CN1161962A - 磺酰氨衍生物 - Google Patents
磺酰氨衍生物 Download PDFInfo
- Publication number
- CN1161962A CN1161962A CN 96121984 CN96121984A CN1161962A CN 1161962 A CN1161962 A CN 1161962A CN 96121984 CN96121984 CN 96121984 CN 96121984 A CN96121984 A CN 96121984A CN 1161962 A CN1161962 A CN 1161962A
- Authority
- CN
- China
- Prior art keywords
- phenyl
- butyric acid
- tetramethyleneimine
- phenylester
- carboxyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 150000001875 compounds Chemical class 0.000 claims abstract description 107
- 229940124530 sulfonamide Drugs 0.000 claims abstract description 61
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 1300
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 580
- -1 nitro, amidino groups Chemical group 0.000 claims description 450
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 132
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 111
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 96
- 150000002148 esters Chemical class 0.000 claims description 85
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 69
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 65
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 62
- 125000000623 heterocyclic group Chemical group 0.000 claims description 50
- 150000003839 salts Chemical class 0.000 claims description 44
- LCFMHXAUNXCFAH-UHFFFAOYSA-N 1-(4-nitrophenyl)cyclobutane-1-carboxylic acid Chemical compound C=1C=C([N+]([O-])=O)C=CC=1C1(C(=O)O)CCC1 LCFMHXAUNXCFAH-UHFFFAOYSA-N 0.000 claims description 39
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 38
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 claims description 33
- 239000002253 acid Chemical class 0.000 claims description 32
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 31
- 229910052739 hydrogen Inorganic materials 0.000 claims description 31
- 239000001257 hydrogen Substances 0.000 claims description 30
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 29
- 229910052760 oxygen Inorganic materials 0.000 claims description 27
- 239000001301 oxygen Substances 0.000 claims description 26
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 25
- 125000005843 halogen group Chemical group 0.000 claims description 25
- 238000000034 method Methods 0.000 claims description 25
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 24
- OBKXEAXTFZPCHS-UHFFFAOYSA-N 4-phenylbutyric acid Chemical compound OC(=O)CCCC1=CC=CC=C1 OBKXEAXTFZPCHS-UHFFFAOYSA-N 0.000 claims description 18
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 18
- 229910052799 carbon Inorganic materials 0.000 claims description 18
- ZCRZCMUDOWDGOB-UHFFFAOYSA-N ethanesulfonimidic acid Chemical compound CCS(N)(=O)=O ZCRZCMUDOWDGOB-UHFFFAOYSA-N 0.000 claims description 18
- 238000002360 preparation method Methods 0.000 claims description 18
- 125000000217 alkyl group Chemical group 0.000 claims description 17
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 claims description 17
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 17
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 16
- 125000002837 carbocyclic group Chemical group 0.000 claims description 16
- 231100000252 nontoxic Toxicity 0.000 claims description 15
- 230000003000 nontoxic effect Effects 0.000 claims description 15
- 125000001118 alkylidene group Chemical group 0.000 claims description 14
- 125000003545 alkoxy group Chemical group 0.000 claims description 13
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 13
- 239000012453 solvate Substances 0.000 claims description 13
- BUKNVYTXWPRTFJ-UHFFFAOYSA-N C(=O)=C1NCCC1.[O] Chemical compound C(=O)=C1NCCC1.[O] BUKNVYTXWPRTFJ-UHFFFAOYSA-N 0.000 claims description 12
- 230000000903 blocking effect Effects 0.000 claims description 12
- 230000000694 effects Effects 0.000 claims description 12
- 125000000468 ketone group Chemical group 0.000 claims description 12
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 claims description 11
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 11
- ZRALSGWEFCBTJO-UHFFFAOYSA-N anhydrous guanidine Natural products NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims description 11
- TXWOGHSRPAYOML-UHFFFAOYSA-N cyclobutanecarboxylic acid Chemical compound OC(=O)C1CCC1 TXWOGHSRPAYOML-UHFFFAOYSA-N 0.000 claims description 11
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 claims description 11
- 230000032050 esterification Effects 0.000 claims description 11
- 238000005886 esterification reaction Methods 0.000 claims description 11
- 125000002252 acyl group Chemical group 0.000 claims description 10
- 150000002825 nitriles Chemical group 0.000 claims description 9
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 claims description 7
- 125000004953 trihalomethyl group Chemical group 0.000 claims description 7
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 6
- 102000016942 Elastin Human genes 0.000 claims description 5
- 108010014258 Elastin Proteins 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 5
- 125000004432 carbon atom Chemical group C* 0.000 claims description 5
- 201000010099 disease Diseases 0.000 claims description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 5
- 229920002549 elastin Polymers 0.000 claims description 5
- 150000003536 tetrazoles Chemical group 0.000 claims description 5
- WLFGGJFWKXTOGJ-UHFFFAOYSA-N 2,3-dihydroindol-1-amine Chemical compound C1=CC=C2N(N)CCC2=C1 WLFGGJFWKXTOGJ-UHFFFAOYSA-N 0.000 claims description 4
- NZNMSOFKMUBTKW-UHFFFAOYSA-N cyclohexanecarboxylic acid Chemical compound OC(=O)C1CCCCC1 NZNMSOFKMUBTKW-UHFFFAOYSA-N 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 4
- 239000003602 elastase inhibitor Substances 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 239000011737 fluorine Substances 0.000 claims description 4
- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 4
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 claims description 4
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 claims description 4
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 claims description 3
- 201000001320 Atherosclerosis Diseases 0.000 claims description 3
- 229940122858 Elastase inhibitor Drugs 0.000 claims description 3
- 239000000654 additive Substances 0.000 claims description 3
- 230000000996 additive effect Effects 0.000 claims description 3
- 201000000028 adult respiratory distress syndrome Diseases 0.000 claims description 3
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 3
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 3
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 3
- 229920001282 polysaccharide Polymers 0.000 claims description 3
- 239000005017 polysaccharide Substances 0.000 claims description 3
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 2
- YYPGGXSABCALFA-UHFFFAOYSA-N 1-(2-chlorophenyl)cyclobutane-1-carboxylic acid Chemical compound C=1C=CC=C(Cl)C=1C1(C(=O)O)CCC1 YYPGGXSABCALFA-UHFFFAOYSA-N 0.000 claims description 2
- XYSRHOKREWGGFE-UHFFFAOYSA-N 1-(4-chlorophenyl)cyclobutane-1-carboxylic acid Chemical compound C=1C=C(Cl)C=CC=1C1(C(=O)O)CCC1 XYSRHOKREWGGFE-UHFFFAOYSA-N 0.000 claims description 2
- QDCPXRWNBXWBPZ-UHFFFAOYSA-N 1-(4-nitrophenyl)cyclopentane-1-carboxylic acid Chemical compound C=1C=C([N+]([O-])=O)C=CC=1C1(C(=O)O)CCCC1 QDCPXRWNBXWBPZ-UHFFFAOYSA-N 0.000 claims description 2
- GWOWMWDHYGMVSZ-UHFFFAOYSA-N 1-(4-nitrophenyl)cyclopropane-1-carboxylic acid Chemical compound C=1C=C([N+]([O-])=O)C=CC=1C1(C(=O)O)CC1 GWOWMWDHYGMVSZ-UHFFFAOYSA-N 0.000 claims description 2
- QXXHHHWXFHPNOS-UHFFFAOYSA-N 1-phenylcyclohexane-1-carboxylic acid Chemical compound C=1C=CC=CC=1C1(C(=O)O)CCCCC1 QXXHHHWXFHPNOS-UHFFFAOYSA-N 0.000 claims description 2
- RHPCYZLXNNRRMB-UHFFFAOYSA-N 1-phenylcyclopentane-1-carboxylic acid Chemical compound C=1C=CC=CC=1C1(C(=O)O)CCCC1 RHPCYZLXNNRRMB-UHFFFAOYSA-N 0.000 claims description 2
- IWWCCNVRNHTGLV-UHFFFAOYSA-N 1-phenylcyclopropane-1-carboxylic acid Chemical compound C=1C=CC=CC=1C1(C(=O)O)CC1 IWWCCNVRNHTGLV-UHFFFAOYSA-N 0.000 claims description 2
- ZFTRKIIOOVMXCS-UHFFFAOYSA-N 2,2-diphenylbutanoic acid Chemical compound C=1C=CC=CC=1C(C(O)=O)(CC)C1=CC=CC=C1 ZFTRKIIOOVMXCS-UHFFFAOYSA-N 0.000 claims description 2
- PYXQBGGQMBEYLO-UHFFFAOYSA-N 2-ethyl-2-phenylbutanoic acid Chemical compound CCC(CC)(C(O)=O)C1=CC=CC=C1 PYXQBGGQMBEYLO-UHFFFAOYSA-N 0.000 claims description 2
- XBYXPOIAKWRVPY-UHFFFAOYSA-N 2-ethyl-2-thiophen-2-ylbutanoic acid Chemical compound CCC(CC)(C(O)=O)C1=CC=CS1 XBYXPOIAKWRVPY-UHFFFAOYSA-N 0.000 claims description 2
- AFRRWJPNQKSTEY-UHFFFAOYSA-N 2-methyl-2-(4-nitrophenyl)propanoic acid Chemical compound OC(=O)C(C)(C)C1=CC=C([N+]([O-])=O)C=C1 AFRRWJPNQKSTEY-UHFFFAOYSA-N 0.000 claims description 2
- YYEROYLAYAVZNW-UHFFFAOYSA-N 2-methyl-2-phenylpropanoic acid Chemical compound OC(=O)C(C)(C)C1=CC=CC=C1 YYEROYLAYAVZNW-UHFFFAOYSA-N 0.000 claims description 2
- 206010009900 Colitis ulcerative Diseases 0.000 claims description 2
- 206010014561 Emphysema Diseases 0.000 claims description 2
- 241000124008 Mammalia Species 0.000 claims description 2
- 229910004727 OSO3H Inorganic materials 0.000 claims description 2
- 229910006069 SO3H Inorganic materials 0.000 claims description 2
- 201000006704 Ulcerative Colitis Diseases 0.000 claims description 2
- NYOXTUZNVYEODT-UHFFFAOYSA-N bicyclo[4.2.0]octa-1,3,5-triene-7-carboxylic acid Chemical compound C1=CC=C2C(C(=O)O)CC2=C1 NYOXTUZNVYEODT-UHFFFAOYSA-N 0.000 claims description 2
- 230000001684 chronic effect Effects 0.000 claims description 2
- YMGUBTXCNDTFJI-UHFFFAOYSA-N cyclopropanecarboxylic acid Chemical compound OC(=O)C1CC1 YMGUBTXCNDTFJI-UHFFFAOYSA-N 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 125000005575 polycyclic aromatic hydrocarbon group Chemical group 0.000 claims description 2
- 235000019260 propionic acid Nutrition 0.000 claims description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 2
- 229940005605 valeric acid Drugs 0.000 claims description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims 7
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims 7
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 claims 2
- JBDSSBMEKXHSJF-UHFFFAOYSA-N cyclopentanecarboxylic acid Chemical compound OC(=O)C1CCCC1 JBDSSBMEKXHSJF-UHFFFAOYSA-N 0.000 claims 2
- NVBFHJWHLNUMCV-UHFFFAOYSA-N sulfamide Chemical class NS(N)(=O)=O NVBFHJWHLNUMCV-UHFFFAOYSA-N 0.000 claims 2
- RLQZIECDMISZHS-UHFFFAOYSA-N 2-phenylcyclohexa-2,5-diene-1,4-dione Chemical compound O=C1C=CC(=O)C(C=2C=CC=CC=2)=C1 RLQZIECDMISZHS-UHFFFAOYSA-N 0.000 claims 1
- 241000790917 Dioxys <bee> Species 0.000 claims 1
- 206010061876 Obstruction Diseases 0.000 claims 1
- 206010039361 Sacroiliitis Diseases 0.000 claims 1
- 125000001931 aliphatic group Chemical group 0.000 claims 1
- 150000001555 benzenes Chemical class 0.000 claims 1
- OVIZSQRQYWEGON-UHFFFAOYSA-N butane-1-sulfonamide Chemical compound CCCCS(N)(=O)=O OVIZSQRQYWEGON-UHFFFAOYSA-N 0.000 claims 1
- 208000010125 myocardial infarction Diseases 0.000 claims 1
- 208000011580 syndromic disease Diseases 0.000 claims 1
- 201000008827 tuberculosis Diseases 0.000 claims 1
- 102000016387 Pancreatic elastase Human genes 0.000 abstract 1
- 108010067372 Pancreatic elastase Proteins 0.000 abstract 1
- 230000002401 inhibitory effect Effects 0.000 abstract 1
- 150000003456 sulfonamides Chemical class 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 991
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 651
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 432
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 371
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 214
- 239000002585 base Substances 0.000 description 196
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 120
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 83
- 235000002639 sodium chloride Nutrition 0.000 description 64
- 239000000203 mixture Substances 0.000 description 43
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 34
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 25
- 239000000243 solution Substances 0.000 description 25
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- 150000003840 hydrochlorides Chemical class 0.000 description 22
- 239000011541 reaction mixture Substances 0.000 description 21
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 14
- 125000004429 atom Chemical group 0.000 description 14
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 11
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 10
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 10
- XSCHRSMBECNVNS-UHFFFAOYSA-N quinoxaline Chemical compound N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 10
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 9
- 150000001721 carbon Chemical group 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- 230000002378 acidificating effect Effects 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 8
- 150000002460 imidazoles Chemical class 0.000 description 8
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 8
- 125000006239 protecting group Chemical group 0.000 description 8
- 150000003527 tetrahydropyrans Chemical class 0.000 description 8
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 7
- 230000005764 inhibitory process Effects 0.000 description 7
- 150000003053 piperidines Chemical class 0.000 description 7
- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 description 6
- LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 description 6
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical group C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 239000003960 organic solvent Substances 0.000 description 6
- FLBAYUMRQUHISI-UHFFFAOYSA-N 1,8-naphthyridine Chemical compound N1=CC=CC2=CC=CN=C21 FLBAYUMRQUHISI-UHFFFAOYSA-N 0.000 description 5
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 5
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 5
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 5
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 5
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 5
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 239000003701 inert diluent Substances 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 5
- 150000002576 ketones Chemical class 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 description 4
- JQIZHNLEFQMDCQ-UHFFFAOYSA-N 1,2,3,4-tetrahydropyridazine Chemical compound C1CC=CNN1 JQIZHNLEFQMDCQ-UHFFFAOYSA-N 0.000 description 4
- OTPDWCMLUKMQNO-UHFFFAOYSA-N 1,2,3,4-tetrahydropyrimidine Chemical compound C1NCC=CN1 OTPDWCMLUKMQNO-UHFFFAOYSA-N 0.000 description 4
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 description 4
- OGYGFUAIIOPWQD-UHFFFAOYSA-N 1,3-thiazolidine Chemical compound C1CSCN1 OGYGFUAIIOPWQD-UHFFFAOYSA-N 0.000 description 4
- CQVKMVQRSNNAGO-UHFFFAOYSA-N 2-[4-formyl-3-methyl-n-(2-methylsulfonyloxyethyl)anilino]ethyl methanesulfonate Chemical compound CC1=CC(N(CCOS(C)(=O)=O)CCOS(C)(=O)=O)=CC=C1C=O CQVKMVQRSNNAGO-UHFFFAOYSA-N 0.000 description 4
- RSEBUVRVKCANEP-UHFFFAOYSA-N 2-pyrroline Chemical compound C1CC=CN1 RSEBUVRVKCANEP-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- WRYCSMQKUKOKBP-UHFFFAOYSA-N Imidazolidine Chemical compound C1CNCN1 WRYCSMQKUKOKBP-UHFFFAOYSA-N 0.000 description 4
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 4
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 4
- 150000001266 acyl halides Chemical class 0.000 description 4
- 229940024606 amino acid Drugs 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- XYOVOXDWRFGKEX-UHFFFAOYSA-N azepine Chemical compound N1C=CC=CC=C1 XYOVOXDWRFGKEX-UHFFFAOYSA-N 0.000 description 4
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 4
- 239000002131 composite material Substances 0.000 description 4
- HJLHTTJLVALHOP-UHFFFAOYSA-N hexane;hydron;chloride Chemical compound Cl.CCCCCC HJLHTTJLVALHOP-UHFFFAOYSA-N 0.000 description 4
- 229910052500 inorganic mineral Inorganic materials 0.000 description 4
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N lactose group Chemical group OC1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O)[C@H](O2)CO)[C@H](O1)CO GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 235000010755 mineral Nutrition 0.000 description 4
- 239000011707 mineral Substances 0.000 description 4
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 4
- QWVGKYWNOKOFNN-UHFFFAOYSA-N o-cresol Chemical compound CC1=CC=CC=C1O QWVGKYWNOKOFNN-UHFFFAOYSA-N 0.000 description 4
- 150000007524 organic acids Chemical class 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 150000004880 oxines Chemical class 0.000 description 4
- 229910052763 palladium Inorganic materials 0.000 description 4
- 125000004193 piperazinyl group Chemical group 0.000 description 4
- 229960002429 proline Drugs 0.000 description 4
- USPWKWBDZOARPV-UHFFFAOYSA-N pyrazolidine Chemical compound C1CNNC1 USPWKWBDZOARPV-UHFFFAOYSA-N 0.000 description 4
- DNXIASIHZYFFRO-UHFFFAOYSA-N pyrazoline Chemical compound C1CN=NC1 DNXIASIHZYFFRO-UHFFFAOYSA-N 0.000 description 4
- ZVJHJDDKYZXRJI-UHFFFAOYSA-N pyrroline Natural products C1CC=NC1 ZVJHJDDKYZXRJI-UHFFFAOYSA-N 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- 150000003512 tertiary amines Chemical class 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 3
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 3
- NENLYAQPNATJSU-UHFFFAOYSA-N 1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline Chemical compound C1NCCC2CCCCC21 NENLYAQPNATJSU-UHFFFAOYSA-N 0.000 description 3
- HZNXIPDYYIWDNM-UHFFFAOYSA-N 1,2,3,4,4a,5,6,7,8,8a-decahydroquinazoline Chemical compound N1CNCC2CCCCC21 HZNXIPDYYIWDNM-UHFFFAOYSA-N 0.000 description 3
- POTIYWUALSJREP-UHFFFAOYSA-N 1,2,3,4,4a,5,6,7,8,8a-decahydroquinoline Chemical compound N1CCCC2CCCCC21 POTIYWUALSJREP-UHFFFAOYSA-N 0.000 description 3
- MDEXMBGPIZUUBI-UHFFFAOYSA-N 1,2,3,4,4a,5,6,7,8,8a-decahydroquinoxaline Chemical compound N1CCNC2CCCCC21 MDEXMBGPIZUUBI-UHFFFAOYSA-N 0.000 description 3
- PKORYTIUMAOPED-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinazoline Chemical compound C1=CC=C2NCNCC2=C1 PKORYTIUMAOPED-UHFFFAOYSA-N 0.000 description 3
- QRDNXAYNXUKMOO-UHFFFAOYSA-N 1,2-dihydrocinnoline Chemical compound C1=CC=C2C=CNNC2=C1 QRDNXAYNXUKMOO-UHFFFAOYSA-N 0.000 description 3
- IOEPOEDBBPRAEI-UHFFFAOYSA-N 1,2-dihydroisoquinoline Chemical compound C1=CC=C2CNC=CC2=C1 IOEPOEDBBPRAEI-UHFFFAOYSA-N 0.000 description 3
- IRFSXVIRXMYULF-UHFFFAOYSA-N 1,2-dihydroquinoline Chemical compound C1=CC=C2C=CCNC2=C1 IRFSXVIRXMYULF-UHFFFAOYSA-N 0.000 description 3
- DKYBVKMIZODYKL-UHFFFAOYSA-N 1,3-diazinane Chemical compound C1CNCNC1 DKYBVKMIZODYKL-UHFFFAOYSA-N 0.000 description 3
- OGHHATWOTABYKY-UHFFFAOYSA-N 2,3,3a,4,5,6,7,7a-octahydro-1,3-benzothiazole Chemical compound C1CCCC2SCNC21 OGHHATWOTABYKY-UHFFFAOYSA-N 0.000 description 3
- LVJPACZOEKXFAY-UHFFFAOYSA-N 2,3,3a,4,5,6,7,7a-octahydro-1h-indazole Chemical compound C1CCCC2CNNC21 LVJPACZOEKXFAY-UHFFFAOYSA-N 0.000 description 3
- FJRPOHLDJUJARI-UHFFFAOYSA-N 2,3-dihydro-1,2-oxazole Chemical compound C1NOC=C1 FJRPOHLDJUJARI-UHFFFAOYSA-N 0.000 description 3
- YTQQIHUQLOZOJI-UHFFFAOYSA-N 2,3-dihydro-1,2-thiazole Chemical compound C1NSC=C1 YTQQIHUQLOZOJI-UHFFFAOYSA-N 0.000 description 3
- ZABMHLDQFJHDSC-UHFFFAOYSA-N 2,3-dihydro-1,3-oxazole Chemical compound C1NC=CO1 ZABMHLDQFJHDSC-UHFFFAOYSA-N 0.000 description 3
- CDULGHZNHURECF-UHFFFAOYSA-N 2,3-dimethylaniline 2,4-dimethylaniline 2,5-dimethylaniline 2,6-dimethylaniline 3,4-dimethylaniline 3,5-dimethylaniline Chemical group CC1=CC=C(N)C(C)=C1.CC1=CC=C(C)C(N)=C1.CC1=CC(C)=CC(N)=C1.CC1=CC=C(N)C=C1C.CC1=CC=CC(N)=C1C.CC1=CC=CC(C)=C1N CDULGHZNHURECF-UHFFFAOYSA-N 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 3
- NTURVSFTOYPGON-UHFFFAOYSA-N Dihydroquinazoline Chemical compound C1=CC=C2C=NCNC2=C1 NTURVSFTOYPGON-UHFFFAOYSA-N 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 3
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 3
- 229930182821 L-proline Natural products 0.000 description 3
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 3
- 241000534944 Thia Species 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 150000008065 acid anhydrides Chemical class 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 229960005261 aspartic acid Drugs 0.000 description 3
- 235000003704 aspartic acid Nutrition 0.000 description 3
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 3
- 239000011575 calcium Substances 0.000 description 3
- 229910052791 calcium Inorganic materials 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- WCZVZNOTHYJIEI-UHFFFAOYSA-N cinnoline Chemical compound N1=NC=CC2=CC=CC=C21 WCZVZNOTHYJIEI-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 125000000753 cycloalkyl group Chemical group 0.000 description 3
- HTFFABIIOAKIBH-UHFFFAOYSA-N diazinane Chemical compound C1CCNNC1 HTFFABIIOAKIBH-UHFFFAOYSA-N 0.000 description 3
- 239000012153 distilled water Substances 0.000 description 3
- 230000003203 everyday effect Effects 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 229960002989 glutamic acid Drugs 0.000 description 3
- 150000002475 indoles Chemical class 0.000 description 3
- GWVMLCQWXVFZCN-UHFFFAOYSA-N isoindoline Chemical compound C1=CC=C2CNCC2=C1 GWVMLCQWXVFZCN-UHFFFAOYSA-N 0.000 description 3
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 210000004072 lung Anatomy 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 3
- 229930182817 methionine Natural products 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 150000003217 pyrazoles Chemical class 0.000 description 3
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 3
- 150000003233 pyrroles Chemical class 0.000 description 3
- 238000010791 quenching Methods 0.000 description 3
- 230000000171 quenching effect Effects 0.000 description 3
- 230000000452 restraining effect Effects 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 239000007921 spray Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- CBDKQYKMCICBOF-UHFFFAOYSA-N thiazoline Chemical compound C1CN=CS1 CBDKQYKMCICBOF-UHFFFAOYSA-N 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- 125000004642 (C1-C12) alkoxy group Chemical group 0.000 description 2
- 125000006652 (C3-C12) cycloalkyl group Chemical group 0.000 description 2
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical compound COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 2
- PIHAUZGWAXLKCA-UHFFFAOYSA-N 1,2,3,4,4a,5,6,7,8,8a-decahydro-1,8-naphthyridine Chemical compound N1CCCC2CCCNC21 PIHAUZGWAXLKCA-UHFFFAOYSA-N 0.000 description 2
- VKJHANNFFHMLBB-UHFFFAOYSA-N 1,2,3,4,4a,5,6,7,8,8a-decahydrocinnoline Chemical compound N1NCCC2CCCCC21 VKJHANNFFHMLBB-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 description 2
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 2
- RWZBNLCRSDKHPP-UHFFFAOYSA-N 1h-azepine;thiophene Chemical compound C=1C=CSC=1.N1C=CC=CC=C1 RWZBNLCRSDKHPP-UHFFFAOYSA-N 0.000 description 2
- XLRZZUUFKAXBGZ-UHFFFAOYSA-N 2,3,3a,4,5,6,7,7a-octahydro-1,3-benzoxazole Chemical compound C1CCCC2OCNC21 XLRZZUUFKAXBGZ-UHFFFAOYSA-N 0.000 description 2
- PDELQDSYLBLPQO-UHFFFAOYSA-N 2,3,3a,4,5,6,7,7a-octahydro-1h-indole Chemical class C1CCCC2NCCC21 PDELQDSYLBLPQO-UHFFFAOYSA-N 0.000 description 2
- OFJWFSNDPCAWDK-UHFFFAOYSA-N 2-phenylbutyric acid Chemical compound CCC(C(O)=O)C1=CC=CC=C1 OFJWFSNDPCAWDK-UHFFFAOYSA-N 0.000 description 2
- VHMICKWLTGFITH-UHFFFAOYSA-N 2H-isoindole Chemical compound C1=CC=CC2=CNC=C21 VHMICKWLTGFITH-UHFFFAOYSA-N 0.000 description 2
- AGIJRRREJXSQJR-UHFFFAOYSA-N 2h-thiazine Chemical compound N1SC=CC=C1 AGIJRRREJXSQJR-UHFFFAOYSA-N 0.000 description 2
- LICHZOBEUWVYSY-UHFFFAOYSA-N 3-azabicyclo[3.2.2]nonane Chemical group C1CC2CCC1CNC2 LICHZOBEUWVYSY-UHFFFAOYSA-N 0.000 description 2
- FTOAOBMCPZCFFF-UHFFFAOYSA-N 5,5-diethylbarbituric acid Chemical compound CCC1(CC)C(=O)NC(=O)NC1=O FTOAOBMCPZCFFF-UHFFFAOYSA-N 0.000 description 2
- VJPPDEZWWKCSIV-UHFFFAOYSA-N 6-azabicyclo[3.2.1]octane Chemical compound C1C2CNC1CCC2 VJPPDEZWWKCSIV-UHFFFAOYSA-N 0.000 description 2
- 239000004475 Arginine Substances 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 2
- 0 C*N(*)S(C(CC(C)=C1)=CC=C1O)(=O)=O Chemical compound C*N(*)S(C(CC(C)=C1)=CC=C1O)(=O)=O 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 241000699800 Cricetinae Species 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- 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 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- XUYPXLNMDZIRQH-LURJTMIESA-N N-acetyl-L-methionine Chemical compound CSCC[C@@H](C(O)=O)NC(C)=O XUYPXLNMDZIRQH-LURJTMIESA-N 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 208000011341 adult acute respiratory distress syndrome Diseases 0.000 description 2
- 125000004450 alkenylene group Chemical group 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 239000003708 ampul Substances 0.000 description 2
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 2
- 229960003121 arginine Drugs 0.000 description 2
- 239000012752 auxiliary agent Substances 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 210000002808 connective tissue Anatomy 0.000 description 2
- MGNZXYYWBUKAII-UHFFFAOYSA-N cyclohexa-1,3-diene Chemical compound C1CC=CC=C1 MGNZXYYWBUKAII-UHFFFAOYSA-N 0.000 description 2
- 125000002433 cyclopentenyl group Chemical class C1(=CCCC1)* 0.000 description 2
- NNBZCPXTIHJBJL-UHFFFAOYSA-N decalin Chemical compound C1CCCC2CCCCC21 NNBZCPXTIHJBJL-UHFFFAOYSA-N 0.000 description 2
- 230000029087 digestion Effects 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000007327 hydrogenolysis reaction Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000010985 leather Substances 0.000 description 2
- 229940040145 liniment Drugs 0.000 description 2
- 239000000865 liniment Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 229910017604 nitric acid Inorganic materials 0.000 description 2
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 235000006408 oxalic acid Nutrition 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 235000015320 potassium carbonate Nutrition 0.000 description 2
- 239000001103 potassium chloride Substances 0.000 description 2
- 235000011164 potassium chloride Nutrition 0.000 description 2
- 235000018102 proteins Nutrition 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 description 2
- 239000012266 salt solution Substances 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000004659 sterilization and disinfection Methods 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- UDYFLDICVHJSOY-UHFFFAOYSA-N sulfur trioxide pyridine complex Chemical compound O=S(=O)=O.C1=CC=NC=C1 UDYFLDICVHJSOY-UHFFFAOYSA-N 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 2
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 2
- 229930192474 thiophene Natural products 0.000 description 2
- 208000037816 tissue injury Diseases 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- 125000004641 (C1-C12) haloalkyl group Chemical group 0.000 description 1
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical class OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- HORKYAIEVBUXGM-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoxaline Chemical compound C1=CC=C2NCCNC2=C1 HORKYAIEVBUXGM-UHFFFAOYSA-N 0.000 description 1
- XEYKWYIXHMEQGM-UHFFFAOYSA-N 1,2-dihydro-1,8-naphthyridine Chemical compound C1=CC=C2C=CCNC2=N1 XEYKWYIXHMEQGM-UHFFFAOYSA-N 0.000 description 1
