WO2004111000A2 - Derives de piperidyle - Google Patents
Derives de piperidyle Download PDFInfo
- Publication number
- WO2004111000A2 WO2004111000A2 PCT/JP2004/008371 JP2004008371W WO2004111000A2 WO 2004111000 A2 WO2004111000 A2 WO 2004111000A2 JP 2004008371 W JP2004008371 W JP 2004008371W WO 2004111000 A2 WO2004111000 A2 WO 2004111000A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- phenyl
- methoxy
- salt
- methyl
- Prior art date
Links
- 102000003141 Tachykinin Human genes 0.000 title claims abstract description 9
- 108060008037 tachykinin Proteins 0.000 title claims abstract description 9
- 125000005936 piperidyl group Chemical group 0.000 title description 8
- 239000005557 antagonist Substances 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 145
- 150000003839 salts Chemical class 0.000 claims abstract description 53
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 20
- 201000010099 disease Diseases 0.000 claims abstract description 12
- 230000001404 mediated effect Effects 0.000 claims abstract description 7
- 239000003814 drug Substances 0.000 claims abstract description 5
- 238000004519 manufacturing process Methods 0.000 claims abstract 2
- 238000002360 preparation method Methods 0.000 claims description 72
- 125000003545 alkoxy group Chemical group 0.000 claims description 37
- 229910052739 hydrogen Inorganic materials 0.000 claims description 35
- 239000001257 hydrogen Substances 0.000 claims description 35
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 34
- 125000000217 alkyl group Chemical group 0.000 claims description 29
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 28
- 238000000034 method Methods 0.000 claims description 14
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 14
- 125000003277 amino group Chemical group 0.000 claims description 10
- 125000001475 halogen functional group Chemical group 0.000 claims description 10
- 125000006239 protecting group Chemical group 0.000 claims description 8
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
- 150000002431 hydrogen Chemical class 0.000 claims description 6
- 241001465754 Metazoa Species 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 claims description 2
- LWMPFIOTEAXAGV-UHFFFAOYSA-N piperidin-1-amine Chemical compound NN1CCCCC1 LWMPFIOTEAXAGV-UHFFFAOYSA-N 0.000 claims description 2
- 239000002462 tachykinin receptor antagonist Substances 0.000 claims description 2
- QNHHSMFYTXKPNS-PMACEKPBSA-N (2s,3s)-n-[(2-cyclopropyl-4-methoxy-6-propan-2-yloxypyrimidin-5-yl)methyl]-2-phenylpiperidin-3-amine Chemical compound C1([C@@H]2NCCC[C@@H]2NCC2=C(OC(C)C)N=C(N=C2OC)C2CC2)=CC=CC=C1 QNHHSMFYTXKPNS-PMACEKPBSA-N 0.000 claims 1
- BJBVPWXVIBPDLU-OALUTQOASA-N (2s,3s)-n-[(2-ethoxy-4-methoxy-6-propan-2-yloxypyrimidin-5-yl)methyl]-2-phenylpiperidin-3-amine Chemical compound CC(C)OC1=NC(OCC)=NC(OC)=C1CN[C@@H]1[C@H](C=2C=CC=CC=2)NCCC1 BJBVPWXVIBPDLU-OALUTQOASA-N 0.000 claims 1
- UVDXXYNGPWOXFJ-FPOVZHCZSA-N (2s,3s)-n-[(4-methoxy-6-propan-2-yloxy-2-propylpyrimidin-5-yl)methyl]-2-phenylpiperidin-3-amine Chemical compound CC(C)OC1=NC(CCC)=NC(OC)=C1CN[C@@H]1[C@H](C=2C=CC=CC=2)NCCC1 UVDXXYNGPWOXFJ-FPOVZHCZSA-N 0.000 claims 1
- XHHCEGYIPMDKHC-IRXDYDNUSA-N (2s,3s)-n-[[2-methoxy-5-[5-(trifluoromethyl)tetrazol-1-yl]pyridin-3-yl]methyl]-2-phenylpiperidin-3-amine Chemical compound C1([C@@H]2NCCC[C@@H]2NCC2=CC(=CN=C2OC)N2C(=NN=N2)C(F)(F)F)=CC=CC=C1 XHHCEGYIPMDKHC-IRXDYDNUSA-N 0.000 claims 1
- MJJNOWKAEOXFMV-UWJYYQICSA-N 7-methoxy-8-[[[(2s,3s)-2-phenylpiperidin-3-yl]amino]methyl]-4-(2,2,2-trifluoroethyl)-1,4-benzoxazin-3-one Chemical compound C1([C@@H]2NCCC[C@@H]2NCC2=C3OCC(=O)N(CC(F)(F)F)C3=CC=C2OC)=CC=CC=C1 MJJNOWKAEOXFMV-UWJYYQICSA-N 0.000 claims 1
- 230000008485 antagonism Effects 0.000 abstract description 13
- 230000000144 pharmacologic effect Effects 0.000 abstract description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 147
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 144
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 128
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 83
- 239000000203 mixture Substances 0.000 description 79
- 239000000243 solution Substances 0.000 description 69
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 62
- -1 organic acid salt Chemical class 0.000 description 55
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 51
- 239000011734 sodium Substances 0.000 description 50
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 39
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 36
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 31
- 235000019341 magnesium sulphate Nutrition 0.000 description 31
- 239000012267 brine Substances 0.000 description 29
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 29
- 239000003921 oil Substances 0.000 description 27
- 235000019198 oils Nutrition 0.000 description 27
- 239000012044 organic layer Substances 0.000 description 27
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 26
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 22
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
