CN102026961B - 酰胺化合物 - Google Patents
酰胺化合物 Download PDFInfo
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- CN102026961B CN102026961B CN200980117392.7A CN200980117392A CN102026961B CN 102026961 B CN102026961 B CN 102026961B CN 200980117392 A CN200980117392 A CN 200980117392A CN 102026961 B CN102026961 B CN 102026961B
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- Prior art keywords
- compound
- salt
- add
- methyl
- acid
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- -1 Amide compound Chemical class 0.000 title abstract description 56
- 150000001875 compounds Chemical class 0.000 claims abstract description 204
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 21
- 208000020832 chronic kidney disease Diseases 0.000 claims abstract description 19
- 208000022831 chronic renal failure syndrome Diseases 0.000 claims abstract description 19
- 208000007342 Diabetic Nephropathies Diseases 0.000 claims abstract description 17
- 208000033679 diabetic kidney disease Diseases 0.000 claims abstract description 17
- 150000003839 salts Chemical class 0.000 claims description 134
- 238000002360 preparation method Methods 0.000 claims description 123
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 70
- NZNMSOFKMUBTKW-UHFFFAOYSA-N cyclohexanecarboxylic acid Chemical compound OC(=O)C1CCCCC1 NZNMSOFKMUBTKW-UHFFFAOYSA-N 0.000 claims description 43
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 35
- AWJUIBRHMBBTKR-UHFFFAOYSA-N iso-quinoline Natural products C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 claims description 26
- 101150109738 Ptger4 gene Proteins 0.000 abstract description 22
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 15
- 201000010099 disease Diseases 0.000 abstract description 13
- 230000003042 antagnostic effect Effects 0.000 abstract description 5
- 239000004480 active ingredient Substances 0.000 abstract 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 187
- 235000002639 sodium chloride Nutrition 0.000 description 124
- 238000003756 stirring Methods 0.000 description 124
- 239000000203 mixture Substances 0.000 description 112
- 230000002829 reductive effect Effects 0.000 description 110
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 104
- 239000011541 reaction mixture Substances 0.000 description 97
- 239000000243 solution Substances 0.000 description 83
- 229920002554 vinyl polymer Polymers 0.000 description 79
- 239000000178 monomer Substances 0.000 description 76
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 73
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 69
- 239000002585 base Substances 0.000 description 68
- 239000012044 organic layer Substances 0.000 description 65
- 238000001816 cooling Methods 0.000 description 63
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 62
- 238000001035 drying Methods 0.000 description 62
- 238000005406 washing Methods 0.000 description 61
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 60
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 59
- 238000010898 silica gel chromatography Methods 0.000 description 55
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 50
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 48
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 45
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 45
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 41
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 39
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 38
- 238000003810 ethyl acetate extraction Methods 0.000 description 36
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 33
- 238000000034 method Methods 0.000 description 32
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 31
- 239000000706 filtrate Substances 0.000 description 31
- 239000007787 solid Substances 0.000 description 31
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 31
- 238000006243 chemical reaction Methods 0.000 description 30
- 125000000623 heterocyclic group Chemical group 0.000 description 28
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 26
- XEYBRNLFEZDVAW-ARSRFYASSA-N dinoprostone Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 description 25
- 229960002986 dinoprostone Drugs 0.000 description 25
- XEYBRNLFEZDVAW-UHFFFAOYSA-N prostaglandin E2 Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CC=CCCCC(O)=O XEYBRNLFEZDVAW-UHFFFAOYSA-N 0.000 description 25
- 238000004519 manufacturing process Methods 0.000 description 23
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 23
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 22
- 229940095102 methyl benzoate Drugs 0.000 description 22
- 238000012360 testing method Methods 0.000 description 22
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 20
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 20
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 18
- 210000004027 cell Anatomy 0.000 description 18
- 229910052736 halogen Inorganic materials 0.000 description 18
- 150000002367 halogens Chemical class 0.000 description 18
- 241000700159 Rattus Species 0.000 description 17
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 17
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 16
- 239000002253 acid Substances 0.000 description 16
- 239000003795 chemical substances by application Substances 0.000 description 16
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- 238000001914 filtration Methods 0.000 description 15
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 14
- 239000012298 atmosphere Substances 0.000 description 14
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
- 235000015320 potassium carbonate Nutrition 0.000 description 14
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 13
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 13
- 229910052786 argon Inorganic materials 0.000 description 13
- 239000007789 gas Substances 0.000 description 13
- 238000010025 steaming Methods 0.000 description 12
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 11
- 239000002994 raw material Substances 0.000 description 11
- 125000000217 alkyl group Chemical group 0.000 description 10
- 239000010410 layer Substances 0.000 description 10
- 229910052757 nitrogen Inorganic materials 0.000 description 10
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 10
- 239000002464 receptor antagonist Substances 0.000 description 10
- 229940044551 receptor antagonist Drugs 0.000 description 10
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 10
- 239000000470 constituent Substances 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 9
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 9
- 150000002500 ions Chemical class 0.000 description 9
- 239000007788 liquid Substances 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 9
- 125000004433 nitrogen atom Chemical group N* 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- 210000002700 urine Anatomy 0.000 description 9
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 8
- 150000003851 azoles Chemical class 0.000 description 8
- 238000000605 extraction Methods 0.000 description 8
- 229910052731 fluorine Inorganic materials 0.000 description 8
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 8
- 125000005956 isoquinolyl group Chemical group 0.000 description 8
- NTLQYGLYWYSUIK-UHFFFAOYSA-N 1-chloroindole-7-carboxylic acid Chemical compound OC(=O)C1=CC=CC2=C1N(Cl)C=C2 NTLQYGLYWYSUIK-UHFFFAOYSA-N 0.000 description 7
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 7
- 235000011054 acetic acid Nutrition 0.000 description 7
- 230000008485 antagonism Effects 0.000 description 7
- 229910052794 bromium Inorganic materials 0.000 description 7
- 125000004122 cyclic group Chemical group 0.000 description 7
- 239000011737 fluorine Substances 0.000 description 7
- MZDGXTXYHXDWIM-UHFFFAOYSA-N methyl benzoate;hydrochloride Chemical compound Cl.COC(=O)C1=CC=CC=C1 MZDGXTXYHXDWIM-UHFFFAOYSA-N 0.000 description 7
