AU675786B2 - Azacyclic compounds - Google Patents
Azacyclic compounds Download PDFInfo
- Publication number
- AU675786B2 AU675786B2 AU40765/93A AU4076593A AU675786B2 AU 675786 B2 AU675786 B2 AU 675786B2 AU 40765/93 A AU40765/93 A AU 40765/93A AU 4076593 A AU4076593 A AU 4076593A AU 675786 B2 AU675786 B2 AU 675786B2
- Authority
- AU
- Australia
- Prior art keywords
- methyl
- methyloxy
- phenylpiperidino
- phenyl
- trifluoromethyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Ceased
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- 150000004030 azacyclic compounds Chemical class 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims description 287
- -1 (2S,3S)-3-((3,5-bis(trifluoromethyl) phenyl)methyloxy) -2-phenylpiperidino Chemical group 0.000 claims description 97
- 238000000034 method Methods 0.000 claims description 96
- 239000000203 mixture Substances 0.000 claims description 95
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 84
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 67
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 44
- 238000006243 chemical reaction Methods 0.000 claims description 38
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 36
- 239000002904 solvent Substances 0.000 claims description 36
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 36
- SNTWKPAKVQFCCF-UHFFFAOYSA-N 2,3-dihydro-1h-triazole Chemical compound N1NC=CN1 SNTWKPAKVQFCCF-UHFFFAOYSA-N 0.000 claims description 33
- 150000003839 salts Chemical class 0.000 claims description 31
- 125000000217 alkyl group Chemical group 0.000 claims description 27
- 208000035475 disorder Diseases 0.000 claims description 25
- 230000008569 process Effects 0.000 claims description 25
- 239000002585 base Substances 0.000 claims description 19
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 17
- 125000001424 substituent group Chemical group 0.000 claims description 17
- 125000001425 triazolyl group Chemical group 0.000 claims description 17
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 15
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 14
- 102000003141 Tachykinin Human genes 0.000 claims description 14
- 125000001715 oxadiazolyl group Chemical group 0.000 claims description 14
- 108060008037 tachykinin Proteins 0.000 claims description 14
- 229910052727 yttrium Inorganic materials 0.000 claims description 14
- 239000000651 prodrug Substances 0.000 claims description 13
- 229940002612 prodrug Drugs 0.000 claims description 13
- 125000000335 thiazolyl group Chemical group 0.000 claims description 13
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- 125000004076 pyridyl group Chemical group 0.000 claims description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 11
- 125000002541 furyl group Chemical group 0.000 claims description 11
- 125000002883 imidazolyl group Chemical group 0.000 claims description 11
- 125000001113 thiadiazolyl group Chemical group 0.000 claims description 11
- 125000001544 thienyl group Chemical group 0.000 claims description 11
- VEUMBMHMMCOFAG-UHFFFAOYSA-N 2,3-dihydrooxadiazole Chemical compound N1NC=CO1 VEUMBMHMMCOFAG-UHFFFAOYSA-N 0.000 claims description 10
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 10
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 9
- 125000004432 carbon atom Chemical group C* 0.000 claims description 9
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 9
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 claims description 9
- 125000002971 oxazolyl group Chemical group 0.000 claims description 9
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 9
- 125000004306 triazinyl group Chemical group 0.000 claims description 9
- 208000002193 Pain Diseases 0.000 claims description 8
- 229910052783 alkali metal Inorganic materials 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 8
- 239000003937 drug carrier Substances 0.000 claims description 8
- 125000001072 heteroaryl group Chemical group 0.000 claims description 8
- 125000004043 oxo group Chemical group O=* 0.000 claims description 8
- 208000019695 Migraine disease Diseases 0.000 claims description 7
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 7
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 7
- 206010027599 migraine Diseases 0.000 claims description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 7
- 125000005493 quinolyl group Chemical group 0.000 claims description 7
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 7
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 6
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical group C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 6
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 6
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical group [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 claims description 6
- 229940124630 bronchodilator Drugs 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- 230000002265 prevention Effects 0.000 claims description 6
- 206010003246 arthritis Diseases 0.000 claims description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 5
- 208000023504 respiratory system disease Diseases 0.000 claims description 5
- 150000003852 triazoles Chemical group 0.000 claims description 5
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 4
- 241000036848 Porzana carolina Species 0.000 claims description 4
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 claims description 4
- 150000001340 alkali metals Chemical class 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 229910052705 radium Inorganic materials 0.000 claims description 4
- 229910052701 rubidium Inorganic materials 0.000 claims description 4
- 125000000464 thioxo group Chemical group S=* 0.000 claims description 4
- 229910000288 alkali metal carbonate Inorganic materials 0.000 claims description 3
- 150000008041 alkali metal carbonates Chemical class 0.000 claims description 3
- 239000003153 chemical reaction reagent Substances 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- 229940035893 uracil Drugs 0.000 claims description 3
- 206010061218 Inflammation Diseases 0.000 claims description 2
- 150000004678 hydrides Chemical class 0.000 claims description 2
- 230000004054 inflammatory process Effects 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims 26
- 125000001475 halogen functional group Chemical group 0.000 claims 11
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims 4
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims 3
- 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims 3
- YGTAZGSLCXNBQL-UHFFFAOYSA-N 1,2,4-thiadiazole Chemical compound C=1N=CSN=1 YGTAZGSLCXNBQL-UHFFFAOYSA-N 0.000 claims 2
- 150000003536 tetrazoles Chemical class 0.000 claims 2
- ZTMDGDHDXPIEIO-VXKWHMMOSA-N (2s,3s)-3-[[3,5-bis(trifluoromethyl)phenyl]methoxy]-1-(1h-imidazol-5-ylmethyl)-2-phenylpiperidine Chemical compound FC(F)(F)C1=CC(C(F)(F)F)=CC(CO[C@@H]2[C@@H](N(CC=3N=CNC=3)CCC2)C=2C=CC=CC=2)=C1 ZTMDGDHDXPIEIO-VXKWHMMOSA-N 0.000 claims 1
- BBVIDBNAYOIXOE-UHFFFAOYSA-N 1,2,4-oxadiazole Chemical compound C=1N=CON=1 BBVIDBNAYOIXOE-UHFFFAOYSA-N 0.000 claims 1
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 claims 1
- UPUWMQZUXFAUCJ-UHFFFAOYSA-N 2,5-dihydro-1,2-thiazole Chemical compound C1SNC=C1 UPUWMQZUXFAUCJ-UHFFFAOYSA-N 0.000 claims 1
- XXFWFTYVCMKLNC-GOTSBHOMSA-N 2-[[(2s,3s)-3-[[3,5-bis(trifluoromethyl)phenyl]methoxy]-2-phenylpiperidin-1-yl]methyl]pyrazine Chemical compound FC(F)(F)C1=CC(C(F)(F)F)=CC(CO[C@@H]2[C@@H](N(CC=3N=CC=NC=3)CCC2)C=2C=CC=CC=2)=C1 XXFWFTYVCMKLNC-GOTSBHOMSA-N 0.000 claims 1
- FJIAUTWSMWNNLK-FPOVZHCZSA-N 3-[[(2s,3s)-3-[[3,5-bis(trifluoromethyl)phenyl]methoxy]-2-phenylpiperidin-1-yl]methyl]-1,2,4-thiadiazole Chemical compound FC(F)(F)C1=CC(C(F)(F)F)=CC(CO[C@@H]2[C@@H](N(CC3=NSC=N3)CCC2)C=2C=CC=CC=2)=C1 FJIAUTWSMWNNLK-FPOVZHCZSA-N 0.000 claims 1
- VSOOWLLBBZTTBC-GOTSBHOMSA-N 3-[[(2s,3s)-3-[[3,5-bis(trifluoromethyl)phenyl]methoxy]-2-phenylpiperidin-1-yl]methyl]pyridazine Chemical compound FC(F)(F)C1=CC(C(F)(F)F)=CC(CO[C@@H]2[C@@H](N(CC=3N=NC=CC=3)CCC2)C=2C=CC=CC=2)=C1 VSOOWLLBBZTTBC-GOTSBHOMSA-N 0.000 claims 1
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 claims 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims 1
- 206010036376 Postherpetic Neuralgia Diseases 0.000 claims 1
- 101100229905 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) GPP1 gene Proteins 0.000 claims 1
- 241001197925 Theila Species 0.000 claims 1
- 241000906446 Theraps Species 0.000 claims 1
- JYZIHLWOWKMNNX-UHFFFAOYSA-N benzimidazole Chemical compound C1=C[CH]C2=NC=NC2=C1 JYZIHLWOWKMNNX-UHFFFAOYSA-N 0.000 claims 1
- MAPRDOKILZKGDP-UHFFFAOYSA-N bromo-chloro-iodomethanesulfonic acid Chemical compound OS(=O)(=O)C(Cl)(Br)I MAPRDOKILZKGDP-UHFFFAOYSA-N 0.000 claims 1
- 108010011222 cyclo(Arg-Pro) Proteins 0.000 claims 1
- 125000000717 hydrazino group Chemical group [H]N([*])N([H])[H] 0.000 claims 1
- 125000001183 hydrocarbyl group Chemical group 0.000 claims 1
- 230000003389 potentiating effect Effects 0.000 claims 1
- 239000003890 substance P antagonist Substances 0.000 claims 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 claims 1
- 150000003918 triazines Chemical class 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 290
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 138
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 108
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 102
- 235000019439 ethyl acetate Nutrition 0.000 description 97
- 229940093499 ethyl acetate Drugs 0.000 description 96
- 239000000243 solution Substances 0.000 description 90
- 201000006417 multiple sclerosis Diseases 0.000 description 85
- 238000005481 NMR spectroscopy Methods 0.000 description 68
- 239000007787 solid Substances 0.000 description 65
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 61
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 60
- 239000000047 product Substances 0.000 description 58
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 58
- 239000003921 oil Substances 0.000 description 53
- 235000019198 oils Nutrition 0.000 description 53
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 51
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 47
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 44
- 239000000377 silicon dioxide Substances 0.000 description 43
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 40
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 38
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 38
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 37
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 37
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 35
- 239000012267 brine Substances 0.000 description 33
- 238000005160 1H NMR spectroscopy Methods 0.000 description 28
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
- 125000005843 halogen group Chemical group 0.000 description 24
- 239000000543 intermediate Substances 0.000 description 24
- 239000011541 reaction mixture Substances 0.000 description 24
- 238000010992 reflux Methods 0.000 description 24
- 238000004587 chromatography analysis Methods 0.000 description 23
- 239000012044 organic layer Substances 0.000 description 23
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 22
- 229910052757 nitrogen Inorganic materials 0.000 description 22
- 239000007858 starting material Substances 0.000 description 21
- 229910000027 potassium carbonate Inorganic materials 0.000 description 20
- 235000011181 potassium carbonates Nutrition 0.000 description 19
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 16
- 239000003480 eluent Substances 0.000 description 16
- 238000003756 stirring Methods 0.000 description 16
- 238000010828 elution Methods 0.000 description 14
- 239000000284 extract Substances 0.000 description 14
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 12
- 238000004440 column chromatography Methods 0.000 description 12
- 239000000725 suspension Substances 0.000 description 12
- QDZOEBFLNHCSSF-PFFBOGFISA-N (2S)-2-[[(2R)-2-[[(2S)-1-[(2S)-6-amino-2-[[(2S)-1-[(2R)-2-amino-5-carbamimidamidopentanoyl]pyrrolidine-2-carbonyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-N-[(2R)-1-[[(2S)-1-[[(2R)-1-[[(2S)-1-[[(2S)-1-amino-4-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]pentanediamide Chemical compound C([C@@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](N)CCCNC(N)=N)C1=CC=CC=C1 QDZOEBFLNHCSSF-PFFBOGFISA-N 0.000 description 11
- 102100024304 Protachykinin-1 Human genes 0.000 description 11
- 101800003906 Substance P Proteins 0.000 description 11
- 201000010099 disease Diseases 0.000 description 11
- 239000003960 organic solvent Substances 0.000 description 10
- 238000000746 purification Methods 0.000 description 10
- 239000000741 silica gel Substances 0.000 description 10
- 229910002027 silica gel Inorganic materials 0.000 description 10
- 229960001866 silicon dioxide Drugs 0.000 description 10
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 239000012458 free base Substances 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 9
- 239000000843 powder Substances 0.000 description 9
- 239000003826 tablet Substances 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 7
- 125000001309 chloro group Chemical group Cl* 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- 230000002496 gastric effect Effects 0.000 description 7
- 239000010410 layer Substances 0.000 description 7
- 239000000463 material Substances 0.000 description 7
- 239000011734 sodium Substances 0.000 description 7
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 7
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 208000024827 Alzheimer disease Diseases 0.000 description 6
- 229920002261 Corn starch Polymers 0.000 description 6
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 239000008120 corn starch Substances 0.000 description 6
- ZKQFHRVKCYFVCN-UHFFFAOYSA-N ethoxyethane;hexane Chemical compound CCOCC.CCCCCC ZKQFHRVKCYFVCN-UHFFFAOYSA-N 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- 229910052708 sodium Inorganic materials 0.000 description 6
- 239000012312 sodium hydride Substances 0.000 description 6
- 229910000104 sodium hydride Inorganic materials 0.000 description 6
- 201000004624 Dermatitis Diseases 0.000 description 5
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 5
- 239000005557 antagonist Substances 0.000 description 5
- 208000006673 asthma Diseases 0.000 description 5
- 125000001246 bromo group Chemical group Br* 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 125000002346 iodo group Chemical group I* 0.000 description 5
- 208000033808 peripheral neuropathy Diseases 0.000 description 5
- 125000003226 pyrazolyl group Chemical group 0.000 description 5
- 125000000168 pyrrolyl group Chemical group 0.000 description 5
- 238000001953 recrystallisation Methods 0.000 description 5
- 206010039073 rheumatoid arthritis Diseases 0.000 description 5
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- 230000007365 immunoregulation Effects 0.000 description 1
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- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 1
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- 206010025135 lupus erythematosus Diseases 0.000 description 1
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- 159000000003 magnesium salts Chemical class 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- CYSFUFRXDOAOMP-UHFFFAOYSA-M magnesium;prop-1-ene;chloride Chemical compound [Mg+2].[Cl-].[CH2-]C=C CYSFUFRXDOAOMP-UHFFFAOYSA-M 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
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- 230000001404 mediated effect Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
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- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- YDCHPLOFQATIDS-UHFFFAOYSA-N methyl 2-bromoacetate Chemical compound COC(=O)CBr YDCHPLOFQATIDS-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- WFJRIDQGVSJLLH-UHFFFAOYSA-N methyl n-aminocarbamate Chemical compound COC(=O)NN WFJRIDQGVSJLLH-UHFFFAOYSA-N 0.000 description 1
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- 208000005264 motor neuron disease Diseases 0.000 description 1
- 210000003097 mucus Anatomy 0.000 description 1
- MIDZOHILFFUXMZ-UHFFFAOYSA-N n'-aminoethanimidamide Chemical compound CC(N)=NN MIDZOHILFFUXMZ-UHFFFAOYSA-N 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
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- 210000000653 nervous system Anatomy 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 230000002981 neuropathic effect Effects 0.000 description 1
- VPCDQGACGWYTMC-UHFFFAOYSA-N nitrosyl chloride Chemical compound ClN=O VPCDQGACGWYTMC-UHFFFAOYSA-N 0.000 description 1
- 235000019392 nitrosyl chloride Nutrition 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000012053 oil suspension Substances 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 125000000962 organic group Chemical group 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- PJCFLHUCYONHAS-UHFFFAOYSA-N oxathiazolone Chemical compound O=C1OC=NS1 PJCFLHUCYONHAS-UHFFFAOYSA-N 0.000 description 1
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000008024 pharmaceutical diluent Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- ZNNZYHKDIALBAK-UHFFFAOYSA-M potassium thiocyanate Chemical compound [K+].[S-]C#N ZNNZYHKDIALBAK-UHFFFAOYSA-M 0.000 description 1
- 229940116357 potassium thiocyanate Drugs 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- 238000004237 preparative chromatography Methods 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
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- MNOALXGAYUJNKX-UHFFFAOYSA-N s-chloro chloromethanethioate Chemical compound ClSC(Cl)=O MNOALXGAYUJNKX-UHFFFAOYSA-N 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
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- 238000000926 separation method Methods 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
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- 239000004208 shellac Substances 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- QZZMKPYPUYLYSK-UHFFFAOYSA-N sodium methanolate hydrochloride Chemical compound C[O-].[Na+].Cl QZZMKPYPUYLYSK-UHFFFAOYSA-N 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- ADNPLDHMAVUMIW-CUZNLEPHSA-N substance P Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(N)=O)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CCCN=C(N)N)C1=CC=CC=C1 ADNPLDHMAVUMIW-CUZNLEPHSA-N 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
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- 210000000331 sympathetic ganglia Anatomy 0.000 description 1
- 210000001258 synovial membrane Anatomy 0.000 description 1
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 1
- 239000002462 tachykinin receptor antagonist Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- QIQITDHWZYEEPA-UHFFFAOYSA-N thiophene-2-carbonyl chloride Chemical compound ClC(=O)C1=CC=CS1 QIQITDHWZYEEPA-UHFFFAOYSA-N 0.000 description 1
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Substances CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 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
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- FFSJPOPLSWBGQY-UHFFFAOYSA-N triazol-4-one Chemical compound O=C1C=NN=N1 FFSJPOPLSWBGQY-UHFFFAOYSA-N 0.000 description 1
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 1
- MASNJXDMMSOROP-UHFFFAOYSA-N triethylsilane 2,2,2-trifluoroacetic acid Chemical compound CC[SiH](CC)CC.OC(=O)C(F)(F)F MASNJXDMMSOROP-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 208000027491 vestibular disease Diseases 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/08—Bronchodilators
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/12—Oxygen or sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/54—Sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Pulmonology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
OPI DATE 18/11/93 APPLN. ID 40765/93 llllll ll lllllllllllllllll AOJP DATE 27/01/94 PCT NUMBER PCT/GB93/00788 AU9340765 IN I CtNA IUNAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) International Patent Classification 5 (11) International Publication Number: WO 93/21181 C07D 413/06, 401/06, 417/06 C07D 405/06, 409/06, 403/06 A (43) International Publication Date: 28 October 1993 (28.10.93) A61K 31/41, 31/445 (21) International Application Number: PCT/GB93/00788 (74) Agent: QUILLIN, Helen, Kaye; Merck Co., Inc., European Patent Department, Terlings Park, Eastwick Road, (22) International Filing Date: 14 April 1993 (14.04.93) Harlow, Essex CM20 2QR (GB).
Priority data: (81) Designated States: AT, AU, BB, BG, BR, CA, CH-, CZ, 92083237 15 April 1992 (15.04.92) GB DE, DK, ES, Fl, GB, HU, JP, KP, KR, LK, LU, MG, 9216065.4 28 July 1992 (28.07.92) GB MN, MW, NL, NO, NZ, PL, PT, RO, RU, SD, SE, SK, 9219686.4 17 September 1992(17.09.92) GB UA, US, European patent (AT, BE, CH, DE, DK, ES, 9226069.4 14 December 1992 (14.12.92) GB FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OAPI patent (BF, BJ, CF, CG, CI, CM, GA, GN, ML, MR, NE, SN, TD, TG).
(71) Applicant (for all designated States except US): MERCK SHARP DOHME LIMITED [GB/GB]; Hertford Road, Hoddesdon, Hertfordshire ENI1 9BU Published With international search report.
(72) Inventors; and Inventors/Applicants (for US only) BAKER, Raymond [GB/GB]; Bulls Cottage, Green Tye, Much Hadham, Hertfordshire SG0I 6JN LADDHWAHETTY, Tamara [GB/GB]; 185 Buckhurst Way, Buckhurst Hill, Essex IG9 6JB SEWARD, Eileen Mary [IE/GB]; The Colts, Thorley Park, Bishops Stortford, Hertfordshire CM23 4DL SWAIN, Christopher, John [GB/ GB]; 8 Mangers Lane, Duxford, Cambridge CB2 4RN (G B).
(54) Title: AZACYCLIC COMPOUNDS R Y-R (57) Abstract Compounds of formula and salts and prodrugs thereof wherein n is 1, 2 or 3; X represents 0 or S; Y represents a hydrocarbon chain of 1, 2, 3 or 4 carbon atoms optionally substituted by oxo; R 1 is phenyl optionally substituted by 1, 2 or 3 of Ci.
6 alkyl, C 2 6 alkenyl, C 2 6 alkynyl, halo, cyano, nitro, trifluoromethyl, trimethylsilyl, -OR a SRa, SORa, SO 2 Ra, -NRaRb, -NRaCORb, -NRaCO2Rb, -CO 2 Ra or -CONRaRb; R 2 is phenyl, indazolyl, thienyl, furyl, pyridyl, thiazolyl, tetrazolyl, quinolyl, benzhydryl, or benzyl; R 4 and R 5 each independently represent H, halo, C 1 6 alkyl, oxo, CH 2 ORa, CO 2 Ra or CONRaR b
R
8 represents an optionally substituted aromatic heterocycle; and R a and Rb are H, trifluoromethyl, C1.
6 alkyl or phenyl optionally substituted by Cl.
6 alkyl, halo or trifluoromethyl; are tachykinin antagonists useful in medecine.
WO 93/21181 PCT/GB93/00788 1 AZACYCLIC COMPOUNDS This invention relates to a class of azacyclic compounds, which are useful as tachykinin antagonists.
More particularly, the compounds of the invention comprise an azacyclic ring system substituted by an arylmethyloxy or arylmethylthio moiety.
The tachykinins are a group of naturallyoccurring peptides found widely distributed throughout mammalian tissues, both within the central nervous system and in the peripheral nervous and circulatory systems.
The structures of three known mammalian tachykinins are as follows: Substance P: Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2 Neurokinin A: His-Lys-Thr-Asp-Ser-Phe-Val-Gly-Leu-Met-NH 2 Neurokinin B: Asp-Met-His-Asp-Phe-Phe-Val-Gly-Leu-Met-NH 2 For example, substance P is believed inter alia to be involved in the neurotransmission of pain sensations [Otsuka et al, "Role of Substance P as a Sensory Transmitter in Spinal Cord and Sympathetic Ganglia" in 1982 Substance P in the Nervous System, Ciba Foundation Symposium 91, 13-34 (published by Pitman) and Otsuka and Yanagisawa, "Does Substance P Act as a Pain Transmitter?" TIPS (Dec. 1987) 506-510], specifically in the transmission of pain in migraine Sandberg et al, J. Med Chem, (1982) 25 1009; S.L. Shepheard et al., Br. J. Pharmacol. (1993), 108, 11-12) and in arthritis [Levine et al in Science (1984) 226 547-549].
These peptides have also been implicated in gastrointestinal (GI) disorders and diseases of the GI WO 93/21181 PCT/GB93/00788 2 tract such as inflammatory bowel disease [Mantyh et al in Neuroscience (1988) 25 817-37 and D. Regoli in "Trends in Cluster Headache" Ed. Sicuteri et al Elsevier Scientific Publishers, Amsterdam (1987) page It is also hypothesised that there is a neurogenic mechanism for arthritis in which substance P may play a role [Kidd et al "A Neurogenic Mechanism for Symmetrical Arthritis" in The Lancet, 11 November 1989 and Grdnblad et al "Neuropeptides in Synovium of Patients with Rheumatoid Arthritis and Osteoarthritis" in J. Rheumatol. (1988) 15(12) 1807-10]. Therefore, substance P is believed to be involved in the inflammatory response in diseases such as rheumatoid arthritis and osteoarthritis [O'Byrne et al in Arthritis and Rheumatism (1990) 33 1023-8]. Other disease areas where tachykinin antagonists are believed to be useful are allergic conditions [Hamelet et al Can.
J. Pharmacol. Physiol. (1988) 66 1361-7], immunoregulation [Lotz et al Science (1988) 241 1218-21 and Kimball et al, J. Immunol. (1988) 141 (10) 3564-9] vasodilation, bronchospasm, reflex or neuronal control of the viscera [Mantyh et al, PNAS (1988) 85 3235-9] and, possibly by arresting or slowing p-amyloid-mediated neurodegenerative changes [Yankner et al Science, (1990) 250, 279-82] in senile dementia of the Alzheimer type, Alzheimer's disease and Down's Syndrome.
Substance P may also play a role in demyelinating diseases such as multiple sclerosis and amyotrophic lateral sclerosis Luber-Narod et. al., poster presented at C.I.N.P. XVIIIth Congress, 28th June- 2nd July, 1992], and in disorders of bladder function such as bladder detrusor hyper-reflexia (Lancet, 16th May, 1992, 1239); It has furthermore been suggested that tachykinins have utility in the following disorders: WO 93/21181 PCT/GB93/00788 3 depression, dysthymic disorders, chronic obstructive airways disease, hypersensitivity disorders such as poison ivy, vasospastic diseases such as angina and Reynauld's disease, fibrosing and collagen diseases such as scleroderma and eosinophillic fascioliasis, reflex sympathetic dystrophy such as shoulder/hand syndrome, addiction disorders such as alcoholism, stress related somatic disorders, neuropathy, neuralgia, disorders related to immune enhancement or suppression such as systemic lupus erythmatosis (European patent application no. 0 436 334), ophthalmic disease such as conjuctivitis, vernal conjunctivitis, and the like, and cutaneous diseases such as contact dermatitis, atropic dermatitis, urticaria, and other eczematoid dermatitis (European patent application no. 0 394 989) and emesis (European patent application no. 0 533 280).
In view of their metabolic instability, peptide derivatives are likely to be of limited utility as therapeutic agents. It is fe.r this reason that nonpeptide tachykinin antagonists are sought.
European patent application no. 0 436 334 discloses 4- to 7-membered azacyclic compounds substituted at the 3-position by a substituted amino moiety. The compounds are said to be tachykinin antagonists.
The present invention provides a compound of formula or a salt or prodrug thereof: WO 93/21181 WO 9321181PCT/GB93/00788 -4- (C R 2 wherein n is 1, 2 or 3; X represents 0 or S; Y represents a hydrocarbon chain of 1, 2, 3 or 4 carbon atoms which may optionally be substituted by oxo;
R
1 represents phenyl optionally substituted by 1, 2 or 3 groups selected from C 1 6 alkyl, C 2 -6 alkenyl,
C
2 6 alkynyl, halo, cyano, nitro, trifluoromethyl, trimethylsilyl, -ORa, SRa, SORa, SO 2 Ra, ._T~aRb, NflaCORb, _N.~Ta C 2 Rb -C0 2 Ra or _CONRaRb;
R
2 represents aryl selected from phenyl and naphthyl; heteroaryl selected from indazolyl, thienyl, furyl, pyridyl, thiazolyl, tetrazolyl and quinolyl; benzhydryl; or benzyl; wherein each aryl or heteroaryl moiety may be substituted by C 1 6 alkyl, C 1 6 alkoxy, halo or trifluoromethyl; Rand R 5 may be present on any available carbon atom of the azacyclic ring and each independently represent H, halo, C 1 6 alkyl, oxo, CH 2 0Ra, C0 2 Ra or CONRaRbI
R
8 represents an optionally substituted aromatic heterocycle; and WO 93/21181 PCr/GB93/00788 5
R
a and Rb each independently represent H, trifluoromethyl, C1- 6 alkyl or phenyl optionally substituted by C 1 -6alkyl, halo or trifluoromethyl.
As used herein, the definition of each expression, when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure.
The alkyl, alkenyl and alkynyl groups referred to with respect to the above formula may represent straight, branched or cyclic groups, or combinations thereof. Thus, for example, suitable alkyl groups include methyl, ethyl, n- or iso-propyl, sec-, isoor tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and cycloalkyl-alkyl groups such as cyclopropylmethyl; suitable alkenyl groups include vinyl and allyl; and suitable alkynyl groups include propargyl.
The term "halo" as used herein includes fluoro, chloro, bromo and iodo, especially chloro and fluoro.
The present invention includes within its scope prodrugs of the compounds of formula above. In general, such prodrugs will be functional derivatives of the compounds of formula which are readily convertible in vivo into the required compound of formula Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H.
Bundgaard, Elsevier, 1985.
The compounds according to the invention may exist both as enantiomers and as diastereomers. In particular, the relative orientation of the 2- and 3substituents on the azacyclic ring may give rise to cis and trans diastereoisomers, of which the cis stereochemistry is preferred. It is to be understood 1994 6 that all such isomers and mixtures thereof are encompassed within the scope of the present invention.
Preferably n is 2 or 3, more preferably 3.
Preferably X represents 0.
Suitably Y represents a hydrocarbon chain of 1 or 2 carbon atoms optionally substituted by oxo, such as
CH
2 C=O, CH(CH 3
CH
2 or (C=0)CH 2 Preferably Y represents CH 2
CH(CH
3 or CH 2 more preferably CH 2 or CH(CH3). A particularly preferred subgroup of compounds according to the invention is represented by compounds of formula wherein Y is CH(CH 3 Preferably R 1 represents substituted phenyl.
When R 1 is substituted phenyl suitable substituents include nitro, trifluoromethyl, trimethylsilyl, bromo, chloro, fluoro, iodo, cyano, C 1 6 alkyl such as methyl, ethyl, i-propyl, i-butyl, t-butyl and cyclopropyl,
C
2 -6alkenyl such as vinyl, C1- 6 alkoxy such as methoxy, ethoxy and i-propoxy, phenoxy, amino, carboxamido and methoxycarbonyl. Preferably R 1 represents phenyl substituted by one or more groups selected from
C
1 -4alkyl, such as methyl and t-butyl, trifluoromethyl and halo such as iodo, bromo chloro and fluoro.
Suitably R 1 represents monosubstituted phenyl, such as 3-substituted phenyl or, preferably, disubstituted phenyl, such as 3,5-disubstituted phenyl.
Preferably R 1 represents phenyl substituted at the 3position by trifluoromethyl or a C1-galkyl group such as t-butyl, or 3,5-disubstituted phenyl wherein the substituents are independently selected from trifluoromethyl, chloro, fluoro, methyl and t-butyl.
Preferred values for R 1 include bis(trifluoromethyl)phenyl, 3,5-dichlorophenyl, 3-t- 3-chloro-5-methylphenyl, 3-t-butyl- 3-bis(trifluoromethyl)phenyl and 3-t- S- .n S T r WO 93/21181 PCT/GB93/00788 7 butylphenyl. Particularly preferred is bis(trifluoromethyl)phenyl.
Suitably R 2 represents benzhydryl or optionally substituted phenyl, such as phenyl optionally substituted by halo such as fluoro or chloro, preferably in the 3position. Preferably R 2 represents unsubstituted phenyl or unsubstituted benzhydryl, more preferably unsubstituted phenyl.
Suitable values for R 4 and R 5 include H,
C
1 -6alkyl, especially methyl, hydroxymethyl and oxo. The substitutents R 4 and R 5 may be located on any available carbon atom of the azacyclic ring including, except in the case where the substituent R 4 or R 5 in question represents oxo, C-2 and C-3. Preferably at least one of
R
4 and R 5 represents H. In one preferred group of compounds R 4 and R 5 both represent H. In a further preferred group of compounds one of R 4 and R 5 is H and the other of R 4 and R 5 is methyl, preferably 2-methyl.
When R 8 represents a substituted aromatic heterocycle, suitable substituents in the heterocyclig ring include one or more of C 1 -6alkyl, C1-6alkoxy, phenyl, oxo, thioxo, halo, trifluoromethyl, NRaRb, NRaCOR b CONRaR b
CO
2 Ra, SRa, SO 2 Ra and CH 2
OR
a where Ra and Rb are as previously defined. Particular examples of suitable substituents include methyl, methoxy, phenyl, oxo, thioxo, bromo, iodo, NH 2
SCH
3
CONH
2 and cyano.
Particularly preferred substituents include oxo and NH 2 Suitable values for R 8 include thienyl, furyl, pyrrolyl, pyridyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, oxazolyl, oxadiazolyl, thiadiazolyl, isoxazolyl, quinolyl, isothiazolyl, imidazolyl, benzimidazolyl, benzoxazolyl, benzothiophenyl, WO 93/21181 PCT/GB93/00788 8 benzofuranyl and indolyl, any of which may be substituted.
