NZ620469B2 - Pyrrolidine-3-ylacetic acid derivative - Google Patents
Pyrrolidine-3-ylacetic acid derivative Download PDFInfo
- Publication number
- NZ620469B2 NZ620469B2 NZ620469A NZ62046912A NZ620469B2 NZ 620469 B2 NZ620469 B2 NZ 620469B2 NZ 620469 A NZ620469 A NZ 620469A NZ 62046912 A NZ62046912 A NZ 62046912A NZ 620469 B2 NZ620469 B2 NZ 620469B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- methyl
- compound
- acetic acid
- group
- mmol
- Prior art date
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- OUENRUZPZZFMCA-UHFFFAOYSA-N 2-pyrrolidin-1-ium-3-ylacetate Chemical class OC(=O)CC1CCNC1 OUENRUZPZZFMCA-UHFFFAOYSA-N 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 276
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 213
- -1 pyrrolidine-3-yl-acetic acid derivative compounds Chemical class 0.000 claims abstract description 101
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 24
- 206010021972 Inflammatory bowel disease Diseases 0.000 claims abstract description 15
- 239000003112 inhibitor Substances 0.000 claims abstract description 12
- 230000037361 pathway Effects 0.000 claims abstract description 9
- 206010011401 Crohn's disease Diseases 0.000 claims abstract description 7
- 206010009900 Colitis ulcerative Diseases 0.000 claims abstract description 6
- 201000006704 ulcerative colitis Diseases 0.000 claims abstract description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 104
- 239000011780 sodium chloride Substances 0.000 claims description 76
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 67
- 150000003839 salts Chemical class 0.000 claims description 64
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 40
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 38
- 125000001424 substituent group Chemical group 0.000 claims description 27
- 239000003814 drug Substances 0.000 claims description 14
- 102100014440 CX3CR1 Human genes 0.000 claims description 11
- 101710039744 CX3CR1 Proteins 0.000 claims description 11
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- 125000004429 atoms Chemical group 0.000 claims description 10
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 10
- 238000004519 manufacturing process Methods 0.000 claims description 10
- 239000004480 active ingredient Substances 0.000 claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims description 8
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 8
- 125000005843 halogen group Chemical group 0.000 claims description 7
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 4
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 claims description 3
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 claims description 3
- 201000010099 disease Diseases 0.000 claims description 3
- 125000005817 fluorobutyl group Chemical group [H]C([H])(F)C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 3
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
- OYZBJRPMFFOVPU-STTRJGPESA-N 2-[(3S,4R)-3-[[(3S)-1-(cyclohexen-1-ylmethyl)pyrrolidin-3-yl]carbamoyl]-1-[(2,6-dichlorophenyl)methyl]-4-methylpyrrolidin-3-yl]acetic acid Chemical compound C([C@@H]([C@](C1)(CC(O)=O)C(=O)N[C@@H]2CN(CC=3CCCCC=3)CC2)C)N1CC1=C(Cl)C=CC=C1Cl OYZBJRPMFFOVPU-STTRJGPESA-N 0.000 abstract 2
- JXBBOBNZJSUUDJ-BNSZOAOKSA-N 2-[(3S,4R)-1-[[2-chloro-6-(trifluoromethyl)phenyl]methyl]-3-[[1-(2-fluoropentyl)piperidin-4-yl]carbamoyl]-4-methylpyrrolidin-3-yl]acetic acid Chemical compound C1CN(CC(F)CCC)CCC1NC(=O)[C@@]1(CC(O)=O)[C@@H](C)CN(CC=2C(=CC=CC=2Cl)C(F)(F)F)C1 JXBBOBNZJSUUDJ-BNSZOAOKSA-N 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 203
- 238000000034 method Methods 0.000 description 113
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 96
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 84
- 238000005160 1H NMR spectroscopy Methods 0.000 description 80
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 65
- 239000000243 solution Substances 0.000 description 64
- 239000002904 solvent Substances 0.000 description 64
- 239000000203 mixture Substances 0.000 description 62
- 101700067048 CDC13 Proteins 0.000 description 53
- 239000011541 reaction mixture Substances 0.000 description 49
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 47
- 238000003756 stirring Methods 0.000 description 47
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 45
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 42
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 40
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 39
- 239000000126 substance Substances 0.000 description 39
- 238000004458 analytical method Methods 0.000 description 38
- 239000012156 elution solvent Substances 0.000 description 36
- 239000002253 acid Substances 0.000 description 35
- 238000006243 chemical reaction Methods 0.000 description 35
- CSNNHWWHGAXBCP-UHFFFAOYSA-L mgso4 Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 33
- 239000012044 organic layer Substances 0.000 description 32
- 239000007787 solid Substances 0.000 description 29
- 239000007858 starting material Substances 0.000 description 29
- 230000014759 maintenance of location Effects 0.000 description 28
- 239000000741 silica gel Substances 0.000 description 28
- 229910002027 silica gel Inorganic materials 0.000 description 28
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 26
- 239000008079 hexane Substances 0.000 description 24
- 239000010410 layer Substances 0.000 description 24
- 239000012295 chemical reaction liquid Substances 0.000 description 23
- 239000002585 base Substances 0.000 description 22
- QTBSBXVTEAMEQO-UHFFFAOYSA-M acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 20
- 239000012267 brine Substances 0.000 description 20
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 19
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 19
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 19
- 230000002829 reduced Effects 0.000 description 19
- 229910052739 hydrogen Inorganic materials 0.000 description 18
- 239000001257 hydrogen Substances 0.000 description 18
- AGGHKNBCHLWKHY-UHFFFAOYSA-N sodium;triacetyloxyboron(1-) Chemical compound [Na+].CC(=O)O[B-](OC(C)=O)OC(C)=O AGGHKNBCHLWKHY-UHFFFAOYSA-N 0.000 description 18
- 238000004440 column chromatography Methods 0.000 description 17
- IMNFDUFMRHMDMM-UHFFFAOYSA-N n-heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 17
- 238000010898 silica gel chromatography Methods 0.000 description 17
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 17
- OKKJLVBELUTLKV-MZCSYVLQSA-N cd3od Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 16
- 238000004128 high performance liquid chromatography Methods 0.000 description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 16
- PMZURENOXWZQFD-UHFFFAOYSA-L na2so4 Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 15
- 239000011734 sodium Substances 0.000 description 15
- 229910052938 sodium sulfate Inorganic materials 0.000 description 15
- 235000011152 sodium sulphate Nutrition 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- 239000012298 atmosphere Substances 0.000 description 13
- 210000004027 cells Anatomy 0.000 description 13
- 239000000706 filtrate Substances 0.000 description 13
- 239000012442 inert solvent Substances 0.000 description 13
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 13
- 235000019341 magnesium sulphate Nutrition 0.000 description 13
- 239000001184 potassium carbonate Substances 0.000 description 13
- 229910000027 potassium carbonate Inorganic materials 0.000 description 13
- 238000001816 cooling Methods 0.000 description 12
- 239000003480 eluent Substances 0.000 description 12
- 238000001914 filtration Methods 0.000 description 12
- 150000002500 ions Chemical class 0.000 description 12
- 239000007788 liquid Substances 0.000 description 12
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 11
- 239000003054 catalyst Substances 0.000 description 11
- 239000012043 crude product Substances 0.000 description 11
- 238000001514 detection method Methods 0.000 description 11
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 11
- 229910052708 sodium Inorganic materials 0.000 description 11
- 239000003795 chemical substances by application Substances 0.000 description 10
- MVFGXYPEQHIKIX-UHFFFAOYSA-M heptane;acetate Chemical compound CC([O-])=O.CCCCCCC MVFGXYPEQHIKIX-UHFFFAOYSA-M 0.000 description 10
- 239000012046 mixed solvent Substances 0.000 description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 10
- VIAFLMPQBHAMLI-UHFFFAOYSA-N PyBOP Chemical compound F[P-](F)(F)(F)(F)F.C1CCCN1[P+](N1CCCC1)(N1CCCC1)ON1C2=CC=CC=C2N=N1 VIAFLMPQBHAMLI-UHFFFAOYSA-N 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- 239000003153 chemical reaction reagent Substances 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- 238000010438 heat treatment Methods 0.000 description 9
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 9
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 9
- 235000017557 sodium bicarbonate Nutrition 0.000 description 9
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 8
- ZCSHNCUQKCANBX-UHFFFAOYSA-N Lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 8
- 235000019270 ammonium chloride Nutrition 0.000 description 8
- QDHHCQZDFGDHMP-UHFFFAOYSA-N monochloramine Chemical compound ClN QDHHCQZDFGDHMP-UHFFFAOYSA-N 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- DNUTZBZXLPWRJG-UHFFFAOYSA-M piperidine-1-carboxylate Chemical compound [O-]C(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-M 0.000 description 8
- 230000035484 reaction time Effects 0.000 description 8
- 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 7
- 102000014464 Chemokine CX3CL1 Human genes 0.000 description 7
- 108010078239 Chemokine CX3CL1 Proteins 0.000 description 7
- 230000000875 corresponding Effects 0.000 description 7
- 150000002170 ethers Chemical class 0.000 description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 7
- 239000000499 gel Substances 0.000 description 7
- 239000003638 reducing agent Substances 0.000 description 7
- BZLVMXJERCGZMT-UHFFFAOYSA-N MeOtBu Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- KXDHJXZQYSOELW-UHFFFAOYSA-M carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 238000006722 reduction reaction Methods 0.000 description 6
- GULMJNUJAVNDBJ-UHFFFAOYSA-N 2-methylpyrrolidine-1-carboxylic acid Chemical compound CC1CCCN1C(O)=O GULMJNUJAVNDBJ-UHFFFAOYSA-N 0.000 description 5
- HSDAJNMJOMSNEV-UHFFFAOYSA-N Benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 5
- 150000001298 alcohols Chemical class 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 5
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 5
- 238000010828 elution Methods 0.000 description 5
- 238000005984 hydrogenation reaction Methods 0.000 description 5
- 238000002372 labelling Methods 0.000 description 5
- 230000003287 optical Effects 0.000 description 5
- NQRYJNQNLNOLGT-UHFFFAOYSA-N piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 5
- 239000000377 silicon dioxide Substances 0.000 description 5
- 239000012453 solvate Substances 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N DMSO-d6 Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 4
- 239000011324 bead Substances 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 4
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- 238000007796 conventional method Methods 0.000 description 4
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- HEDRZPFGACZZDS-MICDWDOJSA-N deuterated chloroform Substances [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 229910052731 fluorine Inorganic materials 0.000 description 4
- 125000001153 fluoro group Chemical group F* 0.000 description 4
- 239000008187 granular material Substances 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
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- XLYOFNOQVPJJNP-ZSJDYOACSA-N water-d2 Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 4
- DMIYKWPEFRFTPY-UHFFFAOYSA-N 2,6-dichlorobenzaldehyde Chemical compound ClC1=CC=CC(Cl)=C1C=O DMIYKWPEFRFTPY-UHFFFAOYSA-N 0.000 description 3
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- 241000755093 Gaidropsarus vulgaris Species 0.000 description 3
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- PAAZCQANMCYGAW-UHFFFAOYSA-N acetic acid;2,2,2-trifluoroacetic acid Chemical compound CC(O)=O.OC(=O)C(F)(F)F PAAZCQANMCYGAW-UHFFFAOYSA-N 0.000 description 3
- ZCHPKWUIAASXPV-UHFFFAOYSA-N acetic acid;methanol Chemical compound OC.CC(O)=O ZCHPKWUIAASXPV-UHFFFAOYSA-N 0.000 description 3
- PKKRJRYNNXJYHB-UHFFFAOYSA-N acetyloxyboron(1-) Chemical compound [B-]OC(C)=O PKKRJRYNNXJYHB-UHFFFAOYSA-N 0.000 description 3
- 230000002378 acidificating Effects 0.000 description 3
- 125000005002 aryl methyl group Chemical group 0.000 description 3
- 125000004432 carbon atoms Chemical group C* 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
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- BCIIMDOZSUCSEN-UHFFFAOYSA-N piperidin-4-amine Chemical compound NC1CCNCC1 BCIIMDOZSUCSEN-UHFFFAOYSA-N 0.000 description 3
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- 238000000746 purification Methods 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
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- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- YONLFQNRGZXBBF-ZIAGYGMSSA-N (2R,3R)-2,3-dibenzoyloxybutanedioic acid Chemical compound O([C@@H](C(=O)O)[C@@H](OC(=O)C=1C=CC=CC=1)C(O)=O)C(=O)C1=CC=CC=C1 YONLFQNRGZXBBF-ZIAGYGMSSA-N 0.000 description 2
- AQJNUQPLURBSLI-JXFKEZNVSA-N (4-methoxyphenyl)methyl (3R,4R)-1-benzyl-4-methylpyrrolidine-3-carboxylate Chemical compound C1=CC(OC)=CC=C1COC(=O)[C@@H]1[C@@H](C)CN(CC=2C=CC=CC=2)C1 AQJNUQPLURBSLI-JXFKEZNVSA-N 0.000 description 2
- AQJNUQPLURBSLI-UHFFFAOYSA-N (4-methoxyphenyl)methyl 1-benzyl-4-methylpyrrolidine-3-carboxylate Chemical compound C1=CC(OC)=CC=C1COC(=O)C1C(C)CN(CC=2C=CC=CC=2)C1 AQJNUQPLURBSLI-UHFFFAOYSA-N 0.000 description 2
- PHLPLMANEZXGPM-UHFFFAOYSA-N 1-(2-fluoropentyl)piperidin-4-amine Chemical compound CCCC(F)CN1CCC(N)CC1 PHLPLMANEZXGPM-UHFFFAOYSA-N 0.000 description 2
- FPYUJUBAXZAQNL-UHFFFAOYSA-N 2-chlorobenzaldehyde Chemical compound ClC1=CC=CC=C1C=O FPYUJUBAXZAQNL-UHFFFAOYSA-N 0.000 description 2
- KLDLRDSRCMJKGM-UHFFFAOYSA-N 3-[chloro-(2-oxo-1,3-oxazolidin-3-yl)phosphoryl]-1,3-oxazolidin-2-one Chemical compound C1COC(=O)N1P(=O)(Cl)N1CCOC1=O KLDLRDSRCMJKGM-UHFFFAOYSA-N 0.000 description 2
- WULIZEOAYMSIHS-UHFFFAOYSA-N 4-chloro-5-methylpyrrolo[3,2-d]pyrimidine-6-carbaldehyde Chemical compound C1=NC(Cl)=C2N(C)C(C=O)=CC2=N1 WULIZEOAYMSIHS-UHFFFAOYSA-N 0.000 description 2
- FLYSYPZJEXSTBV-UHFFFAOYSA-N 4-methylpyrrolidin-1-ium-3-carboxylate Chemical compound CC1CNCC1C(O)=O FLYSYPZJEXSTBV-UHFFFAOYSA-N 0.000 description 2
- 229920000936 Agarose Polymers 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N Benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N Benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N Carbon tetrachloride Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
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- CROBTXVXNQNKKO-UHFFFAOYSA-N borohydride Chemical class [BH4-] CROBTXVXNQNKKO-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
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- 150000007942 carboxylates Chemical class 0.000 description 1
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- 229920003123 carboxymethyl cellulose sodium Polymers 0.000 description 1
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- 125000001162 cycloheptenyl group Chemical group C1(=CCCCCC1)* 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- PFURGBBHAOXLIO-UHFFFAOYSA-N cyclohexane-1,2-diol Chemical compound OC1CCCCC1O PFURGBBHAOXLIO-UHFFFAOYSA-N 0.000 description 1
- OANSOJSBHVENEI-UHFFFAOYSA-N cyclohexene-1-carbaldehyde Chemical compound O=CC1=CCCCC1 OANSOJSBHVENEI-UHFFFAOYSA-N 0.000 description 1
- 125000000522 cyclooctenyl group Chemical group C1(=CCCCCCC1)* 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000298 cyclopropenyl group Chemical group [H]C1=C([H])C1([H])* 0.000 description 1
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- 125000001295 dansyl group Chemical group [H]C1=C([H])C(N(C([H])([H])[H])C([H])([H])[H])=C2C([H])=C([H])C([H])=C(C2=C1[H])S(*)(=O)=O 0.000 description 1
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- ZWWWLCMDTZFSOO-UHFFFAOYSA-N diethoxyphosphorylformonitrile Chemical compound CCOP(=O)(C#N)OCC ZWWWLCMDTZFSOO-UHFFFAOYSA-N 0.000 description 1
- 150000005332 diethylamines Chemical class 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical compound OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 description 1
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- 150000002016 disaccharides Chemical class 0.000 description 1
- OPCPRUQQEJNFIV-UHFFFAOYSA-N disodium;cyanoboron(1-) Chemical compound [Na+].[Na+].[B-]C#N.[B-]C#N OPCPRUQQEJNFIV-UHFFFAOYSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
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- 238000006911 enzymatic reaction Methods 0.000 description 1
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- 125000004185 ester group Chemical group 0.000 description 1
- 239000010696 ester oil Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical class CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- PEZBJHXXIFFJBI-UHFFFAOYSA-N ethanol;phosphoric acid Chemical compound CCO.OP(O)(O)=O PEZBJHXXIFFJBI-UHFFFAOYSA-N 0.000 description 1
- CHDFNIZLAAFFPX-UHFFFAOYSA-N ethoxyethane;oxolane Chemical compound CCOCC.C1CCOC1 CHDFNIZLAAFFPX-UHFFFAOYSA-N 0.000 description 1
- HZZDWLBBNSDYQM-UHFFFAOYSA-N ethyl 4,4-difluorocyclohexane-1-carboxylate Chemical compound CCOC(=O)C1CCC(F)(F)CC1 HZZDWLBBNSDYQM-UHFFFAOYSA-N 0.000 description 1
- QUSNBJAOOMFDIB-UHFFFAOYSA-N ethyl amine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000007888 film coating Substances 0.000 description 1
- 238000009501 film coating Methods 0.000 description 1
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical group O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 238000001215 fluorescent labelling Methods 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N fumaric acid Chemical class OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 125000002791 glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 1
- 150000002306 glutamic acid derivatives Chemical class 0.000 description 1
- 230000020169 heat generation Effects 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- USZLCYNVCCDPLQ-UHFFFAOYSA-N hydron;N-methoxymethanamine;chloride Chemical compound Cl.CNOC USZLCYNVCCDPLQ-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxyl anion Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
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- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N iodine atom Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
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- 150000003893 lactate salts Chemical class 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
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- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- UGVPKMAWLOMPRS-UHFFFAOYSA-M magnesium;propane;bromide Chemical compound [Mg+2].[Br-].CC[CH2-] UGVPKMAWLOMPRS-UHFFFAOYSA-M 0.000 description 1
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- 238000001819 mass spectrum Methods 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- MCVVUJPXSBQTRZ-ONEGZZNKSA-N methyl (E)-but-2-enoate Chemical compound COC(=O)\C=C\C MCVVUJPXSBQTRZ-ONEGZZNKSA-N 0.000 description 1
- KLQYKJMMAPSQCP-UHFFFAOYSA-N methyl 1-benzyl-4-methylpyrrolidine-3-carboxylate Chemical compound C1C(C)C(C(=O)OC)CN1CC1=CC=CC=C1 KLQYKJMMAPSQCP-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- BAVYZALUXZFZLV-UHFFFAOYSA-N methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
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- 229960002216 methylparaben Drugs 0.000 description 1
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- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000007923 nasal drop Substances 0.000 description 1
- 239000006218 nasal suppository Substances 0.000 description 1
- 238000002610 neuroimaging Methods 0.000 description 1
- 230000001264 neutralization Effects 0.000 description 1
- PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N oxane Chemical group C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- LJCNRYVRMXRIQR-OLXYHTOASA-L potassium sodium L-tartrate Chemical compound [Na+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O LJCNRYVRMXRIQR-OLXYHTOASA-L 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propanol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 238000000163 radioactive labelling Methods 0.000 description 1
- 229910001426 radium ion Inorganic materials 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000002603 single-photon emission computed tomography Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- YOQDYZUWIQVZSF-UHFFFAOYSA-N sodium borohydride Substances [BH4-].[Na+] YOQDYZUWIQVZSF-UHFFFAOYSA-N 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 235000011006 sodium potassium tartrate Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- ODGROJYWQXFQOZ-UHFFFAOYSA-N sodium;boron(1-) Chemical compound [B-].[Na+] ODGROJYWQXFQOZ-UHFFFAOYSA-N 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-M stearate Chemical class CCCCCCCCCCCCCCCCCC([O-])=O QIQXTHQIDYTFRH-UHFFFAOYSA-M 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 125000006633 tert-butoxycarbonylamino group Chemical group 0.000 description 1
- LWDGWEFBTSUKPF-OYHNWAKOSA-N tert-butyl 4-[[(3S,4R)-4-methyl-3-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl]pyrrolidine-3-carbonyl]amino]piperidine-1-carboxylate Chemical compound C[C@H]1CNC[C@@]1(CC(=O)OC(C)(C)C)C(=O)NC1CCN(C(=O)OC(C)(C)C)CC1 LWDGWEFBTSUKPF-OYHNWAKOSA-N 0.000 description 1
- LZRDHSFPLUWYAX-UHFFFAOYSA-N tert-butyl 4-aminopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(N)CC1 LZRDHSFPLUWYAX-UHFFFAOYSA-N 0.000 description 1
- NUUWHVHHLRXUHZ-UHFFFAOYSA-N tert-butyl N-[1-[(4,4-difluorocyclohexyl)methyl]piperidin-4-yl]carbamate Chemical compound C1CC(NC(=O)OC(C)(C)C)CCN1CC1CCC(F)(F)CC1 NUUWHVHHLRXUHZ-UHFFFAOYSA-N 0.000 description 1
- CKXZPVPIDOJLLM-UHFFFAOYSA-N tert-butyl N-piperidin-4-ylcarbamate Chemical compound CC(C)(C)OC(=O)NC1CCNCC1 CKXZPVPIDOJLLM-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic Effects 0.000 description 1
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 1
- 229910001929 titanium oxide Inorganic materials 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical class CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 238000003325 tomography Methods 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N β-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- 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
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
Provided are pyrrolidine-3-yl-acetic acid derivative compounds, of the general formula (1), wherein the variables are as defined in the specification. Examples of the compounds include 2-[(3S,4R)-1-{[2-chloro-6-(trifluoromethyl)phenyl]methyl}-3-{[1-(2-fluoropentyl)piperidin-4-yl]carbamoyl}-4-methylpyrrolidin-3-yl]acetic acid and 2-[(3S,4R)-3-{[(3S)-1-(cyclohex-1-en-1-ylmethyl)pyrrolidin-3-yl]carbamoyl}-1-[(2,6-dichlorophenyl)methyl]-4-methylpyrrolidin-3-yl]acetic acid. The compounds are inhibitors of the fractalkine-CX3CR1 pathway. The compounds may be useful in the treatment of inflammatory bowel diseases, such as ulcerative colitis and Crohn’s disease. yrrolidin-3-yl]acetic acid and 2-[(3S,4R)-3-{[(3S)-1-(cyclohex-1-en-1-ylmethyl)pyrrolidin-3-yl]carbamoyl}-1-[(2,6-dichlorophenyl)methyl]-4-methylpyrrolidin-3-yl]acetic acid. The compounds are inhibitors of the fractalkine-CX3CR1 pathway. The compounds may be useful in the treatment of inflammatory bowel diseases, such as ulcerative colitis and Crohn’s disease.
Description
FP11-0417
DESCRIPTION
Title ofInvention
PYRROLIDlNEYLACETICACID DERIVATIVE
cal Field
The present invention relates to a pyrrolidin—3-ylacetic acid derivative. More
particularly, the present invention relates to a pyrrolidin—3-ylacetic acid derivative having
availability as a therapeutic agent for inflammatory bowel disease.
BackgroundArt
Chemokines are major cell migration factors and regulate infiltration of
1’0 lymphOcytes into tissues through the ement of cell nt and the tion of
adhesion molecules. Chemokines are classified into four subfamilies of CC, CXC, C and
CX3C based on their sequences ofthe first two ne residues.
Fractalkine is the sole CX3C chemokine member and has distinct characteristics in
its structure and fimctions which are not found in other Chemokines. Fractalkine binds to a
receptor, CX3CR1, which can mediate strong adhesion without mediation of selectin or
integrin even in the presence of a physiological blood flow. This means that the fiactalkine—
CX3CR1 system mediates multi-stage infiltration mechanism through selectin or integrin by
only a one—stage reaction.
sion of fiactalkine on vascular endothelial cells is induced by inflammatory
cytokines TNF and IL-1. On the other hand, CX3CR1 is expressed on monocytes, almost
all NK cells and some T cells, but is not expressed on neutrophils. Therefore, the fiactalkine—
CX3CR1 system is considered to be an extremely effective mechanism to mobilize immune
cells onto the endothelial cells ofdamaged tissues or into the tissues.
\Vith regard to the relation between the fiactalldne—CXBCRI system and
“pathologies, it is suggested that the fiactalkine—CXBCRI system is involved in the
development and pathologies of autoimmune diseases such as rheumatoid arthritis,
atory bowel disease, lupus tis and multiple sclerosis (Non Patent Literature 1).
In ular, with regard to inflammatory bowel disease, it is reported that expression of
fractalkine is enhanced at inflammatory sites of colonic tissues ents and that CX3CR1
plays an important role in the infiltration of immune cells into the colon tissue (Non Patent
ture 2).
Antibodies bed in Patent Literature 1 and low molecular weight nds
described in Patent Literatures 2 to 6 have been previously known as fractalldne inhibitors.
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In addition, compounds described in Patent Literature 7 are described to be useful
as ine CCR2 receptor nists, but dilfer in the target chemokine family from
such inhibitors.
Citation List
Patent Literature
Patent Literature 1 : Japanese Patent Application Laid-Open Publication No. 2002-345454
Patent Literature 2:
Patent Literature 3:
Patent Literature 4:
Patent Literature 5:
Patent Literature 6: WC 2009/120140
Patent Literature 7: US. Patent Application Laid~0pen PublicationNo. 2010/0210633
Non Patent Literature
[0009]
Non Patent Literature 1: Umehara et a1., "Fractalkine in Vascular Biology", Arterioscler.
Thromb. Vasc. Biol, Vol. 24, pp. 34—40, 2004
Non Patent ture 2: Kobayashi et al., "Exclusive Increase of CX3CR1_CD28_CD4_ T
Cells in Inflammatory Bowel Disease and Their Recruitment as Intraepithelial
Lymphocytes", Inflamm. Bowel. Dis, Vol. 13, pp. 837—846, 2007
y ofInvention
Technical Problem
An object of the present invention is to provide a nd having an tory
efi‘ect in the fractalkine—CX3CR1 pathway.
