WO2013039057A1 - ピロリジン-3-イル酢酸誘導体 - Google Patents
ピロリジン-3-イル酢酸誘導体 Download PDFInfo
- Publication number
- WO2013039057A1 WO2013039057A1 PCT/JP2012/073171 JP2012073171W WO2013039057A1 WO 2013039057 A1 WO2013039057 A1 WO 2013039057A1 JP 2012073171 W JP2012073171 W JP 2012073171W WO 2013039057 A1 WO2013039057 A1 WO 2013039057A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- methyl
- group
- mmol
- compound
- carbamoyl
- Prior art date
Links
- 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 307
- 150000003839 salts Chemical class 0.000 claims abstract description 55
- 125000005843 halogen group Chemical group 0.000 claims abstract description 15
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 13
- 230000037361 pathway Effects 0.000 claims abstract description 8
- 125000006553 (C3-C8) cycloalkenyl group Chemical group 0.000 claims abstract description 5
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims abstract description 4
- -1 difluorocyclohexyl group Chemical group 0.000 claims description 110
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 71
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 57
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 32
- 125000001424 substituent group Chemical group 0.000 claims description 30
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 27
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 24
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 19
- 108010078239 Chemokine CX3CL1 Proteins 0.000 claims description 18
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 14
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 12
- 239000003814 drug Substances 0.000 claims description 11
- 108090000835 CX3C Chemokine Receptor 1 Proteins 0.000 claims description 10
- 102100039196 CX3C chemokine receptor 1 Human genes 0.000 claims description 10
- 239000004480 active ingredient Substances 0.000 claims description 10
- 239000003112 inhibitor Substances 0.000 claims description 10
- 229910052801 chlorine Inorganic materials 0.000 claims description 9
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 8
- 229940124597 therapeutic agent Drugs 0.000 claims description 7
- 206010009900 Colitis ulcerative Diseases 0.000 claims description 5
- 208000011231 Crohn disease Diseases 0.000 claims description 5
- 201000006704 Ulcerative Colitis Diseases 0.000 claims description 5
- 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 5
- NDYGUVWYIVLZCY-HFJWLAOPSA-N 2-[(3s,4r)-1-[(2,6-dichlorophenyl)methyl]-3-[[1-[(4,4-difluorocyclohexyl)methyl]piperidin-4-yl]carbamoyl]-4-methylpyrrolidin-3-yl]acetic acid Chemical compound C([C@@H]([C@](C1)(CC(O)=O)C(=O)NC2CCN(CC3CCC(F)(F)CC3)CC2)C)N1CC1=C(Cl)C=CC=C1Cl NDYGUVWYIVLZCY-HFJWLAOPSA-N 0.000 claims description 4
- WYNQAMDWWABRGP-RBTNQOKQSA-N 2-[(3s,4r)-1-[(2-chloro-6-methylphenyl)methyl]-3-[[1-(cyclohexen-1-ylmethyl)piperidin-4-yl]carbamoyl]-4-methylpyrrolidin-3-yl]acetic acid Chemical compound C([C@@H]([C@](C1)(CC(O)=O)C(=O)NC2CCN(CC=3CCCCC=3)CC2)C)N1CC1=C(C)C=CC=C1Cl WYNQAMDWWABRGP-RBTNQOKQSA-N 0.000 claims description 4
- QQFJWVDGLRZHFD-CCLHPLFOSA-N 2-[(3s,4r)-1-[(2-chloro-6-methylphenyl)methyl]-3-[[1-(cyclopenten-1-ylmethyl)piperidin-4-yl]carbamoyl]-4-methylpyrrolidin-3-yl]acetic acid Chemical compound C([C@@H]([C@](C1)(CC(O)=O)C(=O)NC2CCN(CC=3CCCC=3)CC2)C)N1CC1=C(C)C=CC=C1Cl QQFJWVDGLRZHFD-CCLHPLFOSA-N 0.000 claims description 4
- LKEMIIDHXHVBHO-UZTOHYMASA-N 2-[(3s,4r)-1-[[2-chloro-6-(difluoromethyl)phenyl]methyl]-3-[(1-hexylpiperidin-4-yl)carbamoyl]-4-methylpyrrolidin-3-yl]acetic acid Chemical compound C1CN(CCCCCC)CCC1NC(=O)[C@@]1(CC(O)=O)[C@@H](C)CN(CC=2C(=CC=CC=2Cl)C(F)F)C1 LKEMIIDHXHVBHO-UZTOHYMASA-N 0.000 claims description 4
- VOVPPVIWFOTZMW-UZTOHYMASA-N 2-[(3s,4r)-3-[[1-(cyclohexen-1-ylmethyl)piperidin-4-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)NC2CCN(CC=3CCCCC=3)CC2)C)N1CC1=C(Cl)C=CC=C1Cl VOVPPVIWFOTZMW-UZTOHYMASA-N 0.000 claims description 4
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 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
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 claims description 4
- FHKAMPYJDLORMJ-XRHLQHRESA-N 2-[(3s,4r)-1-[[2-chloro-6-(difluoromethyl)phenyl]methyl]-3-[[1-(cyclopenten-1-ylmethyl)piperidin-4-yl]carbamoyl]-4-methylpyrrolidin-3-yl]acetic acid Chemical compound C([C@@H]([C@](C1)(CC(O)=O)C(=O)NC2CCN(CC=3CCCC=3)CC2)C)N1CC1=C(Cl)C=CC=C1C(F)F FHKAMPYJDLORMJ-XRHLQHRESA-N 0.000 claims description 3
- JTJKDYLEMNXXER-UZTOHYMASA-N 2-[(3s,4r)-1-[[2-chloro-6-(trifluoromethyl)phenyl]methyl]-3-[[1-(cyclohexen-1-ylmethyl)piperidin-4-yl]carbamoyl]-4-methylpyrrolidin-3-yl]acetic acid Chemical compound C([C@@H]([C@](C1)(CC(O)=O)C(=O)NC2CCN(CC=3CCCCC=3)CC2)C)N1CC1=C(Cl)C=CC=C1C(F)(F)F JTJKDYLEMNXXER-UZTOHYMASA-N 0.000 claims description 3
- DSKULBBWMLJIIN-HFJWLAOPSA-N 2-[(3s,4r)-1-[[2-chloro-6-(trifluoromethyl)phenyl]methyl]-3-[[1-(cyclopenten-1-ylmethyl)piperidin-4-yl]carbamoyl]-4-methylpyrrolidin-3-yl]acetic acid Chemical compound C([C@@H]([C@](C1)(CC(O)=O)C(=O)NC2CCN(CC=3CCCC=3)CC2)C)N1CC1=C(Cl)C=CC=C1C(F)(F)F DSKULBBWMLJIIN-HFJWLAOPSA-N 0.000 claims description 3
- 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 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
- MPAOAAFSKXVAHW-HMILPKGGSA-N 2-[(3s,4r)-1-[[2-chloro-6-(difluoromethyl)phenyl]methyl]-3-[[1-(cyclohexen-1-ylmethyl)piperidin-4-yl]carbamoyl]-4-methylpyrrolidin-3-yl]acetic acid Chemical compound C([C@@H]([C@](C1)(CC(O)=O)C(=O)NC2CCN(CC=3CCCCC=3)CC2)C)N1CC1=C(Cl)C=CC=C1C(F)F MPAOAAFSKXVAHW-HMILPKGGSA-N 0.000 claims description 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 claims description 2
- 102100020997 Fractalkine Human genes 0.000 claims 1
- 230000002401 inhibitory effect Effects 0.000 abstract description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 219
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 149
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 111
- 239000000203 mixture Substances 0.000 description 94
- 238000005160 1H NMR spectroscopy Methods 0.000 description 88
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 74
- 239000000243 solution Substances 0.000 description 73
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 71
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 69
- 239000011541 reaction mixture Substances 0.000 description 69
- 239000002904 solvent Substances 0.000 description 65
- 229910052739 hydrogen Inorganic materials 0.000 description 59
- 238000000034 method Methods 0.000 description 59
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 58
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 56
- 238000006243 chemical reaction Methods 0.000 description 56
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 54
- 239000012156 elution solvent Substances 0.000 description 45
- 238000004458 analytical method Methods 0.000 description 43
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 39
- 239000012044 organic layer Substances 0.000 description 38
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 36
- 239000007858 starting material Substances 0.000 description 35
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 33
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 31
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 31
- 239000007787 solid Substances 0.000 description 29
- 239000000126 substance Substances 0.000 description 29
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 28
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 28
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 26
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- 238000010898 silica gel chromatography Methods 0.000 description 24
- 239000000741 silica gel Substances 0.000 description 23
- 229910002027 silica gel Inorganic materials 0.000 description 23
- 230000014759 maintenance of location Effects 0.000 description 22
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 20
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 20
- 239000002585 base Substances 0.000 description 20
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 20
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 19
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 18
- 239000002253 acid Substances 0.000 description 18
- 239000000706 filtrate Substances 0.000 description 18
- 239000001257 hydrogen Substances 0.000 description 18
- 239000010410 layer Substances 0.000 description 18
- 230000002829 reductive effect Effects 0.000 description 18
- 102000013818 Fractalkine Human genes 0.000 description 17
- 238000004440 column chromatography Methods 0.000 description 17
- 229920006395 saturated elastomer Polymers 0.000 description 17
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 17
- 238000004128 high performance liquid chromatography Methods 0.000 description 16
- 239000012442 inert solvent Substances 0.000 description 16
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 15
- 238000001914 filtration Methods 0.000 description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- 239000003480 eluent Substances 0.000 description 14
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 14
- 229910000027 potassium carbonate Inorganic materials 0.000 description 14
- 238000003756 stirring Methods 0.000 description 14
- 238000012360 testing method Methods 0.000 description 14
- 239000012043 crude product Substances 0.000 description 13
- 238000001514 detection method Methods 0.000 description 13
- 238000002360 preparation method Methods 0.000 description 13
- 239000003054 catalyst Substances 0.000 description 12
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 12
- 235000019341 magnesium sulphate Nutrition 0.000 description 12
- 230000008569 process Effects 0.000 description 12
- 239000012298 atmosphere Substances 0.000 description 11
- 238000001816 cooling Methods 0.000 description 11
- 239000007788 liquid Substances 0.000 description 11
- 239000012046 mixed solvent Substances 0.000 description 11
- 239000013078 crystal Substances 0.000 description 10
- 230000003287 optical effect Effects 0.000 description 10
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 10
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 10
- 235000017557 sodium bicarbonate Nutrition 0.000 description 10
- 229910052938 sodium sulfate Inorganic materials 0.000 description 10
- 235000011152 sodium sulphate Nutrition 0.000 description 10
- AYESCXPKJQDVGF-QPUJVOFHSA-N (3s,4r)-4-methyl-3-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl]pyrrolidine-3-carboxylic acid Chemical compound C[C@H]1CNC[C@@]1(CC(=O)OC(C)(C)C)C(O)=O AYESCXPKJQDVGF-QPUJVOFHSA-N 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- 235000019270 ammonium chloride Nutrition 0.000 description 9
- 210000004027 cell Anatomy 0.000 description 9
- 239000003153 chemical reaction reagent Substances 0.000 description 9
- 239000003638 chemical reducing agent Substances 0.000 description 9
- 238000010438 heat treatment Methods 0.000 description 9
- 238000004519 manufacturing process Methods 0.000 description 9
- 229910052763 palladium Inorganic materials 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 230000035484 reaction time Effects 0.000 description 9
- 230000012292 cell migration Effects 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
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 7
- 230000037396 body weight Effects 0.000 description 7
- 238000007796 conventional method Methods 0.000 description 7
- 150000002170 ethers Chemical class 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- DNUTZBZXLPWRJG-UHFFFAOYSA-M piperidine-1-carboxylate Chemical compound [O-]C(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-M 0.000 description 7
- 239000000523 sample Substances 0.000 description 7
- 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 102000019034 Chemokines Human genes 0.000 description 6
- 108010012236 Chemokines Proteins 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 6
- 230000009467 reduction Effects 0.000 description 6
- 238000006722 reduction reaction Methods 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- AZUYLZMQTIKGSC-UHFFFAOYSA-N 1-[6-[4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methylindazol-5-yl)pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl]prop-2-en-1-one Chemical compound ClC=1C(=C2C=NNC2=CC=1C)C=1C(=NN(C=1C)C1CC2(CN(C2)C(C=C)=O)C1)C=1C=C2C=NN(C2=CC=1)C AZUYLZMQTIKGSC-UHFFFAOYSA-N 0.000 description 5
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 5
- DMIYKWPEFRFTPY-UHFFFAOYSA-N 2,6-dichlorobenzaldehyde Chemical compound ClC1=CC=CC(Cl)=C1C=O DMIYKWPEFRFTPY-UHFFFAOYSA-N 0.000 description 5
- FSQANOAIVKWIEU-UHFFFAOYSA-N 2-(bromomethyl)-1-chloro-3-(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC(Cl)=C1CBr FSQANOAIVKWIEU-UHFFFAOYSA-N 0.000 description 5
- 150000001298 alcohols Chemical class 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- OANSOJSBHVENEI-UHFFFAOYSA-N cyclohexene-1-carbaldehyde Chemical compound O=CC1=CCCCC1 OANSOJSBHVENEI-UHFFFAOYSA-N 0.000 description 5
- 229910052731 fluorine Inorganic materials 0.000 description 5
- 238000005984 hydrogenation reaction Methods 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- AOGVUMLGEPPZHP-UHFFFAOYSA-N (4-methoxyphenyl)methyl 1-benzyl-4-methyl-3-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl]pyrrolidine-3-carboxylate Chemical compound C1=CC(OC)=CC=C1COC(=O)C1(CC(=O)OC(C)(C)C)C(C)CN(CC=2C=CC=CC=2)C1 AOGVUMLGEPPZHP-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 4
- 238000011579 SCID mouse model Methods 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000011324 bead Substances 0.000 description 4
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- RALDHUZFXJKFQB-UHFFFAOYSA-N cyclopentene-1-carbaldehyde Chemical compound O=CC1=CCCC1 RALDHUZFXJKFQB-UHFFFAOYSA-N 0.000 description 4
- 230000018044 dehydration Effects 0.000 description 4
- 238000006297 dehydration reaction Methods 0.000 description 4
- 125000001153 fluoro group Chemical group F* 0.000 description 4
- 239000000499 gel Substances 0.000 description 4
- 239000008187 granular material Substances 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 238000002372 labelling Methods 0.000 description 4
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- 235000019198 oils Nutrition 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 239000003755 preservative agent Substances 0.000 description 4
- 230000002335 preservative effect Effects 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 239000012453 solvate Substances 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- 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 3
- 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 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 235000001014 amino acid Nutrition 0.000 description 3
- 229940024606 amino acid Drugs 0.000 description 3
- 125000005002 aryl methyl group Chemical group 0.000 description 3
- 125000004429 atom Chemical group 0.000 description 3
- JSZVHFKTUXLNHT-UHFFFAOYSA-N benzyl 1-benzyl-4-methyl-3-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl]pyrrolidine-3-carboxylate Chemical compound C1C(C(=O)OCC=2C=CC=CC=2)(CC(=O)OC(C)(C)C)C(C)CN1CC1=CC=CC=C1 JSZVHFKTUXLNHT-UHFFFAOYSA-N 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 3
- 230000004709 cell invasion Effects 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 239000003086 colorant Substances 0.000 description 3
- SUFRSQGIIRINMU-UHFFFAOYSA-N dibenzyl 4-methyl-3-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl]pyrrolidine-1,3-dicarboxylate Chemical compound CC1CN(C(=O)OCC=2C=CC=CC=2)CC1(CC(=O)OC(C)(C)C)C(=O)OCC1=CC=CC=C1 SUFRSQGIIRINMU-UHFFFAOYSA-N 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- 230000002757 inflammatory effect Effects 0.000 description 3
- RPZAAFUKDPKTKP-UHFFFAOYSA-N n-(methoxymethyl)-1-phenyl-n-(trimethylsilylmethyl)methanamine Chemical compound COCN(C[Si](C)(C)C)CC1=CC=CC=C1 RPZAAFUKDPKTKP-UHFFFAOYSA-N 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 239000003002 pH adjusting agent Substances 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000006268 reductive amination reaction Methods 0.000 description 3
- 239000000377 silicon dioxide Substances 0.000 description 3
- BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 0.000 description 3
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-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
- LAQIXNDRSOLATB-ONEGZZNKSA-N (4-methoxyphenyl)methyl (e)-but-2-enoate Chemical compound COC1=CC=C(COC(=O)\C=C\C)C=C1 LAQIXNDRSOLATB-ONEGZZNKSA-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
- LTDOZLFWOIARHS-UHFFFAOYSA-N 1-(cyclohexen-1-ylmethyl)piperidin-4-amine Chemical compound C1CC(N)CCN1CC1=CCCCC1 LTDOZLFWOIARHS-UHFFFAOYSA-N 0.000 description 2
- WYDUUQNGNSXLRC-UHFFFAOYSA-N 1-(cyclohexylmethyl)piperidin-4-amine Chemical compound C1CC(N)CCN1CC1CCCCC1 WYDUUQNGNSXLRC-UHFFFAOYSA-N 0.000 description 2
- MVTFJZWPQSMFRW-UHFFFAOYSA-N 1-[(2,6-dichlorophenyl)methyl]-4-methyl-3-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl]pyrrolidine-3-carboxylic acid Chemical compound C1C(C(O)=O)(CC(=O)OC(C)(C)C)C(C)CN1CC1=C(Cl)C=CC=C1Cl MVTFJZWPQSMFRW-UHFFFAOYSA-N 0.000 description 2
- ZRKJGYYOBCLVPV-UHFFFAOYSA-N 1-hexylpiperidin-4-amine Chemical compound CCCCCCN1CCC(N)CC1 ZRKJGYYOBCLVPV-UHFFFAOYSA-N 0.000 description 2
- NHBKXEKEPDILRR-UHFFFAOYSA-N 2,3-bis(butanoylsulfanyl)propyl butanoate Chemical compound CCCC(=O)OCC(SC(=O)CCC)CSC(=O)CCC NHBKXEKEPDILRR-UHFFFAOYSA-N 0.000 description 2
- CFRGBWQMQNMJFD-UHFFFAOYSA-N 2-(bromomethyl)-1-chloro-3-(difluoromethyl)benzene Chemical compound FC(F)C1=CC=CC(Cl)=C1CBr CFRGBWQMQNMJFD-UHFFFAOYSA-N 0.000 description 2
- ZXRUHYZEZUIQGS-HMILPKGGSA-N 2-[(3s,4r)-1-[[2-chloro-6-(difluoromethyl)phenyl]methyl]-3-[[1-(cyclohexylmethyl)piperidin-4-yl]carbamoyl]-4-methylpyrrolidin-3-yl]acetic acid Chemical compound C([C@@H]([C@](C1)(CC(O)=O)C(=O)NC2CCN(CC3CCCCC3)CC2)C)N1CC1=C(Cl)C=CC=C1C(F)F ZXRUHYZEZUIQGS-HMILPKGGSA-N 0.000 description 2
- IRRXYTIQMSBDGL-RNODOKPDSA-N 2-[(3s,4r)-1-[[2-chloro-6-(trifluoromethyl)phenyl]methyl]-4-methyl-3-(piperidin-4-ylcarbamoyl)pyrrolidin-3-yl]acetic acid Chemical compound C([C@@H]([C@](C1)(CC(O)=O)C(=O)NC2CCNCC2)C)N1CC1=C(Cl)C=CC=C1C(F)(F)F IRRXYTIQMSBDGL-RNODOKPDSA-N 0.000 description 2
- ZGROTLWIQCEKFT-UHFFFAOYSA-N 4-methyl-3-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl]-1-phenylmethoxycarbonylpyrrolidine-3-carboxylic acid Chemical compound C1C(C(O)=O)(CC(=O)OC(C)(C)C)C(C)CN1C(=O)OCC1=CC=CC=C1 ZGROTLWIQCEKFT-UHFFFAOYSA-N 0.000 description 2
- AYESCXPKJQDVGF-UHFFFAOYSA-N 4-methyl-3-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl]pyrrolidine-3-carboxylic acid Chemical compound CC1CNCC1(CC(=O)OC(C)(C)C)C(O)=O AYESCXPKJQDVGF-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
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 229920000936 Agarose Polymers 0.000 description 2
- WWGUAFRTAYMNHU-UHFFFAOYSA-N Benzyl 4-piperidinylcarbamate Chemical compound C=1C=CC=CC=1COC(=O)NC1CCNCC1 WWGUAFRTAYMNHU-UHFFFAOYSA-N 0.000 description 2
- 208000031648 Body Weight Changes Diseases 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- TUEFWDYHOHQOFT-ZNQYPQSKSA-N C(C)(C)(C)OC(C[C@]1(CNC[C@@H]1C)C(=O)O)=O.C(C)(C)(C)OC(C[C@]1(CN(C[C@@H]1C)CC1=C(C=CC=C1Cl)Cl)C(=O)O)=O Chemical compound C(C)(C)(C)OC(C[C@]1(CNC[C@@H]1C)C(=O)O)=O.C(C)(C)(C)OC(C[C@]1(CN(C[C@@H]1C)CC1=C(C=CC=C1Cl)Cl)C(=O)O)=O TUEFWDYHOHQOFT-ZNQYPQSKSA-N 0.000 description 2
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 2
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- 239000004677 Nylon Substances 0.000 description 2
- 239000004793 Polystyrene Substances 0.000 description 2
- 102000003800 Selectins Human genes 0.000 description 2
- 108090000184 Selectins Proteins 0.000 description 2
- 210000001744 T-lymphocyte Anatomy 0.000 description 2
- 235000010724 Wisteria floribunda Nutrition 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 238000007112 amidation reaction Methods 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 230000003078 antioxidant effect Effects 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 2
- OTZPYOFFHUDNHE-UHFFFAOYSA-N benzyl n-[1-(2-fluoropentyl)piperidin-4-yl]carbamate Chemical compound C1CN(CC(F)CCC)CCC1NC(=O)OCC1=CC=CC=C1 OTZPYOFFHUDNHE-UHFFFAOYSA-N 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 230000004579 body weight change Effects 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 239000006172 buffering agent Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 206010009887 colitis Diseases 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- PFURGBBHAOXLIO-UHFFFAOYSA-N cyclohexane-1,2-diol Chemical compound OC1CCCCC1O PFURGBBHAOXLIO-UHFFFAOYSA-N 0.000 description 2
- JXTHNDFMNIQAHM-UHFFFAOYSA-N dichloroacetic acid Chemical compound OC(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-N 0.000 description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- DGLRDKLJZLEJCY-UHFFFAOYSA-L disodium hydrogenphosphate dodecahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].OP([O-])([O-])=O DGLRDKLJZLEJCY-UHFFFAOYSA-L 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000003889 eye drop Substances 0.000 description 2
- 229940012356 eye drops Drugs 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- UKJFVOWPUXSBOM-UHFFFAOYSA-N hexane;oxolane Chemical compound C1CCOC1.CCCCCC UKJFVOWPUXSBOM-UHFFFAOYSA-N 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- 210000002865 immune cell Anatomy 0.000 description 2
- 230000008595 infiltration Effects 0.000 description 2
- 238000001764 infiltration Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 229910001867 inorganic solvent Inorganic materials 0.000 description 2
- 239000003049 inorganic solvent Substances 0.000 description 2
- 102000006495 integrins Human genes 0.000 description 2
- 108010044426 integrins Proteins 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 2
- 235000019796 monopotassium phosphate Nutrition 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 239000007923 nasal drop Substances 0.000 description 2
- 229940100662 nasal drops Drugs 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 229920001778 nylon Polymers 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- HGBOYTHUEUWSSQ-UHFFFAOYSA-N pentanal Chemical compound CCCCC=O HGBOYTHUEUWSSQ-UHFFFAOYSA-N 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 2
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 229940068968 polysorbate 80 Drugs 0.000 description 2
- 229920002223 polystyrene Polymers 0.000 description 2
- 238000002600 positron emission tomography Methods 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 2
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 2
- 235000018102 proteins Nutrition 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- JAEIBKXSIXOLOL-UHFFFAOYSA-N pyrrolidin-1-ium-3-carboxylate Chemical compound OC(=O)C1CCNC1 JAEIBKXSIXOLOL-UHFFFAOYSA-N 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000002603 single-photon emission computed tomography Methods 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 2
- 210000000952 spleen Anatomy 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 150000003462 sulfoxides Chemical class 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 229940095064 tartrate Drugs 0.000 description 2
- GKBFRLAMTVIDHL-UHFFFAOYSA-N tert-butyl 4-(phenylmethoxycarbonylamino)piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1NC(=O)OCC1=CC=CC=C1 GKBFRLAMTVIDHL-UHFFFAOYSA-N 0.000 description 2
- 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 2
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical group CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 description 2
- CKXZPVPIDOJLLM-UHFFFAOYSA-N tert-butyl n-piperidin-4-ylcarbamate Chemical compound CC(C)(C)OC(=O)NC1CCNCC1 CKXZPVPIDOJLLM-UHFFFAOYSA-N 0.000 description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Natural products C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 239000013585 weight reducing agent Substances 0.000 description 2
- CPJISNSBMROVSX-LKFCYVNXSA-N (3S,4R)-1-methoxycarbonyl-4-methyl-3-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl]pyrrolidine-3-carboxylic acid Chemical compound C[C@H]1CN(C[C@@]1(CC(=O)OC(C)(C)C)C(=O)O)C(=O)OC CPJISNSBMROVSX-LKFCYVNXSA-N 0.000 description 1
- VSLRNZNOPQZMEE-VBKZILBWSA-N (3s,4r)-1-[(2-chloro-6-methylphenyl)methyl]-4-methyl-3-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl]pyrrolidine-3-carboxylic acid Chemical compound C1[C@](C(O)=O)(CC(=O)OC(C)(C)C)[C@@H](C)CN1CC1=C(C)C=CC=C1Cl VSLRNZNOPQZMEE-VBKZILBWSA-N 0.000 description 1
- LKPCJPHDERIJIW-IFXJQAMLSA-N (3s,4r)-1-benzyl-4-methyl-3-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl]pyrrolidine-3-carboxylic acid Chemical compound C1[C@](C(O)=O)(CC(=O)OC(C)(C)C)[C@@H](C)CN1CC1=CC=CC=C1 LKPCJPHDERIJIW-IFXJQAMLSA-N 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N (R)-alpha-Tocopherol Natural products OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
- MOHYOXXOKFQHDC-UHFFFAOYSA-N 1-(chloromethyl)-4-methoxybenzene Chemical compound COC1=CC=C(CCl)C=C1 MOHYOXXOKFQHDC-UHFFFAOYSA-N 0.000 description 1
- AITFSKLAUDSWMV-UHFFFAOYSA-N 1-[(2,6-dichlorophenyl)methyl]-4-methylpyrrolidine-3-carboxylic acid Chemical compound C1C(C(O)=O)C(C)CN1CC1=C(Cl)C=CC=C1Cl AITFSKLAUDSWMV-UHFFFAOYSA-N 0.000 description 1
- LMUPOQGHGMIUFC-UHFFFAOYSA-N 1-benzyl-4-methylpyrrolidin-1-ium-3-carboxylate Chemical compound C1C(C(O)=O)C(C)CN1CC1=CC=CC=C1 LMUPOQGHGMIUFC-UHFFFAOYSA-N 0.000 description 1
- AIZZFYPYPULRFL-DTWKUNHWSA-N 1-o-tert-butyl 3-o-ethyl (3s,4s)-4-aminopyrrolidine-1,3-dicarboxylate Chemical compound CCOC(=O)[C@H]1CN(C(=O)OC(C)(C)C)C[C@H]1N AIZZFYPYPULRFL-DTWKUNHWSA-N 0.000 description 1
- PTTPXKJBFFKCEK-UHFFFAOYSA-N 2-Methyl-4-heptanone Chemical compound CC(C)CC(=O)CC(C)C PTTPXKJBFFKCEK-UHFFFAOYSA-N 0.000 description 1
- CCYFXIJPJFSTSU-UHFFFAOYSA-N 2-chloro-6-methylbenzaldehyde Chemical compound CC1=CC=CC(Cl)=C1C=O CCYFXIJPJFSTSU-UHFFFAOYSA-N 0.000 description 1
- FZZMTSNZRBFGGU-UHFFFAOYSA-N 2-chloro-7-fluoroquinazolin-4-amine Chemical compound FC1=CC=C2C(N)=NC(Cl)=NC2=C1 FZZMTSNZRBFGGU-UHFFFAOYSA-N 0.000 description 1
- APOYTRAZFJURPB-UHFFFAOYSA-N 2-methoxy-n-(2-methoxyethyl)-n-(trifluoro-$l^{4}-sulfanyl)ethanamine Chemical compound COCCN(S(F)(F)F)CCOC APOYTRAZFJURPB-UHFFFAOYSA-N 0.000 description 1
- DNSDOTKSZMHDOR-UHFFFAOYSA-N 4,4-difluorocyclohexane-1-carbaldehyde Chemical compound FC1(F)CCC(C=O)CC1 DNSDOTKSZMHDOR-UHFFFAOYSA-N 0.000 description 1
- JLAKCHGEEBPDQI-UHFFFAOYSA-N 4-(4-fluorobenzyl)piperidine Chemical compound C1=CC(F)=CC=C1CC1CCNCC1 JLAKCHGEEBPDQI-UHFFFAOYSA-N 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- CJIJXIFQYOPWTF-UHFFFAOYSA-N 7-hydroxycoumarin Natural products O1C(=O)C=CC2=CC(O)=CC=C21 CJIJXIFQYOPWTF-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- PZASAAIJIFDWSB-CKPDSHCKSA-N 8-[(1S)-1-[8-(trifluoromethyl)-7-[4-(trifluoromethyl)cyclohexyl]oxynaphthalen-2-yl]ethyl]-8-azabicyclo[3.2.1]octane-3-carboxylic acid Chemical compound FC(F)(F)C=1C2=CC([C@@H](N3C4CCC3CC(C4)C(O)=O)C)=CC=C2C=CC=1OC1CCC(C(F)(F)F)CC1 PZASAAIJIFDWSB-CKPDSHCKSA-N 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 239000004342 Benzoyl peroxide Substances 0.000 description 1
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 1
- BEDNTTFNHOWXBJ-UHFFFAOYSA-N C(C=CC)(=O)O.C(C=CC)(=O)OCC1=CC=CC=C1 Chemical compound C(C=CC)(=O)O.C(C=CC)(=O)OCC1=CC=CC=C1 BEDNTTFNHOWXBJ-UHFFFAOYSA-N 0.000 description 1
- 102000004497 CCR2 Receptors Human genes 0.000 description 1
- 108010017312 CCR2 Receptors Proteins 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 102000016289 Cell Adhesion Molecules Human genes 0.000 description 1
- 108010067225 Cell Adhesion Molecules Proteins 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical group C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 108010002352 Interleukin-1 Proteins 0.000 description 1
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical class NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical class NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 208000005777 Lupus Nephritis Diseases 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical class CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 102000015636 Oligopeptides Human genes 0.000 description 1
- 108010038807 Oligopeptides Proteins 0.000 description 1
- LQVIXGIXPJCTJI-JIHQIIETSA-N P(=O)(O)(O)O.C(C)(C)(C)OC(C[C@]1(CNC[C@@H]1C)C(=O)O)=O Chemical compound P(=O)(O)(O)O.C(C)(C)(C)OC(C[C@]1(CNC[C@@H]1C)C(=O)O)=O LQVIXGIXPJCTJI-JIHQIIETSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 235000002597 Solanum melongena Nutrition 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 1
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 238000001042 affinity chromatography Methods 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 125000005278 alkyl sulfonyloxy group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 229940087168 alpha tocopherol Drugs 0.000 description 1
- WQZGKKKJIJFFOK-PHYPRBDBSA-N alpha-D-galactose Chemical group OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 239000010775 animal oil Substances 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000000637 arginyl group Chemical class N[C@@H](CCCNC(N)=N)C(=O)* 0.000 description 1
- 125000005279 aryl sulfonyloxy group Chemical group 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- IVRMZWNICZWHMI-UHFFFAOYSA-N azide group Chemical group [N-]=[N+]=[N-] IVRMZWNICZWHMI-UHFFFAOYSA-N 0.000 description 1
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical class C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- RWCCWEUUXYIKHB-UHFFFAOYSA-N benzophenone Chemical group C=1C=CC=CC=1C(=O)C1=CC=CC=C1 RWCCWEUUXYIKHB-UHFFFAOYSA-N 0.000 description 1
- RROBIDXNTUAHFW-UHFFFAOYSA-N benzotriazol-1-yloxy-tris(dimethylamino)phosphanium Chemical compound C1=CC=C2N(O[P+](N(C)C)(N(C)C)N(C)C)N=NC2=C1 RROBIDXNTUAHFW-UHFFFAOYSA-N 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 235000019400 benzoyl peroxide Nutrition 0.000 description 1
- NCPTYZLUYHXITE-QHHAFSJGSA-N benzyl (e)-but-2-enoate Chemical compound C\C=C\C(=O)OCC1=CC=CC=C1 NCPTYZLUYHXITE-QHHAFSJGSA-N 0.000 description 1
- RQWXNWRUQSOSDF-UHFFFAOYSA-N benzyl 1-benzyl-4-methylpyrrolidine-3-carboxylate Chemical compound C1C(C(=O)OCC=2C=CC=CC=2)C(C)CN1CC1=CC=CC=C1 RQWXNWRUQSOSDF-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-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
- 230000000975 bioactive effect Effects 0.000 description 1
- 229960002685 biotin Drugs 0.000 description 1
- 235000020958 biotin Nutrition 0.000 description 1
