WO2014154122A1 - 双环醇氨基酸酯及其制备方法与应用 - Google Patents
双环醇氨基酸酯及其制备方法与应用 Download PDFInfo
- Publication number
- WO2014154122A1 WO2014154122A1 PCT/CN2014/073998 CN2014073998W WO2014154122A1 WO 2014154122 A1 WO2014154122 A1 WO 2014154122A1 CN 2014073998 W CN2014073998 W CN 2014073998W WO 2014154122 A1 WO2014154122 A1 WO 2014154122A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- group
- bicyclic alcohol
- amino acid
- protected
- residue
- Prior art date
Links
- -1 Bicyclol amino-acid ester Chemical class 0.000 title claims abstract description 80
- 238000002360 preparation method Methods 0.000 title claims description 13
- 229940024606 amino acid Drugs 0.000 claims description 53
- 235000001014 amino acid Nutrition 0.000 claims description 53
- 125000002619 bicyclic group Chemical group 0.000 claims description 45
- 239000003814 drug Substances 0.000 claims description 25
- 206010067125 Liver injury Diseases 0.000 claims description 24
- 238000010511 deprotection reaction Methods 0.000 claims description 20
- 238000005886 esterification reaction Methods 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- 150000001413 amino acids Chemical class 0.000 claims description 14
- 239000004472 Lysine Substances 0.000 claims description 13
- 229960003104 ornithine Drugs 0.000 claims description 12
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Chemical group CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 claims description 11
- 229960000310 isoleucine Drugs 0.000 claims description 11
- 125000006239 protecting group Chemical group 0.000 claims description 11
- 239000004474 valine Chemical group 0.000 claims description 11
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Chemical group CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 claims description 10
- 125000003277 amino group Chemical group 0.000 claims description 10
- CKLJMWTZIZZHCS-REOHCLBHSA-N aspartic acid group Chemical group N[C@@H](CC(=O)O)C(=O)O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims description 10
- 229960003136 leucine Drugs 0.000 claims description 10
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical group NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 9
- 239000004471 Glycine Chemical group 0.000 claims description 9
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Chemical group CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 claims description 9
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical group CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 claims description 8
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims description 8
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 claims description 8
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 claims description 8
- 231100000234 hepatic damage Toxicity 0.000 claims description 8
- 230000008818 liver damage Effects 0.000 claims description 8
- 229930182817 methionine Chemical group 0.000 claims description 8
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical group CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 claims description 7
- AHLPHDHHMVZTML-BYPYZUCNSA-N ornithyl group Chemical group N[C@@H](CCCN)C(=O)O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 claims description 7
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Chemical group OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 claims description 7
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims description 6
- 229940009098 aspartate Drugs 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical group CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 claims description 5
- RJFAYQIBOAGBLC-UHFFFAOYSA-N Selenomethionine Natural products C[Se]CCC(N)C(O)=O RJFAYQIBOAGBLC-UHFFFAOYSA-N 0.000 claims description 5
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 claims description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
