours after cisplatin administration are recorded by trained observers.
ASSAY 4: Separation-Induced Vocalisation Male and female guinea-pigs pups are housed in family groups with their mothers and littermates 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 vocalisation response is reproducibly elicited following maternal separation. The pups are placed individually in an observation cage x 39cm x 19cm) in a room physically isolated from the home cage for minutes and the duration of vocalisation during this baseline period is recorded. Only animals which vocalise for longer than 5 minutes are employed for drug challenge studies (approximately 50% of available pups may fail 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 siblings for to 60 minutes (or for up to 4 hours following an oral dose, dependent upon the oral pharmacokinetics of the test compound) before social isolation for minutes as described above. The duration of vocalisation on drug treatment days is expressed as a percentage of the pre-treatment baseline 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 gerbil as hereinafter defined.
Essentially, hind foot-tapping in the gerbil induced by infusion of the NK-1 receptor agonist, GR73632 (d Ala[L-Pro 9 ,Me-Leuo0]-substance P-
.J
WO 98/24439 36 PCT/EP97/06683 under anaesthesia, directly into the central ventricles is inhibited when a CNS-penetrant NK-1 receptor antagonist is administered intravenously immediately prior to GR73632 challenge, wherein hind foottapping over a period of five minutes following recovery from the anaesthesia is inhibited with an IDo_3mg/kg, and preferably with an IDso lmg/kg.
In an alternative method, the NK-1 receptor antagonist is administered orally, 1 hour prior to GR73632 challenge, wherein the foottapping over a period of five minutes following recovery from anaesthesia is inhibited with an ID5o30mg/kg, and preferably with an ID5o<10mg/kg.
CNS-penetrant NK-1 receptor antagonists of use in the present ivnention are also effective in the attenuation of separation-induced vocalisations by guinea-pig pups as hereinafter defined.
Essentially, a vocalisation response in guinea-pig pups is induced by isolation from their mothers and littermates, which response is attenuated when a CNS-penetrant NK-1 receptor antagonist is administered subcutaneously 30 minutes prior to isolation, wherein vocalisations during the first 15 minutes of isolation are attenuated with an IDs5o20mg/kg, preferably with an IDso<10mg/kg, and especially with an In an alternative method, the NK-1 receptor antagonist is administered orally, 4 hours prior to isolation, wherein vocalisations during the first 15 minutes of isolation are attenuated with an IDs5o20mg/kg, preferably with an ID5o10mg/kg, and especially with an A suitable selection cascade for NKi antagonists of use according to the present invention is as follows: Determine affinity for human NKi receptor in radioligand binding studies (Assay select compounds with IC 5 o 1OnM, preferably
IC
50 2nM, especially IC 50 o InM.
Wn R/Ad4 PCT/Ei0in8c v P,.ISn'-I nJ- 37 Auuo, (ii) Determine ability of compounds to penetrate CNS by their ability to inhibit foot tapping in gerbils induced by central injection of an NKI agonist (Assay select compounds that inhibit foot tapping with
ID
5 o 3mg/kg and preferably IDs 0 o 1mg/kg i.v. when administered immediately prior to central NKi agonist challenge, or ID 50 o 30mg/kg p.o., and preferably ID 5 o 10mg/kg p.o. 1 hour prior to challenge.
(iii) Determine central duration of action of compounds in gerbil foot tapping assay following intravenous administration 24 hours prior to central NKi agonist challenge; select compounds showing 25-fold loss of potency compared with ID 5 o determined in step (ii) above with the proviso that ID 5 0 10mg/kg and preferably 5mg/kg i.v. after 24 hour pre-treatment.
(iv) Determine oral bioavailability of compounds by pharmacokinetic analysis, activity in gerbil foot tapping assay following oral administration and/or.by ability to inhibit cisplatin-induced-emesis in ferrets (Assay select compounds with IDgo 5 3mg/kg and preferably IDgo 5 Img/kg p.o.
Particularly preferred compounds of use in the present invention are identified using steps to (iv) followed by step Determine activity of compounds in assays sensitive to conventional antipsychotic drugs (inhibition of distress vocalisations in guinea-pig pups (Assay Select compounds with ID 5 o 20mg/kg, and preferably ID 50 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 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.