- 239000011616 biotin Substances 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 125000005997 bromomethyl group Chemical group 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- OSQPUMRCKZAIOZ-UHFFFAOYSA-N carbon dioxide;ethanol Chemical compound CCO.O=C=O OSQPUMRCKZAIOZ-UHFFFAOYSA-N 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- JYYOBHFYCIDXHH-UHFFFAOYSA-N carbonic acid;hydrate Chemical compound O.OC(O)=O JYYOBHFYCIDXHH-UHFFFAOYSA-N 0.000 description 1
- VQXINLNPICQTLR-UHFFFAOYSA-N carbonyl diazide Chemical group [N-]=[N+]=NC(=O)N=[N+]=[N-] VQXINLNPICQTLR-UHFFFAOYSA-N 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 229940084030 carboxymethylcellulose calcium Drugs 0.000 description 1
- 230000009087 cell motility Effects 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 238000002447 crystallographic data Methods 0.000 description 1
- 238000006352 cycloaddition reaction Methods 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 125000001047 cyclobutenyl group Chemical group C1(=CCC1)* 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 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
- 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
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 1
- 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
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000011033 desalting Methods 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- DIXBSCZRIZDQGC-UHFFFAOYSA-N diaziridine Chemical group C1NN1 DIXBSCZRIZDQGC-UHFFFAOYSA-N 0.000 description 1
- 125000000664 diazo group Chemical group [N-]=[N+]=[*] 0.000 description 1
- 229960005215 dichloroacetic acid Drugs 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical class OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 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
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 239000010696 ester oil Substances 0.000 description 1
- 150000002148 esters Chemical group 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound 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
- 239000003925 fat 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 compound 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 Chemical group 0.000 description 1
- 238000001215 fluorescent labelling Methods 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 238000004108 freeze drying Methods 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
- 229930195712 glutamate Natural products 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical group 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- USZLCYNVCCDPLQ-UHFFFAOYSA-N hydron;n-methoxymethanamine;chloride Chemical compound Cl.CNOC USZLCYNVCCDPLQ-UHFFFAOYSA-N 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 150000002500 ions Chemical class 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
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 229910052747 lanthanoid Inorganic materials 0.000 description 1
- 150000002602 lanthanoids Chemical class 0.000 description 1
- 210000002429 large intestine Anatomy 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- HWYHZTIRURJOHG-UHFFFAOYSA-N luminol Chemical compound O=C1NNC(=O)C2=C1C(N)=CC=C2 HWYHZTIRURJOHG-UHFFFAOYSA-N 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 159000000003 magnesium salts Chemical class 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
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- BZXFVKQUKUJTIM-UHFFFAOYSA-N methyl 2-(bromomethyl)-3-chlorobenzoate Chemical compound COC(=O)C1=CC=CC(Cl)=C1CBr BZXFVKQUKUJTIM-UHFFFAOYSA-N 0.000 description 1
- VVWWZOKQKXPVIV-UHFFFAOYSA-N methyl pyrrolidine-3-carboxylate Chemical compound COC(=O)C1CCNC1 VVWWZOKQKXPVIV-UHFFFAOYSA-N 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- RLKHFSNWQCZBDC-UHFFFAOYSA-N n-(benzenesulfonyl)-n-fluorobenzenesulfonamide Chemical compound C=1C=CC=CC=1S(=O)(=O)N(F)S(=O)(=O)C1=CC=CC=C1 RLKHFSNWQCZBDC-UHFFFAOYSA-N 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
- 239000006218 nasal suppository Substances 0.000 description 1
- 210000000822 natural killer cell Anatomy 0.000 description 1
- 238000002610 neuroimaging Methods 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 210000000440 neutrophil Anatomy 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 238000005222 photoaffinity labeling Methods 0.000 description 1
- BCIIMDOZSUCSEN-UHFFFAOYSA-N piperidin-4-amine Chemical compound NC1CCNCC1 BCIIMDOZSUCSEN-UHFFFAOYSA-N 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 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
- 230000032954 positive regulation of cell adhesion Effects 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- VZOPRCCTKLAGPN-ZFJVMAEJSA-L potassium;sodium;(2r,3r)-2,3-dihydroxybutanedioate;tetrahydrate Chemical compound O.O.O.O.[Na+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O VZOPRCCTKLAGPN-ZFJVMAEJSA-L 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- NGXSWUFDCSEIOO-UHFFFAOYSA-N pyrrolidin-3-amine Chemical compound NC1CCNC1 NGXSWUFDCSEIOO-UHFFFAOYSA-N 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 238000000163 radioactive labelling Methods 0.000 description 1
- 229910001426 radium ion Inorganic materials 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- PYWVYCXTNDRMGF-UHFFFAOYSA-N rhodamine B Chemical compound [Cl-].C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=CC=C1C(O)=O PYWVYCXTNDRMGF-UHFFFAOYSA-N 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 235000011006 sodium potassium tartrate Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000012916 structural analysis Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- YNXOZYDQSWOMAL-URAOTHONSA-N tert-butyl 2-[(3s,4r)-1-[(2,6-dichlorophenyl)methyl]-3-[[1-[(4,4-difluorocyclohexyl)methyl]piperidin-4-yl]carbamoyl]-4-methylpyrrolidin-3-yl]acetate Chemical compound C([C@@H]([C@](C1)(CC(=O)OC(C)(C)C)C(=O)NC2CCN(CC3CCC(F)(F)CC3)CC2)C)N1CC1=C(Cl)C=CC=C1Cl YNXOZYDQSWOMAL-URAOTHONSA-N 0.000 description 1
- XCPKEEIPEVYONA-PTWMLTTCSA-N tert-butyl 2-[(3s,4r)-1-benzyl-3-[[1-(2-fluoropentyl)piperidin-4-yl]carbamoyl]-4-methylpyrrolidin-3-yl]acetate Chemical compound C1CN(CC(F)CCC)CCC1NC(=O)[C@@]1(CC(=O)OC(C)(C)C)[C@@H](C)CN(CC=2C=CC=CC=2)C1 XCPKEEIPEVYONA-PTWMLTTCSA-N 0.000 description 1
- XFFOEASBHPBEKZ-QXNWPYRLSA-N tert-butyl 2-[(3s,4r)-1-benzyl-3-[[1-(cyclohexylmethyl)piperidin-4-yl]carbamoyl]-4-methylpyrrolidin-3-yl]acetate Chemical compound C([C@@H]([C@](C1)(CC(=O)OC(C)(C)C)C(=O)NC2CCN(CC3CCCCC3)CC2)C)N1CC1=CC=CC=C1 XFFOEASBHPBEKZ-QXNWPYRLSA-N 0.000 description 1
- VGNJNQXSEXWIHS-FDDCHVKYSA-N tert-butyl 2-[(3s,4r)-3-[(1-hexylpiperidin-4-yl)carbamoyl]-4-methylpyrrolidin-3-yl]acetate Chemical compound C1CN(CCCCCC)CCC1NC(=O)[C@@]1(CC(=O)OC(C)(C)C)[C@@H](C)CNC1 VGNJNQXSEXWIHS-FDDCHVKYSA-N 0.000 description 1
- LAHKOJCNOMMHMJ-AWEZNQCLSA-N tert-butyl n-[(3s)-1-(cyclohexen-1-ylmethyl)pyrrolidin-3-yl]carbamate Chemical compound C1[C@@H](NC(=O)OC(C)(C)C)CCN1CC1=CCCCC1 LAHKOJCNOMMHMJ-AWEZNQCLSA-N 0.000 description 1
- DFOZCLRRMOORDZ-UHFFFAOYSA-N tert-butyl n-[1-(cyclohexen-1-ylmethyl)piperidin-4-yl]carbamate Chemical compound C1CC(NC(=O)OC(C)(C)C)CCN1CC1=CCCCC1 DFOZCLRRMOORDZ-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
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 238000003354 tissue distribution assay Methods 0.000 description 1
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- AOBORMOPSGHCAX-DGHZZKTQSA-N tocofersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2O[C@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-DGHZZKTQSA-N 0.000 description 1
- 229960000984 tocofersolan Drugs 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 239000012929 tonicity agent Substances 0.000 description 1
- LDHQCZJRKDOVOX-UHFFFAOYSA-N trans-crotonic acid Natural products CC=CC(O)=O LDHQCZJRKDOVOX-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- ORHBXUUXSCNDEV-UHFFFAOYSA-N umbelliferone Chemical compound C1=CC(=O)OC2=CC(O)=CC=C21 ORHBXUUXSCNDEV-UHFFFAOYSA-N 0.000 description 1
- HFTAFOQKODTIJY-UHFFFAOYSA-N umbelliferone Natural products Cc1cc2C=CC(=O)Oc2cc1OCC=CC(C)(C)O HFTAFOQKODTIJY-UHFFFAOYSA-N 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 210000003556 vascular endothelial cell Anatomy 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- 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
Definitions
- the present invention relates to a pyrrolidin-3-ylacetic acid derivative. More particularly, the present invention relates to a pyrrolidin-3-ylacetic acid derivative that can be used as a therapeutic agent for inflammatory bowel disease.
- Chemokines are the main cell migration factors in the body, and control tissue infiltration of lymphocytes through enhancement of cell movement and activation of cell adhesion molecules. Chemokines are classified into four subfamilies, CC, CXC, C, and CX3C, based on the sequence of their first two cysteine residues.
- Fractalkine is the only member of the CX3C chemokine, and its structure and function have distinctive features not found in other chemokines.
- fractalkine binding to the receptor CX3CR1 it is possible to mediate strong adhesion alone without the intervention of selectins and integrins even in the presence of a physiological blood flow rate. That is, the fractalkine-CX3CR1 cell invasion system mediates a function similar to the multistage cell invasion mechanism via selectins and integrins in a single step reaction.
- Fractalkine is induced when vascular endothelial cells are treated with inflammatory cytokines TNF and IL-1.
- CX3CR1 is expressed in a part of T cells in monocytes and NK cells, but is not expressed in neutrophils.
- the fractalkine-CX3CR1 cell invasion system appears to be a very efficient mechanism for recruiting certain immune cells on or into the endothelial cells of damaged tissues.
- Non-Patent Document 1 Regarding the relationship between the fractalkine-CX3CR1 system and pathological conditions, the fractalkine-CX3CR1 system is involved in the onset and pathology of autoimmune diseases such as rheumatoid arthritis, inflammatory bowel disease, lupus nephritis, and multiple sclerosis.
- Non-Patent Document 2 Regarding inflammatory bowel disease in particular, it has been reported that the expression of fractalkine is enhanced at the inflammatory site of the large intestine tissue of the patient, and that CX3CR1 plays an important role in infiltration of immune cells into the intestinal tissue.
- Non-Patent Document 2 Regarding the inflammatory bowel disease in particular, it has been reported that the expression of fractalkine is enhanced at the inflammatory site of the large intestine tissue of the patient, and that CX3CR1 plays an important role in infiltration of immune cells into the intestinal tissue.
- Patent Document 7 is described as being useful as an antagonist of the chemokine CCR2 receptor, the target chemokine family is different.
- the problem to be solved by the present invention is to provide a compound having an inhibitory action in the fractalkine-CX3CR1 pathway.
- a compound represented by the formula (1) or a pharmacologically acceptable salt thereof [R is a C 1-6 alkyl group having 1 to 3 substituents which are unsubstituted or selected from substituent group A, and 1 to 3 substituents which are unsubstituted or selected from substituent group A means a C 3-8 cycloalkyl group or an unsubstituted or a substituent selected from the substituent group a to 1-3 Yes C 3-8 cycloalkenyl group, having, X represents a C 1-6 alkyl group, Y and Z are the same or different and each represents a halogen atom or a C 1-6 alkyl group having 1 to 3 substituents selected from unsubstituted or substituent group B; n means 0 or 1; Substituent group A consists of halogen atoms, Substituent group B consists of halogen
- a medicament comprising the compound according to any one of [1] to [7] or a pharmaceutically acceptable salt thereof as an active ingredient.
- a therapeutic agent for inflammatory bowel disease comprising the compound according to any one of [1] to [7] or a pharmacologically acceptable salt thereof as an active ingredient.
- the therapeutic agent according to [9], wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease.
- An inhibitor of the fractalkine-CX3CR1 pathway comprising as an active ingredient the compound according to any one of [1] to [7] or a pharmacologically acceptable salt thereof.
- a fractalkine inhibitor comprising the compound according to any one of [1] to [7] or a pharmacologically acceptable salt thereof as an active ingredient.
- a CX3CR1 inhibitor comprising the compound according to any one of [1] to [7] or a pharmacologically acceptable salt thereof as an active ingredient.
- a method for treating inflammatory bowel disease comprising administering to the patient a compound according to any one of [1] to [7] or a pharmacologically acceptable salt thereof.
- the method according to [14] wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease.
- a method for inhibiting the fractalkine-CX3CR1 pathway comprising administering the compound of any one of [1] to [7] or a pharmacologically acceptable salt thereof to a patient.
- a method for inhibiting fractalkine comprising administering the compound according to any one of [1] to [7] or a pharmaceutically acceptable salt thereof to a patient.
- a method for inhibiting CX3CR1 comprising administering the compound of any one of [1] to [7] or a pharmaceutically acceptable salt thereof to a patient.
- [24] Use of the compound according to any one of [1] to [7] or a pharmaceutically acceptable salt thereof in the manufacture of a therapeutic agent for inflammatory bowel disease. [25] The use according to [24], wherein the inflammatory bowel disease is ulcerative colitis or Crohn's disease. [26] Use of the compound according to any one of [1] to [7] or a pharmaceutically acceptable salt thereof in the manufacture of a fractalkine-CX3CR1 pathway inhibitor. [27] Use of the compound according to any one of [1] to [7] or a pharmaceutically acceptable salt thereof in the production of a fractalkine inhibitor. [28] Use of the compound according to any one of [1] to [7] or a pharmacologically acceptable salt thereof in the manufacture of a CX3CR1 inhibitor. About.
- the compound according to the present invention has an inhibitory action in the fractalkine-CX3CR1 pathway. Therefore, the compound according to the present invention has applicability as a therapeutic agent for inflammatory bowel disease.
- Example 4 is a graph showing the results of Test Example 2 for the compounds of Examples 3, 6 and 11.
- 6 is a graph showing the results of Test Example 2 for the compounds of Examples 2, 7, and 8.
- 2 is a graph showing the results of Test Example 2 for the compounds of Examples 1, 9, and 10. It is a graph showing the result of the test example 2 regarding the compound of Example 12, 13 and 14.
- the present invention is not limited to a specific crystal form, although a crystal polymorph may exist, and a single substance of any crystal form may be a mixture.
- the present invention includes amorphous forms, and the compounds according to the present invention include anhydrides, hydrates and solvates.
- C 1-6 alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms. Specific examples thereof include a methyl group, an ethyl group, 1 -Propyl group, 2-propyl group, 2-methyl-1-propyl group, 2-methyl-2-propyl group, 1-butyl group, 2-butyl group, 1-pentyl group, 2-pentyl group, 3-pentyl Group, 1-hexyl group, 2-hexyl group, 3-hexyl group and the like.
- C 3-8 cycloalkyl group means a monocyclic saturated aliphatic hydrocarbon group having 3 to 8 carbon atoms. Specific examples thereof include a cyclopropyl group, a cyclobutyl group, A cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, etc. are mentioned.
- C 3-8 cycloalkenyl group means a monocyclic aliphatic hydrocarbon group having 3 to 8 carbon atoms and containing 1 to 4 double bonds in the ring. Specific examples include a cyclopropenyl group, a cyclobutenyl group, a cyclopentenyl group, a cyclohexenyl group, a cycloheptenyl group, and a cyclooctenyl group.
- halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
- R in the compound represented by the formula (1) is selected from an unsubstituted or substituted C 1-6 alkyl group having 1 to 3 substituents selected from Substituent Group A, unsubstituted or Substituent Group A C 3-8 refers to a cycloalkyl group or an unsubstituted or C 3-8 cycloalkenyl group which 1-3 have a substituent selected from substituent group a, and 1-3 have the substituents.
- R represents a fluorobutyl group, a pentyl group, a cyclohexyl group, a difluorocyclohexyl group, a cyclopentenyl group or a cyclohexenyl group.
- X in the compound represented by the formula (1) means a C 1-6 alkyl group.
- X represents a methyl group.
- Y and Z in the compound represented by the formula (1) are the same or different and each is a C 1-6 alkyl group having 1 to 3 substituents selected from a halogen atom or an unsubstituted or substituted group B Means.
- Y represents a chlorine atom.
- Z represents a chlorine atom, a methyl group, a difluoromethyl group or a trifluoromethyl group.
- N in the compound represented by the formula (1) means 0 or 1, preferably 1.
- Substituent group A consists of a halogen atom, preferably a fluorine atom.
- the substituent group B is composed of a halogen atom, preferably a fluorine atom, a chlorine atom or a bromine atom, more preferably a fluorine atom.
- the “pharmacologically acceptable salt” in the present specification is not particularly limited as long as it forms a salt with the compound represented by the formula (1) and is pharmacologically acceptable.
- inorganic acid salts include, for example, hydrochloride, hydrobromide, sulfate, nitrate, phosphate and the like
- organic acid salts include, for example, acetate, succinate and fumarate.
- Preferred examples of the inorganic base salt include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, aluminum salt, ammonium salt and the like, and preferred examples of organic base salts Examples thereof include diethylamine salt, diethanolamine salt, meglumine salt, N, N′-dibenzylethylenediamine salt and the like.
- acidic amino acid salts include aspartate and glutamate
- basic amino acid salts include arginine salt, lysine salt and ornithine salt.
- the compound represented by the formula (1) can be produced by the method described below, and can also be produced by a person skilled in the art improving the method described below based on ordinary knowledge. However, the manufacturing method of the compound represented by Formula (1) is not limited to these.
- the compound represented by the formula (1) (hereinafter also referred to as the compound (1)) is prepared by using the intermediate represented by the formula (2) as a starting material, step A, step B and step C described in detail below. It can be manufactured after that. [Wherein R, X, Y, Z and n are as defined above. ]
- each step may be appropriately changed based on the ordinary knowledge of those skilled in the art, and after each step, it may be purified by a method known to those skilled in the art or may be isolated and purified. You may proceed to the next step without doing so.
- the solvent used is not particularly limited as long as it can dissolve the starting materials to some extent and does not inhibit the reaction.
- N, N-dimethylformamide, N, N-dimethylacetamide, 1 -Amides such as methylpyrrolidinone, ethers such as tetrahydrofuran, sulfoxides such as dimethyl sulfoxide and the like, and N, N-dimethylformamide is preferred.
- benzotriazol-1-yloxytris pyrrolidino
- PyBOP bis (2-oxo-3-oxazolidinyl) phosphinic chloride
- BOP-Cl bis (2-oxo-3-oxazolidinyl) phosphinic chloride
- Benzotriazol-1-yloxytris dimethylamino
- diethyl cyanophosphate PyBOP or BOP-Cl is preferable, and PyBOP is most preferable.
- Examples of the base to be used include triethylamine and diisopropylethylamine, and triethylamine is preferable.
- the reaction temperature varies depending on the starting materials, the solvent, the condensing agent and the base, but is usually ⁇ 20 ° C. to 100 ° C., preferably 0 ° C. to 60 ° C.
- reaction time varies depending on the starting material, solvent, condensing agent and base, but is usually 30 minutes to 5 days, preferably 1 hour to 3 days.
- Step B Arylmethylation reaction [Wherein R, X, Y, Z and n are as defined above. W 1 represents a halogen atom, an alkylsulfonyloxy group or an arylsulfonyloxy group. ]
- This step is a step of producing compound (6) by reacting compound (4) with compound (5) in the presence of a base in an inert solvent.
- the solvent used is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction.
- N, N-dimethylformamide, N, N-dimethylacetamide examples thereof include amides such as 1-methylpyrrolidinone and sulfoxides such as dimethyl sulfoxide, and N, N-dimethylformamide is preferable.
- Examples of the base to be used include inorganic bases such as sodium carbonate and potassium carbonate, and potassium carbonate is preferable.
- the reaction temperature varies depending on the starting materials, the solvent and the base, but is usually ⁇ 20 ° C. to 100 ° C., preferably 0 ° C. to 60 ° C.
- the reaction time varies depending on the starting materials, the solvent and the base, but is usually 30 minutes to 5 days, and preferably 1 to 24 hours.
- Step C Determination of tert-butyl group [Wherein R, X, Y, Z and n are as defined above. ]
- This step is a step of producing compound (1) by reacting compound (6) with an acid in the absence of a solvent or in an inert solvent.
- the solvent to be used is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction.
- halogenated hydrocarbons such as dichloromethane and chloroform, toluene
- Examples include dioxane, water, a mixed solvent of dioxane and water, and dichloromethane is preferable.
- Examples of the acid used include carboxylic acids such as trifluoroacetic acid and inorganic acids such as hydrochloric acid, and trifluoroacetic acid is preferable.
- the reaction temperature varies depending on the starting materials, the solvent and the acid, but is usually ⁇ 20 ° C. to 100 ° C., preferably 0 ° C. to 40 ° C.
- reaction time varies depending on the starting materials, solvent and acid, but is usually 30 minutes to 1 day, preferably 1 to 12 hours.
- Step D Reductive amination reaction [Wherein X, Y and Z are as defined above. ]
- This step is a step 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 particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction.
- ethers such as tetrahydrofuran, alcohols such as methanol and ethanol, etc. Preferred is tetrahydrofuran or methanol.
- Examples of the reducing agent used include sodium triacetoxyborohydride, sodium cyanoborohydride, borohydride compounds such as sodium borohydride, and the like, and preferably sodium triacetoxyborohydride.
- the acid may or may not be used in this step, but when used, the acid used is not particularly limited as long as it does not inhibit the reaction, but is preferably acetic acid.
- the reaction 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.
- reaction time varies depending on the starting material, solvent, reducing agent and acid, but is usually 30 minutes to 5 days, preferably 1 to 48 hours.
- the reaction can be allowed to proceed by adding an organic amine such as triethylamine to the carboxylic acid forming the salt in an equivalent amount or more. Can do.
- Step E Hydrogenation reaction From the compound (6) obtained in the step B, a compound (4) from which an arylmethyl group is eliminated can be obtained by a hydrogenation reaction.
- the compound (4) can be further converted into a compound (6) to which an arylmethyl group having a different substituent is added by Step B.
- R, Z and n are as defined above.
- Y 1 and Y 2 have the same meaning as Y above, and Z 1 and Z 2 have the same meaning as Z above. ]
- This step is a step of producing compound (4) by reacting compound (6) with hydrogen in the presence of a reduction catalyst in an inert solvent to remove the arylmethyl group.
- the solvent used is not particularly limited as long as it can dissolve the starting materials to some extent and does not inhibit the reaction.
- alcohols such as methanol and ethanol, tetrahydrofuran , Ethers such as dioxane and dimethoxyethane, and organic acid esters such as ethyl acetate, preferably ethers, alcohols, organic acid esters or a mixed solvent thereof, and most preferred Is methanol or ethanol.
- Examples of the reduction catalyst used include Pd / C, palladium hydroxide, Raney nickel, platinum oxide, platinum black, and the like, and preferably Pd / C or palladium hydroxide.
- the reaction temperature varies depending on the starting materials and the solvent, but is usually 0 to 70 ° C, preferably 10 to 50 ° C.
- the reaction time varies depending on the starting material, the solvent, and the reaction temperature, but is usually 30 minutes to 5 days, and preferably 1 to 3 days.
- the hydrogen pressure during the reaction is usually 0.5 to 10 atm, preferably 1 to 5 atm.
- the compound obtained in this step can be used in the next step, usually only by filtering the catalyst.
- Step F Compound (1) can also be obtained by Step F. [Wherein R, X, Y, Z and n are as defined above. ]
- Step F-1 Amidation reaction This step is a step of producing a compound (11) by dehydration condensation of the carboxyl group of the compound (8) and the amino group of the compound (10). Can be performed.
- Step F-2 Detert-butylation and detert-butyloxycarbonylation reaction This step is a step for producing compound (12) by reacting compound (11) with an acid. It can be done by a method.
- Step F-3 Reductive amination reaction
- This step is a step for producing compound (1) by reacting compound (12) with aldehyde compound (13) in the presence of a reducing agent.
- the method can be used.
- Compound (2) can also be produced by the following step G. [Wherein X is as defined above. V represents a hydrogen atom or a methoxy group. W 2 represents a halogen atom. ]
- Step G-1 Esterification Reaction This step is a step for producing compound (16) by reacting compound (14) with compound (15) in the presence of a base in an inert solvent. This step can be performed according to step B.
- Step G-2 Cycloaddition reaction
- compound (16) is reacted with N- (methoxymethyl) -N- (trimethylsilylmethyl) benzylamine in the presence of an acid in an inert solvent to give compound (17) is a process of manufacturing.
- the solvent used is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction.
- ethers such as tetrahydrofuran, halogenated compounds such as dichloromethane and chloroform.
- hydrocarbons such as benzene and toluene, and preferred are dichloromethane and toluene, and mixed solvents thereof.
- the acid used is not particularly limited as long as it is usually used by those skilled in the art, but trifluoroacetic acid is preferred.
- 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 depending on the starting material, solvent, reducing agent, and acid, but is usually 30 minutes to 5 days, and preferably 1 to 24 hours.
- N- (methoxymethyl) -N- (trimethylsilylmethyl) benzylamine is added dropwise while paying attention to the exotherm after mixing the compound (16), solvent and acid. Is preferred.
- Step G-3 Alkylation reaction This step is a step of producing compound (18) by reacting compound (17) with a base in an inert solvent and then reacting with tert-butyl bromoacetate.
- the solvent used is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction.
- ethers such as tetrahydrofuran and diethyl ether, and fats such as hexane.
- Preferred are mixed solvents of tetrahydrofuran, tetrahydrofuran and hexane.
- Preferred examples of the base to be used include lithium salts of organic amines such as lithium diisopropylamide and lithium bis (trimethylsilyl) amide, and more preferred are lithium diisopropylamide and lithium bis (trimethylsilyl) amide.
- reaction temperature varies depending on the starting materials, solvent and base, it is generally ⁇ 100 ° C. to 50 ° C., preferably ⁇ 80 ° C. to ⁇ 40 ° C., and most preferably ⁇ 80 ° C. to ⁇ 70 ° C. .
- the reaction time varies depending on the starting materials, the solvent and the base, but is usually 30 minutes to 5 days, preferably 1 to 24 hours, and most preferably 2 to 5 hours.
- Step G-4 Hydrogenation Reaction This step is a step of removing benzyl group by reacting compound (18) with hydrogen in an inert solvent in the presence of a reduction catalyst.
- this process can be performed according to the said process E.
- Step G-5 Chiral Resolution
- the racemate of compound (2) is chirally resolved to obtain compound (2).
- the solvent used for the split mobile phase and sample charge is not particularly limited as long as it dissolves the starting materials to some extent and does not adversely affect the column or sample.
- Alcohols such as methanol, ethanol, 2-propanol, hexane, acetonitrile, tetrahydrofuran, trifluoroacetic acid, diethylamine or a mixed solvent thereof, and the like, preferably acetonitrile, ethanol, a mixed solvent of ethanol and hexane. is there.
- Examples of the column used for the resolution include various commercially available columns for optical resolution, preferably CHIRALPAK AD-H, CHIRALPAK IA, and CHIRALCEL OZ-H manufactured by Daicel Chemical Industries.
- the column temperature during the division is preferably 10 ° C to 45 ° C.
- Step H Compound (3) used in step A and the like can also be produced by the following step H. [Wherein R and n are as defined above. ]
- Step H-1 Reductive amination reaction
- compound (19) and compound (13) are reacted in an inert solvent in the presence or absence of an acid in the presence of a reducing agent. 20), which can be performed according to Step D.
- Step H-2 Determination of tert-butyloxycarbonyl group
- compound (20) is reacted with an acid in the absence of a solvent or in an inert solvent to remove the tert-butyloxycarbonyl group,
- This is a step for producing compound (3), which can be carried out according to step C.
- Compound (2) can also be produced according to the following step I, starting from the racemate of compound (2). [Wherein X and V are as defined above. ]
- Step I-1 Benzyloxycarbonyl group introduction reaction This step introduces a benzyloxycarbonyl group by reacting the racemate of compound (2) with benzylchloroformate in the presence of a base in an inert solvent. It is a process.
- the solvent used is not particularly limited as long as it can dissolve the starting materials to some extent and does not inhibit the reaction.
- ethers such as tetrahydrofuran and 1,4-dioxane, water , N, N-dimethylformamide, dichloromethane, acetone, and a mixed solvent thereof, and the like, and a mixed solvent of water and acetone is preferable.