- 150000003053 piperidines Chemical class 0.000 description 7
- 125000006239 protecting group Chemical group 0.000 description 7
- 125000005493 quinolyl group Chemical group 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 150000001335 aliphatic alkanes Chemical class 0.000 description 6
- 239000003513 alkali Substances 0.000 description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 6
- 239000000460 chlorine Substances 0.000 description 6
- 229910052801 chlorine Inorganic materials 0.000 description 6
- 239000006185 dispersion Substances 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 239000000284 extract Substances 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- ZQWPRMPSCMSAJU-UHFFFAOYSA-N methyl cyclohexanecarboxylate Chemical class COC(=O)C1CCCCC1 ZQWPRMPSCMSAJU-UHFFFAOYSA-N 0.000 description 6
- 230000003287 optical effect Effects 0.000 description 6
- 239000001301 oxygen Substances 0.000 description 6
- 229910052760 oxygen Inorganic materials 0.000 description 6
- 239000002953 phosphate buffered saline Substances 0.000 description 6
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 6
- HBENZIXOGRCSQN-VQWWACLZSA-N (1S,2S,6R,14R,15R,16R)-5-(cyclopropylmethyl)-16-[(2S)-2-hydroxy-3,3-dimethylpentan-2-yl]-15-methoxy-13-oxa-5-azahexacyclo[13.2.2.12,8.01,6.02,14.012,20]icosa-8(20),9,11-trien-11-ol Chemical compound N1([C@@H]2CC=3C4=C(C(=CC=3)O)O[C@H]3[C@@]5(OC)CC[C@@]2([C@@]43CC1)C[C@@H]5[C@](C)(O)C(C)(C)CC)CC1CC1 HBENZIXOGRCSQN-VQWWACLZSA-N 0.000 description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 5
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- 125000003118 aryl group Chemical group 0.000 description 5
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 5
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 5
- 239000000872 buffer Substances 0.000 description 5
- 229910002091 carbon monoxide Inorganic materials 0.000 description 5
- 238000004113 cell culture Methods 0.000 description 5
- 125000000753 cycloalkyl group Chemical group 0.000 description 5
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 5
- 230000018044 dehydration Effects 0.000 description 5
- 238000006297 dehydration reaction Methods 0.000 description 5
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 125000004494 ethyl ester group Chemical group 0.000 description 5
- 239000012634 fragment Substances 0.000 description 5
- 125000001072 heteroaryl group Chemical group 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 5
- 150000002475 indoles Chemical class 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 210000004379 membrane Anatomy 0.000 description 5
- 239000012528 membrane Substances 0.000 description 5
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 5
- 239000011259 mixed solution Substances 0.000 description 5
- 125000002950 monocyclic group Chemical group 0.000 description 5
- 210000004400 mucous membrane Anatomy 0.000 description 5
- 229910052763 palladium Inorganic materials 0.000 description 5
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 5
- 239000012266 salt solution Substances 0.000 description 5
- 238000000926 separation method Methods 0.000 description 5
- 239000012312 sodium hydride Substances 0.000 description 5
- 229910000104 sodium hydride Inorganic materials 0.000 description 5
- XHFLOLLMZOTPSM-UHFFFAOYSA-M sodium;hydrogen carbonate;hydrate Chemical class [OH-].[Na+].OC(O)=O XHFLOLLMZOTPSM-UHFFFAOYSA-M 0.000 description 5
- 125000001424 substituent group Chemical group 0.000 description 5
- 229910052720 vanadium Inorganic materials 0.000 description 5
- WLWNRAWQDZRXMB-YLFCFFPRSA-N (2r,3r,4r,5s)-n,3,4,5-tetrahydroxy-1-(4-phenoxyphenyl)sulfonylpiperidine-2-carboxamide Chemical compound ONC(=O)[C@H]1[C@@H](O)[C@H](O)[C@@H](O)CN1S(=O)(=O)C(C=C1)=CC=C1OC1=CC=CC=C1 WLWNRAWQDZRXMB-YLFCFFPRSA-N 0.000 description 4
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 4
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 4
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 4
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 4
- 206010061218 Inflammation Diseases 0.000 description 4
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 4
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 4
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 4
- 239000000654 additive Substances 0.000 description 4
- 230000000996 additive effect Effects 0.000 description 4
- 235000019270 ammonium chloride Nutrition 0.000 description 4
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 238000011156 evaluation Methods 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 150000002460 imidazoles Chemical class 0.000 description 4
- 229960000905 indomethacin Drugs 0.000 description 4
- 230000004054 inflammatory process Effects 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 229910052500 inorganic mineral Inorganic materials 0.000 description 4
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 4
- 210000003734 kidney Anatomy 0.000 description 4
- 239000012139 lysis buffer Substances 0.000 description 4
- FTLOEULOTNVCGF-UHFFFAOYSA-N methyl 1h-indole-7-carboxylate Chemical class COC(=O)C1=CC=CC2=C1NC=C2 FTLOEULOTNVCGF-UHFFFAOYSA-N 0.000 description 4
- 235000010755 mineral Nutrition 0.000 description 4
- 239000011707 mineral Substances 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- 210000002381 plasma Anatomy 0.000 description 4
- 230000003449 preventive effect Effects 0.000 description 4
- 239000000651 prodrug Substances 0.000 description 4
- 229940002612 prodrug Drugs 0.000 description 4
- 125000004076 pyridyl group Chemical group 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 125000006413 ring segment Chemical group 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 125000003107 substituted aryl group Chemical group 0.000 description 4
- 239000000375 suspending agent Substances 0.000 description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 4
- 239000003981 vehicle Substances 0.000 description 4
- 238000010792 warming Methods 0.000 description 4
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- QGMRQYFBGABWDR-UHFFFAOYSA-N sodium;5-ethyl-5-pentan-2-yl-1,3-diazinane-2,4,6-trione Chemical compound [Na+].CCCC(C)C1(CC)C(=O)NC(=O)NC1=O QGMRQYFBGABWDR-UHFFFAOYSA-N 0.000 description 1
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- 230000009870 specific binding Effects 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 150000004867 thiadiazoles Chemical class 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000004305 thiazinyl group Chemical group S1NC(=CC=C1)* 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 210000001519 tissue Anatomy 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
- 150000003613 toluenes Chemical class 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- CWMFRHBXRUITQE-UHFFFAOYSA-N trimethylsilylacetylene Chemical compound C[Si](C)(C)C#C CWMFRHBXRUITQE-UHFFFAOYSA-N 0.000 description 1
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- 230000036269 ulceration Effects 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
Classifications
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- C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
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Abstract
本发明提供一种化合物,该化合物可用作药物组合物(例如,用于治疗慢性肾功能衰竭和/或糖尿病肾病的药物组合物)的有效成分。本发明人对具有EP4受体拮抗作用的化合物进行了深入研究,结果确认本发明的酰胺化合物具有EP4受体拮抗作用,从而完成本发明。本发明的酰胺化合物具有EP4受体拮抗作用,其可用作预防和/或治疗与EP4有关的各种疾病的药物组合物的有效成分,其中所述与EP4有关的各种疾病为(例如)慢性肾功能衰竭和/或糖尿病性肾病。
Description
技术领域
本发明涉及一种酰胺化合物,该化合物可用作药物组合物(例如,用于治疗慢性肾功能衰竭和/或糖尿病肾病的药物组合物)的有效成分。
背景技术
已知前列腺素E2(在下文中称为“PGE2”)是花生四烯酸发生级联代谢物之一。PGE2显示出多种活性,可以列举(例如)疼痛增强作用、炎症促进作用、炎症抑制作用、子宫收缩作用、消化道蠕动运动促进作用、催醒作用、抑制胃酸分泌作用、降低血压作用、抑制血小板凝集作用、促进骨的再吸收作用、血管新生作用等。
PGE2的受体存在EP1、EP2、EP3和EP4四种亚型,它们广泛分布在各种组织中。据认为,EP1受体的激活会引起细胞内Ca2+的增加。EP3受体是具有不同的第二信使系统途径的受体之一。据认为,EP2和EP4受体的激活会引起腺苷酸环化酶的激活,从而使细胞内的cAMP水平增加。特别是EP4受体与平滑肌的弛缓、炎症反应的促进或抑制、淋巴细胞的分化、系膜细胞的肥大或增殖、胃肠粘液的分泌等有关。