One example of a NK-1 receptor antagonist of use in the present invention is the compound 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1, 2 4 -triazolo)methyl)lO OQ/AA TflP Fnnl7'lr nrut .l~ T V-y 38 morpholine, the preparation of which is described in International Patent Specification No. WO 95/16679. In the aforementioned assays, this compound has the following activity: human NK-1 receptor binding: gerbil foot-tapping (5 mins.): gerbil foot-tapping (24 hrs.): ferret emesis: guinea-pig vocalisation (4 hr. pre-treatment): ICso=0. nM ID5o=0.36mg/kg i.v.
IDso=0.33mg/kg i.v.
IDgo<3mg/kg p.o.
ID5o=0.73mg/kg p.o.
The following example illustrates pharmaceutical compositions according to the invention.
Wn 8/2A43 PC/fT/EM 0 TT V J W A O 5 *flA *1 Q V- 3 9 I EXAMPLE 1 Tablets containing 50-300mg of NK-1 antagonist Amount mg NK-1 antagonist 50.0 100.0 300.0 Microcrystalline cellulose 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 Iuu3 The active ingredient, cellulose, 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, 100mg and 300mg of the NK-1 receptor antagonist per tablet.
Claims (23)
1. A method for the treatment or prevention of agoraphobia, specific phobia or social phobia without concomitant therapy with other anti-anxiety agents which method comprises the oral administration to a patient in need of such treatment of an effective amount of an orally active, long acting, CNS-penetrant NK-1 receptor antagonist.
2. An orally active, long acting, CNS-penetrant NK-1 receptor antagonist when used in the treatment or prevention of agoraphobia, specific phobia or social phobia without concomitant therapy with other anti-anxiety agents.
3. Use of an orally active, long acting, CNS-penetrant NK-1 receptor antagonist for the manufacture of a medicament adapted for oral administration for the treatment or prevention of agoraphobia, specific phobia or social phobia without concomitant therapy with other anti-anxiety agents.
4. A method for the treatment or prevention of agoraphobia, specific phobia or social phobia without concomitant therapy with other anti-anxiety agents, in a patient who S, is is non-responsive to benzodiazepines or for whom benzodiazepines are contraindicated, which method comprises the oral administration to the patient in need of such treatment *of an effective amount of an orally active, long acting, CNS-penetrant NKI-1 receptor antagonist.
5. An orally active, long acting, CNS-penetrant NK-1 receptor antagonist when 20 used in the treatment or prevention of agoraphobia, specific phobia or social phobia without concomitant therapy with other anti-anxiety agents, in a patient who is non- responsive to benzodiazepines or for whom benzodiazepines are contraindicated.
6. Use of an orally active, long acting, CNS-penetrant NK-1 receptor antagonist for the manufacture of a medicament adapted for oral administration for the treatment or prevention of agoraphobia, specific phobia or social phobia without concomitant therapy with other anti-anxiety agents, in a patient who is non-responsive to benzodiazepines or for whom benzodiazaepines are contraindicated.
7. A method for the treatment or prevention of agoraphobia, specific phobia or social phobia without concomitant therapy with other anti-anxiety agents, in a patient who is non-responsive to tricyclic antidepressants or for whom tricyclic antidepressants are contraindicated, which method comprises oral administration to the patient in need of such treatment of an effective amount of an orally active, long acting, CNS-penetrant NK- 1 receptor antagonist.
8. An orally active, long acting, CNS-penetrant NK-1 receptor antagonist when 3 used in the treatment or prevention of agoraphobia, specific phobia or social phobia [R:\LIBAA]8435.doc:mxl -41- without concomitant therapy with other anti-anxiety agents, in a patient who is non- responsive to tricyclic antidepressants or for whom tricyclic antidepressants are contraindicated.
9. Use of an orally active, long acting, CNS-penetrant NK-1 receptor antagonist for the manufacture of a medicament adopted for oral administration for the treatment or prevention of agoraphobia, specific phobia or social phobia without concomitant therapy with other anti-anxiety agents, in a patient who is non-responsive to tricyclic antidepressants or for whom tricyclic antidepressants are contraindicated.
A method for the treatment or prevention of agoraphobia, specific phobia or social phobia without concomitant therapy with other anti-anxiety agents, in a patient who is non-responsive to SSRIs or serotonin agonists or antagonist or for whom SSRIs or serotonin agonists or antagonists are contraindicated, which method comprises oral administration to the patient in need of such treatment of an effective amount of an effective amount of orally active, long acting, CNS-penetrant NK-1 receptor antagonist. i5
11. An orally active, long acting, CNS-penetrant NK-1 receptor antagonist when used in the treatment or prevention of agoraphobia, specific phobia or social phobia without concomitant therapy with other anti-anxiety agents, in a patient who is non- responsive to SSRIs or serotonin agonists or antagonists or for whom SSRIs or serotonin agonists or antagonists are contraindicated.. 20
12. Use of an orally active, long acting, CNS-penetrant NK-1 receptor antagonist for the manufacture of a medicament adapted for oral administration for the treatment or prevention of agoraphobia, specific phobia or social phobia without concomitant therapy with other anti-anxiety agents, in a patient who is non-responsive to SSRIs or serotonin agonists or antagonists or for whom SSRIs or serotonin agonists or antagonists are contraindicated.