- KEIFWROAQVVDBN-UHFFFAOYSA-N 1,2-dihydronaphthalene Chemical compound C1=CC=C2C=CCCC2=C1 KEIFWROAQVVDBN-UHFFFAOYSA-N 0.000 description 1
- XXBQLHATYQHJQC-UHFFFAOYSA-N 1,2-dihydroquinoxaline Chemical compound C1=CC=C2N=CCNC2=C1 XXBQLHATYQHJQC-UHFFFAOYSA-N 0.000 description 1
- RJXNZBKNKLNXLX-UHFFFAOYSA-N 1,2-oxazole;1,3-oxazole Chemical compound C=1C=NOC=1.C1=COC=N1 RJXNZBKNKLNXLX-UHFFFAOYSA-N 0.000 description 1
- HGQBCKVFVUCIML-UHFFFAOYSA-N 1,3,3a,4,5,6,7,7a-octahydro-2-benzofuran Chemical compound C1CCCC2COCC21 HGQBCKVFVUCIML-UHFFFAOYSA-N 0.000 description 1
- FTNJQNQLEGKTGD-UHFFFAOYSA-N 1,3-benzodioxole Chemical compound C1=CC=C2OCOC2=C1 FTNJQNQLEGKTGD-UHFFFAOYSA-N 0.000 description 1
- IFYKYLNMLFUGJG-UHFFFAOYSA-N 1,3-benzoxazole cinnoline Chemical compound O1C=NC2=C1C=CC=C2.N2=NC=CC1=CC=CC=C21 IFYKYLNMLFUGJG-UHFFFAOYSA-N 0.000 description 1
- ULTHEAFYOOPTTB-UHFFFAOYSA-N 1,4-dibromobutane Chemical compound BrCCCCBr ULTHEAFYOOPTTB-UHFFFAOYSA-N 0.000 description 1
- 125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 1
- OXBLVCZKDOZZOJ-UHFFFAOYSA-N 2,3-Dihydrothiophene Chemical compound C1CC=CS1 OXBLVCZKDOZZOJ-UHFFFAOYSA-N 0.000 description 1
- YJUFGFXVASPYFQ-UHFFFAOYSA-N 2,3-dihydro-1-benzothiophene Chemical compound C1=CC=C2SCCC2=C1 YJUFGFXVASPYFQ-UHFFFAOYSA-N 0.000 description 1
- JKTCBAGSMQIFNL-UHFFFAOYSA-N 2,3-dihydrofuran Chemical compound C1CC=CO1 JKTCBAGSMQIFNL-UHFFFAOYSA-N 0.000 description 1
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- UXGVMFHEKMGWMA-UHFFFAOYSA-N 2-benzofuran Chemical compound C1=CC=CC2=COC=C21 UXGVMFHEKMGWMA-UHFFFAOYSA-N 0.000 description 1
- QHOINBKBMJLHPY-UHFFFAOYSA-N 2-chloroethyl formate Chemical compound ClCCOC=O QHOINBKBMJLHPY-UHFFFAOYSA-N 0.000 description 1
- QZNNLFPIPTYBRV-UHFFFAOYSA-N 2-ethyl-2-(4-methoxyphenyl)butanoic acid Chemical compound CCC(CC)(C(O)=O)C1=CC=C(OC)C=C1 QZNNLFPIPTYBRV-UHFFFAOYSA-N 0.000 description 1
- HDECRAPHCDXMIJ-UHFFFAOYSA-N 2-methylbenzenesulfonyl chloride Chemical compound CC1=CC=CC=C1S(Cl)(=O)=O HDECRAPHCDXMIJ-UHFFFAOYSA-N 0.000 description 1
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
- CMLFRMDBDNHMRA-UHFFFAOYSA-N 2h-1,2-benzoxazine Chemical compound C1=CC=C2C=CNOC2=C1 CMLFRMDBDNHMRA-UHFFFAOYSA-N 0.000 description 1
- BCHZICNRHXRCHY-UHFFFAOYSA-N 2h-oxazine Chemical compound N1OC=CC=C1 BCHZICNRHXRCHY-UHFFFAOYSA-N 0.000 description 1
- ATVJJNGVPSKBGO-UHFFFAOYSA-N 3,4-dihydro-2h-thiopyran Chemical compound C1CSC=CC1 ATVJJNGVPSKBGO-UHFFFAOYSA-N 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- XKTYXVDYIKIYJP-UHFFFAOYSA-N 3h-dioxole Chemical compound C1OOC=C1 XKTYXVDYIKIYJP-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- LKDMKWNDBAVNQZ-UHFFFAOYSA-N 4-[[1-[[1-[2-[[1-(4-nitroanilino)-1-oxo-3-phenylpropan-2-yl]carbamoyl]pyrrolidin-1-yl]-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-4-oxobutanoic acid Chemical compound OC(=O)CCC(=O)NC(C)C(=O)NC(C)C(=O)N1CCCC1C(=O)NC(C(=O)NC=1C=CC(=CC=1)[N+]([O-])=O)CC1=CC=CC=C1 LKDMKWNDBAVNQZ-UHFFFAOYSA-N 0.000 description 1
- PNWSHHILERSSLF-UHFFFAOYSA-N 4-methylbenzene-1,3-dicarboxylic acid Chemical compound CC1=CC=C(C(O)=O)C=C1C(O)=O PNWSHHILERSSLF-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- FLLHEJPVLSEJRX-UHFFFAOYSA-N C(CCC)OC(CCCCCC)(OCCCCCC)OCCCCC Chemical compound C(CCC)OC(CCCCCC)(OCCCCCC)OCCCCC FLLHEJPVLSEJRX-UHFFFAOYSA-N 0.000 description 1
- 102000004173 Cathepsin G Human genes 0.000 description 1
- 108090000617 Cathepsin G Proteins 0.000 description 1
- 206010008190 Cerebrovascular accident Diseases 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
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- GRJMIMFTPGNXIC-UHFFFAOYSA-N Dialin Natural products C1=C(OC)C(OC)=CC=C1C1C2=CC(OC)=C(OC)C=C2C=C(C)C1C GRJMIMFTPGNXIC-UHFFFAOYSA-N 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 1
- 239000004278 EU approved seasoning Substances 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- 206010018364 Glomerulonephritis Diseases 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
- 239000004471 Glycine Substances 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- LTEQMZWBSYACLV-UHFFFAOYSA-N Hexylbenzene Chemical compound CCCCCCC1=CC=CC=C1 LTEQMZWBSYACLV-UHFFFAOYSA-N 0.000 description 1
- 102000004157 Hydrolases Human genes 0.000 description 1
- 108090000604 Hydrolases Proteins 0.000 description 1
- 206010061216 Infarction Diseases 0.000 description 1
- JGFBQFKZKSSODQ-UHFFFAOYSA-N Isothiocyanatocyclopropane Chemical compound S=C=NC1CC1 JGFBQFKZKSSODQ-UHFFFAOYSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- LEVWYRKDKASIDU-IMJSIDKUSA-N L-cystine Chemical compound [O-]C(=O)[C@@H]([NH3+])CSSC[C@H]([NH3+])C([O-])=O LEVWYRKDKASIDU-IMJSIDKUSA-N 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-L L-tartrate(2-) Chemical compound [O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-L 0.000 description 1
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 1
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- 208000019693 Lung disease Diseases 0.000 description 1
- 241000699673 Mesocricetus auratus Species 0.000 description 1
- 102000035092 Neutral proteases Human genes 0.000 description 1
- 108091005507 Neutral proteases Proteins 0.000 description 1
- UMDNBJGISQHXMF-UHFFFAOYSA-N O1NC=CC=C1.S1N=CC=C1 Chemical compound O1NC=CC=C1.S1N=CC=C1 UMDNBJGISQHXMF-UHFFFAOYSA-N 0.000 description 1
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 102000012479 Serine Proteases Human genes 0.000 description 1
- 108010022999 Serine Proteases Proteins 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- AVRWEULSKHQETA-UHFFFAOYSA-N Thiophene-2 Chemical compound S1C=2CCCCCC=2C(C(=O)OC)=C1NC(=O)C1=C(F)C(F)=C(F)C(F)=C1F AVRWEULSKHQETA-UHFFFAOYSA-N 0.000 description 1
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 1
- 239000006035 Tryptophane Substances 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- DPDMMXDBJGCCQC-UHFFFAOYSA-N [Na].[Cl] Chemical compound [Na].[Cl] DPDMMXDBJGCCQC-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 150000001241 acetals Chemical class 0.000 description 1
- ODFJOVXVLFUVNQ-UHFFFAOYSA-N acetarsol Chemical compound CC(=O)NC1=CC([As](O)(O)=O)=CC=C1O ODFJOVXVLFUVNQ-UHFFFAOYSA-N 0.000 description 1
- 238000010306 acid treatment Methods 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical group 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- ZSIQJIWKELUFRJ-UHFFFAOYSA-N azepane Chemical compound C1CCCNCC1 ZSIQJIWKELUFRJ-UHFFFAOYSA-N 0.000 description 1
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 1
- FUARZECLQGVOKA-UHFFFAOYSA-N azetidine;piperazine Chemical compound C1CNC1.C1CNCCN1 FUARZECLQGVOKA-UHFFFAOYSA-N 0.000 description 1
- 229960002319 barbital Drugs 0.000 description 1
- 229910052728 basic metal Inorganic materials 0.000 description 1
- 150000003818 basic metals Chemical class 0.000 description 1
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 1
- BNBQRQQYDMDJAH-UHFFFAOYSA-N benzodioxan Chemical compound C1=CC=C2OCCOC2=C1 BNBQRQQYDMDJAH-UHFFFAOYSA-N 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 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
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- PWLNAUNEAKQYLH-UHFFFAOYSA-N butyric acid octyl ester Natural products CCCCCCCCOC(=O)CCC PWLNAUNEAKQYLH-UHFFFAOYSA-N 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- DRWMGJONTCWKES-UHFFFAOYSA-N chloroform;hydrochloride Chemical compound Cl.ClC(Cl)Cl DRWMGJONTCWKES-UHFFFAOYSA-N 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 238000005336 cracking Methods 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- DMEGYFMYUHOHGS-UHFFFAOYSA-N cycloheptane Chemical compound C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 1
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- WJTCGQSWYFHTAC-UHFFFAOYSA-N cyclooctane Chemical group C1CCCCCCC1 WJTCGQSWYFHTAC-UHFFFAOYSA-N 0.000 description 1
- HFXKQSZZZPGLKQ-UHFFFAOYSA-N cyclopentamine Chemical compound CNC(C)CC1CCCC1 HFXKQSZZZPGLKQ-UHFFFAOYSA-N 0.000 description 1
- 229960003263 cyclopentamine Drugs 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
- 230000006378 damage Effects 0.000 description 1
- 238000013016 damping Methods 0.000 description 1
- 230000009849 deactivation Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- ZICQBHNGXDOVJF-UHFFFAOYSA-N diamantane Chemical group C1C2C3CC(C4)CC2C2C4C3CC1C2 ZICQBHNGXDOVJF-UHFFFAOYSA-N 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 125000005448 ethoxyethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 125000000219 ethylidene group Chemical group [H]C(=[*])C([H])([H])[H] 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000011194 food seasoning agent Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 150000002240 furans Chemical class 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 229950006191 gluconic acid Drugs 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 229940097043 glucuronic acid Drugs 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 229960002743 glutamine Drugs 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- BNRNAKTVFSZAFA-UHFFFAOYSA-N hydrindane Chemical class C1CCCC2CCCC21 BNRNAKTVFSZAFA-UHFFFAOYSA-N 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 1
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 125000003454 indenyl group Chemical class C1(C=CC2=CC=CC=C12)* 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000007574 infarction Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- ICIWUVCWSCSTAQ-UHFFFAOYSA-M iodate Chemical compound [O-]I(=O)=O ICIWUVCWSCSTAQ-UHFFFAOYSA-M 0.000 description 1
- 239000011630 iodine Substances 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
- 229940113601 irrigation solution Drugs 0.000 description 1
- 229940045996 isethionic acid Drugs 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 229940116298 l- malic acid Drugs 0.000 description 1
- 238000009533 lab test Methods 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 229960003136 leucine Drugs 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 230000002132 lysosomal effect Effects 0.000 description 1
- 150000002680 magnesium Chemical class 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- UUIQMZJEGPQKFD-UHFFFAOYSA-N n-butyric acid methyl ester Natural products CCCC(=O)OC UUIQMZJEGPQKFD-UHFFFAOYSA-N 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
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 210000004493 neutrocyte Anatomy 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- ZCYXXKJEDCHMGH-UHFFFAOYSA-N nonane Chemical compound CCCC[CH]CCCC ZCYXXKJEDCHMGH-UHFFFAOYSA-N 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- BKIMMITUMNQMOS-UHFFFAOYSA-N normal nonane Natural products CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 description 1
- 125000005447 octyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 150000002916 oxazoles Chemical class 0.000 description 1
- CFHIDWOYWUOIHU-UHFFFAOYSA-N oxomethyl Chemical compound O=[CH] CFHIDWOYWUOIHU-UHFFFAOYSA-N 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 229960005190 phenylalanine Drugs 0.000 description 1
- SFLGSKRGOWRGBR-UHFFFAOYSA-N phthalane Chemical compound C1=CC=C2COCC2=C1 SFLGSKRGOWRGBR-UHFFFAOYSA-N 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000011533 pre-incubation Methods 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 238000004080 punching Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 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
- MZSDGDXXBZSFTG-UHFFFAOYSA-M sodium;benzenesulfonate Chemical compound [Na+].[O-]S(=O)(=O)C1=CC=CC=C1 MZSDGDXXBZSFTG-UHFFFAOYSA-M 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 238000002798 spectrophotometry method Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 239000003206 sterilizing agent Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 1
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 description 1
- 239000000375 suspending agent 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
- 229940095064 tartrate Drugs 0.000 description 1
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical compound C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- BISQTCXKVNCDDA-UHFFFAOYSA-N thiepine Chemical compound S1C=CC=CC=C1 BISQTCXKVNCDDA-UHFFFAOYSA-N 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
- 229950004288 tosilate Drugs 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
- 229940038773 trisodium citrate Drugs 0.000 description 1
- 229960004799 tryptophan Drugs 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 229960004441 tyrosine Drugs 0.000 description 1
- 229940120293 vaginal suppository Drugs 0.000 description 1
- 239000006216 vaginal suppository Substances 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003021 water soluble solvent Substances 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Description
本发明涉及用作药的磺酰氨衍生物,更特别地,本发明涉及:
(1)下文所定义的式(I)磺酰氨衍生物,其无毒性盐,酸加成盐和其溶剂化物,
(2)它们的制备方法,以及
(3)含这些化合物作为活性成分的药物组合物
中性白细胞的溶酶体水解酶在机体抵抗由微生物或炎症引起的组织损伤的防御反应中具有重要作用。
局部存在于嗜苯胺蓝粒体中的中性丝氨酸蛋白酶即弹性蛋白酶和组织蛋白酶G,在结缔组织的分解中起作用。
具体而言,弹性蛋白酶通过裂解直接保持组织弹性例如肺组织弹性的弹性蛋白的交联,通过裂解蛋白质的疏水部分[J.Cell.Biol.,40,366(1969)]和选择性降解胶原蛋白以及弹性蛋白的交联[J.Biochem.,84.559(1978)]来降解弹性结缔组织。它也对蛋白多糖这样的组织蛋白质起作用[J.Clin.Invest.,57,615(1976)]。因此可以看出弹性蛋白酶在结缔组织代谢中起重要作用。
弹性蛋白酶被体内丝氨酸蛋白酶的普通抑制剂α1-蛋白酶抑制剂(α1-PI)灭活,且酶和抑制剂的失调引起组织损伤[Schweiz.Me d.Wshr.,114,895(1984)]。
正常组织弹性蛋白的更新非常慢[Endocrinology,120,92(1978)],但是
已发现在多种疾病情况中有弹性蛋白降解的病理学加速作用,例如肺气肿[Am.Rev.Respir.Dis.,110,254(1974)],动脉粥样硬化[Lab.Invest.22,228(1970)]和类风湿性关节炎[in Neutral Proteases of HumanPolymorphonuclear leukocytes,Urbanand Schwarzenberg,Baltimore-Munich(1978),page 390],这说明了弹性蛋白酶和疾病间的关系[Infection Inflammation Immunity,13-,13(1983)]。
根据这一背景,近来已进行了许多弹性蛋白酶抑制剂的开发研究,已提出了多种抑制弹性蛋白酶的物质,并已申请了很多专利。
例如,
(1)在EP-A-0347168中公开了式(A)化合物(其中YA是磺酰基或羰基;(i)R1A和R2A,可以相同或不同,各自独立地特别为氢原子,C1-16烷基或下式基团(其中XA是一个键,磺酰基,C1-4亚烷基,被-COOH或苄氧羰基取代的C1-4烷基;是碳环或杂环;nA是1-5;且R4A可以相同或不同,尤其分别是氢原子,C1-8烷基,C1-14烷氧基,C1-6烷硫基,羟基,卤原子,硝基,三卤甲基,-Z41A-COOR43A,-CONR41AR42A,下式基团在该式基团中,是-氨基酸残基;R49A是羟基,C1-4烷氧基,氨基,被一个或两个C1-4烷基取代的氨基或氨基甲酰基,等)或者(ii)R1A和R2A和与R1A和R2A键接的氮原子一起代表含至少一个氮原子并被-COOH取代的杂环或含至少一个氮原子的未被取代的杂环;R3A是氢原子,羟基,C1-6烷基,等;且mA是1-4)和其非毒性盐和酸加成盐,具有对弹性蛋白酶的抑制活性。(2)在EP-A-0465802中公开了式(B)化合物其中R1B和R2B可以相同或不同,各自独立地为氢原子,C1-6烷基或C3-6环烷基,或R1B和R2B一起代表-(CH2)nB-(其中nB是1-6);R3B是1个至5个氢原子,卤原子,C1-12卤代烷基,C1-12烷基,C1-12烷氧基,C2-12链烯基,C3-12环烷基,单环或双环芳基,-ZBR5B(其中ZB是O,S,S(O)或SO2;R5B是氢原子,C1-18烷基,C3-12环烷基,或苯基),-NR6 BR 7B(其中R6B和R7B可以相同或不同,每个代表氢原子,C1-12烷基,C3-6环烷基,苯基,C1-12烷氧基或-C(O)-R3B,或R6B和R7B一起代表-C(O)CH2CH2-C(O)-,-C(O)-,C6H4-C(O)-或-(CH2)XB-(XB是2,3,4,5或6)),或在氮原子上与苯环键连的吗啉代,咪唑基或哌嗪基等;且R4B是一个至5个氢原子,卤原子,硝基,-C(O)CH3,S(O)pBR9B(pB是0,1或2;R9B是羟基,-ONa,C1-12任意被取代的烷基,任意被取代的环烷基))
和它们的非毒性药学上可接受的盐,具有对弹性蛋白酶的抑制活性;(3)EP-A-0484949中公开了式(C)化合物(其中R1C和R2C可以相同或不同,各自代表氢原子,C1-6烷基或C3-6环烷基,或R1C和R2C一起代表-(CH2)nc-(其中nC是1-6);ArC是任意取代的苯基;且HetC是含有至少一个氮原子,硫原子或氧原子的杂环)具有对弹性蛋白酶的抑制活性。
所知的对弹性蛋白酶具有抑制活性的化合物中没有几个显示出口服能对弹性蛋白酶具有抑制活性。大多数化合物口服不会显示出有效果。为了显示口服活性,药物试剂必须易于被消化器官吸收,且必须保持它们的活性,直到它们被输送到一个活性位点。因此,只有那些在消化器官中具有良好稳定性,吸收性和/或溶解性的化合物被期望显示足够的口服活性。
已进行了有力的试验去寻找对弹性蛋白酶具有良好抑制活性且也具有高安全性的新化合物。作为结果,本发明人发现可以通过式(I)磺酰氨衍生物实现这些目的。进一步地,我们发现这些新化合物具有良好的稳定性,可吸收性和溶解性,并且口服作为弹性蛋白酶抑制剂具有活性。
本发明提供了式(I)磺酰氨衍生物其中R1是C1-8烷基,C1-8烷氧基,羟基,酮基,硝基,卤原子,三卤代甲基,氰基,脒基,-COOR7(其中R7是氢原子或C1-8烷基),或(其中p是0至4的整数,且R8和R9各自独立地为氢原子,C1-4烷基,C2-5酰基,-COOR10(其中R10是氢原子或C1-8烷基),-CONR11R12(其中R11和R12各自独立地为氢原子或C1-4烷基),(其中是-α-氨基酸残基)或
R8和R9和它们所连接的氮原子一起代表禾取代的或被C1-4烷基或苯基C1-4烷基取代的脂族杂环);n是0至5的整数;是-碳环或杂环;其中R2和R3各自独立地为氢原子,C1-4烷基,C1-4烷氧基,卤原子,三卤代甲基或苯基,或R2和R3一起代表C1-4亚烷基,或其中R2和R3与和它们相连的碳原子一起代表C3-7环烷基;R4是C1-4烷基或C1-4烷氧基或两个R4彼此以邻位与苯核相连,一起代表C3-5亚烷基;m是0至4的整数;且其中R5和R6各自独立地为1)氢原子,2)羟基,3)C1-8烷基,4)C1-8烷氧基,5)苯基C1-4烷氧基,6)脒基,7)-M-R16(其中M是一单键或C1-8亚烷基),且R16是i)-NR17R18(其中R17和R18各自独立地是氢原子或C1-4烷基),ii)-CONR19R20(其中R19和R20各自独立地为氢原子或C1-4烷基),iii)(其中
是一碳环,r是0至5的整数,且R21是C1-4烷基,C1-4烷氧基,硝基,脒基,-COOR22(其中R22是氢原子,C1-8烷基,苯基或苯基C1-4烷基),-SO3H,-CONR23-E-R24(其中R23是氢原子或C1-4烷基,E是1-4亚烷基且R24是-COOR25(其中R25是氢原子,C1-8烷基,苯基或苯基C1-4烷基)或四唑环),四唑环或吗啉代环),iv)未取代的或被一个至四个取代基取代的杂环,取代基选自C1-4烷基,C1-4烷氧基,羟基,苯基C1-4烷基,-COOR26(其中R26是氢原子,C1-8烷基,苯基或苯基C1-4烷基),羟基C1-4烷基或C2-4烷氧基烷基),8)被一个或两个-OR27取代的C1-8烷基(其中R27是氢原子,C1-4烷基,C2-4烷氧烷基或被-OR28取代的C2-4烷基(其中R28是氢原子或C2-4烷氧烷基)),9)-J-COOR29(其中R29是氢原子,C1-8烷基,苯基或苯基C1-4烷基,且J是一单键,-(CH2)s-或(其中S是2至6的整数,且R30和R31各自独立地为i)氢原子,ii)C1-8烷基,iii)-COOR32(其中R32是氢原子,C1-8烷基,苯基或苯基C1-4烷基),iv)碳环或杂环,其未被取代或被一个或多个选自C1-4烷基,C1-4烷氧烷基,氨基,硝基,羟基,卤原子,腈,胍基和脒基的基团取代,或v)被一个或多个取代基取代的C1-8烷基,取代基选自羟基,-COOR33(其中R33是氢原子,C1-8烷基,苯基或苯基C1-4烷基),-NR34R35(其中R34和R35各自独立地为氢原子或C1-4烷基),碳环或杂环,未取代的或被选自C1-4烷基,C1-4烷氧烷基,氨基,硝基,羟基,卤原子,腈,胍基和脒基的一个或几个取代基取代的C1-8烷基,前提是C1-8烷基的碳原子可被硫原子取代),或其中R5和R6与它们连接的氮原子一起代表一个杂环,q是0至4的整数,且R15是1)羟基2)酮基3)被保护酮基,4)C1-4烷基,5)C1-4烷氧基,6)苯基,7)苯氧基,8)苯基C1-4烷基,9)苯基C1-4烷氧基,10)硝基,11)-COOR36(其中R36是氢原子,C1-8烷基,被-CONR37R38取代的C1-4烷基(其中R37和R38各自独立地为氢原子或C1-4烷基),被-NR39R40取代的C1-4烷基(其中R39和R40各自独立地为氢原子或C1-4烷基),被-OR41取代的C1-4烷基(其中R41是被-OR42取代的C2-4烷基(其中R42是氢原子或C2-4烷氧烷基))或被哌嗪基环取代的C1-4烷基),12)-NR43R44(其中R43和R44各自独立地为氢原子,C1-4烷基或C2-5酰基),13)-CONR45R46(其中R45,R46各自独立地为氢原子,羟基,C1-4烷基,苯基C1-4烷氧基或被羟基或-COOR47(其中R47是氢原子或C1-8烷基)取代的C1-4烷基),14)C1-4烷基,其被一个或几个选自羟基,-COOR48(其中R48是氢原子或C1-8烷基),-NR49R50(其中R49和R50各自独立地为氢原子或C1-4烷基),-OSO3H或含一个或两个氮原子的5元或6元杂环取代基取代,15)含一个或两个氮原子的5元或6元杂环,16)卤原子,17-CHO,或18)-NR51-COOR52(其中R51和R52各自独立地为氢原子或C1-8烷基);或其非毒性盐,酸加成盐或溶剂化物。
与现有技术公开的化合物相比,本发明磺酰氨衍生物是新的。
总之,在EP-A-0347168中公开的式(A)化合物一定含有一个三甲基乙酰氧基。相反,本发明化合物具有一个可被各种取代基R1取代的D环。
因此本发明化合物具有与式(A)化合物完全不同的化学结构。
EP-A-0465802中公开的式(B)化合物包括R4B代表S(O)pBR9B的化合物。R9B代表羟基,-ONa,任意取代的C1-12烷基或任意取代的环烷基,但不代表氨基。而且EP-A-0484949中公开的化合物式(C)包括ArC取代基为S(O)pCR9C的那些化合物。R9C可代表羟基,-ONa,任意取代的C1-12烷基或任意取代的环烷基,但不代表氨基。
相反,本发明化合物具有可以被多种取代基取代的磺酰氨基团。因此本发明化合物具有与式(B)和(C)化合物完全不同的化学结构。
并且进一步地,有关化合物口服没有显出活性,但本发明的一些化合物具有良好的稳定性,吸收性和溶解性,因此口服作为弹性蛋白酶抑制剂具有活性。
在式(I)中,由R2,R3,R4,R8,R9,R11,R12,R15,R17,R18,R19,R20,R21,R23,R27,R34,R35,R36,R37,R38,R39,R40,R43,R44,R45,R46,R49,R50和脂族杂环,碳环或杂环的取代基代表的C1-4烷基是甲基,乙基,丙基,丁基和其异构体。
在式(I)中,由R1,R5,R6,R7,R10,R22,R25,R26,R29,R30,R31,R32,R33,R36,R47,R48,R51和R52代表的C1-8烷基是甲基,乙基,丙基,丁基,戊基,己基,庚基,辛基和其异构体。
在式(I)中,R27和R41代表的C2-4烷基指乙基,丙基,丁基和其异构体。
在式(I)中由彼此邻位连接的两个R4代表的C3-5亚烷基指1,3-亚丙基1,4-亚丁基,1,5-亚戊基,和其异构体。
在式(I)中M代表的C1-8亚烷基指亚甲基,亚乙基,1,3-亚丙基,1,4-亚丁基,1,5-亚戊基,1,6-亚己基,1,7-亚庚基,1,8-亚辛基和其异构体。
式(I)中E代表的C1-4亚烷基指亚甲基,亚乙基,1,3-亚丙基,1,4-亚丁基和其异构体。
在式(I)中,苯基C1-4烷基或苯基C1-4烷氧基指C1-4烷基或被苯基取代的C1-4烷氧基。
在式(I)中,由R29,R32,R33,R15和脂肪杂环或杂环的取代基代表的苯基C1-4烷基指甲基,乙基,丙基,丁基和其异构体,它们均被苯基取代。
在式(I)中,由R5,R6,R15,R45和R46代表的苯基C1-4烷氧基指甲氧基,乙氧基,丙氧基,丁氧基和其异构体,它们均是被苯基取代的。
在式(I)中,由R8,R9,R43和R44代表的C2-5酰基指乙酰基,丙酰基,丁酰基,戊酰基和其异构体。
在式(I)中,由R27,R28,R42和杂环取代基代表的C2-4烷氧烷基指甲氧甲基,乙氧甲基,丙氧甲基,甲氧乙基,乙氧乙基,甲氧丙基和其异构体。
在式(I)中,由R1,R5和R6代表的C1-8烷氧基指甲氧基,乙氧基,丙氧基,丁氧基,戊氧基,己氧基,庚氧基,辛氧基和其异构体。
在式(I)中,由R2,R3,R4,R15,R21和碳环或杂环取代基代表的C1-4烷氧基指甲氧基,乙氧基,丙氧基,丁氧基和其异构体。
在式(I)中,由R1,R2,R3和R15代表的卤原子指氟,氯,溴,和碘。在式(I)中,由代表的α-氨基酸残基可以是任何α-氨基酸残基。例如,它可以是甘氨酸,丙氨酸,丝氨酸,苏氨酸,胱氨酸,缬氨酸,蛋氨酸,亮氨酸,异亮氨酸,苯丙氨酸,酪氨酸,色氨酸,天冬氨酸,谷氨酸,精氨酸,谷氨酰胺,赖氨酸,组氨酸或脯氨酸。
在式(I)中,由R2和R3与它们连接的碳原子一起代表的C3-7环烷基指环丙基,环丁基,环戊基,环己基和环庚基。
在式(I)中,由R2和R3一起代表的C1-4亚烷基指亚甲基,亚乙基,亚丙基,亚丁基和其异构体。
在式(I)中,由R8和R9与它们连接的氮原子一起代表的脂肪族杂环优选为5至15元的单环或双环,该环为含一个或两个氮原子或一个氮原子和一个硫原子或氧原子的饱和的杂环或部分饱和的杂环。例子包括吡咯啉,吡咯烷,咪唑啉,咪唑烷,吡唑啉,吡唑烷,哌啶,哌嗪,四氢嘧啶,六氢嘧啶,四氢哒嗪,六氢哒嗪,六氢氢杂_,二氢噁唑,四氢噁唑,二氢异噁唑,四氢异噁唑,二氢噻唑,四氢噻唑,二氢异噻唑,四氢异噻唑,吗啉,硫代吗啉,二氢吲哚,异二氢吲哚,二氢吲唑,全氢吲唑,二氢喹啉,四氢喹啉,全氢喹啉,二氢异喹啉,四氢异喹啉,全氢异喹啉,二氢2,3-二氮杂萘,四氢2,3-二氮杂萘,全氢2,3-二氮杂萘,二氢1,5-二氮杂萘,四氢1,5-二氮杂萘,全氢1,5-二氮杂萘,二氢喹喔啉,四氢喹喔啉,全氢喹喔啉,二氢喹唑啉,四氢喹唑啉,全氢喹唑啉,二氢1,2-二氮杂萘,四氢1,2-二氮杂萘,全氢1,2-二氮杂萘,二氢苯并噁唑,全氢苯并噁脞,二氢苯并噻唑,全氢苯并噻唑,二氢苯并咪唑和全氢苯并咪唑环。
在式(I)中,由
,R30,R31代表的碳环优选指3-l5元单环或多环芳烃环或脂肪烃环。例子包括1,3-环戊二烯,苯,环戊烯,茚,萘,
,环丙烷,环丁烷,环戊烷,环戊烯,环己烷,环己烯,环己二烯,环庚烷,二氢化
,全氢化茚,二氢化萘,四氢化萘,全氢化萘,双环[2.2.1]己烷,双环[3.2.2]壬烷和金刚烷环。
当上述碳环有两个当量时,键位点存在于相同碳原子或不同碳原子上,即当环含有两个自由价时,两个取代基可连接在相同碳原子上或不同碳原子上。在式(I)中,由
R16,R30和R31代表的杂环优选指5-15元单环或双环芳香杂环,饱和杂环或部分饱和杂环,环中含有一至四个氮原子,一或两个硫原子,一或两个氧原子或一个氮原子和一个硫原子或氧原子,例子包括吡咯,咪唑,吡唑,吡啶,哌嗪,嘧啶,哒嗪,氮杂_,二氮杂_,呋喃,吡喃,氮杂革,噻吩,噻喃(硫杂吡喃),噻品(thiepine),噁唑,异噁唑,噻唑,异噻唑,噁嗪,氧代氮杂_,噻嗪,噻氮杂_,吲哚,异吲哚,苯并呋喃,异苯并呋喃,苯并噻吩,异苯并噻吩,吲唑,喹啉,异喹啉,2,3-二氮杂革,1,5-二氮杂萘,喹噁啉,喹唑啉,1,2-二氮杂萘,苯并噁唑,苯并噻唑,苯并咪唑,吡咯啉,吡咯烷,咪唑啉,咪唑烷,吡唑啉,吡唑烷,哌啶,哌嗪,四氢嘧啶,六氢嘧啶,四氢哒嗪,六氢哒嗪,六氢氮杂_,六氢二氮杂_,二氢呋喃,四氢呋喃,二氢吡喃,四氢吡喃,二氢噻吩,四氢噻吩,二氢噻喃(二氢硫杂吡喃),四氢噻喃(四氢硫杂吡喃),二氢噁唑,四氢噁唑,二氢异噁唑,四氢异噁唑,二氢噻唑,四氢噻唑,二氢异噻唑,四氢异噻唑,吗啉,硫代吗啉,二氢吲哚,异二氢吲哚,二氢苯并呋喃,全氢苯并呋喃,二氢异苯并呋喃,全氢异苯并呋喃,二氢苯并噻吩,全氢苯并噻吩,二氢异苯并噻吩,全氢异苯并噻吩,二氢吲唑,全氢吲唑,二氢喹啉,四氢喹啉,全氢喹啉,二氢异喹啉,四氢异喹啉,全氢异喹啉,二氢2,3-二氮杂_,四氢2,3-二氮杂萘,全氢2,3-二氮杂萘,二氢1,5一二氮杂萘,四氢1,5-二氮杂萘,全氢l,5-二氮杂萘,二氢喹噁啉,四氢喹嚼啉,全氢喹噁啉,二氢喹唑啉,四氢喹唑啉,全氢喹唑啉,二氢1,2-二氮杂萘,四氢1,2-二氮杂萘全氢l,2-二氮杂萘,二氢苯并噁唑,全氢苯并噁唑,二氢苯并噻唑,全氢苯并噻唑,二氢苯并咪唑,全氢苯并咪唑,二氢苯并噁嗪,1,3-dioxaindan,1,4-苯并二噁烷,奎宁环,三唑和四唑环。
在式(I)中,由
代表的杂环,即R5和R6与它们连接的氮原子一起优选为3-15元单环或双环芳香杂环,饱和杂环或部分饱和的杂环,环中含有一个或两个氮原子或一个氮原子和一个硫原子或氧原子。实例包括吡咯,咪唑,吡唑,吡啶,哌嗪,嘧啶,哒嗪,氮杂_,二氮杂_,氮丙啶,氮杂环丁烷,吡咯啉,吡咯烷,咪唑啉,咪唑烷,吡唑啉,吡唑烷,哌啶,哌嗪,四氢嘧啶,六氢嘧啶,四氢哒嗪,六氢哒嗪,六氢氮杂_,六氢二氮杂_,噁唑,异噻唑,噻唑,异噻唑,噁嗪,噁氮杂_,噻嗪,噻氮杂_,吲哚,异吲哚,吲唑,喹啉,异喹啉,2,3-二氮杂萘,1,5-二氮杂萘,喹噁啉,喹唑啉,1,2-二氮杂萘,苯并噁唑,苯并噻唑,苯并咪唑,二氢噁唑,四氢噁唑,二氢异噁唑,四氢异噁唑,二氢噻唑,四氢噻唑,二氢异噻唑,四氢异噻唑,吗啉,硫代码啉,吲哚啉,异吲哚啉,全氢吲哚,二氢吲唑,全氢吲唑,二氢喹啉,四氢喹啉,全氢喹啉,二氢异喹啉,四氢异喹啉,全氢异喹啉,二氢2,3-二氮杂萘,四氢2,3-二氮杂萘,全氢2,3-二氮杂萘,氢1,5-二氮杂萘,四氢1,5-二氮杂萘,全氢1,5-二氮杂萘,二氢喹噁啉,四氢喹噁啉,全氢喹噁啉,二氢喹唑啉,四氢喹唑啉,全氢喹唑啉,二氢1,2-二氮杂萘,四氢1,2-二氮杂萘,全氢1,2-二氮杂萘,二氢苯并噁唑,全氢苯并噁唑,二氢苯并噻唑,全氢苯并噻唑,二氢苯并咪唑,全氢苯并咪唑,7-氮杂双环[3.2.1]辛烷,和3-氮杂双环[3.2.2]壬烷环。
在式(I)中,由R15代表的含一个或两个氮原子的5元或6元杂环指,例如,吡咯,咪唑,吡唑,吡啶,哌嗪,嘧啶,哒嗪,吡咯啉,吡咯烷,咪唑啉,咪唑烷,吡唑啉,吡唑烷,哌啶,哌嗪,四氢嘧啶或四氢哒嗪。
在式(I)中:m优选代表0,1或2,更优选0或1。R4优选代表1-4碳原子的烷基或烷氧基,例如甲基,乙基,异丙基,甲氧基,乙氧基,或异丙氧基。甲基是特别优选的。当存在一个或两个取代基R4时,它们优选占有与苯环连接的氧原子邻位的一个或两个位置;在与苯环相连的氧原子邻位和间位有两个取代基的化合物也构成了本发明的一个特征;两个这样的取代基可以一同构成与苯环稠合的五元环。
特别优选的化合物中m是1,R4代表甲基,处于和苯环连接的氧原子邻位上。
R2和R3中的一个优选代表氢原子,甲基,乙基,或甲氧基,另一个代表甲基、乙基,异丙基,苯基或三氟甲基或者R2和R3与它们连接的碳原子一起代表亚乙基或3-6碳原子环烷基。R2和R3中的一个代表的乙基优选β构型。
D优选代表苯基,萘基(优选1-或2-萘基),噻吩基(优选噻吩-2基),环己烷,吡啶基,(优选吡啶-3-基),噻唑基(优选噻唑-4-基),咪唑啉基(优选咪唑啉-2-基),苯并咪唑基(优选苯并咪唑-5-基),2H-1,4-苯并噁嗪-3-酮-6-基,或1,3-苯并二氧戊环-5-基,或1H-1-甲基-2-吡啶酮-3-基。苯基是特别优选的。
n优选代表0,1,2或3,优选0或1。R1优选代表1-4碳原子烷基,例如甲基;1-4碳原子烷氧基,例如甲氧基;氨基;两个1-4碳原子烷基取代的氨基,例如二甲氨基,氨基甲酰基取代的甲基;2-5碳原子烷酰基取代的甲基,例如乙酰基;硝基;羟基;氰基;羧基,三卤代甲基,例如三氟甲基;脒基;烷氧羰基取代的氨基;卤原子,例如氯;吡咯烷基,哌啶基;全氢氮杂_基;或吗啉基或在4位上被苄基任意取代的哌嗪基。
其中D代表一取代苯基的化合物也是本发明一个特征:当D是被取代的苯基时,至少一个取代基优选在4-位上。优选的4-取代苯基是那些其中取代基为5-,6-或7-元含氮环,含氮环与苯基通过氮原子连接:优选吡咯烷-1-基。
在基团NR5R6中,当R5和R6与它们相连的氮原子一起不代表一个杂环时,基团R5R6优选代表氢原子;甲基;乙基;丙基;甲氧基;苄基;甲氧甲氧乙基;1-羟乙基;氢原子是特别优选的,另一个代表苯基;被取代的苯基取代基,例如2-((1-羧甲基)氨基羰基)苯基,4-硝基苯基;杂环,例如奎宁环,哌啶,吡啶,咪唑,吗啉,四唑;被杂环取代的C1-8烷基,例如哌嗪-1-基乙基、哌啶-1-基乙基、吗啉-1-基乙基、吡啶-2-基乙基、吡咯-2-基乙基;吗啉-1-基乙基是特别优选的。
在基团NR5R6中,当R5和R6与和它们连接的氮原子一起代表杂环时,该环优选代表吡咯烷;吲哚;吲哚啉;全氢吲哚;苯并咪唑;吗啉;哌啶;哌嗪;7-氮杂双环[3.2.1]辛烷;3-氮杂双环[3.2.2]壬烷;四氢噁唑;四氢噻唑;咪唑;六氢二氮杂_;氮丙啶;氮杂环丁烷;哌嗪是特别优选的。
在基团NR5R6中,当R5和R6与它们相连的氮原子一起代表杂环时,R15优选代表羟基;羟基取代的C1-4烷基,例如羟甲基;杂环取代的C1-4烷基,例如吡咯烷-1-基甲基;苄氧基;氨基;甲氧基;二甲基氨基;乙酰氨基;甲基,硝基;卤原子,如氟;酮;羧基;酯,例如乙氧羰基、叔丁氧羰基、2-氨基乙氧羰基、2-(2-羟基乙氧基)乙氧羰基、2-(哌嗪-1-基)乙氧羰基;酰胺,例如羧甲基氨基羰基;羧基是特别优选的。
在基团NR5R6中,当R5和R6与它们连接的氮原子一起代表杂环时,q优选代表0,1或2,更优选0或1。
根据包括权利要求在内的整个说明书,本领域熟练技术人员容易理解:所有的异构体均包括在本发明中。例如,烷基,亚烷基和亚烯基包括直链也包括支链基团。亚烯基中的双键包括E,Z和E Z混合物。因此,当存在象支链烷基这样的基团时,由于不对称碳原子的存在而产生的所有异构体均包括在本发明中。
本发明式(I)化合物可以通过实质上已知的方法转化成相应的无毒盐或酸加成盐。
水溶性盐是优选的。合适的盐,例如,包括碱金属盐(例如钾或钠盐),碱土金属(如钙或镁)盐,铵盐,药学上可接受的有机胺(如四甲铵,三乙胺,甲胺,二甲胺,环戊胺,苄胺,苯乙胺,哌啶,一乙醇胺,二乙醇胺,三(羟甲基)胺,赖氨酸,精氨酸或N-甲基-D-葡糖胺)的盐。
水溶性酸加成盐也是优选的。合适的酸加成盐例如包括和无机酸形成的盐,无机酸如盐酸,氢溴酸,硫酸,磷酸和硝酸,以及和有机酸形成的盐,有机酸例如乙酸,三氟乙酸,乳酸,酒石酸,乙二酸,富马酸,马来酸,苯磺酸,甲苯磺酸,羟乙磺酸,葡糖醛酸和葡糖酸。
本发明式(I)化合物可以通过本质上已知的方法转化为相应的溶剂化物。
水溶性溶剂化物是优选的。合适的溶剂化物例如包括和水或和醇溶剂如乙醇形成的盐。
本发明有代表性的化合物用下面表1-46中的化合物和其非毒盐及酸加成盐来说明。
在这些表中,Me是甲基,Et是乙基,Pr是丙基,iPr是异丙基和tBu是叔丁基。
表2
表25
表27
表31
表34
表37
表42
表44
本发明式(I)化合物可以通过式(II)化合物的酯化而制备。
其中R1a是C1-8烷基,C1-8烷氧基,羟基,被保护羟基,酮,硝基,卤原子,三卤代甲基,氰基,脒基,-COOR7a(其中R7a是C1-8烷基或苄基),或(其中p如上文所定义,R8a和R9a各自独立地为氢原子(前提是,R8a和R9a不同时代表氢原子),叔丁氧羰基,苄氧羰基,C1-4烷基,C2-5酰基,-COOR10a(其中R10a是C1-8烷基或苄基),-CONR11R12(其中R11和RU如上文所定义),或者(其中是被保护α-氨基酸残基),或者R8a和R9a和它们相连的氮原子一起代表未取代的或被C1-4烷基或苯基C1-4烷基取代的脂族杂环,其它符号如上文所定义。酯化作用是式(II)化合物与式(III)化合物反应其中
(其中R5a和R6a各自独立地是1)氢原子(前提是R5a和R6a不同时代表氢原子)。2)羟基,3)被保护的羟基,保护基团在酸条件下可去除,4)叔丁氧羰基,5)苄氧羰基,6)C1-8烷基,7)C1-8烷氧基,8)苯基C1-4烷氧基,9)脒基,10)-M-R16a(其中M如上文定义,且R16a是i)-NR17aR18a(其中R17a和R18a各自独立地为氢原子(前提是R17a和R18a不同时代表氢原子),叔丁氧羰基,苄氧羰基或C1-4烷基),ii)-CONR19R20(其中R19和R20如上文所定义),(其中所有符号如上文所定义),iv)杂环,未取代的或被1至4个选自C1-4烷基,C1-4烷氧基,羟基,苯基C1-4烷氢-COOR26(其中R26如上文所定义),羟基C1-4烷基或C2-4烷氧烷基的取代基取代,其中羟基C1-4烷基中的羟基被在酸性条件下可去除的保护基团保护,11)C1-8烷基,被1个或两个-OR27a取代(其中R27a是氢原子,C1-4烷基,C2-4烷氧烷基,叔丁基二甲基甲硅烷基,THP,苄基,或被-OR28a取代的C2-4烷基(其中R28a是氢原子,C2-4烷氧烷基,叔丁基二甲基甲硅烷基,THP或苄基)),12)-Ja-COOR29(其中R29如上文定义,Ja是一单键,-(CH2)s-或(其中S如上文定义,R30a和R31a各自独立地是i)氢原子,ii)C1-8烷基,iii)-COOR32(其中R32如上文所定义),iv)碳环或杂环,未取代的或被一个或几个选自C1-4烷基,C1-4烷氧烷基,氨基,硝基、羟基,被保护羟基,卤原子,腈、胍基和脒基的取代基取代,或者v)C1-8烷基,被一个或多个取代基取代,取代基选自羟基,被保护羟基,-COOR33(其中R33如上文所定义),-NR34aR35a(其中R34a和R35a各自独立地为氢原子(前提是R34a和R35a不同时为氢原子),叔丁氧羰基,苄氧羰基或C1-4烷基),碳环或杂环,该环为未取代的或被一个或几个选自C1-4烷基,C1-4烷氧烷基,被保护氨基,硝基,羟基,被保护羟基,卤原子,腈,胍基和脒基的基团取代,前提是C1-8烷基的碳原子可以被硫原子取代,或者其中R5a和R6a与它们相连的氮原子一起代表杂环,q如上文定义,R15a是1)羟基,2)被保护的羟基,保护基团在酸性条件下可去除3)酮,4)被保护酮,5)C1-4烷基,6)C1-4烷氧基,7)苯基,8)苯氧基,9)苯基C1-4烷基,10)苯基C1-4烷氧基,11)硝基,12)-COOR36a(其中R36a是氢原子,C1-8烷基,被-CONR37R38取代的C1-4烷基(其中R37和R38如上文所定义),被-NR39aR40a取代的C1-4烷基(其中R39a和R40a各自独立地是氢原子(前提是R39a和R40a不同时为氢原子),叔丁氧羰基,苄氧羰基或C1-4烷基),被-OR41a取代的C1-4烷基(其中R41a是-OR42a取代的C2-4烷基(其中R42a是氢原子,C2-4烷氧烷基或苄基))或被保护哌嗪环取代的C1-4烷基),13)-NR43aR44a(其中R43a,R44a各自独立地为氢原子(前提是,R43a和R44a不同时为氢原子),叔丁氧羰基,苄氧羰基,C1-4烷基或C2-5酰基),14)-CONR45aR46a(其中R45a和R46a各自独立地为氢原子,C1-4烷基,羟基,保护基在酸性条件下可去除的被保护的羟基,苯基C1-4烷氧基或被取代的C1-4烷基,取代基为羟基,被保护羟基或-COOR47a(其中R47a是氢原子,C1-8烷基或苄基)15)C1-4烷基,被一个或几个选自羟基,被保护羟基,-COOR48a(其中R48a是氢原子,C1-8烷基或苄基),-NR49aR50a(其中R49a和R50a各自独立地为氢原子(前提是R49a和R50a不同时代表氢原子),叔丁氧羰基,苄氧羰基或C1-4烷基),或含一个或两个氮原子的五元或六元杂环取代基取代,16)含一个或两个氮原子的五元或六元杂环,17)卤原子,18)-CHO,被酸性条件下可去除的保护基团保护,或者19)-NR51a-COOR52a(其中R51a和R52a各自独立地为氢原子或C1-8烷基),其它符号如上文所定义,或者
可通过式(II)化合物和式(III)化合物的酯化来获得具有保护基(S)的化合物,然后去除保护基(S)(例如通过叔丁酯的水解,用酸和/或氢解处理),或者可以通过式(II)化合物与式(III)化合物酯化,如果需要,消除保护基得含R15的化合物,R15代表被羟基取代的C1-4烷基,然后用硫酸进行酯化作用;可任意地将如此得到的式(I)化合物转化为它的非毒盐,酸加成盐或溶剂化物。
被保护羟基指,例如酸性条件下可去除的保护基保护的羟基(例如,C2-4烷氧烷基,叔丁基二甲基甲硅烷基,四氢吡喃(THP),三苯甲基)或者被可氢化去除的保护基保护的羟基(例如苄基)。
被酸性条件下可去除的保护基保护的羟基指,例如,被C2-4烷氧烷基,叔丁基二甲基甲硅烷基,四氢吡喃(THP)或三苯基甲基保护的羟基。
被保护氨基酸,α-氨基酸或哌嗪环指,例如,被叔丁氧羰基(Boc)或苄氧羰基(Cbz)保护的氨基酸,α-氨基酸或哌嗪环。
被酸性条件下可去除的保护基团保护的-CHO指,例如被缩醛(例如二甲醇缩醛或二乙醇缩醛)或缩酮(例如亚乙基二氧缩酮或三亚甲基二氧缩酮)保护的-CHO。
上述酯化作用实质上是已知的,可用例如下面的方法进行:(1)使用酰基卤,(2)使用混合酸酐,(3)使用缩合剂,
这些方法的每一种方法可以如下进行:
(1)可以使用酰基卤的方法,例如,使羧酸与酰卤(例如草酰氯或亚硫酰氯)在惰性有机溶剂(例如,氯仿,二氯甲烷,二乙醚或四氢呋喃)中或在无溶剂条件下,在-20℃至所用溶剂的回流温度下反应,然后将得到的酰基卤与相应的醇在叔胺(例如吡啶,三乙胺,二甲基苯胺或二甲基氨基吡啶)存在下,在惰性有机溶剂中(例如,氯仿,二氯甲烷,二乙醚或四氢呋喃),在0℃至40℃的温度下反应。(2)可以使用混合酸酐的方法,例如使羧酸和酰基卤(例如,三甲基乙酰氯,甲苯磺酰氯或甲磺酰氯)或酸衍生物(例如氯代甲酸乙酯或氯代甲酸异丁酯)在叔胺(例如吡啶,三乙胺,二甲基苯胺或二甲基氨基吡啶)存在下,在惰性有机溶剂(例如氯仿,二氯甲烷,二乙醚或四氢呋喃)中,或在无溶剂条件下,在0℃至40℃温度下反应,然后将得到的酸酐混合物与相应的醇在惰性有机溶剂中(例如氯仿,二氯甲烷,二乙醚或四氢呋喃),在0℃至40℃温度下反应,(3)可以使用缩合剂(例如,1,3-二环己基碳二亚胺(DCC),1-乙基-3-[3-(二甲氨基)丙基]碳二亚胺(EDC)或碘化2-氯-1-甲基吡啶)的方法,例如,使用缩合剂使羧酸和相应的醇反应,在叔胺(例如吡啶,三乙胺,二甲基苯胺或二甲基氨基吡啶)存在或不存在时,在惰性有机溶剂(例如氯仿,二氯甲烷,二甲基甲酰胺或二乙醚)中或无溶剂时,在0℃至40℃温度下进行反应。
上述反应(1),(2)和(3)可以优选在惰性气体(例如氩气或氮气)中在无水条件下进行。
叔丁酯基团的水解或用酸处理反应产物本质上是已知的(例如C2-4烷氧烷基,叔丁氧羰基或二甲缩醛的脱除)并可以实施,例如,用有机酸(例如三氟乙酸)或无机酸(例如盐酸),或其混合物,在惰性有机溶剂中(例如二氯甲烷,氯仿,甲醇,二噁烷,乙酸乙酯或苯甲醚)在0℃至90℃的温度下进行反应。
氢解实质上是已知的,并可以实施,例如在惰性溶剂[如醚(例如四氢呋喃,二噁烷,二乙氧乙烷或二乙醚),醇(例如甲醇或乙醇),苯类似物(例如苯或甲苯),酮(例如丙酮或甲乙酮),腈(例如乙腈),胺(例如二甲基甲酰胺),水,乙酸乙酯,乙酸或它们的两种或多种混合物]中,在氢化催化剂(例如活性炭上的钯,钯黑,钯,碳上的氢氧化钯,氧化铂,镍或阮内镍(注册商标))存在下,存在或不存在无机酸(例如盐酸,硫酸,高氯酸,硼酸或四氟硼酸)或有机酸(例如乙酸,对甲苯磺酸,草酸,三氟乙酸或甲酸),常压或加压氢气氛围下,在0℃至200℃温度下进行。当使用一种酸时,同时也可以使用其盐。
硫酸的酯化作用实质上是已知的,且可以例如通过三氧化硫吡啶配合物在叔胺(例如吡啶)存在下在0℃至40℃的温度下反应进行。
用作起始原料的式(II)和(III)化合物可以通过下面反应式1的方法或本质上已知的方法制备,或者它们是商业上可购得的。例如2-苯基丁酸可购得。这些化合物也可以通过本说明书实施例中说明的方法来制备。
反应式1
上述反应式1中W是碱金属,Y是苄基,苄氧羰基,或酸性条件下可去除的保护基(例如C2-4烷氧烷基,叔丁基二甲基甲硅烷基,四氢呋喃(THP)或三苯基甲基),其它符号如上文所定义。
已经证明本发明式(I)化合物对弹性蛋白酶有抑制活性。例如在实验室试验中获得了下列结果。(1)对人多形核弹性蛋白酶的抑制作用
在37℃将混合物0.5ml 0.2mM HEPES缓冲液(pH8.0),0.2ml 2.5M NaCl,0.1ml 1%聚乙二醇6000,0.13ml蒸馏水,溶于0.01ml二甲亚砜(DMSO)中的试验化合物和0.05ml 0.8单位/ml人多形核弹性蛋白酶(HSE)一起预温育20分钟。然后向上述混合物中加入5mM Meo-Suc-Ala-Ala-Pro-Val-pNA(DMSO溶液,0.01ml)并在37℃保温5分钟。用0.1ml 50%乙酸终止反应并在405nM处用分光光度法测定释放出的对-硝基酰苯胺(pNA)。用下面等式计算化合物抑制百分比。
抑制(%)=1-{ΔOD(试验化合物-空白)/
ΔOD(对比化合物-空白)}×100
结果示于表47中[表47]
(2)在仓鼠体内进行的对人多形核弹性蛋白酶诱导的肺出血的抑制作用。
实施例号 | 1C50(μM) |
