AU2001284307A1 - Tetrahydrofuran derivatives and their use as NK-1 antagonists - Google Patents
Tetrahydrofuran derivatives and their use as NK-1 antagonistsInfo
- Publication number
- AU2001284307A1 AU2001284307A1 AU2001284307A AU2001284307A AU2001284307A1 AU 2001284307 A1 AU2001284307 A1 AU 2001284307A1 AU 2001284307 A AU2001284307 A AU 2001284307A AU 2001284307 A AU2001284307 A AU 2001284307A AU 2001284307 A1 AU2001284307 A1 AU 2001284307A1
- Authority
- AU
- Australia
- Prior art keywords
- hydrogen
- 4alkyl
- ring
- compound
- 4alkoxy
- 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.)
- Granted
Links
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical class C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 title description 37
- 239000005557 antagonist Substances 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims description 137
- 239000001257 hydrogen Substances 0.000 claims description 71
- 229910052739 hydrogen Inorganic materials 0.000 claims description 71
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 52
- -1 Cι-4alkyl Chemical group 0.000 claims description 51
- 150000002431 hydrogen Chemical group 0.000 claims description 36
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 34
- 229910052736 halogen Inorganic materials 0.000 claims description 27
- 150000002367 halogens Chemical group 0.000 claims description 27
- 238000000034 method Methods 0.000 claims description 23
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 21
- 229910052731 fluorine Inorganic materials 0.000 claims description 20
- 239000011737 fluorine Chemical group 0.000 claims description 20
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 20
- 150000003839 salts Chemical class 0.000 claims description 20
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 19
- 125000001424 substituent group Chemical group 0.000 claims description 18
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 17
- 229910052757 nitrogen Inorganic materials 0.000 claims description 15
- 125000006413 ring segment Chemical group 0.000 claims description 13
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 11
- 239000000460 chlorine Chemical group 0.000 claims description 11
- 229910052801 chlorine Inorganic materials 0.000 claims description 11
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 10
- 229910052760 oxygen Inorganic materials 0.000 claims description 10
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 8
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical group C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 8
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical group C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 7
- 206010047700 Vomiting Diseases 0.000 claims description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
- 125000001072 heteroaryl group Chemical group 0.000 claims description 7
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 6
- 208000035475 disorder Diseases 0.000 claims description 6
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 6
- 125000005842 heteroatom Chemical group 0.000 claims description 6
- 229910052705 radium Inorganic materials 0.000 claims description 6
- 229910052701 rubidium Inorganic materials 0.000 claims description 6
- 208000002193 Pain Diseases 0.000 claims description 5
- 102000003141 Tachykinin Human genes 0.000 claims description 5
- 150000001721 carbon Chemical group 0.000 claims description 5
- 125000004122 cyclic group Chemical group 0.000 claims description 5
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- 108060008037 tachykinin Proteins 0.000 claims description 5
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
- 208000019695 Migraine disease Diseases 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 206010027599 migraine Diseases 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 208000019901 Anxiety disease Diseases 0.000 claims description 3
- 125000003118 aryl group Chemical group 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 125000004193 piperazinyl group Chemical group 0.000 claims description 2
- 238000002560 therapeutic procedure Methods 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims 4
- 206010061218 Inflammation Diseases 0.000 claims 2
- 206010036376 Postherpetic Neuralgia Diseases 0.000 claims 2
- 230000036506 anxiety Effects 0.000 claims 2
- 230000004054 inflammatory process Effects 0.000 claims 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 1
- 125000000686 lactone group Chemical group 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 82
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 60
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 51
- 238000006243 chemical reaction Methods 0.000 description 50
- 239000002904 solvent Substances 0.000 description 39
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 27
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 26
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 16
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 16
- 238000005481 NMR spectroscopy Methods 0.000 description 15
- 239000000203 mixture Substances 0.000 description 15
- 239000003054 catalyst Substances 0.000 description 14
- 238000000746 purification Methods 0.000 description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- 229910021529 ammonia Inorganic materials 0.000 description 10
- 238000003818 flash chromatography Methods 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 230000008570 general process Effects 0.000 description 9
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 8
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 8
- 239000012267 brine Substances 0.000 description 8
- 150000008282 halocarbons Chemical class 0.000 description 8
- 239000000741 silica gel Substances 0.000 description 8
- 229910002027 silica gel Inorganic materials 0.000 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- CMXDTBRSVVYDGC-UHFFFAOYSA-N 2-[4-(aminomethyl)-3-phenyloxolan-2-yl]oxy-2-[3,5-bis(trifluoromethyl)phenyl]ethanol Chemical compound C=1C=CC=CC=1C1C(CN)COC1OC(CO)C1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 CMXDTBRSVVYDGC-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- ZXBNZHRICXGLIL-UHFFFAOYSA-N 2-[3,5-bis(trifluoromethyl)phenyl]-2-[4-[(dibenzylamino)methyl]-3-phenyloxolan-2-yl]oxyethanol Chemical compound C=1C(C(F)(F)F)=CC(C(F)(F)F)=CC=1C(CO)OC(C1C=2C=CC=CC=2)OCC1CN(CC=1C=CC=CC=1)CC1=CC=CC=C1 ZXBNZHRICXGLIL-UHFFFAOYSA-N 0.000 description 5
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 5
- 238000012746 preparative thin layer chromatography Methods 0.000 description 5
- 239000000651 prodrug Substances 0.000 description 5
- 229940002612 prodrug Drugs 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 230000009467 reduction Effects 0.000 description 5
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 229910000085 borane Inorganic materials 0.000 description 4
- 239000003638 chemical reducing agent Substances 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- 239000000377 silicon dioxide Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 229920002554 vinyl polymer Polymers 0.000 description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 3
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 3
- DGRGYWUZXWKNID-UHFFFAOYSA-N [4-[(dibenzylamino)methyl]-3-phenyloxolan-2-yl] 3,5-bis(trifluoromethyl)benzoate Chemical compound FC(F)(F)C1=CC(C(F)(F)F)=CC(C(=O)OC2C(C(CN(CC=3C=CC=CC=3)CC=3C=CC=CC=3)CO2)C=2C=CC=CC=2)=C1 DGRGYWUZXWKNID-UHFFFAOYSA-N 0.000 description 3
- 125000003342 alkenyl group Chemical group 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 125000001153 fluoro group Chemical group F* 0.000 description 3
- 208000027866 inflammatory disease Diseases 0.000 description 3
- 239000011630 iodine Substances 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 3
- GDEHUJNPJRSZJX-UHFFFAOYSA-N (5-oxo-4-phenyloxolan-3-yl)methylcarbamic acid Chemical compound OC(=O)NCC1COC(=O)C1C1=CC=CC=C1 GDEHUJNPJRSZJX-UHFFFAOYSA-N 0.000 description 2
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 2
- 125000004793 2,2,2-trifluoroethoxy group Chemical group FC(CO*)(F)F 0.000 description 2
- WAKMMQSMEDJRRI-UHFFFAOYSA-N 3,5-bis(trifluoromethyl)benzoyl chloride Chemical compound FC(F)(F)C1=CC(C(Cl)=O)=CC(C(F)(F)F)=C1 WAKMMQSMEDJRRI-UHFFFAOYSA-N 0.000 description 2
- AUNIPFJRJAYDJO-UHFFFAOYSA-N 3-iodo-3-phenylprop-2-en-1-ol Chemical compound OCC=C(I)C1=CC=CC=C1 AUNIPFJRJAYDJO-UHFFFAOYSA-N 0.000 description 2
- CRLBYVDFTYSNHL-UHFFFAOYSA-N 4-[(dibenzylamino)methyl]-3-phenyloxolan-2-one Chemical compound C=1C=CC=CC=1C1C(=O)OCC1CN(CC=1C=CC=CC=1)CC1=CC=CC=C1 CRLBYVDFTYSNHL-UHFFFAOYSA-N 0.000 description 2
- PBZHVTZQMBGKMT-UHFFFAOYSA-N 4-phenyl-2h-furan-5-one Chemical compound O=C1OCC=C1C1=CC=CC=C1 PBZHVTZQMBGKMT-UHFFFAOYSA-N 0.000 description 2
- 208000008811 Agoraphobia Diseases 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 239000007818 Grignard reagent Substances 0.000 description 2
- 101000831616 Homo sapiens Protachykinin-1 Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- 102100024304 Protachykinin-1 Human genes 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 125000000304 alkynyl group Chemical group 0.000 description 2
- XXROGKLTLUQVRX-UHFFFAOYSA-N allyl alcohol Chemical compound OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 description 2
- 150000001450 anions Chemical class 0.000 description 2
- 208000010668 atopic eczema Diseases 0.000 description 2
- 150000001540 azides Chemical class 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 229910002091 carbon monoxide Inorganic materials 0.000 description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 150000002390 heteroarenes Chemical class 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
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- 150000002596 lactones Chemical group 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 201000008482 osteoarthritis Diseases 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
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- 239000006187 pill Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 230000005855 radiation Effects 0.000 description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 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 2
- 239000003826 tablet Substances 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- 125000004853 tetrahydropyridinyl group Chemical group N1(CCCC=C1)* 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- 230000008733 trauma Effects 0.000 description 2
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- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 201000001716 specific phobia Diseases 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000005062 synaptic transmission Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 108700012359 toxins Proteins 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- CYTQBVOFDCPGCX-UHFFFAOYSA-N trimethyl phosphite Chemical compound COP(OC)OC CYTQBVOFDCPGCX-UHFFFAOYSA-N 0.000 description 1
- 208000027491 vestibular disease Diseases 0.000 description 1
- 235000012431 wafers Nutrition 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Description
TETRAHYDROFURAN DERIVATIVES AND THEIR USE AS THERAPEUTIC AGENTS
This invention relates to a class of tetrahydrofuran compounds which are useful as tachykinin antagonists. More particularly, the compounds of the invention are useful as neurokinin 1 (NK-1) receptor antagonists.