- 239000007864 aqueous solution Substances 0.000 description 19
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 18
- 239000000741 silica gel Substances 0.000 description 18
- 229910002027 silica gel Inorganic materials 0.000 description 18
- 239000007787 solid Substances 0.000 description 18
- 238000001816 cooling Methods 0.000 description 16
- 238000006243 chemical reaction Methods 0.000 description 15
- 239000003480 eluent Substances 0.000 description 15
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
- 239000011541 reaction mixture Substances 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- 238000004440 column chromatography Methods 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
- 238000000746 purification Methods 0.000 description 11
- 206010047700 Vomiting Diseases 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- MVEAAGBEUOMFRX-UHFFFAOYSA-N ethyl acetate;hydrochloride Chemical compound Cl.CCOC(C)=O MVEAAGBEUOMFRX-UHFFFAOYSA-N 0.000 description 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 208000035475 disorder Diseases 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- 239000005909 Kieselgur Substances 0.000 description 7
- 208000002193 Pain Diseases 0.000 description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 description 7
- 238000012746 preparative thin layer chromatography Methods 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- GFMAFYNUQDLPBP-QWRGUYRKSA-N (2s,3s)-2-phenylpiperidin-3-amine Chemical compound N[C@H]1CCCN[C@H]1C1=CC=CC=C1 GFMAFYNUQDLPBP-QWRGUYRKSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
- 230000002829 reductive effect Effects 0.000 description 6
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 230000036407 pain Effects 0.000 description 5
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 5
- 210000003932 urinary bladder Anatomy 0.000 description 5
- 239000003039 volatile agent Substances 0.000 description 5
- QDZOEBFLNHCSSF-PFFBOGFISA-N (2S)-2-[[(2R)-2-[[(2S)-1-[(2S)-6-amino-2-[[(2S)-1-[(2R)-2-amino-5-carbamimidamidopentanoyl]pyrrolidine-2-carbonyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-N-[(2R)-1-[[(2S)-1-[[(2R)-1-[[(2S)-1-[[(2S)-1-amino-4-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]pentanediamide Chemical compound C([C@@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](N)CCCNC(N)=N)C1=CC=CC=C1 QDZOEBFLNHCSSF-PFFBOGFISA-N 0.000 description 4
- RSDUEIIFCVUXMA-UHFFFAOYSA-N 2-cyclopropyl-4-methoxy-6-propan-2-yloxypyrimidine-5-carbaldehyde Chemical compound CC(C)OC1=C(C=O)C(OC)=NC(C2CC2)=N1 RSDUEIIFCVUXMA-UHFFFAOYSA-N 0.000 description 4
- 0 Cc1c(*)nc(*)nc1* Chemical compound Cc1c(*)nc(*)nc1* 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- 102000046798 Neurokinin B Human genes 0.000 description 4
- NHXYSAFTNPANFK-HDMCBQFHSA-N Neurokinin B Chemical compound C([C@@H](C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(N)=O)C(C)C)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CCSC)NC(=O)[C@@H](N)CC(O)=O)C1=CC=CC=C1 NHXYSAFTNPANFK-HDMCBQFHSA-N 0.000 description 4
- 101800002813 Neurokinin-B Proteins 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 102100024304 Protachykinin-1 Human genes 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 101800003906 Substance P Proteins 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 206010006451 bronchitis Diseases 0.000 description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 4
- 239000012230 colorless oil Substances 0.000 description 4
- 238000001647 drug administration Methods 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 4
- 125000004793 2,2,2-trifluoroethoxy group Chemical group FC(CO*)(F)F 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 241000282472 Canis lupus familiaris Species 0.000 description 3
- 229940126062 Compound A Drugs 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 101800000399 Neurokinin A Proteins 0.000 description 3
- HEAUFJZALFKPBA-YRVBCFNBSA-N Neurokinin A Chemical compound C([C@@H](C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(N)=O)C(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CC=1NC=NC=1)C(C)O)C1=CC=CC=C1 HEAUFJZALFKPBA-YRVBCFNBSA-N 0.000 description 3
- 102400000097 Neurokinin A Human genes 0.000 description 3
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- 206010036618 Premenstrual syndrome Diseases 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- 208000006673 asthma Diseases 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 150000001721 carbon Chemical group 0.000 description 3
- 210000003169 central nervous system Anatomy 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- 208000027866 inflammatory disease Diseases 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
- 230000027939 micturition Effects 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 3
- 239000012312 sodium hydride Substances 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 230000008673 vomiting Effects 0.000 description 3