- 235000018417 cysteine Nutrition 0.000 claims description 5
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims description 5
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 claims description 5
- 230000032050 esterification Effects 0.000 claims description 5
- 229960002718 selenomethionine Drugs 0.000 claims description 5
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims description 4
- RJFAYQIBOAGBLC-BYPYZUCNSA-N Selenium-L-methionine Chemical group C[Se]CC[C@H](N)C(O)=O RJFAYQIBOAGBLC-BYPYZUCNSA-N 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 claims description 4
- 125000001360 methionine group Chemical group N[C@@H](CCSC)C(=O)* 0.000 claims description 4
- COLNVLDHVKWLRT-QMMMGPOBSA-N phenylalanine group Chemical group N[C@@H](CC1=CC=CC=C1)C(=O)O COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 claims description 4
- 125000003607 serino group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C(O[H])([H])[H] 0.000 claims description 4
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical group CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 claims description 3
- 235000004279 alanine Nutrition 0.000 claims description 3
- 235000003704 aspartic acid Nutrition 0.000 claims 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 claims description 3
- 230000009615 deamination Effects 0.000 claims description 3
- 238000006481 deamination reaction Methods 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims 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 claims description 3
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical group C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 5
- 125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 claims 2
- 125000000741 isoleucyl group Chemical group [H]N([H])C(C(C([H])([H])[H])C([H])([H])C([H])([H])[H])C(=O)O* 0.000 claims 2
- 125000001909 leucine group Chemical group [H]N(*)C(C(*)=O)C([H])([H])C(C([H])([H])[H])C([H])([H])[H] 0.000 claims 2
- 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 claims 2
- 125000000539 amino acid group Chemical group 0.000 claims 1
- 125000001500 prolyl group Chemical group [H]N1C([H])(C(=O)[*])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims 1
- 125000000430 tryptophan group Chemical group [H]N([H])C(C(=O)O*)C([H])([H])C1=C([H])N([H])C2=C([H])C([H])=C([H])C([H])=C12 0.000 claims 1
- KXMTXZACPVCDMH-UHFFFAOYSA-N methyl 4-[5-(hydroxymethyl)-7-methoxy-1,3-benzodioxol-4-yl]-7-methoxy-1,3-benzodioxole-5-carboxylate Chemical compound COC(=O)C1=CC(OC)=C2OCOC2=C1C1=C2OCOC2=C(OC)C=C1CO KXMTXZACPVCDMH-UHFFFAOYSA-N 0.000 abstract description 48
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 63
- 238000006243 chemical reaction Methods 0.000 description 28
- 239000007787 solid Substances 0.000 description 27
- 239000000243 solution Substances 0.000 description 24
- 229940079593 drug Drugs 0.000 description 23
- 241000700159 Rattus Species 0.000 description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- MSWZFWKMSRAUBD-GASJEMHNSA-N 2-amino-2-deoxy-D-galactopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@H](O)[C@@H]1O MSWZFWKMSRAUBD-GASJEMHNSA-N 0.000 description 14
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 14
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 12
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 12
- 108010003415 Aspartate Aminotransferases Proteins 0.000 description 11
- 102000004625 Aspartate Aminotransferases Human genes 0.000 description 11
- 231100000439 acute liver injury Toxicity 0.000 description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 9
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 8
- 239000002689 soil Substances 0.000 description 8
- 238000005481 NMR spectroscopy Methods 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 238000002474 experimental method Methods 0.000 description 7
- 230000003902 lesion Effects 0.000 description 7
