CN1829682A - 用作给药生物活性剂的辅助剂的非α位上的氨基酸二酰胺 - Google Patents
用作给药生物活性剂的辅助剂的非α位上的氨基酸二酰胺 Download PDFInfo
- Publication number
- CN1829682A CN1829682A CNA2004800220400A CN200480022040A CN1829682A CN 1829682 A CN1829682 A CN 1829682A CN A2004800220400 A CNA2004800220400 A CN A2004800220400A CN 200480022040 A CN200480022040 A CN 200480022040A CN 1829682 A CN1829682 A CN 1829682A
- Authority
- CN
- China
- Prior art keywords
- aromatics
- compound
- pharmaceutical composition
- benzoyl
- amino
- 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.)
- Granted
Links
- -1 Amino acid diamides Chemical class 0.000 title claims abstract description 28
- 239000003124 biologic agent Substances 0.000 title claims abstract description 5
- 239000002671 adjuvant Substances 0.000 title abstract 2
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 19
- 125000000524 functional group Chemical group 0.000 claims abstract description 7
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 6
- 150000002367 halogens Chemical class 0.000 claims abstract description 6
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 5
- 239000003814 drug Substances 0.000 claims abstract description 5
- 206010061218 Inflammation Diseases 0.000 claims abstract description 3
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 3
- 201000011510 cancer Diseases 0.000 claims abstract description 3
- 230000004054 inflammatory process Effects 0.000 claims abstract description 3
- 208000026935 allergic disease Diseases 0.000 claims abstract 2
- 150000001875 compounds Chemical class 0.000 claims description 34
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 claims description 29
- 229960002897 heparin Drugs 0.000 claims description 26
- 229920000669 heparin Polymers 0.000 claims description 26
- 241000209094 Oryza Species 0.000 claims description 14
- 235000007164 Oryza sativa Nutrition 0.000 claims description 14
- 235000009566 rice Nutrition 0.000 claims description 14
- 235000015170 shellfish Nutrition 0.000 claims description 12
- 229920001542 oligosaccharide Polymers 0.000 claims description 8
- 150000002482 oligosaccharides Chemical class 0.000 claims description 7
- 229920002683 Glycosaminoglycan Polymers 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 3
- 229940079593 drug Drugs 0.000 claims description 2
- 229920000045 Dermatan sulfate Polymers 0.000 claims 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims 1
- 230000002785 anti-thrombosis Effects 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- AVJBPWGFOQAPRH-FWMKGIEWSA-L dermatan sulfate Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@H](OS([O-])(=O)=O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](C([O-])=O)O1 AVJBPWGFOQAPRH-FWMKGIEWSA-L 0.000 claims 1
- 229940051593 dermatan sulfate Drugs 0.000 claims 1
- 230000001737 promoting effect Effects 0.000 claims 1
- 229910021653 sulphate ion Inorganic materials 0.000 claims 1
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 abstract 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 abstract 2
- 206010020751 Hypersensitivity Diseases 0.000 abstract 1
- 230000007815 allergy Effects 0.000 abstract 1
- 150000001470 diamides Chemical class 0.000 abstract 1
- 201000010099 disease Diseases 0.000 abstract 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 132
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 105
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 96
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 69
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 66
- 238000003756 stirring Methods 0.000 description 59
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 56
- 229910052799 carbon Inorganic materials 0.000 description 45
- 229910052739 hydrogen Inorganic materials 0.000 description 45
- 239000007787 solid Substances 0.000 description 45
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 44
- 229910052757 nitrogen Inorganic materials 0.000 description 42
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 39
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 38
- 239000012043 crude product Substances 0.000 description 25
- 239000000203 mixture Substances 0.000 description 25
- 238000004458 analytical method Methods 0.000 description 23
- 239000000047 product Substances 0.000 description 23
- 238000005160 1H NMR spectroscopy Methods 0.000 description 22
- 238000001953 recrystallisation Methods 0.000 description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 20
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 20
- 239000000725 suspension Substances 0.000 description 20
- 239000007795 chemical reaction product Substances 0.000 description 19
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 18
- 230000000112 colonic effect Effects 0.000 description 14
- 238000010992 reflux Methods 0.000 description 14
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 12
- 238000010521 absorption reaction Methods 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 240000000203 Salix gracilistyla Species 0.000 description 6
- 150000001263 acyl chlorides Chemical class 0.000 description 6
- 210000001072 colon Anatomy 0.000 description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 6
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 6
- 230000001858 anti-Xa Effects 0.000 description 5
- 239000003055 low molecular weight heparin Substances 0.000 description 5
- 229940127215 low-molecular weight heparin Drugs 0.000 description 5
- 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 description 5
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 4
- 210000002381 plasma Anatomy 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- DVIHKVWYFXLBEM-UHFFFAOYSA-N 2-hydroxybenzoyl chloride Chemical compound OC1=CC=CC=C1C(Cl)=O DVIHKVWYFXLBEM-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 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