13. A method according to any one of claims 1, 4, 7 or 10, wherein the orally active, long acting, CNS-penetrant NK-1 receptor antagonist is selected from the classes of compounds described in EP-A0577394, WO-A-9508549, WO-A-95 18124, WO-A- 9523798, WO-A-9605181 or International Patent Application No. PCT/GB97/01630.
14. An orally active, long acting, CNS-penetrant NK-1 receptor antagonist according to any one of claims 2, 5, 8 or 11, wherein the orally active, long acting, CNS- penetrant NK-1 receptor antagonist is selected from the classes of compounds described in EP-A0577394, WO-A-9508549, WO-A-95 18124, WO-A-9523798, WO-A-9605181 or International Patent Application No. PCT/GB97/01630. [R\LIBAA]8435.doc:mxl 42 Use according to any one of claims 3, 6, 9 or 12, wherein the orally active, long acting, CNS-penetrant NK-1 receptor antagonist is selected from the classes of compounds described in EP-A0577394, WO-A-9508549, WO-A-95 18124, WO-A- 9523798, WO-A-9605181 or International Patent Application No.
PCT/GB97/01630.
16. A method according to any one of claims 1, 4, 7, 10 or 13 wherein the orally active, long acting, CNS-penetrant NK-1 receptor antagonist is: bis(trifluoromethyl)benzyloxy)-3 (S)-(4-fluorophenyl)-4-(3 -(5-oxo-l1H,4H- 1 ,2,4-triazolo)methyl) morpholine; 4-(3-(5-oxo-l1H,4H- 1,2,4-triazolo)methyl)-3-(S)-phenyl-morpholine; bis(trifluoromethyl)benzyloxy)-4-(3-(5-oxo-1 H,4H- 1,2,4-triazolo)methyl)-3-(S)- phenylmorpholine; ,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4- fluorophenyl)-4-(3-(5-oxo- 1H,4H- 1,2,4-triazolo)methyl)morpholine; bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(N,N-dimethylamino)methyl- 1,2,3-triazol-4- yl)methyl-3-(S)-phenyl morpholine; ,5 15 bis(trifluoromethyl)phenyl)ethoxy)-4-(5 -(N,N-dimethylamino)methyl- 1,2,3-triazol-4- yl)methyl-3-(S)-(4-fluorophenyl)morpholine; bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(4-monophosphoryl-5- oxo-l1H-i ,2,4-triazolo)methyl)morpholine; bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-( 1 oxo-1H-1,2,4-triazolo)methyl)morpholine; bis(trifluoromethyl)phenyl)ethoxy-3-(S)-(4-fluorophenyl)-4-(3-(2-monophosphoryl-5- oxo- 1H-i ,2,4-triazolo)methyl)morpholine; bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxyphosphoryl- 1H- 1 ,2,4-triazolo)methyl)morpholine; 1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)- 3-(S)-(4-fluorophenyl)-4-(3 Omonophosphoryl-5-oxo-4H- 1,2,4-triazolo)morpholine; 2 ,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-N,N-dimethylaminobut-2- ynyl)-3-(S)-(4-fluorophenyl)-morpholine; (3S,5R,6S)-3-[2-cyclopropoxy-5- (trifluoromethoxy)phenyl]-6-phenyl-l1-oxa-7-azaspiro[4.5]decane; (3S,5R,6S)-3-[2- cyclopropoxy-5-(trifluoromethoxy)phenyl]-6-phenyl-l1-oxa-7-azaspiro[4. 5]decane; (2R3R,2S3S)-N- {[2-cyclopropoxy-5-(trifluoromethoxy)phenyl]methyl} -2- phenylpiperidin-3-amine or a pharmaceutically acceptable salt thereof.