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 7
- 210000002966 serum Anatomy 0.000 description 7
- 239000000741 silica gel Substances 0.000 description 7
- 229910002027 silica gel Inorganic materials 0.000 description 7
- 239000000203 mixture Substances 0.000 description 6
- 230000035484 reaction time Effects 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 231100000753 hepatic injury Toxicity 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 150000003839 salts Chemical group 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 230000002440 hepatic effect Effects 0.000 description 4
- 210000003494 hepatocyte Anatomy 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 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 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 239000012295 chemical reaction liquid Substances 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 210000004185 liver Anatomy 0.000 description 3
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 2
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- QNAYBMKLOCPYGJ-UHFFFAOYSA-M alaninate Chemical compound CC(N)C([O-])=O QNAYBMKLOCPYGJ-UHFFFAOYSA-M 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000003149 assay kit Methods 0.000 description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 2
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 210000003979 eosinophil Anatomy 0.000 description 2
- 230000002443 hepatoprotective effect Effects 0.000 description 2
- 238000010562 histological examination Methods 0.000 description 2
- 230000008595 infiltration Effects 0.000 description 2
- 238000001764 infiltration Methods 0.000 description 2
- 210000004969 inflammatory cell Anatomy 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 230000000116 mitigating effect Effects 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- ZZYXNRREDYWPLN-UHFFFAOYSA-N pyridine-2,3-diamine Chemical compound NC1=CC=CN=C1N ZZYXNRREDYWPLN-UHFFFAOYSA-N 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- DXWBBEQQKGMAGO-INIZCTEOSA-N (2s)-2-(9h-fluoren-1-ylmethoxycarbonylamino)-3-hydroxypropanoic acid Chemical compound C1C2=CC=CC=C2C2=C1C(COC(=O)N[C@@H](CO)C(O)=O)=CC=C2 DXWBBEQQKGMAGO-INIZCTEOSA-N 0.000 description 1
- IZJDXCIMPCJXTN-SFHVURJKSA-N (2s)-2-(9h-fluoren-1-ylmethoxycarbonylamino)-3-methylbutanoic acid Chemical compound C1C2=CC=CC=C2C2=C1C(COC(=O)N[C@@H](C(C)C)C(O)=O)=CC=C2 IZJDXCIMPCJXTN-SFHVURJKSA-N 0.000 description 1
- YRBYGQQJLQFTDV-IBGZPJMESA-N (2s)-2-(9h-fluoren-1-ylmethoxycarbonylamino)-4-methylpentanoic acid Chemical compound C1C2=CC=CC=C2C2=C1C(COC(=O)N[C@@H](CC(C)C)C(O)=O)=CC=C2 YRBYGQQJLQFTDV-IBGZPJMESA-N 0.000 description 1
- DNVVTLDDZCFJPU-SFHVURJKSA-N (2s)-2-(9h-fluoren-1-ylmethoxycarbonylamino)-4-methylsulfanylbutanoic acid Chemical compound C1C2=CC=CC=C2C2=C1C(COC(=O)N[C@@H](CCSC)C(O)=O)=CC=C2 DNVVTLDDZCFJPU-SFHVURJKSA-N 0.000 description 1
- NDNZKIQATHJUKP-DJJJIMSYSA-N (2s,3s)-2-(9h-fluoren-1-ylmethoxycarbonylamino)-3-methylpentanoic acid Chemical compound C1C2=CC=CC=C2C2=C1C(COC(=O)N[C@@H]([C@@H](C)CC)C(O)=O)=CC=C2 NDNZKIQATHJUKP-DJJJIMSYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 102100036475 Alanine aminotransferase 1 Human genes 0.000 description 1
- 108010082126 Alanine transaminase Proteins 0.000 description 1
- DHMQDGOQFOQNFH-UHFFFAOYSA-M Aminoacetate Chemical compound NCC([O-])=O DHMQDGOQFOQNFH-UHFFFAOYSA-M 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- 239000001116 FEMA 4028 Substances 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 241000272168 Laridae Species 0.000 description 1
- 108091093105 Nuclear DNA Proteins 0.000 description 1
- SJVFAHZPLIXNDH-UHFFFAOYSA-N OC(C(Cc1ccccc1)NC(OCC1c2ccccc2-c2c1cccc2)=O)=O Chemical compound OC(C(Cc1ccccc1)NC(OCC1c2ccccc2-c2c1cccc2)=O)=O SJVFAHZPLIXNDH-UHFFFAOYSA-N 0.000 description 1
- 229910000577 Silicon-germanium Inorganic materials 0.000 description 1