- 238000003810 ethyl acetate extraction Methods 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 235000019260 propionic acid Nutrition 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 229940005605 valeric acid Drugs 0.000 description 3
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 2
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 2
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 2
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 2
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 2
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 2
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 2
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 229940126657 Compound 17 Drugs 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- JGFBQFKZKSSODQ-UHFFFAOYSA-N Isothiocyanatocyclopropane Chemical compound S=C=NC1CC1 JGFBQFKZKSSODQ-UHFFFAOYSA-N 0.000 description 2
- YQEZLKZALYSWHR-UHFFFAOYSA-N Ketamine Chemical compound C=1C=CC=C(Cl)C=1C1(NC)CCCCC1=O YQEZLKZALYSWHR-UHFFFAOYSA-N 0.000 description 2
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 230000037005 anaesthesia Effects 0.000 description 2
- MXMOTZIXVICDSD-UHFFFAOYSA-N anisoyl chloride Chemical compound COC1=CC=C(C(Cl)=O)C=C1 MXMOTZIXVICDSD-UHFFFAOYSA-N 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- PWLNAUNEAKQYLH-UHFFFAOYSA-N butyric acid octyl ester Natural products CCCCCCCCOC(=O)CCC PWLNAUNEAKQYLH-UHFFFAOYSA-N 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 229940125773 compound 10 Drugs 0.000 description 2
- 229940125797 compound 12 Drugs 0.000 description 2
- 229940126543 compound 14 Drugs 0.000 description 2
- 229940125758 compound 15 Drugs 0.000 description 2
- 229940126142 compound 16 Drugs 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940125810 compound 20 Drugs 0.000 description 2
- 229940126086 compound 21 Drugs 0.000 description 2
- 229940126208 compound 22 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 2
- 239000002628 heparin derivative Substances 0.000 description 2
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 2
- 229960003299 ketamine Drugs 0.000 description 2
- NUKZAGXMHTUAFE-UHFFFAOYSA-N methyl hexanoate Chemical compound CCCCCC(=O)OC NUKZAGXMHTUAFE-UHFFFAOYSA-N 0.000 description 2
- UUIQMZJEGPQKFD-UHFFFAOYSA-N n-butyric acid methyl ester Natural products CCCC(=O)OC UUIQMZJEGPQKFD-UHFFFAOYSA-N 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- WAPLXGPARWRGJO-UHFFFAOYSA-N 2-(4-aminophenyl)butanoic acid Chemical compound CCC(C(O)=O)C1=CC=C(N)C=C1 WAPLXGPARWRGJO-UHFFFAOYSA-N 0.000 description 1
- NZCKTGCKFJDGFD-UHFFFAOYSA-N 2-bromobenzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1Br NZCKTGCKFJDGFD-UHFFFAOYSA-N 0.000 description 1
- ONIKNECPXCLUHT-UHFFFAOYSA-N 2-chlorobenzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1Cl ONIKNECPXCLUHT-UHFFFAOYSA-N 0.000 description 1
- LNNDXQSWYNEJAS-UHFFFAOYSA-N 2-hydroxy-4-methoxybenzoyl chloride Chemical compound COC1=CC=C(C(Cl)=O)C(O)=C1 LNNDXQSWYNEJAS-UHFFFAOYSA-N 0.000 description 1
- GIXCHTWQWLWUCY-UHFFFAOYSA-N 2-hydroxy-4-nitrobenzoyl chloride Chemical compound OC1=CC([N+]([O-])=O)=CC=C1C(Cl)=O GIXCHTWQWLWUCY-UHFFFAOYSA-N 0.000 description 1
- FMEWLYXGAMCQSC-UHFFFAOYSA-N 2-hydroxy-5-nitrobenzoyl chloride Chemical compound OC1=CC=C([N+]([O-])=O)C=C1C(Cl)=O FMEWLYXGAMCQSC-UHFFFAOYSA-N 0.000 description 1
- BWWHTIHDQBHTHP-UHFFFAOYSA-N 2-nitrobenzoyl chloride Chemical compound [O-][N+](=O)C1=CC=CC=C1C(Cl)=O BWWHTIHDQBHTHP-UHFFFAOYSA-N 0.000 description 1
- WHIHIKVIWVIIER-UHFFFAOYSA-N 3-chlorobenzoyl chloride Chemical compound ClC(=O)C1=CC=CC(Cl)=C1 WHIHIKVIWVIIER-UHFFFAOYSA-N 0.000 description 1
- CCBOXJLPEZRSSA-UHFFFAOYSA-N 4-chloro-2-hydroxybenzoyl chloride Chemical compound OC1=CC(Cl)=CC=C1C(Cl)=O CCBOXJLPEZRSSA-UHFFFAOYSA-N 0.000 description 1
- SKDHHIUENRGTHK-UHFFFAOYSA-N 4-nitrobenzoyl chloride Chemical compound [O-][N+](=O)C1=CC=C(C(Cl)=O)C=C1 SKDHHIUENRGTHK-UHFFFAOYSA-N 0.000 description 1
- NANJQJRZYOVMLF-UHFFFAOYSA-N 5-chloro-2-hydroxybenzoyl chloride Chemical compound OC1=CC=C(Cl)C=C1C(Cl)=O NANJQJRZYOVMLF-UHFFFAOYSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- 229920001661 Chitosan Polymers 0.000 description 1
- 206010051055 Deep vein thrombosis Diseases 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108010074860 Factor Xa Proteins 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 206010047249 Venous thrombosis Diseases 0.000 description 1
- BYWBCSRCPLBDFU-CYBMUJFWSA-N [3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxyphenyl]-[(3R)-3-aminopyrrolidin-1-yl]methanone Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(C=CC=1)C(=O)N1C[C@@H](CC1)N BYWBCSRCPLBDFU-CYBMUJFWSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000000516 activation analysis Methods 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000010100 anticoagulation Effects 0.000 description 1
- 210000000436 anus Anatomy 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 229960003616 bemiparin Drugs 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 210000001198 duodenum Anatomy 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
- C07C237/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/164—Amides, e.g. hydroxamic acids of a carboxylic acid with an aminoalcohol, e.g. ceramides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
- C07C233/81—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
- C07C233/82—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
- C07C233/83—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom of an acyclic saturated carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C235/56—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C235/58—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C235/64—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Diabetes (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Hematology (AREA)
- Pulmonology (AREA)
- Immunology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Cosmetics (AREA)
Abstract
