NZ622539B2 - Diphenoxyphenyl derivative - Google Patents
Diphenoxyphenyl derivative Download PDFInfo
- Publication number
- NZ622539B2 NZ622539B2 NZ622539A NZ62253912A NZ622539B2 NZ 622539 B2 NZ622539 B2 NZ 622539B2 NZ 622539 A NZ622539 A NZ 622539A NZ 62253912 A NZ62253912 A NZ 62253912A NZ 622539 B2 NZ622539 B2 NZ 622539B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- group
- hydroxy
- phenoxy
- fluorophenoxy
- carbonyl
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 claims abstract description 214
- -1 4-hydroxyl-piperidinyl Chemical group 0.000 claims abstract description 163
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims abstract description 68
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 64
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 63
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 49
- 201000010099 disease Diseases 0.000 claims abstract description 28
- 239000003814 drug Substances 0.000 claims abstract description 19
- 230000001404 mediated Effects 0.000 claims abstract description 11
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims abstract description 8
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 28
- 239000011780 sodium chloride Substances 0.000 claims description 27
- 239000002253 acid Substances 0.000 claims description 25
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 24
- 150000003839 salts Chemical class 0.000 claims description 22
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 18
- 125000005843 halogen group Chemical group 0.000 claims description 15
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 14
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 12
- 125000004122 cyclic group Chemical group 0.000 claims description 12
- 239000000651 prodrug Substances 0.000 claims description 11
- 229940002612 prodrugs Drugs 0.000 claims description 11
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- 239000012453 solvate Substances 0.000 claims description 10
- 150000001204 N-oxides Chemical class 0.000 claims description 9
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 8
- 125000004429 atoms Chemical group 0.000 claims description 8
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 7
- 125000004433 nitrogen atoms Chemical group N* 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- XDTMQSROBMDMFD-UHFFFAOYSA-N cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 5
- 125000004430 oxygen atoms Chemical group O* 0.000 claims description 5
- 125000004450 alkenylene group Chemical group 0.000 claims description 4
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims description 3
- 125000004649 C2-C8 alkynyl group Chemical group 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 3
- KQNPFQTWMSNSAP-UHFFFAOYSA-N Isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 claims description 2
- 125000004043 oxo group Chemical group O=* 0.000 claims description 2
- MHCVCKDNQYMGEX-UHFFFAOYSA-N 1,1'-biphenyl;phenoxybenzene Chemical group C1=CC=CC=C1C1=CC=CC=C1.C=1C=CC=CC=1OC1=CC=CC=C1 MHCVCKDNQYMGEX-UHFFFAOYSA-N 0.000 claims 1
- 230000003042 antagnostic Effects 0.000 abstract description 20
- 206010016654 Fibrosis Diseases 0.000 abstract description 11
- 230000004761 fibrosis Effects 0.000 abstract description 11
- LGYZBTDIGHRUDF-UHFFFAOYSA-N 4-[3-[[4-(2-ethylbutyl)-4-hydroxypiperidine-1-carbonyl]amino]-5-(4-fluorophenoxy)phenoxy]benzoic acid Chemical compound C1CC(CC(CC)CC)(O)CCN1C(=O)NC1=CC(OC=2C=CC(F)=CC=2)=CC(OC=2C=CC(=CC=2)C(O)=O)=C1 LGYZBTDIGHRUDF-UHFFFAOYSA-N 0.000 abstract description 10
- 101700071062 S1PR2 Proteins 0.000 abstract description 8
- 102100014087 S1PR2 Human genes 0.000 abstract description 8
- OHOPIJDKZBJLAT-UHFFFAOYSA-N 4-(2-ethylbutyl)-N-[3-[4-(ethylcarbamoyl)phenoxy]-5-(4-fluorophenoxy)phenyl]-4-hydroxypiperidine-1-carboxamide Chemical compound C1=CC(C(=O)NCC)=CC=C1OC1=CC(NC(=O)N2CCC(O)(CC(CC)CC)CC2)=CC(OC=2C=CC(F)=CC=2)=C1 OHOPIJDKZBJLAT-UHFFFAOYSA-N 0.000 abstract description 7
- 206010038683 Respiratory disease Diseases 0.000 abstract description 7
- PZFBUIYFAFMDBM-UHFFFAOYSA-N 4-[3-(4-fluorophenoxy)-5-[[4-(4-fluorophenyl)-4-hydroxypiperidine-1-carbonyl]amino]phenoxy]benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1OC1=CC(NC(=O)N2CCC(O)(CC2)C=2C=CC(F)=CC=2)=CC(OC=2C=CC(F)=CC=2)=C1 PZFBUIYFAFMDBM-UHFFFAOYSA-N 0.000 abstract description 6
- 239000005557 antagonist Substances 0.000 abstract description 6
- DUTVNCJDZOXHAU-UHFFFAOYSA-N 2-[4-[3-[[4-(2-ethylbutyl)-4-hydroxypiperidine-1-carbonyl]amino]-5-(4-fluorophenoxy)phenoxy]phenyl]-2-methylpropanoic acid Chemical compound C1CC(CC(CC)CC)(O)CCN1C(=O)NC1=CC(OC=2C=CC(F)=CC=2)=CC(OC=2C=CC(=CC=2)C(C)(C)C(O)=O)=C1 DUTVNCJDZOXHAU-UHFFFAOYSA-N 0.000 abstract description 3
- 206010047139 Vasoconstriction Diseases 0.000 abstract 2
- 230000025033 vasoconstriction Effects 0.000 abstract 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 214
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 192
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 148
- 239000000243 solution Substances 0.000 description 117
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 82
- 238000006243 chemical reaction Methods 0.000 description 66
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 62
- 238000005160 1H NMR spectroscopy Methods 0.000 description 56
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 53
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 51
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 51
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 44
- HEDRZPFGACZZDS-MICDWDOJSA-N deuterated chloroform Substances [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 39
- 230000000704 physical effect Effects 0.000 description 39
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 38
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 37
- 239000002904 solvent Substances 0.000 description 37
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 35
- CSNNHWWHGAXBCP-UHFFFAOYSA-L mgso4 Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 34
- 239000000203 mixture Substances 0.000 description 34
- 239000008079 hexane Substances 0.000 description 31
- BZLVMXJERCGZMT-UHFFFAOYSA-N MeOtBu Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 28
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 27
- QTBSBXVTEAMEQO-UHFFFAOYSA-M acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 26
- 239000012044 organic layer Substances 0.000 description 25
- 230000002829 reduced Effects 0.000 description 25
- OKKJLVBELUTLKV-MZCSYVLQSA-N cd3od Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 24
- XKRFYHLGVUSROY-UHFFFAOYSA-N argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 20
- 239000005711 Benzoic acid Substances 0.000 description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
- 125000000217 alkyl group Chemical group 0.000 description 18
- 239000007864 aqueous solution Substances 0.000 description 18
- 235000010233 benzoic acid Nutrition 0.000 description 18
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 17
- 235000019341 magnesium sulphate Nutrition 0.000 description 17
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 16
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 16
- 238000000034 method Methods 0.000 description 16
- PMZURENOXWZQFD-UHFFFAOYSA-L na2so4 Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 16
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 15
- 239000012300 argon atmosphere Substances 0.000 description 15
- 238000010511 deprotection reaction Methods 0.000 description 15
- 239000007787 solid Substances 0.000 description 15
- 238000010898 silica gel chromatography Methods 0.000 description 14
- 239000000126 substance Substances 0.000 description 14
- HKSAGIGRQWXHMH-UHFFFAOYSA-N 2-[4-[3-(4-fluorophenoxy)-5-[[3-hydroxy-3-(2-methylpropyl)azetidine-1-carbonyl]amino]phenoxy]phenyl]-2-methylpropanoic acid Chemical compound C1C(CC(C)C)(O)CN1C(=O)NC1=CC(OC=2C=CC(F)=CC=2)=CC(OC=2C=CC(=CC=2)C(C)(C)C(O)=O)=C1 HKSAGIGRQWXHMH-UHFFFAOYSA-N 0.000 description 13
- 239000003795 chemical substances by application Substances 0.000 description 12
- 238000004821 distillation Methods 0.000 description 12
- 229940079593 drugs Drugs 0.000 description 12
- 238000001704 evaporation Methods 0.000 description 12
- 238000000634 powder X-ray diffraction Methods 0.000 description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 12
- 230000000052 comparative effect Effects 0.000 description 11
- 230000000875 corresponding Effects 0.000 description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 11
- 238000001228 spectrum Methods 0.000 description 11
- 229910052786 argon Inorganic materials 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 239000007924 injection Substances 0.000 description 10
- FXHOOIRPVKKKFG-UHFFFAOYSA-N DMA Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 9
- 238000007792 addition Methods 0.000 description 9
- 239000003960 organic solvent Substances 0.000 description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 9
- LWIHDJKSTIGBAC-UHFFFAOYSA-K Tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 8
- 238000000113 differential scanning calorimetry Methods 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- 239000001257 hydrogen Substances 0.000 description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 8
- 229910052739 hydrogen Inorganic materials 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 229910052938 sodium sulfate Inorganic materials 0.000 description 8
- 235000011152 sodium sulphate Nutrition 0.000 description 8
- LJCZNYWLQZZIOS-UHFFFAOYSA-N 2,2,2-Trichlorethoxycarbonyl chloride Chemical compound ClC(=O)OCC(Cl)(Cl)Cl LJCZNYWLQZZIOS-UHFFFAOYSA-N 0.000 description 7
- KTKOYCRHPHGJBN-UHFFFAOYSA-N 4-(2-ethylbutyl)-N-[3-(4-fluorophenoxy)-5-[4-(4-hydroxypiperidine-1-carbonyl)phenoxy]phenyl]-4-hydroxypiperidine-1-carboxamide Chemical compound C1CC(CC(CC)CC)(O)CCN1C(=O)NC1=CC(OC=2C=CC(F)=CC=2)=CC(OC=2C=CC(=CC=2)C(=O)N2CCC(O)CC2)=C1 KTKOYCRHPHGJBN-UHFFFAOYSA-N 0.000 description 7
- UUKSWUYLKRUYEK-UHFFFAOYSA-N 4-(2-methylpropyl)piperidin-4-ol Chemical compound CC(C)CC1(O)CCNCC1 UUKSWUYLKRUYEK-UHFFFAOYSA-N 0.000 description 7
- 210000004027 cells Anatomy 0.000 description 7
- 239000003112 inhibitor Substances 0.000 description 7
- 230000002401 inhibitory effect Effects 0.000 description 7
- 150000002500 ions Chemical class 0.000 description 7
- 150000002989 phenols Chemical class 0.000 description 7
- 230000001225 therapeutic Effects 0.000 description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
- RHMPLDJJXGPMEX-UHFFFAOYSA-N 4-fluorophenol Chemical compound OC1=CC=C(F)C=C1 RHMPLDJJXGPMEX-UHFFFAOYSA-N 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 125000000623 heterocyclic group Chemical group 0.000 description 6
- CPELXLSAUQHCOX-UHFFFAOYSA-N hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 6
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- 239000002997 ophthalmic solution Substances 0.000 description 6
- 230000000069 prophylaxis Effects 0.000 description 6
- 125000006239 protecting group Chemical group 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 230000002792 vascular Effects 0.000 description 6
- 230000002455 vasospastic Effects 0.000 description 6
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 5
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 5
- FJDQFPXHSGXQBY-UHFFFAOYSA-L Caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 5
- 229940082622 Prostaglandin cardiac therapy preparations Drugs 0.000 description 5
- 229940077717 Prostaglandin drugs for peptic ulcer and gastro-oesophageal reflux disease (GORD) Drugs 0.000 description 5
- 241000700159 Rattus Species 0.000 description 5
- XTHFKEDIFFGKHM-UHFFFAOYSA-N dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 5
- 229910052751 metal Inorganic materials 0.000 description 5
- 239000002184 metal Substances 0.000 description 5
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- 229940060184 oil ingredients Drugs 0.000 description 5
- 235000019198 oils Nutrition 0.000 description 5
- 229940094443 oxytocics Prostaglandins Drugs 0.000 description 5
- 239000008194 pharmaceutical composition Substances 0.000 description 5
- 235000021317 phosphate Nutrition 0.000 description 5
- 150000003180 prostaglandins Chemical class 0.000 description 5
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 5
- 229910052708 sodium Inorganic materials 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 5
- 230000001629 suppression Effects 0.000 description 5
- CIISBYKBBMFLEZ-UHFFFAOYSA-N 1,2-oxazolidine Chemical compound C1CNOC1 CIISBYKBBMFLEZ-UHFFFAOYSA-N 0.000 description 4
- CZSRXHJVZUBEGW-UHFFFAOYSA-N 1,2-thiazolidine Chemical compound C1CNSC1 CZSRXHJVZUBEGW-UHFFFAOYSA-N 0.000 description 4
- PJUPKRYGDFTMTM-UHFFFAOYSA-N 1-hydroxybenzotriazole;hydrate Chemical compound O.C1=CC=C2N(O)N=NC2=C1 PJUPKRYGDFTMTM-UHFFFAOYSA-N 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 4
- VSMDINRNYYEDRN-UHFFFAOYSA-N 4-iodophenol Chemical compound OC1=CC=C(I)C=C1 VSMDINRNYYEDRN-UHFFFAOYSA-N 0.000 description 4
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M Lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 4
- VHRSUDSXCMQTMA-PJHHCJLFSA-N Methylprednisolone Chemical compound C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@](O)(C(=O)CO)CC[C@H]21 VHRSUDSXCMQTMA-PJHHCJLFSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- OIGNJSKKLXVSLS-VWUMJDOOSA-N Prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 4
- OGYGFUAIIOPWQD-UHFFFAOYSA-N Thiazolidine Chemical compound C1CSCN1 OGYGFUAIIOPWQD-UHFFFAOYSA-N 0.000 description 4
- 102000003938 Thromboxane Receptors Human genes 0.000 description 4
- 108090000300 Thromboxane Receptors Proteins 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N Triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- 230000002378 acidificating Effects 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 230000003834 intracellular Effects 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 229960004584 methylprednisolone Drugs 0.000 description 4
- 230000003287 optical Effects 0.000 description 4
- WYNCHZVNFNFDNH-UHFFFAOYSA-N oxazolidine Chemical compound C1COCN1 WYNCHZVNFNFDNH-UHFFFAOYSA-N 0.000 description 4
- 239000010452 phosphate Substances 0.000 description 4
- 239000001184 potassium carbonate Substances 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 229910000160 potassium phosphate Inorganic materials 0.000 description 4
- 102000005962 receptors Human genes 0.000 description 4
- 108020003175 receptors Proteins 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 150000003431 steroids Chemical class 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 235000019798 tripotassium phosphate Nutrition 0.000 description 4
- HCHKCACWOHOZIP-UHFFFAOYSA-N zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 4
- HCNPUNDFLQNIOB-UHFFFAOYSA-N 2-[4-[3-(4-fluorophenoxy)-5-[[4-hydroxy-4-(2-methylpropyl)piperidine-1-carbonyl]amino]benzoyl]oxyphenyl]-2-methylpropanoic acid Chemical compound C1CC(CC(C)C)(O)CCN1C(=O)NC1=CC(OC=2C=CC(F)=CC=2)=CC(C(=O)OC=2C=CC(=CC=2)C(C)(C)C(O)=O)=C1 HCNPUNDFLQNIOB-UHFFFAOYSA-N 0.000 description 3
- 208000006673 Asthma Diseases 0.000 description 3
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Classifications
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
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- A—HUMAN NECESSITIES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
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- A—HUMAN NECESSITIES
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/453—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
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- A—HUMAN NECESSITIES
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Abstract
The disclosure relates to a family of compounds represented by general formula (I-1) (where all of the symbols are as defined in the specification) and its use as a S1P2 antagonist. The disclosure also relates to the use of this compounds use as a therapeutic agent for S1P-mediated disease, such as vasoconstriction-related disease, fibrosis, respiratory disease, and the like. Example compounds include: 4-(2-ethylbutyl)-N-{3-[4-(ethylcarbamoyl)phenoxy]-5-(4-fluorophenoxy)phenyl}-4-hydroxy-1-piperidine carboxamide, 4-[3-(4-fluorophenoxy)-5-({[4-(4-fluorophenyl)-4-hydroxyl-piperidinyl]carbonyl}amino)phenoxy]benzoic acid, 4-(2-ethylbutyl)-N-[3-(4-fluorophenoxy)-5-{4-[(4-hydroxyl-piperidinyl)carbonyl]phenoxy}phenyl]-4-hydroxy-1-piperidinyl)carbonyl]phenoxy}phenyl]-4-hydroxy-1-piperidinecarboxamide, 2-{4-[3-(4-fluorophenoxy)-5-{[(4-'hydroxy-4-isobutyl-1-piperidinyl)carbonyl]amino}phenoxy]phenyl}-2-methylpropanoic acid, 4-[3-({[4-(2-ethylbutyl)-4-hydroxy-1-piperidinyl]carbonyl}amino)-5-(4-fluorophenoxy)phenoxy]benzoic acid, 2-{4-[3-({[4-(2-ethylbutyl)-4-hydroxy-1-piperidinyl]carbonyl}amino)-5-(4-fluorophenoxy)phenoxy]phenyl}-2-methylpropanoic acid, 2-(4-{[3-(4-fluorophenoxy)-5-{[(4-hydroxy-4-isobutyl-lpiperidinyl)carbonyl]amino}benzoyl]oxy}phenyl)-2-methylpropanoic acid. vasoconstriction-related disease, fibrosis, respiratory disease, and the like. Example compounds include: 4-(2-ethylbutyl)-N-{3-[4-(ethylcarbamoyl)phenoxy]-5-(4-fluorophenoxy)phenyl}-4-hydroxy-1-piperidine carboxamide, 4-[3-(4-fluorophenoxy)-5-({[4-(4-fluorophenyl)-4-hydroxyl-piperidinyl]carbonyl}amino)phenoxy]benzoic acid, 4-(2-ethylbutyl)-N-[3-(4-fluorophenoxy)-5-{4-[(4-hydroxyl-piperidinyl)carbonyl]phenoxy}phenyl]-4-hydroxy-1-piperidinyl)carbonyl]phenoxy}phenyl]-4-hydroxy-1-piperidinecarboxamide, 2-{4-[3-(4-fluorophenoxy)-5-{[(4-'hydroxy-4-isobutyl-1-piperidinyl)carbonyl]amino}phenoxy]phenyl}-2-methylpropanoic acid, 4-[3-({[4-(2-ethylbutyl)-4-hydroxy-1-piperidinyl]carbonyl}amino)-5-(4-fluorophenoxy)phenoxy]benzoic acid, 2-{4-[3-({[4-(2-ethylbutyl)-4-hydroxy-1-piperidinyl]carbonyl}amino)-5-(4-fluorophenoxy)phenoxy]phenyl}-2-methylpropanoic acid, 2-(4-{[3-(4-fluorophenoxy)-5-{[(4-hydroxy-4-isobutyl-lpiperidinyl)carbonyl]amino}benzoyl]oxy}phenyl)-2-methylpropanoic acid.
Description
DESCRIPTION
DIPHENOXYPHENYL DERIVATIVE
TECHNICAL FIELD
The present invention relates to a compound
represented by the formula (I-1):
[C 1]
n all the symbols have the same meanings as described
hereinbelow, and a salt thereof, a e thereof, an N-oxide
thereof or a prodrug thereof (hereinafter sometimes
abbreviated as the present compound).
BACKGROUND ART
Sphingosinephosphate R,4E)amino
yoctadecaenylphosphate; hereinafter sometimes
abbreviated as S1P] is a lipid which is synthesized by
lic turnover of sphingolipids or extracellular action of
secretory sphingosine kinases. It is proposed that this lipid
acts as an intercellular transmitter and an intracellular
secondary transmitter.
With regard to S1P2 (EDG-5/AGR16/H218) receptors
among S1P receptors, it has been published that the strong
expression of mRNA thereof is med in tissues of heart,
lung, stomach and small intestine and that the expression
amount of mRNA f in intimal cells in model mice of
carotid balloon injury which are the model for coronary
arteriosclerosis is significantly decreased compared to normal
intimal cells (see Patent Document 1).
It is also reported that SlP receptors (particularly
SlP2 receptors) are involved in portal hypertension, asthma and
the like (see Non Patent Document 1). It is also known that
the receptors are involved in expression of connective tissue
growth factors (CTGFs) associated with onset of fibrosis,
cancer and the like (see Non Patent Document 2).
The following compounds are known as the related art
of the present invention.
As the compounds having Sle antagonistic activity,
pyrazopyridine nds or ceutically acceptable salts
thereof represented by the formula (a):
[C 2]
R33 /\R4a R5a
/ /\\i
I xa:ya:za__wa__ __ Asa/3 (a)
N N/ \Rs"
R1a/
wherein R”, R2a and R3a represent a Cl—8 alkyl group and the
like; R4a represents a hydrogen atom and the like; Rfi'and R6a
are the same or different and represent a hydrogen atom, a Cl—
8 alkyl group, a Cl—6 alkoxy group, a halogen atom and the
like; Xa represents ~NH—, —O—, -CH2— and the like; Ya
represents —NH— and the like; Za represents —CO— and the like;
Wa represents —NH— and the like ; and the ring Aa represents an
aryl group, a heteroaryl group and the like (the definitions
of respective groups are abstracted), have been disclosed
which ically act on Sle ors and are useful as
eutics for fibrosis (see Patent Document 2).
The known compounds having SlP2 antagonistic ty
also include compounds having a piperidine skeleton
represented by the formula (b):
[C 3]
Ab-xb-Yb-zb-Bb (b)
wherein A? represents a cyclic group which may contain a
substituent; Xb represents a single bond or a spacer having 1
to 3 atoms in the main chain; Yb represents a single bond or a
spacer having 1 to 3 atoms in the main chain; Zb is a single
bond or a spacer having 1 to 3 atoms in the main chain; and Bb
represents a cyclic group which may contain a substituent (see
Patent Document 3) and nds having an azetidine skeleton
(see Patent nt 4).
Meanwhile, as the compounds having a benzene
skeleton substituted with two cyclic groups, the compounds
represented by the formula (c):
[C 4]
R ° 0° R10 R3“
1I\<§j\ EQ/él R c
o A p2c BX (c)
wherein Pf and Pf independently represent a bond or a Cb3
alkyl; A? represents CH or N; Bc represents CH or N; Rf
'represents a hydrogen, an amino, —NRf—CO-Z%@CRBC and the like;
Rf represents ?C(NRyf)NH2 or when A? is CH, Rf also represents
an amino CLq alkyl; Rmc, RHC and Rmc independently represent a
hydrogen, a halogen, a C14 alkyl and the like; QC represents a
en or a halogen; Rf represents a hydrogen or a CL7
alkyl; Zc is a 5— to lZ—membered saturated, lly saturated
or aromatic ring which may be monocyclic or bicyclic; Rf and
REC independently represent a en, a halogen, a CLJ alkyl
and the like; szrepresents a qu alkyl, a phenyl which may be
substituted and the like; and RUG represents a hydrogen, —OH,
a C14 alkoxy and the like (the definitions of respective
groups are abstracted), are known as matriptase tors
(see Patent Document 5).
No prior art documents discloses or suggests that
the compound of the invention which contains two cyclic groups,
particularly y groups at specific substitution positions
have significantly improved human Sng antagonistic activity.
Patent Document 1: Japanese Patent Application Laid—
open No. H6-234797
Patent nt 2: WO 01/98301
Patent nt 3: WO 02531
Patent Document 4:
Patent Document 5:
Non Patent Document 1: Biochemical and Biophysical
Research Communications, vol. 320, No. 3, p. 754-759, 2004
Non Patent Document 2: Molecular Cancer Research, vol. 6,
No. 10, p. 1649-1656, 2008
DISCLOSURE OF THE INVENTION
A m of the present invention is to find a
compound having human S1P2 antagonistic activity which was
insufficiently exhibited by the compounds disclosed in Patent
Document 3, to improve the solubility of the nd and to
provide a medicinal product thereof, or at least to provide a
useful alternative to known human S1P2 antagonist nds.
The present ors have carried out extensive
studies in order to solve the above problem to find the
compound having improved human S1P2 antagonistic activity. As
a result, the present inventors have found that the compound
having two cyclic groups, particularly phenoxy groups, at
certain substitution positions have significantly improved
human S1P2 antagonistic activity compared to the nds
disclosed in Patent Document 3, thereby completing the present
invention.
Thus the present invention relates to:
a compound represented by the formula (I-1):
[C 5]
wherein R1 represents (1) a C1—8 alkyl group which may be
substituted with 1 to 5 Rm'group(s), (2) a C2—8 l group
which may be substituted with 1 to 5 R21 group(s), (3)a C2—8
alkynyl group which may be substituted with 1 to 5 R21 group(s),
(4) a C3-7 carbocycle which may be tuted with 1 to 5
tuent(s) selected from the group consisting of a C1—4
alkyl group, a C1—4 haloalkyl group, a C1—4 alkoxy group and a
halogen atom, or (5) —CONRMR”;
Rm'represents (1) a halogen atom, (2) —OR22 (wherein, R22
represents (1) a hydrogen atom, (2) a C1—4 alkyl group or (3)
a C1—4 haloalkyl group), (3) —NR23R24 (wherein, R23 and R24 each
ndently ent (1) a hydrogen atom or (2) a C1-4
alkyl group) or (4) an oxo group;
R31 and R32 each independently represent (1) a hydrogen atom or
(2) a C1—4 alkyl group;
R2 represents (1) a hydrogen atom, (2) a C1—4 alkyl group or
(3) a C1—4 kyl group;
R3 and R4 each independently represent (1) a halogen atom, (2)
a C1—4 alkyl group, (3) a Cl—4 haloalkyl group, (4) a C1—4
alkoxy group, (5) a hydroxy group, (6) —L—CONR6R7, (7) —L-SOZR8
or (8) —L—COOR9;
R5 represents (1) a halogen atom, (2) a C1-4 alkyl group or (3)
a C1—4 haloalkyl group;
L represents (1) a bond, (2) a group represented by the
formula:
[C 6]
wherein A represents (1) a bond or (2) an oxygen atom; R12 and
R13 each independently represent (1) a hydrogen atom, (2) a C1—
4 alkyl group, (3) a hydroxy group or (4) NH2 or (5) R12 and R13
together with the carbon atom to which they are attached may
form a C3—7 carbocycle; and the arrow on the right hand side
binds to -CONR§R7, -SOZR8 or —COOR9, (3) a C2—4 alkenylene group,
(4) a —O—C2—4 alkenylene group, (5) an oxygen atom or (6) a
nitrogen atom which may be tuted with a Cl—4 alkyl
group;
R6 and R7 each independently represent (1) a hydrogen atom, (2)
a Cl—4 alkyl group, (3) a Cl—4 haloalkyl group, (4) a hydroxy
group, (5) —CONR15R16, (6) ~SOZNR15R16, (7) —COR17 or (8) -SOZR17,
or R6 and R7 together with the nitrogen atom to which they are
attached may form a 4— to 7—membered en-containing
saturated heterocycle that may be substituted with a hydroxy
group;
R8 ents (1) a Cl—4 alkyl group, (2) a Cl—4 haloalkyl
group or (3) NRmRiH
R9 represents (1) a hydrogen atom or (2) a Cl—8 alkyl group;
R10 and R11 each independently ent (1) a hydrogen atom,
(2) a c1—4 alkyl group, (3) —CONR15R16, (4) —SOZNR15R16, (5) —
COR” or (6) —SOZR17;
the ring 1 and the ring 2 each independently represent a 5— to
7—membered cyclic group;
R14 represents (1) a hydrogen atom or (2) a hydroxy group;
R15 and R16 each independently ent (1) a hydrogen atom,
(2) a C1—4 alkyl group or (3) a 5— to 7—membered cyclic group;
R17 represents (1) a Cl—4 alkyl group or (2) a 5— to 7—membered
cyclic group;
M1 and M2 each ndently represent (1) a bond, (2) —C(O)—,
(3) —O—, (4) —S—, (5) —C(O)O—, (6) —CH20— or (7) —C(O)NH—;
WHQ'UBS represents an integer of 1 to 2;
represents an integer of to a
represents an integer of to ‘-
represents an integer of to
represents an integer of OOOH to ‘-
represents an integer of l to .musowmm -
when p is 2 or more, a plurality of R3 groups may be the same
or different;
when q is 2 or more, a plurality of R4 groups may be the same
or different;
when r is 2 or more, a plurality of R5 groups may be the same
or different; and
when t is 2 or more, a plurality of R12 and R13 groups may be
respectively the same or different;
a salt thereof, a solvate f, an N—oxide thereof or a
prodrug thereof;
the compound according to [1], wherein R14 is a hydroxy
group;
the compound according to [1] or [2], wherein M1 and M2
each independently are (1) —C(O)—, (2) —O—, (3) —S-, (4) -
C(O)O— or (5) —CH20-;
the compound according to [3], n M1 and M2 are —O—;
the compound according to [1], which is represented by the
formula (I):
[C 7]
WW/N N 0
0 (R3)p
wherein all the symbols have the same meanings as above;
the compound ing to [5], wherein R1 is (1) a C1~8
alkyl group which may be substituted with l to 5 R21 group(s)
or (2) a C3—7 carbocycle which may be substituted with 1 to 5
substituent(s) selected from the group consisting of a C1—4
alkyl group, a C1—4 alkoxy group, a n atom and a
trifluoromethyl group;
the compound according to [5] or [6], wherein R2 is a
en atom;
the compound according to any of [5] to [7], wherein the
ring 1 and the ring 2 each independently are (1) a benzene,
(2) cyclohexane or (3) pyridine ring;
the compound according to any of [1] to [8], which is (1)
4—(2—ethylbutyl)~N—{3~[4—(ethylcarbamoyl)phenoxy]~5—(4—
fluorophenoxy)phenyl}—4—hydroxy—l—piperidinecarboxamide, (2)
4—[3—(4-fluorophenoxy)—5—({[4—(4—fluorophenyl)—4—hydroxy—l—
piperidinyl]carbonyl}amino)phenoxy]benzoic acid, (3) 4—(2—
ethylbutyl)—N—[3—(4—fluorophenoxy)—5—{4—[(4—hydroxy—1—
piperidinyl)carbonyl]phenoxy}phenyl]—4—hydroxy—1—
piperidinecarboxamide, (4) 2—{4—[3—(4—fluorophenoxy)—5—{[(4—
y—4—isobutyl—1—
dinyl)carbonyl]amino}phenoxy]phenyl}—2—methylpropanoic
acid, (5) 1—{4—[3—(4—fluorophenoxy)—5—({[4—hydroxy(3—
pentany1)—1—
piperidinyl]carbonyl}amino)phenoxy]phenyl)cyclopropanecarboxyl
ic acid, (6) 2-{4—[3—(4—fluorophenoxy)¥5—{[(3—hydroxy-3—
isobutyl-l—azetidinyl)carbonyl]amino}phenoxy]phenyl}—2-
methylpropanoic acid, (7) {[4—(2—ethylbutyl)—4—hydroxy—
1—piperidinyl]carbonyl}amino)—5-(4—
fluorophenoxy)phenoxy]benzoic acid, (8) 2—{4—[3—({[4-(2—
ethylbutyl)—4—hydroxy—1—piperidinyl]carbonyl}amino)—54(4—
fluorophenoxy)phenoxy]phenyl)—2—methylpropanoic acid or (9) 2—
(4—{[3—(4—fluorophenoxy)—5-{[(4—hydroxy—4—isobutyl—1—
piperidinyl)carbonyl]amino}benzoyl]oxy}phenyl)—2—
methylpropanoic acid;
a pharmaceutical composition containing the compound
represented by the formula (1—1) according to [1], the salt
thereof, the solvate thereof, the N—oxide thereof or the
g thereof;
the ceutical composition according to [10], which
is a Sng antagonist;
the pharmaceutical composition according to [10], which
is a prophylactic and/or therapeutic agent for a Sle—mediated
disease;
the pharmaceutical composition according to [12], wherein
the Sle—mediated disease is a disease resulting from vascular
constriction, fibrosis, respiratory disease, arteriosclerosis,
peripheral arterial occlusive disease, retinopathy, glaucoma,
age—related macular degeneration, nephritis, diabetes,
dyslipidemia, tis, hepatic cirrhosis, hepatic failure,
neuropathy, rheumatoid arthritis, wound, pain, ria,
systemic lupus erythematosus (SLE) or cancer;
the ceutical ition according to [13], wherein
the disease resulting from vascular constriction is cerebral
vasospastic disease, cardiac vasospastic disease, coronary
vasospastic disease, hypertension, ary hypertension,
myocardial infarction, angina, arrhythmia, portal hypertension,
varix or ischemia—reperfusion injury;
the pharmaceutical composition according to [13], wherein
the fibrosis is pulmonary fibrosis, hepatic fibrosis, kidney
fibrosis, myocardial fibrosis or skin fibrosis;
the pharmaceutical composition according to [13], wherein
the respiratory disease is bronchial asthma, acute lung injury,
sepsis or chronic obstructive ary disease;
a method of ting and/or treating a SlPZ—mediated
disease, comprising administering to a mammal an effective
amount of the nd represented by the formula (I—l)
according to [1], the salt thereof, the solvate thereof, the
N—oxide thereof or the prodrug thereof;
a compound represented by the formula (1—1) according to
, the salt thereof, the solvate thereof, the N-oxide
thereof or the prodrug thereof in use for prophylaxis and/or
therapy of a Sng—mediated disease; and
use of the compound represented by the formula (I—l)
according to [1], the salt thereof, the solvate thereof, the
N—oxide thereof or the prodrug thereof for producing a
prophylactic and/or therapeutic agent for a Sle—mediated
disease.