1 (16)1 (40)1 (56)1 (78)1 (130)1 (139)22 (1)2 (42)2 (62)2 (69)2 (77)2 (111)2 (120)2 (157)2 (173)2 (179)2 (197)2 (274)2 (276) | 0.0170.0190.0140.00800.0220.0240.0550.0120.0130.00680.0110.0180.00970.0230.0080.0140.0490.0100.0120.0093 |
给一组五只Syrian仓鼠口服试验化合物,化合物悬浮于0.5%羧甲基纤维素或80%聚乙二醇400或2%T Ween80中。服后60分钟时,在戊巴比妥麻醉条件下通过外科手术暴露气管,气管内注射10U/0.1ml HSE(巴比妥用量60mg/kg,i.p)以引起肺损伤。注射60分时后,仓鼠被放血杀死,并用2.5ml盐水进行支气管肺泡灌洗,并回收灌洗溶液(BALF)。回收的BALF(0.5ml)用2%碳酸钠水溶液稀释4倍并超声处理10秒钟。回收液再用2%碳酸钠水溶液稀释2.5倍,根据在414nM处的吸收值用标准曲线计算BALF中血的量
结果见表48和49。
【表48】
【表49】
实施例序号 | 500mg/kg时的抑制作用(%) |
1 (68) | 51 |
1 (90) | 65 |
2 | 81 |
2 (42) | 67 |
2 (69) | 83 |
实施例序号 | ED50 |
1 (139) | 192mg/kg |
2 (274) | 132mg/kg |
2 (276) | 73mg/kg |
上述实验表明,即使口服时,本发明化合物对弹性蛋白酶也有抑制活性。
本发明化合物毒性非常低,因此,本发明化合物可以被认为足够安全且适于药用。
本发明式(I)化合物,其无毒盐和酸加成盐具有对弹性蛋白酶的抑制活性。因此它们可用来治疗和/或预防由弹性蛋白,胶原纤维和/或蛋白多糖异常增强的降解作用而产生的疾病,病因源于弹性蛋白酶对哺乳动物特别是人的作用,(例如慢性引起阻塞的肺部疾病,象肺象肿,类风湿性关节炎,动脉粥样硬化,成人呼吸窘迫综合症(ARDS),肾小球性肾炎,必肌梗塞形成,自发性溃疡性结肠炎或龈炎)。
根据上述目的,本发明式(I)化合物,或无毒盐,其酸加成盐或溶剂化物一般可以系统给药,或者通常局部口服或肠胃外给药。
给药剂量根据例如年龄,体重,症状,所期望的治疗效果,给药途径,治疗持续时间而决定。对于成年人,每天至多几次口服给药,每人剂量一般由1mg至1000mg,或每天至多几次非肠道给药或每天静脉内连续给药1至24小时,给药量为0.1mg至100mg。
如上所述,所用剂最取决于多种条件。因此有时剂量也可低于或高于上面使用的特殊范围。
本发明化合物可以以例如固体组合物,液体组合物或其它组合物的形式给药,用于口服,注射,搽剂或用于非肠道给药的栓剂。
口服固体组合物包括压片,丸,胶囊,可分散粉末和颗粒剂。胶囊包括硬胶囊和软胶囊。在这样的组合物中,一种或几种活性化合物可以与至少一种惰性溶剂混合(溶剂例如乳糖,甘露糖醇,葡萄糖,羟丙基纤维素,微晶纤维素,淀粉,聚乙烯吡咯烷酮或硅酸镁铝盐)。根据通常实践,该组合物也可以含有除惰性稀释剂以外的添加物质:例如润滑剂(如硬脂酸镁),崩解剂(象甘醇酸纤维素钙),稳定剂(象乳糖),和助溶剂(象谷氨酸或天冬氨酸)。
如果需要片剂或丸剂,可以用胃膜或肠膜材料包衣(象糖,明胶,羟丙基纤维素,羟丙基甲基纤维素邻苯二甲酸酯),或用两种或多种膜包衣。而且肠溶衣可以包括可吸收材料象明胶胶囊中的内含物。
口服液体组合物包括药学上可接受的溶液,乳液,悬浮液,糖浆和酏剂。在这种组合物中,一种或几种活性化合物含在本领域常用的惰性稀释剂中(例如纯化的乙醇或水)。除惰性稀释剂外,这种组合物也可以含有助剂(象湿润剂或悬浮剂,甜味剂,调味剂,香味剂和防腐剂)。
其它口服组合物包括喷雾剂组合物,其可通过已知方法制备且含有一种或多种活性化合物。喷雾组合物可以含有除惰性稀释剂外的添加物质:例如稳定剂(象硫酸钠),等渗缓冲液(象氯化钠,柠檬酸钠或柠檬酸),为制备这种喷雾组合物,例如可以使用美国专利No.2868691或3095355中说明的方法。
非肠道给药注射剂包括无菌水溶液和非水溶液,悬浮液和乳液。在这种组合物中,一种或几种活性化合物可以与至少一种惰性水溶液稀释剂(例如注射用蒸馏水或生理盐溶液)或惰性非水稀释剂(例如丙二醇,聚乙二醇,橄榄油,乙醇或POLYSORBATE80(注册商标)混合。
注射液可以含有惰性稀释剂以外的其它成分:例如防腐剂,湿润剂,乳化剂,分散剂,稳定剂(例如乳糖),助剂象助溶剂(例如谷氨酸或天冬氨酸)。
可以通过细菌截留过滤器过滤,与组合物中的消毒剂结合,或通过X光照射进行消毒。也可以制成无菌固体组合物的形式,例如通过冻干,其可以在使用前即刻溶解在注射用无菌水或一些其它无菌稀释剂中。
其它肠胃外给药组合物包括外用液体,和皮肤擦剂,软膏,栓剂和阴道栓剂,它们可以含有一种或几种活性化合物,且可以用本质上已知的方法制备。参考实施例和实施例
下面参考实施例和实施例说明但不限制本发明。
括号中的溶剂是展开剂或洗脱剂,所用溶剂比例以色谱分离和TLC中的体积表示。
100℃时向搅拌着的浓硫酸中(26ml)缓慢加入邻甲酚(50ml),混合物在100℃搅拌5小时。反应后,混合物冷却至室温,缓慢加入氢氧化钾(27.5g)水(35ml)溶液中和混合物。向混合物中加入甲醇(100ml)后,滤出沉淀得到有下面物理数据的标题化合物(56.5g)。
TLC:Rf0.18(氯仿∶甲醇∶水=6∶4∶1)参考实施例2
在室温下向参考实施例1中制备的化合物(12.2g)的四氢呋喃(THF)(100ml)悬浮液中加入2N氢氧化钠水溶液(28ml)后,在冰冷却下加入苄氧羰基氯化物(8ml)。将反应混合物搅拌30分钟。减压下浓缩反应混合物,用冰冷却,过滤出沉淀物得到具有下面物理数据的标题化合物(7.3g)。
TLC:Rf 0.51(氯仿∶甲醇∶水=6∶4∶1)。参考实施例3
在冰冷却下向参考实施例2中制备的化合物(46.1g)的二甲基甲酰胺(DMF)(100ml)的悬浮液中缓慢加入亚硫酰氯(15ml)。反应混合物在5℃搅拌30分钟。向反应混合物中加入冰水,滤出沉淀物得到具有下面物理数据的标题化合物(39.4g)。
在冰冷却下向L-脯氨酸叔丁酯(1.9g)的吡啶(10ml)溶液中加入参考实施例3中制备的化合物(3.7g)。将反应混合物搅拌30分钟。加入2N盐酸水溶液使混合物骤冷,并用乙酸乙酯(200ml)萃取混合物。有机层用饱和碳酸氢钠水溶液和饱和氯化钠水溶液洗涤,用无水硫酸镁干燥并浓缩。向残余物(4.9g)的甲醇(200ml)溶液中加入10%活性炭
(500mg)上的钯,反应混合物在室温下氢气中搅拌2小时。混合物通过硅藻土(市售)过滤。浓缩滤液得有下面物理数据的标题化合物(3.4g)。TLC:Rf 0.35(己烷∶乙酸乙酯=1∶1)。参考实施例52RS-(4-硝基苯基)丁酸
在15℃,向2-苯基丁酸(200g)的乙酸溶液(200ml)和浓硫酸(150ml)的混合物溶液中缓慢加入浓硝酸(150ml)。在相同温度下将反应混合物搅拌10分钟。将反应混合物倾入到冰水中,过滤沉淀物。残余物从己烷/乙酸乙酯混合溶液中重结晶得具有下面物理数据的标题化合物(103g)。TLC:Rf 0.50(乙酸乙酯)。参考实施例62RS-(4-氨基苯基)丁酸甲酯
用冰冷却下,向在参考实施例5制备的化合物(15.7g)的DMF(60ml)溶液中加入碳酸钾(12g)。在相同温度下向混合物中加入碘代甲烷(5ml)。反应混合物在室温下搅拌2小时。混合物用1N盐酸水溶液(200ml)骤冷,并用己烷/乙酸乙酯(1∶1,200ml)混合物萃取。有机层用水和饱和氯化钠水溶液洗涤,用无水硫酸镁干燥并浓缩。向残余物的甲醇(300ml)溶液中加入活性炭(1.3g)上的5%钯,混合物在室温下在氢气中搅拌2小时。混合物经硅藻土(市售)过滤。浓缩滤液得有下面物理数据的标题化合物(14.2g)。TLC:Rf 0.47(己烷∶乙酸乙酯=1∶1)。参考实施例72RS-(4-(吡咯烷-1-基)苯基)丁酸
向参考实施例6中制备的化合物(14.2g)的DMSO(75ml)溶液中加入碳酸钾(11g)和1,4-二溴丁烷(9ml)。反应混合物在40℃搅拌1小时。向混合物中加入碘化钠(11.2g)。反应混合物在40℃搅拌3小时,并在60℃搅拌2小时。通过加水使反应混合物骤冷,并用己烷/乙酸乙酯(1∶1,1000ml)混合物萃取反应混合物。有机层用水和饱和氯化钠水溶液洗涤,用无水硫酸镁干燥并浓缩。向残余物的甲醇(80ml)溶液中加入5N氢氧化钠水溶液(20ml),混合物在室温下搅拌5小时。向混合物中加入盐酸水溶液至pH8,并用乙酸乙酯洗涤。加盐酸水溶液中和水层,并用乙酸乙酯萃取。用饱和氯化钠水溶液洗涤萃取液,用无水硫酸镁干燥并浓缩。残余物从己烷/乙酸乙酯(3∶1)混合溶液中重结晶,得具有下面物理数据的标题化合物(9.83g)。TLC:Rf 0.30(己烷∶乙酸乙酯=1∶1)。实施例12RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2S-叔丁氧羰基吡咯烷-1-基磺酰基)-2-甲基苯酯
室温下向参考实施例4中制备的化合物(748mg),参考实施例7中制备的化合物(537mg)和二甲基氨基吡啶(64mg)的二氯甲烷(20ml)溶液中加入1-乙基-3-(3-二甲基氨基丙基)-碳化二亚胺(482mg)。反应混合物在室温下搅拌2小时。向反应混合物中加入乙酸乙酯,并用1N盐酸水溶液洗涤(X2)。有机层用无水硫酸镁干燥并浓缩。残余物用硅胶柱层析纯化(己烷∶乙酸乙酯=5∶1)得有下面物理数据的标题化合物(1.04g)。TLC:Rf 0.23(己烷∶乙酸乙酯=5∶1)。实施例1 (1)~1 (147)
根据实施例1相同的方法及转化成相应盐或酸加成盐的已知方法,用相应的苯酚衍生物代替参考实施例4中制备的化合物,和使用相应的羧酸衍生物代替参考实施例7中制备的化合物,得到具有下面物理数据的化合物。实施例1 (1)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2S-羟基甲基吡咯烷-1-基磺酰基)苯酯·盐酸盐
NMR(DMSO-d6):δ7.85(2H,d,J=9Hz),7.28(2H,d,J=9Hz),7.28(2H,d,J=9Hz),6.83(2H,d,J=9Hz),3.75(1H,t,J=7Hz),3.60-3.44(2H,m),3.40-3.20(6H,m),3.11-2.95(1H,m),2.21-1.90(5H,m),1.90-1.65(3H,m),1.55-1.30(2H,m),0.90(3H,t,J=7Hz);TLC:Rf 0.48(乙酸乙酯∶己烷=1∶1)。实施例1 (2)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2-氧代吡咯烷-1-基磺酰基)苯酯·盐酸盐
NMR(CDCl3):δ8.05(2H,d,J=8.8Hz),7.61(2H,d,J=8.6Hz),7.47(2H,d,J=8.6Hz),7.19(2H,d,J=8.8Hz),3.89(2H,t,J=7.2Hz),3.74(1H,t,J=7.8Hz),3.85-3.45(4H,brS),2.44(2H,t,J=7.8Hz),2.40-2.25(4H,m),2.35-1.75(2H,m),2.20-2.00.(2H,m),0.99(3H,t,J=7.4Hz);TLC:Rf 0.39(乙酸乙酯∶己烷=1∶1).实施例1 (3)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(吡咯烷-1-基磺酰基)-2-甲基苯酯
NMR(CDCl3):δ7.68-7.57(2H,m),7.23(2H,d,J=8Hz),7.06(1H,d,J=8Hz),6.55(2H,d,J=8Hz),3.61(1H,t,J=7Hz),3.35-3.13(8H,m),2.30-1.65(13H,m),0.98(3H,t,J=7Hz);TLC:Rf 0.49(乙酸乙酯∶己烷=3∶7)。实施例1 (4)2RS-(4-(吡咯烷-1-基)苯基丁酸4-(2S-(吡咯烷-1-基甲基)吡咯烷-1-基磺酰基)-2-甲基苯酯·二盐酸盐
NMR(CD3OD):δ7.95-7.75(2H,m),7.65(4H,s),7.22(1H,d,J=8.5Hz),4.26-3.90(2H,m),3.99(1H,t,J=7.5Hz),3.90-3.70(5H,m),3.50-3.10(6H,m),2.40-2.25(4H,m),2.40-1.35(10H,m),2.07(3H,s),1.00(3H,t,J=7.5Hz);TLC:Rf 0.43(水∶甲醇∶氯仿=1∶10∶90)。实施例1 (5)2RS-苯基丁酸4-(吡咯烷-1-基磺酰基)苯酯
NMR(CDCl3):δ7.85-7.74(2H,m),7.41-7.24(5H,m),7.23-7.10(2H,m),3.71(1H,t,J=7Hz),3.30-3.15(4H,m),2.39-2.10(1H,m),2.03-1.80(1H,m),1.80-1.68(4H,m),0.99(3H,t,J=7Hz);TLC:Rf 0.43(己烷∶乙酸乙酯=2∶1)。实施例1 (6)2RS-(4-(吡咯烷-1-基)苯基丁酸4-(二氢吲哚-1-基磺酰基)苯酯·盐酸盐
NMR(CDCl3):δ7.78(2H,d,J=8.8Hz),7.62(1H,d,J=8.0Hz),7.50-7.34(4H,m),7.24-7.12(1H,m),7.08(3H,d,J=8.8Hz),6.97(1H,dt,J=1.0 and7.2Hz),3.90(2H,d,J=8.4Hz),3.68(1H,t,J=7.6Hz),3.70-3.45(4H,m),2.89(2H,t,J=8.4Hz),2.40-2.20(4H,m),2.30-2.05 and 2.00-1.75(each 1H,m),0.96(3H,t,J=7.2Hz);TLC:Rf 0.47(乙酸乙酯∶己烷=1∶2)。实施例1 (7)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2-(乙氧羰基)二氢吲哚-1-基磺酰基)2-甲基苯酯
NMR(CDCl3):δ7.7-7.5(m,3H),7.2-6.9(m,6H),6.8-6.4(m,2H),4.71(q,J=5.2Hz,1H),4.23(q,J=7.2Hz,2H),3.57(t,J=7.6Hz,1H),3.4-3.0(m,6H),2 4-1.8(m,9H),1.29(t,J=7.2Hz,3H),1.0-0.9(m,3H);TLC:Rf 0.63(己烷∶乙酸乙酯=2∶1)。实施例1 (8)2RS-(4-(吡咯烷-1-基)苯基丁酸4-(2-(乙氧羰基)二氢吲哚-1-基磺酰基)苯酯
NMR(CDCl3):δ7.77(2H, d,J=8.5Hz),7.53(1 H,d,J=8.0Hz),7.24-6.93(7H,m),6,52(2H,d,J=8.5Hz),4.71(1H,dd,J=10.0,5.5Hz),4.24(2H,q,J=7.0Hz),3.54(1H,t,J=8.0Hz),3.32-3.22(4H,m),3.22(1H,dd,J=10.0,16.0Hz),3.06(1H,dd,J=16.0,5.5Hz),2.05-1.90(4H,m),2.25-1.70(2H,m),1.29(3H,t,J=7.0Hz),0.95(3H,t,J=7.5Hz);TLC:Rf 0.57(己烷∶乙酸乙酯=1∶1)。实施例1 (9)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2RS-(N,N-二甲基氨基羰基甲氧羰基)二氢吲哚-1-基磺酰基)-2-甲基苯酯
NMR(CDCl3):δ7.7-7.5(m,3H),7.2-6.9(m,6H),6.54(d,J=8.6Hz,2H),4.85(d,J=14.5Hz,1H),4.82(dd,J=1.0,10.8Hz,1H),4.70(d,J=14.5Hz,1 H),3.58(t,J=7,7Hz,1H),3.65-3.50(m,1H),3.45(dd,J=10.8,16.1Hz,1H),3.4-3.2(m,4H),2.96(s,3H),2.94(s,3H),2.3-1.8(m,6H),1.97(s,3H),0.96(t,J=7.4Hz,3H);TLC:Rf 0.52(氯仿∶乙酸乙酯=1∶1)。实施例1 (10)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2RS-(N-苄氧氨甲酰基)二氢吲哚-1-基磺酰基)苯酯
NMR(CDCl3):δ9.22(1H,s),7.60(1H,d,J=8.0Hz),7.51(2H,d,J=9.0Hz),7.29(5H,s),7.17-7.00(8H,m),6.52(2H,d,J=9.0Hz),4.88(2H,s),4.60(1H,dd,J=10.0Hz,1.5Hz),3.53(1H,t,J=7.0Hz),3.26(5H,t-like,J=6.0Hz),2.74(1H,dd,J=16.0Hz,10.0Hz),2.20-1.77(2H,m),2.03-1.98(4H,m),0.92(3H,t,J=7.0Hz);TLC:Rf 0.44(己烷∶乙酸乙酯=1∶1)。实施例1 (11)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(6-硝基二氢吲哚-1-基磺酰基)-2-甲基苯酯
NMR(CDCl3):δ8.10(dd,J=2.4,8.8Hz,1H),7.96(s,1H),7.7-7.6(m,3H),7.1 8(d,J=8.4Hz,2H),7.05(d,J=8.0Hz,1H),6.52(d,J=8.4Hz,2H),4.01(t,J=8.6Hz,2H),3.58(t,J=7.8Hz,1H),3.3-3.2(m,4H),3.08(t,J=8.6Hz,2H),2.3-1.8(m,2H),2.00(S,3H),2.1-1.9(m,4H),0.96(t,J=7.4Hz,3H);TLC:Rf 0.33(己烷∶乙酸乙酯=3∶1)。实施例1 (12)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(6-氨基二氢吲哚-1-基磺酰基)-2-甲基苯酯
NMR(CDCl3):δ7.6-7.4(m,3H),7.20(d,J=8.7Hz,2H),6.94(d,J=8.4Hz,1H),6.53(d,J=8.7Hz,2H),6.6-6.4(m,2H),3.83(t,J=8.2Hz,2H),3.58(t,J=7.7Hz,1H),3.4-3.2(m,4H),2.64(t,J=8.2Hz,2H),2.3-1.8(m,6H),1.95(s,3H),0.97(t,J=7.4Hz,3H);TLC:Rf 0.59(己烷∶乙酸乙酯=1∶1)。实施例1 (13)2RS- (吡咯烷-1-基)苯基)丁酸4-(7-硝基二氢吲哚-1-基磺酰基)-2-甲基苯酯
NMR(CDCl3):δ 8.38(d,J=2.2Hz,1H),7.85(dd,J=2.0,8.4Hz,1H),7.8-7.6(m,2H),7.2-7.1(m,1H),7.18(d,J=8.6Hz,2H),7.03(d,J=8.2Hz,1H),6.52(d,J=8.6Hz,2H),3.99(t,J=8.6Hz,2H),3.58(t,J=7.6Hz,1H),3.3-3.2(m,4H),3.05(t,J=8.6Hz,2H),2.3-1.7(m,9H),0.96(t,J=7.4Hz,3H);TLC:Rf 0.49(己烷∶乙酸乙酯=1∶1)。实施例1 (14)2RS-(4-吡咯烷-1-基)苯基)丁酸4-(7-氨基二氢吲哚-1-基磺酰基)-2-甲基苯酯
NMR(CDCl3)δ7.6-7.5(m,2H),7.15(d,J=8.6Hz,2H),7.0-6.9(m,2H),6 82(d,J=8.0Hz,1H),6.52(d,J=8.6Hz,2H),6.29(dd,J=2.0,8.0Hz,1H),3.84(t,J=8.0Hz,2H),3.58(t,J=7.6Hz,1H),3.4-3.2(m,4H),2.76(t,J=7.6Hz,2H),2.3-1.8(m,9H),0.97(t,J=7.4Hz,3H);TLC:Rf 0.40(己烷∶乙酸乙酯=2∶1)。实施例1 (15)2RS-(4-吡咯烷-1-基)苯基)丁酸4-(苯并咪唑-1-基磺酰基)-2-甲基苯酯
NMR(CDCl3):δ8.35(1H,s),7.79(4H,m),7.35(2H,m),7.17(2H,d,J=8.8Hz),7.08(1H,d,J=9.4Hz),6.52(2H,d,J=8.8Hz),3.57(1H,t,J=7.8Hz),3.26(4H,m),2.10(1H,m),2.00(3H,s),1.97(4H,m),1.88(1 H,m),0.95(3H,t,J=7.4Hz);TLC:Rf 0.49(己烷∶乙酸乙酯=2∶1)。实施例1 (16)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(吗啉-4-基磺酰基)苯酯
NMR(DMSO-d6):δ7.75(2H,d,J=7Hz),7.27(2H,d,J=7Hz),7.16(2H,d,J=7Hz),6.52(2H,d,J=7Hz),3.67(1H,t,J=7Hz),3.61(4H,t-like),3.20(4H,t-like),2.83(4H,t-like),2.04(1H,m),1.94(4H,t-like),1.79(1H,m),0.88(3H,t,J=7Hz);TLC:Rf 0.54(己烷∶乙酸乙酯=1∶1)。实施例1 (17)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(6-氮杂-7-氧代-双环[3.2.1]辛烷-6-基磺酰基)苯酯·盐酸盐
NMR(CDCl3):δ8.19(2H,d,J=9Hz),7.38(2H,d,J=9Hz),7.19(4H,d,J=9Hz),4.65-4.55(1H,m),3.68(1H,t,J=7Hz),3.61-3.37(4H,m),2.59-2.49(1H,m),2.35-1.46(12H,m),1.35-1.10(2H,m),0.99(3H,t,J=7Hz);TLC:Rf 0.17(乙酸乙酯∶己烷=1∶3)。实施例1 (18)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(4-苄基哌嗪-1-基磺酰基)苯酯·二盐酸盐
NMR(CD3OD):δ7.83(2H,d,J=8.6Hz),7.75-7.40(9H,m),7.29(2H,d,J=8.6Hz),4.35(2H,s),4.00-3.62(7H,m),3.60-3.40(2H,m),3.30-3.10(2H,m),2.98-2.72(2H,m),2.38-2.10(5H,m),2.04-1.80(1H,m),0.99(3H,t,J=7.4Hz);TLC:Rf 0.40(乙酸乙酯∶己烷=3∶7)。实施例1 (19)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(4-(2-羟乙基)哌啶-1-基磺酰基)苯酯
NMR(CDCl3):δ7.71(2H,d,J=9.0Hz),7.72(2H,d,J=8.7Hz),7.15(2H,d,J=9.0Hz),6.55(2H,d,J=8.7Hz),3.74(2H,d,J=10.2Hz),3.63(2H,t,J=6.0Hz),3.58(1H,t,J=8.0Hz),3.36-3.22(4H,m),2.35-1.78(8H,m),1.72(2H,d,J=10.0Hz),1.54-1.20(5H,m),0.98(3H,t,J=7.4Hz);TLC:Rf 0.52(氯仿∶甲醇=19∶1)。实施例1 (20)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2RS-羟甲基哌啶-1-基磺酰基)苯酯·盐酸盐
NMR(DMSO-d6):δ7.85(2H,d,J=9Hz),7.27(2H,d,J=9Hz),7.22(2H,d,J=9Hz),6.83(2H,d,J=9Hz),3.93-3.80(1H,m),3.75(1H,t,J=7Hz),3.69-3.45(2H,m),3.45-3.20(5H,m),3.06-2.88(1H,m),2.21-1.80(5H,m),1.80-1.64(2H,m),1.55-1.30(3H,m),1.30-0.99(2H,m),0.90(3H,t,J=7Hz);TLC:Rf 0.46(乙酸乙酯∶己烷=1∶1)。实施例1 (21)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(4-(N,N-二甲基氨基)哌啶-1-基磺酰基)苯酯
NMR(CDCl3):δ7.71(2H,d,J=8.7Hz),7.20(2H,d,J=8.8Hz),7.16(2H,d,J=8.7Hz),6.54(2H,d,J=8.8Hz),3.75(2H,d,J=13.7Hz),3.58(1H,t,J=7.7Hz),3.29(4H,t,J=6.6Hz),2.36-1.53(19H,m),0.98(3H,t,J=7.4Hz);TLC:Rf 0.25(己烷∶乙酸乙酯=2∶1)。实施例1 (22)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-4-(嘧啶-2-基)哌嗪-1-基磺酰基)苯酯NMR(CDCl3):δ8.26(2H,d,J=8.8Hz),7.72(2H,d,J=8.7Hz),7.22-7.12(4H,m),6.56-6.47(3H,m),3.93(4H,t,J=5.2Hz),3.57(1H,t,J=7.7Hz),3.31-3.25(4H,m),3.04(4H,t,J=5.1Hz),2.25-1.65(6H,m),0.97(3H,t,J=7.3Hz);TLC:Rf 0.43(己烷∶乙酸乙酯=1∶1)。实施例1 (23)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(1,4-二氧杂-8-氮杂螺[4.5]癸烷-8-基磺酰基)苯酯
NMR(CDCl3):δ7.72(2H,d,J=8.7Hz),7.24-7.15(4H,m),6.56(2H,d,J=8.7Hz),3.89(4H,s),3.59(1H,t,J=7.7Hz),3.29(4H,t,J=6.6Hz),3.14(4H,t,J=5.7Hz),2.30-1.61(10H,m),0.98(3H,t,J=7.4Hz);TLC:Rf 0.48(己烷∶乙酸乙酯=1∶1)。实施例1 (24)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(3-氮杂双环[3.2.2]壬烷-3-基磺酰基)苯酯·盐酸盐
NMR(CDCl3):δ7.73(2H,d,J=8.6Hz),7.53(2H,d,J=8.6Hz),7.45(2H,d,J=8.6Hz),7.15(2H,d,J=8.8Hz),3.72(1H,t,J=7.6Hz),3.75-3.50(4H,m),3.22(4H,d,J=4.2Hz),2.40-2.20(4H,m),2.40-1.75(2H,m),2.10-2.00(2H,m),1.80-1.50(8H,m),0.99(3H,t,J=7.4Hz);TLC:Rf 0.57(乙酸乙酯∶己烷=1∶3)。实施例1 (25)2RS(4-(吡咯烷-1-基)苯基)丁酸4-(1,3,3-三甲基-6-氮杂双环[3.2.1]辛烷-6-基磺酰基)苯酯·盐酸盐
NMR(CDCl3):δ7.81(2H,d,J=8.8Hz),7.40(2H,d,J=8.4Hz),7.36-7.18(2H,brs),7.15(2H,d,J=8.8Hz),4.08(1H,t-like),3.69(1H,t,J=7.8Hz),3.64-3.38(4H,m),3.32(1H,d,J=9.6Hz),2.76(1H,dd,J=9.6 and 1.4Hz),2.36-2.08(5H,m),2.02-1.76(2H,m),1.52(2H,d,J=1 4.4Hz),1.34(2H,d,J=12.4Hz),1.22(3H,s),1.16-1.02(1H,m),0.99(3H,t,J=7.4Hz),0.94(3H,s),0.92(3H,s);TLC:Rf 0.54(乙酸乙酯∶己烷=1∶3)实施例1 (26)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2-氧代哌啶-1-基磺酰基)苯酯·盐酸盐
NMR(CDCl3):δ8.03(2H,d,J=9.0Hz),7.65(2H,d,J=8.6Hz),7.48(2H,d,J=8.6Hz),7.17(2H,d,J=9.0Hz),3.89(2H,t,J=5.8Hz),3.74(1H,t,J=7.8Hz),3.80-3.50(4H,m),2.42(2H,t,J=6.6Hz),2.50-2.25(4H,m),2.40-1.70(2H,m),2.00-1.70(4H,m),0.99(3H,t,J=7.4Hz);TLC:Rf 0.83(乙酸∶甲醇∶氯仿=1∶2∶40)实施例1 (27)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2-氧代-4S-苄基四氢噁唑-3-基磺酰基)苯酯·盐酸盐
NMR(CDCl3):δ8.13(2H,d,J=8.8Hz),7.64(2H,d,J=8.8Hz),7.48(2H,d,J=8.8Hz),7.23(2H,d,J=8.8Hz),7.40-7.16(5H,m),4.75-4.58(1H,m),4.24-4.05(2H,m),3.76(1H,t,J=7.6Hz),3.85-3.50(4H,brs),3.50(1H,dd,J=13.2,38Hz),2.83(1H,dd,J=13.2,10.2Hz),2.44-2.26(4H,m).2.34-2.10 and 2.10-1.76(each 1H,m),0.99(3H,t,J=7.4Hz);TLC:Rf 0.51(乙酸乙酯∶己烷=1∶2 )实施例1 (28)2RS-(4-吡咯烷-1-基)苯基)丁酸4-(2-氧代-4S-异丙基全氢噁唑-3-基磺酰基)苯酯·盐酸盐
NMR(CDCl3):δ8.10(2H,d,J=9.0Hz),7.63(2H,d,J=8.6Hz),7.48(2H,d,J=8.6Hz),7.22(2H,d,J=9.0Hz),4.43(1H.dt,J=8.2,3.0Hz),4.29(1H,t,J=8.8Hz),4.16(1H,dd,J=8.8,3.0Hz),3.75(1H,t,J=7.6Hz),3.90-3.45(4H,brs),2.56-1.76(7H,m),0.99(3H,t,J=7.2Hz),0.93(3H,d,J=6.8Hz),0.75(3H,d,J=6.8Hz);TLC:Rf 0.62(乙酸乙酯∶己烷=1∶1)实施例1 (29)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2-氧代-4S-甲基-5S-苯基全氢噁唑-3-基磺酰基)苯酯·盐酸盐
NMR(CDCl3):δ8.13(2H,d,J=8.8Hz),7.72(2H,d,J=8.8Hz),7.51(2H,d,J=8.8Hz),7.46-7.34(3H,m),7.23(2H,d,J=8.8Hz),7.30-7.20(2H,m),5.71(1H,d,J=7.2Hz),4.78(1H,dq,J=7.2Hz),3.77(1H,t,J=7.2Hz),3.90-3.50(4H,brs),2.50-2.25(4H,brs),2.40-1.80(2H,m),1.00(3H,t,J=7.2Hz),0.97(3H,d,J=7.2Hz);TLC:Rf 0.66(乙酸乙酯∶己烷=1∶2)实施例1 (30)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(1RS-氧代-4S-甲氧羰基全氢噻唑-3-基磺酰基)苯酯
NMR(CDCl3):δ7.87(2H,d,J=9.0Hz),7.21(2H,d,J=9.0Hz),7.19(2H,d,J=9.0Hz),6.55(2H,d,J=9.0Hz),5.28-5.16(2H,m),4.09-4.01(1H,m),3.69-3.44(5H,m),3.33-3.26(4H,m),3.08-2.97(1H,m),2.24-1.80(6H,m),0.98(3H,t,J=7.4Hz);TLC:Rf 0.50(氯仿∶甲醇∶乙酸=40∶2∶1)实施例1 (31)2RS-(4-(吡咯烷-1-基)苯基)丁酸-4(吗啉-4-基磺酰基)-2-甲基苯酯
NMR(CDCl3):δ7.56-7.51(2H,m),7.26-7.21(2H,m),7.10(1H,d,J=8Hz),6.55(2H,d,J=8Hz),3.75-3.71(4H,m),3.62(1H,t,J=8Hz),3.32-3.26(4H,m),3.01-2.96(4H,m),2.37-1.73(2H,m),2.06(3H,s),2.04-1.96(4H,m),1.00(3H,t,J=8Hz);TLC:Rf 0.27(己烷∶乙酸乙酯=3∶1)实施例1 (32)2RS-(4-(吡啶烷-1-基)苯基)丁酸4-(咪唑-1-基磺酰基)-2-甲基苯酯
NMR(CDCl3):δ7.99(1H,m),7.75(1H,s),7.72(1H,m),7.27-7.08(5H,m),6.54(2H,d,J=8.8Hz),3.60(1H,t,J=7.6Hz),3.28(4H,m),2.14(1H,m),2.04(3H,s),2.01(4H,m),1.91(1H,m),0.97(3H,t,J=7.4Hz);TLC:Rf 0.36(己烷∶乙酸乙酯=2∶1)。实施例1 (33)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(哌嗪-4-基磺酰基)-2-甲基苯酯·二盐酸盐
NMR(CD3OD):δ7.80-7.56(6H,m),7.18(1H,d,J=8.2Hz),4.00(1H,t,J=7.6Hz),3.90-3.72(4H,m),3.30(8H,s-like),2.43-2.15(5H,m),2.06(3H,s),2.15-1.84(1H,m),1.00(3H,t,J=7.2Hz);TLC:Rf 0.53(氯仿∶甲醇∶乙酸=15∶2∶1)实施例1 (34)2RS-(4-硝基苯基)丁酸4-(吗啉-4-基磺酰基)苯酯
NMR(CDCl3):δ8.26(2H,d,J=8Hz),7.77(2H,d,J=8Hz),7.59(2H,d,J=8Hz),7,20(2H,d,J=8Hz),3.86(1H,t,J=7Hz),3.80-3.68(4H,m),3.06-2.94(4H,m),2.30(1H,ddq,J=14Hz,7Hz,7Hz),1.97(1H,ddq,J=14Hz,7Hz,7Hz),1.03(3H,t,J=7Hz)TLC:Rf 0.16(己烷∶乙酸乙酯=7∶3)。实施例1 (35)1-(4-硝基苯基)环丁烷羧酸4-(吗啉-4-基磺酰基)苯酯
NMR(CDCl3):δ8.26(2H,d,J=8Hz),7.77(2H,d,J=8Hz),7.56(2H,d,J=8Hz),7.16(2H,d,J=8Hz),3.79-3.66(4H,m),3.15-2.91(6H,m),2.80-2.60(2H,m),2.39-1.91(2H,m);TLC:Rf 0.16(己烷∶乙酸乙酯=7∶3)实施例1 (36)2-(4-甲氧基苯基)-2-乙基丁酸4-(6-氮杂-7-氧代双环[3.2.1]辛烷-6-基磺酰基)苯酯
NMR(CDCl3):δ8.08(2H,d,J=8.8Hz),7.27(2H,d,J=8.8Hz),7.11(2H,d,J=8.8Hz),6.91(2H,d,J=8.8Hz),4.59(1H,brt,J=4.8Hz),3.82(3H,s),2.53(1H,brs),2.32-1.15(12H,m),0.84(6H,t.J=7.4Hz);TLC:Rf 0.85(乙酸∶甲醇∶氯仿=1∶2∶40)实施例1 (37)2RS-(4-甲基苯基)丁酸4-(吗啉-4-基磺酰基)-2-甲基苯酯
NMR(CDCl3):δ7.57-7.52(2H,m),7.30-7.08(5H,m),3.75-3.67(5H,m),3.01-2.96(4H,m),2.36(3H,s),2.32-2.13 and 2.03-1.82(each 1H,m),2.02(3H,s),1.00(3H,t,J=7Hz);TLC:Rf 0.30(己烷∶乙酸乙酯=3∶1)实施例(38)2RS-苯基丁酸4-(咪唑-1-基磺酰基)苯酯
NMR(CDCl3):δ7.99(1H,s),7.97-7.86(2H,m),7.40-7.28(5H,m),7.28-7.25(1H,m),7.25-7.15(2H,m),7.13-7.05(1H,m),3.68(1H,t,J=7Hz),2.34-2.05(1H,m),2.05-1.98(1H,m),0.96(3H,t,J=7Hz);TLC:Rf 0.29(己烷∶乙酸乙酯=6∶4)实施例1 (39)2RS-苯基丁酸4-(吗啉-4-基磺酰基)苯酯
NMR(CDCl3):δ7.78-7.67(2H,m),7.43-7.24(5H,m),7.24-7.15(2H,m),3.78-3.65(5H,m),3.03-2.93(4H,m),2.36-2.11(1H,m),2.05-1.80(1H,m),0.99(3H,t,J=7Hz);TLC:Rf 0.26(己烷∶乙酸乙酯=2∶1)实施例1 (40)2RS-(4-(吡咯烷-1-基)苯基)丁酸-4(N-1RS-(乙氧羰基)-2-(吗啉-4-基)乙基氨磺酰基)苯酯
NMR(CDCl3):δ7.84(2H,d,J=8.6Hz),7.20(2H,d,J=8.6Hz),7.12(2H,d,J=8.6Hz),6.55(2H,d,J=8.6Hz),4.01(3H,m),3.57(5H,m),3.29(4H,t,J=6.4Hz),2.63(2H,m),2.36(4H,m),2.14(1H,m),2.01(4H,m),1.89(1H,m),1.17(3H,t,J=7.0Hz),0.97(3H,t,J=7.4Hz);TLC:Rf 0.34(己烷∶乙酸乙酯=1∶1)实施例1 (41)2RS-(4-硝基苯基)丁酸4-(N-(RS-(乙氧羰基)-2-(吗啉-4-基)乙基氨磺酰基)苯酯
NMR(CDCl3):δ8.26(2H,d,J=8.8Hz),7.89(2H,d,J=8.6Hz),7.57(2H,d,J=8.8Hz),7.13(2H,d,J=8.6Hz),4.03(2H,q,J=7.2Hz),3.96(1H,t,J=7.0Hz),3.84(1H,t,J=7.0Hz),3.58(4H,m),2.68(1H,dd,J=13.1,7.0Hz),2.61(1H,dd,J=13.1,7.0Hz),2.36(4H,m),2.82(1H,m),1.95(1H,dq,J=13.6,7.2Hz),1.17(3H,t,J=7.2Hz),1.02(3H,t,J=7.2Hz);TLC:Rf 0.45(乙酸乙酯)实施例1 (42)1-(4-硝基苯基)环丁烷羧酸4-(N-1RS-(乙氧羰基)-2-(吗啉-4-基)乙基氨磺酰)苯酯
NMR(CDCl3):δ8.26(2H,d,J=8.8Hz),7.86(2H,d,J=8.8Hz),7.55(2H,d,J=8.8Hz),7.09(2H,d,J=8.8Hz),4.03(2H,q,J=7.2Hz),3.95(1H,t,J=6.2Hz),3.57(4H,t,J=5.2Hz),3.05(2H,m),2.67(2H,m),2.66(1H,dd,J=12.6,6.2Hz),2.60(1H,dd,J=12.6,6.2Hz),2.35(4H,t,J=5.2Hz),2.23(1H,m),2.04(1H,m),1.17(3H,t,J=7.2Hz);TLC:Rf 0.40(氯仿∶甲醇∶水=9∶1∶0.1)实施例1 (43)2RS-苯基-2-甲氧乙酸4-(N-1RS-(乙氧羰基)-2-(吗啉-4-基)乙基氨磺酰基)苯酯
NMR(CDCl3):δ7.86(2H,d,J=8.8Hz),7.52(2H,m),7.42(3H,m),7.12(2H,d,J=8.8Hz),5.00(1H,s),4.01(2H,q,J=7.0Hz),3.94(1H,t,J=6.6Hz),3.57(4H,t,J=5.2Hz),3.49(3H,s),2.66(1H,dd,J=12.8,6.6Hz),2.60(1H,dd,J=12.8,6.6Hz),2.34(4H,t,J=5.2Hz),1.16(3H,t,J=7.0Hz);TLC:Rf 0.26(己烷∶乙酸乙酯=1∶1)实施例1 (44)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-苄氧羰基氨磺酰基)苯酯·盐酸盐
NMR(CDCl3):δ8.3-8.0(1H,brs),8.00(2H,d,J=8.8Hz),7.56(2H,d-like),7.46(2H,d-like),7.38-7.22(5H,m),7.15(2H,d,J=8.8Hz),5.07(2H,s),3.74(1H,t,J=7.8Hz),3.8-3.5(4H,m),2.4-2.2(4H,m),2.40-2.10 and 2.10-1.80(each 1H,m),1.00(3H,t,J=7.2Hz);TLC:Rf 0.50(乙酸∶乙酸乙酯∶己烷=1∶8∶16)实施例1 (45)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-1RS-苯基-2RS-甲基丁基氨磺酰)苯酯·盐酸盐
NMR(CDCl3):δ7.80-7.57(2H,m),7.57-7.32(4H,m),7.12-6.93(3H,m),6.93-6.70(4H,m),5.38(1H,m),4.19-3.99(1H,m),3.90-3.30(5H,m),2.50-2.04(5H,m),1.96-1.40(3H,m),1.28-0.57(10H,m);TLC:Rf 0.24(乙酸乙酯∶己烷=1∶4)实施例1 (46)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-氨磺酰苯酯·盐酸盐
NMR(CD3OD):δ7.88(2H,d,J=8.6Hz),7.18(2H,d,J=8.8Hz),7.11(2H,d,J=8.8Hz),6.57(2H,d,J=8.6Hz),3.6 1(1H,t,J=7.6Hz),3.34-3.19(4H,m),2 26-2.00 and 2.00-1.70(each 1H,m),2.07-1.96(4H,m),0.96(3H,t,J=7.4Hz);TLC:Rf 0.22(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例1 (47)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-2-甲氧乙基氨磺酰基)苯酯
NMR(CDCl3):δ7.83(2H,d,J=9.0Hz),7.22(2H,d,J=8.6Hz),7.14(2H,d,J=9.0Hz),6.56(2h,d,J=8.6Hz),4.85(1H,b r),3.59(1H,t,J=7.7Hz),3.42-3 20(9H,m),3.11(21,m),2.28-1.70(6H,m),0.98(3H,t,J=7.6Hz);TLC:Rf 0.55(己烷∶乙酸乙酯=2∶3)。实施例1 (48)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-2-甲氧乙基-N-苄基氨磺酰基)苯酯
NMR(CDCl3):δ7.82(2H,d,J=6.8Hz),7.29(5H,s),7.19(2H,d,J=8.6Hz),7.13(2H,d,J=6.8Hz),6.56(2H,d,J=8.6Hz),4.40(2H,s),3.60(1H,t,/J=7.4Hz),3.2-3.4(8H,m),3.10(3H,s),1.8-2.3(6H,m),0.99(3H,t,J=7.3Hz);TLC:Rf 0.40(己烷∶乙酸乙酯=3∶1)。实施例1 (49)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-叔丁氧基氨磺酰基)苯酯·盐酸盐
NMR(CDCl3):δ7.88(2H,d,J=8.8Hz),7.24-7.15(4H,m),6.56(2H,d,J=8.2Hz),6.44(1H,s),3.59(1H,t,J=7.2Hz),3.33-3.26(4H,m),2.45-1.80(6H,m),1.21(9H.s),0.98(3H,t,J=7.2Hz);TLC:Rf 0.40(己烷∶乙酸乙酯∶乙酸=5∶2∶0.1)。实施例1 (50)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-4-羟基丁基氨磺酰基)苯酯
NMR(CDCl3):δ7.82(2H,d,J=8.7Hz).7.22(2H,d,J=8.6Hz),7.13(2H,d,J=8.7Hz),6.56(2H,d,J=8.6Hz),5.00(1H,t,J=5.2Hz),3.70-3.48(3H,m),3.40-3.12(4H,m),3.06-2.86(2H,m),2.30-1.76(6H,m),1.78-1.62(1H,brs),1.60-1.40(4H,m),0.97(3H,t,J=7.4Hz);TLC:Rf 0.48(乙酸乙酯)。实施例1 (51)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-1RS-羟甲基-2-甲基丙基氨磺酰基)苯酯
NMR(CDCl3):δ7.85(2H,d,J=8.4Hz),7.21(2H,d,J=8.6Hz),7.12(2H,d,J=8.4Hz),6.55(2H,d,J=8.6Hz),5 06(1H,d,J=8.4Hz),3.58(1H,t,J=5.8Hz),3.56-3.48(2H,m),3.36-3.22(4H,m),3.10-2.90(1H,m),2.23-1.65(8H,m),0.97(3H,t,J=7.2Hz),0.78(6H,d,J=6.8Hz);TLC:Rf 0.25(乙酸乙酯∶己烷=2∶3)。实施例1 (52)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-2RS,3-二羟基丙基氨磺酰基)苯酯
NMR(CDCl3):δ7.80(2H,d,J=8.6Hz),7.20(2H,d,J=8.8Hz),7.11(2H,d,J=8.6Hz),6.54(2H,d,J=8.8Hz),5.63(1H,t,J=6.3Hz),3.80-3.64(1H,m),3.62-3.41(3H,m),3.35-3.20(4H,m),3.10-2.80(3H,m),2.30-1.70(7H,m),0.96(3H,t,J=7.4Hz);TLC:Rf 0.28(乙酸乙酯∶己烷=4∶1)。实施例1 (53)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-苄氧氨磺酰基)苯酯·盐酸盐
NMR(CDCl3):δ7.87(2H,d,J=8.8Hz),7.32-7.12(9H,m),6.93(1H,s),6.54(2H,d,J=8.8Hz),4.94(2H,s),3.57(1H,t,J=7.8Hz),3.31-3.25(4H,m),2.25-1.80(6H,m),0.968(3H,t,J=7.4Hz);TLC:Rf 0.55(己烷∶乙酸乙酯∶乙酸=5∶2∶0.2)。实施例1 (54)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(N’,N’ -二甲氨基)氨磺酰基)苯酯
NMR(CDCl3):δ7.92(2H,d,J=8.7Hz),7.23(2H,d,J=8.7Hz),7.15(2H,d,J=8.7Hz),6.55(2H,d,J=8.7Hz),3.58(1H,d,J=7.7Hz),3.29(4H,t,J=6.6Hz),2.37(6H,s),2.25-1.75(6H,m),0.98(3H,t,J=7.4Hz);TLC:Rf 0.45(己烷∶乙酸乙酯=1∶1)。实施例1 (55)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(N’-甲基氨基)氨磺酰基)苯酯
NMR(CDCl3):δ7.82(2H,d,J=8.7Hz),7.23(4H,m),6.56(2H,d,J=8.6Hz),3.60(1H,m),3.29(4H,t,J=6.6Hz),2.85(3H,s),2.25-1.80(6H,m),0.99(3H,t,J=7.4Hz);TLC:Rf 0.35(己烷∶乙酸乙酯=1∶1)。实施例1 (56)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(氨基甲酰甲基)氨磺酰基)苯酯
NMR(CDCl3):δ7.78(2H,d,J=8.7Hz),7.20(2H,d,J=8.6Hz),7.11(2H,d,J=8.7Hz),6.54(2H,d,J=8.6Hz),6.42-6.30(1H,brs),6.20-5.96(2H,m),3.58(1H,t,J=7.8Hz),3.50(2H,s),3.38-3.18(4H,m),2.26-1.74(6H,m),0.96(3H,t,J=7.3Hz);TLC:Rf 0.41(氯仿∶甲醇=9∶1)。实施例1 (57)2RS-(4-(吡咯烷-1-基)丁酸4-(N-叔丁基氨磺酰基)苯酯·盐酸盐
NMR(CDCl3):δ7.89(2H,d,J=8.8Hz),7.63(2H,d,J=8.6Hz),7.48(2H,d,J=8.6Hz),7.12(2H,d,J=8.8Hz),4.83(1H,s),3.74(1H,t,J=7.6Hz),3.80-3.50(4H,m),2.40-2.25(4H,m),2.40-2.10 and 2.05-1.75(each 1H,m),1.22(9H,s),1.00(3H,t,J=7.4Hz);TLC:Rf 0.55(乙酸乙酯∶己烷=1∶2)。实施例1 (58)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-金刚烷-1-基氨磺酰基)苯酯·盐酸盐
NMR(CDCl3)δ7.89(2H,d,J=8.6Hz),7.60-7.45(4H,m),7.12(2H,d,J=8.6Hz),4.64(1H,brs,NH),3.80-3.55(5H,m),2.40-1.48(21H,m),0.999(3H,t,J=7.2Hz);TLC:Rf 0.44(己烷∶乙酸乙酯∶乙酸=5∶2∶0.2)。实施例1 (59)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-胍基磺酰基-2-甲基苯酯·二盐酸盐
NMR(DMSO-d6):δ7.66-7.53(2H,m),7.28(2H,d,J=8.0Hz),7.04(1H,d,J=8.0Hz),7.10-6.50(6H,m),3.76(1H,t,J=7.5Hz),3.50-3.20(4H,m),2.20-1.70(2H,m),2.10-1.90(4H,m),1.93(3H,s),0.91(3H,t,J=7.5Hz);TLC:Rf 0.36(水∶甲醇∶氯仿=1∶10∶90)。实施例1 (60)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-2RS,3-二羟基丙基氨磺酰基)-2-甲基苯酯
NMR(DMSO-d6):δ7.70-7.60(2H,m),7.47(1H,t,J=6.0Hz),7.18(2H,d,J=8.5Hz),7.13(1H,d,J=8.5Hz),6.55(2H,d,J=8.5Hz),3.70(1H,t,J=7.5Hz),3.55-3.35(6H,m),2.94-2.78(1 H,m),2.66-2.54(1H,m),2.25-1.60(2H,m),2.05-1.90(4H,m),1.96(3H,s),0.91(3H,t,J=7.5Hz);TLC:Rf 0.29(水∶甲醇∶氯仿=1∶10∶90)。实施例1 (61)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N,N-双(2-(甲氧甲氧基)乙基)氨磺酰基)-2-甲基苯酯
NMR(CDCl3):δ7.70-7.58(2H,m),7.22(2H,d,J=9Hz),7.03(1H,d,J=8Hz),6 55(2H,d,J=9Hz),4.54(4H,s),3.67(4H,t,J=6Hz),3.60(1H,t,J=7Hz),3.43(4H,t,J=6Hz),3.35-3.20(10H,m),2.30-1.75(9H,m),0.99(3H,t,J=7Hz);TLC:Rf 0.27(己烷∶乙酸乙酯=2∶1)。实施例1 (62)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N,N-双(2-(2-(甲氧甲氧基)乙氧基)乙基)氨磺酰基)-2-甲基苯酯
NMR(CDCl3):δ7.68-7.58(2H,m),7.22(2H,d,J=9Hz),7.03(1H,d,J=8Hz),6.55(2H,d,J=9Hz),4.63(4H,s),3.70-3.50(1 3H,m),3.45-3.20(8H,m),3.35(6H,s),2.30-1.75(9H,m),0.99(3H,t,J=7Hz);TLC:Rf 0.20(己烷∶乙酸乙酯=1∶1)。实施例1 (63)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-甲基-N-甲氧基氨磺酰基)-2-甲基苯酯
NMR(CDCl3):δ7.68(1H,s),7.66(1H,d,J=8.4Hz),7.22(2H,d,J=8.6Hz),7.11(1H,d,J=8.4Hz),6.55(2H,d,J=8.6Hz),3.78(3H,s),3.62(1H,tJ=7.7Hz),3.28(4H,t,J=6.6Hz),2.76(3H,s),2.3-2.1(1H,m),2.06(3H,s),2.1-1.9(4H,m),2.1-1.8(1H,m),0.99(3H,t,J=7.3Hz):TLC:Rf 0.36(己烷∶乙酸乙酯=4∶1)。实施例1 (64)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-苄基氨磺酰基)-2-甲基苯酯
NMR(CDCl3):δ7.66-7.62(2H,m),7.29-7.15(7H,m),7.05(1H,d,J=9.0Hz),6.55(2H,d,J=8.6Hz),4.65(1H,t,J=5.6Hz),4.11(2H,d,J=5.6Hz),3.62(1H,t,J=7.8Hz),3.33-3.26(4H,m),2.27-1.82(6H,m),2.00(3H,s),1.00(3H,t,J=7.4Hz);TLC:Rf 0.86(己烷∶乙酸乙酯=1∶1)。实施例1 (65)2RS-(4-硝基苯基)丁酸4-(N-2-(N’,N’-二甲基氨基)乙基氨磺酰基)苯酯·盐酸盐
NMR(CD3OD):δ8.27(2H,d,J=8.5Hz),7.93(2H,d,J=8.5Hz),7.68(2H,d,J=8.5Hz),7.28(2H,d,J=8.5Hz),4.04(1H,t,J=7.6Hz),3.22(4H,m),2.93(6H,s),2.28(1H,m),1.97(1H,m),1.00(3H,t,J=7.4Hz);TLC:Rf 0.39(氯仿∶甲醇∶水9∶1∶0.1)。实施例1 (66)1-(4-硝基苯基)环丁烷羧酸4-胍基磺酰基苯酯
NMR(CDCl3):δ8.26(2H,d,J=8.8Hz),7.85(2H,d,J=8.8Hz),7.57(2H,d,J=8.8Hz),7.04(2H.d,J=8.8Hz),6.34(1H,brs),3.14-2.96(2H,m),2.77-2.59(2H,m),2.38-1.90(2H,m);TLC:Rf 0.56(乙酸∶甲醇∶氯仿=1∶5∶25)。实施例1 (67)2RS-(4-硝基苯基)丁酸4-胍基磺酰基苯酯
NMR(DMSO-d6):δ8.27(2H,d,J=8.8Hz),7.78(2H,d,J=8.8Hz),7.71(2H,d,J=8.8Hz),7.19(2H,d,J=8.8Hz).7.0-6.4(4H,brs),4.15(1H,t,J=7.6Hz),2.30-2.05 and 2.05-1.75(each 1H,m),0.92(3H,t,J=7.6Hz);TLC:Rf 0.09(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例1 (68)2RS-(4-甲基苯基)丁酸4-(N-2RS,3-二羟基丙基氨磺酰基)-2-甲基苯酯
NMR(CDCl3):δ7.67-7.61(2H,m),7.27(2H,d,J=8Hz),7.17(2H,d,J=8Hz),7.04(1H,d,J=8Hz),5.54(1H,br),380-3.46(3H,m),3.42(1H,br),3.70(1H,t,J=8Hz),3.11-2.87(2H,m),2.83(1H,br),2.35(3H,s),2.32-2.11and 2.03-1.79(each 1H,m),1.98(3H,s),0.99(3H,t,J=8Hz);TLC:Rf 0.40(氯仿∶甲醇∶水=9∶1∶0.1)。实施例1 (69)2-(4-甲氧苯基)-2-乙基丁酸4-(N-2-甲氧乙基氨磺酰基)苯酯
NMR(CDCl3):δ7.83(2H,d,J=8.8Hz),7.27(2H,d,J=8.8Hz),7.08(2H,d,J=9.2Hz),6.90(2H,d,J=8.8Hz),4.92(1H,t,J=6.5Hz),3.82(3H,s),3.38(2H,t,J=5.4Hz),3.25(3H,s),3.11(2H,t,J=6.0Hz),2.28-2.04(4H,m),0.846(6H,t,J=7.4Hz);TLC:Rf 0.16(己烷∶乙酸乙酯=2∶1)。实施例1 (70)2-(4-甲氧苯基)-2-乙基丁酸4-(N-2-(N’,N’-二甲基氨基)乙基氨磺酰基)苯酯·乙酸盐
NMR(CDCl3):δ7.85(2H,d,J=8.6Hz),7.28(2H,d,J=8.8Hz,),7.09(2H,d,J=8.6Hz),6.92(2H,d,J=8.8Hz),3.83(3H,s),2.53-2.47(4H,m),2.24(6H,s),2.24-2.11(4H,m),0.847(6H,t,J=7.4Hz);TLC:Rf 0.26(氯仿∶甲醇∶水=25∶5∶1)。实施例1 (71)2RS-(4-甲氧苯基)丁酸4-(胍基磺酰基)-2-甲基苯酯·盐酸盐
NMR(DMSO-d6):δ7.62(1H,s),7.60(1H,d,J=8.0Hz),7.30(2H,d,J=8.5Hz),6.96(1H,d,J=8.0Hz),6.90(2H,d,J=8.5Hz),6.6-6.1(4H,brs),3.80(1H,t,J=7.5Hz),2.3-2.0 and 2.0-1.7(each 1H,m),1.65(3H,s),0.98(3H,t,J=7.5Hz);TLC:Rf 0.60(水∶甲醇∶氯仿=1∶10∶40)。实施例1 (72)2RS-苯基丁酸4-(N,N-二乙基氨磺基)苯酯
NMR(CDCl3):δ7.83-7.73(2H,m),7.40-7.23(5H,m),7.16-7.07(2H,m),3.69(1H,t,J=7Hz),3.20(4H,q,J=7Hz),2.35-1.75(2H,m),1.11(6H,t,J=7Hz),0.98(3H,t,J=7Hz);
NMR(CDCl3):δ7.89-7.79(2H,m),7.42-7.08(12H,m),4.61(1H,t,J=7Hz),4.13(2H,d,J=7Hz),370(1H,t,J=7Hz),2.36-2.11(1H,m),2.05-1.80(1H,m),0.99(3H,t,J=7Hz);
NMR(CDCl3):δ7.86-7.76(2H,m),7.43-7.14(12H,m),4.11(2H,s),3.73(1H,t,J=7Hz),2.59(3H,s),2.38-2.13(1H,m),2.06-1.81(1H,m),1.01(3H,t,J=7Hz);
NMR(CDCl3):δ7.81-7.71(2H,m),7.43-7.03(12H,m),4.40(1H,t,J=7Hz),3.71(1H,t,J=7Hz),3.21(2H,q,J=7Hz),2.76(2H,t,J=7Hz),2.24(1H,ddq,J=14Hz,7Hz,7Hz),1.93(1H,ddq,J=14Hz,7Hz,7Hz),1.00(3H,t,J=7Hz);
NMR(CDCl3):δ7.77-7.68(2H,m),7.41-7.08(12H,m),3.71(1H,t,J=7Hz),3.33-3.18(2H,m),2.92-279(2H,m),2.73(3H,s),2.24(1H,ddq,J=14Hz,7Hz,7Hz),1.92(1H,ddq,J=14Hz,7Hz,7Hz),0.99(3H,t,J=7Hz);
NMR(CDCl3):δ7.55(2H,d,J=8Hz),7.41-7.23(5H,m),6.98-6.78(6H,m),4.81(1H,d,J=7Hz),4.23(1H,q,J=7Hz),3.68(1H,t,J=7Hz),2.35-2.08(1H,m),2.20(3H,s),1.91(1H,ddq,J=14Hz,7Hz,7Hz),1.79-1.52(2H,m),1.38-1.06(2H,m),0.99(3H,t,J=7Hz),0.83(3H,t,J=7Hz);TLC:Rf 0.15(己烷∶乙酸乙酯=4∶1)。实施例1 (78)2RS-(4-(吡咯烷-1-基)苯基丁酸4-(N-2-(吡啶-2-基)乙基氨磺酰基)苯酯·二盐酸盐
NMR(DMSO-d6):δ8.79(1H,d,J=5.0Hz),8.50(1H,t,J=7.4Hz),8.04(1H,m),7.90(2H,m),7.79(2H,d,J=8.6Hz),7.28(2H,m),7.21(2H,d,J=8.4Hz),6.90(2H,m),3.76(1H,t,J=7.0Hz),3.34(4H,brs),3.23(4H,brs),2.01(5H,m),1.80(1H,m),0.91(3H,t,J=7.0Hz);T L C:R f 0.4 8 (氯仿∶甲醇∶水=9∶1∶0.1)。实施例1 (79)2RS-(4-(吡咯烷-1-基)苯基丁酸4-(N-2-(哌啶-1-基)乙基氨磺酰基)苯酯·二盐酸盐
NMR(CD3OD):δ7.92(2H,d,J=8.8Hz),7.71(2H,d,J=8.8Hz),7.63(2H,d,J=8.8Hz),7.26(2H,d,J=8.8Hz),3.95(1H,t,J=7.2Hz),3.81(4H,m),3.55(2H,brd,J=12.0Hz),3.24(4H,brs),2.98(2H,brt,J=12.0Hz),2.32(4H,m),1.89(7H,m),1.55(1H,m),0.99(3H,t,J=7.2Hz);/TLC:Rf 0.39(氯仿∶甲醇∶水=9∶1∶0.1)。实施例1 (80)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(四唑-5-基)氨磺酰基)苯酯