本发明涉及式(1)的非α位上的氨基酸二酰胺,其中R1选自官能团烷基、卤素、NO2、OH、OCH3,所述官能团是单独的或联合存在的,且R2选自官能团H、烷基、卤素、NO2、OH、OCH3,所述氨基酸二酰胺可以用作给药生物活性剂的辅助剂,以及含有所述式(1)二酰胺的药物组合物,及其在制备抗血栓形成药物和在制备用于治疗选自炎症、癌症和变态反应的疾病的药物中的应用。
Description
发明领域
本发明涉及用作给药生物活性组分的辅助剂的非α位上的新的氨基酸二酰胺。本发明化合物有助于肝素、低分子量肝素、非常低分子量肝素以及其它葡糖胺基聚糖和衍生物的口服、十二指肠内、结肠内和经肺的给药。
发明背景
肝素目前被用于预防和治疗深静脉血栓的胃肠外给药。肝素和相关衍生物在胃肠道中由于酸或酶的水解而无效或被破坏。另外,分子的大小和离子电荷可阻止吸收。
各种辅助剂(例如非离子表面活性剂)已被用于改善肝素的口服吸收。近来,改性的氨基酸已被用来促进各种生物剂特别是肝素的给药(WO 98/34632,WO 01/51454,WO 97/36480)。
这些化合物本质上衍生自4-氨基-苯基丁酸:
结构A和各种酰胺例如:
结构B
特别是下面的衍生物
结构C主要是其中n=2和n=5的那些衍生物(WO 97/36480)被要求作为促进生物产物口服吸收的物质。
发明描述
在其对于肝素口服吸收所做的研究框架内,本申请人发现了新的一系列化学产物,所述产物能够促进并显著提高肝素及其低分子量衍生物的口服吸收,尤其是经由结肠给药的吸收。
这些产物具有以下结构
其中n=2-8
其中R1选自官能团烷基、卤素、NO2、OH、OCH3,所述官能团是单独的或联合存在的,R2选自官能团H、烷基、卤素、NO2、OH、OCH3。
这些产物是新的。本申请人所进行的研究已经证明了结构的新颖性。事实上,本申请人已经能够证明,本申请人合成的产物(结构C,n=3(实施例1)和n=5(实施例2)在大鼠中对低分子量肝素(贝米肝素(bemiparin))的结肠吸收没有影响。同样,本申请人合成的具有结构D(n=3(实施例3))
结构D的产物对贝米肝素的结肠吸收没有影响(见表1)。
表1显示了在大鼠中结肠内给药贝米肝素和贝米肝素与实施例1、2和3的化合物的组合后,血浆中的抗Xa活性/ml,如表中所示:
给药后时间 | |||||
治疗 | 给药途径 | 剂量(mg/kg) | 0.5 | 2 | 4 |
贝米肝素 | 结肠内 | 30 | 0.103 | 0.222 | 0.345 |
贝米肝素+实施例1 | 结肠内 | 30+30 | 0.299 | 0.196 | 0.147 |
贝米肝素+实施例2 | 结肠内 | 30+30 | 0.367 | 0.193 | 0.111 |
贝米肝素+实施例3 | 结肠内 | 30+30 | 0.520 | 0.316 | 0.240 |
(表1)
这些结果有助于说明本发明产物的O与H原子之间的氢键的重要性。
本发明的另一特征涉及R1取代基的性质和位置以及链长(n值)的重要性。
本申请人还发现,在3位上具有Cl或NO2取代基的衍生物具有与在1位上具有OH的衍生物至少一样的活性。
在本发明产物中,优选的化合物是与n=3以及与OH(实施例4)、Cl(实施例17)、NO2(实施例11)取代基相对应的那些化合物。
本发明产物可以以酸形式或生物学可接受的可溶性盐的形式,或者含有肝素或者肝素衍生物(酯、酰胺、寡糖等)以及因其良好功能而众所周知的辅助剂(聚乙二醇、藻酸盐、脱乙酰壳多糖和衍生物、丙二醇、carbopol等)的药物组合物的形式使用。
一种优选的组合物包含将上述一种产物与低分子量肝素例如贝米肝素,所述组合物口服用于预防和治疗静脉和动脉血栓形成。
本发明产物的另一应用包括将其与肝素的任何非抗凝血衍生物结合,口服用于病症例如炎症、变态反应和癌症。
一般情况下,本发明产物提高了葡糖胺基聚糖和葡糖胺基聚糖寡糖的口服吸收,特别是经由结肠途径的吸收。
在下面所述实验模型中对本发明产物的特性进行研究,包括在大鼠中测定具有平均分子量约为3,500道尔顿和抗-Xa活性约为100单位/mg的低分子量肝素—贝米肝素的结肠内吸收。
特别是对于实施例4(见图1)、11和17(见图2)的产物来说,所获得的结果显示了通过血浆抗-Xa活性来衡量的肝素吸收的强增加。
图1显示了大鼠中贝米肝素和实施例4、5和9的化合物的结肠内吸收,其显示于下。
图2显示了大鼠中实施例10、11和17的化合物的结肠内吸收,其显示于下。
通过非常低分子量肝素RO-14(2,500道尔顿,80-100单位抗-Xa/mg)的结肠内吸收的研究,证明了本发明产物的另一优点和它们作为提高由肝素衍生的寡糖的口服吸收的辅助剂的益处。药物组合物RO-14+实施例4产物(见图3)显示了高而持久的抗-Xa活性。
图3显示了大鼠中药物组合物RO-14+实施例4产物的结肠内吸收。
下面提供一系列实施例以便阐明本发明,而不是限制本发明的范围。这些实施例描述了下面所示化合物1-22的制备方法,以及它们对低分子量肝素—贝米肝素的结肠内吸收的提高效果。
实施例1
4-[4-(羟基苯甲酰基氨基)苯甲酰基氨基]丁酸(化合物1)
(化合物1)
向4.41g(18.69mmol)4-(4-氨基苯甲酰基氨基)丁酸甲酯溶解于80ml乙酸乙酯中的溶液中,缓慢加入溶解于10ml乙酸乙酯中的2.49g(15.97mmol)2-羟基苯甲酰氯。然后加入1.61g(15.97mmol)三乙胺,并将反应混合物保持在室温24小时。低压除去溶剂,向粗产物中加入40ml 10%NaOH,并继续搅拌混合物直到固体完全消失为止。立即用浓盐酸进行酸化,过滤所得固体并用水洗涤数次。将反应产物通过重结晶(EtOH/H2O)纯化。这样就得到1.48g(27%)4-[4-(2-羟基苯甲酰基氨基)苯甲酰基氨基]丁酸,为白色固体。
M.P.:211-213℃
IR(KBr):.v3360,2970,2680,1700,1665,1620,1540,1510,855,770,750,695cm-1 1H NMR(DMSO,400MHz):δ1.75(m,2H,-CH2-),2.27(t,2H,J=7.2Hz,-CH2-CO-),3.27(m,2H,-CH2-N-),6.97(m,2H,),7.43(m,1H,芳族),7.79(d,2H,J=8.5Hz,芳族),7.85(d,2H,J=8.5Hz,芳族),7.94(m,1H,芳族),8.39(t,1H,J=5.3Hz,-NH-CH2-),10.51(s,1H,-NH-Ph)ppm13C NMR(DMSO,100MHz):24.6,31.6,38.6,117.2,117.9,119.1,119.8,127.9,129.3,129.9,133.7,140.7,158.0,165.6,166.4,174.2ppmMS m/z(%):342(M+,4),324(5),239(19),204(18),168(21),120(100),92(19),65(33)
C18H18N2O5的元素分析
计算值:%C=63.15;%H=5.30;%N=8.18
实测值:%C=63.10;%H=5.32;%N=8.04
实施例2
6-[4-(2-羟基苯甲酰基氨基)苯甲酰基氨基]己酸(化合物2)
(化合物2)
向2.81g(10.64mmol)6-(4-氨基苯甲酰基氨基)己酸甲酯溶解于50ml乙腈中的溶液中,缓慢加入溶解于5ml乙腈中的1.42g(9.10mmol)2-羟基苯甲酰氯。然后加入0.92g(9.10mmol)三乙胺,并将反应混合物保持在室温24小时。低压除去溶剂,向粗产物中加入30ml 10%NaOH并继续搅拌混合物直到固体完全消失为止。立即用浓盐酸进行酸化,过滤所得固体并用水洗涤数次。将反应产物通过重结晶(EtOH/H2O)纯化。这样就得到1.11g(33%)6-[4-(2-羟基苯甲酰基氨基)苯甲酰基氨基]己酸,为白色固体。
M.P.:201-203℃
IR(KBr):v3330,3050,2950,2680,2570,1700,1675,1600,1540,855,770,750cm-1 1H NMR(DMSO,400MHz):δ1.32(m,2H,-CH2-CH2-CH2-),1.51(m,4H,-CH2-CH2-CH2-),2.20(t,2H,J=7.3Hz,-CH2-CO-),3.23(m,2H,-CH2-N-),6.97(m,2H,芳族),7.43(m,1H,芳族),7.78(d,2H,J=8.5Hz,芳族),7.84(d,2H,J=8.5Hz,芳族),7.93(m,1H,芳族),8.35(t,1H,J=5.1Hz,-NH-CH2-),10.51(s,1H,-NH-Ph),11.62(s,1H,-OH),11.95(s,1H,-COOH)ppm13C NMR(DMSO,100MHz):δ14.2,24.5,25.5,28.6,34.1,60.3,68.5,114.3,125.9,164.1,173.5ppm
MS m/z(%)263(M-18,3),236(4),218(2),172(5),143(20),115(16),97(49),69(100),55(49),41(65)
C20H22N2O5的元素分析
计算值:%C=64.85;%H=5.99;%N=7.56
实测值:%C=64.51;%H=5.86;%N=7.45
实施例3
4-[3-(2-羟基苯甲酰基氨基)苯甲酰基氨基]丁酸(化合物3)
(化合物3)
向2.60g(11.00mmol)4-(3-氨基苯甲酰基氨基)丁酸甲酯溶解于25ml乙酸乙酯中的溶液中,缓慢加入溶解于5ml乙酸乙酯中的1.40g(10.00mmol)2-羟基苯甲酰氯。然后加入1.00g(10.00mmol)Et3N(三乙胺),并将反应混合物保持在室温24小时。低压除去溶剂,向粗产物中加入40ml 10%NaOH,并继续搅拌混合物直到油状物完全消失为止。立即用浓盐酸进行酸化,过滤所得固体并用水洗涤数次。将反应产物通过重结晶(EtOH/H2O)纯化。这样就得到1.60g(48%)4-[3-(2-羟基苯甲酰基氨基)苯甲酰基氨基]丁酸,为白色固体。
M.P.:172-174℃
IR(ATR):v3291,2940,1714,1611,1551,1455,1335,1232,1214,878,817,735cm-1
1H NMR(DMSO,400MHz):δ1.77(q,2H,J=7.0Hz,-CH2-),2.28(t,2H,J=7.4Hz,-CH2-CO-),3.28(m,2H,-CH2-N-),6.97(m,2H,芳族),7.43(m,2H,芳族),7.59(m,1H,芳族),7.87(m,1H,芳族),7.98(m,1H,芳族)8.12(m,1H,芳族),8.50(t,1H,J=5.0Hz,-NH-CH2-),10.50(s,1H,-NH-)ppm13C NMR(DMSO,100MHz):δ24.5,31.2,38.7,117.3,117.4,119.1,120.2,122.7,123.5,128.6,129.1,133.8,135.4,138.2,158.5,166.1,166.7,174.2ppm
MS m/z(%):238(M+-104,61),210(3),186(2),160(3),137(9),119(100),120(30),92(50),91(12),65(31)
C18H18N2O5的元素分析
计算值:%C=63.14;%H=5.31;%N=8.18
实测值:%C=63.01;%H=5.23;%N=8.21
实施例4
4-[2-(2-羟基苯甲酰基氨基)苯甲酰基氨基]丁酸(化合物4)
(化合物4)
向20.36g(91.71mmol)4-(2-氨基苯甲酰基氨基)丁酸在200ml无水二氯甲烷内的悬浮液中,加入42.33g(391.92mmol)氯化三甲基硅烷,并将反应回流5小时。然后把烧瓶置于冰浴中并加入11.87g(117.57mmol)三乙胺和15.52g(78.38mmol)乙酰基水杨酰氯溶解于20ml无水二氯甲烷中的溶液。将反应在冰浴中搅拌30分钟并在室温搅拌24小时。低压除去溶剂,向粗产物中加入200ml 10%NaOH并继续搅拌混合物直到油状物完全消失为止。立即用浓盐酸进行酸化,过滤所得固体并用水以及用乙醚洗涤数次。将反应产物通过重结晶(EtOH/H2O)纯化。这样就得到21.66g(81%)4-[2-(2-羟基苯甲酰基氨基)苯甲酰基氨基]丁酸,为白色固体。
M.P.:173-174℃
IR(ATR):v3322,2925,2852,1688,1652,1633,1597,1529,1448,1260,1228,756cm-1
1H NMR(DMSO,400MHz):δ1.76(q,2H,J=7.0Hz,-CH2-),2.28(t,2H,J=7.3Hz,-CH2-CO-),3.27(m,2H,-CH2-N-),6.96(m,2H,芳族),7.20(m,1H,芳族),7.42(m,1H,芳族),7.50(m,1H,芳族),7.68(m,1H,芳族),7.83(m,1H,芳族)8.48(m,1H,芳族),8.50(t,1H,J=5.0Hz,-NH-CH2-),11.62s宽,1H,-OH),12.03(s宽,1H,-COOH),12.19(s,1H,-NH-Ph)ppm
13C NMR(DMSO,200MHz):δ24.2,31.1,38.9,117.2,117.9,119.3,121.7,123.1,123.3,128.1,129.2,131.3,133.7,137.8,158.1,165.5,168.1,174.2ppm
MS m/z(%):342(M+,5),265(4),239(100),222(11),121(50),120(64),119(62),92(54),77(10),65(53),39(39)
C18H18N2O5的元素分析
计算值:%C=63.15;%H=5.30;%N=8.18
实测值:%C=63.15;%H=5.38;%N=8.15
实施例5
5-[2-(2-羟基苯甲酰基氨基)苯甲酰基氨基]戊酸(化合物5)