In particular, R 8 may represent optionally substituted thienyl, furyl, pyridyl, triazolyl, tetrazolyl, thiazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, oxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, benzimidazolyl or benzoxazolyl.
In one group of compounds according to the invention R 8 represents optionally substituted pyrrolyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, imidazolyl, benzimidazolyl, benzoxazolyl, benzothiophenyl, benzofuranyl or indolyl.
Preferably R 8 represents a substituted or unsubstituted 5- or 6-membered nitrogen containing aromatic heterocycle such as for example oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, thiadiazolyl, triazolyl, pyrazinyl, pyridyl, pyrimidinyl, pyridazinyl, imidazolyl or triazinyl. More preferably R 8 represents optionally substituted oxazolyl, oxadiazolyl, imidazolyl, thiadiazolyl, triazolyl, pyrazinyl, pyrimidinyl, pyridazinyl or triazinyl, or tetrazolyl substituted by
C
1 -6alkyl,.preferably methyl.
In one preferred group of compounds according to the invention, R 8 represents substituted or unsubstituted oxadiazolyl, for example, oxadiazolyl substituted by halo, amino, dialkylamino or methyl. More preferably R 8 represents 5-(3-aminooxadiazolyl).
In a further preferred group of compounds according to the invention, R 8 represents substituted or unsubstituted triazolyl, for example, unsubstituted triazolyl or triazolyl subtituted by oxo or thioxo, more preferably, triazolyl substituted by oxo.
WO 93/21181 PCT/GB93/00788 9 It will be appreciated that, when the heterocyclic moiety R 8 is substituted by an oxo or thioxo substituent, different tautomeric forms are possible so that the substituent may be represented as =0 or -OH, or =S or -SH, respectively. For the avoidance of doubt, all such tautomeric forms are embraced by the present invention.
One subgroup of compounds according to the invention is represented by compounds of formula (IA), and salts and prodrugs thereof:
R
10 R1 2 (C
R
R R1
(IA)
wherein n is 1, 2 or 3 and where any carbon atom of (CH2)n may be substituted by R 12 and/or R 13 X represents 0 or S;
R
10 represents phenyl optionally substituted by 1, 2 or 3 groups selected from Cl-6alkyl, C 2 -6 alkenyl,
C
2 -6alkynyl, halo, cyano, nitro, trifluoromethyl, trimethylsilyl, -ORc, SRc, SORc, SO 2 Rc, -NRCRd, -NRCCOR d
-NRCCO
2 Rd, -C0 2 Rc or -CONRCRd;
R
11 represents aryl selected from phenyl and naphthyl; heteroaryl selected from indazolyl, thienyl, furyl, pyridyl, thiazolyl, tetrazolyl and quinolyl; benzhydryl; or benzyl; wherein each aryl or heteroaryl moiety may be substituted by Cl-6alkyl, C 1 -6alkoxy, halo or trifluoromethyl; WO 93/21181 PCT/GB93/00788 10
R
12 and R 13 each independently represent H, halo, C 1 -6alkyl, oxo, CO 2 Rc or CONRCRd;
R
14 represents C 1 -4alkyl, optionally substituted by oxo, substituted by an optionally substituted aromatic heterocycle; and Rc and Rd each independently represent H,
C
1 -6alkyl, phenyl optionally substituted by Cl-6alkyl or halo or trifluoromethyl.
Suitable values for the heterocyclic moiety of
R
14 include thienyl, furyl, pyrrolyl, pyridyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, pyrazinyl, pyridazinyl, oxazolyl, oxadiazolyl, thiadiazolyl, isoxazolyl, quinolyl, isothiazolyl, imidazolyl, benzimidazolyl, benzoxazolyl, benzothiophenyl, benzofuranyl and indolyl.
In one sub-class of compounds of formula (IA), Rc and Rd each independently represent H, C1-6alkyl, phenyl or trifluoromethyl.
A further subclass of compounds of formula (IA) is represented by compounds wherein n is 2 or 3; R 12 and
R
13 each independently represent H, halo, Cl-6alkyl,
CO
2 Rc or CONRcRd; R 14 represents C 1 -4alkyl substituted by an optionally substituted 5- or 6-membered aromatic heterocycle; and Rc and Rd each independently represent H, C1-6alkyl, phenyl or trifluoromethyl. For the compounds of this subclass, suitable values for the heterocyclic moiety of R 14 include thienyl, furyl, pyrrolyl, pyridyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, isoxazolyl, isothiazolyl and imidazolyl.
A preferred sub-class of compounds according to the invention is represented by compounds of formula and salts and prodrugs thereof: il,4 APRIL 191 4 11
R
2 0 R 2 2 1
R
2 wherein X represents 0 or S, preferably 0; Y is as defined for formula preferably
C
1 2 alkyl optionally substituted by oxo, more preferably
CH
2 or CH(CH 3
R
2 represents phenyl or benzhydryl wherein any of the phenyl rings of the phenyl or benzhydryl moieties may optionally be substitutec by halo or trifluoromethyl, preferably unsubstituted phenyl;
R
8 is as defined for formula and
R
2 0 and R 21 independently represent H, C1- 6 alkyl, C2-6alkenyl, C2-6alkynyl, bromo, chloro, fluoro, iodo, cyano, nitro, trifluoromethyl, trimethylsilyl, OR a SRa SORa, SO 2 Ra, NRaRb, NRaCOR b NRaC0 2
R
b
COR
a
CO
2 Ra or CONRaRb, where Ra and Rb are as previously defined; and z is 1 or 2.
Particular values of R 20 and R 21 include H, methyl, t-butyl, methoxy, i-propoxy, chloro, fluoro, nitro, amino, methoxycarbonyl, carboxamido and trifluoromethyl. Preferably R 20 and R 21 are both other WO 93/21181 PCT/GB93/00788 12 than H, more preferably C1-6alkyl, halo or trifluoromethyl, and are located at the 3- and positions of the phenyl ring.
One sub-class of compounds according to the invention are compounds of formula (IB) wherein R 8 is optionally substituted pyrrolyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, imidazolyl, benzimidazolyl, benzoxazolyl, benzothiophenyl, benzofuranyl, indolyl, thiadiazolyl or oxadiazolyl, m~re preferably oxadiazolyl.
A further sub-class of compounds according to the invention are compounds of formula (IB) wherein R 8 is optionally substituted oxadiazolyl, pyridinyl, benzimidazolyl, tetrazolyl, thiazolyl, furyl, thienyl, triazolyl, thiadiazolyl, benzoxazolyl, oxazolyl, pyrazinyl, pyridazinyl, triazinyl, pyrimidinyl or imidazolyl.
A particularly preferred group of compounds according to the invention are compounds of formula (Ia) wherein R 8 is optionally substituted triazolyl, especially triazole substituted by oxo.
For use in medicine, the salts of the compounds of formula will be pharmaceutically acceptable salts.
Other salts may, however, be useful in the preparation of the compounds according to the invention (such as the dibenzoyltartrate salts) or of their 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, sulphuric acid, oxalic acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic WO 93/21181 PCT/G B93/00788 13 acid, phosphoric acid or p-toluenesulphonic 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.
Preferred salts of the compounds according to the invention include the hydrochloride and ptoluenesulphonic acid salts.
The invention also provides pharmaceutical compositions comprising one or more compounds of this invention in association with a pharmaceutically acceptable carrier. Preferably these compositions 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.
The invention further provides a process for the preparation of a pharmaceutical composition comprising a compound of formula or a salt or prodrug thereof, and a pharmaceutically acceptable carrier, which process comprises bringing a compound of formula or a salt or prodrug thereof into association with a pharmaceutically acceptable carrier.
For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, WO 93/2%1181 PCT/GB93/00788 14 sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a nontoxic pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils WO 93/21181 PCT/GB93/00788 15 such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin.
Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as set out above. Preferably the compositions are adminsitered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably sterile pharmaceutically acceptable solvents may be nebulised by use of inert gases. Nebulised solutions may be breathed directly from the nebulising device or the nebulising device may be attached to a face mask, tent or intermittent positive pressure breathing machine.
Solution, suspension or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.
The compounds of formula 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. These may include disorders of the central nervous system such as anxiety, depression, psychosis and schizophrenia; neurodegenerative disorders such as dementia, including senile dementia of the Alzheimer type, Alzheimer's disease and Down's syndrome; demyelinating diseases such as multiple sclerosis (MS) and amyotropic lateral sclerosis (ALS; Lou Gehrig's disease) and other WO 93/21181 PCT/GB93/00788 16 neuropathological disorders such as peripheral neuropathy, for example, diabetic or chemotherapy-induced neuropathy, and postherpetic and other neuralgias; respiratory diseases such as chronic obstructive airways disease, bronchopneumonia, bronchospasm and asthma; inflammatory diseases such as inflammatory bowel disease, psoriasis, fibrositis, osteoarthritis and rheumatoid arthritis; allergies such as eczema and rhinitis; hypersensitivity disorders such as poison ivy; ophthalmic diseases such as conjunctivitis, vernal conjunctivitis, and the like; cutaneous diseases such as contact dermatitis, atropic dermatitis, urticaria, and other eczematoid dermatitis; addiction disorders such as alcoholism; stress related somatic disorders; reflex sympathetic dystrophy such as shoulder/hand syndrome; dysthymic disorders; adverse immunological reactions such as rejection of transplanted tissues and disorders related to immune enhancement or suppression such as systemic lupus erythematosis; gastrointestinal (GI) disorders and diseases of the GI tract such as disorders associated with the neuronal control of viscera such as ulcerative colitis, Crohn's disease and incontinence; emesis, including acute, delayed and anticipatory emesis, for example, induced by chemotherapy, radiation, toxins, pregnancy, vestibular disorders, surgery, migraine and variations in intercranial pressure; disorders of bladder function such as bladder detrusor hyper-reflexia; fibrosing and collagen diseases such as scleroderma and eosinophilic fascioliasis; disorders of blood flow caused by vasodilation and vasospastic diseases such as angina, migraine and Reynaud's disease; and pain or nociception, for example, that attributable to or associated with any of the foregoing conditions, especially the transmission of pain in migraine. For example, the compounds of WO 93/21181 PCT/GB93/00788 17 formula may suitably be used in the treatment of disorders of the central nervous system such as anxiety, psychosis and schizophrenia; neurodegenerative disorders such as senile dementia of the Alzheimer type, Alzheimer's disease and Down's syndrome; respiratory diseases, particularly those associated with excess mucus secretion, such as chronic obstructive airways disease, bronchopneumonia, chronic bronchitis, cystic fibrosis and asthma, and bronchospasm; inflammatory diseases such as inflammatory bowel disease, osteoarthritis and rheumatoid arthritis; adverse immunological reactions such as rejection of transplanted tissues; gastrointestinal (GI) disorders and diseases of the GI tract such as disorders associated with the neuronal control of viscera such as ulcerative colitis, Crohn's disease and incontinence; disorders of blood flow caused by vasodilation; and pain or nociception, for example, that attributable to or associated with any of the foregoing conditions or the transmission of pain in migraine.
The compounds of formula are particularly useful in the treatment of pain or nociception and/or inflammation and disorders associated therewith such as, for example, neuropathy, such as diabetic and chemotherapy-induced neuropathy, postherpetic and other neuralgias, asthma, osteroarthritis, rheumatoid arthritis and especially migraine.
The present invention further provides a compound of formula for use in therapy.
According to a further or alternative aspect, the present invention provides a compound of formula (I) for use in the manufacture of a medicament for the treatment of physiological disorders associated with an excess of tachykinins, especially substance P.
WO 93/21181 PCT/GB93/00788 18 The present invention also provides a method for the treatment or prevention of physiological disorders associated with an excess of tachykinins, especially substance P, which method comprises administration to a patient in need thereof of a tachykinin reducing amount of a compound of formula (I) or a composition comprising a compound of formula For the treatment of certain conditions it may be desirable to employ a compound according to the present invention in conjunction with another pharmacologically active agent. For example, for the treatment of respiratory diseases such as asthma, a compound of formula may be used in conjunction with a bronchodilator, such as a p 2 -adrenergic receptor antagonist or tachykinin antagonist which acts at NK-2 receptors. The compound of formula and the bronchodilator may be administered to a patient simultaneously, sequentially or in combination.
The present invention iccordingly provides a method, for the treatment of a respiratory disease, such as asthma, which method comprises administration to a patient in need thereof of an effective amount of a compound of formula and an effective amount of a bronchodilator.
The present invention also provides a composition comprising a compound of formula a bronchodilator, and a pharmaceutically acceptable carrier.
In the treatment of the conditions associated with an excess of tachykinins, 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 mg/kg of a compound of formula per day. For example, in the treatment of conditions involving the WO 93/21181 PCT/GB93/00788 19 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.
According to one general process the compounds according to the invention may be prepared by a process which comprises reacting a compound of formula
(II):
R
1 R H wherein R 1
R
2
R
4
R
5 X and n are as defined for formula above, with a reagent suitable to introduce the group Y-R 8 for example, a halide or acyl halide, or corresponding mesylate or tosylate, of formula R 8
-Y-L,
where L represents halo, such as chloro, bromo or iodo, methylsulphonate or R- toluenesulphonate,or any other suitable leaving group, in the presence of a base.
Suitable bases of use in the reaction include inorganic bases such as alkali metal carbonates, for example, potassium carbonate.
Conveniently the reaction is effected in a suitable organic solvent, for example, dimethylformamide.
According to a second process compounds of formula wherein R 8 represents 5-oxadiazolyl may be WO 93/21181 PCT/GB93/00788 20 prepared by reaction of a compound of formula (III) with a compound of formula (IV):
R
4
XNOH
R
Y
0-
OR
30 I
(IV)
wherein R 1
R
2
R
4
R
5 X, Y and n are as defined for formula R 30 represents an alkyl group and R 31 represents H or a suitable substituent such as C 1 -6alkyl,
C
1 -6alkoxy, halo, NRaR b or NRaCORb, where Ra and Rb are as previously defined, in the presence of a base.
Suitable bases of use in the reaction include alkali metals, such as, for example, sodium, and alkali metal hydrides, such as, for example, sodium hydride.
The reaction is conveniently effected in a suitable organic solvent. Which solvents will be.
appropriate will depend on the nature of the base used.
For example, where the base used is an alkali metal, suitable solvents will include alcohols, for example, ethanol, whereas where the base used is an alkali hydride, suitable solvents will include ethers, for example, tetrahydrofuran.
Preferably the reaction is conducted at elevated temperature, such as the reflux temperature of the chosen solvent.
According to a further process, compounds of formula wherein R 8 represents tetrazolyl may be prepared from intermediates of formula WO 93/21181 PC/GB93/00788 21
R
1 2
I
CN
(V)
wherein R 1
R
2
R
4
R
5 X, Y and n are as defined for formula by treatment with an alkali metal azide, such as sodium azide.
The reaction is conveniently effected in a high boiling organic solvent, such as, for example, N-methylpyrrolidinone.
According to a further process, compounds of formula wherein R 8 represents thiazolyl may be prepared from intermediates of formula (VI):
R
i R 4 x-- (C 2 R
Y
SRNH
2
(VI)
wherein R 1
R
2
R
4
R
5 X, Y and n are as defined for formula by reaction with a compound of formula Hal-CH 2
C(O)-R
60 where Hal represents halo, such as bromo, chloro or iodo, and R 6 0 represents H or a suitable substituent such as C 1 -6alkyl.
WO 93/21181 PCT/GB93/00788 22 The reaction is conveniently effected in a suitable organic solvent, such as a ketone, for example, acetone, or an alcohol, for example, methanol, or a mixture of solvents, preferably at elevated temperature, such as the reflux temperature of the chosen solvent.
According to a futher process, compounds of formula wherein R 8 represents thioxotriazolyl may be prepared from intermediates of formula (VII) R2 R y R0 NHNH
(VII)
wherein R 1
R
2
R
4
R
5 X, Y and n are as defined for formula by reaction with a compound of formula
R
61 NCS, wherein R 6 1 represents H or a suitable substituent such as Ci-6alkyl, in the presence of a base.
Suitable bases of use in the reaction include organic bases such as, for example, 1,8diazabicyclo[5.4.0]undec-7-ene (DBU). The reaction is conveniently effected in a suitable orgainc solvent, such as alcohol, e.g. butanol.
According to a further process, compounds of formula wherein R 8 represents unsubstituted or substituted triazolyl may be prepared by reaction of intermediates of formula (II) with a compound of formula
(VIII):
WO 93/21181 PT/GB93/00788 23 0 R0 N H N Y-H a i
NH
2
(VIII)
wherein Y and Hal are as previously defined and R 18 is H or a group suitable as a substituent of the triazole ring, or convertible to such a group under the reaction conditions, in the presence of a base.
Suitable bases of use in the reaction include alkali metal carbonates, such as, for example, potassium carbonate.
Suitably R 18 represents H, OCH 3 (which is converted to an oxo substituent under the reaction conditions) or CONH 2 The reaction is conveniently effected in an anhydrous organic solvent, such as, for example, anhydrous dimethylformamide, preferably at elevated temperature, such as about 140"C.
According to a further process, compounds of formula wherein R 8 represents substituted or unsubstituted 1,3,5-triazine may be prepared by reaction of intermediates of formula (IX): WO 9'3/21181 PCT/GB93/00788 24
R'
R
4 X (CR2
R
4 R
Y
HN' NH 2
(IX)
wherein R 1
R
2
R
4
R
5 X, Y and n are as defined for formula with substituted or unsubstituted 1,3,5triazine.
The reaction is conveniently effected in a suitable organic solvent, such as acetronitrile, at elevated temperature, such as 80-90'C, preferably about 82'C.
According to a further process, compounds of formula wherein R 8 represents substituted or unsubstituted 1,2,5-triazine may be prepared by reaction of an intermediate of formula with a dicarbonyl compound of formula (XI):
RR
R
4
X--
0 (C 2 R 3 6 R R 3 5 i HN''NHNH 2
(X)
(XI)
WO 93/21181 PCT/GB93/00788 25 wherein R 1
R
2
R
4
R
5 X, Y and n are as defined for formula and R 35 and R 36 each independently represnt H or a suitable substituent such as C 1 -6alkyl, e.g. methyl.
The reaction is conveniently effected in a suitable organic solvent, such as an ether, e.g.
tetrahydrofuran, conveniently at ambient temperature.
Further details of suitable procedures will be found in the accompanying Examples.
Compounds of formula (VIII) may be prepared as described in J. Med. Chem, 27, (1984), 849.
Compounds of formula may also be prepared from other compounds of formula using suitable interconversion procedures. For example, compounds of formula wherein Y represents C 1 -4alkyl substituted by an aromatic heterocycle may be prepared from compounds of formula wherein Y represents C 1 4 alkyl substituted by oxo by reduction, for example, using borane. Suitable interconversion procedures are described in the ac:companying Examples, or will be readily apparent to those skilled in the art..
Intermediates of formula (III) may be prepared from intermediates of formula (II) by reaction with a compound of formula Hal-Y-C0 2
R
30 where Hal represents halo such as chloro, bromo or iodo and R 30 and Y are as above defined, in the presence of a base. Suitable bases include tertiary amines, for example, triethylamine.
Conveniently the reaction is effected in a suitable organic solvent, such as an ether, for example, tetrahydrofuran, at elevated temperature, such as the reflux temperature of the solvent.
Intermediates of formula (IV) are commercially available or may be prepared from commercially available materials by conventional procedures well-known to those skilled in the art.
WO 93/21181 PCT/GB93/00788 26 Intermediates of formula (II) may be prepared as described in published European patent application no.
0 528 495.
Intermediates of formula may be prepared from intermediates of formula (II) by reaction with a compound of formula Hal-Y-CN, wherein Hal is halo such as bromo, chloro or iodo and Y is as previously defined.
Intermediates of formula (VI) may be prepared from intermediates of formula by treatment with an alkylthioamide, such as, for example, thioacetamide.
Intermediates of formula (VII) may be prepared from intermediates of formula (III) by treatment with hydrazine. The reaction is conveniently effected in a suitable organic solvent, such as an alcohol, for example, ethanol, at elevated temperature.
Intermediates of formula (IX) may be prepared from intermediates of formula (II) by reaction with a compound of formula Hal-Y-C(NH)NH 2 where Hal and Y are as previously defined.
Intermediates of formula may be prepared from intermediates of formula (II) by reaction with a compound of formula Hal-Y-C(NH)NHNH-Boc, wherein Hal and Y are as previously defined and Boc stands for t-butoxycarbonyl, followed by deprotection under acidic conditions.
Compounds of formula (XI) are commercially available or may be prepared from commercially available compounds by known methods.
Where the above-described process for the preparation of the compounds according to the invention gives rise to mixtures of stereoisomers these isomers may, if desired, be separated, suitably by conventional techniques such as preparative chromatography.
WO 93/21181 PCT/CB93/00788 27 The novel compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. For example, any suitable intermediates may be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric esters or amides, followed by chromatographic separation or separation by fractional crystallization and removal of the chiral auxiliary. The diastereomeric intermediates can then be used to prepare optically pure compounds of formula During any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective 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 following Examples illustrate the preparation of compounds according to the invention.
The substance P antagonising activity of the compounds described herein was evaluated using the human NK1R assay described in published European patent application no. 0 528 495. The method essentially involves determining the concentration of the test compound required to reduce by 50% the amount of radiolabelled substance P binding to human NK1R, thereby affording an IC 5 0 value for the test compound. The compounds of Examples 1-10, for example, were found to have IC 50 values less than 500nM.
WO 93/21181 PCT/GB93/00788 -28- DESCRIPTION 1: cis-3-((3.5-Bis(trifluoromethvl)phenvl)methvl oxv)-2-henvlpiperidine hydrochloride salt a) A solution of methyl 4-nitrobutyrate (23g) and benzaldehyde (16ml) in acetic acid (39ml) containing ammonium acetate (12.12g) was heated at reflux under nitrogen for 2h. The reaction mixture was cooled to 5°C, whereby a pale-yellow solid crystallised. This was isolated by filtration, then dissolved in dichloromethane, washed cautiously with saturated aqueous sodium bicarbonate solution (2 then dried (MgSO 4 and concentrated to leave a yellow solid. Recrystallisation from ethyl acetate provided 5-nitro-2-oxo-6-phenvlpieridine (12.5g) as a crystalline, white solid. 1H NMR (CDC1) d 7.46-7.26 (br 5.24 (dd, J 1.4, 7.0Hz), 4.70 2.70-2.50 2.38-2.24 b) Potassium t-butoxide (1.68g) was added to a solution of 5-nitro-2-oxo-6-phenylpiperidine (3g) in a mixture of dichloromethane (50ml) and methanol (50ml) and the mixture was cooled to -78C under nitrogen. Ozone was bubbled through the solution for 3h. A yellow-green solution resulted, and TLC indicated no starting material remained. The reaction mixture was purged with oxygen for 5 min to remove excess ozone, then dimethylsulfide (7ml) was added and the reaction mixture was allowed to warm to 23°C. The solvent was removed in vacuo, and the residue was partitioned between dichloromethane and water. The layers were separated, and the aqueous phase was extracted twice with dichloromethane. The combined organic extracts were washed with brine, then dried (K2CO3) and concentrated to leave a yellow solid.
This crude material was slurried in dry tetrahydrofuran and added to lithium aluminium hydride (1M in THF, then heated at reflux for 12h. After cooling to 23°C, the reaction WO 93/21181 PCT/GB93/00788 -29mixture was quenched by the cautious addition of water (dropwise) under nitrogen, then 2M sodium hydroxide. The mixture was filtered through a pad of Hyflo, the filtrate was washed with brine, then dried (K 2
CO
3 and concentrated to leave a yellow solid. Purification by silica-gel chromatography
(CH
2 C12/MeOHINH, 97:3:1 then CH 2 CI /MeOH 95:5) provided 3-hvdroxv- 2-phenvylpieridine as a ra 4:1 mixture of cds- and t~ms-isomers respectively. 1H NMR (CDC13) 7.44-7.20 3.84 3.76 3.54 3.4 3.3 J 8Hz), 3.26 3.04 (m) 2.78 (ddd, J 2.9, 11.9, 11.9Hz), 2.70 (ddd, J 2.9, 11.9, 11.9Hz), 2.18-1.78 1.48 MS (EI) m/z 177 c) Di-t-butyldicarbonate (1.36g) was added to a solution of 3-hydroxy-2-phenylpiperidine (1g) in dichloromethane (8ml) under nitrogen and the mixture stirred at 23 0 C for 3h. The solvent was removed in uacuo, and the residue purified by silica-gel chromatography (CH 2 ClV/MeOHINHs 97:3:0.5) to provide cis- and trans-l-t-butvloxvcarbonvl-3-hvdroxv-2phenvlpiperidine (1.4g) as a clear, viscous oil. 1H NMR (CDC1 3 d 7.50-7.42 7.40-7.14 5.36 J 5.6Hz), 4.50 4.44 4.12-3.92 3.02 (ddd, J 3.0, 12.5, 12.5Hz), 2.87 (ddd, J 3.0, 12.5, 12.5Hz), 1.88-1.66 1.46 1.36 d) To a cooled solution of 1-t-butyloxycarbonyl-3hydroxy-2-phenylpiperidine (1.4g) in dry dimethylformamide was added sodium hydride (80% dispersion in mineral oil; 182mg). The cooling bath was removed and the reaction mixture stirred at 23°C for 30 min. A solution of bis(trifluoromethyl)benzyl bromide (1.87g) in dry dimethylformamide (1ml) was added and stirring was continued for 2h at room temperature. The mixture was diluted with water (100ml) and extracted with ethyl acetate (3 x 40ml). The combined organic extracts were washed with brine (1 x WO 93/21181 WO 9321181PT/G 693/00788 30 dried (MgSO 4 and evaporated to yield a pale yellow oil.
Purification by chromatoigraphy on silica using gradient elution of hexane in ethyl acetate (9:1 4:1) afforded the product kitloxycarbonv1-3-(Q3.5-bid sjrfluoromethvl)phenvl' methvlozy)-2-phenvlpiperidine (350mg) as an oil. 1H NMR (250MHz, CDCl 3 d 7.77 (1H, s, ArH), 7.71 (2H, s, AxH), 7.53-7.57 (2H, mn, ArH), 7.2-7.4 (3H, m, ArH), 5.70 (1H, br d, app. J M.Hz, NCHPh), 4.73 (2H, brs, OCH 2 3.84-3.98 (2H, mn, NCHCHO NCHjH), 2.77 (1H, ddd, J 13.0, 13.0, NCHIH), 2.00 (2H, mc, CR 2 1.6-1.8 (2H, m, CHO), 1.40 (9H, s,
C(CH
3 3 e) Trifluoroacetic acid (3m1) was added to the product of above (800mg) under nitrogen and the resulting solution was stirred for lh. Excess trifluoroacetic acid was removed in vacuo and the residue was partitioned between 2M sodium hydroxide and dichloromethane. The organic phase was washed with brine, dried (MgSO 4 and evaporated to afford a colourless oil, Purification on silica (dichioromethane in methanol, 98:2 95:5) afforded the product cis-3-((3,5-bis(trifluoromethyl)phenyl) methyloxy-2-phenylpiperidine (360mg) as a colourless oil. 1H NMR (360MHz, CDCl 3 d 7.78 (1H, s, ArH), 7.44 (2H, s, ArH), 7.18-7.38 ArH), 4.52 (1H, d, J 12.5Hz, OCHH), 4.13 (1H, d, J 12.5Hz, OCHIJD, 3.84 (iR, d, J 1.0Hz, NCHPh), 3.68 (1H, d, J =1.5Hz), 3.28 (iR, mn, NCHCHO), 2.84 (iR, ddd, J 3.0, 12.5, 12.5Hz, NCHiH), 2.20 (1H, mc, NCII,1.8-1.98 (2H, mn, CR 2 1.64-1.78 (111, m, CHH), 1.50-1.58 (1H, m, CR); MS m/z 404 The oil was dissolved in ether to which was added excess ethereal hydrogen chloride. Upon standing a white solid crystallised. This was filtered and recrystallised from ethyl acetate-methanol to afford the title compound as white crystals: WO 93/21131 WO 9321Th1PCr/GB93/00788 31 mp 200-203*C. 'H NMR (360MHz, DMS0) d 7.95 (1H, s, Arli), 7.81 (2H, s, ArH), 7.37-7.47 (5H, m, ArH), 4.78 (1H, d, J 13.0Hz, OCHH), 4.56 (1H, s, NCHPh), 4.32 (1H, d, J =13.0Hz, 00111), 3.96 (1H, s, NCHCHO), 3.10 (1H, t, J =13.0Hz, NCHH), 2.23 (1H, d, J 13.0Hz, NOHH), 1.64-2.00 (4H, m, OH 2 x MS m/z 404 Found: C, 54.08; H, 4.47; N, 3.13. Calcd. for C 20
H
2
F
6 NOCl.0.25H 2 0: C, 54.06; H, 4.65; N, 3.15%.
DESCRIPTION 2: (2R.*.3R*)-234(3 .5-Bis(trifluoromethvl )nhenvl) rn~Ix~i'~aboMethoxv)methvl-2-phenvlInePiding cis-3-((3,5-Bis(trifluoromethyl)phenyl)methyloxy)-2-pheny Ipiperidine hydrochloride (Description 1, 1g) was liberated from the hydrochloride salt by partitioning between ethyl acetate and 2M sodium hydroxide. The organic phase was washed successively with water, saturated brine, dried (MgSO 4 and evaporated in vacuc. To a solution of the residual oil in tetrahydrofuran (20m1) was added triethylamine (0.4m1) and methyl bromoacetate (400mg) and the solu'Lion was heated at reflux under an atmosphere of nitrogen for 16h. To the cooled solution was added ethyl acetate and water and the organic phase washed further with water and dried (MgSO 4 After the solvent had been removed in vacuo the residue was chromatographed on silica gel eluting with ethyl acetate/petroleum ether The product was recrystallised from diethyl ether/petroleum ether to give the 1sm~jn: mp 81-83'C. Found: C, 57.35; H, 4.98; N, 2.84; C23H23FN 3 ,0,1(H 2 O) requires C, 57.71; H, 4.86; N, 2.93%. MS In/z 476 WO 93/21181 WO 9321181PC7/GB93/00788 32 DESCRIPTION 3: _nhenyflmethyloXy)- 2- ph~y erijmdine hvdrochlori de salt a) The mixture of cis- and trans-isomers of 3-hydroxy-2phenylpiperidline (Description 1, and 4-toluenesulfonic acid monohydrate was crystallized from methanol/ethyl acetate to give cis-3-hydroxy-2-phenylpiperidiniuna tosylate: MP 266-267 0
C.
b) The toyaesl (Description 3(a) above) was dissolved in a mixture of ethyl acetate and 10% aqueous Na 2
CO
3 with warming. The organic phase was washed with saturated brine, dried (K 2 C0 3 and evaporated to give crystalline cis- a-hvdroxv-2-ighenvhpiperi dine, mnp 1l0-1l0.5*C.
c) cis-3-Hydroxy-2-phenylpiperidine (Description 3b) and (-)dibenzoyltartrate were dissolved in methanol and crystallized by addition of ethyl acetate. The solid was recrystallised from hot methanol to give the hemi dibenzovlItartrate salt: mp 223-224'C. This was liberated from the salt as described above to give the single enantiomer (+)-cis-3-hydroxy-2phenylpiperidine, mp 93-95TC. [a] 3 D +98.5' MeOH).