NMR(CD3OD):δ7.89(2H,d,J=8.6Hz),7.15(2H,d,J=8.6Hz),7.02(2H,d,J=8.6Hz),6.55(2H,d,J=8.6Hz),3.58(1H,t,J=7.8Hz),3.35-3.15(4H,m),2.20-1.95 and 1.95-1.70(each 1H,m),2.05-1.95(4H,m),0.93(3H,t,J=7.2Hz);
TLC:Rf 0.46(乙酸∶甲醇∶氯仿=1∶5∶25)。实施例1 (81)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(吗啉-4-基)氨磺酰基)苯酯·盐酸盐
NMR(CDCl3):δ7.97(2H,d,J=8.6Hz),7.61(2H,d-like),7.48(2H,d-like),7.16(2H,d,J=8.6Hz),5.99(1H,s),3.74(1H,t,J=7.8Hz),3.76-3.63(4H,m),3.65-3.54(4H,m),2.70-2.58(4H,m),2.42-229(4H,m),2.37-2.10 and2.04-1.77(each 1H,m),1.00(3H,t,J=7.2Hz);TLC:Rf 0.45(甲醇∶氯仿=1∶20)。实施例1 (82)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(吡咯烷-3-基)氨磺酰基)苯酯·二盐酸盐
NMR(CDCl3)δ7.7-7.5(4H,m),7.42(2H,d,J=8 6Hz),6.96 and 6.92(2H,d,J=8.6Hz),4.35-4.13(1H,m),3.5-2.9(10H,m),2.40-2.25(4H,m),2.20-1.55(4H,m),0.94(3H,t,J=7.2Hz);TLC:Rf 0.35(甲醇∶氯仿=1∶10)。实施例1 (83)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(1-苄基哌啶-4-基)氨磺酰基)苯酯
NMR(CDCl3):δ7.82(2H,d,J=9.0Hz),7.36-7.08(5H,m),7.21(2H,d,J=9.0Hz),7.13(2H,d,J=8.8Hz),6.55(2H,d,J=8.8Hz),4.50(1H,d,J=5.7Hz),3.58(1H,t,J=5.0Hz),3.43(2H,s),3.36-3.21(4H,m),3.21-3.02(1H,m),2.78-2.61(2H,m),2.28-1.65(10H,m),1.56-1.34(1H,m),0.97(3H,t,J=7.2Hz);TLC:Rf 0.60(乙酸乙酯∶己烷=9∶1)。实施例1 (84)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(吡啶-2-基)氨磺酰基)苯酯·二盐酸盐
NMR(CDCl3):δ8.26(1H,d,J=6.0Hz),7.96(2H,d,J=8.6Hz),7.83(1H,t,J=8.6Hz),7.72(2H,d,J=8.6Hz),7.55(1H,d,J=8.6Hz),7.48(2H,d,J=8.6Hz),7.12(2H,d,J=8.6Hz),6.95(1H,t,J=6.0Hz),3.74(1H,t,J=7.6Hz),3.80-3.60(4H,m),2.44-2.24(4H,m),2.32-2.02 and 2.02-1.72(each 1H,m),0.97(3H,t,J=7.2Hz);TLC:Rf 0.51(乙酸乙酯∶己烷=2∶1)。实施例1 (85)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-2-(吗啉-4-基)乙基氨磺酰基)苯酯
NMR(CDCl3):δ7.83(2H,d,J=8.9Hz),7.21(2H,d,J=8.7Hz),7.13(2H,d,J=8.9Hz),6.55(2H,d,J=8.7Hz),6.23-5.06(1H,b rs),3.64-3.52(5H,m),3.36-3.20(4H,m),2.98(2H,t,J=6.0Hz),2.38(2H,t,J=6.0Hz),2.30-2.20(4H,m),2.20-1.70(6H,m),0.97(3H,t,J=7.2Hz);TLC:Rf 0.24(乙酸乙酯∶己烷=7∶3)。实施例1 (86)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(哌嗪-2-基)氨磺酰基)苯酯·三盐酸盐
NMR(CDCl3):δ8.46(1H,s),8.17(2H,s),8.01(2H,d,J=8.2Hz),7.7-7.4(4H,m),7.14(2H,d,J=8.2Hz),3.9-3.5(5H,m),2.5-2.2(4H,m),2.4-2.1 and2.1-1.8(each 1H,m),0.98(3H,t,J=7.2Hz);TLC:Rf 0.18(己烷∶乙酸乙酯=1∶1)。实施例1 (87)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(咪唑-2-基)氨磺酰基)苯酯
NMR(CDCl3):δ7.90(2H,d,J=8.8Hz),7.19(4H,d,J=8.8Hz),5.81(1H,d,J=2.0Hz),6.54(1H,d,J=2.0Hz),6.54(2H,d,J=8.8Hz),3.57(1H,t,J=7.8Hz),3.28(4H,t-like),2.30-2.00 and 2.00-1.70(each 1H,m),2.00(4H,t-like),0.96(3H,t,J=7.4Hz);TLC:Rf 0.67(甲醇∶氯仿=1∶10)。实施例1 (88)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(奎宁环3RS-基)氨磺酰基)苯酯
NMR(CDCl3):δ7.88(2H,d,J=8.8Hz),7.21(2H,d,J=8.8Hz),7.11(2H,d,J=8.8Hz),6,55(2H,d,J=8.8Hz),3.58(1H,t,J=7.6Hz),3.60-3.47(1H,m),3.35-3.20(4H,m),3.30-2.80(6H,m),2.10-1.95(4H,m),2.30-1.40(7H,m),0.98(3H,t,J=7.2Hz);TLC:Rf 0.43(乙酸∶甲醇∶氯仿=1∶5∶25)。实施例1 (89)2RS-(4-吡咯烷-1-基)苯基)丁酸4-(N-(2,2,6,6-四甲基哌啶-4-基)氨磺酰基)苯酯
NMR(CDCl3+CD3OD):δ7.85(2H,d,J=8.8Hz),7.22(2H,d,J=8.6Hz),7.14(2H,d,J=8.8Hz),6.57(2H,d,J=8.6Hz),3.59(1H,t,J=7.8Hz),3.60-3.42(1H,m),3.35-3.20(4H,m),2.30-1.75(2H,m),2.06-1.96(4H,m),1.63(2H,dd,J=13.2 and 3.8Hz),1.33-1.08(2H,m),1.19(12H,s),0.98(3H,t,J=7.3Hz);TLC:Rf 0.55(氯仿∶甲醇∶乙酸=25∶5∶1)。实施例1 (90)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(奎宁环-3RS-基)氨磺酰基)-2-甲基苯酯
NMR(CDCl3):δ7.69(1H,d,J=2Hz),7.66(1H,dd,J=8 and 2Hz),7.30-7.13(2H,m),7.06(1H,d,J=8Hz),6.55(2H,d,J=9Hz),3.62(1H,t,J=8Hz),3.38-3.23(5H,m),3.23-3.05(1H,m),2.90-2.48(5H,m),2.32-2.08(1H,m),2.04(3H,s),2.08-1.03(10H,m),0.99(3H,t,J=7Hz);TLC:Rf 0.43(氯仿∶甲醇∶水=8∶2∶0.2)。实施例1 (91)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-2-(吗啉-4-基)乙基氨磺酰基)-2-甲基苯酯·二盐酸盐
NMR(DMSO-d6):δ11.3-11.1(1H,brs),8.18(1H,brs),7.75(1H,s),7.70(1H,d,J=8.0Hz),7.27(2H,d,J=8.6Hz),7.18(2H,d,J=9.2Hz),4.0-3.7(5H,m),3.4-3.0(12H,m),2.2-2.0(1H,m),2.1-1.9(4H,brs),2.0-1.7(1H,m),1.98(3H,s),0.91(3H,t,J=7.3Hz);TLC:Rf 0.50(氯仿∶甲醇=9∶1)。实施例1 (92)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-2-(哌嗪-4-基)乙基氨磺酰基)-2-甲基苯酯·三盐酸盐
NMR(DMSO-d6):δ9.6-9.2(2H,br),7.71(1H,s),7.67(1H,d,J=8.0Hz),7.18(2H,d,J=8.4Hz),7.14(1H,d,J=8.0Hz),6.53(2H,d,J=8.4Hz),3.69(1H,t,J=7.3Hz),3.7-2.6(16H,br),2.2-2.0(1H,m),2.0-1.9(4H,brs),1.96(3H,s),1.9-1.7(1H,m),0.90(3H,t,J=7.1Hz);TLC:Rf 0.46(氯仿∶甲醇∶乙酸=25∶5∶1)。实施例1 (93)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(哌啶-4-基)氨磺酰基)-2-甲基苯酯·二盐酸盐
NMR(DMSO-d6):δ9.1-8.7(1H,br),8.00(1H,d,J=7.2Hz),7.71(1H,s),7.68(1H,d,J=8.4Hz),7.26(2H,d,J=8.4Hz),7.15(1H,d,J=8.4Hz),6.79(2H,d,J=8.4Hz),3.76(1H,t,J=7.8Hz),3.4-3.2(4H,brs),3.2-3.0(3H,br),3.0-2.7(2H,br),2.2-1.9(1H,m),1.99(4H,brs),1.97(3H,s),1.9-1.5(5H,m),0.91(3H,t,J=7.3Hz);
NMR(CD3OD):δ8.27(2H,d,J=8.6Hz),7.92(2H,d,J=9.0Hz),7.67(2H,d,J=8.6Hz),7.27(2H,d,J=9.0Hz),4.03(1H,t,J=7.6Hz),3.90(2H,m),3.50(2H,m),3.28(8H,m),2.28(1H,m),1.99(1H,m),1.00(3H,t,J=7.4Hz);TLC:Rf0.61(氯仿∶甲醇∶水=9∶1∶0.1)。实施例1(95)1-(4-硝基苯基)环丁烷羧酸4-(N-2-(吡啶-2-基)乙基氨磺酰基)苯酯·盐酸盐
NMR(CD3OD):δ8.72(1H,d,J=8.0Hz),8.53(1H,t,J=8.0Hz),8.28(2H,d,J=8.6Hz),7.96(1H,d,J=8.0Hz),7.93(1H,d,J=8.0Hz),7.79(2H,d,J=8.6Hz),7.66(2H,d,J=8.6Hz),7.17(2H,d,J=8.6Hz),3.30(4H,m),3.06(2H,m),2.72(2H,m),2.23(1H,m),2.04(1H,m);
NMR(CD3OD):δ8.28(2H,d,J=8.4Hz),7.90(2H,d,J=8.4Hz),7.66(2H,d,J=8.4Hz),7.23(2H,d,J=8.4Hz),3.50(2H,m),3.30(4H,m),3.06(4H,m),2.73(2H,m),2.22(1H,m),1.99(1H,m),1.87(6H,m);
NMR(CDCl3):δ8.26(2H,d,J=9.0Hz),7.78(2H,d,J=9.0Hz),7.56(2H,d,J=9.0Hz),7.09(2H,d,J=9.0Hz),6.52(1H,dd,J=2.0,2.4Hz),6.01(1H,dd,J=2.4,2.6Hz),5.80(1H,m),4.64(1H,t,J=6.6Hz),3.42(3H,s),3.16(2H,q,J=6.6Hz),3.05(2H,m),2.74(2H,t,J=6.6Hz),2.66(2H,m),2.25(1H,m),2.03(1H,m);
TLC:Rf0.26(己烷∶乙酸乙酯=2∶1)。实施例1(98)2RS-(4-硝基苯基)丁酸4-(N(四唑-5-基甲基)氨磺酰基)苯酯
NMR(DMSO-d6):δ8.54(1H,t,J=5.8Hz),8.28(2H,d,J=8.8Hz),7.85(2H,d,J=8.8Hz),7.73(2H,d,J=8.8Hz),7.32(2H,d,J=8.8Hz),4.30(2H,d,J=5.8Hz),4.17(1H,t,J=7.6Hz),2.35-2.05 and 2.03-1.75(each 1H,m),0.92(3H,t,J=7.2Hz);TLC:Rf0.45(乙酸∶甲醇∶氯仿=1∶5∶25)。实施例1(99)1-(4-硝基苯基)环丁烷羧酸4-N-(四唑-5-基甲基)氨磺酰基)苯酯
NMR(CD3OD):δ8.28(2H,d,J=8.8Hz),7.85(2H,d,J=8.8Hz),7.67(2H,d,J=8.8Hz),7.19(2H,d,J=8.8Hz),4.37(2H,s),3.16-2.96(2H,m),2.82-2.62(2H,q-like),2.37-2.12 and 2.12-1.90(each 1H,m);
TLC:Rf0.11(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例1(100)1-(4-硝基苯基)环丁烷羧酸4-(N-(四唑-5-基)氨磺酰基)苯酯
NMR(DMSO-d6):δ8.26(2H,d,J=8.8Hz),7.84(2H,d,J=8.8Hz),7.69(2H,d,J=8.8Hz),7.12(2H,d,J=8.8Hz),3.08-2.88(2H,m),2.74-2.54(2H,q-like).2.24-2.04 and 2.04-1.84(each 1H,m);
NMR(DMSO-d6):δ13.88(1H,brs),8.26(2H,d,J=8.8Hz),7.82(2H,d,J=8.8Hz),7.70(2H,d,J=8.8Hz),7.06(2H,d,J=8.8Hz),4.12(1H,t,J=7.4Hz),2.30-2.00 and 2.00-1.70(each 1H,m),0.91(3H,t,J=7.2Hz);TLC:Rf0.26(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例1(102)2RS-(4-甲基苯基)丁酸4-(N-奎宁环-3RS-基)氨磺酰基)-2-甲基苯酯
NMR(CDCl3):δ7.70(1H,d,J=2Hz),7.67(1H,dd,J=8 and 2Hz),7.27(2H,d,J=8Hz),7.18(2H,d,J=8Hz),7.06(1H,d,J=8Hz),3.70(1H,t,J=8Hz),3.38-3.23(1H,m),3.23-3.05(1H,m),2.90-2.49(5H,m),2.36(3H,s),2.35-2.11(1H,m),2.00(3H,s),2.05-1.22(6H,m),1.00(3H,t,J=7Hz);
TLC:Rf0.40(氯仿∶甲醇∶水=8∶2∶0.2)。实施例1(103)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-2R-甲氧-3R-羟基-4S-羟基-5R-羟基全氢吡喃-6R-基甲基氨磺酰基)-2-甲基苯酯
NMR(CDCl3+6 drops of CD3OD):δ7.68-7.63(m,2H),7.22(d,J=8.8Hz,2H),7.05(d,J=8.1Hz,1H),6.55(d,J=8.8Hz,2H),4.63(d,J=3.7Hz,1H),3.70-3.50(m,3H),3.50-3.10(m,11H),2.30-1.80(m,9H),0.99(t,J=7.4Hz,3H);
TLC:Rf0.41(氯仿∶甲醇=8∶1)。实施例1(104)2RS-苯基丁酸4-(N-苯基氨磺酰基)苯酯
NMR(CDCl3):δ7.73(2H,dd,J=2Hz,8Hz),7.40-7.16(7H,m),7.16-7.00(5H,m),6.76(1H,s),3.67(1H,t,J=7Hz),2.20(1H,m),1.89(1H,m),0.96(3H,t,J=7Hz);
TLC:Rf0.57(己烷∶乙酸乙酯=1∶1)。实施例1(105)2RS-苯基丁酸4-(N-4-硝基苯基氨磺酰基)苯酯
NMR(CDCl3):δ8.10 and 7.85(each 2H,dd,J=2Hz,8Hz),7.75(1H,brs),7.35(5H,m),7.20 and 7.14(each 2H,dd,J=2Hz,J=8Hz),3.69(1H,t,J=7Hz),2.20 and 1.90(each 1H,m),0.96(3H,t,J=7Hz);
TLC:Rf0.59(己烷∶乙酸乙酯=1∶1)。实施例1(106)2RS-(4-氨基苯基)丁酸4-(N-苯基氨磺酰基)苯酯
NMR(DMSO-d6):δ7.72(2H,d,J=8Hz),7.42-6.91(9H,m),6.80-6.54(3H,m),3.56(1H,1,J=7Hz),2.23-1.64(2H,m),0.92(3H,t,J=7Hz);
NMR(CDCl3):δ7.76(1H,d,J=7.8Hz),7.59(1H,d,J=7.8Hz),7.48(1H,t-like),7.35(2H,d,J=8.8Hz),7.26(1H,t-like),7.17(2H,d,J=8.4Hz),6.77(2H,d,J=8.6Hz),6.55(2H,d,J=8.4Hz),3.57(1H,t,J=7.2Hz),3.31-3.24(4H,t-like),2.25-1.75(2H,m),2.05-1.95(4H,m),0.97(3H,t,J=7.2Hz);
TLC:Rf0.33(乙酸∶甲醇∶氯仿=1∶20∶200)。实施例1(108)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-4-(吗啉-4-基)苯基氨磺酰基)苯酯·二盐酸盐
NMR(CD3OD):δ7.83(2H,d,J=8.8Hz),7.60(4H,s),7.55(2H,d,J=9.0Hz),7.29(2H,d,J=9.0Hz),7.16(2H,d,J=8.8Hz),4.05(4H,t-like),3.89(1H,t,J=7.4Hz),3.84-3.68(4H,m),3.58(4H,t-like),2.35-2.23(4H,m),2.30-2.09 and 2.04-1.78(each 1H,m),0.96(3H,t,J=7.2Hz);
TLC:Rf0.52(甲醇∶氯仿=1∶20)。实施例1(109)
2-(N-4-(2RS-(4-(吡咯烷-1-基)苯基)丁酰氧基)-3-甲基苯基磺酰基)氨基)苯磺酸钠盐
NMR(DMSO-d6):δ10.6(1H,s),7.81(1H,d,J=2Hz),7.71(1H,dd,J=9,2Hz),7.57(1H,dd,J=8,2Hz),7.37(1H,dd,J=8,1Hz),7.22(1H,td,J=8.1Hz),7.16(2H,d,J=9Hz),7.06(1H,d,J=9Hz),6.97(1H,td,J=8,1Hz),6.57(2H,d,J=9Hz),3.67(1H,t,J=7Hz),3.30-3.15(4H,m),2.18-1.90(5H,m),1.88(3H,s),1.87-1.65(1H,m),0.86(3H,t,J=7Hz);
TLC:Rf0.19(氯仿∶甲醇∶乙酸=25∶5∶1)。实施例1(110)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-3,5-二甲氧苯基氨磺酰)-2-甲基苯基酯
NMR(CDCl3):δ7.62-7.55(2H,m),7.18(2H,d,J=8.4Hz),6.98(1H,d,J=8.2Hz),6.69(1H,s),6.52(2H,d,J=8.4Hz),6.21-6.16(3H,m),3.69(6H,s),3.57(1H,t,J=7.6Hz),3.31-3.24(4H,m),2.25-1.80(9H,m),0.97(3H,t,J=7.4Hz);TLC:Rf0.83(己烷∶乙酸乙酯=1∶1)。实施例1(111)
NMR(CDCl3):δ7.56-7.49(2H,m),7.26-6.94(8H,m),6.68(1H,brs),6.52(2H,d,J=8.4Hz),3.57(1H,t,J=7.8Hz),3.31-3.24(4H,m),2.27-1.75(6H,m),1.95(3H,s),0.97(3H,t,J=7.4Hz);
TLC:Rf0.83(己烷∶乙酸乙酯=3∶1)。实施例1(112)
2RS-(4-硝基苯)丁酸4-(N-2-(N’-(四唑-5-基甲基)氨基甲酰基)苯-1-基-氨磺酰)苯基酯
NMR(DMSO-d6):δ9.60-9.48(1H,m),8.25(2H,d,J=8Hz),7.88-7.63(5H,m),7.55-7.45(2H,m),7.30-7.09(3H,m),4.79-4.65(2H,m),4.13(1H,t,J=7Hz),2.31-2.04(1H,m),2.04-1.78(1H,m),0.88(3H,t,J=7Hz);
TLC:Rf0.28(乙酸∶甲醇∶氯仿=1∶2∶30)。实施例1(113)
NMR(DMSO-d6):δ9.60-9.48(1H,m),8.33-8.20(2H,m),7.85-7.62(5H,m),7.55-7.40(2H,m),7.30-7.10(3H,m),4.78-4.65(2H,m),3.06-2.85(2H,m),2.75-2.55(2H,m),2.26-2.03(1H,m),2.03-1.80(1H,m);
TLC:Rf0.39(乙酸∶甲醇;氯仿=1∶2∶20)。实施例1(114)
2RS-(4-硝基苯基)丁酸4-(N-(4-脒基苯基)氨磺酰)苯基酯·乙酸盐
NMR(DMSO-d6):δ9.40-9.10(2H,m),8.75-8.55(2H,m),8.24(2H,d,J=8Hz),7.78-7.61(4H,m),7.44(2H,d,J=8Hz),7.05(2H,d,J=8Hz),6.83(2H,d,J=8Hz),4.09(1H,t,J=7Hz),2.23-2.00(1H,m),1.95-1.65(4H,m),0.88(3H,t,J=7Hz);
TLC:Rf0.52(乙酸∶甲醇∶氯仿=1∶2∶10)。实施例1(115)
NMR(CD3OD):δ8.26(2H,d,J=8Hz),7.87(2H,d,J=8Hz),7.63(4H,d,J=8Hz),7.23(2H,d,J=8Hz),7.12(2H,d,J=8Hz),3.10-2.94(2H,m),2.78-2.60(2H,m),2.35-1.95(5H,m);
TLC:Rf0.40(乙酸∶甲醇∶氯仿=1∶2∶15)。实施例1(116)
NMR(CD3OD):δ8.22(2H,d,J=8.8Hz),7.86-7.18(8H,m),6.96(2H,d,J=8.8Hz),3.08-2.88(2H,m),2.65(2H,q-like),2.28-2.08(2H,m),2.08-1.88(2H,m);
TLC:Rf0.43(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例1(117)
1-(4-硝基苯基)环丁烷羧酸4-(N-4-(吗啉-4-基)苯基氨磺酰)苯基酯·盐酸盐
NMR(CD3OD):δ8.25(2H,d,J=8.8Hz),7.82(2H,d,J=8.8Hz).7.61(2H,d,J=8.8Hz),7.54(2H,d,J=8.8Hz),7.28(2H,d,J=8.8Hz),7.12(2H,d,J=8.8Hz),4.08(4H,t,J=4.8Hz),3.57(4H,t,J=4.8Hz),3.02(2H,m),2.70(2H,m),2.21(1H,m),2.03(1H,m);
TLC:Rf0.35(己烷∶乙酸乙酯=1∶1)。实施例1(118)
NMR(CD3OD):δ8.22(2H,m),7.93(1H,d,J=7.8Hz),7.68(1H,d,J=7.8Hz),7.64-7.60(2H,t-like),7.60-7.56(2H,m),7.33(1H,t,J=7.8Hz),7.16(1H,t,J=7.8Hz),7.00-6.92(2H,m),3.92(1H,t,J=8.0Hz),2.30-2.05 and 2.05-1.75(each 1H,m),0.93(3H,t,J=7.2Hz);
TLC:Rf0.27(乙酸∶甲醇∶氯仿=1∶20∶200)。实施例1(119)2RS-(4-(N-叔丁基氧羰基氨基)苯基)丁酸4-(N-2-(N’-羧甲基氨基甲酰基(苯基氨磺酰)苯基酯
NMR(DMSO-d6):δ10.77(1H,brs),9.34(1H,t-like),7.82(1H,d,J=7Hz),7.79(2H,d,J=8Hz),7.44(2H,d,J=8Hz),7.28-7.04(7H,m),6.78-6.70(1H,m),3.86(2H,d-like),3.72(1H,t,J=7Hz),2.11-1.90 and 1.81-1.67(each1H,m),1.47(9H,s),0.87(3H,t,j=7Hz);TLC:Rf0.21(氯仿∶甲醇∶水=8∶2∶0.2)。实施例1(120)
2RS-(4-吡咯烷-1-基)辛基)丁酸4-(3,5-二甲氧基苄基氨基磺酰基)-2-甲基苯基酯
NMR(CDCl3):δ7.67-7.62(2H,m),7.22(2H,d,J=8.6Hz),7.05(1H,d,J=9.4Hz),6.54(2H,d,J=8.6Hz),6.32(3H,s),4.64(1H,t,J=6.0Hz),4.05(2H,d,J=6.0Hz),3.72(6H,s),3.61(1H,t,J=7.6Hz),3.33-3.26(4H,m),2.27-1.81(6H,m),2.02(3H,s),0.99(3H,t,J=7.2Hz);
TLC:Rf0.86(己烷∶乙酸乙酯=1∶1)。实施例1(121)
NMR(CDCl3):δ7.55(1H,s),7.53(1H,d,J=8.4Hz),7.23(2H,d,J=8.6Hz),7.08(1H,d,J=8.4Hz),6.55(2H,d,J=8.6Hz),4.40(1H,brs),3.7-3.6(2H,br),3.62(1H,t,J=7.7Hz),3.5-3.2(1H,br),3.28(4H,br),2.6-2.4(2H,m),2.3-2.1(1H,m),2.04(3H,s),2.00(4H,brs),2.1-1.8(1H,m),1.6-1.4(4H,m),1.41(9H,s),0.99(3H,t,J=7.3Hz);
TLC:Rf0.81(己烷∶乙酸乙酯=1∶1)。实施例1(122)
NMR(CDCl3):δ7.74(1H,s),7.72(1H,d,J=9.0Hz),7.32(5H,s),7.24(2H,d,J=8.8Hz),7.14(1H,d,J=9.0Hz),6.56(2H,d,J=8.8Hz),3.98(2H,s),3.64(1H,t,J=7.7Hz),3.43(3H,s),3.29(4H,brs),2.3-2.1(1H,m),2.08(3H,s),2.00(4H,brs),2.1-1.8(1H,m),1.00(3H,t,J=7.4Hz);TLC:Rf0.79(己烷∶乙酸乙酯=2∶1)。实施例1(123)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-苄氧基-N-甲基氨基磺酰基)-2-甲基苯基酯·盐酸盐
NMR(CDCl3):δ7.71(1H,s),7.68(1H,d,J=8.2Hz),7.5-7.2(9H,brs),7.09(1H,d,J=8.2Hz),5.00(2H,s),3.73(1H,t,J=7.5Hz),3.7-3.4(4H,m),2.65(3H,s),2.4-2.1(5H,m),2.03(3H,s),2.1-1.8(1H,m),0.99(3H,t,J=7.2Hz);
TLC:Rf0.66(己烷∶乙酸乙酯=2∶1)。实施例1(124)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2-(N,N-二甲基氨基)乙基氨基磺酰基)-2-甲基苯基酯
NMR(CDCl3):δ7.69-7.63(2H,m),7.22(2H,d,J=8.6Hz),7.05(1H,d,J=8.4Hz),6.55(2H,d,J=8.6Hz),3.61(1H,t,J=8.2Hz),3.32-3.25(4H,m),2.95(2H,t,J=5.8Hz),2.30(2H,t,J=5.8Hz),2.27-1.65(15H,m),0.99(3H,t,J=7.2Hz);
TLC:Rf0.72(氯仿∶甲醇∶水=8∶2∶0.2)。实施例1(125)
NMR(CDCl3):δ7.7-7.4(m,2H),7.23(d,J=8.7Hz,2H),7.05(d,J=8.4Hz,1H),6.56(d,J=8.7Hz,2H),3.61(t,J=7.4Hz,1H),3.4-3.2(m,4H),3.1-2.9(m,2H),2.5-2.4(m,2H),2.4-2.3(m,4H),2.3-1.8(m,2H),2.1-1.9(m,4H),2.03(s,3H),1.6-1.3(m,6H),0.99(t,J=7.4Hz,3H);
TLC:Rf0.55(氯仿∶甲醇=7∶1)。实施例1(126)
NMR(CDCl3):δ7.8-7.4(m,5H),7.3-7.0(m,3H),4.3-3.4(m,11H),3.2-2.8(m,6H),2.4-1.8(m,11H),0.99(t,J=7.2Hz,3H);
TLC:Rf0.56(氯仿∶甲醇=9∶1)。实施例1(127)
2RS-(4-(吡咯烷-1-基)苯基丁酸4-(二氢吲哚-1-基磺酰基)-2-甲基苯基酯
NMR(CDCl3):δ7.66-7.51(3H,m),7.24-6.88(6H,m),6.53(2H,d,J=8.8Hz),3.88 (2H,t,J=8.4Hz),3.58(1H,t,J=7.8Hz),3.27(4H,m),2.89(2H,t,J=8.4Hz),2.29-1.72(9H,m),0.96(3H,t,J=7.2Hz);
TLC:Rf0.8(己烷∶乙酸乙酯=1∶1)。实施例1(128)
NMR(CDCl3):δ7.93(1H,s),7.86(1H,d,J=8.6Hz),7.22(2H,d,J=8.4Hz),7.11(1H,d,J=8.6Hz),6.55(2H,d,J=8.4Hz),4.43-4.33(1H,m),4.26(1H,t,J=8.6Hz),4.15(1H,dd,J=8.6,3.2Hz),3.61(1H,t,J=7.7Hz),3.40-3.20(4H,m),2.55-2.33(1H,m),2.33-1.70(9H,m),0.99(3H,t,J=7.4Hz),0.91(3H,d,J=6.9Hz),0.76(3H,d,J=6.9Hz);
TLC:Rf0.43(己烷∶乙酸乙酯=7∶3)。实施例1(129)
NMR(DMSO-d6):δ7.85-7.65(2H,m),7.27(3H,d,J=8.0Hz),6.95-6.70(2H,brd),4.05-3.70(5H,m),3.85(3H,s),3.50-2.95(12H,m),2.30-1.65(6H,m),2.02(3H,s),0.92(3H,t,J=7.5Hz);
TLC:Rf0.52(己烷∶乙酸乙酯=2∶1)。实施例1(130)
NMR(CDCl3):δ8.10(1H,d,J=9.0Hz),7.95(1H,s),7.72-7.56(3H,m),7.18(2H,d,J=8.0Hz),7.05(1H,d,J=8.0Hz),6.52(2H,d,J=8.0Hz),4.01(2H,t,J=8.5Hz),3.58(1H,t,J=7.5Hz),3.35-3.18(4H,m),3.08(2H,t,J=8.5Hz),2.30-1.70(6H,m),2.00(3H,s),0.96(3H,t,J=7.5Hz);
TLC:Rf0.60(己烷∶乙酸乙酯=2∶1)。实施例1(131)
NMR(CD3OD):δ7.84-7.70(2H,m),7.64(4H,s-like),7.13(1H,d,J=8.2Hz),3.97(1H,t,J=7.4Hz),3.87-3.66(4H,m),3.54(4H,t,J=4.4Hz),2.55(4H,t,J=4.4Hz),2.43-2.14(5H,m),2.14-1.80(4H,m),1.00(3H,t,J=7.4Hz);
TLC:Rf0.51(己烷∶乙酸乙酯=1∶1)。实施例1(132)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(6-氟二氢吲哚-1-基-磺酰基)-2-甲基苯基酯·盐酸盐
NMR(CD3OD∶CDCl3=1∶1):δ7.75-7.40(6H,m),7.29(1H,dd,J=10.0and 2.0Hz),7.15-7.01(2H,m),6.69(1H,td,J=8.6 and 2.0Hz),3.94(2H,t,J=8.4Hz),3.87(1H,t,J=7.6Hz),3.79-3.63(4H,m),2.89(2H,t,J=8.4Hz),2.40-2.12(5H,m),2.08-1.79(4H,m),0.99(3H,t,J=7.4Hz);
TLC:Rf0.29(己烷∶乙酸乙酯=3∶1)。实施例1(133)
NMR(CD3OD):δ7.78-7.64(3H,m),7.60(4H,s-like),7.52-7.42(2H,m),7.11(1H,d,J=8.4Hz),4.01(2H,t,J=8.5Hz),3.93(1H,t,J=8.4Hz),3.87-3.70(4H,m),3.23(6H,s),3.06(2H,t,J=8.5Hz),2.40-2.10(5H,m),2.10-1.80(4H,m),0.97(3H,t,J=7.2Hz);
TLC:Rf0.24(己烷∶乙酸乙酯=3∶1)。实施例1(134)
NMR(CD3OD):δ7.75-7.59(6H,m),7.23(1H,d,J=8.2Hz),4.06-3.84(3H,m),3.84-3.68(4H,m),3.64-3.49(2H,m),3.32-3.11(2H,m),2.89(3H,s),2.84-2.64(2H,m),2.44-2.14(5H,m),2.13-1.82(4H,m),1.00(3H,t,J=7.2Hz);
TLC:Rf0.36(乙酸乙酯)。实施例1(135)
NMR(CDCl3):δ8.10(1H,dd,J=9.0,2.2Hz),7.95(1H,d,J=2.2Hz),7.66(1H,d,J=9.0HZ),7.66(1H,s),7.63(1H,d,J=8.2Hz),7.18(2H,d,J=8.8Hz),7.05(1H,d,J=8.2Hz),6.53(2H,d,J=8.8Hz),4.01(2H,t,J=8.5Hz),3.58(1H,t,J=7.7Hz),3.3-3.2(4H,brs),3.08(2H,t,J=8.5Hz),2.3-2.0(1H,m),2.1-1.9(4H,brs),2.00(3H,s),2.0-1.8(1H,m),0.96(3H,t,J=7.3Hz);TLC:Rf0.60(己烷∶乙酸乙酯=2∶1)。实施例1(136)
NMR(CD3OD):δ7.83-7.58(6H,m),7.18(1H,d,J=8.0Hz),4.12-3.70(9H,m),3.53(2H,d,J=12.0Hz),3.38-3.08(6H,m),2.45-1.80(8H,m),1.00(6H,t,J=7.5Hz);
TLC:Rf0.41(己烷∶乙酸乙酯=1∶4)。实施例1(137)
NMR(CD3OD):δ7.83-7.58(6H,m),7.19(1H,d,J=8.0Hz),4.12-3.70(9H,m),3.53(2H,d,J=12.0Hz),3.40-3.08(6H,m),2.50-1.80(8H,m),0.99(6H,t,J=7.5Hz);
TLC:Rf0.41(己烷∶乙酸乙酯=1∶4)。实施例1(138)
2R-(4-(吡咯烷-1-基)苯基)丁酸4-(2-(吗啉-4-基)乙基氨基磺酰基)-2-甲基苯基酯·2盐酸盐
NMR(DMSO-d6):δ11.0-10.8(1H,brs),7.75(1H,s),7.70(1H,d,J=8.6Hz),7.22(2H,d,J=8.4Hz),7.18(1H,d,J=8.6Hz),6.64(2H,d,J=8.4Hz),4.0-3.7(5H,m),3.4-3.0(12H,m),2.2-2.0(1H,m),2.1-1.9(4H,brs),2.0-1.7(1H,m),1.97(3H,s),0.91(3H,t,J=7.3Hz);
NMR(DMSO-d6):δ11.4-11.2(1H,brs),7.76(1H,s),7.70(1H,d,J=8.6Hz),7.30(2H,d,J=8.4Hz),7.18(1H,d,J=8.6Hz),6.87(2H,d,J=8.4Hz),4.0-3.7(5H,m),3.5-3.3(6H,m),3.3-3.0(6H,m),2.2-2.0(1H,m),2.1-1.9(4H,brs),2.0-1.7(1H,m),1.98(3H,s),0.91(3H,t,J=7.2Hz);TLC:Rf0.50(氯仿∶甲醇=9∶1)。实施例1(140)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(4-甲基-1,4-全氢化二氮杂_-1-基磺酰基)-2-甲基苯基酯·2盐酸盐
NMR(DMSO-d6):δ7.72(1H,d,J=2Hz),7.66(1H,dd,J=2 and 8Hz),7.25(2H,d,J=8Hz),7.19(1H,d,J=8Hz),6.76(2H,d-like),3.76(1H,t,J=7Hz),3.75-3.01(12H,m),2.76 and 2.74(total 3H,each s),2.21-1.66(8H,m),1.99(3H,s),0.91(3H,t,J=7Hz);
NMR(CDCl3):δ7.62-7.51(3H,m),7.23-7.15(3H,m),7.07-6.95(3H,m),6.52(2H,d,J=9Hz),4.75-4.67(1H,m),4.24(2H,q,J=7Hz),3.57(1H,t,J=7Hz),3.31-3.24(4H,m),3.21-3.00(2H,m),2.23-1.75(2H,m),2.04-1.99(4H,m),1.96(3H,s),1.29(3H,t,J=7Hz),0.96(3H,t,J=7Hz);
TLC:Rf0.29(己烷∶乙酸乙酯=3∶1)。实施例1(142)
2S-(4-(吡咯烷-1-基)苯基)丁酸4-(奎宁环-3RS-基氨基磺酰基)-2-甲基苯基酯·2盐酸盐
NMR(DMSO-d6):δ8.35(1H,d,J=7Hz),7.74-7.64(2H,m),7.26(2H,d,J=8Hz),7.17(1H,d,J=8Hz),6.82-6.70(2H,br),3.75(1H,t,J=7Hz),3.61-3.43(1H,br),3.40-3.22(5H,m),3.18-2.94(5H,m),2.90-2.79(1H,m),2.17-1.60(13H,m),0.91(3H,t,J=7Hz);
TLC:Rf0.35(氯仿∶甲醇∶水=8∶2∶0.2)。实施例1(143)
NMR(CD3OD):δ7.80-7.70(2H,m),7.67(4H,s),7.17(1H,d,J=8.0Hz),4.10-3.70(9H,m),3.54(2H,d,J=12.0Hz),3 40-3.10(6H,m),2.70(6H,s),2.40-1.80(6H,m),2.05(3H,s),1.00(3H,t,J=7.5Hz);
TLC:Rf0.31(氯仿∶甲醇∶乙酸乙酯=40∶2∶1)。实施例1(144)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(3,5-二甲氧基苯基氨基磺酰基)-2-甲基苯基酯·甲磺酸盐
NMR(CD3OD):δ7.70-7.50(6H,m),7.05(1H,d,J=8.5Hz),6.24(2H,d,J=2.0Hz),6.16(1H,t,J=2.0Hz),3.94(1H,t,J=7.5Hz),3.77(4H,t-like),3.67(6H,s),2.70(3H,s),2.40-1.80(6H,m),1.96(3H,s),0.98(3H,t,J=7.5Hz);
TLC:Rf0.73(己烷∶乙酸乙酯=1∶1)。实施例1(145)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(5-硝基二氢吲哚-1-基磺酰基)-2-甲基苯基酯·盐酸盐
NMR(CDCl3):δ8.11(1H,dd,J=2.0,9.0Hz),7.96(1H,d,J=2.0Hz),7.72-7.60(3H,m),7.55(2H,d,J=8.0Hz),7.44(2H,d,J=8.0Hz),7.06(1H,d,J=8.0Hz),4.03(2H,t,J=8.5Hz),3.75(1H,t,J=7.5Hz),3.85-3.40(4H,m),3.10(2H,t,J=8.5Hz),2.45-2.20(4H,m),2.40-1.75(2H,m),2.02(3H,s),0.98(3H,t,J=7.5Hz);
TLC:Rf0.60(己烷∶乙酸乙酯=2∶1)。实施例1(146)
NMR(CDCl3):δ8.11(1H,dd,J=2.5,9.0Hz),7.97(1H,d,J=2.5Hz),7.74-7.62(3H,m),7.57(2H,d,J=8.5Hz),7.49(2H,d,J=8.5Hz),7.07(1H,d,)J=8.0Hz),4.03(2H,t,J=8.5Hz),3.77(1H,t,J=7.5Hz),4.10-3.30(4H,m),3.11(2H,t,J=8.5Hz),2.85(3H,s),2.50-2.20(4H,m),2.40-2.10 and 2.10-1.80(each1H,m),2.04(3H,s),0.99(3H,t,J=7.5Hz);TLC:Rf0.60(己烷∶乙酸乙酯=2∶1)。实施例1(147)2RS-(4-(吡咯烷-1-基)苯基丁酸4-(二氢吲哚-1-基磺酰基)-2-甲基苯基酯·盐酸盐
NMR(CDCl3):δ7.65-7.53(3H,m),7.32(2H,d,J=8.4Hz),7.24-6.90(6H,m),3.89(2H,t,J=8.5Hz),3.66(1H,t,J=8.2Hz),3.45(4H,brs),2.89(2H,t,J=8.5Hz),2.34-2.04(5H,m),1.97(3H,s),2.04-1.73(1H,m),0.97(3H,t,J=7.2Hz);
TLC:Rf0.42(己烷∶乙酸乙酯=3∶1)。实施例2
在0℃下将三氟乙酸(5ml)缓慢地加到实施1中制备的化合物(1.04g)在二氯甲烷(5ml)和苯甲醚(5ml)中的混合物溶液中。在室温下,将反应混合物搅拌6小时,浓缩反应混合物,通过硅胶柱色谱(氯仿∶甲醇=20∶1)纯化残余物,得到N-{4-[2RS-(4-(1-吡咯烷基)苯基)丁酰氧基]-3-甲基苯基磺酰基}-L-脯氨酸。通过下面方法将得到的上述化合物转化成盐酸盐。在0℃下将4N盐酸的二恶烷溶液(1ml)加入到N-{4-[2RS-(4-(1-吡咯烷基)苯基)丁酰氧基]-3-甲基苯基磺酰基}-L-脯氨酸的二恶烷(5ml)的溶液中。将反应混合物搅拌5分钟,浓缩反应混合物,得到具有下面物理数据的标题化合物(1g)。
NMR(CDCl3):δ7.70(1H,s),7.67(1H,d,J=8.0Hz),7.59(2H,d,J=8.5Hz),7.49(2H,d,J=8.5Hz),7.07(1H,d,J=8.0Hz),4.26(1H,dd,J=3.5,7.0Hz),3.78(1H,t,J=7.5Hz),3.75-3.60(4H,m),3.52-3.40(1H,m),3.33-3.14(1H,m),2.40-2.25(4H,m),2.40-1.65(6H,m),2.04(3H,s),1.00(3H,t,J=7.5Hz);
TLC:Rf0.39(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(1)~2(296)
通过与实施例1和2相同的方法并通已知的方法转化成相应的盐、酸加成盐或溶剂化物,通过使用相应的酚衍生物代替参考例4制备的化合物及通过使用相应的羧酸衍生物代替参考例7制备的化合物,得到具有下列物理数据的化合物。实施例2(1)
NMR(DMSO-d6):δ7.86(2H,d,J=8Hz),7.24(4H,d,J=8Hz),6.78(2H,d.J=8Hz),4.15-4.05(1H,m),3.73(1H,t,J=7Hz),3.40-3.05(6H,m),2.20-1.45(10H,m),0.89(3H,t,J=7Hz);
TLC:Rf0.26(乙酸∶甲醇∶氯仿=1∶2∶60)。实施例2(2)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2R-羧基吡咯烷-1-基磺酰基)苯基酯·盐酸盐
NMR(DMSO-d6):δ7.86(2H,d,J=8.8Hz),7.25(4H,d,J=8.8Hz),6.78(2H,d,J=8.8Hz),4.16-4.05(1H,m),3.74(1H,t,J=7.2Hz),3.44-3.06(2H,m),3.36-3.24(4H,m),2.22-1.46(10H,m),0.90(3H,t,J=7.2Hz);
TLC:Rf0.39(乙酸∶甲醇:氯仿=1∶2∶40)。实施例2(3)
NMR(DMSO-d6):δ7.83(2H,d,J=9Hz),7.31-7.18(4H,m),6.85-6.68(2H,m),4.25-4.14(1H,m),4.04(1H,t,J=7Hz),3.73(1H,t,J=7Hz),3.50-3.38(5H,m),3.18-3.05(1H,m),2.20-1.65(8H,m),0.90(3H,t,J=7Hz);
TLC:Rf0.27(氯仿∶甲醇∶乙酸=20∶2∶1)。实施例2(4)
NMR(CDCl3):δ7.84(2H,d,J=9Hz),7.62(2H,d,J=9Hz),7.47(2H,d,J=9Hz),7.34-7.19(3H,m),7.17-7.00(4H,m),4.30(1H,t,J=8Hz),4.23(2H,s),4.15-4.03(1H,m),3.86-3.42(7H,m),2.47-2.05(7H,m),2.05-1.74(1H,m),0.97(3H,t,J=7Hz);
TLC:Rf0.35(氯仿∶甲醇∶乙酸=40∶2∶1)。实施例2(5)
NMR(DMSO-d6):δ8.55-8.20(2H,brs),7.89(2H,d,J=9Hz),7.29(2H,d,J=9Hz),7.25(2H,d,J=9Hz),6.73(2H,d,J=9Hz),5.80-4.40(1H,m),4.18(1H,t,J=7Hz),3.74(1H,t,J=7Hz),3.64-3.10(7H,m),2.67-2.40(1H,m),2.20-1.65(7H,m),0.90(3H,t,J=7Hz);TLC:Rf0.49(乙酸乙酯∶乙酸∶水=6∶2∶1)。实施例2(6)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2S-羧基-4R-氨基吡咯烷-1-基磺酰基)苯基酯·2盐酸盐
NMR(DMSO-d6):δ8.60-8.30(2H,brs),7.88(2H,d,J=9Hz),7.28(2H,d,J=9Hz),7.23(2H,d,J=9Hz),6.72(2H,d,J=9Hz),5.40-4.20(1H,m),4.40(1H,dd,J=9Hz,4Hz),3.90-3.50(2H,m),3.50-3.10(6H,m),2.33-1.60(8H,m),0.90(3H,t,J=7Hz);
NMR(CDCl3+CD3OD):δ7.84(2H,d,J=8.8Hz),7.28-7.18(4H,m),6.72(2H,d,J=8.8Hz),4.09-3.85(3H,m),3.71-3.53(2H,m),3.41-3.31(4H,m),3.20-3.08(1H,m),2.26-1.59(10H,m),0.99(3H,t,J=7.4Hz);
TLC:Rf0.24(氯仿∶甲醇∶乙酸=40∶2∶1)。实施例2(8)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2S-(2-氨基乙氧基羰基)吡咯烷-1-基磺酰基)-2-甲基苯基酯·2盐酸盐
NMR(DMSO-d6):δ8.21(2H,brs),7.75(1H,s),7.69(1H,d,J=8.2Hz),7.22(3H,m),6.70(2H,d,J=8.8Hz),4.26(3H,m),3.50-3.36(2H,m),3.31(4H,m),3.20(1H,m),3.08(2H,m),2.12(1H,m),2.00(3H,s),1.96(4H,m),1.87(4H,m),1.66(1H,m),0.92(3H,t,J=7.2Hz);
TLC:Rf0.31(氯仿∶甲醇∶乙酸=12∶1∶1)。实施例2(9)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2S-(2-(2-羟基乙氧基)乙氧基羰基)吡咯烷-1-基磺酰基)-2-甲基苯基酯·盐酸盐
NMR(CDCl3):δ7.69(1H,s),7.67(2H,d,J=8.4Hz),7.23(2H,d,J=8.4Hz),7.07(1H,d,J=8.2Hz),6.56(2H,d,J=8.4Hz),4.29(3H,m),3.75-3.58(7H,m),3.50(1H,m),3.29(4H,m),3.22(1H,m),2.16(1H,m),2.04(3H,s),2.01(4H,m),1.98-1.64(5H,m),0.99(3H,t,J=7.2Hz);TLC:Rf0.62(氯仿∶甲醇=9∶1)。实施例2(10)
NMR(CDCl3):δ7.70-7.58(2H,m),7.22(2H,d,J=8.5Hz),7.09(1H,d,J=8.0Hz),6.55(2H,d,J=8.5Hz),3.80-3.52(3H,m),3.62(1H,t,J=7.5Hz),3.52-3.35(1H,m),3.35-3.12(5H,m),2.90-2.55(1H,brs),2.35-1.70(2H,m),2.05(3H,s),2.05-1.95(4H,m),1.80-1.30(4H,m),0.99(3H,t,J=7.5Hz);
TLC:Rf0.36(己烷∶乙酸乙酯=1∶1)。实施例2(11)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2S-(2-(哌嗪-4-基)乙基)氧羰基吡咯烷-1-基磺酰基)-2-甲基苯基酯·2盐酸盐
NMR(CD3OD):δ7.82-7.63(6H,m),7.00(1H,d,J=8.2Hz),4.62(2H,m),4.41(1H,m),4.00(1H,t,J=7.6Hz),3.81-3.66(8H,m),3.57(1H,m),3.21(1H,m),2.33(7H,m),2.07(3H,s),2.03-1.89(5H,m),1.69(1H,m),1.00(3H,t,J=7.4Hz);
TLC:Rf0.48(氯仿∶甲醇∶水=40∶10∶1)。实施例2(12)
2-(2-甲氧基苯基)-2-乙基丁酸4-(2S-羧基吡咯烷-1-基磺酰基)苯基酯
NMR(DMSO-d6):δ7.89(2H,d,J=9Hz),7.34-7.16(4H,m),7.06-6.95(2H,m),4.03(1H,dd,J=2 and 8Hz),3.82(3H,s),3.36-3.23 and 3.20-3.09(each 1H,m),2.23-1.91(4H,m),1.87-1.47(4H,m),0.72(6H,t,J=7Hz);TLC:Rf0.19(氯仿∶甲醇∶水=9∶1∶0.1)。实施例2(13)
NMR(CDCl3):δ7.69(1H,s),7.68(1H,d,J=9.0Hz),7.35-7.22(2H,m),7.10(1H,d,J=9.0Hz),6.98(1H,d,J=7.6Hz),6.92(1H,d,J=7.8Hz),4.28-4.16(1H,m),4.15(1H,t,J=7.6Hz),3.85(3H,s),3.60-3.43(1H,m),3.26-3.07(1H,m),2,35-1.56(4H,m).2.04(3H,s),0.98(3H,t,J=7.6Hz);TLC:Rf0.54(氯仿∶甲醇∶水=8∶2∶0.2)。实施例2(14)2RS-(4-甲氧基苯基)丁酸-4-(2S-羧基吡咯烷-1-基磺酰基)-2-甲基苯基酯
NMR(DMSO-d6):δ7.74(1H,s),7.69(1H,d,J=8.2Hz),7.33(2H,d,J=8.8Hz),7.17(1H,d,J=8.2Hz),6.95(2H,d,J=8.8Hz),4.11(1H,m),4.14(1H,m),3.76(3H,s),3.30(1H,m),3.17(1H,m),2.10(1H,m),1.96(3H,s),1.82(4H,m),1.56(1H,m),0.91(3H,t,J=7.2Hz);
TLC:Rf0.58(氯仿∶甲醇∶乙酸=12∶1∶1)。实施例2(15)
NMR(CD3OD):δ7.77(1H,s),7.75(1H,d,J=7.4Hz),7.32(2H,d,J=8.6Hz),7.16(1H,d,J=7.4Hz),6.93(2H,d,J=8.6Hz),4.62(2H,brs),4.5-4.3(1H,br),3.8-3.4(12H,br),3.79(3H,s),3.3-3.1(1H,br),2.3-1.8(6H,br),2.00(3H,s),0.98(3H,t,J=7.3Hz);
TLC:Rf0.16(氯仿∶甲醇∶乙酸=40∶2∶1)。实施例2(16)
2RS-(4-甲氧基苯基)丁酸4-(2S-(2-(2-羟基乙氧基)乙氧基羰基)吡咯烷-1-基-磺酰基)-2-甲基苯基酯
NMR(CDCl3):δ7.70(1H,s),7.68(1H,d,J=8.8Hz),7.31(2H,d,J=8.4Hz),7.01(1H,d,J=8.8Hz),6.90(2H,d,J=8.4Hz),4.3-4.2(3H,m),3.82(3H,s),3.8-3.7(6H,m),3.7-3.5(2H,m),3.3-3.2(1H,m),2.4-2.1(2H,m),2.00(3H,s),2.1-1.7(4H,m),0.99(3H,t,J=7.3Hz);
TLC:Rf0.24(己烷∶乙酸乙酯=1∶2)。实施例2(17)
2RS-(4-甲氧基苯基)丁酸4-(2S-(2-氨基乙基)氧羰基吡咯烷-1-基磺酰基)-2-甲基苯基酯·盐酸盐
NMR(CDCl3):δ8.40(2H,brs),7.73(1H,s),7.70(1H,d,J=9.2Hz),7.30(2H,d,J=8.6Hz),7.08(1H,d,J=9.2Hz),6.89(2H,d,J=8.6Hz),4.6-4.3(3H,br),3.80(3H,s),3.67(1H,t,J=7.6Hz),3.6-3.3(3H,br),3.2-3.1(1H,br),2.4-1.8(6H,br),2.00(3H,s),0.98(3H,t,J=7.3Hz);
TLC:Rf0.23(氯仿∶甲醇=9∶1)。实施例2(18)
NMR(CDCl3):δ7.69(1H,s),7.66(1H,d,J=9.0Hz),7.25(2H,d,J=8.0Hz),7.15(2H,d,J=8.0Hz),7.05(1H,d,J=9.0Hz),4.20(1H,m),3.67(1H,)t,J=8.0Hz),3.60-3.40(1H,m),3.20-3.00(1H,m),2.34(3H,s),2.30-1.50(6H,m),1.96(3H,s),0.97(3H,t,J=7.5Hz);
TLC:Rf0.39(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(19)
NMR(CDCl3):δ7.67(1H,s),7.65(1H,d,J=8.0Hz),7.28(2H,d,J=8.0Hz),7.18(2H,d,J=8.0Hz),7.09(1H,d,J=8.0Hz),3.70(1H,t,J=7.5Hz),3.74-3.54(3H,m),3.54-3.38(1H,m),3.30-3.14(1H,m),2.71(1H,t-like),2.36(3H,s),2.40-1.80(2H,m),2.02(3H,s),1.90-1.60(3H,m),1.60-1.40(1H,m),1.00(3H,t,J=7.5Hz);
TLC:Rf0.23(乙酸乙酯∶己烷=1∶2)。实施例2(20)
2RS-(4-甲基苯基)丁酸4-(2S-(2-氨基乙基)氧羰基吡咯烷-1-基磺酰基)-2-甲基苯基酯·盐酸盐
NMR(DMSO-d6):δ8.22(3H,brs),7.75(1H,d,J=1.8Hz),7.70(1H,dd,J=8.4 and 1.8Hz),7.30(2H,d,J=8.0Hz),7.20(3H,d,J=8.0Hz),4.33-4.15(1H,m),4.26(2H,t,J=5.0Hz),3.85(1H,t,J=7.6Hz),3.49-3.01(2H,m),3.09(2H,t,J=5.6Hz),2.32(3H,s),2.25-1.50(6H,m),1.98(3H,s),0.92(3H,t,J=7.2Hz);
TLC:Rf0.56(氯仿∶甲醇∶乙酸=15∶2∶1)。实施例2(21)
2RS-(4-甲基苯基)丁酸4-(2S-(2-(哌嗪-4-基)乙基)氧羰基吡咯烷-1-基磺酰基)-2-甲基苯基酯·2盐酸盐
NMR(CD3OD):δ7.78(1H,s),7.75(1H,dd,J=8.6 and 1.2Hz),7.29(2H,d,J=8.0Hz),7.24-7.12(3H,m),4.66-4.54(2H,m),4.45-4.32(1H,m),3.85-3.60(11H,m),3.60-3.38(1H,m),3.26 -3.15(1H,m),2.34(3H,s),2.30-1.55(6H,m),1.99(3H,s),0.98(3H,t,J=7.2Hz);
TLC:Rf0.45(氯仿∶甲醇∶水=8∶2∶0.2)。实施例2(22)
2RS-(4-甲基苯基)丁酸4-(2S-(2-(2-羟基乙氧基)乙基)氧羰基吡咯烷-1-基磺酰基)-2-甲基苯基酯
NMR(CDCl3):δ7.70(1H,s),7.68(1H,dd,J=7.4 and 2.4Hz),7.28(2H,d,J=8.2Hz),7.18(2H,d,J=8.2Hz),7.07(1H,d,J=8.8Hz),4.40-4.20(3H,m),3.73-3.37(8H,m),3.37-3.16(1H,m).2.24-1.63(6H,m),2.36(3H,s),2.02(3H,s),1.70(1H,s),1.00(3H,t,J=7.2Hz);
TLC:Rf0.28(乙酸乙酯∶己烷=2∶1)。实施例2(23)
2RS-(4-硝基苯基)丁酸4-(2S-羧基吡咯烷-1-基磺酰基)苯基酯
NMR(DMSO-d6):δ8.25(2H,d,J=8Hz),7.90(2H,d,J=8Hz),7.58(2Hd,J=8Hz),7.19(2H,d,J=8Hz),5.70-4.80(1H,brs),4.30(1H,dd,J=7Hz,4Hz),3.85(1H,t,J=7Hz),3.60-3.39(1H,m),3.39-3.15(1H,m),2.45-1.65(6H,m),1.01(3H,t,J=7Hz);
TLC:Rf0.34(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(24)
2R-(4-硝基苯基)丁酸4-(2S-羧基吡咯烷-1-基磺酰基)苯基酯
NMR(CDCl3):δ8.26(d,J=8.8Hz,2H),7.90(d,J=8.8Hz,2H),7.58(d,J=8.8Hz,2H),7.20(d,J=8.8Hz,2H),4.30(dd,J=4.0,7.8Hz,1H),3.86(t,J=7.6Hz,1H),3.5-3.4(m,1H),3.4-3.2(m,1H),2.4-1.7(m,6H)1.02(t,J=7.3Hz,3H);
TLC:Rf0.63(氯仿∶甲醇=6∶1)。实施例2(25)
NMR(CDCl3)δ8.26(d,J=8.8Hz,2H),7.90(d,J=8.8Hz,2H),7.58(d,J=8.8Hz,2H),7.19(d,J=8.8Hz,2H),4.31(dd,J=4.0,7.2Hz,1H),3.86(t,J=7.7Hz,1H),3.6-3.4(m,1H),3.4-3.2(m,1H),2.4-1.7(m,6H),1.03(t,J=7.6Hz,
TLC:Rf0.63(氯仿∶甲醇=6∶1)。实施例2(26)
NMR(DMSO-d6):δ8.27(2H,d,J=8Hz),7.88(2H,d,J=8Hz),7.56(2H,d.J=8Hz),7.16(2H,d,J=8Hz),6.00-5.10(1H,brs),4.29(1H,dd,J=7Hz,4Hz),3.55-3.40(1H,m),3.34-3.19(1H,m),3.15-2.98(2H,m),2.80-2.60(2H,m),2.38-1.66(6H,m);
TLC:Rf0.40(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(27)
NMR(DMSO-d6):δ8.27(2H,d,J=8.8Hz),7.74(2H,d,J=8.8Hz),7.79-7.66(2H,m),7.23(1H,d,J=8.4Hz),4.20(1H,t,J=7.6Hz),4.12-4.06(1H,m),3.40-3.07(2H,m),2.35-1.40(6H,m),2.00(3H,s),0.92(3H,t,J=7.2Hz);TLC:Rf0.19(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(28)
NMR(DMSO-d6):δ13.5-11.6(1H,brs),8.27(2H,d,J=8.8Hz),7.88(2H,d,J=8.8Hz),7.73(2H,d,J=8.8Hz),7.32(2H,d,J=8.8Hz),4.16(1H,t,J=7.2Hz),4.16-4.06(1H,m),3.5-3.0(2H,m),2.35-1.45(6H,m),0.92(3H,t,J=7.2Hz);