(化合物5)
向1.61g(6.81mmol)5-(2-氨基苯甲酰基氨基)戊酸在20ml无水二氯甲烷内的悬浮液中,加入1.41g(11.94mmol)氯化三甲基硅烷,并将反应回流5小时。然后把烧瓶置于冰浴中并加入0.88g(8.73mmol)三乙胺和1.15g(5.82mmol)乙酰基水杨酰氯溶解于5ml无水二氯甲烷中的溶液。将反应在冰浴中搅拌30分钟并在室温搅拌24小时。低压除去溶剂,向粗产物中加入20ml 10%NaOH并继续搅拌混合物直到油状物完全消失为止。立即用浓盐酸进行酸化,过滤所得固体并用水以及用乙醚洗涤数次。将反应产物通过重结晶(EtOH/H2O)纯化。这样就得到1.26g(61%)5-[2-(2-羟基苯甲酰基氨基)苯甲酰基氨基]戊酸,为白色固体。
M.P.:168-170℃
IR(ATR):v3310,1698,1648,1626,1597,1521,1269,1223,1139,746cm-1
1H NMR(400MHz,DMSO):δ1.54(m,4H,-CH2-CH2-CH2-CH2-),2.21(t,2H,J=7.2Hz,-CH2-CO),3.26(m,2H,-CH2-N-),6.97(m,2H,芳族),7.18(m,1H,芳族),7.40(m,1H,芳族),7.51(m,1H,芳族),7.67(m,1H,芳族),7.84(m,1H,芳族),8.47(m,1H,芳族),8.72(t,1H,J=5.4Hz,-NH-CH2-),11.62(s,1H,-OH),11.98(s,1H,-COOH),12.18(s,1H,-NH-Ph)ppm
13C NMR(200MHz,DMSO):δ22.0,28.3,33.3,38.9,117.2,118.0,119.3,121.74,123.2,123.5,128.0,129.3,131.3,133.7,137.8,158.0,165.5,168.0,174.4ppm
MS m/z(%):356(M+,1),337(9),239(72),119(100),99(18),92(59),77(15),65(48),41(25)
C19H20N2O5的元素分析
计算值:%C=64.04;%H=5.66;%N=7.86
实测值:%C=63.90;%H=5.69;%N=7.75
实施例6
8-[2-(2-羟基苯甲酰基氨基)苯甲酰基氨基]辛酸(化合物6)
(化合物6)
向2.00g(7.20mmol)8-(2-氨基苯甲酰基氨基)辛酸在25ml无水二氯甲烷内的悬浮液中,加入1.36g(12.60mmol)氯化三甲基硅烷,并将反应回流5小时。然后把烧瓶置于冰浴中并加入0.93g(9.22mmol)三乙胺和1.21g(6.15mmol)乙酰基水杨酰氯溶解于5ml无水二氯甲烷中的溶液。将反应在冰浴中搅拌30分钟并在室温搅拌24小时。低压除去溶剂,向粗产物中加入20ml 10%NaOH并继续搅拌混合物直到油状物完全消失为止。立即用浓盐酸进行酸化,过滤所得固体并用水并用乙醚洗涤数次。将反应产物通过重结晶(EtOH/H2O)纯化。这样就得到1.41g(58%)8-[2-(2-羟基苯甲酰基氨基)苯甲酰基氨基]辛酸,为白色固体。
M.P.:124-125℃
IR(ATR):v3310,2931,2855,1698,1654,1627,1585,1526,1495,1448,1409,1361,1315,1268,1222,1196,1168cm-1
1H NMR(400MHz,DMSO):δ1.25(m,6H,-CH2-CH2-CH2-CH2-CH2-CH2-CH2-),1.46(m,4H,-CH2-CH2-CH2-CH2-CH2-CH2-CH2-),2.14(t,2H,J=7.5Hz,-CH2-CO),3.23(m,2H,-CH2-N-),6.95(m,2H,芳族),7.18(m,1H,芳族),7.41(m,1H,芳族),7.50(m,1H,芳族),7.65(m,1H,芳族),7.84(m,1H,芳族),8.44(m,1H,芳族),8.67(t,1H,J=5.7Hz,-NH-CH2-),11.61(s,1H,-OH),11.90(s,1H,-COOH),12.13(s,1H,-NH-Ph)ppm
13C NMR(200MHz,DMSO):δ24.5,26.4,28.50,28.52,28.8,33.6,39.2,117.2,117.9,119.3,121.8,123.2,123.8,128.0,129.2,131.2,133.7,137.7,158.1,165.5,167.9,174.5ppm
MS m/z(%):398(M+,1),379(3),351(2),278(5),251(6),239(94),197(9),137(11),119(100),100(17),92(51),77(8),65(37),41(20)
C19H20N2O5的元素分析
计算值:%C=66.32;%H=6.58,%N=7.03
实测值:%C=66.03;%H=6.47;%N=7.05
实施例7
6-[2-(2-羟基苯甲酰基氨基)苯甲酰基氨基]己酸(化合物7)
(化合物7)
向0.30g(1.20mmol)6-(2-氨基苯甲酰基氨基)己酸在5ml无水二氯甲烷内的悬浮液中,加入0.23g(2.10mmol)氯化三甲基硅烷,并将反应回流5小时。把烧瓶置于冰浴中并加入0.15g(1.53mmol)三乙胺和0.20g(2.05mmol)2-乙酰基水杨酰氯溶解于5ml无水二氯甲烷中的溶液。将反应在冰浴中搅拌30分钟并在室温搅拌24小时。低压除去溶剂,向粗产物中加入10ml 10%NaOH并继续搅拌混合物直到油状物完全消失为止。立即用浓盐酸进行酸化,过滤所得固体并用水以及用乙醚洗涤数次。将反应产物通过重结晶(EtOH/H2O)纯化。这样就得到0.24g(62%)6-[2-(2-羟基苯甲酰基氨基)苯甲酰基氨基]己酸,为白色固体。
M.P.:165-167℃
IR(ATR):v3348,2923,2853,1688,1595,1523,1493,1414,1360,1272,903,815,759cm-1
1H-NMR(400MHz,DMSO):δ1.31(m,2H,-CH2-CH2-CH2-),1.51(m,4H,-CH2-CH2-CH2-CH2-CH2-),2.17(t,2H,J=7.4Hz,-CH2-CO-),3.24(m,2H,-CH2-NH-),6.96(m,2H,芳族),7.18(m,1H,芳族),7.41(m,1H,芳族),7.50(m,1H,芳族),7.66(m,1H,芳族),7.84(m,1H,芳族),8.46(m,1H,芳族),8.69(s宽,1H,-NH-CH2-),11.61(s,1H,-OH),11.93(s,1H,-COOH),12.16(s,1H,-NH-Ph)ppm
13C NMR(200MHz,DMSO):δ24.2,26.0,28.5,33.6,39.1,117.2,118.0,119.3,121.8,123.2,123.7,128.0,129.3,131.2,133.7,137.7,158.0,165.4,167.9,174.4,ppm
MS m/z(%):352(M+-18,3),351(4),265(3),251(9),239(56),211(6),132(7),119(100),102(5),92(62),77(15),65(52),41(26)
C20H22N2O5的元素分析
计算值:%C=64.85;%H=5.99;%N=7.56
实测值:%C=64.57;%H=5.93;%N=7.57
实施例8
4-[2-(2-硝基苯甲酰基氨基)苯甲酰基氨基]丁酸(化合物8)
(化合物8)
向3.90g(17.50mmol)4-(2-氨基苯甲酰基氨基)丁酸在40ml无水乙酸乙酯内的悬浮液中,加入溶解于5ml无水乙酸乙酯中的3.26g(17.56mmol)2-硝基苯甲酰氯和1.76g三乙胺。将反应混合物在室温搅拌24小时。低压除去溶剂,向粗产物中加入30ml 10%NaOH并继续搅拌混合物直到固体完全消失为止。立即用浓盐酸进行酸化,并用乙酸乙酯萃取产物。低压除去溶剂,并将粗产物与无水乙醚混合,获得白色固体。将反应产物通过重结晶(EtOH/H2O)纯化。这样就得到3.34g(51%)4-[2-(2-硝基苯甲酰基氨基)苯甲酰基氨基]丁酸,为白色固体。
M.P.:142-144℃
IR(ATR):v3348,2923,2853,1688,1595,1523,1493,1414,1360,1272,903,815,759cm-1
1H-NMR(400MHz,DMSO):δ1.73(m,2H,-CH2-CH2-CH2-),2.26(t,2H,J=7.0Hz,-CH2-CO-),3.24(m,2H,-CH2-NH-),7.24(m,1H,芳族),7.56(m,1H,芳族),7.80(m,4H,芳族),8.10(m,1H,芳族),8.38(m,1H,芳族),8.82(s宽,1H,-NH-CH2-),12.02(s,1H,-COOH),12.06(s,1H,-NH-Ph)ppm
13C NMR(200MHz,DMSO):δ24.1,31.0,38.6,120.8,121.6,123.6,124.6,128.2,128.3,131.5,131.98,132.02,134.1,138.3,147.1,163.3,168.1,174.1ppm
MS m/z(%):371(M+,4),353(6),268(26),236(49),208(36),150(54),134(100),120(55),119(55),104(39),90(47),76(57),44(58)
C18H17N3O6的元素分析
计算值:%C=58.22;%H=4.61;%N=11.32
实测值:%C=58.15;%H=4.55;%N=11.35
实施例9
3-[2-(2-羟基苯甲酰基氨基)苯甲酰基氨基]丙酸(化合物9)
(化合物9)
向0.5g(2.40mmol)3-(2-氨基苯甲酰基氨基)丙酸在10mL无水二氯甲烷内的悬浮液中,加入0.45g(4.20mmol)氯化三甲基硅烷并将反应在氩气氛下回流2小时。然后把烧瓶置于冰浴中并加入0.31g(3.07mmol)三乙胺和0.40g(2.05mmol)2-乙酰基水杨酰氯溶解于5ml无水二氯甲烷中的溶液。将反应在冰浴中搅拌30分钟并在室温搅拌24小时。低压除去溶剂,向粗产物中加入30ml10%NaOH并继续搅拌混合物直到油状物完全消失为止。立即用浓盐酸进行酸化,过滤所得固体并用水以及用乙醚洗涤数次。将反应产物通过重结晶(EtOH/H2O)纯化。这样就得到0.37g(56%)3-[2-(2-羟基苯甲酰基氨基)苯甲酰基氨基]丙酸,为白色固体。
M.P.:200-202℃
IR(ATR):v3331,3051,2657,1718,1649,1626,1593,1523,1269,1225,904,853,749cm-1
1H-NMR(400MHz,DMSO):δ2.52(t,2H,J=7.4Hz,-CH2-CO-),3.46(m,2H,-CH2-NH-),6.97(m,2H,芳族),7.18(m,1H,芳族),7.41(m,1H,芳族),7.51(m,1H,芳族),7.65(m,1H,芳族),7.85(m,1H,芳族),8.45(m,1H,芳族),8.79(s宽,1H,-NH-CH2-),11.61(s,1H,-OH),12.15(s,1H,-COOH),12.25(s,1H,-NH-Ph),ppm
13C NMR(200MHz,DMSO);δ35.4,35.5,117.2,118.02,119.3,121.7,123.1,123.2,128.0,129.4,131.4,131.7,137.8,157.9,165.3,168.1,172.7ppm
MS m/z(%):328(M+,6),293(3),250(5),239(100),208(20),119(65),92(50),65(60),44(42)
C17H16N2O5的元素分析
计算值:%C=62.19;%H=4.91;%N=8.53
实测值:%C=61.82;%H=4.72;%N=8.39
实施例10
2-[2-(2-羟基苯甲酰基氨基)苯甲酰基氨基]乙酸(化合物10)
(化合物10)
向4.74g(24.44mmol)2-(2-氨基苯甲酰基氨基)乙酸在40ml无水二氯甲烷内的悬浮液中,加入5.05g(4.28mmol)氯化三甲基硅烷并将反应回流5小时。然后将烧瓶置于冰浴中并加入3.16g(31.32mmol)三乙胺和4.13g(20.88mmol)乙酰基水杨酰氯溶解于10ml无水二氯甲烷中的溶液。将反应在冰浴中搅拌30分钟并在室温搅拌24小时。低压除去溶剂,向粗产物中加入40ml 10%NaOH并继续搅拌混合物直到油状物完全消失为止。立即用浓盐酸进行酸化,过滤所得固体并用水以及用乙醚洗涤数次。将反应产物通过重结晶(EtOH/H2O)纯化。这样就得到3.54g(54%)2-[2-(2-羟基苯甲酰基氨基)苯甲酰基]乙酸,为白色固体。
M.P.:222-224℃
IR(ATR):v3286,2978,1730,1650,1627,1598,1584,1526,1242,900,835,752cm-1
1H-NMR(400MHz,DMSO):δ3.95(d,2H,J=4.9Hz,-CH2-),6.97(m,2H,芳族),7.21(m,1H,芳族),7.41(m,1H,芳族),7.55(m,1H,芳族),7.80(m,2H,芳族),8.52(m,2H,芳族),9.07(s宽,1H,-NH-CH2-),11.58(s,1H,-OH),12.18(s,1H,-COOH),12.70(s,1H,-NH-Ph)ppm
13C-NMR(200MHz,DMSO):δ41.2,117.2,118.0,119.3,121.8,122.3,123.2,128.1,129.3,131.8,133.7,138.1,157.9,165.4,168.4,171.0ppm.