PGE2受体的抑制剂,即PGE2拮抗剂,对PGE2受体具有结合活性。也就是说,PGE2拮抗剂显示出PGE2拮抗活性或PGE2抑制活性。因此,人们期待PGE2拮抗剂用作治疗由PGE2导致的疾病的药品。其中,人们期待EP4受体拮抗剂用作针对人体和动物的与EP4有关的疾病(例如肾病、炎症性疾病、各种疼痛等)的治疗药。此外,从避免基于其它EP1、EP2和EP3的亚型的副作用的观点考虑,希望为EP4受体拮抗剂。
作为EP4受体拮抗剂,已知下式所示的化合物(专利文献1)。
[式1]
(式中的符号参见相应的专利文献。)
此外,作为EP4受体配体,已知下式所示的化合物(专利文献2)。
[式2]
(式中的符号参见相应的专利文献。)
此外,作为EP4受体拮抗剂,已知下式所示的化合物(专利文献3)。另外,该文献是本申请优先权日之后公开的文献。
[式3]
(式中的符号参见相应的专利文献。)
此外,作为EP4受体拮抗剂,已知下式所示的化合物(专利文献4)。
[式4]
(式中的符号参见相应的专利文献。)
此外,作为EP4受体拮抗剂,已知下式所示的化合物(专利文献5)。
[式5]
(式中的符号参见相应的专利文献。)
此外,作为EP4受体拮抗剂,已知下式所示的化合物(专利文献6)。
[式6]
(式中的符号参见相应的专利文献。)
此外,作为EP4受体配体,已知下式所示的化合物(专利文献7)。
[式7]
(式中的符号参见相应的专利文献。)
此外,作为EP3和/或EP4受体拮抗剂,已知下式所示的化合物(专利文献8)。
[式8]
(式中的符号参见相应的专利文献。)
此外,作为EP4受体阻滞剂,已知下式所示的化合物(专利文献9)。
[式9]
(式中的符号参见相应的专利文献。)
此外,作为EP4受体拮抗剂,已知下式所示的化合物(专利文献10)。
[式10]
(式中的符号参见相应的专利文献。)
此外,作为EP4受体拮抗剂,已知下式所示的化合物(专利文献11)。另外,该文献是本申请优先权日之后公开的文献。
[式11]
(式中的符号参见相应的专利文献。)
在先技术文献
专利文献
专利文献1:国际公开第WO 2007/121578号小册子
专利文献2:国际公开第WO 2007/143825号小册子
专利文献3:国际公开第WO 2008/104055号小册子
专利文献4:国际公开第WO 2005/021508号小册子
专利文献5:国际公开第WO 2005/105732号小册子
专利文献6:国际公开第WO 2005/105733号小册子
专利文献7:国际公开第WO 2008/017164号小册子
专利文献8:国际公开第WO 03/016254号小册子
专利文献9:国际公开第WO 2005/061475号小册子
专利文献10:国际公开第WO 2008/123207号小册子
专利文献11:国际公开第WO 2009/005076号小册子
发明概述
发明所要解决的问题
本发明提供一种化合物,该化合物可用作药物组合物(例如, 用于治疗慢性肾功能衰竭和/或糖尿病肾病的药物组合物)的有效成分。
解决问题所采用的手段
本发明人对具有EP4受体拮抗作用的化合物进行了深入研究,结果发现式(I)所示的化合物显示出优异的有效性,从而完成本发明。
即,本发明涉及式(1)所示的化合物或其盐、以及含有式(1)所示的化合物或其盐以及可药用的赋形剂的药物组合物。
[式12]
(式中,
环D为式(II)、式(III)、式(IV)、式(V)、或者式(VI)的基团,
[式13]
环D1为可被苯基取代的单环或双环式含氮杂环,
环D2为芳基、杂环、或C3-10环烷基,
R41、R42、R43和R44相同或不同,分别为-X2-B4,
R45为-X1-B5,
R46为-H、卤素、可被一个以上的卤素取代的C1-6烷基、或者 -O-C1-6烷基,
V和W相同或不同,为CH或N,但是,不能同时为N,
X1为键、C1-6亚烷基、(C1-6亚烷基)-CONH-、(C1-6亚烷基)-O-、(C1-6亚烷基)-O-(C1-6亚烷基)、或C2-6亚烯基,
X2为键、C1-6亚烷基、(C1-6亚烷基)-CONH-、(C1-6亚烷基)-O-、(C1-6亚烷基)-O-(C1-6亚烷基)、C2-6亚烯基、-O-、-S-、-NH-、-N(C1-6亚烷基)-、-N(C1-6亚烷基)-(C1-6亚烷基)、或-O-(C1-6亚烷基),
B4为可以分别被选自R4中的1~5个相同或不同的基团取代的芳基、杂环、或C3-10环烷基,
R4为由卤素、-OH、-O-(C1-6烷基)、-O-(C1-6亚烷基)-O-(C1-6烷基)、可被取代的芳基、可被取代的杂环、(C1-6亚烷基)-芳基、(C1-6亚烷基)-杂环、-O-(C1-6亚烷基)-芳基和-O-(C1-6亚烷基)-杂环构成的组,
B5表示(i)可被选自由卤素和C1-6烷基构成的组中的1个以上的基团取代的双环式杂环、或者(ii)可以分别被选自由R5中的1~5个相同或不同的基团取代的单环式芳基、单环式杂环、或C3-10单环式环烷基,
R5为由卤素、-OH、-O-(C1-6烷基)、-O-(C1-6亚烷基)-O-(C1-6烷基)、可被取代的芳基、可被取代的杂环、(C1-6亚烷基)-芳基、(C1-6亚烷基)-杂环、-O-(C1-6亚烷基)-芳基、以及-O-(C1-6亚烷基)-杂环构成的组,但是,在X1为键、亚甲基、或亚乙基,Y为CH,R2为甲基,环E为亚苯基,Z为键,R3为-CO2H的情况下,R5为-OH、-O-(C1-6烷基)、-O-(C1-6亚烷基)-O-(C1-6烷基)、可被取代的芳基、可被取代的杂环、(C1-6亚烷基)-芳基、(C1-6亚烷基)-杂环、-O-(C1-6亚烷基)-芳基、以及-O-(C1-6亚烷基)-杂环构成的组,
环E为亚苯基、或C5-7亚环烷基,
R1和R2相同或不同,为H、或C1-6烷基,但是,在R5为可被取代的双环式杂环的情况下,R2为-H,
Y为CH、或N,
Z为键、或C1-6亚烷基,
R3为-CO2H、或者其生物电子等排体,
但是,在环D为可被取代的苯基或者可被取代的吡啶基、Y为CH、且Z为键的情况下,R3表示除了-CO2H、四唑基、以及磺酰胺基之外的基团。)
而且,只要没有特别指出,在本说明书中,当某一化学式中的符号也用于其他的化学式中时,相同的符号表示相同的意思。
此外,本发明涉及一种含有式(I)所示的化合物或其盐的、用于预防或治疗慢性肾功能衰竭和/或糖尿病性肾病的药物组合物。另外,该药物组合物包含含有式(I)所示的化合物或其塩的、慢性肾功能衰竭和/或糖尿病肾病的预防剂或治疗剤。
另外,本发明还涉及式(I)所示的化合物或其盐在制备用于预防或治疗慢性肾功能衰竭或糖尿病肾病药物组合物中的用途、用于预防或治疗慢性肾功能衰竭或糖尿病肾病的式(I)所示的化合物或其盐、并且涉及一种治疗慢性肾功能衰竭或糖尿病肾病的方法,该方法包括给对象施用有效量的式(I)所示的化合物或其盐。另外,“对象”是指需要预防或治疗上述疾病的人类或其它动物,作为一种实施方式,为需要预防或治疗上述疾病的人类。
发明效果
式(I)所示的化合物或其盐具有EP4受体拮抗作用,因此可用作预防或治疗慢性肾功能衰竭和/或糖尿病性肾病的药物组合物的有效成分。
本发明的实施方式
以下对本发明进行详细说明。
本说明书中,术语“烷基”包含的直链或支链烷基。因此,术语“C1-6烷基”为碳原子数为1~6个的直链或支链烷基,具体来说,例如为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、正己基等。作为一种实施方式,为甲基、乙基、正丙基、异丙基,作为其他实施方式,为甲基、乙基,进一步作为其他实施方式,为甲基。
术语“亚烷基”表示将上述“烷基”中的任意一个氢原子除去后形成的二价基团。因此,“C1-6亚烷基”为碳原子数为1~6个的直链或支链亚烷基,具体来说,例如为亚甲基、亚乙基、三亚甲基等,作为其他实施方式,为亚甲基。
术语“亚烯基”为上述“亚烷基”中的任意一个以上的单键为双键的二价基团,因此,“C2-6亚烯基”为碳原子数为2~6个的直链或支链亚烯基,具体来说,例如为亚乙烯基、亚丙烯基、亚异丙烯基,作为其他实施方式,为亚乙烯基。
术语“卤素”表示F、Cl、Br、I。
因此,术语“可被一个以上的卤素取代的C1-6烷基”表示未被卤素取代的C1-6烷基,除此之外,还表示一个以上的相同或不同的卤素取代的C1-6烷基,具体来说,例如为三氟甲基、氟甲基、二氟甲基、2-氟乙基、3-氟丙基等。
术语“环烷基”为饱和环烃基,可以为桥环结构,也可以为与苯环稠合后的结构。因此,术语“C3-10环烷基”为碳原子数为3~10个的直链或支链亚烯基饱和环烃,具体来说,例如为环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环癸基、降冰片基、二环[2.2.2]辛基、金刚烷基、二氢茚基、1,2,3,4-四氢萘基等。作为一种实施方式,为C3-6环烷基,进一步作为其他实施方式,为C5-6环烷基。术语“单环式环烷基”表示单环饱和环烃基,因此,具体来说,术语“C3-10单环式环烷基”例如为环丙基、环丁基、环戊基、环己基等。
术语“亚环烷基”表示将上述“环烷基”中的任意一个氢原子除去后形成的二价基团。因此,具体来说,术语“C5-7亚环烷基”例如为环戊烷-1,3-二基、环己烷-1,3-二基、环己烷-1,4-二基、环庚烷-1,3-二基、环庚烷-1,4-二基,作为一种实施方式,为环己烷-1,4-二基。
术语“芳基”为C6-14的单环至三环式环芳烃基,包括部分被氢化的环基。具体来说,例如为苯基、萘基、四氢萘基、二氢茚基、茚基、等。作为一种实施方式,为苯基和萘基,作为其他实施方式,为苯基。术语“单环式芳基”表示单环的环芳烃基,具体来说,例如为苯基。
术语“杂环”表示包括下述i)和ii)中的基团的环基,其中i)为 含有1~4个选自氧、硫和氮中的杂原子的3~8元单环,作为其他实施方式,为5~7元杂环,ii)为该单环杂环与选自由单环杂环、苯环、C5-8环烷烃和C5-8环烯烃构成的组中的一个或两个环稠合而形成的、含有1~5个选自氧、硫和氮中的杂原子的双环或三环式杂环。作为环原子的硫或氮可被氧化而形成氧化物或二氧化物。
作为“杂环”,可以列举(例如)以下基团。
(1)单环式饱和杂环基
i)含有1~4个氮原子的单环式饱和杂环,其具体可以列举氮杂环庚烷基、二氮杂环庚烷基、氮丙啶基、氮杂环丁烷基、吡咯烷基、咪唑烷基、哌啶基、吡唑烷基、哌嗪基等;
iii)含有1~2个硫原子的单环式饱和杂环,其具体可以列举四氢噻吩基等;
iv)含有1~2个硫原子和1~2个氧原子的单环式饱和杂环,其具体可以列举氧硫杂环戊烷(オキサチオラン)等;
(2)单环式不饱和杂环基
iv)含有1~2个硫原子和1~2个氧原子的杂环,具体可以列举 二氢氧杂噻吩基等;
(3)稠合多环式饱和杂环基
i)含有1~5个氮原子的杂环,其具体可以列举奎宁环、7-氮杂双环[2.2.1]庚基、3-氮杂双环[3.2.2]壬烷基等;
ii)含有1~4个氮原子、以及1~3个硫原子和/或1~3个氧原子的杂环,其具体可以列举三硫代二氮杂茚基、二氧戊环并咪唑烷基等;
iii)含有1~3个硫原子和/或1~3个氧原子的杂环,其具体可以列举2,6-二氧杂双环[3.2.2]辛-7-基等;
(4)稠合多环式不饱和杂环
i)含有1~5个氮原子的杂环,其具体可以列举吲哚基、异吲哚基、吲哚啉基、吲哚嗪基、苯并咪唑基、喹啉基、四氢喹啉基、异喹啉基、四氢异喹啉基、吲唑基、咪唑并吡啶基、苯并三唑基、四唑并哒嗪基、咔唑基、喹喔啉基、二氢吲唑基、苯并嘧啶基、萘啶基、喹唑啉基、噌啉基等;
iii)含有1~3个硫原子的杂环,其具体可以列举苯并噻吩基、苯并二噻吩基等;
v)含有1~3个氧原子的杂环,其具体可以列举苯并二氧杂环戊烯基、苯并呋喃基、异苯并呋喃基、色烯基、苯并二氢呋喃基等;
术语“含氮杂环”是指选自上述杂环中的(1)的i)和ii)、(2)的i)和ii)、(3)的i)和ii)、以及(4)的i)和ii)中的环基。作为一种实施方式,为构成该环的氮原子上具有键的环基。
作为环D1中的“单环或双环式含氮杂环”,具体可以列举(例如)吡咯、吡咯并呋喃、吡咯并噻吩、吲哚、苯并咪唑、吲唑、4,5,6,7-四氢吲哚。
作为环D2中的“杂环”,具体可以列举(例如)苯并噻吩、4,5,6,7-四氢苯并噻吩、吡啶。
作为环B5中的“双环式杂环”,具体可以列举(例如)喹啉、异喹啉、苯并呋喃、苯并噻吩、苯并 唑、苯并噻唑、吲哚、喹喔啉、萘啶、喹唑啉、噌啉、苯并咪唑。作为其他实施方式,为喹啉、异喹啉、苯并呋喃、苯并噻吩、苯并 唑、苯并噻唑。
作为环B5中的“单环式杂环”,具体可以列举(例如)噻唑、 唑、吡啶、噻吩、呋喃、吡咯、咪唑、三唑、 二唑、噻二唑、吡嗪、嘧啶、哒嗪、哌啶、吡咯烷、氮杂环庚烷、四氢吡喃、四氢噻喃、哌嗪。作为其他实施方式,为噻唑、 唑、吡啶、噻吩、哌啶、四氢吡喃。
另外,虽然记载了上述的环作为环本身的命名、或者该环的一价基团,但是,必要时,可以作为具有将任意位置的氢原子除去后形成的一价基团、二价基团或其以上的原子价的环基。
术语“-CO2H或其生物电子等排体”表示-CO2H、或者具有与-CO2H同等的电子或立体构型、从而具有可释放出酸性质子的共同的生物学性质的其他原子或原子团。例如,其可以列举-CO2H、异羟肟酸(R-CO-NH-OH、-CO-NH-O-C1-6烷基)、磺酰胺(-NH-SO2-C1-6烷基)、酰腈(-CO-NH-CN)、酰基磺酰胺(-CO-NH-SO2-C1-6烷基)、-SO2-NH-CO-C1-6烷基、或者四唑基、 二唑酮基、 二唑硫酮基、 氧杂噻二唑基、噻二唑酮基、三唑硫酮基、羟基异 唑基等,作为其他实施方式,可以列举-CO2H、酰基磺酰胺(-CO-NH-SO2-C1-6烷基)、异羟肟酸(R-CO-NH-OH、-CO-NH-O-C1-6烷基)、四唑基,进一步作为其他实施方式,为-CO2H。另外,-CO2H或其生物电子等排体中的C1-6烷基可被-OH或-O-C1-6烷基取代。
在本说明书中,术语“可以被取代”表示“未被取代”或者“具有1~5个相同或不同的取代基”。而且,具有多个取代基时,那些取代基可以相同,也可以相互不同。
作为R4和R5中“可被取代的芳基”以及“可被取代的杂环”中可容许的取代基,可以列举卤素、可被一个以上的卤素取代的C1-6烷基、-O-(可被一个以上的卤素取代的C1-6烷基)、-OH。
另外,式(II)中的R46为代替构成该环的原子上的氢原子的取代基,例如,当V或W表示CH时,该CH的氢原子可被R46取代。因此,术语“V或W为CH”意味着,当该氢原子被R46取代时,V或W可以是C(-R46)。
以下示出式(I)所示的化合物或其盐的一些实施方式。
(1)一种化合物或其盐,其中环D为式(II)所示的基团。
(2)一种化合物或其盐,其中R46为-H、氟、氯、甲基或三氟甲基。作为其他实施方式,为这样的化合物或其盐,其中R46为氟、氯、甲基或三氟甲基。进一步作为其他实施方式,为这样的化合物或其盐,其中R46为三氟甲基。进一步作为其他实施方式,为这样的化合物或其盐,其中R46在由V或W表示的环构成原子上进行取代(即,表示R46在吲哚的5位或6位上进行取代)。进一步作为其他实施方式,为这样的化合物或其盐,其中R46在由V表示的环构成原子上进行取代(即,表示R46在吲哚的5位上进行取代)。进一步作为其他实施方式,为这样的化合物或其盐,其中R46为在由V表示的环构成原子上进行取代的氟、氯、甲基或三氟甲基。进一步作为其他实施方式,为这样的化合物或其盐,其中R46为在由V表示的环构成原子上进行取代的三氟甲基。
(3)一种化合物或其盐,其中V为CH,W为CH。作为其他 实施方式,为这样的化合物或其盐,其中V为N,W为CH。进一步作为其他实施方式,为这样的化合物或其盐,其中V为CH,W为N。
(4)一种化合物或其盐,其中X1为C1-6亚烷基、或(C1-6亚烷基)-O-。作为其他实施方式,为这样的化合物或其盐,其中X1为亚甲基。进一步作为其他实施方式,为这样的化合物或其盐,其中X1为-CH2CH2-O-。
(5)一种化合物或其盐,其中B5为可被选自由卤素和C1-6烷基构成的组中的1个以上的基团取代的双环式杂环取代的双环式杂环。作为其他实施方式,为这样的化合物或其盐,其中B5为可以分别被选自由卤素和C1-6烷基构成的组中的1个以上的基团取代的喹啉基、异喹啉基、苯并呋喃基、或苯并噻吩基。进一步作为其他实施方式,为这样的化合物或其盐,其中B5为喹啉基、异喹啉基、苯并呋喃基、或苯并噻吩基。进一步作为其他实施方式,为这样的化合物或其盐,其中B5为喹啉基。进一步作为其他实施方式,为这样的化合物或其盐,其中B5为异喹啉基。进一步作为其他实施方式,为这样的化合物或其盐,其中B5为苯并呋喃基。进一步作为其他实施方式,为这样的化合物或其盐,其中B5为苯并噻吩基。进一步作为其他实施方式,为这样的化合物或其盐,其中B5为喹啉-2-基。进一步作为其他实施方式,为这样的化合物或其盐,其中B5为喹啉-3-基。进一步作为其他实施方式,为这样的化合物或其盐,其中B5为喹啉-5-基。进一步作为其他实施方式,为这样的化合物或其盐,其中B5为喹啉-6-基。进一步作为其他实施方式,为这样的化合物或其盐,其中B5为喹啉-7-基。进一步作为其他实施方式,为这样的化合物或其盐,其中B5为喹啉-8-基。进一步作为其他实施方式,为这样的化合物或其盐,其中B5为异喹啉-1-基。进一步作为其他实施方式,为这样的化合物或其盐,其中B5为异喹啉-3-基。进一步作为其他实施方式,为这样的化合物或其盐,其中B5为异喹啉-5-基。进一步作为其他实施方式,为这样的化合物或其盐,其中B5为异喹啉-7-基。进一步作为其他实施方式,为这样的化合物或其盐,其中B5为分别被选自R5中的基团取代的单环式芳基、单环式杂环、或C3-10单环式环烷基。 进一步作为其他实施方式,为这样的化合物或其盐,其中B5为被卤素取代的苯基。进一步作为其他实施方式,为这样的化合物或其盐,其中B5为被芳基取代的单环式杂环。进一步作为其他实施方式,为这样的化合物或其盐,其中B5为被苯基取代的噻唑基。进一步作为其他实施方式,为这样的化合物或其盐,其中B5为被苯基取代的吡啶基。
(6)一种化合物或其盐,其中环E为1,4-亚苯基、或环己烷-1,4-二基。作为其他实施方式,为这样的化合物或其盐,其中环E为1,4-亚苯基。进一步作为其他实施方式,为这样的化合物或其盐,其中环E为环己烷-1,4-二基。
(7)一种化合物或其盐,其中R1为-H。
(8)一种化合物或其盐,其中R2为-H、或甲基。作为其他实施方式,为这样的化合物或其盐,其中R2为-H。
(9)一种化合物或其盐,其中Y为CH。
(10)一种化合物或其盐,其中Z为键。
(11)一种化合物或其盐,其中R3为-CO2H。作为其他实施方式,为这样的化合物或其盐,其中R3为-CO2H的生物电子等排体。
(12)一种化合物或其盐,其是上述(1)~(11)所记载的基团中的2个以上组合。