The present invention provides compounds ofthe formula (I):
(I)
wherein
R1 is hydrogen, halogen, Ci-ealkyl, Ci-βalkoxy, fluoroCi-βalkyl, fluoroCi-βalkoxy, C3-7cycloalkyl, C3-7cycloalkylCι-4alkyl, NO2, CN, SRa, SORa, S02Ra, CO2Ra, CONRaR , C2-6alkenyl, C2-6alkynyl or Cι-4alkyl substituted by Cι-4alkoxy, wherein Ra and Rb each independently represent hydrogen or Cι-4alkyl;
R2 is hydrogen, halogen, Ci-βalkyl, fluoroCi-βalkyl or Ci-βalkoxy substituted by Cι-4alkoxy; R3 is hydrogen, halogen or fluoroCi-βalkyl;
R4 is hydrogen, halogen, Ci-βalkyl, Ci-βalkoxy, fluoroCi-βalkyl, fluoroCi-βalkoxy, hydroxy, NO2, CN, SRa, SORa, S02Ra, C02Ra, CONRaRb, C2-βalkenyl, C2-6alkynyl or Cι-4alkyl substituted by Cι-4alkoxy, wherein Ra and Rb are as previously defined;
R5 is hydrogen, halogen, Ci-βalkyl, fluoroCi-βalkyl or Ci-βalkoxy substituted by Cι-4alkoxy;
R6 represents hydrogen or a Cι-4alkyl group optionally substituted by a hydroxy group; R7 represents halogen, hydroxy, C2-4alkenyl, C2-4alkynyl, N3,
-NRiOR11, -NRaCORb, -OS02Ra, -(CH2)pNRa(CH2)qCOOR , CORa, COORa, -N=C=O, or a five membered or six membered nitrogen-containing heteroaromatic ring optionally containing 1, 2 or 3 additional heteroatoms selected from N, O and S which heteroaromatic ring is optionally substituted at any substitutable position by a substituent selected from =0, =S, halogen, hydroxy, -SH, CORa, C02Ra, -ZNRWRU Cι-4alkyl, hydroxyCι-4alkyl, fluoroCι-4alkyl, chloroCι-4alkyl, Cι-4alkoxy, fluoroCι-4alkoxy or Cι-4alkoxy substituted by a Cι-4alkoxy or hydroxyl group, and wherein said C2-4alkenyl and C2-4alkynyl groups are optionally substituted by a substituent selected from halogen, hydroxy, N3, -NR10Rn, -NRaCOR , -OS02Ra, -(CH2)pNRa(CH2)qCOORb, CORa or COORa; or R7 represents a C-linked nitrogen-containing ring of the formula
wherein A represents NR14 or O, and B represents a bond, CH2, NR14 or O, wherein one or both hydrogen atoms in said CH2 moiety may be replaced with one or both of R12 and R13, or alternatively, one of the hydrogen atoms in said CH2 moiety together with a hydrogen atom from an adjacent carbon are replaced by a double bond; with the proviso that when A is O, then B is NR14; and with the further proviso that when R7 represents said C-linked nitrogen-containing ring, n is zero and R8 is hydrogen;
R8 represents hydrogen, Ci-βalkyl, fluoroCι-6alkyl, hydroxy, Ci-βalkoxy or hydroxyCi-βalkyl;
R9 represents hydrogen, halogen, Ci-βalkyl, CH2θRc, oxo, Cθ2Ra or CONRaRb where Ra and Rb are as previously defined and Rc represents hydrogen, Ci-βalkyl or phenyl;
R10 is hydrogen, Cι-4alkyl, C3-7cycloalkyl, C3-7cycloalkylCι-4alkyl, C2-4alkyl substituted by a Cι-4alkoxy or hydroxyl group, or R10 is a five membered or six membered nitrogen-containing heteroaromatic ring as previously defined; R11 is hydrogen or Cι-4alkyl, C3-7cycloalkyl, C3-7cycloalkylCι-4alkyl, or U2-4alkyl substituted by a Cι-4alkoxy or hydroxyl group; or R10, R11 and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms, optionally substituted by one or two groups selected from hydroxy, CORe, CO Re, Cι-4alkyl optionally substituted by a Cι-4alkoxy or hydroxyl group, or Cwalkoxy optionally substituted by a Cι-4alkoxy or hydroxyl group, or a five membered or six membered nitrogen-containing heteroaromatic ring as previously defined, or said heteroaliphatic ring is substituted by a spiro-fused lactone ring or a spiro-fused ring of the formula -(CH2)rO(CH2)s- (where r and s are each independently zero, 1, 2 or 3 and the sum total of r and s is 3), and said heteroaliphatic ring optionally containing a double bond, which heteroaliphatic ring may optionally contain an oxygen or sulphur ring atom, a group S(O) or S(0)2 or a second nitrogen atom which will be part of a NH or NRd moiety, where Rd is Cι-4alkyl optionally substituted by hydroxy or Cι-4alkoxy, and where Re is hydrogen, Cι-4alkyl or benzyl; or R10, R11 and the nitrogen atom to which they are attached form a non-aromatic azabicyclic ring system of 6 to 12 ring atoms; or R10, R11 and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms to which is fused a benzene ring or a five membered or six membered nitrogen-containing heteroaromatic
ring optionally containing 1, 2 or 3 additional heteroatoms selected from N, O and S;
R12 and R13 each independently represent hydrogen, hydroxy, CORe, C02Re, Cι-4alkyl optionally substituted by a Cι-4alkoxy or hydroxyl group, or Cι-4alkoxy optionally substituted by a Cι-4alkoxy or hydroxyl group; or, when they are attached to the same carbon atom, R12 and R13 may together represent =0, =CHC02Ra, -0(CH2)mO-, -CH20(CH2)k-, -CH2OCH2C(0)-, -CH2OCH2CH(OH)-, -CH2OCH2C(CH3)2-, -CH2θC(CH3)2CH2-, -C(CH3)2OCH2CH2-, -CH2C(0)OCH2-, -OC(0)CH2CH2-, -C(0)OCH2CH2-, -C(0)OC(CH3)2CH2-, -C(0)OCH2C(CH3)2-, -OCH2(CH2)k-, -OC(CH3)2CH2CH2-, -OCH2C(CH3)2CH2-, -OCH2CH2C(CH3)2-, -OCH2CH=CHCH2-, -OCH2CH(OH)CH2CH2-, -OCH2CH2CH(OH)CH2-, -OCH2C(0)CH2CH2-, -OCH2CH2C(0)CH2-, or a group of the formula
or, where they are attached to adjacent carbon atoms, R12 and R13 may together represent -OCH2CH2- or -OCH2CH(OH)-, or R12 and R13 may together form a fused benzene ring; or, R12 and R13 together form a Cι-2alkylene bridge across the pyrrolidine, piperidine, morpholine or piperazine ring to which they are attached;
R14 represents hydrogen, benzyl, Cι-4alkyl, C3-7cycloalkyl, C3-7cycloalkylCι-4alkyl, or C2-4alkyl substituted by a Cι-4alkoxy or hydroxyl group; j- i5 represents hydrogen, halogen, hydroxy, Cι-4alkyl, hydroxyCι-4alkyl or fluoroCι-4alkyl;
Z represents a bond, Ci-βalkylene or C3-6cycloalkylene;
k is 1, 2 or 3; m is 1 or 2; n is zero, 1 or 2; p is 1 or 2; and q is 1 or 2; and pharmaceutically acceptable salts thereof.
A preferred class of compounds of formula (I) is that wherein R1 is hydrogen, Cι-4alkyl, Cι-4alkoxy, halogen or CF3.
Another preferred class of compounds of formula (I) is that wherein R2 is hydrogen, Cι-4alkyl, Cι-4alkoxy, halogen or CF3.
Also preferred is the class of compounds of formula (I) wherein R3 is hydrogen, fluorine, chlorine or CF3.
A particularly preferred class of compounds of formula (I) is that wherein R1 is fluorine, chlorine or CF3. Another particularly preferred class of compounds of formula (I) is that wherein R2 is hydrogen, fluorine, chlorine or CF3.
Also particularly preferred is the class of compounds of formula (I) wherein R3 is hydrogen, fluorine, chlorine or CF3.
Preferably R1 and R2 are in the 3 and 5 positions of the pheriyl ring. More preferably R1 is 3-fluoro or 3-CF3.
More preferably R2 is 5-fluoro or 5-CF3.
More preferably R3 is hydrogen.
Most preferably R1 is 3-F or 3-CF3, R2 is 5-CF3 and R3 is hydrogen.
A further preferred class of compound of formula (I) is that wherein R4 is hydrogen or fluorine, especially hydrogen.
Another preferred class of compounds of formula (I) is that wherein R5 is hydrogen, fluorine, chlorine or CF3.
Preferably R4 is hydrogen or 3-fluoro, especially hydrogen, and R5 is hydrogen or 4-fluoro. R6 is preferably Cι-4alkyl optionally substituted by hydroxy. In particular, R6 is preferably a methyl or hydroxymethyl group.
Where -NR10RU is defined as a substituent R7 or as a substituent on a heteroaromatic ring in the definition of R7, then R10 may aptly be a Cι-4alkyl group or a C2-4alkyl group substituted by a hydroxyl or Cι-2alkoxy group, R11 may aptly be a Cι-4alkyl group or a C2-4alkyl group substituted by a hydroxyl or Cι-2alkoxy group, or R10 and R11 may be linked so that, together with the nitrogen atom to which they are attached, they form an azetidinyl, pyrrolidinyl, piperidinyl, morpholino, thiomorpholino, piperazino or piperazino group substituted on the nitrogen atom by a Cι-4alkyl group or a C2-4alkyl group substituted by a hydroxy or Cι-2alkoxy group. Particularly preferred heteroaliphatic rings formed by -NR^R11 are azetidine, pyrolidine, piperidine, morpholine, piperazine and N-methylpiperazine, and especially piperidine.
Where the group NR^R11 represents a heteroaliphatic ring of 4 to 7 ring atoms substituted by two groups, the first substituent is preferably selected from hydroxy, CO2Re (where Re is hydrogen, methyl, ethyl or benzyl), or Cι-2alkyl substituted by hydroxy. The second substituent is preferably a methyl group. Where two substituents are present, said substituents are preferably attached to the same carbon atom of the heteroaliphatic ring. Where the group NR10RU represents a heteroaliphatic ring of 4 to 7 ring atoms substituted by a spiro-fused lactone ring, particularly preferred examples are:
Where the group NR10R1:l represents a heteroaliphatic ring of 4 to 7 ring atoms substituted by a spiro-fused ring ofthe formula -(CH2)rO(CH2)s-, particularly preferred examples are:
Where the group NR10RU represents a heteroaliphatic ring of 4 to 7 ring atoms and said ring contains a double bond, a particularly preferred group is 3-pyrroline.
Where the group NR10Rn represents a non-aromatic azabicyclic ring system, such a system may contain between 6 and 12, and preferably between 7 and 10, ring atoms. Suitable rings include 5-azabicyclo [2.1. l]hexyl, 5-azabicyclo [2.2. l]heptyl, 6-azabicyclo [3.2.1] octyl, 2-azabicyclo[2.2.2]octyl, 6-azabicyclo[3.2.2]nonyl, 6-azabicyclo[3.3.1]nonyl, 6-azabicyclo[3.3.2]decyl, 7-azabicyclo[4.3.1]decyl, 7-azabicyclo[4.4.1]undecyl and 8-azabicyclo[5.4.1]dodecyl, especially 5-azabicyclo[2.2.1]heptyl and 6-azabicyclo[3.2.1]octyl.
Where the group NR10R1:l represents a heteroaliphatic ring of 4 to 7 ring atoms to which is fused a benzene ring or a five membered or six membered nitrogen-containing heteroaromatic ring ring optionally containing 1, 2 or 3 additional heteroatoms selected from N, O and S, said heteroaromatic ring is preferably a five-membered ring, in particular a pyrrole, imidazole or triazole ring, a nitrogen atom of which is preferably included in the heteroaliphatic ring. Suitable examples of such fused ring systems include
Particularly suitable moieties NR10R1:1 include those wherein NR10RU is amino, methylamino, dimethylamino, dieth lamino, azetidino, pyrrolidino, piperidino, morpholino and piperazino.
Where R7 represents an optionally substituted five or six-membered nitrogen-containing heteroaromatic ring optionally containing 1, 2 or 3 additional heteroatoms selected from N, 0 and S, the heteroaromatic ring is selected from pyrrole, pyridine, pyrazole, imidazole, oxazole, isoxazole, thiazole, isothiazole, pyrazine, pyrimidine, pyridazine, triazole, oxadiazole, thiadiazole, triazine, and tetrazole.
Preferred compounds of the present invention are those wherein R7 is a group selected from imidazole, 1,2,3-triazole and 1,2,4-triazole.
Particularly preferred compounds ofthe present invention are those wherein R7 is a group selected from imidazol-1-yl and 1,2,4-triazol-l-yl.
Where R7 represents an optionally substituted five membered or six membered nitrogen-containing heteroaromatic ring, preferred substituents are -ZNR10Rn and Cι-2alkyl (especially methyl). With reference to the group ZNR10R1:l defined as a substituent on a heteroaromatic ring in the definition of R7, Z may be a bond or a linear, branched or cyclic group. Favourably Z is a bond or contains 1 to 4 carbon atoms and most favourably 1 to 2 carbon atoms. A particularly favourable group Z is -CH2-. In this instance, particularly suitable moieties NR10Rn include those wherein NR10Rn is amino, methylamino, dimethylamino, diethylamino, azetidino, pyrrolidino, piperidino, morpholino and piperazino. Most especially, -ZNR10Rn, as a substituent on a heteroaromatic ring in the definition of R7, is preferably CH2N(CH3)2.