- 206010040742 Sinus congestion Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- LEVVHYCKPQWKOP-UHFFFAOYSA-N [Si].[Ge] Chemical compound [Si].[Ge] LEVVHYCKPQWKOP-UHFFFAOYSA-N 0.000 description 1
- YPNPCVTYEPGNDZ-UHFFFAOYSA-H [U+6].[O-]C([O-])=O.[O-]C([O-])=O.[O-]C([O-])=O Chemical compound [U+6].[O-]C([O-])=O.[O-]C([O-])=O.[O-]C([O-])=O YPNPCVTYEPGNDZ-UHFFFAOYSA-H 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 238000011888 autopsy Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical class OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 235000011175 beta-cyclodextrine Nutrition 0.000 description 1
- 229960004853 betadex Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N butyl alcohol Substances CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 239000000571 coke Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- XVOYSCVBGLVSOL-UHFFFAOYSA-N cysteic acid Chemical compound OC(=O)C(N)CS(O)(=O)=O XVOYSCVBGLVSOL-UHFFFAOYSA-N 0.000 description 1
- RAABOESOVLLHRU-UHFFFAOYSA-N diazene Chemical compound N=N RAABOESOVLLHRU-UHFFFAOYSA-N 0.000 description 1
- 229910000071 diazene Inorganic materials 0.000 description 1
- MROCJMGDEKINLD-UHFFFAOYSA-N dichlorosilane Chemical compound Cl[SiH2]Cl MROCJMGDEKINLD-UHFFFAOYSA-N 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 210000000744 eyelid Anatomy 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical class [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- FHLKWVKFEHBUAK-UHFFFAOYSA-H hexachlorouranium Chemical class Cl[U](Cl)(Cl)(Cl)(Cl)Cl FHLKWVKFEHBUAK-UHFFFAOYSA-H 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- 206010020718 hyperplasia Diseases 0.000 description 1
- 125000000593 indol-1-yl group Chemical group [H]C1=C([H])C([H])=C2N([*])C([H])=C([H])C2=C1[H] 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000005229 liver cell Anatomy 0.000 description 1
- 210000005228 liver tissue Anatomy 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical group C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 229960004452 methionine Drugs 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- BXGTVNLGPMZLAZ-UHFFFAOYSA-N n'-ethylmethanediimine;hydrochloride Chemical compound Cl.CCN=C=N BXGTVNLGPMZLAZ-UHFFFAOYSA-N 0.000 description 1
- VHYFNPMBLIVWCW-UHFFFAOYSA-O n,n-dimethylpyridin-1-ium-4-amine Chemical compound CN(C)C1=CC=[NH+]C=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-O 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- YYVGYULIMDRZMJ-UHFFFAOYSA-N propan-2-ylsilane Chemical compound CC(C)[SiH3] YYVGYULIMDRZMJ-UHFFFAOYSA-N 0.000 description 1
- PFZCOWLKXHIVII-UHFFFAOYSA-N pyridin-1-ium-1-amine Chemical compound N[N+]1=CC=CC=C1 PFZCOWLKXHIVII-UHFFFAOYSA-N 0.000 description 1
- 238000009790 rate-determining step (RDS) Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000001603 reducing effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 150000003573 thiols Chemical group 0.000 description 1
- 210000001541 thymus gland Anatomy 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- ZGYICYBLPGRURT-UHFFFAOYSA-N tri(propan-2-yl)silicon Chemical compound CC(C)[Si](C(C)C)C(C)C ZGYICYBLPGRURT-UHFFFAOYSA-N 0.000 description 1
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 1
- 150000003648 triterpenes Chemical class 0.000 description 1
- 229960004799 tryptophan Drugs 0.000 description 1
- 238000002525 ultrasonication Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to atoms of the carbocyclic ring
- C07D317/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
Definitions
- the invention belongs to the field of pharmaceutical organic chemistry, and relates to a class of bicyclic alcohol amino acid derivatives and the preparation thereof
- Bicyclol chemical name 4, 4'-dimethoxy- 5, 6, 5', 6'-dimethyldioxy-2-hydroxymethyl-2'- ⁇ oxycarbonyl biphenyl, its structural formula (Me represents methyl):
- Bicyclol is a multifunctional multi-target drug synthesized with significant hepatoprotective activity.