The mother liquors were converted to the free base as described in Description 3b and crystallization using (+)dibenzoyltartrate in an analogous mannor to that described above gave drox-2-henyjinine, mp 93-95'C. [a] 2 3 D -97.2R MeOH)..
d) (+)-cis-3-Hydroxy-2-phenylpipe-ridine 'was reacted according to the procedure detailed in Description lc-e to give (+)-cis-3-((3,5-bis(trifluoromethyl)phenyl)methyloxy-2phenylpiperidine hydrochloride as a crystalline solid: mp 215-2160C. [a]D +87.30 MeOH). 1 H NMR (360MHz, DMSO-d 6 d 7.95 (1H, s, ArE), 7.81 (1H, s, ArE), '7.47 (2H, mn, ArH), 7.37 (3H, m, ArH), 4.78 (1H, d, J =13.0Hz, OCH), 4.56 WO 93/21181 PCr/B93/00788 -33- (1H, s, NCHPh), 4.32 (1H, d, J 13.0Hz, OCHH), 3.96 (1H, s, NCHCHO), 3.10 (1H, t, J 13.OHz, NCEHH), 2.28 (11, d, J 13.0Hz, NCII), 2.00-1.64 (4H, m, CH 2 x MS n/z 404 Found: C, 54.52; H, 4.60; N, 3.11. Calcd. for
C
2 0HjqF 6 NO.HC1: C, 54.62; H, 4.58; N, 3.18%.
DESCTPTTION 4; n.mthyfl p~henYIlmethvYloxv)- 1-fearbomptb oyhmet -2 -phendpljn i dine The title ompnond was prepared from (+)-cis-3-((3,5-bis (trifluoromethyl)phenyl)methyloxy)-2-phenylpipericiiiie (Description 3) using the procedure detailed in Description 2: mp 60-70'C. [a]D +132.3' MeGH). 11I NIM1vR (360M~z, CDCl 3 d 1.57-1.63 (3H, m, CH 2 CHH), 2.04-2.17 (2H, m, CHH, CHHN), 3.07-3.10 (1H, m, NCHCHIO), 3.20 (1H, d, J 17.0Hz, NCHIICO 2
CH
3 3.31 (1H, d, J 17.0Hz, NCIiH
CO
2 CH), 3.58 (3H, s, CH 3 3.93 (1H, s, NCH~h), 4.07 (1H, d, J 12.0Hz, OCHH), 4.49 (li, d, J 12.0Hz, OCHJ), 7.28-7.34 (3H, M, ArH), 7.43-7.45 (2H, m, ArH), 7.54 (2H, s, ArH), 7.71 (1H, s, ArH). MS m/z 476 100%). Found: C, 58.31; H, 4.90; N, 2.94. Calcd. for C 23 H2F 6
NO
3 58.11; H, 4.88; N, 2.95%.
DECRPION 5: (2R*.3R*)-3-((35-Bs(trifluoromethl)pheny) methyl oxv)- 1-(cyanomethvl )-2-nhenvlpineridinium hydrchklride The compound of Description 1 potassium carbonate (1.7g) and bromoacetonitrile (0.87ml) were suspended in dimethylformainide (15ml) and the mixture was stirred under nitrogen at 6000 for 3 h. The mixture was cooled, diluted with water (200m) and extracted with ethyl acetate (2 x 50m1). The organic extracts were washed with brine, dried (MgSO 4 and WO 93/21181 WO 9321181PCr/GB93100788 34 evaporated, affording a brown oil. This was purified on silica using ethyl acetate in petrol as eluant. This afforded the product as a colourless oil. The hydrochloride salt was prepared by dissolution in ethereal hydrogen chloride and the salt was recrystallised from ether-hexane: mp 133-134*C. 'H NMR (360NMz, CDCl 3 d 1.75 (2H, mc, CH), 1.90 (2H, mc, Clii), 2.31 (ili, mc, CHH), 2.71 (ili, mc, CHHi), 3.19 (1H, mc, CHIHN), 3.72 (ili, mc, CHjHN), 3.81 (IH, d, J 17.5Hz, NCHiHCN), 3.86 (1Hi, s, CHjO), 4.02 (i1H, d, J 17.5Hz, NCHIJCN), 4.09 (ili, s, CEIPh), 4.35 (1H, d, J 13.0Hz, OCHH), 4.73 (1Hi, d, J 13.0Hz, OCHui), 7.4 (3H, mc, Arli), 7.69-7.73 (5H, m, Arli); MS xn/z 443 Found: C, 54.87; H, 4.30; N, 5,66.
Calcd. for C22Hl 8
F
6
N
2 O.HCl C, 55.18; H, 4.42; N, 5.85%.
DESCRTPTION 6: (2R* ,5-Bi s(triflurr etv'oeixl) methyloxv)-2-n~henvl-l-(thiocarboxamidomethvl-loieridin-e The compound of Description 5 (1g) was dissolved in dimethylformamide (anhydrous, l0ml) and the solution was saturated with dry hydrogen chloride gas. The reaction was heated to 100*C under nitrogen and thioacetamide (0.34g) was added; this mixture was allowed to stir at 100'C for 3h.
Diniethylformamide was removed in vacuo. The residue was extracted with ethyl acetate and the organic layer was washed with aqueous sodium bicarbonate, brine,. dried (MgSO 4 and concentrated in vacuo to afford a brown oil. This was purified on silica using a gradient elution of ethyl acetate in petrol The product was further purified by recrystallisation from ethyl acetate-petrol: mp 164-166*C; 1H NMR (360MHz, CDCl 3 d 1.56-1.70 (2H, m, CHO), 1.96-2.10 (1H, m, CHH), 2.15-2.32 (2H, m, CHHN Clii), 2.98-3.06 (i1H, bd, NCHH), 3.09 (il, d, J 18.0Hz, CHI-ISNH 2 3.50 (1Hi, d, J 18.0Hz, WO 93/21181 PTG9108 PCr/GB93/00788
NCHIJCSN{
2 3.50 (1H, s, CHjO), 3.60 (1H, s, NCHPh), 4.04 (1H, d, J 12.0Hz, OCHjHAr), 4.47 (1H, d, J 12.0Hz, OCHHRAr), 7.26-7.36 (5H, m, CH~h), 7.53 (2H, s, Ar-H), 7.75 (H, s, Ar-H), 7.61 (1H, bs, NHH), 8.99 (1H, bs, NRH); MS m/z 477 Found: C, 56.09; H, 4.58; N, 5.97. Calc for C22H 22
F
6
N
2 OS C, 55.46; H, 4.65; N, 5.88.
menhyjoxy)-1-(carboxvhvdrazidometh1 )-2-12heny-liueridinu hydrQobhnride Hydrazine hydrate (3.Oml) was added to a solution of the compound of Description 2 (2.95g) in ethanol (80m1). The solution was heated at reflux for 18h after which the ethanol was removed in vacuo. The residue was extracted into ethyl acetate and the organic layer was washed with brine, dried (MgSO 4 and concentrated to give the title compound (2.79g).
This was dissolved in methanol (Snil) and a methanolic solution of hydrogen chloride was added. Methanol was removed in vacuo and the salt was recrystallised from diethyl ether to give the hydrochloride salt. 'H NMR (360MHz, DM50) d 1.77-1.93 (2H, m, CHA) 2.08-2.21 (1H, m, CHO), 2.22-2.35 (1H, m, CHA) 3.56 (1H, d, NCHHCH 2 3.64 (1H, d, J 16.5Hz, NCHHCO), 3.77 (1H, d, NCHHCH 2 3.92 (1H, d, J 16.5Hz, NCHIACO), 3.96 (1H, brs, CHO), 4.37 (1H, d, J 13.0Hz, OCHH), 4.83 (1H1, d, J 13.0Hz, 0CHHI), 4.95 (1H, s, CHIPh), 7.36-7.46 (3H, m, ArH), 7.53-7.62 (2H, brs, ArH), 7.95 (2H, s, ArH), 7.97 (1H, s, ArH); MS rn/z 475.
DESCRIPTION 8: MethlogXy)- 1-(carboxvhydrazid om ethyfl)-2- henylpiperidinium WO 93/21181 WO 93/1 181PCr/G1193/00788 -36- The title compound was prepared according to the procedure outlined in Description 7 using the compound of Description 4 as a starting material. 'H NMR (360MHz, DMSO) d 1.77-1.93 (2H, m, CHA) 2.08-2.21 (1H, m, OH 2 2.22-2.35 (1H, m, CHA) 3.56 (1H, d, NCHHCH 2 3.64 (1H, d, J 16.5Hz, NCHFHCO), 3.77 (111, d, NCHIACH 2 3.92 (1H, d, J 16.5Hz, NCHHCO), 3.96 (1H, brs, CHO), 4.37 (1H, d, J 13.0Hz, OCHH), 4.83 (1H, d, J 13.0Hz, 00111), 4.95 (1H, s, CHPh), 7.36-7.46 (3H, m, ArH), 7.53-7.62 (2H, brs, ArH), 7.95 (2H, s, ArH), 7.97 (1H, s, ArH); MS m/z 475.
DESCRIPTION 9: (2S.3S)-3-((3,5-Bis(trifluoromethvfl~henvl) xethvl-oXy)-I- (cvanomgthvl-2-nhen lpipeiine The title compound was prepared from the reaction of bromoacetonitrile and the compound of Description 3 according to the procedure detailed in Description 5. Purification by chromatography on silica using 10% hexane in ethyl acetate afforded the product as a colourless oil. 1H NMR (360MHz, CDC1 3 d 1.75 (2H1, mc, CH 2
CH
2 2.14 (2H, mc, CH 2
CH
2
N),
2.63-2.74 (1H, m, CHiHN), 2.96-3.06 (1H, m, CHHjN), 3.35 (111, d, J=17.OHz, CHHCN), 3.48 (1H, d, J=2.OHz, CHO), 3.55 (111, d, J=17.OHz, CHIN), 3.64 (1H, d, J=2.OHz, CHIPh), 4.07 (1H, d, J=12.OHz, OCHH), 4.52 (1H, d, J=12.OHz, OCHH), 7.28-7.38 (311, m, ArH), 7.4-7.48 (2H1, mn, ArH), 7.56 (211, mn ArH), 7.73 (11H, m, ArH).
DESCRIPTION 10: (2S.3S)-3-((3-t-Buty-l-5-r-nethyhphenl) methyloxy)-2-phenylpiperiding This compound was prepared from the compound of Description 3c and 3-t-butyl-5-inethylbenzyl bromide, following the procedure described in Descriptions lc-e. mp 180-182'C. MS WO 93/21181 WO 9321181PCT/G 893100788 -37-% rn/z 338 100%). Found: C, 73.81; H, 8.63; N, 3.74.
Calcd. for C23H 31 NO.HCl: C, 73.87; H, 8.62; N, 3.75%.
DESCRIPTION 11: 2-phenyluineri dine This compound was prepared from the compound of Description 3c and 3,5-clichlorobenzyl chloride, following the procedure described in Descriptions lc-e. iH NMR (CDC1 3 8 1.49-1.53 (1H, m, CHH), 1.60-1.70 (1H, m, CHH), 1.82-1.95 (1H, m, CHHI), 2.14-2.18 OR., mn, CHH), 2.79-2.87 (1H, mn, NCHH), 3.27-3.31 (1H, mn, NOHII), 3.60 (1H, s, CH0), 3.82 (iH, s, CHPh), 4.02-4.05 (iR, d, J=l,3Hz, OCHH), 4.31-4.35 (1H, d, J=l3Hz, OCHH), 6.80 (2H, s, ArH), 7.15 (1H, s, ArH), 7.25-7.35 mn, ArH). Found: C, 58.24; H, 5.38; N, 3.91. Calcd. for
C
18
H
19
C
2 N0.HCl: C, 58.01; H, 5.41; N, 3.76%.
DESCRIPTION 12: (2S.3S)-3-((3-Chloro-5-methvlinhenyl) methvl oxy)- 2-phpny]Piperi dine This compound was prepared from the compound of Description 3c and 3-chloro-5-methylbenzyl bromide, following the procedure described in Descriptions lc-e: mp 235-237C. MS m/z 316 100%). Found: C, 64.68; H, 6.50; N, 3.98.
Calcd. for C 19
H
22 C1N0.HCl: C, 64.78; H, 6.58; N, 3.98%.
DESCRIPTION 13: (25.3S)-3-((3.5-Bis(trifluoromethvl )nhenv methvloxy)-2-(diuphenylmethyV)nvrolidinium hydrochloride N-t-Butvloxycarbonyl-(S')-diphenl alanal A solution of methyl sulfoxide (4.4m1) in dichioromethane (13m1) was added dropwise to a cooled (-781C) solution of oxalyl chloride (4in1) in dichioromethane (50mi). After 15 min, a solution of N-t-butyloxycarbonyl-(S)-diphenylalanoI (10g) in WO 93/21181 WO 9321181PCT/GB93/00788 38 dichioroinethane (iS0mi) was added dropwise at -301C. The solution was allowed to stir for 30 min, triethylamnine (17m1) was added and the solution was allowed to warm to -10'C. Icewater (200m1) was added to the solution which was then poured onto hexane (600m1). The organic phase was separated, washed successively with citric acid (200m1), saturated aqueous sodium bicarbonate (2 x iS0mi), brine (1 x 150m1) then dried (MgSO 4 and concentrated in vacuo to leave a white crystalline solid. IH NMR (250MHz, CDC1 3 8 1.42 (9H, s, C(CH 3 3 4.48 (iR, d), 4.86 (11, 5.10 (li, 7.26 (10H, mn, ArH), 9.6 (111, s, CHO).
Nb N-t-Blutvloxcarbonvl- 1-(dinhienvy1methyv1)-2-hivdroxynent-4-envl- 1-amine A solution of N-t-butyloxycarbonyl-(S)-diphenylalanal (10.9g) in tetrahydrofuran (60m1) was added dropwise to a soluton of allyl magnesium chloride (2M in tetrahydrofuran, 36m1) at -10'C. After 30 min the mixture was poured onto icecold saturated aqueous ammonium chloride and the resulting mixture was extracted with ethyl acetate (3 x 150m1). The combined organic extracts were washed with brine (1 x lO0ml), then dried (MgSO 4 and concentrated in uacuo. The residue was purified by chromatography on silica gel using hexane in ethyl acetate (gradient elution of 9:1 to 4:1) as eluant to afford the compound as a white solid. 1H NMR (36OMHz, CDCl 3 5 1.42 (9H, s, 2.22 (2H, mn), 2.68 (3H, brs), 3.48 3.57 (1H, in), 3.86 (1H, 4.07 J 11IHz), %5,04 (1H, in), 5.71 (1H, in), 6.97-7.36 (10H, mn, ArH).
.5-Bi s(trifluoromethvl hi~henyl )methvloxv)-N-tbutvl oxcarbonvl- I -(diphenvlm ethv-rpent-4-enyvlI-amine Sodium hydride (80% in oil, 0.53g) was added to a solution of 3,5-bis(trifiuoromethyl)benzyl bromide (5m1) and the compound of (13b) above (5g) in diinethylformamide (8m1). After WO 93/21181 PC'/GB93/00788 -39stirring for lh water (80ml) was added and the mixture was extracted with ethyl acetate (3 x 100ml). The combined organics extracts were washed with brine (1 x 100ml) then dried (MgSO 4 and concentrated to leave an oil which was purified on silica using hexane in ethyl acetate as eluant (gradient elution of 97:3 to This afforded the title compound as a colourless oil. 1
H
NMR (360MHz, CDCL s 8 1.25 1.30 2.35 3.31 3.40 (dd, J 5.2, 8.3Hz), 3.97 4.27 4.38 4.65 4.85 5.16-5.02 5.77 7.35-7.13 7.76 7.85 (2S.3S)-3-((3.5-Bis(trifluoromethvl)ohenvl) methvloxv-2-(diphenvlmethyl)vrrolidinium hvdrochloride A solution of the compound of above (5.2g) in dic 'loromethane (40ml) and methanol (40ml) was treated with a str. un of ozone in oxygen at -78 0 C for lh. Methyl sulfide (3ml) was added and the mixture was warmed to 23°C and concentrated in vacuo. The residue was dissolved in chloroform triethylsilane (5.6ml) was added followed by dropwise addition of a solution of trifluoroacetic acid (6.9ml) in chloroform After lh the solvent was evaporated in vacuo and trifluoroacetic acid (10ml) was added to the residue. After stirring for 30 min the mixture was concentrated in vacuo and the residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic layer was dried (K 2
CO
3 and concentrated to leave a brown oil. This was purified on silica gel eluting with dichloromethane/methanol (99:1) to provide the title compound as the free base. This was converted to the salt by treatment with methanolic hydrogen chloride: mp >230 0 C. [a]23 D +46.6o CHOH). Found: C, 59.95; H, 4.74; N, 2.63%. Calcd. for C, 26
HF
6 NO.HC1.0.2H 2 0: C, 60.11; H, 4.73; N, 2.70%.
WO 93/21181 PCr/GB93/00788 DESCRIPTION 14,: (2R.3)-3-((3.5-Bis(trifluorom ehvbhenl) ne~thvloxv)-2-(dilnhenvlmethvl)pvrrolidinium hydrohlori d The title compound was prepared from N-tbutyloxycarbonyl-(R)-diphenylalanol by a procedure analagous to that described in Description 13: mp 230 0 C. 23 D +12.10
CH
3
OH).
DESCRIPTION 15: (2S.3S)-3-((3.5-Dichloronhenl)methvl oxy)- 2-(diuhenyl methvl)uvrrolidinium hydrochloride N-t-Butloxvcarbonvl -2-((3.5-dichlorophenl) methyloxy- 1-(diuhenvlm ethvl)Dent-4-envl- 1-amine The compound of Description 13b was alkylated with dichlorobenzyl chloride by a procedure analagous to that described in Description 13c, to afford the title compound as an oil. 'H NM-R (360MHz, CDCl 3 5 1.25 (9H, 2.41-2.27 (2H, i), 3.32 (1H, 4.07 (1H, d, J=IlHz), 4.13 (111, d, J=l2Hz), 4.30 (1H, d, J=l2Hz), 4.65 (2H, 5.13 (211, 5.76 (1H, 7.35- 6.60 (13H, MS m/z 526, 528 100%, (2.3S)-3-((3.5-Dichlorouphenl )methvloxv)-2- (dipDhenvlmethyl )pvrrolidini hydrochloride The compound of Description 15a above was treated with ozone followed by triethylsilane-trifluoroacetic acid by a procedure analagous to that described in Description 13d to afford the title compound as a white crystalline solid: ip>230 0 C. Found: C, 64.52; H, 5.84; N, 3.12. Calcd. for
C
24 H2C 2 NO.HC1: C, 64.23; H, 5.39; N, 3.12%.
DESCRIPTON 16: (2S.3S)-3-((3-t-Butvl-5-chloronhenyl) methvloxy)-2-henlpiperidinium hvdro§,IhkIiri 4-t-Butvl-2-chloro-6-(methvlthiomethvl )anilin WO 93/21181 PCT/GB93/00788 -41- 4-t-Butyl-2-chloroaniline (30g) was dissolved in dichloromethane (1.21) and the solution was cooled to -50C. Nchlorosuccinimide (21.7g) was added portionwise to the vigorously stirred solution and stirring was continued for 1h.
Dimethyl sulfide (35ml) was added to the solution and stirring was continued for a further Ih. The solution was then cooled to -65°C and triethylamine (27ml) was added. This solution was allowed to warm to room temperature overnight.
The solution was evaporated to half volume, washed with sodium hydroxide water and brine successively. The organic solution was dried and evaporated and the residue was purified on silica using hexane to 3% ether in hexane as eluant.
This afforded the product (31.2g) as a red oil. 1H NMR (CDCL 3 250MHz) 5 1.27 (9H, s, (CH 3 3 1.99 (3H, s, SCIa), 3.69 (2H, s,
CH
2 SCHa), 4.38 (2H, br s, NH 2 6.92 (1H, d, J=2.0Hz, ArH), 7.21 (1H, d, J=2.0Hz, ArH). MS m/z 244 100%).
4-t-Butvl-2-chloro-6-methvlaniline 4-t-Butyl-2-chloro-6-(methylthiomethyl)aniline (1.3g) was dissolved in methanol (50ml) and Raney nickel (prewashed to pH 7) was added portionwise until t.l.c. indicated all starting material had reacted (ether-hexane, 1:10). The Raney nickel was removed by filtration through celite and the filtrate was evaporated. The residue was dissolved in ether and washed with brine, dried (MgSO 4 and evaporated. The residue was purified on silica using hexane 5% ether in hexane as eluant to afford the product as a yellow liquid. 'H NMR (360MHz, CDC1,) 8 1.26 (9H, s, (CH 3 3 2.19 (3H, s, CHa), 3.97 (2H, s, 6.97 (1H, d, ArH), 7.14 (1H, d, J=2.0Hz, ArH).
4-t-Butyl-2-chloro-6-methylaniline (1.97g) was dissolved in ethanol (50ml); sulphuric acid (1.88ml, cone.) was added WO 93/21181 WO 9321181PCT/GB93/00788 42dropwise and the resulting blue solution was heated at refiux.
Sodium nitrite (1.72g) was added portionwise over 30 min. The resulting mixture was heated at refiux for a further 30 min, then cooled and was poured onto ice-water and extracted with ether (2 x 50mI). The ethereal extract was dried (MgSO 4 and evaporated and the residue was purified on silica gel using hexane as eluant. This afforded the product as a colourless oil.
1 H NN'R (360MHz, ODC1 3 8 1.29 (9H, s, (OH 3 3 2.31 (3H, s, CHO), 6.98 (1H, brs, ArH), 7.05 (1H, brs, ArH), 7.15 (1H, brs, ArH). MS m/z 181 (M4-H, 100%).
3-t-Butvl1-5-chlooerizl bromide (5.7g) was dissolved in carbon tetrachloride (8Oml) and N-bromosuccinimnide (5.56g) was added -followed by benzoyl peroxide (750mg). This mixture was heated at reflux for 6h. The mixture was cooled, filtered through celite and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica using hexane as eluant.
This afforded the title compound as a colourless liquid. 1 H NMR (360MHz, CDC1 3 5 1.31 (9H, s, (OH 3 3 4.42 (2H, s, CH2), 7.20 (1H, t, J=1.5Hz, ArH), 7.26 (1H, t, J=1.5Hz, ArH), 7.28 (1H, t, ArH).
(2S.3S)-l-t-ButvLoxvcarbonvl-3-((3-t-buti-5-chlorophenvi~ )rethvloxv)-2-phenvlopiperi dine.
(+)-cis-3-Hydroxy-2-phenylpiperidine (Description 3c) was reacted with 3-t-butyl-5-chlorobenzyl bromide (Description above) according to the procedure detailed in Description lc-d to afford the title compound. 'H NMR (360MHz, ODd 3 5 1.27 (9H, s, C(CH3)3), 1.46 (9H, s, O(0H 3 3 1.52-1.66 (2H, in), 1.8-2.0 (2H, in), 2.69 (1H, td, J=3.SHz, 13.0Hz, NCHH), 3.81 (1H, q, J=5Hz, NCHH), 3.92 (1H, brd, 0CH0), 4.60 (2H, q, J=l2Hz,
OCH
2 5.70 (1H, brs, CHPh), 7.10 (1H1, s, ArH), 7.18 (1H, s, WO 93/21181 PTG9/08 PCT/GB93/00788 43 ArH), 7.22 (2H, s, ArH), 7.43-7.47 (2H, m, ArH), 7.57-7.59 (2H, mn, Arli).
(fQ The compound of Description 15e above was dissolved in methanolic hydrogen chloride overnight. The solution was then concentrated in vacuo and the residue triturated with ether. This afforded the title compound as a white crystalline powder: nap 210-211'C. lIH NMR (360MHz, DMSO-d 6 5 1.21 (9H, s, C(0H 3 1.66-1.80 (2H, in, OH 2 1.86-1.93 (1H, mn, 0111), 2.18-2.22 (1H, in, Clii), 3.04-3.11 (1H, mn, NCkiH), 3.3 (1H, M, NCHHjJ, 3.88 (11, brs, CHO), 4.14 (1H, d, J=l2Hz, 0CHjH), 4.52 (1H, s, CIHPh), 4.53 (1Hi, d, J=l2Hz, OCHIJ), 6.95 (iR, s, ArH), 7.00 (1H1, s, ArH), 7.24 (ili, t, J=1.8Hz, ArH), 7.3- (5H, mn, Arli1), MS (CIi) In/z 358 100%). Found: C, 66.68; H, 7.29; N, 3.40. Calcd. for C 22 H28ClN0.HCl: C, 67.00; H, 7.41; N, 3.55%.
DESCRIPTION 17: (2R*.3R*)-3-((3-Carbomethoxvnheny1) methvloxv)-2-nhenylpiperidine (2*3*---udxcronl--(-ynohnl methvloxv)-2-phenylniperi dine This compound was prepared from 1-t-butyloxyc-arbonyl- 3-hydroxy-2-phenylpiperidine (Description 1c) and c-bromo-intolunitrile according to the procedure described in Example Id.
1H NMR (360MHz, CDCl 3 8 1.49 (9H,s, (OH 3 3 ),1.6-1.72 (2H, mn), 1.87-1.99 (2H, in), 2.72 (111, dt, J 13, 4Hz, NCLTH), 3.80- 3.95 (2H, in, 0110 NCHT"1), 4-.65 (2H, q, J 12Hz, 00112), 5.69 (1H1, brs, CHPh), 7.1-7.5 (9H, in, ArH).
(.2fR.a3(f2-Carbomethoxvnhenvl )methyl oxv-2p2henvinineri dine The compound of above (1.5g) was dissolved in methanol and concentrated hydrochloric acid (aqueous, l0ml) was WO 93/21181 WO 9321181PC1'/GB93/00788 -44added. The contents were heated at reflax for 12h. The solution was cooled and evaporated to leave a brown oil, This was dissolved in methanolic hydrogen chloride and the resulting solution was stirred overnight, then evaporated. The residue was purified by dispersion between water and ethyl acetate and the organic layer was dried (MgSO 4 and concentrated. The residue was purified by chromatography on silica using a gradient elution of methanol in dichloromethane. The first compound to elute was characterised as the hydrochloride salt by dissolution in methanolic hydrogen chloride. The salt was recrystallised fromn ethyl acetate methanol: mp 206-2081C.
(2R*.3R*)-3-((3-(Carbomethoxv)phenvl)methox)- 2-pbhenvlijeri dine 1H NMR (CDCl 3 5 1.45-1.71 (2H, m, NCH 2
CH
2
CH
2 1.83- 2.02 (1H, m, NCH 2 CHH), 2.12-2.23 (1H, m, NCH 2 r.CHH), 2.44 (1H, bs, NH), 2.77-2.90 (1H, m, NOHE), 3.24-3.34 (1H, m, NCHH), 3.61-3.66 (1H, bs, CHO), 3.8-3.83 (1H, d, J CHPh), 3.90 (3H, s, COOCH3), 4.15 (1H, d, J=l2Hz, OCHII), 4.39 (1H, d, J=l2Hz, OCHH), 7.09 (7H, m, ArH), 7.71 (1H, bs, ArH), 7.83-7.89 (1H, m, ArH); MS (CIt) rn/z 326 100%).
Found: C, 66.31; H, 6.36; N, 3.80. Calcd. for C 20
H
23 N0 3 .HCl: C, 66.38; H, 6.69; N, 3.87%.
DESCRIPTION 18: (2R*.3R*)-3-((3-Carboxamidouhenvl) me-thyloxy)-2-phenvlopiped dine The second compound to elute from the column described in 17b above was isolated as a colourless oil. 1 H NIMR (360MHz, ODC1 3 5 1.2-2.2 (4H, in), 2.82 (1H, mc), 3.27 (1H, mc), 3.66 (1Hi, 3.82 (1H, 4.16 (1H, d, J 12Hz, OCHW), 4.48 (1H1, d, J 12Hz, OCHIJ), 5.53 (1H, brs, CONIIH), 6.18 (1H, brs, CONHII), 7.0-7.4 (9H, m, ArH).
WO 93/21181 PCT/GB93/00788 DESCRIPTION 19: (2R*.3R*)-3-((2-Methoxy-3-nitropheny) methvloxy)-2-phenvlpiperidinium hvdrochloride This compound was prepared from the compound of Description Ic and 2-methoxy-5-nitrobenzyl bromide, following the procedure described in Descriptions lc-e. mp 246-248°C. MS m/z 343 Found: C, 60.52; H, 5.96; N, 7.45.
Calcd. for C, 9
H
22
N
2 0 4 .HC1: C, 60.24; H, 6.12; N, 7.39%.
DESCRIPTION 20: (2R*.3R*)-3-((5-Amino-2-mthoxvphenvl) methvloxv)-2-phenvlpiperidinium hvdrochloride The compound of Description 19 (0.342g) was dissolved in methanol (20ml) with hydrochloric acid (1ml, 2N). Palladium on charcoal (50mg) was added and the mixture placed under an atmosphere of hydrogen for lh at room temperature. The solvent was removed in vacuo and the residue basified with sodium hydroxide This solution was extracted with ethyl acetate and the organic extracts were dried (MgSO 4 and concentrated to leave a brown oil; this was purified by column chromatography on silica using 8% methanol in dichloromethane as eluent. The resulting oil was characterised as the salt prepared by treatment with methanolic hydrogen chloride: mp 241-243 0
C.
The following piperidines were prepared according to the procedures outlined in Descriptions 1 and 3, using the appropriate benzyl halide.
DESCRIPTION 21: (2S.3S)-2-Phenvl-((3(3-(trifluoromethl) phenvl)methvloxv)Diperidine WO 93/21181 PTGB9/08 PCr/GB93/00788 46 IH NMR (CDCl 3 8 1.4-2.2 (4H, in), 2.45 (1H, brs), 2.83 (1H, td, J=l3Hz and 4Hz), 3.3 (1H, in), 3.64 (1H, d, J=2Hz), 3.82 (1H, d, J=2Hz), 4.13 (iH, d, J=l2Hz, OCHjH), 4.42 (2H, J=l2Hz, OCHH), 7.75 (mn, 9H, ArH).
DESCRrPTION 22: .4-Di chi oroph envi )methyj oxy)- 2-n)henvlniineridinium hy-drochloride 1H NMR (DMSO-d 6 1.65-1.8 (2H, mn), 1.8 (1H, in), 2.16 (1H, d, J=l2Hz), 3.05 (1H, in), 3.25 (iH, in), 3.83 (iH, 4.12 (iH, d, J=l2Hz), 4.5 (2H, in), 7.05 (1H, dd, J=7 2Hz), 7.28 (iN, d, J=2Hz), 7.35-7.5 (611, in), 9.05 (iH, hr 9.8 (iN, hr s).
DESCRIPTION 23: (2S.3S)-3-((2.3-Dimethylphenvl )methvLoxv)- 2-phenvlpiperidiniuxn hydrochl oride~ Ethyl acetate (l0mi) was saturated with hydrogen chloride by passing HCl gas for 5 min and a solution of 0.254g of (2S,3S)- 1-t-butoxycarbonyl-3-((2,3-diinethylphenyl)methoxy)-2phenylpiperidine (prepared according to Description 3d) in 7m1 of ethyl acetate was added. After stirring for 2h, the reaction mixture was concentrated in vacuo. The residual white solid was washed with ether, filtered and dried to obtain 0.23g of (2S,3S)-3-((2,3-diinethylphenyl)inethyloxy)-2phenylpiperidinlurn hydrochloride. 'H NMR (DMSO-d 6 8 1.6- 1.9 (3H, in), 1.75 (3H, 2.15 (3H, 2.2 (iN, mn), 3.05 (iN, in), 3.25 (iN, in), 3.84 (1H, 4.05 (iN, d, J=l4Nz), 4.45 (1H, d, J=l4Nz), 4.48 (1H, 6.95-7.5 (8H, in), 8.8 (iH, hr 9.4 (1H, br s).
DESCRIPTION .24: (2S.3S)-3-((3-t-Butylnhenvl)methvloxv'j-2phenvlniperidinjuin hydrochlorid-Q WO 93/21181 PCT/GB93/00788 -47 IH NMR (360MHz, CDC1 3 8 1.21 (9H, s, C(CH 3 3 1.45 (3H, 1.52-1.67 (2H, in, OH 2 2.04-2.12 (1H, mn, CHIJ), 2.30- 2.34 (1H, mn, CHH), 2.93-2.96 (1H, mn, NCHH), 3.54 (1H, d, J=13Hz, NCHIJ), 3.72 (1H, s, NCHCHO), 4.14 (1H, d, J=2Hz, NCHCHO), 4.28-4.36 (2H, q, J=l3Hz, OCHH), 6.87-6.89 (1H, in, Aril), 7.05 (1H, s, ArH), 7.11-7.15 (1H, mn, ArH), 7.20-7.34 (4H, in, ArH), 7.55-7.58 (2H, in, ArH). MS m/z 323 (M+1I, 100%).