A further preferred class of compound of formula (I) is that wherein R7 represents halogen (especially iodine), hydroxy, vinyl, N3 or -OS02Ra (especially where Ra is methyl).
Another preferred class of compound of formula (I) is that wherein R8 is hydrogen or methyl, and especially hydrogen.
Another preferred class of compounds of formula (I) is that wherein R12 is hydrogen, hydroxy, Cι-2alkyl substituted by hydroxy, Cι-4alkoxy (especially methoxy) or C02Re (where Re is hydrogen, methyl ethyl or benzyl).
A further preferred class of compounds of formula (I) is that wherein R13 is hydrogen or Cι-4alkyl (especially methyl).
R12 and R13 are preferably attached to the same carbon atom. In particular, when B represents CH2, both hydrogen atoms in said CH2 moiety are replaced by R12 and R13 forming a moiety ofthe formula CRi R13.
Where R12 and R13 are attached to the same carbon atom they may, in particular, together represent -C(0)OCH2CH2-.
In a further preferred class of compounds of formula (I), R14 preferably represents hydrogen, methyl or ethyl. Where A and B both represent NR14, each R14 substituent is independently defined.
A further preferred class of compound of formula (I) is that wherein n is 1 or 2, and especially wherein n is 1.
Another preferred class of compound of formula (I) is that wherein R9 is hydrogen.
One favoured group of compounds of the present invention are of the formula (la) and pharmaceutically acceptable salts thereof:
(la)
wherein
A1 is fluorine or CF3; A2 is fluorine or CF3;
A3 is fluorine or hydrogen;
A4 is fluorine or hydrogen, especially hydrogen;
A5 is methyl or hydroxymethyl; and
R7 and n are as defined in relation to formula (I). When any variable occurs more than one time in formula (I) or in any substituent, its definition on each occurrence is independent of its definition at every other occurrence.
As used herein, the term "alkyl" or "alkoxy" as a group or part of a group means that the group is straight or branched. Examples of suitable alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl and t-butyl. Examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy and t-butoxy.
As used herein, the terms "fluoroCi-βalkyl" and fluoroCi-βalkoxy" means a Ci-βalkyl or Ci-βalkoxy group in which one or more (in particular, 1 to 3) hydrogen atoms have been replaced by fluorine atoms. Similarly, the term "fluoroCι-4alkyl" means a Cι-4alkyl group in which one or more (in particular 1 to 3) hydrogen atoms have been replaced by fluorine atoms. Particularly preferred are fluoroCι-3alkyl and fluoroCι-3alkoxy groups, for example, CF3, CH2CH2F, CH2CHF2, CH2CF3, OCF3, OCH2CH2F, OCH2CHF2 or OCH2CF3, and most especially CF3, OCF3 and OCH2CF3.
The cycloalkyl groups referred to herein may represent, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. A suitable cycloalkylalkyl group may be, for example, cyclopropylmethyl.
Similarly cycloalkoxy groups referred to herein may represent, for example, cyclopropoxy or cyclobutoxy.
As used herein, the terms "alkenyl" and "alkyn l" as a group or part of a group means that the group is straight or branched. Examples of suitable alkenyl groups include vinyl and allyl. A suitable alkynyl group is propargyl.
When used herein the term "halogen" means fluorine, chlorine, bromine and iodine. The most apt halogens are fluorine and chlorine of which fluorine is preferred, unless otherwise stated.
Specific compounds within the scope of this invention include: [(2SR, SSR, 4,S-R)-2-({(lR-S)-l-[3,5-bis(trifluoromethyl)phenyl]-ethyl}oxy)-3- phenyltetrahydro-4-furanyl]methanamine;
[(2SR, 3-S-R, 4S-R)-2-({(l-Si2)-l-[3,5-bis(trifluoromethyl)phenyl]-ethyl}oxy)-3- phenyltetrahydro-4-furanyl]methanamine;
[(2SR, 3--?i?, 4S-R)-2-({(lS'i2)-l-[3,5-bis(trifluoromethyl)phenyl]-ethyl}oxy)-3- phenyltetrahydro-4-furanyl] -iV^V-dimethylmethanamine;
(2SR, SSR, 4SR, 2[(V)]RS) 2-(4-aminomethyl-3-phenyl-tetrahydro-furan-2- yloxy)-2-(3,5-bis(trifluoromethyl)phenyl)-ethanol;
(2SR, 3SR, 4SR, 2[(1')]SR) 2-(4-aminomethyl-3-phenyl-tetrahydrofuran-2- yloxy)-2-(3,5-bis(trifluoromethyl)phenyl)-ethanol; (2-R-S)-2-[3,5-bis(trifluoromethyl)phenyl]-2-({(2S-R,3-S-R,4S-R)-4-[(N,N- dimethylamino)methyl]-3-phenyltetrahydro-2-furanyl}oxy)ethanol;
[(2β-S, 3Λ-S, 4-SΛ)-2-({(l-Si2)-l-[3,5-bis(trifluoromethyl)phenyl]-ethyl}oxy)-3- phenyltetrahydro-4-furanyl]methanamine;
[(2RS, 3-RSf, 4-S-R)-2-({(LR»S)-l-[3,5-bis(trifluoromethyl)phenyl]-ethyl}oxy)-3- phenyltetrahydro-4-furanyι] methanamine;
[(2RS, 3β»S, 4-Sf-R)-5-({(-l-RSf)-l-[3,5-bis(trifluoromethyl)phenyl]-ethyl}oxy)-3- phenyltetrahydro-4-furanyl]--A^rN-dim.ethylπιethanaιnine;
(2RS, SSR, 4SR, 2[(1')]RS) 2-(4-aminomethyl-3-phenyl-tetrahydrofuran-2- yloxy)-2-(3,5-bis(trifluoromethyl)phenyl)-ethanol; (2RS, SSR, 4SR, 2[(V)]SR) 2-(4-aminomethyl-3-phenyl-tetrahydrofuran-2- yloxy)-2-(3,5-bis(trifluoromethyl)phenyl)-ethanol; and pharmaceutically acceptable salts thereof.
In a further aspect of the present invention, the compounds of formula (I) may be prepared in the form of a pharmaceutically acceptable salt, especially an acid addition salt.
For use in medicine, the salts of the compounds of formula (I) will be non-toxic pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds according to the invention or of their non-toxic pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, fumaric acid, p-toluenesulphonic 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 quaternary ammonium salts in which the amino nitrogen atom carries a suitable organic group such as an alkyl, alkenyl, alkynyl or aralkyl moiety. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include metal salts such as alkali metal salts, e.g. sodium or potassium salts; and alkaline earth metal salts, e.g. calcium or magnesium salts.
The salts may be formed by conventional means, such as by reacting the free base form of the product with one or more equivalents ofthe appropriate acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water which is removed in vacuo or by freeze drying or by exchanging the anions of an existing salt for another anion on a suitable ion exchange resin.
The present invention includes within its scope prodrugs of the compounds of formula (I) above. In general, such prodrugs will be functional derivatives ofthe compounds of formula (I) which are readily convertible in vivo into the required compound of formula (I). Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
A prodrug may be a pharmacologically inactive derivative of a biologically active substance (the "parent drug" or "parent molecule") that requires transformation within the body in order to release the active drug, and that has improved delivery properties over the parent drug molecule. The transformation in vivo may be, for example, as the result of some metabolic process, such as chemical or enzymatic hydrolysis of a carboxylic, phosphoric or sulphate ester, or reduction or oxidation of a susceptible functionality.
The present invention includes within its scope solvates ofthe compounds of formula (I) and salts thereof, for example, hydrates.
The compounds according to the invention have at least three asymmetric centres, and may accordingly exist both as enantiomers and as diastereoisomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention.
The preferred compounds of the formula (I) and (la) will have the stereochemistry of the 2-, 3-, 4- and 8-positions as shown in formulae (lb) and (Ic)
(lb)
It will be appreciated that the preferred definitions ofthe various substituents recited herein may be taken alone or in combination and, unless otherwise stated, apply to the generic formula for compounds of the present invention as well as to the preferred classes of compound represented by formula (la), formula (lb) and formula (Ic).
The present invention further provides pharmaceutical compositions comprising one or more compounds of formula (I) in association with a pharmaceutically acceptable carrier or excipient.
Preferably the compositions according to the invention are in unit dosage forms such as tablets, pills, capsules, powders, granules, solutions or suspensions, or suppositories, for oral, parenteral or rectal administration, or administration by inhalation or insufflation. Oral compositions such as tablets, pills, capsules or wafers are particularly preferred. A more detailed description of pharmaceutical compositions that are suitable for the formulation of compounds of the present invention is disclosed in US patent No. 6,071,927, the content of which is incorporated herein by reference (see in particular, column 8, line 50 to column 10, line 4). The present invention further provides a process for the preparation of a pharmaceutical composition comprising a compound of formula (I), which process comprises bringing a compound of formula (I) into association with a pharmaceutically acceptable carrier or excipient.
The compounds of formula (I) are of value in the treatment of a wide variety of clinical conditions which are characterised by the presence of an excess of tachykinin, in particular substance P, activity. A comprehensive listing of clinical conditions, uses and methods of treatment for which the compounds of the present invention will be useful is disclosed in US patent No. 6,071,927, the content of which is incorporated herein by reference (see, in particular, column 10, line 14 to column 22, line 18).
In particular, the compounds ofthe present invention are useful in the treatment of a variety of disorders of the central nervous system. Such disorders include mood disorders, such as depression or more particularly depressive disorders, for example, single episodic or recurrent major depressive disorders and dysthymic disorders, or bipolar disorders, for example, bipolar I disorder, bipolar II disorder and cyclothymic disorder; and anxiety disorders, such as panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, specific phobias, for example, specific animal phobias, social phobias, obsessive-compulsive disorder, stress disorders including post-traumatic stress disorder and acute stress disorder, and generalised anxiety disorders.
The compounds of the present invention are also particularly useful in the treatment of nociception and pain. Diseases and conditions in which pain predominates, include soft tissue and peripheral damage, such as acute trauma, osteoarthritis, rheumatoid arthritis, musculo-skeletal pain, particularly after trauma, spinal pain, myofascial pain syndromes, headache, migraine, episiotomy pain, and burns.
The compounds of the present invention are also particularly useful in the treatment of respiratory diseases, particularly those associated with excess mucus secretion, such as chronic obstructive airways disease, bronchopneumonia, chronic bronchitis, cystic fibrosis and asthma, adult respiratory distress syndrome, and bronchospasm; in the treatment of inflammatory diseases such as inflammatory bowel disease, psoriasis, fibrositis, osteoarthritis, rheumatoid arthritis, pruritis and sunburn; and in the treatment of allergic disorders such as eczema and rhinitis.
The compounds of the present invention are also particularly useful in the treatment of gastrointestinal (GI) disorders, including inflammatory disorders and diseases of the GI tract such as ulcerative colitis, Crohn's disease and irritable bowel syndrome. The compounds of the present invention are also particularly useful in the treatment of emesis, including acute, delayed or anticipatory
emesis, such as emesis induced by chemotherapy, radiation, toxins, pregnancy, vestibular disorders, motion, surgery, migraine, and variations in intercranial pressure. Most especially, the compounds of formula (I) are of use in the treatment of emesis induced by antineoplastic (cytotoxic) agents, including those routinely used in cancer chemotherapy; by radiation including radiation therapy such as in the treatment of cancer; and in the treatment of post-operative nausea and vomiting.