Solution to Problem
As a result of intensive studies, the present inventors have found the present
invention Specifically, the present ion relates to
A compound represented by formula (1) or pharmaceutically acceptable salt
[Chemical Formula 1]
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wherein R represents a C16 alkyl group unsubstituted or having 1 to 3 substituents selected
from Substituent Group A, a C33 lkyl group unsubstituted or having 1 to 3 substituents
ed from Substituent Group A, or a C33 cycloalkenyl group unsubstituted or having 1 to
3 substituents selectedfiom SubstituentG’roup A,
X represents a C16 alkyl group,
Y and Z are the same or nt from each other and each represents a halogen atom or a
C16 alkyl group unsubstituted or having 1 to 3 substituents selected from Substituent Group
n represents 0 or 1,
Substituent GroupA consists ofhalogen atoms, and
Substituent Group B consists ofhalogen atoms;
The nd or pharmaceutically acceptable salt thereof according to [1],
wherein R is a fluorobutyl group, a pentyl group, a cyclohexyl group, a difluorocyclohexyl
group, a cyclopentenyl group or a cyclohexenyl group;
The compound or pharmaceutically acceptable salt thereof according to [1] or [2],
whereinX is amethyl group;
The compound or pharmaceutically acceptable salt faccording to any one of
to [3], wherein Y is a chlorine atom;
[5] The compound or pharmaceutically acceptable salt thereofaccording to any one of
to [4], wherein Z is a ne atom, a methyl group, a difluoromethyl group or a
trifluoromethyl group;
The compound or phannaceutically acceptable salt thereof according to any one of
to [5], whereinnis l;
[7] Acompound selected from the group consisting of:
2-[(3S,4R){[2-chloro(uifluoromethyl)phenyl]methyl}-3—{[1-(2-fluoropentyl)piperidin—
4-yl]carbamoyl}—4-mefl1ylpyrrolidin—3-yl]acetic acid,
,4R)—1-[(2,6-dichlorophenyl)methyl]-3—({ 1-[(4,4-difluorocyclohexyl)methyl]piperidin—
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4-yl}carbamoyl)-4—methylpyrrolidin—3~yl]acetic acid,
,4R)-l-{[2-chloro(11ifluoromethyl)phenyl]methyl}{[l-(cyclohex-l-en-lylmethyl
)piperidin—4—yl]carbamoyl}methylpyrrolidin—3~yl]acetic acid,
2—[(3S,4R)~l-[(2—chloromethylphenyl)methyl]{[l—(cycloheX-1—en—1-
ylmethyl)piperidin—4—yl]carbamoyl}—4—methylpyrrolidin—3-y1]acetic acid,
2-[(3S,4R)—1—{[Z-chloro-6—(trifluoromethyl)phenyl]methyl}{[l-(cyclopent—l-en—l—
yhnethyl)piperidin—4-yl]carbamoyl}—4—methylpyrrolidinyl]acetic acid,
2-[(3S,4R)[(2-chloromethylphenyl)methy1]—3-{[(1 -cyclopent—1-en—l-
ylmethyl)piperidin—4—yl]carbamoyl}—4—methylpyrrolidin~3~yl]acetic acid,
2-[(3S,4R)—(3—{[(3S)—1~(cyclohex~l-en—l~ylmethyl)pyrrolidin~3~yl]carbamoyl}~1-[(2,6-
dichlorophenyl)methy1]—4-methy1pyrrolidin—3-yl]acetic acid,
2—[(3S,4R)—l-{[2-chloro—6—(difluorometliyl)phenyl]mefl1yl}[(1—hexylpiperidin—4—
bamoyl]-4—methylpyrrolidin—3—yl]acetic acid,
2—[(3S,4R){[(l -cyclohex-1~en-l~ylmethyl)pipexidin—4-yl]carbamoyl}-l{(2,6-
dichlorophenyl)methyl]methylpyrrolidinyl]acetic acid,
2-[(3S,4R)—l-{[2-chloro(difluoromethyl)phenyl]methyl}{[1-(cyclohex—1-en—1-
yl)piperidin—4-y1]carbamoyl}-4—methylpy1rolidinyl]acetic acid,
2—[(3S,4R)—l-{[2—chloro(difluoromethyl)phenyl]methyl}—3—{[l-(cyclopent—l—en—l—
ylmethyl)piperidin—4—yl]carbamoyl}—4—methylpy1rolidin—3—yl]acetic acid and
2-[(3S,4R)-l—{[2-chloro-6{difluoromethprhenyflmethyl}{»[1—
(cyclohexyhnethyl)piperidin—4-yl]carbamoyl}—4—methy1pyrrolidin—3-yl]acetic acid,
or a pharmaceutically acceptable salt thereof;
A medicine comprising the compound or pharmaceutically acceptable salt thereof
according to any one of [l] to [7] as an active ient;
[9] A therapeutic agent for inflammatory bowel disease comprising the compound or
pharmaceutically acceptable salt thereof according to any one of [1] to [7] as an active
ingredient;
The therapeutic agent according to [9], wherein the inflammatory bowel disease is
ulcerative colitis or Crohn's e; '
[l l] A kine—CX3CR1 pathway inhibitor comprising the nd or
pharmaceutically acceptable salt thereof according to any one of [1] to [7] as an active
ingredient;
A fractalkine inhibitor comprising the compound or phannaceutically acceptable
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salt thereofaccording to any one of [1] to [7] as an active ingredient;
A CX3CR1 inhibitor sing the compound or pharmaceutically acceptable
salt thereofaccording to any one of [1] to [7] as an active ingredient;
A method for treating inflammatory bowel disease comprising administering the
compound or pharmaceutically acceptable salt thereof according to any one of [1] to [7] to a
patient;
The method according to [14], wherein the inflammatory bowel disease is
ulcerative s or Crohn's disease;
A method for ting the fiactalldne—CDBCR1 pathway comprising
administering the compound or pharrnaceutically able salt thereof according to any
one of [1] to [7] to apatient;
A method for inhibiting lkine comprising administering the compound or
pharmaceutically acceptable salt thereofaccording to any one of [1] to [7] to a patient;
A method for inhibiting CX3CR1 comprising administering the compound or
phannaceutically acceptable salt thereofaccording to any one of [1] to [7] to a patient;
The compound or aceutically acceptable salt thereof according to any one of
to [7], which is used for the treatment ofinflammatory bowel disease;
The compound or pharrnaceutically acceptable salt thereof according to [19],
wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease;
[21] The compoundor pharmaceutically acceptable salt thereof according to any one of
to [7], which is used for the inhibition ofthe lkine-CX3CR1 pathway;
The compound or ceutically acceptable salt thereofaccording to any one of
to [7], which is used for the inhibition offiactalkine;
The compound or pharmaceutically able salt thereof according to any one of
[1] to [7], which is used for the inhibition ofCX3CR1;
Use of the compound or pharmaceutically acceptable salt thereof according to any
one of [1] to [7] in the manufacture ofa therapeutic agent for inflammatory bowel disease;
The use ing to [24], wherein the inflammatory bowel disease is tive
colitis or Crohn's disease;
[26] Use ofthe nd or pharmaceutically acceptable salt thereof according to any
one of [1] to [7] in the manufacture ofa fiactalldne-CX3CR1 pathway inhibitor;
Use ofthe compound or pharrnaceuticaily acceptable salt thereof according to any
one of [1] to [7] in the manufacture ofa lkine inhibitor; and
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Use ofthe compound or phannaceutically acceptable salt thereof ing to any
one of [1] to [7] in the manufacture ofa CX3CR1 tor.
Advantageous Effects ofInvention
According to the results ofthe tests described below, the compounds according to
the present invention have an inhibitory efiect in the fiactalldne—CX3CR1 pathway.
Therefore, the compounds according to the present invention have availability as therapeutic
agents for inflammatory bowel e.
BriefDescription ofDrawings
FIG 1 shows a graph showing the results of Test Example 2 for the compounds of
Examples 3,6 and 11;
FIG 2 shows a graph showing the results of Test Example 2 for the compounds of
Examples 2, 7 and 8;
FIG 3 shows a graph showing the results of Test e 2 for the compounds of
es 1, 9 and 10; and
FIG 4 shows a graph showing the results of Test Example 2 for the compounds of
Examples 12, 13 and 14.
Description ofEmbodiments
The present invention will be described in detail below.
In the present specification, the present invention is not limited to a particular
crystal form but may include any one of l forms or mixtures thereof, although crystal
polymorphs may exist. The present invention also includes amorphous forms, and the
compounds according to the t invention include anhydrides, hydrates and solvates.
Hereinafter, the meanings of terms, symbols and the like described in the present
specification will be described, and the present invention will be bed in detail.
[0017] The "CM; alkyl group" in the present cation means a linear or branched alkyl
group having 1 to 6 carbon atoms, and examples include a methyl group, an ethyl group, a 1-
propyl group, a 2—propy1 group, a 2-methyl—1-propyl group, a 2-methyl—2—propyl group, a 1-
butyl group, a l group, a 1-pentyl group, a 2~penty1 group, a yl group, a 1-hexyl
group, a l group and a 3-hexyl group.
[0018] The "C33 cycloalkyl group" in the present specification means a monocyclic
saturated aliphatic hydrocarbon group having 3 to 8 carbon atoms, and examples include a
cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a
cycloheptyl group and a cyclooctyl group.
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The "ng cycloalkenyl group" in the t specification means a monocyclic
aliphatic hydrocarbon group having 3 to 8 carbon atoms and containing 1 to 4 double bonds
in the ring, and examples include a cyclopropenyl group, a cyclobutenyl group, a
cyclopentenyl group, a exenyl group, a cycloheptenyl group and a cyclooctenyl group.
The "halogen atom" in the present specification means a fluorine atom, a chlorine
atom, a bromine atom or an iodine atom.
R in the compound represented by formula (1) represents a C16 alkyl group
unsubstituted or having 1 to 3 substituents selected from Substituent Group A, a C33
cycloalkyl group unsubstituted or having 1 to 3 substituents selected from tuent Group
A, or a C34; cycloalkenyl group unsubstituted or having 1 to 3 ments ed from
Substituent Group A. Preferably, R represents a fluorobutyl group, a pentyl goup, a
cyclohexyl group, a difluorocyclohexyl group, a entenyl group or a cyclohexenyl
group.
X in the compound represented by formula (1) represents a C16 alkyl group.
Preferably, X represents a methyl group.
YandZ in the compound represented by formula (1) are the same or different from
each other and each represents a halogen atom or a C16 alkyl group unsubstituted or having 1
to 3 substituents selected from Substituent Group B. Preferably, Y represents a chlorine
atom. Preferably, Z represents a chlorine atom, a methyl group, a difluoromefliyl group or a
trifluoromethyl group.
n in the compound represented by formula (1) represents 0 or 1, and preferably
ents 1.
Substituent GroupA consists ofhalogen atoms, and is preferably a fluorine atom.
Substituent Group B consists ofhalogen atoms, and is preferably a fluorine atom, a
chlorine atom or a e atom, more ably a fluorine atom.
The "pharmaceutically acceptable sal " in the present specification is not
particularly limited insofar as it forms a salt with the compound represented by formula (1)
and is pharmaceutically acceptable, and es include inorganic acid salts, organic acid
salts, inorganic base salts, c base salts, and acidic or basic amino acid salts.
[0028] Preferred examples of inorganic acid salts include hydrochlorides, hydrobromides,
sulfates, nitrates and phosphates, and preferred examples of organic acid salts include
acetates, ates, fumarates, maleates, tes, citrates, lactates, stearates, benzoates,
mandelates, methanesulfonates, ethanesulfonates, p—toluenesulfonates and
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benzenesulfonates.
Preferred es ofinorganic base salts include alkali metal salts such as sodium
salts and potassium salts, ne earth metal salts such as calcium salts and ium
salts, aluminum salts and ammonium salts, and preferred examples of organic base salts
include diethylamine salts, diethanolamine salts, meglumine salts and N,N'—
dibenzylethylenediamine salts.
Preferred examples of acidic amino acid salts include aspartates and glutamates,
and red examples of basic amino acid salts include arginine salts, lysine salts and
ornithine salts.
[0031] The compound represented by formula (1) can be produced by the method
described below, and can also be produced by an improvement of the method described
below by those skilled in the art based on the common knowledge. However, the method
for producing the compound represented by formula (1) is not limited to these methods.
The compound represented by formula (1) (hereinafter also ed to as
Compound (1)) can be produced through Process A, Process B and Process C described
below in detail using an intermediate represented by formula (2) as a starting material.
cal Formula 2]
Process A Process B Process C
[In the scheme, R, X, Y, Z and n are as defined above]
[0033] The sequence ofthe respective ses may be changed as appropriate based on
the common knowledge of those skilled in the art. Each process may be followed by
purification methods known to the d in the art, or may progress to next process without
isolation and ation.
(Process A) Amidation
[Chemical Formula 3]
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Process A
0 ) R o
Xé /0 n qu/<
""< HN N—\
N )n
(2) (4)
in X, R and n are as defined above]
This process is a process of producing “Compound (4) by subjecting the carboxyl
group ofCompound (2) and the amino group ofCompound (3) to dehydration condensation
in an inert solvent in the ce ofa condensing agent and a base to form an amide bond.
The solvent used is not ularly limited insofar as it dissolves the starting
material to some degree and does not inhibit the reaction, and examples include amides such
as N,N-dimethylfonnamide, N,N—dimethy1acetamide and l-methylpyrrolidinone, ethers such
as teuahydrofinan, and sulfoxides such as dimethyl sulfoxide, with methylfonnamide
being preferred.
Examples of the condensing agent used include benzotriazol—l-
yloxyuis(pyrrolidino)phosphonium hexafluorophosphate (hereinafter called PyBOP), bis(2-
oxo-3—oxazolidinyl)phosphinic chloride (hereinafter called BOP-Cl), benzotn'azol—l-
yloxytris(dimethylamino)phosphonium hexafluorophosphate, 2-(benzottiazol—1—yl)—1,1,3,3-
tetramethyluronium hexafluorophosphate and diethyl cyanophosphate, with PyBOP or BOP—
Cl being preferred and PyBOP being most preferred.
Examples of the base used include triethylamine and diisopropylethylamine, with
triethylamine being preferred.
The reaction temperature varies depending on the starting material, solvent,
condensing agent and base, but is usually ~20°C to 100°C, preferably 0°C to 60°C.
The reaction time varies depending on the starting material, solvent, condensing
agent and base, but is y 30 s to five days, preferably one hour to three days.
(Process B) thylation
[Chemical Formula 4]
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Process B
[wherein R, X, Y, Z and n are as defined above, and W1 represents a halogen atom, an
alkylsulfonyloxy group or an arylsulfonyloxy group]
This process is a process of ing Compound (6) by reacting Compound (4)
with Compound (5) in an inert t in the presence ofa base.
The solvent used is not particularly limited insofar as it dissolves the starting
material to some degree and does not inhibit the reaction, and examples include amides such
as N,N—dimethylfonnamide, methylacetamide and l—methylpyrrolidinone, and
sulfoxides such as dimethyl sulfoxide, with methylformamide being preferred.
[0044] Examples of the base used include inorganic bases such as sodium carbonate and
potassium carbonate, with potassium carbonate being preferred.
The reaction temperature varies depending on the starting al, solvent and
base, but is usually -20°C to 100°C, preferably 0°C to 60°C.
The reaction time varies depending on the starting material, solvent and base, but is
usually 30 minutes to five days, preferably 1 to 24 hours.
(Process C) Elimination —butyl group
[Chemical Formula 5]
Process C
(6) CC (1)
[wherein R, X, Y, Z and n are as defined above]
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This process is a process of ing Compound (1) by reacting Compound (6)
with an acid in the absence ofa solvent or in an inert solvent.
The solvent used is not particularly limited insofar as it dissolves the ng
material to some degree and does not inhibit the reaction, and examples include halogenated
hydrocarbons such as dichloromethane and chloroform, toluene, dioxane, water and a mixed
solvent ofdioxane and water, with dichloromethane being preferred.
Examples ofthe acid used include carboxylic acids such as trifluoroacetic acid, and
inorganic acids such as hydrochloric acid, with trifluoroacetic acid being red.
The reaction temperature varies depending on the starting material, solvent and
acid, but is usually —20°C to 100°C, preferably 0°C to 40°C.
The reaction time varies depending on the starting material, solvent and acid, but is
usually 30 s to one day, preferably 1 to 12 hours.
A production method through Process D and Process F may also be used as
another method for producing Compound (1).
[0054] (Process D) Reductive amination
[Chemical Formula 6]
in X, Y and Z are as defined above]
This process is a process of producing Compound (8) by reacting Compound (2)
with Compound (7) and a reducing agent in an inert solvent in the presence or absence of an
acid.
The solvent used is not ularly limited insofar as it dissolves the starting
material to some degree and does not inhibit the reaction, and examples include ethers such
as tetrahydrofilran, and alcohols such as methanol and ethanol, with tetrahydrofiiran or
methanol being preferred.
Examples of the reducing agent used include borohydride compounds such as
sodium triacetoxyborohydride, sodium cyanoborohydride and sodium borohydride, with
sodium triacetoxyborohydride being preferred.
The acid may or may not be used in this process, and if used, the acid used is not
particularly limited insofar as it does not inhibit the reaction, and is preferably acetic acid.
The on temperature varies depending on the starting material, solvent,
reducing agent and acid, but is usually —20°C to 100°C, preferably 0°C to 60°C.
The on time varies ing on the starting material, t, ng agent
and acid, but is usually 30 minutes to five days, preferably 1 to 48‘hours.
Even when Compound (2) being the starting material forms a salt, the reaction can
be allowed to proceed by adding an organic amine such as triethylarnine in an amount ofone
or more lents to the amount ofthe carboxylic acid fonning the salt.
(Process E) Hydrogenation
Compound (4) in which the arylmethyl group is eliminated can be obtained by
subjecting Compound (6) obtained in the above Process B to hydrogenation reaction
Compound (4) can further be converted by Process B to Compound (6) to which an
arylmethyl group having a difiemnt substituent is added.
[Chemical Formula 7]
; Process 8
:;Q>n_\RProcess E X Wig?Xc. .../
HN N ”M:N:QN1R~——> HZ‘QL‘”NRN N
Z1 22
[wherein R, Z and n are as defined above, Y1 and Y2 have the same meaning as in Y above,
and Z1 and 22 have the same meaning as in Z above]
This process is a process of producing Compound (4) by reacting Compound (6)
with hydrogen in an inert solvent in the presence of a ion catalyst to remove the
arylmethyl group.
The solvent used is not ularly limited insofar as it dissolves the starting
material to some degree and does not inhibit the reaction, and examples include alcohols
such as methanol and ethanol, ethers such as tetrahydrofiiran, dioxane and dimethoxyethane,
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and organic acid esters such as ethyl acetate, with ethers, alcohols, organic acid esters or
mixed solvents thereofbeing preferred and methanol or ethanol being most red.
Examples ofthe reduction catalyst used include Pd/C, palladium hydroxide, Raney
nickel, platinum oxide and um black, with Pd/C or ium hydroxide being
red.
The on temperature varies depending on the starting material and solvent, but
is usually 0°C to 70°C, preferably 10°C to 50°C.
The reaction time varies depending on the starting material, solvent and reaction
temperature, but is usually 30 minutes to five days, preferably one to three days.
[0068] The hydrogen pressure during the reaction in the case of using the reduction
catalyst is usually 0.5 to 10 atm, preferably 1 to 5 atrn.
Typically, the nd obtained in this process can be used in the next process
only by filtering 011”the catalyst.
(Process F)
Compound (1) can also be obtained by Process F.
[Chemical Formula 8]
Process F
(F4)
(12)
[wherein R, X Y, Z and n are as defined above]
(Process F—1)Amidation
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This process is a s ofproducing Compound (11) by subjecting the carboxyl
group of nd (8) and the amino group of Compound (10) to dehydration
condensation and can be performed by a method similar to that ess A.
(Process F-2) Elimination oftert—butyl group and tert—butyloxycarbonyl group
This process is a process ofproducing nd (12) by reacting Compound (11)
with an acid and can be med by a method similar to that ofProcess C.
(Process F-3) Reductive amination
This process is a process ofproducing Compound (1) by reacting Compound (12)
with aldehyde compound (13) in the presence ofa reducing agent and can be performed by a
method similar to that ofProcess D.
Compounds (10) and (13) can be available as commercially available compounds,
or can be readily produced fiom commercially available compounds by methods usually
performed by those skilled in the art
(Process G)
Compound (2) can also be ed by Process G below.
[Chemical Formula 9]
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Process G
W2/\©\ (15) 0
¥0 0
X 0
racemic-(Z) (2)
[wherein X is as defined above, V ents a hydrogen atom or a methoxy group, and W2
ents a halogen atom]
(Process G—l) Esterification
This process is a process ofproducing Compound (16) by reacting Compound (14)
with Compound (15) in an inert solvent in the presence of a base. This process can be
performed according to s B.
(Process G—2) Cycloaddition
This process is a process ofproducing Compound (17) by reacting Compound (16)
with hoxymethyl)—N—(11irnethylsilylmethyl)benzylamine in an inert solvent in the
presence ofan acid
The solvent used is not particularly limited insofar as it dissolves the starting
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material to some degree and does not inhibit the on, and examples include ethers such
as ydrofinan, halogenated hydrocarbons such as dichloromethane and chloroform, and
ic hydrocarbons such as benzene and toluene, with dichloromethane and toluene and a
mixed solvent thereofbeing preferred.
The acid used may be any acid usually used by those skilled in the art and is
preferably roacetic acid.
(The reaction temperature varies depending on the starting material, solvent,
reducing agent and acid, but is usually ~20°C to 60°C, preferably 10°C to 40°C.
The reaction time varies ing on the starting material, solvent, reducing agent
and acid, but is usually 30 minutes to five days, preferably 1 to 24 hours.
The reaction may be exothermic, it is preferable to add N—(methoxymethyl)-N—
(trimethylsilyhnethyl)benzylamine dropwise While being careful about heat generation, after
nd (16), t and acid are mixed.
(Process G—3) Alkylation
This process is a process ofproducing Compound (1 8) by causing a base to act on
Compound (17) in an inert solvent and then ng with tert—butyl bromoacetate.
The solvent used is not particularly limited insofar as it dissolves the starting
material to some degree and does not inhibit the reaction, and examples include ethers such
as tetrahydrofuran and diethyl ether, aliphatic hydrocarbons such as , aromatic
2O hydrocarbons such as toluene, and mixed solvents thereof, with tetrahydrofinan and a mixed
solvent oftetrahydrofiiran and hexane being preferred.
Preferred examples ofthe base used include lithium salts oforganic amines such as
lithium diisopropylamide and lithium bis(trimethylsily1)arnide, with lithium
diisopropylamide and m bis(trimethylsilyl)amide being more preferred.
[0086] The on temperature varies depending on the starting material, solvent and
base, but is usually -100°C to 50°C, ably —80°C to 40°C, most preferably -80°C to —
70°C.
The reaction time varies depending on the starting material, t and base, but is
usually 30 minutes to five days, preferably 1 to 24 hours, most preferably 2 to 5 hours.
[0088] (Process G—4) Hydrogenation reaction
This process is a process of reacting Compound (18) with hydrogen in an inert
solvent in the presence ofa reduction catalyst to remove the benzyl group.
This process can be performed according to Process E above.
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(Process G—5) Chiral resolution
This process is a process of obtaining Compound (2) by subjecting a racemate of
Compound (2) to chiral resolution.
The solvent used for the mobile phase or sample charge in the resolution is not
particularly limited insofar as it dissolves the starting material to some degree and does not
have adverse efiecw on columns or samples, and examples include water, aqueous saline
solutions, alcohols such as methanol, ethanol and 2-propanol, hexane, acetonitrile,
tetrahydrofiiran, trifluoroacetic acid, diethylarnine, or mixed solvents thereof, with
acetonitrile, ethanol, or a mixed solvent nol and hexane being red.
[0092] Examples of the column used for the resolution include various commercially
ble columns for optical resolution, with CHIRALPAK AD—H, CHIRALPAK IA and
CHIRALCELOZ-H ctured by Daicel Chemical ries, Ltd. being preferred.
The column temperature during the resolution is preferably 10°C to 45°C.
(Process H)
Compound (3) used in s A or the like can also be produced by Process H
below.
[Chemical Formula 10]
Process H
.<_ o (:R ~<O- o
0—5N m HZNCF}?
“‘4'
NH m” ‘\
in H4 )n R H—2 n
(19) (20)
[wherein R and n are as defined above]
[0095] (Process H—l) Reductive ion
This process is a process ofproducing Compound (20) by reacting Compound (19)
with Compound (1 3) in the presence ofa ng agent in an inert solvent in the presence or
absence ofan acid and can be performed according to Process D.
(Process H—2) Elimination oftert—butyloxycarbonyl group
This process is a process ofproducing Compound (3) by ng Compound (20)
with an acid in the absence of a solvent or in an inert solvent to remove the tert-
butyloxycarbonyl group and can be performed according to Process C.
(Process 1)
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Compound (2) can also be produced by Process I below using a te of
Compound (2) as a starting material.
[Chemical Formula 11]
Process I
o >40
yo V o
0 X 0
x o
X 0 l 1
OH N
ii 0A0 ©Ao/ko
racemic-(Z) V
(21) (22)
chiral—(22)
inX andV are as defined above]
(Process I—l) Introduction ofbenzyloxycarbonyl group
This process is a process of reacting a racemate of Compound (2) with benzyl
chlorofonnate in an inert t in the presence of a base to uce a benzyloxycarbonyl
group.
[0099] The solvent used is not particularly limited insofar as it dissolves the starting
material to some degree and does not inhibit the reaction, and es include ethers such
as tetrahydrofiiran and 1,4-dioxane, water, N,N—dimethylformamide, dichloromethane,
acetone and mixed solvents thereof, with a mixed solvent of water and acetone being
preferred.
[0100] Examples of the base used include inorganic bases such as sodium hydroxide,
potassium hydroxide, sodium bicarbonate, sodium carbonate and potassium carbonate, and
c amines such as methylamine and diisopropylethylamine, with sodium hydroxide
being preferred.
The reaction temperature varies depending on the starting al, solvent and
base, but is usually -30°C to 20°C, preferably -10°C to 15°C.
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The reaction time varies depending on the starting material, t and base, but is
usually 30 minutes to five days, preferably 1 to 24 hours.
(Process I-2) Esterification reaction
This process is a process ofproducing Compound (22) by reacting Compound (21)
with benzyl halide in an inert t in the ce of a base. This process can be
performed according to Process B.
‘ (Process 1—3) Chiral resolution
This process is a s of obtaining a chiral form of Compound (22) by
subjecting Compound (22) to chiral resolution. This process can be performed according to
Process GS.
(Process 1-4) Hydrogenation reaction
This s is a process ofobtaining Compound (2) by reacting the chiral form of
Compound (22) with hydrogen in an inert solvent in the presence of a reduction catalyst.
This process can be performed according to Process E.
[0106] (Process J)
nd (2) can also be produced by Process J below using Compound (1 8) as a
starting material.
[Chemical Formula 12]
>40 >1o >4o
0 0 0
x 0 x 0
M +2 xfl
' ...../<0
o ____. o o
N N N
(>2 2 \> ©Ao’go 2 \> ©Ao’go 2 \>
V V V
chiral—(22)
(18) (22)
[whereinX andV have the same meaning as above]
(Process J- 1) Introduction ofbenzyloxycarbonyl group
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This process is a process ining Compound (22) by reacting Compound (18)
with benzyl chloroformate in an inert solvent to replace the benzyl group with a
benzyloxycarbonyl group.
The solvent used is not particularly limited r as it dissolves the starting
material to some degree and does not inhibit the reaction, and examples include
tetrahydrofuran, toluene, dichloromethane, chloroform and mixed solvents thereof, with
dichloromethane being preferred.
The reaction temperature varies depending on the starting material and solvent, but
is usually ~20°C to 60°C, preferably 0°C to 40°C.
[0110] The reactiOn time varies depending on the starting material and solvent, but is
usually 30 minutes to five days, preferably 1 to 24 hours.
(Process J—2) Chiral resolution
This process is a process of obtaining a chiral form of Compound (22) by
subjecting Compound (22) to chiral resolution. This s can be performed according to
Process G—S.
(Process J—3) Hydrogenation reaction
This process is a process ofobtaining Compound (2) by reacting the chiral form of
nd (22) with hydrogen in an inert solvent in the presence of a reduction catalyst.
This process can be performed according to Process E.
[0113] After completion of the reaction in each process of each method described above,
the target compound in each process can be collected fiom the reaction e according to
a tional method.