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- IPCIIKOMFOHEOE-UHFFFAOYSA-N (2-cyclopropyl-4-methoxy-6-propan-2-yloxypyrimidin-5-yl)methanol Chemical compound CC(C)OC1=C(CO)C(OC)=NC(C2CC2)=N1 IPCIIKOMFOHEOE-UHFFFAOYSA-N 0.000 description 2
- SLBVTSNBQAKKLY-UHFFFAOYSA-N 1-(2-cyclopropyl-4-methoxy-6-propan-2-yloxypyrimidin-5-yl)ethanol Chemical compound CC(C)OC1=C(C(C)O)C(OC)=NC(C2CC2)=N1 SLBVTSNBQAKKLY-UHFFFAOYSA-N 0.000 description 2
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 2
- YEQSXCBDSGNZIB-OALUTQOASA-N 1-[(2s,3s)-3-[(2-ethoxy-4-methoxy-6-propan-2-yloxypyrimidin-5-yl)methylamino]-2-phenylpiperidin-1-yl]-2,2,2-trifluoroethanone Chemical compound CC(C)OC1=NC(OCC)=NC(OC)=C1CN[C@@H]1[C@H](C=2C=CC=CC=2)N(C(=O)C(F)(F)F)CCC1 YEQSXCBDSGNZIB-OALUTQOASA-N 0.000 description 2
- FNSAKXLEFPFZOM-UHFFFAOYSA-N 2,4,6-trimethoxyaniline Chemical compound COC1=CC(OC)=C(N)C(OC)=C1 FNSAKXLEFPFZOM-UHFFFAOYSA-N 0.000 description 2
- MOPXHNIVDVYJBN-UHFFFAOYSA-N 2-cyclopropyl-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine Chemical compound FC(F)(F)COC1=CC(OCC(F)(F)F)=NC(C2CC2)=N1 MOPXHNIVDVYJBN-UHFFFAOYSA-N 0.000 description 2
- CAULGDAMWGRUOS-UHFFFAOYSA-N 2-cyclopropyl-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine-5-carbaldehyde Chemical compound FC(F)(F)COC1=C(C=O)C(OCC(F)(F)F)=NC(C2CC2)=N1 CAULGDAMWGRUOS-UHFFFAOYSA-N 0.000 description 2
- GVOLBQRRLIOKEP-UHFFFAOYSA-N 2-cyclopropyl-4-methoxy-6-propan-2-yloxypyrimidine-5-carboxylic acid Chemical compound CC(C)OC1=C(C(O)=O)C(OC)=NC(C2CC2)=N1 GVOLBQRRLIOKEP-UHFFFAOYSA-N 0.000 description 2
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- 125000004104 aryloxy group Chemical group 0.000 description 1
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- 239000012298 atmosphere Substances 0.000 description 1
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical class C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 1
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- 229940077388 benzenesulfonate Drugs 0.000 description 1
- GYFWOBNRWIHHJA-PMACEKPBSA-N benzyl n-[(2s,3s)-1-acetyl-2-phenylpiperidin-3-yl]carbamate Chemical compound N([C@H]1CCCN([C@H]1C=1C=CC=CC=1)C(=O)C)C(=O)OCC1=CC=CC=C1 GYFWOBNRWIHHJA-PMACEKPBSA-N 0.000 description 1
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- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
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- SIOVKLKJSOKLIF-UHFFFAOYSA-N bis(trimethylsilyl)acetamide Chemical compound C[Si](C)(C)OC(C)=N[Si](C)(C)C SIOVKLKJSOKLIF-UHFFFAOYSA-N 0.000 description 1
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- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 description 1
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- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
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- OMUPJWPQNDGREX-UHFFFAOYSA-N methyl 2,3,6-trimethoxy-5-[5-(trifluoromethyl)tetrazol-1-yl]benzoate Chemical compound COC(=O)C1=C(OC)C(OC)=CC(N2C(=NN=N2)C(F)(F)F)=C1OC OMUPJWPQNDGREX-UHFFFAOYSA-N 0.000 description 1
- VAOYVUCKZJGZKF-UHFFFAOYSA-N methyl 2-hydroxy-6-methoxy-3-[(2,2,2-trifluoroacetyl)amino]benzoate Chemical compound COC(=O)C1=C(O)C(NC(=O)C(F)(F)F)=CC=C1OC VAOYVUCKZJGZKF-UHFFFAOYSA-N 0.000 description 1
- AOMWYQBYNONATP-UHFFFAOYSA-N methyl 3-amino-2,5,6-trimethoxybenzoate Chemical compound COC(=O)C1=C(OC)C(N)=CC(OC)=C1OC AOMWYQBYNONATP-UHFFFAOYSA-N 0.000 description 1
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- 229960005181 morphine Drugs 0.000 description 1
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- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 description 1
- LWFWUJCJKPUZLV-UHFFFAOYSA-N n-trimethylsilylacetamide Chemical compound CC(=O)N[Si](C)(C)C LWFWUJCJKPUZLV-UHFFFAOYSA-N 0.000 description 1
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- 239000002746 neurokinin 2 receptor antagonist Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
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- 206010029446 nocturia Diseases 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
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- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 208000020629 overactive bladder Diseases 0.000 description 1
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- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- 125000000612 phthaloyl group Chemical group C(C=1C(C(=O)*)=CC=CC1)(=O)* 0.000 description 1
- UGUDJMXCQREUTA-UHFFFAOYSA-N piperidin-1-amine;dihydrochloride Chemical compound Cl.Cl.NN1CCCCC1 UGUDJMXCQREUTA-UHFFFAOYSA-N 0.000 description 1
- PEUGKEHLRUVPAN-UHFFFAOYSA-N piperidin-3-amine Chemical compound NC1CCCNC1 PEUGKEHLRUVPAN-UHFFFAOYSA-N 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 230000006785 proliferative vitreoretinopathy Effects 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 201000004240 prostatic hypertrophy Diseases 0.000 description 1
- 201000007094 prostatitis Diseases 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 208000008128 pulmonary tuberculosis Diseases 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 208000000649 small cell carcinoma Diseases 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- UKLNMMHNWFDKNT-UHFFFAOYSA-M sodium chlorite Chemical compound [Na+].[O-]Cl=O UKLNMMHNWFDKNT-UHFFFAOYSA-M 0.000 description 1