- Examples of the base used include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, sodium carbonate and potassium carbonate, and organic amines such as triethylamine and diisopropylethylamine. , Sodium hydroxide.
- the reaction temperature varies depending on the starting materials, solvent and base, but is usually ⁇ 30 ° C. to 20 ° C., preferably ⁇ 10 ° C. to 15 ° C.
- the reaction time varies depending on the starting materials, the solvent and the base, but is usually 30 minutes to 5 days, and preferably 1 to 24 hours.
- Step I-2 Esterification Reaction
- This step is a step for producing compound (22) by reacting compound (21) with benzyl halide in the presence of a base in an inert solvent. This step can be performed according to step B.
- Step I-3 Chiral Resolution
- compound (22) is chirally resolved to obtain a chiral form of compound (22). This step can be performed according to Step G-5.
- Step I-4 Hydrogenation Reaction This step is a step of obtaining a compound (2) by reacting a chiral compound of the compound (22) with hydrogen in an inert solvent in the presence of a reduction catalyst. This step can be performed according to step E.
- Compound (2) can also be produced by the following step J using compound (18) as a starting material. [Wherein, X and V are as defined above. ]
- Step J-1 Benzyloxycarbonyl group introduction reaction
- compound (18) is reacted with benzyl chloroformate in an inert solvent to replace the benzyl group with a benzyloxycarbonyl group.
- the solvent used is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction.
- dichloromethane is preferable.
- the reaction temperature varies depending on the starting materials and the solvent, but is usually ⁇ 20 ° C. to 60 ° C., preferably 0 ° C. to 40 ° C.
- the reaction time varies depending on the starting materials and the solvent, but is usually 30 minutes to 5 days, and preferably 1 to 24 hours.
- Step J-2 Chiral Resolution
- compound (22) is chirally resolved to obtain a chiral form of compound (22). This step can be performed according to Step G-5.
- Step J-3 Hydrogenation Reaction
- This step is a step of obtaining a compound (2) by reacting a chiral compound of the compound (22) with hydrogen in an inert solvent in the presence of a reduction catalyst. This step can be performed according to step E.
- the target compound in each step can be collected from the reaction mixture according to a conventional method.
- the reaction mixture may be allowed to warm to room temperature if desired, or ice-cooled, neutralizing acid, alkali, oxidizing agent or reducing agent as appropriate, and immiscible with water and ethyl acetate.
- the organic solvent which does not react with the target compound is added, and the layer containing the target compound is separated.
- a solvent that is immiscible with the obtained layer and does not react with the target compound is added, the layer containing the target compound is washed, and the layer is separated.
- the target compound can be collected by drying using a drying agent such as anhydrous magnesium sulfate or anhydrous sodium sulfate and distilling off the solvent.
- a drying agent such as anhydrous magnesium sulfate or anhydrous sodium sulfate and distilling off the solvent.
- the said layer is an aqueous layer, after desalting electrically, it can extract
- the target compound is collected only by distilling off substances other than the target compound (eg, solvent, reagent, etc.) under normal pressure or reduced pressure. can do.
- the target compound is obtained by filtration.
- the target compound collected by filtration is washed with an appropriate organic or inorganic solvent and dried to treat the mother liquor in the same manner as in the case where the whole reaction mixture is a liquid, thereby further collecting the target compound. it can.
- the reagent or catalyst exists as a solid, or the reaction mixture as a whole is liquid, and only the reagent or catalyst is precipitated as a solid during the collection process, and the target compound
- the reagent or catalyst is filtered off by filtration, and the filtered reagent or catalyst is washed with an appropriate organic or inorganic solvent, and the resulting washing solution is combined with the mother liquor, and the resulting mixture is mixed.
- the target compound can be collected by treating the liquid in the same manner as in the case where the whole reaction mixture is liquid.
- the target compound when a compound other than the target compound contained in the reaction mixture does not inhibit the reaction in the next step, the target compound can be used in the next step as it is without isolating the target compound.
- the purity of the target compound can usually be improved by a recrystallization method.
- a single solvent or a mixed solvent that does not react with the target compound can be used. Specifically, first, the target compound is dissolved in a single or a plurality of solvents that do not react with the target compound at room temperature or under heating. The resulting liquid mixture is cooled with ice water or the like, or stirred or left at room temperature to crystallize the target compound from the liquid mixture.
- the collected target compound can improve the purity of the target compound by various chromatographic methods.
- silica gel 60 70-230 mesh or 340-400 mesh
- BW-300 300 mesh weakly acidic silica gel manufactured by Fuji Silysia Chemical Ltd.
- propylamine coated silica gel 200-350 mesh
- Fuji Silysia Chemical Co., Ltd. or disposable medium pressure preparative packing manufactured by Yamazen Co., Ltd.
- NH silica gels such as a column (high flash amino) can also be used.
- NAM-200H or NAM-300H manufactured by Nam Research Laboratory, or YMC GEL ODS-A manufactured by YMC is used. You can also. Disposable medium pressure preparative packed columns (High Flush) manufactured by Yamazen Co., Ltd., manufactured by Wako Pure Chemical Industries, Ltd., biotage, Inc., or Grace Co., which are preliminarily packed with the above-described fillers can also be used.
- Disposable medium pressure preparative packed columns (High Flush) manufactured by Yamazen Co., Ltd., manufactured by Wako Pure Chemical Industries, Ltd., biotage, Inc., or Grace Co., which are preliminarily packed with the above-described fillers can also be used.
- the purity of the target compound can also be improved by distillation.
- the target compound can be distilled by reducing the pressure of the target compound at room temperature or under heating.
- the above is a representative example of the production method of compound (1), but the raw material compound and various reagents in the production of compound (1) may form solvates such as salts and hydrates. Also, it varies depending on the starting material, the solvent used, etc., and is not particularly limited as long as it does not inhibit the reaction. It goes without saying that the solvent to be used is not particularly limited as long as it varies depending on starting materials, reagents and the like, and can dissolve the starting material to some extent without inhibiting the reaction.
- compound (1) When compound (1) is obtained as a free form, it can be converted into a salt or a solvate that may be formed by compound (1) according to a conventional method.
- compound (1) When compound (1) is obtained as a salt or solvate, the free form of compound (1) can be converted according to a conventional method.
- various isomers for example, geometric isomers, optical isomers, rotational isomers, stereoisomers, tautomers, etc.
- obtained for the compound (1) can be obtained by conventional separation means such as recrystallization, It can be purified and isolated by using a diastereomeric salt method, an enzyme resolution method, and various types of chromatography (for example, thin layer chromatography, column chromatography, gas chromatography, etc.).
- Compound (1) or a pharmacologically acceptable salt thereof can be formulated by a conventional method.
- the dosage form include oral preparations (tablets, granules, powders, capsules, syrups, etc.). , Injections (for intravenous administration, intramuscular administration, subcutaneous administration, intraperitoneal administration), external preparations (transdermal absorption preparations (ointments, patches, etc.), eye drops, nasal drops, suppositories, etc. ).
- solid preparations such as tablets, capsules, granules and powders are usually 0.001 to 99.5% by weight, preferably 0.01 to 90% by weight of the compound (1) or a pharmaceutically acceptable product thereof.
- the resulting salt can be included.
- compound (1) or a pharmaceutically acceptable salt thereof if necessary, an excipient, a binder, a disintegrant, a lubricant, a colorant, etc.
- an excipient if necessary, an excipient, a binder, a disintegrant, a lubricant, a colorant, etc.
- Tablets, granules, powders, capsules and the like may be coated with a film as necessary.
- excipient examples include lactose, corn starch, crystalline cellulose, and the like.
- binder examples include hydroxypropylcellulose and hydroxypropylmethylcellulose.
- disintegrant examples include carboxymethylcellulose calcium and croscarmette. Examples include sodium loose.
- Examples of the lubricant include magnesium stearate and calcium stearate, and examples of the colorant include titanium oxide.
- Examples of the film coating agent include hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose and the like.
- any of the above-mentioned additives is not limited to these.
- a pH adjusting agent, a buffering agent, a suspending agent, a solubilizing agent, an antioxidant, a preservative (preservative), an isotonic agent, and the like can be added to produce a conventional method. Alternatively, it may be freeze-dried to obtain a freeze-dried preparation that is dissolved at the time of use.
- These injections can be administered intravenously, subcutaneously, intramuscularly and the like.
- pH adjusting agents and buffering agents include organic acids or inorganic acids and / or salts thereof.
- suspending agents include methylcellulose, polysorbate 80, sodium carboxymethylcellulose, and the like.
- glucose, sodium chloride, mannitol and the like can be mentioned, but of course not limited thereto.
- injection solutions can contain usually 0.000001 to 99.5% by weight, preferably 0.00001 to 90% by weight of the compound (1) or a pharmacologically acceptable salt thereof.
- a base material is added to the compound (1) or a pharmacologically acceptable salt thereof, and the above-described emulsifier, preservative, pH adjuster, colorant as necessary.
- a base material is added to the compound (1) or a pharmacologically acceptable salt thereof, and the above-described emulsifier, preservative, pH adjuster, colorant as necessary.
- the like, and the like can be produced by a conventional method such as transdermal preparations (ointments, patches, etc.), eye drops, nasal drops, suppositories, and the like.
- various raw materials usually used for pharmaceuticals, quasi drugs, cosmetics and the like can be used.
- animal and vegetable oils, mineral oils, ester oils, waxes, higher alcohols, purified water And other raw materials can be used.
- These external preparations can contain usually 0.000001 to 99.5% by weight, preferably 0.00001 to 90% by weight of the compound (1) or a pharmacologically acceptable salt thereof.
- the dose of the pharmaceutical agent according to the present invention usually varies depending on symptoms, age, sex, weight, etc., but may be an amount sufficient for producing a desired effect.
- about 0.1 to 5000 mg (preferably 0.5 to 1000 mg, more preferably 1 to 600 mg) per day is used once or during a day or 2 to 6 per day. Used in divided times.
- the invention also includes isotope-labeled compounds of compound (1), which have one or more atoms having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. It is the same as compound (1) except that it is replaced by an atom.
- the isotopes that can be incorporated into the compound (1) are, for example, isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, iodine, and chlorine. 2 H, 3 H, 11 C, 14 C, 13 N, 15 O, 18 F, 32 P, 35 S, 123 I, 125 I and the like are included.
- Isotopically-labeled compounds of the present invention eg, compounds incorporating a radioactive isotope such as 3 H and / or 14 C
- 3 H and 14 C are considered useful because of their ease of preparation and detection.
- the isotopes 11 C and 18 F are considered useful in PET (Positron Emission Tomography) and the isotope 125 I is considered useful in SPECT (Single Photon Emission Computed Tomography), all useful in brain imaging. It is.
- isotope-labeled compound of compound (1) undergoes the procedures disclosed in the following schemes and / or examples using readily available isotope-labeled reagents in place of non-isotopically labeled reagents. Can be prepared uniformly.
- Compound (1) can be used as a chemical probe for capturing a target protein of a bioactive low molecular weight compound. That is, the compound (1) is different from the structural part essential for the expression of the activity of the compound in the J. Mass Spectrum. Soc. Jpn. Vol. 51, No. 5 2003, p492-498 or WO2007 / 139149 can be converted into affinity chromatography, photoaffinity probe, etc. by introducing a labeling group, a linker or the like by the method described in WO2007 / 139149.
- Examples of the labeling group and linker used for the chemical probe include groups shown in the following groups (1) to (5).
- Photoaffinity labeling groups for example, benzoyl group, benzophenone group, azide group, carbonyl azide group, diaziridine group, enone group, diazo group and nitro group
- chemical affinity groups for example, alpha carbon atom is halogen
- a protein labeling group such as a ketone group substituted with an atom, a carbamoyl group, an ester group, an alkylthio group, a Michael acceptor such as an ⁇ , ⁇ -unsaturated ketone, an ester, and an oxirane group
- a cleavable linker such as —SS—, —O—Si—O—, monosaccharide (glucose group, galactose group, etc.) or disaccharide (lactose etc.), and oligopeptide cleavable by enzymatic reaction Link
- a probe prepared by introducing a labeling group selected from the group consisting of the above (1) to (5) into the compound (1) according to the method described in the above literature is a new drug discovery target. It can be used as a chemical probe for identifying a labeled protein useful for searching and the like.
- Compound (1) can be produced, for example, by the method described in the following examples, and the effect of compound (1) can be confirmed by the method described in the following test examples. However, these are illustrative, and the present invention is not limited to the following specific examples in any case.
- Example 1a tert-butyl 4- ⁇ [(benzyloxy) carbonyl] amino ⁇ piperidine-1-carboxylate 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 1 hour. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted 3 times with dichloromethane.
- Example 1b Benzyl N- (piperidin-4-yl) carbamate tert-butyl 4- ⁇ [(benzyloxy) carbonyl] amino ⁇ piperidine-1-carboxylate (13.1 g, 39.39) obtained in Example 1a. 2 mmol), a mixture of 5N aqueous hydrochloric acid (40 ml, 200 mmol) and methanol (40 ml) was stirred at room temperature for 23 hours. To the reaction mixture was added 5N aqueous sodium hydroxide solution (40 ml) under ice cooling. Water and the solvent were distilled off from the reaction mixture while azeotroping with ethanol.
- Example 1c Chiral body of benzyl N- [1- (2-fluoropentyl) piperidin-4-yl] carbamate (5S)-( ⁇ )-2,2,3-trimethyl-5-benzyl-4-imidazo Lydinone 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.
- Example 1d Chiral form of 1- (2-fluoropentyl) piperidin-4-amine Chiral form of benzyl N- [1- (2-fluoropentyl) piperidin-4-yl] carbamate obtained in Example 1c ( A mixture having a shorter retention time (318 mg, 0.986 mmol), 10% Pd / C (100 mg) and methanol (7 ml) was stirred at room temperature for 2 hours under a hydrogen atmosphere. The reaction vessel was purged with nitrogen, 10% Pd / C was removed by filtration, and the solvent was distilled off to obtain the title compound (249 mg).
- Example 1e Benzyl (2E) -but-2-enoate Crotonic acid (70 g, 812 mmol) was dissolved in N, N-dimethylformamide (467 ml), cooled in an ice bath under nitrogen, and potassium carbonate (61.6 g). , 447 mmol). To the reaction mixture, benzyl bromide (91.7 ml, 772 mmol) was added dropwise over 20 minutes. The reaction mixture was stirred at room temperature for 18 hours. Ethyl acetate was added to the reaction mixture, and the mixture was filtered through celite.
- Example 1f Benzyl (3RS, 4SR) -1-benzyl-4-methylpyrrolidine-3-carboxylate
- the benzyl (2E) -but-2-enoate obtained in Example 1e (20.5 g, 116 mmol) was dissolved in dichloromethane. (5 ml) and the mixture was cooled in an ice bath with stirring. Trifluoroacetic acid (257 ⁇ l, 3.47 mmol) was added, and the inner temperature was 62 ° C. while washing N- (methoxymethyl) -N- (trimethylsilylmethyl) benzylamine (33.1 g, 139 mmol) with dichloromethane (25 ml). Was added dropwise to the reaction solution over 15 minutes.
- Example 1g Benzyl (3RS, 4SR) -1-benzyl-3- [2- (tert-butoxy) -2-oxoethyl] -4-methylpyrrolidine-3-carboxylate
- the benzyl (3RS obtained in Example 1f) , 4SR) -1-benzyl-4-methylpyrrolidine-3-carboxylate (30 g, 97.4 mmol) was dissolved in tetrahydrofuran (300 ml) and cooled to ⁇ 70 ° C. with stirring under nitrogen.
- the reaction mixture was then immediately diluted with water and ethyl acetate was added.
- the organic layer was washed with saturated brine and 5N aqueous hydrochloric acid solution, dried over magnesium sulfate, filtered and concentrated.
- the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / heptane).
- Example 1h 1,3-dibenzyl (3RS, 4SR) -3- [2- (tert-butoxy) -2-oxoethyl] -4-methylpyrrolidine-1,3-dicarboxylate
- the benzyl (3RS, 4SR) -1-benzyl-3- [2- (tert-butoxy) -2-oxoethyl] -4-methylpyrrolidine-3-carboxylate (11.7 g, 27.6 mmol) (117 ml) and benzyl chloroformate (23.7 ml, 166 mmol) was added dropwise to the reaction solution over 20 minutes so that the internal temperature did not exceed 22 ° C.
- Example 1i (3S, 4R) -3- [2- (tert-Butoxy) -2-oxoethyl] -4-methylpyrrolidine-3-carboxylic acid 1,3-dibenzyl (3RS, obtained in Example 1h) 4SR) -3- [2- (tert-butoxy) -2-oxoethyl] -4-methylpyrrolidine-1,3-dicarboxylate (9.1 g) was subjected to optical resolution under the following two conditions A or B. went.
- Example 1j (3S, 4R) -1-Benzyl-3- [2- (tert-butoxy) -2-oxoethyl] -4-methylpyrrolidine-3-carboxylic acid obtained in Example 1i (3S, 4R ) -3- [2- (tert-butoxy) -2-oxoethyl] -4-methylpyrrolidine-3-carboxylic acid (1.8 g, 7.4 mmol), benzaldehyde (1.51 ml, 14.8 mmol), acetic acid ( A mixture of 0.635 ml, 11.1 mmol), sodium triacetoxyborohydride (3.14 g, 14.8 mmol) and methanol (35 ml) was heated at 40 ° C.
- Example 1k tert-butyl 2-[(3S, 4R) -1-benzyl-3- ⁇ [1- (2-fluoropentyl) piperidin-4-yl] carbamoyl ⁇ -4-methylpyrrolidin-3-yl ] Chiral Acetate (3S, 4R) -1-Benzyl-3- [2- (tert-butoxy) -2-oxoethyl] -4-methylpyrrolidine-3-carboxylic acid (300 mg, 0) obtained in Example 1j .9 mmol), 1- (2-fluoropentyl) piperidin-4-amine chiral compound 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-dimethylformamide (4.5 ml) was stirred at room temperature for 61 hours 30 minutes.
- Triethylamine (0.207 ml, 1.49 mmol) and PyBOP (360 mg, 0.69 mmol) were further added, and the mixture was stirred for 4 hours 30 minutes. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with a saturated aqueous ammonium chloride solution and dried over anhydrous magnesium 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 obtain the title compound (161 mg, yield 35.5%).
- Example 1m 2-[(3S, 4R) -1- ⁇ [2-Chloro-6- (trifluoromethyl) phenyl] methyl ⁇ -3- ⁇ [1- (2-fluoropentyl) piperidine-4- [Ill] carbamoyl ⁇ -4-methylpyrrolidin-3-yl] acetic acid chiral tert-butyl 2-[(3S, 4R) -1- ⁇ [2-chloro-6- (trifluoromethyl) obtained in Example 11 ) Phenyl] methyl ⁇ -3- ⁇ [1- (2-fluoropentyl) piperidin-4-yl] carbamoyl ⁇ -4-methylpyrrolidin-3-yl] acetate chiral form (153 mg, 0.252 mmol), trifluoro A mixture of acetic acid (2 ml, 26.9 mmol) and dichloromethane (dehydrated) (2 ml) was stirred at room temperature for 2 hours and 35 minutes.
- Example 2a 4,4-Difluoro-N-methoxy-N-methylcyclohexane-1-carboxamide ethyl 4,4-difluorocyclohexane-1-carboxylate (1.9 g, 9.88 mmol) in tetrahydrofuran (60 ml) The mixture was cooled to ⁇ 70 ° C. and N, O-dimethylhydroxyamine hydrochloride (1.44 g, 14.8 mmol) was added. Further, 1.05M n-propylmagnesium bromide (24.2 ml, 25.2 mmol) was added dropwise to the reaction mixture at ⁇ 55 ° C.
- Example 2b 4,4-Difluorocyclohexane-1-carbaldehyde 4,4-Difluoro-N-methoxy-N-methylcyclohexane-1-carboxamide (1.7 g, 8.21 mmol) obtained in Example 2a, A mixture of tetrahydrofuran (60 ml) was cooled to ⁇ 70 ° C., 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 minutes.
- Example 2c tert-Butyl N- ⁇ 1-[(4,4-difluorocyclohexyl) methyl] piperidin-4-yl ⁇ carbamate
- Crude of 4,4-difluorocyclohexane-1-carbaldehyde obtained in Example 2b The mixture of the product (1.4 g) and tetrahydrofuran (100 ml) was cooled to 0 ° C., tert-butyl N- (piperidin-4-yl) carbamate (2.27 g, 11.3 mmol) was added thereto, and the mixture was stirred for 20 minutes.
- Example 2d 1-[(4,4-Difluorocyclohexyl) methyl] piperidin-4-amine tert-Butyl N- ⁇ 1-[(4,4-difluorocyclohexyl) methyl] piperidine-obtained in Example 2c
- 4-yl ⁇ carbamate 650 mg, 1.96 mmol
- methanol 11 ml
- 4N hydrogen chloride / 1,4-dioxane solution 11 ml, 43 mmol
- Example 2e (4-Methoxyphenyl) methyl (2E) -but-2-enoate
- Crotonic acid (17.2 g, 200 mmol) was cooled to N, N-dimethylformamide (100 ml) in an ice bath under nitrogen.
- Dissolve and add powdered potassium carbonate (15.2 g, 110 mmol).
- the mixture was stirred for 30 minutes before 4-methoxybenzyl chloride (29.8 g, 190 mmol) was added dropwise over 15 minutes.
- the reaction mixture was stirred at room temperature for 4 hours and at 45 ° C. for 14 hours.
- Ethyl acetate (500 ml) and water (200 ml) were added to the reaction solution.
- Example 2f (4-Methoxyphenyl) methyl (3RS, 4SR) -1-benzyl-4-methylpyrrolidine-3-carboxylate Obtained in Example 2e by a method similar to that described in Example 1f. The title compound (57.86 g, yield: 86.5%) was obtained from (4-methoxyphenyl) methyl (2E) -but-2-enoate (40.6 g, 197 mmol).
- Example 2g (4-Methoxyphenyl) methyl (3RS, 4SR) -1-benzyl-3- [2- (tert-butoxy) -2-oxoethyl] -4-methylpyrrolidine-3-carboxylate
- Example 1g From (4-methoxyphenyl) methyl (3RS, 4SR) -1-benzyl-4-methylpyrrolidine-3-carboxylate (56.7 g, 166 mmol) obtained in Example 2f by a method similar to that described in The title compound (60.3 g, yield: 80.1%) was obtained.
- Example 2h 1-Benzyl 3- (4-methoxyphenyl) methyl (3RS, 4SR) -3- [2- (tert-butoxy) -2-oxoethyl] -4-methylpyrrolidine-1,3-dicarboxyl Rate (4-Methoxyphenyl) methyl (3RS, 4SR) -1-benzyl-3- [2- (tert-butoxy) -2-] obtained in Example 2g by a method similar to that described in Example 1h The title compound (15 g, yield: 65.1%) was obtained from oxoethyl] -4-methylpyrrolidine-3-carboxylate (21 g, 46.3 mmol).
- HPLC CHIRALPAK AD-H (2 cm
- Lot B is a collection of 3 fractions during column purification, and was collected after confirming that the chemical shift of each fraction was the same as the chemical shift of lot A.
- Example 2m 2-[(3S, 4R) -1-[(2,6-dichlorophenyl) methyl] -3-( ⁇ 1-[(4,4-difluorocyclohexyl) methyl] piperidin-4-yl ⁇ Carbamoyl) -4-methylpyrrolidin-3-yl] acetic acid
- Example 3a tert-Butyl 4-[(3S, 4R) -1-benzyl-3- [2- (tert-butoxy) -2-oxoethyl] -4-methylpyrrolidine-3-amido] piperidine-1- Carboxylate (3S, 4R) -1-benzyl-3- [2- (tert-butoxy) -2-oxoethyl] -4-methylpyrrolidine-3-carboxylic acid (942 mg, 942 mg, obtained in a similar manner as Example 1j 2.83 mmol) in N, N-dimethylformamide (20 ml) in tert-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) was added and stirred at room temperature overnight.
- Example 3c tert-butyl 4-[(3S, 4R) -3- [2- (tert-butoxy) -2-oxoethyl] -1- ⁇ [2-chloro-6- (trifluoromethyl) phenyl] Methyl ⁇ -4-methylpyrrolidine-3-amide] piperidine-1-carboxylate tert-butyl 4-[(3S, 4R) -3- [2- (tert-butoxy) -2-oxoethyl obtained in Example 3b ] -4-methylpyrrolidine-3-amide] piperidine-1-carboxylate (345 mg, 0.811 mmol) in a solution of N, N-dimethylformamide (dehydrated) (10 mL) in 2- (bromomethyl) -1-chloro- 3- (Trifluoromethyl) benzene (443 mg, 1.62 mmol) and potassium carbonate (244 mg) were added, and the mixture was heated at 45 ° C.
- Example 3d 2-[(3S, 4R) -1- ⁇ [2-Chloro-6- (trifluoromethyl) phenyl] methyl ⁇ -4-methyl-3-[(piperidin-4-yl) carbamoyl] Pyrrolidin-3-yl] acetic acid tert-butyl 4-[(3S, 4R) -3- [2- (tert-butoxy) -2-oxoethyl] -1- ⁇ [2-chloro-6] obtained in Example 3c
- Example 3e 2-[(3S, 4R) -1- ⁇ [2-Chloro-6- (trifluoromethyl) phenyl] methyl ⁇ -3- ⁇ [1- (Cyclohex-1-ene-1- (Ilmethyl) piperidin-4-yl] carbamoyl ⁇ -4-methylpyrrolidin-3-yl] acetic acid 2-[(3S, 4R) -1- ⁇ [2-chloro-6- (tri Fluoromethyl) phenyl] methyl ⁇ -4-methyl-3-[(piperidin-4-yl) carbamoyl] pyrrolidin-3-yl] acetic acid mixture (344 mg, 0.745 mmol) in tetrahydrofuran (dehydrated) (10 mL) And cyclohex-1-ene-1-carbaldehyde (423 ⁇ l, 3.73 mmol), acetic acid (300 ⁇ l) and sodium triacetoxyborohydride (789 mg, 3.
- Example 4 Alternative Method of Example 3 Compound 2-[(3S, 4R) -1- ⁇ [2-Chloro-6- (trifluoromethyl) phenyl] methyl ⁇ -3- ⁇ [1- (cyclohex S-1-en-1-ylmethyl) piperidin-4-yl] carbamoyl ⁇ -4-methylpyrrolidin-3-yl] acetic acid
- Example 4a tert-butyl N- [1- (cyclohex-1-en-1-ylmethyl) piperidin-4-yl] carbamate tert-butyl N- (piperidin-4-yl) carbamate (5.3 g, 26.5 mmol), 1-cyclohexene-1-carboxaldehyde (3.5 g, 31.8 mmol), sodium triacetoxyborohydride (7.29 g, 34.4 mmol), acetic acid (0.5 ml), and tetrahydrofuran (dehydrated) ) (80 ml) was stirred at room temperature for 85 hours 30 minutes. Water and sodium hydrogen carbonate were added to the reaction mixture and stirred, followed by extraction with ethyl acetate twice.
- Example 4b 1- (Cyclohex-1-en-1-ylmethyl) piperidin-4-amine tert-butyl N- [1- (Cyclohex-1-en-1-ylmethyl) obtained in Example 4a
- a mixture of piperidin-4-yl] carbamate (7.47 g, 25.4 mmol), 5N aqueous hydrochloric acid (25 ml, 125 mmol), and methanol (100 ml) was stirred at 70 ° C. for 1.5 hours.
- the reaction mixture was ice-cooled, 5N aqueous sodium hydroxide solution (25 ml, 125 mmol) was added, and the solvent was evaporated. Water was added to the residue and extracted twice with ethyl acetate.
- Example 4c 1-Benzyl 3- (4-methoxyphenyl) methyl (3RS, 4SR) -3- [2- (tert-butoxy) -2-oxoethyl] -4-methylpyrrolidine-1,3-dicarboxyl (4-Methoxyphenyl) methyl (3RS, 4SR) -1-benzyl-3- [2- (tert-butoxy) -2-oxoethyl] -4-methylpyrrolidine-3-carboxylate obtained in Example 2g ( A solution of 18 g, 39.7 mmol) in dichloromethane (85.7 ml) was adjusted to an internal temperature of 10-20 ° C., and benzyl chloroformate (11.9 ml, 79.4 mmol) was added thereto.
- Example 4f (3S, 4R) -3- [2- (tert-Butoxy) -2-oxoethyl] -4-methylpyrrolidine-3-carboxylic acid 1-Benzyl 3- (3) obtained by the method of Example 4e 4-methoxyphenyl) methyl (3S, 4R) -3- [2- (tert-butoxy) -2-oxoethyl] -4-methylpyrrolidine-1,3-dicarboxylate (3.3 g, 6.63 mmol) Methanol (70 ml), 10% Pd / C (600 mg) was added, and the mixture was stirred at room temperature for 3 days under a hydrogen atmosphere. Water (70 ml) was added to the reaction solution, stirred and filtered. The filtrate was concentrated to obtain the title compound (1.15 g, yield: 71.3%). 1 H-NMR (400 MHz, D 2 O); consistent with the compound obtained in Example 2j.
- Example 4i tert-butyl 2-[(3S, 4R) -1- ⁇ [2-chloro-6- (trifluoromethyl) phenyl] methyl ⁇ -3- ⁇ [1- (cyclohex-1-ene -1-ylmethyl) piperidin-4-yl] carbamoyl ⁇ -4-methylpyrrolidin-3-yl] acetate (3S, 4R) -3- [2- (tert-butoxy) -2-oxoethyl obtained in Example 4h ] 1- (Cyclohex-1-en-1-ylmethyl) piperidin-4-amine obtained in Example 4b (240 mg, 1.24 mmol) to 4-methylpyrrolidine-3-carboxylic acid (200 mg, 0.822 mmol).
- Example 4j 2-[(3S, 4R) -1- ⁇ [2-chloro-6- (trifluoromethyl) phenyl] methyl ⁇ -3- ⁇ [1- (cyclohexyl-1-en-1-ylmethyl) ) Piperidin-4-yl] carbamoyl ⁇ -4-methylpyrrolidin-3-yl] acetic acid tert-butyl 2-[(3S, 4R) -1- ⁇ [2-chloro-6- (tri Fluoromethyl) phenyl] methyl ⁇ -3- ⁇ [1- (cyclohex-1-en-1-ylmethyl) piperidin-4-yl] carbamoyl ⁇ -4-methylpyrrolidin-3-yl] acetate (353 mg,.
- Example 5 Alternative Method of Example 3 Compound 2-[(3S, 4R) -1- ⁇ [2-Chloro-6- (trifluoromethyl) phenyl] methyl ⁇ -3- ⁇ [1- (cyclohex S-1-en-1-ylmethyl) piperidin-4-yl] carbamoyl ⁇ -4-methylpyrrolidin-3-yl] acetic acid
- Example 5a tert-butyl 4-[(3RS, 4SR) -3- [2- (tert-butoxy) -2-oxoethyl] -1-[(2,6-dichlorophenyl) methyl] -4-methylpyrrolidine -3-amido] piperidine-1-carboxylate benzyl (3RS, 4SR) -1-benzyl-3- [2- (tert-butoxy) -2-oxoethyl] -4- obtained by a method similar to that of Example 1g To a solution of methylpyrrolidine-3-carboxylate (3 g, 7.08 mmol) in methanol (200 ml) was added 20% palladium hydroxide (300 mg), and the mixture was stirred overnight at room temperature in a hydrogen atmosphere.