MS m/z(%):278(M+-36,16),239(37)234(17),195(14),107(9),119(100),92(36),77(22)65(28),50(19)
C20H22N2O5的元素分析
计算值:%C=61.14;%H=4.49;%N=8.91
实测值:%C=60.90;%H=4.42;%N=8.98
实施例11
4-[2-(2-羟基-4-硝基苯甲酰基氨基)苯甲酰基氨基]丁酸(化合物11)
(化合物11)
向1.00g(4.50mmol)4-(2-氨基苯甲酰基氨基)丁酸在20ml无水二氯甲烷内的悬浮液中,加入4.50g(38.50mmol)氯化三甲基硅烷并将反应回流5小时。然后把烧瓶置于冰浴中并加入0.58g(5.70mmol)三乙胺和0.77g(38.50mmol)2-羟基-4-硝基苯甲酰氯溶解于10ml无水二氯甲烷中的溶液。将反应在冰浴中搅拌30分钟并在室温搅拌24小时。低除去溶剂,向粗产物中加入30ml10%NaOH并继续搅拌混合物直到油状物完全消失为止。立即用浓盐酸进行酸化,过滤所得固体并用水以及用乙醚洗涤数次。将反应产物通过重结晶(EtOH/H2O)纯化。这样就得到0.50g(34%)4-[2-(2-羟基-4-硝基苯甲酰基氨基)苯甲酰基氨基]丁酸,为黄色固体。
M.P.:209-211℃
IR(ATR):v.3378,2939,1702,1592,1520,1449,1420,1347,1326,1300,1259,1232,1215,1162,813,748,737cm-1
1H-NMR(400MHz,DMSO):δ1.75(m,2H,-CH2-CH2-CH2-),2.28(t,1H,J=7.3Hz,-CH2-CO-),3.26(m,2H,-CH2-N-),7.20(m,1H,芳族),7.52(m,1H,芳族),7.66(m,1H,芳族),7.74(m,2H,芳族),8.10(m,1H,芳族),8.49(m,1H,芳族),8.71(t,J=5.4Hz,-NH-CH2-),12.12(s,2H,-OH,-COOH),12.30(s,1H,-NH)ppm
13C-NMR(200MHz,DMSO):δ24.2,31.1,38.7,111.4,113.6,121.1,123.5,124.0,125.4,128.1,131.2132.1,137.4,149.9,156.8,162.5,167.8,174.2ppm
MS m/z(%):284(M+-103,55),253(4),238(16),222(1),211(2),182(8),154(9),146(13),119(90),92(47),63(48),53(21),30(100)
C18H17N3O7的元素分析
计算值:%C=55.81;%H=4.42;%N=10.85
实测值:%C=55.79;%H=4.44;%N=10.74
实施例12
4-[2-(2-羟基-5-硝基苯甲酰基氨基)苯甲酰基氨基]丁酸(化合物12)
(化合物12)
向1.00g(4.50mmol)4-(2-氨基苯甲酰基氨基)丁酸在20ml无水二氯甲烷内的悬浮液中,加入4.50g(38.50mmol)氯化三甲基硅烷并将反应回流5小时。然后把烧瓶置于冰浴中,并加入0.58g(5.70mmol)三乙胺和0.77g(38.50mmol)2-羟基-5-硝基苯甲酰氯溶解于10ml无水二氯甲烷中的溶液。将反应在冰浴中搅拌30分钟并在室温搅拌24小时。低压除去溶剂,向粗产物中加入30ml 10%NaOH并继续搅拌混合物直到油状物完全消失为止。立即用浓盐酸进行酸化,过滤所得固体并用水以及用乙醚洗涤数次。将反应产物通过在二氧杂环己烷/H2O中重结晶来纯化。这样就得到0.99g(67%)4-[2-(2-羟基-5-硝基苯甲酰基氨基)苯甲酰基氨基]丁酸,为奶油色固体。
M.P.:239-241℃
IR(ATR):v3315,3079,2626,1695,1651,1631,1584,1373,1334,1218,831,756,746cm-1
1H-NMR(400MHz,DMSO):δ1.75(m,2H,-CH2-CH2-CH2-),2.28(t,1H,J=6.8Hz,-CH2-CO-),3.26(m,2H,-CH2-N-),7.15(m,1H,芳族),7.18(m,1H,芳族),7.53(m,1H,芳族),7.65(m,1H,芳族),7.26(m,1H,芳族),8.45(m,1H,芳族),8.70(m,J=5.4Hz,-NH-CH2-),8.76(m,1H,芳族),12.09(s,2H,-OH,-COOH),12.90(s,1H,-NH)ppm
13C-NMR(200MHz,DMSO):δ24.2,31.1,38.7,117.9,119.8,122.2,123.5,124.3,127.2,128.1,128.5,131.1,137.3,139.7,162.0.162.3,167.8,174.2ppm
MS m/z(%):369(M+-18,1),352(10),335(1),311(3),296(3),284(31),253(11),237(3),209(6),166(6),137(8),119(74),92(55),63(43),42(56),41(72),30(100)
C18H17N3O7的元素分析
计算值:%C=55.81;%H=4.42;%N=10.85
实测值:%C=55.89;%H=4.50;%N=10.80
实施例13
4-[2-(2-羟基-4-甲氧基苯甲酰基氨基)苯甲酰基氨基]丁酸(化合物13)
(化合物13)
向1.00g(4.50mmol)4-(2-氨基苯甲酰基氨基)丁酸在20ml无水二氯甲烷内的悬浮液中,加入4.50g(38.50mmol)氯化三甲基硅烷,并将反应回流5小时。然后把烧瓶置于冰浴中,并加入0.58g(5.70mmol)三乙胺和0.71g(38.5mmol)2-羟基-4-甲氧基苯甲酰氯溶解于10ml无水二氯甲烷中的溶液。将反应在冰浴中搅拌30分钟并在室温搅拌24小时。低压除去溶剂,向粗产物中加入30ml 10%NaOH,并继续搅拌混合物直到油状物完全消失为止。立即用浓盐酸进行酸化,过滤所得固体并用水以及用乙醚洗涤数次。将反应产物通过重结晶(EtOH/H2O)纯化。这样就得到0.54g(38%)4-[2-(2-羟基-4-甲氧基苯甲酰基氨基)苯甲酰基氨基]丁酸,为白色固体。
M.P.:201-203℃
IR(ATR):v3306,2939,1711,1643,1622,1582,1524,1508,1438,1383,1244,1208,1178,1144,964,830,751,671cm-1
1H-NMR(400MHz,DMSO):δ1.76(m,2H,-CH2-CH2-CH2-),2.29(t,1H,J=7.3Hz,-CH2-CO-),3.29(m,2H,-CH2-N-),3.78(s,3H,-CH3),6.48(m,1H,芳族),6.58(m,1H,芳族),7.17(m,1H,芳族),7.50(m,1H,芳族),7.71(m,1H,芳族),7.76(m,1H,芳族),8.45(m,1H,芳族),8.77(1,J=5.4Hz,-NH-CH2-),12.05(s,2H,-OH,-NH),12.22(s,1H,-COOH)ppm
13C-NMR(200MHz,DMSO):δ24.2,31.1,38.7,55.4,101.3,106.7,109.9,121.5,122.6,122.9,128.1,129.9,131.5,138.1,160.9,163.8,166.0,168.2,174.2ppm
MS m/z(%):372(M+,3),353(2),269(84),228(16),222(17),182(4),151(100),120(58),119(59),92(47),65(24),52(12),30(53)
C19H20N2O6的元素分析
计算值:%C=61.28;%H=5.41;%N=7.52
实测值:%C=60.89;%H=5.37;%N=7.40
实施例14
4-[2-(2-羟基-5-甲氧基苯甲酰基氨基)苯甲酰基氨基]丁酸(化合物14)
(化合物14)
向1.00g(4.50mmol)of 4-(2-氨基苯甲酰基氨基)丁酸在20ml无水二氯甲烷内的悬浮液中,加入4.50g(38.50mmol)氯化三甲基硅烷,并将反应回流5小时。然后把烧瓶置于冰浴中,并加入0.58g(5.70mmol)三乙胺和0.71g(38.5mmol)2-羟基-5-甲氧基苯甲酰氯溶解于10mL无水二氯甲烷中的溶液。将反应在冰浴中搅拌30分钟并在室温搅拌24小时。低温除去溶剂,向粗产物中加入30ml10%NaOH,并继续搅拌混合物直到油状物完全消失为止。立即用浓盐酸进行酸化,过滤所得固体并用水以及用乙醚洗涤数次。将反应产物通过重结晶纯化(EtOH/H2O)。这样就得到0.791g(56%)4-[2-(2-羟基-5-甲氧基苯甲酰基氨基)苯甲酰基氨基]丁酸,为奶油色固体。
M.P.:191-193℃
IR(ATR):v3330,2877,1702,1593,1523,1494,1473,1449,1419,1356,1328,1306,1266,1205,1188,1174,1047,931,792,746,687cm-1
1H-NMR(400MHz,DMSO):δ1.76(m,2H,-CH2-CH2-CH2-),2.28(t,1H,J=7.3Hz,-CH2-CO-),3.27(m,2H,-CH2-N-),3.73(s,3H,-CH3),6.91(m,1H,芳族),7.04(m,1H,芳族),7.18(m,1H,芳族),7.38(m,1H,芳族),7.50(m,1H,芳族),7.76(m,1H,芳族),8.46(m,1H,芳族),8.70(1,J=5.4Hz,-NH-CH2-),11.10(s,1H,-OH),12.03(s,1H,-NH),12.09(s,1H,-COOH)ppm
13C-NMR(200MHz,DMSO):δ24.2,31.1,38.7,55.4,112.8,118.1,118.3,120.5,121.7,123.1,123.8,128.0,131.2,137.7,151.6,151.9,164.8,168.0,174.2ppm
MS m/z(%):372(M+,5),353(3),269(100),254(88),198(11),150(20),120(55),119(45),92(50),79(33),65(29),52(21),30(51)
C19H20N2O6的元素分析
计算值:%C=61.28;%H=5.41;%N=7.52
实测值:%C=61.21;%H=5.40;%N=7.47
实施例15
4-[2-(4-硝基苯甲酰基氨基)苯甲酰基氨基]丁酸(化合物15)
(化合物15)
向2.14g(9.63mmol)4-(2-氨基苯甲酰基氨基)丁酸在40ml无水二氯甲烷内的悬浮液中,加入1.83g(16.87mmol)氯化三甲基硅烷,并将反应回流5小时。然后把烧瓶置于冰浴中,并加入1.24g(12.33mmol)三乙胺和1.53g(8.22mmol)4-硝基苯甲酰氯在10ml无水乙酸乙酯中的悬浮液。将反应在冰浴中搅拌30分钟并在室温搅拌24小时。低压除去溶剂,向粗产物中加入30ml 10%NaOH,并继续搅拌混合物直到油状物完全消失为止。立即用浓盐酸进行酸化,过滤所得固体并用水以及用乙醚洗涤数次。将反应产物通过在二氧杂环己烷/H2O中重结晶来纯化。这样就得到1.33g(43%)4-[2-(4-硝基苯甲酰基氨基)苯甲酰基氨基]丁酸,为奶油色固体。