- 229960002218 sodium chlorite Drugs 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 230000000392 somatic effect Effects 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 208000022170 stress incontinence Diseases 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000003890 substance P antagonist Substances 0.000 description 1
- UDYFLDICVHJSOY-UHFFFAOYSA-N sulfur trioxide-pyridine complex Substances O=S(=O)=O.C1=CC=NC=C1 UDYFLDICVHJSOY-UHFFFAOYSA-N 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YDJXMGCRISDECF-VXKWHMMOSA-N tert-butyl (2s,3s)-3-[(2-ethoxy-4-methoxy-6-propan-2-yloxypyrimidin-5-yl)methoxy]-2-phenylpiperidine-1-carboxylate Chemical compound CC(C)OC1=NC(OCC)=NC(OC)=C1CO[C@@H]1[C@H](C=2C=CC=CC=2)N(C(=O)OC(C)(C)C)CCC1 YDJXMGCRISDECF-VXKWHMMOSA-N 0.000 description 1
- ATJRDIDZQTXJLY-KBPBESRZSA-N tert-butyl (2s,3s)-3-hydroxy-2-phenylpiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC[C@H](O)[C@@H]1C1=CC=CC=C1 ATJRDIDZQTXJLY-KBPBESRZSA-N 0.000 description 1
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 1
- OSBSFAARYOCBHB-UHFFFAOYSA-N tetrapropylammonium Chemical compound CCC[N+](CCC)(CCC)CCC OSBSFAARYOCBHB-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical class CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 206010046494 urge incontinence Diseases 0.000 description 1
- 210000001635 urinary tract Anatomy 0.000 description 1
- 210000004916 vomit Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent 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
- C07D401/12—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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/56—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- 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
- C07D413/12—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 chain containing hetero atoms as chain links
Definitions
- the present invention relates to new piperidyl derivatives and a salt thereof.
- one object of the present invention is to provide new and useful piperidyl derivatives and a salt thereof which have pharmacological activities such as Tachykinin antagonism, especially Substance P antagonism, Neurokinin A antagonism, Neurokinin B antagonism, and the like.
- Another object of the present invention is to provide a process for the preparation of said piperidyl derivatives and a salt thereof.
- a further object of the present invention is to provide a pharmaceutical composition comprising, as an active ingredient, said piperidyl derivatives and a pharmaceutically acceptable salt thereof.
- Still further object of the present invention is to provide a use of said piperidyl derivatives or a pharmaceutically acceptable salt thereof as Tachykinin antagonist, especially Substance P antagonist, Neurokinin A antagonist or Neurokinin B antagonist, useful for treating or preventing Tachykinin-mediated diseases, for example, respiratory diseases such as asthma, bronchitis, rhinitis, cough, expectoration, and the like; ophthalmic diseases such as conjunctivitis, vernal conjunctivitis, and the like; cutaneous diseases such as contact dermatitis, atopic dermatitis, urticaria, and other eczematoid dermatitis, and the like; inflammatory diseases such as rheumatoid arthritis, osteoarthritis, and the like; pains or aches (e.g., migraine, headache, toothache, cancerous pain, back pain, etc.); and the like in human being or animals.
- respiratory diseases such as asthma, bronchitis, rhinitis, cough, expect
- the object compound of the present invention can be represented by the following general formula (I) :
- -X- is -NH or -0-;
- R ⁇ , R ⁇ and R ⁇ are independently hydrogen, lower alkyl, mono (or di or tri) halo (lower) alkyl, cyclo (lower) alkyl, lower alkoxy, mono (or di or tri) halo (lower) alkoxy, cyclo (lower) alkyloxy or ⁇ tetrahydrofranyloxy;
- R 6 , R 7 and R 17 are independently hydrogen or lower alkoxy;
- R xz is lower alkoxy;
- R ⁇ is hydrogen or lower alkoxy
- R- 1 - ⁇ is hydrogen or lower alkoxy (lower) alkoxy or carbamoyl (lower) alkoxy;
- R-*- ⁇ is hydrogen or isopropoxy;
- R ⁇ " is hydrogen or mono (or di or tri) halo (lower) alkyl;
- R 1 x R o is hydrogen or oxo) ;
- RlI -Z- is bond or I ⁇ CH ⁇
- R- ⁇ is hydrogen or lower alkyl
- R and R are independently hydrogen or lower alkyl, or join together to form oxo
- R 8 is hydrogen, (5-oxo ⁇ 4, 5-dihydro-lH-l, 2, 4-triazol-3- yl)methyl or an amino protective group
- R" and R ⁇ - 0 are independently hydrogen, halogen, lower alkyl or lower alkoxy, and
- R 1 ⁇ , R 14 and R 1 ⁇ are each as defined above, then
- -Z- is ⁇ 11 (in which R- ⁇ is as defined / CH ⁇ above) , and a salt thereof.
- the object compound (I) may include one or more stereoisomers due to asymmetric carbon atom(s) and double bond, and all of such isomers and a mixture thereof are included within the scope of the present invention.