DESCRIPTION 25: inethloxv)-2-nhenylinieridiniuin hydro2chlori de 'H NMR (360MHz, CDCl 3 8 1.48 1.62 1.86 (mn), 2.20 2.82 (ddd, J=3.0. 3.0, 12.6Hz), 3.26 (dt, J=2.15, 2.15, 12.5Hz), 3.63 3.78 4.10 J=12.OHz), 4.33 J=.1,2.OHz), 6.31 7.2-7.4 MS (CIT+) inlz 296 DESCQRITIOQN 26: (2R*.3R± D3-((3.5 flis(trfluromethyphenylL. methloX)-2-(3chI orophenvi)Diperidine Methyl-4-nitrobutyrate and 3-chlorobenzaldehyde were reacted in an analogous manner to that described in Description la to give 2-(3-chloronhbenl)-3-nitro-6-oxooiipeidine: inp 131- 13300. 'H NMR (360MHz, CDC1 3 8 2.26-2.36 (1H, mn), 2.50-2.72 (3H, in), 4.66-4171 (1H, in), 5.24-5.28 (1H, 6.57 (1H, 7.17- 7.40 (4H, mn).
The product of part a) was treated analogously to that described in Description lb to give Z2-(3-chorohnI)- .dix ~ipridn~: mp 144-147CC. 'H 1'UvR (360MHz, ODd 3 5 2.8 (4H, mn), 5.0 (1H, 6.4 (1H1, 7.22-7.42 (4H, mn).
'NO 93/21181 PCI'/G'393/00788 48 c) The product of part b) was treated analogously to that described in Description lc and 3a to give 3-hvdroxypi-pri dine tosvlate salt: mp 2500C. 1H1 NMR (360M1{z, CDC1 3 8 1.60-2.07 (4H, mn), 2.28 (3H, 3.00-3.11 (1Hi, mn), 4.02 (1H, 4.62-4.66 (1H, 5.96 (1H, 7.10-7.20 (2H, 7.41-7.59 (6H, mn).
d) The product of part c) was treated analogously to that described in Description 1c to give cis- 1-t-butyloxycarbonyl-2-(3cblorophenyl)-3-hydlroxypiperidine as a clear, viscous oil. 'H NMR (360MHz, CDCl 3 8 1.40 (9H, 1.61-1.90 (4H, in), 2.88- 3.01 (iR, ddd), 3.93-3.99 (1H, dd), 4.03-4.10 (1H, in), 5.33 (1H, 7.20-7.26 (2H, in), 7.34-7.38 (IH, mn), 7.47-7.52 (1Hl, mn). m/z 310, 312; m/z (CI-1) 312, 314.
e) The product of part d) and bis(trifluoroniethyl)benzylbromide were treated in an analogous manner to that described in Description id to give cis3-(3.6 bis(trifluoromethyl )nhenyvbmetvLoxy)-1-t-butvl oxv-carbonyl-2- (3-chloropnnvfliparidine, IH NMR (250MHz, CDCl 3 5 1.24- 1.30 (1H, in), 1.47 (9H1, 1.60-2.00 (3H, mn), 2.67-2.80 (IH, ddd), 3.81-4.01 (2H, in), 4.8 (2H, 5.61-5.67 (1H, 7.23-7.27 (2H, in), 7.39-7.44 (1H, in), 7.6 (1H, 7.78 (2H, 7.8 (lIH, s).
f) The product of part e) was treated in an analogous manner to that described in Description le to give dj--(M bis(trifluoromethl )nhenvl )methyloxv)-2-(3-chl oroDhenvI Dnidine hydrocqd 5alt, mp 15800. 1H NMR (360AMz, DMSO-d.) 8 1.70-1.96 (4H, in), 2.19-2.28 (1H, mn), 3.02-3.13 (111, in), 3.84 (1H, 4.35-4.39 (2H, 4.60 (1H1, 4.79-4.85 (2H, d), 7.39-7.44 (3H1, mn), 7.58 (1H, 7.84 (2H1, 7.97 (1H1, 9.2 (br 10.05 (br Found: C, 50.44; H, 4.13; N, 3.01.
C
20 Hj8ClF 6 NO.HCl requires C, 50.65; H, 4.04; N, 2.95%. mn/z 438, 440.
WO 93/21181 WO 931181PT/GB93/00788 -49 DESCRIPTION 27: 2S.3S)-3-((3-Fluoro-5-methvlphenvl) methyl oxv)-2-inhenvlpijeri dine mp 219-2211C. 'H NMR (360MHz, CDCl 3 6 1.50-1.68 (2H, in), 2.11-2.15 (1H, in), 2.20 (3H, s, 2.31-2.35 (1H, in), 2.94- 2.98 (1H, mn, NCHIJ), 3.55-3.58 (1H, d, J 12Hz, NCHIJ), 3.69 (1H1, bs, CHO), 4.15-4.18 (111, mn, CHPh), 4.18 (1H, d, J 13Hz, OCHJH), 4.33 (1H, d, J 13Hz, OCHH), 6.47 (1H, d, ArH), 6.59 (1H, s, ArH), 6.66 (1H, d, ArH), 7.26-7.37 (3H, mn, ArH), 7.52- 7.54 (2H, mn, ArH). MS mlz 300 100%).
DESCIPTION 28: (3R*')-3-((.5Bi(tifuromethvl)Dhenvl) methylo )2mty--2*)2rhnligii 3,6-Dioxo-2-phenylpiperidine (Description 1b) (5g) was dissolved in dimethylforinamide (25m1) at 000C. Sodium hydride (873mg, 80% dispersion in oil) was added portionwise and the mixture stirred for 15 min. Methyl iodide was added (1.8m1) and the mixture was stirred for 12h. The mixture was diluted with water (250m1) and extracted with ethyl acetate (3 The combined organic extracts were washed with brine, dried (MgSO 4 and concentrated to leave a solid: 3,6-dioxo-2-inethyl-2phenylpiperidine.
The ketone of above (3.2g) was suspended in methanol under nitrogen and the temperature brought to -401C.
Sodium borohydride (0.3g) was added portionwise. The mixture was stirred for 30 min and then concentrated in vacuo, azeotroping with tetrahydrofuran. Borane tetrahydrofuran complex (64mi, 1.OM in tetrahydrofuran) was added and the mixture was heated at reflux overnight. The mixture was cooled and quenched carefully with methanol, and the mixture was WO 93/21181 PCT/GB93/00788 then concentrated in vacuo. The resulting residue was dissolved in ethanol (100ml) and potassium carbonate (4.2g) was added.
The mixture was heated at reflux for 12h. The mixture was cooled and evaporated and the residue was extracted with ethyl acetate and water. The organic extract was washed with brine, dried (MgSO 4 and evaporated to afford 3-hvdroxv-2-methyl-2- Dhenylpiperidine as a white solid. 1 H NMR (360MHz, CDC13) 7.79 (2H, d, ArH), 7.40 (2H, t, ArH), 7.15-7.19 (1H, m, ArH), 3.89 (1H, mc), 2.89-3.01 (2H, 1.67-1.91 (4H, 1.39 (3H, s, CH3).
The alcohol of above (3g) was dissolved in dichloromethane (50ml) and di-t-butyldicarbonate (3.48g) was added. The solution was allowed to stir for 12h. The solution was concentrated in vacuo and the residue was purified by chromatography on silica using ethyl acetate in petrol (20:80) as eluent. This afforded N-t-butyloxycarbonyl-2-hydroxy-2-methyl- 2-phenylpiperidine as a clear oil. 1H NMR (250MHz, CDCI 3 1.08 (9H,s, (CH,) 3 1.80 (3H, s, CH3), 1.6-2.0 (4H, 3.6-3.74 (2H, 3.8-3.92 (1H, m, CHO), 7.2-7.36 (5H, m, ArH).
The alcohol of above (2.2g) was dissolved in dry dimethylformamide (12rml). Sodium hydride was added (0.36g, dispersion in oil) portionwise and the mixture was allowed to stir at room temperature for 30 min. Bis(trifluoromethyl)benzyl bromide (3.5g) was added dropwise and the mixture was allowed to stir for 5h. The mixture was diluted with aqueous ammonium chloride, extracted with ethyl acetate and the organic extract was washed with brine, dried (MgSO 4 and evaporated in vacuo. The residue as purified by column chromatography on silica using a gradient elution, 100% petrol to 10% ethyl acetate in petrol as eluant, to afford the product 3-((3,5-bis(trifluoromethyl)phenyl)methyloxy-l-t- WO 93/21181 PCT/G B93/00788 51 butyloxycarbonyl-2-inethyl-2-phenylpiperi dine s a colourless oil. 'H NAM (360MHz, CDCl 3 8 1.13 (9H, s (CH 3 1.85 (3H, s, CHOI, 1.85-1.99 (4H, mn, CH 2
CH
2 3.48 (1H, brs, NCHiH), 3.68- 3.75 (111, mn, NCHII), 3.80-3.85 mI, CHO), 3.85 (1H, d, J 12Hz, OCaH), 4.36 (1H, d, J 12Hz, OCHH), 7.17-7.32 (5H, in, ArH), 7.42 (2H, s, ArH), 7.71 (IH, s, ArH).
The compound of above (2.1g) was dissolved in trifluoroacetic acid (30m1) for 10 min and was then evaporated in vacuo, The residue was dissolved in dichioromethane, washed with sodium hydroxide water and brine, then dried (MgSO 4 and concentrated in vacuo. Methanolic hydrogen chloride was added to the residue and when dissolved the solvent was evaporated. The residue was triturated with ether to afford tho product as a white powder: Bis(trifluoromethyl) phnlmtyoy--ehl(R)2 phenyl-piperidine. 'H NMR (360MHz, DMSO) 8 1.67 (3H, s,
CH
3 1.70 (1H, in), 1.84-1.91 (1H, mn), 1.99-2.06 (2H, in), 3.16 (1H, mn), 3.33 (1H, mn), 4.19 (1H, 4.29 (1H, d, J=l2Hz, 00111), 4.75 (1H1, d, J=l2Hz, OCHH), 7.29-7.33 (1H, mn, ArH), 7.37-7.41 (3H, mn, ArH), 7.54 (2H1, s, ArH), 7.56 (111, brs, ArH), 7.89 (1H, s, ArH). Found: C, 55.38; H, 4.92; N, 3.08 Calcd. for C 2 lH 2 ,FrN0: C, 55.58; H, 4.89; N, 3.09%.
DESCP,:TPTT0N 29: (2S.3SA--((3 Dimnethvlphenv]) methvloxv)- -min-pmdn '1H NMIR (CDCl 3 8 1.4-1.9 (3H, mn), 2.11 (3H, 2.17 (3H, s), 2.1-2.3 (1H1, in), 2.78 (1H, mn), 3.25 (11, in), 3.60 (111, 3.76 (111, 4.08 (1H1, d, J=l2Hz), 4.27 (1H, d, J=l2Hz), 6.7 (2H, mn), 6.92 (11, d, J=9Hz), 7.2-7.5 (5H, mn).
WO 93/21181 PCr/GB93/00788 52 DESCRI-PTION 30: (2S.3S)-3-((3-(isoPropoxy)nhenvl) methvloxy)-2-phonvlIner~dine IH NMR (250MHz, CDCl 3 5 1.6-1.9 (3H, in), 1.97 (1H, d, J=7Hz), 2.16 (1H, mn), 3.05 (1H, in), 3.3 (1H, in), 3.84 (1H, s), 4.09 (1H, d, J=12Hz), 4.41 (1H, d, J=12Hz), 4.44 (1H, mn), (1H, 6.6 in), 6.72 (1H, in), 7.09 (1H, t, J=8Hz), 7.3-7.5 in).
DESCRIPTION 31:, .5-Bi s(trifluoromethvl) phenyl)methloxy)-2-(3-fi-uorophenyl)nineidine 1 H NMR (360MHz, CDC1 3 5 1.66-1.9 (3H, mn), 2.2-2.3 (1H, mn), 2.43-2.5 (1H, mn), 3.0-3.2 (1H, mn), 3.98 (1H, 4.37 (1H, d, J=12Hz), 4.62 (1H, 4.79 (1H, d, J=12Hz), 7.04-7.46 (4H,i, ArE), 7.80 (2H, s, ArH), 7.96 (1H, s, ArH).
EXAMPEI
2-Amino-5-rf(2R* methvloxv)-72-nhenybiperidinolinethivl]l-.2.4 -oxadiazole Hydroxyguanidine sulphate hydrate (2.3g) was dissolved 29 in water and freeze-dried overnight. Ethanol (35m1) and powdered molecular sieves (1g) were added to the solid hydroxyguanidine and the suspension was stirred under nitrogen for 1 hour. Sodium (670mg) was added to the mixture which was stirred until all sodium had reacted. The suspension assumed an orange colour at this time and was placed in an ultrasound bath for 15 min. The ester of Description 2 (1.4g) was added, to the mixture which was then heated at reflux for 2h. The reaction mixture was cooled and filtered through celite.
WO 93/21181 PCT/GB93/00788 53 Ethanol was removed in vacuo and the residue was extracted into ethyl acetate anO 1 washed with water and brine. The organic layer was dried (MgSO 4 and evaporated. The red,1.,;e was purified on silica using 25% ethyl acetate in petroi as eluant. This afforded the product (800mg) as a solid which was recrystallised from ether/hexane to afford colourless prisms: mp 160-161 0 C. IH NMIR (360MHz, DMSO-d 6 d 1.47-1.54 (2H, m, CHOI, 1.85-1.9 (1H, m, CHH), 2.14-2.17 (1H, m, CHH), 2.35-2.40 (iB, m, CHIHN), 2.99-3.02 (1H, m, CHHN), 3.35 (1H, d, J 15.0Hz, N-CIIH-oxadiazole), 3.60 (2H, brs, NOHOHO), 3.65 (1H, d, J 15.0Hz, N-CB7H-oxadiazole), 4.06 (1H, d, J 13.0Hz, OCHH), 4.62 (IH, d, J 13.0Hz, OCHH), 6.2 (2H, brs, NH 2 7.23-7.31 (3H, m, ArH), 7.42-7.44 (2H, m, ArH), 7.69 (2H, s, ArH), 7.93 (1H, s, ArH); MS m/z 501 Found: C, 54.81; H, 4.47; N, 11.2. Calcd. for C23H2F 6
N
4
O
2
C,
55.20; H, 4.43; N, 11.2%.
methyloxv)-2-Dhenvlpireri dino)methvll-3-methvl- 1.2.4- Acetamideoxime (117mg) and powdered molecular sieves were suspended in dry tetrahydrofuran (l0mi) and stirred under nitrogen for 1 hour. Sodium hydride (63mg of suspension in oil) was added and the mixture heated to 51§,C until all hydrogen evolution had ceased. The ester of Description 2 (500mg) was dissolved in tetrahydrofuvran (2m1) and added to the above mixture. This mixture was heated at reflux for 2h, cooled, ifitered through celite and evaporated in WO 93/21181 PCI/GB93/00788 -54vacuo. The residue was dissolved in ethyl acetate and washed with water and then brine. The organic layer was dried (MgSO 4 and evaporated in vacuo. The residue was purified by medium pressure chromatography (Lobar) using 25% ethyl acetate in petrol as eluant. This afforded the product as a crystalline solid: mp 85-86'C; 1 H NMR (360MHz, DMSO-d) d 1.47-1.54 (2H, m, 1.85-1.89 (1H, m, CiH), 2.13-2.17 (1H, m, CHIe), 2.31 (3H, s, CH 3 2.34-2.40 (1H, m, CHHN), 2.98-3.01 (1H, m, CHEN), 3.51 (11, d, J 15.0Hz, NCHH-oxadiazole), 3.60 (2H, s, NCHCHO), 3.81 (1H, d, J 15.0Hz, NCHE-oxadiazole), 4.06 (1H, d, J 13.0Hz, OCHH), 4.62 (1H, d, J 13.0Hz, OCHF), 7.25-7.31 (3H, m, ArH), 7.43-7.45 (2H, m, ArH), 7.70 (2H, s, ArH), 7.93 (1H, s, ArH); MS (EI) m/z 500 100%). Founad: C, 57.94; H, 4.79; N, 8.23. Calcd. for
C
24
H
23
F
6
N
3 0 2 C, 57.72; H, 4.64; N, 8.41%.
EXAMPLE3 3-Amino-5-rf(2S.3S)-3-((3,5-bis(trifluoromethlI) phenv1)methloxv)-2-pheavlDineridinolmethyll-1.2.4-oxadiazole The title compound was prepared from the ester of Description 4 using the procedure described in Example 1: mp 138-139 0 C; [a] 23 D +147.70 MeOH). 1H NMR (360MHz, CDC1 3 d 1.47-1.50 (2H, m, CH 2 1.85-1.89 (1H, m, CNH), 2.14-2.17 (1H, m, CHI), 2.35-2.41 (1H, m, CHHN), 2.99-3.02 (1H, m, CHeN), 3.29 (1H, s, NCHCHO), 3.33 (1H, d, J 15.0Hz, NCEH-het), 3.65 (1H, d, J 15.0Hz, NCHi-het), 3.60 (1H, brs, NCHPh), 4.05 (1i, d, J 13.0Hz, OCHH), 4.62 (1H, d, J 13.0Hz, OCHH), 6.20 (2H, s, 7.23-7.31 (3H, m, ArH), 7.42-7.44 (2H, m, ArH), 7.69 (2H, s, ArH), 7.93 (1H, s, ArH); MS WO 93/21181 PCI'/GB93/00788 55 (CIi) xn/z 501 Found: C, 54.81; H, 4.47; N, 11.2.
Calcd. for C23H2F 6
N
4
O
2 C, 54.98; H, 4.54; N, 11.30%.
EXAMPLE4 3-rf(2R*.3R*'-,I-aa methvloxv)-2-phenvl-oiperidin-olmethvfluvri dinium hydoghoid The compound of Description 1 (410mg), 3-picolyl chloride (167mg) and potassium carbonate were suspended in dimethylformamide (3m1) and the mixture heated at 60'C for 12h. The mixture was cooled, diluted with water (50mi) and extracted with ethyl acetate (2 x l0mi). The organic phase was washed with brine, dried (MgSO 4 and evaporated. The residue was purified on silica using a gradient elution of 25-50% ethyl acetate in petrol. The product was dissolved in ethereal hydrogen chloride to form the dihydro chloride salt which was recrystallised from benzene: mp 198-200*C. 1H NNM (360MHz, DMSO-d 6 353K) d 1.68-1.82 (2H1, m, CHO), 2.09-2.18 (2H1, m, CHA) 3.06 (111, mc, CHHIN), 3.37 (1H, mc, CHHIN), 3.89 (1H, s, NCHC11O), 4.16 (1H, brd, NC11H-pyridine), 4.20 (1H, brd, NCHIIIj-pyridine), 4.26 (1H, d, J 13.0Hz, C1HO), 4.56 (1H1, brs, NCHPh), 4.72 (11, d, J 13.0Hz, 01111), 7.37-7.41 (3H1, m, ArH), 7.60-7.64 (1H, m, ArH), 7.71-7.72 (2H, m, ArH), 7.86 (1H, s, ArH), 7.89 (2H, s, ArH), 8.08 (11, d, J 8.0Hz, ArH), 8.64 (111, s, ArH), 8.68 (1H, d, J 5.0Hz, ArH); MS m/z 495 Found: C, 52.45; H, 4.90; N, 4.52. Calcd. for
C
26
H
24
F
6
N
2 0.2HCl.1.5H 2 0 C, 52.54; H, 4.92; N, 4.71%.
WO 93/21181 PCT/G B93/00788 56 2-rf(2R*.3qR .5-Bs(tifluoromethy-1)phenyD methloxy)-2- chenyITipejdino~methvITyvHdinium The compowid of Description 1 was reacted with 2-picolyl chloride following the procedure illustrated in Example 4: mp 175-180 0 C. 'H NMR (360MHz, DMSO-d 6 d 1.65-1.83 (2H, mn, C112), 2.08-2.15 (2H, mn, CHO), 3.16-3.20 (1H1, m, CHI-N), 3.30-3.40 (1H, m, CIHjN), 3.70 (1H, s, NCHCaO), 4.18 (1H1, d, J 14.0H1z, CHH-pyridine), 4.23 (1H1, d, J 14.0Hz, CHH1pyridline), 4.30 (1H, d, J 13.0Hz, OCHHI), 4.79 (1H, d, J 13.0Hz, OCHIJ), 4.78 (1H1, s, CHPh), 7.24 (111, d, J ArH), 7.36-7.4 (3H1, in, ArH), 7.47-7.51 (1H, mn, ArH), 7.62 (2H, mc, ArH), 7.85 (1H, dt, J 7.5, 2.0H1z, ArH), 7.94 (2H, s, ArH), 7.97 (1H, s, ArH), 8.65 (liH, d, J 7.5H1z, ArH); MS ni/z 495 100%). Found: C, 53.01; H, 4.79; N, 4.69. Calcd. for
C
26 H2AF 6
N
2 0.2HCI.H 2 O C, 53.30; H, 4.82; N, 4.78%.
X RL6 2-f2*3n3(35Bs~rilo~ehlpeA meth vloxv)-2-pDhenvlpiperi dino'Imethyflben zimi d azo The compound of Description 1 was reacted with 2-(chloromethyl)benzimidazole following the procedure illustrated in Example 4: mp 152-153*C. 'H1 NMR (360MHz, DMSO-d 6 d 1.44-1.59 (211, mn, NCH 2
CH
2
CH
2 1.85-1.89 (1H, in,
CHHCH
2 2.15-2.18 (2H1, mn, NCHH CHIJCH 2 2.86-2.89 (111, m, NCHH), 3.15-3.19 (111, d, J 14.0Hz, WO 93/21181 WO 9321181PCTIG B93/00788 57 NCIH2imidazole), 3.57 (1H, s, NCHCHO), 3.63 (1H, s, NCHCHO), 3.80-3.84 (1H, d, J 14.0Hz, NCHjH-iinidazole), 4.10-4.13 (1H, d, J 13.0Hz, -OCHIH), 4.63-4.66 (1H, d, J 13.0Hz, -OCIJ), 7.07-7.15 (2H, mn, ArH), 7.24-7.34 (3H, in, ArH), 7.43-7.52 (2H, mn, ArH), 7.60-7.62 (2H, mn, ArH), 7.67 (2H, s, ArH), 7.94 (IH, s, ArH), 12.10 (IB, s, NH); MS m/z 534 100%).
EXA MLE 7 .5-Bis(trifluloromethl )DhenvL) methyloxv)-2-nhenyvhiieridinolmethylltetrazol e The compound of Description 5 triethylamine hydrochloride (467mg)- and sodium azide (441mg) were dissolved in 1-inethyl-2-pyrrolidinone (5mi) and the reaction mixture was heated at reflux under nitrogen for 2h. The mixture was then cooled, and diluted with ice/water (80m1) and acidified to pH 2 with methanolic hydrogen chloride. This precipitated the product as a white solid, which was purified on silica using a gradient elution of methanol in dichloroinethane The product was recrystallised from ether-hexane: mp, 114-115'C.
1 H NMR (360MHz, DMSO-d 6 d 1.59-1.65 (2H, mn,
NCH
2
CH
2 CHi 2 2.02-2.22 (2H, in, NCH 2
CH
2 2.39-2.46 (IH, mn, CHHN), 2.98-3.02 (1Hi, mn, CHIJN), 3.62 (1H, s, NCHCHO), 3.66 (1H, S, NCaCHO), 3.70-3.74 (1H, d, J 15.5Hz, NCHHj-tetrazole), 4.05-4.10 (1H, d, J 15.5Hz, NCflH-tetrazole), 4.08-4.12 (1H, d, J 12.0Hz, OCffH), 4.51-4.54 (1H, d, J 12.0Hz, OCHH), 5.30 (1H, s, NH), 7.30-7.35 (3H, in, ArH), 7.45-7.47 (2H, in, ArH), 7.51 (2H, s, ArH), 7.74 (111, s, ArH); MS mlz 486 Found: C, 53.14; WO 93/21181 WO 9321181PCT/GB93/00788 58 H, 4.58; N, 13.96. Calcd. for 0 22
H
21
F
6 N0.0.5H 2 0 C, 53.44; H, 4.48; N, 14.16%.
methloQxv)-2-jDhenv]Dijperj dinolmethv11-4-m ethyl 3-thiazol e Anhydrous acetone (2m1) and methanol (2m1) and tetrabutylanimoniumn perbrornide (111mg) were stirred under nitrogen to generate a solution of bromoacetone in situ. The compound of Description 6 (150mg) was added to this mixture and the resulting solution was stirred for 2h. A second equivalent of bromoacetone was added and the mixture was stirred. for a further 2h. The volatile solvents were removed in vacuo and the residue was dispersed between aqueous potassium carbonate and ethyl acetate. The organic phase was washed with brine, dried (MgSO 4 and concentrated in vacuo, affording a brown oil. This was purified on silica using a gradient elution of ethyl acetate in petrol (10-30%) which gave the product as a clear oil: 1 H NMR (360MHz, CDCl 3 1.51-1.68 (2H, m, CH 2 1.98-2.22 (2H, m, CH 2 2.26-2.37 (1H, m, NOIIR), 2.38 (3H, s, CR 3 3.18-3.26 (1H, m, NCHIJ), 3.47 (1H, d, J 15.0Hz, NCHH), 3.54 bs, CH0), 3.58 bs, CIIPh), 3.94 (lIH, d, J 15.0Hz, NCHIH), 4.01 (1H, d, J 12.5Hz, OCHH), 4.47 (1H, d, J 12.5Hz, OCHH), 6.80 (ILE, s, SCil), 7.24-7.35 (3H, m, Ar-H), 7.52-7.54 (2H, m, Ar-H), 7.58 (2H, s, Ar-H), 7.72 (1H, s, Ar-H); MS inlz 515 100%). Found: C, 58.59; H, 4.88; N, 5.48 Caic for C25H 24
F
6
N
2 0S 58.36; H, 4.70; N, 5.44%.
WO 93/21181 PCT/GB93/00788 59 E AL 1-(2-furovl)-2-,obenvl periding The compound of Description 1 (400mg) and triethylamine (300mg) were dissolved in dichioromethane and the mixture was stirred for 10 min at 0 0 C. 2-Furoyl chloride (155mg) was added to the solution and the reaction mixture was stirred for 15 min. The mixture was then washed with brine; the organic layer was separated, dried (MgSO 4 and concentrated in vacuo. The residue was purified by chromatography on silica using 20% ethyl acetate in petrol, affording a clear oil. 1H1 NMR (360MHz, DMSO-d 6 d 1.6-1.8 (2H, m, CHA) 1.9-2.1 (2H, m, CH 2 2.99 (1H, mc, CIIH7N), 4.02 (1H, q, J 5.0Hz, CHO), 4.0-4.2 (1H, ma, ONIIN), 4.78 (1H, d, J 13.0H-z, OCHiH), 4.86 (1H, d, J 13.0Hz, OCHH), 5.95 (1H, s, CBIPh), 6.62 (IH, s, ftiran.-H), 6.99 (1H, s, furan-H), 7.25-7.36 (3H, m, ArH), 7.51-7.54 (2H, m, ArH), 7.83 (1H, s, furan-H), 7.90 (2H1, s, ArH), 7.99 (11, s, ArH);, MS (CIi) m/z 498 2-rf(2R* .3R*)-3-((3.5-Bi(trifluoromethy)Dhenyl) methyloxy)-2--nhenvlpip~eridinolmgthvllfiuran The compound of Example 9 (340mg) was dissolved in tetrahydrofuLran. To this solution was added borane-dimethyl sulfide complex (0.l8xnl of IOM solution) and the resulting solution was heated at reflux for 8h. The mixture was cooled, methanol added to quench excess borane, and the solvents were removed in vadilo. The residue was dissolved in methanol WO 93/21181 WO 9321181PCT/GB93/ 00788 60 (l0mi) and potassium carbonate was added (238mg). This ixue was heated at reflux for 1 hour; the methanol was removed in vacua and the residue was dispersed between ethyl acetate and brine. The ethyl acetate layer was dried (MgSO 4 and evaporated. The residue was purified by chromatography on silica using 10% ethyl acetate in petrol. The product was recrystallised from ether-hexane: mp 103-104'C. 'H NMR d 1.4-1.5 (2H, m, CH 2
CH
2 1.8-1.9 (1H, m, CIIHCH 2 2.1-2.2 (2H, m, CHHCH 2 N and CHHN), 2.95-3.0 (1H, m, CIIN), 3.11-3.15 (li, d, J =15.0Hz, NCHH-furan), 3.38 (1H, s, NOHCHO), 3.54-3.58 (1H, d, J 15.0Hz, NCHIJ-furan), 3.56 (1H, s, NCHJCHO), 4.02-4.06 (1H, d, J 13.0Hz, OCHH-), 4.59-4.62 (1H, d, J 13O0H, OGCHH-), 6.08-6.09 (1H, m, furan 6.35-6.36 (1H, m, furan-H), 7.24-7.32 (3H, m, ArH), 7.46-7.48 (2H1, m, ArH), 7.55 (1H, s, furan-H), 7.68 (2H1, s, ArH), 7.93 (111, s, ArH); MS m/z 485 100%). Found: C, 62.11; H, 4.80; N, 2.90. Calcd. for C~zH2NF 6 O: C, 62.27; H, 4.83; N, 2.96.
XML1 Bis(trifluoromethvl)Phenvl) methvloxy)-2-nhenvlpinoeridinolmethvll-3-broo- 1.2 .4-oxadiazol e hydrQohkride Dilsopropylethylamine 2 20 pl) was added to a stirred suspension of the compound of Description 1 (200mg) and 5-bromo-3-(chloromethyl)- 1,2,4-oxadiazole (99mg) (J.
Heterocycic Chem. 1989, 2% 23) in dry acetonitrile. The resulting solution was allowed to stir at room temperature for 48 hrs. After this time the solvent was removed under reduced pressure and the residual oil purified by column WO 93/21181 PCT/GB93/00788 -61chromatography on silica using ethyl acetate in hexane as eluant to afford a waxy solid. Treatment of an ethereal solution of this solid with ethereal hydrogen chloride yielded a white precipitate. Recrystallisation from ether afforded the title compound as an amorphous white solid: mp 100-102C. 1
H
NMR (3601M-Hz, DMSO-d) d 1.67-1.70 (2H, m, 1.83 (1H, m, CIIH), 2.30 (1H, m, CHIE), 2.74 (1H, m, CaHN), 3.10 (1H, m, CHHIN), 3.70 (1H, d, J 11.0Hz, CH-OCH 2 3.82 (1H, brs, N-CH-Ph), 4.34 (1H, d, J= 16.0Hz, NCHH-oxadiazole), 4.36 (1H, d, J 11.0Hz, OCHH-Ar), 4.58 (1H, d, J 16.0Hz, NCflH-oxadiazole), 4.73 (1H, d, J 11.0Hz, OCHH-Ar), 7.34-7.42 (5H, m, ArH), 7.68 (2H, s, ArH), 7.73 (1H, s, ArH); MS (CI m/z 564 Found: C, 45.64; H, 3.63; N, 6.70.