M.P.:206-208℃
IR(ATR):.v3282,3090,1731,1655,1626,1597,1558,1517,1444,1417,1399,1350,1326,1297,1258,1227,1166,854,836,766,715cm-1
1H-NMR(400MHz,DMSO):δ1.77(m,2H,-CH2-CH2-CH2-),2.29(t,1H,J=7.3Hz,-CH2-CO-),3.31(m,2H,-CH2-N-),7.24(m,1H,芳族),7.58(m,1H,芳族),7.85(m,1H,芳族),8.14(d,2H,J=8.7Hz,芳族),8.42(d,2H,J=8.7Hz,芳族),8.58(m,1H,芳族),8.46(m,1H,芳族),8.91(t,J=5.4Hz,-NH-CH2-),12.06(s,1H,-NH),12.72(s,1H,-COOH)ppm
13C-NMR(200MHz,DMSO):δ24.1,31.0,38.9,120.5,120.8,123.4,124.1,128.2,128.5,132.2,138.8,140.1,149.4,162.7,168.5,174.2ppm
MS m/z(%):371(M+,5),353(3),334(1),269(22),268(29),253(6),238(59),224(9),150(23),146(23),120(50),119(100),104(39),92(69),76(48),64(29),50(27),30(50)
C18H17N3O6的元素分析
计算值:%C=58.22;%H=4.61;%N=11.32
实测值:%C=58.15;%H=4.65;%N=11.10
实施例16
4-[2-(4-甲氧基苯甲酰基氨基)苯甲酰基氨基]丁酸(化合物16)
(化合物16)
向2.14g(9.63mmol)4-(2-氨基苯甲酰基氨基)丁酸在20ml无水二氯甲烷内的悬浮液中,加入8.90g(82.39mmol)氯化三甲基硅烷,并将反应回流5小时。然后把烧瓶置于冰浴中,并加入1.25g(12.36mmol)三乙胺和1.40g(8.24mmol)4-甲氧基苯甲酰氯溶解于10ml无水二氯甲烷中的溶液。将反应在冰浴中搅拌30分钟并在室温搅拌24小时。低压除去溶剂,向粗产物中加入30ml 10%NaOH,并继续搅拌混合物直到油状物完全消失为止。立即用浓盐酸进行酸化,过滤所得固体并用水以及用乙醚洗涤数次。将反应产物通过重结晶
(EtOH/H2O)纯化。这样就得到2.32g(79%)4-[2-(4-甲氧基苯甲酰基氨基)苯甲酰基氨基]丁酸,为奶油色固体。
M.P.:172-174℃
IR(ATR):.v3320,2960,2837,1720,1630,1592,1532,1509,1446,1301,1254,1167,1096,1025,841,748cm-1
1H-NMR(400MHz,DMSO):δ1.79(m,1H,-CH1-CH21-CH21-),2.31(t,0H,J=7.4Hz,-CH21-CO-),3.33(m,1H,-CH21-N-),3.83(s,2H,-CH22),7.11(d,1H,J=8.8Hz芳族),7.16(m,0H,芳族),7.53(m,0H,芳族),9(m,1H,芳族),7.89(d,2H,J=8.8Hz,芳族),8.65(m,1H,芳族),8.87(t,J=5.4Hz,-NH-CH32-),12.08(s,1H,-NH),12.49(s,1H,-COOH)ppm
13C-NMR(100MHz,DMSO):δ24.2,31.1,38.7,55.5,114.2,120.0,120.1,122.4,126.7,128.2,128.8,132.1,139.7,162.2,163.9,168.7,174.2ppm
MS m/z(%):356(M+,4),338(9),319(3),253(19),252(18),238(5),209(5),135(100),119(35),107(7),92(22),74(28),64(11),50(7),41(10)
C19H20N2O5的元素分析
计算值:%C=64.04;%H=5.66;%N=7.86
实测值:%C=63.97;%H=5.63;%N=7.79
实施例17
4-[2-(4-氯苯甲酰基氨基)苯甲酰基氨基]丁酸(化合物17)
(化合物17)
向2.00g(9.01mmol)4-(2-氨基苯甲酰基氨基)丁酸在20ml无水二氯甲烷内的悬浮液中,加入8.36g(77.00mmol)氯化三甲基硅烷,并将反应回流5小时。然后把烧瓶置于冰浴中,并加入1.17g(11.55mmol)三乙胺和1.35g(7.70mmol)4-甲氧基苯甲酰氯溶解于10ml无水二氯甲烷中的溶液。将反应在冰浴中搅拌30分钟并在室温搅拌24小时。低压除去溶剂,向粗产物中加入30ml 10%NaOH,并继续搅拌混合物直到油状物完全消失为止。立即用浓盐酸进行酸化,过滤所得固体并用水以及用乙醚洗涤数次。将反应产物通过重结晶(EtOH/H2O)纯化。这样就得到1.79g(65%)4-[2-(4-氯苯甲酰基氨基)苯甲酰基氨基]丁酸,为奶油色固体。
M.P.:182-184℃
IR(ATR):.v3069,2939,1692,1672,1628,1592,1525,1491,1444,1332,1310,1284,1259,1222,1180,1110,1096,1011,902,845,756,745cm-1
1H-NMR(400MHz,DMSO):δ1.79(m,2H,-CH2-CH2-CH2-),2.31(t,1H,J=7.4Hz,-CH2-CO-),3.32(m,2H,-CH2-N-),7.18(m,1H,芳族),7.54(m,1H,芳族),7.64(d,2H,J=8.5Hz,芳族),7.83(m,1H,芳族),7.92(d,2H,J =8.5Hz,芳族),8.61(m,1H,芳族),8.89(t,J=5.4Hz,-NH-CH2-),12.07(s,1H,-NH),12.61(s,1H,-COOH)ppm
13C-NMR(200MHz,DMSO):δ24.2,31.1,38.7,55.5,114.2,120.3,120.4,122.9,128.2,128.8,129.0,132.2,133.3136.9,139.3,163.3,168.6,174.2ppm
MS m/z(%):360(M+,11),342(4),323(1),258(30),238(15),213(6),187(8),162(6),141(33),139(100),119(38),111(56),92(25),75(20),65(11),41(11)
C18H17ClN2O4的元素分析
计算值:%C=59.92;%H=4.75;%N=7.76
实测值:%C=59.71;%H=4.77;%N=7.72
实施例18
4-[2-(4-氯-2-羟基苯甲酰基氨基)苯甲酰基氨基]丁酸(化合物18)
(化合物18)
向2.00g(9.00mmol)4-(2-氨基苯甲酰基氨基)丁酸在40ml无水二氯甲烷内的悬浮液中,加入8.36g(77.00mmol)氯化三甲基硅烷,并将反应回流5小时。然后把烧瓶置于冰浴中,并加入1.17g(11.50mmol)三乙胺和1.45g(7.70mmol)4-氯-2-羟基苯甲酰氯溶解于5ml无水二氯甲烷中的溶液。将反应在冰浴中搅拌30分钟并在室温搅拌24分钟。低压除去溶剂,向粗产物中加入30ml 10%NaOH,并继续搅拌混合物直到油状物完全消失为止。立即用浓盐酸进行酸化,过滤所得固体并用水以及用乙醚洗涤数次。将反应产物通过重结晶(EtOH/H2O)纯化。这样就得到1.35g(47%)4-[2-(4-氯-2-羟基苯甲酰基氨基)苯甲酰基氨基]丁酸,为白色固体。
M.P.:205-206℃
IR(ATR):v3319,3067,2936,1688,1583,1525,1494,1447,1408,1350,1330,1302,1261,1214,919,796,755cm-1
1H-NMR(400MHz,DMSO):δ1.75(m,2H,-CH2-CH2-CH2-),2.28(t,2H,J=7.3Hz,-CH2-CO-),3.26(m,2H,-CH2-N-),7.01(m,2H,芳族),7.18(m,1H,芳族),7.50(m,1H,芳族),7.65(m,1H,芳族),7.87(m,1H,芳族),8.46(m,1H,芳族),8.69(t,1H,J=5.12Hz,-NH-CH2-),12.07(s宽,3H,-OH,-COOH,-NH-Ph)ppm
13C NMR(200MHz,DMSO):δ24.3,31.1,38.6,116.6,117.8,119.3,121.9,123.2,123.9,128.0,131.1,131.7,137.3,137.6,158.4163.9,167.9,174.2ppm.
MS m/z(%):376(M+,2),273(65),238(17),222(7),155(25),146(5),120(39),119(100),99(13),92(43),63(27),30(45)
C18H17ClN2O5的元素分析
计算值:%C=57.38;%H=4.59;%N=7.43
实测值:%C=57.19;%H=4.57;%N=7.41
实施例19
4-[2-(5-氯-2-羟基苯甲酰基氨基)苯甲酰基氨基]丁酸(化合物19)
(化合物19)
向2.30g(10.4mmol)4-(2-氨基苯甲酰基氨基)丁酸在40ml无水二氯甲烷内的悬浮液中,加入9.56g(88.50mmol)氯化三甲基硅烷,并将反应回流5小时。然后把烧瓶置于冰浴中,并加入1.34g(13.30mmol)三乙胺和1.67g(8.85mmol)5-氯-2-羟基苯甲酰氯溶解于5ml无水二氯甲烷中的溶液。将反应在冰浴中搅拌30分钟并在室温搅拌24小时。低压除去溶剂,向粗产物中加入30ml 10%NaOH,并继续搅拌混合物直到油状物完全消失为止。立即用浓盐酸进行酸化,过滤所得固体并用水以及用乙醚洗涤数次。将反应产物通过重结晶(EtOH/H2O)纯化。这样就得到0.95g(29%)4-[2-(5-氯-2-羟基苯甲酰基氨基)苯甲酰基氨基]丁酸,为白色固体。
M.P.:222-223℃
IR(ATR):v3315,2958,1693,1657,1594,1524,1479,1447,1360,1325,1303,1272,1213,914,812,749cm-1
1H-NMR(400MHz,DMSO):δ1.75(m,2H,-CH2-CH2-CH2-),2.28(t,2H,J=7.3Hz,-CH2-CO-),3.26(m,2H,-CH2-N-),7.01(m,2H,芳族),7.18(m,1H,芳族),7.50(m,1H,芳族),7.50(m,1H,芳族),7.63(m,1H,芳族),7.83(m,1H,芳族),8.43(m,1H,芳族),8.67(t,1H,J=5.5Hz,-NH-CH2-),11.99(s宽,3H,-OH,-COOH,-NH-Ph)ppm
13C NMR(200MHz,DMSO):δ24.2,31.1,38.6,118.9,120.5,122.3,122.8,123.3,124.3,128.0,129.4,131.6,132.9,137.4,155.8,163.1,167.8,174.2ppm.