- isomerization or rearrangement of the object compound (I) may occur due to the effect of the light, acid, base or the like, and the compound obtained as the result of said isomerization or rearrangement is also included within the scope of the • present invention.
- the object compound (I) or a salt thereof can be prepared by processes which are illustrated in the following schemes.
- X, Y, Z, R 1 , R 2 , R 8 , R 9 and R 10 are each as defined above, R
- Suitable salts of the starting and object compounds are conventional non-toxic and pharmaceutically acceptable salt and include an acid addition salt such as an organic acid salt (e.g. acetate, trifluoroacetate, fumarate, maleate, tartrate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate, etc.), an inorganic acid salt (e.g.
- an amino acid e.g. arginine, aspartic acid, glutamic acid, etc.
- a metal salt such as an alkali metal salt (e.g. sodium salt, potassium salt, etc.) and an alkaline earth metal salt (e.g
- lower is intended to mean 1 to 6, preferably 1 to 4, carbon atom(s), unless otherwise indicated.
- Suitable “halogen” may include fluorine, chlorine, bromine and iodine.
- Suitable “lower alkyl” and “lower alkyl” moiety in the term of "mono (or di or tri) halo (lower) alkyl” may include straight or branched one having 1 to 6 carbon atom(s), such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl/ hexyl and the like, in which the preferred one is C- ⁇ -C ⁇ alkyl and the most preferred one is methyl, ethyl, propyl or tert-butyl.
- Suitable "mono (or di or tri) halo (lower) alkyl” may be fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, bromomethyl, dibromomethyl, tribromomethyl, 1 or 2-fluoroethyl, 1 or 2-bromoethyl, 1 or 2-chloroethyl, -1, 1-difluoroethyl, 2, 2-difluoroethyl, 2,2,2- trifluoroethyl, and the like, in which the preferred one may be trifluromethyl .
- Suitable "cyclo (lower) alkyl” and “cyclo (lower) alkyl” moiety in the term of "cyclo (lower) alkyloxy” may include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like, in which the preferred One is cyclo (C3 ⁇ Cg) alkyl and the most preferred one is cyclopropyl or cyclobutyl.
- Suitable "lower alkoxy” and “lower alkoxy” moiety in the term of "mono (or di or tri) halo (lower) alkoxy” may include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, tert-pentyloxy, hexyloxy and the like, in which the preferred one is C ⁇ -C ⁇ alkoxy and the most preferred one is methoxy, ethoxy, isopropoxy or tert-butoxy.
- Suitable "mono (or di or tri) halo (lower) alkoxy” may include chloromethoxy, dichloromethoxy, trichloromethoxy, bromomethoxy, dibromomethoxy, tribromomethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1 or 2-chloroethoxy, 1 or 2-bromoethoxy, 1 or 2-fluoroethoxy, 1, 1-difluoroethoxy, .2,2- difluoroethoxy, 2, 2, 2-trifluoroethoxy, and the like, in which the preferred one may be 2, 2, 2-trifluoroethoxy.
- Suitable "leaving group” may include lower alkoxy (e.g.
- Suitable "acid residue” may be halogen (e.g., chlorine, bromine, iodine, etc.), sulfonyloxy (e.g., methanesulfonyloxy, phenylsulfonyloxy, mesitylenesulfonyloxy, toluenesulfonyloxy, etc.) or the like.
- halogen e.g., chlorine, bromine, iodine, etc.
- sulfonyloxy e.g., methanesulfonyloxy, phenylsulfonyloxy, mesitylenesulfonyloxy, toluenesulfonyloxy, etc.
- amino protective group may be common amino protective group such as acyl, for example, substituted or unsubstituted lower alkanoyl [e.g. formyl, acetyl, propionyl, trifluoroacetyl, etc.], phthaloyl, lower alkoxycarbonyl [e.g. tert-butoxycarbonyl, tert-amyloxy- carbonyl, etc.], substituted or unsubstituted aralkyloxy- carbonyl [e.g. benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, etc.], substituted or unsubstituted arenesulfonyl [e.g.
- benzenesulfonyl, tosyl, etc. ] , nitrophenylsulfenyl, ar (lower) alkyl [e.g. trityl, benzyl, etc.], and the like, in which preferable one is tert-butoxycarbonyl.
- Preferred embodiments of the object compound (I) are as follows:
- -X- is -NH or -0-;
- R , R ⁇ and R ⁇ are independently hydrogen, lower alkyl, cyclo (lower) alkyl, lower alkoxy or cyclo (lower) alkoxy;
- R" and R' are independently hydrogen or lower alkoxy; R 1 ⁇ is lower alkoxy; and
- R- ⁇ is hydrogen or lower alkoxy
- R-"- and R ⁇ are independently hydrogen or lower alkyl; R° is hydrogen; and
- R° and R ⁇ are each hydrogen.
- the object compound (Ia) or a salt thereof can be prepared by reacting the compound (II) or its reactive derivative at the amino group or a salt thereof with the compound (III) .
- Suitable reactive derivative at the amino group of the compound (II) may include Schiff's base type imino or its tautomeric enamine type isomer formed by the reaction of the compound (II) with a carbonyl compound such as aldehyde, ketone or the like; a silyl derivative formed by the reaction of the compound (II) with a silyl compound such as bis (trimethylsilyl) acetamide, mono (trimethylsilyl) acetamide, bis (trimethylsilyl) urea or the like; a derivative formed by reaction of the compound (II) with phosphorus trichloride or phosgene and the like.