The present nd has strong human Sle
antagonistic activity, and thus is useful for therapy of Sle—
mediated diseases such as diseases resulting from ar
constriction and fibrosis.
BRIEF DESCRIPTION OF THE GS
Fig. 1 is an X—ray powder diffraction spectrum chart
of a crystal of the present compound le A);
Fig. 2 is a differential ng calorimetric (DSC)
chart of a crystal of the present compound (Example A);
Fig. 3 is an X—ray powder diffraction spectrum chart of a
crystal of the t compound (Example B);
Fig. 4 is a ential scanning calorimetric (DSC)
chart of a l of the present compound (Example B);
Fig. 5 is an X—ray powder diffraction spectrum Chart of a
crystal of the present compound (Example C); and
Fig. 6 is a differential scanning metric (DSC)
chart of a l of the present compound (Example C).
BEST MODE FOR CARRYING OUT THE INVENTION
The present invention is described in detail
hereinbelow.
The halogen atom as used herein may include fluorine,
chlorine, bromine or iodine.
The C1-8 alkyl group as used herein may include
linear or branched C1—8 alkyl groups which may include, for
example, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl,
octyl, isopropyl, isobutyl, sec—butyl, tert—butyl, 1—
methylbutyl, 1—ethylpropy1, 1,1-dimethylpropyl, 1,2—
dimethylpropyl, 2-methylbutyl, 3—methylbutyl, 2,2—
dimethylpropyl, 1—methylpentyl, lbutyl, 2—ethylbutyl, 1—
ethyl—l—methylpropyl, 1—ethyl-2—methylpropyl, 1,1—
dimethylbutyl, 1,2—dimethylbutyl, methylbutyl, 2—
methylpentyl, 3-methylpentyl, 4—methylpentyl, 2,3-
dimethylbutyl, 1—methylhexyl, 1—ethylpentyl, lpentyl, 1—
propylbutyl, 2—methyl—3—hexyl, 1,2—dimethylpentyl, 1,3—
dimethylpentyl, 1,4—dimethy1pentyl, 1—ethyl—1—methylbutyl, 1—
methyl—Z—ethylbutyl, 1—ethyl—2—methylbutyl, 1—ethyl-3—
methylbutyl, 1,1-dimethylpentyl, 1,1,3—trimethylbutyl, 1,1—
lpropyl, 2-methylhexyl, 3-methylhexyl, 4—methylhexyl, 5—
methylhexyl, 3-ethylpentyl, ylheptyl, 2—methylheptyl, 3—
methylheptyl, ylheptyl,~5—methylheptyl, 6—methylheptyl,
l—ethylhexyl, 2—ethylhexyl, 3—ethylhexyl, 1—propylpentyl, 2—
propylpentyl, 1,5-dimethylhexyl, 1—ethyl—4—methylpentyl, 1—
propyl—3—methylbutyl, 1,1—dimethylhexyl, 1—ethyl-1—
methylpentyl or ethylbuty1 groups.
The C1—4 alkyl group as used herein may include
linear or ed C1—4 alkyl groups which may include, for
example, methyl, ethyl, propyl, butyl, isopropyl, isobutyl,
sec—butyl or tert—butyl groups.
The C1—4 haloalkyl group as used herein may include
a fluoromethyl group, a chloromethyl group, a bromomethyl
group, an iodomethyl group, a difluoromethyl group, a
trifluoromethyl group, a l—fluoroethyl group, a 2—fluoroethyl
group, a 2—chloroethyl group, a pentafluoroethyl group, a l—
fluoropropyl group, a 2—chloropropyl group, a 3—fluoropropyl
group, a 3—chloropropyl group, a trifluorobutyl group or
a 4—bromobutyl group.
The C2—8 alkenyl group as used herein may include
linear or branched C2—8 alkenyl groups which may include, for
example, Vinyl, propenyl, l, pentenyl, hexenyl,
hexadienyl, heptenyl, heptadienyl, octenyl, octadienyl, 2-
methylpropen—l—yl, 2-ethyl—l—buten—l—yl, ylbuten—2—yl or
ylpenten~2—yl groups.
The C2—4 alkenylene group as used herein may include
ethenylene, ylene or butenylene groups.
The C2~8 alkynyl group as used herein may include
linear or branched C2—8 alkynyl groups which may include, for
example, ethynyl, yl, butynyl, pentynyl, hexynyl,
hexadiynyl, yl, heptadiynyl, octynyl, ynyl or 3,3—
dimethyl—l-butyn—l—yl groups.
The Cl—4 alkoxy group as used herein may include,
for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy,
isobutoxy, sec—butoxy or tert—butoxy groups.
The C3—7 ycle as used herein means a C3—7
monocyclic carbocycle or a C3—7 carbocycle which may be
partially or fully saturated and may include, for example,
cyclopropane, cyclobutane, cyclopentane, cyclohexane,
cycloheptane, cyclobutene, cyclopentene, cyclohexene,
cycloheptene, cyclobutadiene, cyclopentadiene, cyclohexadiene,
cycloheptadiene or benzene rings.
The C5—7 carbocycle as used herein means a C5—7
monocyclic carbocycle or a C5—7 carbocycle which may be
partially or fully saturated and may include, for e,
cyclopentane, cyclohexane, cycloheptane, cyclopentene,
cyclohexene, cycloheptene, cyclopentadiene, cyclohexadiene,
cycloheptadiene or benzene rings.
The 4— to 7—membered nitrogen—containing saturated
heterocycle as used herein refers to partially or fully
saturated 4— to 7—membered monocyclic heterocycles which
n 1 to 5 hetero atoms selected from an oxygen atom, a
nitrogen atom and a sulphur atom and inevitably contain one or
more nitrogen atoms. For example, ine, pyrroline,
pyrrolidine, imidazoline, imidazolidine, triazoline,
triazolidine, tetrazoline, tetrazolidine, pyrazoline,
lidine, dihydropyridine, tetrahydropyridine, piperidine,
dihydropyrazine, tetrahydropyrazine, piperazine,
dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine,
dihydropyridazine, tetrahydropyridazine, perhydropyridazine,
dihydroazepine, ydroazepine, perhydroazepine,
dihydrodiazepine, tetrahydrodiazepine, perhydrodiazepine,
dihydrooxazole, tetrahydrooxazole (oxazolidine),
dihydroisooxazole, tetrahydroisooxazole (isooxazolidine),
dihydrothiazole, tetrahydrothiazole (thiazolidine),
dihydroisothiazole, tetrahydroisothiazole (isothiazolidine),
dihydrofurazan, ydrofurazan, dihydrooxadiazole,
tetrahydrooxadiazole azolidine), dihydrooxazine,
tetrahydrooxazine, dihydrooxadiazine, tetrahydrooxadiazine,
dihydrooxazepine, tetrahydrooxazepine, perhydrooxazepine,
dihydrooxadiazepine, tetrahydrooxadiazepine,
perhydrooxadiazepine, dihydrothiadiazole,
tetrahydrothiadiazole iazolidine), dihydrothiazine,
tetrahydrothiazine, dihydrothiadiazine, tetrahydrothiadiazine,
dihydrothiazepine, tetrahydrothiazepine, perhydrothiazepine,
dihydrothiadiazepine, tetrahydrothiadiazepine,
perhydrothiadiazepine, line or rpholine rings may
be mentioned.
The 5— to 7—membered cyclic group as used herein
means a C5—7 carbocycle and a 5— to 7—membered heterocycle.
The C5—7 carbocycle has the same meaning as above and the 5—
to 7—membered heterocycle may include 5— to 7—membered
unsaturated heterocycles and 5- to 7—membered saturated
heterocycles. The 5— to 7—membered heterocycles may include,
for example, pyrroline, pyrrolidine, imidazoline,
olidine, triazoline, triazolidine, tetrazoline,
tetrazolidine, pyrazoline, pyrazolidine, dihydropyridine,
tetrahydropyridine, piperidine, dihydropyrazine,
tetrahydropyrazine, piperazine, dihydropyrimidine,
tetrahydropyrimidine, ropyrimidine, dihydropyridazine,
tetrahydropyridazine, perhydropyridazine, dihydroazepine,
ydroazepine, perhydroazepine, dihydrodiazepine,
ydrodiazepine, perhydrodiazepine, dihydrofuran,
tetrahydrofuran, opyran, tetrahydropyran, dihydrooxepin,
tetrahydrooxepin, perhydrooxepin, dihydrothiopehene,
tetrahydrothiopehene, dihydrothiopyran, tetrahydrothiopyran,
dihydrothiepine, tetrahydrothiepine, perhydrothiepine,
dihydrooxazole, tetrahydrooxazole (oxazolidine),
dihydroisooxazole, tetrahydroisooxazole (isooxazolidine),
dihydrothiazole, tetrahydrothiazole (thiazolidine),
dihydroisothiazole, tetrahydroisothiazole (isothiazolidine),
dihydrofurazan, tetrahydrofurazan, dihydrooxadiazole,
tetrahydrooxadiazole (oxadiazolidine), ooxazine,
tetrahydrooxazine, dihydrooxadiazine, tetrahydrooxadiazine,
dihydrooxazepine, tetrahydrooxazepine, perhydrooxazepine,
dihydrooxadiazepine, tetrahydrooxadiazepine,
perhydrooxadiazepine, dihydrothiadiazole,
tetrahydrothiadiazole (thiadiazolidine), dihydrothiazine,
tetrahydrothiazine, dihydrothiadiazine, tetrahydrothiadiazine,
dihydrothiazepine, tetrahydrothiazepine, perhydrothiazepine,
dihydrothiadiazepine, tetrahydrothiadiazepine,
perhydrothiadiazepine, morpholine, thiomorpholine, oxathiane,
dioxolane, dioxane, dithiolane, dithiane, pyrrole, imidazole,
le, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine,
pyridazine, azepine, diazepine, furan, pyran, oxepin,
thiopehene, thiopyran, thiepine, e, isooxazole, thiazole,
azole, furazan, oxadiazole, oxazine, oxadiazine,
oxazepine, oxadiazepine, azole, thiazine, thiadiazine,
thiazepine or thiadiazepine rings.
In the present invention, R1 is preferably a C1—8
alkyl group which may be substituted with 1 to 5 R21 group(s)
or a C3—7 carbocycle which may be substituted with 1 to 5
substituent(s) selected from the group consisting of a C1—4
alkyl group, a C1—4 haloalkyl group, a C1—4 alkoxy group and a
n atom, and more preferably a ed C1—8 alkyl group
or a benzene, cyclopropane, cyclopentane, cyclohexane or
eptane ring which may be substituted with 1 to 5
tuent(s) selected from the group consisting of a halogen
atom and a trifluoromethyl group. The branched Cl-8 alkyl
group is preferably an isopropyl, isobutyl, 2—ethylbutyl, 2—
methylpentyl or 3—methylpentyl group.
In the present invention, R2 is preferably a hydrogen
atom.
In the present invention, R3 is preferably a halogen atom
or —L—COOR9.
In the present invention, R4 is preferably a halogen atom
or R9.
In the present invention, R5 is preferably a halogen atom
or a Cl—4 alkyl group.
In the present invention, the ring I is preferably a
benzene, pyridine or cyclohexane ring and more preferably a
benzene ring.
In the present invention, the ring 2 is preferably a
benzene, ne or exane ring and more preferably a
benzene ring.
In the present invention, R14 is preferably a hydroxy
group.
In the present invention, when M1 represents —C(O)O—,
—CH20— or —C(O)NH—, the orientation of binding of the
respective groups is not ularly limited; however it is
preferable that the bond on the right hand side of the
respective groups binds to the ring 1.
In the present ion, when M2 represents —C(O)O—, —
CHZO— or -C(O)NH—, the orientation of binding of the tive
groups is not particularly limited; however it is preferable
that the bond on the right hand side of the respective groups
binds to the ring 2.
In the present invention, M1 is preferably —C(O)—, —
0—, —S—, —C(O)O— or —CH20— and more preferably —O—.
In the present ion, M2 is preferably —C(O)—, —O—, —
S—, —C(O)O— or —CH20— and more preferably —O—.
In the present ion, the compound represented
by the formula (I—l) is preferably the nd represented by
the formula (I). '
In the present invention, the preferable compounds
include the compounds described in Examples and more
preferably (1) 4—(2—ethylbutyl)—N—{3—[4—
(ethylcarbamoyl)phenoxy]—5-(4—fluorophenoxy)phenyl}—4—hydroxy—
l—piperidine carboxamide, (2) 4—[3—(4—fluorophenoxy)—5—({[4-
(4—fluorophenyl)—4—hydroxy—l—
dinyl]carbonyl)amino)phenoxy]benzoic acid, (3) 4—(2—
ethylbutyl)-N—[3—(4—fluorophenoxy)-5—{4—[(4—hydroxy—l-
piperidinyl)carbonyl]phenoxy}phenyl]—4—hydroxy—l—piperidine
carboxamide, (4) 2—{4—[3—(4—fluorophenoxy)—5—{[(4—hydroxy—4—
yl-l-piperidinyl)carbonyl]amino}phenoxy]phenyl}—2-
methylpropanoic acid, (5) 1—{4—[3—(4—fluorophenoxy)—5—({[4-
hydroxy—4—(3—pentanyl)—l—
piperidinyl]carbonyl}amino)phenoxy]phenyl}cyclopropanecarboxyl
ic acid, (6) 2—{4-[3—(4—fluorophenoxy)—5—{[(3—hydroxy—3-
isobutyl—l—azetidinyl)carbonyl]amino}phenoxy]phenyl}—2—
methylpropanoic acid, (7) 4—[3—({[4—(2—ethylbutyl)—4—hydroxy—
l—piperidinyl]carbonyl}amino)-5—(4-
fluorophenoxy)phenoxy]benzoic acid, (8) 2—{4—[3—({[4—(2—
ethylbutyl)-4—hydroxy—l—piperidinyl]carbonyl}amino)—5—(4—
phenoxy)phenoxy]phenyl}—2—methylpropanoic acid, and (9)
2—(4—{[3—(4—fluorophenoxy)—5—{[(4—hydroxy—4—isobutyl-l-
piperidinyl)carbonyl]amino}benzoyl]oxy}phenyl)
methylpropanoic acid.
[Isomers]
The present ion encompasses all isomers unless
particularly stated. For example, the alkyl group includes
linear and branched groups. Moreover, the t invention
encompasses geometrical isomers for double bonds, rings and
condensed rings (E—forms, Z—forms, cis forms and trans ,
optical isomers due to asymmetrical carbon atoms (R and S
forms, a and B configurations, enantiomers and diastereomers),
optically active substances having optical rotating activity
(D, L, d and 1 , polar substances which can be separated
by chromatography (high polarity substances and low polarity
substances), equilibrium compounds, rotamers, mixtures thereof
at ary proportions and racemic mixtures. The present
invention also encompasses tautomers.
The optical isomers according to the present
invention may include not only the ones with 100% purity but
also the ones ning other optical isomers at less than
50%.
In the present invention, unless particularly stated,
the symbol:
[C 8]
indicates that the bond projects below the plane of the paper
(i.e. a configuration), the symbol:
[C 9]
indicates that the bond projects above the plane of the paper
(i.e. B configuration), and the symbol:
[C 10]
indicates that the bond is the a uration, the B
configuration or the mixture of these configurations at
arbitrary proportions, as apparent to a person skilled in the
art.
The nd represented by the formula (I—l) is
converted to a salt by the well—known method. The salt is
preferably water—soluble. Appropriate salts may include alkali
metal (potassium, sodium and the like) salts, alkaline earth
metal (calcium, magnesium and the like) salts, ammonium salts,
pharmaceutically able organic amine (tetramethylammonium,
triethylamine, methylamine, dimethylamine, cyclopentylamine,
benzylamine, hylamine, piperidine, monoethanolamine,
nolamine, tris(hydroxymethyl)aminomethane, lysine,
arginine, N—methyl—D—glucamine and the like) salts, acid
addition salts (inorganic acid salts (hydrochlorides,
hydrobromides, hydroiodides, sulphates, phosphates, nitrates
and the like), c acid salts (acetates, trifluoroacetates,
lactates, tartrates, oxalates, fumarates, maleates, benzoates,
citrates, methanesulphonates, ethanesulphonates,
benzenesulphonates, toluenesulphonates, isethionates,
glucuronates, gluconates and the like) and the like) and the
like.
The compound represented by the a (I—1) and
the salt thereof can also be converted to a solvate. The
solvate preferably has low toxicity and is water—soluble.
Appropriate solvates may e, for e, solvates with
water and alcoholic solvents (e.g. ethanol).
The N—oxide of the compound represented by the
formula (I—l) refers to the compound represented by the
a (1—1) in which the nitrogen atom is oxidized. The N-
oxide of the compound represented by the formula (I—l) may
also be the alkali (alkaline earth) metal salt, the um
salt, the organic amine salt and the acid addition salt as
described above.
The prodrug of the compound represented by the
a (I—l) refers to a compound which is converted in vivo
to the compound represented by the formula (1—1) by the
reaction with enzymes, gastric acid and the like. The prodrug
of the compound represented by the formula (I—l) may e,
when the compound represented by the formula (I-l) has a
hydroxy group, compounds in which the hydroxy group is
acylated, alkylated, phosphorylated or converted to borate
(e.g. the present compounds in which the hydroxy group is
converted to acetyl, palmitoyl, propanoyl, pivaloyl, succinyl,
fumaryl, alanyl, dimethylaminomethylcarbonyl or the like);
compounds represented by the formula (1—1) in which the
carboxyl group is esterified or amidated (e.g. compounds
represented by the formula (1—1) in which the carboxyl group
is converted to ethyl ester, isopropyl ester, phenyl ester,
carboxymethyl ester, dimethylaminomethyl ester,
pivaloyloxymethyl ester, ethoxycarbonyloxyethyl ester,
phthalidyl ester, hyl—2—oxo-l,3—dioxolen-4—yl)methyl
ester, exyloxycarbonylethyl ester, methylamide or the
like) and the like. These compounds can be produced by the
well-known methods. The prodrug of the compound represented by
the formula (I—l) may be es or non—hydrates. The prodrug
of the compound ented by the formula (I-l) may be the
one which is converted to the nd represented by the
formula (I—l) under the physiological condition such as those
disclosed in "Iyakuhin no Kaihatsu", vol. 7 "Bunshi Sekkei", p.
163—198, 1990, Hirokawa Shoten Co. The compound represented by
the formula (I—l) may be labelled with an isotope (for example,
2H, 3H, 11C, 13C, 14C, 13N, 15N, 150, 170, 180, 355, 18F, 36C1, 123I,
1251 and the like).
[Production method of the present compound]
The present compound can be produced by well—known
methods, for example, the method described in hensive
Organic Transformations: A Guide to Functional Group
Preparations, 2nd Edition (Richard C. , John Wiley &
Sons Inc, 1999) or the method described in Examples with
appropriate cations and combinations.
The compound having the formula (I) in which R2 is a
hydrogen atom, namely the compound represented by the formula
(I—A):
[C 11]
;£&fdk
t“ TN O
0 (R3)p
(R4)q
wherein all the symbols have the same meanings as above, can
be produced as shown in the following reaction step formula 1:
QAnKV
g we»:
o g
Ali mm aAnM—v
Anmv 55
g .55 0 a
o g z
U zxf\
Avmv N
cozommm ma
g2—: m
ifbfl AB
v :23me
Amy—v
g R
Amy—V
o a
H ZNO
MHSEHOM QAMKV I2 E
gA=v :23me
mmum w
vx E ”XI... 9: :28me
SH 8 COHuommm “X
wherein T represents a protecting group of the amino group
having the carbonyl group (e.g. a 2,2,2—
trichloroethoxycarbonyl (Troc) group, a phenoxycarbonyl group,
a p-nitrophenoxycarbonyl group and the like); X1, X2 and X3
each independently represent a halogen atom and X1, X2 and X3
may be the same or different; and other symbols have the same
meanings as above.
In the reaction step a 1, the reaction 1 can
be d out as an fication reaction between the
compound represented by the formula (A) and the compound
represented by the formula (II). This etherification reaction
is well known and is carried out, for example, in an organic
solvent (N,N—dimethylacetamide, N,N—dimethylformamide,
dimethyl sulphoxide, chloroform, dichloromethane, l
ether, ydrofuran, methyl t—butyl ether and the like), in
the presence of an alkali metal hydroxide (sodium hydroxide,
potassium hydroxide, lithium hydroxide and the like), an
alkali metal hydride (sodium hydride and the like), an
- alkaline earth metal hydroxide (barium hydroxide, m
hydroxide and the like), a phosphate sium phosphate and
the like) or a carbonate (caesium carbonate, sodium carbonate,
potassium carbonate and the like) or an aqueous solution
thereof or a mixture thereof and at O to 100°C.
In the reaction step formula 1, the reaction 2 can
be carried out as an etherification reaction, as the on
1, using the compound represented by the formula (B) and the
compound represented by the formula (III).
In the reaction step formula 1, the reaction 3 can
be d out as a reduction reaction of the nitro group of
the compound represented by the formula (C). The reduction
reaction of the nitro group is well known and is carried out,
for example, by the methods described hereinbelow.
(1) The reaction is carried out, for e, in a
solvent [ethers (tetrahydrofuran, e, dimethoxyethane,
diethyl ether and the like), alcohols (methanol, ethanol and
the like), benzenes (benzene, toluene and the like), ketones
(acetone, methyl ethyl ketone and the like), nitriles
(acetonitrile and the like), amides (dimethylformamide and the
like), water, ethyl acetate, acetic acid or mixed solvents of
two or more of the above], in the presence of a hydrogenation
catalyst dium—carbon, palladium black, palladium,
palladium hydroxide, platinum dioxide, platinum—carbon, nickel,
Raney , ium chloride and the like), in the
presence or absence of an acid (hydrochloric acid, sulphuric
acid, hypochlorous acid, boric acid, tetrafluoroboric acid,
acetic acid, p—toluenesulphonic acid, oxalic acid,
trifluoroacetic acid, formic acid and the like), in an
hydrogen here of normal or increased pressure, in the
presence of ammonium e or hydrazine and at a temperature
of 0 to 200°C.
(2) The reaction is carried out, for example, in a
water—miscible solvent (ethanol, methanol, tetrahydrofuran and
the like), in the presence or absence of an acid (hydrochloric
acid, hydrobromic acid, ammonium chloride, acetic acid,
um formate and the like), by using a metal reagent (zinc,
iron, tin, tin chloride, iron chloride, samarium, indium,
sodium borohydride—nickel chloride and the like) at a
temperature of 0 to 150°C.
In the reaction step formula 1, the reaction 4 is
well known and is carried out with the compound ented by
the formula (D) and the compound ented by the formula
(IV), for example, by reaction of the compound represented by
the formula (IV) in the presence of a base (pyridine,
triethylamine, dimethylaniline, ylaminopyridine,
ropylethylamine and the like) with the compound
represented by the formula (D) in an organic solvent
oform, dichloromethane, diethyl ether, tetrahydrofuran
and the like) at a temperature of O to 40°C. The compound
represented by the formula (IV) can also be subjected to the
reaction with the formula (D) in an organic solvent (ethyl
acetate, dioxane, tetrahydrofuran and the like), with using an
alkaline aqueous solution (sodium hydrogen carbonate solution,
sodium hydroxide solution and the like) at O to 40°C.
In the reaction step a 1, the reaction 5 is
well known and is carried out with the compound represented by
the formula (E) and the compound represented by the formula
(V), for example, by reaction of the compound represented by
the formula (E) in the presence of a base (pYridine,
triethylamine, ylaniline, dimethylaminopyridine,
diisopropylethylamine and the like) with the compound
represented by the formula (V) in an organic solvent (N,N—
dimethylacetamide, form, dichloromethane, diethyl ether,
tetrahydrofuran and the like) at a temperature of 0°C to a
reflux temperature.
In the reaction step formula 1, when the compound
represented by the formula has a protecting group, for example,
when R3 or R4 is protected, deprotection reaction may be
carried out if necessary. Deprotection reaction of protecting
groups is well known and can be carried out by following
methods which may include, for example, (1) deprotection
reaction by alkaline ysis, (2) deprotection reaction
under acidic conditions, (3) deprotection reaction by
hydrolysis, (4) deprotection reaction of silyl groups, (5)
deprotection reaction using a metal, (6) deprotection reaction
using a metal x and the like.
These methods are ically described hereinbelow.
(l) Deprotection reaction by alkaline hydrolysis is
carried out, for example, in an organic solvent (e.g. methanol,
tetrahydrofuran and dioxane), by using an alkali metal
hydroxide (e.g. sodium hydroxide, potassium ide and
lithium hydroxide), an alkaline earth metal hydroxide (e.g.
barium hydroxide and calcium hydroxide) or a ate (e.g.
sodium carbonate and potassium carbonate) or an aqueous
solution thereof or a mixture thereof at 0 to 40°C.
(2) Deprotection reaction under acidic ions is
carried out, for example, in an organic solvent (e.g.
dichloromethane, chloroform, dioxane, ethyl acetate, methanol,
isopropyl alcohol, tetrahydrofuran and anisole) and in an
organic acid (e.g. acetic acid, trifluoroacetic acid,
methanesulphonic acid and lic acid) or an inorganic acid
(e.g. hloric acid and sulphuric acid) or a mixture
thereof (e.g. hydrogen bromide/acetic acid) in the presence or
absence of trifluoroethanol at 0 to 100°C.
(3) Deprotection reaction by hydrolysis is carried
out, for example, in a solvent (e.g. ethers (e.g.
tetrahydrofuran, e, dimethoxyethane and diethyl ether),
alcohols (e.g. methanol and ethanol), benzenes (e.g. benzene
and toluene), ketones (e.g. e and methyl ethyl ketone),
nitriles (e.g. acetonitrile), amides (e.g. N,N—
dimethylformamide), water, ethyl acetate, acetic acid or mixed
ts of two or more of the above), in the ce of a
catalyst (e.g. palladium—carbon, palladium black, palladium
hydroxide-carbon, platinum oxide and Raney nickel), in a
hydrogen atmosphere of normal or increased pressure or in the
ce of ammonium formate at O to 200°C.