- methylpyrrolidine-3-carboxylate 3 g, 7.08 mmol
- methanol 200 ml
- reaction solution was filtered and washed with methanol. Hot water of about 40 ° C. was added to the filtered product to dissolve the solid matter and filtered. The filtrate was combined with the first filtrate and concentrated to obtain a deprotected product (1.7 g).
- Neutral buffer prepared from potassium dihydrogen phosphate (13.65 g), disodium hydrogen phosphate dodecahydrate (71.6 g), water (1.5 l)] was added to the reaction solution, and ethyl acetate and heptane were added The mixture was filtered. The filtrate was extracted with ethyl acetate, and the organic layer was dried over sodium sulfate and concentrated. The resulting crude product was purified by column chromatography (silica gel, elution solvent: methanol / ethyl acetate) and combined with the filtrate.
- Example 5c tert-butyl 4-[(3S, 4R) -3- [2- (tert-butoxy) -2-oxoethyl] -1- ⁇ [2-chloro-6- (trifluoromethyl) phenyl] Methyl ⁇ -4-methylpyrrolidine-3-amide] piperidine-1-carboxylate tert-butyl 4-[(3S, 4R) -3- [2- (tert-butoxy) -2-oxoethyl obtained in Example 5b ]-1-[(2,6-dichlorophenyl) methyl] -4-methylpyrrolidine-3-amide] piperidine-1-carboxylate (758 mg, 1.29 mmol) in methanol (20 ml) in 20% palladium hydroxide ( 75.8 mg) was added, and the mixture was stirred at 40 ° C.
- Example 5d 2-[(3S, 4R) -1- ⁇ [2-Chloro-6- (trifluoromethyl) phenyl] methyl ⁇ -4-methyl-3-[(piperidin-4-yl) carbamoyl] Pyrrolidin-3-yl] acetic acid tert-butyl 4-[(3S, 4R) -3- [2- (tert-butoxy) -2-oxoethyl] -1- ⁇ [2-chloro-6] obtained in Example 5c
- piperidine-1-carboxylate 82 mg, 0.133 mmol
- dichloromethane dehydrated
- trifluoroacetic acid 3 mL
- Example 5e 2-[(3S, 4R) -1- ⁇ [2-chloro-6- (trifluoromethyl) phenyl] methyl ⁇ -3- ⁇ [1- (cyclohex-1-ene-1- (Ilmethyl) piperidin-4-yl] carbamoyl ⁇ -4-methylpyrrolidin-3-yl] acetic acid 2-[(3S, 4R) -1- ⁇ [2-chloro-6- ( To a solution of trifluoromethyl) phenyl] methyl ⁇ -4-methyl-3-[(piperidin-4-yl) carbamoyl] pyrrolidin-3-yl] acetic acid (15 mg, 0.0325 mmol) in tetrahydrofuran (dehydrated) (2 mL) Cyclohex-1-ene-1-carbaldehyde (25.9 ⁇ l, 0.227 mmol), acetic acid (30 ⁇ l) and sodium triacetoxyborohydride (68.8 mg, 0.3 25
- Example 6a (3S, 4R) -3- [2- (tert-butoxy) -2-oxoethyl] -1-[(2-chloro-6-methylphenyl) methyl] -4-methylpyrrolidine-3- Carboxylic acid (3S, 4R) -3- [2- (tert-Butoxy) -2-oxoethyl] -4-methyl obtained by a method similar to that described in Example 1i by a method similar to that described in Example 1j The title compound (154 mg, yield 27.2%) was obtained from pyrrolidine-3-carboxylic acid (360 mg, 1.48 mmol) and 2-chloro-6-methylbenzaldehyde (416 mg, 2.69 mmol).
- Example 6b tert-butyl 2-[(3S, 4R) -1-[(2-chloro-6-methylphenyl) methyl] -3- ⁇ [1- (cyclohex-1-en-1-ylmethyl) ) Piperidin-4-yl] carbamoyl ⁇ -4-methylpyrrolidin-3-yl] acetate
- the (3S, 4R) -3- [2- [2] obtained in Example 6a was prepared in a manner similar to that described in Example 1k.
- Example 6c 2-[(3S, 4R) -1-[(2-chloro-6-methylphenyl) methyl] -3- ⁇ [1- (cyclohex-1-en-1-ylmethyl) piperidine- 4-yl] carbamoyl ⁇ -4-methylpyrrolidin-3-yl] acetic acid
- tert-butyl 2-[(3S, 4R) -1- obtained in Example 6b [(2-Chloro-6-methylphenyl) methyl] -3- ⁇ [1- (cyclohex-1-en-1-ylmethyl) piperidin-4-yl] carbamoyl ⁇ -4-methylpyrrolidin-3-yl]
- the title compound (140 mg, yield 73.4%) was obtained from acetate (212 mg, 0.38 mmol).
- Example 7a Cyclopent-1-ene-1-carbaldehyde
- 1,2-cyclohexanediol (12 g, 103 mmol) and diethyl ether (150 ml) was mixed with sodium periodate (28.6 g, 134 mmol) and water ( 250 ml) was added and stirred at room temperature for 35 minutes.
- a 20% aqueous potassium hydroxide solution (40 ml, 206 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours.
- the reaction mixture was extracted twice with diethyl ether.
- the organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off to obtain the title compound (6.1 g, yield 61.6%).
- Example 7b 2-[(3S, 4R) -1- ⁇ [2-Chloro-6- (trifluoromethyl) phenyl] methyl ⁇ -3- ⁇ [1- (cyclopent-1-en-1-ylmethyl) ) Piperidin-4-yl] carbamoyl ⁇ -4-methylpyrrolidin-3-yl] acetic acid
- 2-[(3S, 4R) -1- Performed with ⁇ [2-chloro-6- (trifluoromethyl) phenyl] methyl ⁇ -4-methyl-3-[(piperidin-4-yl) carbamoyl] pyrrolidin-3-yl] acetic acid (334 mg, 0.723 mmol) Cyclopent-1-ene-1-carbaldehyde obtained in Example 7a (209 mg, 2.17 mmol), acetic acid (300 ⁇ l) and sodium triacetoxyborohydride (460 mg, 2.1) The title compound from mmol)
- Example 8 2-[(3S, 4R) -1-[(2-chloro-6-methylphenyl) methyl] -3- ⁇ [(1-cyclopent-1-en-1-ylmethyl) piperidine-4 -Yl] carbamoyl ⁇ -4-methylpyrrolidin-3-yl] acetic acid
- Example 8a tert-butyl 4-[(3S, 4R) -3-[(2-tert-butoxy) -2-oxoethyl] -1-[(2-chloro-6-methylphenyl) methyl] -4 -Methylpyrrolidine-3-amido ⁇ piperidine-1-carboxylate Obtained (3S, 4R) -3-[(2) in a manner similar to that described in Example 6a by a method similar to that described in Example 1k.
- Example 8b 2-[(3S, 4R) -1-[(2-chloro-6-methylphenyl) methyl] -3- ⁇ [(1-cyclopent-1-en-1-ylmethyl) piperidine-4 -Yl] carbamoyl ⁇ -4-methylpyrrolidin-3-yl] acetic acid tert-butyl 4-[(3S, 4R) -3-[(2-tert-butoxy) -2-oxoethyl]-obtained in Example 8a 1-[(2-chloro-6-methylphenyl) methyl] -4-methylpyrrolidine-3-amide ⁇ piperidine-1-carboxylate (237 mg, 0.42 mmol), trifluoroacetic acid (2.3 ml, 31 mmol), And a mixture of dichloromethane (dehydrated) (2.3 ml) was stirred at room temperature for 3 hours 30 minutes.
- Example 9a tert-Butyl N-[(3S) -1- (cyclohex-1-en-1-ylmethyl) pyrrolidin-3-yl] carbamate (3S)-( ⁇ )-3- (tert-butoxy Carbonylamino) pyrrolidine (2.0 g, 10.8 mmol), acetic acid (1.24 ml, 21.6 mmol) and tetrahydrofuran (dehydrated) (27 ml) were mixed with 1-cyclohexene-1-carboxaldehyde (1.48 ml, 13 mmol).
- Example 9b (3S) -1- (Cyclohex-1-en-1-ylmethyl) pyrrolidin-3-amine tert-butyl N-[(3S) -1- (cyclohex-- obtained in Example 9a
- Example 9c tert-butyl 2-[(3S, 4R) -3- ⁇ [(3S) -1- (cyclohex-1-en-1-ylmethyl) pyrrolidin-3-yl] carbamoyl ⁇ -1- [(2,6-Dichlorophenyl) methyl] -4-methylpyrrolidin-3-yl] acetate (3S) -1- (cyclohex-) obtained in Example 9b by a method similar to that described in Example 1k 1-en-1-ylmethyl) pyrrolidin-3-amine (169 mg, 0.94 mmol) and (3S, 4R) -3- [2- (tert-butoxy) -2-oxoethyl]-obtained in Example 2k The title compound (236 mg, 58% yield) was obtained from 1-[(2,6-dichlorophenyl) methyl] -4-methylpyrrolidine-3-carboxylic acid (290 mg, 0.72 mmol).
- Example 9d 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 title compound (173 mg, 81% yield) was obtained from -yl] acetate (236 mg, 0.42 mmol).
- Example 10a 1-Hexylpiperidin-4-amine The title compound was obtained in a manner similar to that described in US2005 / 0222175 A1 and Examples 4a and 4b.
- Example 10b Methyl 3-chloro-2-methylbenzoate 3-chloro-2-methylbenzoic acid (3.58 g, 21 mmol), potassium carbonate (5.8 g, 42 mmol), N, N-dimethylformamide (35. 9 ml) was added with iodomethane (1.96 ml, 31.5 mmol) and stirred at room temperature for 18 hours 30 minutes. Water and ethyl acetate were added to the reaction solution to extract the organic layer. The organic layer was washed successively with saturated aqueous ammonium chloride solution and saturated brine, dried over sodium sulfate, filtered and concentrated.
- Example 10d [2- (Bromomethyl) -3-chlorophenyl] methanol
- Dichloromethane (10 ml) was added to methyl 2- (bromomethyl) -3-chlorobenzoate (500 mg, 1.9 mmol) obtained in Example 10c to -78.
- a 1.04 M diisobutylaluminum hydride / n-hexane solution (4.57 ml, 4.75 mmol) was added, and the mixture was stirred under a nitrogen atmosphere for 1 hour.
- a saturated aqueous Rochelle salt solution and tert-butyl methyl ether were added, and the mixture was extracted with tert-butyl methyl ether.
- Example 10f 2- (Bromomethyl) -1-chloro-3- (difluoromethyl) benzene 2- (Bromomethyl) -3-chlorobenzaldehyde (289 mg, 1.24 mmol) obtained in Example 10e was added to dichloromethane (10 ml). Then, [bis (2-methoxyethyl) amino] sulfur trifluoride (457 ⁇ l, 2.48 mmol) was added at 0 ° C., and the mixture was stirred at room temperature for 1.5 hours under a nitrogen atmosphere. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture at 0 ° C., and the mixture was extracted with diethyl ether.
- Example 10g (3RS, 4SR) -3- [2- (tert-butoxy) -2-oxoethyl] -1-[(2,6-dichlorophenyl) methyl] -4-methylpyrrolidine-3-carboxylic acid
- Benzyl (3RS, 4SR) -1-benzyl-3- [2- (tert-butoxy) -2-oxoethyl] -4-methylpyrrolidine-3-carboxylate (8.35 g, obtained in a similar manner as Example 1g
- Neutral buffer prepared from potassium dihydrogen phosphate (13.65 g), disodium hydrogen phosphate dodecahydrate (71.6 g), water (1.5 L)] and ethyl acetate were added to the reaction mixture, and the solid was added. Filtered. The solid on the filter paper was washed with ethyl acetate to give the title compound as a white solid. The filtrate was extracted with ethyl acetate, and the organic layer was dried over sodium sulfate, concentrated and purified by column chromatography (silica gel, elution solvent: methanol / ethyl acetate). 3.77 g, yield 58.2%).
- Example 10h tert-butyl 2-[(3S, 4R) -1-[(2,6-dichlorophenyl) methyl] -3-[(1-hexylpiperidin-4-yl) carbamoyl] -4-methylpyrrolidine -3-yl] acetate (3RS, 4SR) -3- [2- (tert-butoxy) -2-oxoethyl] -1-[(2,6-dichlorophenyl) methyl] -4-methyl obtained in 10 g of Example 1-hexylpiperidin-4-amine (894 mg, 4.85 mmol) obtained in Example 10a, triethylamine (1.04 ml, 7.46 mmol), N in pyrrolidine-3-carboxylic acid (1.5 g, 3.73 mmol) , N-dimethylformamide (10 ml) and PyBOP (2.52 g, 4.85 mmol) were added and stirred overnight at room temperature.
- Example 10i tert-Butyl 2-[(3S, 4R) -3-[(1-hexylpiperidin-4-yl) carbamoyl] -4-methylpyrrolidin-3-yl] acetate
- the tert obtained in Example 10h -Butyl 2-[(3S, 4R) -1-[(2,6-dichlorophenyl) methyl] -3-[(1-hexylpiperidin-4-yl) carbamoyl] -4-methylpyrrolidin-3-yl] acetate
- Methanol (10 ml) and 20% palladium hydroxide (50 mg) were added to 250 mg of the solution, and the mixture was stirred at room temperature for 2 hours in a hydrogen atmosphere.
- Example 10j tert-butyl 2-[(3S, 4R) -1- ⁇ [2-chloro-6- (difluoromethyl) phenyl] methyl ⁇ -3-[(1-hexylpiperidin-4-yl) carbamoyl ] -4-Methylpyrrolidin-3-yl] acetate
- Example 10k 2-[(3S, 4R) -1- ⁇ [2-chloro-6- (difluoromethyl) phenyl] methyl ⁇ -3-[(1-hexylpiperidin-4-yl) carbamoyl] -4 -Methylpyrrolidin-3-yl] acetic acid
- Example 11a (3S, 4R) -3- [2- (tert-butoxy) -2-oxoethyl] -1-[(2,6-dichlorophenyl) methyl] -4-methylpyrrolidine-3-carboxylic acid (3S, 4R) -3- [2- (tert-Butoxy) -2-oxoethyl] -4-methylpyrrolidine-3-carboxylic acid (300 mg, 1.23 mmol) obtained in the same manner as in Example 1i with methanol ( 3 ml), 2,6-dichlorobenzaldehyde (431 mg, 2.46 mmol), acetic acid (73.8 ul, 1.23 mmol) and sodium triacetoxyborohydride (521 mg, 2.46 mmol) were added and stirred at room temperature for 2 days.
- Example 11b tert-butyl 2-[(3S, 4R)- ⁇ 3-[(1-cyclohex-1-en-1-ylmethyl) piperidin-4-yl] carbamoyl-1-[(2,6 -Dichlorophenyl) methyl] -4-methylpyrrolidin-3-yl ⁇ acetate (3S, 4R) -3- [2- (tert-butoxy) obtained in Example 11a by a method similar to that described in Example 1k.
- Example 11c 2-[(3S, 4R) -3- ⁇ [(1-Cyclohex-1-en-1-ylmethyl) piperidin-4-yl] carbamoyl ⁇ -1-[(2,6-dichlorophenyl ) Methyl] -4-methylpyrrolidin-3-yl] acetic acid
- To give the title compound (169 mg, yield 68.2%).
- Example 12 2-[(3S, 4R) -1- ⁇ [2-Chloro-6- (difluoromethyl) phenyl] methyl ⁇ -3- ⁇ [1- (cyclohex-1-en-1-ylmethyl) ) Piperidin-4-yl] carbamoyl ⁇ -4-methylpyrrolidin-3-yl] acetic acid
- Example 12a tert-Butyl 4-[(3S, 4R) -3- [2- (tert-butoxy) -2-oxoethyl] -1- ⁇ [2-chloro-6- (difluoromethyl) phenyl] methyl ⁇ -4-Methylpyrrolidine-3-amide] piperidine-1-carboxylate tert-butyl 4-[(3S, 4R) -3- [2- (tert-butoxy) -2-oxoethyl] obtained in Example 3b -4-Methylpyrrolidine-3-amide] piperidine-1-carboxylate (375 mg, 0.881 mmol) was dissolved in N, N-dimethylformamide (7 ml).
- Example 12b 2-[(3S, 4R) -1- ⁇ [2-Chloro-6- (difluoromethyl) phenyl] methyl ⁇ -3- ⁇ [1- (cyclohex-1-en-1-ylmethyl) ) Piperidin-4-yl] carbamoyl ⁇ -4-methylpyrrolidin-3-yl] acetic acid tert-butyl 4-[(3S, 4R) -3- [2- (tert-butoxy) -2 obtained in Example 12a -Oxoethyl] -1- ⁇ [2-chloro-6- (difluoromethyl) phenyl] methyl ⁇ -4-methylpyrrolidine-3-amido] piperidine-1-carboxylate (332 mg, 0.553 mmol) was added to dichloromethane (3.
- Example 13 2-[(3S, 4R) -1- ⁇ [2-Chloro-6- (difluoromethyl) phenyl] methyl ⁇ -3- ⁇ [1- (cyclopent-1-en-1-ylmethyl) Piperidin-4-yl] carbamoyl ⁇ -4-methylpyrrolidin-3-yl] acetic acid
- the intermediate (186 mg) obtained in Example 12b and the cyclopent-1-ene-1-carbaldehyde obtained in Example 7a ( 79.9 mg, 0.831 mmol) and the title compound (76 mg) was obtained in the same manner as described for 12b.
- Example 14a 1- (Cyclohexylmethyl) piperidin-4-amine The title compound was obtained in a manner similar to that described in US2005 / 0222175 A1 and Examples 4a and 4b.
- Example 14b tert-butyl 2-[(3S, 4R) -1-benzyl-3- ⁇ [1- (cyclohexylmethyl) piperidin-4-yl] carbamoyl ⁇ -4-methylpyrrolidin-3-yl] acetate (3S, 4R) -1-benzyl-3- [2- (tert-butoxy) -2-oxoethyl] -4-methylpyrrolidine- obtained in Example 1j by a method similar to that described in Example 1k The title compound (250 mg, yield: 81.4%) was obtained from 3-carboxylic acid (200 mg, 0.6 mmol) and 1- (cyclohexylmethyl) piperidin-4-amine (141 mg, 0.72 mmol) obtained in Example 14a.
- Example 14c tert-butyl 2-[(3S, 4R) -1- ⁇ [2-chloro-6- (difluoromethyl) phenyl] methyl ⁇ -3- ⁇ [1- (cyclohexylmethyl) piperidine-4- Yl] carbamoyl ⁇ -4-methylpyrrolidin-3-yl] acetate
- tert-butyl 2-[(3S, 4R) -1-benzyl- obtained in Example 14b 3- ⁇ [1- (Cyclohexylmethyl) piperidin-4-yl] carbamoyl ⁇ -4-methylpyrrolidin-3-yl] acetate (250 mg, 0.489 mmol) was obtained in the same manner as in Example 10f.
- Example 14d 2-[(3S, 4R) -1- ⁇ [2-Chloro-6- (difluoromethyl) phenyl] methyl ⁇ -3- ⁇ [1- (cyclohexylmethyl) piperidin-4-yl] carbamoyl ⁇ -4-Methylpyrrolidin-3-yl] acetic acid
- benzyl chloroformate (6.35 ml, 44.5 mmol) and 2N aqueous sodium hydroxide solution (22.3 ml) were simultaneously added with ice-cooling and stirring (0-1 ° C.) at an internal temperature of 3.5 ° C. or less. It was added dropwise over 20 minutes.
- the reaction solution was stirred in an ice bath and gradually returned to room temperature.
- the mixture was stirred at room temperature overnight.
- the reaction solution was adjusted to pH 12 by adding 1N aqueous sodium hydroxide solution (10 ml) under ice-cooling and stirring (internal temperature around 15 ° C.). The reaction solution was returned to room temperature and washed three times by adding ethyl ether.
- the aqueous layer was adjusted to pH 2-3 by successively adding 2N aqueous hydrochloric acid (20.2 ml) and 1N aqueous hydrochloric acid (13 ml) under ice-cooling and stirring (internal temperature of 5 ° C. or less).
- the aqueous layer was returned to room temperature and extracted three times with ethyl acetate.
- the organic layer was washed with saturated brine, dried over sodium sulfate, filtered and concentrated.
- the residue was dissolved in ethyl acetate, washed 4 times with water and then with saturated brine, dried over sodium sulfate, filtered and concentrated to give the title compound (14.53 g, yield: 95.1%). It was.
- Oxoethyl] -4-methylpyrrolidine-3-carboxylic acid 500 mg
- hydrogen phosphate (R)-( ⁇ )-1,1′-binaphthyl-2,2′-diyl 359 mg
- ethanol 10.0 mL
- water 10.0 mL
- the precipitated solid was collected by filtration and washed with a 1: 1 ethanol-water mixture (2 mL).
- the wet substance was dried under reduced pressure at 40 ° C. for about 1 hour to obtain the title compound (269 mg, yield: 20.5%).
- Example Compounds 1 to 8 are as follows.
- Example Compounds 9 to 14 are as follows.
- T cell transfer colitis model (Test Example 2) Body weight decrease inhibitory effect in T cell transfer colitis model (1) Method Using a colitis model induced by transferring CD4 positive CD45RB high positive cells collected from BALB / c mice into SCID mice, The body weight reduction inhibitory effect of the example compounds was examined. The experiment was carried out for 31 days. On the first day, CD4 positive CD45RB high positive cells (5 ⁇ 10 5 cells / mouse) collected from the spleen of Balb / c mice were intravenously administered to SCID mice. From the 16th day to the 31st day, the Example compounds were orally administered to SCID mice once a day, and body weights were measured on the 19th, 22nd, 24th, 26th, 29th and 31st days.
- the body weight reduction inhibitory effect was evaluated by the body weight change rate (%) on the 19th, 22nd, 24th, 26th, 29th and 31st days.
- the body weight on the 16th day is [A]
- the body weight on each body weight measurement day is [B].
- the rate (%) was determined.
- Body weight change rate (%) B / A ⁇ 100
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Pyrrole Compounds (AREA)
Abstract
Description
[1] 式(1)で表される化合物またはその薬理学的に許容される塩。
XはC1-6アルキル基を意味し、
YおよびZは、同一または相異なって、ハロゲン原子または無置換のもしくは置換基群Bから選択される置換基を1~3個有するC1-6アルキル基を意味し、
nは0または1を意味し、
置換基群Aはハロゲン原子からなり、
置換基群Bはハロゲン原子からなる。]
[2] Rはフルオロブチル基、ペンチル基、シクロヘキシル基、ジフルオロシクロヘキシル基、シクロペンテニル基またはシクロヘキセニル基である、[1]記載の化合物またはその薬理学的に許容される塩。
[3] Xはメチル基である、[1]または[2]記載の化合物またはその薬理学的に許容される塩。
[4] Yは塩素原子である、[1]~[3]いずれか1項記載の化合物またはその薬理学的に許容される塩。
[5] Zは塩素原子、メチル基、ジフルオロメチル基、またはトリフルオロメチル基である、[1]~[4]いずれか1項記載の化合物またはその薬理学的に許容される塩。
[6] nは1である、[1]~[5]いずれか1項記載の化合物またはその薬理学的に許容される塩。
[7] 2-[(3S,4R)-1-{[2-クロロ-6-(トリフルオロメチル)フェニル]メチル}-3-{[1-(2-フルオロペンチル)ピペリジン-4-イル]カルバモイル}-4-メチルピロリジン-3-イル]酢酸、
2-[(3S,4R)-1-[(2,6-ジクロロフェニル)メチル]-3-({1-[(4,4-ジフルオロシクロヘキシル)メチル]ピペリジン-4-イル}カルバモイル)-4-メチルピロリジン-3-イル]酢酸、
2-[(3S,4R)-1-{[2-クロロ-6-(トリフルオロメチル)フェニル]メチル}-3-{[1-(シクロヘキス-1-エン-1-イルメチル)ピペリジン-4-イル]カルバモイル}-4-メチルピロリジン-3-イル]酢酸、
2-[(3S,4R)-1-[(2-クロロ-6-メチルフェニル)メチル]-3-{[1-(シクロヘキス-1-エン-1-イルメチル)ピペリジン-4-イル]カルバモイル}-4-メチルピロリジン-3-イル]酢酸、
2-[(3S,4R)-1-{[2-クロロ-6-(トリフルオロメチル)フェニル]メチル}-3-{[1-(シクロペント-1-エン-1-イルメチル)ピペリジン-4-イル]カルバモイル}-4-メチルピロリジン-3-イル]酢酸、
2-[(3S,4R)-1-[(2-クロロ-6-メチルフェニル)メチル]-3-{[(1-シクロペント-1-エン-1-イルメチル)ピペリジン-4-イル]カルバモイル}-4-メチルピロリジン-3-イル]酢酸、
2-[(3S,4R)-(3-{[(3S)-1-(シクロヘキス-1-エン-1-イルメチル)ピロリジン-3-イル]カルバモイル}-1-[(2,6-ジクロロフェニル)メチル]-4-メチルピロリジン-3-イル]酢酸、
2-[(3S,4R)-1-{[2-クロロ-6-(ジフルオロメチル)フェニル]メチル}-3-[(1-ヘキシルピペリジン-4-イル)カルバモイル]-4-メチルピロリジン-3-イル]酢酸、
2-[(3S,4R)-3-{[(1-シクロヘキス-1-エン-1-イルメチル)ピペリジン-4-イル]カルバモイル}-1-[(2,6-ジクロロフェニル)メチル]-4-メチルピロリジン-3-イル]酢酸、
2-[(3S,4R)-1-{[2-クロロ-6-(ジフルオロメチル)フェニル]メチル}-3-{[1-(シクロヘキス-1-エン-1-イルメチル)ピペリジン-4-イル]カルバモイル}-4-メチルピロリジン-3-イル]酢酸、
2-[(3S,4R)-1-{[2-クロロ-6-(ジフルオロメチル)フェニル]メチル}-3-{[1-(シクロペント-1-エン-1-イルメチル)ピペリジン-4-イル]カルバモイル}-4-メチルピロリジン-3-イル]酢酸および
2-[(3S,4R)-1-{[2-クロロ-6-(ジフルオロメチル)フェニル]メチル}-3-{[1-(シクロヘキシルメチル)ピペリジン-4-イル]カルバモイル}-4-メチルピロリジン-3-イル]酢酸からなる群から選択される化合物またはその薬理学的に許容される塩。
[8] [1]~[7]いずれか1項記載の化合物またはその薬理学的に許容される塩を有効成分とする医薬。
[9] [1]~[7]いずれか1項記載の化合物またはその薬理学的に許容される塩を有効成分とする、炎症性腸疾患治療剤。
[10] 炎症性腸疾患が、潰瘍性大腸炎またはクローン病である、[9]記載の治療剤。
[11] [1]~[7]いずれか1項記載の化合物またはその薬理学的に許容される塩を有効成分とする、フラクタルカイン-CX3CR1経路の阻害剤。
[12] [1]~[7]いずれか1項記載の化合物またはその薬理学的に許容される塩を有効成分とする、フラクタルカイン阻害剤。
[13] [1]~[7]いずれか1項記載の化合物またはその薬理学的に許容される塩を有効成分とする、CX3CR1阻害剤。
[14] [1]~[7]いずれか1項記載の化合物またはその薬理学的に許容される塩を患者に投与する、炎症性腸疾患の治療方法。
[15] 炎症性腸疾患が、潰瘍性大腸炎またはクローン病である、[14]記載の方法。
[16] [1]~[7]いずれか1項記載の化合物またはその薬理学的に許容される塩を患者に投与する、フラクタルカイン-CX3CR1経路の阻害方法。
[17] [1]~[7]いずれか1項記載の化合物またはその薬理学的に許容される塩を患者に投与する、フラクタルカインの阻害方法。
[18] [1]~[7]いずれか1項記載の化合物またはその薬理学的に許容される塩を患者に投与する、CX3CR1の阻害方法。
[19] 炎症性腸疾患の治療に使用する、[1]~[7]いずれか1項記載の化合物またはその薬理学的に許容される塩。
[20] 炎症性腸疾患が、潰瘍性大腸炎またはクローン病である、[19]記載の化合物またはその薬理学的に許容される塩。
[21] フラクタルカイン-CX3CR1経路の阻害に使用する、[1]~[7]いずれか1項記載の化合物またはその薬理学的に許容される塩。
[22] フラクタルカインの阻害に使用する、[1]~[7]いずれか1項記載の化合物またはその薬理学的に許容される塩。
[23] CX3CR1の阻害に使用する、[1]~[7]いずれか1項記載の化合物またはその薬理学的に許容される塩。
[24] 炎症性腸疾患治療剤の製造における、[1]~[7]いずれか1項記載の化合物またはその薬理学的に許容される塩の使用。
[25] 炎症性腸疾患が、潰瘍性大腸炎またはクローン病である、[24]記載の使用。
[26] フラクタルカイン-CX3CR1経路阻害剤の製造における、[1]~[7]いずれか1項記載の化合物またはその薬理学的に許容される塩の使用。
[27] フラクタルカイン阻害剤の製造における、[1]~[7]いずれか1項記載の化合物またはその薬理学的に許容される塩の使用。
[28] CX3CR1阻害剤の製造における、[1]~[7]いずれか1項記載の化合物またはその薬理学的に許容される塩の使用。
に関する。
前記工程Bで得られた化合物(6)から、水素添加反応により、アリールメチル基が脱離した化合物(4)を得ることができる。化合物(4)から、さらに工程Bにより、異なる置換基を有するアリールメチル基を追加した化合物(6)に変換することができる。
本工程は、化合物(8)のカルボキシル基と化合物(10)のアミノ基を脱水縮合し、化合物(11)を製造する工程であり、工程Aと同様の方法により行うことができる。
本工程は、化合物(11)に酸を反応させ、化合物(12)を製造する工程であり、工程Cと同様の方法により行うことができる。
本工程は、化合物(12)にアルデヒド化合物(13)を還元剤の存在下反応させて、化合物(1)を製造する工程であり、工程Dと同様の方法により行うことができる。
本工程は、不活性溶媒中、塩基の存在下、化合物(14)と、化合物(15)とを反応させ、化合物(16)を製造する工程である。本工程は、工程Bに準じて行うことができる。
本工程は、不活性溶媒中、酸の存在下で、化合物(16)にN-(メトキシメチル)-N-(トリメチルシリルメチル)ベンジルアミンを反応させ、化合物(17)を製造する工程である。
本工程は、不活性溶媒中、化合物(17)に塩基を作用させた後、tert-ブチル ブロモアセテートを反応させ、化合物(18)を製造する工程である。
本工程は、不活性溶媒中、還元触媒の存在下、化合物(18)に水素を反応させ、ベンジル基を除去する工程である。
本工程は、化合物(2)のラセミ体をキラル分割して、化合物(2)を得る工程である。
本工程は、不活性溶媒中、酸の存在下または非存在下で、化合物(19)と化合物(13)を還元剤存在下で反応させ、化合物(20)を製造する工程であり、工程Dに準じて行うことができる。
本工程は、溶媒の非存在下または不活性溶媒中、化合物(20)に酸を反応させ、tert-ブチルオキシカルボニル基を除去して、化合物(3)を製造する工程であり、工程Cに準じて行うことができる。
本工程は、不活性溶媒中、塩基の存在下、化合物(2)のラセミ体にベンジル クロロホルメートを反応させて、ベンジルオキシカルボニル基を導入する工程である。
本工程は、不活性溶媒中、塩基の存在下、化合物(21)と、ベンジルハライドとを反応させ、化合物(22)を製造する工程である。本工程は、工程Bに準じて行うことができる。
本工程は、化合物(22)をキラル分割して、化合物(22)のキラル体を得る工程である。本工程は、工程G-5に準じて行うことができる。
本工程は、不活性溶媒中、還元触媒の存在下、化合物(22)のキラル体に水素を反応させ、化合物(2)を得る工程である。本工程は、工程Eに準じて行うことができる。
本工程は、不活性溶剤中、化合物(18)にベンジル クロロホルメートを反応して、ベンジル基をベンジルオキシカルボニル基に置換して、化合物(22)を得る工程である。
本工程は、化合物(22)をキラル分割して、化合物(22)のキラル体を得る工程である。本工程は、工程G-5に準じて行うことができる。
本工程は、不活性溶媒中、還元触媒の存在下、化合物(22)のキラル体に水素を反応させ、化合物(2)を得る工程である。本工程は、工程Eに準じて行うことができる。
(1)光親和性標識基(例えば、ベンゾイル基、ベンゾフェノン基、アジド基、カルボニルアジド基、ジアジリジン基、エノン基、ジアゾ基およびニトロ基等)および化学親和性基(例えば、アルファー炭素原子がハロゲン原子で置換されたケトン基、カルバモイル基、エステル基、アルキルチオ基、α、β-不飽和ケトン、エステル等のマイケル受容体、およびオキシラン基等)等のタンパク質標識基、
(2)-S-S-、-O-Si-O-、単糖(グルコース基、ガラクトース基等)または二糖(ラクトース等)等の開裂可能なリンカー、および酵素反応で開裂可能なオリゴペプチドリンカー、
(3)ビオチン、3-(4,4-ジフルオロ-5,7-ジメチル-4H-3a,4a-ジアザ-4-ボラ-s-インダセン-3-イル)プロピオニル基等のフィッシングタグ基、
(4)125I、32P、3H、14Cなどの放射性標識基;フルオレセイン、ローダミン、ダンシル、ウンベリフェロン、7-ニトロフラザニル、3-(4,4-ジフルオロ-5,7-ジメチル-4H-3a,4a-ジアザ-4-ボラ-s-インダセン-3-イル)プロピオニル基等の蛍光標識基;ルミフェリン、ルミノール等の化学発光基;ランタノイド金属イオン、ラジウムイオン等の重金属イオン等の検出可能なマーカーまたは
(5)ガラスビーズ、ガラスベット、マイクロタイタープレート、アガロースビーズ、アガロースベッド、ポリスチレンビーズ、ポリスチレンベッド、ナイロンビーズ、ナイロンベッド等の固相担体と結合させる基等。
上記の(1)ないし(5)からなる群より選択される標識基等を上記文献に記載の方法等に準じて化合物(1)に導入して調製されるプローブは、新たな創薬ターゲットの探索等に有用な標識タンパクの同定のためのケミカルプローブとして用いることができる。
tert-ブチル 4-アミノピペリジン-1-カルボキシレート(10g,49.9mmol)、N,N-ジイソプロピルエチルアミン(26ml,149mmol)、ベンジル クロロホルメート(8.5ml,59.5mmol)、及びジクロロメタン(脱水)(300ml)を氷冷下混合した。得られた混合物を室温で1時間攪拌した。反応混合物に飽和炭酸水素ナトリウム水溶液を加え、ジクロロメタンで三回抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(シリカゲル,溶出溶媒:酢酸エチル/ヘプタン)にて精製し、標記化合物(13.1g,収率78.5%)を得た。
1H-NMR(400MHz,CDCl3)δppm;1.24-1.38(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),7.26-7.40(5H,m).