- the reaction is usually carried out in a conventional solvent such as water, alcohol (e.g. methanol, ethanol, etc.), acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction, or the mixture thereof.
- a conventional solvent such as water, alcohol (e.g. methanol, ethanol, etc.), acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction, or the mixture thereof.
- the reaction may also be carried out in the presence of a reductive regent such as hydrides (e.g. hydrogen iodide, hydrogen sulfide, lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, etc.), or the like.
- a reductive regent such as hydrides (e.g. hydrogen iodide, hydrogen sulfide, lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, etc.), or the like.
- the reaction temperature is not critical, and the reaction is usually carried out under cooling to heating.
- the object compound (Ib) or a salt thereof can be prepared by reacting the- compound (II) or its reactive derivative at the amino group or a salt thereof with the compound (IV) .
- the object compound (Ic) or a salt thereof can be prepared by reacting the compound (Id) or its reactive derivative at the amino group or a salt thereof with the compound (VI) . This reaction can be carried out in substantially the same manner as in Example 4.
- the object compound (Ie) or a salt thereof can be prepared by elimination of the amino protective group of the compound (Id) or a salt thereof.
- the object compound (I) and a pharmaceutically acceptable salt thereof have pharmacological activities such as Tachykinin antagonism, especially Substance P antagonism, Neurokinin A antagonism or Neurokinin B antagonism, and therefore are useful for treating or preventing Tachykinin- mediated diseases, particularly Substance P-mediated diseases, for example, respiratory diseases such as asthma, bronchitis (e.g.
- ophthalmic diseases such as conjunctivitis, vernal conjunctivitis, and the like
- cutaneous diseases such as contact dermatitis, atopic dermatitis, urticaria, and other eczematoid dermatitis, and the like
- inflammatory diseases such as rheumatoid arthritis, osteoarthritis, and the like
- pains or aches e.g. migraine, headache, cluster headache, toothache, cancerous pain, back pain, neuralgia, etc.
- the object compound (I) and a pharmaceutically acceptable salt thereof of the present invention are useful for treating or preventing ophthalmic diseases such as glaucoma, uveitis, and the like; gastrointestinal diseases such as ulcer, ulcerative colitis, irritable bowel syndrome, food allergy, and the like; inflammatory diseases such as nephritis, and the like; circulatory diseases such as hypertension, angina pectoris, cardiac failure, thrombosis, Raynaud's disease, and the like; epilepsy; ' spastic paralysis; overactive bladder such as nervous pollakiuria, neurogenic bladder dysfunction, nocturia, unstable bladder, cystospasm, chronic cystiris (e.g.
- ophthalmic diseases such as glaucoma, uveitis, and the like
- gastrointestinal diseases such as ulcer, ulcerative colitis, irritable bowel syndrome, food allergy, and the like
- inflammatory diseases such as nephritis, and the like
- circulatory diseases such as hypertension
- interstitial ⁇ cystitis chronic prostatitis, prostatic hypertrophy, and the like
- micturiation disorder such as stress incontinence, urge incontinence, mixed incontinence, functional incontinence, overflow incontinence, and the like
- Parkinson diseases dimentia; AIDS related dementia; Alzheimer's diseases; Down's syndrome; Huntington's chorea; carcinoid syndrome; disorders related to immune enhancement or suppression; disorders caused by Helicobacter pylori or another spiral urease-positive gram-negative bacterium; sunburn; angiogenesis or diseases caused by angiogenesis; and the like.
- the object compound (I) and a pharmaceutically acceptable salt thereof of the present invention are useful for treating or preventing chronic obstructive pulmonary diseases, particularly chronic pulmonary emphysema; blinkis; proliferative vitreoretinopathy; psoriasis; inflammatory intestinal diseases, particularly Crohn's diseases; hepatitis; superficial pain on congelation, burn, herpes zoster or diabetic neuropathy; telalgia attended to hyperlipidemia; postoperative neuroma, particularly of mastectomy; vulvar vestibulitis; hemodialysis-associated itching; lichen planus; laryngopharyngitis; bronchiectasis; coniosis; whooping cough; pulmonary tuberculosis; cystic fibrosis; emesis (e.g., nausea, retching, vomiting, acute emesis, delayed emesis, anticipatory emesis, past operative nausea and vomiting (PONV)
- emesis
- the object compound (I) and a pharmaceutically acceptable salt thereof of the present invention are Central Nervous System '(CNS) penetrant.
- the compound (I) and a pharmaceutically acceptable salt thereof of the present invention can be used in a form of pharmaceutical preparation containing one of said compounds, as an active ingredient, in admixture with a pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient suitable for oral, parenteral, external including topical, internal, intravenous, intramuscular, inhalant, nasal, intraarticular, intraspinal, transtracheal or transocular administration.
- a pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient suitable for oral, parenteral, external including topical, internal, intravenous, intramuscular, inhalant, nasal, intraarticular, intraspinal, transtracheal or transocular administration.
- the pharmaceutical preparations may be solid, semi-solid or solutions such as capsules, tablets, pellets, dragees, powders, granules, suppositories, ointments, creams, lotions, inhalants, injections, cataplasms, gels, tapes, eye drops, solution, syrups, aerosols, suspension, emulsion, or the like.
- auxiliary substances stabilizing agents, wetting or emulsifying agents, buffers and other commonly used additives.