(4) Deprotection reaction of silyl groups is carried
out, for example, in a water—miscible organic solvent (e.g.
tetrahydrofuran and acetonitrile), by using tetrabutylammonium
fluoride at O to 40°C. atively, the reaction is carried
out, for example, in an organic acid (e.g. acetic acid,
oroacetic acid, methanesulphonic acid and p—tosylic
acid) or an inorganic acid (e.g. hydrochloric acid and
sulphuric acid) or a mixture thereof (e.g. hydrogen
bromide/acetic acid) at —10 to 100°C.
(5) Deprotection reaction using a metal is carried
out, for example, in an acidic solvent (e.g. acetic acid, a
buffer of pH 4.2 to 7.2 or a mixed solution thereof with an
organic solvent such as tetrahydrofuran) in the presence of
zinc powder with application of ultrasonic, if necessary, at 0
to 40°C.
(6) Deprotection reaction using a metal complex is
d out, for example, in an organic solvent (e.g.
romethane, N,N—dimethylformamide, tetrahydrofuran, ethyl
acetate, acetonitrile, dioxane and ethanol), water or a mixed
solvent thereof in the presence of a trap reagent (e.g.
tributyltin hydride, triethylsilane, dimedone, morpholine,
diethylamine and pyrrolidine), in the presence of an c
acid (e.g. acetic acid, formic acid and 2—ethylhexanoic acid)
and/or a salt of an organic acid (e.g. sodium 2—ethylhexanoate
and potassium 2—ethylhexanoate), in the presence or absence of
a phosphine reagent (e.g. triphenylphosphine), with using a
metal complex (e.g. tetrakis triphenylphosphine palladium (0),
iphenylphosphine)palladium (II) ride, palladium
(II) acetate and tris(triphenylphosphine)rhodium (I) chloride)
at O to 40°C.
Alternatively, the deprotection reaction can be
carried out by the method described in, for example, T. W.
Greene, Protective Groups in Organic Synthesis, Wiley, New
York, 1999.
The protecting group of a hydroxy group may e,
for example, a methyl group, a trityl group, a ymethyl
(MOM) group, a l—ethoxyethyl (EE) group, a methoxyethoxymethyl
(MEM) group, a ahydropyranyl (THP) group, a
trimethylsilyl (TMS) group, a triethylsilyl (TES) group, a t—
butyldimethylsilyl (TBDMS) group, a t—butyldiphenylsilyl
(TBDPS) group, an acetyl (Ac) group, a pivaloyl group, a
benzoyl group, a benzyl (Bn) group, a p—methoxybenzyl group,
an allyloxycarbonyl (Alloc) group, a 2,2,2—
trichloroethoxycarbonyl (Troc) group and the like.
The protecting group of an amino group may e,
for example, a benzyloxycarbonyl group, a t—butoxycarbonyl
group, an allyloxycarbonyl (Alloc) group, a 1~methyl—1—(4-
biphenyl)ethoxycarbonyl (Bpoc) group, a trifluoroacetyl group,
a 9—fluorenylmethoxycarbonyl group, a benzyl (Bn) group, a p—
methoxybenzyl group, a benzyloxymethyl (BOM) group, a 2—
(trimethylsilyl)ethoxymethyl (SEM) group and the like.
The protecting group of a hydroxy group and an amino
group is not particularly limited to those ned above as
far as it can be readily and selectively eliminated. For
example, the_ones described in T. W. Greene, Protective Groups
in Organic Synthesis, Wiley, New York, 1999 may be used.
In the reactions described herein, the compounds
used as starting materials such as the formulae (A), (II),
(III), (IV) and (V) are well known or can be readily produced
ing to well—known methods.
In the reactions described herein, reactions
accompanied by heating can be carried out, as apparent to a
person d in the art, with a water bath, an oil bath, a
sand bath or a microwave.
In the reactions described herein, a solid phase
immobilized reagent which is immobilized on a high molecular
polymer (e.g. polystyrene, polyacrylamide, polypropylene and
polyethylene glycol) may be used.
In the reactions described herein, reaction products
can be purified according to a conventional purification means
such as lation at normal or d pressure, high
performance liquid chromatography using silica gel or
magnesium silicate, thin layer chromatography, ion exchange
resins, scavenger resins or column tography or washing
and re—crystallization. Purification can be carried out after
each reaction or after a few reactions.
[Toxicity]
The present compound has sufficiently low toxicity and
thus can be used safely as a medicament.
[Application to medicaments]
The present compound has Sle antagonistic ty and
thus is useful as a prophylactic and/or therapeutic agent for‘
a Sng—mediated disease. The Sle—mediated disease may include
a disease resulting from vascular constriction, fibrosis, a
respiratory disease, arteriosclerosis, peripheral arterial
occlusive disease, retinopathy, glaucoma, age—related macular
degeneration, nephritis, diabetes, dyslipidemia, hepatitis,
hepatic sis, hepatic failure, neuropathy, rheumatoid
arthritis, wound, pain, urticaria, systemic lupus
erythematosus (SLE), cancer and the like.
The disease resulting from vascular constriction as
used herein may e cerebral vasospastic disease, cardiac
vasospastic disease, coronary vasospastic disease,
hypertension, pulmonary hypertension, myocardial tion,
, arrhythmia, portal hypertension, varix, ischemia—
reperfusion injury and the like.
The fibrosis as used herein may include pulmonary
fibrosis, hepatic is, kidney is, myocardial
fibrosis, skin fibrosis and the like.
The respiratory disease as used herein may include
bronchial asthma, acute lung injury, , chronic
obstructive pulmonary disease and the like.
The present compound may be combined with another
drug so as to be administered as a concomitant drug in order
l) ment and/or enhance the prophylactic and/or
therapeutic effect of the present compound;
2) improve cs and uptake and reduce the dosage of the
present compound; and/or
3) decrease side effect of the present compound.
The concomitant drug of the present compound and
another drug may be administered as a ed agent
containing both components in one formulation or administered
separately. This separate administration includes simultaneous
administration and sequential administration. The sequential
administration may include the administration of the t
compound prior to another drug and the administration of
another drug prior to the present compound. The manners of
administration of the components may be the same or different.
The concomitant drug may exhibit prophylactic and/or
therapeutic effect for any diseases without limitation as far
as the prophylactic and/or therapeutic effect of the present
compound is complemented and/or enhanced.
Another drug which is used for complementation
and/or enhancement of the prophylactic and/or therapeutic
effect of the t compound for the disease resulting from
vascular constriction may include, for example, calcium
nists, thrombolytic agents, thromboxane synthase
inhibitors, endothelin antagonists, antioxidants, l
scavengers, PARP tors, astrocyte function improving
agents, Rho kinase inhibitors, angiotensin II antagonists,
angiotensin-converting enzyme inhibitors, diuretic agents,
phosphodiesterase (PDE) 4 inhibitors, prostaglandins
(hereinafter sometimes abbreviated as PG or PGs), aldosterone
antagonists, endothelin antagonists, prostacyclin formulations,
nitrates, B—blockers, lators and the like.
Another drug which is used for complementation
and/or enhancement of the prophylactic and/or therapeutic
effect of the present compound for fibrosis may include, for
e, steroids, immunosuppressants, TGF—B inhibitors, PDE5
inhibitors and the like.
Another drug which is used for complementation
and/or ement of the prophylactic and/or therapeutic
effect of the present compound for the respiratory disease may
include, for example, PDE4 inhibitors, steroids, B—agonists,
leukotriene receptor antagonists, thromboxane synthase
inhibitors, thromboxane A2 receptor antagonists, mediator
release suppressing agents, antihistamines, xanthine
derivatives, anticholinergic agents, cytokine inhibitors, PGs,
forskolin formulations, elastase inhibitors, metalloprotease
inhibitors, orants, otics and the like.
The calcium antagonists may include, for example,
nifedipine, benidipine hydrochloride, diltiazem hydrochloride,
verapamil hydrochloride, nisoldipine, nitrendipine, bepridil
hydrochloride, amlodipine besylate, lomerizine hydrochloride,
efonidipine hydrochloride and the like.
The thrombolytic agents may include, for example,
ase, urokinase, nase, nasaruplase, nateplase,
tissue plasminogen tor, pamiteplase, lase and the
like.
The thromboxane se inhibitors may include, for
example, ozagrel hydrochloride, imitrodast sodium and the like.
The radical scavengers may include, for example, Radicut
and the like.
The PARP inhibitors may include, for example, 3—
aminobenzamide, 1,3,7—trimethylxanthine, PD—141076, PD-l4l703
and the like.
The astrocyte on improving agents may include, for
e, ONO—2506 and the like.
The Rho kinase inhibitors may include, for example,
fasudil hydrochloride and the like.
The angiotensin II antagonists may include, for example,
losartan, candesartan, valsartan, irbesartan, olmesartan,
telmisartan and the like.
The angiotensin—converting enzyme inhibitors may
include, for example, alacepril, imidapril hydrochloride,
quinapril hloride, temocapril hydrochloride, il
hloride, benazepril hydrochloride, captopril,
trandolapril, perindopril erbumine, enalapril maleate,
lisinopril and the like.
The diuretic agents may include, for example,
mannitol, mide, acetazolamide, dichlorphenamide,
methazolamide, ormethiazide, ide, spironolactone,
aminophyline and the like.
The PDE4 inhibitors may include, for example,
rolipram, cilomilast, Bayl9—8004, NIK-6l6, roflumilast,
cipamfylline, atizoram, SCH—351591, YM—976, 4A, PD—
l68787, ONO—6126, , IC—485 and the like.
The prostaglandins (PGs) may include, for example,
PG receptor agonists, PG receptor antagonists and the like.
The PG receptor may include, for example, PGE receptors
(EPl, EP2, EP3 and EP4), PGD receptors (DP and , a PGF
receptor (FP), a PGI receptor (IP), a thromboxane receptor
(TP) and the like.
The aldosterone antagonists may include, for example,
drospirenone, metyrapone, canrenoate potassium, canrenone,
eplerenone, ZK—91587 and the like.
The prostacyclin formulations may include, for example,
treprostinil sodium, epoprostenol sodium, beraprost sodium and
the like.
The nitrates may include, for example, amyl nitrite,
nitroglycerin, isosorbide dinitrate and the like.
The B—blockers may include, for example, alprenolol
hydrochloride, bupranolol hydrochloride, bufetolol
hydrochloride, oxprenolol hydrochloride, atenolol, olol
fumarate, betaxolol hydrochloride, bevantolol hydrochloride,
metoprolol tartrate, acebutolol hydrochloride, celiprolol
hydrochloride, ilol, tilisolol hydrochloride, nadorol,
propranolol hydrochloride, indenolol hydrochloride, carteolol
hloride, pindolol, bunitrolol hloride, landiolol
hloride, esmolol hydrochloride, arotinolol hydrochloride,
carvedilol, timolol maleate and the like.
The vasodilators may include, for example, diltiazem
hydrochloride, azidine hydrochloride, damole,
etanofen hydrochloride, dilazep hydrochloride, trapidil,
nicorandil and the like.
The steroids may include, as agents for oral
stration or injection, for e cortisone acetate,
ortisone, hydrocortisone sodium phosphate,
hydrocortisone sodium succinate, fludrocortisone acetate,
prednisolone, prednisolone acetate, prednisolone sodium
succinate, prednisolone cetate, prednisolone sodium
phosphate, halopredone acetate, methylprednisolone,
methylprednisolone e, methylprednisolone sodium
succinate, triamcinolone, triamcinolone ate,
triamcinolone acetonide, dexamethasone, dexamethasone acetate,
dexamethasone sodium phosphate, dexamethasone palmitate,
paramethasone acetate, betamethasone and the like. The
steroids for inhalation may include, for example,
beclomethasone propionate, fluticasone propionate, nide,
flunisolide, triamcinolone, ST—126P, ciclesonide,
dexamethasone palomithionate, mometasone furonate, prasterone
sulphonate, deflazacort, methylprednisolone sleptanate,
methylprednisolone sodium succinate and the like.
The immunosuppressants may include, for example,
azathioprine, mizoribine, methotrexate, mycophenolate mofetil,
cyclophosphamide, cyclosporine A, imus, sirolimus,
everolimus, prednisolone, methylprednisolone, orthoclone OKT3,
anti-human cyte globulin, deoxyspergualin and the like.
The PDES inhibitors may include, for example,
sildenafil, tadalafil, vardenafil, udenafil and the like.
The B agonists may include, for example, fenoterol
hydrobromide, salbutamol sulphate, terbutaline sulphate,
formoterol te, salmeterol xinafoate, isoproterenol
sulphate, orciprenaline sulphate, clorprenaline sulphate,
epinephrine, trimetoquinol hydrochloride, hexoprenaline mesyl
sulphate, procaterol hydrochloride, tulobuterol hloride,
tulobuterol, pirbuterol hydrochloride, Clenbuterol
hloride, rol hydrochloride, ine
hydrochloride, bambuterol, dopexamine hydrochloride,
meluadrine tartrate, AR~C68397, levosalbutamol, R,R—formoterol,
KUR—1246, KUL—7211, AR—C89855, S—l3l9 and the like.
The leukotriene receptor antagonists may include,
for example, pranlukast hydrate, ukast, zafirlukast,
seratrodast and the like.
The thromboxane A2 receptor antagonists may include, for
example, seratrodast, ramatroban, domitroban calcium hydrate
and the like.
The mediator e suppressing agents may e,
for example, tranilast, cromolyn sodium, amlexanox, repirinast,
ibudilast, tazanolast, last ium and the like.
The antihistamines may include, for example,
ketotifen fumarate, mequitazine, azelastine hydrochloride,
oxatomide, adine, emedastine fumarate, tine
hydrochloride, astemizole, ebastine, cetirizine hydrochloride,
bepotastine, fexofenadine, loratadine, desloratadine,
olopatadine hloride, TAK-427, ZCR—2060, NIP—530,
mometasone furoate, mizolastine, BP—294, st, auranofin,
acrivastine and the like.
The xanthine derivatives may include, for example,
aminophylline, theophylline, doxofylline, cipamfylline,
diprophylline and the like.
The anticholinergic agents may include, for example,
ipratropium bromide, oxytropium bromide, pium bromide,
cimetropium bromide, temiverine, tiotropium bromide,
revatropate and the like.
The cytokine inhibitors may include, for example,
suplatast tosilate and the like.
The elastase inhibitors may include, for example, ONO—
5046, ONO—6818, MR—889, PEI—1101, EPI—HNE—4, R—665 and the
like.
The expectorants may include, for example,
foeniculated ammonia spirit, sodium hydrogen carbonate,
bromhexine hydrochloride, carbocysteine, ambroxol
hydrochloride, ambroxol hydrochloride sustained release
ation, methylcysteine hydrochloride, acetylcysteine, L—
ysteine hydrochloride, tyloxapol and the like.
The antibiotics may include, for example, cefuroxime
sodium, meropenem rate, netilmicin sulphate, sisomicin
te, ceftibuten, PA—l806, IB-367, tobramycin, PA—l420,
doxorubicin, astromicin sulphate, cefetamet pivoxil
hloride and the like. The antibiotics for inhalation may
e, for example, PA—1806, IB—367, tobramycin, PA-l420,
doxorubicin, astromicin sulphate, cefetamet pivoxil
hydrochloride and the like.
The drug which is combined with the present compound
encompasses not only the known compounds but also the
compounds which will be found in future.
The present compound is usually administered
systemically or locally in an oral or parenteral form. Oral
formulations may include, for example, liquids for oral
administration (e.g. s, syrups, pharmaceutically
acceptable solutions, sions and emulsions), solid agents
for oral administration (e.g. tablets (including sublingual
tablets and oral disintegration tablets), pills, capsules
(including_hard es, soft capsules, gelatine capsules and
microcapsules), s, granules and troches) and the like.
Parenteral formulations may include, for e, s (e.g.
injections (subcutaneous injections, intravenous ions,
intramuscular injections, intraperitoneal injections,
infusions and the like), ophthalmic solutions (e.g. aqueous
ophthalmic solutions (aqueous ophthalmic solutions, aqueous
ophthalmic suspensions, viscous ophthalmic solutions and
solubilized ophthalmic ons), non—aqueous ophthalmic
solutions (non—aqueous ophthalmic solutions, non—aqueous
ophthalmic suspensions and the like)) and the like), topical
formulations (e.g. ointments (ophthalmic ointments and the
, eardrops and the like. These formulations may be
controlled—release preparations such as prompt release
preparations or sustained release preparations. These
formulations can be produced according to well—known methods
such as the method bed in Japanese Pharmacopoeia and the
like.
The liquids for oral administration are produced by,
for example, dissolving, suspending or emulsifying the active
ingredient in a diluent that is generally used (e.g. purified
water, ethanol and a mixture thereof). The liquids may r
contain a g agent, a suspending agent, an emulsifying
agent, a sweetening agent, a flavouring agent, an aroma, a
preservative, a buffering agent and the like.
The solids for oral administration are formulated
according to conventional methods by, for example, mixing the
active ingredient with a vehicle (e.g. lactose, mannitol,
glucose, microcrystalline cellulose and starch), a binder (e.g.
hydroxypropyl cellulose, polyvinylpyrrolidone and magnesium
aluminometasilicate), a disintegrant (e.g. m
carboxymethyl ose), a lubricant (e.g. magnesium
stearate), a stabiliser, a on adjuvant (glutamic acid,
aspartic acid and the like) and the like. The solids may be,
if desired, coated with a coating agent (e.g. sucrose,
gelatine, ypropyl cellulose and hydroxypropyl
cellulose phthalate) and may be coated with two or more
The topical formulations as parenteral ations
are produced according to well—known methods or conventional
formulations. For example, ointments are produced by
triturating or melting the active ingredient in a base. The
base for ointments is selected among those well—known or
conventionally used. One or more ed from the followings,
for example, may be used solely or in combination: a higher
fatty acid or higher fatty acid ester (e.g. adipic acid,
myristic acid, palmitic acid, stearic acid, oleic acid,
adipate ester, myristate ester, palmitate ester, te
ester and oleate ester), a wax (e.g. beeswax, whale wax and
ceresin), a surfactant (e.g. yethylene alkyl ether
phosphate esters), a higher alcohol (e.g. cetanol, stearyl
alcohol and cetostearyl alcohol), a silicone oil (e.g.
dimethylpolysiloxane), a hydrocarbon (e.g. hydrophilic
petrolatum, white petrolatum, purified lanolin and liquid
paraffin), a glycol (e.g. ethylene glycol, lene glycol,
propylene glycol, polyethylene glycol and macrogol), vegetable
oil (e.g. castor oil, olive oil, sesame oil and turpentine
oil), animal oil (e.g. mink oil, egg—yolk oil, squalane and
squalene), water, an absorption enhancing agent and a rash
preventing agent. The formulations may further contain a
humectant, a preservative, a stabilizer, an antioxidant, an
aroma ring agent and the like.
The injections as parenteral formulations encompass
solutions, suspensions, emulsions and solid injections which
are dissolved or ded in a solvent upon use. The
injections are used by, for example, dissolving, suspending or
emulsifying the active ingredient in a solvent. The solvent
used is, for example, distilled water for injections, saline,
vegetable oil, propylene glycol, polyethylene glycol, alcohols
such as ethanol or a combination thereof. The injections may
further n a stabilizer, a solution adjuvant (e.g.
glutamic acid, aspartic acid and Polysolvate 80®), a
suspending agent, an emulsifying agent, a soothing agent, a
buffering agent, a preservative and the like. The injections
are ed by sterilization at the final stage or through an
aseptic manipulation. Alternatively, c solid
formulations, for example freeze—dried ations, may be
produced which may be dissolved, before use, in sterilized or
aseptic distilled water for injection or another solvent.
For the purposes bed above, the present
compound or a concomitant agent of the present compound and
another drug is generally administered systemically or locally
in an oral or parenteral form. The dosage may vary according
to the age, , symptoms, therapeutic effect, the manner
of administration, treatment period and the like, and may be
lly administered orally at a single dose for an adult of
from 1 ng to 1000 mg with one or a few times daily, or
administered parenterally at a single dose for an adult of
from 0.1 ng to 10 mg with one or a few times daily, or
continuously administered intravenously for 1 hour to 24 hours
daily. The dosage may vary, as described above, ing to
various ions, of course, and thus the dosage which is
less than the range described above may be sufficient in some
cases and the dosage which is more than the range described
above may be required in some cases.
Examples
The present invention is hereinbelow described in
detail by way of Examples which do not limit the present
invention.
The solvents described in brackets in the sections of
chromatography separation and TLC indicate the elution
solvents or ping solvents used and the proportions are
represented by volume ratios.
The solvents described in brackets in the sections of NMR
indicate the solvents used for the measurements.
The compounds are denominated in the present
specification by using a computer programme, ACD/Name from
Advanced Chemistry Development which generally denominates
according to the rules from IUPAC, or according to the IUPAC
nomenclature system.
Example 1: [4-(benzyloxy)phenyl]acetate
At room ature, to a 3-L pear—shaped evaporating
flask was added (4—hydroxyphenyl)acetate (202 g) and
potassium carbonate (233 g) which were dissolved in N,N—
ylacetamide (DMA) (1 L). To the solution was added
benzyl chloride (117 mL) at room temperature and stirred. The
solution was then heated to 60°C and stirred for 16 hours. The
reaction solution was cooled to room temperature, diluted with
methyl tert—butylether (MTBE) (1.3 L) and added with water (3
L) and an organic layer was extracted. The ing organic
layer was washed three times with a 1 N sodium hydroxide
aqueous solution, then with water and a saturated sodium
chloride solution and then dried over anhydrous magnesium
sulphate. The solvent was distilled off at reduced pressure to
give the titled compound (245 g) having the following physical
properties.
TLC: Rf 0.68 (hexanezethyl e = 3:1);
lH—NMR (CDC13): 5 3.56 (3H), 3.68 (3H), 5.05 (2H), 6.93 (3H),
7.19 (2H), 7.26—7.50 (SH).
Example 2: Methyl 2—[4—(benzyloxy)phenyl]—2—
methylpropanoate
Under an argon atmosphere, to a 1—L four—neck flask was
added the compound prepared in Example 1 (66.5 g) which was
dissolved in tetrahydrofuran (THE) (260 mL). The solution was
cooled to —10°C and sequentially added with methyl iodide (8.1
mL) and a 1.53 M solution of potassium tert—butoxide (85 mL)
in THF while the al temperature of the reaction solution
was ined at —10°C to —7.5°C. This procedure was repeated
eight times. The solution was then d at —10°C for 10
minutes and slowly added dropwise with acetic acid (50.5 mL).
The solution was neutralized with a 2 N sodium hydroxide
aqueous solution and saturated s sodium bicarbonate and
extracted with ethyl acetate and hexane. The extract was
washed with water and a saturated sodium chloride on and
then dried over anhydrous ium sulphate. The solvent was
then distilled off under reduced pressure. Activated carbon (4
g) was then added thereto, the mixture was stirred at room
temperature for 30 minutes, the activated carbon was filtered
off, and the solvent was distilled off under reduced pressure
to give the titled compound (73.0 g) having the following
al properties.
TLC: Rf 0.54 (hexanezethyl acetate = 5:1);
1H—NMR (CDC13): 5 1.55 (6H), 3.64 (3H), 5.05 (2H), 6.93 (2H),
7.26 (2H), 7.30—7.48 (5H).
e 3: Methyl 2—(4—hydroxypheny1)—2—
methylpropanoate
Under an argon here, to a 2—L pear-shaped
evaporating flask was added a solution of the compound
prepared in Example 2 (72.0 g) in methanol (420 mL) mixed with
ethyl acetate (150 mL). After purged with argon, 20% palladium
carbon (7.60 g) was added. The flask was degassed and charged
with hydrogen gas. The flask was vigorously stirred at room
temperature for 4 hours. The reaction system was purged with
argon, filtered with celite and washed with ethyl acetate. The
filtrate was subjected to distillation under reduced pressure
followed by dilution with ethyl acetate (150 mL) and hexane
(50 mL). The diluted solution was dried over anhydrous
magnesium sulphate and the solvent was distilled off to obtain
a gray-white solid (50 g). The solid was dissolved in ethyl
acetate (70 mL) while heating which was then added with hexane
(700 mL) and stirred at room temperature. The itated
solid was collected by filtration, washed with hexane/ethyl
e (10:1) and dried to give the titled compound (41.1 g)
having the following physical properties.
TLC: Rf 0.27 e:ethyl acetate = 5:1);
1H—NMR (CDCl3): 8 1.55 (6H), 3.65 (3H), 6.77 (2H), 7.19 (2H).
Example 4: Methyl 2—[4—(3—fluoro—5—
nitrophenoxy)phenyl]-2—methy1propanoate
Under an argon atmosphere and at room temperature, to a
500—mL pear-shaped evaporating flask were added the compound
ed in Example 3 (41.1 g) and potassium phosphate (81.5
g). To the on system was added 1,3—difluoro—5—
enzene (30.6 g) dissolved in DMA (128 mL) and stirred.
The reaction system was then heated to 70°C and stirred for 6.5
hours. The reaction solution was cooled to room ature,
diluted with MTBE (150 mL) and added with ice water (150 mL)
before stirring. An organic layer was extracted by adding MTBE
and water. The aqueous layer was added with MTBE and water to
extract an c layer. The organic layer was combined,
washed twice with a 1 N sodium hydroxide aqueous solution and
then with a saturated sodium de solution and dried over
anhydrous magnesium sulphate, and the solvent was distilled
off under reduced pressure. The titled compound (66.0 g)
having the following physical properties was obtained.
TLC: Rf 0.68 (hexanezethyl e = 3:1);
lH—NMR (CDC13): 8 1.62 (6H), 3.69 (3H), 6.91 (2H), 6.96—7.08
(4H), 7.40 (2H), 7.65 (1H).
Example 5: Methyl 2—{4—[3—(4-fluorophenoxy)-5—
nitrophenoxy]phenyl}methylpropanoate
Under an argon atmosphere and at room temperature, to a
500—mL haped evaporating flask were added the compound
prepared in Example 4 (64 g), 4—fluorophenol (40 g) and
potassium phosphate (102 g) which were dissolved in DMA (130
mL) before stirring. The solution was then heated to 100°C and
stirred for 10 hours. The reaction solution was cooled to room
temperature, diluted with MTBE (200 mL) and added with ice
water (400 mL) before stirring. The reaction solution was
further washed with MTBE, a 1 N sodium hydroxide aqueous
solution and water. An aqueous layer was extracted twice with
MTBE. The organic layer was combined, washed twice with a 1 N
sodium hydroxide aqueous solution and then with water and a
saturated sodium chloride solution and dried over anhydrous
magnesium sulphate, and the t was distilled off under
reduced pressure. The obtained residue was added with l
(104 mL), heated and dissolved. To the solution was gradually
added hexane (520 mL) and stirred at room temperature to allow
precipitation of solids. The precipitate was collected by
filtration with a Kiriyama funnel (#5B—¢95) and washed with
hexane/ethanol (10:1) and the obtained residue was dried under
reduced pressure at 50°C. The titled compound (54.8 g) having
the following al properties was obtained.
TLC: Rf 0.57 (hexanezethyl acetate II 5:1);
lH—NMR (CDC13): 8 1.60 (6H), 3.68 (3H), 6.91 (1H), 6.91 (1H),
6.98—7.14 (4H), 7.36 (1H), 7.39 (1H), 7.40 (1H), 7.46 (1H).
Example 6: Methyl 2—{4—[3—amino—5—(4—
fluorophenoxy)phenoxy]phenyl}—2—methylpropanoate
Under an argon atmosphere, to a 500-mL pear—shaped
evaporating flask was added the compound prepared in Example 5
(53.6 g) to which a mixed solution of ol (50 mL) and
ethyl acetate (175 mL) was added. The mixture was heated until
dissolution, and the flask was purged with argon prior to
addition of 5% palladium carbon (10.8 g). The flask was
degassed and charged with hydrogen gas. The flask was
vigorously stirred at room temperature for 3 hours. The
on system was purged with argon, filtered with celite
and washed with ethyl acetate. The ed filtrate was
subjected to lation under reduced pressure to give the
titled compound (43.9 g) having the following al
properties.
TLC: Rf 0.13 (hexanezethyl acetate = 5:1);
1H—NMR ): 5 1.57 (6H), 3.66 (3H), 3.69 (NH, 2H), 5.97
(1H), 6.02 (2H), 6.96 (2H), 6.99 (2H), 7.01 (2H), 7.28 (2H).
Example 7: Methyl 2—{4—[3-(4—fluorophenoxy)—5—
{[(2,2,2-trichloroethoxy)carbonyl]amino}phenoxy]phenyl}—2—
methylpropanoate
Under an argon atmosphere and at room temperature, to a
500—mL pear—shaped evaporating flask were added the compound
prepared in Example 6 (43.9 g) and sodium hydrogen carbonate
(18.6 g) which were dissolved in ethyl acetate (111 mL). The
solution was cooled to 0°C and 2,2,2—trichloroethyl
chloroformate (15.7 mL) was gradually added dropwise over 15
minutes so that the internal ature did not exceed 10°C.
The solution was then stirred at room temperature for 60
minutes. After elimination of 2,2,2—trichloroethyl
chloroformate was confirmed by thin layer chromatography, the
reaction solution was added with water and stirred. The solid
was precipitated by addition of hexane. The itate was
ted by filtration with a Kiriyama funnel (#5B—¢95) and
washed with water and hexane/ethyl acetate (3:1) and the
obtained residue was dried under reduced re at 50°C. The
titled nd (58.5 g) having the fOllowing physical
properties was obtained.
TLC: Rf 0.45 (hexane:ethyl acetate = 5:1);
1H—NMR (CDCl3): 5 1.58 (6H), 3.66 (3H), 4.77 (2H), 6.36 (1H),
6.73 (1H), 6.78 (br, 1H), 6.82 (br, 1H), 6.93—7.10 (6H), 7.31
(2H).