TLC:Rf0.43(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(29)
1-(4-硝基苯基)环丁烷羧酸4-(2R-羧基吡咯烷-1-基磺酰基)苯基酯
NMR(DMSO-d6):δ12.9-12.6(1H,brs),8.28(2H,d,J=8.8Hz),7.87(2H,d,J=8.8Hz),7.71(2H,d,J=8.8Hz),7.31(2H,d,J=8.8Hz),4.16-4.04(1H,m),3.43-3.10(2H,m),3.10-2.90(2H,m),2.75-2.55(2H,q-like),2.28-1.46(6H,m);
TLC:Rf0.46(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(30)
NMR(CDCl3):δ7.93-7.83(2H,m),7.50-7.14(5H,m),7.23-7.14(2H,m),7.14-6.70(1H,brs),4.26(1H,dd,J=10Hz,5Hz),3.71(1H,t,J=7Hz),3.56-3.43(1H,m),3.33-3.17(1H,m),2.35-1.65(6H,m),0.98(3H,t,J=7Hz);TLC:Rf0.67(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(31)
NMR(CDCl3):δ7.73(2H,d,J=8.6Hz),7.58(1H,d,J=8.2Hz),7.17(2H,d,J=8.6Hz),7.12-6.94(5H,m),6.53(2H,d,J=8.8Hz),4.73(1H,dd,J=8.9Hzand 6.8Hz),3.54(1H,t,J=7.8Hz),3.35-3.21(4H,m),3.17(2H,d,J=6.8Hz),2.25-1.70(2H,m),2.05-1.94(4H,m),0.95(3H,t,J=7.2Hz);TLC:Rf0.46(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(32)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2-羧基吲哚-1-基磺酰基)苯基酯
NMR(DMSO-d6):δ8.08(2H,d,J=8.8Hz),8.01(1H,d,J=8.4Hz),7.68(1H,d,J=8.0Hz),7.46(1H,m),7.40-7.16(2H,m),7.24(2H,d,J=8.8Hz),7.20(2H,d,J=8.6Hz),6.85-6.60(2H,m),3.69(1H,t,J=7.4Hz),3.40-3.15(4H,m),2.20-1.84(5H,m),1.84-1.60(1H,m),0.86(3H,t,J=7.4Hz);
TLC:Rf0.20(氯仿∶甲醇∶水=9∶1∶0.1)。实施例2(33)
NMR(CDCl3):δ7.72(2H,d,J=8.6Hz),7.57(1H,d,J=7.8Hz),7.17(2H,d,J=8.6Hz),7.28-6.88(5H,m),6.53(2H,d,J=8.6Hz),4.72(1H,dd,J=5.8Hzand 9.1Hz),3.54(1H,t,J=7.8Hz),3.35-3.22(4H,m),3.22-3.08(2H,m),2.25-1.70(2H,m),2.05-1.95(4H,m),0.95(3H,t,J=7.2Hz);
TLC:Rf0.46(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(34)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2S-羧基全氢化吲哚-1-基磺酰基)苯基酯·盐酸盐
NMR(CDCl3):δ7.89(2H,d,J=8.8Hz),7.71(2H,d,J=8.6Hz),7.51(2H,d,J=8.6Hz),7.17(2H,d,J=8.8Hz),4.20(1H,t,J=8.6Hz),4.0-3.5(6H,m),2.5-2.2(4H,m),2.4-1.0(13H,m),0.99(3H,t,J=7.4Hz);
TLC:Rf0.60(氯仿∶甲醇∶乙酸=40∶2∶1)。实施例2(35)
NMR(DMSO-d6):δ7.79(1H,d-like),7.67(1H,dd,J=2.2 and 8.4Hz),7.35-6.95(7H,m),6.71-6.67(2H,m),4.97(1H,dd,J=4.4 and 10.7Hz),3.71(1H,t,J=7.6Hz),3.35-2.96(6H,m),2.14-1.68(2H,m),2.00-1.94(4H,m),1.91(3H,s),0.87(3H,t,J=7.2Hz);TLC:Rf0.45(氯仿∶甲醇∶水=8∶2∶0.2)。实施例2(36)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2RS-(N-羧基甲基氨基甲酰基)二氢吲哚-1-基磺酰基)苯基酯
NMR(CDCl3):δ7.70(1H,d,J=7.8Hz),7.58(2H,d,J=8.8Hz),7.28-7.02(8H,m),6.66(2H,d,J=8.8Hz),4.64(1H,dd,J=10.4,2.8Hz),4.02(2H,d,J=3.0Hz),3.56(1H,t,J=7.6Hz),3.37-3.05(5H,m),2.81(1H,dd,J=16.0,10.4Hz),2.35-1.74(6H,m),0.95(3H,t,J=7.6Hz);
TLC:Rf0.33(氯仿∶甲醇∶乙酸=40∶2∶1)。实施例2(37)
NMR(CDCl3):δ7.72(2H,d,J=8Hz),7.59(1H,d,J=8Hz),7.27-7.03(7H,m),6.54(2H,d,J=8Hz),6.08(1H,br),4.77-4.69(1H,m),3.55(1H,t,J=8Hz),3.31-3.24(4H,m),3.19-3.15(2H,m),2.20-1.76(2H,m),2.03-1.96(4H,m),0.95(3H,t,J=8Hz);TLC:Rf0.45(氯仿∶甲醇∶水=8∶2∶0.2)。实施例2(38)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2RS-羧基-3,3-二甲基二氢吲哚-1-基磺酰基)苯基酯
NMR(CDCl3):δ7.83(2H,d,J=8.5Hz),7.55(1H,d,J=8.0Hz),7.25-6.93(3H,m),7.17(2H,d,J=8.5Hz),7.09(2H,d,J=8.5Hz),6.53(2H,d,J=8.5Hz),4.36(1H,s),3.54(1H,t,J=8.0Hz),3.35-3.10(4H,m),2.05-1.90(4H,m),2.25-1.70(2H,m),1.31(3H,s),1.04(3H,s),0.94(3H,t,J=7.5Hz);
TLC:Rf0.48(氯仿∶甲醇∶乙酸=40∶2∶1)。实施例2(39)
NMR(CDCl3):δ7.7-7.6(m,1H),7.5-6.9(m,8H),6.5-6.4(m,2H),4.8-4.6(m,1H),3.8-3.5(m,4H),3.4-3.0(m,6H).2.2-1.7(m,6H),1.1-0.9(m,3H);TLC:Rf0.65(氯仿∶甲醇:=3∶1)。实施例2(40)
NMR(CDCl3):δ7.8-6.8(m,11H),4.7-4.5(m,1H),3.8-3.5(m,7H),3.3-3.1(m,1H),3.0-2.8(m,1H),2.7-2.5(m,2H),2.3-2.1(m,4H),2.1-1.8(m,5H),0.97(t,J=7.2Hz,3H);
TLC:Rf0.76(甲醇∶氯仿=1∶3)。实施例2(41)
NMR(CDCl3):δ7.72(1H,d,J=8.0Hz),7.45-6.92(9H,m),6.51(2H,d,J=8.6Hz),4.57(1H,dd,J=2.8,10.6Hz),3.77-3.52(5H,m),3.39-3.17(5H,m),2.88(1H,dd,J=10.6,16.8Hz),2.23-1.78(6H,m),1.92(3H,s),0.96(3H,t,J=7.4Hz);
TLC:Rf0.43(氯仿∶甲醇∶乙酸=25∶5∶1)。实施例2(42)
NMR(CDCl3):δ7.78-7.62(3H,m),7.35(1H,s),7.18(2H,d,J=9Hz),7.00(1H,d,J=8Hz),6.95(1H,s),6.52(2H,d,J=9Hz),4.00(3H,s),3.91(3H,s),3.70-3.10(1H,brs),3.57(1H,t,J=7Hz),3.35-3.18(4H,m),2.25-1.75(9H,m),0.96(3H,t,J=7Hz).TLC:Rf0.19(乙酸乙酯∶己烷∶乙酸=5∶10∶0.5)。实施例2(43)
2RS-(4-吡咯烷-1-基)苯基)丁酸4-(2RS-(2-氨基乙基)氧羰基二氢吲哚-1-基磺酰基)-2-甲基苯基酯·2盐酸盐
NMR(DMSO-d6):δ8.30(2H,brs),7.76(1H,s),7.66(1H,d,J=8.0Hz),7.37(1H,d,J=8.0Hz),7.23-7.00(6H,m),6.70(2H,d,J=8.0Hz),5.08(1H,dd,J=6.2,9.4Hz),4.37-4.32(2H,m),3.69(1H,t,J=7.2Hz),3.35-3.07(8H,m),2.14-1.69(9H,m),0.89(3H,t,J=7.2Hz);
TLC:Rf0.46(氯仿∶甲醇∶乙酸=25∶5∶1)。实施例2(44)
NMR(CDCl3):δ8.13(1H,d,J=9Hz),7.90-7.78(2H,m),7.60(1H,d,J=9Hz),7.46(1H,td,J=8.1Hz),7.39(1H,s),7.35-7.25(1H,m),7.21(2H,d,J=9Hz),6.75-6.50(2H,m),3.59(1H,t,J=7Hz),3.38-3.23(4H,m),3.23-2.90(1H,brs),2.25-1.75(6H,m),0.96(3H,t,J=7Hz);TLC:Rf0.20(乙酸乙酯∶己烷∶乙酸=5∶10∶0.5)。实施例2(45)2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2RS-羧基-5,6-二甲氧基二氢吲哚-1-基磺酰基)-2-甲基苯基酯
NMR(CDCl3+CD3OD):δ7.6-7.4(m,2H),7.26(s,1H),7.19(d,J=8.7Hz,2H),6.96(dd,J=1.2,8.4Hz,1H),6.58(s,1H),6.54(d,J=8.7Hz,2H),4.7-4.6(m,1H),3.91(s,3H),3.79(s,3H),3.58(t,J=7.7Hz,1H),3.4-3.2(m,4H),3.1-2.9(m,2H),2.3-1.8(m,6H),1.94(s,3H),0.96(t,J=7.4Hz,3H);TLC:Rf0.45(氯仿∶甲醇=4∶1)。实施例2(46)
NMR(CD3OD):δ7.85-7.63(3H,m),7.03(2H,d,J=8Hz),6.93(1H,d,J=8Hz),6.87-6.70(3H,m),6.53(2H,d,J=8Hz),3.56(1H,1,J=7Hz),3.30-3.10(4H,m),2.20-1.90(5H,m),1.90-1.65(1H,m),1.84(3H,s),0.91(3H,t,J=7Hz);
TLC:Rf0.23(乙酸乙酯∶己烷∶乙酸=10∶10∶0.5)。实施例2(47)
NMR(CDCl3):δ7.61-7.51(3H,m),7.23-7.10(3H,m),7.10-6.95(3H,m),6.51(2H,d,J=8.0Hz),4.75(1H,dd,J=5.6,10.2Hz),4.38-4.33(2H,m),3.75-3.51(7H,m),3.30-3.22(5H,m),3.09(1H,dd,J=5.6,16.6Hz),2.23-1.78(6H,m),1.96(3H,s),0.96(3H,t,J=7.4Hz);
TLC:Rf0.65(氯仿∶甲醇=15∶1)。实施例2(48)
2RS-(4-吡咯烷-1-基)苯基)丁酸4-(2RS-羟基甲基二氢吲哚-1-基磺酰基)-2-甲基苯基酯·盐酸盐
NMR(DMSO-d6):δ7.60(1H,s-like),7.51-7.40(2H,m),7.22-6.97(6H,m), 6.51(2H,d,J=8Hz),4.40-4.24(1H,m),3.68-3.37(3H,m),3.65(1H,t,J=7Hz),3.23-3.17(4H,m),2.87-2.69(2H,m),2.19-1.62(each 1H,m),1.99-1.93(4H,m),1.86(3H,s),0.87(3H,t,J=7Hz);
TLC:Rf0.29(己烷∶乙酸乙酯=2∶1)。实施例2(49)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2RS-羧基-5-羟基二氢吲哚-1-基磺酰基)-2-甲基苯基酯
NMR(CDCl3+3 drops of CD3OD):δ7.5-7.4(m,3H),7.2-7.1(m,3H),7.0-6.9(m,1H),6.5-6.4(m,3H),4.7-4.6(m,1H),3.58(t,J=7.8Hz,1H),3.4-3.2(m,4H),3.1-2.9(m,2H),2.2-1.8(m,6H),1.94(s,3H),0.97(t,J=7.2Hz,3H);
TLC:Rf0.2(氯仿∶甲醇=6∶1)。实施例2(50)
2RS-(4-吡咯烷-1-基)苯基)丁酸4-(2RS-(2-(哌嗪-1-基)乙基)氧羰基二氢吲哚-1-基磺酰基)-2-甲基苯基酯·3盐酸盐
NMR(CD3OD):δ7.72-7.64(3H,m),7.57-7.49(4H,m),7.26-7.00(4H,m),5.12(1H,dd,J=6.0,8.8Hz),4.63-4.59(2H,m),3.90(1H,t,J=8.0Hz),3.77-3.59(14H,m),3.23-3.20(2H,m),2.32-1.83(6H,m),1.96(3H,s),0.97(3H,t,J=7.4Hz);
TLC:Rf0.41(氯仿∶甲醇∶乙酸=25∶5∶1)。实施例2(51)
NMR(CD3OD):δ7.75(2H,d,J=8.6Hz),7.60(1H,d,J=8.0Hz),7.58-7.48(4H,m),7.21(1H,dd,J=6.5Hz,1.5Hz),7.12(2H,d,J=8.6Hz),7.09-7.01(2H,m),4.68(1H,dd,J=9.0Hz,5.0Hz),3.87(1H,t,J=7.0Hz),3.77-3.70(4H,m),3.03-2.98(2H,m),2.28-2.23(4H,m),2.20-2.13(0.5H,m),1.97-1.81(1.5H,m),0.90(3H,t,J=7.0Hz);TLC:Rf0.49(己烷∶乙酸乙酯∶乙酸=8∶8∶1)。实施例2(52)
NMR(CDCl3):δ7.74(2H,d,J=8.8Hz),7.58(1H,d,J=8.0Hz),7.29-7.02(7H,m),6.87(2H,d,J=8.8Hz),4.90(1H,brs),4.73(1H,dd,J=9.2,5.8Hz),3.80(3H,s),3.60(1H,t,J=7.8Hz),3.20-3.15(2H,m),2.23-2.05(1H,m),1.94-1.76(1H,m).0.951(3H,t,J=7.6Hz);
TLC:Rf0.36(氯仿∶甲醇∶乙酸=40∶2∶1)。实施例2(53)
NMR(DMSO-d6):δ7.82(1H,d-like),7.72(1H,d-like),7.38(2H,d,J=8.6Hz),7.32(1H,d,J=7.8Hz),7.23-7.10(3H,m),7.03-6.96(3H,m),4.73(1H,dd,J=5.2 and 9.3Hz),3.88(1H,t,J=7.6Hz),3.82(3H,s),3.14-3.05(2H,m),2.25-2.10 and 1.96-1.79(each 1H,m),0.96(3H,t,J=7.2Hz);
TLC:Rf0.41(氯仿∶甲醇∶水=8∶2∶0.2)。实施例2(54)
NMR(CDCl3):δ7.79-7.64(3H,m),7.36(1H,s),7.23(2H,d,J=9Hz),7.01(1H,d,J=9Hz),6.96(1H,s),6.88(2H,d,J=9Hz),4.00(3H,s),3.91(3H,s),3.80(3H,s),3.64(1H,t,J=7Hz),2.27-2.03(1H,m),2.00-1.80(1H,m),1.96(3H,s),0.96(3H,t,J=7Hz);
TLC:Rf0.10(乙酸乙酯∶己烷∶乙酸=5∶10∶0.5)。实施例2(55)
2RS-(4-甲氧基苯基)丁酸4-(2-羧基吲哚-1-基磺酰基)-2-甲基苯基酯
NMR(CDCl3):δ8.14(1H,d,J=9Hz),7.90-7.78(2H,m),7.60(1H,d,J=9Hz),7.52-7.40(1H,m),7.38(1H,s),7.35-7.20(3H,m),7.03(1H,d,J=9Hz),6.87(2H,d,J=9Hz),3.79(3H,s),3.64(1H,t,J=7Hz),2.28-2.05(1H,m),2.00-1.79(1H,m),1.96(3H,s),0.96(3H,t,J=7Hz);
TLC:Rf0.26(乙酸乙酯∶己烷∶乙酸=5∶10∶0.5)。实施例2(56)
2RS-(4-甲氧基苯基)丁酸4-(2-羧基-5-羟基吲哚-1-基磺酰基)-2-甲基苯基酯
NMR(CDCl3):δ7.94(1H,d,J=9Hz),7.80-7.69(2H,m),7.26(2H,d,J=9Hz),7.17(1H,s),6.99(1H,d,J=9Hz),6.96(1H,dd,J=9,2Hz),6.87(2H,d,J=9Hz),6.87(1H,d,J=2Hz),3.80-3.40(1H,brs),3.79(3H,s),3.64(1H,t,J=7Hz),2.26-2.05(1H,m),2.00-1.75(1H,m),1.93(3H,s),0.95(3H,t,J=7Hz);
TLC:Rf0.16(乙酸乙酯∶己烷∶乙酸=10∶10∶0.5)。实施例2(57)
NMR(DMSO-d6):δ7.61(1H,s-like),7.50-7.40(2H,m),7.28(2H,d,J=8Hz),7.21-6.96(4H,m),6.92(2H,d,J=8Hz),5.02(1H,t-like),4.32(1H,m)3.78(1H,t,J=7Hz),3.74(3H,s),3.67-3.57 and 3.47-3.37(each 1H,m),2.83-2.70(2H,m),2.10-1.95 and 1.86-1.65(each 1H,m),1.85(3H,s),0.88(3H,tJ=7Hz);TLC:Rf0.21(己烷∶乙酸乙酯=2∶1)。实施例2(58)
NMR(DMSO-d6):δ8.25(3H,brs),7.78-7.65(2H,m),7.39-7.00(5H,m),7.28(2H,d,J=8.8Hz),6.91(2H,d,J=8.8Hz),5.08(1H,dd,J=5.8,10.0Hz),4.34(2H,t,J=5.2Hz),3.83-3.74(1H,m),3.74(3H,s),3.30-3.09(4H,m),2.17-1.75(2H,m),1.90(3H,s),0.89(3H,t,J=7.2Hz);
TLC:Rf0.53(氯仿∶甲醇∶乙酸=25∶5∶1)。实施例2(59)
NMR(CD3OD)∶δ7.68-7.63(2H,m),7.51(1H,d,J=7.8Hz),7.27(2H,d,J=8.4Hz),7.22-7.02(4H,m),6.90(2H,d,J=8.4Hz),5.10(1H,t,J=7.2Hz),4.60(2H,brs),3.78(3H,s),3.75-3.19(13H,m),2.23-1.78(2H,m),1.89(3H,s),0.95(3H,t,J=7.4Hz):
TLC:Rf0.16(氯仿∶甲醇=10∶1)。实施例2(60)
2RS-(4-甲氧基苯基)丁酸4-(2RS-(2-(2-羟基乙氧基)乙基)氧羰基二氢吲哚-1-基磺酰基)-2-甲基苯基酯
NMR(CDCl3):δ7.62-7.51(3H,m),7.26(2H,d,J=8.4Hz),7.28-6.96(4H,m),6.87(2H,d,J=8.4Hz),4.76(1H,dd,J=5.4,10.6Hz),4.38-4.34(2H,m),3.80(3H,s),3.75-3.55(7H,m),3.31-3.04(2H,m),2.26-1.80(2H,m),1.93(3H,s),0.97(3H,t,J=7.4Hz);
TLC:Rf0.11(己烷∶乙酸乙酯=1∶1)。实施例2(61)
NMR(CDCl3):δ7.75(2H,d,J=8.8Hz),7.57(1H,d,J=7.8Hz),7.30-6.79(9H,m),4.73(1H,t,J=8.0Hz),3.80(3H,s),3.62(1H,t,J=7.8Hz),3.20-3.17(2H,m),2.28-2.05(1H,m),1.99-1.77(1H,m),0.96(3H,t,J=7.4Hz);
TLC:Rf0.66(氯仿∶甲醇∶乙酸=40∶2∶1)。实施例2(62)
2RS-(2-甲氧基苯基)丁酸4-(2RS-羧基二氢吲哚-1-基磺酰基)苯基酯
NMR(CDCl3):δ7.75(2H,d,J=8.8Hz),7.58(1H,d,J=8.0Hz),7.25(2H,d,J=8.8Hz),7.31-6.87(7H,m),4.74(1H,t,J=8.0Hz),4.04(1H,t,J=7.2Hz),3.84(3H,s),3.18(2H,brd,J=7.2Hz),2.22-2.05(1H,m),1.96-1.74(1H,m),0.95(3H,t,J=7.6Hz);
TLC:Rf0.48(氯仿∶甲醇∶乙酸=40∶2∶1)。
实施例2(63)
NMR(DMSO-d6):δ13.19(1H,br),7.79(1H,d,J=2.0Hz),7.68(1H,dd,J=2.0 and 8.5Hz),7.36-6.92(9H,m),4.96(1H,dd,J=4.2 and 10.9Hz).4.08(1H,t,J=7.6Hz),3.80(3H,s),3.39-2.96(2H,m),2.19-1.69(2H,m),1.95(3H,s),0.87(3H,t,J=7.2Hz);
TLC:Rf0.39(氯仿∶甲醇∶水=8∶2∶0.2)。实施例2(64)
2RS-(3,4-二甲氧基苯基)丁酸4-(2RS-羧基二氢吲哚-1-基磺酰基)苯基酯
NMR(CDCl3):δ7.76(2H,d,J=8.8Hz),7.57(1H,d,J=8.0Hz),7.25-7.02(5H,m),6.86-6.85(3H,m),4.73(1H,t,J=8.0Hz),3.87(6H,s),3.59(1H,t,J=7.8Hz),3.21-3.17(2H,brd),2.24-2.05(1H,m),1.97-1.76(1H,m),0.97(3H,t,J=7.6Hz);
TLC:Rf0.50(氯仿∶甲醇∶乙酸=40∶2∶1)。实施例2(65)
NMR(DMSO-d6):δ13.14(1H,br),7.80(1H,s),7.68(1H,d-like),7.35-7.11(4H,m),7.02-6.86(4H,m),4.97(1H,dd,J=4.2 and 10.5Hz),3.79(1H,t,J=7.4Hz),3.74(6H,s),3.39-2.97(2H,m),2.16-1.98 and 1.95-1.72(each 1H,m),1.91(3H,s),0.89(3H,t,J=7.2Hz);TLC:Rf0.39(氯仿∶甲醇∶水=8∶2∶0.2)。实施例2(66)
NMR(CDCl3):δ7.74(2H,d.J=8.8Hz),7.58(1H,d,J=8.0Hz),7.24-7.02(9H,m),4.74(1H,t,J=8.6Hz),3.62(1H,t,J=7.8Hz),3.18(2H,brd),2.34(3H,s),2.27-2.05(1H,m),1.97-1.75(1H,m),0.96(3H,t,J=7.4Hz);
TLC:Rf0.43(氯仿∶甲醇∶乙酸=40∶2∶1)。实施例(67)
2RS-(4-甲基苯基)丁酸4-(2RS-羧基二氢吲哚-1-基磺酰基)-2-甲基苯基酯
NMR(DMSO-d6):δ13.08(1H,br),7.73(1H,d,J=2.0Hz),7.61(1H,dd,J=2.0 and 8.6Hz),7.28-6.87(9H,m),4.90(1H,dd,J=4.0 and 10.8Hz),3.75(1H,t,J=7.6Hz),3.32-2.90(2H,m),2.22(3H,s),2.13-1.91 and 1.86-1.64(each1H,m),1.82(3H,s),0.80(3H,t,J=7.2Hz);
TLC:Rf0.43(氯仿∶甲醇∶水=8∶2∶0.2)。实施例2(68)
NMR(CDCl3):δ7.78-7.64(3H,m),7.35(1H,s),7.23(2H,d,J=9Hz),7.15(2H,d,J=9Hz),7.00(1H,d,J=9Hz),6.95(1H,s),4.00(3H,s),3.91(3H,s),3.85-3.30(1H,br),3.65(1H,t,J=7Hz),2.33(3H,s),2.30-2.10(1H,m),2.00-1.80(1H,m),1.96(3H,s),0.96(3H,t,J=7Hz),TLC:Rf0.23(乙酸乙酯∶己烷∶乙酸=5∶10∶0.5)。实施例2(69)
NMR(CDCl3):δ8.14(1H,d,J=9Hz),7.90-7.78(2H,m),7.60(1H,d,J=9Hz),7.52-7.41(1H,m),7.39(1H,s),7.35-7.10(5H,m),7.03(1H,d,J=9Hz),4.00-3.60(1H,br),3.66(1H,t,J=7Hz),2.33(3H,s),2.30-2.07(1H,m),2.00-1.75(1H,m),1.97(3H,s),0.96(3H,t,J=7Hz);
TLC:Rf0.28(乙酸乙酯∶己烷∶乙酸=5∶10∶0.5)。实施例2(70)
NMR(CDCl3)∶δ7.95(1H,d,J=9Hz),7.81-7.69(2H,m),7.22(2H,d,J=8Hz),7.20(1H,s),7.15(2H,d,J=8Hz),7.00(1H,d,J=8Hz),6.97(1H,dd,J=9,2Hz),6.89(1H,d,J=2Hz),3.80-3.30(1H,br),3.66(1H,t,J=7Hz),2.33(3H,s),2.28-2.10(1H,m),2.00-1.80(1H,m),1.94(3H,s),0.96(3H,t,J=7Hz);
TLC:Rf0.24(乙酸乙酯∶己烷∶乙酸=10∶10∶0.5)。实施例2(71)
NMR(CDCl3+CD3OD):δ7.8-7.5(m,4H),7.3-7.0(m,7H),5.0-4.8(m,1H),4.6-4.4(m,2H),3.67(t,J=9.2Hz,1H),3.4-3.3(m,2H),3.3-3.2(m,2H),2.34(S,3H),2.3-1.8(m,2H),1.95(s,3H),0.97(1,J=7.0Hz,3H);
TLC:Rf0.5(氯仿∶甲醇=4∶1)。实施例2(72)
NMR(DMSO-d6):δ7.61(1H,s-like),7.51-7.40(2H,m),7.27-6.96(8H,m),5.04(1H,t-like),4.34(1H,m),3.81(1H,t,J=7Hz),3.67-3.57 and 3.48-3.39(each 1H,m),2.83-2.68(2H,m),2.29(3H,s),2.20-1.97 and 1.88-1.67(each1H,m),1.86(3H,s),0.87(3H,t,J=7Hz);
TLC:Rf0.30(己烷∶乙酸乙酯=2∶1)。实施例2(73)
2RS-(4-甲基苯基)丁酸4-(2RS-(2-(2-羟基乙氧基)乙基)氧羰基二氢吲哚-1-基磺酰基)-2-甲基苯基酯
NMR(CDCl3)δ7.7-7.5(m,3H),7.3-6.9(m,8H),4.9-4.7(m,1H),4.4-4.3(m,2H),3.8-3 5(m,7H),3.4-3.0(m,2H),2.34(s,3H),2.4-1.8(m,2H),1.93(s,3H),0.97(t,J=7.2Hz,3H);
TLC:Rf0.25(己烷∶乙酸乙酯=1∶1)。实施例2(74)
2RS-(4-甲基苯基)丁酸4-(2RS-(2-(哌嗪-4-基)乙基)氧羰基二氢吲哚-1-基磺酰基)-2-甲基苯基酯·盐酸盐
NMR(CDCl3)δ7.7-7.5(m,3H),7.5-7.4(m,1H),7.3-6.9(m,7H),5.2-5.0(m,1H),4.7-4.5(m,2H),4.0-3.5(m,11H),3.4-3.0(m,2H),2.30(s,3H),2.4-2.0(m,1H),1.88(s,3H),2.0-1.8(m,1H),0.93(t,J=7.2Hz,3H);
TLC:Rf0.3(氯仿∶甲醇=2∶1)。实施例2(75)
NMR(CDCl3):δ7.7-7.5(3H,m),7.3-7.1(3H,m),7.1-6.9(3H,m),6.80(2H,d,J=8.4Hz),4.8-4.7(1H,m),3.7-3.3(1H,m),3.3-3.1(2H,m),2.3-2.0(1H,m),2.0-1.8(1H,m),1.91(3H,s),0.96(3H,t,J=7.4Hz);
TLC:Rf0.42(氯仿∶甲醇∶水=8∶2∶0.2)。实施例2(76)
2RS-(4-氨基苯基)丁酸4-(2RS-羧基二氢吲哚-1-基磺酰基)苯基酯NMR(DMSO-d6):δ7.83(2H,d,J=8.4Hz),7.30(1H,d,J=8.2Hz),7.12(2H,d,J=8.4Hz),6.97(2H,d,J=8.4Hz),7.17-6.90(3H,m),6.53(2H,d,J=8.4Hz),4.80-4.73(1H,m),3.54(1H,t,J=7.6Hz),3.25-2.93(2H,m),2.09-1.90(1H,m),1.78-1.60(1H,m),0.86(3H,t,J=7.2Hz);
TLC:Rf0.20(氯仿∶甲醇∶乙酸=40∶2∶1)。实施例2(77)
NMR(CDCl3):δ7.85(2H,d,J=8.8Hz),7.21(2H,d,J=8.8Hz),7.17(2H,d.J=8.8Hz),6.57(2H,d,J=8.8Hz),4.83(1H,dd,J=7.0 and 3.4Hz),4.67(1H,d,J=9.0Hz),4.40(1H,d,J=9.0Hz),3.59(1H,t,J=7.6Hz),3.40-3.18(5H,m),3.01(1H,dd,J=11.4 and 7.0Hz),2.30-2.05 and 2.05-1.75(each 1H,m),2.10-1.95(4H,m),0.98(3H,t,J=7.6Hz);
TLC:Rf0.36(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(78)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(4-羧基哌啶-1-基磺酰基)苯基酯·盐酸盐
NMR(CDCl3):δ7.71(2H,d,J=8.8Hz),7.21(2H,d,J=8.8Hz),7.17(2H,d,J=8.8Hz),6.55(2H,d,J=8.8Hz),3.72-3.54(2H,m),3.59(1H,t,J=7.6Hz),3.36-3.20(4H,m),2.45(2H,t-like)2.38-1.70(7H,m),2.08-1.94(4H,m),0.98(3H,t,J=7.4Hz);
TLC:Rf0.34(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(79)
NMR(CDCl3):δ7.75(2H,d,J=8.8Hz),7.21(2H,d,J=8.8Hz),7.08(2H,d,J=8.8Hz),6.55(2H,d,J=8.8Hz),4.8-4.7(1H,m),3.8-3.7(1H,m),3.58(1H,t,J=7.5Hz),3.4-3.1(5H,m),2.3-1.2(12H,m),0.97(3H,t,J=7.4Hz);
TLC:Rf0.48(乙酸∶甲醇∶氯仿∶1∶2∶50)。实施例2(80)
NMR(CDCl3):δ7.75(2H,d,J=8.4Hz),7.7-7.3(4H,m),7.19(2H,d,J=8.4Hz),4.0-3.4(8H,m),2.7-2.5(2H,m),2.5-2.1(5H,m),2.1-1.3(5H,m),1.00(3H,t,J=7.4Hz);
TLC:Rf0.32(乙酸∶甲醇∶氯仿=1∶2∶100)。实施例2(81)
2RS-(4-(吡咯烷-1-基)苯基丁酸4-(4S-羧基全氢化噻唑-3-基磺酰基)-2-甲基苯基酯
NMR(CDCl3+CD3OD):δ7.69(1H,s),7.66(1H,d,J=8.0Hz),7.21(2H,d,J=8.6Hz),7.07(1H,d,J=8.0Hz),6.55(2H,d,J=8.6Hz),4.71(1H,dd,J=7.2,3.2Hz),4.63(1H,d,J=9.8Hz),4.45(1H,d,J=9.8Hz),3.61(1H,t,J=7.7Hz),3.4-3.2(5H,m),2.84(1H,dd,J=11.2,7.2Hz),2.3-2.1(1H,m),2.1-1.8(4H,br),2.02(3H,s),0.98(3H,d,J=7.3Hz);
TLC:Rf0.55(氯仿∶甲醇∶乙酸=25∶5:1)。实施例2(82)
NMR(CD3OD):δ7.65-7.54(2H,m),7.20(2H,d,J=8Hz),7.15(1H,d,J=8Hz),6.58(2H,d,J=8Hz),4.03-3.80(3H,m),3.71-3.38(3H,m),3.37-3.15(4H.m),2.50-1.78(11H,m),0.97(3H,t,J=7Hz);
TLC∶Rf0.25(甲醇∶氯仿=3∶17)。实施例2(83)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(1S-氧代-4S-羧基全氢化噻唑-3-基磺酰基)-2-甲基苯基酯·盐酸盐
NMR(CD3OD):δ7.90-7.75(2H,m),7.61(4H,s),7.18(1H,d,J=8.5Hz),5.25(1H,dd,J=8.5,2.0Hz),5.19(1H,d,J=12.0Hz),4.13(1H,d,J=12.0Hz),3.98(1H,t,J=7.5Hz),3.85-3.70(4H,m),3.41(1H,dd,J=14.5,2.0Hz),3.03(1H,dd,J=14.5,8.5Hz),2.35-2.20(4H,m),2.40-1.80(2H,m),2.04(3H,s),1.00(3H,t,J=7.5Hz);
TLC:Rf0.18(氯仿∶甲醇∶乙酸=40∶10∶1)。实施例2(84)
NMR(CDCl3):δ7.75-7.65(2H,m),7.48(4H,s),7.10(1H,d,J=8.5Hz),5.06(1H,dd,J=8.5,4.0Hz),4.68(1H,d,J=11.0Hz),4.26(1H,d,J=11.0Hz),3.78(1H,t,J=7.5Hz),3.70-3.55(4H,m),3.55-3.35(2H,m),2.40-2.25(4H,m),2.40-1.80(2H,m),2.07(3H,s),1.01(3H,t,J=7.5Hz);
TLC:Rf0.14(氯仿∶甲醇∶乙酸=40∶10∶1)。实施例2(85)
NMR(CD3OD):δ7.75-7.47(6H,m),7.23(1H,d,J=8.8Hz),4.03-3.79(5H,m),3.79-3.57(6H,m),3.40-3.14(4H,m),2.77(2H,t-like,J=13.8Hz),2.38-2.15(5H,m),2.06(3H,s),2.15-1.84(1H,m),1.00(3H,t,J=7.4Hz);
TLC:Rf0.21(己烷∶乙酸乙酯=1∶1)。实施例2(86)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(4-羧基甲基哌嗪-1-基磺酰基)-2-甲基苯基酯·2盐酸盐
NMR(CD3OD):δ7.79-7.53(6H,m),7.24(1H,d,J=8.0Hz),4.14(2H,s),4.00(1H,t,J=7.8Hz),3.87-3.70(4H,m),3.52(8H,brs),2.44-2.15(5H,m),2.07(3H,s),2.15-1.82(1H,m),1.00(3H,t,J=7.2Hz);
TLC:Rf0.63(氯仿∶甲醇∶乙酸=15∶2∶1)。实施例2(87)
2RS-(4-硝基苯基)丁酸4-(4S-羧基全氢化噻唑-3-基磺酰基)苯基酯
NMR(CDCl3):δ8.27(2H,d,J=8.8Hz),7.94(2H,d,J=8.8Hz),7.68(2H,d,J=8.8Hz),7.26(2H,d,J=8.8Hz),4.86(1H,dd,J=3.6 and 7.4Hz),4.73(1H,d,J=8.0Hz),4.41(1H,d,J=8.0Hz),4.03(1H,t,J=7.6Hz),3.17(1H,dd,J=11.5and 3.6Hz),2.93(1H,dd,J=11.5 and 7.4Hz),2.40-2.15 and 2.10-1.85(each1H,m),1.00(3H,t,J=7.2Hz);
TLC:Rf0.38(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(88)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-羧基甲基-N-2-甲氧基乙基氨磺酰)苯基酯·三氟乙酸盐
NMR(CD3OD):δ7.85(2H,d,J=8.6Hz),7.41(2H,d,J=8.6Hz),7.17(2H,d,J=8.6Hz),7.11(2H,d,J=8.6Hz),4.10(2H,s),3.77(1H,t,J=6.0Hz),3.46(8H,m),3.20(3H,s),2.20(1H,m),2.15(4H,m),1.90(1H,m),0.97(3H,t,J=7.0Hz);
TLC:Rf0.32(氯仿∶甲醇∶水=9∶1∶0.1)。实施例2(89)
NMR(CD3OD):δ7.87(2H,d,J=8.6Hz),7.36(2H,brd,J=8.6Hz),7.14(2H,d,J=8.6Hz),7.00(2H,brd,J=8.6Hz),4.21(1H,t,J=6.0Hz),3.74(1H,m),3.48(4H,m),2.72(2H,d,J=6.2Hz),2.18(1H,m),2.13(4H,m),1.87(1H,m),0.97(3H,t,J=7.4Hz);TLC:Rf0.26(氯仿∶甲醇∶水=9∶1∶0.1)。实施例2(90)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(1-羧基环丁烷)氨磺酰)苯基酯·盐酸盐
NMR(CDCl3):δ7.81(2H,d,J=8.8Hz),7.15(2H,d,J=8.8Hz),7.05(2H,d,J=8.8Hz),6.55(2H,d,J=8.8Hz),5.66(1H,s),3.58(1H,t,J=7.6Hz),3.36-3.18(4H,t-like),2.30-2.00 and 2.00-1.75(each 1H,m),2.06-1.96(4H,m),1.56-1.35(4H,m),0.97(3H,t,J=7.4Hz);
TLC:Rf0.38(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(91)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-1RS-羧基-2-苯基乙基氨磺酰)苯基酯·盐酸盐
NMR(DMSO-d6):δ8.38(1H,d,J=10Hz),7.55(2H,d,J=9Hz),7.30-7.00(9H,m),6.76(2H,d,J=9Hz),3.95-3.79(1H,m),3.71(1H,t,J=7Hz),3.40-3.20(4H,m),2.94(1H,dd,J=15Hz,5Hz),2.70(1H,dd,J=15Hz,8Hz),2.20-1.90(5H,m),1.90-1.65(1H,m),0.90(3H,t,J=7Hz);
TLC:Rf0.19(乙酸乙酯∶己烷∶乙酸=5∶5∶0.1)。实施例2(92)
NMR(DMSO-d6):δ8.05(1H,d,J=9Hz),7.78(2H,d,J=8Hz),7.25(2H,d,J=8Hz),7.17(2H,d,J=8Hz),6.86-6.70(2H,m),3.73(1H,t,J=7Hz),3.50(1Hdd,J=9Hz,6Hz),3.38-3.20(4H,m),2.20-1.68(7H,m),0.88(3H,t,J=7Hz),0.80(3H,d,J=7Hz),0.76(3H,d,J=7Hz);
TLC:Rf0.34(乙酸乙酯)实施例2(93)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(1S-羧基-2-羧基甲硫基乙基)氨磺酰)苯基酯·盐酸盐
NMR(CD3OD):δ7.89(2H,d,J=8.8Hz),7.63(2H,d,J=15.0Hz),7.62(2H,d,J=15.0Hz),7.18(2H,d,J=8.8Hz),4.08(1H,dd,J=5.9,7.5Hz),3.91(1H,t,J=7.5Hz),3.82-3.70(4H,m),3.19(2H,s),3.00(1H,dd,J=5.9,14.0Hz),2.84(1H,dd,J=7.5,14.0Hz),2.40-2.12(5H,m),2.02-1.80(1H,m),0.98(3H,t,J=7.0Hz);TLC:Rf0.20(氯仿∶甲醇∶水=7∶3∶0.3)。实施例2(94)
NMR(DMSO-d6):δ8.88(1H,d,J=9.0Hz),7.77(2H,d,J=8.8Hz),7.40(1H,dd,J=1.2,5.0Hz),7.24(2H,d,J=8.4Hz),7.14(2H,d,J=8.8Hz),7.00-6.91(1H,m),6.88(1H,dd,J=3.7,5.0Hz),6.85-6.72(2H,m),5.16(1H,d,J=9.0Hz),3.71(1H,t,J=7.2Hz),3.40-3.20(4H,m),2.20-1.90(5H,m),1.88-1.70(1H,m),0.89(3H,t,J=7.2Hz);
TLC:Rf0.27(氯仿∶甲醇∶水=4∶1∶0.1)。实施例2(95)
NMR(DMSO-d6):δ8.78(1H,d,J=9.0Hz),7.75(2H,d,J=8.6Hz),7.46(1H,m),7.24(2H,d,J=8.2Hz),7.12(2H,d,J=8.6Hz),6.90-6.70(2H,m),6.31-6.24(1H,m),6.19(1H,d,J=2.8Hz),5.02(1H,d,J=9.0Hz),3.71(1H,t,J=7.6Hz),3.40-3.20(4H,m),2.20-1.86(5H,m),1.86-1.68(1H,m),0.89(3H,t,J=7.4Hz);
TLC:Rf0.27(氯仿∶甲醇∶水=4∶1∶0.1)。实施例2(96)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(羧基甲基-N-2-甲氧基乙基氨磺酰)-2-甲基苯基酯
NMR(CDCl3):δ7.64(1H,d,J=2.0Hz),7.61(1H,dd,J=8.0,2.0Hz),7.21(2H,d,J=8.5Hz),7.04(1H,d,J=8.0Hz),6.55(2H,d,J=8.5Hz),4.08(2H,s),3.61(1H,t,J=7.5Hz),3.55(2H,t,J=4.5Hz),3.40(2H,t,J=4.5Hz),3.35-3.20(4H,m),3.29(3H,s),2.30-1.70(2H,m),2.05-1.95(4H,m),2.01(3H,s),0.99(3H,t,J=7.5Hz);TLC∶Rf0.47(氯仿∶甲醇∶乙酸=40∶2∶1)。实施例2(97)
NMR(CDCl3):δ7.70-7.55(2H,m),7.23(2H,d,J=8Hz),7.01(1H,d,J=8Hz),6.55(2H,d,J=8Hz),4.20-3.80(1H,br),3.98(2H,s),3.60(1H,t,J=7Hz),3.35-3.07(6H,m),2.28-1.75(9H,m),1.60-1.38(2H,m),0.98(3H,t,J=7Hz),0.90(3H,t,J=7Hz);
TLC:Rf0.23(氯仿∶甲醇=19∶1)。实施例2(98)
NMR(CD3OD):δ7.80-7.47(6H,m),7.10(1H,d,J=8Hz),3.95(1H,t,J=7Hz),3.90-3.68(5H,m),2.95-2.80(2H,m),2.35-2.20(5H,m),2.10-1.85(1H,m),1.99(3H,s),1.85-1.30(6H,m),0.98(3H,t,J=7Hz);
TLC:Rf0.22(氯仿∶甲醇∶水=8∶2∶0.1)。实施例2(99)
NMR(CDCl3):δ7.80(2H,d,J=8.8Hz),7.25(2H,d,J=8.8Hz),7.04(2H,d,J=8.6Hz),6.90(2H,d,J=8.8Hz),3.80(3H,s),3.73(2H,brs),2.25-2.00(4H,m),0.82(6H,t,J=7.4Hz);
TLC:Rf0.10(己烷∶乙酸乙酯=2∶1)。实施例2(100)
NMR(CDCl3)δ8.25(2H,d,J=9.0Hz),7.82(2H,d,J=9.0Hz),7.55(2H,d,J=9.0Hz),7.11(2H,d,J=9.0Hz),4.13(2H,s),3.53(2H,t,J=5.0Hz),3.41(2H,t,J=5.0Hz),3.27(3H,s),3.06(2H,m),2.67(2H,m),2.26(1H,m),2.04(1H,m);
TLC:Rf0.29(氯仿∶甲醇∶水=9∶1∶0.1)。实施例2(101)
NMR(CD3OD)):δ8.27(2H,d,J=8.8Hz),7.87(2H,d,J=8.8Hz),7.65(2H,d,J=8.8Hz),7.15(2H,d,J=8.8Hz),4.21(1H,t,J=5.8Hz),3.05(2H,m),2.71(4H,m),2.25(1H,m),2.04(1H,m);
TLC:Rf0.17(氯仿∶甲醇∶水=8∶2∶0.2)。实施例2(102)
2RS-苯基丁酸4-(N-羧基甲基氨磺酰)苯基酯
NMR(DMSO-d6):δ8.04(1H,brs),7.82(2H,d,J=8Hz),7.45-7.25(5H,m),7.21(2H,d,J=8Hz),3.86(1H,t,J=7Hz),3.56(2H,s),2.10 and 1.85(each1H,m),0.91(3H,t,J=7Hz);
TLC:Rf0.32(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(103)
2RS-苯基丁酸4-(N-丙基-N-羧基甲基氨磺酰)苯基酯
NMR(DMSO-d6):δ12.65(1H,brs),8.04(1H,brs),7.84(2H,d,J=8Hz),7.45-7.25(5H,m),7.21(2H,d,J=8Hz),3.92(2H,s),3.85(1H,t,J=7Hz),3.10(2H,t),2.10 and 1.86(each 1H,m),1.44(2H,m),0.92(3H,t,J=7Hz),0.77(3H,t,J=7Hz);
TLC:Rf0.54(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(104)
2RS-苯基丁酸4-(N-苄基-N-羧基甲基氨磺酰)苯基酯
NMR(CDCl3):δ7.90-7.79(2H,m),7.43-7.08(12H,m),6.34(1H,br),4.46(2H,s),3.90(2H,s),3.70(1H,t,J=7Hz),2.22(1H,ddq,J=14Hz,7Hz,7Hz),1.92(1H,ddq,J=14Hz,7Hz,7Hz),0.98(3H,t,J=7Hz);
TLC:Rf0.42(二氯甲烷∶甲醇=9∶1)。实施例2(105)
NMR(CDCl3):δ7.77(2H,d,J=8Hz),7.40-7.04(12H,m),5.89(1H,br),3.95(2H,s),3.69(1H,t,J=7Hz),3.53-3.40(2H,m),2.91-2.80(2H,m),2.21(1H,ddq,J=14Hz,7Hz,7Hz),1.90(1H,ddq,J=14Hz,7Hz,7hz),0.97(3H,t,J=7Hz);
TLC:Rf0.41(二氯甲烷∶甲醇=9∶1)。实施例2(106)
2RS-苯基丁酸4-(N-苯基-N-羧基甲基氨磺酰)苯基酯
NMR(CDCl3):δ7.63(2H,d,J=8Hz),7.45-7.04(12H,m),6.20(1H,br),4.40(2H,s),3.70(1H,t,J=7Hz),2.23(1H,ddq,J=14Hz,7Hz,7hz),1.91(1H,ddq,J=14Hz,7Hz,7Hz),0.99(3H,t,J=7Hz);
TLC:Rf0.41(二氯甲烷∶甲醇=9∶1)。实施例2(107)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N,N-二(2-羟基乙基)氨磺酰)-2-甲基苯基酯·盐酸盐
NMR(CD3OD):δ7.78-7.50(6H,m),7.15(1H,d,J=8Hz),3.96(1H,tJ=7Hz),3.95-3.80(8H,m),3.35-3.18(4H,m),2.40-2.15(5H,m),2.10-1.80(1H,m),2.02(3H,s),0.99(3H,t,J=7Hz);
TLC:Rf0.23(己烷∶乙酸乙酯=1∶1)。实施例2(108)
NMR(CDCl3):δ7.70-7.55(2H,m),7.23(2H,d,J=9Hz),7.06(1H,d,J=8Hz),6.55(2H,d,J=9Hz),3.75-3.45(13H,m),3.43-3.23(8H,m),3.05(2H,brs),2.30-1.73(9H,m),0.98(3H,t,J=7Hz);
TLC:Rf0.33(乙酸乙酯)。实施例2(109)
NMR(DMSO-d6):δ9.67(1H,s),7.80(2H,d,J=9Hz),7.20(2H,d,J=9Hz),7.13(2H,d,J=9Hz),6.84-6.57(5H,m),4.78(1H,1,J=3Hz),4.28(1H,dd,J=11Hz,3Hz),4.13-4.00(1H,m),3.68(1H,t,J=7Hz),3.35-3.18(4H,m),2.15-1.88(5H,m),1.88-1.60(1H,m),0.88(3H,t,J=7Hz);
TLC:Rf0.18(氯仿∶甲醇∶乙酸=40∶2∶1)。实施例2(110)
NMR(DMSO-d6+3 drop of CD3OD):δ7.80-7.60(2H,m),7.20(2H,d,J=8.5Hz),7.05(1H,d,J=8.5Hz),6.60(2H,d,J=8.5Hz),4.78(1H,d,J=3.5Hz),3.70(1H,t,J=7.5Hz),3.65-3.35(4H,m),3.30-3.15(4H,m),3.03(1H,t,J=9.0Hz),2.90(1H,dd,J=10.5,3.5Hz),2.20-1.60(2H,m),2.00-1.90(4H,m),1.94(3H,s),0.91(3H,t,J=7.5Hz);
TLC:Rf0.55(氯仿∶甲醇∶水=40∶10∶1)。实施例2(111)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-3-羧基金刚烷-1-基氨磺酰)苯基酯
NMR(CDCl3):δ7.85(2H,d,J=8.8Hz),7.22(2H,d,J=8.8Hz),7.12(2H,d,J=8.8Hz),6.54(2H,d,J=8.8Hz),4.60(1H,s),3.59(1H,t,J=7.4Hz),3.40-3.15(4H,m),2.30-1.40(20H,m),0.98(3H,t,J=7.6Hz);
TLC:Rf0.60(氯仿∶甲醇∶乙酸=40∶2∶1)。实施例2(112)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(1S,4R,3R-羧基二环[2.2.1]庚烷-2S-基)氨磺酰)苯基酯
NMR(CDCl3):δ7.83(2H,d,J=8.6Hz),7.21(2H,d,J=8.6Hz),7.11(2H,d,J=8.6Hz),6.55(2H,d,J=8.6Hz),7.6-7.4(1H,br),3.58(1H,t,J=7.6Hz),3.58(1H,t,J=8.0Hz),3.40-3.20(4H,m),2.64(1H,d,J=8.0Hz),2.42(1H,s),2.30-1.70(4H,m),2.10-1.90(4H,m),1.50-1.30(2H,m),1.30-0.90(3H,m),0.97(3H,t,J=7.3Hz);
TLC:Rf0.33(氯仿∶甲醇∶乙酸=40∶2∶1)。实施例2(113)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-3S-羧基环己烷-1R-基氨磺酰)苯基酯·盐酸盐
NMR(DMSO-d6):δ7.90-7.70(3H,m),7.30-7.10(4H,m),6.70(2H,d,J=9Hz),3.71(1H,t,J=7Hz),3.35-3.15(4H,m),3.09-2.86(1H,m),2.27-1.45(11H,m),1.33-0.95(4H,m),0.89(3H,t,J=7Hz);
TLC:Rf0.36(乙酸乙酯∶己烷∶乙酸=5∶5∶0.1)。实施例2(114)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-2RS-羧基环己烷-1RS-基氨磺酰)苯基酯
NMR(CDCl3):δ7.84(2H,d,J=8.8Hz),7.23-7.08(4H,m),6.55(2H,d,J=8.6Hz),5.70(1H,brs),3.59(1H,t,J=8.0Hz),3.45(1H,brs),3.32-3.26(4H,m),2.65(1H,brs),2.25-1.20(14H,m),0.98(3H,t,J=7.0Hz);
TLC:Rf0.22(己烷∶乙酸乙酯=1∶1)。实施例2(115)
NMR(DMSO-d6):δ10.73(1H,s),7.88(2H,d,J=8.6Hz),7.26(2H,d,J=8.6Hz),6.95(3H,s),4.57(2H,s),4.13-4.00(1H,m),3.79(1H,t,J=7.6Hz),3.40-3.08(2H,m),2.20-1.40(6H,m),0.91(3H,t,J=7.2Hz);
TLC:Rf0.35(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(116)
NMR(DMSO-d6):δ13.4-12.2(1H,br),10.72(1H,s),7.88(2H,d,J=8.6Hz),7.29(2H,d,J=8.6Hz),6.95(3H,s),4.57(2H,s),4.16-4.08(1H,m),3.80(1H,t,J=7.6Hz),3.50-3.05(2H,m),2.05-1.45(6H,m),0.91(3H,t,J=7.2Hz);
TLC:Rf0.36(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(117)
NMR(CD3OD):δ7.90-7.61(5H,m),7.23(2H,d,J=9Hz),4.23-4.17(1H,m),4.06(1H,t,J=8Hz),3.51-3.40(1H,m),3.31-3.20(2H,m),2.87(3H,s),2.38-2.24(1H,m),2.06-1.86(3H,m),1.76-1.64(1H,m),1.01(3H,t,J=7Hz);
TLC:Rf0.21(氯仿∶甲醇∶水=8∶2∶0.2)。实施例2(118)
NMR(DMSO-d6):δ12.74(1H,br),11.58(1H,br),9.20(1H,t,J=5Hz),8.08-7.70(6H,m),7.63-7.42(6H,m),7.29(2H,d,J=9Hz),7.17-7.10(1H,m),4.46(2H,s),3.89(2H,d,J=6Hz);
TLC:Rf0.28(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(119)
NMR(DMSO-d6):δ12.67(1H,b r),11.63(1H,br),9.24(1H,t-like),7.93-7.71(7H,m),7.54-7.43(5H,m),7.36-7.29(2H,m),7.18-7.10(1H,m),4.15(2H,s),3.90(2H,d,J=6Hz);
TLC:Rf0.31(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(120)
2RS-(1,3-苯并二氧戊环-5-基)丁酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
NMR(DMSO-d6):δ12.73(1H,br),11.62(1H,br),9.22(1H,t,J=6Hz),7.82-7.71(3H,m),7.53-7.42(2H,m),7.26-7.10(3H,m),6.94-6.79(3H,m),6.01(2H,s),3.89(2H,d,J=5Hz),3.75(1H,t,J=8Hz),2.16-1.95 and 1.86-1.64(each 1H,m),0.86(3H,t,J=7Hz);
TLC:Rf0.68(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(121)
NMR(DMSO-d6):δ9.4-9.2(1H,br),7.9-7.7(3H,m),7.6-7.4(3H,m),7.3-7.0(5H,m),4.19(1H,t,J=7Hz),3.90(2H,d,J=5Hz),2.2-2.0(1H,m),2.0-1.8(1H,m),0.92(3H,t,J=7Hz);
TLC:Rf0.18(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(122)
NMR(DMSO-d6):δ12.62(1H,br),11.66(1H,br),9.24(1H,t-like),7.82-7.71(3H,m),7.52-7.42(2H,m),7.31-7.10(3H,m),6.91-6.76(3H,m),6.01(2H,s),3.89(2H,d,J=5Hz),2.09-1.96(4H,m),0.75(6H,t,J=8Hz);
TLC:Rf0.39(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(123)
2RS-(噻吩-2-基)-3-甲基丁酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
NMR(DMSO-d6):δ12.64(1H,br),11.70(1H,br),9.24(1H,t-like),7.82(2H,d,J=8Hz),7.74(1H,d,J=8Hz),7.54-7.43(3H,m),7.26-7.00(5H,m),3.95(1H,d,J=7Hz),3.90(2H,d,J=6Hz),2.36-2.18(1H,m),1.07 and 0.83(each 3H,each d,J=7Hz);
TLC:Rf0.24(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(124)
2RS-(环己烷-1-基)丁酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
NMR(DMSO-d6)∶δ12.72(1H,br),11.64(1H,br),9.27(1H,br),7.83(2H,d,J=10Hz),7.75(1H,d,J=10Hz),7.51(1H,t,J=10Hz),7.48(1H,t,J=8Hz)7.27(2H,d,J=12Hz),7.15(1H,t,J=10Hz),3.90(2H,d,J=3Hz),2.35-2.30(1Hm),1.78(1H,d-like),1.71-1.55(7H,m),1.25-0.98(5H,m),0.92(3H,t,J=7Hz);
TLC:Rf0.30(乙酸∶甲醇∶氯仿=1∶2∶20)。实施例2(125)
NMR(DMSO-d6):δ12.00(2H,br),9.36(1H,br),8.68-8.46(2H,br),7.85-7.78(4H,m),7.50-7.10(6H,m),4.04-3.75(3H,br),2.27-2.02 and 1.96-1.74(each 1H,m),0.90(3H,br);
TLC:Rf0.37(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(126)
2RS-(2H-1,4-苯并噁嗪-3-酮-6-基)丁酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
NMR(DMSO-d6):δ10.69(1H,s),9.53(1H,t-like),8.29(1H,s),7.83-7.73(3H,m),7.49-7.39(2H,m),7.20-6.91(6H,m),4.55(2H,s),3.90-3.86(2H,d-like),3.73(1H,t,J=7Hz),2.14-1.98 and 1.80-1.66(each 1H,m),0.88(3H,t,J=7Hz);
TLC:Rf0.38(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(127)
NMR(DMSO-d6):δ12.30(1H,br),11.81(2H,br),9.24(1H,t-like),7.81(2H,d,J=7Hz),7.74(1H,d,J=8Hz),7.51-7.45(2H,m),7.25-7.10(3H,m),7.07(1H,s),3.90(1H,t,J=7Hz),3.89(2H,d,J=4Hz),3.73(3H,s),2.12-1.81(2H,m),0.90(3H,t,J=7Hz);