The excellent pharmacological profile of the compounds of the present invention offers the opportunity for their use in therapy at low doses thereby minimising the risk of unwanted side effects.
In the treatment of the conditions associated with an excess of tach kinins, a suitable dosage level is about 0.001 to 50 mg/kg per day, in particular about 0.01 to about 25 mg kg, such as from about 0.05 to about 10 mg/kg per day. For example, in the treatment of conditions involving the neurotransmission of pain sensations, a suitable dosage level is about 0.001 to 25 mg/kg per day, preferably about 0.005 to 10 mg/kg per day, and especially about 0.005 to 5 mg/kg per day. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
In the treatment of emesis, a suitable dosage level is about 0.001 to 10 mg/kg per day, preferably about 0.005 to 5 mg/kg per day, and especially 0.01 to 3 mg/kg per day. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day. In the treatment of psychiatric disorders, a suitable dosage level is about 0.001 to 10 mg/kg per day, preferably about 0.005 to 5 mg/kg per day, and especially 0.01 to 3 mg/kg per day. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day. It will be appreciated that the amount of a compound of formula (I) required for use in any treatment will vary not only with the particular
compounds or composition 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 attendant physician.
According to a general process (A), compounds of formula (I), in which n is 1, may be prepared by the reaction of a compound of formula (II)
(ID
wherein LG is a suitable leaving group such as an alkyl- or arylsulfonyloxy group (e.g. mesylate or tosylate) or a halogen atom (e.g. bromine, chlorine or iodine); with an appropriate amine of the formula HNR10Rn, or a heteroaromatic compound suitable for the addition of a five or six-membered nitrogen containing heteroaromatic ring as defined in relation to formula (I), or an azide such as sodium azide.
In each case, the reaction is preferably effected at an elevated temperature, for example, between 40°C and 80°C, especially between 50°C and 60°C. The reaction with a heteroaromatic compound is preferably effected in the presence of a suitable organic solvent such as dimethylformamide. The reaction with an azide is preferably effected in the presence of di ethylsulfoxide.
A particularly preferred compound of formula (II) is that wherein the group LG is mesylate - i.e. a compound of formula (I) in which R7 is the group -OSO2CH3.
According to another general process (B), compounds of formula (I), in which R7 is hydroxy and n is 1 or 2, may be prepared by the interconversion of a corresponding compound of formula (I) in which n is zero and R7 is vinyl, hereinafter referred to as formula (III)
(HI)
by reaction with ozone, followed by a reaction with a reducing agent such as sodium borohydride (n is 1), or by reaction with a reducing agent such as borane.tetrahydrofuran complex, followed by hydrogen peroxide in the presence of a base such as sodium hydroxide.
According to another general process (C), compounds of formula (I) may be prepared by the reaction of a compound of formula (IV) with a compound of formula (V)
(IV) (V)
preferably in the presence of a resin catalyst such as Amberlyst™ 15, and 3 Angstrom molecular sieves.
The reaction is conveniently effected in a suitable solvent such as a halogenated hydrocarbon, for example, dichloromethane, conveniently at room temperature.
According to another general process (D), compounds of formula (I), in which R6 is either methyl or hydroxymethyl, may be prepared by the reaction of a compound of formula (VI)
(VI)
wherein R7a is as defined for R7 in relation to formula (I) or, more preferably, is a precursor therefor; under either:
(a) (where R6 is methyl) catalytic hydrogenation conditions (e.g. H2, Pd(OH)2 on carbon) in a suitable solvent such as an ester, for example, ethyl acetate; or
(b) (where R6 is hydroxymethyl) reducing conditions (e.g. borane or BH3.THF) followed by treatment with hydrogen peroxide and a base such as sodium hydroxide, conveniently in a solvent such as an ether, for example, tetrahydrofuran.
Where R7a is a precursor group (such as a TBDMS-protected hydroxyl group) deprotection is conveniently effected by treatment with an organic acid such as tetrabutylammonium fluoride.
According to another general process (E), compounds of formula (I) in which R7 is a C-linked nitrogen-containing ring wherein A is NR14 and B is CH2 may be prepared by the reaction of a compound of formula (XII)
(XII)
in the presence of a suitable catalyst, and if desired reducing the tetrahydropyridinyl moiety, and also if desired removing or replacing the benzyl moiety.
Suitable catalysts of use in this reaction include any catalyst or multicomponent catalyst system that initiates olefin metathesis.
Preferred catalysts are single component metal carbene complexes. Particularly preferred catalysts include:
An especially preferred catalyst of use in the present invention is RuCl2(PCv3)2=CHPh, also referred to as Grubbs' catalyst. These catalysts and their use is described, for instance, in the following literature: Bazan et al., J. Am. Chem. Soc, 1991, 113, 6899 and references cited therein.
Nguyen et al, J. Am. Chem. Soc, 1992, 114, 3974. Nguyen and Grubbs, J. Organomet. Chem., 1995, 497, 195 Schwab et al., Angew. Chem. Int. Ed. Eng., 1995, 34, 2039. Schwab et al., J. Am. Chem. Soc, 1996, 118, 100. Grubbs and Chang, Tetrahedron, 1998, 54, 4413.
Suitable organic solvents of use in the reaction include halogenated hydrocarbons, such as dichloromethane or chloroform. The reaction is conveniently effected at room temperature and pressure, for example at about 20°C.
Reduction of the tetrahydropyridinyl moiety may be effected by conventional methodology, for example, by catalytic hydrogenation in the presence of a suitable catalyst such as palladium on carbon, in a suitable solvent such as an alcohol, for example, methanol. These conditions will also conveniently remove the benzyl moiety (R14) which may be replaced using conventional methodology.
According to another general process (F), compounds of formula (I) in which R7 is a C-linked nitrogen-containing ring wherein A is NR14 and B is a bond may be prepared by the reaction of a compound of formula (XIII)
(XIII)
under reducing conditions, for instance, in the presence of borane or borane.tetrahydrofuran complex, followed by treatment with hydrogen peroxide and a base such as sodium hydroxide. The reaction is conveniently effected in a solvent such as an ether, for example, tetrahydrofuran .
If desired, the benzyl moiety (R14) may be removed as described above.
According to another general process (G), compounds of formula (I) in which R7 is a C-linked nitrogen-containing ring wherein A is NR14 and B is O may be prepared by the reaction of a compound of formula (XIV)
(XIV)
with an amine ofthe formula R1 NH2, followed by reduction of the keto function using a suitable reducing agent such as a borohydride, for example sodium cyanoborohydride. The reduction is conveniently effected in a solvent such as an ether, for example, tetrahydrofuran.
According to another general process (H), compounds of formula (I) in which R7 is a C-linked nitrogen-containing ring wherein A is O and B is NR14 may be prepared by the reaction of a compound of formula (XV)
(XV)
under suitable dehydrating conditions, for example, using triphenylphosphine and diethylazodicarboxylate in a suitable solvent such as tetrahydrofuran, at an elevated temperature such as at reflux, or alternatively using methanesulfonyl chloride or benzenesulfonyl chloride in pyridine or triethylamine, in a suitable organic solvent such as dichloromethane, conveniently at a temperature between room temperature and 80°C.
Further details of suitable procedures will be found in the accompanying Examples.
Compounds of formula (II) may be prepared by conventional methods from, for example, a corresponding compound of formula (I) in which R7 is a hydroxyl group. Thus, for example, when LG is a mesylate group a corresponding compound of formula (I) in which R7 is hydroxyl may be reacted with methanesulfonyl chloride in the presence of a base, such as triethylamine. The reaction is conveniently effected in a solvent such as a halogenated hydrocarbon, for example, dichloromethane.
Compounds of formula (III) may be prepared, for example, by the method of general process (C), above Compounds of formula (IV) may be prepared by the reduction of a compound of formula (VII)
(VII)
using conventional conditions such as sodium borohydride in the presence of a transition metal catalyst such as cerium chloride hexahydrate, in a
solvent such as alcohol, for example, ethanol; or using DiBAL in a solvent such as a halogenated hydrocarbon, for example, dichloromethane.
Compounds of formula (VII) in which R7 is vinyl, R8 is hydrogen and n is 1 may be prepared from a compound of formula (VIII)
(VIII) by reaction with a vinyl Grignard reagent such as vinylMgBr, preferably in the presence of copper(I)iodide, and a suitable solvent such as an ether, for example, tetrahydrofuran. This reaction is effected at reduced temperature, for example, below -40°C and preferably at -78°C.
Compounds of formula (VI) may be prepared by the reaction of a compound of formula (X)
(X) with dimethyltitanocene in a solvent such as toluene, pyridine or tetrahydrofuran, or a mixture thereof.
Compounds of formula (X) may be prepared by the reaction of a compound of formula (VII) with L-Selectride™ (lithium tri-sec- butylborohydride) followed by treatment with a compound of formula (XI)
(XI) wherein Hal is a halogen atom, preferably chlorine.
Compounds of formula (XII) may be prepared from a compound of formula (XIII) above, by N-alkylation with an allyl halide, for example, allyl bromide. The reaction is preferably effected in the presence of an inorganic base such as potassium carbonate and a suitable solvent such a dimethylformamide. The reaction is conveniently effected at a temperature between room temperature and 100°C.
Compounds of formula (XIII) may be prepared from a compound of formula (XVI)
(XVI)
by reaction with benzylamine in a suitable solvent such as a halogenated hydrocarbon, for example, dichloromethane. Following basification, using for example basic alumina, the reaction mixture is filtered, evaporated and
the residue dissolved in a suitable solvent such as an ether, for example, tetrahydrofuran. Reaction with a suitable alkylating reagent such as a Grignard reagent, for example, allyl magnesium bromide, in the presence of a suitable solvent such as an ether, for example, diethyl ether, affords the compound of formula (XIII).
Compounds of formula (XVI) may be prepared from a compound of formula (III) by an ozonolysis reaction, using ozone at a low temperature, for example, between -60°C and -100°C, in a suitable solvent such as a halogenated hydrocarbon, for example, dichloromethane, or an alcohol, for example, methanol, or a mixture thereof. The intermediate ozonide thus formed need not be isolated but instead is decomposed using a suitable reducing agent, for example, dimethyl sulfide, trimethyl phosphite or thiourea.
Compounds of formula (XIV) may be prepared from a compound of formula (XVII)
(XVII)
by reaction with allyl alcohol in the presence of a suitable reducing reagent, such as a hydride, for example sodium hydride, in a suitable solvent such as an ether, for example tetrahydrofuran, at an elevated temperature, for example, between 60°C and 100°C, followed in a second
step by an oxidation reaction, for example using a mild oxidizing reagent such as Dess-Martin periodinane, in a suitable solvent such as a halogenated hydrocarbon, for example dichloromethane, conveniently at room temperature. Compounds of formula (XVII) may be prepared from a compound of formula (III) by an epoxidization reaction using a peracid, for example, -chloroperbenzoic acid. The reaction is effected in a solvent such as a halogenated hydrocarbon, for example, dichloromethane, conveniently at room temperature. Compounds of formula (XV) may be prepared from a compound of formula (XVII) by reaction with a suitable amine ofthe formula R1 NHCH2CH2OH. The reaction is conveniently effected in a solvent such as an alcohol, for example methanol, at an elevated temperature, for example at the reflux temperature of the solvent. Compounds of formula (V), (VIII) and (XI) are either known compounds or may be prepared by methods analogous to those described herein.
It will be appreciated that the general methodology described above may be adapted, using methods that are readily apparent to one of ordinary skill in the art, in order to prepare further compounds of the present invention.
During any ofthe above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art. The exemplified compounds of this invention were tested by the methods set out at pages 36 to 39 of International Patent Specification No.
WO 93/01165. The compounds were found to be active with IC50 at the NKi receptor of less than lOOnM on said test method.