For e, when the Whole reaction mixture is a liquid, the reaction mixture is
cooled to room temperature or cooled with ice as desired, and neutralized with an acid, alkali,
ing agent or reducing agent as appropriate, an organic solvent immiscible with water
and not ve with the target nd such as ethyl acetate is added, and the layer
containing the target compound is separated. Next, a solvent immiscible with the resulting
layer and not reactive with the target compound is added, the layer containing the target
compound is washed, and the layer is separated. Moreover, when the layer is an organic
layer, the target compound can be ted by drying with a drying agent such as anhydrous
magnesium sulfate or ous sodium sulfate and ling ofi" the solvent. When the
layer is an aqueous layer, the target compound can be collected by electrically demineralizing
and then lyophilizing the layer.
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In addition, when the whole reaction mixture is a liquid and if le, the target
compound can be collected only by distilling off substances other than the target nd
(such as a solvent or a reagent) under normal pressure or reduced pressure.
Further, when only the target compound is precipitated as a solid, or when the
whole reaction mixture described above is a liquid and only the target nd is
precipitated in the course of collection, the target compound can be further ted by
collecting the target compound by filtration first, washing the target compound collected by
filtration with an appropriate c or inorganic solvent and drying, such that the mother
liquor is treated in a manner similar to the case where the whole reaction mixture described
above is‘a liquid.
Still r, when only the reagent or catalyst is present as a solid, or the whole
reaction mixture described above is a liquid and only the reagent or catalyst is precipitated as
a solid in the course of collection, and the target compound is dissolved in the solution, the
target compound can be collected by filtering off the reagent or st first, washing the
reagent or catalyst filtered offwith an appropriate organic or inorganic solvent, combining the
resulting washings with the mother liquor, and ng the resulting mixture in a manner
similar to the case where the whole reaction mixture described above is a liquid
In particular, when substances other than the target compound which are contained
in the reaction mixture do not inhibit the reaction in the next step, the reaction mixture may
also be used in the next step as is Without particularly isolating the target nd.
Recrystallization, various chromatography methods and distillation may be carried
out as riate in order to improve the purity of the target compound ted by the
above method.
Typically, when the collected target compound is a solid, the purity of the target
compound can be ed by recrystallization. In recrystallization, a single solvent or a
mixture of a plurality of solvents not reactive with the target compound may be used
Specifically, the target compound is first dissolved in one or more solvents not reactive with
the target compound at room temperature or under heating. The resulting mixture is cooled
with ice water or the like or is stirred or left to stand at room temperature, such that the target
compound can be crystallized fiom the mixture.
The purity of the collected target compound can be ed by various
chromatography methods. Generally, it is possible to use weak acidic silica gels such as
Silica gel 60 manufactured by Merck KGaA (70-230 mesh or 340—400 mesh) and BW—300
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manufactured by Fuji Silysia Chemical Ltd. (300 mesh). When the target compound is
basic and is adsorbed onto the above silica gels too strongly, it is also possible to use NH
silica gels such as propylarnine coated silica gel manufactured by Fuji Silysia Chemical Ltd.
(200—350 mesh) and disposable medium pressure preparative packed column manufactured
by Yamazen Corporation (Hi—Flash Amino). When the target compound is dipolar or must
be eluted with a more polar solvent such as methanol, for example, it is also possible to use
NAM-200H or NAM-300H manufactured by NAM Laboratory or YMC "GEL ODS—A
manufactured by YMC Co. Ltd. It is also possible to use disposable medium pressure
preparative packed columns as bed above that are previously packed with fillers and
manufactured by Yamaze’n 'CorpOration, Wako Pure Chemical Industries, Ltd., Biotage AB
or W. R Grace & Co. (Hi-Flash Amino). The target compound whose purity is improved
can be obtained by eluting the target compound with one or more solvents not ve with
the target compound using these silica gels, and distilling offthe solvent(s).
When the ted target compound is a liquid, the purity ofthe target compound
can also be improved by distillation. In distillation, the target compound can be distilled out
by subjecting the target compound to reduced pressure at room ature or under heating.
Representative es of the method for producing Compound (1) have been
described above. Raw material compounds and various reagents in the production of
Compound (1) may form salts or solvates such as hydrates, all vary depending on the ng
al, the solvent used or the like, and are not particularly limited insofar as they do not
inhibit the reaction. Also, the solvent used varies depending on the ng al, the
reagent or the like, and is not particularly limited insofar as it does not inhibit the reaction and
dissolves the starting material to some degree, sly. When Compounds (1) are
obtained as free forms, they can be converted to salts that may be formed by nds (1)
or solvates ofthe compounds or salts by conventional methods.
When Compounds (1) are obtained as salts or solvates, they can be converted to
free forms ofCompounds (1) by conventional s.
Various isomers obtained for Compounds (1) (such as geometric isomers, optical
isomers, rotarners, stereoisomers and tautomers) can be purified and isolated using common
3O separation means, for example, recrystallization, reomeric salt ion, enzymatic
resolution and various chromatography methods (such as thin layer tography, column
chromatography and. gas chromatography).
Compounds (1) or pharmaceutically acceptable salts thereof can be formulated by
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conventional methods, and examples of dosage forms include oral formulations (such as
tablets, granules, powders, capsules and syrups), injections (for intravenous administration,
intramuscular administration, subcutaneous administration and intraperitoneal
administration) and external ations (such as tiansderrnal absorption formulations (such
as ointments and patches), ophthalmic preparations, nasal ations and suppositories).
These solid formulations such as tablets, capsules, granules and powders may
contain usually 0.001 to 99.5 wt%, preferably 0.01 to 90 wt% or the like, ofCompounds (1)
or phannaceutically acceptable salts thereof.
When oral solid formulations are manufactured, tablets, granules, powders and
capsules can be prepared by adding diluents, binders, disintegrants, lubricants, colorants or
the like to compounds (1) or pharrnaceutically acceptable salts thereof as necessary and
treating by tional methods. Tablets, granules, s, capsules and the like may
also be film coated as necessary.
es of diluents include lactose, corn starch and microcrystalline cellulose,
examples ofbinders include hydroxypropylcellulose and hydroxypropylmethylcellulose, and
examples of disintegrants e carboxymethylcellulose m and nnellose
sodium.
Examples of lubricants include magnesium stearate and calcium stearate, and
examples ofcolorants include titanium oxide.
[0131] Examples of film coating agents include hydroxypropylcellulose,
ypropylmethylcellulose and cellulose.
Any excipients described above are not limited to these examples, obviously.
When injections (for intravenous administration, intramuscular administration,
subcutaneous administration and intraperitoneal administration) are manufactured, they can
be ctured by adding pH adjusters, buifers, suspending agents, solubilizing agents,
antioxidants, preservatives (antiseptics), tonicity adjusting agents or the like to nds
(1) or phannaceutically acceptable salts thereof as necessary and ng by conventional
methods. Lyophilized formulations to be ved before use may also be prepared by
lyophilization. These injections can be administered intravenously, subcutaneously and
intramuscularly, for example.
es of pH adjusters and buflem include c acids or inorganic acids
and/or salts thereof, examples of suspending agents include methylcellulose, polysorbate 80
and carboxymethylcellulose sodium, examples of solubilizing agents include polysorbate 80
FP11—0417
and polyoxyethylene sorbitan monolaurate, examples of idants include or-tocopherol,
examples of preservatives include methyl parahydroxybenzoate and ethyl
droxybenzoate, and examples of tonicity adjusting agents include glucose, sodium
chloride and tol; however, the excipients are not limited to these es, obviously.
These injections may contain usually 0.000001 to 99.5 wt%, preferably 0.00001 to
90 wt% or the like, ofCompounds (1) or pharrnaceutically acceptable salts thereof.
"ii/When external formulations are manufactured, transdermal absorption
ations (such as ointments and patches), eye drops, nasal drops, suppositories and the
like can be manufactured by adding base materials and, as necessary, the fiers,
preservatives, pH ers, colorants and the like described above to nds (1) or
pharmaceutically acceptable salts thereof, and treating by conventional methods.
s raw materials tionally used for pharmaceuticals, quasi drugs,
ics and the like can be used as base materials, and examples include raw materials
such as animal and vegetable oils, mineral oils, ester oils, waxes, higher alcohols and purified
water.
These external formulations may contain usually 0.000001 to 99.5 wt%, preferably
0.00001 to 90 wt% or the like, of Compounds (1) or pharrnaceutically acceptable salts
thereof.
The dosage of the medicine according to the present invention typically varies
depending on the symptom, age, sex, weight or the like, but is acceptable if it is a dosage
sufficient to produce a desired elfect. For example, for an adult, a dosage of about 0.1 to
5000 mg (preferably 0.5 to 1000 mg, more preferably 1 to 600 mg) per day is used in one
dose during one or more days or in 2 to 6 divided doses for one day.
The present invention also include isotopically labeled Compounds (1), and such
compounds are the same as Compounds (1), except that one or more atoms are replaced with
an atom(s) having an atomic mass or mass number different fiom an atomic mass or mass
number commonly found in nature. Isotopes that can be incorporated into Compounds (1)
are es of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluoride, iodine and
chlorine, for example, and include 2H, 3H, 11C, 14C, 13N, 15O, 18F, 32F, 35S, 123I and 1251.
[0141] nds (1) ning the above—described isotopes and/or other isotopes or
pharmaceutically acceptable derivatives thereof (such as salts) fall within the claims of the
present specification. The isotopically labeled compounds of the present invention, for
example, compounds into which radioisotopes such as H and/or 14C are incorporated, are
FP11—0417
useful for tissue distribution assays for medicines and/or substrates. 3H and 14C are
considered to be useful because oftheir ease in preparation and detection. Isotopes 11C and
18F are considered to be usefiil for PET ron emission tomography), an isotope 1251 is
considered to be useful for SPECT e photon emission computed aphy), and all
these es are useful for brain imaging. Replacement with heavier isotopes such as 2H
es certain therapeutic advantages such as an increase in the in vivo half-er due to
higher metabolic stability, or a reduction in the required dose, and is therefore considered to
be useful under certain circumstances. Isotopically labeled Compounds (1) can be
uniformly prepared by performing the procedures disclosed in the following schemes and/or
examples using readily available ically labeled reagents in place of non—"isotopica‘lly
labeled reagents.
Compounds (1) can be used as chemical probes to trap target proteins in bioactive
low molecular weight compounds. Specifically, Compound (1) can be converted to an
affinity chromatography probe, a photoafiinity probe or the like by introducing a labeling
group, a linker or the like into a moiety difiefing fiom a structural moiety essential for
expression of activity of the compound by a que bed in J. Mass Spectrum. Soc.
Jpn, Vol. 51, No. 5, 2003, pp. 492-498 orW0 2007/139149 or the like.
Examples of labeling groups, linkers or the like used for chemical probes include
groups shown in the group consisting of(l) to (5) below:
(1) protein labeling groups such as photoaflinity labeling groups (such as a benzoyl group, a
benzophenone group, an azido group, a carbonylazido group, a diaziridine group, an enone
group, a diazo group and a nitro group) and chemical alfinity groups (such as a ketone group
in which an oc-carbon atom is replaced with a halogen atom, a carbamoyl group, an ester
group, an alkylthio group, Michael receptors such as or,B-unsaturated ketones and esters, and
an oxirane group),
(2) cleavable linkers such as -S-S-, O-, monosaccharides (such as a glucose group and
a ose group) or disaccharides (such as e), and oligopeptide s cleavable by
enzymatic reaction,
(3) fishing tag groups such as biotin and a 3-(4,4-difluoro-5,7-dimethyl—4H—3a,4a—diaza—4—
bora—s—indacen—3-yl)propionyl group,
(4) detectable markers such as radiolabeling groups such as 1251, 32F, 3H and 14C; fluorescence
labeling groups such as fluorescein, rhodamine, dansyl, umbelliferone, 7-nitrofinazanyl and a
3—(4,4-difluoro—5,7-dimethyl—4H—3a,4a-dia2a—4—bora—s—indacen—3-yl)propionyl group;
FP11—0417
chemiluminescent groups such as luciferin and luminol; and heavy metal ions such as
lanthanoid metal ions and radium ions; or
(5) groups bound to solid phase carriers such as glass beads, glass beds, microfiter plates,
agarose beads, agarose beds, polystyrene beads, polystyrene beds, nylon beads and nylon
beds.
Probes prepared by introducing labeling groups or the like ed from the group
consisting of (1) to (5) above into Compounds (1) according to the method desCribed in the
above documents or the like can be used as chemical probes for identification of labeled
proteins useful for searching for novel drug targets, for example.
1'0 Examples
Compounds (1) can be produced by the s described in examples below, for
example, and the effects of Compounds (1) can be confirmed by the methods described in
test examples below. However, these methods are illustrative and the present invention is
not limited to the following specific examples in any case.
[0145] When deuterium oxide is used as a measurement solvent in 1H—NMR for
confirmation of the structures of compounds, the chemical shift of the spectrum of each
compound is shown as a value corrected with the chemical shift ofthe solvent residual peak
in deuterium oxide as 4.79.
(Example 1) Chiral form of ,4R)—1—{[2—chloro—6-
(trifluoromethyl)phenyl]methyl}{[1-(2~fluoropentyl)piperidin—4~yl]carbamoyl}~4-
methylpyrrolidin—3—yl]acetic acid
(Example 1a) tert—Butyl 4—{[(benzyloxy)carbonyl]amino}piperidine—1—carboxy1ate
tert—Butyl 4-aminopiperidine—1-carboxylate (10 g, 49.9 mmol), N,N-
diisopropylethylamine (26 ml, 149 mmol), benzyl chloroformate (8.5 ml, 59.5 mmol) and
dichloromethane (dehydrated) (300 ml) were mixed under ice—cooling. The resulting
mixture was stirred at room temperature for one hour. An aqueous ted sodium
bicarbonate on was added to the reaction mixture, which was extracted with
dichloromethane three times. The c layer was washed with brine and dried over
anhydrous sodium sulfate, and the solvent was distilled oif. The e was purified by
silica gel column chromatography a gel, elution solvent: ethyl e/heptane) to give
the title nd (13.1 g, yield 78.5%).
1H—NMR (400 MHz, CDC13) 5 ppm; .38 (2H, m), 1.45 (9H, s), 1.88-2.00 (2H, br),
2.80-2.94 (2H, br), 3.60-3.72 (1H, br), 3.92-4.10 (2H, br), 4.63-4.75 (1H, m), 5.09 (2H, s),
FP11-0417
.40 (5H, m).
(Example lb) Benzyl N—(piperidin—4-yl)carbamate
A mixture of tert-butyl 4-{[(benzyloxy)earbonyl]amino}piperidine—l-carboxylate
obtained in e la (13.1 g, 39.2 mmol), a 5 N aqueous hydrochloric acid solution (40
ml, 200 mmol) and methanol (40 ml) was stirred at room temperature for 23 hours. A 5 N
aqueous sodium hydroxide solution (40 ml) was added to the reaction mixture under ice-
cooling. “Water and the solvent were distilled on from the reaction e While the
mixture was azeotropically distilled with ethanol. l was added to the residue, the
insoluble matter was removed by filtration, and the filtrate was concentrated to give the title
compound (9.10 g, yield 99.1%).
1H—NMR (400 MHz, CDC13) 8 ppm; 1.31—1.42 (2H, m), 1.92—2.04 (2H, br), 2.70 (2H, d,
J=12 Hz), 3.10 (2H, d, J=12 Hz), 3.56-3.68 (1H, br), 4.72—4.81 (1H, br), 5.09 (2H, s), 7.26-
7.40 (5H, m).
(Example 1c) Chiral form ofbenzyl N—[1-(2-fluoropentyl)piperidin—4-yl]carbamate
(SS)-(-)—2,2,3-Trimethylbenzyl—4—imidazolidinone dichloroacetic acid (90 mg,
0.259 mmol), N—fluorobenzenesulfonimide (484 mg, 1.53 mmol), 2-propanol (0.4 ml) and
tetrahydrofuran (dehydrated) (3.6 ml) were mixed at room temperature. The on
mixture was cooled to —10°C, and pentanal (0.175 ml, 1.67 mmol) was then added, ed
by stirring for three hours and 20 minutes while naturally warming from —10°C to room
temperature. Benzyl N—(piperidin—4—yl)carbamate obtained in Example lb (304 mg, 1.3
mmol) and sodium triacetoxyborohydride (600 mg, 2.83 mmol) were added to the reaction
mixture, which was stirred at room temperature for 15 hours and 40 minutes. Water and an
aqueous sodium onate solution were added to the reaction mixture, the insoluble
matter was removed by filtration, and the resulting e was extracted with ethyl acetate
twice. The organic layer was washed with brine and dried over ous sodium sulfate,
and the solvent was distilled ofi". The e was purified by silica gel column
chromatography (silica gel, elution solvent: ethyl acetate/heptane) to give a chiral form
mixture ofthe title compound (44 mg, yield 10.5%).
1H—NMR (400 MHZ, CDC13) 5 ppm; 0.94 (3H, t, J=7 Hz), .70 (6H, m), 1.85-2.00 (2H,
br), 2.14-2.24 (2H, m), 2.35—2.48 (1H, m), 2.55—2.64 (1H, m), 2.80-3.00 (2H, m), 3.48-3.60
(1H, m), 4.59-4.72 (2H, m), 5.09 (2H, s), 7.26—7.37 (5H, m).
Optical resolution by HPLC
(Analysis conditions) Column: CHlRALPAK AD-H (manufactured by Daicel Chemical
FP11-0417
Industries, Ltd.) (0.46 cm diameter x 15 cm), eluent: hexane/ethanol = 9/1 (v/v), flow rate: 1
ml/mirr, detection: UV (210 nm)
(Analysis result) The resulting chiral form mixture was analyzed under the above analysis
conditions, and a peak with a retention time of 7.30 minutes (enantiomeric : 80% ee)
and apeak with a retention time of 8.28 minutes were observed.
Further two lots of the chiral form mixture were ed by a method similar to
the above method. Three lots in total ofthe chiral form mixture (451 mg, 1.4 mmol) were
dissolved in ethanol (18 ml) and optically resolved repeatedly under the following
onation conditions, and the peak with a shorter retention time was fiactionated to give
the title compound (3 1 8 mg).
(Fractionation conditions) Column: CHIRALPAK AD-H (manufactured by Daicel Chemical
ries, Ltd.) (2 cm er x 25 cm), eluent: hexane/ethanol = 9/1 (v/v), flow rate: 10
ml/min, detection: UV (220 nm)
1H—NMR (400 MHz, CDC13) 8 ppm; 0.94 (3H, t, J=7 Hz), 1.38-1.70 (6H, m), 1.85—2.00 (2H,
br), 2.14-2.24 (2H, m), 2.35-2.48 (1H, m), 2.55-2.64 (1H, m), 2.80-3.00 (2H, m), 3.48—3.60
(1H, m), .72 (2H, m), 5.09 (2H, s), 7.26—7.37 (5H, m).
The resulting title compound was analyzed under the above analysis conditions to
find that the retention time was 7.41 minutes and the enantiomeric excess was >99% ee.
(Example 1d) Chiral form of 1-(2-fluoropentyl)piperidin—4—amine
A mixture of the chiral form (with a shorter retention time) of benzyl N—[l—(2—
fluoropentyl)piperidin—4—yl]carbamate obtained in Example 10 (318 mg, 0.986 mmol), 10%
Pd/C (100 mg) and methanol (7 ml) was stirred at room temperature for two hours under a
hydrogen atmosphere. The atmosphere in the reaction vessel was replaced with nitrogen,
% Pd/C was d ofli and the solvent was distilled off to give the title nd (249
mg).
1H—NMR (400 MHz, CDC13) 5 ppm; 0.95 (3H, t, J=7 Hz), 1.35-1.70 (4H, m), 1.92-2.10 (2H,
br), 2.20-2.32 (2H, br), 2.48-2.62 (2H, br), 2.65-2.91 (2H, m), 3.18—3.30 (2H, br), 331—3 .42
(1H, br), 4.72—4.93 (1H, m).
(Example 1e) Benzyl (2E)-but—2-enoate
Crotonic acid (70 g, 812 mmol) was dissolved in N,N—dimethylfom1amide (467
ml), which was cooled in an ice bath under nitrogen, and potassium carbonate (61.6 g, 447
mmol) was added. Benzyl bromide (91.7 ml, 772 mmol) was added dropwise to the
reaction e over 20 minutes. The on mixture was stirred at room temperature for
FPll-0417
18 hours. Ethyl acetate was added to the reaction mixture, which was filtered through
Celite. The filtered ethyl acetate solution was washed with water, a saturated aqueous
sodium bicarbonate solution and a saturated aqueous sodium de solution. The organic
layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure to
give the title compound (142 g, yield: 99.4%).
1H—NMR (400 MHz, CDC13) 5 ppm; 1.87-1.90 (3H, m), 5.17 (2H, s), 5.87-5.92 (1H, m),
6.98-7.07 (1H, m), 7.26-7.39 (5H, m).
(Example If) Benzyl (3RS,4SR)~1—benzyl-4—methylpyrrolidinecarboxylate
Benzyl ut—2—enoate obtained in Example le (20.5 g, 116 mmol) was
ved in dichloromethane (5 ml), and the mixture was cooled in an ice bath with stirring.
Trifluoroacetic acid (257 til, 3.47 mmol) was added, and N~(methoxymethy1)-N—
(trimethylsilylmethyl)benzylamine (33.1 g, 139 mmol) was added dropwise to the reaction
liquid over 15 minutes so that the internal temperature did not exceed 62°C, while washing
with dichloromethane (25 ml). The reaction liquid was left to stand until it reached room
temperature and was stirred for 15 hours. The reaction liquid was concentrated and purified
by silica gel column chromatography (elution solvent: ethyl acetate/heptane) to give the title
compound (38 g).
1H—NMR (400 MHz, CDC13) 5 ppm; 1.14 (3H, d, J=6 Hz), 2.18-2.22 (1H, m), 2.48—2.65
(2H, m), 2.75—2.85 (2H, m), .94 (1H, m), 3.54-3.66 (2H, m), 5.13 (2H, s), 7.20—7.40
(10H, m).
(Example lg) Benzyl (3RS,4SR)benzyl—3—[2-(tert-butoxy)—2—oxoethyl]—4-
methylpyrrolidine—3-carboxylate
Benzyl (3RS,4SR)—1—benzy1—4—methylpyrrolidine~3—carboxy1ate obtained in
Example 1f(30 g, 97.4 mmol) was dissolved in tetrahydrofuran (300 rrrl), which was cooled
to -70°C with g under nitrogen A 1.11 M lithium diisopropylamide/n—hexane—
tetrahydrofiiran solution (105 mi, 116 mmol) was added dropvvise over 20 minutes so that
the internal temperature did not exceed ~64.3°C. The e was stirred at - 0°C for 1
hour, and tetrahydrofuran (30 ml) and utyl bromoacetate (26.6 g, 136 mmol) were then
added dropwise over 10 minutes so that the internal ature did not exceed -60°C. The
reaction mixture was stirred at -70°C for further one hour, and a saturated aqueous
um chloride solution was then added to the reaction e. Immediately
thereafter, flue reaction mixture was diluted with water and ethyl e was added. The
organic layer was washed with brine and a 5 N aqueous hydrochloric acid solution, and then
FP11-0417
dried over magnesium sulfate, filtered and concentrated. The e was purified by silica
gel column chromatography (elution solvent: ethyl acetate/heptane). The residue was
fiirther purified by NH silica gel column chromatography (elution solvent: heptane/ethyl
acetate = 98/2) to give the title compound (6 g, yield: 14.5%).
1H—NMR (400 MHz, CDC13) 5 ppm; 0.86 (3H, d, J=6 Hz), 1.34 (9H, s), 2.05—2.15 (2H, m),
2.53 (1H, d, J=17 Hz), .00 (3H, m), 3.28 (1H, d, J=10 Hz), 3.59-3.72 (2H, m), 5.08-
.16’(2H, m), 7.19—7.39 (10H, m).
By a similar method, 18.1 g ofthe title compound was obtained.
(Example 1h) 1,3—Dibenzyl '(3RS,4SR)[2-(tert-butoxy)oxoethyl]—4—
1‘0 methylpyrrolidine—l,3—dicarboxylate
Benzyl (3RS,4SR)benzyl[2-(tert—butoxy)—2—oxoethyl]—4-methylpyrrolidine—3-
carboxylate obtained in a manner similar to that in Example 1g (11.7 g, 27.6 mmol) was
dissolved in dichloromethane (117 ml), and benzyl chloroformate (23.7 ml, 166 mmol) was
added dropwise to the on liquid over 20 minutes so that the al temperature did not
exceed 22°C. The mixture was stirred at room temperature for 12 hours, and then solvent
was distilled ofi‘. The residue was purified by NH silica gel column chromatography
(elution solvent: ethyl acetate/heptane) to give the title compound (9.1 g, yield: 70.5%).
1H—NMR (400 MHZ, CDC13) 5 ppm; 0.84-0.90 (3H, m), 1.32—1.46 (9H, m), 2.09-2.16 (1H,
m), 2.21—2.27 (1H, m), 3.04—3.14 (2H, m), 3.33-3.38 (1H, m), 3.60-3.68 (1H, m), 4.32 (1H, t,
J=12 Hz), 507-5.20 (4H, m), 7.26-7.36 (10H, m).
Analysis by HPLC;
(Analysis conditions 1) Column: PAK AD-H (manufactured by Daicel al
Industries, Ltd.) (0.46 cm diameter x 15 cm), eluent: hexane/ethanol = 95/5 (v/v), flow rate: 1
ml/min., detection: UV (210 nm)
(Analysis result) The resulting title compound was analyzed under the above analysis
conditions 1, and a peak with a retention time of 8.56 s and a peak with a retention
time of 1085 minutes were observed.
The title compound separately obtained was analyzed in a chiral column different
from the above .
(Analysis ions 2) Column: CHIRALPAK IA (manufactured by Daicel Chemical
Industries, Ltd.) (0.46 cm diameter x 15 cm), : hexane/ethanol = 95/5 (V/v), flow rate: 1
ml/min, detection: UV (210 nm)
(Analysis result) The resulting title compound was analyzed under the above analysis
ions 2, and a peak with a retention time of 6.78 minutes and a peak with a retention
time of8.20 minutes were observed.
(Example 1i) )[2-(tert-Butoxy)-2—oxoethyl]methylpyrrolidine—3-
carboxylic acid
1,3-Dibenzy1 (3RS,4SR)[2-(tert—butoxy)—2-oxoethyl]—4-methy1pyrrolidine—1,3—
dicarboxylate ed in Example lb (9.1 g) was optically resolved repeatedly under the
following two types ofconditionsA or B.
Optical resolution by HPLC;
(Fractionation conditions A) Column: CHIRALPAK AD—H (manufactured by Daicel
Chemical Industries, Ltd.) (2 cm diameter x 25 cm), eluent: hexane/ethanol = 85/15 (V/V),
flow rate: 8—10 mI/min.
(Fractionation conditions B) Column: CHIRALPAK IA (manufactmed by Daicel Chemical
Industries, Ltd.) (3 cm diameter x 25 cm), eluent: hexane/ethanol = 95/5 (v/v), flow rate: 22
ml/min.
The peak with a shorter retention time was fractionated, and the resulting three lots
were then analyzed under the following is conditions.
Analysis by HPLC;
sis conditions) Column: CHIRALPAK AD—H (manufactured by Daicel Chemical
Industries, Ltd.) (0.46 cm diameter x 15 cm), eluent: hexane/ethanol = 95/5 (v/v), flow rate: 1
ml/min., detection: UV (210 nm)
(Analysis result) The retention time was 9.0 minutes to 9.3 s, and the enantiomeric
excess was >99% ee for all lots.