- a multi-faceted study on the mechanism of action of the drug shows that the mechanism of hepatoprotective enzymes of bicyclol is mainly to protect the integrity of the cells, protect the nuclear DNA of the liver cells from damage and reduce the occurrence of apoptosis by clearing the self-ffi basis. Thereby playing a role in liver protection.
- the bicyclol tablets (trade name: Baisino) were listed in 2001 and are now listed in the National Basic Medical Insurance and Industrial Injury Insurance Drugs Catalogue B.
- An important physicochemical property of bicyclol is poor solubility, low oral bioavailability ( ⁇ 9%), and absorption is susceptible to the gastrointestinal environment and food. Therefore, it is necessary to optimize the molecular structure of bicyclol to improve its pharmaceutical properties. It has been reported that its molecular properties are improved by modifying the 2-hydroxyl group on the bicyclic benzene ring. Disclosure of the Invention An object of the present invention is to provide a bicyclic alcohol amino acid derivative which is excellent in water solubility and high in oral utilization, and a preparation method and application of the bicyclic alcohol amino acid ester.
- the inventors introduced various amino acid fragments at the 2-hydroxymethyl site on the bicyclic benzene ring, and conducted extensive research and comparison. It was found that certain amino acid fragment structures can effectively improve the water solubility of the molecule, thereby improving the bioavailability of the drug. The degree is significant for improving the activity of the drug, thereby completing the creation of the present invention.
- the bicyclic alcohol amino acid ester provided by the invention has the following structural formula :
- the bicyclic alcohol amino acid esters of the present invention also include various salt forms such as acid salts, including hydrochlorides, sulfates, fumarates, maleates, p-benzenesulfonates, and the like.
- the invention also provides a preparation method of a bicyclic alcohol amino acid derivative - when R. is selenomethionine, methionine, leucine, tryptophan, isoleucine, phenylalanine, lysine, valine, c
- R. is selenomethionine, methionine, leucine, tryptophan, isoleucine, phenylalanine, lysine, valine, c
- the residue is a residue, the following steps are included;
- R is an ornithine, lysine residue, the following steps are included;
- lysine and ornithine which are protected by a straight chain and a side chain amino group, are respectively esterified with a bicyclic alcohol to obtain a protected bicyclic alcohol-lysine ester and a protected bicyclol-ornithine ester;
- the protected bicyclic alcohol-lysine ester and the protected bicyclic alcohol-ornithine ester are respectively subjected to a deprotection group to obtain a bicyclol-lysine ester and a bicyclol-ornithine ester.
- the amino acid used is protected selenomethionine, methionine, leucine, tryptophan, isoleucine, phenyl-W-, glycine, leucine
- the amino protecting groups used for alanine, ornithine, lysine, and serine are all fluorenylmethoxycarbonyl (Fmoc), and the hydroxy protecting group used is trityl (Trt).
- the carboxy protecting group used is benzyl (Bzl/Bn) and the amino protecting group used is benzyloxycarbonyl (Cbz).
- the thiol protecting group used is a triphenylsulfonyl group (TVt), and the amino protecting group used is a fluorenylmethoxycarbonyl group (Fm 0C ).
- the present invention also optimizes the reaction conditions for preparing the bicyclic alcohol amino acid derivative
- R is a selenomethionine, methionine, leucine, tryptophan, isoleucine, phenylalanine, glycine, valine, w acid, ornithine, lysine residue, of
- the esterification reaction temperature is 540 C; the reaction time is 2-10 h ; and the esterification reaction system further includes diaminopyridine (DMAP) and 1-(3-di-ylaminopropyl)-3- Ethylcarbodiimide hydrochloride (EDC'HCi); the molar ratio of bicyclol to protected amino acid is 1: (l ⁇ L2)o
- DMAP diaminopyridine
- EDC'HCi 1-(3-di-ylaminopropyl)-3- Ethylcarbodiimide hydrochloride
- the deprotection group reaction temperature is 0.5 to 2 h between the reaction B and the deprotection reaction system is a mixture of piperidine and dichloromethane (DCM).