The following non-limiting Examples serve to illustrate the preparation of compounds ofthe present invention:
DESCRIPTION 1 3-Iodo-3-phenyl-prop-2-en-l-ol
Red-Al™ (3.4M in toluene, 33ml) was dissolved in diethyl ether (100ml) and cooled to -10°C to which 3-phenyl-2-propyn-l-ol (lOg, 0.076mol) dissolved in diethyl ether (10ml) was added dropwise, causing the solution to turn a dark red/brown colour. The reaction was stirred for 1 hour. The solution was cooled to -78°C and iodine monochloride (1.0M solution in dichloromethane, 114ml) was added causing the solution to turn a dark brown colour. The mixture was allowed to warm to room temperature and stirred for 1 hour. A 10% solution of potassium sodium tartaric acid
(800ml) was added, producing a white precipitate, this was removed by filtration and the filtrate was extracted with diethyl ether (3x75ml). The combined organic extracts were washed with sodium thiosulphate (5x60ml), brine, dried (MgSθ4) and the solvent removed in vacuo to afford the crude title compound as a light brown oil (19.5g, 95%). iH NMR (250MHz, CDC13) δ 1.76 (1H, t, J 5.7Hz), 4.39 (2H, t, J 5.6Hz), 6.25 (IH, t, J 5.8Hz), 7.10-7.50 (5H, m).
DESCRIPTION 2 3-phenyl-5H-furan-2-one
3-Iodo-3-phenyl-prop-2-en-l-ol (Description 1; lg, 3.8mM)was dissolved in tetrahydrofuran (20ml) and Hunig's base (2.67ml, 15.4mM) and degassed using a Firestone valve (x3). Carbon monoxide was bubbled through the solution for 10 minutes after which tris(dibenzylideneacetone)dipalladium (141mg; 4mol%) and 1,4 bis(diphenylphosphino) butane (65mg; 4mol%) were added. The reaction was heated at 50°C under an atmosphere of carbon monoxide. After 2 hours, when the reaction was 50% complete, an extra addition ofthe palladium source and phosphine ligand were made. After a further 2 hours the reaction was cooled, filtered, the solvent removed in vacuo and the residue was dispersed between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (2x 40ml),
the combined organic layers were washed with brine, dried over MgS04 and the solvent removed in vacuo. Purification was carried out by silica chromatography eluting in increasing concentrations of ethyl acetate in hexane (0-15%) to afford the title compound as a tan-coloured solid (0.56g, yield 91%).
DESCRIPTION 3 5-Oxo-4-phenyl-tetrahydrofurε-n-3-carbonitrile
3-Phenyl-5H-furan-2-one (Description 2; 4.5g, 0.028mol), and acetone cyanohydrin (3.06ml) were dissolved in CH3CN (80ml) and cooled to -0°C. Tetramethylguanidine (3.5ml) was added dropwise over 15 minutes and the reaction left to stand for a further 15 minutes. 0.5M HCI (100ml) was added and the reaction mixture de-colourised and the product extracted with ethyl acetate (2x40ml), washed with brine (2x30ml) and dried over MgSO4. The solvent was removed in vacuo to afford a brown oil which was a mixture of the cis and trans isomers. Purification was carried out using flash column chromatography on silica gel eluting in increasing concentrations of ethyl acetate in hexane (0-60%) to yield the title compound (2.93g, 56%). The only isolated product from the column was the more thermodynamically stable trans isomer.
Η-NMR (250MHZ, CDCI3) δ trans isomer: 3.54 (IH, ddd, J 10.9Hz, 9.6Hz, 8.1Hz), 4.10 (IH, d, J 11.0Hz), 4.43 (IH, t, J 9.4Hz), 4.69 (IH, t, J 9.2Hz), 7.40 (5H, m). Η-NMR (250MHZ, CDCI3) δ cis isomer: 3.87 (IH, m), 4.10 (IH, d, J 2.3Hz), 4.56 (2H, d, J 6.0Hz), 7.41 (5H, m).
DESCRIPTION 4 (5-Oxo-4-phenyl-tetrahydrofuran-3-ylmethyl) carbamic acid £er-.-butyl ester 5-Oxo-4-phenyl-tetrahydrofuran-3-carbonitrile (Description 3; 7.1g,
0.038mol) was added to di-tertr-butyldicarbonate (24g), platinum dioxide
catalyst (1.4g), ethyl acetate (150ml) and acetic acid (20ml) and shaken under an atmosphere of hydrogen (50 psi) for 24 hours. The catalyst was removed by filtration, solvent removed in vacuo and the residue was purified using flash column chromatography on silica gel eluting in increasing concentrations of ethyl acetate in hexane (5-50%) to give the title compound as a brown oil (2.16g).
DESCRIPTION 5 (3RS, 4RS) 4-Aminomethyl-3 henyl-dihydrofuran-2-one (5-Oxo-4-phenyl-tetrahydrofuran-3-ylmethyl)carbamic acid -:ert:-butyl ester (Description 4; 2.16g, 7.4mmol) was dissolved in dichloromethane (10ml), cooled to 0°C, trifluoroacetic acid (1ml) was added and the reaction was left to stand for 20 minutes to warm to room temperature. TLC showed the reaction to be incomplete so extra trifluoroacetic acid (1ml) was added and the reaction was left for a further 30 minutes. The solvent was removed in vacuo and the residue was dispersed between ethyl acetate and saturate potassium carbonate solution. The aqueous layer was extracted with ethyl acetate (2x30ml), the combined organic layers were washed with brine, dried over MgSU4, filtered and evaporated to dryness. Purification was carried out by flash column chromatography on silica gel eluting in increasing concentrations of methanol in dichloromethane and 0.2% ammonia (1-10%) to afford the title compound (2.15g). m/z (ES+) 191 (M+H, 100%).
DESCRIPTION 6
(3RS, 4RS) 4-[(N,N-Dibenzylamino)-methyl]-3-phenyl- dihydrofuran-2-one
(SRS, 4RS) 4-Aminomethyl-3-phenyl-dihydrofuran-2-one (2.15g, O.Ollmol) was added to potassium carbonate (15.5g), benzyl bromide (6.69ml) and dimethylformamide (lOml) and stirred for 3 hours at 50°C. dimethylformamide was removed in vacuo and the reaction was dispersed
between ethyl acetate (40ml) and water (60ml), the aqueous phase was washed with ethyl acetate (2x30ml) and the organic layers were combined and washed with brine solution (100ml) and dried over MgSθ4. The solvent was removed in vacuo and purified by flash column chromatography on silica gel and eluting in increasing concentrations of ethyl aceate in hexane (5-50%) to give the title compound (1.15g, 46%). Η-NMR (250MHz, CDCI3) δ 2.57 (2H, dd, J 6.1Hz, 2.7Hz), 2.86 (IH, m), 3.20 (IH, d, J 13.5Hz), 3.35 (2H, d, J 13.4Hz), 3.63 (2H, d, J 13.3Hz), 3.83 (IH, t, J 8.9Hz), 4.55 (IH, t, J 7.6Hz). mlz (ES+) 371 (M+H, 100%).
DESCRIPTION 7
faster eluting slower eluting (2SR, 3SR, 4SR) (2RS, SSR, 4SR)
(a) (2S-R, 3SR, 4SR) 3,5-Bis(trifluoromethyl)benzoic acid 4-[(N,N- dibenzylamino)methyl] -3-phenyl-tetrahydrofuran-2-yl ester; and
(b) (2RS, 3SR, 4SR) 3,5-Bis(trifluoromethyl)benzoic acid 4-[(N,N- dibenzyla---ιino)-tnethyl]-3-phenyl-tetrahydrofuran-2-yl ester
(SRS, 4RS) 4- [(N,N-Dibenzylamino)-methyl] -3-phenyl-dihydrofuran-2-one (Description 6; 1.53g, 4mmol) was dissolved in tetrahydrofuran (15ml) under an atmosphere of nitrogen and cooled to — 78°C. L-Selectride™ (8.25ml) was added dropwise and the reaction was left to stand for 30
minutes. Further L-Selectride™ (1.65ml) was added, 3,5-bis- trifluoromethyl-benzoyl chloride (1.86ml) was added dropwise and the solution was left to stand for 16 hours at — 78°C. Further 3,5-bis- trifluoromethyl-benzoyl chloride (0.372ml) was added and the reaction was warmed to room temperature for 20 minutes. The reaction was then quenched with saturated sodium carbonate (400ml), dispersed between ethyl acetate (100ml) and the aqueous layers washed with ethyl acetate (3x50ml). The organic extracts were combined and dried over MgS04. The solvent was removed in vacuo and purified by flash column chromatography on silica gel and eluting in increasing concentrations of ethyl acetate in hexane (0-20%) to yield the title compounds. Faster eluting isomer (a) (2SR, SSR, 4SR) (0.8g, yield 32%). iH-NMR (360MHz, CDCls) δ 2.40-2.56 (IH, m), 2.61 (IH, dd, J 8.9Hz, 2.4Hz), 3.14 (2H, br s), 3.43 (2H, d, J 13.4Hz), 3.67 (2H, d, J 13.4Hz), 3.71 (IH, t, J 8.0Hz), 4.47 (IH, t, J 7.9Hz), 6.38 (IH, d, J 4.1Hz), 7.21-7.33 (15H, m), 7.98 (IH, s), 8.17 (2H, s).
Slower eluting isomer (b) (2RS, SSR, 4SR) (0.32g, yield 13%). Η-NMR (360MHZ, CDCI3) δ 2.63 (IH, d, J 8.4Hz), 2.65 (IH, d, J 4.8Hz), 2.78 (IH, m), 3.22 (IH, dd, J 4.1Hz, 2.0Hz), 3.48 (4H, dd, J 26Hz, 13.5Hz), 3.83 (IH, t, J 8.5Hz), 4.47 (IH, t, J 8.4Hz), 6.34 (IH, d, J 2.2Hz), 7.10-7.38 (15H, m), 8.06 (IH, s), 8.30 (2H, s).
DESCRIPTION 8 (2SR, SSRf 4SR) N,N-Dibenzyl-{5-[l-(3,5-bis(trifluoromethyl)- phenyl)vinyloxy]-4 henyl etrahydrofuran-3-ylm.ethyl}anιine
(2SR, SSR, 4SR) 3,5-Bis(trifluoromethyl)benzoic acid 4-[(N,N- dibenzylamino)methyl] -3-phenyl-tetrahydrofuran-2-yl ester (Description 7(a); 1.03g, 1.7mmol) was azeotroped with tetrahydrofuran (2x10ml), dissolved in tetrahydrofuran (15ml) and degassed with Firestone™ valve (x3). Bis(cyclopentadiene) titanium dimethyl (1.8ml, 2.8M in toluene) was added and the mixture was heated to 60°C in the dark. Further
bis(cyclopentadiene) titanium dimethyl (1ml) was added and the reaction was left to stand for 18 hours. The reaction was quenched with a slurry of sodium carbonate (4g), water (2.5ml) and methanol (50ml), which caused it to turn yellow, and the reaction was left to stand at 40°C for 16 hours under nitrogen. The solid was removed by filtration and the solvent removed in vacuo to afford a yellow solid. The solid was dispersed between water (50ml) and ethyl acetate (40ml), the aqueous layer was washed with ethyl acetate (3x20ml) and brine (1x50ml), and dried over MgSθ4. The solvent was removed in vacuo and the product purified by flash column chromatography on silica gel and eluting in increasing concentrations of dichloromethane in hexane (10-100%) to give the title compound (299mg, yield 29%). iH-NMR (360MHz, CDCls) δ 3.14 (IH, dd, J 4.7Hz, 2.3Hz), 3.37 (2H, dd, J 22.4 Hz, 13.5Hz), 3.49 (IH, m), 3.59 (2H, d, J 13.6Hz), 3.76 (2H, d, J 13.5Hz), 3.75 (IH, t, J 8.8Hz), 4.40 (IH, t, J 2.3Hz), 4.62 (IH d, J 3.2Hz), 4.84 (IH, d, J 3.1Hz), 6.69 (IH, d, J 1.4Hz), 7.11-7.37 (15H, m), 7.78 (IH, s), 7.88 (IH, s). mlz (ES+) 611 (M+H, 44%).