Calcd. for CH 20
N,
3
O
2
,F
6 Br.HC1: C, 45.98; H, 3.52; N, 6.99%.
EXAMPLE 12 5-rf(2R*.3R*)-3-((3,5-Bis trifluoromethyl)ph-enyl) methyloxv)-2-phenylpineridinolmethyl-3-dimethylami 14oxadiazole hydrochloride The compound of Example 11 (169mg) in dimethylamine (33% in ethanol) was heated to 40 0 C for 30 min. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica using ethyl acetate in hexane as eluant. The compound was dissolved in ether and treated with excess ethereal hydrogen chloride to afford a white precipitate. Recrystallisation from ether afforded the product as white powder (110mg): mp 179-180 0 C. 'H NMR (360MHz, DMSO-d 6 d 1.59 (2H, m, CH 2 2.1-2.21 (2H, m, CH 2 2.4-2.45 (1H, m, CHIEN), 3.01 (6H, s, N(CH 3 3.10 (1H, m, WO 93/21181 PCT/GB93/00788 -62- CHHN), 3.60 (1H, brs, CII-O-CH 2 3.70 (1H, d, J 16.0Hz, NCHH-oxadiazole), 3.78 (1H, d, J 1.Hz, N-CH-Ph), 3.82 (1H, d, J 16.0Hz, NCHH-oxadiazole), 4.01 (1H, d, J 15.0Hz, O-CjH-Ar), 4.49 (1H, d, J 15.0Hz, O-CH1-Ar), 7.3 (3H, m, ArHf), 7.4 (2H, m, ArH), 7.49 (2H, s, ArH), 7.64 (11, s, ArH); MS m/z 529. Found: C, 51.87; H, 4.93; N, 9.62. Calcd.
for C 25
H
26
N
4 0 2
F
6
.HC.H
2 0. C, 51.51; H, 5.01; N, 9.61%.
EXAMPE1L3 .5-Bis(trifluororethvl )phenvl methloxv)- 2-nhenvl- -(2-thienovyli eridine The compound of Description 1 was reacted with 2-thiophenecarbonyl chloride as outlined in Example 9. The oil obtained after work-up and removal of solvent was purified by chromatography on silica, eluting with 10% ethyl acetate in petroleum ether to afford the pure product as a clear oil. 1
H
MR (250MHz, CDC1 3 d 1.6-1.8 (2H, m, CH), 2.1-2.2 (2H, m, CH), 3.0 (11, m, CHN), 4.0 (1H, dt, J 5Hz, 2Hz, CHi), 4.1 (1H, brs, CHN), 4.7 (11, d, J 7Hz, CHAr), 4.8 (1H, d, J 7Hz, CHAr), 6.2 (1H, brs, NCfljPh), 7.02 (1H, dd, J 1, 2Hz, thiophene-H), 7.3-7.44 (4H1, m, Ar-H), 7.5 (1H, dd, J 1, 3Hz, thiophene-H), 7.6-7.92 (5H, m, Ar-H).
(2R*.3R*)-3-((3.5-Bis(trifluoromnethyvnhenvl )methloxy)- 2-phenl-l-(2-thienvlmethvlpineridine The compound of Example 13 was reacted with borane dimethylsulfide as described in Example 10. The free base was WO 93/21181 PGT/GB93/00788 63 recrystallised from ether and hexane to give the product as a white crystalline solid. IH NMR (250MHz, CDCI 3 d 1.44-1.64 (2H, m, CO 2 1.9-2.2 (2H, m, CHO), 2.24 (iR, d, J 7Hz, CHIN), 3.14 (1H, d, J 7Hz, CHIN), 3.4 (1H, s, CHiO), 3.56 (1H, s, NCRj7h), 3.6 (1H, s, CH1-thiophene), 4.88 (1H, d, J CH-thiophene), 4.0 (1H, d, J 10Hz, QHAr), 4.24 (1H, d, J CaAr), 6.7 (1H, d, J =1Hz, thiophene-H), 6.9 dd, J= 2Hz, 3Hz, thiophene-H), 7.2 (1H, d, J 3Hz, thiophene-H), 7.28 (4H1, m, Ar-H), 7.5 (3H, m, Ar-H), 7.68 (11, s, Ar-H). MS m/z 500 100%).
KPAMLE 5-f2R.R)--(.5-Bis.(trifbioromethvl )Dhenvl) methvloxv)-2-phenylnineridinolmethll-2 .3-dihydro-4-meth-Vl-3thioxo-1.2.4-triazole hydrochloide A suspension of the compound of Description 7 (0.50g) and methyl isotbiocyanate (0.09in1) in 1-butanol (10mi) was heated under reflux fo r 10 nn 1,8-Diazabicyclo[5.4.0]undec-7-ene (0.lml) was added and the reaction mixture was heated under reflux for 2.5h. The solvent was removed in vacua and the re.jidue was partitioned between water and ethyl acetate. The organic layer was dried (MgSO 4 and evaporated. The residue was purified on silica using methanol in dichioromethane as eluant to give the title compound. The product (470mg) was characterised as the hydrochloride salt. 'H NMR (360MHz, DMSO-d 6 d 1.77-1.93 (2H, in, OH 2 2.05-2.22 (1H, mn, 0111), 2.31 (1H1, d, J 13.5Hz, CHUj), 3.42 (3H, s, 3.45-3.51 (1H1, m, NCHHCH 2 3.83 (1H1, d, J 12.0Hz, NCHHOH 2 3.97 (1H, brs, 0110), 4.24 (111, d, J 15.5Hz, N-CHH-het), 4.32 (111, d, J =15.5Hz, WO 93/21181 PCT/GB93/00788 -64- N-CHIJ-het), 4.33 (1H, d, J 12.5Hz, O-CHH), 4.76 (1H, s NCI), 4.80 (11, d, J 12.5Hz, O-CHH), 7.42-7.50 (3H, m, ArH), 7.59 (2H, brs, ArH), 7.85 (2H, s, ArH), 7.89 (iN, s, ArH), 9.15 (iH, brs, Nil); MS (FAB) mn/z 530 13%).
E A~LE 16 3-rf(2*.3R*)-3-((3.5-Bis(trifluoromethvl)yhenvD) methvloxy)-2-uhenyl'r ierldinolmethl1-1.2 .4-triazoje The compound of Description 1 anhydrous potassium carbonate (0.94g) and N-formyl-2chioroacetanaidohydrazone (0.46g), (prepared according to Yanagisawa, J. Med. Chem. 1984, ZZ, 849) were heated to 6000 in anhydrous dimethylformamide for 3h, followed by heating at 13000 for 12h. The reaction mixture was cooled, diluted with ethyl acetate (lO0mi) and washed with water, (3 x 20m1). The ethyl acetate layer was dried (MgSO 4 filtered and evaporated to give a brown oil. This was purified on silica using ethyl acetate in petrol (70:30) as eluant. This afforded the product as a white solid. 1H NMR (250MHz, ODCd 3 d 1.6 (2H, m, OH 2 1.95-2.24 (2H, m, CHO), 2.34 (1H, m, NCHH), 3.06 (iH, m, NCHW), 3.44 (1H, d, NCHfl-triazole), 3.5 (iN, bs, CHO), 3.6 (iN, bs, NCIIPh), 3.8 (iN, d, N-OHNI-triazole), 4.04 (iN, d, OCliN-Ar), 4.50 (1H, d, OCHHjAr), 7.3 (3H, m, ArN), 7.44 (2H, m, ArNl), 7.5 (2H, s, ArNl), 7.7 (iN, s, ArH), 7.9 (iH, s, triazole-H). MS (CIi) xnlz 485 WO 93/21181 WO 9321181PCIF/GB193/00788 65 .5-Bi s(trifluoromethvl-)nhenvl) methyl oxy)-2-ph enyluineri din o Imethvllj-2.2 -di hvdro4(4H)- 3thioxo-1 .2.4-triazole The compound of Description 7, potassium thiocyanate (0.45g) and conc. hydrochloric acid (2.3m1) in water (12m1) were heated under refiux for 2h. After cooling, solid sodium hydroxide was added until pH 8 and the aqueous layer was extracted with ethyl acetate. The organic layer was dried (MgSO 4 filtered and evaporated to give the crude senii-car1bazide which was heated at reflux in 2N sodium hydroxide solution (l1inl) for 2h. After cooling the solution was acidified to pH 5-6 and the product extracted into ethyl acetate.
The organic layer was dried (MgSO 4 filtered and evaporated.
The crude triazole was cliromatographed on silica eluting with ethyl acetate/60-80 petroleum ether to give the title compound as a white solid. 'H NMR (250\Mz, CDCl 3 d 1.6 (2H1, m, CH 2 1.9-2.3 (3H1, m, CH 2 NCHIH), 2.95 (111, bd, NCHH), 3.16 (11, d, N-CHH-Het), 3.20 (11, bs, 0CH0), 3.6 (11, bs, NCHjPh), 3.78 (111, d, N-CHH-Het), 4.1 (111, d, CflIF-Ar), 4.58 (1H1, d, 0111-Ar), 7.32 (5H1, m, 7.5 (2H1, s, Ar-H), 7.78 (iH, s, ArH). MS (FAB) m/z 517 3 .5-Bistrifluoromehy.):)1nyl) methvloxy)-2-phenylpineri dinolmethyvH-2-rret1ktaY l The compound of Example 7 (500mg) was suspended in water (4m1) and sodium hydroxide (44mg) added. This was WO 93/21181 PCT/GB93/00788 -66heated to an external temperature of 96°C and dimethyl sulphate (65mg) added. The reaction mixture was allowed to stir under nitrogen at 96°C for Ih after which time stirring was continued for 24h at 50C. After this time, the product was extracted into dichloromethane and washed with water and brine. The organic layer was dried (MgSO 4 and evaporated.
The residue was purified on silica using medium pressure chromatography (Lobar), and eluted with 25% ethyl acetate in petrol. The first compound to be eluted was isolated, and this afforded the product (50mg) as a crystalline solid, which was recrystallised from ether/hexane to afford white crystals: mp 139-141°C. 1H NMR (360MHz, DMSO) d 1.44-1.51 (2H, m,
CH
2 1.79-1.82 (1H, m, CHH), 2.12-2.15 (1H, m, CHH), 2.19-2.25 (1H, m, CHHN), 2.97-3.00 (IH, m, CHHN), 3.37 (1H, d, J 14Hz, N-CHH-tetrazole), 3.52 (1H, s, NCHCHO), 3.58 (1H, s, NCHCHO), 3.81 (1H, d, J 14Hz, N-CHH-tetrazole), 4.03 (1H, d, J 13Hz, OCHH), 4.31 (3H, s, CH 3 4.60 (1H, d, J 13Hz, OCHH), 7.23-7.33 (3H, m, ArH), 7.49-7.51 (2H, m, ArH), 7.68 (2H, s, ArH), 7.93 (1H, s, ArH); MS (CI m/z 500 100%). Found: C, 55.56; H, 4.76; N, 14.20. Calculated for C 23 H2NOF 6 C, 55.31; H, 4.64; N, 14.02%.
EXAMPLE 19 5-rf(2R*.3R*)-3-((3.5-Bis(trifluoromethy )phenvy) methvloxv)-2-phenvlpiperidino)methyll-1-methvltetrazole The title compound was prepared as described in Example 18. During purification, the second compound to be eluted was isolated, and this afforded the product (120mg) as a crystalline solid, which was recrystallised from ether/hexane to WO 93/21181 PCT/G B93/00788 67 afford yellow crystals: mp 75-.77'C. 1H1 NMR (360MHz, DMS0) d 1.51-1.55 (2H, m, CH 2 1.84-1.87 (1H1, m, CHIJ), 2.12-2.16 (iH, m, CHjH), 2.31-2.37 (1H, m, CHkIN), 2.81-2.84 (1H, m, CLUHN), 3.52 (1H, d, J 15Hz, NCHIH-tet), 3.54 (1H1, s, NCHCHIO), 3.60 (1H1, s, NCEaCHO), 3.82 (1H, d, J 14Hz, NCHH-tet), 3.84 (3H, s, CH 3 4.14 (111, d, J 13Hz, OCHII), 4.85 (1H1, d, J =13Hz, 0CHIH), 7.26-7.32 (3H1, m, ArH), 7.45-7.48 (211, m, ArH), 7.74 (2H, s, ArH), 7.94 (1H1, s, ArH); MS mhz 500 3-rf(2R* .5-Bis(trifluloromethvl )Denvl) methyoxy)}2-henlipeidinolmetv1-5-dimethylamino- 1.2.4a) 5-Dimethvlarnno-3-(chloromethvl)-1 .2 .4-thiadiazol A solution of dimethylamine in ethanol (0.5m1 x 33%) was added to a stirred suspension of 5-chloro-3-(chloromethyl)- 1,2,4-thiadiazole (540mg) Goerdeler, Chem. Ber. 1957, 2Q, p 182 or ICI EP 0006679) and potassium carbonate (1.0g) in methanol. The solution was stirred at room temperature for three hours, and then the solvent removed under reduced pressure. The residue was taken up in ethyl acetate (40m1), washed with water (20m1) and brine (20m1). The organic layers were dried (MgSO 4 filtered and the solvent removed to afford a yellow guim. Flash chromatography using 10% ethyl acetate in hexane as eluent, afforded the product as a yellow oil (330mg).
IH 1NMR (360MHz, CDCl 3 d 3.15 (6H1, s, N(CH 3 2 4.51 (2H1, s, Cl-CH 2 MS m/z 178 b) A solution of the compound of Description 1 (223mg), 5-dimethylamino-3-(cbloromethyl)- 1,2,4-thiadliazole (100mg) WO 93/21181 WO 9321181PCr/c;n93/00788 68 and dilsopropylethylamine (0.2m1) were heated at reflux in dry acetonitrile for three hours. The reaction was then allowed to cool to rooma temperature and the solvent removed under reduced pressure. Purification of the residue by flash chromatography (40% EtOAc/ni~ex) gave a yellow gum.
Recrystallisation from n-hexane afforded the product as yellow plates: mp, 144-145TC. 1H NMR (360MHz, CDCl 3 d 1.57 (2H, m, CaH), 2.11 (3H, mn, Cli 2 +CHH), 2.42 (ili, ra, CHH), 3.11 (6H, s, N(C11 3 2 3.20 (il, In, Cii-OCH2), 3.47 (11, d, J =14.5Hz, C1ili-thiadiazole), 3.56 m, CIiPh), 3.75 (1Hi, d, J =14.5Hz, CHH-thiadiazole), 4.03 (1H, d, J 10.5Hz, OCHH-Ar), 4.45 (1Hi, d, J 10.5Hz, OCHHi-Ar), 7.30 (3H, mn, ArHE), 7.51 (2H, s, ArH), 7.53 (2H, mn, ArH), 7.69 (i1H, s, ArH); MS m/z 545 Found: C, 55.12; H, 4.75; N, 10.38. Calcd. for
C
25
H
2 0
F
6
N
4 S0: C, 55.14; H, 4.81; N, 10.30%).
2-rf(2R* methloxv)-2-pheny-lpineri din ol methvll dim eth vlbenzoxazol e A solution of 2-(chloromethyl)-4,7-dimethylben -oxazole (285mg) in dry acetonitrile (l0mi) was added to a solution of the compound of Desciiption 1 in dry acetonitrile (l0mi) containinig diisopropylethylamine (0.4m1). The resulting mixture was heated at reflux for three hours, cooled to room temperature and the residue purified by flash chromatography on silica gel using ethyl acetate/n-hexane as eluant. Recryjstallisation of the isolated material from n-hexane afforded the product as white needles: mp 109-110TC. 'H NMR (CDCl 3 1.49-1.53 (2H, in, CHA) 1.56-1.60 (1H, mn, CHJH), 2.03-2.09 (ili, mn, Clii), 2.10-2.16 (ili, mn, CHHN), 2.36-2.40 (il, m, C.HHN), 2.47 (3H, WO 93/21181 PCT/GB193/00788 69 s, Ar-C-H 3 2.54 (3H, s, ArCH.), 3.24 (1H, m, ChrN), 3.59 m
CHOCH
2 3.67 (1H, d, J 12.0Hz, N-CHH-benzoxazole), 3.79 (1H, d, J 12.0Hz, N-CHH-benzoxazole), 3.96 (1H, d, J 10.0Hz, OCjiH), 4.47 (1H, d, J 10.0Hz, OCHH), 6.99 (2H, s, ArH), 7.32 (3H, m, ArH), 7.54 (2H, s, ArH), 7.57 (2H, m, ArH), 7.71 (1H, s, ArH); MS rn/z 563 Found: C, 64.09; H, 5.04; N, 5.12. Calcd for C 30 H~sN 2
O
2
F
6 C, 64.05; H, 5.01; N, 5.00%.
EAPE2 2-rf(2R*.39R*)-3-((3 methyloxy)-2-phenylpiperidinolImethvllbenzoxazole.
This compound was prepared followin~ the procedure described in Example 21, using 2-(chloromethyl)benzoxazole as the alkylating agent: mp 95-97'C. 'H NMR (CDCl 3 d 1.47-1.60 (2H, m, Ca 2 2.06-2.19 (2H, m, OH 2 2.42-2.56 (1H, dd, IH, J 4.0Hz, NCHH), 3.26 (1H, dd, J 4.0, 2.0Hz, NCHH), 3.61 (1H, s, CHO), 3.66 (1H, d, J 15.0Hz, NCHH-benzoxazole), 3.66 (1H, d, J 2.0Hz, CHPh), 4.02 (1H, d, J 15.0Hz, CHH-benzoxazole), 4.04 (1H, d, J 12.0Hz, OCHH), 4.48 (1H, d, J 12.0Hz, OCHH), 7.26-7.67 (12H, m, ArH); MS m/z 535 Found: C, 62.36; H, 4.67; N, 5.27. Calc for C28H2F 6
N
2
O
2 '/4H20: C, 62.39; H, 4.58; N, 5.20%.
EXAMPLE 23 4-f(2S.3S)-3-((3 .5-Bis(trifluoromethyj )Dhenvl)methvloxy)- 2-nhenylnpiperidinolmgthlloxazole WO 93/21181 PCT/GB93/00788 1,3-oxazole-4-carboxaldehyde was prepared following the procedure described by J. Hodges, W. Patt and C. Connolly, sL DrM Chem 1991, 5i, 449-452.
a) 4-(Hvdroxvmethvl) 1.3-oxazole 1,3-Oxazole-4-carboxaldehyde (0.38g) was dissolved in anhydrous methanol and stirred under nitrogen; sodium borohydride (0.074g) was added carefully. After 1 hour no starting material was present by TLC using 50% ethyl acetate in hexane as eluent. The methanol was removed by rotary' evaporator (water bath temp 40°C). The residue was purified by chromatography on silica eluting with 100% diethyl ether. This afforded the alcohol (0.27g) as a white solid. 1 H NMR d (360 MHz, CDC1 3 2.93 4.63 (2H, s, CH 2 OH), 7.64 (1H, s, oxazole-H), 7.90 (1H, s, oxazole-H).
b) 4-[{(2S.3S)-3-((3.5-Bis(trifluoromethvl)phenv1) methvloxv)-2-phenvlpiperidino}methylloxazole 4-(Hydroxymethyl)-l,3-oxazole (0.13g) was dissolved in anhydrous dichloromethane (4ml) under an atmosphere of nitrogen. Triethylamine (0.19ml) and p-toluenesulfonyl chloride (0.13g) were added to the reaction mixture which was stirred for 1 hour at room temperature. A further portion of p-toluenesulfonyl chloride (0.13g) and a catalytic amount of dimethylaminopyridine were added to the reaction mixture.
The compound of Description 3 (1.2g, free base) was dissolved in dimethy]formamide (5ml) and was added to the reaction mixture followed by triethylamine (0.19ml). The mixture was heated at for 2h and the resulting mixture was diluted with water and extracted with dichloromethane (3 x 20ml). The combined organic layers were dried (MgSO 4 and concentrated in vacuo to afford a yellow oil. This was purified by WO 93/21181 PCT/GB93/00788 -71chromatography on silica gel using a gradient elution of 30-60% ether in hexane to afford the title compound as a white solid.
This was recrystallised from ether/hexane: np 102-104 0 C. 'H NMR (360MHz, CDCl 3 d 1.46-1.64 (1H, m, NCH 2
CH
2
CIIH),
1.7-1.87 (1H, m, NCH 2
CH
2 CHH), 1.96-2.20 (2H, m, NCH 2 Cfi 2 2.32-2.48 m, NCHH), 3.20-3.46 (3H, m, NCHH NCHH-oxazole CHOCH 2 Ar), 3.55 (1H, brs, CHPh), 3.68 (1H, d, J 14.5Hz, NCHH-oxazole), 4.01 (11, d, J 11.5Hz, OCHEAr), 4.46 (11, d, J 11.5Hz, OCHHAr), 7.24-7.58 (8H, m, ArH), 7.70 (1H, s, ArH), 7.80 (1H, s, ArH); MS 485 1, 100%) E~XAMPLE 24 2-[(2S.3S)-3-((3.5-Bis(trifluoromethvl)phenl)methvlo 2-phenvh~iperidinolmethylnvurazine a) 2-(Chloromethvl)pvra7ine 2-Methylpyrazine (ig) was dissolved in carbon tetrachloride (5Omi) under nitrogen. N-Chlorosuccinimnide (1.42g) and benzoyl peroxide (50mg) were added and the mixture was heated at reflux for 24h. The reaction mixture was cooled and filtered through celite and the filtrate was concentrated in vacuo. The resulting oil was purified on silica using 30% ethyl acetate in petrol. 'H NMR (360MHz, CDCI) d 4.72 (2H, s, CH 2 CI), 8.56 (2H, s, ArE), 8.76 (1H, s, ArH).
b) 2-rf(2.3S-3-(f.5-Bis(trifluoromethy.. )iohenvl) methvloxv)-2-nhenvnineri dinolmethvlvrazine 2-(Chloromethyl)pyrazine (0.17g), potassium carbonate (0.6g) and the compound of Description 3 (0.35g) were suspended in dimethylformamide (3m1); the reaction mixture was heated at 60C for 12h. The mixture was cooled, diluted WO 93/21181 PCT/GB93/00788 -72with water (30ml) and extracted with ethyl acetate (2 x The combined organic layers were washed with brine, dried (MgSO 4 and concentrated in vacuo to afford a brown oil. The product was purified by column chromatography on silica gel using a gradient elution of 15-35% ethyl acetate in hexane. This afforded the product as a white solid, which was recrystallised from pentane to give colourless crystals: mp 108-1100C 1H NNMIR (360MHz, DMSO-d) d 1.42-1.60 (2H, m NCH 2
CH
2
CH
2 1.77-1.92 (1H, m, NCHCHH), 2.13-2.25 (2H, m, NCIJH NCHCH), 2.84-2.92 (1H, m, NCIH), 3.12 (1H, d, J 14.0Hz, NCHH-pyrazine), 3.55 (1H, m, CHIO), 3.63 (1H, m, CHPh), 3.78 (1H, d, 14.0Hz, NCHI-pyrazine), 4.11 (1H, d, J 13.0Hz, OCHHAr), 4.64 (1H, d, J 13.0Hz, OCHHAr), 7.20-7.33 (3H, m, ArH), 7.49-7.56 (2H, m, ArH), 7.71 (2H, s, ArH), 7.93 (1H, s, ArH), 8.48-8.63 (3H, m, ArH); MS (CI 496 (M Found: C, 60.90; H, 4.86; N, 8.48. Calcd. for CzH23F 6
N
3 O: C, 60.60; H, 4.68; N, 8.48%.
EXAMPLE 4-r(2S.3S)-3-((3 2-nhenvivineridinolmethyll-2-methyl-1.3-thiazolium dihydrochloride 4-(Chloromethyl)-2-methylthiazole hydrochloride (83mg) was added to a suspension of the compound of Description 3 and potassium carbonate in dimnethylformamide (5ml). The resulting mixture was heated at 60 0 C for 18h, cooled to room temperature and diluted with water (50in). This solution war extracted with ethyl acetate (2 x 25ml) and the combined organic extracts were washed with water (2 x 20mnl), brine (20ml), dried (MgSO 4 and filtered. The resulting solution was WO 93/21181 PCT/GB93/00788 -73evaporated under reduced pressure to afford a yellow oil. This was purified by medium pressure liquid chromatography using ethyl acetate in hexane to afford the product as a white solid. This was treated with ethereal hydrogen chloride and recrystallised from methyl-t-butyl ether to afford the title compound: mp 58-60°C. IH NMR (360MHz, DMSO-d 6 d 1.71 (2H, m, CH 2 2.11 (2H, me, CH 2 2.49 (1H, m, CHHN), 2.69 (3H, s, Ar-CH), 3.15 (1H, m, CHHN), 3.54 (1H, m, CHO), 4.12 (2H, m, CH 2 -thiazole), 4.16 (1H, d, J 10.0Hz, OCHHAr), 4.58 (1H, brs, CHPh), 4.76 (1H, d, J 10.0Hz, OCHAr), 7.40-7.43 m, ArH), 7.64 (1H, brs, ArH), 7.92 (2H, s, ArH), 7.97 (1H, s, ArH); MS (CI m/z 515 (M Found: C, 48.17; H, 4.76; N, 4.52. Calcd. for C2H24F 6
N
2 OS.2HC1.2H20: C, 48.16; H, 4.85; N, 4.49%.
EXAMELE 26 3-ff(2S.3S)-34(3.5-Bis(trifluoromethyv)phenvl)methvloxv)- 2-phenvlnineridinolmethvll-1.2.4-oxadiazole hydrochloride 3-(Chloromethyl)-l,2,4-oxadiazole (270mg) was added to a rapidly stirred suspension of the compound of Description 3 and potassium carbonate in dimethylformamide (10ml). The reaction mixture heated at 60 0 C for 4h, cooled to room temperature and diluted with water (rJml). The aqueous solution was extracted with ethyl aceta e (3 x 50ml) and the organic extracts were combined, washed with water (3 x brine (50ml), dried (MgSO 4 and filtered. The resulting solution was concentrated under reduced pressure and purified by column chromatography on silica gel using 20% ethyl acetate in hexane as eluent. The resulting oil was treated with ethereal hydrogen chloride to afford the title compound as a white WO 93/21181 WO 93?1181PCr/GB93/00788 74 powder: mp 74-751C. 1H N7MR (360MHz, DMSO-d 6 d 1.62 (2H, m, CHOI, 1.97-2.1 (2H, m, OH 2 2.50 (1H, m, CIN), 3.16 (1H, m, CaHN), 3.51 (1H, m, CHDQ), 3.69-3.72 (3H, m,
CH
2 -oxadia,-,ole CHPh), 4.14 (1H, d, J 10.0Hz, OCIHAr), 4.70 (1H, d, J 10.0Hz, OCEHAr), 7.32 (3H, m, ArH), 7.45 (2H, m, ArH), 7.78 (3H, mn, ArH), 7.94 (1H, s, ArH).
~XAMILE 27 3-[U(2S.38)-3-((3.5-Bis(tifluorometvV)DhenvPl)methvlox)- 2-nphenvlpineridinohyiethvll-5-iodo-1 .2 .4-thiadiazole.
a) 5-Iodo-3-iodomethvl)-1 .2,4-thi adiazole Sodium iodide (excess) was added to a stirred solution of 5-chloro-3-(chloromethyl)- 1,2,4-thiadliazole (3 .0g) Goerdeler, Chem. Ber. 1957, 182) in dry butanone (i1ini). The resulting solution was heated at reflux for four hours, cooled to room temperature and filtered. The filtrate was diluted with water (20m1) and extracted with ethyl acetate (50m1). The ethyl acetate layer was dried (MgSO 4 filtered and concentrated in vacua to afford a red oil, which was used in the following reaction without further purification.
b) Z32 S)-3-((3.5-Bis(trifluoromethv1)phenv1) methvlo nhg-h lineridinolmethvll-5-iodo- 1.2 .4-thiadiazole Diisopropylethylamine (116mg) was added to a stirred solution of 5-iodo-3-(iodomethyl)- 1,2,4,thiadiazeole (160mg) and the compound of Description 3 (200mg) in dry acetonitrile (l0mi). The resulting solution was stirred at room temperature for 18h. The reaction mixture was filtered and the solvent was removed in vacua to afford a red oil. This was purified using column chromatography on silica gel using 20% ethyl acetate in hexane as eluent. This afforded the product as a powder: mp WO 93/21181 PTG9/08 PCT/GB93/00788 75 98-101 0 C. 1H NM~R (360MHz, ODCd 3 d 1.55 (3H, m,
NCH
2
CH
2
CH
2
NCH
2 CHH), 2.13 (2H, m, NCH 2 CHH NCHJH), 2.42 (1H, m, OBIIN, 3.21 (1H, mn, CHO), 3.69 (2H, m, CIIPh CHH-thiadiazole), 4.02 (2H, mn, CHH-thiadiazole 001111), 4.48 (1H, d, J 8.Hz, OCHIW, 7.32 (5H, mn ArH), 7.51 (2H, s ArH), 7.70 (1H, s, ArH).
EXAI-\L 2 3-rf(2S,3s)-3-((3.5-Bis(fi fhoromethv1 )ohenvlI)methyloxv)- 2-nhenvlnineriinolmethll- 1 .24-thiadiazole hydrochloride Sodium borohydride (280mg) was added to a stirred solution of the compound of Example 27 (500mg) and palladium (II) chloride (280mg) in dry methanol (25m1). The resulting mixture was stirred for 30 min and then filtered through celite; the filtrate was concentrated in uacuo. The solid residue thus obtained was dissolved in ethyl acetate and the solution was washed with water (l1ini), the organic extract was dried (MgSO 4 filtered and concentrated in vacuo, to afford a yellow oil. Treatment of this oil with ethereal hydrogen chloride afforded the title compound as a white powder: mp 89-901C. 'H NMR (360MHz, DMSO-d 6 d 1.79 (2H1, mn, OH 2 1.9-2.20 (3H, mn, CHFjN NCH 2
CH
2 2.6 (111, in, CHHN), 3.8 (111, bin, CHO), 3.89 (1H1, brs, CHjPh), 4.2-4.3 (3H, m, CHi 2 -thiadiazole 00111), 4.76 (111, d, J M.Hz, 00111), 7.39 (311, mn, ArH), 7.55 (211, mn, ArH), 7.89 (211, s, ArH), 8.32 (111, s, ArH), 10.32 (111, s, N-CHj-S); MS mfz 502 (M Found: C, 49.31; H, 4.09; N, 7.18%. Calcd. for C23H 2 jF 6
N
3 0S.HCl.1.25H 2 O C, 49.48; H, 4.37; N, 7.52%.
WO 93/21181 PrG9/o8 PCr/GB93/00788 76 3-Ii(2S.3S)-3-((3 1.2.thiadiazok hydroghkride Sodium methoxide (34mg) was added to a stirred solution of the compound of Example 27 (200mg) in methanol (5mi). The solution was heated at reflux for 2h, cooled to room temperature and the solvent removed under reduced pressure affording a solid residue. The solid was dissolved in ethyl acetate and the organic phase was washed with water separated, dried (MgSO 4 and the solvent was removed under reduced pressure. The residual solid was treated with ethereal hydrogen chloride and the resulting solid was recrystallised from ethyl acetate to afford the product as white needles: mp 74-750C. 'H NMR (360MHz, DMSO-d 6 d 1.55 (2H, m, CHO), 1.73 (1H, m, CHiH), 2.09 (2H, M OH 2 2.43 (1H, m, CHfl9, 3.20 (1H, m, CHO), 3.49 (2H, m, CajPh CHHI-thiadiazole), 3.75 (1H, m, CHH-thiadiazole), 4.02 (1H, d, J 10.0Hz, OCH.11), 4.14 (3H, S, OCH 3 4.45 (1H, d, J 10.0Hz, OCHH), 7.30 (3H, m ArH), 7.51 (4H, brs, ArH), 7.54 (1H, s, ArH); MS m/z 532 Found: C, 49.89; H, 4.10; N, 7.41. Calcd, for
C
24 H23F 6
N
3
O
2 S.HCl.0.5H 2 O: C, 49.96; H, 4.37; N, 7.28%.
EAMPLE 3Q 84{f(2S.3S)-3-((3,5-Bis(trifluoromethvl-Dphenyl)methylox)- 2-nhenvIyipoerdinolmethyll1-1.2.4-triazole dihydrochloride, The title compound was preppred according to the procedure described in Example 16, using the compound of WO 93/21181 PCT/GB193/00788 77 Description 3 as starting material. The free base was treated with ethereal hydrogen chloride to afford the product as a white crystalline solid: nip (free base) 209-210'C Found: C, 49.36; H, 4.57; N, 10.05. Calcd. for C23H2F 6
N
4 O.2HCl: C, 49.56; H, 4.34; N, 10.05%.
(2S -3s)-3-((3.5-Bisaftriflu oromethvl)ph enYI)m ethyl oxv)- 2-Ph envl pin eri dinol methll- 2,3-dihvdr!2-(4H)-3-thioxo-1 .2.4triazole hydrochloride The title compound was prepared according to the procedure doscribed in Example 17, using the compound of Description 8 as a starting material. This afforded the product as a white solid which was treated with ethereal hydrogen chloride to yield the crystalline hydrochloride: ip 154-1571C.