The three lots were combined, the resulting chiral form (4.04 g) was dissolved in
methanol (121 ml), 10% Pd/C (0.77 g) was added, and the atmosphere was replaced with
hydrogen gas. The mixture was stirred at room temperature for 13 hours and then stirred
with addition ofwarm water (30 to 40°C, 122 ml), and the precipitated solid was dissolved.-
Afier Pd/C was filtered off, the solvent was concentrated and dried to give the title nd
(2.1 g).
IR (400 MHz, D20) 5 ppm; 0.97 (3H, d, J=7 Hz), 1.42 (9H, s), 2.15-2.22 (1H, m),
2.30 (1H, d, J=17 Hz), 2.93 (1H, d, J=17 Hz), 3.04 (1H, t, J=12 Hz), 3.18 (1H, d, J=12 Hz),
3.49 (1H, dd, J=8, 12 Hz), 4.03 (1H, d, J=12 Hz).
(Example 1j) (3S,4R)Benzyl[2-(tert-butoxy)oxoethyl]-4—
methylpyrrolidine—3-carboxylic acid
FP11—0417
A mixture of (3S,4R)-3—[2-(tert-butoxy)—2—oxoethyl]~4—methylpyrrolidine—3-
carboxylic acid obtained in e 1i (1.8 g, 7.4 mmol), benzaldehyde (1.51 ml, 14.8
mmol), acetic acid (0.635 ml, 11.1 mmol), sodium toxyborohydride (3.14 g, 14.8
mmol) and methanol (35 ml) was heated at 40°C for 38 hours and 30 s. The
on mixture was concentrated, and the resulting residue was purified by silica gel
column chromatography (ODS silica gel, elution solvent: water/methanol) to give the title
compound as LotA (584 mg) and Lot B’(708 mg).
1H—NMR (400 MHz, CDC13) of Lot A 8 ppm; 1.02 (3H, d, J=7 Hz), 1.38 (9H, s),
2.14 (1H, d, J=17 Hz), 2.15-2.28 (1H, br), 2.97 (1H, d, J=17 Hz), 3.10—3.42 (3H, m), 4.00-
4.10 (1H, m), 4.30—4.40 (1H, br), 4.46 (1H, d, J=12 Hz), 7.45-7.53 (5H, m).
lH—NMR ofLot B: identical to NMR ofLotA.
(Example 1k) Chiral form of tert—butyl 2-[(3 S,4R)—1—benzyl—3~{[1—(2~
entyl)piperidin—4—yl]carbamoyl}—4—methylpyrrolidin—3—yl]aeetate
A e of (3S,4R)~1~benzyl—3-[2—(tert—butoxy)—2—oxoethyl]—4—
methylpyrrolidinecarboxylic acid obtained in Example 1j (300 mg, 0.9 mmol), the chiral
form of 1-(2-fluoropentyl)piperidin—4—amine obtained in Example 1d (182 mg, 0.967 mmol),
triethylamine (0.376 ml, 2.7 mmol), PyBOP (656 mg, 1.26 mmol) and N,N-
dimethylfonnamide (4.5 ml) was d at room temperature for 61 hours and 30 minutes.
Triethylamine (0.207 ml, 1.49 mmol) and PyBOP (360 mg, 0.69 mmol) were further added,
followed by stirring for four hours and 30 minutes. Water was added to the reaction
mixture, which was extracted with ethyl acetate twice. The organic layer was washed with
a saturated aqueous ammonium chloride solution and dried over ous magnesium
e, and the solvent was distilled off. The residue was purified by silica gel column
chromatography (NH silica gel, elution solvent: ethyl acetate/heptane) to give the title
compound (161 mg, yield 35.5%).
lH—NIVIR (400 MHz, CDC13) 8 ppm; 0.92 (3H, d, J=7 Hz), 0.96 (3H, t, J=7 Hz), 1.40 (9H, s),
1.40-1.60 (6H, m), 1.82—2.09 (4H, m), 2.16-2.28 (2H, m), 2.36 (1H, d, J=10 Hz), 2.35-2.50
(1H, m), 2.56-2.67 (3H, m), 2.80-2.90 (2H, br), 3.09 (1H, d, J=16 Hz), 3.58379 (4H, m),
4.59-4.80 (1H, m), 7.25—7.40 (5H, m), 8.58 (1H, d, J=8 Hz).
[0158] (Example 11) Chiral form of tert-butyl 2-[(3S,4R)—1-{[2-chloro—6—
(uifluoromethyl)phenyl]methyl}{[1-(2-fluoropentyl)piperidin—4-y1]carbamoyl}
methylpyrrolidinyl]acetate
A mixture of the chiral form of tert-butyl 2—[(3S,4R)-1—benzyl—3-{[1-(2—
FP11—0417
fluoropentyl)piperidin—4~yl]carbarnoyl}-4—methylpyrrolidin—3-yl]acetate obtained in
Example 1k (161 mg, 0.32 mrnol), 20% palladium hydroxide (135 mg) and methanol (5 ml)
was stirred at room ature for 15 hours under a hydrogen atmosphere. The
atmosphere in the reaction vessel was replaced with nitrogen, 20% palladium hydroxide was
filtered OE, and the solvent was distilled off. 2—(Bromomethyl)—1-chloro-3—
(trifluoromethyDbenzene (159 mg, 0.581 , ium carbonate (97 mg, 0.702 mmol)
and N,N-dimethylformamide (2 ml) were added to the ing residue, which was heated at
45°C for three hours and 15 minutes. Water was added to the reaction mixture, which was
extracted with ethyl acetate twice. The c layer was washed with a saturated aqueous
ammonium chloride solution and dried over anhydrous magnesium sulfate, and the solvent
was distilled ofi‘. The residue was d by silica gel column chromatography (NH silica
gel, elution solvent: ethyl acetate/heptane) to give the title compound (153 mg, yield 78.9%).
1H—NMR (400 MHz, CDC13) 8 ppm; 0.91 (3H, d, J=7 Hz), 0.95 (3H, t, J=7 Hz), 1.38~1.70
(7H, m), 1.39 (9H, s), 1.82-1.90 (1H, br), 1.97 (1H, d, J=16 Hz), 2.00—2.20 (3H, m), 2.31-
2.45 (1H, m), 2.50-2.68 (3H, m), 2.80-2.92 (3H, m), 3.12 (1H, d, J=16 Hz), 3.57 (1H, d, J=1O
Hz), 3.60—3.72 (1H, m), 3.92 (1H, d, J=13 Hz), 3.98 (1H, d, J=13 Hz), 4.56-4.74 (1H, m),
7.37 (1H, t, J=8 Hz), 7.61-7.68 (2H, m), 7.85 (1H, d, J=8 Hz).
(Example 1m) Chiral form of 2—[(3S,4R)—l—{[2-chloro
(trifluoromethyl)phenyl]methyl}{[l-(2-fluoropentyl)piperidin—4—yl]carbamoyl}—4—
methylpyrrolidin—3-y1]acetic acid
A mixture of the chiral form of tert—butyl 2-[(3S,4R)—1-{[2—chloro-6—
oromethyl)phenyl]methyl}-3—{[1-(2-fluoropentyl)piperidin—4—yl]carbamoyl}-4—
methylpyrrolidin—3-yl]acetate obtained in Example 11 (153 mg, 0.252 mmol), trifluoroacetic
acid (2 ml, 26.9 mmol) and dichloromethane (dehydrated) (2 ml) was stirred at room
temperature for two hours and 35 minutes. The reaction mixture was concentrated, and the
ing residue was purified by silica gel column tography (ODS silica gel, elution
t: water/methanol) to give the title compound (122 mg, yield 88%).
1H—NMR (400 MHz, CDC13) 8 ppm; 0.94—1.02 (6H, m), 1.32—1.70 (5H, m), 1.82-1.90 (1H,
br), 2.07-2.20 (3H, m), 2.35-2.75 (8H, m), 2.81-3.05 (3H, m), 3.19 (1H, d, J=10 Hz), 3.63-
3.75 (1H, m), 3.89 (1H, d, J=13 Hz), 4.00 (1H, d, J=13 Hz), 4.56-4.76 (1H, m), 7.40 (1H, t,
J=8 Hz), 7.62-7.70 (2H, m), 8.52 (1H, d, J=7 Hz).
(Example 2) 2—[(3S,4R)[(2,6-Dichloropheny1)methyl]({l-[(4,4-
difluorocyclohexyl)methyl]piperidin—4-yl}carbarnoyl)—4-methylpyrrolidin—3-yl]acetic acid
(Example 2a) 4,4-Difluoro—N—methoxy—N~methylcyclohexane—l-carboxamide
A mixture of ethyl 4,4-difluorocyclohexane-l-carboxylate (1.9 g, 9.88 mmol) and
tetrahydrofiiran (60 ml) was cooled to -70°C, and N,O-dimethylhydroxyamine
hydrochloride (1.44 g, 14.8 mmol) was added. r, 1.05 M n—propylmagnesium
bromide (24.2 ml, 25.2 mmol) was added dropwise to the reaction mixture at -55°C over five
minutes so that the internal temperature did not exceed -35°C, and the reaction mixture was
stirred at 0°C for 30 s. A saturated aqueous ammonium chloride solution was added
to the reaction mixture, which was extracted with ethyl acetate. The organic layer was dried
over magnesium sulfate, and the solvent was distilled otf. The residue was purified by
silica gel column chromatography (elution solvent: ethyl e/heptane) to give the title
compound (1.7 g, yield 83%).
1H—NMR (400 MHz, CDC13) 5 ppm; 1.65-1.95 (6H, br), 2.13—2.30 (2H, br), 2.70~2.82 (1H,
br), 3.20 (3H, s), 3.70 (3H, s).
(Example 2b) 4,4-Difluorocyclohexane—1~carba1dehyde
A mixture of 4,4—difluoro-N-methoxy—N—methylcyclohexane—1-carboxamide
obtained in e 2a (1.7 g, 8.21 mmol) and tetrahydrofinan (60 ml) was cooled to ~70°C,
a 1.0 M diisobutylaluminum hydride/toluene solution (9.85 ml, 9.85 mmol) was added, and
the reaction mixture was stirred at -60°C for 35 s. A 1.0 M diisobutylaluminum
hydride/toluene solution (5 ml, 5 mmol) was finther added at -65°C, and the reaction mixture
was stirred at —70°C for two hours. A2 N aqueous hydrochloric acid solution was added to
the reaction mixture, which was ted with ethyl acetate. The organic layer was dried
over magnesium sulfate, and the solvent was distilled off to give a crude t of the title
compound (1.4 g).
1H—NMR (400 MHz, CDC13) 5 ppm; 1.72-1.92 (4H, br), 1.95—2.18 (4H, br), 2.30-2.40 (1H,
br), 9.68 (1H, s).
(Example 20) tert-Butyl N—{1-[(4,4-difluorocyclohexyl)methyl]piperidin—4-
yl}carbamate
A mixture of the crude product of 4,4—difluorocyclohexane—1~carbaldehyde
obtained in Example 2b (1.4 g) and tetrahydrofiiran (100 ml) was cooled to 0°C, tert-butyl N-
(piperidin—4—yl)carbamate (2.27 g, 11.3mmol) was added thereto, followed by stirring for 20
minutes. Sodium triacetoxyborohydride (2.2 g, 10.4 mmol) was then added to the on
mixture, which was stirred at room temperature for eight hours. Brine was added to the
reaction mixture, which was extracted with ethyl acetate. The organic layer was dried over
FP11~0417
magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel
column chromatography (elution t: ethyl acetate/heptane). The resulting residue was
dissolved in ethyl acetate and washed with a saturated aqueous sodium bicarbonate solution,
and the solvent was then distilled ofito give the title compound (650 mg, yield 20.7%).
1H—NMR (400 MHz, CDC13) 5 ppm; 1.15-2.20 (17H, m), 1.44 (9H, s), 2.70-2.85 (2H, br),
3.38-3.53 (1H, br), .50 (1H, br).
(Example 2d) l-[(4,4-Difluorocyclohexyl)methyl]piperidin—4-amine
A 4 N hydrogen de/1,4—dioxane solution (11 ml, 43 mmol) was added to a
e of tert—butyl N~{l~[(4,4—difluorocyclohexyl)methyl]piperidin—4—yl}carbarnate
ed in Example 2c (650 mg, 1.96 mmol) and methanol (11 ml), followed by stirring at
room temperature for three hours. After concentrating the reaction liquid, the residue was
dissolved in ethyl acetate, a l N aqueous sodium hydroxide solution was added, and the
organic layer was separated. The aqueous layer was flirther extracted with ethyl acetate
twice, the organic layers were dried over sodium sulfate, and the solvent was then distilled 01f
to give the title compound (419 mg, yield 92%).
1H—NMR (400 MHZ, CDC13) 8 ppm; 1.16-1.42 (7H, m), 1.59-2.16 (12H, m), .68 (1H,
m), 2.74-2.82 (2H, m).
(Example 2e) (4-Methoxypheny1)methyl(2E)—but—2-enoate
Crotonic acid (17.2 g, 200 mmol) was ved in NN—dimethylfonnamide (100
ml) with cooling in an ice bath under nitrogen, and powdered potassium carbonate (15.2 g,
110 mmol) was added. The mixture was d for 30 minutes, and 4—methoxybenzyl
chloride (29.8 g, 190 mmol) was then added dropwise over 15 minutes. The reaction
mixture was stirred at room temperature for four hours and at 45°C for 14 hours. Ethyl
acetate (500 ml) and water (200 ml) were added to the reaction liquid. The separated
organic layer was washed with water (100 ml x 2) and brine (100 ml). The aqueous layer
was extracted with ethyl acetate (100 ml). The organic layers were combined, dried over
magnesium sulfate, filtered and concentrated under reduced re to give a crude product
ofthe title compound (40.51 g, yield: 98.2%).
1H—NMR (400 MHz, CDC13) 8 ppm; 1.87 (3H, dd, J=2, 7 Hz), 3.81 (3H, s), 5.10 (2H> s),
5.87 (1H, dq, J=2, 16 Hz), 6.86-6.92 (2H, m), 7.00 (1H, dq, J=7, 16 Hz), .34 (2H, m).
(Example 2f) (4-Methoxyphenyl)methyl (3RS,4SR)benzyl-4—
methylpyrrolidine—3—carboxylate
The title nd (57.86 g, yield: 86.5%) was obtained from (4-
FPll-0417
methoxyphenyl)methyl ut-2~enoate obtained in Example 2e (40.6 g, 197 mmol) by a
method similar to the method described in Example 1f.
1H-NMR (400 MHz, CDC13) 6 ppm; 1.12 (3H, d, J=7 Hz), 2.17—2.24 (1H, m), 2.46-2.62
(2H, m), 2.73-2.86 (2H, m), 2.87—2.93 (1H, m), 3.55 (1H, d, J=13 Hz), 3.63 (1H, d, J=l3 Hz),
3.81 (3H, s), .10 (2H, m), 6.86—6.92 (2H, m), .35 (7H, m).
(Example 2g) (4—Methoxyphenyl)methyl (3RS,4SR)-l~benzyl-3—[2—(tert—butoxy)-
2-ox0ethyl]methy1py1rolidine—3-carboxy1ate
The title compound (60.3 g, yield: 80.1%) was obtained fiom (4-
methoxyphenyl)methyl SR)-1—benzyl—4—methylpyrrolidine~3-carboxylate obtained in
Example 2f(56.7 g, 166 mmol) by a method similartothe method described ’i‘n'Example 1g.
1H—NMR (400 MHz, CDC13) 8 ppm; 0.83 (3H, d, J=7 Hz), 1.35 (9H, s), 2.05—2.14 (2H, m),
2.51 (1H, d, J=17 Hz), 2.90-2.98 (2H, m), 3.60 (1H, d, .1213 Hz), 3.70 (1H, d, J=13 Hz), 3.81
(3H, s), 5.04 (1H, d, J=12 Hz), 5.07 (1H, d, J=12 Hz), 6.85-6.91 (2H, m), 7.19-7.34 (7H, m).
(Example 2h) l-Benzyl 3—(4—methoxyphenyl)methyl (3RS,4SR)-3—[2~(te1t—
butoxy)-2—oxoethy1]methylpyrrolidine—1,3-dicarboxylate
The title compound (15 g, yield: 65.1%) was obtained from (4-
methoxyphenyl)methyl (3RS,4SR)benzyl[2-(tert—butoxy)oxoethyl]~4-
methylpyrrolidinecarboxylate obtained in Example 2g (21 g, 46.3 mmol) by a method
similar to the method described in e 1h.
1H—NMR (400 MHz, CDC13) 5 ppm; .88 (3H, m), 1.38 (9H, d, J=5 Hz), 2.04-2.15
(1H, m), 2.22 (1H, dd, J=3, 7 Hz), .12 (2H, m), 3.30-3.36 (1H, m), 3.57-3.67 (1H, m),
3.79 (3H, d, J=4 Hz), 4.30 (1H, t, J=12 Hz), 5.00-5.16 (4H, m), 6.82—6.86 (2H, m), 7.23—7.39
(7H, m).
Analysis by HPLC;
(Analysis conditions) Column: CHIRALPAK AD—H (manufactured by Daicel Chemical
Industries, Ltd.) (0.46 cm diameter x 15 cm), 40°C, eluent: hexane/ethanol = 9/1 (V/V), flow
rate: 1 ml/min., detection: UV (210 nm)
(Analysis result) The resulting title compound was analyzed under the above is
conditions, and a peak with a retention time of7.14 minutes and a peak with a retention time
of9.06 minutes were observed.
(Example 2i) l-Benzyl 3-(4-methoxyphenyl)methyl (3S,4R)-3~[2~(tert—butoxy)-2—
oxoethyl]-4~methylpyrrolidjne-l,3-dicarboxylate
l-Benzyl 3—(4-methoxyphenyl)methyl (3RS,4SR)[2-(te1t—butoxy)—2—oxoethyl]—
FP11-0417
4—methylpyrrolidine—l,3-dicarboxylate ed in Example 2h (7.2 g, 14.5 mmol) was
optically resolved repeatedly by HPLC (CHIRALPAK AD-H (2 cm er x 25 cm),
elution solvent: hexane/ethanol = 85/15, flow rate: 8-10 ml/min) to give a chiral form
corresponding to the peak with a shorter retention time (2.92 g, yield: 40.5%).
Analysis by HPLC;
sis conditions) Column: CHlRALPAK AD-H (manufactured by Daicel Chemical
Industries, Ltd.) (0.46 cm er x 15 cm), 40°C, eluent: hexane/ethanol = 9/1 (V/v), flow
rate: 1 ml/min., ion: UV (210 nm)
(Analysis result) The resulting chiral form was analyzed under the above analysis conditions
to find”thatthe retention time was 7.18 minutes e enantiome'ric excess was >99% ee.
(Example 2j) (3S,4R)—3-[2-(tert—Butoxy)—2-oxoethyl]methylpyrrolidine—3—
carboxylic acid
Ethanol (50 ml) and 10% Pd/C (500 mg) were added to l-benzyl 3-(4-
methoxyphenyl)methyl (3S,4R)—3~[2—(tert—butoxy)-2—oxoethyl]—4-methylpyrrolidine—1 ,3-
.15 ’ dicarboxylate ed in Example 2i (2.92 g, 5.87 mmol), followed by stirring at room
temperature for 38 hours and five minutes under a hydrogen atmosphere. Water (100 ml)
was added to the reaction liquid, which was stirred and filtered. The filtrate was
concentrated to give the title compound (1.37 g, yield: 95.9%).
1H—NMR (400 MHZ, D20) 5 ppm; 1.00 (3H, d, J=7 Hz), 1.45 (9H, s), 2.16-2.37 (1H, m),
2.33 (1H, d, J=17 Hz), 2.96 (1H, d, J=17 Hz), 3.05—3.11 (1H, m), 3.22 (1H, d, J=12 Hz),
3.50—3.56 (1H, m), 4.07 (1H, d, J=12 Hz).
(Example 2k) (3S,4R)[2-(tert—Butoxy)—2—oxoethyl]-1—[(2,6-
dichlorophenyl)methyl]-4—methylpyrrolidine—3—carboxylic acid
2,6—Dichlorobenzaldehyde (646 mg, 3.7 mmol) and sodium triacetoxyborohydn'de
(782 mg, 3.7 mmol) were added to a mixture of (3S,4R)—3-[2-(tert—butoxy)—2—oxoethyl]~4-
methylpyrrolidine—3-carboxylic acid obtained by the method of Example 2j (600 mg, 2.47
mmol), acetic acid (0.14 ml, 2.47 mrnol) and methanol (10 ml), and the reaction mixture was
stirred at room ature for two hours. 2,6—Dichlorobenzaldehyde (430 mg, 2.5 mmol)
and sodium triacetoxyborohydride (522 mg, 2.5 mrnol) were further added, followed by
stirring at an al temperature of40°C for 10.5 hours. Water was added to the reaction
mixture, which was extracted with dichloromethane five times, and the organic layer was
concentrated. The residue was purified by silica gel column chromatography (elution
solvent: ethyl acetate/methanol) to give Lot A (32 mg) and Lot B (551 mg) of the title
FP11—0417
compound.
The chemical shift of Lot A is shown below. Lot B is a combination of thee
fiactions upon column purification, and they were combined after confirming that the
chemical shift ofeach fiaction is similar to the chemical shift ofLot A.
1H—NMR (400 MHz, CDCl}) 6 ppm; 1.01 (3H, d, J=7 Hz), 1.42 (9H, s), 2.05—2.11 (1H, m),
2.16—2.22 (ll-I, m), .69 (2H, m), 2.97—3.04 (2H, m), 3.70 (1H, d, J=10 Hz), 4.07—4.15
(2H, m), 7.22 (1H, dd, J=8, 9 Hz), 7.35 (2H, d, J=8 Hz).
(Example 21) tert—Butyl 2—[(3S,4R)—1-[(2,6-dichlorophenyl)methyl]—3-({1-[(4,4—
difluorocyclohexyl)methyl]piperidin—4—yl}carbamoyl)—4—mefl1ylpyrrolidin—3-yl]acetate
The title compound (409 mg, yield: 92%) was obtained from l~[(4,4—
difluorocyclohexyl)methyl]piperidin—4~amine ed in Example 2d (201 mg, 0.87 mmol)
and (3S,4R)~3-[2—(tert~butoxy)—2—oxoethyl]-1—[(2,6-dichlorophenyl)methyl]-4—
methylpyrrolidine—3-carboxylic acid obtained in Example 2k (290 mg, 0.72 mmol) by a
method similar to the method described in Example 1k
1H—NMR (400 MHz, CDC13) 5 ppm; 0.85-0.93 (3H, m), 1.15-2.14 (19H, m), 1.41 (9H, s),
2.57-2.71 (4H, m), 2.92 (1H, t, J=10 Hz), 3.12 (1H, d, J=16 Hz), 3.59-3.72 (2H, m), 3.96
(2H, s), 7.18 (1H, t, J=8 Hz), 7.33 (2H, d, J=8 Hz), 8.11 (1H, d, J=8 Hz).
(Example 2m) 2—[(3S,4R)-1—[(2,6-Dichlorophenyl)methyl]—3—({1-[(4,4-
difluorocyclohexyl)methy1]pipen'din—4—yl}carbamoyl)-4—methylpy1rolidin—3—yl]acetic acid
The title compound (242 mg, yield: 66%) was obtained from text—butyl ,4R)-
l-[(2,6-dichlorophenyl)methy1]—3-({ l-[(4,4-difluorocyclohexyl)methyl]pipen'din—4-
bamoyl)—4—methylpyrrolidin—3-yl]acetate obtained in Example 21 (409 mg, 0.66 mmol)
by a method similar to the method bed in Example 1m.
1H—NMR (400 MHz, CD3OD) 5 ppm; 0.87-0.93 (3H, m), 1.20-2.38 (19H, m), 2.62-2.71
(2H, m), 2.86—3.12 (4H, m), 3.61-3.73 (2H, m), 4.01—4.09 (2H, m), 7.29 (1H, dd, J=8, 9 Hz),
7.43 (2H, d, J=8 Hz).
(Example 3) 2-[(3 S,4R)—1~{[2—Chloro-6—(tiifluoromethyl)phenyl]methyl}-3—{[1—
(cyclohex—l -en-1 —ylmethyl)piperidin—4—yl]carbamoyl}-4—methylpy1rolidin—3—yl]acetic acid
le 3a) utyl 4-[(3S,4R)benzyl[2-(tert—butoxy)-2—oxoethy1]
methylpyrrolidin—3-amido]piperidine—l-carboxylate
text-Butyl 4-aminopiperidine—1-carboxylate (849 mg, 4.24 mmol), triethylamine
(1.18 ml, 8.48 mmol) and PyBOP (2.21 g, 4.24 mmol) were added to a solution of (3S,4R)-
1~benzyl—3-[2-(tert—butoxy)—2~oxoethyl]—4-methylpyrrolidine—3-carboxylic acid obtained by a
method similar to that of Example 1j (942 mg, 2.83 mmol) in N,N-dimethy1formamide (20
ml), followed by stirring at room temperature overnight. Ethyl acetate was added to the
reaction liquid, which was washed with a 1 N aqueous sodium hydroxide solution and brine.
This was dried over anhydrous magnesium sulfate and concentrated. The residue was
purified by silica gel column chromatography on solvent: heptane/ethyl acetate) to give
the title compound (1.33 g, yield: 91.1%).
\4R’(400‘Ilez,"CDC13) 5 ppm; 0.92’(3H, d, J=7 Hz), 1.20-1.40‘(2H, m), 1.40 (9H, s),
1.48 (9H, s), .88 (1H, m), 1.92-1.98 (1H, br), 1.96 (1H, d, J=16 Hz), 2.03—2.09 (1H,
m), 2.36 (1H, d, J=10 Hz), 2.58-2.68 (2H, m), 2.89—2.95 (2H, m), 3.10 (1H, d, J=16 Hz), 3.59
(1H, d, J=10 Hz), 3.66 (2H, s), .00 (3H, m), 7.23-7.35 (5H, m), 8.65 ‘(1H, d, J=7 Hz).
MS (ESI) m/z: 538.2 (M+Na)+.
(Example 3b) tert-Butyl 4—[(3S,4R)—3-[2—(tert—butoxy)—2~oxoethyl]—4~
methylpyrrolidin—3-amido]piperidine—1carboxylate
% palladium hydroxide (724 mg) was added to a solution of tert-butyl 4—
[(38,4R)-l~benzyl—3—[2-(tert—butoxy)—2-oxoethyl]methylpyrrolidin—3-amido]piperidine~l-
carboxylate obtained in Example 3a (1.33 g, 2.58 mmol) in methanol (30 ml), which was
stirred under a hydrogen atmosphere overnight The reaction liquid was filtered and
concentrated under reduced pressure to give the title compound (1.04 g, yield: 94.7%).
1H—NMR (400 MHZ, CDC13) 5 ppm; 0.92 (3H, d, J=7 Hz), 1.20-1.52 (2H, m), 1.41 (9H, s),
1.43 (9H, s), 1.80—2.10 (5H, m), 2.00 (1H, d, J=16 Hz), 2.55-2.61 (1H, m), 2.80—3.06 (2H,
m), 2.92 (1H, d, J=10 Hz), 3.12 (1H, d, J=16 Hz), 3.35 (1H, d, J=9 Hz), 3.70 (1H, d, J=10
Hz), 3.80—4.00 (3H, m), 8.30 (1H, d, l=7 Hz).