Example 8: Methyl 2—{4—[3—(4—fluorophenoxy)—5—{[(4—
hydroxy—4—isobutyl—1—
piperidinyl)carbonyl]amino}phenoxy]phenyl}—2—methylpropanoate
Under an argon here and at room temperature, in a
500 mL pear—shaped evaporating flask, the compound ed in
Example 7 (26.6 g) was dissolved in DMA (31 mL), added with 4—
isobutyl—4—piperidinol (9.53 g) and stirred. The solution was
then heated to 90°C and stirred for 2 hours. The solution was
further added with 4eisobutyl—4—piperidinol (1.45 g) and
diisopropylethylamine (818 uL) and stirred for 2 hours. The
reaction solution was allowed to cool to room ature,
diluted with MTBE, and added with ice water to extract an
organic layer. The obtained aqueous layer was extracted with
MTBE. The organic layer was combined, washed twice with a 1 N
hydrochloric acid s solution, three times with a 1 N
sodium hydroxide aqueous solution, with water and with a
saturated sodium chloride solution and dried over anhydrous
sodium sulphate and the solvent was distilled off under
reduced pressure. The titled compound (24.8 g) having the
following physical properties was obtained.
TLC: Rf 0.46 (hexanezethyl acetate 1:1);
lH—NMR (CDC13): 5 0.97 (6H), 1.05 (1H), 1.41 (2H), .70
(10H), 1.75—1.90 (1H), 3.20—3.35 (2H), 3.66 (3H), 3.70—3.80
(2H), 6.25—6.35 (2H), 6.71 (1H), 6.81 (1H), 6.90—7.05 (6H),
7.29 (2H).
Example 9: 2—{4—[3—(4—fluorophenoxy)—5—{[(4—hydroxy-
4—isobutyl—1—piperidinyl)carbonyl]amino}phenoxy]phenyl}—2-
methylpropanoic acid
[C 13]
CH; OH
H30 H
N N OU.
0We”
H3O CH3
At room temperature, in a 1L pear-shaped evaporating
flask, the compound prepared in Example 8 (24.8 g) was
ved in a mixed solution of ol (150 mL) and THF
(150 mL) and the solution was d. The solution was then
heated to 45°C, gradually added with a 1 N sodium hydroxide
aqueous on (107 mL) and stirred overnight at 45°C. The
solution was added with a 2 N sodium hydroxide aqueous
solution (20 mL). After stirring for 1 hour, the solvent was
distilled off under reduced pressure and the solution was
further stirred for 1.5 hours at 45°C. A 2 N sodium ide
aqueous solution (12 mL) was further added and the solution
was stirred for 45 minutes at 55°C. The solution was cooled to
0°C and added with ice and a 5 N hydrochloric acid aqueous
solution until the reaction system was acidic (pH = 2). The
reaction system was diluted with ethyl acetate and extracted.
An organic layer was further washed with a saturated sodium
chloride solution and then dried over anhydrous magnesium
sulphate and the solvent was led off under d
pressure. The residue was purified by silica gel
chromatography (hexane:ethyl acetate = 65:35 —9 44:56 ~§ 30:70)
to give the titled compound (20 g) having the following
physical properties.
TLC: Rf 0.53 (dichloromethane:methanol = 10:1);
lH—NMR (CDCl3): 5 7.28—7.33 (m, 2H), 6.94—7.01 (m, 4H), 6.89—
6.93 (m, 2H), 6.80 (t, 1H), 6.61 (t, 1H), 6.25 (t, 1H), 3.60—
3.73 (m, 2H), 3.12—3.25 (m, 2H), 1.71—1.85 (m, 1H), 1.46—1.59
(m, 10H), 1.34 (d, 2H), 0.92 (d, 6H).
Examples 9(1) to 9(64)
The compounds of the following Examples were obtained by
carrying out the processes with the same purposes as Example 4
—9 Example 5 —9 Example 6 —9 Example 7 —é Example 8 —9 Example 9
using fluoro—5—nitrobenzene; the nd prepared in
Example 3 or a corresponding phenol derivative thereof; 4—
fluorophenol or a corresponding phenol derivative thereof;
2,2,2—trichloroethyl chloroformate; and 4—isobutyl—4-
piperidinol or a corresponding piperidine derivative thereof.
Example 9(1): 4-[3—({[4—(2—ethylbUtyl)—4-hydroxy—1—
dinyl]carbonyl}amino)—5—(4—fluorophenoxy)phenoxy]benzoic
acid
[C 14]
TLC: Rf 0.28 (dichloromethane:methanol = 10:1);
lH—NMR (CDfiHM: 5 8.01 (d, 2H) 7.18—6.99 (m, 6H) 6.94—6.87 (m,
2H) 6.29 (t, 1H) 3.90—3.75 (m, 2H) 3.28—3.15 (m, 2H) 1.63—1.47
(m, 4H) 1.45—1.26 (m, 7H) 0.87 (t, 6H).
Example 9(2): {[4—(4—bromophenyl)—4—hydroxy—1—
piperidinyl]carbonyl}amino)—5—(4—fluorophenoxy)phenoxy]benzoic
acid
TLC: Rf 0.38 (dichloromethane:methanol = 10:1);
lH—NMR (DMSO—d5)3 5 8.63 (s, 1H), 7.95 (d, 2H), 7.48 (d, 2H),
7.41 (d, 2H), 7.24 (t, 2H), 7.15—7.07 (m, 5H), 7.02 (dd, 1H),
6.31 (dd, 1H), 5.18 (s, 1H), 3.98—3.94 (m, 2H), 3.17—3.10 (m,
2H), 1.83-1.76 (m, 2H), .53 (m, 2H).
Example 9(3): 4—[3—(4—fluorophenoxy)—5—({[4—(4—
fluorophenyl)—4—hydroxy—1—
piperidinyl]carbony1}amino)phenoxy]benzoic acid
[C 15]
TLC: Rf 0.38 (dichloromethane:methanol = 10:1);
lH—NMR (DMSO—ds): 5 8.63 (s, 1H), 7.95 (d, 2H), 7.48 (dd, 2H),
7.24 (t, 2H), 7.15—7.07 (m, 7H), 7.02 (dd, 1H), 6.31 (dd, 1H),
.13 (s, 1H), 3.98—3.93 (m, 2H), 3.18—3.10 (m, 2H), .77
(m, 2H), 1.59—1.54 (m, 2H).
e 9(4): 4—[3—(4—chlorophenoxy)—5—({[4—(2—
ethylbutyl)—4—hydroxy—1—
piperidinyl]carbonyl}amino)phenoxy]benzoic acid
TLC: Rf 0.33 (dichloromethane:methanol = 10:1);
1H—NMR (CDfiHD: 5 8.48 (s, 1H), 8.02 (d, 2H), 7.36 (d, 2H),
7.00—7.12 (m, 4H), 6.95 (t, 2H), 6.34 (t, 1H), 3.83 (d, 2H),
3.14—3.29 (m, 2H), 1.28—1.68 (m, 11H), 0.87 (t, 6H).
Example 9(5): 4—[3—({[4—(2—ethy1buty1)—4—hydroxy—1—
piperidinyl]carbonyl}amino)—5—(4—
methoxyphenoxy)phenoxy]benzoic acid
TLC: Rf 0.33 (dichloromethane:methanol = 10:1);
lH—NMR UHhOD): 5 8.43 (s, 1H), 7.97—8.04 (m, 2H), 7.04 (d, 2H),
6.90—7.02 (m, 4H), 6.86—6.89 (m, 1H), 6.85 (t, 1H), 6.15—6.29
(m, 1H), 3.78—3.85 (m, 5H), 3.13—3.28 (m, 2H), 1.49—1.71 (m,
4H), .44 (m, 7H), 0.87 (t, 6H).
e 9(6): 4—[3—(3,4—dif1uorophenoxy)—5—({[4-(2—
ethylbutyl)—4—hydroxy—1—
piperidinyl]carbonyl}amino)phenoxy]benzoic acid
TLC: Rf 0.37 (dichloromethane:methanol = 9:1);
1H-NMR (CDCl3): 5 8.03 (d, 2H), 7.06—7.18 (m, 1H), 7.03 (d, 2H),
6.84—6.93 (m, 3H), 6.73—6.81 (m, 1H), 6.53 (br. s., 1H), 6.37—
6.41 (m, 1H), 3.73—3.83 (m, 2H), 3.22—3.34 (m, 2H), 1.55—1.65
(m, 5H), 1.28—1.42 (m, 7H), 0.79—0.90 (m, 6H).
Example 9(7): 4—[3—({[4—(2—ethylbutyl)—4—hydroxy—1—
piperidinyl]carbonyl}amino)—5—(4—methylphenoxy)phenoxy]benzoic
acid
TLC: Rf 0.24 (dichloromethane:methanol = 1:2);
lH—NMR (CDCl3): 5 8.02 (d, 2H), 7.14 (d, 2H), 7.02 (d, 2H),
6.97—6.91 (m, 3H), 6.72 (t, 1H), 6.42—6.31 (m, 2H), 3.84—3.73
(m, 2H), 3.37—3.14 (m, 2H), 2.33 (s, 3H), 1.75—1.50 (m, 5H),
1.44—1.28 (m, 8H), 0.85 (t, 6H).
Example 9(8): 4—{3—({[4—(2—ethylbutyl)—4—hydroxy—1—
piperidinyl]carbonyl}amino)—5—[4—
(trifluoromethyl)phenoxy]phenoxy}benzoic acid
TLC: Rf 0.26 (dichloromethane:methanol = 10:1);
lH—NMR ): 5 8.09—7.97 (m, 2H), 7.58 (d, 2H), 7.09 (d, 2H),
7.07—7.01 (m, 2H), 6.97 (t, 1H), 6.92 (t, 1H), 6.48 (s, 1H),
6.45 (t, 1H), 3.85—3.73 (m, 2H), 3.39—3.17 (m, 2H), 1.65—1.51
(m, 4H), 1.45—1.26 (m, 9H), 0.84 (t, 6H).
Example 9(9): 2—chloro—4—[3—({[4—(2—ethy1buty1)—4—
y—l—piperidinyl]carbonyl}amino)—5—(4—
fluorophenoxy)phenoxy]benzoic acid
TLC: Rf 0.33 (chloroformzmethanol = 5:1);
lH—NMR (cpgon): 5 7.60 (d, 1H), 7.08—6.80 (m, 8H), 6.25 (t, 1H),
3.83 (m, 2H), 3.22 (m, 2H), 1.66—1.30 (m, 11H), 0.86 (t, 6H).
Example 9(10): 4—[3—(cyclohexyloxy)—5—({[4—(2—
ethylbuty1)—4—hydroxy—l—
piperidinyl]carbonyl}amino)phenoxy]benzoic acid
TLC: Rf 0.38 oromethane:methanol = 10:1);
lH—NMR (CDCl3): 5 7.97—8.05 (m, 2H), 6.97—7.05 (m, 2H), 6.87 (t,
1H), 6.66 (t, 1H), 6.38 (s, 1H), 6.31 (t, 1H), .25 (m,
1H), 3.79 (d, 2H), 3.23—3.35 (m, 2H), 1.84—2.00 (m, 2H), 1.69—
1.84 (m, 2H), 1.46—1.65 (m, 6H), 1.22—1.45 (m, 11H), 0.85 (t,
6H).
Example 9(11): 4—[3—(2—chlorophenoxy)—5—({[4—(2—
ethylbutyl)—4—hydroxy—1—
piperidinyl]carbonyl}amino)phenoxy]benzoic acid
TLC: Rf 0.25 (dichloromethane:methanol = 10:1);
lH—NMR (CDCl3): 5 .95 (m, 2H), 7.44 (dd, 1H), 7.30—7.20
(m, 1H), 7.15—7.05 (m, 2H), 7.05—6.99 (m, 2H), 6.96 (t, 1H),
6.75 (t, 1H), 6.45 (s, 1H), 6.34 (t, 1H), 3.85—3.72 (m, 2H),
3.38—3.14 (m, 2H), 1.65—1.57 (m, 4H), 1.45-1.24 (m, 8H), 0.84
(t, 6H).
Example 9(12): 4—[3—(3—chlorophenoxy)—5—({[4-(2—
ethylbutyl)—4—hydroxy—1—
piperidinyl]carbonyl)amino)phenoxy]benzoic acid
TLC: Rf 0.24 (dichloromethane:methanol = 10:1);
1H-NMR (CDCl3): 6 8.11—7.96 (m, 2H), 7.31—7.20 (m, 1H), 7.11~
7.02 (m, 4H), 6.99 (t, 1H), 6.96—6.89 (m, 1H), 6.83 (t, 1H),
6.43 (s, 1H), 6.41 (t, 1H), 3.86—3.74 (m, 2H), 3.39—3.14 (m,
2H), 1.75—1.50 (m, 6H), 1.44—1.25 (m, 7H), 0.85 (t, 6H).
Example 9(13): {4—[3—({[4—(2-ethylbutyl)—4—hydroxy—
1—piperidinyl]carbonyl}amino)—5~(4—
fluorophenoxy)phenoxy]phenyl}acetic acid
TLC: Rf 0.36 oromethane:methanol = 10:1);
1H—NMR (CDCl3): 6 7.24 (d, 2H), 7.03—6.96 (m, 6H), 6.81 (dd,
1H), 6.65 (dd, 1H), 6.40 (brs, 1H), 6.31 (dd, 1H), 3.76—3.72
(m, 2H), 3.62 (s, 2H), 3.28—3.20 (m, 2H), 1.60—1.58 (m, 4H),
.33 (m, 8H), 0.84 (t, 6H).
Example 9(14): 4—[3—(2,4—difluorophenoxy)—5~({[4—(2—
ethylbutyl)—4—hydroxy—1—
piperidinyl]carbonyl}amino)phenoxy]benzoic acid
TLC: Rf 0.29 oromethane:methanol = 10:1);
1H—NMR (CDC13): 5 8.01 (d, 2H), .06 (m, 1H), 7.06—6.69 (m,
6H), 6.51 (br. s., 1H), 6.33 (t, 1H), 3.85-3.65 (m, 2H), 3.35—
3.11 (m, 2H), 1.67—1.50 (m, 4H), 1.43—1.18 (m, 8H), 0.84 (t, 6
Example 9(15): 4—[3—({[4~(2—ethylbutyl)—4—hydroxy—1~
piperidinyl]carbonyl}amino)—5—(4-fluorophenoxy)phenoxy]~2—
hydroxybenzoic acid
TLC: Rf 0.16 (dichloromethane:methanol:ethanol = 100:10:1);
lH—NMR (CDCl3): 5 7.48—7.62 (m, 1H), 6.91-7.10 (m, 5H), 6.77—
6.87 (m, 1H), 6.67 (t, 1H), 6.57 (br. s., 1H), 6.25 (br. s.,
1H), 3.55—3.83 (m, 2H), 3.03-3.30 (m, 2H), 1.41—1.57 (m, 4H),
1.21—1.40 (m, 7H), 0.81 (t, 6H).
Example 9(16): 4—[3—({[4—(2—ethylbutyl)—4—hydroxy—1—
piperidinyl]carbonyl}amino)—5—(4—fluor0phenoxy)phenoxy]—3—
fluorobenzoic acid
TLC: Rf 0.48 (dichloromethane:methanol = 8:2);
lH—NMR : 8 8.46 (s, 1H), .86 (m, 2H), 7.00—7.20 (m,
5H), 6.83—6.91 (m, 2H), 6.25—6.30 (m, 1H), 3.82 (d, 2H), 3.14—
3.28 (m, 2H), 1.20—1.67 (m, 11H), 0.86 (t, 6H).
Example 9(17): {4—[3—({[4—(2-ethylbutyl)-4—hydroxy—
1—piperidinyl]carbonyl}amino)(4—f1uorophenoxy)phenoxy]—2—
fluorophenyl}acetic acid
TLC: Rf 0.19 (chloroformzmethanol = 19:1);
lH—NMR (CDC13): 5 6.54—7.20 (m, 10H), 6.30 (s, 1H), 3.71 (br.
s., 2H), 3.56 (br. s., 2H), 3.19 (br. s., 2H), 1.13-1.47 (m,
13H), 0.64—0.93 (m, 6H).
Example 9(18): 4—[3—(4—fluorophenoxy)—5—{[(4—
hydroxy—4-isobutyl—l—
piperidinyl)carbonyl]amino}phenoxy]benzoic acid
TLC: Rf 0.22 (dichloromethane:methanol = 9:1);
1H—NMR (CD3OD): 5 7.95—8.05 (m, 2H), 6.99—7.16 (m, 6H), 6.89—
6.90 (m, 2H), 6.27 (dd, 1H), .82 (m, 2H), 3.18—3.28 (m,
2H), 1.76—1.93 (m, 1H), 1.46—1.65 (m, 4H), 1.38 (d, 2H), 0.96
(d, 6H).
Example 9(19): 4—[3—({[4—(2—ethylbutyl)—4—hydroxy—1—
piperidinyl]carbony1}amino)—5—(4—fluorobenzoyl)phenoxy]benzoic
acid
TLC: Rf 0.25 (dichloromethane:methanol = 10:1);
1H—NMR (CDC13): 5 7.88—7.96 (m, 2H), 7.71—7.80 (m, 2H), 7.40—
7.47 (m, 2H), 7.02—7.11 (m, 2H), 6.90—6.97 (m, 3H), 3.69—3.73
(m, 2H), .20 (m, 2H), 1.45—1.54 (m, 4H), 1.19—1.33 (m,
7H), 0.75 (t, 6H).
Example 9(20): 2—{4—[3-({[4~(2—ethy1buty1)—4—
hydroxy—l—pipefidinyl]carbonyl}amino)—5—(4—
fluorophenoxy)phenoxy]phenyl}—2—methylpropanoic acid
TLC: Rf 0.39 (dichloromethane:methanol = 10:1);
1H—NMR (CDCl3)I 6 7.33 (d, 2H), 6.92—7.05 (m, 6H), .78 (m,
1H), 6.65—6.68 (m, 1H), 6.44 (s, 1H), 6.24—6.32 (m, 1H), 3.70—
3.77 (m, 2H), 3.14—3.31 (m, 2H), 1.52—1.65 (m, 10H), 1.29—1.42
(m, 7H), 0.84 (t, 6H).
Example 9(21): 2—chloro—4—[3-(4—fluorophenoxy)—5—
{[(4—hydroxy—4—isobutyl—1—
piperidinyl)carbonyl]amino}phenoxy]benzoic acid
TLC: Rf 0.30 (chloroformzmethanol = 5:1);
lH—NMR (CDCl3+CD3OD): 5 7.69 (d, 1H), 7.20—6.84 (m, 9H), 6.26
(t, 1H), 3.80 (m, 2H), 3.23 (m, 2H), 1.87 (m, 1H), 1.66—1.48
(m, 4H), 1.37 (d, 2H), 0.95 (d, 6H).
Example 9(22): 4—[3—({[4—(2—ethylbuty1)—4—hydroxy—1—
piperidinyl]carbonyl}amino)—5—(4-f1uorophenoxy)phenoxy]—2-
methylbenzoic acid
TLC: Rf 0.33 oromethane:methanol = 10:1);
lH—NMR ): 8 7.81 (d, 1H), 6.96—7.05 (m, 4H), 6.67—6.82 (m,
4H), 6.29 (t, 1H), 3.66—3.76 (m, 2H), 3.14—3.25 (m, 2H), 2.46
(s, 3H), 1.49—1.62 (m, 4H), .39 (m, 7H), 0.82 (t, 6H).
Example 9(23): 4—[3—(4—fluorophenoxy)—5—{[(4—
hydroxy—4—isobutyl—1—piperidinyl)carbonyl]amino}phenoxY]—2—
benzoic acid
TLC: Rf 0.70 (chlorcformzmethanol = 5:1);
lH—NMR (CDC13+CD30D): 5 7.81 (d, 1H), 7.18—6.78 (m, 8H), 6.24
(t, 1H), 3.80 (m, 2H), 3.23 (m, 2H), 2.52 (s, 3H), 1.84 (m,
1H), 1.68—1.48 (m, 4H), 1.40 (d, 2 ), 0.95 (d, 6H).
Example 9(24): 3-f1uoro—4—[3—(4—fluorophenoxy)
{[(4—hydroxy—4—isobuty1—1-
piperidinyl)carbonyl]amino}phenoxy]benzoic acid
TLC: Rf 0.20 (dichloromethane:methanol = 9:1);
lH—NMR (CD3OD): 8 7.68—7.77 (m, 2H), 6.98—7.12 (m, 5H), 6.90
(dd, 1H), 6.73 (dd, 1H), 6.21 (dd, 1H), 3.76—3.80 (m, 2H),
3.15—3.28 (m, 2H), 1.83—1.93 (m, 1H), 1.43—1.69 (m, 4H), 1.37
(d, 2H), 0.96 (d, 6H).
Example 9(25): 4—[3-(4—fluorophenoxy)—5—{[(4—
hydroxy—4—isobutyl—1—piperidinyl)carbonyl]amino}phenoxy]—2—
methoxybenzoic acid
TLC: Rf 0.47 oromethane:methanol = 9:1);
lH—NMR (CDfiHD: 5 7.87 (d, 1H), 7.03—7.13 (m, 4H), 6.88-6.94 (m,
2H), 6.76 (d, 1H), 6.58 (dd, 1H), 6.30 (dd, 1H), 3.85 (s, 1H),
3.76—3.86 (m, 2H), 3.19—3.28 (m, 2H), 1.81—1.90 (m, 1H), 1.48—
1.64 (m, 4H), 1.38 (d, 2H), 0.96 (d, 6H).
Example 9(26): 2—{4—[3—(4—fluorophenoxy)—5—{[(4—
hydroxy—4—isobutyl—1—
piperidinyl)carbonyl]amino}phenoxy]phenyl}propanoic acid
TLC: Rf 0.31 (dichloromethane:methanol = 10:1);
lH—NMR (CDCl3): 6 7.24 (d, 2H), .05 (m, 4H), 6.92 (d, 2H),
6.82 (t, 1H), 6.60—6.66 (m, 1H), 6.27 (t, 1H), .75 (m,
3H), 3.11-3.26 (m, 2H), 1.70—1.88 (m, 1H), 1.48—1.60 (m, 4H),
1.44 (d, 3H), 1.36 (d, 2H), 0.94 (d, 6H).
e 9(27): {2—fluoro—4—[3—(4—fluorophenoxy)—5—
{[(4—hydroxy—4—isobutyl—1—
piperidinyl)carbonyl]amino}phenoxy]pheny1)acetic acid
TLC: Rf 0.17 (dichloromethane:methanol = 10:1);
1H—NMR (CDC13): 5 7.10 (t, 1H), 6.93—7.02 (m, 4H), 6.87 (s, 1H),
6.59—6.73 (m, 3H), 6.27 (s, 1H), 3.61—3.75 (m, 2H), 3.47 (br.
s., 2H), 3.08—3.26 (m, 2H), 1.77 (dquin, 1H), 1.38—1.59 (m,
4H), 1.32 (d, 2H), 0.91 (d, 6H).
Example 9(28): {4-[3-(4—fluorophenoxy){[(4—
hydroxy—4—isobutyl—1—
piperidinyl)carbonyl]amino}phenoxy]phenyl}acetic acid
TLC: Rf 0.17 (dichloromethane:methanol = 10:1);
lH—NMR (CDfiHD: 8 8.38 (s, 1H3, 7.27 (d, 2H), 7.01—7.12 (m, 4H),
6.94—7.00 (m, 2H), 6.81 (dq, 2H), 6.21 (t, 1H), 3.75—3.84 (m,
2H), 3.59 (s, 2H), 3.16—3.29 (m, 2H), 1.77—1.93 Km, 1H), 1.45—
1.64 (m, 4H), 1.38 (d, 2H), 0.97 (d, 6H).
Example 9(29): 2—fluoro—4—[3—(4—fluorophenoxy)—5—
({[4—(4—fluoropheny1)—4—hydroxy-1—
piperidinyl]carbonyl}amino)phenoxy]benzoic acid
TLC: Rf 0.34 oformzmethanol = 4:1);
lH—NMR (CDfiHD: 5 7.91 (t, 1H), 7.53—7.47 (m, 2H), 7.16—6.95 (m,
8H), .76 (m, 2H), 6.33 (t, 1H), 4.08—3.97 (m, 2H), 3.40—
3.30 (m, 2H), 2.07—1.94 (m, 2H), 1.77—1.67 (m, 2H).
Example 9(30): {2—fluoro—4-[3—(4—fluorophenoxy)—5—
({[4—(4—fluoropheny1)hydroxy—1—
piperidinyl]carbony1}amino)phenoxy]phenyl}acetic acid
TLC: Rf 0.41 (chloroform:methanol = 4:1);
lH—NMR (CD3OD): 5 7.53—7.46 (m, 2H), 7.28 (t, 1H), 7.15—7.00 (m,
6H), 6.91—6.87 (m, 2H), 6.83—6.76 (m, 2H), 6.28 (t, 1H), 4.06—
3.97 (m, 2H), 3.63 (s, 2H), 3.38—3.30 (m, 2H), 2.06—1.93 (m,
2H), 1.77—1.68 (m, 2H).
Example 9(31): 2—{4—[3—(4—fluorophenoxy)—5—({[4—(4—
fluorophenyl)—4—hydroxy—1—
piperidinyl]carbonyl}amino)phenoxy]phenyl}propanoic acid
TLC: Rf 0.32 (chloroform:methanol = 9:1);
lH—NMR (CDfiHN: 8 7.41—7.56 (m, 2H), 7.24—7.36 (m, 2H), 6.91-
7.15 (m, 8H), 6.85 (t, 1H), 6.80 (t, 1H), 6.21 (t, 1H), 4.00
(d, 2H), 3.69 (q, 1H), 3.19—3.41 (m, 2H), 1.98 (td, 2H), 1.71
(d, 2H), 1.44 (d, 3H).
Example 9(32): 4—[3—(2,4—dif1uorophenoxy)—5—{[(4—
hydroxy—4—isobutyl—1—
piperidinyl)carbonyl]amino}phenoxy]benzoic acid
TLC: Rf 0.63 (chloroform:methanol:ethanol = 9:1:0.1);
lH—NMR (CDC13): 5 7.97 (d, 2H), 7.18—7.06 (m, 1H), 7.02—6.75 (m,
6H), 6.28 (m, 1H), 3.73 (m, 2H), 3.30—3.19 (m, 2H), 1.89—1.75
(m, 1H), 1.65—1.43 (m, 4H), 1.38 (d, 2H) 1.29—1.23 (m, 1H),
0.95 (d, 6H).
Example 9(33): (2,4—difluorophenoxy)—5—{[(4—
yisobutyl—1—
piperidinyl)carbonyl]amino}phenoxy]phenyl}acetic acid
TLC: Rf 0.63 (chloroformzmethanol:ethanol = 9:1:0.1);
lH—NMR (CDC13): 5 7.22 (d, 2H), 7.10 (td, 1H), 7.00—6.79 (m,
5H), 6.60 (t, 1H), 6.27 (t, 1H), 3.70 (m, 2H), 3.52 (s, 2H),
3.28—3.13 (m, 2H), 1.90—1.73 (m, 1H), 1.64—1.47 (m, 4H), 1.37
(d, 2H), 0.95 (d, 6H).
Example 9(34): 2—chloro—4—[3—(2,4—difluorophenoxy)—
—{[(4—hydroxy—4—isobutyl—1-
piperidinyl)carbonyl]amino}phenoxy]benzoic acid
TLC: Rf 0.68 (chloroform:methanol:ethanol = 1);
lH—NMR (CDC13): 6 7.70 (d, 2H), 7.13 (m, 1H), 7.03—6.81 (m, 5H),
6.72 (t, 1H), 6.27 (t, 1H), 3.74 (m, 2H), 3.31—3.12 (m, 2H),
1.92—1.72 (m, 1H), 1.48—1.65 (m, 4H), 1.33—1.42 (m, 2H), 1.21—
1.30 (m, 1H), .01 (d, 6H).
Example 9(35): {4—[3—(2,4-difluorophenoxy)—5—{[(4—
hydroxy—4~isobuty1—1-piperidinyl)carbonyl]amino}phenoxy]—2—
fluoropheny1}acetic acid
TLC: Rf 0.56 (dichloromethane:methanol = 8:2);
1H—NMR (CD3OD): 5 7.16—7.33 (m, 2H), 7.11 (ddd, 1H), 6.92—7.03
(m, 1H), 6.85 (S, 2H), 6.72—6.82 (m, 2H), 6.24 (t, 1H), 3.80
(dt, 2H), 3.62 (s, 2H), .29 (m, 2H), 1.77—1.95 (m, 1H),
1.43—1.67 (m, 4H), 1.38 (d, 2H) 0.97 (d, 6H).
Example 9(36): 2—{4—[3—(2,4—difluorophenoxy)—5—{[(4—
hydroxy—4—isobutyl—1—
piperidinyl)carbonyl]amino}phenoxy]phenyl}propanoic acid
TLC: Rf 0.72 (dichloromethane:methanol = 8:2);
lH—NMR ): 5 7.31 (d, 2H), 7.19 (td, 1H), 7.06-7.15 (m,
1H), 6.91—7.02 (m, 3H), 6.81 (t, 1H), 6.78 (t, 1H), 6.18 (t,
1H), 3.74—3.84 (m, 2H), 3.69 (q, 1H), 3.16—3.29 (m, 2H), 1.75—
1.94 (m, 1H), 1.48—1.64 (m, 4H), 1.45 (d, 3H), 1.38 (d, 2H),
0.97 (d, 6H).