Found: C, 46.59; H, 4.52, N, 9.26; Cl, 5.84. Calcd. for CmH22F 6
N
4 O.HCl.2H 2 O: C, 46.90; H, 4.62; N, 9.51; Cl, 6.02%.
EXAMPLE, 3 2-rf(2S.3S)-3-(3.5-Bi s(trifluoromethvl )ohenvl)methyloxv)- 2-phenylpiperi din olmethll- 1412-toluene sul forvl)i mi dazol e N-(a-ToluenesulfoQnylmidazol e-2-carboxa d ehyde.
Imidazole-2-carboxaldehyde (1.92g) was suspended in dichloromethane (2Oinl). p-Toluenesulfonyl chloride (3.8g) and triethylamine (2.8inl) were added to the mixture which was stirred at room temperature for 12 hours. The resulting slurry was diluted with water and the organic layer was washed with WO 93/21181 WO 9321181PCT/G B93/00788 78 brine, dried (MgSO 4 and filtered. The dichioromethane layer was concentrated in vacuo and the residue was purified by column chromatography on silica using 50% ethyl acetate in hexane as eluent. This afforded the product as a yellow oil which crystallised on standing. 1H NMR (360MHz, ODd 3 d 2.44 (3H, s, ArCH 3 7.31 (1H, d, J=1.5Hz, iniidazole-H), 7.37 (2H, d, J=8.OHz, ArH), 7.83 (1H, d, J=1.5Hz, imidazole-H), 8.00 (2H, d, J=8.OHz, ArH), 9.78 (1H, s, CHO). MS (CIt) m/z 251 2-(HvdroxvmethvDl- -(r;:-toluenesuilfonvl')imidazole The aldehyde of above (3g) was dissolved in methanol (i1ini) and sodium borohydride (114mg) was added portionwise.
This solution was stirred for 10 rain. Methanol was removed in vacuo, and the residue was dispersed between ethyl acetate and water. The organic layer was separated, dried (MgSO 4 and filtered and the solvent was removed in vacuc to afford a crystalline solid. 'H NMR (250MHz, CDCl 3 d 2.42 (3H, s, ArCH 3 4.84 (2H, s, CH 2 7.00 (1H, d, imidazole-H), 7.36 (2H, d, J=8.OHz, ArH), 7.40 (1H, d, imidazole-H), 7.84 (2H, d, J=8.OHz, ArH).
((N-p-To~iuenesulfonyvbimidazol-2-_1Lmathv methanesulfonate The alcohol described in above (12.6mg) was dissolved in dichioromethane (2.5inl) and triethylamine (.07m1). This solution was cooled to 000. Methanesulfonyl chloride (.04m1) was added to the solution dropwise. After stirring for 10 inins the solution was diluted with water and the organic layer was separated, dried (MgSO 4 filtered and the solvent removed in vacuo to yield a white solid which was used in the following reaction without further purification. 1H NMR (250MHz, ODC1 3 d 2.44 (3H, s, ArH), 2.94 (3H, S, SO 2
CH
3 5.51 (2H, s, WO 93/21181 WO 9321181PCT/G B93/00788 79
CH
2
SO
2 7.08 (1H, d, J=l.5Hz, imidazole-H), 7.40 (2H, d, J=8.OHz, ArH), 7.49 (1H, d, J=1.5Hz, iinidazole-H), 7.92 (2H, d, J=8.OHz, ArH).
((N-p-Toluenesulfonyl)imidazol-2-yl)methylnaethanesulfonate (1.6g) was added to a suspension of the compound of Description 3 (2.47g) and potassium carbonate (800mg) in dimethylformamide (l0mi) and the resulting mixture was heated at 10000 for 2h. The mixture was cooled, diluted with water (lO0mi) and extracted with ethyl -acetate (3 x 20m1). The organic extracts were combined, washed with brine, dried (MgSO 4 and concentrated in vacuo. This afforded a colourless oil which was purified by column chromatography on silica using 25-30% ethyl acetate in hexane. This afforded the product as a white crystalline solid which was recrystallised from dichioromethane/petrol: mp 125-126'C 1H NMR (360MHz, DMSO-d 6 d 1.4-1.5 (1H, mi, NCH 2
CH
2 CIIH), 1.5-1.67 (1H, m,
NCH
2
CH
2 CHI 1.8-2.0 (1Hi, m, NCH 2 CHiH), 2.06-2.1 (1H, m,
NCH
2 CHH), 2.35 (3H, s, CO 3 2.4 (1H, mc, NCIHH), 2.7-2.86 (1H, m, NCHH), 3.50 (111, d, J =14.0Hz, CHH-inidazole), 3.56 (1H, brs, CHO), 3.76 (1H, d, J =1.5Hz, CEPh), 4.08 (1H, d, J= 14.0Hz, CHHI-imidazole), 4.09 (1H, d, J 12.0Hz, OCHH), 4.48 (1H, d, J =12.0Hz, 00111), 6.96 (1H, d, J imidazole-H), 7.12 (2H, d, J 8.5Hz, ArH), 7.2-7.3 (3H, m, ArH), 7.34 (1H, d, J 1.0Hz, imidazole-H), 7.46-7.58 (2H, m, ArH), 7.60 (2H1, s, ArH), 7.71 (111, ArH), 7.79 (2H1, d, J 8.5Hz, ArH); MS m/z 638 Found: C, 58.48; H, 4.78; N, 6.72; S, 4.81. Calcd. for C 3 lH 29
F
6
N
3 0 3 S: C, 58.39; H, 4.58; N, 6.59; S, 5.03%.
WO) 93/21181 rc83/78 I'Cl'/GB93/00788 80 [1r2.$)jI((3 2-phenvlniTeridinoimethv1]imidazole dihydrochioride The compound of Example 32 was dissolved in dichloromethane and ethereal hydrogen chloride was added.
The resulting solution was stirred for 30 minutes whereupon the title compound crystallised from solution. This was i emoved by filtration and recrystallised from ethyl acetate/methanol to afford the title compound as a white crystalline compound. 1
H
NMR (360MHz, D 2 0) d 1.61-1.74 (1H, m, CflH), 1.76-1.88 (1H, m, CHH), 2.04-2.21 (2H, m, CO 2 3.07-3.23 (1H, m, NCLjH), 3.41-3.51 (1H, m, NCHJH), 3.66 (1H, s, CHO), 4.09 (1H, d, J=13.OHz, OCHE), 4.25 (1H, d, J=15.5Hz, CHH-imidazole), 4.30 (1H, s, CHPh), 4.39 (1H, d, J=15.5Hz, CHII-irnidazole), 4.55 '1H, d, J=13.OHz, OCHil), 7.1-7.2 (3H, mn, ArH), 7.2-7.3 (2H, mn, ArH), 7.38 (2H, s, imidazole-H), 7.48 (2H, s, ArHl), 7.51 (1H, s, ArH); MS3 m/z 484 Found: C, 50.32; H, 4.92; N, 7.23; Cl, 12.58. Calcd. br C2,.-I2F 6
N
3 O.2HCl.H 2 O: C, 50.18; H, 4.74; N, 7.32; Ci, 12.34%.
EXAMPLEa4 4-r{2S.3S)-3-((3.5-Bis(teifluorometbyl)p~henl)methloxv)- 2-hnyppi urdinolmetbyflimida7,ole dihydrochlorift This was prepared following the procedure described for Example 33 using the compound of Description 3 and 4-(hydroxymethyl)imidazole as starting materials. This afforded the title compound as a white crystalline compound: mp 206-210'C. 1 H NMR (360MHz, D 2 0) d 1173 (111, mn, WO 93/21181 WO 93/1181 cric 1193/00788 -81
NCHXCH
2 CHH-), 1.94-2.06 (1H, m, NCH 2
CH
2 CHIJ), 2.22-2.40 (2H, m, NCH 2
CH
2 3.33 (1H, mc, NCHH), 3.70-3.81 (1H, m, NCHH), 3.97 (1H, brs, CHO), 4.30 (1H, d, J=12.5Hz, OCIH), 4.42(2H, s, NCH 2 -imidazole), 4.50 (1H, s, NCHPh), 4.75 (1H, d, J=12.5Hz, OCHfl), 7.48 (6H, brs, ArH+imidazole-H), 7.74 (2H, s, ArH), 7.95 s, ArH), 8.80 (1H, s, imidazole-H); MS (CI+) in/z 484 Found: C, 50.22; H, 4.82; N, 7.18; Cl, 12.49.
Caled, for C 24
H
23
F
6 N.2HCl.H 2 0: C, 50.18; H, 4.74; N, 7.32; Cl, 12.34% methyl oxy)- 2-phenylpipeii din ol methl- 2.3- divr4H)-3 -xo 1.2.4-triazole hydrochloride Nl-C arbomegthoxv-2-chl oro acetami dra zone Sodium methoxdde (0.032g) was added to a solution of chioroacetonitrile (1.26m1) in anhydrous methanol (I5mi) at 0 0 C. The reaction mixture was stirred at room temperature for 0.5 hour and then neviralised with acetic acid (0.034m1).
Methyl hydrazinocarboxylate (1.79g) was added and the reaction mixture stirred at room temperature for 0.5 hour. The solution was concentrated in vacuo to give the title compound as an orange solid. MS m/z 166.
The compound of Description 1 (0.50g) was stirred with N-carbomethoxy-2-chlkroacetamidrazone (0.19g) and potassium carbonate (0.47g) in dimethylformamide (l0mi) at 7000 for 18 hours. The reaction mixture was then stirred at 140'C for 1 hour. After cooling, the material was partitioned between ethyl acetate and water. The organic layer was washed WO 93/21181 WO 9321181PCT/GB93/0,9788 82 with 'water, dried (MgSO 4 filtered and concentrated. The residue wa .s purified by chromatography on silica using methanol in ethyl acetate as eluent. The product was recrystallised from ethyl acetate/petrol to give the title compound as a white crystalline solid. This was characterised as its hydrochloride salt: mp 168-172'C. MS m/z 500 Found: C, 50.65; H, 4.43; N, 10.22; Cl, 6.71.
Calcd. for C 2
,H
24
N
4 0 2
.,F
6 C1: C, 50.60; H, 4.43; N, 10.26; Cl, 6.49%.
EXAMPLE,36 methyloxv)-2-nhenvhlpineridinolmetby-11-3-(N.N-dimethvy~amn-L 1 .2.4--thiadiazole 5-(Nl.N-Dimethylamino)-1 .3 .4-oxathi azolin-2-one A solution of chiorocarbonylsulfenyl chloride (11.5g) in acetonitrile was added to a suspension of N,N-dimethylurea (25.0g) in acetonitrile (200m1), over a period of 20 minutes. The reaction mixture was stirred for 1 hour at 2300, then filtered.
Methanol (20m1) was added to the filtrate to decompose excess chlorocarbonylsulfenyl chloride. The solvents were removed in vacuo. The residue was purified by chromatography on silica using dichloromethane in hexane to afford the product as a yellow oil. 'H NMIR (250MHz, CDCl 3 d 3.04 (6H, s, (CH 3 2
MS
m/z 164 4 5-(Chloromethvl)-3-(N.N-dimethvlamino)thiadiazole Chloroacetonitrile (1.3m1) in dimethylformamide (imi) was heated to 150-155'C and 1,3,4-oxathiazolin-2-one (1.0g) was added in portions. After minutes the reaction mixture was cooled and concentrated in WO 93/21181 PCTIG B93/00788 83 vacuo. The residue was purified by chromatography on silica using hexane/ethyl acetate as eluent. This afforded the product as a white crystalline solid. 1H NMR (250MHz, CDCl 3 d 3.19 (6H, s, (CU 3 2 4.82 (2H, s, CH 2 MS Mhz 178 methylgxy)-2-phenyl ineri dinoQIm ethyl dim gthyl amino)- 1.2.4-thiadiazole hydrochloride The compound of Description 1 was reacted with 5-(chloromethyl)-3-(N,N-diinethylarnino)thiadiazole according to the procedure described in Example 4. This afforded the title compound as a white solid: mp 160-161'C; 'H NMR (360MHz, DMSO-d 6 TFA) d 1.69-1.87 (2H, mn, CU 2 2.01-2.26 (2H, mn, CHO), 3.10 (6H, s, (CU 3 2 3.22-3.34 (1H, mn, CHH), 3.64-3.72 (1H, m, CkHH), 3.90 (1H, s, CHO), 4.26-4.34 (2H, mn, CU 2 4.61 (1H, d, J=20.0Hz, OCHIH), 4.76-4.82 (2H, mn, 00111 C~jPh), 7.36-7.62 (5H, mn, ArH), 7.87 (2H, s, ArH), 7.99 (1H, s, ArH).
EXAMPLE 37 5-[f(2S,3S)-3-(3 .5 Bis(trifluoromethvl )nhenvl)methloxy)- 2-YnhenylpiD eri din plmethylltetrazQole This compound was prepared according to the procedure described in Example 7, using the compound of Description 9 as a starting material: mp 179-181'C. MS (CIt) m/z 486 (MH{, Found: C, 54.61; H, 4.53; N, 14.37. Calcd. for C22H 2 lF 6
N
5 0: C, 54.43; H, 4.36; N, 14.43%.
WO 93/21181PC/B3008 PCT/GB93/00788 84 EXAMPLE 38 5-r{2S.3S)-3-((3 .5-Bis(trifluoroQmethvyl)uhenvl)methvl oxv)- 2-phenylniTneridinolmethll-2-methltetrazole This compound was prepared according to the procedure described in Example 18 using the compound of Example 37 as a starting material. This afforded the title compound as a white crystallin-e material: mp 158-159-C. MS m/z 500 (MIH+, Found: C, 55.84; H, 4.66, N, 14.13. Calcd. for CmH23F 6
N
5 O: C, 55.31; H, 4.64; N, 14.02%.
EXAM7PLE 39 5-rf(2S.3s)-3-((3 2-phe~nylpiperidinolmethl1-1-methyltetrazole This compound was prepared according to the procedure described in Example 19 using the compound of Example 37 as a starting material. This afforded the title compound as a clear oil. MS 500 Found: C, 55.27; H 4.69; N, 13.67. Calcd. for C23H.F 6
N
5 O C, 55.31; H, 4.64; N, 14.02%.
EXAMPLE 3-rU2S.S-2(2, 2-phenylpiperi din olmethvllnvridazine 3-(Hydroxvmethyl)-1.2-nvridazine 1,2-pyridazine-3-carboxaldehyde (0.89g) Heinisch, E.
Luszczak and M. Pailer, Mh. Chem 104, 1372 (1973)) was dissolved in water and sodium borohydride (0.081g) was added carefully. After 1 hour no starting material was present by TLC WO 93/21181 PCT/GB93/00788 using 10% methanol in dichloromethane as eluent. The water was removed in vacuo to afford a gum. The gum was extracted with dichloromethane, the combined organics were dried (MgSO 4 and concentrated in vacuo to afford the alcohol as a solid, which was used in the following experiment without further purification. 1H NMR (360MHz, CDC13) d 5.04 (2H, s,
CH
2 0H), 7.54 (1H, dd, pyridazine-H), 7.65 (1H, dd, pyridazine-H), 9.17 (1H, dd, pyridazine-H).
3-r{(2S.3S)-3-((3.5-Bis(trifluoromethvl)phenvl) methvloxy)-2-phenvlpiperidino}methvllpvridazine 3-(Hydroxymethyl)-l,2-pyridazine was dissolved in anhydrous dichloromethane under an atmosphere of nitrogen and cooled in an ice/water bath. Triethylamine (0.68ml) and methanesulfonyl chloride (0.378ml) were added and the reaction stirred for 1 hour. No starting material was present by TLC using 5% methanol in dichloromethane as eluent. The solvent was removed in vacuo to afford a solid. The compound of Description 3 (0.48g of free base) was dissolved in dimethylformamide (5ml) and added to the solid followed by potassium carbonate (0.85g). The mixture was heated at for 12 hours then poured into water (75ml), extracted with ethyl acetate (3x40ml), dried (MgSO 4 and concentrated to afford a brown oil. This was purified by chromatography on silica gel using a gradient elution of 10-30% ethyl acetate in petrol.
Further purification was carried out by medium pressure chromatography; elution with 50/50 ethyl acetate/petrol afforded the title compound as a white solid: mp 111-113 0 C. 1H NMR d (360MHz, DMSO-d 6 1.43-1.66 (2H, m, NCH 2
CH
2
CH
2 1.77-1.91 (1H, m, NCH 2 CHH), 2.13-2.24 (2H, m, NCHHCHH), 2.75-2.87 (1H, NCHH), 3.27-3.35 (1H, d, NCHH-pyridazine), 3.57-3.70 (2H, NCHPh CHO), 3.83-3.93 (1H, d, WO 93/21181PC/ 9078 PCT/GB93/00788 86 NCHIH-pyridazine), 4.14 (1H, d, J=l3Hz, OCHHAr), 4.66 (1H, d, J=l3Hz, OC}{llAr), 7.23-7.35 (3H, in, Ar-H), 7.50-7.56 (2H, in, ArH), 7.66 (2H, s, pyridazine-H), 7.71 (2H, s, ArB), 7.94 (1H, s, ArH), 9.11 (1H, mn, 4H) MS m/z 496 2-rf(2S.3S)-3-((3 2-phenv-luineridinolinethvll-1.3 The compound of Description 3 chioroacetamidine hydrochloride 17g) and diisopropylethylamine 17m1) were dissolved in acetoritrile (l0mi) and the resulting mixture was stirred at 60'C, under nitrogen, for 12h. The resulting mixture was evaporated and the residue was dispersed between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate (2x50m1) and dichioromethane (2x50m1). The combined organic fractions were washed with bri ae, dried (MgSO 4 and evaporated. The residue was purified by chromatography on silica using 5% methanol in dichioromethane and gradient elution to 10% methanol, 1% aqueous ammonia in dichioromethane. This afforded the intermediate amidine as a semi-solid material, which was not further purified.
The intermediate amidine (2g) and 1,3,5-triazine (0.35g) were dissolved in acetonitrile (7in1) and heated at reflux for 12h.
The solution was cooled and evaporated and the residue was purified by chromatography on silica using 50% petrol in ethyl acetate as eluent. This afforded the product as a crystalline solid which was recrystallised from hexane: mp 117-119'C. 'H NMR (360MHz, DMSO-d 6 5 1.41-1.60 (2H, mn, NCH 2
OH
2
CH
2 1.81- 1.94 (1H, nm, NCH 2 CHH), 2.12-2.21 (1H, mn, NCH 2 CHH9, 2.34- WO 93/21181 X'/O 9/21181PT/GB193/00788 87 2.41 (1H, mn, NCHH), 2.99-3.06 (1H, in, CHH), 3.26-3.30 (1K, NCflH-triazine), 3.61. (1H, bs, CHO), 3.71 (1H, bs, CHPh), 3.80 (iR, d, J=15.OHz, NCH-H-triazine), 4.08 (1H, d, J=13.OHz, OCHHAr), 4.63 (1H, d, J=13.0Hz, OCHIJAr), 7.18- 7.29 (3H, mn, ArH), 7.48-7.52 (2H, m, ArK), 7.68 (2H, s, ArK), 7.13 (1H, s, ArH), 9.20 (2H, s, triazine-ID. MS (CIt) ni/z, 497 100%).
EXAMPLE 42 5-r{(2S .3S)-3-((3-t-Butvl -5-methyin-henyi )methloxvc)-2- (phenypiijeridinolmethll-2.3-dihydro-3-oxo-1.2.4-triazle The compound of Description 10 was reacted according to the procedure described in Example 35 to afford the title compound as a crystalline solid: inp 185-187*C. 1K NMR (36OMiHz, CDC1 3 5 1.22 (10H, m, C(CHA) NCH 2
CH
2
CHH),
1.38-1.58 (2H, in, NCH 2 CHHCKH), 1.98-2.26 (5H, mn, CH, NCHKCKII), 2.89 (1H, d, J=15.O~z, NCHHi-triazole), 2.96-3.04 (1K, in, NOHII), 3.29 (1H, bs, CHO), 3.56 (1H, bs, CHPh), 3.65 (1K, J=15.OHz, NCKIH-triazole), 4.13 (1H, d, J=12.0Kz, OCHHKAr), 4.28 (1K, d, J=12.OHz, OCKIJAr), 6.53 (1H, s, ArK).
6.89 (1H, s, ArH), 7.00 (1K, s, ArK), 7.26-7.38 (3K, mn, ArK), 7.45-7.50 (2H, mn, ArK). MS (CIt) zm/z 435 Found: C, 72.10; H, 7.94; N, 13.05. Calcd for C 26 H34N 4
O
2 C, 71.86; H, 7.89; N, 12.89%.
EXAMPLE43 2-[1(26S.3S)-3-((3.5-Dichloronhenl)methyloxvc)-2- (phenylpiperidinolmgthyllimidazol e dihydrochiorid e WO 93/21181 WO 9321181PCT/G B93/00788 88 The compound of Description 11 was reacted according to the procedure described in Examples 32/33, to afford the title compound: mp 129-131'C. 'H NMR (360MHz, DMSO-d.) 5 1.84- 1.98 (2H, m, NCH 2
CH
2
CH
2 2.14-2.24 (1H, m, NCH 2
CHH),
2.44-2.62 (1H, m, NCH 2 CHH), 3.09-3.20 (1H, m, NCHH), 3.69- 3.86 (2H, In, NCHHI CHO), 4.25 (1H, d, J=13.OHz, OCHHAr), 4.53 (1H, d, J=13.OHz, OCHIHAr), 4.83 (iN, d, J=15.0Hz, NCHjH-iinidazole), 4.91 (1H, bs, CH!Ph), 5.14 (1H, d, NOHIH-imidazole), 7.16-7.48 (iON, m, ArH), 7.84 (1H, bs, N-H).
MS mlz 415 Found: C, 50.71; H, 5.28; N, 8.05.
C
22
H
23 IC1 2 NO.2HCl.2H 2 0 requires: C, 50.30; H, 5.56; N, 7.99%.
EXAM7PLE 44 5-ru(2S.3s')-3-((3-Clhloro-5-methyvluhenl)methylox)-2phenlpiperidinQ~methy11-2.3-dihydro-3-oxo- 1.2.4-triazole The compound of Description 12 was reacted according to the procedure described in Example 35 to afford the title compound as a white crystalline solid: mp 227-228'C. 'H NMR (360MHz, DMSO-d 6 8 1.35-1.55 (2H, m, NCH 2
CH
2 CHj 2 1.78- 1.88 (1H, m, NCH 2 CHH), 2.06-2.13 (2H, m, NCHHICHHD, 2.20 (3H, s, 2.73 (1H, d, J=i4.OHz, NCHjH-triazole), 2.89 (1H, d, J=11.OHz, N-0HIJ), 3.32-3.39 (iN, m, CHO), 3.42 (iH, d, J=14.OHz, NCBHHtriazole), 3.47 (iN, s, CEH), 3.86 (iN, d, d=12.OHz, OCENH), 4.29 (IN, d, J=12.0Hz, OCHH), 6.65 (iN, s, ArH), 6.79 (iN, s, ArN), 7.07 (iN, s, ArH), 7.25-7.34 (3H, m, ArN), 7.51-7.53 (2H, M, ArN). MS mhz 412 Found: C, 64.30; H, 6.13; N, 13.67. C2H2,CN 4
O
2 requires: C, 63.99; H, 6.10; N, 13.57%.
WO 93/21181 PCI/GB93/00788 -89- EXA RLE -r5(2S3S)-3-((35-Bi s(trifluoromethvl )nhenvl )methvloxv- 2-(diphenvlmethl)pdvolidinolrnethll]-2 .3-dihdro-3-oxo- 1.2.4triaml The compound of Description 13 was reacted with Ncarbomethoxy-2-chloroacetamidrazone according to the procedure described in Example 35 to afford the product as a white crystalline solid. 'H NM7R (250MHz, CDC 3 5 1.92 (2H, 2.62 (1H, 2.90 (1H, d, J=l5Hz), 3.14 (2H, 3.78 (2H, 4.08 (1H, 4.28 (2H, 7.1-7.4 (10H, m, ArH), 7.48 (2H, s, ArH), 7.77 (1H, s, ArH). MS mlz 577 100%).
EXAMPLI 46 5-rf(2R.3S .5-Bis(trifluoromethvl)Dhenl )mpethloxv- 2-(diphenvlinethvl)vrrolidinolmethvll-2,3-dihvdr-3-oxo-1.2.4t~iazole The compound of Description 14 was reacted with Ncarboinethoxy-2-chloroacetamidrazone according to the procedure described in Example 35 to afford the title compound as a white crystalline solid. 'H NMR (360M1z, CDCI.) 5 2.00- (2H, 2.69 (IH, 3.03 (1H, t, J=7.5Hz), 3.26 (1H, d, J=14.5Hz), 3.32 (111, d, J=14.SHz), 3.68 (2H, 3.76 (1H, d, 4.31 (1H, d, J=12.5Hz), 4.42 (1H, d, J=12.5Hz), 7.40- 7.19 (10H, m, ArH), 7.64 (2H, s, ArH), 7.76 (1H, s, ArH). MS r/z 577 100%).
WO 93/21181 PCT/GB93/00788 EXA~TELE 47 3-Ii2S .5-Dichlor!ihenyl )methvloxrv)Y2- (dignevlmetvl )pd olidinolmethll- 1.2.4-tniazole The compound of Description 15 was reacted with Nformyl-2-coloroacetamidrazone according to the procedure in Example 16 to afford the title compound as a crystalline solid: mp 128-129 0 C. 'H NMR (360MHz, DMSO-d 6 5 1.65 (1H, brs), 1.76 (11, brs), 3.10 (2H, 3.61 (1H, d, J=12.OHz), 3.92 (1H, brs), 4.01 (1H, brs), 4.22 (2H, 7.02 (2H, d, J=1.8Hz, ArH), 7.10 (1H, m, ArH), 7.14 (3H, m, ArH), 7.22 (211, t, ArH), 7.39 (2H, d, ArH), 7.46 (3H, m, ArH). MS m/z 493 Found: C, 65.95; H, 5.22; N, 11.33. Calcd for C 27
H
26 C1 2
N
4 0: C, 65.72; H, 5.31; N, 11.35%.
EXA ALE 48 5-rf(2S.3S)-3-((3-t-Butyl--5-chloron~henl)methylx)-2.
phenyDiperidino methvll-2.3-dihvdro-3-oxo- .2.4-triazole The compound of Description 16 was reacted with Ncarbomethoxy-2-chloroacetamidrazone, according to the procedure described in Example 35, to afford the title compound as a white crystalline solid: mp 181-182 0 C. MS m/z 455 100%). Found: C, 65.99; H, 6.87; N, 12.31. Calcd for
C,H
31
CN
4 O: C, 66.47; H, 6.91; N, 12.45%.
WO 93/21181 WO 9321181PCr/GB93/00788 91 EXAELE 49 5-[{(2S.3S)-3-((3-Bis(trifluoromethvfl~henvflmethvl oxv-2yhnlpineridinolmethvll-2.3-dihvdro-3-oxo- 1.2 .4-triazole hdohIrd The title compound was prepared according to the procedure described in Examnple 35, using the compound of Description 3 as starting material. The hydrochloride salt was recrystallised from ethyl acetate-methanol to give a white crystalline solid: mp 265-266'C. 'H NMR (360MHz, DMSO-d. TFA) 5 1.75-1.95 (2H, I, CHA) 2.04-2.30 (2H, mn, CH 2 3.20-3.32 (lE, mn, NCHH), 3.58-3.69 (lE, mn, NCHII), 3.90 (lE, d, NCHH-triazole), 3.93 (1H, s, CHO), 3.94 (lE, d, J=15.O~z, NCHIJ-triazole), 4.30 (1H, d, J=12.O~z, OCHH), 4.73 (1H, bs, CliPh), 4.80 (1H, d, J=12.OHz, ORE-), 7.42 (3H, brs, ArE), 7.56 (2H, brs, ArH), 7.89 (2H, s, ArI-), 7.95 (lE, s, ArE).
MS nI/z 501 Found: C, 51.41; H, 4.15; N, 10.58; Cl, 6.46. Calcd for CmH22 6
N
4 O.HCI: C, 51.45; H, 4.32; N, 10.44; Cl, 6.60%.
.5-Bis(trifluoromethvl)pbenvl )methyloxv)- 2-phenvliperid' olnetl.1.-1ðl-1 .2.4-triazole hydrochloride The compound of Example 30 (0.5g) was dissolved in methanol in a tube. Sodium (0.03g) and iodomethane (0.075ni1) were added and the container was sealed. The resulting solution was heated at 6500 for 1h, cooled and evaporated. The residue WO 93/21181 PCT/GB93/00788 92 was suspended between water and ethyl acetate. The organic layer was dried (MgSO 4 filtered and the solvent removed in vacuo. The residue was purified by chromatography on silica using ethyl acetate as eluent. This afforded the product as a colourless oil, which was converted to the hydrochloride salt by addition of ethereal hydrogen chloride. The salt was recrystallised from ether/petrol. 1 H NMR (360MHz, DMSO-d 6 8 1.70-1.84 (2H, m, CHA) 2.12-2.51 (2H, m, CR 2 3.36 (3K, s,
NCR
3 3.52 (1K, brs, CHlHN), 3.73 (1H, brs, CH]HN), 3.87 (1H, s, CH0), 4.25 (2K, m, CHH-triazole), 4.28 (1H, d, OCHRAr), 4.65 (1H, brs, NCHPh), 4.78 (1H, d, OCHHJAr), 7.41 (3H, s, ArK), 7.60 (2H, brs, ArK), 7.93 (2H, s, ArK), 7.96 (1H, s, ArH), 8.05 (1K, s, CH=NH (triazole)); MS (CIt) m/z 499 EXAMPLE 51 3-rf(2s.3s)-3-((3.5-Bis(trifluorometh1 )Dhenyl )methvloxv)- I.2.4-oxadiazole hydrochloride The compound of Description 3 was reacted with 3- 1,2 ,4-oxadiazole according to the procedure described in Example 26. The product was characterised as its hydrochloride salt: mp 88-90'C. 'K NMR (360MHz, CDC1 3 free base) 5 1.50-1.64 (2K, m, CR 2 2.06-2.22 (2K, m, CR 2 2.44-2.56 (1K, m, CHHN), 3.18-3.28 (1K, m, CHiHN), 3.60 (1K, s, CR0), 3.66-3.74 (1K, d, J=15.O~z, NCHKoxadiazole), 3.78 (1K, s, CKPh), 3.88-3.98 (1K, d, NCKIJ-oxadiazole), 4.02-4.10 (1K, d, J=12.O~z, OCHjHAr), 4.44- 4.52 (1K, d, J=12.O~z, OCKIHAr), 7.28-7.64 (10K, m, ArK), 7.68 (1H, s, ArK), 8.08-8.18 (2K, m, ArK); MS rnlz 562 WO 93/21181 WO 9321181PCI'/GB93/00788 93 3-rf ethl- 1.2,4triazole hydrochloride Sodium methoxide (.001g) was added to a solution of the compound of Example 17 (.10g) in ethanol (5mi) and the mixture was heated at reflux for 10 min. Methyl iodide (0.Ol2ml) in ethanol (lxnl) was added and the mixture was heated at reflux for 3h. The solvent was then removed in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was dried (MgSO 4 and concentrated in vacuo. The residue was purified by chromatography on silica using 50% ethyl acetate in petrol as eluent. The compound was isoilated as the hydrochloride salt by treatment of the free base with methanolic hydrogen chloride: mp 105-107'C. 1H NMR (360MHz, DMSO-d 6 TEA) 5 1.73-1.91 (2H, m, CH 2 2.05-2.20 (1H, m, CHH), 2.21-2.30 (1H, m, CIII), 2.63 (3H, S, CE 3 3.28 (1H, m, NCHHCH 2 3.73 (1H, m, NCHHCH 2 3.92 (li, brs, CHO), 4.10 (2H, dd, J=2OHz, 14.5Hz, NCH 2 4.29 (1H, d, J=l3Hz, OCHIH), 4.68 (1H, s, CE7Ph), 4.79 (1H, d, J=l3Hz, OCHIJ), 7.42-7.48 (3H, m, ArH), 7.57 (2H, brs, ArE), 7.88 (2H, s, ArE), 7.95 (1H, s, ArH). MS mn/z 531 Found: C, 51.29; H, 4.62; N, 9.79; Cl, 6.06. Calcd for C 29
H
24
F
6
N
4 0S.HCI: C, 50.84; H, 4.44; N, 9.88; Cl, 6.25%.