実施例1aで得たtert-ブチル 4-{[(ベンジルオキシ)カルボニル]アミノ}ピペリジン-1-カルボキシレート(13.1g、39.2mmol)、5N塩酸水溶液(40ml、200mmol)およびメタノール(40ml)の混合物を室温で23時間攪拌した。反応混合物に氷冷下、5N水酸化ナトリウム水溶液(40ml)を加えた。エタノールで共沸させながら反応混合物から水と溶媒を留去した。残渣にエタノールを加え、不溶物を濾過して取り除き濾液を濃縮することで標記化合物(9.10g,収率99.1%)を得た。
1H-NMR(400MHz,CDCl3)δppm;1.31-1.42(2H,m),1.92-2.04(2H,br),2.70(2H,d,J=12Hz),3.10(2H,d,J=12Hz),3.56-3.68(1H,br),4.72-4.81(1H,br),5.09(2H,s),7.26-7.40(5H,m).
(5S)-(-)-2,2,3-トリメチル-5-ベンジル-4-イミダゾリジノン ジクロロ酢酸(90mg、0.259mmol)、N-フルオロベンゼンスルホンイミド(484mg、1.53mmol)、2-プロパノール(0.4ml)およびテトラヒドロフラン(脱水)(3.6ml)を室温で混合した。反応混合物を-10℃に冷やした後、ペンタナール(0.175ml、1.67mmol)を加え、-10℃から室温まで自然昇温させながら3時間20分攪拌した。反応混合物に実施例1bで得たベンジル N-(ピペリジン-4-イル)カルバメート(304mg、1.3mmol)とナトリウム トリアセトキシボロヒドリド(600mg、2.83mmol)を加え、室温で15時間40分攪拌した。反応混合物に水と炭酸水素ナトリウム水溶液を加え、不溶物を濾過により取り除き、得られた濾液を酢酸エチルで二回抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(シリカゲル,溶出溶媒:酢酸エチル/ヘプタン)にて精製し、標記化合物のキラル体混合物(44mg,収率10.5%)を得た。
1H-NMR(400MHz,CDCl3)δppm;0.94(3H,t,J=7Hz),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),4.59-4.72(2H,m),5.09(2H,s),7.26-7.37(5H,m).
HPLCによる光学分割
(分析条件)カラム:CHIRALPAK AD-H(ダイセル化学工業社製)(0.46cmφ×15cm)、溶離液:ヘキサン/エタノール=9/1(v/v)、流速:1ml/min.、検出:UV(210nm)
(分析結果)得られたキラル体混合物を上記分析条件で分析したところ、保持時間7.30分のピーク(鏡像体過剰率:80%ee)と8.28分のピークが認められた。
上記と同様の方法でさらに2ロット分のキラル体混合物を得た。トータル3ロット分のキラル体混合物(451mg、1.4mmol)をエタノール(18ml)に溶解し、下記分取条件で繰り返し光学分割し、保持時間の短いピークを分取することで、標記化合物(318mg)を得た。
(分取条件)カラム:CHIRALPAK AD-H(ダイセル化学工業社製)(2cmφ×25cm)、溶離液:ヘキサン/エタノール=9/1(v/v)、流速:10ml/min.、検出:UV(220nm)
1H-NMR(400MHz,CDCl3)δppm;0.94(3H,t,J=7Hz),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),4.59-4.72(2H,m),5.09(2H,s),7.26-7.37(5H,m).
得られた標記化合物を上記分析条件で分析したところ、保持時間は7.41分、鏡像体過剰率は>99%eeであった。
実施例1cで得たベンジル N-[1-(2-フルオロペンチル)ピペリジン-4-イル]カルバメートのキラル体(保持時間のより短い方)(318mg、0.986mmol)、10%Pd/C(100mg)およびメタノール(7ml)の混合物を水素雰囲気下にて室温で2時間攪拌した。反応容器中を窒素置換し、10%Pd/Cを濾去し、溶媒を留去することにより、標記化合物(249mg)を得た。
1H-NMR(400MHz,CDCl3)δppm;0.95(3H,t,J=7Hz),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),3.31-3.42(1H,br),4.72-4.93(1H,m).
クロトン酸(70g,812mmol)をN,N-ジメチルホルムアミド(467ml)に溶解し、窒素下氷浴で冷却し、炭酸カリウム(61.6g,447mmol)を加えた。反応混合物に、ベンジルブロミド(91.7ml,772mmol)を20分かけて滴下した。反応混合物を室温にて18時間攪拌した。反応混合物に酢酸エチルを加え、セライトでろ過した。ろ過した酢酸エチル溶液を水、飽和炭酸水素ナトリウム水溶液、飽和塩化ナトリウム水溶液にて洗浄した。有機層を硫酸マグネシウムにて乾燥、濾過、減圧下濃縮し、標記化合物(142g,収率:99.4%)を得た。
1H-NMR(400MHz,CDCl3)δppm;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).
実施例1eで得たベンジル (2E)-ブト-2-エノエート(20.5g,116mmol)をジクロロメタン(5ml)に溶解し、混合物を攪拌しながら氷浴にて冷却した。トリフルオロ酢酸(257μl,3.47mmol)を加え、N-(メトキシメチル)-N-(トリメチルシリルメチル)ベンジルアミン(33.1g,139mmol)をジクロロメタン(25ml)にて洗い込みながら内温が62℃を超えないよう、15分かけて反応液に滴下した。反応液を室温になるまで放置し、15時間攪拌した。反応液を濃縮し、シリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘプタン)により精製し、標記化合物(38g)を得た。
1H-NMR(400MHz,CDCl3)δppm;1.14(3H,d,J=6Hz),2.18-2.22(1H,m),2.48-2.65(2H,m),2.75-2.85(2H,m),2.90-2.94(1H,m),3.54-3.66(2H,m),5.13(2H,s),7.20-7.40(10H,m).
実施例1fで得たベンジル (3RS,4SR)-1-ベンジル-4-メチルピロリジン-3-カルボキシレート(30g,97.4mmol)をテトラヒドロフラン(300ml)に溶解させ、窒素下攪拌しながら-70℃まで冷却した。1.11Mリチウム ジイソプロピルアミド/n-ヘキサン-テトラヒドロフラン溶液(105ml,116mmol)を滴下し、内温が-64.3℃を超えないよう20分かけて滴下した。混合物を-70℃にて1時間攪拌した後、テトラヒドロフラン(30ml)とtert-ブチル ブロモアセテート(26.6g,136mmol)を内温が-60℃を超えないよう10分かけて滴下した。反応混合物を-70℃にてさらに1時間攪拌した後、反応混合物に飽和塩化アンモニウム水溶液を加えた。反応混合物をその後すぐに水で希釈し、酢酸エチルを加えた。有機層を飽和食塩水、5N塩酸水溶液にて洗浄後、硫酸マグネシウムにて乾燥、濾過、濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘプタン)により精製した。さらに残渣を、NHシリカゲルカラムクロマトグラフィー(溶出溶媒:ヘプタン/酢酸エチル=98/2)により精製し、標記化合物(6g,収率:14.5%)を得た。
1H-NMR(400MHz,CDCl3)δppm;0.86(3H,d,J=6Hz),1.34(9H,s),2.05-2.15(2H,m),2.53(1H,d,J=17Hz),2.91-3.00(3H,m),3.28(1H,d,J=10Hz),3.59-3.72(2H,m),5.08-5.16(2H,m),7.19-7.39(10H,m).
同様の方法で標記化合物18.1gを得た。
実施例1gと同様にして得た ベンジル (3RS,4SR)-1-ベンジル-3-[2-(tert-ブトキシ)-2-オキソエチル]-4-メチルピロリジン-3-カルボキシレート(11.7g,27.6mmol)をジクロロメタン(117ml)に溶解させ、ベンジル クロロホルメート(23.7ml,166mmol)を、内温が22℃を超えないよう、20分かけて反応液に滴下した。混合物を室温にて12時間攪拌した後、溶媒を留去した。残渣をNHシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘプタン)により精製し、標記化合物(9.1g,収率:70.5%)を得た。
1H-NMR(400MHz,CDCl3)δppm;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=12Hz),5.07-5.20(4H,m),7.26-7.36(10H,m).
HPLCによる分析;
(分析条件1)カラム:CHIRALPAK AD-H(ダイセル化学工業社製)(0.46cmφ×15cm)、溶離液:ヘキサン/エタノール=95/5(v/v)、流速:1ml/min.、検出:UV(210nm)
(分析結果)得られた標記化合物を上記分析条件1で分析したところ、保持時間8.56分のピークと10.85分のピークが認められた。
また、別途得た標記化合物を上記と別のキラルカラムにて分析した。
(分析条件2)カラム:CHIRALPAK IA(ダイセル化学工業社製)(0.46cmφ×15cm)、溶離液:ヘキサン/エタノール=95/5(v/v)、流速:1ml/min.、検出:UV(210nm)
(分析結果)得られた標記化合物を上記分析条件2で分析したところ、保持時間6.78分のピークと8.20分のピークが認められた。
実施例1hで得た1,3-ジベンジル (3RS,4SR)-3-[2-(tert-ブトキシ)-2-オキソエチル]-4-メチルピロリジン-1、3-ジカルボキシレート(9.1g)を以下の2つの条件AあるいはBで繰り返し光学分割を行った。
HPLCによる光学分割;
(分取条件A)カラム:CHIRALPAK AD-H(ダイセル化学工業社製)(2cmφ×25cm)、溶離液:ヘキサン/エタノール=85/15(v/v)、流速:8-10ml/min.
(分取条件B)カラム:CHIRALPAK IA(ダイセル化学工業社製)(3cmφ×25cm)、溶離液:ヘキサン/エタノール=95/5(v/v)、流速:22ml/min.
保持時間の短いピークを分取後、得られた3ロットを以下の分析条件にて分析した。
HPLCによる分析;
(分析条件)カラム:CHIRALPAK AD-H(ダイセル化学工業社製)(0.46cmφ×15cm)、溶離液:ヘキサン/エタノール=95/5(v/v)、流速:1ml/min.、検出:UV(210nm)
(分析結果)保持時間は9.0分-9.3分であり、すべてのロットで鏡像体過剰率は>99%eeであった。
3ロットをまとめて、得られたキラル体(4.04g)をメタノール(121ml)に溶解させ、10%Pd/C(0.77g)を加えて、水素ガスで置換した。混合物を室温にて13時間攪拌した後、温水(30-40℃、122ml)を加えて攪拌し、析出している固体を溶解させた。Pd/Cをろ過後、溶媒を濃縮、乾燥し、標記化合物(2.1g)を得た。
1H-NMR(400MHz,D2O)δppm;0.97(3H,d,J=7Hz),1.42(9H,s),2.15-2.22(1H,m),2.30(1H,d,J=17Hz),2.93(1H,d,J=17Hz),3.04(1H,t,J=12Hz),3.18(1H,d,J=12Hz),3.49(1H,dd,J=8,12Hz),4.03(1H,d,J=12Hz).
実施例1iで得た(3S,4R)-3-[2-(tert―ブトキシ)-2-オキソエチル]-4-メチルピロリジン-3-カルボン酸(1.8g、7.4mmol)、ベンズアルデヒド(1.51ml、14.8mmol)、酢酸(0.635ml、11.1mmol)、ナトリウム トリアセトキシボロヒドリド(3.14g、14.8mmol)およびメタノール(35ml)の混合物を40℃で38時間30分加熱した。反応混合物を濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー(ODSシリカゲル,溶出溶媒:水/メタノール)にて精製し、標記化合物をロットA(584mg),ロットB(708mg)として得た。
ロットAの1H-NMR(400MHz,CDCl3)δppm;1.02(3H,d,J=7Hz),1.38(9H,s),2.14(1H,d,J=17Hz),2.15-2.28(1H,br),2.97(1H,d,J=17Hz),3.10-3.42(3H,m),4.00-4.10(1H,m),4.30-4.40(1H,br),4.46(1H,d,J=12Hz),7.45-7.53(5H,m).
ロットBの1H-NMR:ロットAのNMRと一致した。
実施例1jで得た(3S,4R)-1-ベンジル-3-[2-(tert-ブトキシ)-2-オキソエチル]-4-メチルピロリジン-3-カルボン酸(300mg、0.9mmol)、実施例1dで得た1-(2-フルオロペンチル)ピペリジン-4-アミンのキラル体(182mg、0.967mmol)、トリエチルアミン(0.376ml、2.7mmol)、PyBOP(656mg、1.26mmol)、およびN,N-ジメチルホルムアミド(4.5ml)の混合物を室温で61時間30分攪拌した。さらにトリエチルアミン(0.207ml、1.49mmol)、PyBOP(360mg,0.69mmol)を加え、4時間30分攪拌した。反応混合物に水を加え、酢酸エチルで二回抽出した。有機層を飽和塩化アンモニウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(NHシリカゲル,溶出溶媒:酢酸エチル/ヘプタン)にて精製し、標記化合物(161mg,収率35.5%)を得た。
1H-NMR(400MHz,CDCl3)δppm;0.92(3H,d,J=7Hz),0.96(3H,t,J=7Hz),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=10Hz),2.35-2.50(1H,m),2.56-2.67(3H,m),2.80-2.90(2H,br),3.09(1H,d,J=16Hz),3.58-3.79(4H,m),4.59-4.80(1H,m),7.25-7.40(5H,m),8.58(1H,d,J=8Hz).
実施例1kで得たtert-ブチル 2-[(3S,4R)-1-ベンジル-3-{[1-(2-フルオロペンチル)ピペリジン-4-イル]カルバモイル}-4-メチルピロリジン-3-イル]アセテートのキラル体(161mg、0.32mmol)、20%水酸化パラジウム(135mg)およびメタノール(5ml)の混合物を水素雰囲気下にて室温で15時間攪拌した。反応容器中を窒素置換し、20%水酸化パラジウムを濾去し、溶媒を留去した。得られた残渣に2-(ブロモメチル)-1-クロロ-3-(トリフルオロメチル)ベンゼン(159mg、0.581mmol)、炭酸カリウム(97mg、0.702mmol)、およびN,N-ジメチルホルムアミド(2ml)を加え、45℃で3時間15分加熱した。反応混合物に水を加え、酢酸エチルで二回抽出した。有機層を飽和塩化アンモニウム水溶液で洗浄し、無水硫酸マグネシウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(NHシリカゲル,溶出溶媒:酢酸エチル/ヘプタン)にて精製し、標記化合物(153mg,収率78.9%)を得た。
1H-NMR(400MHz,CDCl3)δppm;0.91(3H,d,J=7Hz),0.95(3H,t,J=7Hz),1.38-1.70(7H,m),1.39(9H,s),1.82-1.90(1H,br),1.97(1H,d,J=16Hz),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=16Hz),3.57(1H,d,J=10Hz),3.60-3.72(1H,m),3.92(1H,d,J=13Hz),3.98(1H,d,J=13Hz),4.56-4.74(1H,m),7.37(1H,t,J=8Hz),7.61-7.68(2H,m),7.85(1H,d,J=8Hz).
実施例1lで得たtert-ブチル 2-[(3S,4R)-1-{[2-クロロ-6-(トリフルオロメチル)フェニル]メチル}-3-{[1-(2-フルオロペンチル)ピペリジン-4-イル]カルバモイル}-4-メチルピロリジン-3-イル]アセテートのキラル体(153mg,0.252mmol)、トリフルオロ酢酸(2ml,26.9mmol)、およびジクロロメタン(脱水)(2ml)の混合物を室温で2時間35分攪拌した。反応混合物を濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー(ODSシリカゲル,溶出溶媒:水/メタノール)にて精製し、標記化合物(122mg,収率88%)を得た。
1H-NMR(400MHz,CDCl3)δppm;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=10Hz),3.63-3.75(1H,m),3.89(1H,d,J=13Hz),4.00(1H,d,J=13Hz),4.56-4.76(1H,m),7.40(1H,t,J=8Hz),7.62-7.70(2H,m),8.52(1H,d,J=7Hz).
エチル 4,4-ジフルオロシクロヘキサン-1-カルボキシレート(1.9g,9.88mmol)、テトラヒドロフラン(60ml)の混合物を-70℃に冷却し、N,O-ジメチルヒドロキシアミン 塩酸塩(1.44g,14.8mmol)を加えた。さらに-55℃で反応混合物に1.05M n-プロピルマグネシウム ブロミド(24.2ml,25.2mmol)を内温が-35℃を超えないよう、5分かけて滴下し、反応混合物を0℃で30分間攪拌した。反応混合物に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を硫酸マグネシウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘプタン)にて精製し、標記化合物(1.7g,収率83%)を得た。
1H-NMR(400MHz,CDCl3)δppm;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).
実施例2aで得た4,4-ジフルオロ-N-メトキシ-N-メチルシクロヘキサン-1-カルボキサミド(1.7g,8.21mmol)、テトラヒドロフラン(60ml)の混合物を-70℃に冷却し、1.0M ジイソブチルアルミニウムヒドリド/トルエン溶液(9.85ml,9.85mmol)を加え、反応混合物を-60℃で35分攪拌した。さらに、1.0M ジイソブチルアルミニウムヒドリド/トルエン溶液(5ml,5mmol)を-65℃で加え、反応混合物を-70℃で2時間攪拌した。反応混合物に2N塩酸水溶液を加え、酢酸エチルで抽出した。有機層を硫酸マグネシウムで乾燥し、溶媒を留去し、標記化合物の粗体(1.4g)を得た。
1H-NMR(400MHz,CDCl3)δppm;1.72-1.92(4H,br),1.95-2.18(4H,br),2.30-2.40(1H,br),9.68(1H,s).
実施例2bで得た4,4-ジフルオロシクロヘキサン-1-カルバルデヒドの粗体(1.4g)およびテトラヒドロフラン(100ml)の混合物を0℃に冷却し、そこにtert-ブチル N-(ピペリジン-4-イル)カルバメート(2.27g,11.3mmol)を加え20分攪拌後、反応混合物にナトリウム トリアセトキシボロヒドリド(2.2g,10.4mmol)を加え、室温で8時間攪拌した。反応混合物に飽和食塩水を加え、酢酸エチルで抽出した。有機層を硫酸マグネシウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘプタン)にて精製した。得られた残渣を酢酸エチルに溶解し、飽和炭酸水素ナトリウム水溶液で洗浄後、溶媒を留去し、標記化合物(650mg,収率20.7%)を得た。
1H-NMR(400MHz,CDCl3)δppm;1.15-2.20(17H,m),1.44(9H,s),2.70-2.85(2H,br),3.38-3.53(1H,br),4.37-4.50(1H,br).
実施例2cで得たtert-ブチル N-{1-[(4,4-ジフルオロシクロヘキシル)メチル]ピペリジン-4-イル}カルバメート(650mg,1.96mmol)およびメタノール(11ml)の混合物に、4N塩化水素/1,4-ジオキサン溶液(11ml,43mmol)を加え、室温で3時間攪拌した。反応液を濃縮後、残渣を酢酸エチルに溶解し、1N水酸化ナトリウム水溶液を加え、有機層を分離した。さらに水層を酢酸エチルで2回抽出し、有機層を硫酸ナトリウムで乾燥後、溶媒を留去し、標記化合物(419mg,収率92%)を得た。
1H-NMR(400MHz,CDCl3)δppm;1.16-1.42(7H,m),1.59-2.16(12H,m),2.58-2.68(1H,m),2.74-2.82(2H,m).
クロトン酸(17.2g,200mmol)をN,N-ジメチルホルムアミド(100ml)に窒素下、氷浴で冷却しながら溶解し、粉状の炭酸カリウム(15.2g,110mmol)を加えた。混合物を30分間攪拌してから、4-メトキシベンジルクロリド(29.8g,190mmol)を15分かけて滴下した。反応混合物を室温にて4時間、45℃にて14時間攪拌した。反応液に酢酸エチル(500ml)と水(200ml)を加えた。分離した有機層を水(100ml×2)、飽和食塩水(100ml)にて洗浄した。水層を酢酸エチル(100ml)にて抽出した。有機層を合わせ、硫酸マグネシウムにて乾燥、濾過、減圧下濃縮し、標記化合物の粗体(40.51g,収率:98.2%)を得た。
1H-NMR(400MHz,CDCl3)δppm;1.87(3H,dd,J=2,7Hz),3.81(3H,s),5.10(2H,s),5.87(1H,dq,J=2,16Hz),6.86-6.92(2H,m),7.00(1H,dq,J=7,16Hz),7.28-7.34(2H,m).
実施例1fに記載した方法と同様の方法により、実施例2eで得た(4-メトキシフェニル)メチル (2E)-ブト-2-エノエート(40.6g,197mmol)から、標記化合物(57.86g,収率:86.5%)を得た。
1H-NMR(400MHz,CDCl3)δppm;1.12(3H,d,J=7Hz),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=13Hz),3.63(1H,d,J=13Hz),3.81(3H,s),5.03-5.10(2H,m),6.86-6.92(2H,m),7.21-7.35(7H,m).
実施例1gに記載した方法と同様の方法により、実施例2fで得た(4-メトキシフェニル)メチル (3RS,4SR)-1-ベンジル-4-メチルピロリジン-3-カルボキシレート(56.7g,166mmol)から標記化合物(60.3g,収率:80.1%)を得た。
1H-NMR(400MHz,CDCl3)δppm;0.83(3H,d,J=7Hz),1.35(9H,s),2.05-2.14(2H,m),2.51(1H,d,J=17Hz),2.90-2.98(2H,m),3.60(1H,d,J=13Hz),3.70(1H,d,J=13Hz),3.81(3H,s),5.04(1H,d,J=12Hz),5.07(1H,d,J=12Hz),6.85-6.91(2H,m),7.19-7.34(7H,m).
実施例1hに記載した方法と同様の方法により、実施例2gで得た(4-メトキシフェニル)メチル (3RS,4SR)-1-ベンジル-3-[2-(tert-ブトキシ)-2-オキソエチル]-4-メチルピロリジン-3-カルボキシレート(21g,46.3mmol)から、標記化合物(15g,収率:65.1%)を得た。
1H-NMR(400MHz,CDCl3)δppm;0.80-0.88(3H,m),1.38(9H,d,J=5Hz),2.04-2.15(1H,m),2.22(1H,dd,J=3,7Hz),3.00-3.12(2H,m),3.30-3.36(1H,m),3.57-3.67(1H,m),3.79(3H,d,J=4Hz),4.30(1H,t,J=12Hz),5.00-5.16(4H,m),6.82-6.86(2H,m),7.23-7.39(7H,m).
HPLCによる分析;
(分析条件)カラム:CHIRALPAK AD-H(ダイセル化学工業社製)(0.46cmφ×15cm),40℃,溶離液:ヘキサン/エタノール=9/1(v/v),流速:1ml/min.,検出:UV(210nm)
(分析結果)得られた標記化合物を上記分析条件で分析したところ、保持時間7.14分のピークと9.06分のピークが認められた。
実施例2hで得た1-ベンジル 3-(4-メトキシフェニル)メチル (3RS,4SR)-3-[2-(tert-ブトキシ)-2-オキソエチル]-4-メチルピロリジン-1,3-ジカルボキシレート(7.2g,14.5mmol)をHPLC(CHIRALPAK AD-H(2cmφ×25cm)、溶出溶媒:ヘキサン/エタノール=85/15、流速:8-10ml/min.)により光学分割を繰り返すことにより保持時間の短いピークに相当するキラル体(2.92g,収率:40.5%)を得た。
HPLCによる分析;(分析条件)カラム:CHIRALPAK AD-H(ダイセル化学工業社製)(0.46cmφ×15cm),40℃,溶離液:ヘキサン/エタノール=9/1(v/v),流速:1ml/min.,検出:UV(210nm)
(分析結果)得られたキラル体を上記分析条件で分析したところ、保持時間は7.18分であり、鏡像体過剰率は>99%eeであった。
実施例2iで得た1-ベンジル 3-(4-メトキシフェニル)メチル (3S,4R)-3-[2-(tert-ブトキシ)-2-オキソエチル]-4-メチルピロリジン-1,3-ジカルボキシレート(2.92g,5.87mmol)にエタノール(50ml)、10%Pd/C(500mg)を加え、水素雰囲気下38時間5分室温撹拌した。反応液に水(100ml)を加え撹拌し、濾過した。濾液を濃縮し、標記化合物(1.37g,収率:95.9%)を得た。
1H-NMR(400MHz,D2O)δppm;1.00(3H,d,J=7Hz),1.45(9H,s),2.16-2.37(1H,m),2.33(1H,d,J=17Hz),2.96(1H,d,J=17Hz),3.05-3.11(1H,m),3.22(1H,d,J=12Hz),3.50-3.56(1H,m),4.07(1H,d,J=12Hz).
実施例2jの方法により得られた(3S,4R)-3-[2-(tert-ブトキシ)-2-オキソエチル]-4-メチルピロリジン-3-カルボン酸(600mg,2.47mmol)、酢酸(0.14ml,2.47mmol)、メタノール(10ml)の混合物に、2,6-ジクロロベンズアルデヒド(646mg,3.7mmol)、ナトリウム トリアセトキシボロヒドリド(782mg,3.7mmol)を加え、反応混合物を室温で2時間攪拌した。さらに、2,6-ジクロロベンズアルデヒド(430mg,2.5mmol)、ナトリウム トリアセトキシボロヒドリド(522mg,2.5mmol)を加え、外温40℃で10.5時間攪拌した。反応混合物に水を加え、ジクロロメタンで5回抽出し、有機層を濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/メタノール)にて精製し、標記化合物のロットA(32mg)およびロットB(551mg)を得た。
ロットAの化学シフトを下記に示す。ロットBは、カラム精製時の3フラクションをまとめたものであり、各フラクションの化学シフトがロットAの化学シフトと同様であることを確認後にまとめた。
1H-NMR(400MHz,CDCl3)δppm;1.01(3H,d,J=7Hz),1.42(9H,s),2.05-2.11(1H,m),2.16-2.22(1H,m),2.65-2.69(2H,m),2.97-3.04(2H,m),3.70(1H,d,J=10Hz),4.07-4.15(2H,m),7.22(1H,dd,J=8,9Hz),7.35(2H,d,J=8Hz).
実施例1kに記載した方法と同様の方法により、実施例2dで得た1-[(4,4-ジフルオロシクロヘキシル)メチル]ピペリジン-4-アミン(201mg,0.87mmol)および実施例2kで得た(3S,4R)-3-[2-(tert-ブトキシ)-2-オキソエチル]-1-[(2,6-ジクロロフェニル)メチル]-4-メチルピロリジン-3-カルボン酸(290mg,0.72mmol)より、標記化合物(409mg,収率:92%)を得た。
1H-NMR(400MHz,CDCl3)δppm;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=10Hz),3.12(1H,d,J=16Hz),3.59-3.72(2H,m),3.96(2H,s),7.18(1H,t,J=8Hz),7.33(2H,d,J=8Hz),8.11(1H,d,J=8Hz).