TLC:Rf0.28(氯仿∶甲醇∶水=8∶2∶0.2)。实施例2(128)
NMR(CD3OD):δ7.75-7.68(4H,m),7.63-7.57(3H,m),7.46-7.37(1H,m),7.16-7.07(3H,m),4.00(1H,t,J=8Hz),3.94(2H,s),2.85(3H,s),2.34-2.15and 2.06-1.88(each 1H,m),0.97(3H,t,J=7Hz);TLC:Rf0.26(氯仿∶甲醇∶水=8∶2∶0.2)。实施例2(129)
NMR(DMSO-d6):δ12.59(1H,br),11.65(1H,br),9.23(1H,t-like),7.82-7.63(4H,m),7.49-7.40(3H,m),7.25-7.09(3H,m),6.23(1H,t,J=7Hz),3.90(2H,d,J=6Hz),3.72(1H,t,J=7Hz),3.45(3H,s),2.04-1.70(2H,m),0.88(3H,t,J=7Hz);
TLC:Rf0.27(氯仿∶甲醇∶水=8∶2∶0.2)。实施例2(130)
2RS-苯基丁酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
NMR(CDCl3)δ7.67(3H,m),7.50-7.20(7H,m),7.08(1H,t,J=8Hz),6.97(2H,d,J=8Hz),6.60(1H,s),5.69(2H,brs),4.00(2H,m),3.66(1H,t,J=7Hz),2.16(1H,m),1.86(1H,m),0.94(3H,t,J=7Hz);
TLC:Rf0.23(氯仿∶甲醇=5∶1)。实施例2(131)
2-苯基-2-乙基丁酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
NMR(DMSO-d6):δ12.63(1H,br),11.67(1H,br),9.22(1H,t-like),7.82-7.70(3H,m),7.51-7.07(10H,m),3.89(2H,d,J=6Hz),2.09(4H,m),0.76(6H,m);
TLC:Rf0.58(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(132)
NMR(d6-DMSO):δ12.73(1H,br),11.59(1H,br),9.25-9.19(1H,t-like),7.82-7.70(3H,m),7.50-7.10(10H,m),4.10(1H,q,J=7Hz),3.89(2H,d,J=5Hz),1.49(3H,d,J=7Hz);
TLC:Rf0.32(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(133)
2R-苯基丁酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
NMR(CDCl3):δ10.22(1H,s),7.71-7.65(3H,m),7.49-7.26(6H,m),7.15-7.10(2H,m),6.99-6.95(2H,m),6.49(1H,br),6.36(1H,br),4.01(2H,d,J=5Hz),3.65(1H,t,J=7Hz),2.24-2.11 and 1.95-1.81(each 1H,m),0.95(3H,t,J=7Hz);
TLC:Rf0.36(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(134)
NMR(CDCl3):δ10.29(1H,s),7.70-7.65(3H,m),7.45-7.26(6H,m),7.13-7.05(2H,m),7.00-6.96(2H,m),6.60(1H,br),4.01(2H,d,J=5Hz),3.66(1H,t,J=8Hz),2.24-2.10 and 1.95-1.81(each 1H,m),0.95(3H,t,J=7Hz);
TLC:Rf0.36(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(135)
NMR(DMSO-d6):δ12.67(1H,br),11.65(1H,br),9.22(1H,t-like)7.82-7.71(3H,m),7.52-7.09(10H,m),3.89(2H,d,J=6Hz),1.63(6H,s);
TLC:Rf0.34(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(136)
NMR(DMSO-d6):δ12.72(1H,br),11.61(1H,br),9.24(1H,t-like),7.81-7.70(3H,m),7.48-7.25(7H,m),7.14-7.10(3H,m),3.88(2H,d,J=6Hz),2.56-2.41(2H,m),1.85-1.23(8H,m);
TLC:Rf0.48(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(137)
NMR(DMSO-d6):δ9.3-9.1(1H,brt),7.8-7.6(3H,m),7.5-7.0(10H,m),3.88(2H,d,J=5Hz),1.68(2H,dd,J=6,4Hz),1.39(2H,dd,J=6,4Hz);
TLC:Rf0.20(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(138)
NMR(DMSO-d6):δ9.3-9.1(1H,bH),7.8-7.7(3H,m),7.5-7.2(7H,m),7.2-7.0(3H,m),3.87(2H,d,J=5Hz),2.7-2.5(2H,m),2.1-1.9(2H,m),1.9-1.6(4H,m);
TLC∶Rf0.21(乙酸∶甲醇∶氯仿=1∶2∶40)实施例2(139)
1-苯基环丁烷羧酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
NMR(DMSO-d6):9.3-9.1(1H,brt),7.8-7.6(3H,m),7.5-7.2(7H,m),7.2-7.1(3H,m),3.88(2H,d,J=5Hz),3.0-2.8(2H,m),2.6-2.4(2H,m),2.1-1.8(2H,m);
TLC:Rf0.19(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(140)
2-苯基乙酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
NMR(DMSO-d6):δ10.01-9.76(1H,br),7.82-7.76(4H,m),7.41-7.22(9H,m),7.03-6.90(1H,m),3.96(2H,s),3.86(2H,m);
TLC:Rf0.66(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(141)
NMR(DMSO-d6):δ9.2-9.1(1H,brt),7.82(2H,d,J=8Hz),7.71(1H,d,J=8Hz),7.6-7.4(7H,m),7.29(2H,d,J=8Hz),7.2-7.1(1H,m),6.26(1H,s),3.88(2H,d,J=5Hz);
TLC:Rf0.18(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(142)
NMR(DMSO-d6):δ9.3-9.2(1H,br),7.93(2H,d,J=8Hz),7.72(1H,d,J=8Hz),7.65-7.55(2H,m),7.6-7.4(5H,m),7.37(2H,d,J=8Hz),7.2-7.1(1H,m),3.88(2H,d,J=5Hz),2.6-2.4(2H,m),0.97(3H,t,J=7Hz);
TLC:Rf0.20(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(143)
NMR(DMSO-d6):δ9.51-9.38(1H,m),7.86-7.68(4H,m),7.51-7.20(11H,m),7.19-7.01(4H,m),3.84(2H,d,J=6Hz),2.53-2.41(2H,m),0.79(3H,tJ=7Hz);
TLC:Rf0.44(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(144)
2RS-甲基-2-苯基丁酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
NMR(DMSO-d6):δ9.3-9.2(1H,br),7.88(2H,d,J=8Hz),7.70(1H,d,J=8Hz),7.5-7.1(10H,m),3.88(2H,d,J=5Hz),2.2-1.9(2H,m),1.57(3H,s),0.85(3H,t,J=7Hz);
TLC:Rf0.15(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(145)
2R-三氟甲基-2-苯基-2-甲氧基乙酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
NMR(CD3OD):δ7.81(2H,d,J=8.8Hz),7.62(4H,m),7.48(4H,m),7.27(2H,d,J=8.8Hz),7.15(1H,t,J=7.6Hz),3.97(2H,s),3.65(3H,s);
TLC:Rf0.28(氯仿∶甲醇∶水=9∶1∶0.1)。实施例2(146)
NMR(CD3OD):δ7.81(2H,d,J=8.6Hz),7.62(4H,m),7.47(4H,m)7.27(2H,d,J=8.6Hz),7.15(1H,t,J=7.6Hz),3.97(2H,s),3.65(3H,s);
TLC:Rf0.27(氯仿∶甲醇∶水=9∶1∶0.1)。实施例2(147)
NMR(CDCl3):δ7.70-7.64(2H,m),7.42(2H,t,J=8Hz),7.27-7.06(4H,m),6.97(2H,d,J=9Hz),6.88(2H,d,J=9Hz),6.55(1H,t-like),4.82(2H,brs),3.99(2H,d,J=5Hz),3.79(3H,s),3.61(1H,t,J=8Hz),2.12 and 1.85(each 1H,m),0.94(3H,t,J=7Hz);TLC:Rf0.50(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(148)2RS-(4-甲氧基苯基)-3-甲基丁酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
NMR(CDCl3):δ10.20(1H,s),7.73-7.64(3H,m),7.48-7.39(2H,m),7.33-7.22(2H,m),7.12(1H,t,J=8Hz),6.98-6.85(4H,m),6.46(1H,t-like),5.08(1H,br),4.00(2H,d,J=4Hz),3.80(3H,s),3.31(1H,d,J=10Hz),2.46-2.27(1H,m),1.12 and 0.76(each 3H,each d,J=7Hz);
TLC:Rf0.58(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(149)
NMR(DMSO-d6):δ12.66(1H,br),11.64(1H,br),9.23(1H,t-like),7.81-7.70(3H,m),7.52-7.10(7H,m),6.92(2H,d,J=9Hz),3.89(2H,d,J=6Hz),3.74(3H,s),1.60(6H,s);
TLC:Rf0.35(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(150)
NMR(DMSO-d6):δ12.67(1H,br),11.64(1H,br),9.21(1H,t-like),7.81-7.70(3H,m),7.52-7.41(2H,m),7.30-7.09(5H,m),6.91(2H,d,J=8Hz),4.00(1H,q,J=7Hz),3.88(2H,d,J=5Hz),3.73(3H,s),1.46(3H,d,J=7Hz);
TLC:Rf0.30(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(151)
NMR(DMSO-d6):δ12.68(1H,br),11.62(1H,br),9.24(1H,t-like),7.82-7.71(3H,m),7.52-7.46(2H,m),7.30-7.09(5H,m),6.93(2H,d,J=9Hz),3.89(2H,d,J=6Hz),3.75(3H,s),2.10-1.98(4H,m),0.75(6H,t,J=7Hz);
TLC:Rf0.34(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(152)
NMR(DMSO-d6):δ12.71(1H,br),11.57(1H,br),9.19(1H,t-like),7.77-7.66(3H,m),7.44-7.30(4H,m),7.13-7.04(3H,m),6.89(2H,d,J=8Hz),3.85(2H,d,J=6Hz),3.69(3H,s),2.47-2.36(2H,m),1.77-1.20(8H,m);
TLC:Rf0.51(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(153)
NMR(DMSO-d6):δ12.69(1H,br),11.66(1H,br),9.23(1H,t-like),7.80-7.71(3H,m),7.51-7.29(4H,m),7.18-7.07(3H,m),6.92(2H,dd,J=1 and8Hz),3.89(2H,d,J=5Hz),3.74(3H,s),2.66-2.53(2H,m),2.01-1.87(2H,m),1.79-1.67(4H,m);
TLC:Rf0.68(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(154)
1-(4-甲氧基苯基)环丁烷羧酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
NMR(DMSO-d6):δ9.2-9.1(1H,brt),7.8-7.7(3H,m),7.5-7.4(2H,m),7.30(2H,d,J=8Hz),7.2-7.0(3H,m),6.92(2H,d,J=8Hz),3.87(2H,d,J=5Hz),3.74(3H,s),2.9-2.7(2H,m),2.6-2.4(2H,br),2.1-1.7(2H,br);
TLC:Rf0.21(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(155)
1-(4-甲氧基苯基)环丙烷羧酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
NMR(DMSO-d6):δ9.53-9.38(1H,m),7.79-7.72(3H,m),7.51-7.28(4H,m),7.26-7.19(2H,m),7.16-7.00(1H,m),6.89-6.84(2H,m),3.88(2H,d,J=6Hz),3.73(3H,s),1.70-1.61(2H,m),1.38-1.29(2H,m);
TLC:Rf0.49(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(156)
NMR(DMSO-d6):δ9.52-9.38(1H,br),7.83-7.71(3H,m),7.53-7.39(2H, m),7.19-7.02(3H,m),7.00-6.78(3H,m),3.89(2H,d,J=6Hz),3.76(6H,s),2.06(4H,q,J=7Hz),0.78(6H,t,J=7Hz);
TLC:Rf0.39(乙酸∶甲醇∶氯仿=1∶3∶30)。实施2(157)
2RS-(3,4-二甲氧基苯基)丁酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
NMR(CDCl3+CD3OD):δ7.45-7.41(2H,m),7.30-7.19(2H,m),7.18-7.01(1H,m),6.82-6.69(3H,m),6.56-6.52(3H,m),3.63(2H,s),3.53(6H,s),3.28(1H,t,J=7Hz),1.98-1.42(2H,m),0.63(3H,t,J=7Hz):
TLC:Rf0.64(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(158)
NMR(DMSO-d6):δ12.71(1H,br),11.65(1H,br),9.23(1H,t-like),7.83-7.71(3H,m),7.53-7.42(2H,m),7.35-7.10(4H,m),6,92-6,84(3H,m),3.89(2H,d,J=6Hz),3.75(3H,s),2.12-2.01(4H,m),0.76(6H,t,J=7Hz);
TLC:Rf0.39(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(159)
NMR(DMSO-d6):δ11.58(1H,s),9.24-9.18(1H,m),7.86-7.64(3H,m),7.57-7.44(2H,m),7.38-7.09(5H,m),7.08-6.91(3H,m),4.02-3.98(1H,m),3.88(2H,d,J=6Hz),3.77(3H,s),2.18-1.84(2H,m),0.87(3H,t,J=7Hz);
TLC:Rf0.41(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(160)
NMR(DMSO-d6):δ9.28-9.19(1H,m),7.82-7.69(3H,m),7.48-7.41(2H,m),7.28-7.08(4H,m),7.00-6.75(4H,m),3.89(2H,d,J=6Hz),3.77(3H,s),2.18-1.82(4H,m),0.86(6H,t,J=7Hz);
TLC:Rf0.39(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(161)
NMR(DMSO-d6):δ10.79(1H,b r),7.85-7.79(3H,m),7.33-7.25(2H,m),7.17-7.06(3H,m),6.95-6.85(3H,m),6.74(1H,t,J=7Hz),3.85(2H,d-like),3.80-3.69(1H,m),3.75(3H,s),2.15-2.01 and 1.91-1.71(each 1H,m),0.89(3H,t,J=7Hz);
TLC:Rf0.47(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(162)
NMR(DMSO-d6):δ12.9-12.5(1H,br),11.7-11.4(1H,br),9.20(1H,t-like),7.78(2H,d,J=8.6Hz),7.72(1H,d,J=7.4Hz),7.52-7.38(3H,m),7.28(1H,t-like),7.20-7.08(3H,m),7.00(2H,d,J=7.8Hz),3.89(2H,d,J=5.6Hz),3.77(3H,s),2.85-2.65(2H,m),2.55-2.35(2H,m)2.20-2.00 and 2.00-1.80(each 1H,m);
TLC:Rf0.30(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(163)
2RS-(4-甲氧基苯基)丁酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)-2,6-二甲基苯基酯
NMR(DMSO-d6):δ9.8-9.5(brs,1H),7.8-7.7(m,1H),7.5-7.2(m,6H),7.1-6.8(m,4H),4.0-3.7(m,3H),3.74(s,3H),2.2-1.7(m,8H),0.90(t,J=7.0Hz,3H);
TLC:Rf0.30(己烷∶乙酸乙酯=1∶1)。实施例2(164)
2RS-(4-甲氧基苯基)丁酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)-2-异丙基苯基酯
NMR(CDCl3):δ10.0-9.9(m,1H),7.8-7.7(m,1H),7.6-7.2(m,6H),7.2-7.0(m,1H),7.0-6.8(m,3H),6.5-6.3(m,1H),4.0-3.4(m,2H),3.80(s,3H),3.64(t,J=7.8Hz,1H),2.7-2.5(m,1H),2.3-2.1(m,1H),2.0-1.8(m,1H),0.95(t,J=7.6Hz,3H),0.83(dd,J=2.0,6.9Hz,6H);TLC:Rf0.49(氯仿∶甲醇=3∶1)实施例2(165)
2RS-(4-(2-甲基丙氧基)苯基)丁酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
NMR(DMSO-d6):δ9.25-9.07(1H,br),8.02-7.98(1H,d-like),7.89-7.80(2H,d-like),7.79-7.65(2H,m),7.59-7.38(3H,m),7.18-7.09(1H,m),7.01-6.77(2H,m), 3.97-3.65(3H,m),3.80(3H,s),3.97-3.65(3H,s),1.19(6H,d,J=7Hz):
TLC:Rf0.37(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(166)
NMR(DMSO-d6):δ11.58(1H,s),9.22-9.13(1H,m),7.80-7.63(4H,m),7.49-7.40(2H,m),7.25-7.06(5H,m),6.88-6.84(2H,m),4.63-4.48(1H,m),3.88(2H,d,J=6Hz),3.72(1H,t,J=7Hz),2.18-1.63(2H,m),1.26(6H,d,J=6Hz),0.88(3H,t,J=7Hz);
TLC:Rf0.34(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(167)
NMR(DMSO-d6):δ9.38-9.20(1H,m),7.81-7.77(2H,d-like),7.77-7.70(2H,m),7.49-7.31(2H,m),7.28-7.03(5H,m),6.93-6.89(2H,d-like),3.94-3.87(4H,m),3.72(1H,t,J=6Hz),2.20-1.98(1H,m),1.83-1.62(3H,m),0.98(3H,t,J=7Hz),0.88(3H,t,J=7Hz);
TLC:Rf0.35(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(168)
2RS-(4-甲基苯基)戊酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
NMR(CDCl3)δ10.20(1H,s),7.68(1H,d,J=8Hz),7.65(2H,d,J=8Hz),7.50-7.35(2H,m),7.25-7.05(5H,m),6.95(2H,d,J=8Hz),6.6-6.5(1H,br),4.00(2H,d,J=5Hz),3.72(1H,t,J=7Hz),2.35(3H,s),2.2-2.0(1H,m),1.9-1.7(1H,m),1.4-1.2(2H,m),0.92(3H,t,J=7Hz);
TLC:Rf0.25(氯仿∶甲醇∶乙酸=40∶2∶1)。实施例2(169)
NMR(DMSO-d6):δ12.70(1H,br),11.66(1H,br),9.23(1H,t-like),7.80-7.70(3H,m),7.51-7.41(2H,m),7.33-7.29(2H,m),7.19-7.09(5H,m),3.89(2H,d,J=6Hz),2.65-2.55(2H,m),2.29(3H,s),2.04-1.90(2H,m),1.79-1.65(4H,m);
TLC:Rf0.69(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(170)1-(3-甲基苯基)环戊烷羧酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
NMR(DMSO-d6):δ9.22-9.18(1H,m),7.80-7.68(3H,m),7.49-7.41(2H,m),7.29-7.10(7H,m),3.89(2H,d,J=6Hz),2.70-2.51(2H,m),2.32(3H,s),2.04-1.83(2H,m),1.74-1.60(4H,m);
TLC:Rf0.40(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(171)
NMR(DMSO-d6):δ9.4-9.2(1H,br),7.8-7.7(3H,m),7.5-7.4(2H,m),7.3-7.0(7H,m),4.06(1H,t,J=7Hz),3.88(2H,d,J=5Hz),2.37(3H,s),2.2-2.0(1H,m),1.9-1.7(1H,m),0.87(3H,t,J=7Hz);
TLC:Rf0.16(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(172)
NMR(DMSO-d6):δ9.5-9.3(1H,br),7.9-7.6(3H,m),7.6-7.0(9H,br),4.0-3.8(2H,br),2.27(3H,s),2.3-1.9(4H,br),0.8-0.6(6H,br);
TLC:Rf0.15(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(173)
2RS-(4-甲基苯基)丁酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
NMR(DMSO-d6):δ10.61-10.32(1H,m),7.85-7.74(3H,m),7.36-7.04(8H, m),6.90-6.75(1H,m),3.92-3.83(2H,m),3.77(1H,t,J=7.6Hz),2.29(3H,s),2.21-1.96 and 1.89-1.63(each 1H,m),0.87(3H,t,J=7.4Hz);
TLC:Rf0.23(氯仿∶甲醇∶水=8∶2∶0.2)。实施例2(174)
NMR(CDCl3+CD3OD):δ8.24(2H,d,J=8Hz),7.85-7.55(6H,m),7.10(4H,m),3.95(2H,s),3.87(1H,t,J=7Hz),2.25 and 1.98(each 1H,m),0.99(3H,t,J=7Hz);
TLC:Rf0.33(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(175)
NMR(DMSO-d6):δ13.50-11.00(2H,br),9.30-9.16(1H,m),8.23(2H,d,J=8Hz),7.88-7.68(5H,m),7.55-7.40(2H,m),7.25(2H,d,J=8Hz),7.20-7.09(1H,m),3.89(2H,d,J=6Hz),1.68(6H,s),
TLC:Rf0.41(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(176)
1-(4-硝基苯基)环丙烷羧酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
NMR(DMSO-d6):δ9.2-9.1(1H,brt),8.18(2H,d,J=8Hz),7.8-7.6(5H,m),7.5-7.4(2H,m),7.29(2H,d,J=8Hz),7.2-7.0(1H,m),3.90(2H,d,J=5Hz),1.77(2H,dd,J=6,4Hz),1,48(2H,dd,J=6,4Hz);
TLC:Rf0.17(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(177)
NMR(DMSO-d6):δ9.2-9.1(1H,brt),8.22(2H,d,J=8Hz),7.8-7.6(5H,m),7.5-7.4(2H,m),7.2-7.1(3H,m),3.88(2H,d,J=5Hz),2.8-2.6(2H,m),2.2-1.9(2H,m),1.9-1.6(4H,m);
TLC:Rf0.20(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(178)
NMR(DMSO-d6):δ13.40-11.20(2H,br),9.35-9.15(1H,m),8.24(2H,d,J=8Hz),7.82(2H,d,J=8Hz),7.74(1H,t,J=8Hz),7.67(2H,d,J=8Hz),7.55-7.40(2H,m),7.23(2H,d,J=8Hz),7.19-7.08(1H,m),3.89(2H,d,J=6Hz),2.25-1.98(4H,m),0.76(6H,t,J=7Hz);
TLC:Rf0.28(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(179)
1-(4-硝基苯基)环丁烷羧酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
NMR(DMSO-d6):δ9.2-9.1(1H,brt),8.24(2H,d,J=8Hz),7.8-7.6(5H,m),7.5-7.4(2H,m),7.3-7.1(3H,m),3.88(2H,d,J=5Hz),3.0-2.8(2H,br),2.7-2.5(2H,m),2.2-1.8(2H,m);
TLC:Rf0.22(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(180)
2RS-(4-硝基苯基)丁酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)-2-甲基苯基酯
NMR(DMSO-d6):δ13.00-12.40(1H,br),11.80-11.40(1H,br),9.19(1H,t,J=5Hz),8.24(2H,d,J=8Hz),7.80-7.55(5H,m),7.55-7.40(2H,m),7.23-7.06(2H,m),4.15(1H,t,J=7Hz),3.88(2H,d,J=5Hz),2.19(1H,ddq,J=14Hz,7Hz,7Hz),2.05-1.75(4H,m),0.88(3H,t,J=7Hz);
TLC:Rf0.20(乙酸∶甲醇∶氯仿=1∶2∶20)。实施例2(181)
NMR(DMSO-d6):δ12.80-11.00(2H,br),9.20(1H,t,J=5Hz),8.24(2H,d,J=8Hz),7.80-7.55(5H,m),7.55-7.37(2H,m),7.25-7.05(2H,m),3.86(2H,d,J=5Hz),3.04-2.85(2H,m),2.74-2.54(2H,m),2.23-1.78(5H,m);
TLC:Rf0.20(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(182)
1-(4-硝基苯基)环丁烷羧酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)-3-甲基苯基酯
NMR(DMSO-d6):δ13.30-12.30(1H,br),12.00-11.56(1H,br),9.34-9.16(1H,m),8.26(2H,d,J=8Hz),7.85-7.65(4H,m),7.50-7.35(2H,m),7.22(1H,d,J=8Hz),7.18-7.05(1H,m),6.85(1H,s),3.97(2H,d,J=5Hz),3.22-3.03(2H,m),2.78-2.58(2H,m),2.28(3H,s),2.28-2.08(1H,m),2.05-1.80(1H,m);
TLC:Rf0.43(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(183)
1-(4-硝基苯基)环丁烷羧酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)-2,3-二甲基苯基酯
NMR(DMSO-d6):δ13.10-12.40(1H,br),12.00-11.70(1H,br),9.35-9.22(1H,m),8.27(2H,d,J=8Hz),7.88-7.73(3H,m),7.65(1H,d,J=8Hz),7.51-7.39(2H,m),7.20(1H,d,J=8Hz),7.15-7.06(1H,m),4.08-3.95(2H,m),3.18-2.99(1H,m),2.99-2.78(1H,m),2.66-2.47(1H,m),2.33-2.05(1H,m),2.18(3H,s),2.05-1.82(1H,m),1.35(3H,s);
TLC:Rf0.43(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(184)
NMR(DMSO-d6):δ13.10-12.30(1H,br),12.00-11.46(1H,br),9.22(1H,t,J=5Hz),8.25(2H,d,J=8Hz),7.80-7.60(4H,m),7.50-7.34(2H,m),7.18-7.02(2H,m),3.90(2H,d,J=5Hz),3.14-2.78(4H,m),2.74-2.33(4H,m),2.20-1.78(4H,m);
TLC:Rf0.20(乙酸∶甲醇∶氯仿=1∶2∶60)。实施例2(185)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯·盐酸盐
NMR(d6-DMSO):δ11.60(1H,s),9.23(1H,t,J=6Hz),7.85-7.70(3H,m),7.55-7.40(2H,m),7.27-7.08(5H,m),6.80-6.55(2H,m),3.88(2H,d,J=6Hz),3.68(1H,t,J=7Hz),3.38-3.19(4H,m),2.20-1.86(5H,m),1.86-1.62(1H,m),0.86(3H,t,J=7Hz);
TLC:Rf0.44(氯仿∶甲醇∶乙酸=30∶2∶1)。实施例2(186)
NMR(DMSO-d6):δ11.56(1H,s),9.23(1H,t,J=5Hz),7.83-7.55(3H,m),7.55-7.40(2H,m),7.30-7.05(4H,m),6.84-6.60(2H,m),3.88(2H,d,J=5Hz),3.70(1H,t,J=7Hz),3.40-3.13(4H,m),2.20-1.65(9H,m),0.86(3H,t,J=7Hz);
TLC:Rf0.45(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(187)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)-3-甲基苯基酯·盐酸盐
NMR(DMSO-d6):δ12.20(1H,s),9.28(1H,t,J=5Hz),7.85(2H,d,J=8Hz),7.50-7.35(2H,m),7.30-7.18(3H,m),7.18-7.03(1H,m),6.80(1H,s),6.73(2H,d,J=8Hz),4.00(2H,d,J=5Hz),3.93-3.75(1H,m),3.38-3.20(4H,m),2.28(3H,s),2.20-2.00(1H,m),2.03-1.92(4H,m),1.92-1.65(1H,m),0.88(3H,t,J=7Hz);
TLC:Rf0.41(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(188)
NMR(DMSO-d6):δ12.09(1H,s).9.35-9.18(1H,m),7.92-7.77(1H,m),7.77-7.63(1H,m),7.46-7.38(2H,m),7.30-7.17(3H,m),7.17-7.03(1H,m),6.86-6.60(2H,m),4.02(2H,d,J=5Hz),3.93-3.80(1H,m),3.40-3.15(4H,m),2.19(3H,s),2.05-1.90(4H,m),1.90-1.50(1H,m),1.45(3H,s),1.30-0.98(1H,m),0.88(3H,t,J=7Hz);TLC:Rf0.40(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(189)
1-(4-(吡咯烷-1-基)苯基)环丁烷羧酸4-(N-2-(N′-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
NMR(CD3OD):δ7.75-7.50(4H,m),7.50-7.25(3H,m),7.20-6.90(5H,m),3.92(2H,s),3.46(4H,brs),2.90(2H,m),2.56(2H,m),2.25-1.85(6H,m);TLC:Rf0.36(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(190)
NMR(DMSO-d6):δ11.69(1H,s),9.24(1H,t,J=5Hz),7.75(1H,d,J=8Hz),7.69(1H,d,J=8Hz),7.50-7.38(2H,m),7.19(2H,d,J=8Hz),7.15-7.04(1H,m),6.98(1H,d,J=8Hz),6.68(2H,d,J=8Hz),3.89(2H,d,J=5Hz),3.66(1H,t,J=5Hz),3.35-3.15(4H,m),3.15-3.00(2H,m),2.55-2.40(2H,m),2.18-1.85(7H,m),1.85-1.60(1H,m),0.86(3H,t,J=7Hz);
TLC:Rf0.34(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(191)
NMR(DMSO-d6):δ11.49(s,1H),9.3-9.2(m,1H),7.8-7.1(m,10H),6.8-6.6(m,1H),4.0-3.7(m,3H),3.4-3.1(m,4H)2.2-1.7(m,12H),0.89(t,J=7.0Hz,3H);
TLC:Rf0.60(氯仿∶甲醇=2∶1)。实施例2(192)
NMR(CDCl3):δ10.04(s,1H),7.8-7.7(m,3H),7.6-7.5(m,7H),7.2-7.1(m,1H),6.9-6.8(m,1H),6.4-6.3(m,1H),4.0-3.6(m,7H),2.8-2.7(m,1H),2.4-2.2(m,5H),2.0-1.8(m,1H),0.98(t,J=7.0Hz,3H),0.91(d,J=7.0Hz,6H);
TLC:Rf0.61(氯仿∶甲醇=2∶1)。实施例2(193)
2RS-(4-(哌啶-1-基)苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯·三氟乙酸盐
NMR(d6-DMSO):δ12.60-11.50(1H1,br),9.43-9.23(1H,br),7.83-7.68(3H,m),7.52-7.35(2H,m),7.30-7.02(5H,m),6.88(2H,d,J=8Hz),3.88(2H,d,J=7Hz),3.66(1H,t,J=8Hz),3.20-3.05(4H,m),2.15-1.91(1H,m),1.85-1.43(7H,m),0.93(3H,t,J=7Hz);
TLC:Rf0.28(氯仿∶甲醇∶乙酸=30∶3∶1)。实施例2(194)
NMR(DMSO-d6):δ11.57(1H,s),9.19(1H,t,J=7Hz),7.85-7.65(3H,m),7.55-7.40(2H,m),7.30-7.05(5H,m),6.64(2H,d,J=8Hz),3.88(2H,d,J=7Hz),3.60(1H,t,J=8Hz),3.48-3.28(4H,m),2.10-1.93(1H,m),1.88-1.55(5H,m),1.55-1.30(4H,m),0.86(3H,t,J=7Hz);
TLC:Rf0.35(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(195)
NMR(DMSO-d6):δ11.58(1H,br),9.22(1H,t,J=5Hz),7.80-7.70(3H,m),7.53-7.42(2H,m),7.18-7.14(3H,m),6.98(2H,d,J=8Hz),6.56(2H,d,J=8Hz),3.89(2H,d,J=6Hz),2.09-1.88(4H,m),0.74(6H,t,J=7Hz);
TLC:Rf0.40(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(196)
NMR(DMSO-d6):δ10.65(1H,br),7.83-7.76(3H,m),7.31-6.96(6H,m),6.80-6.73(1H,m),6.53(2H,d,J=8.6Hz),3.86(2H,d-like),3.55(1H,t,J=7.4Hz),2.12-1.90 and 1.83-1.62(each 1H,m),0.87(3H,t,J=7.0Hz);
TLC:Rf0.16(氯仿∶甲醇∶水=8∶2∶0.2)。实施例2(197)
NMR(DMSO-d6):δ11.62(1H,s),9.25(1H,t,J=6Hz),7.80(2H,d,J=9Hz),7.76(1H,d,J=8Hz),7.50-7.44(5H,m),7.27-7.14(4H,m),3.89(2H,d,J=6Hz),3.86(1H,t,J=8Hz),3.04(6H,s),2.17-2.03 and 1.91-1.71(each 1H,m),0.88(3H,t,J=7Hz);
TLC:Rf0.48(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(198)
NMR(DMSO-d6):δ11.62(1H,s),9.24(1H,t-like),7.79(2H,d,J=8.8Hz), 7.74(1H,d,J=8.0Hz),7.81-7.70(9H,m),3.89(2H,d,J=5.0Hz),3.02(6H,s), 2.93-2.80(2H,m),2.59-2.39(2H,m),2.09-1.81(2H,m);
TLC:Rf0.26(氯仿∶甲醇∶水=8∶2∶0.2)。实施例2(199)
2RS-4-(N,N-二乙基氨基甲基)苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯·盐酸盐
NMR(DMSO-d6):δ13.00-11.00(2H,br),9.35-9.18(1H,m),7.90-7.71(3H,m),7.68-7.56(2H,m),7.56-7.38(4H,m),7.30-7.08(3H,m),4.24(2H,s),3.99-3.79(2H,m),3.71-3.65(1H,m),3.10-2.90(4H,m),2.11(1H,ddq,J=14Hz,7Hz,7Hz),1.82(1H,ddq,J=14Hz,7Hz,7Hz),1.23(6H,t,J=7Hz),0.88(3H,t,J=7Hz);
TLC:Rf0.18(乙酸∶甲醇∶氯仿=1∶2∶20)。实施例2(200)
NMR(DMSO-d6):δ12.90-11.20(2H,br),9.39(1H,br),9.22(1H,t-like),7.79(2H,d,J=8.8Hz),7.73(1H,d,J=7.8Hz),7.53-7.42(2H,m),7.19-7.12(5H,m),6.74(2H,d,J=8.6Hz),3.89(2H,d,J=5.6Hz),3.68(1H,t,J=7.6Hz),2.11-1.93 and 1.84-1.62(each 1H,m),0.86(3H,t,J=7.2Hz);
TLC:Rf0.12(氯仿∶甲醇∶水=8∶2∶0.2)。实施例2(201)
NMR(DMSO-d6):δ10.72-10.41(1H,m),7.88-7.69(5H,m),7.59(2H,d,J=8.2Hz),7.29(2H,d,J=8.2Hz),7.22-7.06(3H,m),6.78(1H,t,J=8.2Hz),4.01(1H,t,J=7.4Hz),3.91-3.77(2H,m),2.24-2.01 and 1.95-1.70(each 1H,m),0.88(3H,t,J=7.4Hz);
TLC:Rf0.24(氯仿∶甲醇∶水=8∶2∶0.2)。实施例2(202)
NMR(DMSO-d6):δ11.36(1H,s),10.45(1H,s),9.16(1H,t-like),7.90(2H,d,J=8Hz),7.71(1H,d,J=8Hz),7.60-7.38(7H,m),7.18-7.03(1H,m),6.81(2H,d,J=8Hz),3.89(2H,d,J=6Hz),3.40(1H,t,J=7Hz),2.04-1.58(2H,m),0.83(3H,t,J=7Hz);TLC:Rf0.53(乙酸∶甲醇∶氯仿=1∶5∶15)。实施例2(203)
NMR(DMSO-d6):δ10.75-10.45(1H,m),7.87-7.56(7H,m),7.35-7.07(4H,m),6.87-6.72(1H,m),4.02(1H,t,J=7.7Hz),3.93-3.82(2H,m),2.25-2.02and 1.95-1.71(each 1H,m),0.89(3H,t,J=7.0Hz),
TLC:Rf0.23 (氯仿∶甲醇∶水=8∶2∶0.2)。实施例2(204)
2RS-(4-脒基苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯·三氟乙酸盐
NMR(DMSO-d6):δ10.42-10.20(1H,m),9.95-9.44(2H,m),9.44-8.90(2H,m),7.86-7.66(4H,m),7.66-7.30(4H,m),7.30-7.04(3H,m),6.88-6.75(1H,m),4.01(1H,t,J=7Hz),3.90-3.79(2H,m),2.26-2.03(1H,m),1.95-1.74(1H,m),0.96-0.76(3H,m);
TLC:0.40(乙酸∶甲醇∶氯仿=1∶2∶10)。实施例2(205)
2RS-(4-咪唑啉-2-基)苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯·三氟乙酸盐
NMR(DMSO-d6):δ10.60-10.34(1H,m),7.95(2H,d,J=8Hz),7.82-7.71(3H,m),7.64(2H,d,J=8Hz),7.34(1H,d,J=8Hz),7.26-7.00(4H,m),6.80(1H,t,J=8Hz),4.60-3.93(7H,m),2.15(1H,ddq,J=14Hz,7Hz,7Hz),1.94-1.71(1H,m),0.87(3H,t,J=7Hz);
TLC:Rf0.2(乙酸∶甲醇∶氯仿=1∶2∶10)。实施例2(206)
1-(4-氯苯基)环丁烷羧酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
NMR(DMSO-d6):δ9.3-9.1(1H,bH),7.8-7.6(3H,m),7.5-7.3(6H,m),7.2-7.0(3H,m),3.88(2H,d,J=5Hz),3.0-2.8(2H,m),2.6-2.4(2H,m),2.2-1.8(2H,m):
TLC:Rf0.22(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(207)
2RS-(2-氯苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
NMR(DMSO-d6):δ9.4-9.2(1H,br),7.8-7.7(3H,m),7.5-7.3(6H,m),7.3-7.0(3H,m),4.24(1H,t,J=7Hz),3.88(2H,d,J=5Hz),2.2-2.0(1H,m),2.0-1.8(1H,m),0.87(3H,t,J=7Hz);
TLC:0.16(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(208)
NMR(DMSO-d6):δ9.5-9.3(1H,br),7.82(2H,d,J=8Hz),7.72(1H,d,J=8Hz),7.6-7.3(6H,m),7.23(2H,d,J=8Hz),7.09(1H,t,J=8Hz),3.90(2H,d,J=5Hz),2.4-2.1(2H,m),2.2-1.9(2H,m),0.70(6H,t,J=7Hz);
TLC:Rf0.12(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(209)
1-(2-氯苯基)环丁烷羧酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
NMR(CDCl3+CD3OD).δ7.72(2H,d,J=8.5Hz)7.68-7.05(8H,m),7.02(2H,d,J=8.5Hz),3.99(2H,s),3.01-2.82(2H,m),2.75-2.50(2H,m),2.41-2.15(1H,m),2.10-1.80(1H,m);
RLC:Rf0.30(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(210)
2RS-(4-氯苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
NMR(DMSO-d6):δ10.47-10.18(1H,m),7.86-7.74(3H,m),7.51-7.08(8H,m),6.93-6.81(1H,m),3.95-3.82(3H,m),2.20-1.96 and 1.90-1.66(each1H,m),0.87(3H,t,J=7.4Hz);TLC:Rf0.26(氯仿∶甲醇∶水=8∶2∶0.2)。实施例2(211)
NMR(DMSO-d6):δ9.36(1H,t-like),7.90-7.72(4H,m),7.58-7.40(3H,m),7.24-7.07(4H,m),3.90(2H,d,J=6Hz),2.20-1.97 and 1.89-1.69(each 1Hm),0.88(3H,t,J=7Hz);
TLC:Rf0.21(乙酸:甲醇∶氯仿=1∶2∶40)。实施例2(212)
2RS-(2-氯-5-硝基苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
NMR(DMSO-d6):δ12.10(2H,br),9.26(1H,t-like),8.32(1H,t,J=3Hz),8.20(1H,dd,J=3 and 9Hz),7.85-7.79(3H,m),7.73(1H,d,J=8Hz),7.52-7.41(2H,m),7.27(2H,d,J=9Hz),7.15-7.08(1H,m),4.43(1H,t,J=6Hz),3.89(2H,d,J=6Hz),2.32-2.18 and 2.09-1.91(each 1H,m),0.90(3H,t,J=7Hz);
TLC:Rf0.51(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(213)
NMR(CDCl3+CD3OD):δ8.32(1H,d,J=2.5Hz),8.14(1H,dd,J=2.5,8.5Hz),7.76(2H,d,J=8.5Hz),7.62(2H,t,J=8.5Hz),7.53(1H,d,J=8.5Hz),7.43(1H,d,J=8.5Hz),7.12(1H,d,J=8.5Hz),7.06(2H,d,J=8.5Hz),3.99(2H,brs),3.10-2.90(2H,m),2.80-2.59(2H,m),2.52-2.20(1H,m),2.15-1.90(1H,m);TLC:Rf0.23(乙酸∶甲醇;氯仿=1∶2∶40)。实施例2(214)
NMR(DMSO-d6):δ12.73(1H,brs),11.60(1H,brs),9.17(1H,t,J=7Hz),8.04(1H,s),7.90-7.65(4H,m),7.55-7.40(2H,m),7.35-7.05(4H,m),3.90(2H,d,J=7Hz),2.90(2H,m),2.60(2H,m),2.25-1.80(2H,m);TLC:Rf0.34(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(215)
2RS-(3-硝基-4-氯苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
NMR(DMSO-d6):δ10.79(1H,br),8.12(1H,s),7.85-7.75(5H,m),7.28-7.08(4H,m),6.74(1H,t-like),4.08(1H,t,J=7.4Hz),3.84(2H,d-like),2.22-2.04 and 1.98-1.76(each 1H,m),0.89(3H,t,J=7.2Hz);
TLC:Rf0.30(氯仿∶甲醇∶水=8∶2∶0.2)。实施例2(216)
NMR(DMSO-d6):δ10.5(1H,br),8.61(1H,s),7.81-7.70(3H,m),7.41-7.05(10H,m),6.80(1H,t,J=7.6Hz),5.85(2H,s),3.84(2H,s),3.70(1H,t,J=7.2Hz),2.30(2H,s),2.60-1.95 and 1.90-1.65(each 1H,m),0.88(3H,t,J=7.0Hz);RLC:Rf0.22(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(217)
NMR(DMSO-d6):δ10.0(1H,brs),8.50(1H,s),7.67(4H,d,J=8.8Hz),7.32-7.09(2H,m),7.30(2H,d,J=8.6Hz),7.11(2H,d,J=8.8Hz),6.96(2H,d,J=8.6Hz),6.76(1H,t,J=6.8Hz),5.74(2H,s),3.75-3.73(2H,m),2.80-2.63(2H,m),2.53-2.26(2H,m),2.23-2.00(2H,m);
TLC:Rf0.10(氯仿∶甲醇∶乙酸=40∶2∶1)。实施例2(218)
NMR(DMSO-d6):δ10.92(1H,s),9.47-9.32(1H,m),7.85-7.73(3H,m),7.66(2H,d,J=9Hz),7.54-7.42(2H,m),7.34(2H,d,J=9Hz),7.27-7.04(4H,m),4.16-3.99(1H,m),3.89(2H,d,J=5Hz),3.81(1H,t,J=6Hz),2.19-1.98 and1.88-1.67(each 1H,m),1.47(3H,d,J=8Hz),0.97(3H,t,J=8Hz);
TLC:Rf0.11(氯仿∶甲醇∶水=8∶2∶0.2)。实施例2(219)
2RS-(4-(N-(2S-氨基-3-甲基丁酰基)氨基)苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯·盐酸盐
NMR(DMSO-d6):δ10.96-10.85(1H,m),9.45-9.30(1H,m),7.85-7.72(2H,m),7.66(2H,d,J=8.4Hz),7.54-7.42(2H,m),7.34(2H,d,J=8.4Hz),7.27-7.06(4H,m),3.90(2H,d,J=6.0Hz),3.81(1H,t,J=7.8Hz),2.33-1.98 and 1.92-1.66(each 1H,m),1.01(6H,d,J=7.2Hz),0.87(3H,t,J=7.4Hz);
TLC:Rf0.19(氯仿∶甲醇∶水=8∶2∶0.2)。实施例2(220)
2RS-(4-(N-(吡咯烷-2S-基羰基)氨基)苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯·盐酸盐
NMR(DMSO-d6):δ10.62-10.52(1H.m),9.95-9.70(1H,m),7.86-7.70(3H,m),7.62(2H,d,J=8.8Hz),7.48-7.27(4H,m),7.13(2H,d,J=8.8Hz),7.04-6.93(1H,m),4.34-4.20(1H,m),3.95-3.85(2H,m),3.81(1H,t,J=7.1Hz),3.33-3.16(2H,m),2.45-2.21(1H,m),2.21-1.68(5H,m),0.77(3H,t,J=7.1Hz);
TLC:Rf0.09(氯仿∶甲醇∶水=8∶2∶0.2)。实施例2(221)
NMR(DMSO-d6):δ12.71(1H,br),11.69(1H,br),9.22(1H,t-like),7.80(2H,d,J=8Hz),7.73(1H,d,J=8Hz),7.53-7.41(2H,m),7.25-7.09(3H,m),6.63(2H,s),3.89(2H,d,J=5Hz),3.77(6H,s),3.65(3H,s),3.63(1H,t,J=7Hz),2.19-1.97 and 1.88-1.67(each 1H,m),0.90(3H,t,J=7Hz);TLC:Rf0.57(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(222)
NMR(CD3OD):δ7.80-6.80(12H,m),4.21(1H,dd,J=8.0 and 6.0Hz),3.93(2H,s),2. 30-2.20(each 3H,s),1.90-1.60(2H,m),0.90(3H,t,J=7.2Hz);
TLC:Rf0.46(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(223)
2RS-(3-硝基-4-甲氧基苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯
NMR(DMSO-d6):δ12.72(1H,br),11.60(1H,br),9.18(1H,t-like),7.89-7.59(5H,m),7.53-7.46(2H,m),7.36(1H,d,J=9Hz),7.24(2H,d,J=9Hz),7.13(1H,t,J=8Hz),3.95(1H,t,J=8Hz),3.92(3H,s),3.89(2H,d,J=6Hz),2.23-2.02 and 1.94-1.72(each 1H,m),0.88(3H,t,J=7Hz);
TLC:Rf0.51(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(224)
NMR(DMSO-d6):δ12.14(2H,br),9.36(1H,t-like),7.95(1H ,d,J=2.0Hz),7.79(2H,d,J=8.8Hz),7.76(1H,d,J=6.6Hz),7.51-7.38(5H,m),7.21(2H,m),7.15-7.02(2H,m),3.89(2H,d,J=5.6Hz),3.80(1H,t,J=7.6Hz),2.13-1.99 and 1.84-1.69(each 1H,m),0.88(3H,t,J=7.6Hz);
TLC:Rf0.18(氯仿∶甲醇∶水=8∶2∶0.2)。实施例2(225)
NMR(DMSO-d6):δ12.76(1H,br),11.58(1H,s),9.94(1H,s),9.20(1H,t,J=6Hz),7.81-7.70(3H,m),7.58-7.46(4H,m),7.29-7.10(5H,m),3.89(2H,d,J=6Hz),3.76(1H,t,J=7Hz),2.14-1.99 and 1.83-1.69(each 1H,m),2.03(3H,s),0.87(3H,t,J=7Hz);
TLC:Rf0.20(氯仿∶甲醇∶水= 8∶2∶0.2)。实施例2(226)
NMR(DMSO-d6):δ11.59(1H,s),9.19(1H,t,J=5Hz),7.80(2H,d,J=9Hz),7.73(1H,d,J=8Hz),7.53-7.41(4H,m),7.34-7.10(5H,m),3.89(2H,d,J=6Hz),3.69(1H,t,J=7Hz),3.16(3H,s),2.18-2.01 and 1.92-1.71(each 1H,m),1.78(3H,s),0.90(3H,t,J=7Hz);
TLC:Rf0.27(氯仿∶甲醇∶水=8∶2∶0.2)。实施例2(227)
NMR(DMSO-d6):δ12.00-11.20(2H,br),9.28-9.15(1H,m),7.88-7.68(3H,m),7.56-7.27(6H,m),7.27-7.08(3H,m),3.95-3.79(4H,m),3.68-3.59(5H,m),2.90-2.60(4H,m),2.20-1.95(1H,m),1.95-1.65(1H,m),0.95-0.80(3H,m);
TLC:Rf0.47(乙酸∶甲醇∶氯仿=1∶2∶20)。实施例2(228)
NMR(CDCl3+CD3OD):δ9.21(1H,d-like),7.95-7.86(4H,m),7.78-7.71(1H,m),7.65-7.58(2H,n),7.54-7.46(6H,m),7.40-7.32(2H,m),7.21-7.10(2H,m),3.91(2H,d,J=7Hz),3.50-3.06(11H,m),1.68-1.45(2H,m),0.78(3H,t,J=7Hz);