Example 9(37): 4-[3—(4—fluorophenoxy)—5—({[4—
y—4—(3—pentany1)—1—
piperidinyl]carbonyl)amino)phenoxy]benzoic acid
TLC: Rf 0.58 (chloroform:methanol = 5:1);
lH—NMR (CDfiHfl: 8 7.98 (d, 1H), 7.18—6.98 (m, 6H), 6.88 (d, 2H),
6.25 (m, 1H), 3.90 (m, 2H), 3.11 (m, 2H), 1.66—1.40 (m, 7H),
.10 (m, 2H), 0.86 (t, 6H).
Example 9(38): (2E)—3—{4—[3—(4—fluorophenoxy)—5—
{[(4—hydroxy—4—isobutyl—1—
piperidinyl)carbonyl]amino}phenoxy]pheny1}acrylic acid
TLC: Rf 0.31 (dichloromethane:methanol = 10:1);
1H—NMR (CDC13): 5 7.49 (dd, 1H), 7.37—7.45 (m, 2H), 6.89—7.01
(m, 6H), 6.75—6.81 (m, 2H), 6.21—6.33 (m, 2H), 3.61-3.73 (m,
2H), 3.09—3.23 (m, 2H), 1.68—1.82 (m, 1H), 1.41—1.59 (m, 4H),
1.31 (dd, 2H), 0.88 (dd, 6H).
Example 9(39): 4—[3—(2,4—difluorophenoxy)-5—({[4—(4—
fluorophenyl)—4-hydroxy—1—
piperidinyl]carbonyl}amino)phenoxy]benzcic acid
TLC: Rf 0.68 (chloroformzmethanol:ethanol = 9:1:0.1);
1H—NMR (CDCl3): 6 7.99 (d, 2H), 7.50—7.35 (m, 2H), 7.19—6.80 (m,
9H), 6.30 (t, 1H), 3.94 (m, 2H), 3.39—3.24 (m, 2H), 1.98 (m,
2H), 1.75 (d, 2H).
Example 9(40): 3-(4-fluorophenoxy)—5—{[(4—
hydroxy—4—isobutyl-1—
piperidinyl)carbonyl]amino}phenoxy]phenyl}propanoic acid
TLC: Rf 0.40 (dichloromethane:methanol = 10:1);
1H—NMR (CDC13): 5 7.13 (d, 2H), 6.95—7.05 (m, 4H), 6.90 (d, 2H),
6.72—6.77 (m, 1H), 6.62e6.67 (m, 1H), 6.24—6.29 (m, 1H), 3.62—,
3.74 (m, 2H), 3.15—3.25 (m, 2H), .93 (m, 2H), 2.48—2.59
(m, 2H), 1.80 (dquin, 1H), 1.43—1.62 (m, 4H), 1.35 (d, 2H),
0.93 (d, 6H).
Example 9(41): {4—[3—(4-fluorophenoxy)—5—({[4—
hydroxy—4—(3—pentanyl)~1—
piperidinyl]carbonyl)amino)phenoxy]phenyl}acetic acid
TLC: Rf 0.58 (chloroform:methanol:ethanol = 9:1:0.1);
lH—NMR ): 8 7.22 (d, 2H), .90 (m, 6H), 6.83 (t, 1H),
6.63 (t, 1H), 6.30 (t, 1H), 3.79 (m, 2H), 3.56 (s, 2H), 3.26—
3.01 (m, 2H), 1.67—1.41 (m, 6H), 1.34—1.08 (m, 3H), 1.06—0.84
(m, 7H).
Example 9(42): 2—chloro—4—[3-(4—fluorophenoxy)—5—
({[4—hydroxy—4—(3—pentanyl)-1—
piperidinyl]carbonyl}amino)phenoxy]benzoic acid
TLC: Rf 0.51 (chloroform:methanol:ethanol = 9:1:0.1);
1H—NMR (CDC13): 5 7.80 (m, 1H), 7.07—6.95 (m, 5H),6.93—6.72 (m,
3H), 6.30 (t, 1H) 3.82 (m, 2H) 3.28—3.03 (m, 2H), 1.73—1.45 (m,
6H), .11 (m, 3H), 1.06—0.83 (m, 7H).
Example 9(43): 2—{4-[3-(4—fluorophenoxy)—5—({[4—
hydroxy—4-(3-pentanyl)—1—
piperidinyl]carbonyl}amino)phenoxy]phenyl}—2—ethylpropanoic
acid
TLC: Rf 0.56 (chloroformzmethanol:ethanol = 9:1:0.1);
lH—NMR (CDC13): 5 7.39—7.29 (m, 2H), 7.07—6.92 (m, 6H), 6.81 (t,
1H), 6.65 (t, 1H), 6.29 (t, 1H), 3.79 (m, 2H), 3.27—3.08 (m,
2H), 1.66—1.42 (m, 12H), .10 (m, 3H), 1.05—0.87 (m, 7H).
Example 9(44): 4-[3—(3,4—difluorophenoxy)—5—({[4—
hydroxy—4—(3-pentanyl)~1-
piperidinyl]carbonyl}amino)phenoxy]benzoic acid
TLC: Rf 0.76 (dichloromethane:methanol = 3:1);
1H—NMR : 6 8.49 (s, 1H), 8.07—7.97 (m, 2H), 7.32—7.23 (m,
1H), 7.11—6.92 (m, 5H), 6.90—6.80 (m, 1H), 6.35 (t, 1H), 3.95—
3.80 (m, 2H), 3.27—3.07 (m, 2H), 1.70—1.44 (m, 6H), .08
(m, 2H), 1.06—0.91 (m, 7H).
Example 9(45): 2—chloro—4—[3—(3,4—difluorophenoxy)—
-({[4-hydroxy—4—(3—pentany1)—1—
piperidinyl]carbonyl}amino)phenoxy]benzoic acid
TLC: Rf 0.51 (dichloromethane:methanol = 3:1);
lH—NMR (CDfiND): 8 8.52 (s, 1H), 7.92 (d, 1H), 7.31—7.19 (m, 1H),
7.10 (d, 1H), 7.07—6.95 (m, 4H), 6.92—6.81 (m, 1H), 6.38 (t,
1H), 4.00-3.80 (m, 2H), 3.26—3.08 (m, 2H), 1.73—1.46 (m, 6H),
.06 (m, 2H), 1.05—0.90 (m, 7H).
Example 9(46): 3—(3,4—difluorophenoxy)—5—{[(4—
hydroxy—4—isobutyl-1—
piperidinyl)carbonyl]amino}phenoxy]phenyl}—2-methylpropanoic
acid
TLC: Rf 0.32 oromethane:methanol = 10:1);
1H—NMR (CDfifln: 5 7.43—7.35 (m, 2H), 7.31—7.16 (m, 1H), 7.04—
6.91 (m, 3H), 6.90~6.86 (m, 1H), 6.86—6.78 (m, 2H), 6.25 (t,
1H), 3.90—3.70 (m, 2H), 3.28—3.14 (m, 2H), 1.95—1.75 (m, 1H)
.45 (m, 10H), 1.39 (d, 2H), 0.97 (d, 6H).
Example 9(47): 4—[3—(3,4-difluorophenoxy)-5—{[(4—
hydrcxy—4—isobutyl—1—pipefidinyl)carbonyl]amino}phenoxy]—3—
fluorobenzoic acid
TLC: Rf 0.52 (dichloromethane:methanol = 3:1);
1H—NMR (CDfiND): 5 8.47 (s, 1H), .78 (m, 2H), 7.34—7.09 (m,
2H), 7.05—6.94 (m, 1H), 6.94—6.89 (m, 2H), 6.89—6.79 (m, 1H),
6.33 (t, 1H), 3.86—3.69 (m, 2H), 3.28—3.16 (m, 2H), 1.93—1.72
(m, 1H), 1.67-1.43 (m, 4H), 1.38 (d, 2H), 0.96 (d, 6H).
Example 9(48): {4—[3—(3,4—difluorophenoxy)—5—{[(4—
hydroxy—4-isobutyl-1—piperidinyl)carbonyl]amino}phenoxy]~2-
fluorophenyl}acetic acid
TLC: Rf 0.72 (dichloromethane:methanol = 3:1);
lH—NMR (CD3OD): 8 8.45 (s, 1H), 7.34—7.15 (m, 2H), 7.05—6.94 (m,
1H), 6.93—6.87 (m, 2H), 6.86—6.73 (m, 3H), 6.30 (t, 1H), 3.88—
3.72 (m, 2H), 3.62 (d, 2H), 3.27—3.17 (m, 2H), 1.92—1.75 (m,
1H), 1.67—1.44 (m, 4H), 1.38 (d, 2H), 0.96 (d, 6H).
Example 9(49): 3—(3,4—difluorophenoxy)—5—{[(4—
hydroxy—4—isobutyl—1-
piperidinyl)carbonyl]amino}phenoxy]phenyl}propanoic acid
TLC: Rf 0.29 (dichloromethane:methanol = 10:1);
lH—NMR (CDfiHD: 5 8.42 (s, 1H), 7.36—7.29 (m, 2H), 7.29—7.17 (m,
1H), 7.05—6.90 (m, 3H), 6.89—6.78 (m, 3H), 6.25 (t, 1H), 3.87—
3.76 (m, 2H) 3.71 (q, 1H), 3.28—3.14 (m, 2H), 1.96—1.76 (m,
1H), 1.66—1.50 (m, 4H), 1.45 (d, 3H), 1.39 (d, 2H), 0.97 (d,
6H).
Example 9(50): {4—[3—({[4—(2—ethylbutyl)—4—hydroxy—
1—piperidinyl]carbonyl}amino)—5—(4—
fluorophenoxy)phenoxy]phenoxy}acetic acid
TLC: Rf 0.29 (chloroform:methanol:ethanol = 9:1:0.1);
lH—NMR (CDC13): 8 7.01—6.89 (m, 4H), 6.85—6.66 (m, 5H), 6.58 (m,
1H), 6.18 (m, 1H), 4.37—4.20 (m, 2H), 3.69 (m, 2H), 3.14 (m,
2H), 1.59—1.21 (m, 11H), 0.72—0.87 (m, 6H).
Example 9(51): 2-[4-[3—(4—fluorophenoxy)—5—({[4—
hydroxy—4—(3—methylbutyl)—1-
piperidinyl]carbonyl}amino)phenoxy]phenyl}—2—methylpropanoic
acid
TLC: Rf 0.28 (dichloromethane:methanol = 10:1);
1H—NMR (CDC13): 5 7.33—7.39 (m, 2H), 6.96—7.06 (m, 6H), 6.78—
6.81 (m, 1H), 6.69 (t, 1H), 6.38 (s, 1H), 6.30—6.32 (m, 1H),
3.71—3.77 (m, 2H), .31 (m, 2H), 1.53—1.64 (m, 8H), 1.43—
1.53 (m, 4H), 1.19—1.31 (m, 4H), 0.90 (d, 6H).
Example 9(52): 3—[(4,4—
difluorocyclohexyl)oxy]—5—({[4—(2—ethylbuty1)—4—hydroxy—1—
dinyl]carbonyl}amino)phenoxy}phenyl)—2—methy1propanoic
acid
TLC: Rf 0.45 (chloroformzmethanol = 9:1);
1H*NMR ): 5 7.29 (d, 2H), 6.97—6.84 (m, 3H), 6.63 (m, 1H),
6.41 (m, 1H), 6.27 (m, 1H), 4.43 (m, 1H), 3.80—3.63 (m, 2H),
3.32—3.13 (m, 2H), 2.10—1.71 (m, 7H), 1.21—1.53 (m, 18H),
0.90—0.75 (t, 6H).
Example 9(53): 2—{4—[3—({[4—(2—ethylbutyl)—4—
hydroxy-l-piperidinyl]carbonyl}amino)—5-(2—
fluorophenoxy)phenoxy]phenyl}methylpropanoic acid
TLC: Rf 0.40 (chloroformzmethanol = 9:1);
lH—NMR (CDC13): 5 7.33 (d, 2H), 7.16—7.03 (m, 3 H), 6.96 (d,
2H), 6.79—6.64 (m, 2H), 6.42 (m, 1H), .23 (m, 1H), 3.70
(m, 2H), 3.32—3.10 (m, 2H), 1.62—1.52 (m, 8H), 1.46—1.20 (m,
4H), 0.93—0.69 (t, 6H).
Example 9(54): 2—{4—[3—({[4-(2—ethylbutyl)—4—
hydroxy-l—piperidinyl]carbonyl}amino)—5—(2—
methylphenoxy)phenoxy]phenyl}—2—ethylpropanoic acid
TLC: Rf 0.45 (chloroformzmethanol = 9:1);
1H—NMR (CDC13): 8 7.31—7.17 (m, 2H), 7.15-6.98 (m, 2H), 6.95—
6.81 (m, 4H), 6.62 (m, 1H), 6.58 (m, 1H), 6.24 (m, 1H), 3.64
(m, 2H), 3.10 (m, 2H), 2.19 (s, 3H), 1.47 (m, 4H), 1.36—1.18
(m, 8H), 0.88—0.73 (t, 6H).
Example 9(55): 2—{4—[3—{[(4—cyclopentyl—4—hydroxy—1—
piperidinyl)carbonyl]amino}—5—(4—
fluorophenoxy)phenoxy]phenyl}—2—methylpropanoic acid
TLC: Rf 0.49 (chloroformzmethanol = 9:1);
lH—NMR (CDCl3): 8 7.32 (m, 2H), 7.08—6.90 (m, 6H), 6.76 (m, 1H),
6.66 (m, 1H), 6.48 (m, 1H), 6.29 (m, 1H), 3.74 (m, 2H), 3.18
(m, 2H), 2.11 (m, 4H), 1.78 (m, 1H), 1.74—1.50 (m, 6H), 1.57
(s, 6H), 1.33 (m, 2H).
Example 9(56): 2—{4-[3-{[(4—cyclohexyl—4—hydroxy—1—
piperidinyl)carbonyl]amino}—5—(4—
fluorophenoxy)phenoxy]phenyl}—2—methylpropanoic acid
TLC: Rf 0.33 (chloroformzmethanol = 19:1);
lH—NMR (CDfiHM: 8 1.00—1.30 (m, 6H), 1.49—1.71 (m, 11H), 1.76—
1.86 (m, 4H), 3.10—3.22 (m, 2H), .96 (m, 2H), 6.19 (t,
1H), 6.78—6.84 (m, 2H), 6.95—7.12 (m, 6H), 7.35—7.41 (m, 2H),
8.36 (brs, 1H).
Example 9(57): 2—{3—[3—(4—fluorophenoxy)—5—{[(4—
hydroxy—4—isobutyl—1—
dinyl)carbonyl]amino}phenoxy]phenoxy}—2—methylpropanoic
acid
TLC: Rf 0.35 (dichloromethane:methanol = 10:1);
lH—NMR (CDCl3): 5 7.21 (t, 1H), 7.04 (d, 4H), 6.82 (t, 1H),
6.71 (d, 1H), 6.69 (d, 1H), 6.50 (t, 1H), 6.46 (t, 1H), 6.33—
6.29 (m, 2H), 3.74 (s, 2H), 3.36—3.21 (m, 2H), 2.09 (s, 1H),
1.82 (dt, 1H), 1.63—1.55 (m, 10H), 1.40 (d, 2H), 0.96 (d, 6H).
Example 9(58): 2—{3—[3—(4—fluorophenoxy)—5—{[(4—
hydroxy—4—isobutyl—l—
piperidinyl)carbonyl]amino}phenoxy]phenyl}—2—methylpropanoic
acid
TLC: Rf 0.41 (dichloromethane:methanol = 10:1);
1H—NMR (CDC13): 5 7.34—7.28 (m, 1H), .10 (m, 2H), 7.05—
6.99 (m, 4H), 6.92 (dd, 1H), 6.68—6.65 (m, 1H), 6.60 (t, 1H),
6.40 (s, 1H), 6.35 (t, 1H), .66 (m, 2H), 3.30—3.17 (m,
2H), 1.83 (dt, 1H), 1.62—1.55 (m, 10H), 1.40 (d, 2H), 0.97 (d,
6H).
Example 9(59): 2—[4—(3—[(4,4—
difluorocyclohexyl)oxy]—5—{[(4—hydroxy—4—isobutyl—l—
piperidinyl)carbonyl]amino}phenoxy)phenyl]-2—methylpropanoic
acid
TLC: Rf 0.38 (dichloromethane:methanol = 10:1);
lH—NMR (CD3OD): 8 7.41—7.33 (m, 2H), 7.01—6.91 (m, 2H), 6.91—
6.84 (m, 1H), 6.63 (t, 1H), 6.25 (t, 1H), 4.54—4.40 (m, 1H),
3.90—3.73 (m, 2H), 3.28—3.16 (m, 2H), 2.19—1.75 (m, 9H), 1.55
(s, 6H), 1.68-1.45 (m, 4H), 1.40 (d, 2H), 0.98 (d, 6H).
Example 9(60): 2—{3—fluoro-4—[3—(4—fluorophenoxy)—5—
{[(4—hydroxy—4-isobutyl—1—
piperidinyl)carbonyl]amino}phenoxy]phenyl}—2—methylpropanoic
acid
TLC: Rf 0.40 (dichloromethane:methanol = 10:1);
1H—NMR (CD3OD): 5 7.29—7.22 (m, 1H), 7.22—7.16 (m, 1H), 7.14—
6.98 (m, 5H), 6.85—6.81 (m, 1 H), 6.75 (t, 1H), 6.17 (t, 1H),
3.86—3.71 (m, 2H), 3.29—3.15 (m, 2H), 1.95—1.73 (m, 1H), 1.55
(s, 6H), 1.64—1.45 (m, 4H), 1.39 (d, 2H), 0.97 (d, 6H).
Example 9(61): 1—{4-[3—(4—fluorophenoxy)—5—{[(4—
hydroxy—4—isobutyl—1—
piperidinyl)carbonyl]amino}phenoxy]phenoxy}cyclopropanecarboxy
lic acid
TLC: Rf 0.31 (dichloromethane:methanol = 10:1);
1H—NMR (CDCl3): 5 .86 (m, 8H), 6.69 (t, 1H), 6.58 (s, 1H),
6.53 (t, 1H), 6.28 (t, 1H), 3.70 (dt, 2H), 3.26—3.13 (m, 2H),
1.90-1.75 (m, 1H), 1.69—1.62 (m, 2H), .53 (m, 4H), 1.42—
1.33 (m, 4H), 0.97 (d, 6H).
Example 9(62): N—{3—(4—fluorophenoxy)—5-[(6-
isopropyl—3—pyridinyl)oxy]phenyl}-4—hydroxy—4—isobutyl—1—
dinecarboxamide
TLC: Rf 0.53 (dichloromethane:methanol = 10:1);
1H—NMR (CDCl3): 8 8.32 (d, 1H), 7.31—7.27 (m, 1H), 7.15 (d, 1H),
7.07—6.98 (m, 4H), 6.80—6.75 (m, 2H), 6.34 (s, 1H), 6.29 (t,
1H), 3.81-3.70 (m, 2H), 3.34—3.23 (m, 2H), 3.12—2.96 (m, 1H),
1.85 (dt, 1H), 1.64—1.59 (m, 4H), 1.42 (d, 2H), 1.30 (d, 6H),
1.07 (s, 1H), 0.98 (d, 6H).
Example 9(63): 2—{4—[3—{[(4—cyclopentyl—4—hydroxy—1—
dinyl)carbonyl]amino}-5—(4—
fluorophenoxy)phenoxy]phenoxy}—2—methylpropanoic acid
TLC: Rf 0.13 (dichloromethane:methanol = 10:1);
1H—NMR (CDC13): 8 7.37 (s, 1H), 6.99—6.89 (m, 4H), 6.83 (s,
4H),6.77—6.71 (m, 1H), 6.62—6.56 (m, 1H), .12 (m, 1H),
3.77—3.66 (m, 2H), 3.18—3.02 (m, 2H), 1.83—1.68 (m, 1H), 1.62—
1.38 (m, 16H), 1.35—1.23 (m, 2H).
e 9(64): 3—{[(4~cyclopentyl—4—hydroxy—1—
piperidinyl)carbonyl]amino}-5—(4—fluorophenoxy)phenoxy]—2—
fluorophenyl}—2—methylpropanoic acid
TLC: Rf 0.47 (dichloromethane:methanol = 10:1);
lH—NMR (CDC13): 5 7.30—7.21 (m, 1H), 7.08—6.97 (m, 4H), 6.84 (t,
1H), 6.81—6.65 (m, 3H), 6.50 (s, 1H), 6.34—6.31 (m, 1H), 3.85—
3.74 (m, 2H), 3.30—3.17 (m, 2H), 1.93—1.79 (m, 1H), 1.73—1.49
(m, 16H), 1.42—1.31 (m, 2H).
Example 10: l-fluoro—3—(4-fluorophenoxy)—5—
nitrobenzene
Under an argon atmosphere and at room temperature, in a
500—mL pear—shaped evaporating flask, 4—fluorophenol (18.5 g)
and fluoro—5—nitrobenzene (25.0 g) were dissolved in DMA
(300 mL). The reaction system was added with cesium carbonate
(15.3 g) and stirred. The on system was then heated to
50°C, d for 3 hours, then heated to 65°C, stirred for 1
hour and further heated to 85°C and stirred for 1 hour. The
reaction solution was allowed to cool to room temperature,
diluted with ethyl acetate and added with water to extract an
organic layer. The aqueous layer was added with ethyl acetate
to extract an organic layer. The organic layer was combined
and washed with water and a saturated sodium chloride solution
and the t was then distilled off under reduced re
to give the titled compound (35.0 g) having the following
physical properties.
TLC: Rf 0.83 (hexane:ethyl acetate = 5:1);
lH—NMR (CDCl3): 8 6.98 (dt, J=9.3, 2.3 Hz, 1H), 7.03—7.18 (m,
4H), 7.56 (td, J=2.1, 1.1 Hz, 1H), 7.62 (dt, J=8.1, 2.2 Hz,
1H).
Example 11: 1-(4-fluorophenoxy)—3—(4—iodophenoxy)—5—
nitrobenzene
At room temperature, to a 300—mL three—neck flask were
added 4—iodophenol (44.4 g) and further the compound prepared
in Example 10 (34.9 g) dissolved in DMA (140 mL) and potassium
phosphate (59.2 g) and the flask was purged with argon. The
on solution was heated to 105°C and stirred for 7 hours.
The on solution was d to cool to room temperature,
diluted with ethyl acetate and added with water to t an
organic layer. The organic layer was washed twice with water,
twice with 1 N sodium hydroxide and with a saturated sodium
chloride solution and then dried over anhydrous sodium
sulphate and the solvent was distilled off under reduced
pressure. The resulting residue was added with a seed crystal
(5 mg) and the solid was precipitated under reduced pressure.
The solid was added with hexane (300 mL), stirred and left to
stand at room temperature to precipitate the solid. The solid
was collected by filtration with a Kiriyama funnel and washed
with hexane. The resulting residue was dried under reduced
pressure at 60°C to give the titled compound (53.1 g). The
filtrate was subjected to silica gel column chromatography
(hexanezMTBE = 99:1 —9 95:5) to give a pale yellow oily
substance. Re—crystallization was carried out with a mixed
solvent of hexane and MTBE, and the titled compound (14.4 g)
was obtained after filtration with a Kiriyama funnel and
washing with hexane. The titled compound having the ing
physical properties was obtained at a total amount of 67.5 g.
TLC: Rf 0.31 ezethyl acetate = 10:1);
lH—NMR (CDCl3): 5 6.81—6.87 (m, 2H), 6.91 (dd, J=2.1 Hz, 1H),
7.02—7.14 (m, 4H), 7.42—7.45 (m, 2H), 7.68—7.73 (m, 2H).
e 12: Methyl 1—{4—[3—(4—bromophenoxy)—5—
henoxy]phenyl}cyclopropanecarboxylate
Under an argon atmosphere and at room ature, to a
solution of zinc (87 mg) in dimethoxyethane (DME) (1.0 mL) in
a 100-mL three—neck flask were added sequentially lithium
Chloride (37.6 mg) and chlorotrimethylsilane (TMSCl) (11.3 uL).
The mixture was heated to 75°C, added dropwise with methyl 1—
bromocyclopropane carboxylate and further stirred at 75°C for 2
hours (this solution is referred to as the solution 1). Under
an argon atmosphere and at room temperature, N—methyl—Z—
pyrrolidone (NMP) (1.0 mL) was added, degassed and charged
with argon. i—tert—butylphosphine)palladium (0) (Pd(t—
Bu3P)2) (23 mg) was added thereto, stirred for 10 minutes
before addition of the compound prepared in Example 11 (200
mg). The e was heated to 95°C and the solution 1
prepared as above was added dropwise over 30 minutes. The
mixture was further stirred at 95°C for 1.5 hours. The
reaction solution was allowed to cool, d with ethyl
e and filtered with celite. The filtrate was washed with
water and a ted sodium chloride solution and dried over
anhydrous sodium sulphate and the solvent was distilled off
under reduced pressure. The solid was filtered, the resulting
residue was purified by silica gel tography
(hexane:ethyl acetate = 90:10 ~> 80:20 —9 50:50 —> 0:100) to
give the titled compound (143 mg) having the following
physical ties.
TLC: Rf 0.42 (hexane:ethyl acetate 4:1).
Example 13: 1—{4—[3—(4—fluorophenoxy)—5—({[4—
hydroxy—4—(3—pentanyl)—l—
piperidinyl]carbonyl}amino)phenoxy]phenyl}cyclopropanecarboxyl
ic acid
[C 16]
"TN 0
. OF
O©ka
The titled compound (12.0 g) having the ing
physical properties was obtained by carrying out the processes
with the same purposes as Example 6 ~9 Example 7 —% Example 8
—9 Example 9 using the compound prepared in Example 12 (22.4 g),
2,2,2-trichloroethyl chloroformate and 4—(2—ethylbutyl)—4—
piperidinol in the place of 4—isobutyl—4—piperidinol.
TLC: Rf 0.32 (chloroform:ethanol = 20:1);
1HfiNMR (CDCl3): 5 7.30—7.25 (m, 2H), 7.05—6.97 (m, 3H), 6.96—
6.90 (m, 2H), 6.88 (t, 1H), 6.65 (t, 1H), 6.30 (t, 1H), 3.81
(m, 2H), 3.25—3.09 (m, 2H), 1.69—1.43 (m, 8H), 1.23—1.10 (m,
5H), 1.07—0.88 (m, 7H).
Examples 13(1) to 13(8)
The compounds of the following Examples were ed by
carrying out the processes with the same purposes as Example
—9 Example 11 —9 Example 12 —9 Example 13 using 1,3-
difluoro-S-nitrobenzene; 4-iodophenol or a corresponding
phenol derivative instead thereof; 4—f1uorophenol or a
corresponding phenol derivative instead thereof; 2,2,2-
trichloroethyl chloroformate; methyl 1—bromocyclopropane
carboxylate or a corresponding bromide instead thereof; and 4—
isobuty1—4—piperidinol or a corresponding dine
derivative instead thereof.
Example 13(1): 1—{4—[3—({[4—(2—ethy1buty1)—4—
hydroxy—l—piperidinyl]carbonyl}amino)—5—(4—
fluorophenoxy)phenoxy]phenyl}cyclopropanecarboxy1ic acid
TLC: Rf 0.30 (dichloromethane:methanol = 10:1);
lH—NMR (CDC13): 8 7.29—7.32 (m, 2H), 7.01 (d, 4H), 6.88—6.97 (m,
3H), 6.55—6.61 (m, 1H), 6.31-6.32 (m, 1H), 3.74 (d, 2H), 3.13—
3.20 (m, 2H), 1.51—1.58 (m, 4H), .45 (m, 2H), 1.27—1.39
(m, 7H), 0.97 (m, 2H), 0.84 (t, 6H).
Example 13(2): 1—{4—[3—(4-f1uorophenoxy)—5—{[(4—
y—4—isobutyl—1—
piperidinyl)carbonyl]amino}phenoxy]phenyl}cyclopropanecarboxyl
ic acid
TLC: Rf 0.16 (dichloromethane:methanol = 10:1);
1H—NMR ): 5 7.24—7.29 (m, 2H), 6.95—7.02 (m, 4H), 6.91 (d,
2H), 6.85 (t, 1H), 6.60 (t, 1H), 6.27 (t, 1H), 3.62—3.75 (m,
2H), 3.13—3.27 (m, 2H), 1.79 (dquin, 1H), .64 (m, 6H),
1.34 (d, 2H), 1.06—1.13 (m, 2H), 0.92 (d, 6H).
Example 13(3): 1-{4—[3—(3,4—dif1uorophenoxy)—5—{[(4—
hydroxy—4-isobutyl—1—
piperidinyl)carbonyl]amino}phenoxy]pheny1)cyclopropanecarboxyl
ic acid
TLC: Rf 0.47 (ethyl acetatezmethanol = 10:1);
lH—NMR (CDC13): 5 7.39—7.30 (m, 2H), 7.31—7.16 (m, 1H), 7.04—
6.92 (m, 3H), 6.88 (t, 1H), 6.86—6.81 (m, 2H), 6.26 (t, 1H),
3.90—3.75 (m, 2H), 3.28—3.16 (m, 2H), 1.95—1.75 (m, 1H), 1.67—
1.45 (m, 6H), 1.39 (d, 2H), 1.22—1.13 (m, 2H), 0.97 (d, 6H).
Example 13(4): 1—{4—[3—(4—fluorophenoxy)—5—({[4—(4—
fluorophenyl)—4—hydroxy—1—
piperidinyl]carbonyl}amino)phenoxy]phenyl}cyclopropanecarboxyl
ic acid
TLC: Rf 0.38 (chloroform:methanol = 9:1);
lH—NMR (CDfifln: 5 7.43—7.57 (m, 2H), .39 (m, 2H), 6.91—
7.16 (m, 8H), 6.86 (t, 1H), 6.77—6.84 (m, 1H), 6.22 (t, 1H),
4.00 (d, 2H), 3.25—3.41 (m, 2H), 1.88—2.07 (m, 2H), 1.71 (d,
2H), 1.48—1.63 (m, 2H), 1.07—1.24 (m, 2H).