実施例1mに記載した方法と同様の方法により、実施例2lで得たtert-ブチル 2-[(3S,4R)-1-[(2,6-ジクロロフェニル)メチル]-3-({1-[(4,4-ジフルオロシクロヘキシル)メチル]ピペリジン-4-イル}カルバモイル)-4-メチルピロリジン-3-イル]アセテート(409mg,0.66mmol)から、標記化合物(242mg,収率:66%)を得た。
1H-NMR(400MHz,CD3OD)δppm;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=8,9Hz),7.43(2H,d,J=8Hz).
実施例1jと同様の方法で得た(3S,4R)-1-ベンジル-3-[2-(tert-ブトキシ)-2-オキソエチル]-4-メチルピロリジン-3-カルボン酸(942mg,2.83mmol)のN,N-ジメチルホルムアミド(20ml)溶液にtert-ブチル 4-アミノピペリジン-1-カルボキシレート(849mg,4.24mmol)、トリエチルアミン(1.18ml,8.48mmol)とPyBOP(2.21g,4.24mmol)を加え、室温で終夜攪拌した。反応液に酢酸エチルを加え、1N水酸化ナトリウム水溶液、飽和食塩で洗浄した。無水硫酸マグネシウムで乾燥し、濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:ヘプタン/酢酸エチル)にて精製し、標記化合物(1.33g,収率:91.1%)を得た。
1H-NMR(400MHz,CDCl3)δppm;0.92(3H,d,J=7Hz),1.20-1.40(2H,m),1.40(9H,s),1.48(9H,s),1.78-1.88(1H,m),1.92-1.98(1H,br),1.96(1H,d,J=16Hz),2.03-2.09(1H,m),2.36(1H,d,J=10Hz),2.58-2.68(2H,m),2.89-2.95(2H,m),3.10(1H,d,J=16Hz),3.59(1H,d,J=10Hz),3.66(2H,s),3.83-4.00(3H,m),7.23-7.35(5H,m),8.65(1H,d,J=7Hz).
MS(ESI)m/z:538.2(M+Na)+.
実施例3aで得たtert-ブチル 4-[(3S,4R)-1-ベンジル-3-[2-(tert-ブトキシ)-2-オキソエチル]-4-メチルピロリジン-3-アミド]ピペリジン-1-カルボキシレート(1.33g,2.58mmol)のメタノール(30ml)溶液に20%水酸化パラジウム(724mg)を加え、水素雰囲気下終夜攪拌した。反応液をろ過、減圧濃縮し標記化合物(1.04g,収率:94.7%)を得た。
1H-NMR(400MHz,CDCl3)δppm;0.92(3H,d,J=7Hz),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=16Hz),2.55-2.61(1H,m),2.80-3.06(2H,m),2.92(1H,d,J=10Hz),3.12(1H,d,J=16Hz),3.35(1H,d,J=9Hz),3.70(1H,d,J=10Hz),3.80-4.00(3H,m),8.30(1H,d,J=7Hz).
MS(ESI)m/z:426.1(M+H)+
実施例3bで得たtert-ブチル 4-[(3S,4R)-3-[2-(tert-ブトキシ)-2-オキソエチル]-4-メチルピロリジン-3-アミド]ピペリジン-1-カルボキシレート(345mg,0.811mmol)のN,N-ジメチルホルムアミド(脱水)(10mL)の溶液に2-(ブロモメチル)-1-クロロ-3-(トリフルオロメチル)ベンゼン(443mg,1.62mmol)と炭酸カリウム(244mg)を加え、45℃にて6時間、40℃にて2日間攪拌した。反応液に酢酸エチルを加え、1N水酸化ナトリウム水溶液、飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥し、濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:ヘプタン/酢酸エチル)にて精製し、標記化合物(320mg,収率:63.8%)を得た。
1H-NMR(400MHz,CDCl3)δppm;0.92(3H,d,J=7Hz),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=16Hz),2.02-2.10(1H,m),2.51(1H,d,J=10Hz),2.60-2.80(3H,m),2.88(1H,t,J=10Hz),3.12(1H,d,J=16Hz),3.53(1H,d,J=10Hz),4.09-4.25(5H,m),7.38(1H,t,J=8Hz),7.63(2H,d,J=8Hz),7.96(1H,d,J=8Hz).
MS(ESI)m/z:640.2(M+Na)+.
実施例3cで得たtert-ブチル 4-[(3S,4R)-3-[2-(tert-ブトキシ)-2-オキソエチル]-1-{[2-クロロ-6-(トリフルオロメチル)フェニル]メチル}-4-メチルピロリジン-3-アミド]ピペリジン-1-カルボキシレート(320mg,0.518mmol)のジクロロメタン(脱水)(8mL)溶液に氷冷下トリフルオロ酢酸(8mL)を加え、室温で2.5時間攪拌した。反応液を減圧濃縮し、残渣をODSカラムクロマトグラフィー(溶出溶媒:水/メタノール)にて精製し、標記化合物を含む混合物(344mg)を得た。
1H-NMR(400MHz,CD3OD)δppm;0.83(3H,d,J=5Hz),1.43-1.63(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,m).
MS(ESI)m/z:462.3(M+H)+
実施例3dの方法により得た2-[(3S,4R)-1-{[2-クロロ-6-(トリフルオロメチル)フェニル]メチル}-4-メチル-3-[(ピペリジン-4-イル)カルバモイル]ピロリジン-3-イル]酢酸の混合物(344mg,0.745mmol)のテトラヒドロフラン(脱水)(10mL)の溶液にシクロヘキス-1-エン-1-カルバルデヒド(423μl,3.73mmol)、酢酸(300μl)とナトリウム トリアセトキシボロヒドリド(789mg,3.73mmol)を加え、終夜攪拌した。反応液に水とメタノールを加え、減圧濃縮し、残渣をODSカラムクロマトグラフィー(溶出溶媒:水/メタノール)にて精製した。精製した物をジクロロメタンに溶解し、ヘキサンを加え懸濁させ、濃縮することで標記化合物(180mg,収率:43.4%)を得た。
1H-NMR(400MHz,CD3OD)δppm;0.89(3H,d,J=7Hz),1.23-1.38(2H,m),1.44-1.82(6H,m),1.82-1.96(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=10Hz),3.64-3.78(1H,m),3.95(1H,d,J=10Hz),4.05(1H,d,J=10Hz),5.76(1H,s),7.47-7.52(1H,m),7.72(1H,d,J=7Hz),7.77(1H,d,J=8Hz).
MS(ESI)m/z:578.3(M+Na)+
tert-ブチル N-(ピペリジン-4-イル)カルバメート(5.3g,26.5mmol)、1-シクロヘキセン-1-カルボキサルデヒド(3.5g,31.8mmol)、ナトリウム トリアセトキシボロヒドリド(7.29g,34.4mmol)、酢酸(0.5ml)、及びテトラヒドロフラン(脱水)(80ml)の混合物を室温で85時間30分攪拌した。反応混合物に水と炭酸水素ナトリウムを加えて攪拌した後、酢酸エチルで2回抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥し、溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(NHシリカゲル,溶出溶媒:酢酸エチル/ヘプタン)にて精製し、標記化合物(7.47g,収率:95.7%)を得た。
1H-NMR(400MHz,CDCl3)δppm;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),4.38-4.48(1H,m),5.54(1H,s).
実施例4aで得たtert-ブチル N-[1-(シクロヘキス-1-エン-1-イルメチル)ピペリジン-4-イル]カルバメート(7.47g,25.4mmol)、5N塩酸水溶液(25ml,125mmol)、及びメタノール(100ml)の混合物を70℃で1.5時間攪拌した。反応混合物を氷冷し、5N水酸化ナトリウム水溶液(25ml,125mmol)を加え、溶媒を留去した。残渣に水を加え酢酸エチルで2回抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥し、溶媒を留去することで、標記化合物(4.73g,収率:95.8%)を得た。
1H-NMR(400MHz,CDCl3)δppm;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).
実施例2gで得た(4-メトキシフェニル)メチル (3RS,4SR)-1-ベンジル-3-[2-(tert-ブトキシ)-2-オキソエチル]-4-メチルピロリジン-3-カルボキシレート(18g,39.7mmol)のジクロロメタン(85.7ml)溶液を内温10~20℃に調整し、そこにベンジル クロロホルメート(11.9ml,79.4mmol)を加えた。室温に戻して0.5時間撹拌した後、反応混合物をそのまま濃縮した。得られた粗生成物をカラムクロマトグラフィー(シリカゲル,溶出溶媒:酢酸エチル/ヘプタン)で精製し、標記化合物(12.89g,収率:65.3%)を得た。
1H-NMR(400MHz,CDCl3)δppm;0.80-0.88(3H,m),1.38(9H,d,J=5Hz),2.04-2.15(1H,m),2.22(1H,dd,J=3,17Hz),3.00-3.12(2H,m),3.62(1H,m),3.79(3H,d,J=4Hz),4.30(1H,t,J=12Hz),5.00-5.16(4H,m),6.82-6.86(2H,m),7.23-7.39(8H,m).
実施例4cで得た1-ベンジル 3-(4-メトキシフェニル)メチル (3RS,4SR)-3-[2-(tert-ブトキシ)-2-オキソエチル]-4-メチルピロリジン-1,3-ジカルボキシレート(12.7g,26mmol)をHPLC(CHIRALPAK AD-H(2cmφ×25cm)、溶出溶媒:ヘキサン/エタノール=85/15、流速:8-10ml/min.)により光学分割を繰り返すことにより保持時間の短いピークに相当するキラル体(5.7g,収率:44.9%)を得た。得られたキラル体(5.3g)を2回に分けてシリカゲルカラムクロマトグラフィー(溶出溶媒;ヘプタン/酢酸エチル)にてさらに精製し、標記化合物5.2gを得た。
1H-NMR(400MHz,CDCl3)δppm;0.81-0.88(3H,m),3.37-3.38(9H,m),2.04-2.16(1H,m),2.19-2.25(1H,m),3.00-3.12(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),7.27-7.37(7H,m).
HPLCによる分析;
(分析条件)カラム:CHIRALPAK AD-H(ダイセル化学工業社製)(0.46cmφ×15cm),40℃,溶離液:ヘキサン/エタノール=9/1(v/v),流速:1ml/min.,検出:UV(210nm)
(分析結果)精製したキラル体を上記分析条件で分析したところ、保持時間は7.15分であり、鏡像体過剰率は>99%eeであった。
実施例4cと同様の方法で得た1-ベンジル 3-(4-メトキシフェニル)メチル (3RS,4SR)-3-[2-(tert-ブトキシ)-2-オキソエチル]-4-メチルピロリジン-1,3-ジカルボキシレート(7.8g,16.5mmol)をHPLC(CHIRALPAK AD-H、溶出溶媒:ヘキサン/エタノール=85/15)により光学分割を繰り返すことにより保持時間の短いキラル体(3.3g,収率:42.3%)を得た。
実施例4eの方法により得た1-ベンジル 3-(4-メトキシフェニル)メチル (3S,4R)-3-[2-(tert-ブトキシ)-2-オキソエチル]-4-メチルピロリジン-1,3-ジカルボキシレート(3.3g,6.63mmol)にメタノール(70ml)、10%Pd/C(600mg)を加え、水素雰囲気下3日間室温撹拌した。反応液に水(70ml)を加え撹拌し、濾過した。濾液を濃縮し、標記化合物(1.15g,収率:71.3%)を得た。
1H-NMR(400MHz,D2O);実施例2jで得られた化合物と一致した。
実施例4dで得た1-ベンジル 3-(4-メトキシフェニル)メチル (3S,4R)-3-[2-(tert-ブトキシ)-2-オキソエチル]-4-メチルピロリジン-1,3-ジカルボキシレートのシリカゲルカラムクロマトグラフィー精製前の化合物(104mg,0.21mmol)にメタノール(3ml)、10%Pd/C(30mg)を加え、水素雰囲気下一夜室温撹拌した。反応液に水を加え撹拌し、濾過した。濾液を濃縮し、標記化合物(48.7mg,収率:95.3%)を得た。
1H-NMR(400MHz,D2O);実施例2jで得られた化合物と一致した。
実施例4dで得た1-ベンジル 3-(4-メトキシフェニル)メチル (3S,4R)-3-[2-(tert-ブトキシ)-2-オキソエチル]-4-メチルピロリジン-1,3-ジカルボキシレート(5.2g,10.5mmol)にメタノール(100ml)、10%Pd/C(559mg)を加え、水素雰囲気下8時間15分室温撹拌した。反応液に水(100ml)を加え1時間撹拌し、濾過した。濾液を濃縮した。残渣と実施例2j、4f、4gで得た、(3S,4R)-3-[2-(tert-ブトキシ)-2-オキソエチル]-4-メチルピロリジン-3-カルボン酸を合わせたもの(3.2g,13.2mmol)にメタノール(25ml)を加え懸濁させ、30分間室温撹拌し、濾取することにより標記化合物3.02gを得た。
1H-NMR(400MHz,D2O)δppm;0.98(3H,d,J=7Hz),1.43(9H,s),2.14-2.24(1H,m),2.31(1H,d,J=17Hz),2.94(1H,d,J=17Hz),3.06(1H,t,J=11Hz),3.20(1H,d,J=12Hz),3.51(1H,dd,J=8,12Hz),4.05(1H,d,J=12Hz).
実施例4hで得た(3S,4R)-3-[2-(tert-ブトキシ)-2-オキソエチル]-4-メチルピロリジン-3-カルボン酸(200mg,0.822mmol)に実施例4bで得た1-(シクロヘキス-1-エン-1-イルメチル)ピペリジン-4-アミン(240mg,1.24mmol)、N,N-ジメチルホルムアミド(3ml)、トリエチルアミン(344μl,2.47mmol)、PyBOP(856mg,1.64mmol)を加え、45℃の油浴で1.5時間加熱攪拌した。反応混合物に水を加え酢酸エチルで抽出した。有機層を硫酸マグネシウムで乾燥し濃縮した。そこに、2-(ブロモメチル)-1-クロロ-3-(トリフルオロメチル)ベンゼン(247mg,0.903mmol)、炭酸カリウム(170mg,1.23mmol)、N,N-ジメチルホルムアミド(1ml)を加え、45℃の油浴で3時間加熱攪拌した。反応混合物に水を加え酢酸エチルで抽出した。有機層を水と飽和食塩水で洗浄後、硫酸マグネシウムで乾燥した。得られた粗生成物をカラムクロマトグラフィーで2度精製し(NHシリカゲル,溶出溶媒:酢酸エチル/ヘプタン及びシリカゲル,溶出溶媒:酢酸エチル/ヘプタン)、標記化合物(353mg,収率70.1%)を得た。
1H-NMR(400MHz,CDCl3)δppm;0.91(3H,d,J=7Hz),1.31-1.42(2H,m),1.39(9H,s),1.54-1.66(5H,m),1.81-2.09(9H,m),2.53(1H,d,J=10Hz),2.63-2.77(5H,m),2.88(1H,t,J=10Hz),3.11(1H,d,J=16Hz),3.56(1H,d,J=10Hz),3.61-3.72(1H,m),3.92(1H,d,J=13Hz),3.98(1H,d,J=13Hz),5.54(1H,s),7.36(1H,t,J=8Hz),7.62(1H,d,J=4Hz),7.64(1H,d,J=4Hz),7.83(1H,d,J=8Hz).
実施例4iで得たtert-ブチル 2-[(3S,4R)-1-{[2-クロロ-6-(トリフルオロメチル)フェニル]メチル}-3-{[1-(シクロヘキス-1-エン-1-イルメチル)ピペリジン-4-イル]カルバモイル}-4-メチルピロリジン-3-イル]アセテート(353mg,0.577mmol)のジクロロメタン(400μl)溶液にトリフルオロ酢酸(1.5ml,20.3mmol)を加え、室温で2時間攪拌した。反応混合物を減圧濃縮し、ODSカラムクロマトグラフィー(溶出溶媒:メタノール/水)で精製し、標記化合物(215mg,収率67%)を得た。
1H-NMR(400MHz,CDCl3)δppm;1.01(3H,d,J=7Hz),1.22-1.34(2H,m),1.42-1.68(7H,m),1.79-2.07(6H,m),2.38-2.46(1H,m),2.49(1H,d,J=10Hz),2.56(1H,d,J=14Hz),2.67-2.82(6H,m),3.00(1H,t,J=10Hz),3.16(1H,d,J=10Hz),3.63-3.76(1H,m),3.88(1H,d,J=14Hz),4.01(1H,d,J=14Hz),5.55(1H,s),7.40(1H,t,J=8Hz),7.64(1H,d,J=4Hz),7.66(1H,d,J=4Hz),8.56(1H,d,J=8Hz)
比旋光度:[α] D 29 +37.1(c 0.11,MeOH)
実施例1gと同様の方法で得たベンジル(3RS,4SR)-1-ベンジル-3-[2-(tert-ブトキシ)-2-オキソエチル]-4-メチルピロリジン-3-カルボキシレート(3g,7.08mmol)のメタノール(200ml)溶液に、20%水酸化パラジウム(300mg)を加え水素雰囲気下室温で終夜攪拌した。反応液を濾過し、メタノールで洗浄した。濾取物に約40℃の温水を加え固形物を溶解し濾過した。ろ液を初めの濾液とあわせて濃縮し、脱保護体(1.7g)を得た。
前記と同様の方法により得られた脱保護体(4.47g,18.4mmol)にメタノール(44ml)、2,6-ジクロロベンズアルデヒド(4.83g,27.6mmol)、酢酸(1.1ml,18.4mmol)、を加え室温で15分間攪拌し、ナトリウム トリアセトキシボロヒドリド(6.16g,27.6mmol)を加え40℃で終夜加熱攪拌した。反応液に中性バッファー[リン酸二水素カリウム(13.65g)、リン酸水素二ナトリウム12水和物(71.6g)、水(1.5l)より調製]を加え酢酸エチルとヘプタンを加えて、混合物を濾過した。濾液を酢酸エチルで抽出し、有機層を硫酸ナトリウムで乾燥、濃縮後、得られた粗生成物をカラムクロマトグラフィー(シリカゲル,溶出溶媒:メタノール/酢酸エチル)で精製し、濾取物と合わせて、(3RS,4SR)-3-[2-(tert-ブトキシ)-2-オキソエチル]-1-[(2,6-ジクロロフェニル)メチル]-4-メチルピロリジン-3-カルボン酸(3.9g)を得た。この化合物(1.64g,4.07mmol)にtert-ブチル 4-アミノピペリジン-1-カルボキシレート(974mg,4.89mmol)、N,N-ジメチルホルムアミド(10ml),トリエチルアミン(1.14ml、8.13mmol)およびPyBOP(2.54g,4.89mmol)を加え、室温で終夜攪拌した。反応液に水を加え酢酸エチルで抽出後、有機層を水と飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した。濃縮し得られた粗生成物をカラムクロマトグラフィー(NHシリカゲル,溶出溶媒:酢酸エチル/ヘプタン)で精製し、標記化合物(2.10g,収率88.1%)を得た。
1H-NMR(400MHz,CDCl3)δppm;0.91(3H,d,J=7Hz),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=16Hz),2.03-2.13(1H,m),2.54-2.65(2H,m),2.66-2.88(2H,br),2.92(1H,t,J=10Hz),3.11(1H,d,J=16Hz),3.59(1H,d,J=10Hz),3.81-3.90(1H,m),3.95(2H,s),3.90-4.07(2H,br),7.18(1H,dd,J=7,8Hz),7.33(1H,d,J=8Hz),8.23(1H,d,J=8Hz).
HPLCによる分析;
(分析条件)カラム:CHIRALPAK IA(ダイセル化学工業社製)(0.46cmφ×15cm),40℃,溶離液:ヘキサン/エタノール=95/5(v/v),流速:1ml/min.,検出UV(210nm)
(分析結果)得られた標記化合物を上記分析条件で分析したところ、保持時間3.46分のピークと6.04分のピークが認められた。
実施例5aで得られたtert-ブチル 4-[(3RS,4SR)-3-[2-(tert-ブトキシ)-2-オキソエチル]-1-[(2,6-ジクロロフェニル)メチル]-4-メチルピロリジン-3-アミド]ピペリジン-1-カルボキシレート(2.04g,3.49mmol)をHPLC(CHIRALPAK IA(3cmφ×25cm)、溶出溶媒:ヘキサン/エタノール=94/6、流速:22ml/min.)により光学分割を繰り返すことにより保持時間の短いピークに相当するキラル体である表記化合物(859mg,42.1%)と保持時間の長いピークに相当するキラル体である光学異性体(817mg,40%)をそれぞれ得た。
保持時間の短いピークに相当するキラル体;1H-NMR(400MHz,CDCl3)δppm;0.91(3H,d,J=7Hz),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=16Hz),2.01-2.11(1H,m),2.57(1H,d,J=10Hz),2.57-2.64(1H,m),2.69-2.82(2H,m),2.92(1H,t,J=10Hz),3.11(1H,d,J=16Hz),3.59(1H,d,J=10Hz),3.80-4.09(2H,m),3.95(2H,s),7.18(1H,t,J=8Hz),7.33(2H,d,J=8Hz),8.23(1H,d,J=8Hz).
HPLCによる分析;
(分析条件)カラム:CHIRALPAK IA(ダイセル化学工業社製)(0.46cmφ×15cm),40℃,溶離液:ヘキサン/エタノール=95/5(v/v),流速:1ml/min.,検出:UV(210nm)
(分析結果)得られた保持時間の短いピークに相当するキラル体を上記分析条件で分析したところ、保持時間は3.44分であり、鏡像体過剰率は>99%eeであった。
実施例5bで得たtert-ブチル 4-[(3S,4R)-3-[2-(tert-ブトキシ)-2-オキソエチル]-1-[(2,6-ジクロロフェニル)メチル]-4-メチルピロリジン-3-アミド]ピペリジン-1-カルボキシレート(758mg,1.29mmol)のメタノール(20ml)溶液に20%水酸化パラジウム(75.8mg)を加え、水素雰囲気下40℃で3時間攪拌した。反応液を濾過し、ろ液を濃縮し粗生成物(501mg)を得た。この粗生成物(174mg)のN,N-ジメチルホルムアミド(脱水)(6mL)溶液に2-(ブロモメチル)-1-クロロ-3-(トリフルオロメチル)ベンゼン(145mg,0.532mmol)と炭酸カリウム(53.2mg)を加え終夜撹拌した。2-(ブロモメチル)-1-クロロ-3-(トリフルオロメチル)ベンゼン(145mg,0.532mmol)と炭酸カリウム(106mg)を追加し4時間撹拌した。反応液に酢酸エチルを加え、1N水酸化ナトリウム水溶液、飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥し、濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:ヘプタン/酢酸エチル)にて精製し、標記化合物(82mg,収率:32.4%)を得た。
1H-NMR(400MHz,CDCl3)δppm;0.92(3H,d,J=7Hz),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=16Hz),2.02-2.10(1H,m),2.51(1H,d,J=10Hz),2.61-2.81(3H,m),2.89(1H,t,J=10Hz),3.12(1H,d,J=16Hz),3.53(1H,d,J=10Hz),3.80-4.10(5H,m),7.38(1H,t,J=8Hz),7.63(2H,d,J=8Hz),7.96(1H,d,J=8Hz).
MS(ESI)m/z:618.1(M+H)+
実施例5cで得たtert-ブチル 4-[(3S,4R)-3-[2-(tert-ブトキシ)-2-オキソエチル]-1-{[2-クロロ-6-(トリフルオロメチル)フェニル]メチル}-4-メチルピロリジン-3-アミド]ピペリジン-1-カルボキシレート(82mg,0.133mmol)のジクロロメタン(脱水)(3mL)溶液に氷冷下トリフルオロ酢酸(3mL)を加え、室温で2.5時間攪拌した。反応液を減圧濃縮し、残渣をODSカラムクロマトグラフィー(溶出溶媒:水/メタノール)にて精製し、標記化合物(72mg,収率:定量的)を得た。
1H-NMR(400MHz,CD3OD)δppm;0.90(3H,d,J=5Hz),1.51-1.70(2H,m),1.82-1.91(1H,m),1.99-2.08(1H,m),2.12-2.23(2H,m),2.61(1H,d,J=9Hz),2.60-2.70(2H,m),2.95-3.12(4H,m),3.25-3.36(2H,m),3.53(1H,d,J=9Hz),3.83-3.92(1H,m),3.97(1H,d,J=13Hz),4.07(1H,d,J=13Hz),7.51(1H,t,J=8Hz),7.73(1H,d,J=8Hz),7.78(1H,d,J=8Hz).
MS(ESI)m/z:462.2(M+H)+
実施例5dの方法により得られた2-[(3S,4R)-1-{[2-クロロ-6-(トリフルオロメチル)フェニル]メチル}-4-メチル-3-[(ピペリジン-4-イル)カルバモイル]ピロリジン-3-イル]酢酸(15mg,0.0325mmol)のテトラヒドロフラン(脱水)(2mL)の溶液にシクロヘキス-1-エン-1-カルバルデヒド(25.9μl,0.227mmol)、酢酸(30μl)とナトリウム トリアセトキシボロヒドリド(68.8mg,0.325mmol)を加え、終夜攪拌した。反応液に水とメタノールを加え、減圧濃縮し、残渣をODSカラムクロマトグラフィー(溶出溶媒:水/メタノール)にて精製し標記化合物(12.8mg,収率:70.8%)を得た。
1H-NMR(400MHz,CD3OD)δppm;0.89(3H,d,J=7Hz),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=10Hz),3.64-3.78(1H,m),3.95(1H,d,J=13Hz),4.05(1H,d,J=13Hz),5.76(1H,s),7.49(1H,t,J=8Hz),7.72(1H,d,J=8Hz),7.77(1H,d,J=8Hz).
MS(ESI)m/z:556.3(M+H)+
実施例1jに記載した方法と同様な方法により、実施例1iと同様の方法で得た(3S,4R)-3-[2-(tert-ブトキシ)-2-オキソエチル]-4-メチルピロリジン-3-カルボン酸(360mg,1.48mmol)と2-クロロ-6-メチルベンズアルデヒド(416mg,2.69mmol)から、標記化合物(154mg,収率27.2%)を得た。
1H-NMR(400MHz,CDCl3)δppm;1.01(3H,d,J=7Hz),1.41(9H,s),2.10(1H,d,J=17Hz),2.15-2.23(1H,m),2.42(3H,s),2.63-2.69(2H,m),2.97(1H,t,J=10Hz),3.01(1H,d,J=17Hz),3.68(1H,d,J=9Hz),4.00(2H,s),7.09-7.26(3H,m).
実施例1kに記載した方法と同様の方法により、実施例6aで得た(3S,4R)-3-[2-(tert-ブトキシ)-2-オキソエチル]-1-[(2-クロロ-6-メチルフェニル)メチル]-4-メチルピロリジン-3-カルボン酸(154mg,0.403mmol)と実施例4bで得られた1-(シクロヘキス-1-エン-1-イルメチル)ピペリジン-4-アミン(110mg,0.564mmol)から、標記化合物(212mg,収率94.2%)を得た。
1H-NMR(400MHz,CDCl3)δppm;0.92(3H,d,J=7Hz),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=16Hz),2.44(3H,s),2.52(1H,d,J=10Hz),2.61(1H,dd,J=6,9Hz),2.68(2H,brd,J=9Hz),2.75(2H,s),2.86(1H,t,J=10Hz),3.10(1H,d,J=16Hz),3.58(1H,d,J=10Hz),3.60-3.70(1H,m),3.79(1H,d,J=13Hz),3.84(1H,d,J=13Hz),5.54(1H,s),7.08-7.14(2H,m),7.23-7.26(1H,m),8.00(1H,d,J=8Hz).
実施例1mに記載した方法と同様の方法により、実施例6bで得たtert-ブチル 2-[(3S,4R)-1-[(2-クロロ-6-メチルフェニル)メチル]-3-{[1-(シクロヘキス-1-エン-1-イルメチル)ピペリジン-4-イル]カルバモイル}-4-メチルピロリジン-3-イル]アセテート(212mg,0.38mmol)から、標記化合物(140mg,収率73.4%)を得た。
1H-NMR(400MHz,CD3OD)δppm;0.93(3H,d,J=7Hz),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).
1,2-シクロヘキサンジオール(12g,103mmol)とジエチルエーテル(150ml)の混合物に、過ヨウ素酸ナトリウム(28.6g,134mmol)と水(250ml)の混合物を加え、室温で35分間攪拌した。反応混合物に20%水酸化カリウム水溶液(40ml,206mmol)を加え、室温で2時間攪拌した。反応混合物をジエチルエーテルで二回抽出した。有機層を無水硫酸マグネシウムで乾燥し溶媒を留去することで、標記化合物(6.1g、収率61.6%)を得た。
1H-NMR(400MHz,CDCl3)δppm;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).
実施例3eに記載した方法と同様な方法により、実施例3dで得た2-[(3S,4R)-1-{[2-クロロ-6-(トリフルオロメチル)フェニル]メチル}-4-メチル-3-[(ピペリジン-4-イル)カルバモイル]ピロリジン-3-イル]酢酸(334mg,0.723mmol)と実施例7aで得たシクロペント-1-エン-1-カルバルデヒド(209mg,2.17mmol)、酢酸(300μl)とナトリウム トリアセトキシボロヒドリド(460mg,2.17mmol)から標記化合物(288mg,収率:73.5%)を得た。
1H-NMR(400MHz,CD3OD)δppm;0.89(3H,d,J=7Hz),1.24-1.35(2H,m),1.50-1.66(2H,m),1.70-1.78(1H,m),1.85-1.99(3H,m),2.11-2.22(2H,m),2.29-2.42(4H,m),2.61(1H,d,J=10Hz),2.60-2.68(1H,m),2.91-3.02(2H,m),3.07(1H,d,J=16Hz),3.54(1H,d,J=10Hz),3.64-3.78(1H,m),3.95(1H,d,J=14Hz),4.05(1H,d,J=14Hz),5.74(1H,s),7.50(1H,t,J=8Hz),7.71(1H,d,J=8Hz),7.78(1H,d,J=8Hz).
MS(ESI)m/z:564.3(M+Na)+
実施例1kで記載した方法と同様な方法により、実施例6aに記載の方法と同様に得た(3S,4R)-3-[(2-tert-ブトキシ)-2-オキソエチル]-1-[(2-クロロ-6-メチルフェニル)メチル]-4-メチルピロリジン-3-カルボン酸(175mg,0.458mmol)とtert-ブチル 4-アミノピペリジン-1-カルボシレート(137mg,0.684mmol)から、標記化合物(237mg,収率91.7%)を得た。
1H-NMR(400MHz,CDCl3)δppm;0.92(3H,d,J=8Hz),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=8Hz),2.05-2.11(1H,m),2.42(3H,s),2.50(1H,d,J=10Hz),2.60-2.66(1H,m),2.70-2.81(2H,br),2.85(1H,t,J=10Hz),3.10(1H,d,J=16Hz),3.55(1H,d,J=10Hz),3.74-4.10(4H,m),7.07-7.15(2H,m),7.22-7.27(1H,m),8.14(1H,d,J=8Hz).