DESCRIPTION 9
slower eluting faster eluting (2SR, SSR, 4SR, 2[(V)]RS) (2SR, SSR, 4SR, 2[(1')]S-R)
(a) (2SR, 3SR, 4SR, 2[(l')]-S-β) 2-(3,5-Bis(trifluoro ethyl)phenyl)- 2-{4-[(^,N-dibenzylamino)methyl]-3 henyl-tetrahydro--uran- 2-yloxy}-ethanol; and
(b) (2S-R, 3SR, 4SR, 2[(1')1RS) 2-(3,5-Bis(trifluoromethyl)phenyl)- 2-{4-[(N,N-dibenzylan ino)ιnet--ιyl]-3-phenyl-tetra--ιydrofuran-
2-yloxy}-ethanol (2SR, SSR, 4SR) Dibenzyl-{5-[l-(3,5-bis(trifluoromethyl)phenyl)vinyloxy]- 4-phenyl-tetrahydrofuran-3-ylmethyl}amine (Description 8; 299mg, 49mmol) was azeotroped in tetrahydrofuran (3xlml), dissolved in tetrahydrofuran (10ml) and cooled to -10°C. Borane-THF (1.47ml, l.OM in THF) was added dropwise and the reaction left to stand for 6 hours at room temperature. The mixture was quenched with a solution of sodium hydroxide (1.85ml, 2M) and hydrogen peroxide (30ml) at -10°C and left to stand for 45 minutes. The mixture was then dispersed between ethyl acetate (20ml) and water (40ml) and the water layer was washed with ethyl acetate (2x15ml). The organic extracts were combined and washed with brine (1x30ml) and dried over MgSθ4. The solvent was removed in vacuo and the residue purified by flash column chromatography on silica gel and eluting in increasing concentrations of ethyl acetate in hexane (2.5-50%) to give the title compounds.
Slower eluting isomer (a) (2SR, SSR, 4SR, 2[(V)]RS) (53mg, yield 17%). Η-NMR (360MHz, CDCls) δ 2.59 (IH, d, J 7.5Hz), 2.63-2.66 (IH, m), 2.71 (IH, d, J 7.3Hz), 2.99 (IH, dd, J 7.0Hz, 3.0Hz), 3.38 (IH, d, J 13.4Hz), 3.41-3.47 (IH, m), 3.53 (2H, d, J 13.1Hz), 3.58 (2H, d, J 13.5Hz), 3.74 (IH, t, J 8.4Hz), 4.36 (IH, t, J 7.6Hz), 4.68 (IH, dd, J 7.5Hz, 3.1Hz), 4.86 (IH, d, J 3.0Hz), 7.01-7.32 (15H, m), 7.59 (2H, s), 7.72 (IH, s). Faster eluting isomer (b) (2SR, SSR, 4SR, 2[(V)]SR) (33mg, yield 11%). iH-NMR (360MHz, CDCI3) δ 1.78 (IH, br d), 2.42 (IH, dd, J 12.1Hz, 7.2Hz), 2.56-2.61 (IH, m), 2.70 (IH, dd, J 12.1Hz, 7.5Hz), 3.10 (IH, dd, J 6.1Hz, 2.3Hz), 3.25 (IH, t, J 8.4Hz), 3.41 (2H, d, J 13.4Hz), 3.38-3.46 (IH, m), 3.52 (2H, d, J 13.4Hz), 3.47-3.55 (IH, m), 4.09 (IH, t, J 8.1Hz), 4.54
(IH, dd, 7.5Hz, 3.7Hz), 5.15 (IH, d, 2.4Hz), 7.18-7.35 (15H, m), 7.63 (2H, s), 7.78 (IH, s).
DESCRIPTION 10 (2RS, 3SR, 4SR) N,N-Dibenzyl-{5-[l-(3,5-bis(trifluoromethyl)- phenyl)vinyloxy]-4-phenyl-tetrahydrofuran-3-yhnethyl}aιnine
(2RS, SSR, 4SR) 3,5-Bis(trifluoromethyl)benzoic acid 4-[(N,N- dibenzylamino)methyl] -3-phenyl-tetrahydrofuran-2-yl ester (Description 7(b); 0.64g) was used treated according to the procedure described in Description 8. Purification was carried out by flash column chromatography on silica gel and eluting in increasing concentrations of ethyl acetate in hexane (0-10%) to give the title compound (0.32g, 50%). mlz 612 (M+H, 100).
DESCRIPTION 11
faster eluting slower eluting (2RS, SSR, 4SR, 2[(V)]RS) (2RS, SSR, 4SR, 2[(V)]SR)
(a) (2RS, 3SR, 4SR, 2[(V)]RS) 2-(3,5-Bis(trifluoromethyl)phenyl)- 2-{4-[(N,N-dibenzylamino)methyl]-3-phenyl-tetrahydrofuran- 2-yloxy}-ethanol; and
(b) (2RS, 3SR, 4SR, 2[(1')]S-K) 2-(3,5-Bis(trifluoromethyl)phenyl)- 2-{4-[(N,N-dibenzylamino)methyl]-3 henyl etrahydroft-ran- 2-yloxy}-ethanol
(2RS, 3SR, 4SR) N,N-Dibenzyl-{5-[l-(3,5-bis(trifluoromethyl)phenyl)- vinyloxy]-4-phenyl-tetrahydrofuran-3-ylmethyl}amine (Description 10; 0.129g) was hydroborated using the method described in Description 9. Purification was carried out by flash silica chromatography eluting with increasing concentrations of ethyl acetate (0-20%) in hexane. Faster eluting isomer (a) (2RS, SSR, 4SR, 2[(T)]RS) (23.7mg, yield 18%). Ή-NMR (360MHz, CDC13) δ 1.21(1H, dd, J 9.7Hz, 4.0Hz), 2.41(1H, dd, J 12.7Hz, 9.7Hz), 2.53 (IH, dd, J 12.7Hz, 4.7Hz), 2.90 (IH, dd, J 11.2Hz, 4.6Hz), 3.12-3.28 (IH, m), 3.30-3.52 (5H, m), 3.64 (2H, d, J 13.4Hz), 4.12 (IH, t, J 8.5Hz), 4.50 (IH, dd, J 8.0Hz, 3.5Hz), 5.11 (IH, d, J 4.7Hz), 7.10- 7.44 (15H, m), 7.71 (2H, s), 7.79 (IH, s). Slower eluting isomer (b) (2RS, SSR, 4SR, 2[(V)]SR) (37mg, yield 28%). Η-NMR (360MHz, CDCI3) δ 2.43 (IH, dd, J 12.7Hz, 9.9Hz), 2.53(1H, 12.7Hz, 4.6Hz), 2.85(1H, dd, J 11.3Hz, 4.8Hz), 3.01 (IH, dd, J 9.1Hz, 3.6Hz), 3.11-3.24 (IH, m), 3.37 (2H, d, J 13.5Hz), 3.48-3.74 (5H, m), 4.42 (IH, t, J 8.4Hz), 4.69 (IH, dd, J 7.6Hz, 3.0Hz), 4.92(1H, d, J 4.8Hz), 7.16- 7.20 (17H, m), 7.66 (IH, s).
EXAMPLE 1
faster eluting slower eluting (2SR, SSR, 4SR, 2[(V)RS]) (2SR, SSR, 4SR, 2[(V)SR])
(a) l(2SR, 3S-R, 4S22)-2-({(l-R,S)-l-[3,5-Bis(trifluoromethyl)phenyl]- ethyl}oxy)-3 henyltetrahydro-4---ι-ranyl]--nethanaιnine; and
(b) [(2SR, 3S-R, 4S-R)-2-({(l-S-R)-l-[3,5-Bis(trifluoromethyl)phenyl]- ethyl}oxy)-3 henyltetrahydro-4-ftιranyl]--nethanaιnme
(2SR, SSR, 4SR) N,N-Dibenzyl-{5-[l-(3,5-bis(trifluoromethyl)phenyl)- vinyloxy] -4-phenyl-tetrahydrofuran-3-ylmethyl}amine (Description 8; 0.25g) was dissolved in methanol (20ml), ammonium formate (130mg) was added and the mixture degassed with nitrogen for 10 minutes. 10% palladium on carbon (80mg) was added heated at reflux for 3 hours. The reaction was filtered and evaporated to dryness in vacuo and purification was carried out by flash chromatography elution in increasing concentrations (0-2%) methanol in dichloromethane with 0.2% ammonia. Faster eluting isomer (a) (2SR, SSR, 4SR, 2[(1')RS]) (43mg, yield 24%). Η-NMR (250MHz, CDCls) δ 1.40 (3H, d, J 6.6Hz), 2.29-2.47 (IH, m), 2.80 (IH, dd, J 12.5Hz, 7.8Hz), 2.95 (IH, dd, J 12.5Hz, 6.1Hz), 3.11 (IH, dd, J 7.0Hz, 2.4Hz), 3.58 (IH, t, J 8.7Hz), 4.16 (IH, t, J 8.1Hz), 4.80 (IH, q, J 6.5Hz), 5.25 (IH, d, 2.4Hz), 7.18-7.41 (5H, m), 7.77 (2H, s), 7.80 (IH, s). mlz (ES+) 434 (H+l, 4%), 176 (M-273, 100%). Slower eluting isomer (b) (2SR, SSR, 4SR, 2[(V)SR\) ( 35mg, yield 20%). Η-NMR (360MHZ, CDCls) δ 1.48 (3H, d, J 6.6Hz), 2.38-2.49 (IH, m), 2.84 (IH, dd, J 12.5Hz, 7.9Hz), 2.97 (IH, dd, J 12.4Hz, 5.8Hz), 3.07 (IH, dd, J 7.5Hz, 3.1Hz), 3.90 (IH, t, J 8.7Hz), 4.32 (IH, t, J 8.0Hz), 4.81 (IH, d, J 3.1Hz), 4.90 (IH, q, J 6.6Hz), 7.14-7.36 (5H, m), 7.63 (2H, s), 7.74 (IH, s). mlz (ES+) 434 (H+l, 50%), 176 (M-273, 100%).
EXAMPLE 2 [(2S-R, 3S-R, 4SJ2)-2-({(lSie)-l-[3,5-Bis(trifluoromethyl)phenyl]- ethyl}oxy)-3 henyltetrahydro-4--- ranyl] -VJV- dimethylmethanamine [(2SR, SSR, 4-S-R)-2-({(l--?-R)-l-[3,5-Bis(trifluoromethyl)phenyl]ethyl}oxy)-3- phenyltetrahydro-4-furanyl]methanamine (Example 1(b); 52mg), was dissolved in isopropanol (30 ml) and one equivalent of etheral HCI was added. The reaction mixture was degassed with nitrogen before the addition of formaldehyde (37% in water, 0.25ml) and 10% palladium on carbon (15mg). The reaction was shaken under 50psi of hydrogen for 3 hours. The solvent was removed in vacuo and the residue was dispersed between ethyl acetate and saturated potassium carbonate solution. The aqueous layer was extracted with ethyl acetate (2x25ml), the combined organic extracts were washed with brine, dried over MgSθ4, filtered and solvent removed in vacuo. Purification was carried out by preparative
TLC eluting with 5% methanol in ethyl acetate with 0.2% ammonia to give the title compound (17mg, yield 31%).