MS (ESI) m/z: 426.1 (M+H)+.
le 3c) tert-Butyl 4—[(3 S,4R)—3—[2-(tert~butoxy)-2—oxoethyl]~1—{[2-chloro
(tnfluoromethyl)pheny1]methyl}—4-methylpyrrolidin—3—amido]piperidine-l-carboxylate
2-(Bromomethyl)—1-chloro(t1ifluoromethyl)benzene (443 mg, 1.62 mmol) and
potassium carbonate (244 mg) were added to a solution of tert—butyl 4-[(3S,4R)[2-(tert—
)-2—oxoethyl]—4-methylpyrrolidin—3—amido]piperidine—1—carboxylate obtained in
Example 3b (345 mg, 0.811 mmol) in N,N—dimethylformamide (dehydrated) (10 mL),
3O which was stirred at 45°C for six hours and at 40°C for two days. Ethyl acetate was added
to the reaction liquid, which was washed with a l N s sodium hydroxide solution and
brine. This was dried over anhydrous magnesium sulfate and trated. The residue
was purified by silica gel column tography (elution solvent: heptane/ethyl acetate) to
FP11-0417
give the title nd (320 mg, yield: 63.8%).
1H-NMR (400 MHz, CDC13) 5 ppm; 0.92 (3H, d, J=7 Hz), 1.13-1.18 (2H, m), 1.39 (9H, s),
1.49 (9H, s), 1.53—1.65 (1H, m), 1.76-1.86 (1H, m), 1.98 (1H, d, J=16 Hz), 2.02-2.10 (1H,
m), 2.51 (1H, d, J=10 Hz), 2.60-2.80 (3H, m), 2.88 (1H, t, J=10 Hz), 3.12 (1H, d, J=16 Hz),
3.53 (1H, d, J=10 Hz), 4.09-4.25 (5H, m), 7.38 (1H, t, J=8 Hz), 7.63 (2H, d, J=8 Hz), 7.96
(1H, d, J=8 Hz).
MS (1381) m/z: 640.2 (M+Na)+.
(Example 3d) 2—[(3S,4R)—1-{[2-Chloro—6-(trifluoromethyl)phenyl]methyl}~4-
methyl—3-[(piperidin—4—yl)carbamoyl]pyrrolidin—3—yl]acetic acid
Trifluoroacetic acid (8 mL) was added to a solution of tert—butyl 4-‘[(3S,4R)[2—
(tert-butoxy)-2—oxoethyl]—1~{[2—chloro—6—(trifluoromethyl)phenyl]methyl}—4-
pyrrolidin—3-amido]piperidine—l-carboxylate obtained in Example 3c (320 mg, 0.518
mmol) in dichloromethane (dehydrated) (8 mL) under ice-cooling, followed by stirring at
room temperature for 2.5 hours. The on liquid was concentrated under reduced
‘15 pressure, and the residue was purified by ODS column chromatography (elution solvent:
water/methanol) to give a mixture containing the title nd (344 mg).
1H—NMR (400 MHz, CD30D) 6 ppm; 0.83 (3H, d, J=5 Hz), .63 (2H, m), 1.76-1.89
(1H, m), 1.92-2.00 (1H, m), 2.03-2.19 (2H, m), 2.55—2.68 (2H, m), 2.91-3.10 (4H, m), 3.25—
3.36 (2H, m), 3.45-3.59 (1H, m), 3.75—4.18 (3H, m), 7.41—7.76 (3H, 111).
MS (ESI) m/z: 462.3 (M+H)+
(Example 3e) 2—[(3S,4R)~1~{[2—Chloro(trifluoromethyl)phenyl]methyl}—3-{[1-
(cyclohex—l—en—l-ylmethyl)piperidin—4—yl]carbamoyl}—4—methylpyrrolidin—3-yl]acetic acid
ex—l~ene-1—carbaldehyde (423 1.11, 3.73 mmol), acetic acid (300 pl) and
sodium triacetoxyborohydride (789 mg, 3.73 mmol) were added to a solution ofthe mixture
of 2—[(3S,4R)—1~{[2—chloro-6—(trifluoromethyl)phenyl]methyl}~4—methy1—3-[(piperidin—4—
yl)carbamoyl]pyrrolidin—3-yl]acetic acid obtained by the method of Example 3d (344 mg,
0.745 mmol) in tetrahydrofiiran (dehydrated) (10 mL), followed by stirring overnight.
Water and methanol were added to the reaction liquid, which was trated under
reduced re, and the residue was purified by ODS column chromatography (elution
solvent: water/methanol). The purified product was dissolved in dichloromethane,
suspended by adding hexane and concentrated to give the title compound (180 mg, yield:
43.4%).
1H—NMR (400 MHZ, CD3OD) 8 ppm; 0.89 (3H, d, J=7 Hz), 1.23—1.38 (2H, m), 1.44-1.82
FP11-0417
(6H, m), .96 (1H, m), 1.96-2.25 (5H, m), 2.30-2.45 (2H, m), 2.55-2.68 (2H, m), 2.92-
3.20 (5H, m), 3.54 (1H, d, J=10 Hz), 3.64—3.78 (1H, m), 3.95 (1H, d, J=10 Hz), 4.05 (1H, d,
J=10 Hz), 5.76 (1H, s), 7.47-7.52 (1H, m), 7.72 (1H, d, J=7 Hz), 7.77 (1H, d, J=8 Hz).
MS (ESI) m/z: 578.3 (M+Na)+
(Example 4: Another method for compound of Example 3) 2~[(3S,4R)—1-{[2—
Chloro(trifluoromethyl)phenyl]methyl}-3—{[1-(cyclohex—l-en-1—ylmethyl)piperidin—4—
yl]carbamoyl}-4—methylpyrrolidin—3-yl]acetic acid
(Example 4a) tert—Butyl N—[1-(cyclohex—l—en—1~ylmethyl)piperidin—4—yl]carbamate
A mixture of tert-butyl eridin—4—yl)carbamate (5.3 g, 26.5 mmol), l—
cyclohexene—l-carboxaldehyde (3.5 g, 31.8 mn’ml), sodium triac’etoxyborohydiide (7.29 g,
34.4 mmol), acetic acid (0.5 ml) and tetrahydrofuran (dehydrated) (80 ml) was stirred at
room ature for 85 hours and 30 minutes. Water and sodium bicarbonate were added
to the reaction mixture, which was stirred and then extracted with ethyl e twice. The
organic layer was washed with brine and dried over anhydrous sodium sulfate, and the
solvent was distilled off. The residue was purified by silica gel column chromatography
(NH silica gel, elution solvent: ethyl acetate/heptane) to give the title compound (7.47 g,
yield: 95.7%).
1H—NMR (400 IVHiz, CDC13) 8 ppm; 1.35—1.50 (2H, m), 1.44 (9H, s), 1.51-1.65 (4H, m),
1.84-2.03 (8H, m), 2.68-2.80 (4H, m), 3.39—3.50 (1H, m), .48 (1H, m), 5.54 (1H, s).
[0182] (Example 4b) l—(Cyclohex—1-en—1—ylmethyl)piperidin—4-amine
A e of tert—butyl N—[l—(cyclohexen—1-ylmethy1)piperidin—4~yl]carbamate
obtained in Example 4a (7.47 g, 25.4 mmol), a 5 N aqueous hydrochloric acid solution (25
ml, 125 mmol) and methanol (100 ml) was stirred at 70°C for 1.5 hours. The reaction
mixture was ice-cooled, a 5 N aqueous sodium hydroxide solution (25 ml, 125 mmol) was
added, and the solvent was led off. Water was added to the residue, which was
extracted with ethyl acetate twice. The organic layer was washed with brine and dried over
anhydrous sodium sulfate, and the t was distilled offto give the title compound (4.73
g, yield: 95.8%).
1H—NMR (400 MHz, CDC13) 6 ppm; 1.30-1.50 (4H, m), 1.51—1.70 (4H, m), 1.75-2.08 (8H,
m), 2.59-2.68 (1H, m), 2.72-2.88 (4H, m), 5.55 (1H, s).
(Example 40) l-Benzyl 3-(4—methoxyphenyl)methyl (3RS,4SR)[2-(tert—
)oxoethyl]methy1pyrrolidine—1,3—dicarboxylate
A solution of (4—methoxyphenyl)methyl (3RS,4SR)—1~benzyl—3—[2—(tert—butoxy)—2—
FP11-0417
oxoethyl]—4—methylpyrrolidine—3—carboxylate obtained in Example 2g (18 g, 39.7 mmol) in
dichloromethane (85.7 ml) was ed to an internal temperature of 10 to 20°C, and benzyl
chloroformate (11.9 ml, 79.4 mmol) was added thereto. After returning to room
temperature and ng for 0.5 hour, the on mixture was concentrated directly. The
resulting crude product was purified by column chromatography (silica gel, elution solvent:
ethyl acetate/heptane) to give the title compound (12.89 g, yield: 65.3%).
1H—NMR (400 MHz, CDC13) 5 ppm; 0.80-0.88 "(3H, m), 1.38 (9H, d, J=5 Hz), 2.04—2.15
(1H, m), 2.22 (1H, dd, J=3, 17 Hz), 3.00—3.12 (2H, m), 3.62 (1H, m), 3.79 (3H, d, J=4 Hz),
4.30 (1H, t, J=12 Hz), 5.00-5.16 (4H, m), 6.82-6.86 (2H, m), 723—739 (8H, m).
[0184] (Example 4d) l—Benzyl ethoxyphenyl)methyl (3S,4R)[2-(tert—butoxy)—2—
oxoethyl]—4-methylpyrrolidine—1,3-dicarboxylate
l-Benzyl 3—(4-methoxyphenyl)methyl (3RS,4SR)—3—[2-(tert—butoxy)—2~oxoethyl]-
4—methylpyrrolidine—l,3-dicarboxylate obtained in Example 4c (12.7 g, 26 mrnol) was
optically ed repeatedly by HPLC (CHIRALPAK AD-H (2 cm diameter x 25 cm),
elution solvent: hexane/ethanol = 85/15, flow rate: 8—10 mJ/min.) to give a chiral form
corresponding to the peak with a shorter retention time (5.7 g, yield: 44.9%). The resulting
chiral form (5.3 g) was fiirther purified by silica gel column chromatography (elution solvent;
heptane/ethyl acetate) in two portions to give 5.2 g ofthe title compound.
1H—NMR (400 MHz, CDC13) 8 ppm; 0.81-0.88 (3H, m), 3.37-3.38 (9H, m), 2.04—2.16 (1H,
m), 2.19-2.25 (1H, m), .12 (2H, m), 3.30-3.36 (1H, m), 3.56-3.67 (1H, m), 3.75-3.79
(3H, m), 4.26-4.33 (1H, m), 5.00-5.16 (4H, m), 6.82-6.86 (2H, m), 727-7.37 (7H, m).
Analysis by HPLC;
sis conditions) Column: CHIRALPAK AD—H (manufactured by Daicel Chemical
Industries, Ltd.) (0.46 cm diameter x 15 cm), 40°C, eluent: hexane/ethanol = 9/1 (v/v), flow
rate: 1 m]/min., ion: UV (210 nm)
(Analysis result) The d chiral form was analyzed under the above analysis conditions
to find that the retention time was 7.15 minutes and the enantiomeric excess was >99% ee.
(Example 4e) l-Benzyl 3-(4—methoxyphenyl)methyl (3S,4R)[2~(tert—butoxy)—2—
oxoethyl]—4-methylpyrrolidine-l,3-dicarboxylate
l-Benzyl 3-(4—methoxyphenyl)methyl (3RS,4SR)[2—(tert—butoxy)—2~oxoethyl]-
4-methylpy1rolidine—l,3—dicarboxylate obtained by a method r to that of e 4c
(7.8 g, 16.5 mmol) was optically resolved repeatedly by HPLC (CI-HRALPAK AD-H,
elution solvent: hexane/ethanol = 85/15) to give a chiral form with a r retention time
FPll-0417
(3.3 g, yield: 42.3%).
(Example 41) (3S,4R)[2-(tert—Butoxy)oxoethyl]-4—methylpy1rolidine
ylic acid
Methanol (70 ml) and 10% Pd/C (600 mg) were added to l—benzyl 3-(4-
methoxyphenyl)methyl (3 S,4R)—3—[2—(tert—butoxy)—2-oxoethyl]—4—methylpyrrolidine—1,3-
dicarboxylate obtained by the method ofExample 4e (3.3 g, 6.63 mmol), followed by stirring
at room temperature for three days under a hydrogen here. Water (70 ml) was added
to the reaction liquid, which was stirred and filtered. The filtrate was concentrated to give
the title compound (1.15 g, yield: 71.3%).
1H-NMR (400 MHz, D20) was identical to that ofthe compound ed in Exarnple 2].
(Example 4g) (3S,4R)—3~[2-(tert—Butoxy)oxoethy1]-4—methylpyrrolidine—3-
ylic acid
Methanol (3 ml) and 10% Pd/C (30 mg) were added to l-benzyl 3-(4-
methoxyphenyl)methyl (3S,4R)[2-(tert—butoxy)—2—oxoethyl]—4—methylpyrrolidine—1,3-
dicarboxylate which is obtained in Example 4d and which is without silica gel column
tography purification (104 mg, 0.21 mmol), followed by stirring at room temperature
overnight under a hydrogen atmosphere. Water was added to the reaction liquid, which was
stirred and filtered. The filtrate was concentrated to give the title compound (48.7 mg,
yield: 95.3%).
1H—NMR (400 MHZ, D20) was cal to that ofthe compound obtained in Example 2j.
(Example 4h) (3S,4R}3-[2—(tert—Butoxy)—2~oxoethyl]—4—methylpyirolidine—3—
carboxylic acid
Methanol (100 ml) and 10% Pd/C (559 mg) were added to l-benzyl 3-(4-
methoxyphenyl)methyl (3S,4R)-3—[2-(tert—butoxy)—2—oxoethyl]—4—methylpyrrolidine—1 ,3~
dicarboxylate ed in Example 4d (5.2 g, 10.5 mmol), followed by stirring at room
temperature for eight hours and 15 minutes under a hydrogen atmosphere. Water (100 ml)
was added to the reaction liquid, which was stirred for one hour and filtered. The filtrate
was concentrated. A combination (3.2 g, 13.2 mmol) ofthe residue and (3S,4R)—3-[2-(tert—
)-2—oxoethyl]methylpyrrolidine—3-carboxylic acid obtained in es 2j, 4f and
4g was suspended by adding methanol (25 ml) and stirred at room temperature for 30
minutes, and collection by filtration gave 3 .02 g ofthe title compound.
1H-NMR (400 MHz, D20) 5 ppm; 0.98 (3H, d, J=7 Hz), 1.43 (9H, s), 2.14—2.24 (1H, m),
2.31 (1H, d, J=17 Hz), 2.94 (1H, d, J=17 Hz), 3.06 (1H, t, J=11 Hz), 3.20 (1H, d, J=12 Hz),
FP11—0417
3.51 (1H, dd, J=8, 12 Hz), 4.05 (1H, d, J=12 Hz).
(Example 4i) tert—Butyl 2-[(3 S,4R)-l-{[2-chloro
(trifluoromethyl)phenyl]methyl}{[1-(cyclohexenylmethy1)piperidin—4-
yl]carbamoyl}—4-methy1pyrrolidin—3—yl]acetate
lohex~l—enylmefliyl)piperidin—4-amine obtained in Example 4b (240 mg,
1.24 mmol), N,N—dimethylformamide (3 ml), triethylamine (344 pl, 2.47 mmol) and PyBOP
(856 mg, 1.64 mmol) were added to (3S,4R)—3—[2-(tert—butoxy)~2~oxoethyl]—4—
methylpyrrolidine—3—carboxylic acid obtained in Example 4h (200 mg, 0.822 mmol),
followed by stirring with heating in a 45°C oil bath for 1.5 hours. Water was added to the
reaction mixture, which was extracted with ethyl acetate. The organic layer was dried over
magnesium sulfate and concentrated. 2—(Bromomethyl)—1~chloro
(trifluoromethyl)benzene (247 mg, 0.903 mmol), potassium carbonate (170 mg, 1.23 mmol)
and N,N—dimethy1formarnide (1 ml) were added thereto, followed by heating with stirring in
a 45°C oil bath for three hours. Water was added to the reaction mixture, which was
extracted With ethyl acetate. The organic layer was washed with water and brine and then
dried over magnesium sulfate. The ing crude product was purified by column
chromatography twice (NH silica gel, n t: ethyl acetate/heptane and silica gel,
elution t: ethyl acetate/heptane) to give the title compound (353 mg, yield 70.1%).
1H—NMR (400 MHz, CDC13) 6 ppm; 0.91 (3H, d, J=7 Hz), 1.31-1.42 (2H, m), 1.39 (9H, s),
.66 (5H, m), .09 (9H, m), 2.53 (1H, d, J=10 Hz), 2.63-2.77 (5H, m), 2.88 (1H, t,
J=10 Hz), 3.11 (1H, d, J=16 Hz), 3.56 (1H, d, J=10 Hz), 3.61-3.72 (1H, m), 3.92 (1H, d, J=13
Hz), 3.98 (1H, d, J=13 Hz), 5.54 (1H, s), 7.36 (1H, t, J=8 Hz), 7.62 (1H, d, J=4 Hz), 7.64
(1H, d, J=4 Hz), 7.83 (1H, d, J=8 Hz).
(Example 4j) 2—[(3 S,4R)—1-{[2—Chloro—6—(trifluoromethyl)phenyl]methyl}{[1~
(cyclohex—l-en-1~ylmethy1)piperidin—4—yl]carbamoyl}~4~methylpyrrolidin—3-yl]acetic acid
Trifluoroacetic acid (1.5 ml, 20.3 mmol) was added to a solution of tert—butyl 2—
[(3S,4R){[2-chloro-6—(trifluoromethyl)phenyl]methyl}~3-{[1-(cyclohexen-1—
ylmethyl)piperidin—4—yl]carbamoyl}~4—methylpyrrolidin—3-yl]acetate obtained in Example 4i
(353 mg, 0.577 mrnol) in dichloromethane (400 pl), which was stirred at room temperature
for two hours. The reaction mixture was concentrated under reduced re and purified
by ODS column chromatography (elution solvent: methanol/water) to give the title
compound (215 mg, yield 67%).
1H—NMR (400 MHZ, CDC13) 8 ppm; 1.01 (3H, d, J=7 Hz), 1.22-1.34 (2H, m), 1.42-1.68
FP11-0417
(7H, m), 1.79-2.07 (6H, m), 2.38-2.46 (1H, m), 2.49 (1H, d, J=10 Hz), 2.56 (1H, d, J=14 Hz),
2.67-2.82 (6H, m), 3.00 (1H, t, J=10 Hz), 3.16 (1H, d, J=10 Hz), 3.63-3.76 (II-I, m), 3.88
(1H, d, J=14 Hz), 4.01 (1H, d, J=14 Hz), 5.55 (1H, s), 7.40 (1H, t, J=8 Hz), 7.64 (1H, d, J=4
Hz), 7.66 (1H, d, J=4 Hz), 8.56 (1H, d, J=8 Hz)
Specific on: [(111329 + 37.1 (c 0.11, MeOH)
(Example 5: Another method for compound of Example 3) 2—[(3S,4R){[2—
Chloro—6—(tn'fluoromethyl)phenyl]methyl}~3—{[1—(cyclohex-1—en—1-y1rnethyl)piperidin—4—
yl]carbamoyl}methylpyrrolidin—3~y1]acetic acid
(Example 5a) tert—Butyl 4-[(3RS,4SR)[2—(tert—butoxy)~2—oxoethyl]—1~[(2,6-
dichlorophenyl)methyl]—4-methylpyrrolidin—3—amido]piperidine—1-carboxylate
% palladium hydroxide (300 mg) was added to a solution ofbenzyl (3RS,4SR)—
1-benzy1-3—[2-(tert-butoxy)—2~oxoethyl]—4—methylpyrrolidine—3-carboxylate obtained by a
method r to that of Example 1g (3 g, 7.08 mmol) in methanol (200 n11), followed by
stirring at room temperature overnight under a hydrogen atmosphere. The on liquid
was filtered and washed with methanol. Warm water at about 40°C was added to the
product collected by filtration to dissolve the solid, followed by filtration. The filtrate was
concentrated together with the first filtrate to give a deprotected form (1.7 g).
ol (44 ml), 2,6—dichlorobenzaldehyde (4.83 g, 27.6 mmol) and acetic acid
(1.1 ml, 18.4 mmol) were added to the deprotected form obtained by a method similar to the
above method (4.47 g, 18.4 rmnol), followed by stirring at room ature for 15 minutes,
and sodium triacetoxyborohydride (6.16 g, 27.6 mmol) was added, followed by heating with
stirring at 40°C overnight. l buffer [prepared fiom potassium dihydrogenphosphate
(13.65 g), disodium hydrogenphosphate dodecahydrate (71.6 g) and water (1.5 1)] was added
to the on liquid, ethyl acetate and heptane were added, and the mixture was filtered.
The filtrate was ted with ethyl acetate, the organic layer was dried over sodium sulfate
and concentrated, and the ing crude t was then purified by column
chromatography (silica gel, elution solvent: methanol/ethyl acetate) and combined with the
product collected by filtration to give (3RS,4SR)~3—[2-(tert—butoxy)-2—oxoethyl][(2,6—
rophenyl)methyl]—4—methylpyrrolidjnecarboxylic acid (3.9 g). tert—Butyl 4-
aminopiperidjne-l—carboxylate (974 mg, 4.89 mmol), N,N-djmethy1formamide (10 ml),
triethylamine (1.14 ml, 8.13 mmol) and PyBOP (2.54 g, 4.89 mrnol) were added to this
compound (1.64 g, 4.07 mmol), followed by stining at room temperature overnight. Water
was added to the reaction liquid, which was extracted with ethyl acetate, and the organic
FP11—0417
layer was then washed with water and brine and dried over magnesium sulfate. The crude
product ed by concentration was purified by column chromatography (NH silica gel,
elution t: ethyl acetate/heptane) to give the title compound (2.10 g, yield: 88.1%).
1H-NMR (400 MHZ, CDCl3) 5 ppm; 0.91 (3H, d, J=7 Hz), 1.15-1.34 (2H, m), 1.40 (9H, s),
1.49 (9H, s), 1.58—1.70 (2H, m), 1.76-1.84 (1H, br), 1.98 (1H, d, J=16 Hz), 2.03-2.13 (1H,
m), 2.54—2.65 (2H, m), 2.66-2.88 (2H, br), 2.92 (1H, t, J=10 Hz), 3.11 (1H, d, J=16 Hz), 3.59
(1H, d, J=10 Hz), 3.81—3.90 (1H, m), 3.95”(2H, s), 3.90—4.07 (2H, br), 7.18 (1H, dd, J=7, 8
Hz), 7.33 (1H, d, J=8 Hz), 8.23 (1H, d, J=8 Hz).
Analysis by HPLC;
(Analysis conditions) : CHIRALPAK IA actured by Daicel Chemical
Industries, Ltd.) (0.46 cm diameter x 15 cm), 40°C, eluent: hexane/ethanol = 95/5 (v/v), flow
rate: 1 ml/min., detection: UV (210 nm)
(Analysis result) The resulting title nd was analyzed under the above analysis
conditions, and a peak with a retention time of 3.46 minutes and a peak with a retention time
of6.04 minutes were observed.
(Example 5b) tert-Butyl 4-[(3 S,4R)—3-[2—(tert—butoxy)~2—oxoethyl]—1-[(2,6-
dichloropheny1)methy1]—4-methylpyrrolidin—3-amido]piperidine-1—carboxylate
tert—Butyl 4—[(3RS,4SR)[2—(tert—butoxy)—2—oxoethyl]—1-[(2,6-
dichlorophenyl)methy1]—4—rnethylpyrrolidin~3—arnido]piperidine—1-carboxylate obtained in
Example 5a (2.04 g, 3.49 mmol) was optically resolved repeatedly by HPLC (CHRALPAK
IA (3 cm diameter x 25 cm), n solvent: hexane/ethanol = 94/6, flow rate: 22 ml/min.) to
give the title compound (a chiral form corresponding to the peak with a r retention
time) (859 mg, 42.1%) and the optical isomer (a chiral form corresponding to the peak with a
longer ion time) (817 mg, 40%), respectively.
Chiral form corresponding to the peak with a shorter retention time; 1H—NMR (400 MHz,
CDC13) 5 ppm; 0.91 (3H, d, J=7 Hz), 1.15-1.33 (2H, m), 1.40 (9H, s), 1.49 (9H, s), 1.76-1.84
(1H, m), 1.98 (1H, d, J=16 Hz), 2.01—2.11 (1H, m), 2.57 (1H, d, J=10 Hz), 2.57-2.64 (1H, m),
2.69-2.82 (2H, m), 2.92 (1H, t, J=10 Hz), 3.11 (1H, d, J=16 Hz), 3.59 (1H, d, J=10 Hz), 3.80-
4.09 (2H, m), 3.95 (2H, s), 7.18 (1H, t, J=8 Hz), 7.33 (2H, d, J=8 Hz), 8.23 (1H, d, J=8 Hz).
Analysis by HPLC;
(Analysis conditions) Column: CHIRALPAK IA (manufactured by Daioel Chemical
Industries, Ltd.) (0.46 cm diameter x 15 cm), 40°C, : hexane/ethanol = 95/5 (V/v), flow
rate: 1 m1/min., detection: UV (210 nm)
(Analysis ) The resulting chiral form corresponding to the peak with a shorter retention
time was analyzed under the above analysis conditions to find that the retention time was
3.44 minutes and the enantiomeric excess was >99% ee.
(Example 50) utyl 4—[(3 S,4R)—3-[2—(tert—butoxy)—2—oxoethyl]—1-{[2—chloro-6—
(trifluoromethyl)phenyl]methyl}—4—methylpyrrolidin—3—amido]piperidine—1-carboxylate
% palladium hydroxide (75.8 mg) was added to a solution of tert-butyl 4-
[(3S,4R)~3-[2-(tert—butoxy)—2—oxoethyl]~1~[(2,6-dichlorophenyl)mefliyl]methylpyrrolidin—
3-amido]piperidine—1-carboxylate obtained in Example 5b (758 mg, 1.29 mmol) in methanol
(20 ml), followed by stirring at 40°C for three hours under a hydrogen here. The
reaction liquid was filtered, and the filtrate was concentrated to give a crude product (501
mg). 2~(Bromomethy1)—1-chloro—3-(trifluoromethyl)benzene (145 mg, 0.532 mmol) and
potassium carbonate (53.2 mg) were added to a solution of this crude product (174 mg) in
N,N-dimethylformamide rated) (6 mL), followed by stirring ght. 2—
(Bromomethyl)—1—chloro(trifluoromethyl)benzene (145 mg, 0.532 mmol) and potassium
carbonate (106 mg) were further added, followed by stirring for four hours. Ethyl acetate
was added to the reaction liquid, which was washed with a 1 N aqueous sodium hydroxide
solution and brine. This was dried over anhydrous magnesium sulfate and concentrated.
The e was purified by silica gel column tography (elution solvent:
heptane/ethyl acetate) to give the title compound (82 mg, yield: 32.4%).
1H—NMR (400 MHz CDC13) 8 ppm; 0.92 (3H, d, J=7 Hz), 1.12-1.18 (2H, m), 1.39 (9H, s),
1.49 (9H, s), 1.53—1.65 (1H, m), 1.76—1.86 (1H, m), 1.98 (1H, d, J=16 Hz), .10 (1H,
m), 2.51 (1H, d, J=10 Hz), 2.61-2.81 (3H, m), 2.89 (1H, t, J=10 Hz), 3.12 (1H, d, J=16 Hz),
3.53 (1H, d, J=1O Hz), 3.80—4.10 (5H, m), 7.38 (1H, t, J=8 Hz), 7.63 (2H, d, J=8 Hz), 7.96
(1H, d, J=8 Hz).