実施例8aで得たtert-ブチル 4-[(3S,4R)-3-[(2-tert-ブトキシ)-2-オキソエチル]-1-[(2-クロロ-6-メチルフェニル)メチル]-4-メチルピロリジン-3-アミド}ピペリジン-1-カルボキシレート(237mg,0.42mmol)、トリフルオロ酢酸(2.3ml,31mmol)、およびジクロロメタン(脱水)(2.3ml)の混合物を室温で3時間30分攪拌した。反応混合物を濃縮し、得られた残渣に実施例7aで得たシクロペント-1-エン-1-カルバルデヒド(121mg,1.26mmol)、トリエチルアミン(0.176ml,1.26mmol)、テトラヒドロフラン(5ml)を加え、35分間攪拌した。反応混合物にナトリウム トリアセトキシボロヒドリド(267mg,1.26mmol)を加え、室温で13時間攪拌した。反応混合物を濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー(ODSシリカゲル,溶出溶媒:水/メタノール)にて二回精製し、標記化合物(88mg,収率42.9%)を得た。
1H-NMR(400MHz,CD3OD)δppm;0.92(3H,d,J=7Hz),1.50-1.68(2H,br),1.74-1.83(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=10Hz),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).
(3S)-(-)-3-(tert-ブトキシカルボニルアミノ)ピロリジン(2.0g,10.8mmol)、酢酸(1.24ml,21.6mmol)、テトラヒドロフラン(脱水)(27ml)の混合物に1-シクロヘキセン-1-カルボキサルデヒド(1.48ml,13mmol)を加えて室温で15分攪拌後、ナトリウム トリアセトキシボロヒドリド(4.58g,21.6mmol)を加え、反応混合物を室温で17時間45分攪拌した。反応混合物に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を硫酸ナトリウムで乾燥し、溶媒を留去した。残渣をNHシリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル/ヘプタン)にて精製し、標記化合物(1.3g,収率42.9%)を得た。
1H-NMR(400MHz,CDCl3)δppm;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).
実施例9aで得たtert-ブチル N-[(3S)-1-(シクロヘキス-1-エン-1-イルメチル)ピロリジン-3-イル]カルバメート(1.3g,4.64mmol)、エタノール(9.2ml)の混合物を氷冷下攪拌し、5N塩酸水溶液(9.28ml,46.4mmol)を加え、反応混合物を室温で14時間30分攪拌した。反応混合物を氷冷下攪拌し、5N水酸化ナトリウム水溶液(9.28ml,46.4mmol)を加え溶媒を留去した。残渣にエタノールを加え、析出している固体をろ去、ろ液の溶媒を留去した。さらに残渣にエタノールを加え、析出している固体をろ去、ろ液の溶媒を留去し、標記化合物(0.8g,収率95.6%)を得た。
1H-NMR(400MHz,CD3OD)δppm;1.50-1.68(6H,m),1.90-2.05(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).
実施例1kに記載した方法と同様の方法により、実施例9bで得た(3S)-1-(シクロヘキス-1-エン-1-イルメチル)ピロリジン-3-アミン(169mg,0.94mmol)と実施例2kで得られた(3S,4R)-3-[2-(tert-ブトキシ)-2-オキソエチル]-1-[(2,6-ジクロロフェニル)メチル]-4-メチルピロリジン-3-カルボン酸(290mg,0.72mmol)から、標記化合物(236mg,収率58%)を得た。
1H-NMR(400MHz,CDCl3)δppm;0.91(3H,d,J=7Hz),1.41(9H,s),1.50-1.63(6H,m),1.87-2.14(6H,m),2.20-2.25(1H,m),2.33-2.40(1H,m),2.51-2.67(4H,m),2.79-2.94(3H,m),3.11(1H,d,J=16Hz),3.62(1H,d,J=10Hz),3.92-4.02(2H,m),4.28-4.38(1H,m),5.74(1H,br s),7.17(1H,dd,J=7,8Hz),7.32(2H,d,J=8Hz),8.30(1H,d,J=7Hz).
実施例1mに記載した方法と同様の方法により、実施例9cで得られたtert-ブチル 2-[(3S,4R)-3-{[(3S)-1-(シクロヘキス-1-エン-1-イルメチル)ピロリジン-3-イル]カルバモイル}-1-[(2,6-ジクロロフェニル)メチル]-4-メチルピロリジン-3-イル]アセテート(236mg,0.42mmol)から、標記化合物(173mg,収率81%)を得た。
1H-NMR(400MHz,CD3OD)δppm;0.89(3H,d,J=7Hz),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),2.96-3.15(4H,m),3.20-3.34(2H,m),3.61(1H,d,J=10Hz),4.00-4.08(2H,m),4.18-4.27(1H,m),5.74(1H,br s),7.29(1H,dd,J=7,9Hz),7.40-7.44(2H,m).
標記化合物は、US2005/0222175 A1ならびに実施例4aおよび4bに記載の方法と同様の方法で得た。
1H-NMR(400MHz,CDCl3)δppm:0.80(3H,t,J=7Hz),1.05-1.45(12H,m),1.73(2H,d,J=6Hz),1.88(2H,t,J=6Hz),2.21(2H,dd,J=6,8Hz),2.52-2.62(1H,m),2.79(2H,d,J=12Hz)
3-クロロ-2-メチル安息香酸(3.58g,21mmol)、炭酸カリウム(5.8g、42mmol)、N,N-ジメチルホルムアミド(35.9ml)の混合物に、ヨードメタン(1.96ml,31.5mmol)を加えて室温下、18時間30分攪拌した。反応液に水、酢酸エチルを加えて有機層を抽出した。有機層を、飽和塩化アンモニウム水溶液、飽和食塩水で順次洗浄後、硫酸ナトリウムにて乾燥、濾過、濃縮した。残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:ヘプタン/酢酸エチル)により精製し、標記化合物(3.67g,収率:97%)を得た。
1H-NMR(400MHz,CDCl3)δppm;2.60(3H,s),3.91(3H,s),7.13-7.21(1H,m),7.50(1H,dd,J=1,8Hz),7.70(1H,dd,J=1,8Hz).
前記(10b)で得たメチル 3-クロロ-2-メチルベンゾエート(1g, 5.42mmol)、四塩化炭素(13.3ml)、N-ブロモコハク酸イミド(1.06g, 5.96mmol)、過酸化ベンゾイル(3.5mg,0.0108mmol)の懸濁液を窒素気流下にて90℃のオイルバスにて加熱した。3時間45分後、加熱を終了し、混合物を水、酢酸エチルおよび飽和炭酸水素ナトリウム水溶液にて希釈した。有機層を飽和炭酸水素ナトリウム水溶液にて洗浄、無水硫酸マグネシウムにて乾燥、濾過、濃縮し、標記化合物(1.43g, 収率:100%)を得た。
1H-NMR(400MHz, CDCl3) δ ppm; 4.00 (3H, s), 5.12 (2H, s), 7.32 (1H, t, J=8Hz), 7.58 (1H, dd, J=2, 8Hz), 7.86 (1H, dd, J=2, 8Hz).
実施例10cで得たメチル 2-(ブロモメチル)-3-クロロベンゾエート(500mg,1.9mmol)にジクロロメタン(10ml)を加え-78℃で、1.04M ジイソブチルアルミニウムヒドリド/n-ヘキサン溶液(4.57ml,4.75mmol)を加え窒素雰囲気下1時間攪拌した。飽和ロッシェル塩水溶液とtert-ブチルメチルエーテルを加え、tert-ブチルメチルエーテルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥後シリカゲルパッドに通した。溶出液を濃縮し、標記化合物(440mg,収率98.3%)を得た。
1H-NMR(400MHz,CDCl3)δppm;1.82(1H,t,J=6Hz),4.78(2H,s),4.85(2H,d,J=5Hz),7.25-7.28(1H,m),7.31-7.40(2H,m).
実施例10dで得た[2-(ブロモメチル)-3-クロロフェニル]メタノール(440mg,1.87mmol)にジクロロメタン(15ml)と二酸化マンガン(1.69g,19.4mmol)を加え室温で終夜攪拌した。さらに二酸化マンガン(1.2g,13.8mmol)を加え40℃で2.5時間加熱攪拌した。反応混合物をセライトで濾過し、酢酸エチルで洗った。濾液を減圧濃縮し、得られた粗生成物をカラムクロマトグラフィー(シリカゲル,溶出溶媒:ヘプタン/酢酸エチル=99/1→90/10)で精製し標記化合物(289mg,収率66.2%)を得た。
1H-NMR(400MHz,CDCl3)δppm;5.13(2H,s),7.48(1H,t,J=8Hz),7.66(1H,dd,J=1,8Hz),7.77(1H,dd,J=1,8Hz),10.23(1H,s).
実施例10eで得た2-(ブロモメチル)-3-クロロベンズアルデヒド(289mg,1.24mmol)にジクロロメタン(10ml)を加え0℃で[ビス(2―メトキシエチル)アミノ]サルファー トリフルオリド(457μl,2.48mmol)を加え窒素雰囲気下室温で1.5時間攪拌した。反応混合物に0℃で飽和炭酸水素ナトリウム水溶液を加えジエチルエーテルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥後濃縮した。得られた粗生成物をカラムクロマトグラフィー(シリカゲル,溶出溶媒:ヘプタン/酢酸エチル=99/1→95/5)で精製し、標記化合物(238.3mg,収率75.2%)を得た。
1H-NMR(400MHz,CDCl3)δppm;4.74(2H,s),6.93(1H,t,J=55Hz),7.37(1H,t,J=8Hz),7.53(2H,t,J=8Hz).
実施例1gと同様の方法で得たベンジル(3RS,4SR)-1-ベンジル-3-[2-(tert-ブトキシ)-2-オキソエチル]-4-メチルピロリジン-3-カルボキシレート(8.35g,19.7mmol)のメタノール(200ml)溶液に、20%水酸化パラジウム(500mg)を加え水素雰囲気下室温で終夜攪拌した。反応混合物を濾過し、濾紙上のパラジウムを50℃のお湯でよく洗浄した。ろ液を濃縮し、メタノール及びトルエンでそれをよく共沸し、白色固体(3.92g)を得た。これに、メタノール(20ml)、2,6-ジクロロベンズアルデヒド(5.64g,32.2mmol)、酢酸(966μl,16.1mmol)、ナトリウムトリアセトキシボロヒドリド(6.82g,32.2mmol)を加え室温で終夜攪拌した。さらに50℃湯浴で3時間加熱攪拌した。反応混合物に中性バッファー[リン酸二水素カリウム(13.65g)、リン酸水素二ナトリウム12水和物(71.6g)、水(1.5L)より調製]と酢酸エチルを加え固形物を濾過した。濾紙上の固形物を酢酸エチルで洗浄し、標記化合物を白色固体として得た。また、ろ液は酢酸エチルにより抽出後、有機層を硫酸ナトリウムで乾燥、濃縮し、カラムクロマトグラフィー(シリカゲル,溶出溶媒:メタノール/酢酸エチル)で精製し、濾紙上の固体とまとめて標記化合物(3.77g,収率58.2%)を得た。
1H-NMR(400MHz,CDCl3)δppm;1.01(3H,d,J=7Hz),1.42(9H,s),2.09(1H,d,J=16Hz),2.14-2.24(1H,m),2.62-2.69(2H,m),2.99(1H,t,J=10Hz),3.02(1H,d,J=10Hz),3.71(1H,d,J=10Hz),4.08(1H,d,J=12Hz),4.12(1H,d,J=12Hz),7.21(1H,d,J=8Hz),7.23(1H,d,J=8Hz),7.37(1H,d,J=8Hz).
実施例10gで得た(3RS,4SR)-3-[2-(tert-ブトキシ)-2-オキソエチル]-1-[(2,6-ジクロロフェニル)メチル]-4-メチルピロリジン-3-カルボン酸(1.5g,3.73mmol)に実施例10aで得た1-ヘキシルピペリジン-4-アミン(894mg,4.85mmol)、トリエチルアミン(1.04ml,7.46mmol)、N,N-ジメチルホルムアミド(10ml)、PyBOP(2.52g,4.85mmol)を加え室温で終夜攪拌した。反応混合物に水を加え酢酸エチルで抽出した。有機層を水と飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。それを濃縮し、粗生成物をカラムクロマトグラフィー(NHシリカゲル,溶出溶媒:酢酸エチル/ヘプタン)で精製し白色固体(1.85g)を得た。これをHPLC(CHIRALPAK IA(3cmφ×25cm)、溶出溶媒:エタノール/ヘキサン=6/94、流速:20ml/min.)により光学分割し、保持時間の短いピークに相当するキラル体(875mg)を得た。
HPLCによる分析;
(分析条件)カラム:CHIRALPAK IA(ダイセル化学工業社製)(0.46cmφ×15cm),40℃,溶離液:ヘキサン/エタノール=9/1(v/v),流速:1ml/min.,検出:UV(210nm)
(分析結果)得られたキラル体を上記分析条件で分析したところ、保持時間は4.85分であり、鏡像体過剰率は>99%eeであった。
実施例10hで得たtert-ブチル 2-[(3S,4R)-1-[(2,6-ジクロロフェニル)メチル]-3-[(1-ヘキシルピペリジン-4-イル)カルバモイル]-4-メチルピロリジン-3-イル]アセテートのうちの250mgにメタノール(10ml)、20%水酸化パラジウム(50mg)を加え水素雰囲気下室温で2時間攪拌した。反応混合物を濾過し、濾液を濃縮し標記化合物(180mg)を得た。
1H-NMR(400MHz,CDCl3)δppm;0.85-0.90(3H,m),1.04(3H,d,J=6Hz),1.25-1.35(5H,m),1.42(9H,s),1.78-2.10(6H,m),2.26-2.50(4H,m),2.88-3.05(3H,m),3.23(1H,d,J=13Hz),3.29-3.54(5H,m),3.55-3.67(1H,m),4.17(1H,d,J=13Hz),4.27-4.40(1H,br),7.82-7.92(1H,br).
実施例10iで得たtert-ブチル 2-[(3S,4R)-3-[(1-ヘキシルピペリジン-4-イル)カルバモイル]-4-メチルピロリジン-3-イル]アセテート(20mg,0.0488mmol)にN,N-ジメチルホルムアミド(400μl)、実施例10fで得た2-(ブロモメチル)-1-クロロ-3-(ジフルオロメチル)ベンゼン(24.9mg,0.0976mmol)、炭酸カリウム(20.2mg,0.146mmol)を加え室温で終夜攪拌した。反応混合物に酢酸エチルと水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥した。これを濃縮し得られた粗生成物をカラムクロマトグラフィー(NHシリカゲル,溶出溶媒:ヘプタン/酢酸エチル=98/2→80/20)で精製し、標記化合物(14.4mg,収率50.2%)を得た。
1H-NMR(400MHz,CDCl3)δppm;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),1.77-2.12(7H,m),2.24-2.28(2H,m),2.54(1H,d,J=10Hz),2.59-2.63(1H,m),2.74-2.88(3H,m),3.13(1H,d,J=16Hz),3.61(1H,d,J=10Hz),3.61-3.72(1H,m),3.91(1H,d,J=13Hz),3.95(1H,d,J=13Hz),6.96(1H,t,J=55Hz),7.35(1H,t,J=8Hz),7.54(2H,d,J=8Hz),7.65(1H,d,J=8Hz).
実施例1mに記載した方法と同様の方法により、実施例10jと同様の方法で得たtert-ブチル 2-[(3S,4R)-1-{[2-クロロ-6-(ジフルオロメチル)フェニル]メチル}-3-[(1-ヘキシルピペリジン-4-イル)カルバモイル]-4-メチルピロリジン-3-イル]アセテート(25mg,0.0428mmol)から、標記化合物(13.9mg, 収率61.5%)を得た。
1H-NMR(400MHz,CDCl3)δppm;0.82-0.90(3H,m),0.93(3H,d,J=7Hz),1.23-1.34(6H,m),1.52-1.64(2H,m),1.76-1.98(4H,m),2.22-2.44(4H,m),2.50-2.78(5H,m),2.91(1H,t,J=8Hz),3.22-3.35(1H,br),3.36-3.43(1H,m),3.70-3.82(1H,m),3.92(1H,d,J=14Hz),3.96(1H,d,J=14Hz),7.21(1H,t,J=55Hz),7.30(1H,t,J=8Hz),7.48(1H,d,J=8Hz),7.55(1H,d,J=8Hz),8.92-9.08(1H,br).
実施例1iと同様の方法で得た(3S,4R)-3-[2-(tert-ブトキシ)-2-オキソエチル]-4-メチルピロリジン-3-カルボン酸(300mg, 1.23mmol)にメタノール(3ml)、2,6-ジクロロベンズアルデヒド(431mg, 2.46mmol)、酢酸(73.8ul, 1.23mmol)、ナトリウムトリアセトキシボロヒドリド(521mg, 2.46mmol)を加え室温で2日間攪拌した。系に水を加え酢酸エチルで抽出し、有機層を硫酸ナトリウムで乾燥し濃縮した。得られた粗生成物をカラムクロマトグラフィー(シリカゲル,溶出溶媒:メタノール/酢酸エチル)で精製し、標記化合物(180mg)を得た。一方、分液時の水層を濃縮し、ODSカラムクロマトグラフィー(溶出溶媒,メタノール/水)で精製し、(3S,4R)-3-[2-(tert-ブトキシ)-2-オキソエチル]-4-メチルピロリジン-3-カルボン酸(120mg)を回収した。回収した上記原料を用いて再度同様の反応を行うことにより、標記化合物(42.7mg)を得て、一度目の標記化合物(180mg)と合わせた。
1H-NMR(400MHz,CDCl3);実施例10gで得られた化合物と同じであることを確認した。
実施例1kに記載した方法と同様の方法により、実施例11aで得た(3S,4R)-3-[2-(tert-ブトキシ)-2-オキソエチル]-1-[(2,6-ジクロロフェニル)メチル]-4-メチルピロリジン-3-カルボン酸(222mg,0.55mmol)、実施例4bで得た1-(シクロヘキス-1-エン-1-イルメチル)ピペリジン-4-アミン(150mg,0.772mmol)から、標記化合物(274mg,収率85.8%)を得た。
1H-NMR(400MHz,CDCl3)δppm;0.91(3H,d,J=8Hz),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=10Hz),3.12(1H,d,J=16Hz),3.60-3.72(2H,m),3.96(2H,s),5.54(1H,s),7.18(1H,t,J=8Hz),7.33(2H,d,J=8Hz),8.09(1H,d,J=8Hz).
実施例1mに記載した方法と同様の方法により、実施例11bで得たtert-ブチル 2-[(3S,4R)-{3-[(1-シクロヘキス-1-エン-1-イルメチル)ピペリジン-4-イル]カルバモイル-1-[(2,6-ジクロロフェニル)メチル]-4-メチルピロリジン-3-イル}アセテート(274mg,0.474mmol)から、標記化合物(169mg,収率68.2%)を得た。
1H-NMR(400MHz,CD3OD)δppm;0.89(3H,d,J=7Hz),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=10Hz),2.95-3.19(6H,m),3.62(1H,d,J=10Hz),3.68-3.80(1H,br),3.99-4.07(2H,m),5.76(1H,s),7.29(1H,t,J=8Hz),7.43(2H,d,J=8Hz).
実施例3bで得たtert-ブチル 4-[(3S,4R)-3-[2-(tert-ブトキシ)-2-オキソエチル]-4-メチルピロリジン-3-アミド]ピペリジン-1-カルボキシレート(375mg,0.881mmol)をN,N-ジメチルホルムアミド(7ml)に溶かした。そこへ炭酸カリウム(304mg,2.2mmol)と実施例10fと同様の方法で得た2-(ブロモメチル)-1-クロロ-3-(ジフルオロメチル)ベンゼン(450mg,1.76mmol)を加え、混合物を45℃のオイルバスにて2時間加熱した。反応混合物を酢酸エチルと飽和塩化アンモニウム水溶液にて分液した。分離した有機層を飽和塩化アンモニウム水溶液にて3回洗浄、無水硫酸マグネシウムにて乾燥、濾過、濃縮した。残渣をシリカゲルカラムクロマトグラフィー(シリカゲル,溶出溶媒:ヘプタン/酢酸エチル)にて精製し、標記化合物(332mg,収率:62.8%)を得た。
1H-NMR(400MHz,CDCl3)δppm;0.92(3H,d,J=7Hz),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=16Hz),2.04-2.15(1H,m),2.52(1H,d,J=10Hz),2.56-2.83(3H,m),2.86(1H,t,J=10Hz),3.12(1H,d,J=10Hz),3.57(1H,d,J=10Hz),3.80-4.16(3H,m),3.90(1H,d,J=13Hz),3.96(1H,d,J=13Hz),6.93(1H,t,J=55Hz),7.37(1H,t,J=8Hz),7.55(2H,d,J=8Hz),7.77(1H,d,J=8Hz).
実施例12aで得たtert-ブチル 4-[(3S,4R)-3-[2-(tert-ブトキシ)-2-オキソエチル]-1-{[2-クロロ-6-(ジフルオロメチル)フェニル]メチル}-4-メチルピロリジン-3-アミド]ピペリジン-1-カルボキシレート(332mg,0.553mmol)をジクロロメタン(3.0ml)に溶かし、そこへトリフルオロ酢酸(3.0ml)を加えた後、混合物を室温にて放置した。2時間30分後、反応液を濃縮、ジクロロメタンで2回共沸し、中間体を得た。得られた中間体(372mg)のうち186mgをテトラヒドロフラン(5ml)に溶解し、トリエチルアミン(116μl,0.831mmol)とシクロヘキス-1-エン-1-カルバルデヒド(91.5mg,0.831mmol)を加え、室温にて放置した。30分後、そこへナトリウム トリアセトキシボロヒドリド(176mg,0.831mmol)を加え、混合物を室温にて攪拌した。10時間50分後、混合物を濃縮した。残渣をシリカゲルカラムクロマトグラフィー(ODS,溶出溶媒:水/メタノール)にて精製し、標記化合物(80mg)を白色固体として得た。
1H-NMR(400MHz,CD3OD)δppm;0.90(3H,d,J=7Hz),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=16Hz),2.46-2.65(3H,m),2.61(1H,d,J=10Hz),2.95(1H,t,J=9Hz),2.97(1H,d,J=16Hz),3.03-3.16(2H,m),3.20-3.27(2H,m),3.50(1H,d,J=10Hz),3.74-3.83(1H,m),3.98(1H,d,J=13Hz),4.02(1H,d,J=13Hz),5.78-5.86(1H,br),7.26(1H,t,J=55Hz),7.42(1H,t,J=8Hz),7.60(2H,d,J=8Hz).
実施例12bにおいて得られた中間体(186mg)、および実施例7aで得たシクロペント-1-エン-1-カルバルデヒド(79.9mg,0.831mmol)を用い、12bに記載の方法と同様に、標記化合物(76mg)を得た。
1H-NMR(400MHz,CD3OD)δppm;0.90(3H,d,J=7Hz),1.58-1.75(2H,m),1.80-2.00(4H,m),2.15-2.27(1H,m),2.47(1H,d,J=16Hz),2.32-2.42(4H,m),2.46-2.65(3H,m),2.62(1H,d,J=10Hz),2.95(1H,t,J=9Hz),2.99(1H,d,J=16Hz),3.03-3.16(2H,m),3.36-3.43(2H,m),3.51(1H,d,J=10Hz),3.73-3.82(1H,m),3.98(1H,d,J=13Hz),4.03(1H,d,J=13Hz),5.78-5.83(1H,br),7.25(1H,t,J=55Hz),7.43(1H,t,J=8Hz),7.61(2H,d,J=8Hz).
標記化合物は、US2005/0222175 A1ならびに実施例4aおよび4bに記載の方法と同様の方法で得た。
1H-NMR(400MHz,CDCl3)δppm:0.77-0.87(2H,m),1.11-1.49(8H,m),1.61-1.80(5H,m),1.97(2H,t,J=12Hz),2.14(2H,d,J=7Hz),2.50-2.64(1H,m),2.96(2H,d,J=12Hz).
実施例1kに記載した方法と同様の方法により、実施例1jで得た(3S,4R)-1-ベンジル-3-[2-(tert-ブトキシ)-2-オキソエチル]-4-メチルピロリジン-3-カルボン酸(200mg,0.6mmol)と実施例14aで得た1-(シクロヘキシルメチル)ピペリジン-4-アミン(141mg,0.72mmol)から、標記化合物(250mg,収率:81.4%)を得た。
1H-NMR(400MHz,CDCl3)δppm;0.80-0.98(2H,m),0.92(3H,d,J=7Hz),1.07-2.15(17H,m),1,58(9H,s),1.95(1H,d,J=16Hz),2.10(1H,d,J=7Hz),2.36(1H,d,J=10Hz),2.55-2.83(4H,m),3.08(1H,d,J=16Hz),3.59(1H,d,J=10Hz),3.63-3.77(1H,m),3.64(1H,d,J=13Hz),3.69(1H,d,J=13Hz),7.21-7.36(5H,m),8.56(1H,d,J=8Hz).
実施例1lで記載した方法と同様の方法により、実施例14bで得たtert-ブチル 2-[(3S,4R)-1-ベンジル-3-{[1-(シクロヘキシルメチル)ピペリジン-4-イル]カルバモイル}-4-メチルピロリジン-3-イル]アセテート(250mg,0.489mmol)と実施例10fと同様の方法で得た2-(ブロモメチル)-1-クロロ-3-(ジフルオロメチル)ベンゼン(250mg,0.978mmol)から、標記化合物(198mg,収率:67.9%)を得た。
1H-NMR(400MHz,CDCl3)δppm;0.78-0.97(2H,m),0.91(3H,d,J=7Hz),1.08-2.13(18H,m),1.40(9H,s),2.00(1H,d,J=17Hz),2.05(1H,d,J=7Hz),2.54(1H,d,J=10Hz),2.61(1H,dd,J=6,10Hz),2.66-2.77(2H,m),2.85(1H,t,J=10Hz),3.60(1H,d,J=17Hz),3.58-3.72(1H,m),3.92(1H,d,J=13Hz),3.96(1H,d,J=13Hz),6.97(1H,t,J=55Hz),7.36(1H,t,J=8Hz),7.51-7.58(2H,m),7.62(1H,d,J=8Hz).
実施例1mに記載した方法と同様の方法により、実施例14cで得たtert-ブチル 2-[(3S,4R)-1-{[2-クロロ-6-(ジフルオロメチル)フェニル]メチル}-3-{[1-(シクロヘキシルメチル)ピペリジン-4-イル]カルバモイル}-4-メチルピロリジン-3-イル]アセテート(194mg,0.325mmol)から、標記化合物(140mg,収率:79.8%)を得た。
1H-NMR(400MHz,CD3OD)δppm;0.90(3H,d,J=7Hz),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=16Hz),2.41-2.50(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=10Hz),3.76-3.86(1H,m),3.97(1H,d,J=13Hz),4.01(1H,d,J=13Hz),7.28(1H,t,J=55Hz),7.42(1H,t,J=8Hz),7.56-7.63(2H,m).
実施例2eから2gに記載の方法と同様の方法で、(4-メトキシフェニル)メチル (3RS,4SR)-1-ベンジル-3-[2-(tert-ブトキシ)-2-オキソエチル]-4-メチルピロリジン-3-カルボキシレート44.7gを得た。この一部(20g, 44.1mmol)をメタノール(316ml)に溶解させ、10%Pd/C(3.93g)を加えて、水素ガスで置換した。混合物を室温にて終夜攪拌した後、温水(36℃、160ml)を加えて30分攪拌し、析出している固体を溶解させた。Pd/Cをろ過後、水が20-40ml残る程度に濃縮、水を含んだ白濁した残渣に、メタノール(80ml)を加えて30分攪拌した。析出している固体をろ過した(ロットA)。ロットAの1H-NMRを下記に示す。
(4-メトキシフェニル)メチル (3RS,4SR)-1-ベンジル-3-[2-(tert-ブトキシ)-2-オキソエチル]-4-メチルピロリジン-3-カルボキシレート(21g,46.3mmol)を用い、同様の方法で(ロットB)を得た。ロットBの1H-NMRがロットAの1H-NMRと同様であることを確認した後、ロットAとロットBをあわせて乾燥し、標記化合物(9.91g)を得た。
1H-NMR(400MHz,D2O)δppm;0.97(3H,d,J=6Hz),1.42(9H,s),2.12-2.24(1H,m),2.29(1H,d,J=17Hz),2.93(1H,d,J=17Hz),3.04(1H,t,J=12Hz),3.18(1H,d,J=12Hz),3.49(1H,dd,J=8,12Hz),4.03(1H,d,J=12Hz).
参考例1aで得た(3RS,4SR)-3-[2-(tert-ブトキシ)-2-オキソエチル]-4-メチルピロリジン-3-カルボン酸(9.84g,40.5mmol)とアセトン(39ml)、水(49ml)の混合物に、氷冷攪拌下(0-1℃)、2N水酸化ナトリウム水溶液(20.2ml)を加えて45分攪拌し、反応混合物を溶解させた。反応混合物に氷冷攪拌下(0-1℃)、ベンジル クロロホルメート(6.35ml,44.5mmol)と2N水酸化ナトリウム水溶液(22.3ml)を同時に、内温3.5℃以下で、20分かけて滴下した。反応液を氷浴中にて攪拌させ、徐々に室温に戻した。そのまま室温にて終夜攪拌した。反応液に氷冷攪拌下(内温15℃前後)、1N水酸化ナトリウム水溶液(10ml)を加えてpH12に調整した。この反応液を室温に戻し、エチルエーテルを加えて3回洗浄した。水層に氷冷攪拌下(内温5℃以下)、2N塩酸水溶液(20.2ml)、1N塩酸水溶液(13ml)、を順次加えてpH2-3に調整した。水層を室温に戻し、酢酸エチルで3回抽出した。有機層を飽和食塩水で洗浄後、硫酸ナトリウムにて乾燥、濾過、濃縮した。残渣を酢酸エチルに溶解し、水で4回洗浄後、飽和食塩水で洗浄し、硫酸ナトリウムにて乾燥、濾過、濃縮し、標記化合物(14.53g,収率:95.1%)を得た。
1H-NMR(400MHz,CDCl3)δppm;1.02(3H,t,J=8Hz),1.42(9H,s),2.14-2.22(1H,m),2.27(1H,d,J=17Hz),3.04(1H,d,J=5,17Hz),3.12-3.19(1H,m),3.35(1H,dd,J=7,12Hz),3.65-3.72(1H,m),4.29(1H,dd,J=7,12Hz),5.09-5.19(2H,m),7.26-7.38(5H,m).
参考例1bで得た(3RS,4SR)-1-[(ベンジルオキシ)カルボニル]-3-[2-(tert-ブトキシ)-2-オキソエチル]-4-メチルピロリジン-3-カルボン酸(14.5g,38.5mmol)と炭酸カリウム(10.6g、77mmol)、N,N-ジメチルホルムアミド(50ml)の混合物に、氷冷攪拌下(内温3-7℃)、ベンジルブロミド(4.48ml,37.7mmol)を加えて1時間攪拌し、室温に戻して終夜攪拌した。反応液に水を加えて酢酸エチルで3回抽出した。有機層を併せて、飽和塩化アンモニウム水溶液(5回)、水(2回)、飽和食塩水で順次洗浄後、硫酸ナトリウムにて乾燥、濾過、濃縮し、標記化合物(17.67g,収率:98.2%)を得た。
1H-NMR(400MHz,CDCl3)δppm;0.84-0.89(3H,m),1.36-1.39(9H,m),2.09-2.18(1H,m),2.24(1H,dd,J=3,17Hz),3.04-3.13(2H,m),3.35(1H,dd,J=8,12Hz),3.59-3.68(1H,m),4.32(1H,t,J=12Hz),5.06-5.20(4H,m),7.29-7.36(10H,m).