- an average single dose of about 0.1 mg, 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg and 1000 mg of the compound (I) may be effective for treating Tachykinin-mediated diseases such as asthma and the like.
- amounts between 0.1 mg/body and about 1,000 mg/body may be administered per day.
- Test compound showed 100% inhibition rate of emesis in the dog at the dose of 1.0 mg/kg.
- Test compound The object compound of the
- Test Method Male Hartley guinea pigs (3-4 weeks old) were anesthetized with urethane (1.2 g/kg body weight, s.c), and the lower abdomen was opened along the midline to expose the urinary bladder. After performing a small dissection at the apex of the bladder, a catheter was inserted into the bladder. The catheter was connected through a three-way stopcock attached to a pressure transducer for measurement of intravesical pressure. A tube for drug administration was inserted into the jugular vein.
- Acetic acid (0.1%) was infused at a rate of 0.3 ml/min for over 30 minutes.
- the micturition pressure, threshold pressure and time to the micturition (bladder capacity) were measured.
- the mean value from the three trials was taken as the value before drug administration.
- the mean value from the three trials for 30 minutes was taken as the value after administration.
- a test compound was administered intravenously at a dose of 0.1 mg/kg.
- the data were analyzed by Dunnett's multiple comparison test following randomized block designed analysis of variance compared with the value before drug administration.
- test compound significantly increased bladder capacity, but did not significantly change micturition pressure and threshold pressure.
- Test compound The object compound of Example 9- (24)
- Some of the object compound (I) and a pharmaceutically acceptable salt thereof of the present invention are less subject to metabolism in human being or animals.
- This compound was obtained as a mixture of reactant and dehydroxylated compound and was used to the next reaction without purification.
- the pH of the extract was made acidic with IN hydrochloric acid, and was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and evaporated in vacuo to give the, title compound (96.8mg) as solid.
- butyllithium (1.58M solution in hexane) (1.57ml) was dropwise added to 5-bromo-2-cyclopropyl- 4, 6-bis (2,2, 2-trifluoroethoxy) pyrimidine (888.7mg) in a mixture of ether (20ml) and tetrahydrofuran (4ml), and stirred for lhr at the same temperature.
- isopropyl formate (1.13ml) was added at one portion at -70°C.
- Example 5 The following compound was obtained in substantially the same manner as that of Example 4.
- Trifluoroacetic acid (2.2ml) was added to tert-butyl (2S, 3S) -3- [ (2-cyclopropyl-4-isopropoxy-6-methoxy-5- pyrimidinyl) methoxy] -2-pheny1-1-piperidinecarboxylate (143mg) and the resulting solution was stirred at 5O 0 C bath for 2h. After cooling, saturated sodium hydrogen carbonate solution and ethyl acetate were added to the mixture. The organic layer was separated, washed with brine, dried over magnesium sulfate, and evaporated in vacuo.
- Example 9 The following compounds were obtained in substantially the same manner as that of Example 8.
- Example 11 To a solution of cis-2-phenyl-3-piperidinamine (30 mg) in dichloromethane (0.7 ml) were added 2-cyclopropyl-4- isopropoxy-6-methoxy-5-pyrimidinecarbaldehyde (40 mg) and sodium triacetoxyborohydride (55 mg) , and the whole was stirred at room temperature overnight. To the mixture were added saturated sodium bicarbonate solution and ethyl acetate, the organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over potassium carbonate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography
- reaction mixture was added with 2 ml of saturated sodium bicarbonate aqueous solution, then extracted with dichloromethane (5 ml x 3), dried over diatomaceous earth. The organic layer was evaporated under reduced pressure to give the title compound as a crude white foam (10.9 mg) , that was used crude in the next reaction.
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Abstract
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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AU2003902882A AU2003902882A0 (en) | 2003-06-10 | 2003-06-10 | Piperidyl derivatives |
AU2003902882 | 2003-06-10 |
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WO2004111000A2 true WO2004111000A2 (fr) | 2004-12-23 |
WO2004111000A3 WO2004111000A3 (fr) | 2005-05-26 |
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Application Number | Title | Priority Date | Filing Date |
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PCT/JP2004/008371 WO2004111000A2 (fr) | 2003-06-10 | 2004-06-09 | Derives de piperidyle |
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Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005113503A2 (fr) * | 2004-05-21 | 2005-12-01 | Pfizer Products Inc. | Metabolites de (+)-(2s, 3s)-3-(2-methoxy-5-trifluoromethoxybenzylamino)-2-phenyl-piperidine |