EXAMPLE 5-rf2S.S-3(3.-ihoohnl)ehox)2 nhenvlpinoeridinolmethvll-2.3-dihydro-3-o2xo-1 .2.4-triol 93/21 181 rPrn'G 1193/00788 94 The compound of Description 11 was reacted according to the procedure described in Example 35 to afford the title compound which was recrystaliised from hot diinethylforinamide: mp >2200C. 1H N7MR (360MHz, DMSO-d 6 353K) 8 1.45-1.58 (2K, mn, CO, 1.81-1.95 (1H, in, CHH), 2.02- 2.12 (1H, mn, CKI.E), 2.18 (1H, dt, J=2.5, 11.5Hz, NCHHCH2), 2.82 (1K, d, J=14.2Hz, NCHH), 2.94 (1H, brd, NCHHCH 2 3.40 (1K, d, J=14.5Hz, NCKHj), 3.45 (1K, d, CHG), 3.52 (1K, d, CH{Ph), 3.91 (1K, 0, T=12.5Hz, OCUK), 4.34 (1K, d, 0CHHj), 7.21-7.37 (5H, m, ArKl), 7.47-7.55 (3H, mn, ArK).
EXAMLE54 ehxpey)methyloxv)-2uhenvlineridinolmethlljvridinium dichlorid.
The compound of Description 17 was reacted with 4picolyl chloride according to the procedure described in Example 4 to afford the title compound. 'H NMR (250MHz, ODd 3 5 1.42- 1.61 (2K, mn, NCH 2
CH
2 CHj 2 1.98-2.18 (3H, mn, NCL-IHCH 2 2.87-3.04 (2K, in, NCHK-pyridine NUHdH), 3.31-3.39 (1K, mn, CKO), 3.48-3.54 (1H, in, NCHPh), 3.86 (1H, d, J=l4Kz, NOKIHpyridine), 3.93 (3H, s, 00K 3 4.06 (1H, d, J=ll~z, OCIIKAr), 4.30 (1K, d, J=llHz, OCKIJAr), 7.12 (1H, mn, ArK), 7.22-7.39 (6K, in, ArK), 7.45-7.56 (2H, dd, pyridine-K), 7.77 (1K, bs, ArK), 7.85-7.92 (1K, ArH), 8.46-8.55 (2H, dd, pyridine-H), MS (C1+) in/z 417 Found: C, 64.10; K, 6.06; N, 5.62.
C
26 H2AN 2
O
3 .2KO1 requires: 0, 63.80; K, 6.18; N, 5.72%.
WO 93/21181 IPCf/GB193/00788 E 4-rf(2R*.3R*)-3-((3-Carboxamidonhenvl)methvloxy)-2- 91ienyT~iperidino~mehv~pvijtdjn& The compound of Description 18 was reacted with 4picolyl chloride according to the procedure described in Example 4 to afford the title compound. 'H NMR (360MHz, CDC 3 1.43- 1.56 (2H, m, NCH 2
CH
2 Ca 2 2.00-2.17 (3H, m, NCHHCH 2 2.88-3.04 (2H, m, NCHH NCHHAr), 3.35 (1H, m, CHO), 3.54 (1H, bs, CHPh), 3.83 (1H, d, J=14.5Hz, NCHHAr), 4.08 (1H1, d, J=12z, OCLTHAr), 4.35 (11, d, J=l2Hz, OCHHAr), 5.6-6.16 (21, bs, CONl 2 7.11-7.74 (11H, m, ArH), 8 48 (2H, d, J=4Hz, pyridine-H). MS (CIt) mlz 402 EYU PLE U 5-rf(2R*.3R*)-3-((2-Methoxv-3-nitroh envbmethvl-oxy2uhenvlnipridinolmethyil-3-methvl-1.2.4-oxadiazole The compound of Description 19 was reacted according to the procedure described in Example 2 to afford the title compound. 'H NMR (360MHz, CDC1 3 8 1.48-1.64 (2H, m,
NCH
2
CH
2 Ca 2 2.09-2.25 (2H1, m, NCH 2
CH
2 2.37 (311, s, CHl), 2.41-2.51 (111, m, NCHH), 3.12-3.20 (1H, m, NCHH), 3.59 (11, bs, CIO), 3.64 (111, bs, CHPh), 3.73 (11, d, J=16Hz, NCHHhet), 3.80 (31, s, OCH3), 3.91 (11, d, J=16Hz, NCHIJ-het), 3.98 (111, d, J=13Hz, OCLIHAr), 4.48 (1H, d, J=13Hz, OCHHiAr), 6.78 (11, d, J=9Hz, 7.22-7.37 (3H, m, ArH), 7.48-7.54 (2H, bd, Arfi), 8.09-8.14 (11, dd, J=9Hz, J=3Hz, ArH), 8.15-8.18 (11, d, J=3Hz, ArH). MS m/z 439 (M+1I, 100%).
WO 93/21181 WO 9321181PCT/G B93/00788 96 methlox)-2 Dhenvlliperidino~methy_]- 1 .2.4-oxac~iazole The compound of Description 20 was reacted according to the procedure described in Example 1 to afford the title compound. 'H NMIR (360MHz, CDC1 3 5 1.41-1.60 (2H, in,
NCH
2
CH
2
CH
2 2.13-2.24 (2H, mn, NCH 2
CH
2 2.31 (1H, in, NCHH), 3.12-3.21 (IH, m, NCH~H, 3.39 (1H, d, J=16Hz, NCHlHhet), 3.47 (1H, m, CHO), 3.56 (1H, mn, NCUPh), 3.61 (3H, s, OCH3), 3.82 (1H, d, J=l6Hz, NCkiH-Het), 4.13 (1H, d, J=l3Hz, OCTIHAr), 4.34 (1H, d, J=l3Hz, OCHHAr), 5.17 (2H, bs, Nil 2 6.38 (1H, bs, ArH), 6.43-6.48 (1H, in, ArH), 6.54-6.58 (1H, d, J=8.5Hz, ArH), 7.26-7.58 (3H, mn, ArH), 7.48-7.54 (2H, mn, ArH).
6-[ru2S.2S)-3-t( 2-henyvlnipridinolmethylluracil The compound of Description 3 was reacted with 6- (chloroinethyl)uracil following the conditions described in Example 4 to afford the title compound. 'H NMR (360MHz, CDC1 3 1.52-1.71 (2H, mn, NCH 2
CH
2 Cil 2 1.99-2.25 (3H, mn,
NCHHCH
2 2.69 (lE, d, J=l6Hz, NCHH-uracil), 2.92-3.01 (1H, mn, NCHH), 3.38-3.40 (1H1, mn, CHO), 3.52-3.62 (2H, mn, NCHHuracil NCHIPh), 4.08 (1H, d, J=l2Hz, OCHjHAr), 4.49 (1H, d, J=l2Hz, OCIHAr), 5.41 (1H, s, HA), 7.32-7.40 (5H, mn, ArH), 7.50 (2H, s, 7.56 (1H, s, 8.64-9.04 (2H, bs, NiH NH). MS WO 93/21181 PCT/GB93/00788 -97m/z 528 100%). C 25 ,H23N 3 0,F, requires C, 56.93; H, 4.40; N, 7.97%. Found C, 57.16; H, 4.03; N, 7.88%.
EXA MLE59 3-frf(2R*.3R*)-3-((3,5-Bis(trifluoromethvl)phenv1) methyQloxy)-2-2henvlpineridinol1methyll-5-carboxamido-1.2.4triamlIe The compound of Description 1 was reacted with 2-chloro- N-carboxanmidoacetamidhydrazone according to the procedure described in Example 35 to afford the title compound as a white solid: mp 1950C. u. (KBr) 1680cm- 1 Found: C, 55.14; H, 4.58; N, 12.82. Cald for C2H2FNO 2 C, 54.65; H, 4.40; N, 13.27%.
EXAMPLE 3-rf(2R*.3R*)-3-((3,5-Bis(trifluoromethll)henyl) methvyloxy)-2-phenv1iueridinolmethyll-5-cyano-1.2.4-triazole The compound of Example 59 (0.61g) was dissolved in chloroform (10ml) and the resulting solution was cooled to 0 0
C
in an ice bath. Triethylamine (2ml) was added followed by phosphorus oxychloride (1.2ml), dropwise. The solution was stirred at room temperature for lh. The solvent was removed in vacuo and the residue was dispersed between chloroform and sodium hydrogen carbonate. The organic layer was washed with brine, dried (MgSO 4 filtered and concentrated in vacuo. The residue was purified by column chromatography on silica using 30% petrol in ethyl acetate as eluent. The product was isolated WO 93/21181 WO 9321181PCT/GB193/00788 98 as the hydrochloride salt using ethereal hydrogen chloride: mp 81 0 C. MS mlz 510 EAMPL 1 .5-Dichlorophenyl.)methvloxv)-2phen_ j~rsjol eth1 I .2.-trazol N-ForMl-2-chloroproipionamidohydrazone Sodium methoxide (.162g) was added to a solution of 2chioropropionitrile (10.5g) in anhydrous methanol (150m1) at 00 C. The reaction mixture was stirred at room temperature for 1h, then neutralised -with acetic acid (.18ral). N-Formylhydrazine (7.04g) was added and the mixture was stirred overnight. The resulting pink solution was concentrated in vacuo to give the title compound as a pink solid.
The compound of Description 11 (5.9g) was dissolved in dimethylformamide (46m1) and N-forinyl-2chioropropionainidohydrazone (3.5g) was added, followed by potassium carbonate The mixture was stirred at room temperature for 2h, then. diluted with xylene (150m1) and heated at refiux for 2h. When cool, the mixture was filtered and concentrated in vacua- to afford a brown residue. Crude IH NM indicated a mix'ure of diastereoisomers in 3:1 ratio. The residue was purified by medium pressure chromatography (Lobar) on silica using 4% methanol in dichloromethane as eluent. The first product eluted, diastereoisomer 1, was isolated as a foam which was recrystallised from ether-hexane: mp 105-10711C 1 H NMR (360MHz, CDCl 3 8 1.31 (3H, d, J=-7.0Hz, -CHCH9), 1.52-1.59 (2H, m, NCH 2 CHHCHH), 2.02-2.05 (1Hi, m, NCH 2 'CHH), 2.05- 2.16 (iN, mn, NCH 2
CH
2 CHHi), 2.51 (iN, t, J=11.5E1z, NCkiI), WO 93/21181 WO 9321181PCT/GB93/00788 99 2.62 (1H, mn, NCHIJ), 3.56 (1H, s, CHO), 3.77 (1H, s, CH-Ph), 3.99 (1H, d, J=12.OHz, OCHH), 4.22 (1H1, q, J=7.OHz, -CHJCH 3 4.30 (1H, d, J=12.OHz, OCHTJ), 6.89 (2H, d, J=2.0Hz, ArH), 7.21 (1H, t, J=2.OHz, ArH), 7.3-7.4 (3H, m, ArH), 7.40-7.47 (2H, ArH), 7.89 (1H, s, triazole-2H). MS inlz.
3-.(IR1-LI2S3S)-3-((3 .5-Dichiorophenvi )methvloxv)-2-: Dhenvlnir2eridino~ethvll- 1.2,4-triazole The second product isolated from the column described in Example 61 was recrystallised from ether to afford the title compcund whose stereochemistry was established from 'H NMR n.O.e. experiments: mp 132-134'C 1H NMR ('360M7Hz, DMSO-d 6 1.06-1.15 (1H, mn, NCH 2
CH
2 CHH), 1.35 (3H, d, J=7.OHz, CHC~i 3 1.34-1.42 (1H, mn, NCH 2 CkiIF), 1.66-1.85 (2H, m, NCflT{CHH), 1.98-2.02 (1H, mn, NCH 2 CH2CHfl), 3.01-3.03 (1H, d, J=1O.5Hz, NCIIH), 3.39 (1H, s, CHO), 3.86 (1H, d, J=13.OHz, OCHIH), 3.98 (1H, q, J=7Hz, CHCH 3 4.33 (1H, d, J=13.OHz, OCHHj), 6.92 (iH, d, J=2.OHz, ArH), 7.26-7.46 (6H, mn, ArH, EXAMPLE 63 3-f2 S-q(22D ehlhny-mtyoxx-2uhenvlpin)eridinolmethyl- I 1.2.4-triazole Following the method described in Example 16, the compound of Description 23 (100mg) was reacted with 69mg of N-formyl-2-chloroacetaniidohydrazone, to give the title compound. 1H NMR (CDCl 3 8 1.50 (2H, in), 1.94 (3H, WO 93/21181 PCr/GB93/00788 -100- 2.35 (3H, 2.2 (3H, 3.02 (1H; 3.45 (2H, 3.57 (1H, s), 3.95 (1H, hr 3.95 (1H, d, J=IlHz), 4.26 (11, d, J=llHz), 6.86 (1H, d, J=7Hz), 7.06 (1H1, d, J=7Hz), 7.2-7.5 (6H, 7.7 (1H, br The following compounds were prepared by the procedure described in Example EX6YPLE 64 L-j (..3S)-3-23-Dimeihvlphenyl methvyoxv)-2phenvliperiinlmethvll-23-dihdro-(4H)-3-xo-1 ,2.4-triazole The compound of Description 23 was used as starting material. 'H NM7R (CDC 3 5 1.4-1.55 (2H1, 1.89 (3H, 1.9- 2.2 (3H, 2.15 (3H, 2.91 (1H, d, J=l5Hz), 2.95 (1H, i), 3.28 (1H, 3.50 (1H, 3.66 (11, d, J=15Hz), 4.06 (1H, d, J=l2Hz), 4.29 (1H, d, J=12Hz), 6.77 (11, d, J=7Hz), 6.9 (111, t, J=7Hz), 6.97 (1H, d, J=7Hz), 7.2-7.45 (5H, m).
E XA E 5-rff2S.3S)-2-Phenvyl-3-((3-(trifluoromehv1)1henv1) methyloxv)niuieridinlmethll-3-oxo-1 .2.4-triazole The compound of Description 21 was used as starting material. 'H N7R (CDC1 3 8 1.5 (2H, 1.9-2.2 (3H, 2.91 (11, d, J=l5Hz), 3.0 (1H, 3.3 (111, 3.5 (1H, 3.64 (11, d, 4.12 (11, d, J=l2Hz), 4.41 (1H, d, J=12Hz), 7.0-7.45 (9H, 9.9 (2H, hr s).
WO 93/21181 PCT/GB93/00788 10 EXAMPLEU6 5-rf(2S,3S)-3-((3.4-Dichlorphenvl )methvl oxv)-2- Pihenylpiueridinm ethyv11-2-oxo- 1.2.4-triaz21g The compound of Description 22 was used as starting material. 'H NMIR (CDC1 3 5 1.5 (2H, 1.85-2.2 (3H, 2.88 (1H, d, J=15Hz), 3.0 (1H, in), 3.27 (IH, 3.48 (1H, 3.67 (1H, d, J=l5Hz), 4.05 (1H, d, J=l2Hz), 4.35 (1H, d, J=12Hz), 6.7 (1H, hr d, J=7Hz), 6.95 (1H, hr 7.16 (1H, d, J=7Hz), 7.2-7.45 9.8 (1H, hr 10.5 (1H, hr s).
XAMPLE 67 5-r(2S.3S)-3-((3-t-BuLtvh1-henl)methvloxy)-2phenvInT~ieridinomethy1-3-oxo-1.2.4-triazole The compound of Description 24 was used as starting material. 'H NMR (CDC13) 5 1.23 (91, s, 1.40-1.51 (2H, n, Cl-,f 1.82-1.85 (1H, i, CLI-H), 2.01-2.14 (2H, mn, CIIH and NCHjH), 2.74 (1H, d, J=l4Hz, NCHH-triazolone), 2.88 (1H, i, NCHrj), 3.38 (11, d, J=l4Hz, NCEHi-triazolone), 3.40 (1H, in, NCHCaO), 3.51 (1H, s, NCHCHO), 3.85 (1H, d, J=l2Hz, OCH), 4.23 (1H, d, J=l2Hz, OCHH), 6.80-6.82 (1H, n, ArH), 7.06-7.34 (6H, i, Ari), 7.53-7.55 (2H, i, ArH), 11.16 (1H, s, NH), 11.24 (1H, s, NH); MS (CI) n/z 420 Found: C, 71.51; H, 7.51; N, 13.08. Cacid. for C 25
H,
2
N
4 0: C, 71.40; H, 7.67; N, 13.32%.
WO 93/21181 WO 9321181PCT/GB93/00788 102 E2IBIE 68 5rfl(2R*.3R*)-3-((3 .5-Dimethvlp~henvl)methvloxv)-2- DhenyltiTneldinolm ethyfl- 3 -oxo- 1. 2.4-tri azol e The compound of Description 25 was used as starting material. 'H NMR (360MHz, DMSO-d 6 5 1.41-1.47 (2H, mn,
OH
2 1.81-1.85 (1H, mn, CHIH), 2.05-2.11 (2H, mn, 0111 and NCHH), 2.15 (6H, s, OH 3 2.72 (IH, d, J=l4Hz, NCHHtriazolone), 2.86-2.89 (11, mn, NCHH), 3.36 (1H, d, CHO), 3.40 (111, d, J=l4Hz, NCHH-triazolone), 3.44 (1H, brs, CHPh), 3.82 (1H, d, J=l2Hz, 001111), 4.20 (1H, d, J=l2Hz, 0CHIJ), 6.50 (2H1, s, ArH), 6.79 (1H1, s, AxH), 7.25-7.33 (3H1, mn, ArH), 7.51-7.53 (2H, m, ArH), 11.16 (1H, s, NH), 11.25 (1H1, s, NHl), (2S.3S)-3- i .9ri fluorometv)phenymetyox)-2phenyl-1-(34(1.2.4" oudine 1-Hydroxybenzotriazole hydrate (308mg), 1-(3dinaethylaminopropyl)-3-ethylearbodimide hydrochloride (436mg), triethylamine (0 .3in1) and 1,2,4-triazoie-3-carboxylic acid (129mg) were dissolved in dimethylformamide (5mi) and the resulting mixture was stirred for 15 min. The compound of Description 3 (0.5g) was added and the resulting mixture was stirred at room temperature for 12h. The reaction mixture was diluted with water (lO0ini) and the product was extracted into ethyl acetate (3 x S5ini). The organic fractions were washed WO 93/21181 WO 93/21181PC1/G B93/00788 103 successively with citric acid (aqueous), water, potassium carbonate and brine, then dried (MgSO 4 filtered and concentrated. The residue was purified by column chromatography on silica using 70% ethyl acetate in hexane as eluant. The product was recrystallised from ethyl acetate/petrol to afford a crystalline white solid: mp 77-791C. MS m/z 478 100%).
EXAMP'LE .5-Bis(trifluoromethl)phenl)metlhvloxv-l1.
(1-oxo-2-1nvrid-4-vl )ethvl-2-nhenvluineridinium hvdroc~hIde The compound of Description 3 was reacted with 4pyridylacetic acid following the procedure outlined in Example 69. This afforded a colourless oil which was treated with ethereal hydrogen chloride and the solid obtained was recrystallised from benzenelhexane. MS rn/z 523 (MI++1, 100%). Found: C, 54.67; H, 4.86; N, 4.66; Cl, 6.16. Calcd. for
C
27 H2AF 6
N
2
O
2 .2H 2 O: C, 54.50; H, 4.91; N, 4.70; Cl, 5.96%.
(SS)(3 'M Bi(trifluoiromethvI )nhenvl )methvLoxy-l- (2-oxo-2-ydvr d-3-vl )ethyj -2-phepnyvhpin~erdine 3-(Bromoacetyl)pyridinium hydrobromide (336mg) was dissolved in dimethylformamide (3m1) and to this solution was added the compound of Description 3 (440mg) followed by potassium carbonate (550mg). The mixture was stirred at room temperature for 2h, diluted with water and extracted into ethyl WO 93/21181 I"rri 193/00788 104 acetate. The organic phase was washed with brine, dried (MgSO 4 and evaporated. The residue was purified by chromatography on silica using 70% ether in hexmie as eluant and further purified by medium pressure chromatography (Lobar) using ethyl acetate in hexane (60:40) as eluant. IH NMR (250MHz, DMSO-d 6 5 1.4-1.6 (2H, in), 1.8-1.98 (1Hi, in, CHH), 2.06-2.2 (1H, in, CHIJ), 2.5-2.6 (1H, in), 2.9-3.0 (1H, in), 3.54 (1H, d, NCNIHCO), 3.62 (1H, brs, CHO), 3.74 (1H, d, CH-IPh), 3.84 (1H, d, OCI-U), 7.2-7.3 (2H, mn, ArH), 7.38-7.5 (3H, in, ArH), 7.5 (ili, dd, pyr-H), 7.85 (2H, s, Arli), 7.92 (il, s, Arli), 8.14 (1H, dt, pyr-li), 8.62 (ili, dd, pyr-li), 8.94 (1H, d, pyr-H).
EXAMPLE 72 1S)-1-f( methloxv)-2-phenylpineridino) ethyl]-i,2.4-triazole This was prepared from the compound of Description 3 and N-forinyl-2-chloropropionamidohydlrazone following the procedure described in Example 61. The first compound to be eluted from the column (using 3% methanol in dichioromethane as eluant on silica) was isolated and characterised as the title compound: mp 66-6800. MS m/z 499 100%).
EXAT=a 3-r( 1R)-1.4(2S.3S)-3-((3.5-Bis(trifluoromethvl.)Dhenv) mnethl oxy)-2-phenvlpioeri din o)ethyll 1 .2,4-tri azol e The second product isolated from the column described in Example 72 was recrystallised from ethyl acetate/hexane to WO 93/21181 PCT/GB93/00788 -105afford the title compound: mp 108-111'C. MS n/z 499 100%).
EXAMPEL7A 54(1S)-1i1(2S.3S)-3-((3.5-Bis(trifluoromethvornhev methvloxv)- 2-rDhenvlnineridinolethll-2,3-dihdro- 3-oxo-1 2.4triazle This compound was prepared according to the procedure described in Example 35 using the compound of Description 3 and N-carbomethoxy-2-chloropropionamidohydrazone (CICH(CH3)C(=NH)NHNHCOOCH 3 as starting materials. 'H NMR (CDC 3 8 0.94 (3H, d, J=7Hz), 1.4-1.58 (2H, 1.8 (1H, mc), 2.06-2.2 (1K, 2.26-2.4 (1H, 3.3 (1H, mc), 3.52 (1, 3.64-3.72 (2H, 4.06 tIH, d, J=l2Hz), 4.64 (1K, d, J=l2Hz), 7.2-7.38 (3H, 7 F'K7 (2H, 7.74 (2H, 7.94 (11, MS m/z 515 23%).
EXAMPLE .5-Dichloronhenvi )methvloxv)-2ipheny-p1iperidinolmethv-1--l.2.4-tn-'ria.
This was prepared from the compound of Description 11 according to the procedure described in Example 16 to afford the title compound: mp 208-2120C. MS n/z 417 100%).
WO 93/21181 TGB9/08 PCr/GB93/00788 106 EXMPLE7 22-3-hlorgphpenvl)p'p rdi]2olmehl-2,3-dihdro-(4H)-..pxo- 1.2.4tazrilw This was prepared from the compound of Description 26 according to the procedure described in Example 35: mp 125- 127'C. 'H NMR (360M1{z, DMSO) 5 1.46-1.52 (2H, in), 1.9-1.95 (11, in), 2.0-2.2 (2H, mn) 2.92 (1H, d, J=lSHz, NCHHtriazolone), 2.98 (1H, mc), 3.35 (MH, s, CHO), 3.44 (1H, d, J=lSHz, NCHHtriazolone), 3.50 (1H, brs, CHPh), 3.96 (1H, d, J=12Hz, OCHH), 4.43 (1H, d, J=l2Hz, OCHa), 7.15-7.22 (2H, mn, ArH), 7.37-7.41 (2H, mn, ArH), 7.48 (2H, s, ArH), 7.65 (1H, s, ArH). MS m./z 535, 537 100, EXAM-PLE7 5-ri(2S.3S)-3-((3 .4-Dimethyvlphenvl)methloxy)-2phenlpiperi din ol methyl--2.3-dihvdro-(4H)- 3-oxo- 1. 2.4-ti azoleg This compound was prepared according to the procedure described in Example 35 using the compound of Description 29 as starting material. 1H NMR (ODC1 3 8 1.37-1.55 (2H, in), 1.9- 2.2 (3H, in), 2.1 (3H, 2.15 (3H, 2.85 (1H, d, J=l5Hz), 2.97 (IH, in), 3.26 (1H, 3.51 (1H, 3.65 (1H, d, J=l5Hz), 4.06 (1H, d, J=llHz), 4.26 (1H, d, J=llHz),6.65 (2H, in), 6.9 (1H, d, J=8Hz), 7.2-7.45 (5H, in), 9.5 (1H, brs).
EXAMPLE 78 5-rf(2Sq.3S)-3-((3-iPropoxv-henv)methyjoxy)-2p~henylpiuperidinolmethll-2.3-dihvdro-(4H-)-3-oxo- 1 .2.4-triazole WO 93/21181 WO 93/21181PCTW/ II93/00788 107 This compound was prepared according to the procedure described in Example 35 using the compound of Description as starting material. 'H NMR (CDCl 3 8 1.25 (6H, d, J=6Hz), 1.35-1.55 (2H, in), 1.9-2.2 (3H, in), 2.89 (1H, d, J=l5Hz), 2.99 (1H, d, J=lOHz), 3.27 (1H, 3.51 (1H, 3.66 (1H, d, 4.1 (1H, d, J=l2Hz), 4.38 (1H1, in), 6.48 (1H, d, J=7Hz), 6.57 (1H, 6.66 (1H, d, J=7Hz), 7.2-7.5 (5H, in).
EXAPLE79 5Lr(2.3S(f3-F ioro-5-mgthylDhenl)methox)-2nhenylniperidi,olnehll-2.3-dihdro-(4H)-3-oxo-1 .2 .4-triazole This was prepared by the reaction of the compound of Description 27 according to the procedure outlined in Example mp, 228-2291C. 'H NNMI (360MHz, DMSO) 8 1.4-1.55 (2H, m, 0112), 1.8-1.9 (1H, m, CO 2 2.02-2.18 (2H, mn, CH 2 and NCHIA), 2.21 (3H, s, OHA) 2.73 (1H1, d, NCHHi-het, J=l4Hz), 2.87-2.90 (1H1, d, NCHH, J=llHz), 3.32-3.40 (1H, mn, NCHCHO), 3.41 (1H, d, NOHfl-het, J=l4Hz), 3.46 (1H1, s, NCHCHO), 3.87 (1H, d, OCHII-Ar, J=12.5Hz), 4.28 (1H, d, OCHH-Ar, J=12.5Hz), 6.50- 6.55 (2H, m, ArH), 6.80-6.83 (1H, mn, ArH), 7.29-7.31 (3H, m, ArH), 7.51-7.53 (2H, mn, Aff), 11.18 (1H, s, NH), 11.28 (111, s, NIH). MS xnlz 397 EXAMPLE )phenyl)inethloxv)-2mehyBl-4 *,henvieridino~methy]-2.3-dihdro-(4H)-3oxo- 1.2.4-triazole This was prepared from the compound of Description 28 according to the procedure outlined in Example 35. 'H NMR WO 93/21181 WO 9321181PCT/G B93/00788 108 (360MHz, MeOD) 8 1.43 (3H, s, CH 3 1.46 (1H, mn), 1.91 (3H, in), 2.57 (2H, in), 2.98 (1H, d, J=l5Hz, NCHHtriazolone), 3.21 (2H, in), 3.58 (1H, d, J=lSHz, NCHHj triazolone), 3.72 (1H, d, J=l2Hz, OCHHI), 4.36 (1H, d, J=l2Hz, OCHH), 7.18 (1H, t, ArH), 7.25 (2H, t, ArH), 7.37 (2H1, s, ArH), 7.53 (111, s, ArH), 7.56 (1H1, s, ArH), 7.71 (1H, s, ArH).
EXAMPLE 81 5-ru(2S.3s)-3-((3 .5-Bis(trifluoromethvlhhnvl )methvloxv)-2- (3-fluorou~henvl)niueridinolmethvll12,3-dihdr-(4H)-3-oxo- 1.2,4- 1 H NMR (CDCl 3 5 1.42-1.62 (2H, mn), 1.84-2.2 (3H, in), 2.86- 3.1 (2H1, in), 3.38-3.58 (3H1, in), 4.08 (1H, d, J=l.2Hz, 00111), 4.54 (111, d, J=l2Hz, OCHjE), 6.92-7.04 (1H, mn, ArH), 7.16-7.32 (3H, mn, ArH), 7.54 (2H1, s, ArH), 7.76 (1H1, s, ArH).
VIM 2S3S)-3-((3,.-Bi s(triflu oroinethL~ph enl)m ethl oz)-2phenvylpineridinolmethyl-1 .2.4-triazine The compound of Description 3 (1g) was dissolved in diinethylforinamide (8xnl) and N-t-butyloxycarbonyl-2chloroacetamidraz-one (0.6g) was added, followed by potassium carbonate The mixture was stirred at rooin temperature overnight. The mixture was diluted with water, extracted with ethyl acetate and the organic layer was washed with brine, dried (MgSO 4 and evaporated. The residue was purified by column chromatography on silica using ethyl acetate as eluant.
This afforded the compound as a white solid which war, WO 93/21181 PCT/GB93/00788 109 recrystallised friim ether-hexane. IH NMR (360MHz, CDCla) 1.40 (9H1, s, (CHYI) 1.42-1.6 (3H, in), 2.13-2.2 (2H, in), 2.62 (1H, d, J=l5Hz, NCIIHC=NH), 3.07-3.10 (1H1, mn, CHHN), 3.36 (111, d, J=15Hz, NCHHjC=NH), 3.38 (1H, s, CHO), 3.57 (1H, brs, CRPh), 4.02 (11, d, J=l2Hz, OCIjH), 4.45 (11, d, J=12H, OCHHiD, 7.25-7.40 (511, mn, ArH), 7.53 (2H, s, ArH), 7.73 (1H, s, ArH).
The Boc-protected amidrazone (1g) was dissolved in methanolic hydrogen chloride and stirred for 12h. The solvent was evaporated and the crude product was used in subsequent reactions without further purification.