Η-NMR (360MHz, CDC13) δ 1.48 (3H, d, J 6.6Hz), 2.19 (6H, s), 2.42-2.58 (3H, m), 3.05 (IH, dd, J 6.4Hz, 2.8Hz), 3.90 (IH, t, J 8.1Hz), 4.33 (IH, dd, J 8.7Hz, 6.6Hz), 4.80 (IH, d, J 2.9Hz), 4.90 (IH, q, J 6.6Hz), 7.12-7.31 (5H, m), 7.64 (2H, s), 7.69 (IH, s). mlz (ES+) 462 (H+l, 100%).
EXAMPLE 3 (2SR, 3SR, 4SR, 2[(1>)]RS) 2-(4--Aminomethyl-3-phenyl-tetrahydro- furan-2-yloxy)-2-(3,5-bis(trifluorom.ethyl)p-hLenyl)-ethanol
(2SR, SSR, 4SR, 2[(V)]SR) 2-(3,5-Bis(trifluoromethyl)phenyl)-2-{4-[(N,N- dibenzylamino)methyl]-3-phenyl-tetrahydrofuran-2-yloxy}-ethanol (Description 9(a); 53mg, 0.084mmol) was dissolved in methanol (5ml) and paladium on carbon (lOmg) and ammonium formate (37.1mg) were added and the mixture refluxed for 1 hour. Further ammonium formate (20mg) was added and the mixture refluxed for another hour. The catalyst was
filtered off, the solvent was removed in vacuo and the residue purified using preparative TLC plates in 6% methanol in dichloromethane and 0.2% ammonia. The product was removed from the silica by washing with methanol (2x20ml) and the solvent removed in vacuo. The residue was dissolved in dichloromethane (10ml) and dried over MgS04 to give the title compound (20.2mg, 54%). iH-NMR (360MHz, CDC13) δ 2.52-2.54 (IH, m), 2.8-3.05 (2H, m), 3.17 (IH, d, J 4.4Hz), 3.69 (2H, d, J 5.0Hz), 4.07 (IH, t, J 8.6Hz), 4.35 (IH, t, J 8.3Hz), 4.89 (IH, t, J 5.7Hz), 4.97 (IH, d, J 2.5Hz), 7.16-7.35 (5H, m), 7.70 (2H, s), 7.74 (IH, s). mlz (ES+) 450 (M+H, 3%), 176 (M-273, 100%).
EXAMPLE 4 (2SR, 3SR, 4SR, 2[(V)]SR) 2-(4-Aminomethyl-3-phenyl- tetrah.ydrofuran-2-yloxy)-2-(3,5-bis(trifluoroιnethyl)phenyl)- ethanol
(2SR, SSR, 4SR, 2[(V)]RS) 2-(3,5-Bis(trifluoromethyl)phenyl)-2-{4-[(N,N- dibenzylamino)methyl]-3-phenyl-tetrahydrofuran-2-yloxy}-ethanol (Description 9(b); 33mg) was hydrogenated using procedure described in Example 3. Purification was carried out on preparative TLC eluting with 6% methanol in dichloromethane containing 0.2% ammonia to give the title compound (9.2mg yield 41%). iH-NMR (360MHz, CDCI3) δ 2.38 (IH, m), 2.82 (IH, dd, J 12.5Hz, 7.3Hz), 2.97 (IH, dd, J 12.5Hz, 7.3Hz), 3.25(1H, dd, J 6.9Hz, 2.4Hz), 3.58 (IH, t, J 8.7Hz), 3.64-3.70 (2H, m), 4.13 (IH, t, J 8.3Hz), 5.3 (IH, t, J 5.5Hz), 5.26 (IH, d, J 2.5Hz), 7.18-7.38 (5H, m), 7.2 (3H, s). mlz (ES+) 450 (M+H, 3%), 176 (M-273, 100%).
EXAMPLE 5 (2βS)-2 3,5-Bis(trifluoromethyl)phenyU dimethyla--mno)methyl]-3 henyltetrahydro-
(2SR, SSR, 4SR, 2[(1')]SR) 2-(4-Aminomethyl-3-phenyl-tetrahydrofuran-2- yloxy)-2-(3,5-bis(trifluoromethyl)phenyl)-ethanol ((Example 4;76mg) was reductively animated using the procedure described in Example 2. Purification was carried out by flash silica chromatography eluting with increasing concentrations of methanol (1-4%) in dichloromethane with 0.2% ammonia to give the title compound (50mg, yield 62%). Η-NMR (400MHZ, CDCls) δ 2.18 (6H, s), 2.41 (IH, dd, J 11.9Hz, 5.3Hz), 2.51 (IH, t, J 9.4Hz), 2.55-2.67 (IH, m), 3.13 (IH, dd, J 7.7Hz, 4.4Hz), 3.65-3.74 (2H, m), 3.97 (IH, t, J 8.8Hz), 4.37 (IH, dd, J 8.6Hz, 7.3Hz), 4.82 (IH, dd, J 7.1Hz, 3.6Hz), 5.01 (IH, d, J 3.3Hz), 7.13-7.32 (5H, m), 7.69 (2H, s), 7.74 (IH, s). mlz (ES+) 478 (M+l, 15%), 204 (M-273, 100%).
EXAMPLE 6
faster eluting slower eluting
(2RS, SRS, 4SR, 2[(1')]SR) (2RS, SRS, 4SR, 2[(V)]RS)
(a) [(2RS, 3RS, 4S-R)-2-({(lS-R)-l-[3,5-Bis(trifluoromethyl)phenyl]- ethyl}oxy)-3-phenyltetrahydro-4-furanyl]-παethananιine; and
(b) [(2RS, 3RS, 4-S-R)-2-({(l-RS)-l-[3,5-Bis(trifluoromethyl)phenyl]- ethyl}oxy)-3-phenyltetrahydro-4-furanyl]nιet--ιanamine
(2RS, SSR, 4SR) N,N-Dibenzyl-{5-[l-(3,5-bis(trifluoromethyl)phenyl)- vinyloxy] -4-phenyl-tetrahydrofuran-3-ylmethyl}amine (Description 10;
166mg) was hydrogenated using the procedure described in Example 1.
Purification was carried out by flash chromatography elution in increasing concentrations (0-5%) methanol in ethyl acetate with 0.2% ammonia.
Faster eluting isomer (a) (2RS, SRS, 4SR, 2[(V)]SR) (12mg, yield 10%).
!H-NMR (360MHz, CDC13) δ 1.21 (3H, d, J 6.5Hz), 2.67 (IH, dd, J 14.1Hz),
2.84-2.96 (2H, m), 3.05 (IH, dd, J 10.7Hz, 4.4Hz), 3.69 (IH, t, J 8.2Hz),
4.10 (IH, t, J 8.2Hz), 4.72 (IH, q, J 6.4Hz), 5.24 (IH, d, J 4.5Hz), 7.24 (5H, m), 7.72 (2H, s), 7.75 (IH, s). mlz (ES+) 434 (H+l, 20%), 176 (M-273,
100%).
Slower eluting isomer (b) (2RS, SRS, 4SR, 2[(V)]RS) (30mg, yield 25%). iH-NMR (360MHz, CDCI3) δ 1.40 (3H, d, J 6.6Hz), 2.70 (IH, dd, J 12.4Hz),
2.86-3.06 (3H, m), 3.82 (IH, t, J 7.4Hz), 4.40 (IH, t, J 7.4Hz), 4.82- 4.92 (2H, m), 7.22-7.36 (7H, m), 7.64 (IH, s). mlz (ES+) 434 (H+l, 30%), 176
(M-273, 100%).
EXAMPLE 7 [(2RS, 3RS, 4,S-R)-5-({(l-RS)-l-[3,5-Bis(trifluoromethyl)p--ιenyl]- ethyl}oxy)-3-ph.enyltetrahydro-4-furanyl]-ΛyV- dimethylmethanamine
[(2RS, 3-R-S, 4-Si?)-2-({(lR-S)-l-[3,5-Bis(trifluoromethyl)phenyl]ethyl}oxy)-3- phenyltetrahydro-4-furanyl]methanamine (Example 6b; 30mg) was methylated using the same procedure as described in Example 2. Purification was carried out by preparative TLC eluting with 3.5% methanol in ethyl acetate with 0.2% ammonia to give the title compound
(3.6mg).
Η-NMR (360MHz, CDCI3) δ 1.39 (3H, d, J 6.6Hz), 2.25 (6H, s), 2.35-2.40
(2H, m), 2.88 (IH, dd, J 11.2Hz, 4.6Hz), 3.06-3.08 (IH, m), 3.85 (IH, t, J 8.3Hz), 4.43 (IH, t, J 8.3Hz), 4.84 (IH, q, J 7.6Hz), 7.24-7.38 (7H,m), 7.64 (IH, s). mlz (ES+) 462 (H+l, 100%).
EXAMPLE 8 (2BS, 3S-R, 4SR, 2[(1')]-RS) 2-(4-Aminomethyl-3-phenyl- tetrahydro--uran-2-yloxy)-2-(3,5-bis(trifluoroιnethyl)phenyl)- ethanol
(2RS, SSR, 4SR, 2[(V)]RS) 2-(3,5-Bis(trifluoromethyl)phenyl)-2-{4-[(N,N- dibenzylamino)methyl]-3-phenyl-tetrahydrofuran-2-yloxy}-ethanol (Description 11a; 23mg) was hydrogenated as described in Example 3. Purification was carried out on preparative TLC eluting with 6% methanol in dichloromethane containing 0.2% ammonia (10.6mg yield 65%).
Η-NMR (360MHZ, CDCls) δ 2.70 (lH,dd, J 13.3Hz, 7.2Hz), 2.92 (IH, dd, J 13.3Hz, 5.5Hz), 2.99-3.06 (IH, m), 3.15 (IH, dd, J 11.7Hz, 5.5Hz), 3.40 (IH, dd, J 12.1Hz, 4.7Hz), 3.48 (IH, dd, J 12.1Hz, 4.7Hz), 3.69 (IH, t, J 8.2Hz), 4.09 (IH, t, J 8.2Hz), 4.58 (IH, dd, J 8.2Hz, 4.7Hz), 5.24 (IH, d, J 5.5Hz), 7.30-7.45 (5H, m), 7.74 (2H, s), 7.79 (IH, s). mlz (ES+) 450 (M+H, 3%) 176 (M-273, 100%).
EXAMPLE 9 (2RS, 3SR, 4SR, 2[(V)]SR) 2-(4-Aminomethyl-3-phenyl- tetrahydrofuran-2-yloxy)-2-(3,5-bis(trifluoromethyl)phenyl)- ethanol
(2RS, SSR, 4SR, 2[(r)]SR) 2-(3,5-Bis(trifluoromethyl)phenyl)-2-{4-[(N,N- dibenzylamino)methyl]-3-phenyl-tetrahydrofuran-2-yloxy}-ethanol (Description lib; 33mg) was hydrogenated as described in Example 3. Purification was carried out on preparative TLC eluting with 5% methanol in dichloromethane containing 0.2% ammonia (14.9mg yield 65%). Η-NMR (360MHz, CDCls) δ 2.66-2.79 (IH, m), 2.95-3.17 (3H, m), 3.58 (IH, dd, J 11.8Hz, 7.5Hz), 3.68 (IH, dd, J 11.8Hz, 3.2Hz), 3.88 (IH, t, J 8.0Hz), 4.47 (IH, t, J 8.0Hz), 4.77 (IH, dd, J 7.4Hz, 3.1Hz), 5.04 (IH, d, J 4.2Hz), 7.21-7.37 (7H, m), 7.68 (IH, s). mlz (ES+) 450 (M+H, 3%) 176 (M- 273, 100%).