本发明包含如上述(12)所记载的、上述(1)~(11)所记载的基团中的2个以上组合的化合物或其盐,作为其具体例子,可以列举以下实施方式。
(13)一种化合物或其盐,其中环D为式(II)所示的基团。
(14)上述(13)所述的化合物或其盐,其中V为CH,W为CH。
(15)上述(14)所述的化合物或其盐,其中环E为1,4-亚苯基、或环己烷-1,4-二基,Z为键。R3为-CO2H。
(16)上述(15)所述的化合物或其盐,其中R1为-H,R2为-H、或甲基。
(17)上述(16)所述的化合物或其盐,其中Y为CH,R2为-H。
(18)上述(17)所述的化合物或其盐,其中X1为-CH2CH2-O-,B5为被卤素取代的苯基。
(19)上述(18)所述的化合物或其盐,其中E为1,4-亚苯基。
(20)上述(18)所述的化合物或其盐,其中E为环己烷-1,4-二基。
(21)上述(17)所述的化合物或其盐,其中X1为亚甲基。
(22)上述(21)所述的化合物或其盐,其中E为1,4-亚苯基。
(23)上述(21)所述的化合物或其盐,其中E为环己烷-1,4-二基。
(24)上述(22)或(23)所述的化合物或其盐,其中B5为可被选自由卤素和C1-6烷基构成的组中的1个以上基团取代的双环式杂环。
(25)上述(24)所述的化合物或其盐,其中B5为可以分别被选自由氟、氯和甲基构成的组中的1个以上基团取代的喹啉基、异喹啉基、苯并呋喃基、或苯并噻吩基。
(26)上述(25)所述的化合物或其盐,其中B5为可被氟取代的喹啉基。作为其他实施方式,为这样的上述(25)所述的化合物或其盐,其中B5为氟可被氟取代的喹啉-2-基。进一步作为其他实施方式,为这样的上述(25)所述的化合物或其盐,其中B5为喹啉-3-基。进一步作为其他实施方式,为这样的上述(25)所述的化合物或其盐,其中B5为喹啉-5-基。进一步作为其他实施方式,为这样的上述(25)所述的化合物或其盐,其中B5为喹啉-6-基。进一步作为其他实施方式,为这样的上述(25)所述的化合物或其盐,其中B5为喹啉-7-基。进一步作为其他实施方式,为这样的上述(25)所述的化合物或其盐,其中B5为喹啉-8-基。
(27)上述(25)所述的化合物或其盐,其中B5为异喹啉基。作为其他实施方式,为这样的上述(25)所述的化合物或其盐,其中B5为异喹啉-1-基。进一步作为其他实施方式,为这样的上述(25)所述的化合物或其盐,其中B5为异喹啉-3-基。进一步作为其他实施方式,为这样的上述(25)所述的化合物或其盐,其中B5为异喹啉 -5-基。进一步作为其他实施方式,为这样的上述(25)所述的化合物或其盐,其中B5为异喹啉-7-基。
(28)上述(22)或(23)所述的化合物或其盐,其中B5为被选自前述R5中的1~5个基团取代的单环式杂环,R5为芳基。
(29)上述(28)所述的化合物或其盐,其中B5为噻唑基,R5为苯基。
(30)上述(28)所述的化合物或其盐,其中B5为吡啶基,R5为苯基。
作为包含在式(I)所示的化合物或其盐的具体例子,可以列举以下化合物。
4-[({[5-氯-1-(喹啉-2-基甲基)-1H-吲哚-7-基]羰基}氨基)甲基]苯甲酸、
反式-4-[({[5-甲基-1-(喹啉-2-基甲基)-1H-吲哚-7-基]羰基}氨基)甲基]环己烷羧酸、
反式-4-[({[5-氟-1-(喹啉-2-基甲基)-1H-吲哚-7-基]羰基}氨基)甲基]环己烷羧酸、
4-[({[1-(喹啉-2-基甲基)-5-(三氟甲基)-1H-吲哚-7-基]羰基}氨基)甲基]苯甲酸、
反式-4-[({[1-(喹啉-2-基甲基)-5-(三氟甲基)-1H-吲哚-7-基]羰基}氨基)甲基]环己烷羧酸、
反式-4-[({[5-氯-1-(异喹啉-3-基甲基)-1H-吲哚-7-基]羰基}氨基)甲基]环己烷羧酸、
反式-4-[({[1-(异喹啉-3-基甲基)-5-(三氟甲基)-1H-吲哚-7-基]羰基}氨基)甲基]环己烷羧酸、
反式-4-{[({5-氯-1-[(2-苯基-1,3-噻唑-4-基)甲基]-1H-吲哚-7-基}羰基)氨基]甲基}环己烷羧酸、
4-{[({5-氯-1-[2-(4-氯苯氧基)乙基]-1H-吲哚-7-基}羰基)氨基]甲基}苯甲酸、
反式-4-{[({5-氯-1-[2-(4-氯苯氧基)乙基]-1H-吲哚-7-基}羰基)氨基]甲基}环己烷羧酸、
4-{[({1-[(2-苯基-1,3-噻唑-4-基)甲基]-5-(三氟甲基)-1H-吲哚-7-基}羰基)氨基]甲基}苯甲酸、
反式-4-{[({1-[(2-苯基-1,3-噻唑-4-基)甲基]-5-(三氟甲基)-1H-吲哚-7-基}羰基)氨基]甲基}环己烷羧酸、
反式-4-{[({1-[(5-苯基吡啶-2-基)甲基]-5-(三氟甲基)-1H-吲哚-7-基}羰基)氨基]甲基}环己烷羧酸、
4-{[({1-[2-(4-氯苯氧基)乙基]-5-(三氟甲基)-1H-吲哚-7-基}羰基)氨基]甲基}苯甲酸、
反式-4-[({[1-(异喹啉-3-基甲基)-5-甲基-1H-吲哚-7-基]羰基}氨基)甲基]环己烷羧酸、
反式-4-[({[5-氟-1-(异喹啉-3-基甲基)-1H-吲哚-7-基]羰基}氨基)甲基]环己烷羧酸、
反式-4-[({[6-氟-1-(异喹啉-3-基甲基)-1H-吲哚-7-基]羰基}氨基)甲基]环己烷羧酸、
反式-4-[({[1-(1-苯并呋喃-2-基甲基)-5-氯-1H-吲哚-7-基]羰基}氨基)甲基]环己烷羧酸、
反式-4-[({[1-(1-苯并呋喃-2-基甲基)-5-(三氟甲基)-1H-吲哚-7-基]羰基}氨基)甲基]环己烷羧酸、
反式-4-[({[(5-氯吡啶-2-基)甲基]-5-(三氟甲基)-1H-吲哚-7-基}羰基)氨基]甲基}环己烷羧酸、
反式-4-{[({1-[(5-氯-1-苯并呋喃-2-基)甲基]-5-(三氟甲基)-1H-吲哚-7-基]羰基}氨基)甲基]环己烷羧酸、
以及它们的盐。
此外,作为包含在式(I)所示的化合物或其盐的具体例子,还可以列举以下化合物。
4-{(1S)-1-[({1-[2-(4-氯苯氧基)乙基]-1H-吲哚-7-基}羰基)氨基]乙基}苯甲酸、
4-[2-({1-[2-(4-氯苯氧基)乙基]-1H-吲哚-7-基}羰基)-1-甲基肼基]苯甲酸、
反式-4-[({[5-氯-1-(喹啉-2-基甲基)-1H-吲哚-7-基]羰基}氨基)甲 基]环己烷羧酸、
反式-4-[({[1-(4-氯苄基)-5-(三氟甲基)-1H-吲哚-7-基]羰基}氨基)甲基]环己烷羧酸、
反式-4-[({[1-(4-氯苄基)-5-甲基-1H-吲哚-7-基]羰基}氨基)甲基]环己烷羧酸、
4-[({[5-甲基-1-(喹啉-2-基甲基)-1H-吲哚-7-基]羰基}氨基)甲基]苯甲酸、
4-[({[1-(1-苯并呋喃-2-基甲基)-1H-吲哚-7-基]羰基}氨基)甲基]苯甲酸、
反式-4-[({[1-(1-苯并呋喃-2-基甲基)-1H-吲哚-7-基]羰基}氨基)甲基]环己烷羧酸、
反式-4-[({[1-(1-苯并噻吩-2-基甲基)-1H-吲哚-7-基]羰基}氨基)甲基]环己烷羧酸、
4-[1-甲基-2-({1-[(2-苯基-1,3-噻唑-4-基)甲基]-1H-吲哚-7-基}羰基)肼基]苯甲酸、
4-{[({5-氯-1-[(2-苯基-1,3-噻唑-4-基)甲基]-1H-吲哚-7-基}羰基)氨基]甲基}苯甲酸、
以及它们的盐。
根据取代基的种类,几种式(I)所示化合物或其盐中可存在互变异构体或几何异构体。在本说明书中,虽然仅记载了式(I)所示化合物的异构体的一种形态,但是除此之外其他的异构体、异构体经分离后得到的物质、或这些异构体的混合物也包括在本发明之内。
另外,当几种式(I)所示化合物或其盐中具有不对称碳原子或轴不对称时,可以存在基于这些不对称碳原子或轴不对称的光学异构体。本发明也包括几种式(I)所示化合物或其盐的光学异构体经分离后得到的物质、或者它们的混合物。
此外,本发明还包括式(I)所示化合物的可药用的前药。可药用的前药为具有这样的基团的化合物,该基团通过溶剂分解或者在生理学条件下可以转换为氨基、羟基、羧基等。作为形成前药的基团,可以列举例如在Prog.Med.,5,2157-2161(1985)或“医薬品の開発” (廣川书店、1990年)第7卷分子设计第163-198页中所记载的基团。
而且,式(I)所示化合物的盐为式(I)所示化合物的可药用的盐,根据取代基的种类,几种式(I)所示化合物有时候形成酸加成盐或者与碱形成加成盐。具体而言,可以列举与无机酸(例如盐酸、氢溴酸、氢碘酸、硫酸、硝酸、磷酸等)形成的酸加成盐、与有机酸(例如甲酸、醋酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、扁桃酸、酒石酸、二苯甲酰酒石酸、二对甲基苯甲酰酒石酸、柠檬酸、甲磺酸、乙磺酸、苯磺酸、对甲苯磺酸、天门冬氨酸、谷氨酸等)形成的酸加成盐、与无机碱(例如钠、钾、镁、钙、铝等)形成的盐、与有机碱(例如甲胺、乙胺、乙醇胺、赖氨酸、鸟氨酸等)形成的盐、与各种氨基酸(例如乙酰基亮氨酸等)以及氨基酸衍生物形成的盐、或铵盐等。
此外,本发明还包括式(I)所示化合物及其盐的各种水合物、溶剂合物以及多晶态物质。而且,本发明还包括用各种放射性同位素或非放射性同位素标记的化合物。
(制备方法)
式(I)所示化合物及其盐,可利用基于其基本骨架或取代基种类的特征,采用各种已知的合成方法来制备。在制备过程中,根据官能团的种类,在原料至中间体的阶段中,采用适当的保护基(其是能够容易地转化成为该官能团的基团)来替换该官能团,这在制备技术中有时是有效的。作为这样的保护基团,可以列举(例如)在P.G.M.Wuts和T.W.Greene著的“Greene’s Protective Groups in OrganicSynthesis(第4版,2006年)”中所记载的保护基等,并且可以根据反应条件来适当地选择使用这些保护基。在这样的方法中,引入该保护基团并进行反应之后,根据需要除去该保护基团,从而可以制备所期望的化合物。
另外,与上述保护基的情况相同,在原料至中间体的阶段中引入特定的基团、或者使用所获得的式(I)所示化合物来进一步进行反应,从而可以制备式(I)所示化合物的前药。可采用通常的酯化、 酰胺化、脱水等本领域技术人员公知的方法来进行所述反应。
以下,对式(I)所示化合物的代表性制备方法进行说明。也可以参照本说明书随附的参考文献来进行各制备方法。另外,式(I)所示化合物的制备方法并不局限于以下所示的例子。
(第一制法)
[式14]
本制法是这样的方法:使化合物1a与化合物1b反应,来制备式(I)所示化合物。
在缩合剂的存在下,在对于反应呈惰性的溶剂中,在从冷却至加热的条件下、优选在-20℃~60℃下,使用等量或其中一者为过量的化合物1a和化合物1b,通常搅拌0.1小时~5天,以进行反应。此处,对溶剂没有特别的限定,可以列举如芳烃类(例如苯、甲苯或二甲苯等)、卤代烃类(例如二氯甲烷(DCM)、1,2-二氯乙烷(DCE)或氯仿等)、醚类(例如二乙醚、四氢呋喃(THF)、二 烷、二甲氧基乙烷(DME)等)、N,N-二甲基甲酰胺(DMF)、二甲基亚砜(DMSO)、醋酸乙酯、乙腈、或水、或者它们的混合物。作为缩合剂,有时优选使用1-[双(二甲基氨基)亚甲基]-1H-1,2,3-三唑并[4,5-b]吡啶-1- -3-氧化物六氟磷酸盐(HATU)、1-(3-二甲氨基丙基)-3-乙基碳化二亚胺盐酸盐(EDCI·HCl)、二环己基碳化二亚胺(DCC)、1,1′-羰基二咪唑(CDI)、叠氮磷酸二苯酯、三氯氧磷、或负载有缩合剂的聚苯乙烯树脂(例如PS-碳化二亚胺(PS-Carbodiimide),美国ArgonautTechnologies公司)等,但是并不局限于这些。有时使用添加剂(例如1-羟基苯并三唑(HOBt)等)对反应是有利的。为了使反应顺利进行,有时有利的是,在有机碱(例如三乙胺、N,N-二异丙基乙胺(DIPEA)或N-甲基吗啉等)、或者无机碱(例如碳酸钾、碳酸钠或氢氧化钾 等)的存在下进行反应。此外,为了除去反应结束后的过量的胺,可以使用负载有异氰酸酯的聚苯乙烯树脂(例如PS-异氰酸酯(PS-Isocyanate),美国Argonaut Technologies公司等)。此外,为了除去反应结束后的过量的羧酸和上述的添加剂等,可以使用负载有季铵盐的聚苯乙烯树脂(例如MP-碳酸酯(MP-Carbonate),美国ArgonautTechnologies公司等)。
此外,还可以使用这样的方法:将化合物1a衍生为反应性衍生物后,再与化合物1b进行反应。此处,作为化合物1a的反应性衍生物,可以列举与卤化剂(例如三氯氧磷、亚硫酰氯等)进行反应而获得的酰卤、与氯甲酸异丁酯等反应而获得的混合酸酐、与HOBt等进行缩合而获得的活性酯等。可在对反应呈惰性的溶剂(例如卤代烃类、芳烃类、醚类等)中,在从冷却到加热的条件下、优选在-20℃~60℃下,进行这种反应性衍生物与化合物1b的反应。
而且,通过附加水解条件,将R3为羧酸酯的化合物衍生为R3为羧酸的式(I)所示的化合物。同样,通过附加适当的脱保护条件,将R3为具有保护基的取代基的式(I)所示的化合物衍生为R3为具有所述保护基被除去的取代基的式(I)所示的化合物。
(第二制法)
[式15]
(式中,环F表示单环或双环式杂环、或者单环式芳基,U表示离去基团,U’表示-B(OH)2或-B(OL)OL’。此处,L和L’相互相同或不同而表示C1-6烷基,或者L与L’形成一体而表示C2-6亚烷基。)
通过化合物(I-a)与化合物2a的偶联反应,可以得到本发明化合物(I-b)。
作为由U表示的离去基团的例子,包含卤素、甲磺酰基氧基、三氟甲磺酰基氧基基团等。
在对于反应呈惰性的溶剂中,在碱和钯催化剂的存在下,在从室温~加热回流的条件下,使用等量或其中一者为过量的化合物I-a)和化合物2a,通常搅拌0.1小时~5天,以进行反应。优选的是,在惰性气体气氛下进行该反应。此处,对溶剂没有特别的限定,但是可以列举芳烃类、醚类、卤代烃类、醇类(例如甲醇、乙醇、2-丙醇、丁醇等)DMF、DMSO、水以及它们的混合物。作为碱,可以使用碳酸钠、碳酸钾、氢氧化钠等无机碱。作为钯催化剂,可以使用四(三苯基膦)钯、二氯双(三苯基膦)钯、氯化钯-1,1’-双(二苯基膦基)二茂铁等。此外,可以参照A.d.Meijere和F.Diederich著的“Metal-CatalyzedCross-Coupling Reactions”(第1版,VCH Publishers Inc.,1997年)或者日日本化学会编“实验化学讲座(第5版)”第13卷(2005年)(丸善)。
(原料合成)
原料制法1
[式16]
根据取代基的种类,将化合物3a作为原料,通过上述路线A或路线B的任意一种方法,可以制备原料化合物1b-1。路线A是这样的方法:通过化合物3b的还原而形成化合物3d,并通过叠氮化以及还原氨基来制备原料化合物1b-1。另一方面,路线B是这样的方法:通过在化合物3b的肟化反应后进行还原反应来制备原料化合物1b-1。
原料制法1
[式17]
通过化合物4a与化合物4b的N-烷基化反应和酯水解,可以制备化合物1a-1。通过化合物1a-1与化合物1b的胺化反应,可以制备化合物(I-a)。
式(I)所示的化合物被分离并纯化成为游离化合物、其盐、水合物、溶剂合物或者多晶态物质。也可通过常规的成盐方法来制备式(I)所示的化合物。
可采用萃取、分步结晶、各种分段色谱法等常规的化学操作来进行分离、纯化。
可通过选择适当的原料化合物来制备各种异构体、或者利用异构体间的物理化学性质的差别来分离各种异构体。例如,可以采用常用的外消旋体光学拆分法(例如,诱导外消旋体与有光学活性的碱或酸形成非对映异构体盐以便分步结晶、以及利用手性柱等的色谱法等)来制得光学异构体、或者采用合适的光学活性原料化合物也可以制备光学异构体。
通过以下的试验来证实式(I)所示化合物或其盐的药理活性。
试验例1:大鼠EP4受体亲和性评价试验
细胞培养和转染(transfection)
采用10cm的被覆有胶原的培养皿(Asahi Glass公司生产),用D-MEM培养基来培养HEK293细胞,在铺满状态(90-100%的密集状态)下除去培养基,用磷酸盐缓冲盐水(PBS)洗涤后,在N,N,N′,N′-四(羧甲基)乙二胺(EDTA)中剥离细胞。计算细胞数,将其播种到15cm的被覆有胶原的培养皿中,使得呈70%的铺满状态。第二天,向1.2mL/培养皿的Opti-MEM培养基中添加60μL/培养皿的Lipofectamine2000(Invitrogen公司生产),在室温下静置5分钟。然后添加质粒(在pcDNA3.1-V5-His-topo的TA克隆位点中插入有大鼠EP4(序列编号1)),使得15μg/培养皿。在室温下静置30分钟后,添加到培养皿中,并培养20-24小时。在CO2培养箱(37℃,5%CO2)中进行细胞培养。
膜片段的调制
吸除培养基,每15cm的培养皿中加入10mL冷却的PBS,用细胞刮匙(Sumitomo Bakelite公司生产)来收集细胞。用冷却的PBS洗涤(1,200rpm,4℃,5分钟)后,将其悬浮于每培养皿6mL冷却的20mM Tris-HCl(pH7.4;nacalai tesque公司生产,其含有5mMEDTA(nacalai tesque公司生产))中,采用Polytron匀浆器进行匀浆,将均浆物进行离心(26,000rpm,20分钟,4℃)。将所获得的沉淀再悬浮于冷却的20mM Tris-HCl中,再采用Polytron匀浆器进行匀浆,将均浆物进行离心(26,000rpm,20分钟,4℃)。将所获得的沉淀悬浮于50mM HEPES(pH 7.5;Dojindo Laboratories公司生产)中,使得每培养皿为1mL,采用Polytron匀浆器进行匀浆,将均浆物作为膜片段而在-80℃下保存。此时,将一部分该膜片段用来测定蛋白质的浓度。采用Bio-Rad Protein assay kit(Bio-Rad Laboratories公司生产)来进行蛋白质浓度的测定,按照附带的标准操作程序测定双份。
结合测定
将50μL的[3H]PGE2(最终浓度为0.3nM;Perkin Elmer公司生产)、由大鼠EP4表达细胞制备的膜片段100μL(20μg/孔)、以及50μL的测试化合物在96孔微孔板(Sumitomo Bakelite公司生产)中进行混合,于室温孵育1小时后,采用FilterMate细胞收集器(Perkin Elmer公司生产),将其吸滤到UniFilter-96GF/B(Perkin Elmer公司生产)上,用300μL/孔的冷却的分析缓冲液洗涤3次。用分析缓冲液(50mM HEPES、10mM MgCl2)稀释[3H]PGE2和膜片段,用DMSO和分析缓冲液来稀释测试化合物和未标记的PGE2。此外,当添加人血清白蛋白(HSA)时,用含有4%HAS(最终浓度为1%;Sigma公司生产)的分析缓冲液进行稀释。预先用200μL/孔的冷却的分析缓冲液洗涤UniFilter-96GF/B 2次以使其适应环境。将过滤后的UniFilter-96GF/B在干燥机中干燥过夜,添加50μL/孔的MicroScint20(Perkin Elmer公司生产)后,采用TopCount(PerkinElmer公司生产)测定放射活性。在测定非特异性结合时,添加未标记的PGE2(最终浓度为1μM;Cayman公司生产)。测定时均做双份,并且,总结合量减去非特异性结合量就得到特异性结合量。根据规定方法,计算Ki值。