The aniidrazone hydrochloride of above (200mg) was dissolved in ethanol (2m1). Magnesium sulphate was added (100mg) and the mixture stirred for 30min. Triethylamine (0.06m1) was added followed by glyoxal (90mg, triineric dihydrate). This mixture was allowed to stir for 12h. The solvent was removed in vacuo and the residue was dispersed between ethyl acetate and water. The organic layer was dried (MgSO 4 and concentrated to afford a brown oil. This was purified by column chromatography on silica using hexane in ethyl acetate to afford the title compound. 111 NM R (360MHz, CDCl 3 8 1.53-1.72 (2H1, mn, CH 2 1.98-2.22 (211, mn, CH 2 2.42-2.53 (1H, mn, NCHH), 3.14-3.22 (111, mn, NCHH), 3.61 (111, bs, CHO0), 3.74- 3.81 (2H1, mn, NCHPh 001111), 4.04 (1H1, d, J=l2Hz, NCllHtriazine), 4.19 (1H1, d, J=l2Hz, OCHH), 4.47 (1H1, d, J=1211z, NCIHjtriazine), 7.24-7.37 (411, mn, ArH), 7.48-7.6 (411, in, ArH), 7.70 (111, s, ArH), 8.6 (111, s, ArH). MS m/z 497 100%).
WO 93/21 IF,! PCT/GB93/00788 110 The following examples illustrate pharmaceutical compositions according to the invention.
EXAMPLE 83A Tablets containing 1-25mq of compound Compound of formula (I) Microcrystalline cellulose Modified food corn starch Lactose Magnesium Stearate Amount mg 1.0 2.0 20.0 20.0 20.0 20.0 58.5 57.5 0.5 0.5 25.0 20.0 20.0 34.5 EXAMPLE 83B Tablets containing 26-100ma of compound Amount mg Compound of formula 26.0 50.0 100.0 Microcrystalline cellulose 80.0 80.0 80.0 Modified food corn starch 80.0 80.0 80.0 Lactose 213.5 189.5 139.5 Magnesium Stearate 0.5 0.5 The compound of formula cellulose, lactose and a portion of the corn starch are mixed and granulated with corn starch paste. The resulting granulation is sieved, dried and blended with the remainder of the corn starch and the magnesium stearate. The resulting granulation is then compressed into tablets containing 1.0mg, 2.0mg, 25.0mg, 26.0mg, 50.0mg and 100mg of the active compound per tablet.
EXAMPLE 84 Parenteral iniection Compound of formula (I) Citric Acid Monohydrate Sodium Phosphate Sodium Chloride Water for Injections Amount mq 1 to 100mg 0.75mg 9mg to iml WO 93/21181 PCF/GB93/00788 111 The sodium phosphate, citric acid monohydrate and sodium chloride are dissolved in a portion of the water. The compound of formula is dissolved or suspended in the solution and made up to volume.
EXAMPLE 85 Topical formulation Amount mg Compound of formula 1-10g Emulsifying Wax Liquid paraffin White Soft Paraffin to The white soft paraffin is heated until molten. The liquid paraffin and emulsifying wax are incorporated and stirred until dissolved. The compound of formula is added and stirring continued until dispersed. The mixture is then cooled until solid.
Claims (11)
1. A compound of formula or a salt or prodrug thereof: R 1 (C R R 2 R Y-RB wherein n is 1, 2 or 3; X represents 0 or S; Y represents a hydrocarbon chain of 1, 2, 3 or 4 carbon atoms which may optionally be substituted by oxo; Rrepresents phenyl optionally substituted by 1, 2 or 3 groups selected from Cl- 6 alkyl, C 2 6 alkenyl, C 2 6 alkynyl, halo, cyano, nitro, trifluoromethyl, trimethylsilyl, -0Ra, SRa, SORa, SO 2 Ra, _.NTaRb, _N~aCORb _NRa CO 2 Rb, -CO 2 Ra or -CONRaRb; R 2 represents aryl selected from phenyl and naphthyl; heteroaryl selected from indazolyl, thienyl, furyl, pyridyl, thiazolyl, tetrazolyl and quinolyl; benzhydryl; or benzyl; wherein each aryl or heteroaryl moiety may be substituted by C 1 6 alkyl, C 1 6 alkoxy, halo or trifluoromethyl; Rand R 5 may be present on any available carbon atom of the azacyclic ring and each independently WO 93/21181 WO 9321181PCr/GB93/00788 113 represent H, halo, C 1 6 alkyl, oxo CH 2 0R C0 2 Ra or CONRaRb 0 R 8 represents an optionally substituted aromatic heterocycle; and Ra and Rb each indt-pandently represent H{, trifluoromethyl, CI- 6 alkyl or phenyl optionally substituted by C 1 6 alkyl, halo or trifluoromethyl.
2. A compound as claimed in claim 1 of formula (IA) R 1 R 12 (C 2). R 1 R R (IA) wherein n is 1, 2 or 3 and any carbon atom of (CH2)n may be substituted by R 12 and/or R 13 X represents 0 or S; Rio represents phenyl optionally substituted by 1, 2 or 3 groups selected from C 1 6 al]kyl, C 2 6 alkenyl, C 2 6 alkynyl, halo, cyano, nitro, trifluoromethyl, trimethylsilyl, ORc, SRc, SORc, SO 2 Rc, IRcRd, -N..cCORd, -NRccO 2 Rd -C0 2 RC or -CONRcRd; R 11 represents aryl selected. from phenyl and naphthyl; heteroaryl selected from indazolyl, thienyl, furyl, pyridyl, thiazolyl, tetrazolyl and quinolyl; benzhydryl; or benzyl; wherein each aryl or heteroaryl moiety may be substituted by C 1 6 alkyl, C 1 6 alkoxy, halo or trifluoromethyl; 3PT/m 9 0 0 7 8 8 114 R 12 and R 13 each independently represent H, halo, C1-6alkyl, oxo, C0 2 Rc or CONRCRd; R 14 represents Cl-4alkyl, optionally substituted by oxo, substituted by an optionally substituted aromatic heterocycle; and Rc and Rd each independently represent H, C 1 -6alkyl, phenyl optionally substituted by C1-6alkyl, halo or trifluoromethyl; or a salt or prodrug thereof.
3. A compound as claimed in claim 2 wherein n is 2 or 3; R 12 and R 13 each independently represent H, halo, C 1 6 -alkyl, CO 2 Rc or CONRcRd; R 14 represents CI 4 alkyl substituted by an optionally substituted 5- or 6- membered aromatic heterocycle; and Rc and Rd each independently represent H, C1-6alkyl, phenyl or trifluoromethyl.
4. A compound as claimed in any preceding claim wherein R 1 represents phenyl substituted by one or more groups selected from Cl-4alkyl, trifluoromethyl and halo. A compound as claimed in any preceding claim wherein R 2 epresents benzhydryl or optionally substituted phenyl.
6. A compound as claimed in any preceding claim wherein R 8 represents optionally substituted thienyl, furyl, pyridyl, triazolyl, tetrazolyl, thiazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, oxazolyl, oxadiazolyl, thiadiazolyl, imidazolyl, benzimidazolyl or benzoxazolyl. 1 i I WO 93/21181 PCr/GB93/00788
7. A compound, as claimed in any of claims 1 to 5 whri 8represents a substituted or unsubstituted or 6-membered nitrogen-containing aromatic heterocycle.
8. A compound as claimed in claim 7 wherein Rrepresents optionally substituted oxazolyl, oxadiazolyl, imidazolyl, thiadiazolyl, triazolyl, pyrazinyl, pyrimidinyl, pyridazinyl or triazinyl, or tetrazolyl substituted by C 1 6 alkyl.
9. A compound as claimed in claim 8 wherein Rrepresents unsubstituted triazolyl or triazolyl substituted by oxo or thioxo. A compound as claimed in any preceding claim wherein n is 3.
11. A compound as claimed in claim 1 selected from: ((2R*,3R methyloxy) -2-phenylpiperidino)methylj 4-oxadiazole; ,3R *)-3-((3,5-bis(trifluoromethyl)phenyl) methyloxy) -2-phenylpiperidino) methyl] -3-methyl-l,2,4- oxadiazole; ((2S,3S)-3-((3,5-bis(trifluoromethyl) phenyl)methyloxy) -2-phenylpiperidino)methyl]-l, 2,4- oxadiazole; 3-[(C2R *,3R )-3-((3,5-bis(trifluoromethyl)phenyl) methyloxy) -2-phenylpiperidino) methyl) pyridine; ((2R methyloxy) -2 -phenylpiperidino) methyl) pyridine; 2-E( (2R* methyloxy) -2-phenylriparidino) methyl )benzimidazole; WO 93/21181 WO 9321181PCr/GB93/00788 116 ,3R* )-3-((3,5-his(trifluoromethyl,)phenyl) methyloxy) -2-pheniylpiperidino) methyl) tetrazole; ((2R 3R *)-3-((3,5-bis(trifluoromethyl)phenyl) methyloxy) -2-phenylpiperidino) methyl) -4-methyl-i, 3- thiazole; 3R*) 5-bis (trifluoromethyl)phenyl)methyloxy) 1- (2-furoyl) -2-phenylpiperidine; 2-E((2R *,3R *)-3-((3,5-bis(trifluoromethyl)pheiyl) methyloxy) -2-phenylpiperidino)methyl) furan; *,3R *)-3-((3,5-bis(trifluoromethyl)phernyl) methyloxy) -2-phenylpiperidino)methyl) -3-bromo-1, 2,4- oxadiazole; ((2R 3R methyloxy) -2-phenylpiperidino)methyl) -3-dimethylamino- 1,2, 4-oxadiazole; O2R *,3R (3 2-phenyl-1- (2-thienoyl) piperidine; (2R *,3R (3,5-bis(trifluoromethyl)phenyl)methyloxy) 2-phenyl-1- (2-thienyl) methylpiperidine; *,3R *)-3-((3,5-bis(trifluoromethyl)phenyl) methyloxy) -2-phenylpiperidino)methyl) 3-dihydro-4- methyl-3-thioxo-l, 2, 4-triazole; ,3R*)-3-((3,5-bis(trifluoromethy1)phenyl) methyloxy) -2-phenylpiperidino) methyl) 4-triazole; 5-U((2R*,3R*)-3-((3,5-bis(trifluoromethyl)phenyl) methyloxy) -2-phenylpiperidino)methyl) 3-dilhydro- (4H) -3- thioxo-1, 2, 4-triazole; ((2R*,3R*)-3-((3,5-bis(trifluoromethyl) pheriyl) methyloxy) -2-phenylpiperidino)methyl) -2- methyltetrazole; 5-[((2R*,3R*)3-((3,5-bis(trifluoromethyl) phenyl) methyloxy) -2-phenylpiperidino) methyl) -1- methyltetrazole; WO 93/21181 WO 9321181PCr/GB93/00788 117 ((2R *,3R methyloxy) -2-phenylpiperidino) methyl) 1,2, 4-thiadiazole; ((2R *,3R *)-3-((3,5-bis(trifluoromethyl)phenyl) methyloxy) -2-phenylpiperidino) rethyl] -4,7- dimethylbenzoxazole; ((2R*,3R*)-3-((3,5-bis(trifluoromethyl)phenyl) methyloxy) -2-phenylpiperidino) methyl]benzoxazole; 4-E 3S) 5-bis (trifluoromethyl) phenyl) methyloxy) -2-phenylpiperidino) methyl] oxazole; 2-[((2S,3S)-3-((3,5-bis(trifluoromethyl) phenyl) methyloxy) -2-phenylpiperidino) methyl ]pyrazine; phenyl) methyloxy) -2-phenylpiperidino) methyl] -2-methyl- 1,3-thiazole; 3-E((2S,3S)-3-((3,5-bis(trifluoromethyl) phenyl) methyloxy) -2-phenylpiperidino) methyl] -1,2,4- oxadiazole; 3-[((2S,3S)--3-((3,5-bis(trifluoromethyl) phenyl) methyloxy) -2-phenylpiperidino) methyl] 1,2, 4-thiadiazole; 3-[((2S,3S -3-((3,5-bis(trifluoromethyl) phenyl) methyloxy) -2-phenylpiperidino) methyl] -1,2,4- thiadiazole; 3-[((2S,3S)-3-(C3,5-bis(trifluoromethyl) phenyl) methyloxy) -2-phenylpiperidino) methyl] 1,2, 4-thiadiazole; 3-[((2S,3S)-3-((3,5-bis(trifluoromethyl)phenyl) methyloxy) -2-phenylpiperidino)methyl]-l, 2, 4-triazole; 5-[{(2S,3S)o.3-((3,5-bis(trifluoromethyl)phenyl) methyloxy) -2-phenylpiperidino)methyl]-2, 3-dihydro- (4H) -3- thioxo-1, 2, 4-triazole; WO 93/21131 WO 93/2fl31PCJ/G B93/O 0788 118 2-[((2S,3S)-3-((3,5-bis(trifluoromethyl)phenyl) methyloxy) -2-phenylpiperidino) methyl]-1- (p- tolueriesuiphonyl) imidazole; ((2S,3S)-3-((3,5-bis(trifluoromethyl)phenyl) methyloxy) -2-phenylpiperidino) methyl) imidazole; 4-[((2S,3S)-3-((3,5-bis(trifluoromethyl)phenyl) methyloxy) -2-phenylpiperidino) methyl] imidazole; ((2R*,3R*)-3-((3,5-bis(trifluoromethyl)phenyl) methyloxy) -2-phenylpiperidino)methyl) 3-dihydro- (4H) -3- oxo-1,2,4-triazole; ((2P *,3R methyloxy) -2-phenylpiperidino)methyl) (N,N- dimethylamino) 4-thiadiazole; methyloxy) -2-phenylpiperidino)methyl]tetrazole; ((2S,3S)-3-((3,5-bis(trifluoromethyl)phenyl) methyloxy) -2-phenylpiperidino) methyl) -2-methyltetrazole; ((2S,3S)-3-((3,5-bis(trifluoromethyl)phenyl) methyloxy) -2-phenylpiperidino) methyl] -1-methyltetrazole; 3-(((2S,3S)-3-((3,5-bis(trifluoromethyl)phenyl) methyloxy) -2-phenylpiperidino) methyl) pyridazine; ((2S,3S)-3-((3,5-bis(trifluoromethyl)phenyl) methyloxy) -2-phenylpiperidino) methyl] (3-t-butyl-5-methylphenyl)methyloxy) -2- phenylpiperidino)methyl]-2, 3-dihydro-(4H) -3-oxo-l, 2,4- triazole; 2-[((2S,3S)-3-((3,5-dichlorophenyl)methyloxy)-2- phenylpiperidino) methyl) imidazole; (3-chloro-5-methylphenyl)methyloxy) -2- phenylpiperidino)methyl)-2, 3-dihydro- (4H) -3-oxo-l, 2,4- triazole; (3 methyloxy) -2-diphenylmethyl) pyrrolidino) methyl) -2,3- dihydro- (4H) -3-oxo-1, 2,4-triazole; WO 93/21181 WO 9321181PCI'/G B93/00788 119 5-[((2R,3S)-3-((3,5-bis(trifluoromethyl) pohetyl) methyloxy) -2-diphenylmethyl) pyrrolidino) methyl)- 2, 3-dihydro- (4H) -3-oxo-1, 2, 4-triazole; 3-[((2S,3S)-3-((3,5-dichiorophenyl)methyloxy)-2- diphenylmethyl) pyrrolidino)methylJ-1, 2, 4-triazole; (3-t-butyl-5-chlorophenyl)methyloxy) -2- phenylpiperidino)methyl)-2,3-dihydro-(4H) -3-oxo-1,2,4- triazole; 2-phenylpiperidino)methyl)-2,3-dihydro-(4H)-3-oxo-1,2,4- triazole; 3-f ((2S,3S) (3,5-bistrifluoromethyl)phenyl)methyloxy) 2-phenylpiperidiio)methyl) -1-methyl-i, 2, 4-triazole; 3S) ,5-bistrifluoromethyl) phenyl) methyloxy) 2-phenylpiperidino)methyl)-5-phenyl-1, 2, 4-oxadiazole; 3- (2R* ,3R methylcxy) -2-phenylpiperidino) methyl) -5-thi~omethyl-1, 2,4- triazole; (3,5-dichlorophenyl)methyloxy) -2- phenylpiperidino)methyl-2, 3-dihydro- (4H) -3-oxo-1, 2,4- triazole; ((2R ,3R (3-carbomethoxyphenyl)methyloxy) -2- phenylpiperidino) methyl] pyridine; ((2R 3R (3-carboxamidophenyl)methyloxy) -2- phenylpiperidino) methyl)pyridine; ((2R *,3R (2-methoxy-3-nitrophenyl)methyloxyl)-2- phenylpiperidino) methyl) -3-methyl-i, 2, 4-oxadiazole; 3-amino-5-(((2R *,3R *)-3-((5-amino-2- methoxyphenyl) methyloxy) -2-phenylpiperidino) methyl) 1,2,4-oxadiazole; 6-f methyloxy) -2-phenylpiperidino) methyl) uracil; WO 93/21181 WO 9321181PCr/GB93/00788 120 3-[((2R*,3R*)-3-((3,5-bis(trifluoromethyl) phenyl) methyloxy) -2-phenylpiperidino) methyl) carboxamido-l, 2, 4-triazole; 3-[((2R*,3R*)-3-((3,5-bis(trifluoromethyl) phenyl) methyloxy) -2-pheriylpiperidino) methyl) 1,2, 4-triazole; phenylpiperidino) ethyl) -1,2 ,4-triazole; 3-E(lIR)-1-((2S,3S)-3-((3,5-dichlorophenyl)methyloxy)-2- phenylpiperidino) ethyl)-1, 2, 4-triazole;. 3-[((2S,3S)-3-((2,3-dimethylphenyl)methyloxy)-2- phenyJlpiperidino) methyl) 4-triazole;- 5-[((2S,3S)-3-((2,3-dimethylphenyl)methyloxy)-2- phenylpiperidino)methyl)-2, 3-dihydro-(4H) -3-oxo-1, 2,4- triazole; ((2S,3S) -2-phenyl-3-( (3-trifluoromethyl)phenyl) methyloxy) piperidino) methyl) 3-dihydro- (4H) -3-oxo- 1,2, 4-triazole;I 3S) (3 ,4-dichlorophenyl)methyloxy) -2- phenylpiperidino)methyl]-2,3-dihydro-(4H)-3-oxo-1,2,4- triazole; ((2S,3S)-3-((3-t-butylphenyl)methyloxy)-2- phenylpiperidino)methyl)-2, 3-dihydro- (4H) -3-oxo-l, 2,4- triazole; 5-[((2R*,3R*)-3-((3,5-dimethylphenyl)methyloxy)-2- phenylpiperidino)methyl) 3-dihydro- (4H) -3-oxo-l, 2,4- triazole; (3,5-bis tri 1luoromethyl) phenyl)methyloxy) -2- phenyl-l-(3-(1,2,4,- )piperidine; (3,5-bis(trifluoromethyl)phenyl)methyloxy)-1- (l-oxo-2-pyrid-4-yl) ethyl-2-phenylpiperidine; (3,5-bis(trifluoromethy1)phny)nethyloxy) -1- (2-oxo-2-pyrid-3-yl) ethyl-2-phenylpiperidine; WO 93/21181 WO 9321181PCT/GB93/00788 121 3-(lS)-l-((2S,3S)-3-((3,5-bis(trifluoromethyl)phenyl) methyloxy) -2-phenylpiperidino) ethyl]-1,2 ,4-triazole; 3- (iR) ,3S) ,5-bis (trifluoromethyl) phenyl) methyloxy) -2-phenylpiperidino) ethyl] 4-triazole; 5-(lS)-l-((2S,3S)-3-((3,5-bis(trifluoromethyl)phenyl) methyloxy) -2-phenylpiperidino) ethyl] 3-dihydro- (4H) -3- oxo-1, 2, 4-triazole; 3-[((2S,3S)-3-((3,5-dichlorophenyl)methyloxy)-2- phenylpiperidiio) methyl)-1.,2, 4-triazole; *,3R *)-3-((3,5-bis(trifluoromethyl)phenyl) methyloxy) (3-chiorophenyl) piperidino) methyl] -2,3- dihydro- (4H) -3-oxo-l, 2, 4-triazole; ((2S,3S)-3-((3,4-dimethylphenyl)methyloxy)-2- phenylpiperidino) methyl] 3-dihydro- (4H) -3-oxo-l,2,4- triazole; ((2S,3S)-3-((3-i-propoxyphenyl)methyloxcy) -2- phenylpiperidino) methyl)-2, 3-dihydro- (4H) -3-oxo-1, 2,4- triazole; (3-fluoro-5-methylphenyl)methyloxy) -2- phenylpiperidino)methyl)-2, 3-dihydro-(4H) -3-oxo-1, 2,4- triazole; )-((3,5-bis(trifluoromethyl)phenyl)methyloxy) 2-methyl-2- -phenylpiperidino) methyl-2, 3-dihydro- (4H) -3-oxo-l, 2, 4-triazole; 5-f ((2S,3S)-3-((3,5-bis(trifluoromethiyl)phenyl) methyloxy) (3-f luorophenyl) piperidino) methyl] -2,3- dihydro- (4H) -3-oxo-1, 2, 4-triazole; 3-(((2S,3S)-3-((3,5-bis(trifluoromethyl)phenyl) methyloxy) -2-phenylpiperidino) methyl] 4-triazine; and salts arnd prodrugs thereof.
12. A process for the preparation of a compound as claimed in claim 1, which process comprises: reacting a compound of formula (II): WO 93/21181 WO 9321181PCrIGI93/00788 122 (1 1) wherein R 1 R 2 R 4 R 5 X and n are as defined for formi a with a reagent suitable to introduce the group ZR;or reacting a compound of formula (III) with a compound of formula (IV): R4 C. x J (CR 2 R KyR~ (Ii')O 3 NOH H 2 N A 3 I v) wherein R 1 R 2 R 4 R 5 x, Y and n are as defined for formula R 30 represents an alkyl group and R 31 represents H or a suitable substituent, in the presence of a base; or reacting a compound of formula WO 93/21181 WO 9321181PCT/GB93/00788
123- (C 1 2 CN (V) wherein RI, R 2 R4, R 5 X, Y and n are as defined for formula with an alkali metal azide; or reacting a compound of formula (VI): RRI (2).2 (VI) wherein RI, R 2 R 4 R 5 X, Y and n are as defined for formula with a compound of formula Hal-CH 2 C(=O)R 60 where Hal represents halo and R 60 represents H or a suitable substituent; or reacting a compound of formula (VII): WO 93/21181 PCT/GB93/00788 124 R 1 (CR 2 R y 0 -N HNH 2 (V I I wherein R 1 R 2 R 4 R 5 X, Y and n are as defined for formula with a compound of formula R 61 NCS, wherein R 61 is H or a suitable substituent, in the presence of a base; or reacting a compound of formula (II) as previously defined with a compound of formula (VIII): 0 R NHN Y--Ha NH 2 (V I I wherein Y and Hal are as previously defined and R 18 is H or a group suitable as a substituent of the triazole ring, or convertible to such a group under the reaction conditions, in the presence of a base; or reacting a compound of formula (IX): WO 93/21181 PCT/GB93/00788 125 (C 3) R1 RHR2 (IX) wherein R I R 2 R 4 R 5 X, Y and n are as defined for formula with a substituted or unsubstituted triazine; or reacting a compound of formula with a compound of formula (XI): (C R H NHNH2 (X) 0 RR 3 6 R 3 0 (X I wherein R 1 R 2 R 4 R 5 X, Y and n are as defined for formula and R 35 and R 36 each independently represent H or a suitable substituent. 13. A process as claimed in claim 12 wherein, for or the base is an alkali metal carbonate. 14. A process as claimed in claim 12 or claim 13 wherein, for the reagent suitable to introduce WO 93/21181 PCT/GB93/00788 126 the group Y-R 8 is R 8 -Y-L where L is chloro, bromo, iodo, methylsulphonate or p-toluenesulphonate. for hydride. for reaction for A process as claimed in claim 12 wherein, the base is an alkali metal or an alkali metal 16. A process as claimed in claim 12 wherein, the alkali metal azide is sodium azide and the is effected in N-methylpyrrolidinone as solvent. 17. A process as claimed in claim 12 wherein, R 60 is H or Cl-6alkyl. 18. A process as claimed in claim 12 wherein, the base is 1,8-diazabicyclo[5.4.0]undec-7-ene. 19. A process as claimed in claim 12 wherein, R 18 is methoxy. A process as claimed in claim 12 wherein, the reaction temperature is 80-90'C. 21. A process as claimed in claim 12 wherein, R 35 and R 36 each represent H. for for for for .t311-fr u in =therap. 3 L)T. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 11 in association with a pharmaceutically acceptable carrier. 127 23. A ro'irmaceutical composition as claimed in claim 22 further comprising a" bronchodilator. 24. A method for the treatment or prevention of a physiological disorder 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. A method according to claim 24 for the treatment or prevention of pain or inflammation. 26. A method according to claim 24 for the treatment or prevention of migraine. 27. A method according to claim 24 for the treatment or prevention of arthritis. 28. A method according to claim 24 for tie treatment or prevention of postherpetic neuralgia. 29. A method for the treatment of a respiratory disease, which method comprises administration to a patient in need thereof of an effective amount of a compound as claimed in claim 1 and an effective amount of bronchodilator. A compound as claimed in any one of claims 1 to 11 when prepared by the process of claim 12. 31. A process for preparing a composition as claimed in claim 22 which process comprises bringing a compound as claimed in any one of claims 1 to 11 into association S 20 with a pharmaceutically acceptable carrier. 32. A compound, composition or process as claimed in any one of the preceding claims, substantially as herein before described. Dated 20 August, 1996 Merck Sharp Dohme Limited Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON T O e• C SlN:\LIBuu00821:KEI I NT 0 INTERNATIONAL SEARCH REP~ORT Intermaioeai Application No PCT/GB 93/00788 1. CLASSIFICATION OF SUBJECT MATT'ER (if several dusnificatlon symbols apply, indicate ali)6 According to International Patent Classification (IPC) or to both National Classification and [PC Int.Cl. 5 C07D413/06; C07D401/06; C07D417/06; C07D405/06 C07D409/06; C07D403/06; A61K31/41; A61K31/445 U. FIELDS SEARCNED Minimum Documentation Seurdhad7 Classification Sy Iem Classification Symbols Int.Cl. 5 A61K ;C07D Documentation Searched other than Minimum Documentation to the Extent that such Documents are Included In the Fields Searched 3 HM. DOCUMENTS CONSIDERED TO BE REEVN Category 0 Citation of Doc,~men, 1 1 with Indication, where appropriate, of the relevant passages 12Relevant to Climt No9 Y EP,A,0 436 334 (PFIZER INC.) 1-24, July 1991 31-34 cited in the application *see definitions of R3, R2, R6 and R8, and examples, especially example 84* P,Y EP,A,0 528 495 (MERCK SHARP OOHME LTD.) 1-24, 24 February 1993 31-34 cited in the application *see definitions of X,RI,R2* A WO,A,9 005 729 (PFIZER TNC) 1-24, 31 May 1990 31-34 P,Y J. MED. CHEM. 1-24, vol. 35, no. 26, 1992, 31-34 pages 4911 4913 'Discovery of a Potent Substance P Antagonist: Recognition of the Key Molecular Determinant' 0Special catcg ores of cited documents :1 toT later document published after the international filing date ~A dcumnt efiingthegenralstae o th ar whch s ~or priority date and not In conflict with the application but ''dcnde tr to e ea e of theila ree an whcdsrRcted to understand the principle or theory underlying the consderd t be partcuir rlevnceinvention earlier document but published on or after the international document opaiclrrelevance; the claimed Invention filin datecannot be c.nidred novel or cannot be considered to 0 LV document which may throw doubts ongprority claim(s) or Involve an inventive step which is cited to establish the publication date of ante 'Y document of particulr relevance; the claimed Invention citation or other special reaon (is specified) cannot be considered to involve an lnwntive step when the '0 document referring to an oral disclosure, use, exhibition or document Is combined with one or more other such docu- other mean ments such combination being obvious to a person skilled 'r document published prior to the interational filing date but Ink the am later than te priority date claimed document member of the same paent family 2 IV. CERTIFICATION Date of the Actual Completion of the International Search Date of Mailing of this International Search Report 29 JUNE 1993 3.o International Searching Authority Signaure of Authorized Officer EUROPEAN PATENT OFFICE SCRUTON-EVANS 1. Fun. PCTILsAPI0 (mamd kkwu4 02Meer 195) PCT/GB 93/00788 IntewnazdoW Application No M* U1JUUNVIla O LNIDERED TO HE REkLEVAINT (~CONTINUED FRM THE SECOND SIEET Ctegory attajon of Douinaret, with indication, where appropriate, Vj the relevawnt pasuges Reant to ait.m No. EP,A,0 499 313 (MERCK SHARP DOHME LTD.) 19 August 1992 see definition of X* 1-24, 31-34 run. Pclt/sAJzIo (0llzw eaw) (J 7 y 1963) ANNEX TO THE INTERNATIONAL SEARCH REPORT ON INTERNATIONAL PATENT APPLICATION NO. 9300788 73117 This annex lists the patent family members relating to the patent documents cited in the above-entioncd international search report. The members are as contained in the European Patent Office EDP file on The European Patent Office is in no way liable for theai particulars which are merely given for the purpose of information. 29/06/93 Patent document Publication Patent family Publication cited in search report date member(s) date EP-A-0436334 10-07-91 WO-A- 9109844 11-07-91 EP-A-0528495 24-02-93 WO-A- 9304040 04-03-93 WO-A-9005729 31-05-90 WO-A- 9005525 31-05-90 CA-A- 2003441 23-05-90 EP-A- 0409931 30-01-91 US-A- 5162339 10-11-92 EP-A-0499313 19-08-92 JP-A- 5078354 30-03-93 CA-A- 2060949 12-08-92 w For more details about this anne see Official Journal of the European Patent Office, No. 12/82
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GB929208323A GB9208323D0 (en) | 1992-04-15 | 1992-04-15 | Therapeutic agents |
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GB929216065A GB9216065D0 (en) | 1992-07-28 | 1992-07-28 | Therapeutic agents |
GB9216065 | 1992-07-28 | ||
GB9219686 | 1992-09-17 | ||
GB929219686A GB9219686D0 (en) | 1992-09-17 | 1992-09-17 | Therapeutic agents |
GB929226069A GB9226069D0 (en) | 1992-12-14 | 1992-12-14 | Therapeutic agents |
GB9226069 | 1992-12-14 | ||
PCT/GB1993/000788 WO1993021181A1 (en) | 1992-04-15 | 1993-04-14 | Azacyclic compounds |
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AU5780890A (en) * | 1989-06-26 | 1991-01-03 | Eli Lilly And Company | Tetrazole excitatory amino acid receptor antagonists |
EP0499313A1 (en) * | 1991-02-11 | 1992-08-19 | MERCK SHARP & DOHME LTD. | Azabicyclic compounds, pharmaceutical compositions containing them and their use in therapy |
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-
1993
- 1993-04-14 EP EP93910151A patent/EP0636130A1/en not_active Withdrawn
- 1993-04-14 WO PCT/GB1993/000788 patent/WO1993021181A1/en not_active Application Discontinuation
- 1993-04-14 JP JP5518131A patent/JPH07505648A/en active Pending
- 1993-04-14 AU AU40765/93A patent/AU675786B2/en not_active Ceased
- 1993-04-14 CA CA002133077A patent/CA2133077A1/en not_active Abandoned
Patent Citations (3)
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AU5780890A (en) * | 1989-06-26 | 1991-01-03 | Eli Lilly And Company | Tetrazole excitatory amino acid receptor antagonists |
EP0499313A1 (en) * | 1991-02-11 | 1992-08-19 | MERCK SHARP & DOHME LTD. | Azabicyclic compounds, pharmaceutical compositions containing them and their use in therapy |
AU7911194A (en) * | 1993-11-29 | 1995-06-08 | Fujisawa Pharmaceutical Co., Ltd. | Piperazine derivatives |
Also Published As
Publication number | Publication date |
---|---|
EP0636130A1 (en) | 1995-02-01 |
WO1993021181A1 (en) | 1993-10-28 |
AU4076593A (en) | 1993-11-18 |
JPH07505648A (en) | 1995-06-22 |
CA2133077A1 (en) | 1993-10-28 |
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