Claims (18)
- CLAIMS:A compound of the formula (I):(I)whereinR1 is hydrogen, halogen, Cι-6alkyl, Ci-βalkoxy, fluoroCi-βalkyl, fluoroCi-βalkoxy, C3-7cycloalkyl, C3-7cycloalkylCι-4alkyl, N02, CN, SRa, SORa, SO2Ra, C02Ra, CONRaRb, C2-ealkenyl, C2-6alkynyl or C1-4alkyl substituted by Cι-4alkoxy, wherein Ra and Rb each independently represent hydrogen or Cι-4alkyl;R2 is hydrogen, halogen, Ci-βalkyl, fluoroCi-δalkyl or Ci-βalkoxy substituted by Cι-4alkoxy; R3 is hydrogen, halogen or fluoroCi-βalkyl;R4 is hydrogen, halogen, Ci-βalkyl, Ci-βalkoxy, fluoroCι-6alkyl, fluoroCi-βalkoxy, hydroxy, N02, CN, SRa, SORa, S02Ra, C02Ra, CONRaR , C2-βalkenyl, C2-6alkynyl or Cι-4alkyl substituted by Cι-4alkoxy, wherein Ra and Rb are as previously defined; R5 is hydrogen, halogen, Ci-βalkyl, fluoroCi-βalkyl or Cι-6alkoxy substituted by Cι-4alkoxy;R6 represents hydrogen or a Cι-4alkyl group optionally substituted by a hydroxy group; R7 represents halogen, hydroxy, C2-4alkenyl, C2-4alkynyl, N3, -NRWR11, -NRaCORb, -OS02Ra, -(CH2)pNRa(CH2)qCOORb, CORa, COORa, -N=C=O, or a five membered or six membered nitrogen-containing heteroaromatic ring optionally containing 1, 2 or 3 additional heteroatoms selected from N, O and S which heteroaromatic ring is optionally substituted at any substitutable position by a substituent selected from =0, =S, halogen, hydroxy, -SH, CORa, C02Ra, -ZNR10Rn, Cι-4alkyl, hydroxyCι-4alkyl, fluoroCι-4alkyl, chloroCι-4alkyl, Cι-4alkoxy, fluoroCι-4alkoxy or Cι-4alkoxy substituted by a Cι-4alkoxy or hydroxyl group, and wherein said C2-4alkenyl and C2-4alkynyl groups are optionally substituted by a substituent selected from halogen, hydroxy, N3, -NR10Rn, -NRaCORb, -OS02Ra, -(CH2)pNRa(CH2)qCOOR , CORa or COORa; or R7 represents a C-linked nitrogen-containing ring of the formulawherein A represents NR14 or O, and B represents a bond, CH2, NR14 or O, wherein one or both hydrogen atoms in said CH2 moiety may be replaced with one or both of R12 and R13, or alternatively, one of the hydrogen atoms in said CH2 moiety together with a hydrogen atom from an adjacent carbon are replaced by a double bond; with the proviso that when A is O, then B is NR14; and with the further proviso that when R7 represents said C-linked nitrogen-containing ring, n is zero and R8 is hydrogen; R8 represents hydrogen, Ci-βalkyl, fluoroCi-βalkyl, hydroxy,Ci-βalkoxy or hydroxyCι-6alkyl;R9 represents hydrogen, halogen, Ci-βalkyl, CH2ORc, oxo, CU2Ra or CONRaRb where Ra and Rb are as previously defined and Rc represents hydrogen, Ci-βalkyl or phenyl; R10 is hydrogen, Cι-4alkyl, C3-7cycloalkyl, C3-7cycloalkylCι-4alkyl, C2-4alkyl substituted by a Cι-4alkoxy or hydroxyl group, or R10 is a five membered or six membered nitrogen-containing heteroaromatic ring as previously defined; R11 is hydrogen or Cι-4alkyl, C3-7cycloalkyl, C3-7cycloalkylCι-4alkyl, or C2-4alkyl substituted by a Cι-4alkoxy or hydroxyl group; or R10, R11 and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms, optionally substituted by one or two groups selected from hydroxy, CORe, C02Re, Cι-4alkyl optionally substituted by a Cι-4alkoxy or hydroxyl group, or Cι-4alkoxy optionally substituted by a Cι-4alkoxy or hydroxyl group, or a five membered or six membered nitrogen-containing heteroaromatic ring as previously defined, or said heteroaliphatic ring is substituted by a spiro-fused lactone ring or a spiro-fused ring of the formula -(CH2)rO(CH2)s- (where r and s are each independently zero, 1, 2 or 3 and the sum total of r and s is 3), and said heteroaliphatic ring optionally containing a double bond, which heteroaliphatic ring may optionally contain an oxygen or sulphur ring atom, a group S(O) or S(0)2 or a second nitrogen atom which will be part of a NH or NRd moiety, where Rd is Cι-4alkyl optionally substituted by hydroxy or Cι-4alkoxy, and where Re is hydrogen, Cι-4alkyl or benzyl; or R10, R11 and the nitrogen atom to which they are attached form a non-aromatic azabicyclic ring system of 6 to 12 ring atoms; or R10, R11 and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms to which is fused a benzene ring or a five membered or six membered nitrogen-containing heteroaromatic ring optionally containing 1, 2 or 3 additional heteroatoms selected from N, O and S;R12 and R13 each independently represent hydrogen, hydroxy, CORe, CU2 e, Cι-4alkyl optionally substituted by a Cι-4alkoxy or hydroxyl group, or Cι-4alkoxy optionally substituted by a Cι-4alkoxy or hydroxyl group; or, when they are attached to the same carbon atom, R12 and R13 may together represent =0, =CHC02Ra, -0(CH2)mO-, -CH20(CH2)k-, -CH2OCH2C(0)-, -CH2OCH2CH(OH)-, -CH2OCH2C(CH3)2-, -CH2OC(CH3)2CH2-, -C(CHs)2θCH2CH2-, -CH2C(0)OCH2-, -OC(0)CH2CH2-, -C(O)OCH2CH2-, -C(0)OC(CH3)2CH2-, -C(0)OCH2C(CH3)2-, -OCH2(CH2)k-, -OC(CH3)2CH2CH2-, -OCH2C(CHs)2CH2-, -OCH2CH2C(CH3)2-, -OCH2CH=CHCH2-, -OCH2CH(OH)CH2CH2-, -OCH2CH2CH(OH)CH2-, -OCH2C(0)CH2CH2-, -OCH2CH2C(0)CH2-, or a group of the formulaor, where they are attached to adjacent carbon atoms, R12 and R13 may together represent -OCH2CH2- or -OCH2CH(OH)-, or R12 and R13 may together form a fused benzene ring; or, R12 and R13 together form a Cι-2alkylene bridge across the pyrrolidine, piperidine, morpholine or piperazine ring to which they are attached;R14 represents hydrogen, benzyl, Cι-4alkyl, C3-7cycloalkyl, C3-7cycloalkylCι-4alkyl, or C2-4alkyl substituted by a Cwalkoxy or hydroxyl group;R15 represents hydrogen, halogen, hydroxy, Ci-4alkyl, hydroxy Cι-4alkyl or fluoroCι-4alkyl;Z represents a bond, Ci-βalkylene or Cs-βcycloalkylene; k is 1, 2 or 3; m is 1 or 2; n is zero, 1 or 2; p is 1 or 2; and q is 1 or 2; or a pharmaceutically acceptable salt thereof.
- 2. A compound as claimed in Claim 1 wherein R1 is hydrogen, Cι-4alkyl, Cι-4alkoxy, halogen or CF3.
- 3. A compound as claimed in Claim 1 or Claim 2 wherein R2 is hydrogen, Cnalkyl, Cι-4alkoxy, halogen or CF3.
- 4. A compound as claimed in any one of Claims 1 to 3 wherein R3 is hydrogen, fluorine, chlorine or CF3.
- 5. A compound as claimed in any one of Claims 1 to 4 wherein R4 is hydrogen or fluorine..
- 6. A compound as claimed in any one of Claims 1 to 5 whereinR5 is hydrogen, fluorine, chlorine or CF3.
- 7. A compound as claimed in any one of Claims 1 to 6 wherein R6 is Cι-4alkyl optionally substituted by hydroxy.
- 8. A compound as claimed in any one of Claims 1 to 7 wherein R7 is NR10RU where the group NR10Rn represents a heteroaliphatic ring of 4 to 7 ring atoms substituted by two groups, the first substituent being selected from hydroxy, CO2 e (where Re is hydrogen, methyl, ethyl or benzyl), or Cι-2alkyl substituted by hydroxy, and the second substituent being a methyl group.
- 9. A compound as claimed in any one of Claims 1 to 8 wherein R8 is hydrogen or methyl. /2467350
- 10. A compound as claimed in any one of Claims 1 to 9 wherein n is 1 or 2.
- 11. A compound as claimed in any one of Claims 1 to 10 wherein R9 is hydrogen.
- 12. A compound as claimed in Claim 1 ofthe formula (la):da)whereinA1 is fluorine or CF3;A2 is fluorine or CF3;A3 is fluorine or hydrogen;A4 is fluorine or hydrogen;A5 is methyl or hydroxymethyl; andR7 and n are as defined in Claim 1; or a pharmaceutically acceptable salt thereof.
- 13. A compound as claimed in any preceding claim for use in therapy.
- 14. A pharmaceutical composition comprising a compound as claimed in any one of Claims 1 to 12, together with at least one pharmaceutically acceptable carrier or excipient.
- 15. A method for the treatment or prevention of physiological disorders associated with an excess of tachykinins, which method comprises administration to a patient in need thereof of a tachykinin reducing amount of a compound according to Claim 1.
- 16. A method for the treatment or prevention of pain or inflammation, migraine, emesis, postherpetic neuralgia, depression or anxiety, which method comprises administration to a patient in need thereof of a therapeutically effective amount of a compound according to Claim 1.
- 17. Use of a compound as claimed in any one of Claims 1 to 12 for the manufacture of a medicament for the treatment or prevention of physiological disorders associated with an excess of tachykinins.
- 18. Use of a compound as claimed in any one of Claims 1 to 12 for the manufacture of a medicament for the treatment or prevention of pain or inflammation, migraine, emesis, postherpetic neuralgia, depression or anxiety.
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EA200970706A1 (en) | 2007-01-24 | 2010-02-26 | Глэксо Груп Лимитед | NEW PHARMACEUTICAL COMPOSITIONS |
CA2683584C (en) * | 2007-04-10 | 2015-07-07 | Merck & Co., Inc. | Hydroxymethyl ether hydroisoindoline tachykinin receptor antagonists |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2099233A1 (en) * | 1992-06-29 | 1993-12-30 | Conrad P. Dorn | Morpholine and thiomorpholine tachykinin receptor antagonists |
US5750549A (en) * | 1996-10-15 | 1998-05-12 | Merck & Co., Inc. | Cycloalkyl tachykinin receptor antagonists |
-
2000
- 2000-09-19 GB GBGB0022988.0A patent/GB0022988D0/en not_active Ceased
-
2001
- 2001-09-10 CA CA002421869A patent/CA2421869A1/en not_active Abandoned
- 2001-09-10 AU AU8430701A patent/AU8430701A/en active Pending
- 2001-09-10 US US10/381,077 patent/US6964981B2/en not_active Expired - Fee Related
- 2001-09-10 WO PCT/GB2001/004038 patent/WO2002024673A1/en not_active Application Discontinuation
- 2001-09-10 EP EP01963279A patent/EP1322629A1/en not_active Withdrawn
- 2001-09-10 AU AU2001284307A patent/AU2001284307B2/en not_active Ceased
- 2001-09-10 JP JP2002529083A patent/JP2004509881A/en not_active Withdrawn
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