MS (ESI) m/z: 618.1 (M+H)+
(Example 5d) 2—[(3S,4R)—1~{[2-Chloro~6-(trifluoromethyl)phenyl]methyl}
methyl-3—[(piperidin—4-yl)carbamoyl]pyrrolidin—3-y1]acetic acid
Trifluoroacetic acid (3 mL) was added to a solution of tert-butyl 4—[(3S,4R)[2-
(tert-butoxy)—2—oxoethyl]— 1-{ [2-chloro(trifluoromethyl)phenyl]methyl}
methylpyrrolidin—3—amido]piperidine-l—carboxylate obtained in Example 5c (82 mg, 0.133
mmol) in dichloromethane (dehydrated) (3 mL) under ice—cooling, followed by stirring at
room temperature for 2.5 hours. The on liquid was concentrated under reduced
pressure, and the residue was purified by ODS column chromatography (elution solvent:
FP11-0417
water/memanol) to give the title compound (72 mg, yield: quant.)
1H-NMR (400 MHz, CD3OD) 5 ppm; 0.90 (3H, d, J=5 Hz), .70 (2H, m), .91
(1H, m), 1.99-2.08 (1H, m), 2.12-2.23 (2H, m), 2.61 (1H, d, J=9 Hz), 2.60—2.70 (2H, m),
2.95—3.12 (4H, m), 3.25—3.36 (2H, m), 3.53 (1H, d, J=9 Hz), 3.83—3.92 (1H, m), 3.97 (1H, d,
J=13 Hz), 4.07 (1H, d, J=l3 Hz), 7.51 (1H, t, J=8 Hz), 7.73 (1H, d, J=8 Hz), 7.78 (1H, d, J=8
Hz).
MS (ESI) m/z: 462.2 (M+H)+
(Example 5e) 2—[(3S,4R)—1—{[2~Chloro(trifluoromethyl)phenyl]methyl}~3—{[l-
(cyclohex—l~en—1—ylmethyl)piperidin—4—yl]carbamoyl}—4—methylpyrrolidin~3—yl]acetic acid
ex-l-ene-1—carbaldehyde (25.9 ul, 0.227 mmol), acetic acid (30 ul) and
sodium tn'acetoxyborohydride (68.8 mg, 0.325 mmol) were added to a solution of 2-
[(3S,4R)-l—{[2—chloro—6-(11ifluoromethyl)phenyl]methyl}—4-methyl[(piperidin4-
bamoyl]pyrrolidin—3-yl]acetic acid obtained by the method of Example 5d (15 mg,
0.0325 mrnol) in tetrahydrofiiran (dehydrated) (2 mL), followed by stirring overnight.
Water and methanol were added to the reaction liquid, which was concentrated under
reduced pressure, and the residue was purified by ODS column chromatography on
solvent: water/methanol) to give the title compound (12.8 mg, yield: 70.8%).
1H—NMR (400 MHz, CD3OD) 8 ppm; 0.89 (3H, d, J=7 Hz), 1.50—1.90 (2H, m), 1.83-1.95
(1H, m), 2.00-2.22 (5H, m), 2.30—2.45 (2H, m), 2.57—2.68 (2H, m), 2.92-3.14 (5H, m), 3.54
(1H, d, J=10 Hz), 3.64-3.78 (1H, m), 3.95 (1H, d, J=13 Hz), 4.05 (1H, d, J=13 Hz), 5.76 (1H,
s), 7.49 (1H, t, J=8 Hz), 7.72 (1H, d, J=8 Hz), 7.77 (1H, d, J=8 Hz).
MS (ESI) m/z: 556.3 (M+H)+
(Example 6) 2—[(3S,4R)[(2—Chloro—6~methylphenyl)methyl]~3—{[1-(cyclohex—l-
enyhnethyl)piperidin—4—yl]carbamoyl}—4—methylpyrrolidin—3-yl]acetic acid
[0198] (Example 6a) (3S,4R)—3-[2—(tert—Butoxy)—2—oxoethyl]—1-[(2—chloro-6—
methylphenyl)methyl]—4—methylpyrrolidine~3~carboxylic acid
The title compound (154 mg, yield 27.2%) was ed from (3S,4R)[2—(te1t~
butoxy)-2—oxoethyl]methylpyrrolidine-3~carboxylic acid obtained by a method similar to
that ofExample li (360 mg, 1.48 mmol) and 2—chloro-6—methylbenzaldehyde (416 mg, 2.69
mmol) by a method similar to the method described in Example 1j.
1H-NMR (400 MHz, CDC13) 8 ppm; 1.01 (3H, d, J=7 Hz), 1.41 (9H, s), 2.10 (1H, d, J=17
Hz), 2.15223 (1H, m), 2.42 (3H, s), 2.63-2.69 (2H, m), 2.97 (1H, t, J=10 Hz), 3.01 (1H, d,
J=17 Hz), 3.68 (1H, d, J=9 Hz), 4.00 (2H, s), 7.09—7.26 (3H, m).
FP11—0417
(Example 6b) tert—Butyl 2-[(3S,4R)—1—[(2—chloro-6—methylphenyl)methyl]~3—{[1-
(cyclohex-l-eny1methy1)piperidin—4-y1]carbarnoyl}—4-methy1pyrrolidin—3-yl]acetate
The title nd (212 mg, yield 942%) was obtained from (3S,4R)—3-[2-(tert—
butoxy)—2—oxoethy1]-1—[(2-chloro—6—methy1phenyl)methy1]—4—methylpyrrolidinecarboxylic
acid obtained in Example 6a (154 mg, 0.403 mmol) and 1-(cyclohex—1-en—1—
ylmethyl)piperidin—4—amine obtained in Example 4b (110 mg, 0.564 mmol) by a method
similar to the method desoribed in Example 1k.
1H—NMR (400 MHz, CDC13) 8 ppm; 0.92 (3H, d, J=7 Hz), 1.21-1.39 (3H, m), 1.40 (9H, s),
1.52-1.69 (5H, m), 1.81-2.12 (8H, m), 1.99 (1H, d, J=16 Hz), 2.44 (3H, s), 2.52 (1H, d, J=10
Hz), 2.61 (1H, dd, J=6, 9 Hz), 2.68 (2H, br d, J=9 Hz), 2.75 (2H, s), 2.86 (1H, t, J=10 Hz),
3.10 (1H, d, J=16 Hz), 3.58 (1H, d, J=10 Hz), 3.60-3.70 (1H, m), 3.79 (1H, d, J=13 Hz), 3.84
(1H, d, J=13 Hz), 5.54 (1H, s), 7.08-7.14 (2H, m), 7.23—7.26 (1H, m), 8.00 (1H, d, J=8 Hz).
(Example 60) 2—[(3S,4R)—1-[(2-Chloro~6-methylphenyl)methyl]—3-{[1-(cyclohex—
l-en-l -ylmethyl)piperidin—4—y1]carbamoyl}~4-methy1pyrrolidin—3-y1]acetic acid
The title compound (140 mg, yield 73.4%) was ed from utyl 2—
[(3S,4R)- chloro-6—methylphenyl)methy1]—3—{ [1 ohexen-1 -y1methyl)piperidin—
4-y1]carbamoyl}—4-methy1pyrrolidin—3-y1]acetate obtained in Example 6b (212 mg, 0.38
mmol) by a method similar to the method described in Example 1m.
1H—NMR (400 MHz, CD30D) 8 ppm; 0.93 (3H, d, J==7 Hz), 1.57—1.80 (6H, m), 1.90-2.39
(8H, m), 2.49 (3H, s), 2.61-3.38 (8H, m), 3.59—4.20 (4H, m), 5.95 (1H, s), 7.18-7.39 (3H, m).
(Example 7) ,4R)—1~{[2—Chloro—6-(t1ifluoromethyl)phenyl]methyl}{[1-
(cyclopent—l—en—l -y1methy1)piperidin—4-yl]carbamoyl}—4-methylpyrrolidin—3-yl]acetic acid
(Example 7a) Cyclopent—l—ene—l-carbaldehyde
Amixture of sodium periodate (28.6 g, 134 mrnol) and water (250 ml) was added
to a mixture of 1,2-cyclohexanediol (12 g, 103 mmol) and diethyl ether (150 ml), which was
stirred at room temperature for 35 minutes. A20% aqueous potassium hydroxide solution
(40 ml, 206 mmol) was added to the reaction e, which was stirred at room temperature
for two hours. The on mixture was extracted with diethyl ether twice. The organic
layer was dried over anhydrous magnesium sulfate, and the solvent was distilled offto give
the title compound (6.1 g, yield 61.6%).
1H-NMR (400 MHZ, CDC13) 5 ppm; 1.96-2.04 (2H, m), 2.50-2.57 (2H, m), 2.58-2.66 (2H,
m), 6.87-6.90 (1H, m), 9.80 (1H, s).
(Example 7b) 2—[(3S,4R)—1—{[2—Chloro(trifluoromethyl)pheny1]methy1}-3~{[1-
FP11—0417
(cyclopent—1~enylmethyl)piperidin—4—yl]carbamoyl}—4~methylpyrrolidin—3-yl]acetic acid
The title compound (288 mg, yield: 73.5%) was obtained from 2-[(3S,4R)-1—{[2-
chloro(uifluoromethyl)pheny1]methyl}methyl—3-[(piperidjn
yl)carbamoyl]pyrrolidin—3~y1]acetic acid obtained in e 3d (334 mg, 0.723 mmol),
cyclopent-l-ene—l-carbaldehyde obtained in Example 7a (209 mg, 2.17 mmol), acetic acid
(300 pd) and sodium triacetoxyborohydride (460 mg, 2.17 mmol) by a method similar to the
method described in Example 3e.
1H—NMR (400 MHZ, CD30D) 5 ppm; 0.89 (3H, d, J=7 Hz), 1.24-1.35 (2H, m), .66
(2H, m), 1.70-1.78 (1H, m), 1.85-1.99 (3H, m), .22 (2H, m), 2.29—2.42 (4H, m), 2.61
(1H, d, J=10 Hz), 2.60-2.68 (1H, m), 2.91—3.02 (2H, m), 3.07 (1H, ’d, J=1'6 Hz), 3.54 '(1H, d,
J=10 Hz), 3.64—3.78 (1H, m), 3.95 (1H, d, J=l4 Hz), 4.05 (1H, d, J=14 Hz), 5.74 (1H, s),
7.50 (1H, t, J=8 Hz), 7.71 (1H, d, J=8 Hz), 7.78 (1H, d, J=8 Hz).
MS (ESI) m/z: 564.3 (M+Na)+
(Example 8) 2-[(3S,4R)~1-[(2~Chloro~6—methylphenyl)methyl]~3-{[(l—cyclopent-l-
enylmethyl)piperidin—4—yl]carbamoyl}—4-mefl1ylpyrrolidin—3—yl]acetic acid
(Example 8a) tert—Butyl 4-[(3S,4R)—3-[(2—tert—butoxy)—2—oxoethyl]—l-[(2—chloro-6—
methylphenyl)methyl]methylpyrrolidin—3~amido}piperidine-l-carboxylate
The title compound (237 mg, yield 91.7%) was obtained fiom (3S,4R)-3—[(2-te1t—
butoxy)—2—oxoethyl][(2-chloro—6—methylphenyl)methyl]—4-methylpyrrolidine~3—carboxylic
acid ed by a method r to the method described in Example 6a (175 mg, 0.458
mmol) and tert—butyl 4-aminopipe1idine~1—carboxylate (137 mg, 0.684 mmol) by a method
similar to the method described in Example 1k.
1H—NMR (400 MHZ, CDC13) 8 ppm; 0.92 (3H, d, J=8 Hz), 1.15-1.30 (2H, m), 1.40 (9H, s),
1.49 (9H, s), 1.58-1.68 (2H, m), 1.78-1.88 (1H, br), 1.99 (1H, d, J=8 Hz), 2.05—2.11 (1H, m),
2.42 (3H, s), 2.50 (1H, d, J=10 Hz), 2.60—2.66 (1H, m), 2.70-2.81 (2H, br), 2.85 (1H, t, J=10
Hz), 3.10 (1H, d, J=16 Hz), 3.55 (1H, d, J=10 Hz), 3.74-4.10 (4H, m), 7.07-7.15 (2H, m),
7.22-7.27 (1H, m), 8.14 (1H, d, J=8 Hz).
(Example 8b) 2—[(3S,4R)—1-[(2—Chloro—6—methylpheny1)methyl]—3-{[(l-cyclopent—
1—en-l-ylmethyl)piperidin—4~yl]carbamoyl}methylpyrrolidin—3—y1]acetic acid
A mixture of tert-butyl 4-[(3S,4R)-3—[(2—tert—butoxy)-2—oxoethyl]—1-[(2-chloro
methylphenyl)methyl]—4-methylpyrrolidin—3-amido}piperidine~1-carboxylate obtained in
Example 8a (237 mg, 0.42 mmol), m'fluoroacetic acid (2.3 ml, 31 mmol) and
romethane (dehydrated) (2.3 ml) was stiired at room temperature for three hours and
FP11—0417
minutes. The reaction mixture was concentrated, and ent—l-ene—l—carbaldehyde
obtained in Example 7a (121 mg, 1.26 mmol), triethylamine (0.176 ml, 1.26 mmol) and
tetrahydrofiiran (5 ml) were added to the g residue, followed by stirring for 35
minutes. Sodium tn'acetoxyborohydride (267 mg, 1.26 mmol) was added to the reaction
mixture, which was d at room temperature for 13 hours. The reaction mixture was
concentrated, and the resulting residue was purified by silica gel column tography
(ODS silica gel, elution solvent: water/methanol) twice to give the title compound (88 mg,
yield 42.9%).
1H—NlVLR (400 MHZ, CD30D) 8 ppm; 0.92 (3H, d, J=7 Hz), 1.50-1.68 (2H, br), .83
1‘0 (1H, br), 1.88—2.00 (3H, m), 2.19-2.30 (2H, m), 2.31—2.43 (6H, m), 2.48 ‘(3H, s), 2.62-2.72
(2H, m), 2.90—3.09 (4H, m), 3.25—3.40 (2H, m), 3.61 (1H, d, J=10 Hz), 3.66-3.78 (1H, m),
3.89-4.06 (2H, m), 5.73 (1H, s), 7.14-7.20 (2H, m), 7.25—7.30 (1H, m).
(Example 9) 2—[(3S,4R)—3-{[(3S)—1-(Cyclohex—1—eny1methyl)pyrrolidin—3-
yl]carbamoyl}~l—[(2,6-dichlorophenyl)methyl]—4—methylpyrrolidin—3—y1]acetic acid
[0208] (Example 9a) tert—Butyl N—[(3S)(cyclohex—1-eny1methyl)py1rolidin—3-
yl]carbamate
l-Cyclohexene-l-carboxaldehyde (1.48 ml, 13 mmol) was added to a mixture of
(3S)—(—)—3~(tert—butoxycarbonylamino)pyrrolidine (2.0 g, 10.8 mmol), acetic acid (1.24 ml,
21.6 mmol) and tetrahydrofiiran (dehydrated) (27 ml), ed by stirring at room
temperature for 15 minutes, and sodium triacetoxyborohydn'de (4.58 g, 21.6 mmol) was then
added and the reaction mixture was stirred at room ature for 17 hours and 45 minutes.
A ted aqueous sodium bicarbonate solution was added to the reaction mixture, which
was extracted with ethyl acetate. The c layer was dried over sodium sulfate, and the
solvent was distilled 011‘. The residue was purified by NH silica gel column
chromatography (elution solvent: ethyl acetate/heptane) to give the title compound (1.3 g,
yield: 42.9%). ,
1H—NMR (400 MHZ, CDC13) 6 ppm; 1.44 (9H, s), 1.50-1.65 (5H, m), 1.95-2.03 (4H, br),
2.17-2.29 (2H, m), 2.40-2.55 (2H, m), 2.65-2.74 (1H, m), 2.84-2.94 (2H, m), 4.10—4.19 (1H,
br), 4.77-4.87 (1H, br), 5.56 (1H, br s).
[0209] (Example 9b) (3S)(Cyclohex—1-en—1-y1methy1)pyrrolidin—3-amine
A mixture of tert—butyl N—[(3S)(cyclohexen—1~ylmethyl)py1rolidin—3-
yl]carbamate obtained in Example 9a (1.3 g, 4.64 mmol) and ethanol (9.2 ml) was stirred
under ice-cooling, a 5 N aqueous hloric acid solution (9.28 ml, 46.4 mmol) was
FP11—0417
added, and the reaction mixture was stirred at room temperature for 14 hours and 30 minutes.
The reaction mixture was stirred under ice-cooling, a 5 N aqueous sodium hydroxide
solution (9.28 ml, 46.4 mmol) was added, and the solvent was distilled off. Ethanol was
added to the residue, the precipitated solid was filtered 011°, and the solvent in the filtrate was
distilled off. Ethanol was fiirther added to the residue, the precipitated solid was filtered off,
and the t in the filtrate was distilled 011"to give the title compound (0.8 g, yield 95.6%).
1H-NTVIR (400 MHZ, CD3OD) 5 ppm; 1.50—1.68 (6H, m), .05 (3H, m), 2.14-2.23’(1H,
m), 2.28—2.32 (1H, m), 2.43-2.49 (1H, m), 2.63-2.73 (2H, m), 2.91-2.98 (2H, m), 3.44—3.50
(1H, m), 5.62 (1H, br s).
[0210] (Example 9c) tert—Butyl 2-[(3S,4R){[(3S)—1~(Cyclohex—l-en—1—
ylmethyl)pyrrolidin—3-yl]carbamoyl}~l~[(2,6~dichlorophenyl)methyl]~4—methylpyrrolidin—3-
yl]acetate
The title compound (236 mg, yield 58%) was obtained from (3S)—1—(cyclohex—l-
en—l-yhnethyl)pyrrolidin—3-amine obtained in e 9b (169 mg, 0.94 mmol) and
(3S,4R)[2—(tert-butoxy)-2—oxoethyl]-1—[(2,6—dichlorophenyl)methyl]—4-methylpyrrolidine—
oxylic acid obtained in Example 2k (290 mg, 0.72 mmol) by a method similar to the
method described in e 1k.
1H—NMR (400 MHZ, CDC13) 6 ppm; 0.91 (3H, d, J=7 Hz), 1.41 (9H, s), .63 (6H, m),
1.87—2.14 (6H, m), 2.20-2.25 (1H, m), 2.33-2.40 (1H, m), .67 (4H, m), 2.79-2.94 (3H,
m), 3.11 (1H, d, J==16 Hz), 3.62 (1H, d, J=10 Hz), 3.92-4.02 (2H, m), 4.28—4.38 (1H, In), 5.74
(1H, br s), 7.17 (1H, dd, J=7, 8 Hz), 7.32 (2H, d, J=8 Hz), 8.30 (1H, d, J=7 Hz).
(Example 9d) 2-[(3S,4R)—3~{[(3S)—l—(Cyclohex—1-en-1—ylmethyl)pyrrolidin—3—
yl]carbamoyl}—1—[(2,6—diclflorophenyl)methyl]—4-methylpyrrolidin—3~y1]acetic acid
The title compound (173 mg, yield 81%) was obtained fiom tert—butyl 2-[(3S,4R)—
3-{[(3S)(cyclohex—l-en—1—yhnethyl)pyrrolidin—3-yl]carbamoyl}—1-[(2,6—
dichlorophenyl)methyl]~4—methylpyrrolidin—3-yl]acetate obtained in Example 90 (236 mg,
0.42 mmol) by a method similar to the method descfibed in Example 1m.
1H—NMR (400 MHZ, CD3OD) 5 ppm; 0.89 (3H, d, J=7 Hz), 1.55—1.67 (4H, m), 1.73—1.84
(1H, m), 1.92-2.32 (7H, m), 2.58-2.68 (2H, m), 2.74-2.85 (2H, m), .15 (4H, m), 3.20-
3.34 (2H, m), 3.61 (1H, d, J=10 Hz), 4.00-4.08 (2H, m), .27 (1H, m), 5.74 (1H, br s),
7.29 (1H, dd, J=7, 9 Hz), 7.40-7.44 (2H, m).
(Example 10) 2-[(3S,4R){[2-Chloro(difluoromethyl)phenyl]methyl}[(l-
hexylpiperidin—4—yl)carbam0yl]—4-methylpy1rolidin—3—yl]acetic acid
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(Example 10a) l-Hexylpiperidin—4—arnine
The title compound was obtained by a method r to the method described in
U82005/0222175 A1 and Examples 4a and 4b.
1H—NMR (400 MHz, CDCl3) 5 ppm: 0.80 (3H, t, J=7 Hz), 1.05—1.45 (12H, m), 1.73 (2H, d,
J=6 Hz), 1.88 (2H, t, J=6 Hz), 2.21 (2H, dd, J=6, 8 Hz), 2.52-2.62 (1H, m), 2.79 (2H, d, J=12
(Example 1%) Methyl 3-chloro-2—methy1benzoate
Iodomethane (1.96 ml, 31.5 mmol) was added to a mixture of 3—chloro—2—
methylbenzoic acid (3.58 g, 21 mmol), potassium carbonate (5.8 g, 42 mmol) and N,N-
dimethylformarnide (35.9 ml), followed by stirring at room temperature for 18 “hours and 30
minutes. Water and ethyl acetate were added to the reaction liquid, and the organic layer
was extracted. The organic layer was sequentially washed with a saturated aqueous
ammonium chloride solution and brine, and then dried over sodium sulfate, filtered and
concentrated. The residue was purified by silica gel column tography (elution
solvent: heptane/ethyl acetate) to give the title compound (3.67 g, yield: 97%).
1H—NMR (400 lVH-Iz, CDC13) 5 ppm; 2.60 (3H, s), 3.91 (3H, s), 7.13-7.21 (1H, m), 7.50 (1H,
dd, J=1, 8 Hz), 7.70 (1H, dd, J=1, 8 Hz).
(Example 10c) Methyl 2—(bromomethyl)—3-chlorobenzoate
A suspension ofmethyl 3-chloro—2—methylbenzoate obtained in Example 10b (1 g,
5.42 mmol), carbon tetrachloride (13.3 ml), N—bromosuccinimide (1.06 g, 5.96 mrnol) and
benzoyl peroxide (3.5 mg, 0.0108 mmol) was heated in a 90°C oil bath under a nitrogen
stream. After three hours and 45 minutes, heating was completed, and the mixture was
diluted with water, ethyl e and a ted aqueous sodium bicarbonate solution. The
organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over
ous magnesium sulfate, d and concentrated to give the title compound (1.43 g,
yield: 100%).
1H—NMR (400 MHz, CDClg) 5 ppm; 4.00 (3H, s), 5.12 (2H, s), 7.32 (1H, t, J=8 Hz), 7.58
(1H, dd, J=2, 8 Hz), 7.86 (1H, dd, J=2, 8 Hz).
(Example 10d) [2—(Bromomethyl)—3—chlorophenyl]methanol
Dichloromethane (10 ml) was added to methyl 2—(bromomethyl)—3-chlorobenzoate
obtained in Example 100 (500 mg, 1.9 mmol), a 1.04 M diisobutylalurninum hydride/n-
hexane solution (4.57 ml, 4.75 mmol) was added at -78°C, ed by stirring for one hour
under a nitrogen here. A saturated aqueous Rochelle salt on and tert—butyl
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methyl ether were added, followed by extraction with tert—butyl methyl ether. The organic
layer was washed with brine, dried over magnesium sulfate and then allowed to pass through
a silica gel pad. The eluate was concentrated to give the title compound (440 mg, yield
98.3%).
1H—NMR (400 MHz, CDC13) 5 ppm; 1.82 (1H, t, J=6 Hz), 4.78 (2H, s), 4.85 (2H, d, J=5 Hz),
7.25-7.28 (1H, m), 7.31-7.40 (2H, m).
"(Example 10e) momethyl)~3~chlorobenzaldehyde
Dichloromethane (15 ml) and ese dioxide (1.69 g, 19.4 mmol) were added
to [2-(bromomethyl)chlorophenyl]methanol ed in Example 10d (440 mg, 1.87
1'0 mmol), followed by stirring at room temperature overnight. Manganese dioxide (1.2 g,
13.8 mmol) was fiirther added, followed by heating with stirring at 40°C for 2.5 hours. The
reaction mixture was filtered through Celite and washed with ethyl acetate. The e was
concentrated under reduced re, and the resulting crude product was purified by column
chromatography (silica gel, elution solvent: heptane/ethyl acetate = 99/1 ——> 90/10) to give the
title compound (289 mg, yield 66.2%).
1H—NMR (400 MHz, CDC13) 5 ppm; 5.13 (2H, s), 7.48 (1H, t, J=8 Hz), 7.66 (1H, dd, J=l, 8
Hz), 7.77 (1H, dd, J=1, 8 Hz), 10.23 (1H, s).
(Example 10f) 2-(Bromomethyl)—l-chloro-3—(difluoromethyl)benzene
Dichloromethane (10 ml) was added to 2—(bromomethyl)—3—chlorobenzaldehyde
obtained in Example lOe (289 mg, 1.24 mmol), [bis(2-methoxyethyl)amino]sulfi1r ride
(457 pl, 2.48 mmol) was added at 0°C, ed by ng at room ature for 1.5
hours under a nitrogen atmosphere. A saturated aqueous sodium bicarbonate solution was
added at 0°C to the reaction mixture, which was extracted with diethyl ether. The organic
layer was washed with brine, dried over magnesium sulfate and then concentrated. The
resulting crude product was purified by column chromatography (silica gel, elution solvent:
heptane/ethyl acetate = 99/1 ——-> 95/5) to give the title compound (238.3 mg, yield 75.2%).
1H—NMR (400 MHz, CDC13) 5 ppm; 4.74 (2H, s), 6.93 (1H, t, J=55 Hz), 7.37 (1H, t, J=8
Hz), 7.53 (2H, t, J=8 Hz).
(Example 10g) (3RS,4SR)[2-(tert-Butoxy)-2~oxoethyl]-l-[(2,6-
dichlorophenyl)methyl]—4-methy1pyrrolidine—3-carboxy1ic acid
% palladium hydroxide (500 mg) was added to a solution ofbenzyl (3RS,4SR)-
1-benzyl[2-(te1t—butoxy)-2—oxoethyl]—4-methylpyrrolidinecarboxy1ate obtained by a
method r to that ofExample 1g (8.35 g, 19.7 mmol) in methanol (200 ml), followed by
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stirring at room temperature overnight under a hydrogen atmosphere. The reaction mixture
was filtered, and palladium on the filter paper was washed well with hot water at 50°C. The
e was concentrated and azeotropically distilled with methanol and toluene well to give a
white solid (3.92 g). Methanol (20 ml), chlorobenzaldehyde (5.64 g, 32.2 mmol),
acetic acid (966 pl, 16.1 mmol) and sodium triacetoxyborohydn'de (6.82 g,32.2 mmol) were
added thereto, followed by stirring at room temperature overnight. The reaction mixture
was fiirther heated with stining in a 50°C hot water bath for three hours. Neutral bufi‘er
[prepared fiom ium dihydrogenphosphate (13.65 g), disodium hydrogenphosphate
dodecahydrate (71.6 g) and water (1.5 L)] and ethyl acetate were added to the reaction
mixture, and the solid was filtered ofi‘. The solid on the filter paper was washed with ethyl
acetate to give the title nd as a white solid. The filtrate was extracted with ethyl
acetate, and the organic layer was then dried over sodium sulfate, concentrated, purified by
column tography (silica gel, elution solvent: methanol/ethyl acetate) and combined
with the solid on the filter paper to give the title compound (3.77 g, yield 58.2%).
1H—NMR (400 MHZ, CDC13) 5 ppm; 1.01 (3H, d, J=7 Hz), 1.42 (9H, s), 2.09 (1H, d, J=16
Hz), 2.14-2.24 (1H, m), 2.62—2.69 (2H, m), 2.99 (1H, t, J=10 Hz), 3.02 (1H, d, J=10 Hz),
3.71 (1H, d, J=10 Hz), 4.08 (1H, d, J=12 Hz), 4.12 (1H, d, J=12 Hz), 7.21 (1H, d, J=8 Hz),
7.23 (1H, d, J=8 Hz), 7.37 (1H, d, J=8 Hz).