几种式(I)所示的化合物的Ki值示于表1中。另外,Ex表示后述的实施例化合物编号。
[表1]
Ex | Ki(nM) |
3 | 0.76 |
4 | 0.82 |
6 | 31 |
23 | 0.35 |
32 | 12 |
52 | 1.8 |
53 | 1.4 |
57 | 0.85 |
69 | 1.4 |
96 | 1.7 |
115 | 1.0 |
124 | 1.4 |
132 | 2.6 |
137 | 9.1 |
140 | 0.61 |
Ex | Ki(nM) |
143 | 1.0 |
146 | 1.8 |
159 | 2.1 |
164 | 6.3 |
187 | 0.75 |
188 | 1.2 |
206 | 1.2 |
207 | 1.1 |
208 | 1.8 |
209 | 1.9 |
210 | 1.3 |
211 | 1.7 |
212 | 2.4 |
213 | 2.0 |
214 | 2.2 |
Ex | Ki(nM) |
215 | 2.6 |
216 | 16 |
217 | 3.0 |
218 | 2.9 |
219 | 3.3 |
220 | 16 |
222 | 2.8 |
223 | 3.5 |
224 | 2.1 |
225 | 2.1 |
226 | 2.8 |
227 | 1.7 |
228 | 2.1 |
229 | 3.9 |
231 | 1.4 |
试验例2:根据测定人Jurkat细胞中cAMP量的EP4受体拮抗作用评价试验
细胞培养
使用F75培养瓶,用RPMI1640(添加了10%的胎牛血清)来培养Jurkat细胞(来源于人白血病T淋巴肿瘤)。使该细胞增殖,直到半铺满状态之后,加入终浓度为5μM的吲哚美辛(indomethacin),并进一步培养18小时。将该细胞收集于15mL的试验管(Spitz tube)内,使用セルバンカ一(三菱化学ヤトロン公司生产),将该细胞调制成1×106个/mL之后,保存在-80℃,直到用于测定。在CO2培养箱(37℃,5%CO2)中进行细胞培养。
HTRF测定
采用cAMP HiRange试剂盒(Cisbio international公司生产),测定cAMP。用测定缓冲液来稀释调制测试化合物、PGE2和细胞。将测试化合物调制成使其浓度为终浓度的3倍,将PGE2调制成300nM,并将冷冻保存的Jurkat细胞在37℃下解冻后调制成1×106个/mL。在384孔U形底黑色微孔板(コ一ニング公司生产)中,依次加入测试化合物、细胞、PGE2各5μL,用板振荡器来搅拌后,在室温下孵育30分钟。孵育后,将用裂解缓冲液稀释成0.6倍的d2试剂以每孔5μL加入到各孔中,并用板振荡器搅拌。接着,将用裂解缓冲液稀释成0.6倍的铕穴合物(Europium Cryptate)试剂以每孔5μL加入到各孔中,用板振荡器来搅拌后,在遮光下、于室温下,孵育60分钟。孵育后,采用ARVO1420(PerkinElmer公司生产),在620nm下测定穴合物的荧光,并在655nm下测定d2的荧光。为了绘制标准曲线,同时测定280nM、70nM、17.5nM、4.38nM、1.09nM、0.27nM、0.068nM的cAMP。测定时均做四份,并且,计算出相对于添加了100nM的PGE2的组中减去未添加PGE2的组的cAMP量的值的各测试物的cAMP量,从而计算抑制率。根据Logistic回归法,计算IC50值。
另外,上述“测定缓冲液”和“裂解缓冲液”分别使用了以下 所示的物质:
测定缓冲液:1xHBSS(Hanks平衡盐溶液,日水制药公司生产)、20mM HEPES(pH 7.4,ナカライ公司生产)、0.5mM IBMX(3-异丁基-1-甲基黄嘌呤,WAKO公司生产)、0.02%CHAPS(Sigma)、0.1%牛血清白蛋白(Sigma公司生产)、2μM吲哚美辛(Sigma公司生产)
裂解缓冲液:50mM NaPO4、0.8M KF、1%Triton X-100、0.2%牛血清白蛋白
评价的结果,实施例3、实施例53、实施例57、以及实施例124的化合物的IC50值分别示出0.11nM、0.094nM、0.037nM、以及0.15nM。
试验例3:根据测定cAMP量的大鼠EP4受体拮抗作用评价试验
rEP4 cAMP HTRF测定
在96孔板中,以2×104个/100μL播种强制性表达大鼠EP4的CHO细胞,并培养过夜。将培养基替换成2μM的吲哚美辛/0.1%BSA/alpha-MEM,在60分钟后,进一步替换成1mM的IBMX/2μM吲哚美辛/0.1%BSA/alpha-MEM。在10分钟后,加入被测试化合物,再过10分钟后,加入PGE2,以使终浓度为100nM。在CO2培养箱(37℃,5%CO2)中进行细胞培养并反应。在30分钟后,除去培养基,加入100μL/孔的0.2%TritonX-PBS,以裂解细胞。采用cAMPHiRange试剂盒(Cisbio international公司生产),测定所述细胞裂解液中所含有的cAMP。在384孔U形底黑色微孔板(コ一ニング公司生产)中,分别注入10μL的细胞裂解液,然后以每孔5μL的d2试剂、铕穴合物试剂依次加入到各孔中。在遮光下、于室温孵育60分钟。孵育后,采用ARVO1420(PerkinElmer公司生产),在620nm下测定穴合物的荧光,并在655nm下测定d2的荧光。为了绘制标准曲线,同时测定280nM、70nM、17.5nM、4.38nM、1.09nM、0.27nM、0.068nM的cAMP。测定时均做四份,并且,计算出相对于添加了100nM的PGE2的组中减去未添加PGE2的组的cAMP量的值的各测试物的cAMP量,从而计算抑制率。根据Logistic回归法,计 算IC50值。
评价的结果,实施例3、实施例53、实施例57、以及实施例124的化合物的IC50值分别示出0.99nM、0.90nM、0.76nM、以及1.1nM。
试验例4:大鼠EP4受体拮抗作用体内(in vivo)评价试验
在非绝食下,将被测试化合物在PEG400∶20%Tween80∶1MNaHCO3水溶液=1∶4∶5中形成的溶液经口给药于SD大鼠(雄性,6周龄),在1小时后,将ONO-4819皮下给药于大鼠背部。在30分钟后,在无麻醉的条件下,向尾静脉内给予脂多糖(LPS,0.01mg/kg),在60分钟后,在乙醚麻醉的条件下,应用肝素从眼底抽血0.5mL。通过离心操作(3000rpm,10分钟),从血液样品分离血浆后,采用ELISA试剂盒,测定血浆中的大鼠TNF-α浓度。(参照Hepatology Research杂志,21卷,252-260,2001年)。将未经ONO-4819处理的组的TNF-α浓度减去经ONO-4819处理的组的TNF-α浓度的值定为100%,并计算出相对于该值的被测试化合物组的抑制率。
几种式(I)所示的化合物抑制率示于表2中。另外,Ex表示后述的实施例化合物编号。
[表2]
试验例5:对链脲佐菌素(STZ)诱发糖尿病大鼠的尿中白蛋白的效果研究试验
预先将8周龄的雄性Wister(Crj)大鼠分组,使各组的尿中白 蛋白排泄量(UAE)无差别,然后静脉内施用STZ(50mg/kg)。施用STZ的第二天开始连续经口给药,在代谢笼中定期地收集24小时的尿液,并测定UAE,由此,可以确认糖尿病模型大鼠中的被测试化合物对早期肾病有改善效果。
试验例6:对摘除5/6肾脏的慢性肾功能衰竭(5/6Nx)大鼠的肾功能的效果研究试验
将8周龄的雄性Wister大鼠用于试验。在戊巴比妥麻醉下,切除大鼠的2/3的左肾,一周后,把右肾全部摘除。摘除5/6肾脏2周后,在代谢笼中收集24小时的尿液,测定尿中蛋白排泄量,并进行分组,使各组的尿中蛋白排泄量无差别。然后,用6~8周经口施用5mg/kg的悬浮于0.5%MC中的被测试化合物。给仅进行开腹手术的假手术组、以及5/6Nx-对照组经口施用相同容量的溶剂(0.5%MC)。每隔2周收集24小时的尿液。
通过测定尿中蛋白排泄量、血浆肌酐、血浆尿素氮、肌酐清除率,可以证实对于慢性肾功能衰竭的被测试化合物的改善效果,并且,在本试验中,证实了示出有效性的化合物的存在。
此外,对式(I)所示的化合物或其盐对于PGE2受体的四种亚型(EP1、EP2、EP3和EP4)的选择性进行评价。具体来说,采用上述试验例3相同的方法,对来源于大鼠的各亚型受体分别添加被测试化合物而对cAMP量的抑制进行评价。结果显示,式(I)所示的化合物或其盐对EP4受体具有选择性拮抗作用。
由上述试验结果,可以证实式(I)所示化合物或其盐具有EP4受体拮抗作用,因此,其可用作用于预防或治疗与EP4有关的各种疾病的药物组合物的有效成分。作为与EP4有关的各种疾病,可以列举(例如)肾病(例如,急性肾炎、复发性血尿、持续性血尿、慢性肾炎、急进性肾炎、急性肾功能衰竭、慢性肾功能衰竭、糖尿病性肾病、巴特综合征等)、炎症性皮肤病(例如,晒伤、火伤、湿疹、皮肤炎等)、由动脉硬化症引起的缺血性心脏病(例如,心肌梗塞、心绞痛等)、由动脉硬化症引起的脑血管病(例如,脑卒中、包括腔隙性脑梗死在内的脑卒中、脑血栓、脑出血、蛛网膜下 腔出血、脑梗塞等)、消化性溃疡(例如,胃溃疡、十二指肠溃疡等)、恶性肿瘤及其转移(例如,结肠癌、乳癌等)等人或动物的同种的疾病,作为一种实施方式,可以列举慢性肾功能衰竭和糖尿病性肾病等肾病。
式(I)所示的化合物或其盐可用作具有利尿作用的化合物。通过具有利尿作用,式(I)所示的化合物或其可药用的盐可用作下列疾病的治疗剂或预防剂,所述疾病包括:各种水肿(例如,心源性水肿、脑水肿等)、恶性高血压症等高血压症、月经前紧张症、尿路结石、急性或慢性疾病所致的少尿症、高磷血症等。
使用本领域中通常所使用的赋形剂(即,药用赋形剂或药用载体等),根据通常采用的方法,可以制备含有以一种或两种以上的式(I)所示化合物或其盐作为有效成分的药物组合物。
给药时,可以采用口服给药的剂型(例如片剂、丸剂、胶囊剂、颗粒剂、散剂、液体制剂等),或者采用非经口给药的剂型(例如,关节内、静脉内、肌肉内等的注射剂、栓剂、滴眼剂、眼软膏、经皮用的液体制剂、软膏剂、经皮贴剂、经粘膜的液体制剂、经粘膜贴剂、吸入剂等)。
作为用于经口给药的固体组合物,可以使用片剂、散剂、颗粒剂等。在这种固体组合物中,将一种或两种以上的有效成分与至少一种惰性赋形剂混合。按照常规方法,组合物也可以含有惰性添加剂,例如润滑剂、崩解剂、稳定剂和溶解助剂。根据需要,片剂或丸剂也可以用糖衣或者胃溶性或肠溶性物质的膜进行包衣。
用于经口给药的液体组合物包括可药用的乳液剂、溶液剂、悬浮剂、糖浆剂或酏剂等,并且含有通常可使用的惰性稀释剂,例如纯化水或乙醇。除了惰性稀释剂以外,该液体组合物中也可以含有诸如增溶剂、润湿剂、悬浮剂之类的助剂以及甜味剂、矫味剂、芳香剂、防腐剂。
用于非经口给药的注射剂包括无菌的水性或非水性溶液制剂、悬浮剂或乳剂。水性溶剂包括(例如)注射用蒸馏水或生理盐水。非水性溶剂包括(例如)醇类(如乙醇)。该组合物还可以含有等渗剂、 防腐剂、润湿剂、乳化剂、分散剂、稳定剂、或溶解助剂。例如,可以采用通过可截留细菌的过滤器进行过滤、添加杀菌剂或者进行辐射的方法来对所述组合物进行灭菌。此外,也可以将这些组合物制成无菌的固体组合物,在使用前用无菌水或无菌的注射用溶剂来溶解或混悬而使用。
外用剂包括软膏剂、硬膏剂、霜剂、凝胶剂、贴剂、喷雾剂、洗液、滴眼剂、眼软膏等。这种外用剂含有常用的软膏基剂、洗液基剂、水性或非水性的液体制剂、悬浮剂、乳剂等。
吸入剂或经鼻剂等经粘膜剂,可以以固体、液体或半固体的状态使用,并且可以按照以往的公知方法来制备这些经粘膜剂。还可以适当地添加(例如)公知的赋形剂、还有pH调节剂、防腐剂、表面活性剂、润滑剂、稳定剂或增稠剂等。给药时可以使用合适的用于吸入或吹送的装置。例如,可以使用计量给药吸入装置等公知的装置或喷雾器,将化合物单独地或作为配方后的混合物的粉末来给药、或者可以将化合物与可药用的载体组合后作为溶液或悬浮液来给药。干燥粉末吸入器等可用于单次给药或多次给药,并可以使用干燥粉末或含有粉末的胶囊。另外,也可以采用加压气溶胶喷雾等形式,通过使用适当的抛射剂(例如,氯氟烷烃、氢氟烷烃或二氧化碳等适当的气体)来给药。
通常口服给药时,1天的给药量按体重约为0.001~100mg/kg,优选为0.1~30mg/kg,更优选为0.1~10mg/kg,并将该给药量1次服用或分2~4次服用。静脉内给药时,1天的给药量按体重约为0.001~10mg/kg是适当的,并将该给药量每日一次或分为多次给药。而且,使用经粘膜剂时,按体重约为0.001~100mg/kg,每日一次或分多次给药。应考虑症状、年龄和性别等,根据每个患者的情况,来适当地选择给药量。
虽然根据给药途径、剂型、给药部位、赋形剂或添加剂的种类而有所不同,但是,本发明的药物组合物中含有0.01~100重量%的一种或一种以上的(I)所示的化合物或其盐作为有效成分,作为一种实施方式,含有0.01~50重量%的一种或一种以上的(I)所示的 化合物或其盐作为有效成分。
式(I)所示的化合物或其盐可以与认为上述式(I)所示化合物或其盐对其有效的那些疾病的各种治疗剂或预防剂并用。在并用时,可以同时给药,或者分别连续给药、或按所希望的时间间隔给药。同时给药时的制剂可以分别制成制剂,也可以是含有上述式(I)所示化合物或其盐对其有效的那些疾病的各种治疗剂或预防剂和式(I)所示的化合物或其盐的药物组合物。
实施例
以下基于实施例对式(I)所示化合物或其盐的制备方法进行更详细的说明。而且,本发明并不局限于以下实施例中所记载的化合物。此外,将原料化合物的制备方法分别表示在制备例中。另外,式(I)所示化合物或其盐的制备方法并不只局限于以下所示的具体实施例的制备方法,可以通过这些制备方法的组合或本领域技术人员已知的方法来制备式(I)所示化合物或其盐。
制备例1
在室温下,向5-氯-1H-吲哚-7-羧酸(500mg)、三苯基膦(1.01g)、乙醇(235mg)、以及甲苯(20mL)的混合物中,滴加偶氮二甲酸二乙酯(2.2M甲苯溶液,1.74mL)。在室温下搅拌2小时,并减压浓缩反应混合物。通过硅胶柱色谱法(己烷-醋酸乙酯)纯化所获得的残余物,从而得到5-氯-1H-吲哚-7-羧酸乙酯(550mg)的白色固体。
制备例2
在冰浴冷却下,向5-(1-羟乙基)噻吩-2-羧酸乙酯(1.01g)、叠氮磷酸二苯酯(1.67g)、甲苯(10mL)的混合物中,加入1,8-二氮杂双环[5.4.0]十一碳-7-烯(905μL),并搅拌30分钟。将反应混合物升温至室温并搅拌15小时。将反应液依次用水、1M盐酸洗涤,用无水硫酸钠干燥。减压浓缩,并通过硅胶柱色谱法(己烷-醋酸乙酯)纯化所获得的残余物,从而得到5-(1-叠氮乙基)噻吩-2-羧酸乙酯(1.03g)的无色油状物。
制备例3
在室温下,向5-(1-叠氮乙基)噻吩-2-羧酸乙酯(1.03g)、THF(20mL)、以及水(4mL)的混合物中,加入三苯基膦(2.35g)。将该混合物在60℃下搅拌3小时。将反应混合物冷却至室温后,减压浓缩,并与甲苯进行共沸。通过硅胶柱色谱法(氯仿-甲醇)纯化所获得的残余物,之后,向通过浓缩而获得的残余物中加入4M氯化氢/醋酸乙酯溶液(1.5mL)。搅拌3分钟后,在在减压条件下再次浓缩。向其中加入二异丙基醚、过滤收集所析出的白色固体,从而得到5-(1-氨基乙基)噻吩-2-羧酸乙酯盐酸盐(979mg)的白色固体。
制备例4
在0℃下,向1,2,3,4-四氢喹啉-8-羧酸乙酯(1.1g)和DMF(9.0mL)的混合物中,加入氢化钠(液体石蜡中的55%的分散体,280mg),并在室温下搅拌30分钟。在冰浴冷却下,向反应混合物中,加入1-(溴乙基)-4-氯苯(1.2g)在DMF(2.0mL)中所形成的溶液,并在室温下搅拌3天。向反应混合物中,加入氢化钠(液体石蜡中的55%的分散体,280mg),并搅拌1天。向反应混合物中,加入水和醋酸乙酯,进行分液操作。将有机层用饱和食盐水洗涤,用无水硫酸钠干燥。过滤后,减压浓缩滤液。通过硅胶柱色谱法硅胶柱色谱法(己烷-醋酸乙酯)纯化残余物,从而得到1-(4-氯苄基)-1,2,3,4-四氢喹啉-8-羧酸乙酯(510mg)。
制备例5
向3-氨基-2-羟基苯甲酸甲酯(700mg)和THF(21mL)的混合物中,加入4-氯苯基异硫氰酸酯(717mg),并在室温下搅拌过夜。向反应混合物中依次加入碘化铜(0.87g)、三乙胺(641μL),并在60℃下搅拌过夜。减压浓缩反应混合物,加入甲醇,用Celite(セライト)过滤,并减压浓缩滤液。向残余物中加入醋酸乙酯(20mL),过滤除去不溶物,并减压浓缩滤液。通过硅胶柱色谱法(己烷∶醋酸乙酯=2∶1)纯化残余物之后,用正己烷-醋酸乙酯(10∶1,11mL)研磨,从而得到2-[(4-氯苯基)氨基]-1,3-苯并 唑-7-羧酸甲酯(270mg)的淡黄色固体。
制备例6
在室温下,向1H-吲哚-7-羧酸甲酯(100mg)、DMF(1mL)的混合物中,加入叔丁醇钾(75mg)并搅拌5分钟。向反应混合物中加入4-(溴甲基)苄腈(131mg),在室温下搅拌2小时。加入水,并用醋酸乙酯萃取。将有机层依次用水、饱和食盐水洗涤、用无水硫酸钠干燥后,蒸除溶剂,从而得到1-(4-氰基苄基)-1H-吲哚-7-羧酸甲酯的粗品(211mg)。向1-(4-氰基苄基)-1H-吲哚-7-羧酸甲酯的粗品(211mg)、THF(10mL)、甲醇(5mL)的混合物中,加入1M氢氧化钠水溶液(2.5mL),并将所获得的混合液在60℃下搅拌过夜。冷却至室温后,在减压条件下蒸除溶剂,向所获得的残余物中加入醋酸乙酯,并用水萃取。向水层中加入1M盐酸(2.5mL)进行中和,并用醋酸乙酯萃取。将该有机层用无水硫酸钠干燥后,蒸除溶剂,从而得到1-(4-氨基甲酰基苄基)-1H-吲哚-7-羧酸的粗品(230mg)。向1-(4-氨基甲酰基苄基)-1H-吲哚-7-羧酸的粗品(229mg)、(S)-4-[1-氨基乙基]苯甲酸甲酯盐酸盐(123mg)、HOBt(23mg)和DMF(3mL)的混合物中,加入EDCI·HCl(150μL),在室温下搅拌3小时。加入水,并用醋酸乙酯-二乙醚萃取。将有机层依次用水、饱和食盐水洗涤,并用无水硫酸钠干燥。蒸除溶剂后,向所获得的残余物中加入甲醇。过滤收集所析出的固体,干燥,从而得到(S)-4-[1-({[1-(4-氨基甲酰基苄基)-1H-吲哚-7-基]羰基}氨基)乙基]苯甲酸甲酯(142mg)。