17. An orally active, long acting, CNS-penetrant NK- 1 receptor antagonist according to any one of claims 2, 5, 8 or 11, wherein the orally active, long acting, CNS- RAL 1 ~penetrant NK- 1 receptor antagonist is: ,5-bis(trifluoromethyl)benzyloxy)-3(S)-(4- fluorophenyl)-4-(3-(5 -oxo- 1H,4H- 1,2,4-triazolo)methyl) morpholine; [R'iXLIBAA]8435.doc:mxI 43 bis(trifluoromethyl)phenyl)ethoxy)-4-(3-(5-oxo-l1H,4H- 1,2,4-triazolo)methyl)-3-(S)- phenyl-morpholine; 2-(S)-(3,5-bis(trifluoromethyl)benzyloxy)-4-(3 -(5-oxo-l1H,4H- 1,2,4- triazolo)methyl)-3-(S)-phenylmorpholine; bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo- 1H,4H- 1,2,4-, s triazolo)methyl)morpholine; ,5-bis(trifluoromethyl)phenyl)ethoxy)-4- 1,2,3-triazol-4-yl)methyl-3-(S)-phenyl morpholine; 2- 1 ,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(5-(N,N-dimethylamino)methyl- 1 ,2,3-triazol-4-yl)methyl-3-(S)-(4-fluorophenyl)morpholine; bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3 oxo- 1H-i ,2,4-triazolo)methyl)morpholine; bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3 -(I1 oxo-1H-1 ,2,4-triazolo)methyl)morpholine; ,5 bis(trifluoromethyl)phenyl)ethoxy-3-(S)-(4-fluorophenyl)-4-(3 oxo-1H-1 ,2,4-triazolo)methyl)morpholine; bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxyphosphoryl- 1H- 1 ,2,4-triazolo)methyl)morpholine; 1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)- 3-(S)-(4-fluorophenyl)-4-(3-( 1 monophosphoryl-5-oxo-4H- 1,2,4-triazolo)morpholine; -(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-N,N-dimethylaminobut-2- ynyl).-3-(S)-(4-fluorophenyl)-morpholine; (3S,5R,6S)-3-[2-cyclopropoxy-5- 20 (trifluoromethoxy)phenyl]-6-phenyl-l1-oxa-7-azaspiro[4.5]decane; (3 S,5R,6S)-3-[2- cyclopropoxy-5-(trifluoromethoxy)phenyl]-6-phenyl-l1-oxa-7-azaspiro[4.5]decane; (2R3R,2S3S)-N- {[2-cyclopropoxy-5-(trifluoromethoxy)phenyl]methyl} -2- phenylpiperidin-3-amine or a pharmaceutically acceptable salt thereof.
18. Use according to any one of claims 3, 6, 9,12 or 15 wherein the orally active, long acting, CNS-penetrant NK-1 receptor antagonist is: bis(trifluoromethyl)benzyloxy)-3(S)-(4-fluorophenyl)-4-(3-(5-oxo- 1H,4H- 1 ,2,4-triazolo)methyl) morpholine; 1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)- 4-(3-(5-oxo-l1H,4H- 1,2,4-triazolo)methyl)-3-(S)-phenyl-morpholine; bis(trifluoromethyl)benzyloxy)-4-(3-(5-oxo-lIH,4H- 1,2,4-triazolo)methyl)-3-(S)- phenylmorpholine; 1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4- fluorophenyl)-4-(3-(5-oxo- 1H,4H- 1,2,4-triazolo)methyl)morpholine; 1,2,3-triazo1-4- yl)methyl-3-(S)-phenyl morpholine; 1,2,3-triazol-4- yl)methyl-3-(S)-(4-fluorophenyl)morpholine; RA, bstrifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(4-monophosphoryl-5- -c 4 is( C.) -44 oxo- 1H-i ,2,4-triazolo)methyl)morpholine; bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(l1-monophosphoryl-5- oxo- 1H- 1,2,4-triazolo)methyl)morpholine; bis(trifluoromethyl)phenyl)ethoxy-3-(S)-(4-fluorophenyl)-4-(3-(2-monophosphoryl-5- oxo-l1H-i ,2,4-triazolo)methyl)morpholine; bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxyphosphoryl- 1H- 1 ,2,4-triazolo)methyl)morpholine; 3-(S)-(4-fluorophenyl)-4-(3-( 1 monophosphoryl-5-oxo-4H- 1,2,4-triazolo)morpholine; 1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-4-(4-N,N-dimethylaminobut-2- ynyi)-3-(S)-(4-fluorophenyl)-morpholine; (3 S,5R,6S)-3-[2-cyclopropoxy-5- (trifluoromethoxy)phenyl]-6-phenyl-l1-oxa-7-azaspiroi4. 5]decane; (3 S,5R,6S)-3-[2- -(trifluoromethoxy)phenyl]-6-phenyi-l1-oxa-7-azaspiro[4.5]decane; (2R3R,2S3S)-N- {[2-cyclopropoxy-5-(trifluoromethoxy)phenyl]methyl} -2- phenylpiperidin-3-aniine or a pharmaceutically acceptable salt thereof.