- the esterification reaction temperature is 540 C; the reaction time is 2-10 h ; the esterification reaction system further includes diaminopyridine (DMAP) and 1-(3-dicarbylamino W group) 3- Ethylcarbodiimide hydrochloride (EDC'HCl); the molar ratio of bicyclol to protected amino acid is 1: (1-L2),
- the deprotection group reaction temperature is 5-40 ⁇ ; the reaction interval is 0.5-2 h; the deprotection group reaction system is a mixture of trifluoroacetic acid and dichloromethane (DCM), the reaction system Also included is a capture agent triiso W-based silicon germanium.
- DCM dichloromethane
- the deprotection group has a reaction temperature of 5 to 40 Torr; and the reaction is 0, 5 to 2 hours; and the deprotection reaction system is a mixture of piperidine and dichloromethane (DCM).
- the esterification reaction temperature is 5-4 CTC; the reaction time is 2-10 h; and the esterification reaction system further includes dimethylaminopyridine (DMAP) and 1-(3-dicarbylaminopropyl). -3-ethylcarbodiimide hydrochloride (ED HC1); the molar ratio of bicyclol to protected amino acid is 1: (1 - 1.2).
- the deprotection reaction temperature is 5-40" C; the reaction time is 2-6 h; the deprotection reaction system is palladium carbon (Pd/C); and the solvent used is methanol.
- the esterification reaction temperature is 5-4 CTC; the reaction time is 2-10 h; and the esterification reaction system further comprises 2 aminopyridine (DMAP) and 1-(3-dimethylaminopropyl). - 3-ethylcarbodiimide hydrochloride (EDOHCl); the molar ratio of bicyclol to protected amino acid is 1: (1 - 1.2).
- the deprotection group reaction temperature is 5-401:; the reaction time is 0.5-2 h; the deprotection reaction system is a mixture of trifluoroacetic acid and dichlorocycloalkane (DCM), and the reaction system is further Includes the capture agent isopropyl silane.
- the deprotection group reaction temperature is 5 - 40 'C: the reaction is between 0.5 and 2 h ; and the deprotection reaction system is a mixture of piperidine and dichloromethane (DCM).
- the preparation method of the bicyclic alcohol amino acid ester provided by the invention is simple in operation, low in cost and high in yield.
- the invention also provides a pharmaceutical composition
- a pharmaceutical composition comprising one or more of the above bicyclic alcohol amino acid esters.
- the bicyclic alcohol amino acid ester of the present invention or a salt thereof can be formulated into various liquid or solid forms together with one or more pharmaceutically acceptable excipients, such as tablets, powder injections, suspending agents, granules, and the like.
- the route of administration includes enteral or parenteral administration, such as oral administration, injection, etc., preferably oral.
- the invention also relates to the use of the above bicyclic alcohol amino acid ester for the preparation of a medicament for treating liver damage.
- Pharmacological experiments show that the bicyclic alcohol amino acid derivatives provided by the present invention can significantly alleviate the degree of acute liver injury induced by D-galactosamine in rats.
- bicyclic alcohol amino acid esters are easy to form into salts and have good water solubility. They are easily prepared into various dosage forms such as tablets and injections, and have high oral utilization rate. Injections are of particular importance for the treatment of acute liver injury. detailed description
- the solid obtained in the step (1) is dissolved in 10 1111_, 20% piperidine / 0 () ⁇ [mixed system, 30 mill at room temperature, the reaction is complete by TLC.
- the preparation method of this example is basically the same as that of Example 1, except that the selected amino acids are N-fluorenylmethoxycarbonyl-methionine, N-fluorenylmethoxycarbonyl-leucine, N-. ⁇ methoxycarbonyl-tryptophan, N-fluorenylmethoxycarbonyl-isoleucine, N-oxime oxyphenylphenylalanine, ⁇ - ⁇ oxycarbonyl-glycine, ⁇ - ⁇ oxycarbonyl- ⁇ ammonia Acid, ⁇ - ⁇ oxycarbonyl-alanine, the side chain amino group is oxycarbonyl-protected oxycarbonyl-lysine, and the side chain amino group is fluorenylmethoxycarbonyl-protected ⁇ - ⁇ methoxycarbonylornithine.