Example 13(5): 1—{4—[3—(2,4—difluorophenoxy)—5—{[(4—
y—4—isobutyl—1—
piperidinyl)carbonyl]amino}phenoxy]phenyl}cyclopropanecarboxyl
ic acid
TLC: Rf 0.62 (chloroformzmethanol:ethanol = 9:1:0.1);
1H—NMR (CDC13): 5 7.35—7.22 (m, 2H), 7.10 (td, 1H), 6.99-6.81
(m, 5H), 6.62 (t, 1H), 6.28 (t, 1H), 3.72 (m, 2H), 3.30—3.16
(m, 2H), 1.90—1.70 (m, 1H), .44 (m, 6H), 1.38 (d, 2H),
1.15—1.07 (m, 2H), 0.95 (d, 6H).
Example 13(6): 1—{2-fluoro—4—[3—(4—fluorophenoxy)—5—
{[(4—hydroxy-4—isobutyl-1—
piperidinyl)carbonyl]amino}phenoxy]phenyl}cyclopropanecarboxyl
ic acid
TLC: Rf 0.32 (dichloromethane:methanol = 10:1);
1H—NMR (CDCl3): 5 7.11—7.20 (m, 1H), 6.95—7.07 (m, 4H), 6.88 (t,
1H), 6.60—6.74 (m, 3H), 6.28 (t, 1H), 3.63—3.76 (m, 2H), 3.12—
3.27 (m, 2H), 1.73—1.86 (m, 1H), 1.49—1.65 (m, 6H), 1.36 (d,
2H), 1.06—1.14 (m, 2H), 0.93 (d, 6H).
Example 13(7): 1—{4—[3—{[(4—cyclopentyl—4—hydroxy—1—
piperidinyl)carbonyl]amino}—5—(4—
fluorophenoxy)phenoxy]phenoxy}cyclopropanecarboxylic acid
TLC: Rf 0.15 (dichloromethane:methanol = 10:1);
lH—NMR ): 5 7.07—6.84 (m, 8H), 6.73 (s, 1H), 6.60-6.50 (m,
2H), 6.28 (t, 1H), 3.80—3.69 (m, 2H), 3.24—3.10 (m, 2H), 1.91—
1.76 (m, 1H), 1.70—1.47 (m, 12H), .31 (m, 4H).
Example 13(8): 1—{3—[3—(4—fluorophenoxy)—5—{[(4—
hydroxy—4—isobutyl—1—
piperidinyl)carbonyl]amino}phenoxy]phenoxy}cyclopropanecarboxy
lic acid
TLC: Rf 0.16 (dichloromethane:methanol = 10:1);
lH—NMR ): 5 7.26—7.21 (m, 1H), 7.07—7.01 (m, 4H), 6.77-
6.64 (m, 4H), 6.48—6.43 (m, 1H), 6.40—6.33 (m, 1H), .24
(m, 1H), 3.79—3.66 (m, 2H), 3.35—3.20 (m, 2H), 1.82 (dt, 1H),
1.63—1.51 (m, 6H), 1.39 (d, 2H), 1.33—1.25 (m, 2H), 0.96 (d,
6H).
Example 14: N—[3-(4-carbamoylphenoxy)—5—(4—
fluorophenoxy)phenyl]—4—(2—ethylbutyl)—4—hydroxy—1-
piperidinecarboxamide
[C 17]
NTN 0
o OF
O\QYNHZ
The titled compound having the following physical
ties was obtained by ng out the processes with the
same purposes as Example 10 —9 Example 11 —9 Example 6 —9
e 7 —9 Example 8 using 1,3—dif1uoro—5—nitrobenzene; a
corresponding phenol derivative in the place of 4—iodophenol;
4—fluorophenol; 2,2,2—trichloroethyl chloroformate; and 4—(2—
ethylbutyl)piperidinol in the place of 4—isobutyl—4—
piperidinol.
TLC: Rf 0.59 (ethyl acetate);
lH—NMR (CDC13): 5 7.74 (d, 2 H), 6.99—7.08 (m, 6H), 6.79 (s,
1H), 6.83 (s, 1H), 6.62 (s, 1H), 6.33 (t, 1H), 3.76 (d, 2H),
3.11—3.36 (m, 2H), 1.25—1.62 (m, 11H), 1.15 (s, 1H), 0.78—0.94
(m, 6H).
Examples 14(1) to 14(30)
The compounds of the following Examples were obtained by
carrying out the processes with the same purposes as Example
—9 Example 11 —9 Example 6 —9 Example 7 —9 Example 8 using
1,3—difluoro—5—nitrobenzene; a corresponding phenol derivative
in the place of 4—iodophenol; 4—fluorophenol or a
corresponding phenol derivative instead thereof; 2,2,2-
oroethyl chloroformate; and a ponding piperidine
derivative in the place of 4-isobutyl—4—piperidinol.
Example 14(1): 4—(2—ethy1buty1)-N~{3—(4—
fluorophenoxy)—5—[4—(methylsulphonyl)phenoxy]phenyl}—4—
hydroxy—1—piperidinecarboxamide
TLC: Rf 0.34 (dichloromethane:methanol = 30:1);
lH—NMR (CDC13): 5 7.79—7.94 (m, 2H), 6.90—7.17 (m, 7H), 6.77 (t,
1H), 6.42 (s, 1H), 6.29—6.39 (m, 1H), 3.77 (d, 2H), 3.18—3.38
(m, 2H), 3.04 (s, 3H), 1.19-1.66 (m, 11H), 1.06 (s, 1H), 0.75—
0.92 (m, 6H).
e 14(2): 5—[3-({[4—(2—ethylbutyl)—4—hydroxy—1—
piperidinyl]carbonyl}amino)—5—(4~f1uorophenoxy)phenoxy]—2—
pyridinecarboxamide
TLC: Rf 0.31 (dichloromethane:methanol = 10:1);
1H—NMR (CDC13): 5 8.30 (d, 1H), 8.14 (d, 1H), 7.68 (d, 1H),
7.38 (dd, 1H), 7.11—6.91 (m, 5H), 6.77 (t, 1H), 6.45 (s, 1H),
6.34 (t, 1H) 5.52 (br. s., 1H), 3.85—3.72 (m, 2H), 3.40—3.18
(m, 2H), 1.69—1.52 (m, 4H), 1.47—1.20 (m, 7H), 1.06 (s, 1H),
0.85 (t, 6H).
Example 14(3): N—[3—(4—carbamoylphenoxy)—5—(4—
fluorophenoxy)phenyl]—4—(4—chlorophenyl)—4—hydroxy—1—
dinecarboxamide
TLC: Rf 0.41 (dichloromethane:methanol = 9:1);
lH—NMR (CDC13+CD3OD): 5 7.78 (m, 2H), 7.41—7.29 (m, 6H), 7.06—
7.01 (m, 4H), 6.88—6.82 (m, 2H), 6.33 (t, 1H), 3.94 (m, 2H),
3.33 (m, 2H), 1.95 (m, 2H), 1.72 (m, 2H).
Example 14(4): N—[3—(4—carbamoylphenoxy)—5—(4—
f1uorophenoxy)phenyl]~4~(4—fluorophenyl)—4-hydroxy—1-
piperidinecarboxamide
TLC: Rf 0.39 oformzmethanol = 9:1);
1H—NMR (CDCl3+CD3OD): 8 7.78 (m, 2H), 7.45—7.40 (m, 4H), 7.06-
6.85 (m, 7H), 6.89—6.84 (m, 2H), 6.33 (t, 1H), 3.94 (m, 2H),
3.33 (m, 2H), 1.95 (m, 2H), 1.72 (m, 2H).
Example 14(5): 4—(2—ethylbuty1)—N—{3—(4—
fluorophenoxy)—5—[(3—methyl—4—pyridinyl)oxy]phenyl}—4—hydroxy—
1—piperidinecarboxamide
TLC: Rf 0.45 (ethyl acetatezmethanol = 20:1);
1H—NMR (CDC13): 5 8.36 (br. s., 1H), 8.28 (d, 1H), 7.09—6.95 (m,
4H), 6.91 (t, 1H), 6.80 (t, 1H), 6.67 (d, 1H), 6.46 (s, 1H),
6.32 (t, 1H) 3.87—3.72 (m, 2H), 3.36—3.16 (m, 2H), 2.26 (s,
3H) 1.79—1.46 (m, 4H), 1.46-1.21 (m, 7H) 1.11 (br. s., 1H),
0.85 (t, 6H).
Example 14(6): (2,6—dimethyl—3—pyridinyl)oxy]—
—(4—fluorophenoxy)phenyl}—4—(2—ethylbutyl)—4—hydroxy—1—
» piperidinecarboxamide'
TLC: Rf 0.17 e:ethyl e = 3:7);
lH—NMR (CDCl3): 5 7.16 (d, 1H), 7.09—6.92 (m, 5H), 6.72 (t, 1H),
6.63 (t, 1H), 6.35 (s, 1H), 6.20 (t, 1H), 3.83—3.70 (m, 2H),
3.35—3.17 (m, 2H), 2.51 (s, 3H), 2.42 (s, 3H), 1.67—1.55 (m,
4H), 1.44—1.27 (m, 7H), 1.04 (s, 1H), 0.85 (t, 6H).
Example 14(7): 4—(2—ethylbutyl)—N—[3—(4—
phenoxy)(4-sulphamoylphenoxy)phenyl]~4—hydroxy-1—
piperidinecarboxamide
TLC: Rf 0.36 (hexanezethyl acetate = 2:1);
1H—NMR (DMSO—d6): 5 8.57 (s, 1H), 7.81 (d, 2H), 7.31 (s, 2H),
7.27—7.09 (m, 6H), 7.05 (dd, 1H), 6.99 (dd, 1H), 6.30 (dd, 1H),
4.08 (s, 1H), 3.74—3.69 (m, 2H), 3.11—3.03 (m, 2H), 1.46—1.24
(m, 11H), 0.78 (t, 6H).
Example 14(8): 4—(4—bromophenyl)—N—[3—(4—
f1uorophenoxy)—5—(4—sulphamoylphenoxy)phenyl]—4—hydroxy—1—
dinecarboxamide
TLC: Rf 0.27 (hexanezethyl acetate = 1:2);
lH—NMR (DMSO—de): 5 8.64 (s, 1H), 7.82 (d, 2H), 7.48 (d, 2H),
7.41 (d, 2H), 7.32 (s, 2H), 7.27—7.10 (m, 6H), 7.08 (dd, 1H),
7.02 (dd, 1H), 6.32 (dd, 1H), 5.18 (s, 1H), 3.98—3.94 (m, 2H),
3.18—3.10 (m, 2H), 1.83—1.76 (m, 2H), 1.58—1.53 (m, 2H).
Example 14(9): 4—(4—bromophenyl)—N—{3—(4-
fluorophenoxy)~5—[4—(methylsulphonyl)phenoxy]phenyl}—4—
hydroxy—1—piperidinecarboxamide
TLC: Rf 0.35 (hexanezethyl acetate 1:2);
lH—NMR (CDCl3): 5 7.87 (d, 2H), 7.48 (d, 2H), 7.33 (d, 2H),
7.11 (d, 2H), 7.05—7.01 (m, 4H), 6.97 (dd, 1H), 6.79 (dd, 1H),
6.50 (brs, 1H), 6.36 (dd, 1H), 3.96—3.92 (m, 2H), 3.42—3.34 (m,
2H), 3.04 (s, 3H), 2.06-1.95 (m, 2H), .75 (m, 2H), 1.66
(brs, 1H).
Example 14(10): N—{3—(4—fluorophenoxy)—5—[4—
(methylsulphonyl)phenoxy]phenyl}—4—hydroxy—4—[4—
(trifluoromethyl)phenyl]—1—piperidinecarboxamide
TLC: Rf 0.35 (hexanezethyl e = 1:2);
lH—NMR (CDC13): 5 7.87 (d, 2H), 7.63 (d, 2H), 7.58 (d, 2H),
7.11 (d, 2H), 7.07—7.01 (m, 4H), 6.97 (dd, 1H), 6.79 (dd, 1H),
6.48 (brs, 1H), 6.37 (dd, 1H), 3.99—3.95 (m, 2H), 3.45—3.37 (m,
2H), 3.05 (s, 3H), 2.11—2.01 (m, 2H), 1.82—1.77 (m, 2H), 1.71
(brs, 1H).
le : N—[3—(4-carbamoy1-3—methylphenoxy)—
—(4—fluorophenoxy)phenyl]~4—(2—ethylbutyl)—4-hydroxy—1—
piperidinecarboxamide
TLC: Rf 0.15 (hexane:ethyl acetate = 3:7);
lH—NMR (CDCl3): 5 7.40 (d, 1H), 7.09—6.95 (m, 4H), 6.86 (d, 1H),
6.83—6.77 (m, 2H), 6.73 (t, 1H), 6.54 (s, 1H), 6.32 (t, 1H),
.95 (br. s., 1H), 5.60 (br. s., 1H), 3.83—3.70 (m, 2H), 3.33—
3.09 (m, 2H), 2.46 (s, 3 H) 1.64—1.45 (m, 4H), 1.43-1.26 (m,
7H), 1.12 (s, 1H), 0.84 (t, 6H).
Example 14(12): N—[3—(2—carbamoylphenoxy)(4—
fluorophenoxy)phenyl]—4-(2—ethylbutyl)—4—hydroxy—1—
piperidinecarboxamide
TLC: Rf 0.20 (hexanezethyl acetate H 3:7);
1H—NMR (CDCl3): 8 8.20 (dd, 1H), 7.48—7.37 (m, 2H), 7.21 (t,
1H), 7.08—6.96 (m, 4H), 6.93 (d, 1H), 6.87 (t, 1H), 6.79 (t,
1H), 6.41 (s, 1H), 6.33 (t, 1H), 5.73 (br. s., 1H), 3.83—3.72
(m, 2H), 3.34—3.15 (m, 2H), 1.66—1.50 (m, 4H), 1.44—1.29 (m,
7H), 1.06 (s, 1H), 0.85 (t, 6H).
' Example 14(13): N—[3—(4—carbamoylphenoxy)—5—(4—
fluorophenoxy)phenyl]—4-hydroxy—4—(3—pentanyl)—1—
piperidinecarboxamide
TLC: Rf 0.37 (chloroformzmethanol = 9:1);
1H—NMR (CDCl3+CD3OD): 5 7.74 (m, 2H), 7.10—6.84 (m, 6H), 6.84
(m, 1H), 6.79 (m, 1H), 6.69 (m, 1H), 6.33 (t, 1H), 3.81 (m,
2H), 3.19 (m, 2H), 1.80—1.40 (m, 5H), .08 (m, 4H), 0.94
(t, 6H).
Example 14(14): N—[3~(4—carbamoylphenoxy)—5—(4—
fluorophenoxy)pheny1]—4—hydroxy—4—phenyl—1—
piperidinecarboxamide
TLC: Rf 0.35 (dichloromethane:methanol = 10:1);
lH—NMR (DMSO—da): 5 8.61 (s, 1H), 7.90 (d, 3H), 7.45 (d, 2H),
7.32-7.05 (m, 11H), 7.00 (dd, 1H), 6.27 (dd, 1H), 5.05 (s, 1H),
3.97—3.93 (m, 2H), .11 (m, 2H), 1.85—1.78 (m, 2H), 1.60—
1.55 (m, 2H).
e 14(15): N—[3—(4—f1uorophenoxy)—5—(4—
sulphamoylphenoxy)phenyl]—4—(4—fluorophenyl)—4—hydroxy—1—
piperidinecarboxamide
TLC: Rf 0.38 (hexanezethyl acetate 1:2);
lH—NMR (CDC13): 6 7.87 (d, 2H), 7.44 (d, 2H), 7.41 (d, 2H),
7.09—7.01 (m, 6H), 6.94 (dd, 1H), 6.77 (dd, 1H), 6.45 (brs,
1H), 6.36 (dd, 1H), 4.77 (brs, 2H), 3.95—3.92 (m, 2H), 3.44—
3.35 (m, 2H), 2.07—1.97 (m, 2H), 1.82—1.78 (m, 2H).
e 14(16): N—{3—(4—f1uorophenoxy)—5—[4—
(methylsulphonyl)phenoxy]phenyl)—4—(4—fluorophenyl)—4—hydroxy—
1—piperidinecarboxamide
TLC: Rf 0.38 (hexanezethyl acetate = 1:2);
lH—NMR (CDC13): 8 7.87 (d, 2H), 7.43 (dd, 2H), 7.12 (d, 2H),
7.09—7.01 (m, 6H), 6.98 (dd, 1H), 6.79 (dd, 1H), 6.45 (brs,
1H), 6.36 (dd, 1H), 3.97—3.92 (m, 2H), 3.45—3.36 (m, 2H), 3.05
(s, 3H), 2.08—1.98 (m, 2H), 1.83—1.79 (m, 2H).
Example 14(17): N—[3—(4—carbamoylphenoxy)(4—
f1uorophenoxy)phenyl]—4—(3—fluoropheny1)—4—hydroxy—1—
piperidinecarboxamide
TLC: Rf 0.53 (ethyl e);
lH—NMR (CDCl3): 5 .71 (m, 2H), 7.40—7.30 (m, 1H), 7.23—
7.13 (m, 2H), 7.09—6.91 (m, 7H), 6.86 (t, 1H), 6.81 (t, 1H),
6.42 (s, 1H) 6.36 (t, 1H) 6.20—5.40 (m, 2H), 4.02—3.91 (m, 2H),
3.47—3.33 (m, 2H) 2.12—1.92 (m, 2H) 1.85—1.75 (m, 2H), 1.60 (s,
1H).
Example 14(18): N—[3—(4—carbamoyl—2—chlorophenoxy)—
—(4—f1uorophenoxy)phenyl]~4—(2—ethylbutyl)—4—hydroxy—1—
piperidinecarboxamide
TLC: Rf 0.67 (chloroformzmethanol = 9:1);
1H—NMR (CDfiHD: 5 8.02 (d, 1H), 7.79 (m, 1H), 7.18—7.00 (m, 5H),
6.85 (m, 2H), 6.23 (t, 1H), 3.82 (m, 2H), 3.20 (m, 2H), 1.64—
1.42 (m, 11H), 0.86 (t, 6H).
e 14(19): N—[3—(4—carbamoylphenoxy)—5—(4—
fluorophenoxy)phenyl]—4—(3,3—dimethyl—1—butyn—1—yl)-4—hydroxy—
1—piperidinecarboxamide
TLC: Rf 0.49 (chloroformzmethanol = 9:1);
1H—NMR (CDCl3); 5 7.76 (d, 2H), 6.93—7.12 (m, 6H), 6.81—6.85 (m,
1H), 6.78 (t, 1H), 6.44 (br. s., 1H), 6.35 (t, 1H), 5.77 (br.
s, 2H), 3.63—3.84 (m, 2H), 3.27 (ddd, 2H), 2.01 (s, 1H), 1.63—
1.94 (m, 4H), 1.21 (s, 9H).
Example 14(20): N-[3—(4—carbamoylphenoxy)—5—(4—
fluorophenoxy)phenyl]—4—hydroxy—4—isopropyl-1—
piperidinecarboxamide
TLC: Rf 0.39 (dichloromethane:methanol = 10:1);
lH—NMR (DMSO—de): 5 8.54 (s, 1H), 7.92 (brs, 1H), 7.89 (d, 2H),
7.30 (brs, 1H), 7.23 (t, 2H), 7.13-7.04 (m, 4H), 7.02 (dd, 1H),
6.98 (dd, 1H), 6.26 (dd, 1H), 4.00 (s, 1H), 3.84—3.80 (m, 2H),
3.04—2.95 (m, 2H), 1.49—1.27 (m, 5H), 0.81 (d, 6H).
Example 14(21): N—[3—(4—carbamoyl—3—chlorophenoxy)—
—(4—fluorophenoxy)phenyl]—4—(2—ethylbutyl)—4—hydroxy—1—
piperidinecarboxamide
TLC: Rf 0.54 oform:methanol = 9:1);
1H—NMR (CDCl3): 5 7.74 (m, 2H), 7.10—6.80 (m, 8H), 6.58—6.30 (m,
3H), 5.78 (m, 1H), 3.76 (m, 2H), 3.28 (m, 2H), .20 (m,
11H), 1.04 (s, 1H), 0.85 (t, 6H).
Example : N—[3—(4*carbamoylphenoxy)—5—(4—
fluorophenoxy)phenyl]—4—cycloheptyl—4—hydroxy—1—
piperidinecarboxamide
TLC: Rf 0.27 (ethyl acetate);
lH—NMR (CDCl3): 5 7.77 (d, 2H), 6.96—7.09 (m, 6H), 6.85 (t, 1H),
6.79 (t, 1H), 6.44 (s, 1H), 6.34 (t, 1H) 6.04 (br. s., 1H),
.52 (br. s., 1H), 3.73—3.87 (m, 2H), 3.22 (td, 2H) 1.16—1.88
(m, 17H), 1.07 (s, 1H).
Example 14(23): N—[3—(4—carbamoylphenoxy)—5—(4—
phenoxy)phenyl]—4—(2—ethyl—1—buten—1—yl)—4—hydroxy—1—
piperidinecarboxamide
TLC: Rf 0.48 (chloroformzmethanol = 9:1);
lH—NMR (CDCl3): 5 7.75 (d, 2H), 6.93~7.18 (m, 6H), 6.70—6.93 (m,
2H), 6.55 (s, 1H), 6.33 (s, 1H), 5.77 (br. d, 2H), 5.17 (s,
1H), 3.62 (d, 2H) 3.18—3.52 (m, 2H), 2.36 (q, 2H), 2.01 (q,
2H), 1.46—1.88 (m, 4H), 1.31—1146 (m, 1H), 0.99 (q, 6H).
Example 14(24): 4—(2—ethylbutyl)—N—{3—(4—
fluorophenoxy)—5—[4—(methylsulphamoyl)phenoxy]phenyl}
hydroxy-1—piperidinecarboxamide
TLC: Rf 0.38 (hexanezethyl acetate = 3:7);
lH—NMR ): 8 7.83—7.71 (m, 2H), 7.12—6.96 (m, 6H), 6.93 (t I
1H), 6.78 (t, 1H), 6.47 (s, 1H), 6.34 (t, 1H), 4.36 (q, 1H),
3.85—3.65 (m, 2H), .09 (m, 2H), 2.66 (d, 3H), 1.69—1.49
(m, 4H), 1.42—1.29 (m, 7H), 1.08 (s, 1H), 0.85 (t, 6H).
Example 14(25): 4—
(dimethylsulphamoyl)phenoxy]—5—(4—f1uorophenoxy)pheny1}—4~(2-
ethylbutyl)—4~hydroxy—1—piperidinecarboxamide
TLC: Rf 0.46 (hexanezethyl acetate 3:7);
lH—NMR (CDC13): 5 7.77—7.66 (m, 2H), 7.12—6.98 (m, 6H), 6.95 (t,
1H), 6.79 (t, 1H), 6.41 (s, 1H), 6.34 (t, 1H), .70 (m,
2H), 3.36—3.19 (m, 2H), 2.70 (s, 6H), 1.68—1.50 (m, 4H), 1.44—
1.28 (m, 7H), 1.04 (s, 1H), 0.85 (t, 6H).
Example 14(26): 4—(2—ethylbutyl)—N—{3—[2—f1uoro-4—
(methylsulphonyl)phenoxy]—5—(4—f1uorophenoxy)phenyl}—4—
hydroxy—1—piperidinecarboxamide
TLC: Rf 0.60 (chloroformzmethanol = 9:1);
1H—NMR (CDC13): 8 7.74 (m, 1H), 7.66 (m, 1H), 7.14 (t, 1H),
7.10—6.98 (m, 5H), 6.76 (t, 1H), 6.47 (m, 1H), 6.34 (t, 1H),
3.78 (m, 2H), 3.28 (m, 2H), 3.07 (s, 3H), 1.66—1.20 (m, 11H),
1.07 (s, 1H), 0.85 (t, 6H).
Example 14(27): 4-(2—ethylbutyl)—N—{3—(4—
fluorophenoxy)—5—[3—hydroxy
(methylsulphonyl)phenoxy]phenyl}—4—hydroxy—1—
piperidinecarboxamide
TLC: Rf 0.39 (dichloromethane:methanol = 10:1);
lH—NMR (CDC13): 5 7.58 (d, 1H), 6.89—7.07 (m, 5H), 6.82(br. s.,
1H), 6.39—6.63 (m, 3H), 6.30 (br. s., 1H), 3.78 (d, 2H), 3.18—
3.36 (m, 2H), 3.03 (br. s., 3H), .63 (m, 4H), 1.30—1.42
(m, 6H), 0.85 (t, 6H).
Example 14(28): N—[3—(4-carbamoyl-3—hydroxyphenoxy)—
—(4—fluor0phenoxy)phenyl]—4—(2—ethylbutyl)—4—hydroxy—1-
piperidinecarboxamide
TLC: Rf 0.16 (hexane:ethy1 acetate = 2:3);
1H-NMR ): 8 7.30 (d, 1H), 7.15 (dd, 1H), 6.93—7.08 (m,
5H), 6.80—6.83 (m, 1H), 6.49 (t, 1H), 6.42 (s, 1H), 6.26—6.31
(m, 1H), 3.71—3.80 (m, 2H), 3.18—3.33 (m, 2H), 1.54—1.61 (m,
4H), 1.29—1.43 (m, 7H), 0.85 (t, 6H).
Example : 4—(2-ethy1butyl)—N—{3—[4—
(ethylsulphony1)phenoxy]—5—(4—fluorophenoxy)phenyl}—4—hydroxy—
1—piperidinecarboxamide
TLC: Rf 0.29 ezethyl acetate = 2:3);
lH—NMR (CDC13): 5 7.83 (dd, 2H), 7.10 (dd, 2 H), 7.01—7.05 (m,
4H), 6.95—6.97 (m, 1H), 6.76—6.79 (m, 1H), 6.37 (s, 1H), 6.33—
6.36 (m, 1H), 3.77 (dt, 2H), 3.21—3.34 (m, 2H), 3.10 (q, 2H),
1.57—1.65 (m, 4H), 1.32—1.44 (m, 7H), 1.24—1.32 (m, 3H), 1.02
(s, 1H), 0.85 (t, 6H).
Example 14(30): 4—(2—ethy1buty1)—N—{3—(4—
f1uorophenoxy)—5—[4—(methylcarbamoyl)phenoxy]pheny1}—4—
hydroxy—1—piperidinecarboxamide
TLC: Rf 0.20 (hexanezethyl acetate = 3:7);
lH—NMR (CDC13): 5 7.83—7.58 (m, 2H), 7.10—6.93 (m, 6H), 6.80 (d,
2H), 6.37 (s, 1H), 6.33 (t, 1H), 6.07 (br. s., 1H), 3.85—3.70
(m, 2H), .14 (m, 2H), 3.00 (d, 3H), 1.62—1.55 (m, 4H),
1.44—1.28 (m, 7H), 1.03 (s, 1H), 0.86 (t, 6H).
Example 15: 4—(2—ethylbuty1)—N—[3—(4—f1uorophenoxy)—
—{4—[(tetrahydro—ZH—pyran—Z—yloxy)carbamoyl]phenoxy}phenyl]—
4—hydroxy—1—piperidinecarboxamide
[C 18]
N\”/N o
. pr0
\o o
The compound prepared in Example 9(1) (20 mg) was
dissolved in DMF (200 pL), added with O—(tetrahydro—ZH—pyran—
2—yl)hydroxylamine (4.2 mg), 1—ethyl—3—(3—
dimethylaminopropyl)carbodiimide hydrochloride (EDC) (19 mg)
and 1—hydroxybenzotriazole monohydrate (HOBt) (15 mg) and
stirred at room temperature for 24 hours. The reaction
solution was diluted with ethyl acetate and added with water
and the aqueous layer was extracted with MTBE. The organic
layer was combined, washed with water, a saturated sodium
hydrogen carbonate aqueous solution and a saturated ammonium
chloride aqueous solution and then concentrated. The resulting
residue was purified by silica gel column chromatography
(dichloromethane:methanol = 20:1) to give the titled nd
(19.6 mg) having the ing physical properties.
TLC: Rf 0.42 oromethane:methanol = 10:1).
Examples 15(1) to 15(7)
The compounds of the following Examples were obtained by
carrying out the process with the same purpose as Example 15
using the compound prepared in Example 9(1) and a
ponding amine tive in the place of O—(tetrahydro-
2H—pyran-2—y1)hydroxylamine.
Example 15(1): 4—(2-ethylbutyl)—N—{3—[4—
(ethylcarbamoyl)phenoxy]—5—(4—f1uorophenoxy)phenyl}—4—hydroxy—
1—piperidinecarboxamide
[C 19]
N\”/N 0
. U0
TLC: Rf 0.39 oromethane:methanol = 10:1);
1H—NMR (CDC13): 5 7.77—7.64 (m, 2H), 7.08—6.94 (m, 6H), 6.83—
6.75 (m, 2H), 6.42 (s, 1H), 6.33 (t, 1H), 6.13~5.96 (m, 1H),
3.83—3.72 (m, 2H), 3.55—3.44 (m, 2H), 3.34—3.16 (m, 2H), 1.64—
1.50 (m, 4H), 1.43—1.29 (m, 7H) 1.25 (t, 3H), 1.04 (s, 1H)
0.85 (t, 6H).