MS m/z(%):376(M+,3),273(100),238(22),155(18),120(40),119(80),99(13),92(46),63(26),30(35)
C18H17ClN2O5的元素分析
计算值:%C=57.38;%H=4.59;%N=7.43
实测值:%C=57.27;%H=4.58;%N=7.41
实施例20
4-[2-(2-氯苯甲酰基氨基)苯甲酰基氨基]丁酸(化合物20)
(化合物20)
向2.00g(9.01mmol)4-(2-氨基苯甲酰基氨基)丁酸在20mL无水二氯甲烷内的悬浮液中,加入8.36g(77.00mmol)氯化三甲基硅烷,并将反应回流5小时。然后把烧瓶置于冰浴中,并加入1.17g(11.55mmol)三乙胺和1.35g(7.70mmol)2-氯苯甲酰氯溶解于5mL无水二氯甲烷中的溶液。将反应在冰浴中搅拌30分钟并且在室温搅拌24小时。低压除去溶剂,向粗产物中加入30ml 10%NaOH,并继续搅拌混合物直到油状物完全消失为止。立即用浓盐酸进行酸化,并用乙酸乙酯萃取数次。将有机相用无水MgSO4干燥并低压除去。将粗产物用乙醚洗涤数次,并且最后通过重结晶(EtOH/H2O)纯化。这样就得到1.27g(36%)4-[2-(2-氯苯甲酰基氨基)苯甲酰基氨基]丁酸,为褐色固体。
M.P.:110-112℃
IR(ATR):v3308,1730,1659,1627,1598,1560,1513,1445,1433,1310,1287,1255,1168cm-1
1H-NMR(400MHz,DMSO):δ1.73(m,2H,-CH2-CH2-CH2-),2.26(t,2H,J=7.0Hz,-CH2-CO-),3.24(m,2H,-CH2-N-),7.21(m,1H,芳族),7.51(m,4H,芳族),7.65(m,1H,芳族),7.79(m,1H,芳族),8.53(m,1H,芳族),8.82(s宽,1H,-NH-CH2-),11.89(s,1H,-COOH),12.05(s,1H,-NH)ppm
13C NMR(100MHz,DMSO):δ24.1,31.1,38.6,120.4,121.1,123.3,127.6,128.2,128.9,129.8,130.2,131.7,132.0,136.3,138.5,164.3,168.2,174.1ppm.
MS m/z(%):360(M+,1),342(7),289(9),269(8),257(50),213(57),178(16),139(97)120(22),119(100),111(60),85(67),75(81),63(32),50(63),30(76)
C18H17ClN2O4的元素分析
计算值:%C=59.92;%H=4.75;N=7.76
实测值:%C=59.95;%H=4.77;%N=7.68
实施例21
4-[2-(2-溴苯甲酰基氨基)苯甲酰基氨基]丁酸(化合物21)
(化合物21)
向2.00g(9.01mmol)4-(2-氨基苯甲酰基氨基)丁酸在20mL无水二氯甲烷内的悬浮液中,加入8.36g(77.00mmol)氯化三甲基硅烷,并将反应回流5小时。然后把烧瓶置于冰浴中,并加入1.17g(11.55mmol)三乙胺和1.68g(7.70mmol)2-溴苯甲酰氯溶解于5mL无水二氯甲烷中的溶液。将反应在冰浴中搅拌30分钟并在室温搅拌24小时。低压除去溶剂,向粗产物中加入30ml 10%NaOH,并继续搅拌混合物直到油状物完全消失为止。立即用浓盐酸进行酸化,过滤所得固体并用水以及用乙醚洗涤数次。最后,通过重结晶纯化。这样就得到1.95g(63%)4-[2-(2-溴苯甲酰基氨基)苯甲酰基氨基]丁酸,为奶油色固体。
M.P.:117-118℃
IR(ATR):v3280,3176,1731,1654,1628,1598,1557,1510,1444,1428,1312,1286,1251,1166,743,664cm-1
1H-NMR(400MHz,DMSO):δ1.74(m,2H,-CH2-CH2-CH2-),2.26(t,2H,J=7.3Hz,-CH2-CO-),3.23(m,2H,-CH2-N-),7.21(m,1H,芳族),7.45(m,1H,芳族),7.53(m,2H,芳族,7.61(m,1H,芳族),8.53(m,1H,芳族),8.81(t,1H,J=5.28Hz,-NH-CH2-),11.84(s,1H,-COOH),12.03(s,1H,-NH)ppm
13C NMR(100MHz,DMSO):δ24.1,31.1,38.6,118.6,120.4,121.1,123.3,128.1,128.2,128.7,131.7,132.0,133.2,138.5,138.6,165.2,168.1,174.2ppm.
MS C18H17N2O4 79Br m/z(%):404(M+,1),303(32),257(20),238(20),221(22),185(100),178(12),157(31)143(26),119(60),90(31),76(41),50(39)
C18H17BrN2O4的元素分析
计算值:%C=53.35;%H=4.23;N=6.91
实测值:%C=53.32;%H=4.26;%N=6.89
实施例22
4-[2-(3-氯苯甲酰基氨基)苯甲酰基氨基]丁酸(化合物22)
(化合物22)
向2.00g(9.01mmol)4-(2-氨基苯甲酰基氨基)丁酸在20mL无水二氯甲烷内的悬浮液中,加入8.36g(77.00mmol)氯化三甲基硅烷,并将反应回流5小时。然后把烧瓶置于冰浴中,并加入1.17g(11.55mmol)三乙胺和1.35g(7.70mmol)3-氯苯甲酰氯溶解于5mL无水二氯甲烷中的溶液。将反应在冰浴中搅拌30分钟并在室温搅拌24小时。低压除去溶剂,向粗产物中加入30ml 10%NaOH,并继续搅拌混合物直到油状物完全消失为止。立即用浓盐酸进行酸化,并用乙酸乙酯萃取数次。将有机相用无水MgSO4干燥并低压除去。将粗产物用乙醚洗涤数次,并且最后通过重结晶(EtOH/H2O)纯化。这样就得到0.83g(30%)4-[2-(3-氯苯甲酰基氨基)苯甲酰基氨基]丁酸,为奶油色固体。
M.P.:165-166℃
IR(ATR):v 3307,3159,1741,1721,1669,1626,1589,1523,1447,1419,1326,1308,1256,1180,759cm-1
1H-NMR(400MHz,DMSO):δ1.78(m,2H,-CH2-CH2-CH2-),2.30(t,2H,J=7.0Hz,-CH2-CO-),3.30(m,2H,-CH2-N-),7.21(m,1H,芳族),7.56(m,1H,芳族),7.65(m,1H,芳族),7.71(m,1H,芳族),7.84(m,2H,芳族),7.91(m,1H,芳族),8.57(m,1H,芳族),8.88(t,1H,J=5.3Hz,-NH-CH2-),12.05(s,1H,-COOH),12.57(s,1H,-Ph-NH)ppm
13C NMR(100MHz,DMSO):δ24.1,31.1,38.6,120.4,121.1,123.3,127.6,128.2,128.9,129.8,130.2,131.7,132.0,136.3,138.5,164.3,168.2,174.1ppm.