TLC:Rf0.65(乙酸∶甲醇∶氯仿=1∶3∶30)。实施例2(229)
NMR(DMSO-d6):δ9.65(1H,brs),7.77(2H,d,J=8Hz),7.73(1H,d,J=8Hz),7.45-7.30(6H,m),7.14(2H,d,J=8Hz),6.99(1H,d,J=8Hz),4.03-3.93(2H,m),3,93-3.80(3H,m),2.88(4H,brs),2.09(1H,ddq,J=14Hz,7Hz,7Hz),1.88-1.73(5H,m),0.88(3H,t,J=7Hz);
TLC:Rf0.10(乙酸∶甲醇∶氯仿=1∶2∶20)。实施例2(230)
NMR(DMSO-d6):δ9.5-9.3(1H,brs),7.9-7.7(3H,m),7.5-7.4(3H,m),7.3-7.0(5H,m),3.87(2H,d,J=5Hz),2.3-1.9(4H,m),0.82(6H,t,J=7Hz);
TLC:Rf0.19(乙酸∶甲醇∶氯仿=1∶2∶40)。实施例2(231)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((1R-氧代-4S-羧基全氢化噻唑-3-基)磺酰基)-2-甲基苯基酯
NMR(DMSO-d6):δ7.85-7.70(2H,m),7.18(2H,d,J=8.5Hz),7.09(1H,d,J=8.5Hz),6.53(2H,d,J=8.5Hz),4.85-4.65(2H,m),4.30(1H,d,J=12.5Hz),3.69(1H,t,J=7.5Hz),3.35-3.05(6H,m),2.20-1.60(2H,m),1.99(3H,s),2.00-1.85(4H,m),0.90(3H,t,J=7.5Hz);
TLC:Rf0.36(氯仿∶甲醇∶乙酸=25∶5∶1)。实施例2(232)
NMR(CD3OD):δ7.89-7.69(2H,m),7.54 and 7.41(each 2H,d,J=8Hz),7.15(1H,d,J=8Hz),4.28-4.16(1H,m),3.90(1H,t,J=7Hz),3.69-3.64(4H,m),3.51-3.40 and 3.31-3.21(each 1H,m),2.28-2.21(5H,m),2.02(3H,s),2.01-1.89(4H,m),1.80-1.65(1H,m),0.99(3H,t,J=7Hz);
TLC:Rf0.17(氯仿∶甲醇∶水=9∶1∶0.1)。实施例2(233)
NMR(CD3OD):δ7.81-7.68(2H,m),7.56 and 7.45(each 2H,d,J=8Hz),7.15(1H,d,J=8Hz),4.28-4.16(1H,m),3.91(1H,t,J=7Hz),3.71-3.64(4H,m),3.50-3.40 and 3.33-3.22(each 1H,m),2.31-2.22(5H,m),2.03(3H,s),2.02-1.84(4H,m),1.80-1.64(1H,m),1.00(3H,t,J=7Hz);
TLC:Rf0.18(氯仿∶甲醇∶水=9∶1∶0.1)。实施例2(234)
NMR(CD3OD):δ7.80-7.68(2H,m),7.50 and 7.31(each 2H,d,J=8Hz),7.14(1H,d,J=8Hz),4.22-4.16(1H,m),3.87(1H,t,J=7Hz),3.68-3.56(4H,m),3.50-3.42 and 3.35-3.20(each 1H,n),2.32-2.18(5H,m),2.02(3H,s),2.01-1.83(4H,m),1.79-1.65(1H,m),0.99(3H,t,J=7Hz);
TLC:Rf0.17(氯仿∶甲醇∶水=9∶1∶0.1)。实施例2(235)
2R-(4-(吡咯烷-1-基)苯基)丁酸4-((2R-羧基吡咯烷-1-基)磺酰基)-2-甲基苯基酯
NMR(CD3OD):δ7.77-7.68(2H,m),7.57 and 7.48(each 2H,d,J=8Hz),7.15(1H,d,J=8Hz),4.22-4.17(1H,m),3.93(1H,t,J=7Hz),3.74-3.66(4H,m),3.52-3.42 and 3.35-3.21(each 1H,m),2.28-2.22(5H,m),2.02(3H,s),2.01-1.87(4H,m),1.80-1.64(1H,m),0.99(3H,t,J=7Hz);
TLC:Rf0.18(氯仿∶甲醇∶水=9∶1∶0.1)。实施例2(236)
NMR(CD3OD):δ7.85-7.70(2H,m),7.64(4H,s),7.22(1H,d,J=8.0Hz),3.98(1H,t,J=8.0Hz),4.00-3.80(1H,m),3.85-3.70(4H,m),3.55-3.20(2H,m),3.15-2.95(2H,m),2.40-1.80(2H,m),2.35-2.25(4H,m),2.06(3H,s),2.00-1.40(4H,m),1.00(3H,t,J=7.5Hz);
TLC:Rf0.29(氯仿∶甲醇∶水=4∶1∶0.1)。实施例2(237)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((4-氨基哌啶-1-基)磺酰基)-2-甲基苯基酯·二盐酸盐
NMR(DMSO-d6):δ8.14(2H,brs),7.63(1H,s),7.60(1H,d,J=8.4Hz),7.21(2H,d,J=8.4Hz),7.20(1H,d,J=8.4Hz),6.64(2H,d,J=8.4Hz),3.8-3.5(4H,br),3.3-3.2(5H,br),3.2-3.0(1H,br),2.5-2.3(2H,m),2.2-2.0(1H,m),2.0-1.9(4H,br),1.98(3H,s),1.9-1.7(1H,m),1.7-1.5(2H,m),0.90(3H,t,J=7.2Hz);
TLC:Rf0.20(氯仿∶甲醇=9∶1)。实施例2(238)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((2S-羧基氮杂环丁烷-1-基)磺酰基)-2-甲基苯基酯
NMR(CD3OD):δ7.72(1H,s),7.71(1H,d,J=8.0Hz),7.22(2H,d,J=8.8Hz),7.17(1H,d,J=8.0Hz),6.58(2H,d,J=8.8Hz),4.30(1H,t,J=8.5Hz),3.8-3.6(3H,m),3.4-3.2(4H,m),2.4-2.1(3H,m),2.1-2.0(4H,brs),2.0-1.8(1H,m),2.04(3H,s),1.00(3H,t,J=7.4Hz);
TLC:Rf0.59(氯仿∶甲醇∶乙酸=25∶5∶1)。实施例2(239)
NMR(CDCl3):δ7.65(1H,s),7.63(1H,d,J=8.2Hz),7.21(2H,d,J=8.6Hz),6.99(1H,d,J=8.2Hz),6.53(2H,d,J=8.6Hz),4.7-4.6(1H,brs),4.7-4.1(1H,br),3.59(1H,t,J=7.7Hz),3.5-3.2(6H,brs),2.3-2.1(1H,m),2.1-1.9(4H,brs),2.0-1.8(1H,m),1.98(3H,s),1.6-1.2(6H,br),0.96(3H,t,J=7.4Hz)
TLC:Rf0.12(氯仿∶甲醇=9∶1)。实施例2(240)
2R-(4-(吡咯烷-1-基)苯基)丁酸4-((2-氧代-5S-羧基吡咯烷-1-基)磺酰基)-2-甲基苯基酯·盐酸盐
NMR(CD3OD):δ7.96-7.82(2H,m),7.57(2H,d,J=8.5Hz),7.42(2H,d,J=8.5Hz),7.13(1H,d,J=8.0Hz),4.90-4.80(1H,m),3.92(1H,t,J=7.5Hz),3.74-3.60(4H,m),2.65-1.80(10H,m),2.02(3H,s),0.99(3H,t,J=7.5Hz);
TLC:Rf0.35(氯仿∶甲醇∶乙酸=4∶1∶0.1)实施例2(241)
2RS-(3-(吡咯烷-1-基)苯基)丁酸4-((2S-羧基吡咯烷1-基)磺酰基)-2-甲基苯基酯
NMR(CDCl3):δ7.70-7.64(2H,m),7.20(1H,t,J=7.8Hz),7.09(1H,d,J=7.8Hz),6.66(1H,d,J=7.8Hz),6.53-6.47(2H,m),4.3-4.2(1H,m),3.8-3.4(2H,m),3.4-3.2(5H,m),2.3-1.7(13H,m),1.01(3H,t,J=7.4Hz);
TLC:Rf0.58(氯仿∶甲醇∶乙酸=9∶1∶0.2)。实施例2(242)
NMR(DMSO-d6):δ7.73(1H,s),7.66(1H,d,J=8.6Hz),7.26(2H,d,J=8.8Hz),7.15(1H,d,J=8.6Hz),6.78(2H,d,J=8.8Hz),5.00(1H,brs),4.02(1H,t,J=7Hz),3.82(1H,m),3.76(1H,t,J=7Hz),3.41(2H,m),3.31(4H,m),2.83(3H,s),2.15(2H,m),2.00(4H,m),1.98(3H,s),1.95(2H,m),0.92(3H,t,J=7.4Hz);
TLC:Rf0.34(氯仿∶甲醇∶水-4∶1∶0.1)。实施例2(243)
NMR(DMSO-d6):δ7.77(1H,d,J=2.4Hz),7.70(1H,dd,J=8.4Hz,2.4Hz),7.26(2H,d,J=8.2Hz),7.16(1H,d,J=8.4Hz),6.75(2H,d,J=8.2Hz),4.80(1H,brs),4.31(1H,dd,J=9.2Hz,3.2Hz),3.76(2H,m),3.33(6H,m),3.12(3H,s),2.12(2H,m),2.02(4H,m),1.98(3H,s),1.80(2H,m),0.91(3H,t,J=7.2Hz);
TLC:Rf0.47(氯仿:甲醇∶水=4∶1∶0.1)。实施例2(244)
NMR(CD3OD):δ7.76-7.66(2H,m),7.60-7.40(3H,m),7.15(1H,d,J=8.0Hz),4.30-4.10(2H,m),3.85-3.70(4H,m),3.55-3.15(2H,m),2.57(3H,s),2.40-2.15(5H,m),2.00(3H,s),2.10-1.60(5H,m),1.01(3H,t,J=7.5Hz);
TLC:Rf0.33(氯仿∶甲醇∶乙酸=4∶1∶0.1)。实施例2(245)
NMR(CD3OD):δ7.72(1H,s),7.70(1H,m),7.20(2H,d,J=8.6Hz),7.09(1H,d,J=8.0Hz),6.58(2H,d,J=8.6Hz),4.32(1H,m),4.21(1H,m),3.73-3.42(2H,m),3.38-3.16(5H,m),2.35-1.68(11H,m),0.98(3H,t,J=7.0Hz);
TLC:Rf0.55(氯仿∶甲醇∶乙酸=15∶2∶1)。实施例2(246)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-甲氧基-N-羧基甲基氨基磺酰基)-2-甲基苯基酯·盐酸盐
NMR(CDCl3):δ7.66(1H,s),7.63(1H,d,J=8.0Hz),7.22(2H,d,J=8.8Hz),7.08(1H,d,J=8.0Hz),6.54(2H,d,J=8.8Hz),5.3-4.6(1H,br),3.81(3H,s),3.70(2H,s),3.69(1H,t,J=7.8Hz),3.3-3.2(4H,brs), 2.2-2.0(1H,m),2.1-1.9(4H,brs),2.01(3H,s),2.0-1.8(1H,m),0.97(3H,t,J=7.4Hz);
TLC:Rf0.44(hexane∶ethyl acetate=2∶1).
TLC:Rf0.44(己烷∶乙酸乙酯=2∶1)。实施例2 (247)
2RS-(2-甲氧基-4-(吡咯烷-1-基)苯基)丁酸4-((2S-羧基吡咯烷-1-基)磺酰基)-2-甲基苯基酯·盐酸盐
NMR(DMSO-d6):δ7.74(1H,s),7.68(1H,d,J=8.5Hz),7.24-7.06(2Hm),6.50-6.30(2H,m),4.18-4.06(1H,m),4.00(1H,t,J=7.0Hz), 3.83(3H,s),3.40-3.05(6H,m),2.20-1.45(10H,m),2.05(3H,s),0.89(3H,t,J=7.5Hz);
TLC:Rf0.40(氯仿∶甲醇∶乙酸=4∶1∶0.1)。实施例2 (248)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((2S-羧基氮丙啶-1-基)磺酰基)-2-甲基苯基酯
NMR(CDCl3+CD3OD):δ7.74(1H,s),7.70(1H,d,J=8.4Hz),7.20(2H,d,J=8.4Hz),7.08(1H,d,J=8.4Hz),6.54(2H,d,J=8.4Hz), 3.61(1H,t,J=7.5Hz),3.3-3.2(4H,brs),2.6-2.3(3H,brs),2.3-2.1(1H,m),2.1-1.9(4H,brs),2.0-1.8(1H,m), 1.99(3H,s),0.97(3H,t,J=7.4Hz);
TLC:Rf0.28(氯仿∶甲醇=4∶1)。实施例2 (249)
NMR(DMSO-d6):δ8.25(4H,m),7.80(1H,d,J=1.0Hz),7.71(1H,dd,J=8.6Hz,1.0Hz),7.26(3H,m),6.82(2H,m),3.78(1H,t,J=7.8Hz),3.35(8H,m),3.04(4H,m),2.13(1H,m),2.02(3H,s),1.98(4H,m),1.85(1H,m),0.92(3H,t,J=7.2Hz);
TLC:Rf0.31(氯仿∶甲醇∶水=6∶4∶1)。实施例2 (250)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-羧基甲基-N-(2-(N’,N’-二甲基氨基)乙基)氨基磺酰基)-2-甲基苯基酯·三氟乙酸盐
NMR(CDCl3):δ7.61-7.55(2H,m),7.21(2H,d,J=8.7Hz),7.07(1H,d,J=8.2Hz),6.54(2H,d,J=8.7Hz),3.80(2H,s),3.60(1H,t,J=7.8Hz),3.55-3.10(8H,m),2.83(6H,s),2.30-1.70(9H,m),0.98(3H,t,J=7.4Hz);
TLC:Rf0.43(氯仿∶甲醇∶水=8∶2∶0.2)。实施例2 (251)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((2S-羧基吡咯烷-1-基)磺酰基)-2-乙基苯基酯
NMR(CDCl3):δ7.8-7.6(m,2H),7.36(d,J=8.4Hz,2H),7.07(d,J=8.4Hz,1H),7.02(d,J=8.4Hz,2H),4.3-4.2(m,1H),3.70(t,J=7.2Hz,1H),3.6-3.4(m,5H),3.3-3.1(m,1H),2.37(q,J=7.6Hz,2H),2.3-1.6(m,10H),1.03(t,J=7.6Hz,3H),0.99(t,J=7.6Hz,3H);
TLC:Rf0.33(氯仿∶甲醇∶乙酸=50∶2∶1)。实施例2 (252)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-羧基甲基-N-苄氧基氨基磺酰基)-2-甲基苯基酯·盐酸盐
NMR(DMSO-d6):δ7.70(1H,s),7.68(1H,d,J=8.6Hz),7.32(5H,s),7.20(2H,d,J=8.2Hz),7.16(1H,d,J=8.6Hz),6.52(2H,d,J=8.2Hz),5.25(2H,s),3.8-3.4(2H,m),3.5-3.4(2H,brs),3.3-3.1(4H,brs),2.2-2.0(1H,m),2.0-1.8(4H,brs),1.9-1.7(1H,m),1.93(3H,s),0.89(3H,t,J=7.2Hz);
TLC:Rf0.29(氯仿∶甲醇=9∶1)。实施例2 (253)
NMR(DMSO-d6+2 drops of D2O):δ7.66(1H,s-like),7.63(1H,dd,J=2and8Hz),7.24(2H,d,J=8Hz),7.14(2H,d,J=8Hz),6.69(2H,d,J=8Hz),3.74(1H,t,J=7Hz),3.31-3.25(4H,m),2.71(2H,t,J=7Hz),2.18-1.72(2H,m),2.15(2H,t,J=7Hz),2.01-1.94(4H,m),1.96(3H,s),1.53-1.34(4H,m),0.91(3Ht,J=7Hz);
TLC:Rf0.38(氯仿∶甲醇∶水=9∶1∶0.1)。实施例2 (254)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(1,1-二甲基-1-羧基甲基)氨基磺酰基)-2-甲基苯基酯
NMR(DMSO-d6):δ7.68(1H,s-like),7.64(1H,dd,J=2 and 8Hz),7.39(1H,br),7.18(2H,d,J=8Hz),7.07(1H,d,J=8Hz),6.53(2H,d,J=8Hz),3.69(1H,t,J=7Hz),3.24-3.18(4H,m),2.20-1.65(2H,m),1.98-1.91(4H,m),1.93(3H,s),1.18(6H,s),0.90(3H,t,J=7Hz);
TLC:Rf0.19(氯仿∶甲醇∶水=9∶1∶0.1)。实施例2 (255)
NMR(CDCl3):δ7.71(1H,s),7.69(1H,d,J=8.6Hz),7.23(2H,d,J=8.8Hz),7.13(1H,d,J=8.6Hz),6.55(2H,d,J=8.8Hz),6.54(1H,s),3.63(1H,t,J=7.7Hz),3.3-3.2(4H,brs),2.81(3H,s),2.3-2.1(1H,m),2.1-1.9(4H,brs),2.06(3H,s),2.0-1.8(1H,m),0.99(3H,t,J=7.3Hz);
TLC:Rf0.43(己烷∶乙酸乙酯=2∶1)。实施例2 (256)
NMR(CDCl3):δ8.15-8.05(2H,m),7.75-7.65(2H,m),7.56(1H,d,J=8.0Hz),7.09(1H,d,J=9.0Hz),4.25(1H,dd,J=3.5,7.0Hz),4.13(1H,t,J=7.5Hz),3.60-3.40(1H,m),3.30-3.10(1H,m),2.59(3H,s),2.45-1.60(6H,m),1.99(3H,s),1.02(3H,t,J=7.5Hz);
TLC:Rf0.24(氯仿∶甲醇∶水=9∶1∶0.1)。实施例2 (257)
2RS-(4-(吡啶烷-1-基)苯基)丁酸4-(N-羧基甲基氨基磺酰基)-2-甲基苯基酯
NMR(CDCl3):δ7.70-7.58(2H,m),7.25(2H,d,J=8Hz),7.01(1H,d,J=8Hz),6.65(2H,d,J=8Hz),5.43-5.23(1H,br),5.18-4.80(1H,br),3.75(2H,brs),3.63(1H,t,J=7Hz),3.40-3.20(4H,m),2.28-1.80(9H,m),0.98(3H,t,J=7Hz);
TLC:Rf0.11(氯仿∶甲醇∶乙酸=40∶2∶1)。实施例2 (258)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(1,1-二甲基-1-羧基甲基)-N-丙基氨基磺酰基)-2-甲基苯基酯
NMR(DMSO-d6+2 drops of D2O):δ7.80(1H,s-like),7.78(1H,dd,J=2 and 8Hz),7.18(2H,d,J=8Hz),7.11(1H,d,J=8Hz),6.54(2H,d,J=8Hz),3.70(1H,t,J=7Hz),3.25-3.17(4H,m),3.12-3.04(2H,m),2.20-1.70(2H,m),1.99-1.92(4H,m),1.95(3H,s),1.57-1.42(2H,m),1.45(6H,s),0.91(3H,t,J=7Hz),0.71(3H,t,J=7Hz);
TLC:Rf0.57(氯仿∶甲醇∶水=9∶1∶0.1)。实施例2 (259)
NMR(CD3OD):δ7.83-7.68(2H,m),7.63(4H,s-like),7.22(1H,d,J=8.2Hz),4.21(1H,dd,J=9.2 and 3.4Hz),3.98(1H,t,J=7.8Hz),3.90-3.43(7H,m),2.70-1.84(8H,m),2.06(3H,s),1.00(3H,t,J=7.4Hz);
TLC:Rf0.46(乙酸乙酯∶乙酸∶水=6∶2∶1)。实施例2 (260)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((2S-羧基-4R-氨基吡咯烷-1-基)磺酰基)-2-甲基苯基酯·二盐酸盐
NMR(CD3OD):δ7.84-7.68(2H,m),7.63(4H,s-like),7.18(1H,d,J=8.0Hz),4.55(1H,dd,J=8.4 and 4.2Hz),4.07-3.90(2H,m),3.90-3.63(5H,m),3.47-3.26(1H,m),2.53-1.82(8H,m),2.05(3H,s),1.00(3H,t,J=7.4Hz);
TLC:Rf0.42(乙酸乙酯∶乙酸∶水=6∶2∶1)。实施例2 (261)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-羧基甲基-N-(2-(吗啉-4-基)乙基)氨基磺酰基)-2-甲基苯基酯·盐酸盐
NMR(CDCl3):δ7.66-7.52(2H,m),7.21(2H,d,J=8.5Hz),7.09(1H,d,J=8.5Hz),6.55(2H,d,J=8.5Hz),3.95-3.80(4H,m),3.75(2H,s),3.61(1H,t,J=7.5Hz),3.45-3.20(6H,m),3.10-2.70(6H,m),2.30-1.75(6H,m),2.04(3H,s),0.99(3H,t,J=7.5Hz);
TLC:Rf0.24(氯仿∶甲醇∶水=9∶1∶0.1)。实施例2 (262)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((2S-羧基-4S-乙酰基氨基吡咯烷-1-基)磺酰基)-2-甲基苯基酯·盐酸盐
NMR(DMSO-d6):δ8.02(1H,d,J=7.8Hz),7.74(1H,d,J=2.2Hz),6.69(1H,dd,J=8.4Hz,2.2Hz),7.17(2H,d,J=8.6Hz),7.17(1H,d,J=8.4Hz),6.54(2H,d,J=8.6Hz),4.13(1H,t,J=7.8Hz),3.82(1H,m),3.70(1H,t,J=7.6Hz),3.50(1H,m),3.22(4H,m),3.06(1H,m),2.31(1H,m),2.07(1H,m),1.99(3H,s),1.96(4H,m),1.82(2H,m),1.75(3H,s),0.91(3H,t,J=7.4Hz);
TLC:Rf0.18(氯仿∶甲醇∶水=4∶1∶0.1)。实施例2 (263)
2RS-(4-(吡咯烷-1-基)苯基)-2-丁烯酸4-((2S-羧基吡咯烷-1-基)磺酰基)-2-甲基苯基酯
NMR(CDCl3):δ7.80-7.65(2H,m),7.32(1H,q,J=7Hz),7.23(1H,d,J=8Hz),7.13(2H,d,J=8Hz),6.59(2H,d,J=8Hz),4.30-4.20(1H,m),4.10-3.60(1H,b),3.60-3.45(1H,m),3.40-3.20(5H,m),2.30-1.65(8H,m),2.25(3H,s),1.88(3H,d,J=7Hz);
TLC:Rf0.28(氯仿∶甲醇∶乙酸=4∶2∶0.1)。实施例2 (264)
NMR(DMSO-d6):δ7.78(1H,d,J=5Hz),7.68(1H,s),7.64(1H,d,J=8.0Hz),7.19(2H,d,J=8.6Hz),7.16(1H,d,J=8.0Hz), 6.56(2H,d,J=8.6Hz),4.28(1H,t,J=7.8Hz),4.12(1H,m),3.75(1H,m),3.48(1H,m),3.23(4H,m),3.06(1H,m),2.12(1H,m),2.03(2H,m),1.99(3H,s),1.96(4H,m),1.80(1H,m),1.54(3H,s),0.91(3H,t,J=7.2Hz);
TLC:Rf0.19(氯仿∶甲醇∶水=4∶1∶0.1)。实施例2 (265)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((2RS-羧基-5-硝基二氢吲哚-1-基)磺酰基)-2-甲基苯基酯
NMR(CDCl3):δ8.33(1H,d,J=2Hz),7.89(1H,dd,J=8.2Hz),7.67(1H,s),7.62(1H,d,J=8Hz),7.20(1H,d,J=8Hz),7.18(2H,d,J=8Hz),7.02(1H,d,J=8Hz),6.55(2H,d,J=8Hz),4.85(1H,dd,J=10,5Hz),4.60-4.25(1H,br),3.59(1H,t,J=7Hz),3.40-3.15(6H,m),2.25-1.75(9H,m),0.95(3H,t,J=7Hz);
TLC:Rf0.30(氯仿∶甲醇∶乙酸=4∶2∶0.1)。实施例2 (266)
NMR(CDCl3):δ7.88(1H,dd,J=2.0,8.5Hz), 7.78(1H,d,J=2.0Hz),7.75-7.65(2H,m),7.49(1H,d,J=8.5Hz),7.12(1H,d,J=9.0Hz),4.30-4.15(2H,m),3.98(3H,s),3.60-3.40(1H,m),3.30-3.10(1H,m),2.40-1.60(6H,m),2.08(3H,s),1.00(3H,t,J=7.5Hz);
TLC:Rf0.38(氯仿∶甲醇∶乙酸=4∶2∶0.1)。实施例2 (267)
NMR(CD3OD):δ7.77(1H,s),7.75(1H,d,J=8.0Hz),7.37(2H,d,J=8.6Hz),7.19(1H,d,J=8.0Hz),6.98(2H,d,J=8.6Hz),4.18(1H,m),3.69(3H,m),3.59(1H,m),3.46(4H,m),2.72(3H,s),2.57(1H,m),2.21(2H,m),2.13(4H,m),2.02(3H,s),1.93(1H,m),0.98(3H,t,J=7.4Hz);
TLC:Rf0.28(氯仿∶甲醇∶水=4∶1∶0.1)。实施例2 (268)
NMR(CD3OD):δ7.81(1H,s),7.78(1H,d,J=8.2Hz),7.62(4H,s),7.21(1H,d,J=8.2Hz), 4.25(1H,t,J=7Hz),3.98 (1H,t,J=7Hz),3.77(4H,m),3.65(3H,m),2.90(6H,s),2.80(1H,m),2.29(4H,m),2.24(2H,m),2.06(3H,s),1.99(1H,m),1.00(3H,t,J=7.4Hz);
TLC:Rf0.42(氯仿∶甲醇∶水=6∶4∶1)。实施例2 (269)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-羟基氨基磺酰基)-2-甲基苯基酯·盐酸盐
NMR(CDCl3):δ7.73(1H,s),7.68(1H,d,J=8.6Hz),7.23(2H,d,J=8.0Hz),7.2-7.0(2H,br),7.04(1H,d,J=8.6Hz),6.63(2H,d,J=8.0Hz),3.63(1H,t,J=7.7Hz),3.4-3.2(4H,brs),2.3-2.1(1H,m),2.1-1.9(4H,brs),2.00(3H,s),2.0-1.8(1H,m),0.97(3H,t,J=7.3Hz);
TLC:Rf0.25(己烷∶乙酸乙酯=2∶1)。实施例2 (270)
NMR(CDCl3):δ7.76-7.62(6H,m),7.23(1H,d,J=8.5Hz),4.01(1H,t,J=7.5Hz),4.00-3.75(6H,m),3.55-3.30(2H,m),2.68(6H,s),2.45-1.80(8H,m),2.07(3H,s),1.31(6H,d,J=6.5Hz),1.00(3H,t,J=7.5Hz);
TLC:Rf0.66(氯仿∶甲醇∶水=4∶1∶0.1)。实施例2 (271)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((2RS-甲基哌嗪-4-基)磺酰基)-2-甲基苯基酯·二甲磺酸盐
NMR(CDCl3):δ7.76-7.60(6H,m),7.23(1H,d,J=8.0Hz),4.01(1H,t,J=7.5Hz),3.90-3.72(6H,m),3.55-3.35(2H,m),3.32-3.13(1H,m),2.82-2.62(1H,m),2.67(6H,s),2.49(1H,dd,J=13.0,10.0Hz),2.40-1.80(6H,m),2.07(3H,s),1.32(3H,d,J=6.5Hz),1.00(3H,t,J=7.5Hz);
TLC:Rf0.45(氯仿∶甲醇∶水=9∶1∶0.1)。实施例2 (272)
NMR(DMSO-d6):δ11.38(1H,m),7.77(1H,s),7.72(1H,d,J=8.2Hz),7.19(3H,m),6.63(2H,d,J=8.6Hz),4.38(1H,m),4.01(1H,m),3.82(1H,m),3.73(1H,t,J=7.4Hz),3.49(1H,t,J=8.6Hz),3.24(4H,m),2.70(6H,s),2.36(2H,m),2.11(1H,m),1.99(3H,s),1.97(4H,m),1.83(1H,m),0.91(3H,t,J=7.2Hz);
TLC:Rf0.44(氯仿∶甲醇∶水=6∶4∶1)。实施例2 (273)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((2S-羧基-4R-甲基氨基吡咯烷-1-基)磺酰基)-2-甲基苯基酯·二盐酸盐
NMR(CD3OD):δ7.76(1H,s),7.73(1H,d,J=8.0Hz),7.25(2H,d,J=8.4Hz),7.13(1H,d,J=8.0Hz),6.71(2H,d,J=8.4Hz),4.53(1H,m),3.97(1H,m),3.86(1H,m),3.70(1H,t,J=8Hz),3.41(1H,m),3.35(4H,m),2.70(3H,s),2.49(1H,m),2.31(1H,m),2.17(1H,m),2.06(4H,m),2.00(3H,s),1.92(1H,m),0.98(3H,t,J=7.2Hz);
TLC:Rf0.46(氯仿∶甲醇∶水=6∶4∶1)。实施例2 (274)
NMR(CD3OD):δ7.75-7.50(6H,m),7.25(1H,d,J=9.0Hz), 3.97(1H,t,J=7.5Hz),3.85-3.70(4H,m),3.35-3.15(8H,m),2.50-1.80(8H,m),1.00(6H,t,J=7.5Hz);
TLC:Rf0.46(氯仿∶甲醇∶水=9∶1∶0.1)。实施例2 (275)
NMR(CD3OD):δ7.75-7.58(6H,m),7.25(1H,d,J=9.0Hz),3.98(1H,t,J=7.5Hz),3.90-3.70(4H,m),3.40-3.20(8H,m),2.50-1.80(8H,m),1.00(6H,t,J=7.5Hz);
TLC:Rf0.46(氯仿∶甲醇∶水= 9∶1∶0.1)。实施例2 (276)
2S-(4-(吡咯烷-1-基)苯基)丁酸4-(哌嗪-4-基磺酰基)-2-甲基苯基·二盐酸盐
NMR(CD3OD):δ7.71(6H,m),7.22(1H,d,J=8.0Hz),4.00(1H,t,J=8Hz),3.81(4H,m),3.31(8H,s),2.33(4H,m),2.24(1H,m),2.07(3H,s),1.98(1H,m),1.01(3H,t,J=7.4Hz);
TLC:Rf0.66(氯仿∶甲醇∶水=4∶1∶0.1)。实施例2 (277)
2R-(4-(吡咯烷-1-基)苯基)丁酸4-(哌嗪-4-基磺酰基)-2-甲基苯基酯·二盐酸盐
NMR(CD3OD):δ7.70(6H,m),7.22(1H,d,J=8.0Hz),4.00(1H,t,J=8Hz),3.81(4H,m),3.30(8H,s),2.32(4H,m),2.24(1H,m),2.06(3H,s),1.99(1H,m),1.00(3H,t,J=7.4Hz);
TLC:Rf0.66(氯仿∶甲醇∶水=4∶1∶0.1)。实施例2 (278)
NMR(CDCl3):δ7.70-7.58(2H,m),7.23(2H,d,J=8Hz),7.09(1H,d,J=8Hz),6.55(2H,d,J=8Hz),4.00-3.84(1H,m),3.62(1H,t,J=7Hz),3.50-3.35(1H,m),3.35-3.20(4H,m),3.18-3.03(2H,m),2.54(1H,dd,J=15,10Hz),2.30-1.40(13H,m),0.98(3H,t,J=7Hz);
TLC:Rf0.39(己烷∶乙酸乙酯∶乙酸=50∶50∶1)。实施例2 (279)
NMR(DMSO-d6):δ8.02(1H,d,J=6Hz),7.74(1H,s),7.69(1H,dJ=8.8Hz),7.24(2H,d,J=8.6Hz),7.18(1H,d,J=8.6Hz),6.69(1H,d,J=8.8Hz),4.15(1H,t,J=7Hz),3.75(2H,m),3.51(1H,m),3.28(4H,m),3.05(1H,m),2.33(1H,m),2.12(1H,m),1.99(7H,s-like),1.83(2H,m),1.75(3H,s),0.91(3H,t,J=7.4Hz);
TLC:Rf0.67(氯仿∶甲醇∶水=6∶4∶1)。实施例2 (280)
NMR(DMSO-d6):δ7.87(1H,d,J=2.2Hz),7.79(1H,dd,J=8.6Hz,2.2Hz),7.50(1H,s),7.25-7.13(5H,m),6.66(2H,d,J=8.0Hz),3.88(3H,s),3.78(3H,s),3.71(1H,t,J=7.2Hz),3.26(4H,m),2.08(1H,m),1.97(4H,m),1.93(3H,s),1.78(1H,m),0.88(3H,t,J=7.6Hz),
TLC:Rf0.45(氯仿∶甲醇∶水=4∶1∶0.1)。实施例2 (281)
2S-(4-(吡咯烷-1-基)苯基)丁酸4-((2RS-羧基二氢吲哚-1-基)磺酰基)-2-甲基苯基酯·盐酸盐
NMR(DMSO-d6):δ7.78(1H,s),7.67(1H,dd,J=2 and 8Hz),7.35-6.94(7H,m),6.80-6.64(2H,br),5.00-4.93(1H,m),3.70(1H,t,J=7Hz),3.39-2.96(6H,m),2.17-1.64(2H,m),2.04-1.94(4H,m),1.91(3H,s),0.87(3H,t,J=7Hz);
TLC:Rf0.30(氯仿∶甲醇∶水=4∶1∶0.1)。实施例2 (282)
NMR(CD3OD):δ7.75-7.60(6H,m),7.23(1H,d,J=8.5Hz),4.00(1H,t,J=7.5Hz),3.90-3.70(6H,m),3.55-3.35(2H,m),3.35-3.10(1H,m),2.80-2.65(1H,m),2.66(6H,s),2.47(1H,t,J=10.0Hz),2.06(3H,s),1.31(3H,d,J=6.5Hz)1.00(3H,t,J=7.5Hz);
TLC∶Rf0.45(氯仿∶甲醇∶水=9∶1∶0.1)。实施例2 (283)
2RS-(4-(吡咯烷-1-基)苯基丁酸4-((4-甲酰基哌嗪-1-基)磺酰基)-2-甲基苯基酯·盐酸盐
NMR(CD3OD):δ7.96(1H,s),7.73-7.52(6H,m),7.19(1H,d,J=8.4Hz),3.97(1H,t,J=7.6Hz),3.88-3.67(4H,m),3.67-3.44(4H,m),3.12-2.93(4H,m),2.43-2.14(5H,m),2.12-1.81(4H,m),1.00(3H,t,J=7.2Hz);
TLC:Rf0.38(己烷∶乙酸乙酯=1∶2)。实施例2 (284)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((2S-羧基吡咯烷-1-基)磺酰基)-2-甲基苯基酯·钠盐
NMR(d6-DMSO):δ7.78-7.64(2H,m),7.18(2H,d,J=8.0Hz),7.08(1H,d,J=8.0Hz),6.53(2H,d,J=8.0Hz),3.95-3.80(1H,m),3.69(1H,t,J=7.5Hz),3.50-3.00(6H,m),2.20-1.30(10H,m),1.96(3H,s),0.91(3H,t,J=7.5Hz);
TLC∶Rf0.32(氯仿∶甲醇∶水=9∶1∶0.1)。实施例2 (285)
NMR(CDCl3):δ7.65(4H,d,J=8.5Hz),7.54(2H,d,J=8.5Hz),7.05(1H,d,J=8.5Hz),4.30-4.15(1H,m),4.10-3.50(4H,m),3.80(1H,t,J=7.5Hz),3.55-3.35(1H,m),3.30-3.10(1H,m),2.87(3H,s),2.50-1.60(10H,m),2.03(3H,s),0.99(3H,t,J=7.5Hz);
TLC:Rf0.32(氯仿∶甲醇∶水=9∶1∶0.1)。实施例2 (286)
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((哌嗪-4-基)磺酰基)-2-甲基苯基酯·二甲磺酸盐
NMR(CD3OD):δ7.75-7.60(6H,m),7.23(1H,d,J=8.0Hz),4.01(1H,tJ=7.5Hz),3.90-3.70(4H,m),3.35-3.20(8H,m),2.68(6H,s),2.40-1.80(6H,m),2.06(3H,s),1.00(3H,t,J=7.5Hz);
TLC∶Rf0.14(氯仿∶甲醇∶乙酸=40∶2∶1)。实施例2 (287)
NMR(CD3OD):δ7.66(1H,brs),7.62(1H,brd,J=8.0Hz),7.20(2H,d,J=8.5Hz),7.18(1H,d,J=8.0Hz),6.58(2H,d,J=8.5Hz),3.67(1H,t,J=7.5Hz),3.60(2H,q,J=7.0Hz),3.40-3.15(12H,m),2.76(4H,dd,J=8.0,14.0Hz),2.30-1.70(9H,m),1.17(3H,t,J=7.0Hz),0.97(3H,t,J=7.5Hz);
TLC:Rf0.11(氯仿∶甲醇∶乙酸=40∶2∶1)。实施例2 (288)
2S-(4-(吡咯烷-1-基)苯基)丁酸4-(哌嗪-4-基磺酰基)-2-甲基苯基酯·琥珀酸盐
NMR(CD3OD):δ7.64(1H,brs),7.61(1H,brd,J=8.0Hz),7.19(2H,d,J=8.5Hz),7.17(1H,d,J=8.0Hz),6.57(2H,d,J=8.5Hz),3.64(1H,t,J=7.5Hz),3.40-3.20(4H,m),3.12(8H,s),2.51(4H,s),2.30-1.76(9H,m),0.97(3H,t,J=7.5Hz);
TLC:Rf0.11(氯仿∶甲醇∶乙酸=40∶2∶1)。实施例2 (289)
NMR(CD3OD):δ7.67(1H,brs),7.62(1H,brd,J=8.0Hz),7.22(2H,d,J=8.5Hz),7.19(1H,d,J=8.0Hz),6.58(2H,d,J=8.5Hz),4.28(1H,dd,J=5.0,7.5Hz),3.68(1H,t,J=7.5Hz),3.40-3.05(12H,m),2.78(1H,dd,J=5.0,15.0Hz),2.52(1H,dd,J=7.5,15.0Hz),2.40-1.72(9H,m),0.98(3H,t,J=7.5Hz);
TLC:Rf0.11(氯仿∶甲醇∶乙酸=40∶2∶1)。实施例2 (290)
NMR(CD3OD):δ7.68(1H,brs),7.63(1H,brd,J=8.0Hz),7.21(2H,d,J=8.5Hz),7.19(1H,d,J=8.0Hz),6.82(2H,s),6.59(2H,d,J=8.5Hz),3.65(1H,t,J=7.5Hz),3.40-3.10(12H,m),2.30-1.70(9H,m),0.98(3H,t,J=7.5Hz);
TLC:Rf0.11(氯仿∶甲醇∶乙酸=40∶2∶1)。实施例2 (291)
2S-(4-(吡咯烷-1-基)苯基)丁酸4-(哌嗪-4-基磺酰基)-2-甲基苯基酯·草酸盐
NMR(CD3OD):δ7.68(1H,s),7.63(1H,brd,J=8.0Hz),7.20(2H,d,J=8.5Hz),7.19(1H,d,J=8.0Hz),6.60(2H,d,J=8.5Hz),3.66(1H,t,J=7.5Hz),3.45-3.10(12H,m),2.30-1.75(9H,m),0.98(3H,1,J=7.5Hz);
TLC:Rf0.11(氯仿∶甲醇∶乙酸=40∶2∶1)。实施例2 (292)
NMR(CD3OD):δ7.65(1H,s),7.61(1H,brd,J=8.0Hz),7.20(2H,d,J=8.5Hz),7.17(1H,d,J=8.0Hz),6.57(2H,d,J=8.5Hz),4.04(1H,q,J=7.0Hz),3.65(1H,t,J=7.5Hz),3.40-3.20(4H,m),3.14(8H,s),2.15(3H,s),2.20-1.75(6H,m),1.31(3H,d,J=7.0Hz),0.97(3H,t,J=7.5Hz);
TLC:Rf0.11(氯仿∶甲醇∶乙酸=40∶2∶1)。实施例2 (293)
NMR(CD3OD):δ7.68(1H,s),7.64(1H,brd,J=8.0Hz),7.21(2H,d,J=8.5Hz),7.18(1H,d,J=8.0Hz),6.59(2H,d,J=8.5Hz),4.43(2H,s),3.68(1H,t,J=7.5Hz),3.45-3.10(12H,m),2.40-1.78(9H,m),0.98(3H,t,J=7.5Hz);
TLC:Rf0.11(氯仿∶甲醇∶乙酸=40∶2∶1)。实施例2 (294)
2S-(4-(吡咯烷-1-基)苯基)丁酸4-(哌嗪-4-基磺酰基)-2-甲基苯基酯·二对甲苯磺酸盐
NMR(CD3OD):δ7.68(6H,d,J=8.0Hz),7.63(4H,d,J=9.0Hz),7.22(5H,d,J=8.0Hz),3.99(1H,t,J=7.4Hz),3.83-3.65(4H,m),3.30(8H,m),2.36(6H,s),2.36-2.20(5H,m),2.04(3H,s),1.95(1H,m),0.99(3H,t,J=7.4Hz);
TLC:Rf0.11(氯仿∶甲醇∶乙酸=40∶2∶1)。实施例2 (295)
2S-(4-(吡咯烷-1-基)苯基)丁酸4-(哌嗪-4-基磺酰基)-2-甲基苯基酯·磷酸盐
NMR(DMSO-d6):δ8.00-7.40(3H,m),7.67(1H,brs),7.62(1H,brd,J=8.8Hz),7.25(1H,d,J=8.8Hz),7.21(2H,d,J=8.8Hz),6.56(2H,d,J=8.8Hz),3.75(1H,t,J=7.4Hz),3.23(4H,brs),2.94(8H,brs),2.01(3H,s),2.20-1.80(6H,m),0.93(3H,t,J=7.4Hz);
TLC:Rf0.11(氯仿∶甲醇∶乙酸=40∶2∶1)。实施例2 (296)
NMR(CD3OD):δ7.67(1H,s),7.62(1H,brd,J=8.0Hz),7.20(2H,d,J=8.5Hz),7.19(1H,d,J=8.0Hz),6.58(2H,d,J=8.5Hz),6.23(2H,s),3.65(1H,t,J=7.5Hz),3.40-3.05(12H,m),2.30-1.78(6H, m),1.98(3H,s),0.97(3H,t,J=7.5Hz);
TLC:Rf0.11(氯仿∶甲醇∶乙酸=40∶2∶1)。实施例3
2RS-(4-甲基苯基)丁酸4-(2S-羟基磺酰基氧甲基吡咯烷-1-基磺酰基)-2-甲基苯基酯
将三氧化硫吡啶配合物(766mg)加入到实施例2(19)制备的化合物(690mg)的吡啶(10ml)溶液中,在室温下搅拌反应混合物30分钟。浓缩反应混合物,通过硅胶柱色谱(氯仿∶甲醇=10∶1)纯化残余物,得到具有下面物理数据的标题化合物(700mg)。
NMR(DMSO-d6):δ7.74(1H,d,J=2.0Hz),7.67(1H,dd,J=8.5,2.0Hz),7.30(2H,d,J=8.5Hz),7.20(2H,d,J=8.5Hz),7.18(1H,d,J=8.5Hz),3.94-3.78(2H,m),3.76-3.60(1H,m),3.58(1H,t,J=7.0Hz),3.3-3.2(1H,m),3.12-2.94(1H,m),2.31(3H s),2.25-2.00 and 1.95-1.70(each 1H,m),1.97(3H,s),1.90-1.60(2H,m),1.60-1.30(2H,m),0.91(3H,t,J=7.5Hz);
TLC:Rf0.39(水∶甲醇∶氯仿=1∶10∶40)。实施例3 (1)
通过与实施例3相同的方法,使用实施例2(10)制备的化合物,得到具有下面物理数据的标题化合物。
NMR(DMSO-d6):δ7.74(1H,s),7.67(1H,d,J=8.5Hz),7.25-7.10(3H,m),6.55(2H,d,J=8.0Hz),3.91(1H,d,J=8.5Hz),3.80-3.50(3H,m),3.40-3.20(1H,m),3.35-3.20(4H,m),3.15-2.90(1H,m),2.20-1.60(2H,m),1.98(3H,s),
2.05-1.90(4H,m),1.90-1.60(2H,m),1.60-1.30(2H,m),0.91
(3H,t,J=7.5Hz);
TLC:Rf0.38(水∶甲醇∶氯仿=1∶10∶40)。剂型实施例剂型实施例1
用常规方法混合下面组分,冲压得到每片含有50mg活性组分的100片片剂。
2S-(4-(吡咯烷-1-基)苯基)丁酸4-(哌嗪-4-基磺酰基)-2-甲基苯基酯·二盐酸盐 5.0g羧甲基纤维素钙(崩解剂) 0.2g硬脂酸镁(润滑剂) 0.1g微晶纤维素 4.7g剂型实施例2
用常规方法混合下面组分。用常规方法将该溶液消毒,将5ml部分放入安瓿中,冻干得到每安瓿含有20mg活性组分的100安瓿。
2S-(4-(吡咯烷-1-基)苯基)丁酸4-(哌嗪-4-基磺酰基)-2-甲基苯基酯·2盐酸盐 2.0g甘露糖醇 20g蒸馏水 1000ml
Claims (13)
1.下列式(I)的磺酰胺衍生物,或其无毒盐、酸加成盐或溶剂化物式中R1为C1-8烷基、C1-8烷氧基、羟基、酮基、硝基、卤原子、三卤甲基、氰基、脒基、-COOR7(其中R7为氢原子或C1-8烷基),或(其中p为0至4的整数,且R8和R9各自独立地为氢原子、C1-4烷基、C2-5酰基、-COOR10(其中R10为氢原子或C1-8烷基)、-CONR11R12(其中R11和R12各自独立地为氢原子或C1-4烷基),(其中为α-氨基酸残基),或R8和R9与它们相连的氮原子一起代表未取代或被C1-4烷基或苯基C1-4烷基取代的脂族杂环);n为0至5的整数;为碳环或杂环;其中R2和R3各自独立地为氢原子、C1-4烷基、C1-4烷氧基、卤原子、三卤甲基或苯基,或R2和R3一起代表C1-4亚烷基,或其中R2和R3与它们相连的碳原子一起代表C3-7环烷基;R4为C1-4烷基或C1-4烷氧基,或相互在邻位与苯核相连的2个R4一起代表C3-5亚烷基;m为0至4的整数;且其中R5和R6各自独立地为1)氢原子,2)羟基,3)C1-8烷基,4)C1-8烷氧基,5)苯基C1-4烷氧基,6)脒基,7)-M-R16(其中M为单键或C1-8亚烷基),且R16为i)-NR17R18(其中R17和R18各自独立地为氢原子或C1-4烷基),ii)-CONR19R20(其中R19和R20各自独立地为氢原子或C1-4烷基),iii)(其中为碳环,r为0至5的整数,且R21为C1-4烷基、C1-4烷氧基、硝基、脒基、-COOR22(其中R22为氢原子、C1-8烷基、苯基或苯基C1-4烷基)、-SO3H、-CONR23-E-R24(其中R23为氢原子或C1-4烷基,E为1-4个亚烷基,且R24为-COOR25(其中R25为氢原子、C1-8烷基、苯基或苯基C1-4烷基)或四唑环)、四唑环或吗啉代环),iv)杂环,该杂环为未取代的或被1-4个选自C1-4烷基、C1-4烷氧基、羟基、苯基C1-4烷基、-COOR26(其中R26为氢原子、C1-8烷基、苯基或苯基C1-4烷基)、羟基C1-4烷基或C2-4烷氧基烷基的取代基所取代),8)C1-8烷基,其被1个或2个-OR27(其中R27为氢原子、C1-4烷基、C2-4烷氧基烷基或被-OR28(其中R28为氢原子或C2-4烷氧基烷基)取代的C2-4烷基)所取代,9)-J-COOR29(其中R29为氢原子、C1-8烷基、苯基或苯基C1-4烷基,且J为单键、-(CH2)3-或(其中s为2至6的整数,且R30和R31各自独立地为i)氢原子,ii)C1-8烷基,iii)-COOR32(其中R32为氢原子、C1-8烷基、苯基或苯基C1-4烷基),iv)碳环或杂环,其为未取代或被1个或多个选自C1-4烷基、C1-4烷氧基烷基、氨基、硝基、羟基、卤原子、腈、胍基和脒基的取代基所取代,或v)C1-8烷基,其被1个或多个选自羟基、COOR33(其中R33为氢原子、C1-8烷基、苯基或苯基C1-4烷基)、NR34R35(其中R34和R35各自独立地为氢原子或C1-4烷基)、未取代或被1个或多个选自C1-4烷基、C1-4烷氧基烷基、氨基、硝基、羟基、卤原子、腈、胍基和脒基的取代基取代的碳环或杂环的取代基所取代,条件是C1-8烷基的碳原子可被硫原子替换,或其中R5和R6与它们相连的氮原子一起代表杂环,q为0至4的整数,且R15为1)羟基,2)酮基,3)被护酮基,4)C1-4烷基,5)C1-4烷氧基,6)苯基,7)苯氧基,8)苯基C1-4烷基,9)苯基C1-4烷氧基,10)硝基,11)-COOR36(其中R36为氢原子,C1-8烷基,被-CONR37R38(其中R37和R38各自独立地为氢原子或C1-4烷基)取代的C1-4烷基,被-NR39R40(其中R39和R40各自独立地为氢原子或C1-4烷基)取代的C1-4烷基,被OR41(其中R41为被OR42(其中R42为氢原子或C2-4烷氧基烷基)取代的C1-4烷基),或被哌嗪环取代的C1-4烷基),12)-NR43R44(其中R43和R44各自独立地为氢原子、C1-4烷基或C2-5酰基),13)-CONR45R46(其中R45和R46各自独立地为氢原子、羟基、C1-4烷基、苯基C1-4烷氧基或被羟基或-COOR47(其中R47为氢原子或C1-8烷基)取代的C1-4烷基),14)C1-4烷基,其被1个或多个选自羟基、-COOR48(其中R48为氢原子或C1-8烷基)、-NR49R50(其中R49和R50各自独立地为氢原子或C1-4烷基)、OSO3H或含有1或2个氮原子的5或6元杂环的取代基所取代,15)含有1或2个氮原子的5或6元杂环,16)卤原子,17)-CHO,或18)-NR51-COOR52(其中R51和R52各自独立地为氢原子或C1-8烷基)。
2.根据权利要求1的化合物,其中为3-15元单或多环芳烃环或脂族烃环。
8.根据权利要求1的化合物,其为下列化合物,或其无毒盐、酸加成盐或溶剂化物,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2S-叔丁氧基羰基吡咯烷-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2S-羟基甲基吡咯烷-1-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2-氧代吡咯烷-1-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(吡咯烷-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2S-(吡咯烷-1-基甲基)吡咯烷-1-基磺酰基)-2-甲基苯基酯,
2RS-苯基丁酸4-(吡咯烷-1-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(二氢吲哚-1-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基丁酸4-(2-(乙氧基羰基)二氢吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2-(乙氧基羰基)二氢吲哚-1-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2RS-(N,N-二甲基氨基羰基甲氧基羰基)二氢吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2RS-(N-苄氧基氨基甲酰基)二氢吲哚-1-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(6-硝基二氢吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(6-氨基二氢吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(7-硝基二氢吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(7-氨基二氢吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(苯并咪唑-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(吗啉-4-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(6-氮杂-7-氧代-二环[3.2.1]辛烷-6-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(4-苄基哌嗪-1-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(4-(2-羟基乙基)哌啶-1-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2RS-羟基甲基哌啶-1-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(4-N,N-二甲基氨基)哌啶-1-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(4-(嘧啶-2-基)哌嗪-1-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(1,4-二噁-8-氮杂螺[4.5]癸烷-8-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(3-氮杂二环[3.2.2]壬烷-3-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(1,3,3-三甲基-6-氮杂二环[3.2.1]辛烷-6-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2-氧代哌啶-1-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2-氧代-4S-苄基四氢化唑-3-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2-氧代-4S-异丙基全氢化噁唑-3-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2-氧代-4S-甲基-5S-苯基全氢化唑-3-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(1RS-氧代-4S-甲氧基羰基全氢化噻唑-3-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(吗啉-4-基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(咪唑-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(哌嗪-4-基磺酰基)-2-甲基苯基酯,
2RS-(4-硝基苯基)丁酸4-(吗啉-4-基磺酰基)苯基酯,
1-(4-硝基苯基)环丁烷羧酸4-(吗啉-4-基磺酰基)苯基酯,
2-(4-甲氧基苯基)-2-乙基丁酸4-(6-氮杂-7-氧代二环[3.2.1]辛烷-6-基磺酰基)苯基酯,
2RS-(4-甲基苯基)丁酸4-(吗啉-4-基磺酰基)-2-甲基苯基酯,
2RS-苯基丁酸4-(咪唑-1-基磺酰基)苯基酯,
2RS-苯基丁酸4-(吗啉-4-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-1RS-(乙氧基羰基)-2-(吗啉-4-基)乙基氨磺酰)苯基酯,
2RS-(4-硝基苯基)丁酸4-(N-1RS-(乙氧基羰基)-2-(吗啉-4-基)乙基氨磺酰)苯基酯,
1-(4-硝基苯基)环丁烷羧酸4-(N-1RS-(乙氧基羰基)-2-(吗啉-4-基)乙基氨磺酰)苯基酯,
2RS-苯基-2-甲氧基乙酸4-(N-1RS-(乙氧基羰基)-2-(吗啉-4-基)乙基氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-苄氧羰基氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-1RS-苯基-2RS-甲基丁基氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-氨磺酰苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-2-甲氧基乙基氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基丁酸4-(N-2-甲氧基乙基-N-苄基氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-叔丁氧基氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-4-羟基丁基氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-1RS-羟基甲基-2-甲基丙基氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-2RS,3-二羟基丙基氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-苄氧基氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(N’,N’-二甲基氨基)氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(N’-甲基氨基)氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(氨基甲酰基甲基)氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-叔丁基氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-金刚烷-1-基氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-胍基磺酰基-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-2RS,3-二羟基丙基氨磺酰)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N,N-二(2-(甲氧基甲氧基)乙基)氨磺酰)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N,N-二(2-(2-(甲氧基甲氧基)乙氧基)乙基)氨磺酰)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-甲基-N-甲氧基氨磺酰)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-苄基氨磺酰)-2-甲基苯基酯,
2RS-(4-硝基苯基)丁酸4-(N-2-(N’,N’-二甲基氨基)乙基氨磺酰)苯基酯,
1-(4-硝基苯基)环丁烷羧酸4-胍基磺酰基苯基酯,
2RS-(4-硝基苯基)丁酸4-胍基磺酰基苯基酯,
2RS-(4-甲基苯基)丁酸4-(N-2RS,3-二羟基丙基氨磺酰)-2-甲基苯基酯,
2-(4-甲氧基苯基)-2-乙基丁酸4-(N-2-甲氧基乙基氨磺酰)苯基酯,
2-(4-甲氧基苯基)-2-乙基丁酸4-(N-2-(N’,N’-二甲基氨基)乙基氨磺酰)苯基酯,
2RS-(4-甲氧基苯基)丁酸4-(胍基磺酰基)-2-甲基苯基酯,
2RS-苯基丁酸4-(N,N 二乙基氨磺酰)苯基醌,
2RS-苯基丁酸4-(N-苄基氨磺酰)苯基酯,
2RS-苯基丁酸4-(N-甲基-N-苄基氨磺酰)苯基酯,
2RS-苯基丁酸4-(N-2-苯基乙基氨磺酰)苯基酯,
2RS-苯基丁酸4-(N-甲基-N-2-苯基乙基氨磺酰)苯基酯,