Example 15(2): 4—(2—ethylbutyl)—N—{3—(4—
f1uorophenoxy)—5—[4-(isopropylcarbamoyl)phenoxy]phenyl}—4—
hydroxy—1—piperidinecarboxamide
TLC: Rf 0.42 (dichloromethane:methanol = 10:1);
lH—NMR (CDC13): 5 7.71 (d, 2H), 7.07—6.97 (m, 6H), 6.83—6.78 (m,
2H), 6.37 (d, 1H), 6.32 (t, 1H), 5.92—5.78 (m, 1H), 4.36—4.14
(m, 1H), 3.83—3.72 (m, 2H), 3.38—3.13 (m, 2H), 1.66—1.49 (m,
4H), 1.45—1.30 (m, 7H), 1.26 (d, 6H), 1.03 (s, 1H), 0.85 (t,
6H).
e 15(3): 4—(2—ethylbutyl)-N—{3—(4—
fluorophenoxy)—5—[4—(4—morpholinylcarbonyl)phenoxy]phenyl}—4—
hydroxy—1—piperidinecarboxamide
TLC: Rf 0.42 (dichloromethane:methanol = 1:2);
lH—NMR (CDC13): 5 7.45—7.34 (m, 2H), 7.08—6.97 (m, 6H), 6.83 (t,
1H), 6.74 (t, 1H), 6.39 (s, 1H), 6.33 (t, 1H) 3.89—3.49 (m,
10H), 3.34—3.17 (m, 2H), 1.62—1.52 (m, 4H), 1.45—1.27 (m, 7H),
1.05 (s, 1H), 0.85 (t, 6H).
Example 15(4): 4—(2—ethylbutyl)—N—[3—(4—
fluorophenoxy){4—[(3—hydroxy—1—
azetidinyl)carbonyl]phenoxy}phenyl]—4—hydroxy—1—
piperidinecarboxamide
TLC: Rf 0.25 (dichloromethane:methanol = 10:1);
1H-NMR (CDC13): 5 7.58—7.49 (m, 2H), 7.08—6.95 (m, 6H), 6.89 (t,
1H), 6.83 (d, 1H), 6.74 (t, 1H), 6.32 (t, 1H), 4.78—4.52 (m,
1H), 4.39 (br. s., 2H), 4.24—3.83 (m, 2H), 3.85—3.70 (m, 2H),
3.34—3.01 (m, 2H), 1.61 (s, 1H), 1.60—1.52 (m, 4H), 1.45—1.27
(m, 7H), 1.24 (d, 1H), 0.83 (t, 6H).
Example 15(5): 4—(2—ethylbutyl)—N—[3—(4—
fluorophenoxy)—5—{4—[(3—hydroxy—1—
idinyl)carbonyl]phenoxy}phenyl]—4—hydroxy—1—
piperidinecarboxamide
TLC: Rf 0.23 (dichloromethane:methanol = 10:1);
1H—NMR (CDC13): 5 7.55—7.40 (m, 2H), 7.10—7.00 (m, 6H), 6.99—
6.92 (m, 1H), .79 (m, 1H), 6.65 (t, 1H), 6.32 (t, 1H),
4.65—4.35 (m, 1H), .68 (m, 4H), 3.67—3.34 (m, 2H), 3.30—
3.05 (m, 2H), 2.28—2.18 (m, 1H), 2.15—1.92 (m, 2H), 1.64—1.51
(m, 4H), 1.42—1.25 (m, 7H), 1.16 (br. s., 1H) 0.84 (t, 6H).
Example 15(6): 4—(2—ethylbutyl)—N—[3—(4—
fluorophenoxy)—5—{4—[(4—hydroxy—1—
piperidinyl)carbonyl]phenoxy}phenyl]—4—hydroxy—1—
piperidinecarboxamide
[C 20]
TLC: Rf 0.30 (dichloromethane:methanol = 10:1);
lH—NMR (CDC13): 8 7.39—7.31 (m, 2H), 7.06—6.96 (m, 6H), 6.93 (t,
1H), .70 (m, 1H), 6.65 (t, 1H), 6.32 (t, 1H), 4.40—3.90
(m, 3H), 3.85—3.70 (m, 2H), 3.41—3.07 (m, 4H), 2.10—1.80 (m,
2H), 1.80—1.70 (m, 1H), 1.66—1.45 (m, 6H), 1.43—1.24 (m, 7H),
1.17 (br. s., 1H), 0.84 (t, 6H).
Example 15(7): 4—(2—ethylbutyl)—N—[3—(4—
fluorophenoxy)—5—{4—[(3—hydroxy—1—
piperidinyl)carbonyl]phenoxy}phenyl]—4—hydroxy—1—
piperidinecarboxamide
TLC: Rf 0.35 (dichloromethane:methanol = 10:1);
lH—NMR (CDC13): 5 7.36 (d, 2H), 7.06—6.94 (m, 6H), 6.93—6.72 (m,
3H), 6.64 (s, 1H), 6.32 (t, 1H), 4.05—3.50 (m, 4H), 3.49—3.10
(m, 5H), 2.45—2.25 (m, 1H), 2.00—1.75 (m, 2H), .40 (m,
6H), 1.40—1.20 (m, 7H), 1.20 (d, 1H), 0.84 (t, 6H).
e 16: 4—(2—ethylbutyl)—N—{3—(4—fluorophenoxy)—
—[4—(hydroxycarbamoyl)phenoxy]phenyl}—4—hydroxy—l—
piperidinecarboxamide
[C 21]
NT“ 0
o OF
The compound prepared in Example 15 (19 mg) was ved
in ethyl acetate (0.5 mL), added with a hydrochloric
acid/ethyl acetate solution (4 mol/L, 0.1 mL) and stirred at
room temperature for 20 minutes. The reaction solution was
concentrated before purification on preparative TLC
(dichloromethane:methanol 10:1) to give the titled compound
(5.1 mg) having the following physical properties.
TLC: Rf 0.23 (dichloromethane:methanol = 10:1);
1H—NMR (CDfiIM: 5 7.75 (d, 2H), 7.15—6.99 (m, 6H), 6.91 (t, 1H),
6.87 (t, 1H), 6.27 (t, 1H), 3.88—3.70 (m, 2H), 3.28—3.14 (m,
2H), 1.68—1.48 (m, 4H), 1.44—1.26 (m, 7H), 0.87 (t, 6H).
Example 17: 2—methyl—2—propanyl—3*hydroxy—3—
isobutyl—1—azetidinecarboxylate
Under an argon atmosphere, to a 100—mL three—neck flask
was added a 0.6 M lanthanum chloride/2 lithium chloride
(LaC13/2LiCl) solution in THF (31.0 mL) which was added with a
2.0 M ylmagnesium chloride solution in THF (6.9 mL)
while cooling to 0°C. The mixture was stirred at 0°C for 3
hours before addition of 2—methyl—2—propanyl-3—oxo—1—
azetidinecarboxylate (1.6 g) dissolved in THF (4.0 mL) at 0°C.
The reaction solution was stirred from 0°C to room temperature
over 15 hours before addition of a 5% acetic acid aqueous
on (30 mL) and extraction twice with ethyl acetate. The
organic layer was washed with a saturated sodium chloride
on and dried over anhydrous sodium sulphate and the
solvent was distilled off to give a brown oily substance (3.2
g). The substance was purified by column tography
(medium pressure preparative liquid chromatography W—prep 2XY
from Yamazen Corporation (column: main column 2L, injection
column L; hexane:ethyl acetate 9:1 —9 7:3)) to give the titled
nd (2.0 g) having the following physical properties.
TLC: Rf 0.53 (hexane:ethyl acetate = 2:1).
Example 18: 3—isobutyl—3—azetidinol
To a 200—mL pear—shaped evaporating flask were added the
nd prepared in Example 17 (2.0 g) and methanol (9 mL)
and then a 4 N hydrochloric acid/ethyl acetate solution (11
mL) at 0°C. The mixture was stirred at room temperature for 7
hours, again cooled to 0°C, added with a 5 N sodium hydroxide
aqueous solution (43.5 mL) and extracted twice with methylene
chloride. The organic layer was dried over anhydrous sodium
sulphate and the solvent was distilled off under reduced
re to give the titled compound (973.5 mg) having the
ing physical properties. The resulting titled compound
was directly used for the next reaction without purification.
TLC: Rf 0.69 (ethyl acetate:methanol = 3:1).
e 19: 2—{4—[3—(4—fluorophenoxy)—5—{[(3—
hydroxy—3—isobutyl—1—
azetidinyl)carbonyl]amino}phenoxy]phenyl}-2—methylpropanoic
acid
[C 22]
N R
I T)
' H3C CH3
The titled compound (41 mg) having the following physical
properties was obtained by carrying out the ses with the
same purposes as Example 8 —9 Example 9 using the compound
prepared in Example 18 (64.6 mg) and the compound prepared in
Example 7 (342.5 mg).
TLC: Rf 0.15 (dichloromethanezethanol = 20:1);
lH—NMR ): 5 7.31 (d, 2H), 6.87—7.11 (m, 6H), 6.76 (s, 1H),
6.66 (s, 1H), .37 (m, 2H), 3.70—4.01 (m, 4H), 2.55 (br.
s., 2H), 1.72—1.97 (m, 1H), 1.61 (d, 2H), 1.56 (s, 6H), 0.91
(d, 6H).
Examples 19(1) to 19(9)
The compounds of the following Examples were ed by
carrying out the process with the same purpose as Example 19
using a ponding cyclic amine derivative in the place of
the compound prepared in Example 18 and the compound prepared
in Example 7.
Example 19(1): 2-{4—[3—(4—fluorophenoxy)—5—{[(3—
hydroxy-3—isobuty1—1—
pyrrolidinyl)carbonyl]amino}phenoxy]phenyl}—2—methylpropanoic
acid
TLC: Rf 0.13 (dichloromethane:ethanol = 20:1);
lH—NMR (CDC13): 5 7.29—7.39 (m, 2H), 6.89—7.07 (m, 6H), 6.84 (t,
1H), 6.71 (t, 1H), 6.30 (t, 1H), 6.20 (s, 1H), 3.39~3.66 (m,
3H), 3.26 (d, 1H), 2.52 (br. s., 2H), 1.73—2.06 (m, 3H), 1.44—
1.68 (m, 8H), 0.97 (dd, 6H).
Example 19(2): 2—{4—[3—({[(3R,4S)—3—fluoro—4—
y—4—isobuty1—1—piperidinyl]carbonyl}amino)—5—(4—
fluorophenoxy)phenoxy]phenyl}—2—methylpropanoic acid
TLC: Rf 0.31 (dichloromethanezethanol = 20:1);
1H—NMR (CDC13): 8 7.29—7.43.(m, 2H), 6.90—7.10 (m, 6H), 6.77 (t,
1H), 6.65 (t, 1H), 6.43 (s, 1H), 6.31 (t, 1H), 4.20—4.48 (m,
1H), 3.94 (ddd, 1H), 3.54 (d, 1H), 3.19—3.42 (m, 2H), 1.99—
2.25 (m, 2H), 1.73—1.97 (m, 2H), 1.34—1.69 (m, 9H), 0.98 (dd,
6H).
Example 19(3): 2—{4—[3-(4—fluorophenoxy){[(3—
y—3—isopropyl—1—
pyrrolidinyl)carbonyl]amino}phenoxy]phenyl}—2—methylpropanoic
acid
TLC: Rf 0.45 (dichloromethane:methanol = 10:1);
lH—NMR (CDfiHD: 5 7.42—7.34 (m, 2H), 7.14—6.94 (m, 6H), 6.93—
6.90 (m, 1H), 6.87 (t, 1H), 6.21 (t, 1H), 3.57 (dd, 2H), 3.48—
3.32 (m, 2H), 2.04—1.68 (m, 3H), 1.55 (s, 6H), 0.98 (d, 6H).
Example 19(4): 2—{4—[3—{[(3—cyclopentylhydroxy—1—
pyrrolidinyl)carbonyl]amino}—5—(4—
fluorophenoxy)phenoxy]phenyl}~2~methylpropanoic acid
TLC: Rf 0.47 (dichloromethane:methanol = 10:1);
1H—NMR (CD3OD): 6 7.41—7.34 (m, 2H), 7.15—6.95 (m, 6H), 6.94—
6.91 (m, 1H), 6.87 (t, 1H), 6.21 (t, 1H), 3.61—3.50 (m, 2H),
3.45—3.32 (m, 2H), 2.15—1.97 (m, 1H), 1.89 (t, 2H), 1.55 (s,
6H), 1.78—1.40 (m, 8H).
Example 19(5): 2—{4-[3—{[(3—cyclohexyl—3—hydroxy—1—
idinyl)carbonyl]amino}—5—(4—
fluorophenoxy)phenoxy]phenyl}—2—methy1propanoic acid
TLC: Rf 0.48 (dichloromethane:methanol = 10:1);
1H—NMR (CDfiflN: 5 7.41—7.35 (m, 2H), 7.13—6.94 (m, 6H), 6.93—
6.90 (m, 1H), 6.87 (t, 1H), 6.21 (t, 1H), 3.60—3.50 (m, 2H),
3.47—3.32 (m, 2H), 1.98—1.61 (m, 7H), 1.55 (s, 6H), 1.49—1.09
(m, 6H).
Example 19(6): 1—{4—[3—{[(3—cyclopentyl—3-hydroxy—1—
pyrrolidinyl)carbonyl]amino}—5-(4—
fluorophenoxy)phenoxy]phenyl}cyclopropanecarboxylic acid
TLC: Rf 0.49 (dichloromethane:methanol = 10:1);
lH-NMR (CDCl3): 6 7.32—7.26 (m, 2H), 7.07—6.97 (m, 4H), 6.96—
6.91 (m, 2H), 6.90 (t, 1H), 6.70 (t, 1H), 6.32 (t, 1H), 6.20
(s, 1H), 3.64—3.47 (m, 2H), 3.43 (d, 1H), 3.30 (d, 1H), 2.04—
1.95 (m, 1H), 1.93—1.84 (m, 2H), 1.77—1.49 (m, 8H), 1.46—1.33
(m, 2H), 1.27—1.19 (m, 2H).
Example 19(7): 1—{4—[3—{[(3—cyclohexyl—3-hydroxy—1—
pyrrolidinyl)carbonyl]amino}—5—(4—
fluorophenoxy)phenoxy]phenyl}cyclopropanecarboxylic acid
TLC: Rf 0.49 (dichloromethane:methanol = 10:1);
1H—NMR ): 5 7.31—7.26 (m, 2H), 7.06—6.97 (m, 4H), 6.96—
6.91 (m, 2H), 6.90 (t, 1H), 6.70 (t, 1H), 6.32 (t, 1H), 6.21
(s, 1H), 3.64—3.50 (m, 2H), 3.46 (d, 1H), 3.27 (d, 1H), 1.99—
1.55 (m, 9H), .31 (m, 2H), 1.30—1.07 (m, 6H).
Example 19(8): 3—{[(3-cyclohexyl—3—hydroxy—1—
pyrrolidinyl)carbonyl]amino}—5—(4—
fluorophenoxy)phenoxy]phenoxy}—2—methylpropanoic acid
TLC: Rf 0.28 (dichloromethane:methanol = 10:1);
lH—NMR,(CDCl3): 5 7.05—6.94 (m, 4H), 6.92—6.86 (m, 4H), 6.75 (t,
1H), 6.60 (t, 1H), 6.30—6.25 (m, 2H), 3.57—3.47 (m, 2H), 3.43
(d, 1H), 3.25 (d, 1H), 1.96—1.85 (m, 1H), 1.85—1.66 (m, 6H),
1.58 (s, 6H), 1.45—1.33 (m, 1H), 1.24—1.11 (m, 5H).
e 19(9): 1—{4—[3—{[(3—cyclohexyl~3~hydroxy
pyrrolidinyl)carbonyl]amino}-5—(4—
fluorophenoxy)phenoxy]phenoxy}cyclopropanecarboxylic acid
TLC: Rf 0.28 oromethane:methanol = 10:1);
1H—NMR (CDC13): 5 7.06— 6.92 (m, 4H), 6.89—6.78 (m, 4H), 6.63—
6.51 (m, 3H), 6.29 (t, 1H), 3.50—3.29 (m, 3H), 3.15 (d, 1H),
1.89—1.59 (m, 6H), .48 (m, 3H), 1.35-1.03 (m, 8H).
Example 20: Methyl 4—{[3—(4-fluorophenoxy)—5—
nitrophenyl]thio}benzoate
Under an argon atmosphere, the nd prepared in
Example 10 (6.01 g) was dissolved in DMA (60 mL), potassium
carbonate (7.62 g) and 4—carbomethoxybenzene thiol (2.80 g)
were added thereto and the reaction mixture was stirred at 75°C
for 3 hours. The reaction mixture was cooled to room
temperature, poured to water, extracted with MTBE,
sequentially washed with water and a saturated sodium chloride
solution, dried over anhydrous sodium sulphate and
concentrated under reduced pressure. The concentrate was
purified by silica gel column chromatography (hexanezethyl
acetate = 9:1 —> 4:1) to give the titled compound (2.28 g)
having the following physical properties.
TLC: Rf 0.59 (hexane:ethyl e = 4:1).
Example 21: Methyl 4—{[3—amino—5—(4—
fluorophenoxy)phenyl]thio}benzoate
The compound prepared in Example 20 (1.12 g) and acetic
acid (11.2 mL) were ved in water (0.86 mL), added with
iron (777 mg) with small portions and the reaction was d
to proceed at 90°C for 1.5 hours. The reaction solution was
cooled to room temperature, added with ethyl acetate (30 mL)
and stirred for 20 minutes. Celite (trade name) was used for
filtration and the filtrate was concentrated under reduced
re after on of toluene. The resulting residue was
added with ethyl acetate, washed with water, a saturated
sodium hydrogen carbonate solution and a saturated sodium
chloride solution, dried over anhydrous sodium sulphate and
concentrated. The resulting residue was purified by silica gel
column chromatography (hexane:ethyl acetate = 9:1 —9 1:1) to
give the titled compound (830 mg) having the following
physical properties.
TLC: Rf 0.17 (hexanezethyl acetate = 4:1).
Example 22: 4—{[3—(4—fluorophenoxy)—5—({[4—(4—
fluorophenyl)—4—hydroxy—1—
piperidinyl]carbonyl}amino)phenyl]thio}benzoic acid
The titled compound (12.0 g) having the following
physical properties was obtained by carrying out the processes
with the same es as Example 7 —9 Example 8 —9 Example 9
using the compound prepared in Example 21; 2,2,2—
trichloroethyl chloroformate; and 4-(4—fluorophenyl)—4—
piperidinol in the place of 4—isobutylpiperidinol.
TLC: Rf 0.52 (chloroform:methanol:ethanol = 9:1:0.1);
lH—NMR (CD30D): 8 1.73, 2.00, 3.32—3.44, 4.03, 6.62, 6.95—7.18,
7.24—7.36, 7.46—7.55, 7.86—7.99.
Example 23: tert—butyl 4—hydroxy—4—isobutyl—2—
methylpiperidine—1—carboxylate
Under an argon atmosphere, in a 50—mL pear—shaped
evaporating flask was weighed a solution of lanthanum chloride
lithium chloride complex in THF (15.6 mL) and cooled to 0°C.
To the solution was added dropwise a solution of
isobutylmagnesium chloride in THF (3.5 mL) and stirred at 0°C
for 3 hours. A solution of tert—butyl 2—methyl—4—
oxopiperidine—l—carboxylate (1 g) in THE (2.0 mL) was further
added dropwise. The reaction solution was stirred at 0°C for 1
hour, heated to 25°C, poured to hydrochloric acid and extracted
with ethyl e. The organic layer was washed with water
and a saturated sodium de solution and dried over
anhydrous magnesium sulphate. The filtrate was concentrated
and the ing residue was purified by silica gel
chromatography (hexanezethyl acetate = 9:1 —9 3:1) to give the
titled nd (450 mg) having the following physical
properties.
TLC: Rf 0.51 (hexanezethyl acetate = 3:1).
e 24: 2—methyl—4—isobutyl-4—hydroxypiperidine
hydrochloride
In a 100—mL haped evaporating flask was weighed the
nd ed in Example 23 (440 mg) and added a solution
of hydrogen chloride (4 mol/L) in 1,4—dioxane (5.0 mL). The
reaction solution was stirred at 25°C for 30 minutes before
concentration to give the titled compound (336 mg) having the
following physical properties.
1H-NMR (CD
3OD): δ 1.01 (d, 6H), 1.34 (d, 3H), 1.50-1.58 (m, 3H),
1.67-1.88 (m, 2H), .02 (m, 2H), 3.03 (dt, 1H), 3.27-3.38
(m, 2H).
e 25: 2-{4-[3-(4-fluorophenoxy){[(4-
hydroxyisobutylmethyl
piperidinyl)carbonyl]amino}phenoxy]phenyl}methylpropanoic
acid
The titled compound (60 mg) having the ing physical
properties was obtained by carrying out the processes with the
same purposes as Example 8 → e 9 using the compound
prepared in Example 24 (48 mg) and the compound prepared in
Example 7 (100 mg).
TLC: Rf 0.33 (chloroform:methanol = 19:1);
1H-NMR (CDCl
3): δ 0.97 (dd, 6H), 1.36 (t, 2H), 1.38 (d, 3H),
1.47-1.75 (m, 10H), 1.77-1.89 (m, 1H), 3.36 (dt, 1H), 3.71-
3.79 (m, 1H), 4.26-4.35 (m, 1H), 6.29 (t, 1H), 6.38 (s, 1H),
6.69 (t, 1H), 6.81 (t, 1H), 6.96-7.02 (m, 6H), 7.35 (d, 2H).
Example 26: Ethyl 2-(benzhydrylideneamino)[4-{3-
(4-fluorophenoxy)nitro-phenoxy}phenyl]acetate
To the compound prepared in Example 11 (1.0 g) were added
ethyl[(diphenylmethylene)amino]acetate (652 mg) and ium
phosphate (1.41 g) and suspended in toluene (7.4 mL). The
reaction system was degassed, purged with argon, added with
Pd(t-Bu 3P) 2 (23 mg), ed again and purged with argon. The
reaction solution was stirred at 100°C for 17 hours, cooled to
0°C, adjusted to pH 7 by addition of water and 1 N hydrochloric
acid and extracted with ethyl acetate. The organic layer was
sequentially washed with water and a saturated sodium chloride
solution and dried over anhydrous magnesium sulphate. The
resulting residue obtained after concentration was purified by
silica gel chromatography (hexane:ethyl e = 100:0 → 9:1)
to give the titled compound (456 mg) having the following
physical properties.
TLC: Rf 0.36 (hexane:ethyl acetate = 3:1).
Example 27: Ethyl amino{4-[3-(4-fluorophenoxy)
nitrophenoxy]phenyl}acetate
The compound prepared in Example 26 (356 mg) was
dissolved in ethanol (4 mL) and DME (3 mL), added with l N
hydrochloric acid (1.8 mL) and stirred at room temperature for
hours. The concentrated reaction solution was cooled to 0°C,
neutralized with saturated aqueous sodium onate and
extracted with ethyl acetate. The organic layer was
sequentially washed with water and a saturated sodium de
solution and dried over anhydrous magnesium sulphate. The
resulting residue obtained after concentration was purified by
silica gel tography e:ethyl acetate = 80:20 —9
60:40) to obtain the titled compound (253 mg) having the
following physical properties.
TLC: Rf 0.28 (hexanezethyl acetate = 1:1).
e 28: Ethyl 2—(benzyloxycarbonylamino)—2—{4—
[3—(4—fluorophenoxy)—5—nitrophenoxy]pheny1}acetate
The compound prepared in Example 27 (253 mg) was
dissolved in ethyl acetate (2.5 mL) and added with sodium
hydrogen carbonate (100 mg) and benzyl chloroformate (112 mg)
at 0°C. The on solution was stirred at room temperature
for 13 hours, added with water and extracted with ethyl
acetate. The organic layer was sequentially washed with water
and a saturated sodium chloride solution and dried over
anhydrous magnesium sulphate. The resulting residue obtained
after tration was purified by silica gel chromatography
(hexane:ethyl acetate = 100:0 —9 85:15) to give the titled
compound (234 mg) having the following physical properties.
TLC: Rf 0.32 (hexanezethyl acetate 5:1).
Example 29: Ethyl 2—{4—[3—amino—5—(4—
fluorophenoxy)phenoxy]phenyl}—2—
(benzyloxycarbonylamino)acetate
To the compound prepared in Example 28 (253 mg) were
added iron (166 mg), zinc (194 mg), um chloride (32 mg),
water (0.2 mL) and ethanol (1.5 mL) and stirred at 70°C for 3
hours. The on solution was cooled to room temperature,
diluted with water and ethyl acetate and filtered with celite.
The resulting filtrate was added with saturated aqueous sodium
bicarbonate and extracted with ethyl acetate. The organic
layer was sequentially washed with water and a saturated
sodium chloride solution and dried over anhydrous magnesium
sulphate to give the titled compound (278 mg) having the
following physical ties.
TLC: Rf 0.17 (hexane:ethyl acetate = 3:1).
Example 30: Amino{4—[3—(4—fluorophenoxy)—5—{[(4—
hydroxy—4—isobutyl—1—
piperidinyl)carbonyl]amino}phenoxy]phenyl}acetic acid
The titled compound (28.4 mg) having the following
physical properties was obtained by carrying out the processes
with the same purposes as Example 7 —9 Example 8 —9 Example 9
—9 Example 6 using the compound prepared in Example 29 and 4-
yl—4-piperidinol.
TLC: Rf 0.15 (dichloromethane:methanol:aqueOus ammonia =
160:30:1);
lH—NMR (CDfifln: 5 7.45 (d, 2H), 7.13—6.97 (m, 6H), 6.83 (dt,
2H), 6.20 (t, 1H), 4.50 (s, 1H), 3.80 (d, 2H), 3.29—3.16 (m,
2H), .80 (m, 1H), 1.67—1.45 (m, 4H), 1.39 (d, 2H), 0.97
(d, 6H).
Example 31: Benzyl 3—(diethylcarbamoyl)—1—
idinecarboxylate
Under an argon atmosphere, 1—[(benzyloxy)carbonyl]—3-
pyrrolidinecarboxylic acid (500 mg) was dissolved in DMF (5
mL), added with N,N—diethylamine (0.293 g), further with EDC
(769 mg) and HOBt (542 mg) and d at room temperature for
72 hours. The on solution was diluted with ethyl acetate,
tially washed with 1 N hydrochloric acid, a 1 N sodium
hydroxide s solution, water and a saturated sodium
chloride solution and dried over anhydrous magnesium sulphate
before distillation of the solvent. The resulting residue was
purified by silica gel chromatography (hexane:ethyl e =
95:5 —9 0:1) to give the titled compound (556 mg) having the
following physical properties.
lH—NMR (CDC13): 5 7.38—7.25 (m, 5H), 5.13 (s, 2H), 3.75—3.04(m,
8H), 2.20 (m, 2H), 1.20 (t, 3H), 1.11 (t, 3H).
Example 32: N,N—diethy1—3~pyrrolidinecarboxamide
The compound prepared in Example 31 (556 mg) was
dissolved in ethanol (10 mL) and ethyl acetate (20 mL) and
added with 5% palladium carbon (100 mg) and the reaction
solution was stirred under a hydrogen atmosphere at room
temperature for 8 hours. The on solution was filtered
with celite and the solvent was distilled off to give the
titled compound having the following physical properties. The
resulting titled compound was used for the next reaction
without further purification.
lH—NMR (CDC13): 5 3.50—2.74 (m, 8H), 1.97 (m, 2H), 1.20 (t, 3H),
1.11 (t, 3H).
Example 33: 2-{4—[3—({[3—(diethylcarbamoyl)-1—
pyrrolidinyl]carbonyl}amino)—5—(4—
phenoxy)phenoxy]phenyl}—2-methylpropanoic acid
The titled compound (59.4 g) having the following
physical properties was obtained by carrying out the processes
with the same purposes as e 8 —9 Example 9 using the
compound prepared in Example 32 (29.8 mg) and the compound
prepared in Example 7 (100 mg).
[C 23]
H..F”:’GT“O°OF
ifiC CH?“
TLC: Rf 0.60 (chloroform:methanol = 9:1);
lH—NMR (CDC13): 8 7.31 (m, 2H), 7.98—6.88 (m, 7H), 6.68 (m, 1H),
6.44 (m, 1H), 6.30 (m, 1H), 3.74—3.12 (m, 8H), 2.25—2.00 (m,
2H), 1.55 (s, 6H), 1.19 (t, 3H), 1.09 (t, 3H).
Example 33(1): 3—(4—f1uorophenoxy)—5—({[3-
(isopropylcarbamoyl)—1—
pyrrolidinyl]carbonyl}amino)phenoxy]phenyl}—2—methylpropanoic
acid
The titled compound (63.6 mg) having the following
physical properties was ed by carrying out the process
with the same e as Example 33 using the compound
prepared in Example 7 (100 mg) and a corresponding pyrrolidine
derivative (27.4 mg) in the place of the compound prepared in
Example 32.
TLC: Rf 0.54 oformzmethanol = 9:1);
lH—NMR (CDC13): 5 7.31 (m, 2H), 7.04—6.80 (m, 7H), 6.68 (m, 1H),
6.48 (m, 1H), 6.30 (m, 1H), 5.64 (d, 1H), 4.03 (m, 1H), 3.62—
3.50 (m, 3H), 3.33 (m, 1H), 2.79 (m, 1H), 2.09 (m, 2H), 1.56
(s, 6H), 1.11 (m, 6H).
e 34: Methyl 3,5—dinitrobenzoate
In methanol (100 mL) was dissolved 3,5—dinitrobenzoy1
chloride and ropylethylamine (4.53 mL) was added o
while cooling With ice. The reaction solution was stirred for
1 hour and then the solvent was distilled off. The resulting
substance was diluted with ethyl acetate, sequentially washed
with water and a saturated sodium chloride solution and dried
over anhydrous magnesium sulphate before distillation of the
solvent to give the titled compound (4.73 g) having the
following physical properties.