制备例7
将1-(4-氯苄基)-1,2,3,4-四氢喹啉-8-羧酸(310mg)、4-[(1S)-1-氨基乙基]苯甲酸甲酯盐酸盐(240mg)、EDCI·HCl(210mg)、HOBt(160mg)、吡啶(0.25mL)、以及DMF(3.00mL)的混合物,在室温下搅拌3天。向反应混合物中加入水,并用醋酸乙酯萃取。将有机层用水、和饱和食盐水洗涤,并用无水硫酸钠干燥。过滤后,减压浓缩滤液。通过硅胶柱色谱法(己烷-醋酸乙酯)纯化残余物,从而得到4-[(1S)-1-({[1-(4-氯苄基)-1,2,3,4-四氢喹啉-8-基]羰基}氨基)乙基]苯甲酸甲酯(129mg)。
制备例8
在冰浴冷却下,向反式-4-乙酰基环己烷羧酸甲酯(0.5g)、吡啶(5.0mL)的混合物中,加入羟胺盐酸盐(0.57g),并在室温下搅拌24小时。减压浓缩反应混合物。向残余物中加入醋酸乙酯、10%柠檬酸水溶液,并用醋酸乙酯萃取水层。合并有机层,用10%柠檬酸水溶液、饱和碳酸氢钠水溶液、水、饱和食盐水洗涤。将有机层用无水硫酸镁干燥,减压浓缩,从而得到反式-4-(N-羟基乙烷酰亚胺基)环己烷羧酸甲酯(0.45g)。
制备例9
向反式-4-(N-羟基乙烷酰亚胺基)环己烷羧酸甲酯(0.44g)、乙醇(8.0mL)的混合物中,加入浓氨水(2.0mL)、雷尼镍(2.0mL)在乙醇中所形成的悬浮液(6.0mL),并在3.4气压的氢气气氛下,于室温下搅拌12小时。用Celite过滤反应混合物,减压浓缩滤液。向残余物中加入二乙醚,在冰浴冷却下加入4M氯化氢-二 烷溶液(1.0mL),过滤收集所析出的固体,并用二乙醚洗涤,从而得到反式-4-(1-氨基乙基)环己烷羧酸甲酯盐酸盐(0.42g)。
制备例10
向5,6,7,8-四氢-2H-[1]苯并噻吩[2,3-d][1,3]二 嗪-2,4(1H)-二酮(1.5g)和碳酸钾(1.4g)中,加入DMF(15mL),在冰浴冷却下、加入碘甲烷(1.2mL),于室温搅拌6小时。加入碘甲烷(0.61mL)在室温下搅拌过夜后,向反应混合物中加入水(15mL),过滤收集固体,用水洗涤,并在减压条件下干燥,从而得到1-甲基-5,6,7,8-四氢-2H-[1]苯并噻吩[2,3-d][1,3]二 嗪-2,4(1H)-二酮(1.3g)。
制备例11
向1-甲基-5,6,7,8-四氢-2H-[1]苯并噻吩[2,3-d][1,3]二 嗪-2,4(1H)-二酮(0.50g)中,加入乙醇(20mL),然后依次加入三乙胺(0.44mL)、甲基4-[(1S)-1-氨基乙基]苯甲酸酯盐酸盐,并加热回流18小时。将反应混合物冷却至室温后,加入10%柠檬酸水溶液(15mL)。向混合物中加入醋酸乙酯,用水洗涤,将所获得的有机层用无水硫酸钠干燥。进行过滤、减压浓缩,并通过硅胶柱色谱法(己烷/醋酸乙酯:90/10-75/25)纯化残余物,从而得到4-[(1S)-1-({[2-(甲基 氨基)-4,5,6,7-四氢-1-苯并噻吩-3-基]羰基}氨基)乙基]苯甲酸甲酯(0.42g)。
制备例12
向4-[(1S)-1-({[2-(甲基氨基)-4,5,6,7-四氢-1-苯并噻吩-3-基]羰基}氨基)乙基]苯甲酸甲酯(0.41g)中加入1,3-二甲基-2-咪唑烷酮(4.0mL),在冰浴冷却下,加入碳酸钾(0.30g)、1-(溴甲基)-4-氯苯(0.34g),于50℃搅拌过夜。将反应混合物冷却至室温后,加入水(50mL),并用醋酸乙酯萃取。将所获得的有机层用食盐水洗涤后,用无水硫酸钠干燥,然后进行过滤、减压浓缩。通过硅胶柱色谱法(己烷/醋酸乙酯:15/1-4/1)纯化残余物、从而得到4-{(1S)-1-[({2-[(4-氯苄基)(甲基)氨基]-4,5,6,7-四氢-1-苯并噻吩-3-基}羰基)氨基]乙基}苯甲酸甲酯(0.15g)。
制备例13
在室温下,向5-溴-1-(4-氯苄基)-1H-吲哚-7-羧酸甲酯(300mg)、三甲基环三硼氧烷(100mg)、碳酸钾(165mg)、以及1,4-二 烷(9mL)的混合物中,加入四(三苯基膦)钯(0)(46mg)。将该混合物在加热回流下搅拌15小时。将反应混合物冷却至室温,加入水后,用醋酸乙酯萃取。将有机层用无水硫酸钠干燥,蒸除溶剂,并通过硅胶柱色谱法(己烷-醋酸乙酯)纯化所获得的残余物,从而得到1-(4-氯苄基)-5-甲基-1H-吲哚-7-羧酸甲酯(60mg)。
制备例14
在氩气气氛下,于室温下,向(3-氧代-1,3-二氢-2-苯并呋喃-1-基)(三苯基)鏻溴化物(5.1g)、以及四氢呋喃(50mL)的混合物中,加入叔丁醇钾(1.3g)、以及5-氯-2-硝基苯甲醛(1.0g),并搅拌5分钟。向反应混合物中加入水,并用醋酸乙酯萃取。将有机层用饱和食盐水洗涤,并用无水硫酸钠干燥。过滤后,减压浓缩滤液。通过硅胶柱色谱法(己烷-醋酸乙酯)纯化残余物,从而得到3-(5-氯-2-硝基苯亚甲基)-2-苯并呋喃-1(3H)-酮(808mg)。
制备例15
将3-(5-氯-2-硝基苯亚甲基)-2-苯并呋喃-1(3H)-酮(808mg)、还 原铁(750mg)、氯化铵(72mg)、水(2.5mL)、以及乙醇(25mL)的混合物在80℃下搅拌4小时。用Celite过滤反应混合物,并在减压条件下蒸除溶剂。通过硅胶柱色谱法(己烷-醋酸乙酯)纯化残余物,从而得到3-(2-氨基-5-氯苯亚甲基)-2-苯并呋喃-1(3H)-酮(466mg)。
制备例16
将1-(6-溴吡啶-3-基)乙酮(5.00g)、丙烷-1,3-二基双(二苯基膦)(1.546g)、DMF(55mL)、甲醇(30mL)、三乙胺(10.5mL)混合后,除去反应容器内的气体,并用氩气置换。向其中加入醋酸钯(II)(842mg)后,将反应容器内的气体用一氧化碳置换,并在70℃下搅拌2天。冷却至室温后,将反应混合物用二乙醚-醋酸乙酯的混合液稀释后,依次用水、饱和食盐水洗涤。将有机层用无水硫酸钠干燥后,在减压条件下,蒸除溶剂,并通过硅胶柱色谱法(己烷-醋酸乙酯)纯化所获得的残余物,从而得到5-乙酰基吡啶-2-羧酸甲酯(1.16g)。
制备例17
在室温下,向3-(2-氨基-5-氯苯亚甲基)-2-苯并呋喃-1(3H)-酮(466mg)在乙醇(3.5mL)中所形成的溶液中,加入1M氢氧化钠水溶液(3.4mL),并加热回流45分钟。在冰浴冷却下,向反应混合物中,加入1M盐酸使其呈酸性,并在室温下搅拌1小时。过滤所生成的析出物,并用二乙醚萃取滤液。将有机层用饱和食盐水洗涤,用无水硫酸钠干燥。过滤后,减压浓缩滤液,从而得到2-(5-氯-1H-吲哚-2-基)苯甲酸(395mg)。
制备例18
在氩气气氛下,于室温下,向2-(5-氯-1H-吲哚-2-基)苯甲酸(217mg)、DMF(4.0mL)、以及THF(1.0mL)的混合物中,加入氢化钠(液体石蜡中的55%的分散体,77mg),并搅拌5分钟。在室温下,加入碘甲烷(0.50mL),并搅拌12小时。向反应混合物中,加入水、并用醋酸乙酯萃取。将有机层用水和饱和食盐水洗涤,并用无水硫酸钠干燥。过滤后,减压浓缩滤液,从而得到2-(5-氯-1-甲基-1H-吲哚-2-基)苯甲酸甲酯(270mg)。
制备例19
在冰浴冷却下,向4-丙酰基苯甲酸甲酯(0.50g)和吡啶(5.0mL)的混合物中,加入羟胺盐酸盐(0.54g),并在室温下搅拌4小时。减压浓缩反应混合物,向残余物中加入醋酸乙酯和10%柠檬酸水溶液,并用醋酸乙酯萃取水层。合并有机层,用10%柠檬酸水溶液、饱和碳酸氢钠水溶液、水、饱和食盐水洗涤。将有机层用无水硫酸镁干燥,减压浓缩后,向残余物中加入乙醇(15mL)。向反应混合物中加入雷尼镍(2.0mL)在乙醇(15mL)中所形成的悬浮液、浓氨水(3.0mL),并在3气压的氢气气氛下、于室温下搅拌14小时。用Celite过滤反应混合物中的不溶物,并减压浓缩滤液。向残余物中加入二乙醚(10mL),在冰浴冷却下,加入4M-氯化氢/二 烷溶液(1.0mL)。过滤收集所析出的结晶,用二乙醚洗涤,从而得到4-(1-氨基丙基)苯甲酸甲酯盐酸盐(0.51g)。
制备例20
向5-乙酰基吡啶-2-羧酸甲酯(1.00g)、THF(24mL)、甲醇(12mL)的混合物中,加入硼氢化钠(110mg),并在室温下搅拌2小时。减压浓缩混合物后,向所获得的残余物中加入饱和氯化钠水溶液。用醋酸乙酯萃取后,将有机层用无水硫酸钠干燥。蒸除溶剂后,在减压条件下干燥,从而得到5-(1-羟乙基)吡啶-2-羧酸甲酯(897mg)。
制备例21
将5-(1-羟乙基)吡啶-2-羧酸甲酯(895mg)、二氯甲烷(10mL)的混合物用冰浴冷却后,加入三乙胺(1.72mL)和甲磺酰氯(765μL)。在冰浴冷却下,将混合物搅拌3分钟后,在室温下搅拌30分钟。向混合物中加入水,并用氯仿萃取。将该有机层用无水硫酸钠干燥后,在减压条件下蒸除溶剂,从而得到淡黄色油状残余物(1.457g)。将该残余物与DMF(5mL)和叠氮化钠(965mg)混合后,在60℃下搅拌1小时。将混合物冷却至室温后,加入水,并用醋酸乙酯-二乙醚的混合液萃取。将有机层依次用水、饱和食盐水洗涤后,用无水硫酸钠干燥。在减压条件下蒸除溶剂,通过硅胶柱色谱法(己烷-醋酸乙酯)纯化所获得的残余物,从而得到5-(1-叠氮乙基)吡啶-2-羧酸甲酯(828mg)。
制备例22
在冰浴冷却下,向3-羟基-4-甲基苯甲酸(3.0g)、碳酸钾(10.9g)、乙腈(60mL)的混合物中,加入乙基碘(4.8mL),并在60℃下搅拌过夜。其后,再加入乙基碘(4.8mL),在70℃下搅拌3天。进一步加入乙基碘(4.8mL)、碳酸钾(5.5g),并搅拌过夜。向反应混合物中加入水(100mL),用醋酸乙酯萃取,将所获得的有机层用饱和食盐水洗涤,用无水硫酸钠脱水后,进行减压浓缩。通过硅胶柱色谱法(醋酸乙酯/己烷:5/95)纯化所获得的残余物,从而得到3-乙氧基-4-甲基苯甲酸乙酯(4.0g)。
制备例23
在室温下,将(S)-4-(1-乙酰胺基乙基)苯甲酸甲酯(4.40g)和浓硫酸(15mL)混合,搅拌至均匀后,用冰浴冷却。在使内部温度维持在10℃以下的状态下,用30分钟向其中滴加发烟硝酸(3mL)与浓硫酸(2mL)的混合液。滴加结束后,在室温下搅拌混合物5小时。将反应液注入到冰水中,搅拌后,用醋酸乙酯萃取。将有机层用饱和碳酸氢钠水溶液洗涤后,用无水硫酸钠干燥。在减压条件下蒸除溶剂,从而得到(S)-4-(1-乙酰胺基乙基)-3-硝基苯甲酸甲酯(4.83g)。
制备例24
在氢气气氛下,将(S)-4-(1-乙酰胺基乙基)-3-硝基苯甲酸甲酯(4.83g)、醋酸乙酯(30mL)、10%钯/碳(500mg)的混合物在室温下搅拌18小时。反应后,过滤除去催化剂,并在减压条件下蒸除溶剂。向所获得的残余物中,加入醋酸乙酯,并进行加热回流。将其冷却至室温后,过滤收集析出物,从而得到(S)-3-氨基-4-(1-乙酰胺基乙基)苯甲酸甲酯(3.31g)。
制备例25
向3-乙氧基-4-甲基苯甲酸乙酯(2.0g)、N-溴代琥珀酰亚胺(1.9g)和醋酸乙酯(40mL)的混合物中,加入2,2′-偶氮二(2-甲基丙腈)(15mg),并在加热回流下搅拌14小时。冷却混合物,加入己烷,过滤所析出的固体,并减压浓缩所获得的滤液。通过硅胶柱色谱法(醋酸乙酯/己烷:5/95)纯化残余物,从而得到4-(溴甲基)-3-乙氧基苯 甲酸乙酯(2.4g)。
制备例26
在冰浴冷却下,向4-氯-1H-吡咯-2-羧酸(0.20g)和DMF(2.0mL)的混合物中,加入叔丁醇钾(0.31g),并在室温下搅拌15分钟。在冰浴冷却下,向反应混合物中加入1-溴甲基-4-氯苯(0.29g),并在室温下搅拌14小时。在室温下,向反应混合物中加入水,并用醋酸乙酯萃取。将有机层用水、饱和食盐水洗涤,用无水硫酸镁干燥后进行过滤。减压浓缩滤液,通过硅胶柱色谱法纯化残余物,从而得到4-氯-1-(4-氯苄基)-1H-吡咯-2-羧酸(0.06g)。
制备例27
向亚硝酸钠(193mg)和浓硫酸(2mL)的混合物中,滴加(S)-3-氨基-4-(1-乙酰胺基乙基)苯甲酸甲酯(600mg)在醋酸(6mL)中所形成的溶液,并在室温下搅拌30分钟。向用冰浴冷却的氯化铜(I)(550mg)在浓盐酸(6mL)中所形成的溶液中,滴加上述的反应混合物后,在室温下搅拌5小时。将反应液注入到冰水中,并用氯仿萃取。将有机层用水洗涤后,用无水硫酸钠干燥。蒸除溶剂,并通过硅胶柱色谱法(氯仿-甲醇)纯化所获得的残余物,从而得到(S)-4-(1-乙酰胺基乙基)-3-氯苯甲酸甲酯(465mg)。
制备例28
在冰浴冷却下,向4-甲酰基-3-甲氧基苯甲酸甲酯(3.30g)和THF(30mL)的混合物中,滴加甲基溴化镁(3M,二乙醚溶液,3.60mL)。滴加后,将混合物在冰浴冷却下搅拌1小时。加入饱和氯化铵水溶液使反应停止,并用醋酸乙酯萃取。将有机层用饱和食盐水洗涤后,用无水硫酸钠水溶液干燥。在减压条件下蒸除溶剂,通过硅胶柱色谱法(己烷-醋酸乙酯)纯化所获得的残余物,从而得到4-(1-羟乙基)-3-甲氧基苯甲酸甲酯(1.92g)。
制备例29
向1-(4-溴苯基)-1-环丙基甲胺(1.08g)和THF(10mL)的混合物中,加入三乙胺(1mL)和二碳酸二叔丁酯(1.25mL),将混合物在室温下搅拌16小时。减压浓缩溶剂,通过硅胶柱色谱法(己烷-醋酸乙 酯)纯化所获得的残余物,从而得到[(4-溴苯基)(环丙基)甲基]氨基甲酸叔丁酯(1.36g)。
制备例30
在室温下,向4-(1-羟乙基)-3-甲氧基苯甲酸甲酯(1.92g)、叠氮磷酸二苯酯(2.76g)和甲苯(20mL)的混合物中,加入1,8-二氮杂双环[5.4.0]十一碳-7-烯(1.5mL),并在室温下搅拌2天。在室温下,向该混合物中加入THF(10mL)、水(5mL)和三苯基膦(3.0g),并将混合物在60℃下搅拌3小时。将混合物冷却至室温,在减压条件下,蒸除溶剂后,用醋酸乙酯萃取。向该有机层中,加入1M盐酸水溶液(50mL),并将目标物萃取到水层中。向该水层中加入1M氢氧化钠水溶液(60mL)后,将目标物用醋酸乙酯萃取3次。合并有机层,用饱和食盐水洗涤后,用无水硫酸钠干燥。在减压条件下蒸除溶剂后,向所获得的残余物(748mg)中,加入4M氯化氢的1,4-二 烷溶液(4mL),并搅拌3分钟后,进行减压浓缩。向该残余物中加入醋酸乙酯,在室温下搅拌10分钟后,过滤收集析出物,从而得到4-(1-氨基乙基)-3-甲氧基苯甲酸甲酯盐酸盐(439mg)。
制备例31
将(S)-4-(1-乙酰胺基乙基)-3-氯苯甲酸甲酯(464mg)和2M盐酸(12mL)的混合物在100℃下搅拌2天。冷却至室温后,将混合物减压浓缩,进一步用乙醇共沸,干燥,从而得到(S)-4-(1-氨基乙基)-3-氯苯甲酸盐酸盐(428mg)。
制备例32
在冰浴冷却下,向氢化钠(0.29g,液体石蜡中的55%的分散体)和DMF(10mL)的混合物中,加入4H-呋喃并[3,2-b]吡咯-5-羧酸甲酯(0.5g)并搅拌10分钟,进一步加入1-(溴甲基)-4-氯苯(0.81g),然后在室温下搅拌4小时。向反应混合物中加入10%柠檬酸水溶液(10mL),并用醋酸乙酯萃取。将有机层用无水硫酸钠干燥后,减压浓缩,并通过硅胶柱色谱法(己烷/醋酸乙酯:5/1-3/1)纯化残余物,从而得到4-(4-氯苄基)-4H-呋喃并[3,2-b]吡咯-5-羧酸(0.35g)。
制备例33
将4-{[(叔丁氧羰基)氨基](环丙基)甲基}苯甲酸甲酯(793mg)、甲醇(5mL)和4M氯化氢/二噁烷(5mL)混合,并在室温下搅拌2小时。在减压条件下蒸除溶剂后,向残余物中加入醋酸乙酯。过滤收集所析出的固体,在减压条件下干燥,从而得到4-[氨基(环丙基)甲基]苯甲酸甲酯盐酸盐(561mg)。
制备例34
在氩气气氛下、于-78℃下,搅拌7-溴-5-甲氧基-1H-吲哚(1.2g)和THF(12mL)的混合物。在-50℃以下的条件下,向反应混合物中滴加正丁基锂的正己烷溶液(1.65M,9.6mL)。将反应混合物在冰浴冷却下搅拌0.5小时。将反应混合物冷却至-78℃,加入干冰(10g),徐徐升温至室温。将反应混合物注入到10%柠檬酸水溶液中,用醋酸乙酯萃取。将有机层用饱和食盐水洗涤,用无水硫酸镁干燥后,过滤。减压浓缩滤液,并通过硅胶柱色谱法(THF/己烷=20→60%)纯化残余物,从而得到5-甲氧基-1H-吲哚-7-羧酸(0.60g)。
制备例35
向4-(溴甲基)-3-乙氧基苯甲酸乙酯(2.4g)中,加入DMF(24mL)后,加入叠氮化钠(0.54g)并在室温下搅拌过夜。向反应混合物中加入水(50mL),用醋酸乙酯萃取,将所获得的有机层用饱和食盐水洗涤,用无水硫酸钠干燥后,减压浓缩。向残余物中加入THF(21mL)和水(4.0mL)后,加入三苯基膦(6.6g),在室温下搅拌1小时后,在75℃下进一步搅拌1小时。将反应混合物用冰浴冷却,加入1M盐酸水溶液使pH为2后,用二乙醚洗涤。将水层用饱和碳酸氢钠水中和,并用醋酸乙酯萃取。将所获得的有机层用无水硫酸钠干燥,并减压浓缩。在冰浴冷却下,向残余物中加入醋酸乙酯(4.0mL)、4M氯化氢的醋酸乙酯溶液(4.0mL),过滤收集所析出的固体,用醋酸乙酯洗涤后,在60℃下、于减压条件下干燥,从而得到4-(氨基甲基)-3-乙氧基苯甲酸乙酯盐酸盐(1.1g)。
制备例36
在氩气气氛下,向用冰浴冷却的四氟硼酸亚硝 (355mg)和二氯甲烷(15mL)的混合物中,加入(S)-3-氨基-4-(1-乙酰胺基乙基)苯甲 酸甲酯(650mg),将反应混合物在室温下搅拌20小时。向其中加入1,2-二氯苯(15mL),在减压条件下蒸除二氯甲烷后,将混合物在160℃下搅拌2小时。冷却至室温后,加入饱和碳酸氢钠水溶液,用氯仿萃取。将有机层用无水硫酸钠干燥后,在减压条件下蒸除溶剂。通过硅胶柱色谱法(氯仿-甲醇)纯化残余物,从而得到(S)-4-(1-乙酰胺基乙基)-3-氟苯甲酸甲酯(266mg)。
制备例37
在冰浴冷却下,向4-氰基-2-甲基苯甲酸甲酯(3.0g)和甲醇(60mL)的混合物中,加入二氯化钴六水合物(8.1g)并搅拌。向混合物中缓慢地加入硼氢化钠(3.9g),并在室温下搅拌2小时。在冰浴冷却下,向反应混合物中加入饱和氨水(20mL),并在室温下搅拌30分钟。将该溶液用Celite过滤,并用甲醇洗涤。减压浓缩滤液,向所获得的残余物中加入1M盐酸(50mL),并用二乙醚洗涤。向水层中加入饱和碳酸氢钠水使pH为8,进一步加入1M氢氧化钠水溶液,使pH为10。向混合物中加入氯仿并萃取,将有机层用无水硫酸镁干燥。加入4M氯化氢的二 烷溶液(10mL),并减压浓缩。将固体用二乙醚洗涤后,过滤收集,在60℃下、于减压条件下干燥,从而得到4-(氨基甲基)-3-甲基苯甲酸甲酯盐酸盐(3.0g)。