(Example 10h) tert—Butyl 2—[(3 S,4R)—l-[(2,6—dichlorophenyl)methyl]~3-[(1-
hexylpiperidin—4—yl)carbamoyl]—4-methylpyrrolidin—3-yl]acetate
1-Hexy1piperidin-4—amine obtained in Example 10a (894 mg, 4.85 mmol),
tn'ethylamine (1.04 ml, 7.46 mmol), N,N~dimethylformamide (10 ml) and PyBOP (2.52 g,
4.85 mmol) were added to (3RS,4SR)[2—(tert—butoxy)-2—oxoethyl]—1{(2,6-
dichlorophenyl)methyl]methylpyrrolidine—3—carboxylic acid obtained in Example 10g (1.5
g, 3.73 mmol), followed by stirring at room temperature ght. Water was added to the
reaction mixture, which was extracted with ethyl acetate. The organic layer was washed
with water and brine and dried over sodium sulfate. This was trated, and the crude
t was purified by column chromatography (NH silica gel, elution solvent: ethyl
acetate/heptane) to give a white solid (1.85 g). This was optically ed by HPLC
LPAK IA (3 cm diameter x 25 cm), elution solvent: ethanol/hexane = 6/94, flow
rate: 20 ml/min.) to give a chiral form corresponding to the peak with a shorter retention time
(875 mg).
Analysis by HPLC;
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(Analysis ions) Column: PAK IA (manufactured by Daicel Chemical
Industries, Ltd.) (0.46 cm diameter x 15 cm), 40°C, eluent: hexane/ethanol = 9/1 (v/V), flow
rate: 1 ml/min., detection: UV (210 nm)
(Analysis result) The resulting chiral form was analyzed under the above analysis conditions
to find that the retention time was 4.85 minutes and the omeric excess was >99% ee.
(Example 10i) utyl 2—[(3S,4R)[(1—hexylpiperidin—4—yl)carbamoyl]—4—
methylpyxrolidin—B—ylkcetate
Methanol (10 ml) and 20% palladium hydroxide (50 mg) were added to 250 mg of
tert-butyl 2-[(3S,4R)—1-[(2,6-dichlorophenyl)methyl][(1—hexylpiperidin—4—yl)carbamoyl]—
4—methylpyrrolidin-3—yl]aeetate obtained in Example l’Oh, f0110wed ”by stirring at room
temperature for two hours under a hydrogen atmosphere. The reaction e was filtered,
and the filtrate was concentrated to give the title compound (180 mg).
1H—NMR (400 MHz, CDC13) 5 ppm; 0.85—0.90 (3H, m), 1.04 (3H, d, J=6 Hz), 1.25-1.35
(5H, m), 1.42 (9H, s), 1.78-2.10 (6H, m), 2.26-2.50 (4H, m), .05 (3H, m), 3.23 (1H, d,
J=13 Hz), 3.29-3.54 (5H, m), 3.55-3.67 (1H, m), 4.17 (1H, d, J=13 Hz), 4.27—4.40 (1H, br),
7.82-7.92 (1H, br).
(Example 103') tert—Butyl 2-[(3 S,4R)—1-{[2~chloro—6-
(difluoromethyl)phenyl]methyl}[(l-hexylpiperidin-4—yl)carbamoyl]-4~methylpyrrolidin—
3-yl]acetate
2O N,N—Dimethylformamide (400 pl), momethyl)—1—chloro—3-
(difluoromethyl)benzene obtained in Example 10f (24.9 mg, 0.0976 mmol) and potassium
carbonate (20.2 mg, 0.146 mmol) were added to utyl 2—[(3S,4R)—3-[(1-hexylpiperidin-
4—yl)carbamoy1]~4—methylpyrrolidin—3-yl]aeetate obtained in Example mi (20 mg, 0.0488
mmol), followed by stirring at room temperature overnight. Ethyl acetate and water were
added to the reaction mixture, which was extracted with ethyl acetate. The organic layer
was washed with brine and dried over magnesium sulfate. This was concentrated, and the
resulting crude product was purified by column chromatography (NH silica gel, elution
t: heptane/ethyl acetate = 98/2 —~> 80/20) to give the title compound (14.4 mg, yield
50.2%).
1H—NMR (400 MHz, CDC13) 5 ppm; 0.87-0.94 (6H, m), 1.22-1.35 (6H, m), 1.40 (9H, s),
1.40-1.49 (2H, m), 1.68-1.76 (1H, m), .12 (7H, m), 2.24-2.28 (2H, m), 2.54 (1H, d,
J=1O Hz), 2.59-2.63 (1H, m), 2.74-2.88 (3H, m), 3.13 (1H, d, J=16 Hz), 3.61 (1H, d, J=10
Hz), 3.61-3.72 (1H, m), 3.91 (1H, (1, 1:13 Hz), 3.95 (1H, d, J=13 Hz), 6.96 (1H, t, J=55 Hz),
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7.35 (1H, t, J=8 Hz), 7.54 (2H, d, J=8 Hz), 7.65 (1H, d, J=8 Hz).
(Example 10k) 2-[(3S,4R)-l-{[2-Chloro-6—(difluoromethyl)phenyl]methyl}[(l-
hexylpiperidin—4-yl)carbamoyl]—4-methylpyrrolidin—3-yl]acetic acid
The title compound (13.9 mg, yield 61.5%) was obtained fiom tert—butyl 2-
[(3S,4R)—1-{[2-chloro-6—(difluoromethyl)phenyl]methy1}—3-[(l-hexylpiperidin—4—
yl)carbamoyl]—4—methylpyrrolidin-3—yl]acetate obtained by a method r to that of
Example 10j (25 mg, 0.0428 mmol) by a method similar to the method described in
Example 1m.
1H—NMR (400 MHz, CDC13) 5 ppm; 0.82090 (3H, m), 0.93 (3H, d, J=7 Hz), 1.23-1.34
1'0 (6H, m), .64 (2H, rn), 1.76—1198“(4H, In), 2.22-2.44 '(4H, m), 2.50—2.78 (SH, m), 2.91
(1H, t, J=8 Hz), 3.22—3.35 (1H, br), .43 (1H, m), 3.70-3.82 (1H, m), 3.92 (1H, d, J=14
Hz), 3.96 (1H, d, J=l4 Hz), 7.21 (1H, t, J=55 Hz), 7.30 (1H, t, J=8 Hz), 7.48 (1H, d, J=8 Hz),
7.55 (1H, d, J=8 Hz), 8.92-9.08 (1H, br).
le 11) 2—[(3S,4R){[(l—Cyclohex-l—en-l~ylmethyl)piperidin—4—
yl]carbamoyl}-1~[(2,6—dichlorophenyl)methyl]methylpyrr01idin—3-yl]acetic acid
(Example 11a) (3S,4R)—3-[2-(tert-Butoxy)—2—oxoethyl]—1-[(2,6—
dichlorophenyl)methyl]-4—methylpyrrolidine—3-carboxylic acid
Methanol (3 ml), 2,6—dichlorobenzaldehyde (431 mg, 2.46 mmol), acetic acid (73.8
r11, 1.23 mmol) and sodium triacetoxyborohydride (521 mg, 2.46 mmol) were added to
(3S,4R)—3-[2—(tert—butoxy)-2—oxoethyl]—4—methylpyrrolidine—3—carboxylic acid obtained by a
method similar to that of Example 1i (300 mg, 1.23 mmol), followed by stirring at room
temperature for two days. Water was added to the system, which was extracted with ethyl
acetate, and the c layer was dried over sodium sulfate and concentrated. The
ing crude product was purified by column chromatography (silica gel, elution solvent:
methanol/ethyl acetate) to give the title compound (180 mg). On the other hand, the
aqueous layer upon partitioning was concentrated and purified by ODS column
chromatography (elution solvent, methanol/water) to recover )[2-(tert~butoxy)-2—
oxoethyl]—4—methylpyrrolidinecarboxylic acid (120 mg). "Ihe title compound (42.7 mg)
was obtained by performing similar reaction again using the red raw material, and was
combined with the first title compound (180 mg).
1H—NMR (400 MHZ, CDC13) was confirmed to be identical to that ofthe compound obtained
in Example 10g.
(Example 11b) tert—Butyl 2—[(3S,4R)-{3-[(1—cyclohex—l—en—l—ylmethyl)pipe1idin—4—
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yl]carbamoyl}-1 -[(2,6—dichlorophenyl)methyl]—4—methylpyrr01idinyl]acetate
The title compound (274 mg, yield 85.8%) was obtained from (3S,4R)[2—(tert—
butoxy)oxoethyl]—1-[(2,6-dichlorophenyl)methyl]methy1pyrrolidinecarboxy]ic acid
obtained in Example lla (222 mg, 0.55 mmol) and l-(cyclohex—1~enylmethyl)piperidin~
4-amine obtained in Example 4b (150 mg, 0.772 mmol) by a method similar to the method
described in Example 1k.
/IR‘(400 DCl3) 5 ppm; 0.91 (3H, d, J=8 Hz), 1.31-1.50 (2H, m), 1.42 (9H, s),
1.52-1.72 (5H, m), 1.81—2.12 (9H, m), 2.55-2.70 (4H, m), 2.75 (2H, s), 2.92 (1H, t, J=10 Hz),
3.12 (1H, d, J=l6 Hz), 3.60-3.72 (2H, m), 3.96 (2H, s), 5.54 (1H, s), 7.18 (1H, t, J=8 Hz),
7.33 (2H, d, J=8 Hz), 8.09 (1H, d, J=8 Hz).
(Example 110) 2-[(38,4R){[(l-Cyclohex-l—en—l-ylmethyl)piperidin
bamoy1}-l-[(2,6-dichlorophenyl)methyl]—4-methylpyrrolidin~3-y1]acetic acid
The title nd (169 mg, yield 68.2%) was obtained from tert—butyl 2—
[(3S,4R)—{3~[(1~cyclohex-l-enylmethy1)piperidin—4-y1]carbamoyl}[(2,6-
dichlorophenyl)methyl]-4—methy1pyrrolidin—3-yl]acetate obtained in Example 11b (274 mg,
0.474 mmol) by a method similar to the method described in Example 1m.
1H—NMR (400 MHZ, CD30D) 5 ppm; 0.89 (3H, d, J=7 Hz), 1.56-1.75 (6H, m), 1.78-1.94
(2H, m), 2.00-2.26 (6H, m), 2.36—2.48 (2H, m), 2.60-2.64 (1H, m), 2.68 (1H, d, J=10 Hz),
2.95-3.19 (6H, m), 3.62 (1H, d, J=10 Hz), 3.68-3.80 (1H, br), 3.99—4.07 (2H, m), 5.76 (1H,
. s), 7.29 (1H, t, J=8 Hz), 7.43 (2H, d, J=8 Hz).
(Example 12) ,4R)—1—{[2—Chloro(difluoromethyl)phenyl]methyl}-3—{[1—
(cyclohex~1~en—1~ylmethyl)pipe1idin—4~yl]carbamoyl}—4-methylpyrrolidin—3—yl]acetic acid
(Example 12a) tert—Butyl 4—[(3S,4R)[2-(tert—butoxy)~2~oxoethyl]~1-{[2—chloro—
6~(difluoromethyl)pheny1]methyl}—4-methylpyrrolidin~3~amido]piperidine—1-carboxylate
tert-Butyl 4—[(3S,4R)—3—[2—(tert—butoxy)—2-oxoethyl]—4—methylpyrrolidin—3-
amido]piperidine-l-carboxylate obtained in Example 3b (375 mg, 0.881 mmol) was
ved in N,N-dimethylformamide (7 ml). Potassium carbonate (304 mg, 2.2 mmol)
and 2—(bromomethy1)chloro(difluoromethyl)benzene obtained by a method similar to
that ofExample 10f(450 mg, 1.76 mmol) were added thereto, and the mixture was heated in
a 45°C oil bath for two hours. The reaction e was partitioned between ethyl acetate
and a ted aqueous ammonium chloride solution. The ted organic layer was
washed with a saturated aqueous ammonium chloride solution three times, dried over
anhydrous magnesium sulfate, filtered and concentrated The residue was purified by silica
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gel column chromatography (silica gel, elution solvent: heptane/ethyl acetate) to give the title
compound (332 mg, yield: 62.8%).
1H—NMR (400 MHz, CDC13) 6 ppm; 0.92 (3H, d, J=7 Hz), 1.13-1.74 (3H, m), 1.39 (9H, s),
1.49 (9H, s), 1.75—1.87 (1H, m), 2.00 (1H, d, J=16 Hz), 2.04-2.15 (1H, m), 2.52 (1H, d, J=10
Hz), 2.56-2.83 (3H, m), 2.86 (1H, t, J=10 Hz), 3.12 (1H, d, J=10 Hz), 3.57 (1H, d, J=10 Hz),
3.80—4.16 (3H, m), 3.90 (1H, d, J=13 Hz), 3.96 (1H, d, J=13 Hz), 6.93 (1H, t, J=55 Hz), 7.37
(1H, t, J=8 Hz), 7.55 (2H, d, J=8 Hz), 7.77 (1H, d, J=8 Hz).
(Example 12b) 2—[(3S,4R)—1-{[2-Chloro(difluoromethyl)phenyl]metl'ryl}{[1-
(cyclohex—l~en—l—ylmethy1)piperidin~4—yl]carbamoyl}—4~methylpyrrolidin—3—yl]acetic acid
1‘0 tert-Butyl 4-‘[(3‘S,4R)—3-’[2—(tert~but0xy)oxoethyl]-1—{[2—chloro46-
(difluoromethyl)phenyl]methyl}—4—methylpyrrolidin~3-amido]piperidine—1-carboxylate
obtained in Example 12a (332 mg, 0.553 mmol) was dissolved in romethane (3.0 ml),
trifluoroaoetic acid (3 .0 ml) was added thereto, and the mixture was then left to stand at room
temperature. After two hours and 30 minutes, the reaction liquid was concentrated and
azeotropically distilled with dichloromethane twice to give an ediate. 186 mg of the
resulting intermediate (372 mg) was dissolved in ydrofuran (5 ml), ylamine (116
141, 0.831 mmol) and cyclohex—l-ene-l-carbaldehyde (91.5 mg, 0.831 mmol) were added,
and the mixture was left to stand at room temperature. After 30 minutes, sodium
tn'acetoxyborohydride (176 mg, 0.831 mmol) was added thereto, and the mixture was d
at room temperature. After 10 hours and 50 minutes, the mixture was concentrated. The
residue was purified by silica gel column chromatography (ODS, elution solvent:
water/methanol) to give the title compound (80 mg) as a white solid.
1H—NMR (400 MHz, CD3OD) 8 ppm; 0.90 (3H, d, J=7 Hz), 1.57—1.75 (6H, m), 1.83—1.96
(2H, m), 2.02-2.13 (4H, m), 2.15-2.27 (1H, m), 2.27 (1H, d, J=16 Hz), 2.46-2.65 (3H, m),
2.61 (1H, d, J=10 Hz), 2.95 (1H, t, J=9 Hz), 2.97 (1H, d, J=16 Hz), 3.03-3.16 (2H, m), 3.20-
3.27 (2H, m), 3.50 (1H, d, J=10 Hz), 3.74-3.83 (1H, m), 3.98 (1H, d, J=13 Hz), 4.02 (1H, d,
J=13 Hz), 5.78-5.86 (1H, br), 7.26 (1H, t, J=55 Hz), 7.42 (1H, t, J=8 Hz), 7.60 (2H, d, J=8
Hz).
(Example 13) 2-[(3S,4R)—1-{[2—Chloro(difluoromethyl)phenyl]methyl} {[l-
3O (cyclopent—l -en—1 -ylmethyl)piperidin—4—yl]carbamoyl}methylpyrrolidin—3-yl]acetic acid
The title compound (76 mg) was obtained by a method similar to the method
described in e 12b using the intermediate ed in e 12b (186 mg) and
cyclopent—l-ene—l~carbaldehyde obtained in Example 721 (79.9 mg, 0.831 mmol).
FP11-0417
1H—NMR (400 MHz, CD30D) 5 ppm; 0.90 (3H, d, J=7 Hz), 1.58-1.75 (2H, m), .00
(4H, m), 2.15-2.27 (1H, m), 2.47 (1H, d, J=16 Hz), 2.32-2.42 (4H, m), 2.46-2.65 (3H, m),
2.62 (1H, d, J=10 Hz), 2.95 (1H, t, J=9 Hz), 2.99 (1H, d, J=l6 Hz), 3.03-3.16 (2H, m), 3.36-
3.43 (2H, m), 3.51 (1H, d, J=10 Hz), 3.73—3.82 (1H, m), 3.98 (1H, d, J=13 Hz), 4.03 (1H, d,
J=13 Hz), 5.78—5.83 (1H, br), 7.25 (1H, t, 1:55 Hz), 7.43 (1H, t, J=8 Hz), 7.61 (2H, d, J=8
Hz).
6 (Example 14) 2—'[(3S,4R)—1—'{[2-Chloro—6~(difluoromethyl)phenyl]methyl}~3—{[1—
(cyclohexylmethyl)piperidin—4—y1]carbamoyl}-4~methy1pyrrolidin—3-y1]acetic acid
(Example 14a) 1-(Cyclohexylmethy1)piperidinamine
The title nd was obtained by a method similar to the method described in
/0222175 A1 and Examples 4a and 4b.
1H—NMR (400 MHZ, CDCl3) 8 ppm: 0.77—0.87 (2H, m), 1.11-1.49 (8H, m), 1.61~1.80 (5H,
m), 1.97 (2H, t, J=12 Hz), 2.14 (2H, d, J=7 Hz), 2.50-2.64 (1H, m), 2.96 (2H, d, J=12 Hz).
(Example 14b) tert~Buty1 2—[(3S,4R)—1-benzyl—3—{[1—(cyclohexy1methyl)piperidin—
4—yl]carbamoyl}—4—methylpyrrolidin—3—yl]acetate
The title compound (250 mg, yield: 81.4%) was obtained from (3S,4R)—1-benzyl-
3~[2-(tert-butoxy)—2—oxoethy1]—4-methy1pyrrolidine—3-carboxy1ic acid obtained in Example 1j
(200 mg, 0.6 mmol) and 1—(cyc1ohexylmethyl)pipe1idine—4~amine obtained in Example 14a
(141 mg, 0.72 mmol) by a method r to the method described in Example 1k
1H—NMR (400 MHz, CDC13) 5 ppm; 0.80—0.98 (2H, m), 0.92 (3H, d, J=7 Hz), 1.07—2.15
(17H, m), 1, 58 (9H, s), 1.95 (1H, d, J=16 Hz), 2.10 (1H, d, J=7 Hz), 2.36 (1H, d, J=10 Hz),
2.55—2.83 (4H, m), 3.08 (1H, d, J=16 Hz), 3.59 (1H, d, J=10 Hz), 3.63—3.77 (1H, m), 3.64
(1H, d, J=13 Hz), 3.69 (1H, d, J=13 Hz), 7.21—7.36 (5H, m), 8.56 (1H, d, J=8 Hz).
(Example 14c) tert—Butyl 2—[(3S,4R)—1~{[2—chloro—6—
(difluommethyl)phenyl]methyl}{[1-(cyclohexylmethyl)piperidin~4—yl]carbamoyl}
methylpynolidin—3—yl]acetate
The title compound (198 mg, yield: 67.9%) was obtained from tert—butyl 2-
[(3S,4R)-1—benzy1—3-{[1-(cyclohexylmethyl)pipe1idin—4-y1]carbamoyl}—4-methylpynolidin—
3-yl]acetate obtained in Example 14b (250 mg, 0.489 mmol) and 2—(bromomethyl)—1-chloro~
3-(difluoromethyl)benzene obtained by a method similar to that of Example 10f (250 mg,
0.978 mmol) by a method similar to the method bed in e 11.
1H—NMR (400 MHZ, CDC13) 8 ppm; 0.78-0.97 (2H, m), 0.91 (3H, d, J=7 Hz), 1.08-2.13
(18H, m), 1.40 (9H, s), 2.00 (1H, d, J=17 Hz), 2.05 (1H, d, J=7 Hz), 2.54 (1H, d, J=10 Hz),
FPll-04l7
2.61 (1H, dd, J=6, 10 Hz), .77 (2H, m), 2.85 (1H, t, J=10 Hz), 3.60 (1H, d, J=17 Hz),
3.58-3.72 (1H, m), 3.92 (1H, d, J=13 Hz), 3.96 (1H, d, J=13 Hz), 6.97 (1H, t, J=55 Hz), 7.36
(1H, t, J=8 Hz), 7.51-7.58 (2H, m), 7.62 (1H, d, J=8 Hz).
(Example 14d) 2-[(3S,4R)-1—{[2-Chloro(difluoromethy1)phenyl]methyl}-3—{[1-
hexylmethyl)piperidin—4—yl]carbamoyl}—4—methylpyrrolidin—3-yl]acetic acid
The title compound (140 mg, yield: 79.8%) was obtained from tert-butyl 2—
[(3S,4R)—1~{[2-chloro—6-(difluoromethyl)phenyl]methyl}~3-{[1—
(cyclohexyhnethyl)piperidin—4—y1]carbamoyl}-4—methylpyrrolidin—3—yl]acetate obtained in
Example 140 (194 mg, 0.325 mmol) by a method similar to the method described in
Example 1m.
1H—NMR (400 MHz, CD3OD) 6 ppm; 0.90 (3H, d, J=7 Hz), 0.93-1.06 (2H, m), 1.16—1.40
(4H, m), 1.62-1.83 (8H, m), 1.85-1.98 (2H, m), 2.17—2.28 (1H, m), 2.29 (1H, d, J=16 Hz),
.50 (1H, m), 2.56-2.80 (4H, m), 2.90-2.99 (2H, m), 3.10-3.25 (2H, m), 3.49 (1H, d,
J=10 Hz), 3.76-3.86 (1H, m), 3.97 (1H, d, J=13 Hz), 4.01 (1H, d, J=13 Hz), 7.28 (1H, t, J=55
Hz), 7.42 (1H, t, J=8 Hz), 7.56-7.63 (2H, m).
(Reference Example 1) 1,3-Dibenzyl (3RS,4SR)—3-[2—(tert—butoxy)-2—oxoethyl]—4-
methylpyrrolidine-l,3-dicarboxylate
(Reference Example 1a) (3RS,4SR)—3-[2-(tert-Butoxy)—2—oxoethyl]
methylpyrrolidinecarboxylic acid
2O 44.7 g of (4—methoxyphenyl)methyl (3RS,4SR)~1~benzyl[2—(tert—but0xy)—2—
oxoethyl]—4-methylpy1rolidine—3—carboxylate was obtained by a method similar to the
method described in es 2e to 2g. A part of this nd (20 g, 44.1 mmol) was
dissolved in methanol (316 ml), 10% Pd/C (3.93 g) was added, and the atmosphere was
replaced with hydrogen gas. The mixture was stirred at room temperature overnight and
then stirred with addition ofwarm water (36°C, 160 ml) for 30 minutes, and the precipitated
solid was dissolved. Pd/C was filtered off, the e was then concentrated so that about
to 40 ml of water remained, and methanol (80 ml) was added to the cloudy residue
containing water, which was stirred for 30 minutes. The precipitated solid was filtered off
(LotA). lH—NMR ofLotA is shown below.
Lot B was obtained by a similar method using (4-methoxyphenyl)methyl
(3RS,4SR)benzyl[2-(tert-butoxy)-2—oxoethyl]—4-methy1pyrrolidine—3-carboxylate (21
g, 46.3 mmol). After confirming that 1H—NMR ofLot B is identical to 1H—NMR ofLot A,
LotA and Lot B were combined and dried to give the title compound (9.91 g).
FP11—0417
1H—NMR (400 MHz, D20) 5 ppm; 0.97 (3H, d, J=6 Hz), 1.42 (9H, s), 2.12-2.24 (1H, m),
2.29 (1H, d, J=17 Hz), 2.93 (1H, d, J=17 Hz), 3.04 (1H, t, J=12 Hz), 3.18 (1H, d, J=12 Hz),
3.49 (1H, dd, J=8, 12 Hz), 4.03 (1H, d, J=12 Hz).
(Reference e 1b) (3RS,4SR)—1-[(Benzyloxy)carbonyl][2—(tert—butoxy)—
thyl]—4-methylpyrrolidine—3—carboxylic acid
A 2 N aqueous sodium hydroxide solution (20.2 ml) was added to a mixture of
(3RS,4SR)—3—[2—(tert—butoxy)—2~oxoethyl]methylpyrrolidinecarboxylic acid obtained in
Reference Example 1a (9.84 g, 40.5 mmol), acetone (39 ml) and water (49 ml) with stirring
under ice-cooling (0 to 1°C), and the on mixture was dissolved by stirring for 45
minutes. Benzyl chloroformate (6.35 ml, 44.5 mmol) and a 2 N s sodium hydroxide
solution (22.3 ml) were simultaneously added dropwise to the reaction mixture at an internal
temperature of 35°C or lower with stirring under ice-cooling (O to 1°C) over 20 minutes.
The reaction liquid was stirred in an ice bath and gradually returned to room temperature.
This was stirred at room temperature overnight. A 1 N aqueous sodium hydroxide solution
(10 ml) was added to the reaction liquid with stirring under ice—cooling (internal temperature:
about 15°C), and the mixture was adjusted to pH 12. This reaction liquid was returned to
room temperature and washed three times by adding ethyl ether. The aqueous layer was
adjusted to pH 2 to 3 by tially adding a 2 N aqueous hydrochloric acid solution (20.2
ml) and a l N aqueous hydrochloric acid solution (13 ml) with stirring under ice-cooling
(internal temperature: 5°C or lower). The aqueous layer was returned to room temperature
and ted with ethyl acetate three times. The organic layer was washed with brine, and
then dried over sodium sulfate, filtered and concentrated. The residue was ved in
ethyl acetate, washed with water four times and then with brine, dried over sodium sulfate,
filtered and trated to give the title compound (14.53 g, yield: 95.1%).
1H—NMR (400 MHz, CDC13) 8 ppm; 1.02 (3H, t, J=8 Hz), 1.42 (9H, s), 2.14-2.22 (1H, m),
2.27 (1H, d, J=17 Hz), 3.04 (1H, d, J=5, 17 Hz), 3.12-3.19 (1H, m), 3.35 (1H, dd, J=7, 12
Hz), 3.65—3.72 (1H, m), 4.29 (1H, dd, J=7, 12 Hz), 5.09-5.19 (2H, m), 7.26—7.38 (5H, m).
(Reference Example 10) 1,3—Dibenzyl SR)[2-(tert-butoxy)—2-oxoethyl]—
4—methylpyrrolidine-1,3—dicarboxylate
Benzyl bromide (4.48 ml, 37.7 mrnol) was added to a e of (3RS,4SR)
[(benzyloxy)carbonyl][2-(tert-butoxy)-2—oxoethyl]—4—met1’1ylpyrrolidinecarboxylic acid
obtained in Reference Example lb (14.5 g, 38.5 mmol), potassium carbonate (10.6 g, 77
mmol) and N,N—dimethylformamide (50 ml) with ng under ice-cooling (internal
FP11-0417
temperature: 3 to 7°C), and the mixture was stirred for one hour, ed to room
temperature and stirred overnight. Water was added to the reaction , which was
extracted with ethyl acetate three times. The organic layers were combined, tially
washed with a saturated s ammonium chloride solution (five times), water (twice) and
brine, and then dried over sodium sulfate, filtered and concentrated to give the title
nd (17.67 g, yield: 98.2%).