WO2009072643A1 (fr) * | 2007-12-03 | 2009-06-11 | Takeda Pharmaceutical Company Limited | Composé hétérocyclique contenant de l'azote et son utilisation |
WO2010032856A1 (fr) | 2008-09-19 | 2010-03-25 | 武田薬品工業株式会社 | Composé hétérocyclique contenant de l'azote et son utilisation |
JP2012505173A (ja) * | 2008-10-09 | 2012-03-01 | エフ.ホフマン−ラ ロシュ アーゲー | ピロリジンn−ベンジル誘導体 |
JP2012507485A (ja) * | 2008-11-03 | 2012-03-29 | エフ.ホフマン−ラ ロシュ アーゲー | 3−(ベンジルアミノ)−ピロリジン誘導体及びnk−3受容体アンタゴニストとしてのその使用 |
US10894787B2 (en) | 2010-09-22 | 2021-01-19 | Arena Pharmaceuticals, Inc. | Modulators of the GPR119 receptor and the treatment of disorders related thereto |
US11007175B2 (en) | 2015-01-06 | 2021-05-18 | Arena Pharmaceuticals, Inc. | Methods of treating conditions related to the S1P1 receptor |
US11534424B2 (en) | 2017-02-16 | 2022-12-27 | Arena Pharmaceuticals, Inc. | Compounds and methods for treatment of primary biliary cholangitis |
US11884626B2 (en) | 2015-06-22 | 2024-01-30 | Arena Pharmaceuticals, Inc. | Crystalline L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-penta [b]indol-3-yl)acetic acid(Compound1) for use in S1P1 receptor-associated disorders |
Families Citing this family (1)
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GEP20084540B (en) | 2003-01-14 | 2008-11-25 | Arena Pharm Inc | 1,2,3-trisubstituted aryl and heteroaryl derivatives as modulators of metabolism and the prpphylaxis and treatment of disorders related thereto such as diabetes and hyperglycemia |
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WO2001077100A2 (fr) * | 2000-04-10 | 2001-10-18 | Pfizer Products Inc. | Composes contenant benzoamide piperidine et composes apparentes |
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- 2003-06-10 AU AU2003902882A patent/AU2003902882A0/en not_active Abandoned
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WO1993001170A1 (fr) * | 1991-07-01 | 1993-01-21 | Pfizer Inc. | Derives de 3-aminopiperidine et heterocycles associes contenant de l'azote |
WO1996029326A1 (fr) * | 1995-03-21 | 1996-09-26 | Glaxo Group Limited | 3-benzylamino-2-phenylpiperidines en tant qu'antagonistes de neurokinine |
WO2001077100A2 (fr) * | 2000-04-10 | 2001-10-18 | Pfizer Products Inc. | Composes contenant benzoamide piperidine et composes apparentes |
Cited By (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005113503A2 (fr) * | 2004-05-21 | 2005-12-01 | Pfizer Products Inc. | Metabolites de (+)-(2s, 3s)-3-(2-methoxy-5-trifluoromethoxybenzylamino)-2-phenyl-piperidine |
WO2005113503A3 (fr) * | 2004-05-21 | 2006-03-16 | Pfizer Prod Inc | Metabolites de (+)-(2s, 3s)-3-(2-methoxy-5-trifluoromethoxybenzylamino)-2-phenyl-piperidine |
WO2009072643A1 (fr) * | 2007-12-03 | 2009-06-11 | Takeda Pharmaceutical Company Limited | Composé hétérocyclique contenant de l'azote et son utilisation |
US8470816B2 (en) | 2007-12-03 | 2013-06-25 | Takeda Pharmaceutical Company Limited | Nitrogen-containing heterocyclic compound and use thereof |
EP2336105A1 (fr) * | 2008-09-19 | 2011-06-22 | Takeda Pharmaceutical Company Limited | Composé hétérocyclique contenant de l'azote et son utilisation |
EP2336105A4 (fr) * | 2008-09-19 | 2012-03-28 | Takeda Pharmaceutical | Composé hétérocyclique contenant de l'azote et son utilisation |
WO2010032856A1 (fr) | 2008-09-19 | 2010-03-25 | 武田薬品工業株式会社 | Composé hétérocyclique contenant de l'azote et son utilisation |
US8592454B2 (en) | 2008-09-19 | 2013-11-26 | Takeda Pharmaceutical Company Limited | Nitrogen-containing heterocyclic compound and use of same |
JP5580741B2 (ja) * | 2008-09-19 | 2014-08-27 | 武田薬品工業株式会社 | 含窒素複素環化合物およびその用途 |
USRE48334E1 (en) | 2008-09-19 | 2020-12-01 | Takeda Pharmaceutical Company Limited | Nitrogen-containing heterocyclic compound and use of same |
USRE49686E1 (en) | 2008-09-19 | 2023-10-10 | Takeda Pharmaceutical Company Limited | Nitrogen-containing heterocyclic compound and use of same |
JP2012505173A (ja) * | 2008-10-09 | 2012-03-01 | エフ.ホフマン−ラ ロシュ アーゲー | ピロリジンn−ベンジル誘導体 |
JP2012507485A (ja) * | 2008-11-03 | 2012-03-29 | エフ.ホフマン−ラ ロシュ アーゲー | 3−(ベンジルアミノ)−ピロリジン誘導体及びnk−3受容体アンタゴニストとしてのその使用 |
US10894787B2 (en) | 2010-09-22 | 2021-01-19 | Arena Pharmaceuticals, Inc. | Modulators of the GPR119 receptor and the treatment of disorders related thereto |
US11007175B2 (en) | 2015-01-06 | 2021-05-18 | Arena Pharmaceuticals, Inc. | Methods of treating conditions related to the S1P1 receptor |
US11884626B2 (en) | 2015-06-22 | 2024-01-30 | Arena Pharmaceuticals, Inc. | Crystalline L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-penta [b]indol-3-yl)acetic acid(Compound1) for use in S1P1 receptor-associated disorders |
US11534424B2 (en) | 2017-02-16 | 2022-12-27 | Arena Pharmaceuticals, Inc. | Compounds and methods for treatment of primary biliary cholangitis |
Also Published As
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WO2004111000A3 (fr) | 2005-05-26 |
AU2003902882A0 (en) | 2003-06-26 |
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