19. A method according to any one of claims 1, 4, 7, 10, 13 or 16, wherein the orally active, long acting CNS-penetrant NK-l receptor antagonist is substantially as hereinbefore described with reference to any one of the Examples.
20. An orally active long acting, CNS-penetrant NK-1 receptor antagonist according to any one of claims 2, 5, 8, 11, 14 or 17, which is substantially as hereinbefore described with reference to any one of the Examples.
21. Use according to any one of claims 3, 6, 9, 12, 15 or 18, wherein the orally active, long acting, CNS-penetrant NK- 1 receptor antagonist is substantially as hereinbefore described with reference to any one of the Examples.
22. A method according to any one of claims 1, 4, 7, 10, 13, 16 or 19, wherein the orally active, long acting CNK-penetrant NK-l receptor antagonist is combined with a pharmaceutically acceptable carrier or excipient in the form of a composition.
23. An orally active long acting CNS-penetrant NK-1 receptor antagonist according to any one of claim 2, 5, 8, 11, 14, 17 or 20, wherein the orally active, long acting CNK-penetrant NK-1 receptor antagonist is combined with a pharmaceutically acceptable carrier or excipient in the form of a composition. Dated 30 November, 2000 Merck Co., Inc. Patent Attorneys for the Applicant/Nominated Person 1 SPRUSON FERGUSON [R\LIBAA]43.doc:ml
Applications Claiming Priority (11)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB9625051 | 1996-12-02 | ||
GB9625051A GB9625051D0 (en) | 1996-12-02 | 1996-12-02 | Therapeutic agents |
GB9701459A GB9701459D0 (en) | 1997-01-24 | 1997-01-24 | Therapeutic agents |
GB9701459 | 1997-01-24 | ||
GB9713715A GB9713715D0 (en) | 1997-06-27 | 1997-06-27 | Therapeutic agents |
GB9713715 | 1997-06-27 | ||
GB9716471 | 1997-08-04 | ||
GBGB9716471.9A GB9716471D0 (en) | 1997-08-04 | 1997-08-04 | Therapeutic agents |
GBGB9721220.3A GB9721220D0 (en) | 1997-10-07 | 1997-10-07 | Therapeutic use |
GB9721220 | 1997-10-07 | ||
PCT/EP1997/006683 WO1998024439A1 (en) | 1996-12-02 | 1997-11-25 | Use of nk-1 receptor antagonists for treating severe anxiety disorders |
Publications (2)
Publication Number | Publication Date |
---|---|
AU5752798A AU5752798A (en) | 1998-06-29 |
AU729708B2 true AU729708B2 (en) | 2001-02-08 |
Family
ID=27517384
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
AU57527/98A Ceased AU729708B2 (en) | 1996-12-02 | 1997-11-25 | Use of NK-1 receptor antagonists for treating severe anxiety disorders |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP0942734A1 (en) |
JP (1) | JP2001504848A (en) |
AU (1) | AU729708B2 (en) |
CA (1) | CA2273785A1 (en) |
WO (1) | WO1998024439A1 (en) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2002517446A (en) * | 1998-06-11 | 2002-06-18 | メルク シャープ エンド ドーム リミテッド | Use of an NK-1 receptor antagonist for the treatment of a mental disorder |
AU4279699A (en) * | 1998-06-11 | 1999-12-30 | Merck Sharp & Dohme Limited | Use of a nk-1 receptor antagonist for treating psychiatric disorders |
ES2150378B1 (en) * | 1998-08-07 | 2001-07-01 | Esteve Labor Dr | EMPLOYMENT OF ARIL (OR HETEROARIL) AZOLILCARBINOLES DERIVATIVES IN THE PREPARATION OF A MEDICINAL PRODUCT FOR THE TREATMENT OF DISORDERS MEDIATED BY AN EXCESS OF SUBSTANCE P. |
AP2002002501A0 (en) * | 1999-10-07 | 2002-06-30 | Warner Lambert Co | Synergistic combinations of an NK1 receptor antagonist and a gaba structural analog. |
BRPI0807972A2 (en) | 2007-01-24 | 2014-06-10 | Glaxo Group Ltd | PHARMACEUTICAL COMPOSITIONS UNDERSTANDING 3,5-DIAMINO-6- (2,3-DICHLOPHENYL) -L, 2,4-TRIAZINE OR R (-) - 2,4-DIAMINO-5- (2,3-DICHLOROPHENYL) -6- FLUOROMETILPIRIM IDINA AND ONE NK1 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0577394A1 (en) * | 1992-06-29 | 1994-01-05 | Merck & Co. Inc. | Morpholine and thiomorpholine tachykinin receptor antagonists |