2RS-苯基丁酸4-(N-1RS-(4-甲基苯基)丁基氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-2-(吡啶-2-基)乙基氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-2-哌啶-1-基)乙基氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(四唑-5-基)氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-吗啉-4-基)氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-吡咯烷-3-基)氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(1-苄基哌啶-4-基)氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-吡啶-2-基)氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-2-(吗啉-4-基)乙基氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(吡嗪-2-基)氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(咪唑-2-基)氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(奎宁环-3RS-基)氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(2,2,6,6-四甲基哌啶-4-基)氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(奎宁环-3RS-基)氨磺酰)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-2-(吗啉-4-基)乙基氨磺酰)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-2-(哌嗪-4-基)乙基氨磺酰)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(哌啶-4-基)氨磺酰)-2-甲基苯基酯,
2RS-(4-硝基苯基)丁酸4-(N-2-(吗啉-4-基)乙基氨磺酰)苯基酯,
1-(4-硝基苯基)环丁烷羧酸4-(N-2-(吡啶-2-基)乙基氨磺酰)苯基酯,
1-(4-硝基苯基)环丁烷羧酸4-(N-2-(哌啶-1-基)乙基氨磺酰)苯基酯,
1-(4-硝基苯基)环丁烷羧酸4-(N-2-(1-甲基吡咯-2-基)乙基氨磺酰)苯基酯,
2RS-(4-硝基苯基)丁酸4-(N-(四唑-5-基甲基)氨磺酰)苯基酯,
1-(4-硝基苯基)环丁烷羧酸4-(N-(四唑-5-基甲基)氨磺酰)苯基酯,
1-(4-硝基苯基)环丁烷羧酸4-(N-(四唑-5-基)氨磺酰)苯基酯,
2RS-(4-硝基苯基)丁酸4-(N-(四唑-5-基)氨磺酰)苯基酯,
2RS-(4-甲基苯基)丁酸4-(N-(奎宁环-3RS-基)氨磺酰)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-2R-甲氧基-3R-羟基-4S-羟基-5R-羟基全氢化吡喃-6R-基甲基氨磺酰)-2-甲基苯基酯,
2RS-苯基丁酸4-(N-苯基氨磺酰)苯基酯,
2RS-苯基丁酸4-(N-4-硝基苯基氨磺酰)苯基酯,
2RS-(4-氨基苯基)丁酸4-(N-苯基氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(2-(四唑-5-基)苯基)氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-4-(吗啉-4-基)苯基氨磺酰)苯基酯,
2-(N-(4-(2RS-(4-(吡咯烷-1-基)苯基)丁酰氧基)-3-甲基苯基磺酰基)氨基)苯磺酸,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-3,5-二甲氧基苯基氨磺酰)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-苯基氨磺酰)-2-甲基苯基酯,
2RS-(4-硝基苯基)丁酸4-(N-2-(N’-四唑-5-基甲基)氨基甲酰基)苯-1-基氨磺酰)苯基酯,
1-(4-硝基苯基)环丁烷羧酸4-(N-2(N’-(四唑-5-基甲基)氨基甲酰基)苯-1-基氨磺酰)苯基酯,
2RS-(4-硝基苯基)丁酸4-(N-(4-脒基苯基)氨磺酰)苯基酯,
1-(4-硝基苯基)环丁烷羧酸4-(N-(4-脒基苯基)氨磺酰)苯基酯,
1-(4-硝基苯基)环丁烷羧酸4-(N-2-(四唑-5-基)苯基氨磺酰)苯基酯,
1-(4-硝基苯基)环丁烷羧酸4-(N-4(吗啉-4-基)苯基氨磺酰)苯基酯,
2RS-(4-硝基苯基)丁酸4-(N-2-(四唑-5-基)苯基氨磺酰)苯基酯,
2RS-(4-(N-叔丁氧基羰基氨基)苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(3,5-二甲氧基苄基氨基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((4-叔丁氧基羰基氨基哌啶-1-基)磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-甲氧基-N-苄基氨基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-苄氧基-N-甲基氨基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2-(N,N-二甲基氨基)乙基氨基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2-(哌啶-1-基)乙基氨基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(3-(吗啉-4-基)丙基氨基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(二氢吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((2-氧代-4R-异丙基全氢化噁唑-3-基)磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-2-(吗啉-4-基)乙基-N-甲氧基氨基磺酰基)-2-甲基苯基酯,
2S-(4-(吡咯烷-1-基)苯基)丁酸4-(5-硝基二氢吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(吗啉-4-基氨基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(6-氟二氢吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(5-(N,N-二甲基氨基)二氢吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(4-甲基哌嗪-1-基磺酰基)-2-甲基苯基酯,
2R-(4-(吡咯烷-1-基)苯基)丁酸4-(5-硝基二氢吲哚-1-基磺酰基)-2-甲基苯基酯,
2S-(4-(吡咯烷-1-基)苯基)丁酸4-(2-(吗啉-4-基)乙基氨基磺酰基)-2-乙基苯基酯,
2R-(4-(吡咯烷-1-基)苯基)丁酸4-(2-(吗啉-4-基)乙基氨基磺酰基)-2-乙基苯基酯,
2R-(4-(吡咯烷-1-基)苯基)丁酸4-(2-(吗啉-4-基)乙基氨基磺酰基)-2-甲基苯基酯,
2S-(4-(吡咯烷-1-基)苯基)丁酸4-(2-(吗啉-4-基)乙基氨基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(4-甲基-1,4-全氢化二氮杂草-1-基磺酰基)-2-甲基苯基酯,
2S-(4-(吡咯烷-1-基)苯基)丁酸4-(2RS-乙氧基羰基二氢吲哚-1-基磺酰基)-2-甲基苯基酯,
2S-(4-(吡咯烷-1-基)苯基)丁酸4-(奎宁环-3RS-基氨基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2-(吗啉-4-基)乙基氨基磺酰基)-2-甲基苯基酯,
2RS-(4-吡咯烷-1-基)苯基)丁酸4-(3,5-二甲氧基苯基氨基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2S-羧基吡咯烷-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2S-羧基吡咯烷-1-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2R-羧基吡咯烷-1-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2S-羧基-4R-羟基吡咯烷-1-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2S-羧基-4R-苄氧基吡咯烷-1-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2S-羧基-4S氨基吡咯烷-1-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2S-羧基-4R-氨基吡咯烷-1-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2S-(N-羧基甲基氨基甲酰基)吡咯烷-1-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2S-(2-氨基乙氧基羰基)吡咯烷-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2S-(2-(2-羟基乙氧基)乙氧基羰基)吡咯烷-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2S-羟基甲基吡咯烷-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2S-(2-(哌嗪-4-基)乙基)氧羰基吡咯烷-1-基磺酰基)-2-甲基苯基酯,
2-(2-甲氧基苯基)-2-乙基丁酸4-(2S-羧基吡咯烷-1-基磺酰基)苯基酯,
2RS-(2-甲氧基苯基)丁酸4-(2S-羧基吡咯烷-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-甲氧基苯基)丁酸4-(2S-羧基吡咯-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-甲氧基苯基)丁酸4-(2S-(2-(哌嗪-1-基)乙基)氧羰基吡咯烷-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-甲氧基苯基)丁酸4-(2S-(2-(2-羟基乙氧基)乙氧基羰基)吡咯烷-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-甲氧基苯基)丁酸4-(2S-(2-氨基乙基)氧羰基吡咯烷-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-甲基苯基)丁酸4-(2S-羧基吡咯烷-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-甲基苯基)丁酸4-(2S-羧基甲基吡咯烷-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-甲基苯基)丁酸4-(2S-(2-氨基乙基)氧羰基吡咯烷-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-甲基苯基)丁酸4-(2S-(2-(哌嗪-4-基)乙基)氧羰基吡咯烷-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-甲基苯基)丁酸4-(2S-(2-(2-羟基乙氧基)乙基)氧羰基吡咯烷-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-硝基苯基)丁酸4-(2S-羧基吡咯烷-1-基磺酰基)苯基酯,
2R-(4-硝基苯基)丁酸4-(2S-羧基吡咯烷-1-基磺酰基)苯基酯,
2S-(4-硝基苯基)丁酸4-(2S-羧基吡咯烷-1-基磺酰基)苯基酯,
1-(4-硝基苯基)环丁烷羧酸4-(2S-羧基吡咯烷-1-基磺酰基)苯基酯,
2RS-(4-硝基苯基)丁酸4-(2S-羧基吡咯烷-1-基磺酰基)苯基酯,
2RS-(4-硝基苯基)丁酸4-(2R-羧基吡咯烷-1-基磺酰基)苯基酯,
1-(4-硝基苯基)环丁烷羧酸4-(2R-羧基吡咯烷-1-基磺酰基)苯基酯,
2RS-苯基丁酸4-(2S-羧基吡咯烷-1-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2RS-羧基二氢吲哚-1-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2-羧基吲哚-1-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2S-羧基二氢吲哚-1-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2S-羧基全氢化吲哚-1-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2RS-羧基二氢吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2RS-(N-羧基甲基氨基甲酰基)二氢吲哚-1-基磺酰基)苯基酯,
2S-(4-(吡咯烷-1-基)苯基)丁酸4-(2RS-羧基二氢吲哚-1-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2RS-羧基-3,3-二甲基二氢吲哚-1-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2RS-羧基二氢吲哚-1-基磺酰基)-2-甲氧基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2RS-(N-2-羧基乙基氨基甲酰基)二氢吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2RS-(N-2-羟基乙基氨基甲酰基)二氢吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2-羧基-5,6-二甲氧基吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2RS-(2-氨基乙基)氧羰基二氢吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2-羧基吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2RS-羧基-5,6-二甲氧基二氢吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2-羧基-5-羟基吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2RS-(2-2-羟基乙氧基)乙基)氧羰基二氢吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2RS-羟基甲基二氢吲哚-1-基磺酰基)-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2RS-羧基-5-羟基二氢吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2RS-(2-哌嗪-1-基)乙基)氧羰基二氢吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2RS-(N-羟基氨基甲酰基)二氢吲哚-1-基磺酰基)苯基酯,
2RS-(4-(甲氧基苯基)丁酸4-(2RS-羧基二氢吲哚-1-基磺酰基)苯基酯,
2RS-(4-(甲氧基苯基)丁酸4-(2RS-羧基二氢吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-甲氧基苯基)丁酸4-(2-羧基-5,6-二甲氧基吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-甲氧基苯基)丁酸4-(2-羧基吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-甲氧基苯基)丁酸4-(2-羧基-5-羟基吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-甲氧基苯基)丁酸4-(2RS-羟基甲基二氢吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-甲氧基苯基)丁酸4-(2RS-(2-氨基乙基)氧羰基二氢吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-甲氧基苯基)丁酸4-(2RS-(2-(哌嗪-4-基)乙基)氧羰基二氧吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-甲氧基苯基)丁酸4-(2RS-(2-(2-羟基乙氧基)乙基)氧羰基二氢吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(3-甲氧基苯基)丁酸4-(2RS-羧基二氢吲哚-1-基磺酰基)苯基酯,
2RS-(2-甲氧基苯基)丁酸4-(2RS-羧基二氢吲哚-1-基磺酰基)苯基酯,
2RS-(2-甲氧基苯基)丁酸4-(2RS-羧基-二氢吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(3,4-二甲氧基苯基)丁酸4-(2RS-羧基二氢吲哚-1-基磺酰基)苯基酯,
2RS-(3,4-二甲氧基苯基)丁酸4-(2RS-羧基二氢吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-甲基苯基)丁酸4-(2RS-羧基二氢吲哚-1-基磺酰基)苯基酯,
2RS-(4-甲基苯基)丁酸4-(2RS-羧基二氢吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-甲基苯基)丁酸4-(2-羧基-5,6-二甲氧基吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-甲基苯基)丁酸4-(2-羧基吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-甲基苯基)丁酸4-(2-羧基-5-羟基吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-甲基苯基)丁酸4-(2RS-(2-氨基乙基)氧羰基二氢吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-甲基苯基)丁酸4-(2RS-羟基甲基二氢吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-甲基苯基)丁酸4-(2RS-(2-(2-羟基乙氧基)乙基)氧羰基二氢吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-甲基苯基)丁酸4-(2RS-(2-哌嗪-4-基)乙基)氧羰基二氢吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-羟基苯基)丁酸4-(2RS-羧基二氢吲哚-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-氨基苯基)丁酸4-(2RS-羧基二氢吲哚-1-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(4S-羧基全氢化噻唑-3-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(4-羧基哌啶-1-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2RS-羧基哌啶-1-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(3RS-羧基哌啶-1-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(4S-羧基全氢化噻唑-3-基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(2RS-羧基吗啉-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(1S-氧代-4S-羧基全氢化噻唑-3-基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(4 S-羧基-1,1-二氧代全氢化噻唑-3-基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(4-(2-羟基乙基)哌嗪-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(4-羧基甲基哌嗪-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-硝基苯基)丁酸4-(4S-羧基全氢化噻唑-3-基磺酰基)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-羧基甲基-N-2-甲氧基乙基氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-1RS,2-二羧基乙基氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(1-羧基环丁烷)氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-1RS-羧基-2-苯基乙基氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-1S-羧基-2-甲基丙基氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(1S-羧基-2-羧基甲硫基乙基)氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-1RS-羧基-1-(噻吩-2-基)甲基氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-1RS-羧基-1-(呋喃-2-基)甲基氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-羧基甲基-N-2-甲氧基乙基氨磺酰)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-丙基-N-羧基甲基氨磺酰)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-1S-羧基-5-氨基戊基氨磺酰)-2-甲基苯基酯,
2-(4-甲氧基苯基)-2-乙基丁酸4-(N-羧基甲基氨磺酰)苯基酯,
1-(4-硝基苯基)环丁烷羧酸4-(N-2-甲氧基乙基-N-羧基甲基氨磺酰)苯基酯,
1-(4-硝基苯基)环丁烷羧酸4-(N-1RS,2-二羧基乙基氨磺酰)苯基酯,
2RS-苯基丁酸4-(N-羧基甲基氨磺酰)苯基酯,
2RS-苯基丁酸4-(N-丙基-N-羧基甲基氨磺酰)苯基酯,
2RS-苯基丁酸4-(N-苄基-N-羧基甲基氨磺酰)苯基酯,
2RS-苯基丁酸4-(N-2-苯基乙基-N-羧基甲基氨磺酰)苯基酯,
2RS-苯基丁酸4-(N-苯基-N-羧基甲基氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N,N-二(2-羟基乙基)氨磺酰)-2-甲基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N,N-二(2-(2-羟基乙氧基)乙基)氨磺酰)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(3RS-羧基-1,4-苯并二噁烷-5-基)氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(2RS-羟基-4R-羟基-5R-羟基-6R-羟基甲基全氢化吡喃-3R-基氨磺酰)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-3-羧基金刚烷-1-基氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(1S,4R,3R-羧基二环[2.2.1]庚烷-2S-基)氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-3S-羧基环己烷-1R-基氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-2RS-羧基环己烷-1RS-基氨磺酰)苯基酯,
2-(萘-1-基)乙酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2-(萘-2-基)乙酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(环己烷-1-基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-苯基丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2-苯基-2-乙基丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-苯基丙酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2R-苯基丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2S-苯基丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2-苯基-2-甲基丙酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
1-苯基环己烷羧酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
1-苯基环丙烷羧酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
1-苯基环戊烷羧酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
1-苯基环丁烷羧酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2-苯基乙酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-氯-2-苯基乙酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-氯-2-苯基丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2,2-二苯基丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-甲基-2-苯基丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2R-三氟甲基-2-苯基-2-甲氧基乙酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2S-三氟甲基-2-苯基-2-甲氧基乙酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(4-甲氧基苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(4-甲氧基苯基)-3-甲基丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2-(4-甲氧基苯基)-2-甲基丙酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(4-甲氧基苯基)丙酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2-(4-甲氧基苯基)-2-乙基丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
1-(4-甲氧基苯基)环己烷羧酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
1-(4-甲氧基苯基)环戊烷羧酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
1-(4-甲氧基苯基)环丁烷羧酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
1-(4-甲氧基苯基)环丙烷羧酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2-(3,4-二甲氧基苯基)-2-乙基丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(3,4-二甲氧基苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2-(3-甲氧基苯基)-2-乙基丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(2-甲氧基苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2-(2-甲氧基苯基)-2-乙基丁酸4-(N-2-(N’ -羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(3-甲氧基苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
1-(2-甲氧基苯基)环丁烷羧酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(4-甲氧基苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)-2,6-二甲基苯基酯,
2RS-(4-甲氧基苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)-2-异丙基苯基酯,
2RS-(4-(2-甲基丙氧基)苯基)丁酸4-(N-2-(N’ -羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(4-异丙氧基苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(4-(丙氧基苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(4-甲基苯基)戊酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
1-(4-甲基苯基)环戊烷羧酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
1-(3-甲基苯基)环戊烷羧酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(2-甲基苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2-(2-甲基苯基)-2-乙基丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(4-甲基苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(4-硝基苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2-(4-硝基苯基)-2-甲基丙酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
1-(4-硝基苯基)环丙烷羧酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
1-(4-硝基苯基)环戊烷羧酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2-(4-硝基苯基)-2-乙基丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
1-(4-硝基苯基)环丁烷羧酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(4-硝基苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)-2-甲基苯基酯,
1-(4-硝基苯基)环丁烷羧酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)-2-甲基苯基酯,
1-(4-硝基苯基)环丁烷羧酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)-3-甲基苯基酯,
1-(4-硝基苯基)环丁烷羧酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)-2,3-二甲基苯基酯,
1-(4-硝基苯基)环丁烷羧酸7-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)-2,3-二氢茚-4-基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)-3-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)-2,3-二甲基苯基酯,
1-(4-(吡咯烷-1-基)苯基)环丁烷羧酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸7-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)-2,3-二氢茚-4-基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)-2,6-二甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)-2-异丙基苯基酯,
2RS-(4-(哌啶-1-基)苯基丁酸4-(N-2-(N’-羧基
甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(4-(全氢化吖庚因-1-基)苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2-(4-(氨基苯基)-2-乙基丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(4-氨基苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(4-(N,N-二甲基氨基)苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
1-(4-(N,N-二甲基氨基)苯基)环丁烷羧酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(4-(N,N-二乙基氨基甲基)苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(4-羟基苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(4-氰基苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(4-羧基苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(4-三氟甲基苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(4-(脒基苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(4-咪唑啉-2-基)苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
1-(4-氯苯基)环丁烷羧酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(2-氯苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2-(2-氯苯基)-2-乙基丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
1-(2-氯苯基)环丁烷羧酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(4-氯苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(3-硝基-4-羟基苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(2-氯-5-硝基苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
1-(2-氯-5-硝基苯基)环丁烷羧酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
1-(3-硝基-4-氯苯基)环丁烷羧酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(3-硝基-4-氯苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(4-脲基苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
1-(4-脲基苯基)环丁烷羧酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(4-(N-(2S-氨基丙酰基)氨基)苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(4-(N-(2S-氨基-3-甲基丁酰基)氨基)苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(4-(N-(吡咯烷-2S-基羰基)氨基)苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(3,4,5-三甲氧基苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(2,4,6-三甲基苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(3-硝基-4-甲氧基苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(3-硝基-4-氨基苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(4-(N-乙酰基氨基)苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(4-(N-甲基-N-乙酰基氨基)苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(4-(吗啉-4-基甲基)苯基丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(4-(4-苄基哌嗪-1-基)苯基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基甲基)苯基丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((1R-氧代-4S-羧基全氢化噻唑-3-基)磺酰基)-2-甲基苯基酯,
2S-(4-(吡咯烷-1-基)苯基丁酸4-((2S-羧基吡咯烷-1-基)磺酰基)-2-甲基苯基酯,
2S-(4-(吡咯烷-1-基)苯基)丁酸4-((2R-羧基吡咯烷-1-基)磺酰基)-2-甲基苯基酯,
2R-(4-(吡咯烷-1-基)苯基)丁酸4-((2S-羧基吡咯烷-1-基)磺酰基)-2-甲基苯基酯,
2R-(4-(吡咯烷-1-基)苯基)丁酸4-((2R-羧基吡咯烷-1-基)磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((2S-氨基甲基吡咯烷-1-基)磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((4-氨基哌啶-1-基)磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((2S-羧基氮杂环丁烷-1-基)磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((2RS-羧基哌啶-1-基)磺酰基)-2-甲基苯基酯,
2R-(4-(吡咯烷-1-基)苯基)丁酸4-((2-氧代-5S-羧基吡咯烷-1-基)磺酰基)-2-甲基苯基酯,
2RS-(3-(吡咯烷-1-基)苯基)丁酸4-((2S-羧基吡咯烷-1-基)磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((2S-羧基-4R-甲氧基吡咯烷-1-基)磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基丁酸4-((2R-羧基-4R-甲氧基吡咯烷-1-基)磺酰基)-2-甲基苯基酯,
2RS-(2-甲基-4-(吡咯烷-1-基)苯基)丁酸4-((2S-羧基吡咯烷-1-基)磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((2S-羧基-4R-羟基吡咯烷-1-基)磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-甲氧基-N-羧基甲基氨基磺酰基)-2-甲基苯基酯,
2RS-(2-甲氧基-4-(吡咯烷-1-基)苯基)丁酸4-((2S-羧基吡咯烷-1-基)磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((2S-羧基氮丙啶-1-基)磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N,N-二(2-氨基乙基)氨基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-羧基甲基-N-(2-(N’,N’-二甲基氨基)乙基)氨基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((2S-羧基吡咯烷-1-基)磺酰基)-2-乙基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-羧基甲基-N-苄氧基氨基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(4-羧基丁基)氨基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(1,1-二甲基-1-羧基甲基)氨基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-甲基-N-羟基氨基磺酰基)-2-甲基苯基酯,
2RS-(2-甲基-4-硝基苯基)丁酸4-((2S-羧基吡咯烷-1-基)磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-羧基甲基氨基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-(1,1-二甲基-1-羧基甲基)-N-丙基氨基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((2S-羧基-4S-氨基吡咯烷-1-基)磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((2S-羧基-4R-氨基吡咯烷-1-基)磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-羧基甲基)-N-(2-(吗啉-4-基)乙基)氨基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((2S-羧基-4S-乙酰基氨基吡咯烷-1-基)磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)-2-丁酸4-((2S-羧基吡咯烷-1-基)磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((2S-羧基-4R-乙酰基氨基吡咯烷-1-基)磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((2RS-羧基-5-硝基二氢吲哚-1-基)磺酰基)-2-甲基苯基酯,
2RS-(2-甲氧基-4-硝基苯基)丁酸4-((2S-羧基吡咯烷-1-基)磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((2S-羧基-4S-甲基氨基吡咯烷-1-基)磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((2S-羧基-4S-(N,N-二甲基氨基)吡咯烷-1-基)磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-(N-羟基氨基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((2S,6S-二甲基哌嗪-4-基)磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((2RS-甲基哌嗪-4-基)磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((2S-羧基-4R-(N,N-二甲基氨基)吡咯烷-1-基)磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((2S-羧基-4R-甲基氨基吡咯烷-1-基)磺酰基)-2-甲基苯基酯,
2S-(4-(吡咯烷-1-基)苯基)丁酸4-(哌嗪-4-基磺酰基)-2-乙基苯基酯,
2R-(4-(吡咯烷-1-基)苯基)丁酸4-(哌嗪-4-基磺酰基)-2-乙基苯基酯,
2S-(4-(吡咯烷-1-基)苯基)丁酸4-(哌嗪-4-基磺酰基)-2-甲基苯基酯,
2R-(4-(吡咯烷-1-基)苯基)丁酸4-(哌嗪-4-基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((2S-羧基甲基吡咯烷-1-基)磺酰基)-2-甲基苯基酯,
2S-(4-(吡咯烷-1-基)苯基)丁酸4-((2S-羧基-4-乙酰基氨基吡咯烷-1-基)磺酰基)-2-甲基苯基酯,
2S-(4-(吡咯烷-1-基)苯基)丁酸4-((2-羧基-5,6-二甲氧基吲哚-1-基)磺酰基)-2-甲基苯基酯,
2S-(4-(吡咯烷-1-基)苯基)丁酸4-((2RS-羧基二氢吲哚-1-基)磺酰基)-2-甲基苯基酯,
2S-(4-(吡咯烷-1-基)苯基)丁酸4-((2RS-甲基哌嗪-4-基)磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基)丁酸4-((4-甲酰基哌嗪-1-基)磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基丁酸4-((2S-羧基吡咯烷-1-基)磺酰基)-2-甲基苯基酯,
2RS-(4-甲基苯基)丁酸4-(2S-羧基磺酰氧基甲基吡咯烷-1-基磺酰基)-2-甲基苯基酯,
2RS-(4-(吡咯烷-1-基)苯基丁酸4-(2S-羟基磺酰氧基甲基吡咯烷-1-基磺酰基)-2-甲基苯基酯。
9.根据权利要求1的化合物,其为下列化合物,或其无毒盐、酸加成盐或溶剂化物,
2RS-(2H-1,4-苯并噁嗪-3-酮-6-基)丁酸4-(2S-羧基吡咯烷-1-基磺酰基)苯基酯,
2RS-(2 H-1,4-苯并噁嗪-3-酮-6-基)丁酸4-(2 R-羧基吡咯烷-1-基磺酰基)苯基酯,
2RS-(2-甲基苯并咪唑-5-基)丁酸4-(2S-羧基吡咯烷-1-基磺酰基)苯基酯,
2RS-(1,3-苯并二氧环戊-5-基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(噻吩-2-基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2-(1,3-苯并间二氧杂环戊-5-基)-2-乙基丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(噻吩-2-基)-3-甲基丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(吡啶-3-基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(2H-1,4-苯并噁嗪-3-酮-6-基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(2-(N-甲氧基羰基氨基)噻唑-4-基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(2-甲基苯并咪唑-5-基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2RS-(1H-1-甲基-2-吡啶酮-3-基)丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯,
2-(噻吩-2-基)-2-乙基丁酸4-(N-2-(N’-羧基甲基氨基甲酰基)苯基氨磺酰)苯基酯。
10.一种药物组合物,其包括作为活性成分的有效量的权利要求1所定义的式(I)化合物,其无毒盐、酸加成盐或溶剂化物,以及载体或包衣。
11.式(I)化合物或其无毒盐或无毒酸加成盐或溶剂化物用于生产作为弹性蛋白酶抑制剂的药物组合物。
12.式(I)化合物或其无毒盐或无毒酸加成盐或溶剂化物用于生产预防和/或治疗由于哺乳动物,尤其是人类的弹性蛋白酶的作用导致的弹性蛋白、胶原纤维和/或蛋白多糖的降解的异常增加引起的疾病例如慢性阻塞肺病如肺气肿、风湿病样关节炎、动脉粥样硬化、成人呼吸不适综合症(ARDS)、血管小球肾炎、心肌梗塞、自发性溃疡性结肠炎或龈炎的药物组合物。
13.权利要求1所定义的式(I)的磺酰胺衍生物的制备方法,该方法包括酯化下式化合物其中R1a为C1-8烷基、C1-8烷氧基、羟基、被护羟基、酮基、硝基、卤原子、三卤甲基、氰基、脒基、-COOR7a(其中R7a为C1-8烷基或苄基),或(其中p如权利要求1所定义,R8a和R9a各自独立地为氢原子(条件是R8a和R9a不同时代表氢原子)、叔丁氧基羰基、苄氧基羰基、C1-4烷基、C2-5酰基、-COOR10a(其中R10a为C1-8烷基或苄基)、-CONR11R12(其中R11和R12如权利要求1所定义),或(其中为被护的α-氨基酸残基),或R8a和R9a与它们相连的氮原子一起代表未取代或被C1-4烷基或苯基C1-4烷基取代的脂族杂环,其它符号如权利要求1所定义,酯化所用的化合物为式(III)化合物其中(其中R5a和R6a各自独立地为1)氢原子(条件是R5a,R6a不同时代表氢原子),2)羟基,3)被在酸性条件下可除去的保护基团保护的羟基,4)叔丁氧基羰基,5)苄氧基羰基,6)C1-8烷基,7)C1-8烷氧基,8)苯基C1-4烷氧基,9)胍基,10)-M-R16a(其中M如权利要求1所定义,R16a为i)-NR17aR18a(其中R17a和R18a各自独立地为氢原子(条件是R17a和R18a不同时代表氢原子)、叔丁氧基羰基、苄氧基羰基或C1-4烷基),ii)-CONR19R20(其中R19和R20如权利要求1所定义),(其中所有符号如前文所定义),iv)杂环,该杂环为未取代的或被1至4个选自C1-4烷基、C1-4烷氧基、羟基、苯基C1-4烷基、-COOR26(其中R26如权利要求1所定义)、其中羟基被在酸性条件下可除去的保护基团保护的羟基C1-4烷基或C2-4烷氧基烷基的取代基所取代),11)C1-8烷基,其被1个或2个-OR27a所取代,其中R27a为氢原子、C1-4烷基、C2-4烷氧基烷基、叔丁基二甲基甲硅烷基、THP、苄基或被-OR28(其中R28a为氢原子、C2-4烷氧基烷基、叔丁基二甲基甲硅烷基、THP或苄基)取代的C2-4烷基,12)-Ja-COOR29(其中R29如权利要求1所定义,Ja为单键、-(CH2)s-或(其中s如权利要求1所定义,R30a和R31a各自独立地为i)氢原子,ii)C1-8烷基,iii)-COOR32(其中R32如权利要求1所定义),iv)碳环或杂环,其为未取代或被1个或多个选自C1-4烷基、C1-4烷氧基烷基、氨基、硝基、羟基、被护羟基、卤原子、腈、胍基和脒基的取代基所取代,或v)C1-8烷基,其被1个或多个选自羟基、被护羟基、-COOR33(其中R33如权利要求1所定义)、-NR34aR35a(其中R34a和R35a各自独立地为氢原子(条件是R34a和R35a不同时代表氢原子)、叔丁氧基羰基、苄氧基羰基或C1-4烷基)、未取代或被1个或多个选自C1-4烷基、C1-4烷氧基烷基、被护氨基、硝基、羟基、被护羟基、卤原子、腈、胍基和脒基的取代基取代的碳环或杂环的取代基所取代,条件是C1-8烷基的碳原子可被硫原子替换,或其中R5a和R6a与它们相连的氮原子一起代表杂环,q如权利要求1所定义,R15a为1)羟基,2)被在酸性条件下可被除去的保护基团保护的羟基,3)酮基,4)被护酮基,5)C1-4烷基,6)C1-4烷氧基,7)苯基,8)苯氧基,9)苯基C1-4烷基,10)苯基C1-4烷氧基,11)硝基,12)-COOR36a(其中R36a为氢原子、C1-8烷基、被-CONR37R38(其中R37和R38如权利要求1所定义)取代的C1-4烷基、被-NR39aR40a(其中R39a和R40a各自独立地为氢原子(条件是R39a和R40a不同时代表氢原子)、叔丁氧基羰基、苄氧基羰基或C1-4烷基)取代的C1-4烷基、被-OR41a(其中R41a为被-OR42a(其中R42a为氢原子、C2-4烷氧基烷基、苄基)取代的C2-4烷基)取代的C1-4烷基或被护哌嗪环取代的C1-4烷基),13)-NR43aR44a(其中R43a和R44a各自独立地为氢原子(条件是R43a和R44a不同时代表氢原子)、叔丁氧基羰基、苄氧基羰基、C1-4烷基或C2-5酰基),14)-CONR45aR46a(其中R45a和R46a各自独立地为氢原子、C1-4烷基、羟基、被在酸性条件可被除去的保护基团保护的羟基、苯基C1-4烷氧基或被羟基、被护羟基或-COOR47a(其中R47a为氢原子、C1-8烷基或苄基)取代的C1-4烷基),15)C1-4烷基,其被1个或多个选自羟基、被护羟基、-COOR48a(其中R48a为氢原子、C1-8烷基或苄基)、-NR49aR50a(其中R49a和R50a各自独立地为氢原子(条件是R49a和R50a不同时代表氢原子)、叔丁氧基羰基、苄氧基羰基或C1-4烷基),或含有1个或2个氮原子的5或6元杂环的取代基所取代,16)含有1个或2个氮原子的5或6元杂环,17)卤原子,18)被在酸性条件下可除去的保护基团保护的-CHO,19)-NR51a-COOR52a(其中R51a和R52a各自独立地为氢原子或C1-8烷基),并且其它符号如权利要求1所定义,
或者其制备通过用式(III)化合物酯化式(II)化合物,得到具有被保护基团的化合物,然后消去保护基团,
或者其制备通过用式(III)化合物酯化式(II)化合物,如果需要,消去保护基团,得到具有R15代表被羟基取代的C1-4烷基的化合物,然后进行硫酸酯化,并且任意将如此获得的式(I)化合物转化为其无毒盐、酸加成盐或溶剂化物。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN 96121984 CN1161962A (zh) | 1995-09-27 | 1996-09-27 | 磺酰氨衍生物 |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP272058/95 | 1995-09-27 | ||
JP045663/96 | 1996-02-08 | ||
CN 96121984 CN1161962A (zh) | 1995-09-27 | 1996-09-27 | 磺酰氨衍生物 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN1161962A true CN1161962A (zh) | 1997-10-15 |
Family
ID=5127040
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN 96121984 Pending CN1161962A (zh) | 1995-09-27 | 1996-09-27 | 磺酰氨衍生物 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN1161962A (zh) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106631974A (zh) * | 2017-02-17 | 2017-05-10 | 杭州中美华东制药有限公司 | 制备吲哚布芬的方法 |
CN115894607A (zh) * | 2022-11-02 | 2023-04-04 | 四川大学 | 一种抗肿瘤的苯丙氨酸缬氨酰衍生物及其制备方法 |
-
1996
- 1996-09-27 CN CN 96121984 patent/CN1161962A/zh active Pending
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106631974A (zh) * | 2017-02-17 | 2017-05-10 | 杭州中美华东制药有限公司 | 制备吲哚布芬的方法 |
CN106631974B (zh) * | 2017-02-17 | 2019-03-19 | 杭州中美华东制药有限公司 | 制备吲哚布芬的方法 |
CN115894607A (zh) * | 2022-11-02 | 2023-04-04 | 四川大学 | 一种抗肿瘤的苯丙氨酸缬氨酰衍生物及其制备方法 |
CN115894607B (zh) * | 2022-11-02 | 2024-01-30 | 四川大学 | 一种抗肿瘤的苯丙氨酸缬氨酰衍生物及其制备方法 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1044117C (zh) | 用于抑制人免疫缺陷病毒蛋白酶的化合物及其制备方法和药物用途 | |
CN1273128C (zh) | 取代的n-[(氨基亚氨基甲基或氨基甲基)苯基]丙基酰胺 | |
CN1303067C (zh) | 用作半光氨酸蛋白酶可逆抑制剂的螺杂环腈 | |
CN1273444C (zh) | 二肽腈 | |
CN1149191C (zh) | 氮杂环丁烷衍生物,它们的制备以及含有它们的药物 | |
CN1130351C (zh) | 1,5-苯并二氮杂䓬衍生物 | |
CN1164574C (zh) | 苯氧基丙胺类化合物 | |
CN1192018C (zh) | 抑制细胞附着的抗炎和免疫抑制的化合物 | |
CN1518541A (zh) | 苯基衍生物 | |
CN1230110A (zh) | 细胞粘连抑制剂 | |
CN1192729A (zh) | 苯甲酰胺衍生物和它们作为后叶加压素拮抗剂的应用 | |
CN1578767A (zh) | 哌啶-2-酮衍生化合物及包含其作为活性成分的药学组合物 | |
CN1902171A (zh) | 用作ccr-5拮抗剂的苄醚胺化合物 | |
CN1741986A (zh) | 酰胺衍生物及其作为11-β羟类固醇脱氢酶抑制剂的用途 | |
CN1387514A (zh) | 芳族砜异羟肟酸金属蛋白酶抑制剂 | |
CN1471536A (zh) | 趋化因子受体拮抗剂及其使用方法 | |
CN1198804C (zh) | 酰胺化合物及其用途 | |
CN1481358A (zh) | 酰胺衍生物和它们在治疗血栓栓塞性疾病和肿瘤中的用途 | |
CN101031555A (zh) | 具有vap-1抑制活性的噻唑衍生物 | |
CN1950351A (zh) | 适用作h3配体的3-或4-单取代酚及苯硫酚衍生物 | |
CN1305454A (zh) | 作为cgmp-磷酸二酯酶抑制剂的邻氨基苯甲酸衍生物 | |
CN1076345C (zh) | 2,3-二氨基丙酸衍生物 | |
CN1353691A (zh) | 抑制细胞附着的抗炎和免疫抑制的化合物 | |
CN1674893A (zh) | 苯并咪唑衍生物 | |
CN1296354C (zh) | 具有药物活性的吡咯烷衍生物 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
AD01 | Patent right deemed abandoned | ||
C20 | Patent right or utility model deemed to be abandoned or is abandoned |