1H—NMR (400 MHz, CDC13) 5 ppm; 0.84-0.89 (3H, m), 1.36—1.39 (9H, m), 2.09218 (1H,
m), 2.24 (1H, dd, J=3, 17 Hz), 3.04-3.13 (2H, m), 3.35 (1H, dd, J=8, 12 Hz), 3.59—3.68 (1H,
m), 4.32 (1H, t, J=12 Hz), 506-5.20 (4H, m), 7.29—7.36 (10H, m).
[0241] (Reference Example 2) (3 S,4R)—3-[2-(tert—Butoxy)—2—0xoethyl]-4~
methylpyrrolidinecarboxylic acid
(Reference Example 2a) (-)-Dibenzoyl—L—tartrate of (4-methoxyphenyl)methyl
(3R,4R)-1—benzyl—4-methylpyrrolidjne-3—carboxy1ate
(4-Methoxyphenyl)methyl RS)-1~benzyl—4—methylpyrrolidine—3—
carboxylate tely obtained by a method similar to the method described in Example 2f
(1000 mg, 2.946 mmol) was dissolved in methyl isobutyl ketone (4 ml), and benzoyl-L—
tartaric acid (1055 mg) was added and dissolved. Crystals obtained from (4-
methoxyphenyl)methyl (3RS,4RS)—1—benzyl—4—methylpyrrolidine—3—carboxylate separately
obtained by a method similar to that of Example 2f and (-)—dibenzoyl-L—tartaric acid were
added to the resulting solution as seed crystals, and the ing precipitate was filtered offto
give the title compound (757 mg, yield: 36.8%). l (3.02 mL) was added to 755 mg
ofthe resulting solid, which was heated and dissolved, and then tert—butyl methyl ether (6.04
mL) was added. The resulting precipitate was filtered off to give the title compound (658
mg, yield: 87.2%) as crystals.
(4-Methoxypheny1)methyl (3RS,4RS)—1-benzyl-4—methylpyrrolidine—3—
carboxylate separately obtained by a method similar to the method described in Example 2f
(150.0 g, 441 mmol) was dissolved in methyl isobutyl ketone (600 ml), and (-)—dibenzoyl-L-
tartaric acid (157.0 g) was added and dissolved with stirring. (4-Methoxyphenyl)methyl
(3R,4R)-l-benzyl—4-methylpyrrolidine-3carboxylate (—)—dibenzoyl—L-tartrate obtained by the
method described in the previous paragraph was added to the resulting solution as seed
crystals (7.5 mg), followed by stirring for 18 hours and 18 minutes. The precipitated solid
was filtered OEand washed with methyl isobutyl ketone (150 ml). The resulting solid was
dried under d pressure at 50°C to give the title compound (152.07 g, yield: 49.4%).
FP11—0417
Ethanol (600 ml) was added to 150.00 g of the resulting solid, which was heated to 80°C
with stirring, and ution of the solid was ed, after which heating was stopped.
Fifiy—nine minutes after stopping heating, tert-butyl methyl ether (300 ml) was added over
nine minutes; after further six minutes, seed crystals (5 mg) were added. After 12 minutes,
tert—butyl methyl ether (900 ml) was added over two hours and 38 minutes, followed by
stirring for fiirther 10 hours and 43 s. The precipitated solid was filtered OE and
washed with a mixture of l and tert-butyl methyl ether (75 ml + 150 ml). The
resulting solid was dried under reduced pressure at 50°C to give the title compound (106.40
g, yield: 70.9%).
1H—NMR (400 MHz, DMSO—d6) 6 ppm; 1.05 (3H, d, J=6 Hz), 2.32-2.45 (2H, m), 2.64-2.78
(1H, m), 2.92-3.12 (3H, m), 3.75 (3H, s), 3.80-3.94 (2H, m), 5.04 (2H, dd, J=12, 16 Hz), 5.77
(2H, s), 6.90-6.96 (2H, m), 7.26-7.38 (7H, m), 7.52-7.58 (4H, m), 7.66-7.72 (2H, m), 7.95-
8.05 (2H, m).
Analysis by HPLC;
(Analysis conditions) Column: CHIRALCEL OJ-H (manufactured by Daicel al
Industries, Ltd.) (0.46 cm diameter x 25 cm), eluent: hexane/emanol/diethylanfine =
850/150/1 (v/V/v), flow rate: 1 ml/min., detection: UV (226 mn)
sis result) The resulting title compound was analyzed under the above analysis
conditions, and a peak with a retention time of 8.62 minutes (enantiomeric excess: 98.0% cc)
and a peak with a retention time of 10.9 s were observed.
(Reference Example 2b) (4-Methoxypheny1)methy1 )benzyl—4—
methylpyrrolidine—3-carboxylate
Ethyl acetate (900 ml) was added to (—)—dibenzoyl—L—tartrate of (4-
methoxyphenyl)methyl (3R,4R)—1-benzyl-4—methylpy1rolidine—3~carboxylate obtained in
Reference Example 2a (104.0 g), and a 1 N aqueous sodium hydroxide solution (600 ml)
was added with stirring. The aqueous layer was discarded, and the c layer was
washed with water twice (100 ml, 50 ml). The resulting organic layer was concentrated
under reduced pressure at 50°C to give the title compound (49.8 g, yield: 98.5%).
1H—NMR (400 MHz, CDCl3) 6 ppm; 1.12 (3H, d, J=7 Hz), 2.19 (1H, dd, J=6, 9 Hz), 2.44-
2.62 (2H, m), 2.73—2.84 (2H, m), 2.85-2.92 (1H, m), 3.55 (1H, d, J=13 Hz), 3.63 (1H, d, J=l3
Hz), 3.81 (3H, s), 5.02-5.10 (2H, m), .90 (2H, m), 7.21-7.33 (7H, m).
(Reference Example 2c) (3S,4R)[2-(tert-Butoxy)-2—oxoethyl]-4—
methylpyrrolidine—3-carboxy1ic acid
FPll-0417
Tetrahydrofinan (200 ml) was added to (4-methoxyphenyl)methyl (3R,4R)—1-
benzyl-4—methylpyrrolidine—3-carboxylate obtained in Reference Example 2b (29.50 g, 87
mmol), ed by azeotropic dehydration. Tetrahydrofinan (200 ml) was finther added,
followed by azeotropic dehydration. Tetrahydrofuran (400 ml) was added to this product,
which was cooled in a dry ice-ethanol bath, and a lithium diisopropylamide/n—hexane—
tetrahydrofuran solution (129 ml, 1.11 M, 144 rnmol) was added over 27 s. After 30
minutes, a solution of tert—butyl bromoacetate (21.20 g, 144 mmol) in tetrahydrofuran (30
ml) was added over seven minutes. After 39 minutes, a 20% s ammonium chloride
solution (440 ml) was added, and ethyl acetate (440 ml) was further added to perform
extraction The resulting organic layer was washed with Water twice (60 ml, 60 ml) and
concentrated under reduced pressure at 30°C. Methanol (150 ml) and palladium hydroxide
(885 mg) were added to the resulting concentrate, followed by stirring under en
pressure (0.35 lVH’a) for seven hours and 20 minutes. Water (200 ml) and tetrahydrofuran
(100 ml) were added to the reaction liquid, followed by filtration, and the catalyst was
sequentially washed with ol (50 ml) and water (50 ml x 2). The filter washings
were concentrated under reduced re at 50°C, the resulting aqueous layer was washed
with tert-butyl methyl ether (100 ml), and the aqueous layer after washing was concentrated
under reduced pressure at 50°C. Methanol (150 ml) was added to the ing residue, and
the mixture was ultrasonically treated and then filtered. The resulting solid was dried under
‘20 reduced pressure at 50°C to give the title compound (8.16 g, yield: 38.5%).
1H—NMR (400 MHZ, D20) 5 ppm; 1.00 (3H, d, J=7 Hz), 1.45 (9H, s), 2.16-2.28 (1H, m),
2.33 (1H, d, J=17 Hz), 2.97 (1H, (1, 1:17 Hz), 3.08 (1H, t, J=12 Hz), 3.22 (1H, d, J=12 Hz),
3.50—3.58 (1H, m), 4.07 (1H, (1, 1:12 Hz).
(Reference Example 3) (3S,4R)~3~[2—(tert—Butoxy)-2—oxoethyl]—4~
methylpyrrolidine—3-carboxylic acid (R)-(-)—1,1'—binaphthy1—2,2'—diyl hydrogenphosphate
ethanol solvate
SR)-3~[2-(tert-Butoxy)oxoethyl]—4—methylpyrrolidine—3-carboxylic acid
obtained by a method similar to that of Reference Example 1a (500 mg), (R)—(-)-1,1'—
binaphthyl—2,2'-diyl hydrogenphosphate (359 mg), ethanol (10.0 mL) and water (10.0 mL)
were sequentially added to a 50 mL round bottom flask, ed by stirring at room
temperature for about 22 hours. The precipitated solid was collected by filtration and
washed with a 1:1 ethanol-water mixture (2 mL). The wet product was dried under reduced
pressure at 40°C for about one hour to give the title nd (269 mg, yield: 20.5%).
FP11—0417
1H-NMR (400 MHZ, DMSO-d6) 5 ppm:0.88 (3H, d, J=7 Hz), 1.06 (3H, t, J=7 Hz), 1.38 (9H,
s), 2.09-2.16 (1H, m), 2.44 (1H, d, J=18 Hz), 2.74 (1H, t, J=12 Hz), 2.87 (1H, d, J=18 Hz),
3.11 (1H, d, J=l2 Hz), 3.41-3.47 (2H, m), 3.81 (1H, d, J=12 Hz), 4.36 (1H, t, J=5 Hz), 7.21
(2H, d, J=9 Hz), 7.28-7.31 (2H, t, J=8 Hz), 7.38-7.45 (4H, m), 8.02 (4H, t, J=8 Hz).
8.85 mg of the above white solid was weighed out in a screw glass vessel. 0.2
mL ofMilliQ water and 0.8 mL of 99.5% ethanol were added thereto. Thereafter, this was
equally divided into three portions in 1.5 mL LCMS vials, and the vials were loosely capped
and left to stand at room temperature. After nine days, crystals were ed to be
precipitated in the vials. An X—ray diffraction experiment was performed with R—AXIS
RAPID II (Rigaku Corporation) using the ing single crystals (0.40 x 0.40 x 0.06 mm).
The llographic data and structural analysis results are shown in Table 1, and the atomic
coordinate data are shown in Tables 2 to 4. The absolute structure of the title compound
was specified from such results.
[Table 1]
t = 95.637 (2)°
Volume 3346.4 (2) A
Z value, calculated y 4, 1.357 g/cm
Absorption coefiicient 12.406 cm”1
Crystal size 0.40 x 0.40 x 0.06 mm
Maximum measured 20 l36.5°
Total number ofreflections/ 35631/11955 [R (Strength)=0.0631]
number ofunique reflections
Completeness 98.5%
Structure solution Direct method (SlR92)
Refinement Least-squares method for F
Data/parameter 835
Goodness offit indicator 1.103
R factor (all data) 0.0739
0.0477
-0.00 (3)
0.43 and —0.40 e/A
[Table 2]
FP11~0417
-x z y Wm)
0.2859(3) 0.0336(1)
167(3) 0.1343 (I)
m—0.0428(3) 0.0300(2)
0.0464 (3) 0.1033 (1)
0.1764(4) 0.1547(2) 702(9)
0.5024(3) 0.2371 (3) 0.2258(2) 5.75 (7)
0.1574(3) 0.4519(2)
014 0.4273 (2) (3) (2)
0.3547(3) 0.0085 (4) 0.3501(2)
0.1998(2) (3) 0.3086(1)
~0.5826(4) (2)
0.4322(1) 0.3597(7)
0.2939(4) 0.016012)
0.0052 (4) 0.4183 (2)
0.0909(4) 0.3854(2)
0.0875(5) 0.326312)
0.1735 (6) 0.2967 (3)
0.2649(6) 0.3240(4) 8.6 (2)
0.2729(5) 0.3811(3) 7.3 (2)
0.1871 (4) 0.4143(3) 5.2 (1)
0.1966(5) 0.4725(3)
0.0627(3) 0.1192(4) 0.5031(2) 500(9)
0.1083(4) (2) 14.33 (8)
C12 0.0971(4) 0.3927(2) )
C13 0.1444(3) 0.1916(4) 0.3603(2)
0.1966(4) 0.3516(2)
0.2881(5) 0.3224(3)
0.3792(5) 0.2969(3) 6.9 (2)
0.1655(5) 0.3780(5) 0.3048(3)
C18 0.2101(4) 0.2867(5) 0.3367(2)
0.0837(3) 0.2113(4)
FP11-0417
0.0923 (2) 349(7)
0.0561(4) 0.0784(2)
029 0.0149(4) 0.0295(4) (2)
0.1038(4) 0.0199(2) 5.28 (9)
[Table 3]
0. 4005 (4) 0.1378 (2) 3.83 (7)
0.3697 (3) 0.1190 (2) 3.36 (7)
0.4594(4) 0.1223 (2) l 365 (7)
-O.1383 (3) | 0.4398(4) 0.1003(2) | 4.30 (8)
0.2124(4) } 0.5278 (5) 0.1034(2) 15.5 (1)
(5) 0.6406(5) 0.1268(3)
0.0872(5) 0.6641(4) 0.1475(3)
0.0064(4) 0.5749(4) 0.1465(2) ( )
C39 0.0979(4) 0.5978(4) 0.1669(2)
0.5145(4) 0.1631(2)
~0.2809 (4) 0.0451(2)
0.2360 (3) 0.0731(2)
9.2979(4) 0.0362 (2)
0.2987 (6) 0.0228 (2)
C45 0.4161(3) 0.0981(4) 0.0671(2)
0.4261(3) 0.2755(4) 0.1337(2)
0.5158(4) 0.2244(4) 0.1718(2)
0.2262(4) 0.2444(5) 0.0384(2)
(4) 0.1967(7) 0.2712(2) 6.9 (2)
0.6778(5) 0.2758(8) 0.2683(4) 11.6 (3) .
0.5293 (6) (9) 0.3237(3)
0.6039(6) 0.0633 (8) 0.2658(3)
(3) 0.1337(4) 0.4509(2) 417(8)
0.3066(3) 0.0503(3) 0.4574(2) 328(6)
0.2645 (3) 0.1071 (4)
0.3633(4) (5) 527(9)
0.3424(3) 0.0754(3) 3.97 (7)
(3) 0.0656(4) 0.4074(2) 3.86 (7)
0.2682(4) 0.0315(4) 0.3529(2) 459(8)
C60 0.1912(4) 0.0265(5) 0.5417(2) 6.3 (1)
.5 (1)
8.1(2)
0.4183 0.3988 0.0833 9.66
0.0381 0.1706 0.2575 9.35
0. 3213 0.3030
H7 0.0762 0.3357 | 0.3988
0.2466 0.4886 6.92
-—-—m_
H14 0.0067 0.1351 0.3665 6.33
0.4395 0.2749 8.32
[Table 4]
90919 0.0732
0.0400 0.0115
1130 0.0826 0.0090
-—-—
05777 92223
0.0486 5.38
0.3723 0.0427 7.84
FP11-0417
0.2771 13.90
0.2950 13.90
0.2814 0.3457 14.10
-0.2417 0.3134 14.10
12.22
0.5411 -0.0226 0.2509 12.22
. 5.00
.00
4.93
, 6.32
6.32
H58A 0.1662
H58B 4.9 i‘s‘i‘s
7.56
7.56
- 7.56
0.1922 0.2570 9.71
0.1250 0.1995 9.71
0.0759 0.2548 9.71
-O.1136 0.2050 8.68
H63B 0 1821 -0.1466 0.2443 8.68
H63C 02981 0.1297 0.2700 8.68
01146 0.1581 0.2229 10.35
0.0701 0.0253 0.2250 10.35
0.1370 I10.35
The absolute structures of the compounds of Examples 1 to 14 are specified and
named based on the ation obtained in Reference Example 3.
The structural formulas ofExample Compounds 1 to 8 are as follows.
cal Formula 13]
FP11—0417
Example 1
* Chiral, stereochemistry
was not determined
Example 7 Example 8
The ural formulas ofExample Compounds 9 to 14 are as follows.
[Chemical Formula 14]
FP11-0417
2' INIIIZ
C6 ””05
CHF2
Example 10
: :CHF2
Example 13 Example 14
(Test Example 1) Inhibition of cell ion in fractalldne—induced chemotaxis
assay
(1) Method
The inhibitory efi‘ects of the example compounds on fiactalldne—induced cell
migration were ed using CX3CR1—transfected B300 cells
After equilibrating the Transwell plate (24-well clusters, pore size: 5 pm,
manufactured by Corning Incorporated), a fiactalkine solution (0.3 nM, manufactured by
R&D Systems, Inc.) was added to the lower wells. CX3CR1-expressing B300 cells which
FP11—0417
were preincubated with the test compound (0.001, 0.003, 0.01 or 0.03 pM) for 30 minutes
were placed in the upper layer wells, followed by tion under the condition of5% C02
for 3.5 hours at 37°C. The number of cells migrated to the lower wells was evaluated using
CellTiter (manufactured by Promega Corporation).
The inhibitory rate ofthe test compound on fi‘actalldne-induced cell migration was
calculated by the following formula, where [A] is the number of migrated cells in the
presence ofboth fractalldne and the test compound, [B] is the number ofmigrated cells in the
presence of fractalkine and in the absence of the test nd, and [C] is the number of
migrated cells in the absence of both fractalkine and the test compound; the 50% inhibitory
concentration (IC50) was calculated based on the inhibitory rate.
Inhibitory rate (%) = [1—{(A—C)/(B—C)}] x 100
(2) Results
The results ofthis test example are shown in the following table.
[Table 5]
Test compound C50 (
Exam1e 1 —13
Exam.le 2 —21
Examle3 _
Example 6
Exarnple 8 3
__16
Example 11 6
—1—Example14 16
[0251] (Test Example 2) Amelioration ofbody weight loss in T cell transfer—induced colitis
model
(1) Method
By using colitis-induced SCID mice in which sitive, CD45RB-high cells
isolated fiom BALB/c mice cytes were injected, the y of the example
compounds was evaluated by the body weight changes. The experiment was performed over
31 days. On Day 1, CD4-positive, CD45RB—high cells isolated from the spleen ofBALB/c
mice (5 x 105 cells/mouse) were intravenously administered to SCID mice. From Day 16
to 31, the e compound was orally administered to the SCID mice once a day,
FP11-0417
followed by measuring body weights ofall animals on Day 19, 22, 24, 26, 29 and 31.
The efiicacy was evaluated by body weight changes on Day 19, 22, 24, 26, 29 or
31. The body weight change (%) was determined by the formula shown below, where [A]
is the body weight on Day 16, and [B] is the body weight on each day of body weight
measurement (Day 19, 22, 24, 26, 29 or 31).
body weight change (%) = B/A x 100
(2) Results
The results are shown in Figs. 1 to 4. The abscissa in the figures indicates the
number ofdays d, where the day on which CD4-posifive, CD45RB-high cells isolated
1'0 fiom the spleen of BALB/c mice ‘(5 x 1‘05 mouse) were in1IaVenously administered to
SCID mice is Day 0.
Claims (24)
1. A compound represented by formula (1) or phannaceutically acceptable wherein R ents a C16 alkyl group unsubstituted or having 1 to 3 substituents selected from Substituent Group A, a C34; cycloalkyl group unsubstituted or having 1 to 3 substituents selected from Substituent Group A, or a C34; cycloalkenyl group unsubstituted or having 1 to 3 substituents selected fiom Substituent Group A, X represents a Cm alkyl group, 10 Y and Z are the same or different from each other and each ents a halogen atom or a C16 alkyl group unsubstituted or having 1 to 3 substituents selected from Substituent Group n represents 0 or 1, Substituent GroupA consists ofhalogen atoms, and 15 tuent Group B ts ofhalogen atoms.
2. The nd or phannaceutically able salt thereof according to claim 1, wherein R is a fluorobutyl group, a pentyl group, a cyclohexyl group, a difluorocyclohexyl group, a cyclopentenyl group or a cyclohexenyl group.
3. The compound or pharmaceutically acceptable salt thereof according to 2O claim 1 or 2, whereinX is a methyl group.
4. The compound or pharmaceutically acceptable salt thereof according to any one ofclaims 1 to 3, nY is a chlorine atom.
5. The compound or phannaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein Z is a chlorine atom, a methyl group, a difluoromethyl 25 group or a trifluoromethyl group.
6. The compound or phannaceutically able salt thereof according to any one ofclaims 1 to 5, wherein n is 1.
7. Acompound according to claim 1, selected from the group consisting of: 2-[(3S,4R)— 1 — {[2-chloro(t1ifluoromethy1)phenyl]methyl}—3- {[ l -(2-fluoropentyl)piperidin— 4-y1]carbamoy1} hy1pyrrolidin—3~y1]acetic acid, 2-[(3S,4R)— 1 -[(2,6—dichloropheny1)methy1]( { 1 -[(4,4-difluorocyclohexyl)methyl]piperidin- 4-yl} carbamoyl)~4-methy1pyrrolidin—3~y1]acetic acid, 2-[(3S,4R)— 1 — {[2-chloro(t1ifluoromethyl)pheny1]methyl} {[ 1 -(cyclohex—1 -en-1 - yhnethyl)piperidin—4—y1]carbamoyl}—4—methylpy1rolidin~3~yl]acetic acid, 2~[(3S,4R)-1 hloro-6—methy1pheny1)methyl] {[1 ohex~1—en—1— yl)piperidin—4—y1]carbamoyl}—4—methylpyrrolidin—3~y1]acetic acid, 2~[(3S,4R)—1 — {[2—chloro-6~(t1ifluoromethy1)phenyl]methy1}—3~ { [ l -(cyclopent— 1 -en—1 - 10 ylmethy1)piperidin—4-yl]carbamoy1}—4—methylpyrrolidin—3-y1]acetic acid, 2-[(3S,4R)- l —[(2-chloro~6—methylpheny1)methyl]—3— {[(l -cyclopent— 1 -en— 1 - ylmethyl)piperidin—4—y1]carbamoyl}—4~methy1py1rolidin—3~y1]acetic acid, 2-[(3S,4R)—3- {[(3S)- l -(cyclohex— 1 —en— 1 -yhnethy1)py1rolidin—3-y1]carbamoyl} — 1 -[(2,6- dichloropheny1)methyl]-4~methy1pyrrolidin—3~yl]acetic acid, 15 2—[(3S,4R)— 1 - {[2-chloro—6—(difluoromethy1)pheny1]methyl}—3-[( 1 ~hexy1pipen'din—4— yl)carbamoy1]—4—methylpy1rolidjny1]acetic acid, , 2-[(3S,4R)—3—{[(1 -cyclohex-l-eny1methy1)pipe1idin—4-y1]carbamoyl}[(2,6— dichloropheny1)methy1]—4—methylpyrrolidin—3-y1]acetic acid, 2—[(3S,4R)— 1 — {[2-chloro-6—(difluoromethyl)pheny1]methyl}~3— {[ 1 -(cyclohex— 1 —en 20 ylmethyl)pipeiidin—4-yl]carbamoyl}-4—methylpyirolidin—3~yl]acetic acid, 2-[(3S,4R)-1 - {[2-chloro—6-(difluoromethyl)pheny1]methyl}—3- {[1 opent-1 -en-l - ylmethyl)piperidin—4—yl]carbamoyl}~4~methy1pyrrolidin~3-yl]acetic acid and 2—[(3S,4R)-l — {[2—chloro(difluoromethyl)pheny1]methyl }-3— {[ 1 — (cyclohexylmethyl)piperidin-4—y1]carbamoyl}—4~methy1pyrrolidin—3—yl]acetic acid, 25 or a phannaceutically acceptable salt thereof.
8. A medicine comprising the compound or phannaceutically acceptable salt thereofaccording to any one ms 1 to 7 as an active ingredient.
9. A therapeutic agent for inflammatory bowel disease comprising the compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7 3O as an active ingredient.
10. The therapeutic agent according to claim 9, n the inflammatory bowel disease is ulcerative colitis or s disease.
11. A fiactalkine—CX3CR1 pathway inhibitor comprising the compound or phannaceutically able salt thereof according to any one of claims 1 to 7 as an active ient.
12. A fiactalkine inhibitor comprising the compound or pharmaceutically acceptable salt thereofaccording to any one ofclaims 1 to 7 as an active ingredient
13. A CX3CR1 inhibitor comprising the compound or pharmaceutically acceptable salt thereofaccording to any one ms 1 to 7 as an active ingredient
14. A compound according to claim 1, comprising 2—[(3S,4R)—1—[(2,6— Dichlorophenyl)methyl]-3—(-({1—[(4,4-difluorocyclohexyl)methyl]piperidin—4— yl}carbamoyl)4—methylpyrrolidin—3—yl]acetic acid or a phannaceutically acceptable salt 10 thereof:
15. A compound according to claim 1, comprising 2—[(3S,4R)—l-{[2—Chloro- 6-(trifluorometliyl)phenyl]methyl}—3-{[1-(cycloheX—l~en-l-ylmethlyl)pipeiidin—4— yl]carbamoyl}—4—methylpyrrolidin—3-yl]acetic acid or a pharmaceutically acceptable salt 15 thereof:
16. A compound according to claim 1, comprising 2-[(3S,4R)[(2-Chloro- y1phenyl)methyl] { [ l ohexenyhnethyl)piperidin-4—yl]carbamoy1} methylpyrrolidin—3-yl]acetic acid or a pharrnaceutically acceptable salt thereof:
17. A compound according to claim 1, comprising 2—[(3S,4R)—1-{[2—Chloro— fluoromethy1)phenyl]methyl}-3— {[1 ~(cyclopent—1—en—l—ylmethy1)piperidin—4— y1]carbamoy1}—4—methylpyrrolidin—3-yl]acetic acid or a phannaceutically acceptable salt thereof: HSQ-w O CI HN-CN of b
18. A compound according to claim 1, comprising 2—[3S,4R)-l~[(2—Chloro— 6—me’rhylpheny1)methyl]—3- {[(1 -cyclopent— 1 -en— 1 -ylmethy1)piperidin4—yl]carbamoyl}—4— methylpyn'olidinyl]acetic acid or a phannaceutically acceptable salt thereof:
19. A nd according to claim 1, comprising 2-[(3S,4R){[(3S) (CycloheX—l-en—l-yhnethy1)pyrrolidin—3—y1]carbamoy1}—1—[(2,6-dichlorophenyl)methyl] pyrrolidiny1]acetic acid or a pharmaceutically acceptable salt thereof:
20. A compound according to claim 1, comprising 2-[(3S,4R)—3-{[(1- Cyclohex—1-en—l -y1methyl)piperidin—4—yl]carbamoyl}-1 —[(2,6—dichlorophenyl)methy1]—4— methylpyrrolidin—3—y1]acetic acid or a pharmaceutically acceptable salt thereof:
21. The use of the compound according to any one of claims 1 to 7 or 14 to 20, in the production ofa medicament for treating atory bowel e.
22. Use ing to claim 21, wherein the inflammatory bowel disease is 10 ulcerative colitis or Crohn’s disease.
23. A compound according to any one of claims 1 or 14 to 20, substantially as herein described with reference to any one ofthe accompanying examples thereof.
24. Use according to claim 21, substantially as herein described with reference to any one ofthe examples thereof.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2011199482 | 2011-09-13 | ||
JP2011-199482 | 2011-09-13 | ||
PCT/JP2012/073171 WO2013039057A1 (en) | 2011-09-13 | 2012-09-11 | Pyrrolidine-3-ylacetic acid derivative |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ620469A NZ620469A (en) | 2015-06-26 |
NZ620469B2 true NZ620469B2 (en) | 2015-09-29 |
Family
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