制备例38
向1-(联苯-4-基甲基)-1H-吲哚-7-羧酸(0.20g)、4-[(1S)-1-氨基乙基]苯甲酸甲酯盐酸盐、HATU中,加入DMF(4.0mL),在冰浴冷却下,加入二异丙基乙胺(0.26mL)后,在室温下搅拌22小时。再次用冰浴冷却,加入10%柠檬酸水溶液(4.0mL),过滤收集所析出的固体,用水洗涤,在60℃下、于减压条件下干燥,从而得到4-[(1S)-1-({[1-(联苯-4-基甲基)-1H-吲哚-7-基]羰基}氨基)乙基]苯甲酸甲酯(0.30g)。
制备例39
向顺式-4-(丁氧羰基)环己烷羧酸(3.3g)、亚硫酰氯(13mL)的混合物中,加入DMF(2滴),并在50℃下搅拌0.5小时。减压浓缩反应混合物,与甲苯进行共沸,从而得到残余物。在氩气气氛下、于 -40℃的内温下,搅拌碘化铜(5.2g)和THF(13mL)的混合物。在内温为-30℃~-40℃下,向反应混合物中,用15分钟滴加甲基锂在二乙醚中所形成的溶液(1.1M,55mL),于同温下搅拌1小时。将反应混合物冷却至内温-60℃,在内温为-50℃~-60℃下,用5分钟滴加上述残余物的THF溶液(10mL)。于同温下搅拌0.5小时,滴加甲醇(15mL),升温至室温。向反应混合物中加入饱和氯化铵水溶液和醋酸乙酯,将水层用醋酸乙酯萃取。合并有机层,用饱和氯化铵水溶液、饱和食盐水洗涤,用无水硫酸镁干燥后,过滤,减压浓缩滤液。通过硅胶柱色谱法(己烷∶醋酸乙酯=9∶1)纯化残余物,从而得到顺式-4-乙酰基环己烷羧酸丁酯(2.2g)。
制备例40
向5-甲基-1H-吲哚-7-羧酸(1.1g)和碳酸钾(1.3g)中,加入DMF(22mL),并在冰浴冷却下,加入碘甲烷(1.3mL)。在室温下搅拌过夜后,向反应混合物中加入10%柠檬酸水溶液,使pH为3。用醋酸乙酯萃取,将所获得的有机层用水洗涤,用无水硫酸钠脱水后,过滤,减压浓缩。通过硅胶柱色谱法(己烷/醋酸乙酯:95/5-85/15)纯化残余物,从而得到5-甲基-1H-吲哚-7-羧酸甲酯(1.2g)。
制备例41
向用冰浴冷却的6-羟基吡啶-2-羧酸甲酯(800mg)和DME(10.5mL)、DMF(2.6mL)的混合物中,加入氢化钠(55%的油分散物,240mg),并搅拌10分钟。向其中加入溴化锂(910mg)后,将混合物在室温下搅拌15分钟后,进一步加入4-氯苄溴(2.15g)。将该混合物在65℃下搅拌20小时。加入水,用醋酸乙酯-二乙醚萃取后,将有机层依次用水、饱和食盐水洗涤,并用无水硫酸钠干燥。蒸除溶剂,并通过硅胶柱色谱法(己烷-醋酸乙酯)纯化所获得的残余物,从而分别得到1-(4-氯苄基)-6-氧代-1,6-二氢吡啶-2-羧酸甲酯(270mg;实施例41a)的无色油状物和6-[(4-氯苄基)氧基]吡啶-2-羧酸甲酯(448mg;实施例41b)的无色油状物。
制备例42
将5-溴-1H-吲哚-7-羧酸甲酯(300mg)、1-甲基-2-吡咯烷酮(6 mL)、甲基亚磺酸钠(600mg)和碘化铜(I)(1.10g)的混合物,在氩气气氛下、于150℃下搅拌17小时。将反应混合物冷却至室温,加入醋酸乙酯后,过滤除去不溶物。向滤液中加入水,并用醋酸乙酯萃取。将有机层依次用水、饱和食盐水洗涤后,用无水硫酸钠干燥。在减压条件下蒸除溶剂,并通过硅胶柱色谱法(己烷-醋酸乙酯)纯化所获得的残余物,从而得到5-(甲磺酰基)-1H-吲哚-7-羧酸甲酯(91mg)。
制备例43
向氨基甲酸叔丁酯(5.60g)和正丙醇(50mL)的混合物中,加入0.5M氢氧化钠水溶液(94mL)和次氯酸叔丁酯(5.32mL),并在室温下搅拌20分钟。在冰浴冷却下,向反应混合物中,滴加(DHQD)2Phal(766.5mg)在正丙醇(50mL)中所形成的溶液。进一步在同温下,用30分钟滴加4-乙烯基苯甲酸甲酯(2.5g)在正丙醇(80mL)中所形成的溶液后,加入锇酸钾二水合物(253.8mg)。将反应混合物在冰浴冷却下搅拌1小时后,于4℃下搅拌过夜。减压浓缩反应混合物,向残余物中加入水(250mL)。将水层用醋酸乙酯(100mL×3)萃取。合并有机层,用1M盐酸水溶液(200mL)和饱和食盐水洗涤,用无水硫酸镁干燥后,在减压条件下蒸除溶剂。通过硅胶柱色谱法(己烷-醋酸乙酯=3∶1)纯化残余物,从而得到4-{(1R)-1-[(叔丁氧羰基)氨基]-2-羟乙基}苯甲酸甲酯(850mg)的白色固体。
制备例44
向1-(4-溴苄基)-1H-吲哚-7-羧酸甲酯(0.63g)、4,4,4′,4′,5,5,5′,5′-八甲基-2,2′-二-1,3,2-二氧杂环戊硼烷(0.56g)、醋酸钾(0.27g)、双(三苯基膦)二氯化钯(II)(39mg)、三苯基膦(29mg)中,加入甲苯(6.0mL),在氩气气氛下、于110℃下搅拌。搅拌5小时后,通过硅胶柱色谱法(己烷-醋酸乙酯=20/1-10/1)纯化反应混合物,从而得到1-[4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苄基]-1H-吲哚-7-羧酸甲酯(0.45g)。
制备例45
在室温下,向7-溴茚满-1-醇(1.06g)、三苯基膦(1.86g)、4- 氯苯酚(911mg)和甲苯(30mL)的混合物中,滴加偶氮二甲酸二乙酯(2.2M甲苯溶液,3.3mL)。滴加后,将混合物在室温下搅拌2小时。在减压条件下蒸除溶剂后,通过硅胶柱色谱法(己烷-醋酸乙酯)纯化所获得的残余物,从而得到7-溴-1-(4-氯苯氧基)茚满(306mg)。
制备例46
在室温下,向7-溴-1H-吡咯并[3,2-c]吡啶(0.16g)和THF(6.0mL)的混合物中,加入二碳酸二叔丁酯(0.26g)和N,N-二甲基-4-氨基吡啶(0.010g),并在室温下搅拌17小时。减压浓缩反应混合物,并通过硅胶柱色谱法(醋酸乙酯/己烷=0~25%)纯化残余物,从而得到7-溴-1H-吡咯并[3,2-c]吡啶-1-羧酸叔丁酯(0.22g)。
制备例47
在室温下,向7-溴吲哚(3.3g)和1,3-二甲基-3,4,5,6,-四氢-2(1H)-嘧啶酮(33mL)的混合物中,加入2-苯基环氧乙烷(2.5mL)和碳酸铯(11g),于80℃下搅拌12小时。向反应混合物中,加入醋酸乙酯和水,并用醋酸乙酯萃取。将有机层用水和饱和食盐水洗涤,用无水硫酸钠干燥,并减压蒸除。通过硅胶柱色谱法(己烷∶醋酸乙酯=4∶1)纯化残余物,从而得到2-(7-溴-1H-吲哚-1-基)-1-苯基乙醇(5.1g)。
制备例48
在一氧化碳气氛下、于80℃下,将7-溴-1H-吡咯并[3,2-c]吡啶-1-羧酸叔丁酯(0.20g)、1,3-双(二苯基膦基)丙烷(0.028g)、醋酸钯(0.015g)、DMF(4.0mL)、甲醇(6.0mL)和三乙胺(0.28mL)的混合物搅拌2天。冷却反应混合物,并用氩气置换。将反应混合物用醋酸乙酯稀释,用水和饱和食盐水洗涤,用无水硫酸镁干燥后,过滤。通过硅胶柱色谱法(醋酸乙酯/己烷=30~60%)纯化残余物,从而得到1H-吡咯并[3,2-c]吡啶-7-羧酸甲酯(0.081g)。
制备例49
在室温下,向4-[(1S)-1-({[1-(4-氯苄基)-1H-吲哚-7-基]羰基}氨基)乙基]苯甲酸(250mg)和DMF(5mL)的混合物中,加入1,1’-羰基 二咪唑(187mg),搅拌5分钟后,依次加入乙酸3-(氨基磺酰基)丙酯(209mg)、1,8-二氮杂双环[5.4.0]十一碳-7-烯(173μL),并搅拌3天。将反应混合物用冰浴冷却,加入10%柠檬酸水(30mL)并搅拌30分钟。过滤收集所析出的固体,用冷却的乙醇(4mL)洗涤,从而得到1-(4-氯苄基)-N-[(1S)-1-(4-{[(3-乙酰氧基丙基)磺酰基]氨基甲酰基}苯基)乙基]-1H-吲哚-7-甲酰胺(210mg)的淡黄色固体。
制备例50
向1-[4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苄基]-1H-吲哚-7-羧酸甲酯(0.30g)、三氟甲烷磺酸吡啶-2-基酯(0.35g)、磷酸三钾(0.49g)、氯化钯(II)(27mg)、联苯-2-基(二环己基)膦(0.11g)中,加入二 烷(12mL)和水(3.0mL),于100℃下搅拌4小时。通过硅胶柱色谱法(己烷/醋酸乙酯=5/1-4/1)纯化反应混合物,从而得到1-(4-吡啶-2-基苄基)-1H-吲哚-7-羧酸甲酯(0.15g)。
制备例51
向2-(7-溴-1H-吲哚-1-基)-1-苯基乙醇(0.70g)中加入DMF(7.0mL)、叔丁基(氯)二甲基硅烷(0.47g)、咪唑(0.23g),在室温下搅拌25小时。向反应混合物中加入10%柠檬酸水溶液(15mL),用醋酸乙酯萃取,将所获得的有机层用食盐水洗涤。用无水硫酸钠干燥,减压浓缩,并通过硅胶柱色谱法(己烷/醋酸乙酯=99/1-90/10)纯化所获得的残余物,从而得到7-溴-1-(2-{[叔丁基(二甲基)甲硅烷基]氧基}-2-苯基乙基)-1H-吲哚(0.92g)。
制备例52
向7-溴-1-(2-{[叔丁基(二甲基)甲硅烷基]氧基}-2-苯基乙基)-1H-吲哚(0.91g)中,加入脱水THF(30mL),在氩气置换下、于-78℃下,加入正丁基锂己烷溶液(1.6M,5.2mL)。从-78℃升温至-5℃,并搅拌30分钟。将反应混合物再次冷却至-78℃,加入干冰后,在室温下搅拌。向混合物中加入二乙醚、用1M氢氧化钠水溶液洗涤。向所获得的水层加入10%柠檬酸水溶液使pH为3,将其用醋酸乙酯萃取。将有机层用水和饱和食盐水洗涤,用无水硫酸钠干燥后,减压浓缩。通过硅胶柱色谱法(己烷/醋酸乙酯=3/1)纯化残余物,从而 得到1-[(E)-2-苯基乙烯基]-1H-吲哚-7-羧酸(0.34g)。
制备例53
向1H-吲哚-7-羧酸甲酯(1.5g)中加入DMF(15mL),在冰浴冷却下,加入叔丁醇钾(1.5g)并搅拌10分钟。向其中加入4-(溴甲基)联苯(2.8g),于室温下搅拌19小时。将反应混合物再次用冰浴冷却,加入10%柠檬酸水溶液(20mL),并用醋酸乙酯萃取。将有机层用饱和食盐水洗涤后,用无水硫酸钠干燥,减压浓缩。通过硅胶柱色谱法(己烷/醋酸乙酯=97/3-95/5)纯化残余物,从而得到1-(联苯-4-基甲基)-1H-吲哚-7-羧酸甲酯(2.5g)。
制备例54
向1-(联苯-4-基甲基)-1H-吲哚-7-羧酸甲酯(2.5g)中,加入甲醇(20mL)、THF(20mL)、1M氢氧化钠水溶液(10mL),于60℃下搅拌16小时。向反应混合物中加入10%柠檬酸水溶液(20mL),用醋酸乙酯萃取,用食盐水洗涤有机层。用无水硫酸钠脱水后,过滤,减压浓缩,向所获得的残余物中加入二异丙基醚并使其固化,然后过滤收集。通过硅胶柱色谱法(氯仿/甲醇=99/1-97/3)纯化该固体,从而得到1-(联苯-4-基甲基)-1H-吲哚-7-羧酸(0.99g)。
制备例55
向(6-哌啶-1-基吡啶-3-基)甲醇(0.61g)中,加入二氯甲烷(6.0mL),并在冰浴冷却下滴加亚硫酰氯(1.0mL)。进一步加入催化剂量的DMF后,于室温下搅拌2小时。加入二氯甲烷(5.0mL)、亚硫酰氯(1.0mL),于60℃下搅拌过夜。减压浓缩反应混合物,加入DMF(10mL),在冰浴冷却下,加入1H-吲哚-7-羧酸甲酯(0.56g)、叔丁醇钾(1.3g),在室温下搅拌3小时。向反应混合物中加入醋酸乙酯和水并萃取,将有机层用食盐水洗涤,用无水硫酸钠干燥后,过滤,减压浓缩。通过硅胶柱色谱法(己烷/醋酸乙酯=95/5-70/30)纯化残余物,从而得到1-[(6-哌啶-1-基吡啶-3-基)甲基]-1H-吲哚-7-羧酸甲酯(0.12g)。
制备例56
向1-[4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)苄基]-1H-吲 哚-7-羧酸甲酯(0.15g)、1,1′-双(二苯基膦基)二茂铁钯(14mg)、氟化铯(0.17g)和3-溴吡啶(79mg)中,加入二噁烷(4.5mL),在氩气气氛下、于100℃下搅拌21小时。通过硅胶柱色谱法(己烷/醋酸乙酯=2/1-1/1)纯化反应混合物,从而得到1-(4-吡啶-3-基苄基)-1H-吲哚-7-羧酸甲酯(0.13g)。
制备例57
在室温下,向(1-苯基哌啶-4-基)甲醇(958mg)、1H-吲哚-7-羧酸甲酯(590mg)和甲苯(20mL)的混合物中,加入(三丁基膦烯)乙腈(1.0g)。在100℃下搅拌1天。将反应混合物冷却至室温后,减压浓缩。通过硅胶柱色谱法(己烷-醋酸乙酯)纯化残余物,从而得到1-[(1-苯基哌啶-4-基)甲基]-1H-吲哚-7-羧酸甲酯(163mg)。
制备例58
加入4-苯基噻吩-2-甲醇(0.21g)、甲苯(2.0mL)、和催化剂量的吡啶,在冰浴冷却下,滴加亚硫酰氯(0.16mL)。在室温下搅拌3小时后,减压浓缩反应混合物,用甲苯共沸,并在60℃下、于减压条件下干燥,从而得到2-(氯甲基)-4-苯基噻吩(0.22g)。
制备例59
向4-溴-1-(4-氯苄基)-1H-吡咯-2-羧酸甲酯(0.72g)和DMF(21mL)的混合物中,加入苯基硼酸(0.30g)、碳酸钠(0.58g)、水(3.0mL)和四(三苯基膦)钯(0.13g),于100℃下搅拌24小时。向反应混合物中加入醋酸乙酯和水,用Celite过滤不溶物。将有机层用水、饱和食盐水洗涤,用无水硫酸镁干燥后,过滤。减压浓缩滤液,通过硅胶柱色谱法(醋酸乙酯/己烷=0~10%)纯化残余物,从而得到1-(4-氯苄基)-4-苯基-1H-吡咯-2-羧酸甲酯(0.26g)。
制备例60
在室温下,向4-{[7-({(1S)-1-[4-(甲氧基羰基)苯基]乙基}氨基甲酰基)-1H-吲哚-1-基]甲基}哌啶-1-羧酸叔丁酯(1.67g)、以及THF(20mL)的混合物中,加入4M氯化氢的醋酸乙酯溶液(2.0mL),并搅拌1小时。将反应混合物在60℃下搅拌6小时。减压浓缩反应混合物。将残余物用醋酸乙酯和二乙醚洗涤,过滤收集,在减压条件下干 燥,从而得到4-[(1S)-1-({[1-(哌啶-4-基甲基)-1H-吲哚-7-基]羰基}氨基)乙基]苯甲酸甲酯盐酸盐(1.46g)。
制备例61
在室温下,向4-[(1S)-1-({[1-(哌啶-4-基甲基)-1H-吲哚-7-基]羰基}氨基)乙基]苯甲酸甲酯盐酸盐(150mg)和二氯甲烷(2.0mL)的混合物中,加入三乙酰氧基硼氢化钠(210mg)和苯甲醛(70mg),并搅拌3天。向反应混合物中,加入水。进一步加入1M氢氧化钠水溶液使其呈碱性,并用醋酸乙酯萃取。将有机层用饱和食盐水洗涤,用无水硫酸钠干燥。过滤后,减压浓缩滤液,从而得到4-{(1S)-1-[({1-[(1-苄基哌啶-4-基)甲基]-1H-吲哚-7-基}羰基)氨基]乙基}苯甲酸甲酯的白色固体(121mg)。
制备例62
加入1-(1,3-苯并 唑-2-基甲基)-1H-吲哚-7-羧酸甲酯(0.22g)、甲醇(2.0mL)、THF(2.0mL)、1M氢氧化钠水溶液(1.0mL),于70℃下搅拌14小时。将反应混合物用冰浴冷却,加入10%柠檬酸水溶液(5.0mL),过滤收集所析出的固体,用水、二乙醚/己烷(1/1)洗涤,从而得到1-{2-[(2-羟基苯基)氨基]-2-氧代乙基}-1H-吲哚-7-羧酸(0.18g)。
制备例63
向4-{[(1H-苯并咪唑-2-基羰基)氨基]甲基}苯甲酸甲酯(230mg)、碳酸钾(257mg)和DMF(4.6mL)的混合物中,加入对氯溴苄(191mg),并在室温下搅拌2.5天。向反应混合物中加入水(30mL),并用醋酸乙酯(30mL)萃取。将有机层依次用饱和碳酸氢钠水、饱和食盐水洗涤,用无水硫酸镁干燥。将通过过滤、浓缩而获得的残余物用甲醇(2mL)洗涤,从而得到4-[({[1-(4-氯苄基)-1H-苯并咪唑-2-基]羰基}氨基)甲基]苯甲酸甲酯(269mg)的白色固体。
制备例64
向5-氯-1H-吲哚-7-羧酸乙酯(3.0g)和醋酸(30mL)的混合物中,加入氰基硼氢化钠(2.5g),并在室温下搅拌19小时。减压浓缩反应混合物,向残余物中加入饱和碳酸氢钠水使pH为8。用氯仿萃 取,将有机层用无水硫酸钠干燥,过滤,并减压浓缩。向残余物中加入二乙醚/己烷(1/5)并固化,然后过滤收集。向该固体中加入醋酸乙酯(10mL),加入4M氯化氢的醋酸乙酯溶液(10mL)后,减压浓缩。向残余物中加入二乙醚/己烷混合物(1/5),过滤收集固体,在减压条件下干燥,从而得到5-氯吲哚啉-7-羧酸乙酯盐酸盐(1.6g)。
制备例65
向1-[(5-溴吡啶-2-基)甲基]-5-氯-1H-吲哚-7-羧酸乙酯(0.30g)、(9,9-二甲基-9H-呫吨-4,5-二基)双(二苯基膦)(88mg)、叔丁醇钠(0.12g)、哌啶(84mg)、三(二亚苄基丙酮)二钯(0)(70mg)和脱水甲苯(6.0mL)的混合物中,使氩气冒泡10分钟后,于110℃下搅拌2小时。将反应混合物用Celite过滤,用二乙醚洗涤。向滤液中加入饱和碳酸氢钠水,用二乙醚萃取,将有机层用饱和食盐水洗涤。用无水硫酸钠干燥,过滤,减压浓缩,并通过硅胶柱色谱法(己烷/醋酸乙酯=1/1)纯化残余物,从而得到5-氯-1-[(5-哌啶-1-基吡啶-2-基)甲基]-1H-吲哚-7-羧酸乙酯(0.23g)。
制备例66
将2-氟-5-(三氟甲基)苄腈(1000mg)、5-氯-1H-吲哚(800mg)、碳酸钾(1.8g)和DMSO(10m1)的混合物,在100℃下搅拌14小时。将反应混合物冷却至室温,加入水,并用醋酸乙酯萃取。将有机层用水和饱和食盐水洗涤,用无水硫酸钠干燥。过滤后,减压浓缩滤液,从而得到2-(5-氯-1H-吲哚-1-基)-5-(三氟甲基)苄腈(1.66g)。
制备例67
在室温下,向2-(5-氯-1H-吲哚-1-基)-5-(三氟甲基)苄腈(1.66g)和乙二醇(18mL)的混合物中,加入1M氢氧化钠水溶液(26mL),于180℃下搅拌16小时。将反应混合物冷却至室温,加入1M盐酸(26mL)进行中和,用醋酸乙酯萃取。将有机层用饱和食盐水洗涤,用无水硫酸钠干燥。过滤后,减压浓缩滤液,从而得到2-(5-氯-1H-吲哚-1-基)-5-(三氟甲基)苯甲酸(1.67g)。
制备例68
在室温下,向1-(1,2,3,4-四氢异喹啉-7-基甲基)-5-(三氟甲基)-1H- 吲哚-7-羧酸乙酯(0.14g)和醋酸乙酯(10mL)的混合物中,加入二氧化锰(0.30g)。将反应液在加热回流条件下搅拌6.5小时。在室温下,向反应液中进一步加入甲苯(10mL)和二氧化锰(0.30g),于110℃下搅拌1天后,于130℃搅拌1天。将反应液冷却至室温,用Celite过滤,并减压浓缩滤液。通过硅胶柱色谱法(己烷∶醋酸乙酯=75∶25-30∶70)纯化残余物,从而得到1-(异喹啉-7-基甲基)-5-(三氟甲基)-1H-吲哚-7-羧酸乙酯(85mg)。