WO1995010124A1 (en) * | 1993-10-04 | 1995-04-13 | Eveready Battery Company, Inc. | Process for ultrasonic sealing an anode cup into a gasket for electrochemical cells |
WO1996005181A1 (en) * | 1994-08-15 | 1996-02-22 | Merck Sharp & Dohme Limited | Morpholine derivatives and their use as therapeutic agents |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB9201179D0 (en) * | 1992-01-21 | 1992-03-11 | Glaxo Group Ltd | Chemical compounds |
IL111002A (en) * | 1993-09-22 | 1998-09-24 | Glaxo Group Ltd | Piperidine derivatives their preparation and pharmaceutical compositions containing them |
ES2164758T3 (en) * | 1993-12-29 | 2002-03-01 | Merck Sharp & Dohme | SUBSTITUTED MORPHOLINE DERIVATIVES AND ITS USE AS THERAPEUTIC AGENTS. |
-
1997
- 1997-11-25 CA CA002273785A patent/CA2273785A1/en not_active Abandoned
- 1997-11-25 JP JP52517098A patent/JP2001504848A/en active Pending
- 1997-11-25 EP EP97953721A patent/EP0942734A1/en not_active Withdrawn
- 1997-11-25 WO PCT/EP1997/006683 patent/WO1998024439A1/en not_active Application Discontinuation
- 1997-11-25 AU AU57527/98A patent/AU729708B2/en not_active Ceased
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0577394A1 (en) * | 1992-06-29 | 1994-01-05 | Merck & Co. Inc. | Morpholine and thiomorpholine tachykinin receptor antagonists |
WO1995010124A1 (en) * | 1993-10-04 | 1995-04-13 | Eveready Battery Company, Inc. | Process for ultrasonic sealing an anode cup into a gasket for electrochemical cells |
WO1996005181A1 (en) * | 1994-08-15 | 1996-02-22 | Merck Sharp & Dohme Limited | Morpholine derivatives and their use as therapeutic agents |
Also Published As
Publication number | Publication date |
---|---|
CA2273785A1 (en) | 1998-06-11 |
EP0942734A1 (en) | 1999-09-22 |
JP2001504848A (en) | 2001-04-10 |
AU5752798A (en) | 1998-06-29 |
WO1998024439A1 (en) | 1998-06-11 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU731349B2 (en) | Use of NK-1 receptor antagonists for treating sexual dysfunctions | |
AU731672B2 (en) | Use of NK-1 receptor antagonists for treating bipolar disorders | |
EP0942732B1 (en) | Use of nk-1 receptor antagonists for treating movement disorders | |
US5977104A (en) | Use of NK-1 receptor antagonists for treating bipolar disorders | |
AU729708B2 (en) | Use of NK-1 receptor antagonists for treating severe anxiety disorders | |
US6114315A (en) | Use of NK-1 receptor antagonists for treating major depressive disorders with anxiety | |
EP0941092B1 (en) | Use of nk-1 receptor antagonists for treating major depressive disorders | |
AU731674B2 (en) | Use of NK-1 receptor antagonists for treating substance use disorders | |
AU732633B2 (en) | Use of NK-1 receptor antagonists for treating schizophrenic disorders | |
AU736042B2 (en) | Use of NK-1 receptor antagonists for treating major depressive disorders with anxiety | |
EP0942733B1 (en) | Use of nk-1 receptor antagonists for treating cognitive disorders | |
AU731676B2 (en) | Use of NK-1 receptor antagonists for treating stress disorders | |
US6271230B1 (en) | Use of NK-1 receptor antagonists for treating cognitive disorders | |
US6087348A (en) | Use of NK-1 receptor antagonists for treating stress disorders | |
US6613765B1 (en) | Use of NK-1 receptor antagonists for treating major depressive disorders |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
FGA | Letters patent sealed or granted (standard patent) | ||
MK14 | Patent ceased section 143(a) (annual fees not paid) or expired |