MS m/z(%):360(M+,8),323(5),258(38),238(41),213(19),139(100)120(64),119(95),111(96),92(55),75(40),65(32),50(28),39(39)
C18H17ClN2O4的元素分析
计算值:%C=59.92;%H=4.75;%N=7.76
实测值:%C=59.87;%H=4.78;%N=7.76
按照下面的实验模型,在动物中对上述实施例的全部化合物的活性进行研究:
1.目的和基本原理
在经由结肠内途径给药大鼠后,于存在或不存在辅助剂的情况下,评估试验产物的吸收。通过分析因子Xa抑制能力来测定血浆的浓度。使用大鼠是因为它是在这种类型测试中通常使用的动物之一。
2.试验方法的描述
2.1.试验系统
◆描述: 威斯塔(Wistar)雄性鼠,得自委托的供应商。
◆重量 200-250g
◆龄期 9-11周
2.2.给药模型
一次直肠内给药。
2.3.剂量水平和给药体积
◆剂量水平 30mg/kg试验产物+30mg/kg辅助剂
◆给药体积 1ml/kg
2.4.载体
在双蒸馏水中的25%(v/v)丙二醇。将试验产物与辅助剂一起(如果可适用)溶解后,用NaOH将pH调节至7.4。
3.5.试验方案
使动物处于禁食状态大约18小时,同时动物可以自由获取水。
将动物随机分配到不同的实验组,每组保留一个动物作为备用。
在测试的当天,用氯胺酮麻醉后,经由结肠内途径给药来进行治疗。用连接到1-ml注射器的约8cm导管进行给药。将导管经由肛门全部导入结肠内,然后把试验产物缓慢给药到结肠内。
给药试验产物后,在图表中确定的时间内,在用氯胺酮麻醉的状态下,通过心内穿刺抽取柠檬酸盐化的血样(3.8%以1∶9的比例)。
血液离心:3000rpm,10分钟,4℃。血浆冷冻(-20+5℃)直到确定抗因子Xa活性为止。
不接受治疗的对照组包括在内,只是在与治疗组同样的条件下抽取血样,将其看作抗Xa活性的基线值。
通过显色法(抗-FXa活性分析试剂盒)分析抗Xa活性。
3.结果的评估
对于每一参数,计算每一试验组平均值的平均标准偏差(RSD)和标准误差。如果认为是充分的,则将得自不同试验组的值用统计学分析进行比较。
Claims (14)
5.权利要求1-4的药物组合物,其特征在于所述药物组合物包含肝素寡糖和至少一种式(1)化合物。
6.权利要求5的药物组合物,其特征在于所述药物组合物包含式(2)化合物和葡糖胺基聚糖寡糖。
7.权利要求5的药物组合物,其特征在于所述药物组合物包含式(3)化合物和葡糖胺基聚糖寡糖。
8.权利要求5的药物组合物,其特征在于所述药物组合物包含式(4)化合物和葡糖胺基聚糖寡糖。
11.权利要求5和8的药物组合物,其特征在于所述药物组合物包含至少一种下面结构的化合物
和贝米肝素。
12.前述权利要求任一项的药物组合物,其特征在于所述药物组合物包含式(1)化合物和至少一种选自下列的活性剂:肝素、硫酸皮肤素、condroitin sulphate、硫酸乙酰肝素和寡糖衍生物。
13.权利要求1-4任一项的化合物在制备抗血栓形成药物中的应用。
14.权利要求1-4任一项的化合物在制备用于治疗选自炎症、癌症和变态反应的疾病的药物中的应用。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
ES200301781A ES2222822B1 (es) | 2003-07-28 | 2003-07-28 | Diamidas de aminoacidos en posicion no alfa utiles como adyuvantes para la administracion de agentes biologicos activos. |
ESP200301781 | 2003-07-28 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1829682A true CN1829682A (zh) | 2006-09-06 |
CN100475776C CN100475776C (zh) | 2009-04-08 |
Family
ID=34112519
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNB2004800220400A Expired - Fee Related CN100475776C (zh) | 2003-07-28 | 2004-07-23 | 用作给药生物活性剂的辅助剂的非α位上的氨基酸二酰胺 |
Country Status (17)
Country | Link |
---|---|
US (1) | US7462735B2 (zh) |
EP (1) | EP1652836B1 (zh) |
JP (1) | JP4343227B2 (zh) |
KR (1) | KR100970216B1 (zh) |
CN (1) | CN100475776C (zh) |
AT (1) | ATE367373T1 (zh) |
AU (1) | AU2004261417C1 (zh) |
BR (1) | BRPI0413032A (zh) |
CA (1) | CA2533639A1 (zh) |
DE (1) | DE602004007665T2 (zh) |
DK (1) | DK1652836T3 (zh) |
ES (2) | ES2222822B1 (zh) |
PL (1) | PL1652836T3 (zh) |
PT (1) | PT1652836E (zh) |
RU (1) | RU2368599C2 (zh) |
WO (1) | WO2005012230A1 (zh) |
ZA (1) | ZA200600165B (zh) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2060253A1 (en) | 2007-11-14 | 2009-05-20 | Laboratorios Farmaceuticos Rovi, S.A. | Pharmaceutical forms for the release of active compounds |
ES2296529B1 (es) * | 2006-08-07 | 2009-04-01 | Laboratorios Farmaceuticos Rovi, S.A. | Composicion farmaceutica con promotores de absorcion. |
EP2213282A1 (en) | 2009-01-30 | 2010-08-04 | Laboratorios Farmaceuticos Rovi, S.A. | Pharmaceutical forms for the release of active compounds |
US8802156B2 (en) | 2007-11-14 | 2014-08-12 | Laboratorios Farmacéuticos Rovi, S.A. | Pharmaceutical forms for the release of active compounds |
CN104230745B (zh) * | 2014-07-10 | 2016-06-22 | 南京医科大学 | 一类n-苄基取代的氨基水杨酸与4-氨基丁酸的酰胺衍生物及其药物用途 |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6001347A (en) * | 1995-03-31 | 1999-12-14 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
US6358504B1 (en) * | 1997-02-07 | 2002-03-19 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
KR100659753B1 (ko) * | 1998-08-07 | 2006-12-20 | 에미스페어 테크놀로지스, 인코포레이티드 | 활성제 전달용 화합물 및 조성물 |
WO2000031536A2 (en) * | 1998-11-23 | 2000-06-02 | President And Fellows Of Harvard College | Detecting structural or synthetic information about chemical compounds |
SE0102764D0 (sv) * | 2001-08-17 | 2001-08-17 | Astrazeneca Ab | Compounds |
-
2003
- 2003-07-28 ES ES200301781A patent/ES2222822B1/es not_active Expired - Lifetime
-
2004
- 2004-07-23 DE DE602004007665T patent/DE602004007665T2/de not_active Expired - Lifetime
- 2004-07-23 AU AU2004261417A patent/AU2004261417C1/en not_active Ceased
- 2004-07-23 US US10/563,994 patent/US7462735B2/en not_active Expired - Fee Related
- 2004-07-23 ZA ZA200600165A patent/ZA200600165B/xx unknown
- 2004-07-23 PT PT04742074T patent/PT1652836E/pt unknown
- 2004-07-23 DK DK04742074T patent/DK1652836T3/da active
- 2004-07-23 WO PCT/ES2004/000346 patent/WO2005012230A1/es active IP Right Grant
- 2004-07-23 JP JP2006521597A patent/JP4343227B2/ja not_active Expired - Fee Related
- 2004-07-23 CA CA002533639A patent/CA2533639A1/en not_active Abandoned
- 2004-07-23 RU RU2006101630/04A patent/RU2368599C2/ru not_active IP Right Cessation
- 2004-07-23 PL PL04742074T patent/PL1652836T3/pl unknown
- 2004-07-23 KR KR1020067001803A patent/KR100970216B1/ko not_active IP Right Cessation
- 2004-07-23 EP EP04742074A patent/EP1652836B1/en not_active Expired - Lifetime
- 2004-07-23 AT AT04742074T patent/ATE367373T1/de active
- 2004-07-23 CN CNB2004800220400A patent/CN100475776C/zh not_active Expired - Fee Related
- 2004-07-23 ES ES04742074T patent/ES2289534T3/es not_active Expired - Lifetime
- 2004-07-23 BR BRPI0413032-4A patent/BRPI0413032A/pt not_active IP Right Cessation
Also Published As
Publication number | Publication date |
---|---|
PL1652836T3 (pl) | 2007-12-31 |
JP4343227B2 (ja) | 2009-10-14 |
RU2006101630A (ru) | 2007-09-10 |
AU2004261417B2 (en) | 2010-07-01 |
ZA200600165B (en) | 2007-03-28 |
DK1652836T3 (da) | 2007-11-05 |
WO2005012230A1 (es) | 2005-02-10 |
PT1652836E (pt) | 2007-10-23 |
ES2222822A1 (es) | 2005-02-01 |
EP1652836B1 (en) | 2007-07-18 |
AU2004261417C1 (en) | 2011-02-24 |
DE602004007665D1 (de) | 2007-08-30 |
JP2007533600A (ja) | 2007-11-22 |
BRPI0413032A (pt) | 2006-10-03 |
ES2222822B1 (es) | 2005-12-16 |
DE602004007665T2 (de) | 2008-05-15 |
KR100970216B1 (ko) | 2010-07-16 |
CN100475776C (zh) | 2009-04-08 |
RU2368599C2 (ru) | 2009-09-27 |
EP1652836A1 (en) | 2006-05-03 |
AU2004261417A1 (en) | 2005-02-10 |
US7462735B2 (en) | 2008-12-09 |
US20070191302A1 (en) | 2007-08-16 |
CA2533639A1 (en) | 2005-02-10 |
ATE367373T1 (de) | 2007-08-15 |
ES2289534T3 (es) | 2008-02-01 |
KR20060079184A (ko) | 2006-07-05 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1128139C (zh) | 新哌嗪衍生物及其制造方法 | |
CN1198613C (zh) | 氨基苯氧基乙酸衍生物和含有它们的药用组合物 | |
CN1298703C (zh) | 氰基吡咯烷衍生物 | |
CN1646531A (zh) | 作为髓过氧化物酶抑制剂的硫代黄嘌呤衍生物 | |
CN1202107A (zh) | 选择性β3肾上腺素兴奋剂 | |
CN1539828A (zh) | 含氮杂环羧酰胺衍生物或其盐 | |
CN1340049A (zh) | 作为内皮素受体拮抗剂的4-(杂环基磺酰氨基)-5-甲氧基-6-(2-甲氧基苯氧基)-2-苯基-或-吡啶基嘧啶 | |
CN101050194A (zh) | 双环辛烷类衍生物、其制备方法及其在医药上的用途 | |
CN1538967A (zh) | 杂环化合物和以其为有效成分的抗肿瘤药 | |
CN1476434A (zh) | 新化合物 | |
CN1812980A (zh) | 哌啶基-和哌嗪基-烷基氨基甲酸酯衍生物,其制备及治疗用途 | |
CN1535264A (zh) | 精氨酸衍生物 | |
CN1374962A (zh) | 8-苯基-6,9-二氢-[1,2,4]三唑并[3,4-i]嘌呤-5-酮衍生物 | |
CN1901917A (zh) | 作为糖原磷酸化酶抑制剂用于治疗糖尿病和肥胖症的(3-氧代-3,4-二氢-喹喔啉-2-基-氨基)-苯甲酰胺衍生物和相关化合物 | |
CN1296477A (zh) | 哌嗪衍生物及其制备方法 | |
CN1615299A (zh) | 黄嘌呤氧化酶抑制剂 | |
CN1231472C (zh) | 嘧啶无环核苷衍生物、其制备方法及其用途 | |
CN1878750A (zh) | 芳基烷基氨基甲酸酯衍生物、其制备方法和其在治疗学中的用途 | |
CN1254334A (zh) | 新颖的对苯二甲酰胺衍生物 | |
CN1564811A (zh) | 作为类固醇硫酸酯酶抑制剂的酰基磺酰胺化合物 | |
CN1100425A (zh) | 噻唑并嘧啶衍生物 | |
CN1829682A (zh) | 用作给药生物活性剂的辅助剂的非α位上的氨基酸二酰胺 | |
CN1522250A (zh) | 带有五元环基团的环状二胺化合物 | |
CN1968957A (zh) | 新的氧杂双哌啶化合物及其在治疗心律不齐中的用途 | |
CN1101914A (zh) | 新的甾族化合物及其中间体的制法和用途 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
C17 | Cessation of patent right | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20090408 Termination date: 20120723 |