TLC: Rf 0.31 (hexane:ethy1 acetate = 5:1).
e 35: Methyl 3—(4—fluorophenoxy)~5-
nitrobenzoate
The compound prepared in Example 34 (4.73 g) was
dissolved in DMF (40 mL), added with 4—f1uorophenol (2.34 g)
and potassium phosphate (5.32 g) and stirred overnight at 80°C.
The reaction solution was diluted with ethyl acetate,
sequentially washed with water and a saturated sodium chloride
solution and dried over anhydrous magnesium sulphate before
distillation of the solvent. The ing residue was
purified by silica gel chromatography e:ethyl acetate =
9:1 —9 1:1) to give the titled nd (4.81 g) having the
following physical properties.
TLC: Rf 0.47 (hexanezethyl acetate = 5:1).
Example 36: Methyl 3—(4—fluorophenoxy)—5-{[(4—
hydroxy—4—isobutyl—1—piperidinyl)carbony1]amino}benzoate
The titled compound (495 mg) having the following
physical properties was obtained by carrying out the processes
with the same purposes as Example 6 —9 Example 7 —9 Example 8
using the nd prepared in Example 35 and 4—isobuty1—4—
piperidinol.
lH—NMR (CDCl3): 8 7.40—7.20 (m, 7H), 5.13 (s, 2H), 3.94 (m,
2H), 3.22 (m, 2H), 2.46 (m, 1H), 1.83 (m, 2H), 1.57 (m, 6H).
Example 37: 3—(4—fluorophenoxy)—5—{[(4—hydroxy—4—
isobutyl—l—piperidinyl)carbonyl]amino}benzoic acid
The compound prepared in Example 36 (495 mg) was
dissolved in ol (5 mL), added with a 2 N sodium
hydroxide aqueous on (1.11 mL) and stirred at 45°C for 2
hours. The reaction Solution was neutralized with the
equivalent amount of hydrochloric acid before distillation of
the solvent, dilution with ethanol, tion and desalting
to give the titled compound (490 mg). The resulting titled
compound was used for the next reaction without further
purification.
Example 38: 2—(4—{[3—(4—fluorophenoxy)—5—{[(4—
hydroxy-4—isobutyl-1—
piperidinyl)carbonyl]amino}benzoyl]oxy}phenyl)—2—
methylpropanoic acid
[C 24]
cm H
Hfi H
NTN. i .o.
o : F
O o
Hac 0H
H3c :
Under an argon atmosphere, the compound prepared in
Example 37 (75 mg) was ved in DMF (1 mL), added with EDC
(55.5 mg), HOBt (39.1 mg), ropylethylamine (0.05 mL) and
benzyl 2—(4—hydroxyphenyl)-2—methylpropanoate (56.5 mg) and
stirred overnight at room temperature. The reaction solution
was diluted with ethyl acetate, sequentially washed with water
and a saturated sodium chloride solution and dried over
anhydrous magnesium sulphate before distillation of the
solvent. The ing residue was dissolved in methanol (1
mL) and ethyl e (1 mL), added with 5% palladium carbon
(50 mg) and stirred at room temperature for 2 hours in a
hydrogen atmosphere. The reaction solution was ed with
celite and the solvent was distilled off. The resulting
residue was purified by thin layer chromatography
(chloroform:methanol = 5:1) to give the titled compound (59.1
mg) having the following physical properties.
TLC: Rf 0.62 (chloroform:methanol = 5:1);
1H—NMR (CDCl3): 6 7.58 (m, 2H), 7.32 (m, 3H), 7.18—6.90 (m, 6H),
3.79 (m, 2H), 3.24 (m, 2H), 1.80 (m, 1H), 1.70—1.45 (m, 4H),
1.52 (s, 6H), 1.37 (d, 2H), 0.95 (d, 6H).
Example 39: 4—cyclopropyl—N—[3—(4—fluorophenoxy)—5—
(hydroxymethyl)phenyl]—4—hydroxy-1—piperidinecarboxamide
Under an argon atmosphere, methyl 3-{[(4—cyclopropyl—4—
y—l—piperidinyl)carbonyl]amino}—5—(4—
fluorophenoxy)benzoate (201 mg) which was obtained with the
same procedure as Example 36 using the compound prepared in
Example 35 and 4—cyclopropyl—4—piperidinol in the place of 4—
isobutyl-4—piperidinol was dissolved in THF (10 mL), added
with diisobutylaluminium hydride (1.407 mL, 1.0 M, a solution
in toluene) and stirred at 0°C for 1.5 hours. The on
solution was added with a sodium sulphate aqueous solution and
filtered with celite and the solvent was distilled off. The
reaction solution was further diluted with ethyl acetate,
sequentially washed with water and a saturated sodium chloride
solution and dried over ous magnesium sulphate before
distillation of the solvent. The resulting residue was
purified by silica gel chromatography (hexane:ethyl acetate =
95:5 —9 0:1) to give the titled nd (161 mg) having the
following physical ties.
1H—NMR (CDCl3): 5 7.06 (m, 1H), 7.00—6.88 (m, 5H), 6.79 (m, 1H),
6.58 (m, 1H), 4.52 (s, 2H), 3.78 (m, 2H), 3.18 (m, 2H), 1.68—
1.44 (m, 4H), 0.89 (m, 1H), 0.39—0.32 (m, 4H).
Example 40: 2-(4—{[3—{[(4—cyclopropyl—4~hydroxy—1—
piperidinyl)carbonyl]amino}—5—(4—
fluorophenoxy)benzyl]oxy}phenyl)~2—methylpropanoic acid
Under an argon atmosphere, the compound prepared in
e 39 (153 mg) was dissolved in THF (12 mL), added with
the compound prepared in Example 3 (89.2 mg), diisopropyl
azodicarboxylate (0.114 mL) and triphenylphosphine (110 mg)
and stirred overnight at room temperature. The on
solution was diluted with ethyl acetate, sequentially washed
with water and a saturated sodium chloride solution and dried
over ous magnesium sulphate before lation of the
solvent. The resulting residue was purified by silica gel
chromatography e:ethyl acetate II 9:1 —9 0:1). The
resulting product was further dissolved in methanol (2 mL),
added with a 2 N sodium ide aqueous solution (0.575 mL)
and stirred at 45°C for 2 hours. The reaction solution was
neutralized with the equivalent amount of hydrochloric acid
before concentration and the resulting residue was purified by
thin layer chromatography (chloroform:methanol = 5:1) to give
the titled nd (99.0 mg) having the following physical
properties.
TLC: Rf 0.58 (chloroform:methanol = 5:1);
lH—NMR (CDCl3): 5 7.30—6.70 (m, 10H), 6.67 (m, 1H), 6.51 (s,
1H), 4.96 (s, 2H), 3.80 (m, 2H), 3.24 (m, 2H), 1.70—1.48 (m,
4H), 1.56 (s, 6H), 0.93 (m, 1H), 0.44—0.32 (m, 4H).
Example 41: N—[3—(4—fluorophenoxy)—5—hydroxyphenyl]—
4—hydroxy—4—isobutyl—1—piperidinecarboxamide
The titled compound having the following physical
properties was obtained by carrying out the processes with the
same purposes as Example 4 —9 Example 5 —9 Example 6 —+ Example
7 —9 Example 8 using 1,3—difluoro—5—nitrobenzene,
phenylmethanol, 4—fluorophenol and 4-isobutyl—4—piperidinol.
TLC: Rf 0.52 (hexanezethyl e = 1:2).
Example 42: Ethyl {4—[3—(4—fluorophenoxy)—5—{[(4—
hydroxy—4—isobutyl—1—
piperidinyl)carbonyl]amino}phenoxy]phenyl} (oxo)acetate
The compound prepared in Example 41 (100 mg) and ethyl 2—
orophenyl)-2—oxoacetate (73 mg) were dissolved in DMF
(0.7 mL), added with cesium carbonate (79 mg) and stirred at
60°C. After 2 hours and 4 hours from the initiation of the
reaction, ethyl 2—(4-fluorophenyl)—2—oxoacetate (73 mg), and
ethyl 2—(4—fluorophenyl)—2—oxoacetate (73 mg) and cesium
carbonate (132 mg) were respectively added and stirring was
continued for in total 18 hours. The reaction solution was
allowed to cool to room temperature, added with water and
extracted with ethyl acetate. The organic layer was
sequentially washed with water and a saturated sodium chloride
solution and dried over anhydrous ium te. The
residue obtained after distillation under reduced pressure was
purified by silica gel chromatography (hexane:ethyl acetate =
90:10 —9 50:50) to give the titled compound (43 mg) having the
following physical properties.
TLC: Rf 0.28 (hexanezethyl acetate = 1:1).
Example 43: Ethyl {4—[3—(4-fluorophenoxy)—5—{[(4—
hydroxy—4-isobutyl—l—
piperidinyl)carbonyl]amino}phenoxy]phenyl} (hydroxy)acetate
The compound prepared in Example 42 (43 mg) was ved
in methanol (1 mL) and stirred at 0°C. The reaction on
was added with sodium borohydride (3 mg), stirred for 15
minutes, added with water and extracted with ethyl acetate.
The organic layer was sequentially washed with water and a
saturated sodium chloride on and dried over anhydrous
magnesium te. The residue obtained after distillation
under reduced pressure was purified by silica gel
tography (hexane:ethyl acetate = 75:25 —9 50:50) to give
the titled compound (24 mg) having the following physical
properties.
TLC: Rf 0.12 (hexanezethyl acetate = 1:1).
Example 44: (4—fluorophenoxy)—5—{[(4ehydroxy—
4—isobutyl—l—piperidinyl)carbonyl]amino}phenoxy]phenyl}
(hydroxy)acetic acid ‘
The compound prepared in Example 43 (24 mg) was dissolved
in methanol (0.4 mL), added with a 2 N sodium hydroxide
aqueous solution (52 ML) and stirred at 35°C for 13 hours. The
solution was added with l N hydrochloric acid for
neutralization at 0 °C and added with water and ethyl e
for extraction. The organic layer was sequentially washed with
water and a saturated sodium chloride solution and dried over
anhydrous magnesium sulphate. Distillation under reduced
pressure gave the titled compound (21.6 mg) having the
following physical properties.
TLC: Rf 0.16 (dichloromethane:methanol:acetic acid =
100:10:l);
1H—NMR (CDC13): 5 7.38 (d, 2H), 7.03—6.90 (m, 6H), 6.78 (s, 1H),
6.64 (s, 1H), 6.27 (t, 1H), 5.08 (s, 1H), 3.67 (d, 2H), 3.30—
3.18 (m, 2H), 1.77 (td, 1H), 1.63—1.46 (m, 4H), 1.34 (d, 2H),
0.92 (d, 6 H).
Example 45: N—[3—(4—fluorophenoxy)—5—(4—{2—methyl—1—
[(methylsulphonyl)amino]—1—oxo—2—propanyl}phenoxy)phenyl]44—
hydroxy-4—isobutyl—1—piperidinecarboxamide
The compound prepared in Example 9 (320 mg),
methanesulphonamide (80 mg), EDC (160 mg) and 4—
dimethylaminopyridine (104 mg) were suspended in
romethane (12 mL) and the suspension was heated to 70°C
for 2 hours with a microwave. The reaction solution was
subjected to distillation under reduced pressure, then
ved in ethyl acetate and washed twice with 1 N
hydrochloric acid and once with a saturated sodium chloride
solution. The organic layer was subjected to distillation of
the solvent and the resulting residue was purified by silica
gel chromatography (dichloromethane:methanol = 16:1). The
resulting residue was further washed with hexane and t—butyl
methyl ether to give the titled nd (215 mg) having the
following physical properties.
TLC: Rf 0.45 (dichloromethane:methanol = 8:1);
lH—NMR (CDfifln: 5 7.32 (d, 2H), 7.16—6.97 (m, 6H), 6.85 (t, 1H),
6.79 (t, 1H), 6.21 (t, 1H), 3.88—3.72 (m, 2H), 3.27—3.15 (m,
5H), .76 (m, 1H), 1.54 (s, 6H), 1.66—1.47 (m, 4H), 1.39
(d, 2H), 0.97 (d, 6H).
'[Method for preparing crystals of the present
compound]
The compounds of Examples in the t invention can be
crystallized ing to the methods described in Examples or
similar methods thereto.
The crystals were subjected to ement under the
following conditions and the physical properties described in
es were obtained.
X—ray powder diffraction spectrum
<Measurement conditions>
Instrument: BRUKER D8 DISCOVER with GADDS from BRUKER axs;
Target: Cu;
Filter: none;
e: 40 kV;
Current: 40 mA;
Exposure time: 3 min.
[2] ential scanning calorimetry (DSC)
<Measurement conditions>
Instrument: DSC 822e from METTLER TOLEDO;
Sample amount: 1 to 2 mg;
Sample cell: 40—uL aluminium pan;
Nitrogen gas flow: 40 mL/min;
Heating rate: lO°C/min (25 to 220°C, 25 to 240°C, 25 to 250°C).
Example A: Crystal of 2-{4-[3-(4—fluorophenoxy)—5—
{[(4—hydroxy—4—isobutyl—l—
dinyl)carbonyl]amino}phenoxy]phenyl}—2-methylpropanoic
acid (type A l)
In Example 9, the obtained purified product was added
with ethyl acetate (7 v/w) and stirred at 0 to 30°C. The
solution was filtered once, added with toluene (3 v/w), added
with a seed crystal and stirred at 25°C for 3 hours. The
e was added with toluene (10 v/w), cooled to 0°C and
stirred for 1.5 hours. The resulting crystal was filtered and
washed with toluene (2 V/w) to give the titled crystal. The X—
ray powder diffraction spectrum and the differential scanning
calorimetry (DSC) chart of the resulting crystal are shown in
Figs. 1 and 2, respectively. The ction angle 29 and
relative intensity in the X—ray powder diffraction spectrum
are shown in the following table.
X—ray powder ction spectrum:
[Table 1]
Diffraction angle 29 (degree) Relative intensity (%)
KO\1 U70 14.8
91.9
.1 25.4
13.0
13.4 42.9
14.0 24.2
.3 18.5
16-6
17-3
18.3 49.5
19-0
50-1
_21.1 18
23-6
23.5
23.8 23.8
24.4 14
The present crystal showed the onset of the endothermic
peak at about 143°C.
Example B: Crystal of 2—{4—[3—({[4—(2—ethylbutyl)-4—
hydroxy-l—piperidinyl]carbonyl}amino)—5—(4—
fluorophenoxy)phenoxy]phenyl}—2—methylpropanoic acid (type A
crystal)
The compound prepared in Example 9(20) was added with
ethanol (35 v/w) and water (10 v/w). The mixture was heated in
an oil bath at 70°C for dissolution. The solution was allowed
to cool from 70°C to 25°C and the resulting crystal was then
ted by filtration and dried under reduced re to
give the titled crystal. The resulting crystal was analyzed
and the X-ray powder diffraction spectrum and the differential
scanning calorimetry chart thereof are shown in Figs. 3 and 4,
respectively. The diffraction angle 28 and relative ity
in the X—ray powder diffraction spectrum are shown in the
following table.
X—ray powder diffraction um:
[ Hm0‘ }_A (D N
Diffraction angle 20 ve intensity
(degree) (%)
.8 17.4
7.3 100
8.8 10.5
- 9-7
.5
11.4 16.6
11.6 17.3
12-4
14-6
14.3 14.1
.1 32.9
.7 ,_1 0'1
16.7 63 ]_|
17.3
18.3 (JON l—‘\l-
19.5 40.5
.3
21.0 (JUN moo
21.4 38.6
22.7 23.6
23.5 11.5
24.7 40.1
The present crystal showed the onSet of the ermic
peak at about 170°C.
Example C: Crystal of 1—{4—[3—(4—fluorophenoxy)—5—
({[4—hydroxy—4—(3—pentany1)—1—
piperidinyl]carbonyl}amino)phenonyphenyl}cyclopropanecarboxy1
ic acid (type A crystal)
The compound prepared in Example 13 was added with 15 ML
of ethanol (15 v/w). The mixture was heated in an oil bath at
70°C for dissolution. The solution was allowed to cool from
70°C to 25°C and the resulting crystal was then collected by
filtration and dried under reduced pressure to give the titled
crystal. The resulting crystal was analyzed and the X-ray
powder diffraction spectrum and the differential scanning
metry (DSC) chart f are shown in Figs. 5 and 6,
respectively. The diffraction angle 20 and relative intensity
in the X—ray powder diffraction um are shown in the
following table.
X—ray powder diffraction spectrum:
[Table 3]
The present crystal showed the onset of the endothermic
peak at about 182°C.
[Experimental examples]
The effects of the present compounds were verified based
on the experimental methods shown hereinbelow as the
biological experimental example and physical experimental
example.
Biological Experimental Example 1: Evaluation of SlP2
antagonistic activity by monitoring the change in
intracellular calcium ion concentration
Chinese hamster ovary (CHO) cells overexpressing the
human Sle gene were cultured in a Ham's F12 medium containing
% fetal bovine serum (FBS), an antibiotic/antifungal agent
and G418. CHO cells overexpressing the rat SlP2 gene were
cultured in a Ham's F12 medium containing 10% FBS,
penicillin/streptomycin and blasticidin S. The cultured cells
were incubated in a FuraZ—AM solution (5 uM) [a Ham's F12
medium containing PBS (10%), HEPES buffer (20 mM, pH 7.2 to
7.5) and probenecid (2.5 mM)] at 37°C for 60 minutes. The
cells were washed twice with a Hanks' balanced saline
containing HEPES buffer (20 mM, pH 7.2 to 7.5) and probenecid
(2.5 mM) and immersed in the same solution. A plate was
mounted on a fluorescence—based drug screening system and the
intracellular calcium ion concentration was measured for 30
seconds without stimulation. A test substance (the final
concentration of human SlPZ: 0.25 nM to 25 uM and the final
concentration of rat SlPZ: 0.25 nM to 2.5 nM) or a dimethyl
sulphoxide (DMSO) solution was added and after 3 minutes SlP
(final concentration: 300 nM) was added and the increase in
the intracellular calcium ion concentration before and after
the addition of SlP was ed with an interval of 3 seconds
(excitation wavelength: 340 nm and 380 nm, fluorescence
wavelength: 540 nm).
The SlP2 antagonistic activity was calculated using
the suppression ed from the ing formula, wherein A
is a control value which was a peak value after on of
SlP (final concentration: 300 nM) in the wells added with DMSO
without a test substance and B is an increased amount after
on of SlP in the cells treated with the test substance:
[E 1]
Suppression (%) = [(A—B)/A] x 100
ICw value was calculated as the concentration of the
present nd which showed the 50% suppression.
Comparative nds used were the compounds
disclosed in Example 1(64) (hereinafter referred to as
comparative compound A) and Example 1(85) (hereinafter
referred to as comparative compound B) in Patent Document 3
(WO 02531). The structural formulae of the comparative
compounds are shown below respectively.
[C 25]
\l/b F
N H
T F
Comparative nd A
[C 26]
va‘fir”H o
a UK)
Comparative compound B
The human and rat SlP2 antagonistic activities of the
present compounds and comparative compounds are shown in the
following Table 4.
[Table 4]
Example 15(6)
e 9 NU! UJI—‘NO
Example 13 (JJ O
Example 19 l—‘UJNU‘IUJKO
Example 38 (JJ ,5 [—1 m
As a result, it was found that the present compounds
have significantly improved human Sle antagonistic activity
compared to the comparative compounds. In addition, the
present compounds also have improved difference in the SlP2
antagonistic activity between species, i.e. between human and
rat and thus may allow extrapolation of the cy obtained
in rat pathological models to human.
Physical Experimental Example 2: Solubility
measurement
A solution for ing a calibration curve was prepared
by diluting a test substance (10 mmol/L, DMSO solution) in
acetonitrile and adding acetonitrile containing an internal
standard substance (warfarin) to adjust to 0.1, 0.4 and 2
umol/L. A sample solution was prepared by adding to 495 ML (pH
6.8) of the second solution defined in Japanese Pharmacopoeia
(a solution used was obtained by adding water to 250 mL of a
0.2 mol/L potassium dihydrogen phosphate reagent solution and
118 mL of a 0.2 mol/L sodium hydroxide reagent solution to
adjust to 1000 mL) 5 uL of a test substance (10 , DMSO
solution), stirring at room temperature for 5 hours,
transferring the obtained solution to a plate with a filter
for vacuum filtration, diluting 20 uL of the filtrate with
acetonitrile and adding acetonitrile containing the al
standard. The solution for ing a ation curve and
the sample on (5 uL each) were injected to LC—MS/MS
very Max from Thermo Scientific) for quantification
ification range: 0.1 to 2 umol/L). The solubility was
calculated by multiplying the quantified value by 50. When the
caluculated value was outside of the quantification range, the
solubility was expressed as < 5 umol/L or 100 umol/L.
The lity of the present compounds and the
comparative compounds is shown in the following Table 5.
[Table 5]
Solubility (Hmol/L)
Comparative compound A —<5
_—' < 5
As a result, it was found that the t compounds have
superior solubility than the comparative compounds.
[Formulation Examples]
Formulation Example 1
The following components were mixed and then compressed
to make tablets according to the conventional method to obtain
,000 tablets respectively containing 10 mg of the active
ingredient.
o 4—(2—ethylbutyl)—N—[3—(4—fluorophenoxy)—5—{4—[(4—hydroxy—l—
piperidinyl)carbonyl]phenoxy}phenyl]—4—hydroxy—l—piperidine
carboxamide 100 g
0 Carboxymethylcellulose calcium (disintegrating agent)20 g
0 ium stearate (lubricant) 10 g
0 Microcrystalline cellulose 870 g
ation Example 2
The following components were mixed according to the
conventional method, then filtered through a dust removal
filter, divided at 5 ml per ampoule, sterilized by heating in
an autoclave to obtain 10,000 ampoules tively containing
mg of the active ingredient.
o 1—{4—[3—(4—fluorophenoxy)—5—({[4—hydroxy—4—(3—pentanyl)—l~
piperidinyl]carbonyl}amino)phenonyphenyl}cyclopropanecarboxyl
ic acid
200 g
o Mannitol 20 g
o Distilled water 50 L
INDUSTRIAL APPLICABILITY
The present nd has high human Sng antagonistic
activity and thus is useful for therapy of Sle—mediated
diseases such as diseases resulting from vascular constriction
and fibrosis.
Claims (12)
1. A nd represented by the formula (I-1): wherein R1 represents (1) a C1-8 alkyl group which may be substituted with 1 to 5 R21 group(s), (2) a C2-8 alkenyl group which may be substituted with 1 to 5 R21 s), (3)a C2-8 alkynyl group which may be substituted with 1 to 5 R21 group(s), (4) a C3-7 carbocycle which may be substituted with 1 to 5 substituent(s) selected from the group consisting of a C1-4 alkyl group, a C1-4 haloalkyl group, a C1-4 alkoxy group and a halogen atom, or (5) -CONR31R32; R21 represents (1) a halogen atom, (2) -OR22 (in the group, R22 represents (1) a hydrogen atom, (2) a C1-4 alkyl group or (3) a C1-4 haloalkyl group), (3) 24 (in the group, R23 and R24 each independently represent (1) a hydrogen atom or (2) a C1-4 alkyl group) or (4) an oxo group; R31 and R32 each independently represent (1) a en atom or (2) a C1-4 alkyl group; R2 represents (1) a hydrogen atom, (2) a C1-4 alkyl group or (3) a C1-4 haloalkyl group; R3 and R4 each ndently represent (1) a halogen atom, (2) a C1-4 alkyl group, (3) a C1-4 haloalkyl group, (4) a C1-4 alkoxy group, (5) a hydroxy group, (6) -L-CONR6R7, (7) -L-SO2R8 or (8) -L-COOR9; R5 represents (1) a halogen atom, (2) a C1-4 alkyl group or (3) a C1-4 haloalkyl group; L represents (1) a bond, (2) a group represented by the formula: wherein A represents (1) a bond or (2) an oxygen atom; R12 and R13 each ndently represent (1) a hydrogen atom, (2) a C1- 4 alkyl group, (3) a hydroxy group or (4) NH2 or (5) R12 and R13 together with the carbon atom to which they are attached may form a C3-7 carbocycle; and the arrow on the right hand side binds to -CONR6R7, -SO2R8 or -COOR9, (3) a C2-4 alkenylene group, (4) a -O-C2-4 lene group, (5) an oxygen atom or (6) a nitrogen atom which may be substituted with a C1-4 alkyl group; R6 and R7 each independently represent (1) a hydrogen atom, (2) a C1-4 alkyl group, (3) a C1-4 haloalkyl group, (4) a hydroxy group, (5) -CONR15R16, (6) -SO2NR15R16, (7) -COR17 or (8) -SO2R17, or R6 and R7 together with the nitrogen atom to which they are attached may form a 4- to ered nitrogencontaining saturated heterocycle that may be substituted with a hydroxy group; R8 represents (1) a C1-4 alkyl group, (2) a C1-4 haloalkyl group or (3) NR10R11; R9 represents (1) a hydrogen atom or (2) a C1-8 alkyl group; R10 and R11 each independently represent (1) a hydrogen atom, (2) a C1-4 alkyl group, (3) -CONR15R16, (4) -SO2NR15R16, (5) -COR17 or (6) -SO2R17; the ring 1 and the ring 2 each independently ent a 5- to 7-membered cyclic group; R14 represents (1) a hydrogen atom or (2) a hydroxy group; R15 and R16 each ndently represent (1) a hydrogen atom, (2) a C1-4 alkyl group or (3) a 5- to 7-membered cyclic group; R17 represents (1) a C1-4 alkyl group or (2) a 5- to 7- membered cyclic group; M1 and M2 each independently ent (1) a bond, (2) - C(O)-, (3) -O-, (4) -S-, (5) -C(O)O-, (6) -CH2O- or (7) - C(O)NH-; n represents an integer of 1 to 2; m represents an integer of 1 to 2; p represents an integer of 0 to 5; q represents an integer of 0 to 5; r represents an integer of 0 to 4; t represents an integer of 1 to 4; when p is 2 or more, a plurality of R3 groups may be the same or different; when q is 2 or more, a plurality of R4 groups may be the same or different; when r is 2 or more, a plurality of R5 groups may be the same or different; and when t is 2 or more, a ity of R12 and R13 groups may be respectively the same or different; a salt thereof, a solvate thereof, an N-oxide thereof or a prodrug thereof.
2. The compound according to claim 1, wherein R14 is a y group.
3. The compound according to claim 1 or 2, wherein M1 and M2 each independently are (1) -C(O)-, (2) -O-, (3) -S-, (4) - C(O)O- or (5) -CH2O-.
4. The nd according to claim 3, wherein M1 and M2 are -O-.
5. The compound according to claim 1, which is ented by the formula (I): wherein all the symbols have the same meanings as above.
6. The compound ing to claim 5, wherein R1 is (1) a C1- 8 alkyl group which may be substituted with 1 to 5 R21 group(s) or (2) a C3-7 carbocycle which may be substituted with 1 to 5 substituent(s) selected from the group consisting of a C1-4 alkyl group, a C1-4 alkoxy group, a n atom and a oromethyl group.
7. The compound according to claim 5 or 6, wherein R2 is a hydrogen atom.
8. The nd according to any one of claims 5 to 7, wherein the ring 1 and the ring 2 each independently are (1) a benzene, (2) cyclohexane or (3) pyridine ring.
9. The compound according to any one of claims 1 to 8, which is (1) 4-(2-ethylbutyl)-N-{3-[4-(ethylcarbamoyl)phenoxy](4- fluorophenoxy)phenyl}hydroxypiperidine carboxamide, (2) 4-[3-(4-fluorophenoxy)({[4-(4-fluorophenyl)hydroxy piperidinyl]carbonyl}amino)phenoxy]benzoic acid, (3) 4-(2- ethylbutyl)-N-[3-(4-fluorophenoxy){4-[(4-hydroxy piperidinyl)carbonyl]phenoxy}phenyl]hydroxypiperidine carboxamide, (4) 2-{4-[3-(4-fluorophenoxy){[(4-hydroxy isobutylpiperidinyl)carbonyl]amino}phenoxy]phenyl} methylpropanoic acid, (5) 1-{4-[3-(4-fluorophenoxy)({[4- hydroxy(3-pentanyl) piperidinyl]carbonyl}amino)phenoxy]phenyl}cyclopropanecarboxyl ic acid, (6) 2-{4-[3-(4-fluorophenoxy){[(3-hydroxy isobutylazetidinyl)carbonyl]amino}phenoxy]phenyl} methylpropanoic acid, (7) 4-[3-({[4-(2-ethylbutyl)hydroxy- 1-piperidinyl]carbonyl}amino)(4- fluorophenoxy)phenoxy]benzoic acid, (8) 2-{4-[3-({[4-(2- ethylbutyl)hydroxypiperidinyl]carbonyl}amino)(4- fluorophenoxy)phenoxy]phenyl}methylpropanoic acid or (9) 2- (4-{[3-(4-fluorophenoxy){[(4-hydroxyisobutyl dinyl)carbonyl]amino}benzoyl]oxy}phenyl) methylpropanoic acid.
10. A compound according to claim 9, which is 2-{4-[3-(4- fluorophenoxy){[(4-hydroxyisobutyl piperidinyl)carbonyl]amino}phenoxy]phenyl}methylpropanoic acid.
11. Use of the nd represented by the a (I-1) according to any one of claims 1 to 10, the salt thereof, the e thereof, the N-oxide thereof or the prodrug thereof for producing a prophylactic and/or therapeutic agent for an S1P 2-mediated disease.
12. The compound according to claim 1, substantially as herein described with reference to any one of the Examples and/or
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2011213987 | 2011-09-29 | ||
JP2011-213987 | 2011-09-29 | ||
PCT/JP2012/074968 WO2013047701A1 (en) | 2011-09-29 | 2012-09-27 | Phenyl derivative |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ622539A NZ622539A (en) | 2015-05-29 |
NZ622539B2 true NZ622539B2 (en) | 2015-09-01 |
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