- the selected amino acids are N-fluorenylmethoxycarbonyl-methionine, N-fluorenylmethoxycarbonyl-le
- the mixture is washed successively with saturated sodium hydrogen carbonate solution and saturated sodium chloride solution, dried, filtered, concentrated, and eluted with silica gel column gradient.
- the 1,19 g of the white solid obtained in the step (2, 2) was dissolved in a 10111 [20% piperidine /] (1) mixed system, and the reaction was completed by a reaction at room temperature for 30 mi TLC.
- the reaction liquid was successively saturated with a dilute acetic acid solution.
- the sodium solution was washed, dried, concentrated, and eluted with a silica gel column gradient.
- the reaction liquid was washed successively with saturated sodium hydrogen carbonate solution and saturated sodium chloride solution, dried, filtered, concentrated, and eluted with silica gel column gradient.
- Bicyclol methionine 0.42 g of white blister solid, yield 81.3%.
- Bicyclol leucine 0, 40 g of white blister solid, yield 79.4%.
- Bicyclic alcohol tryptophan ester 0.41 g of a white solid, yield 71.2%.
- Bicyclic alcohol isoleucine ester 0.35 g of white coke, yield 69.6%.
- Bicyclol lysine ester 0.45 g of white blister solid, yield 86.8%.
- Bicyclol serine ester 0.48 g of white blister solid, yield 50.5%.
- Bicyclol aspartate 0.2 g of a white solid, yield 39.6%.
- Bicyclic alcohol glycinate 0,27 g of a white solid, yield 67%.
- ESI-MS: m/z [ ⁇ + ⁇ ] + 448.2 Bis-butyl alcohol oxime ester: 0.29 g of a white solid, yield 59.3%.
- ESI-MS: m/z [M+H] + 488.2 bicycloalcohol alaninate: 0.27 g of pale yellow solid, yield 67.2%.
- Bicyclic alcohol ornithine ester 0.43 g of pale yellow solid, yield 65.8%.
- the solubility of the if bicyclic alcohol at 37 ° C is about 56 g / mL, and the solubility of the bicyclic alcohol amino acid ester derivative ranges from 5 to 52 mg / mL.
- SPF grade SD rats weighing 180g ⁇ 220g, male and female, were provided by the Comparative Medical Center of Nanjing Military Region General Hospital.
- the bicyclic alcohol amino acid esters provided in Examples 1, 2, 3, 4, and 5 were tested in more samples, and the animal experiments were carried out in two batches; the first batch: randomly divided into 9, each group of 10, that is, (1) blank Control group, (2) model control group, (3) bicyclol group, (4) bicyclo methionine group, (5) bicyclol leucine group, (6) bicyclol isoleucinate group, ( 7) bicyclol fi-west methionine group, (8) bicyclol serine group, (9) bicyclol valine group.
- the second batch randomly divided into 12 groups, 10 in each group, namely (1) blank control group, (2) model control group, (3) bicyclol group, (4) bicyclol phenylalanine group, ( 5) bicyclic alcohol t's ester group, (6) bicyclol valine ester group, (7) bicyclol alanine group, (8) bicyclo alcohol tryptophan group, (9) bicyclol Group, (10) bicyclol cysteine group, (11) bicyclol aspartate group, (12) bicyclol octoate group.
- the first batch of experiments was divided into nine groups, including:
- Bicyclol group Bicyclol was administered at a dose of 6.75 mg kg (according to the clinical daily dose of 75 mg, converted to the dose of the rat according to the body surface area);
- bicyclol methionine group administration of bicyclol methionine at a dose of 6.75 mg/kg ;
- Bicyclic alcohol leucine group Administration of bicyclol leucine ester, the amount of Qi ij was 6,75 mg/kg.