実施例2fに記載の方法と同様の方法で別途得た(4-メトキシフェニル)メチル (3RS,4RS)-1-ベンジル-4-メチルピロリジン-3-カルボキシレート(1000mg,2.946mmol)をメチルイソブチルケトン(4ml)に溶解させ、(-)-ジベンゾイル-L-酒石酸(1055mg)を加え、溶解させた。得られた溶液に、実施例2fと同様の方法で別途得た(4-メトキシフェニル)メチル (3RS,4RS)-1-ベンジル-4-メチルピロリジン-3-カルボキシレートと(-)-ジベンゾイル-L-酒石酸から得られた結晶を種結晶として加え、得られた析出物をろ過し、標記化合物(757mg,収率:36.8%)を得た。得られた固体のうち755mgにエタノール(3.02mL)に加え、加熱溶解後にtert-ブチルメチルエーテル(6.04mL)を加えた。得られた析出物をろ過し、標記化合物(658mg,収率:87.2%)を結晶として得た。
実施例2fに記載の方法と同様の方法で別途得た(4-メトキシフェニル)メチル (3R,4R)-1-ベンジル-4-メチルピロリジン-3-カルボキシレート(150.0g,441mmol)をメチルイソブチルケトン(600ml)に溶解させ、攪拌下(-)-ジベンゾイル-L-酒石酸(157.0g)を加え、溶解させた。得られた溶液に、前段落記載の方法で得られた(4-メトキシフェニル)メチル (3RS,4RS)-1-ベンジル-4-メチルピロリジン-3-カルボキシレートの(-)-ジベンゾイル-L-酒石酸塩を種結晶(7.5mg)として加え18時間18分攪拌した。析出固体をろ過し、メチルイソブチルケトン(150ml)で洗浄した。得られた固体を50℃で減圧乾燥し、標記化合物(152.07g,収率:49.4%)を得た。得られた固体のうち150.00gにエタノール(600ml)を加え、攪拌しながら80℃に加熱し、固体の溶解を確認した後に加熱を停止した。加熱停止59分後に、tert-ブチルメチルエーテル(300ml)を9分間かけて加え、さらに6分後に種結晶(5mg)を添加した。12分後にtert-ブチルメチルエーテル(900ml)を2時間38分間かけて加え、さらに10時間43分間攪拌した。析出固体をろ過し、エタノールとtert-ブチルメチルエーテルの混合液(75ml+150ml)で洗浄した。得られた固体を50℃で減圧乾燥し、標記化合物(106.40g,収率:70.9%)を得た。
1H-NMR(400MHz,DMSO-d6)δppm;1.05(3H,d,J=6Hz),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=12,16Hz),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).
HPLCによる分析;
(分析条件)カラム:CHIRALCEL OJ-H(ダイセル化学工業社製)(0.46cmφX25cm)、溶離液:ヘキサン/エタノール/ジエチルアミン=850/150/1(v/v/v)、流速:1ml/min.、検出:UV(226nm)
(分析結果)得られた標記化合物を上記分析条件で分析したところ、保持時間8.62分のピーク(鏡像体過剰率:98.0%ee)と10.9分のピークが認められた。
参考例2aで得た(4-メトキシフェニル)メチル (3R,4R)-1-ベンジル-4-メチルピロリジン-3-カルボキシレートの(-)-ジベンゾイル-L-酒石酸塩(104.0g)に酢酸エチル(900ml)を加え、攪拌下1N水酸化ナトリウム水溶液(600ml)を加えた。水層を廃棄し、有機層を水で2回(100ml,50ml)洗浄した。得られた有機層を50℃で減圧濃縮し、標記化合物(49.8g,収率:98.5%)を得た。
1H-NMR(400MHz,CDCl3)δppm;1.12(3H,d,J=7Hz),2.19(1H,dd,J=6,9Hz),2.44-2.62(2H,m),2.73-2.84(2H,m),2.85-2.92(1H,m),3.55(1H,d,J=13Hz),3.63(1H,d,J=13Hz),3.81(3H,s),5.02-5.10(2H,m),6.85-6.90(2H,m),7.21-7.33(7H,m).
参考例2bで得た(4-メトキシフェニル)メチル (3R,4R)-1-ベンジル-4-メチルピロリジン-3-カルボキシレート(29.50g,87mmol)にテトラヒドロフラン(200ml)を加え、共沸脱水した。さらに、テトラヒドロフラン(200ml)を加え、共沸脱水した。このものに、テトラヒドロフラン(400ml)を加え、ドライアイス-エタノール浴で冷却し、リチウム ジイソプロピルアミド/n-ヘキサン-テトラヒドロフラン溶液(129ml,1.11M,144mmol)を27分間かけて加えた。30分後、tert-ブチル ブロモアセテート(21.20g,144mmol)のテトラヒドロフラン(30ml)溶液を7分間かけて加えた。39分後に、20%塩化アンモニウム水溶液(440ml)を加え、さらに酢酸エチル(440ml)を加えて抽出を行った。得られた有機層を水で2回(60ml,60ml)洗浄し、30℃で減圧濃縮した。得られた濃縮物に、メタノール(150ml)、水酸化パラジウム(885mg)を加え、水素加圧下(0.35MPa)で7時間20分間攪拌した。反応液に、水(200ml)とテトラヒドロフラン(100ml)を加えてろ過し、触媒をメタノール(50ml)、水(50mlx2)で順次洗浄した。ろ洗液を50℃で減圧濃縮し、得られた水層をtert-ブチルメチルエーテル(100ml)で洗浄し、洗浄後の水層を50℃で減圧濃縮した。得られた残渣にメタノール(150ml)を加え、超音波で処理した後に、ろ過を行った。得られた固体を50℃で減圧乾燥し、標記化合物(8.16g,収率:38.5%)を得た。
1H-NMR(400MHz,D2O)δppm;1.00(3H,d,J=7Hz),1.45(9H,s),2.16-2.28(1H,m),2.33(1H,d,J=17Hz),2.97(1H,d,J=17Hz),3.08(1H,t,J=12Hz),3.22(1H,d,J=12Hz),3.50-3.58(1H,m),4.07(1H,d,J=12Hz).
50mLナスフラスコに、参考例1aと同様な方法で得られた、(3RS,4SR)-3-[2-(tert-ブトキシ)-2-オキソエチル]-4-メチルピロリジン-3-カルボン酸(500mg)、リン酸水素(R)-(-)-1,1’-ビナフチル-2,2’-ジイル(359mg)、エタノール(10.0mL)、水(10.0mL)を順次加えて室温で約22時間撹拌した。析出した固体をろ取し、1:1エタノール-水混合液 (2mL)で洗浄した。湿体を40℃で約1時間減圧乾燥し、標記化合物(269mg、収率:20.5%)を得た。
1H-NMR (400MHz, DMSO-d6) δppm: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=12 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).
上記白色固体8.85mg をスクリューガラス容器に秤取した。これにMilliQ 水0.2mL、99.5%エタノール0.8mL を加えた。その後これを1.5mL LCMSバイアルに3等分し、キャップをゆるく締め室温で放置した。9日後、バイアル中に結晶が析出しているのを認めた。得られた単結晶(0.40×0.40×0.06 mm)を用いてR-AXIS RAPID II(株式会社リガク)にてX線回折実験を行った。結晶学的データおよび構造解析結果を表1に、原子座標データを表2~4に示す。かかる結果より、標記化合物の絶対構造を特定した。
(1)方法
CX3CR1を強制発現させたB300細胞を用いて、フラクタルカイン誘導の細胞遊走に対する実施化合物の阻害効果を検討した。
Transwell(24well clasters,pore size:5μm,Corning社製)を平衡化した後にフラクタルカイン溶液(0.3nM,R and D社製)を下層に添加した。続けて被験化合物(0.001,0.003,0.01,または0.03μM)と30分間プレインキュベートしたCX3CR1発現B300細胞をTranswellの上層に加え、5%CO2,37℃の条件で3.5時間インキュベートした。下層に遊走した細胞数の評価は、CellTiter(Promega社製)を用いて行った。
フラクタルカイン誘導の細胞遊走に対する被験化合物の阻害率の算出は、フラクタルカイン・被験化合物共存下での細胞遊走量を[A],フラクタルカイン存在下・被験化合物非存在下での細胞遊走量を[B],フラクタルカイン・被験化合物双方とも非存在下での細胞遊走量を[C]として以下の式によって求め、これをもとに50%阻害濃度(IC50)を算出した。
阻害率(%)=[1-{(A-C)/(B-C)}]×100
(1)方法
BALB/cマウスから採取したCD4陽性CD45RB高陽性細胞をSCIDマウスに移入することで誘導する大腸炎モデルを用い、実施例化合物の体重量減少抑制効果を検討した。実験は31日間にわたって実施した。第1日目はBalb/cマウスの脾臓から分取したCD4陽性CD45RB高陽性細胞(5×105個/mouse)をSCIDマウスに静脈内投与した。第16日目から第31日目まで、実施例化合物を1日1回SCIDマウスに経口投与すると共に、第19、22、24、26、29、31日目に体重量測定を行った。
体重量減少抑制効果は第19、22、24、26、29、31日目の体重量変化率(%)で評価した。第16日目の体重量を[A]、各体重量測定日(第19、22、24、26、29、31日目)の体重量を[B]とし、以下に示す式より体重量変化率(%)を求めた。
体重量変化率(%)=B/A×100
結果を図1~図4に示す。なお、図中の横軸は、BALB/cマウスの脾臓から分取したCD4陽性CD45RB高陽性細胞(5×105個/mouse)をSCIDマウスに静脈内投与した日を0日とした場合の経過日数を示す。
Claims (13)
- 式(1)で表される化合物またはその薬理学的に許容される塩。
XはC1-6アルキル基を意味し、
YおよびZは、同一または相異なって、ハロゲン原子または無置換のもしくは置換基群Bから選択される置換基を1~3個有するC1-6アルキル基を意味し、
nは0または1を意味し、
置換基群Aはハロゲン原子からなり、
置換基群Bはハロゲン原子からなる。] - Rはフルオロブチル基、ペンチル基、シクロヘキシル基、ジフルオロシクロヘキシル基、シクロペンテニル基またはシクロヘキセニル基である、請求項1記載の化合物またはその薬理学的に許容される塩。
- Xはメチル基である、請求項1または2記載の化合物またはその薬理学的に許容される塩。
- Yは塩素原子である、請求項1~3いずれか1項記載の化合物またはその薬理学的に許容される塩。
- Zは塩素原子、メチル基、ジフルオロメチル基、またはトリフルオロメチル基である、請求項1~4いずれか1項記載の化合物またはその薬理学的に許容される塩。
- nは1である、請求項1~5いずれか1項記載の化合物またはその薬理学的に許容される塩。
- 2-[(3S,4R)-1-{[2-クロロ-6-(トリフルオロメチル)フェニル]メチル}-3-{[1-(2-フルオロペンチル)ピペリジン-4-イル]カルバモイル}-4-メチルピロリジン-3-イル]酢酸、
2-[(3S,4R)-1-[(2,6-ジクロロフェニル)メチル]-3-({1-[(4,4-ジフルオロシクロヘキシル)メチル]ピペリジン-4-イル}カルバモイル)-4-メチルピロリジン-3-イル]酢酸、
2-[(3S,4R)-1-{[2-クロロ-6-(トリフルオロメチル)フェニル]メチル}-3-{[1-(シクロヘキス-1-エン-1-イルメチル)ピペリジン-4-イル]カルバモイル}-4-メチルピロリジン-3-イル]酢酸、
2-[(3S,4R)-1-[(2-クロロ-6-メチルフェニル)メチル]-3-{[1-(シクロヘキス-1-エン-1-イルメチル)ピペリジン-4-イル]カルバモイル}-4-メチルピロリジン-3-イル]酢酸、
2-[(3S,4R)-1-{[2-クロロ-6-(トリフルオロメチル)フェニル]メチル}-3-{[1-(シクロペント-1-エン-1-イルメチル)ピペリジン-4-イル]カルバモイル}-4-メチルピロリジン-3-イル]酢酸、
2-[(3S,4R)-1-[(2-クロロ-6-メチルフェニル)メチル]-3-{[(1-シクロペント-1-エン-1-イルメチル)ピペリジン-4-イル]カルバモイル}-4-メチルピロリジン-3-イル]酢酸、
2-[(3S,4R)-3-{[(3S)-1-(シクロヘキス-1-エン-1-イルメチル)ピロリジン-3-イル]カルバモイル}-1-[(2,6-ジクロロフェニル)メチル]-4-メチルピロリジン-3-イル]酢酸、
2-[(3S,4R)-1-{[2-クロロ-6-(ジフルオロメチル)フェニル]メチル}-3-[(1-ヘキシルピペリジン-4-イル)カルバモイル]-4-メチルピロリジン-3-イル]酢酸、
2-[(3S,4R)-3-{[(1-シクロヘキス-1-エン-1-イルメチル)ピペリジン-4-イル]カルバモイル}-1-[(2,6-ジクロロフェニル)メチル]-4-メチルピロリジン-3-イル]酢酸、
2-[(3S,4R)-1-{[2-クロロ-6-(ジフルオロメチル)フェニル]メチル}-3-{[1-(シクロヘキス-1-エン-1-イルメチル)ピペリジン-4-イル]カルバモイル}-4-メチルピロリジン-3-イル]酢酸、
2-[(3S,4R)-1-{[2-クロロ-6-(ジフルオロメチル)フェニル]メチル}-3-{[1-(シクロペント-1-エン-1-イルメチル)ピペリジン-4-イル]カルバモイル}-4-メチルピロリジン-3-イル]酢酸および
2-[(3S,4R)-1-{[2-クロロ-6-(ジフルオロメチル)フェニル]メチル}-3-{[1-(シクロヘキシルメチル)ピペリジン-4-イル]カルバモイル}-4-メチルピロリジン-3-イル]酢酸からなる群から選択される化合物またはその薬理学的に許容される塩。 - 請求項1~7いずれか1項記載の化合物またはその薬理学的に許容される塩を有効成分とする医薬。
- 請求項1~7いずれか1項記載の化合物またはその薬理学的に許容される塩を有効成分とする、炎症性腸疾患治療剤。
- 炎症性腸疾患が、潰瘍性大腸炎またはクローン病である、請求項9記載の治療剤。
- 請求項1~7いずれか1項記載の化合物またはその薬理学的に許容される塩を有効成分とする、フラクタルカイン-CX3CR1経路の阻害剤。
- 請求項1~7いずれか1項記載の化合物またはその薬理学的に許容される塩を有効成分とする、フラクタルカイン阻害剤。
- 請求項1~7いずれか1項記載の化合物またはその薬理学的に許容される塩を有効成分とする、CX3CR1阻害剤。
Priority Applications (23)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
RU2014107536A RU2615135C2 (ru) | 2011-09-13 | 2012-09-11 | Производное пирролидин-3-илуксусной кислоты |
DK12831085.1T DK2757103T3 (en) | 2011-09-13 | 2012-09-11 | Pyrrolidin-3-yl-acetic acid derivative |
EP12831085.1A EP2757103B1 (en) | 2011-09-13 | 2012-09-11 | Pyrrolidine-3-ylacetic acid derivative |
MEP-2016-37A ME02383B (me) | 2011-09-13 | 2012-09-11 | Derivat pirolidin-3-ilsirćetne kiseline |
CN201280041634.0A CN103764648B (zh) | 2011-09-13 | 2012-09-11 | 吡咯烷-3-基乙酸衍生物 |
SI201230463T SI2757103T1 (sl) | 2011-09-13 | 2012-09-11 | Derivati pirolidin-3-ilocetne kisline |
BR112014004267-5A BR112014004267B1 (pt) | 2011-09-13 | 2012-09-11 | Derivado de ácido pirrolidina-3-ilacético |
JP2013533669A JP5829689B2 (ja) | 2011-09-13 | 2012-09-11 | ピロリジン−3−イル酢酸誘導体 |
CA2844617A CA2844617C (en) | 2011-09-13 | 2012-09-11 | Pyrrolidine-3-ylacetic acid derivative |
SG11201400163WA SG11201400163WA (en) | 2011-09-13 | 2012-09-11 | Pyrrolidine-3-ylacetic acid derivative |
ES12831085.1T ES2564732T3 (es) | 2011-09-13 | 2012-09-11 | Derivado de ácido pirrolidin-3-ilacético |
PL12831085T PL2757103T3 (pl) | 2011-09-13 | 2012-09-11 | Pochodna kwasu pirolidyn-3-ylooctowego |
RS20160106A RS54582B1 (en) | 2011-09-13 | 2012-09-11 | PYROLIDINE-3-ILSIRCETIC ACID DERIVATIVE |
NZ620469A NZ620469B2 (en) | 2011-09-13 | 2012-09-11 | Pyrrolidine-3-ylacetic acid derivative |
AU2012309556A AU2012309556B2 (en) | 2011-09-13 | 2012-09-11 | Pyrrolidine-3-ylacetic acid derivative |
KR1020147003630A KR101963922B1 (ko) | 2011-09-13 | 2012-09-11 | 피롤리딘-3-일 아세트산 유도체 |
MX2014002210A MX358494B (es) | 2011-09-13 | 2012-09-11 | Derivado de acido pirrolidin-3-ilacetico. |
UAA201401661A UA112873C2 (uk) | 2011-09-13 | 2012-11-09 | Похідна піролідин-3-ілоцтової кислоти |
IL230804A IL230804A (en) | 2011-09-13 | 2014-02-03 | Annals of pyrrolidine-3-acetic acid ram and medical components for the treatment of inflammatory bowel disease |
ZA2014/00918A ZA201400918B (en) | 2011-09-13 | 2014-02-06 | Pyrrolidine-3-ylacetic acid derivative |
HK14106800.1A HK1193407A1 (en) | 2011-09-13 | 2014-07-04 | Pyrrolidine-3-ylacetic acid derivative -3- |
HRP20160166TT HRP20160166T1 (hr) | 2011-09-13 | 2016-02-16 | Derivat pirolidin-3-iloctene kiseline |
SM201600071T SMT201600071B (it) | 2011-09-13 | 2016-03-10 | Derivato di acido pirrolidina-3-ilacetico |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2011199482 | 2011-09-13 | ||
JP2011-199482 | 2011-09-13 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2013039057A1 true WO2013039057A1 (ja) | 2013-03-21 |
Family
ID=47883287
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2012/073171 WO2013039057A1 (ja) | 2011-09-13 | 2012-09-11 | ピロリジン-3-イル酢酸誘導体 |
Country Status (32)
Country | Link |
---|---|
EP (1) | EP2757103B1 (ja) |
JP (1) | JP5829689B2 (ja) |
KR (1) | KR101963922B1 (ja) |
CN (1) | CN103764648B (ja) |
AR (1) | AR087788A1 (ja) |
AU (1) | AU2012309556B2 (ja) |
BR (1) | BR112014004267B1 (ja) |
CA (1) | CA2844617C (ja) |
CL (1) | CL2014000484A1 (ja) |
CY (1) | CY1117460T1 (ja) |
DK (1) | DK2757103T3 (ja) |
ES (1) | ES2564732T3 (ja) |
HK (1) | HK1193407A1 (ja) |
HR (1) | HRP20160166T1 (ja) |
HU (1) | HUE026824T2 (ja) |
IL (1) | IL230804A (ja) |
JO (1) | JO3082B1 (ja) |
ME (1) | ME02383B (ja) |
MX (1) | MX358494B (ja) |
MY (1) | MY169869A (ja) |
PE (1) | PE20141353A1 (ja) |
PL (1) | PL2757103T3 (ja) |
PT (1) | PT2757103E (ja) |
RS (1) | RS54582B1 (ja) |
RU (1) | RU2615135C2 (ja) |
SG (1) | SG11201400163WA (ja) |
SI (1) | SI2757103T1 (ja) |
SM (1) | SMT201600071B (ja) |
TW (1) | TWI543975B (ja) |
UA (1) | UA112873C2 (ja) |
WO (1) | WO2013039057A1 (ja) |
ZA (1) | ZA201400918B (ja) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2014142056A1 (ja) * | 2013-03-12 | 2014-09-18 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | ピロリジン-3-イル酢酸誘導体の塩およびその結晶 |
WO2014142086A1 (ja) * | 2013-03-13 | 2014-09-18 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | ピロリジン-3-イル酢酸誘導体およびピペリジン-3-イル酢酸誘導体 |
WO2024083933A1 (en) | 2022-10-19 | 2024-04-25 | Astrazeneca Ab | 2,4,6-trisubstituted 1,3,5-triazines as modulators of cx 3cr1 |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20050143372A1 (en) * | 2001-10-30 | 2005-06-30 | Shomir Ghosh | Compounds, pharmaceutical compositions and methods of use therefor |
JP2007507494A (ja) * | 2003-10-07 | 2007-03-29 | アストラゼネカ・アクチエボラーグ | ケモカイン受容体アンタゴニストとりわけCX3CR1として有用な新規な2−置換4−アミノ−チアゾロ[4,5−d]ピリミジン |
JP2008535834A (ja) * | 2005-04-06 | 2008-09-04 | アストラゼネカ・アクチエボラーグ | 新規な5,7−二置換された[1,3]チアゾロ[4,5−d]ピリミジン−2(3h)−オン誘導体 |
US20100210633A1 (en) * | 2006-10-12 | 2010-08-19 | Epix Delaware, Inc. | Carboxamide compounds and their use |
JP2011513371A (ja) * | 2008-03-07 | 2011-04-28 | アジェンデ・キミケ・リウニテ・アンジェリニ・フランチェスコ・ア・チ・エレ・ア・エフェ・ソシエタ・ペル・アチオニ | 新規な1−ベンジル−3−ヒドロキシメチルインダゾール誘導体およびそのmcp−1およびcx3cr1の発現に基づく疾患の治療への使用 |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP4263391B2 (ja) | 2001-03-19 | 2009-05-13 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | 抗cx3cr1抗体、抗フラクタルカイン抗体及びフラクタルカインの利用 |
UA90707C2 (en) | 2005-04-06 | 2010-05-25 | Астразенека Аб | Novel 5-substituted 7-amino-[1,3]thiazolo[4,5-d]pyrimidine derivatives |
TW200820973A (en) | 2006-09-29 | 2008-05-16 | Astrazeneca Ab | Novel compounds 480 |
CN101522693B (zh) | 2006-09-29 | 2012-01-04 | 阿斯利康(瑞典)有限公司 | 5,7-二取代的[1,3]噻唑并[4,5-d]嘧啶-2(3h)-胺衍生物和它们在治疗中的用途 |
AR071036A1 (es) | 2008-03-26 | 2010-05-19 | Astrazeneca Ab | Derivados 5, 7-disustituidos de [1, 3]tiazolo[4, 5-d]pirimidin-2 (3h)-ona, una composicion farmaceutica que los comprende y su uso en el tratamiento de enfermedades mediadas por el receptor cx3cr1. |
-
2012
- 2012-09-05 TW TW101132401A patent/TWI543975B/zh not_active IP Right Cessation
- 2012-09-05 JO JOP/2012/0251A patent/JO3082B1/ar active
- 2012-09-06 AR ARP120103280A patent/AR087788A1/es active IP Right Grant
- 2012-09-11 RU RU2014107536A patent/RU2615135C2/ru active
- 2012-09-11 KR KR1020147003630A patent/KR101963922B1/ko active IP Right Grant
- 2012-09-11 AU AU2012309556A patent/AU2012309556B2/en not_active Ceased
- 2012-09-11 CN CN201280041634.0A patent/CN103764648B/zh active Active
- 2012-09-11 JP JP2013533669A patent/JP5829689B2/ja active Active
- 2012-09-11 ME MEP-2016-37A patent/ME02383B/me unknown
- 2012-09-11 MY MYPI2014700213A patent/MY169869A/en unknown
- 2012-09-11 SG SG11201400163WA patent/SG11201400163WA/en unknown
- 2012-09-11 WO PCT/JP2012/073171 patent/WO2013039057A1/ja active Application Filing
- 2012-09-11 EP EP12831085.1A patent/EP2757103B1/en active Active
- 2012-09-11 PE PE2014000266A patent/PE20141353A1/es active IP Right Grant
- 2012-09-11 BR BR112014004267-5A patent/BR112014004267B1/pt active IP Right Grant
- 2012-09-11 PL PL12831085T patent/PL2757103T3/pl unknown
- 2012-09-11 DK DK12831085.1T patent/DK2757103T3/en active
- 2012-09-11 RS RS20160106A patent/RS54582B1/en unknown
- 2012-09-11 HU HUE12831085A patent/HUE026824T2/en unknown
- 2012-09-11 PT PT128310851T patent/PT2757103E/pt unknown
- 2012-09-11 SI SI201230463T patent/SI2757103T1/sl unknown
- 2012-09-11 MX MX2014002210A patent/MX358494B/es active IP Right Grant
- 2012-09-11 ES ES12831085.1T patent/ES2564732T3/es active Active
- 2012-09-11 CA CA2844617A patent/CA2844617C/en active Active
- 2012-11-09 UA UAA201401661A patent/UA112873C2/uk unknown
-
2014
- 2014-02-03 IL IL230804A patent/IL230804A/en active IP Right Grant
- 2014-02-06 ZA ZA2014/00918A patent/ZA201400918B/en unknown
- 2014-02-27 CL CL2014000484A patent/CL2014000484A1/es unknown
- 2014-07-04 HK HK14106800.1A patent/HK1193407A1/xx not_active IP Right Cessation
-
2016
- 2016-02-16 HR HRP20160166TT patent/HRP20160166T1/hr unknown
- 2016-03-10 SM SM201600071T patent/SMT201600071B/xx unknown
- 2016-03-16 CY CY20161100224T patent/CY1117460T1/el unknown
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20050143372A1 (en) * | 2001-10-30 | 2005-06-30 | Shomir Ghosh | Compounds, pharmaceutical compositions and methods of use therefor |
JP2007507494A (ja) * | 2003-10-07 | 2007-03-29 | アストラゼネカ・アクチエボラーグ | ケモカイン受容体アンタゴニストとりわけCX3CR1として有用な新規な2−置換4−アミノ−チアゾロ[4,5−d]ピリミジン |
JP2008535834A (ja) * | 2005-04-06 | 2008-09-04 | アストラゼネカ・アクチエボラーグ | 新規な5,7−二置換された[1,3]チアゾロ[4,5−d]ピリミジン−2(3h)−オン誘導体 |
US20100210633A1 (en) * | 2006-10-12 | 2010-08-19 | Epix Delaware, Inc. | Carboxamide compounds and their use |
JP2011513371A (ja) * | 2008-03-07 | 2011-04-28 | アジェンデ・キミケ・リウニテ・アンジェリニ・フランチェスコ・ア・チ・エレ・ア・エフェ・ソシエタ・ペル・アチオニ | 新規な1−ベンジル−3−ヒドロキシメチルインダゾール誘導体およびそのmcp−1およびcx3cr1の発現に基づく疾患の治療への使用 |
Non-Patent Citations (1)
Title |
---|
See also references of EP2757103A4 * |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2014142056A1 (ja) * | 2013-03-12 | 2014-09-18 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | ピロリジン-3-イル酢酸誘導体の塩およびその結晶 |
JP5872105B2 (ja) * | 2013-03-12 | 2016-03-01 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | ピロリジン−3−イル酢酸誘導体の塩およびその結晶 |
US9550732B2 (en) | 2013-03-12 | 2017-01-24 | Eisai R&D Management Co., Ltd. | Salt of pyrrolidin-3-yl acetic acid derivative and crystals thereof |
AU2014231863B2 (en) * | 2013-03-12 | 2017-07-27 | Eisai R&D Management Co., Ltd. | Salt of pyrrolidin-3-yl acetic acid derivative and crystals thereof |
WO2014142086A1 (ja) * | 2013-03-13 | 2014-09-18 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | ピロリジン-3-イル酢酸誘導体およびピペリジン-3-イル酢酸誘導体 |
WO2024083933A1 (en) | 2022-10-19 | 2024-04-25 | Astrazeneca Ab | 2,4,6-trisubstituted 1,3,5-triazines as modulators of cx 3cr1 |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6212644B2 (ja) | フェノキシエチル環状アミン誘導体およびep4受容体モジュレーターとしてのその活性 | |
EA034015B1 (ru) | Модуляторы р2х7 | |
JP5829689B2 (ja) | ピロリジン−3−イル酢酸誘導体 | |
KR101378260B1 (ko) | 세로토닌 및 노르에피네프린 재흡수 억제제 | |
US8476301B2 (en) | Pyrrolidin-3-ylacetic acid derivative | |
JP5872105B2 (ja) | ピロリジン−3−イル酢酸誘導体の塩およびその結晶 | |
WO2015092804A1 (en) | Indazole compounds as 5-ht4 receptor agonists | |
KR102553613B1 (ko) | 페닐디플루오로메틸 치환 프롤린아미드 화합물 | |
WO2014142086A1 (ja) | ピロリジン-3-イル酢酸誘導体およびピペリジン-3-イル酢酸誘導体 | |
EP2976337A1 (en) | 5-amino-quinoline-8-carboxamide derivatives as 5-ht4 receptor agonists | |
US9371311B2 (en) | Benzoimidazol-2-yl pyrimidine derivatives | |
CN103228644A (zh) | Ccr2的4-取代-环己基氨基-4-哌啶基-乙酰胺拮抗剂 | |
NZ620469B2 (en) | Pyrrolidine-3-ylacetic acid derivative | |
JP2006056830A (ja) | 2−アリールアミノベンゾオキサゾール誘導体 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 12831085 Country of ref document: EP Kind code of ref document: A1 |
|
ENP | Entry into the national phase |
Ref document number: 2013533669 Country of ref document: JP Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 230804 Country of ref document: IL |
|
ENP | Entry into the national phase |
Ref document number: 2844617 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2012831085 Country of ref document: EP |
|
ENP | Entry into the national phase |
Ref document number: 20147003630 Country of ref document: KR Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: A201401661 Country of ref document: UA |
|
WWE | Wipo information: entry into national phase |
Ref document number: MX/A/2014/002210 Country of ref document: MX |
|
WWE | Wipo information: entry into national phase |
Ref document number: 000266-2014 Country of ref document: PE |
|
ENP | Entry into the national phase |
Ref document number: 2012309556 Country of ref document: AU Date of ref document: 20120911 Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2014000484 Country of ref document: CL |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
ENP | Entry into the national phase |
Ref document number: 2014107536 Country of ref document: RU Kind code of ref document: A |
|
REG | Reference to national code |
Ref country code: BR Ref legal event code: B01A Ref document number: 112014004267 Country of ref document: BR |
|
WWE | Wipo information: entry into national phase |
Ref document number: P-2016/0106 Country of ref document: RS |
|
ENP | Entry into the national phase |
Ref document number: 112014004267 Country of ref document: BR Kind code of ref document: A2 Effective date: 20140224 |