制备例505
在水浴冷却下,向4-溴-3-氯-2-甲基苯胺盐酸盐(1.0g)、醋酸钠(0.5g)和醋酸(15mL)的混合物中,加入N-碘代丁二酰亚胺(1.0g)。将反应混合物在在室温下搅拌3.5小时。向反应混合物中加入醋酸乙酯和水,用碳酸钾使其呈碱性之后,进行分液操作,将有机层用饱和食盐水洗涤,用无水硫酸钠干燥后,减压蒸除。通过硅胶柱色谱法(己烷∶醋酸乙酯=100∶0-90∶10)纯化残余物,从而得到4-溴-3-氯-6-碘-2-甲基苯胺(1.3g)。
制备例506
在水浴冷却下,向N-[2-甲基-3-(三氟甲基)苯基]乙酰胺(6.2g)和醋酸(40ml)的混合物中,加入溴(1.8ml)在醋酸中所形成的溶液(10ml)。将反应液在室温下搅拌过夜,然后在50℃下搅拌2小时。在水浴冷却下,向反应液中进一步加入溴(1.5ml),于50℃下搅拌1天。在水浴冷却下,向反应液中进一步加入溴(2.0ml),于50℃下搅拌1天。在水浴冷却下,向反应液中进一步加入溴(2.0ml),于50℃下搅拌1天。在水浴冷却下,向反应液中进一步加入溴(2.0ml),于50℃下搅拌4天。将反应液注入到冰水(约200g)中,加入醋酸乙酯,用碳酸钾进行中和。进行分液操作,将有机层依次用硫代硫酸钠水溶液、饱和食盐水洗涤,用无水硫酸钠干燥后,减压蒸除,从而得到N-[4-溴-2-甲基-3-(三氟甲基)苯基]乙酰胺(9.0g)。
制备例507
在室温下,向5-溴-7-(溴甲基)-6-氯-1H-吲哚-1-羧酸叔丁酯(7.2g)和乙腈(50mL)的混合物中,加入4-甲基吗啉-4-氧化物(2.7g)。 将反应混合物在50℃下搅拌7小时,然后在70℃下搅拌过夜。减压浓缩反应混合物,加入醋酸乙酯和水,进行分液操作,将有机层用饱和食盐水洗涤,用无水硫酸钠干燥后,减压蒸除。硅胶柱色谱法(己烷∶醋酸乙酯=100∶0-90∶10)纯化残余物,从而得到5-溴-6-氯-7-甲酰基-1H-吲哚-1-羧酸叔丁酯(2.9g)。
制备例508
在冰浴冷却下,向5-溴-6-氯-7-甲酰基-1H-吲哚-1-羧酸叔丁酯(2.9g)、磷酸二氢钠(2.0g)、2-甲基-2-丁烯(2.6g)、水(10mL)、和1,4-二噁烷(30mL)的混合物中,加入亚氯酸钠(1.8g)。将反应混合物在冰浴冷却下搅拌1小时,然后在室温下搅拌5小时。减压浓缩反应混合物,加入醋酸乙酯和水,进行分液操作,将有机层用饱和食盐水洗涤,用无水硫酸钠干燥后,减压蒸除,从而得到5-溴-1-(叔丁氧羰基)-6-氯-1H-吲哚-7-羧酸(3.1g)。
制备例509
在室温下,向5-溴-1-(叔丁氧羰基)-6-氯-1H-吲哚-7-羧酸(0.3g)、水(2.0mL)和甲醇(6.0mL)的混合物中,加入碳酸钾(0.6g)。将反应混合物在70℃下搅拌5.5小时。减压浓缩反应混合物,加入醋酸乙酯和水,用1M盐酸使其呈酸性之后,进行分液操作,将有机层用饱和食盐水洗涤,用无水硫酸钠干燥后,减压蒸除,从而得到5-溴-6-氯-1H-吲哚-7-羧酸(0.22g)。
制备例510
在室温下,向N-[4-溴-2-甲基-3-(三氟甲基)苯基]乙酰胺(9.0g)和乙醇(40mL)的混合物中,加入浓盐酸(40mL)。将反应混合物在100℃下搅拌4小时。将反应混合物冷却至室温,加入醋酸乙酯和水,用碳酸钾使其呈碱性之后,进行分液操作,将有机层用饱和食盐水洗涤,用无水硫酸钠干燥后,减压蒸除。通过硅胶柱色谱法(己烷∶醋酸乙酯90∶10-60∶40)纯化残余物,从而得到4-溴-2-甲基-3-(三氟甲基)苯胺(6.9g)。
制备例511
在氩气气氛下,向4-氨基-3-溴-5-碘苄腈(1.0g)、碘化铜(60mg) 和三乙胺(10mL)的混合物中,加入双三苯基膦二氯化钯((0.22g),并用氩气脱气2次。在冰浴冷却下,加入乙炔基三甲基硅烷(0.47mL),于室温下搅拌24小时。用Celite过滤反应混合物中的不溶物,并减压浓缩滤液。向残余物中加入10%柠檬酸水溶液和醋酸乙酯,再次过滤不溶物。将有机层用饱和碳酸氢钠水溶液、水、饱和食盐水洗涤,用无水硫酸镁干燥后,过滤。减压浓缩滤液,并通过硅胶柱色谱法(己烷∶氯仿=2∶1)纯化残余物,从而得到4-氨基-3-溴-5-[(三甲基甲硅烷基)乙炔基]苄腈(0.81g)。
制备例512
在冰浴冷却下,向4-氨基-3-溴-5-[(三甲基甲硅烷基)乙炔基]苄腈(0.80g)和四氢呋喃(3.0mL)的混合物中,加入1M四丁基氟化铵-THF溶液(3.0mL),在室温下搅拌0.5小时。向反应混合物中,在冰浴冷却下加入水,用醋酸乙酯萃取。将有机层饱和食盐水洗涤,用无水硫酸镁干燥后,过滤。减压浓缩滤液,并通过硅胶柱色谱法(氯仿/己烷=30-50%)纯化残余物,从而得到4-氨基-3-溴-5-乙炔基苄腈(0.57g)。
制备例513
在室温下,向5-溴-7-甲基-6-(三氟甲基)-1H-吲哚-1-羧酸叔丁酯(1.2g)和四氯化碳(20mL)的混合物中,加入N-溴代琥珀酰亚胺(0.70g)和2,2’-偶氮二(2-甲基丙腈)(20mg)。将反应混合物在90℃下搅拌18小时。将反应混合物冷却至室温,用Celite过滤除去不溶物。减压蒸除滤液,向残余物中加入乙腈(20mL),并在冰浴冷却下加入4-甲基吗啉-4-氧化物(0.50g)。将反应混合物在室温下搅拌24小时。减压蒸除反应混合物,加入醋酸乙酯和水,进行分液操作,将有机层用饱和食盐水洗涤,用无水硫酸钠干燥后,减压蒸除。通过硅胶柱色谱法(己烷∶醋酸乙酯=100∶0-90∶10)纯化残余物,从而得到5-溴-7-甲酰基-6-(三氟甲基)-1H-吲哚-1-羧酸叔丁酯(0.26g)。
制备例514
在冰浴冷却下,向4-氨基-3-溴-5-乙炔基苄腈(0.57g)和1-甲基-2-吡咯烷酮(12mL)的混合物中,加入氨基甲酸叔丁酯(0.57g),于 室温下搅拌24小时。在冰浴冷却下,向反应混合物中,加入10%柠檬酸水溶液,并用醋酸乙酯萃取。将有机层用水、饱和碳酸氢钠水溶液、水、饱和食盐水洗涤,用无水硫酸镁干燥后,过滤。减压浓缩滤液,从而得到7-溴-1H-吲哚-5-甲腈(0.55g)。
制备例515
在室温下,向反式-4-[({[5-溴-6-氯-1-(异喹啉-3-基甲基)-1H-吲哚-7-基]羰基}氨基)甲基]环己烷羧酸甲酯(0.28g)、甲酸钠(0.10g)和DMSO(5.0mL)的混合物中,加入四(三苯基膦)钯(20mg)。将反应混合物在70℃下搅拌2小时,然后在90℃下搅拌3小时。在室温下,进一步向反应混合物中依次加入甲酸钠(0.10g)、四(三苯基膦)钯(40mg),于90℃下搅拌过夜。向反应液中加入醋酸乙酯和水,用Celite过滤除去不溶物。对滤液进行分液操作,将有机层用饱和食盐水洗涤,用无水硫酸钠干燥后,减压蒸除。通过硅胶柱色谱法(甲醇∶氯仿=0∶100-5∶95)纯化残余物,从而得到反式-4-[({[6-氯-1-(异喹啉-3-基甲基)-1H-吲哚-7-基]羰基}氨基)甲基]环己烷羧酸甲酯(0.14g)。
制备例516
在冰浴冷却下,向反式-4-[({[5-溴-6-(三氟甲基)-1H-吲哚-7-基]羰基}氨基)甲基]环己烷羧酸甲酯(75mg)、三乙胺(0.1mL)和甲醇(5.0mL)的混合物中,加入10%钯-碳(80mg)。将反应液在1个气压的氢气下、于室温下搅拌1天。用Celite过滤除去反应液的不溶物,并减压蒸除。向残余物中加入醋酸乙酯和水,进行分液操作,将有机层依次用5%柠檬酸水溶液、饱和食盐水洗涤,用无水硫酸钠干燥后,减压蒸除。通过硅胶柱色谱法(己烷∶醋酸乙酯=80∶20-50∶50)纯化残余物,从而得到反式-4-[({[6-(三氟甲基)-1H-吲哚-7-基]羰基}氨基)甲基]环己烷羧酸甲酯(41mg)。
根据与上述制备例中相同的方法,分别使用相应的原料,制备了后述表中所示的制备例化合物。制备例化合物的化学结构示于表3~表136中,制法和物理学数据示于表201~表211中。
实施例1
在室温下,向4-[(1S)-1-({[1-(4-氯苄基)-1,2,3,4-四氢喹啉-8-基]羰基}氨基)乙基]苯甲酸甲酯(129mg)在THF(2.0mL)和甲醇(1.0mL)中所形成的溶液中,加入1M氢氧化钠水溶液(1.0mL),并搅拌2天。在室温下,向反应混合物中,加入1M盐酸(1.0mL)进行中和,并用醋酸乙酯萃取。将有机层用饱和食盐水洗涤,用无水硫酸钠干燥。过滤后,减压浓缩滤液。通过硅胶柱色谱法(己烷-醋酸乙酯)纯化残余物。将所获得的生成物溶解于醋酸乙酯(2.0mL)中,在室温下,向该溶液中,加入4M氯化氢的醋酸乙酯溶液(2.0mL),并搅拌1天。在减压条件下蒸除溶剂,将残余物用醋酸乙酯洗涤后,过滤收集,在减压条件下干燥,从而得到4-[(1S)-1-({[1-(4-氯苄基)-1,2,3,4-四氢喹啉-8-基]羰基}氨基)乙基]苯甲酸盐酸盐(97mg)。
实施例2
向1-(4-氯苄基)-1H-吲哚-7-羧酸(0.20g)、4-(氨基甲基)-3-氯苯甲酸甲酯盐酸盐(0.18g)、HATU(0.32g)的混合物中,加入DMF(4.0mL),在冰浴冷却下,加入二异丙基乙基胺(0.29ml)后,于室温下搅拌14小时。再次用冰浴冷却,加入5%柠檬酸水溶液(8.0mL),过滤收集所析出的固体,依次用水、二异丙基醚洗涤,在60℃下、于减压条件下干燥。向所获得的固体中加入甲醇(3.0mL)、THF(3.0mL)、1M氢氧化钠水溶液(2.0mL),于60℃下搅拌2小时。冷却反应混合物,加入10%柠檬酸水溶液(5.0mL),过滤收集所析出的固体,用水洗涤,于60℃下减压干燥,从而得到3-氯-4-[({[1-(4-氯苄基)-1H-吲哚-7-基]羰基}氨基)甲基]苯甲酸(0.24g)。
实施例3
向4-[(1S)-1-({[1-(联苯-4-基甲基)-1H-吲哚-7-基]羰基}氨基)乙基]苯甲酸甲酯(0.30g)中,加入甲醇(4.0mL)、THF(4.0mL)和1M氢氧化钠水溶液(3.0mL),于65℃下搅拌2小时,在室温下进一步搅拌3天。向反应混合物中加入10%柠檬酸水溶液(4.0mL),过滤收集所析出的固体,用水、二乙醚/己烷(1/1)混合物洗涤,在60℃下、于减压条件下干燥,从而得到4-[(1S)-1-({[1-(联苯-4-基甲基)-1H-吲哚-7-基]羰基}氨基)乙基]苯甲酸(0.25g)。
实施例4
向4-{(1S)-1-[({1-[(6-氯吡啶-3-基)甲基]-1H-吲哚-7-基}羰基)氨基]乙基}苯甲酸(0.15g)、苯硼酸(84mg)、磷酸三钾(0.22g)、氯化钯(II)(9.2mg)和联苯-2-基(二环己基)膦(36mg)的混合物中,加入二 烷(6.0mL)和水(1.5mL),于100℃下搅拌1小时。向反应混合物中加入10%柠檬酸水溶液,使pH为3。用Celite过滤混合液,用醋酸乙酯萃取滤液。将有机层用食盐水洗涤,用无水硫酸钠干燥后,过滤,减压浓缩滤液。通过硅胶柱色谱法(己烷/THF=2/1-1/1)纯化残余物,从而得到4-{(1S)-1-[({1-[(6-苯基吡啶-3-基)甲基]-1H-吲哚-7-基}羰基)氨基]乙基}苯甲酸(66mg)。
实施例5
向4-{(1S)-1-[({1-[(6-氯吡啶-3-基)甲基]-1H-吲哚-7-基}羰基)氨基]乙基}苯甲酸(95mg)中,加入乙醇(2.0mL)和哌啶(65μL),于室温下搅拌过夜。减压浓缩后,加入DMSO(1.0mL)、哌啶(65μL)和叔丁醇钾(61mg),于80℃下搅拌2小时。向反应混合物中加入10%柠檬酸水溶液(10mL),用醋酸乙酯萃取。将所获得的有机层用水洗涤,用无水硫酸钠干燥,过滤,并减压浓缩。通过硅胶柱色谱法(氯仿/甲醇=99/1-95/5)纯化残余物,从而得到4-{(1S)-1-[({1-[(6-乙氧基吡啶-3-基)甲基]-1H-吲哚-7-基}羰基)氨基]乙基}苯甲酸(9.0mg)。
实施例6
向1-(4-氯苄基)-N-[(1S)-1-(4-{[(3-乙酰氧基丙基)磺酰基]氨基甲酰基}苯基)乙基]-1H-吲哚-7-甲酰胺(200mg)、THF(3mL)和甲醇(3mL)的混合物中,加入1M氢氧化钠水溶液(1.7mL),于室温下搅拌过夜。向反应混合物中,加入1M盐酸(1.7mL)使pH为4,进一步加入水(20mL),于室温下搅拌30分钟。过滤收集所析出的固体,用水(4mL)洗涤后,用冷乙醇(3mL)洗涤,从而得到1-(4-氯苄基)-N-[(1S)-1-(4-{[(3-羟基丙基)磺酰基]氨基甲酰基}苯基)乙基]-1H-吲哚-7-甲酰胺(80mg)的淡黄色固体。
根据与上述实施例中相同的方法,分别使用相应的原料,制备了后述表中所示的实施例化合物。实施例化合物的化学结构示于表 137~表200中,制法和物理学数据示于表212~表223中。
此外,式(I)所示的化合物或其盐的其他实施方案示于表224~表228中。通过使用上述的制备方法或实施例中记载的方法、以及本领域技术人员已知的方法、或者这些方法的变化方法,可以容易地制备这些化合物。
此外,在下述表中,使用以下的缩写。
Pr:制备例编号(在制备例编号的后面记载了“/C1”的制备例表示该制备例化合物被作为盐酸盐分离。),Ex:实施例编号(在实施例编号的后面记载了“/C1”的制备例表示该实施例化合物被作为盐酸盐分离。),No:化合物编号,Structure:结构式(Ac:乙酰基、TMS:三甲基甲硅烷基、TBS:叔丁基二甲基甲硅烷基),Syn:制备方法(其表示通过采用上述实施例或制备例中的相应的的制备方法来制备的制备例编号或实施例编号。例如,制备例69的化合物表示通过采用与制备例38的化合物相同的方法来制备。),Data:物理化学数据(通过NMR-C:CDCl3中的1H NMR的δ(ppm)、NMR-D:DMSO-d6中的1H NMR的δ(ppm)、FAB+:FAB-MS(阳离子)、FAB-:FAB-MS(阴离子)、ESI+:ESI-MS(阳离子)、ESI-:ESI-MS(阴离子)、APCI+:APCI-MS(阳离子)、EI:EI-MS(阳离子)、CI+:CI-MS(阳离子)、APCI/ESI+:用APCI-MS(阳离子)或ESI-MS(阳离子)测定的值、mp:熔点(℃、dec:分解))。
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工业实用性
式(I)所示的化合物或其盐具有EP4受体拮抗作用,其可用作预防和/或治疗慢性肾功能衰竭和/或糖尿病性肾病的药物组合物的有效成分。
序列表全文
下面的序列表数字标题<400>中记载了大鼠EP4的碱基序列(序列编号1)。
Claims (10)
1.反式-4-[({[5-氟-1-(异喹啉-3-基甲基)-1H-吲哚-7-基]羰基}氨基)甲基]环己烷羧酸或其盐。
2.反式-4-[({[1-(异喹啉-3-基甲基)-5-(三氟甲基)-1H-吲哚-7-基]羰基}氨基)甲基]环己烷羧酸或其盐。
3.反式-4-[({[1-(喹啉-2-基甲基)-5-(三氟甲基)-1H-吲哚-7-基]羰基}氨基)甲基]环己烷羧酸或其盐。
4.一种药物组合物,其含有权利要求1所述的化合物或其盐、以及可药用的赋形剂。
5.一种药物组合物,其含有权利要求2所述的化合物或其盐、以及可药用的赋形剂。
6.一种药物组合物,其含有权利要求3所述的化合物或其盐、以及可药用的赋形剂。
7.一种用于治疗慢性肾功能衰竭或糖尿病肾病的药物组合物,其含有权利要求1至3中任意一项所述的化合物或其盐。
8.权利要求1所述的化合物或其盐在制备用于治疗慢性肾功能衰竭或糖尿病肾病的药物组合物中的用途。
9.权利要求2所述的化合物或其盐在制备用于治疗慢性肾功能衰竭或糖尿病肾病的药物组合物中的用途。
10.权利要求3所述的化合物或其盐在制备用于治疗慢性肾功能衰竭或糖尿病肾病的药物组合物中的用途。
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JPWO2009139373A1 (ja) | 2011-09-22 |
MX2010012357A (es) | 2010-12-07 |
TW201000460A (en) | 2010-01-01 |
AU2009247262A1 (en) | 2009-11-19 |
ZA201007686B (en) | 2012-02-29 |
BRPI0912778B1 (pt) | 2019-04-30 |
EP2277858A4 (en) | 2012-06-13 |
PL2565191T3 (pl) | 2015-03-31 |
WO2009139373A1 (ja) | 2009-11-19 |
EP2565191B1 (en) | 2014-10-08 |
KR101612971B1 (ko) | 2016-04-15 |
RU2010150911A (ru) | 2012-06-20 |
ES2518919T3 (es) | 2014-11-05 |
CA2724077A1 (en) | 2009-11-19 |
US8598355B2 (en) | 2013-12-03 |
RU2479576C2 (ru) | 2013-04-20 |
US20110144153A1 (en) | 2011-06-16 |
JP5375824B2 (ja) | 2013-12-25 |
CA2724077C (en) | 2016-04-26 |
IL208955A0 (en) | 2011-01-31 |
RU2479576C9 (ru) | 2014-03-10 |
BRPI0912778A2 (pt) | 2015-10-13 |
EP2565191A1 (en) | 2013-03-06 |
DK2565191T3 (da) | 2014-11-10 |
HRP20141248T1 (en) | 2015-03-13 |
KR20110006654A (ko) | 2011-01-20 |
CN102026961A (zh) | 2011-04-20 |
CY1115944T1 (el) | 2017-01-25 |
EP2277858A1 (en) | 2011-01-26 |
AU2009247262B2 (en) | 2013-01-31 |
SI2565191T1 (sl) | 2014-12-31 |
PT2565191E (pt) | 2014-12-04 |
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