- Bicyclic alcohol isoleucine ester group The bicyclic alcohol isoleucine ester was administered at a dose of 6.75 ffig/kg.
- Bicyclol selenomethionine group Bicyclol selenomethionate was administered at a dose of 6.75 nig/k 3 ⁇ 4.
- Bicyclol serine group Bicyclol serine ester was administered at a dose of 6.75 mg/kg.
- Bicyclic alcohol valine ester group The bicyclol valine ester was administered at a dose of 6.75 ffig/kg.
- Bicyclol group Bicyclol was administered at a dose of 6.75 mg kg (according to the clinical daily dose of 75 mg, converted to the dose of the rat according to the body surface area);
- Bicyclol benzene R-acid ester group Bicyclol phenylalanine ester was administered at a dose of 6.75 mg/kg.
- Bicyclol alcoholic acid group Administration of bicyclol glycine ester, the amount of Qi ij is 6,75 mg/kg.
- bicyclol valine ester group bicyclol valine ester was administered at a dose of 6.75 mg/kg.
- bicyclol alaninate group administration of bicyclol alaninate at a dose of 6.75 mg/kg;
- Bicyclic alcohol tryptophan ester group The bicyclic alcohol tryptophan ester was administered at a dose of 6.75 mg/kg.
- Bicyclol lysine ester group Bicyclol lysine ester was administered at a dose of 6.75 ffig/kg.
- Bicyclol cysteine group Bicyclol cysteine was administered at a dose of 6.75 mg/kg.
- Bicyclic alcohol ornithine group The bicyclic alcohol ornithine ester was administered at a specific amount of 6.75 mg/kg.
- the model group was given an equal volume of vehicle.
- the above groups of drugs were dissolved in DMSO, adjusted to a concentration of 6.75 mg/ml, and diluted with 1:10 in 10% ⁇ -cyclodextrin in PBS.
- the dosage volume is l.O mL/100 g
- AST Aspartate aminotransferase
- Modeling Except for the blank control group, the other groups of rats were injected intraperitoneally with D-galactosamine 600 mg/kg 24 times after the seventh administration, and the injection volume was 1.0 mL/100 g body weight; Inject the same amount of physiology & water.
- Detection rats were intraperitoneally injected with D-galactosamine 24 hours, weighing, eyelid recovery and separation clear, determination of AUi' and AST. After the rats were sacrificed by cervical dislocation, an autopsy was performed, liver, spleen, and thymus were taken, the organ coefficient (organ weight/body weight ⁇ %) was weighed, and histological examination of the liver tissue was performed.
- the liver was dissected, fixed in 10% formalin solution, routinely taken, dehydrated, embedded in paraffin, prepared (4 ⁇ thick), stained with HE, and examined under an optical microscope to check for the following lesions: (1) With or without hepatocyte lipids
- test drugs can alleviate the degree of liver damage, including bicyclol leucine, bicyclol isoleucine, bicyclo methionine, bicyclol t's ester, bicyclol cysteine
- the effect was particularly significant, and its mitigating effect was significantly higher than that of the positive drug bicyclol group, which was statistically significant compared with the model group (see Table 2-1, 2-2).
- Table 2-1 Results of the first batch of different drugs on rat [)-galactosamine liver injury ( ⁇ SD) group another t] number of animals (only) lesion score
- Bicyclol leucine group 10 3,5 ⁇ 1.65" bicyclol isoleucine group 10 3.75 ⁇ ] - , 27 ** bicyclol selenomethionine group 10 4.35 ⁇ 2.12 bicyclic alcohol ester ester 10 5.20 ⁇ 2.39 bicyclic alcohol valine ester group 10 5,35 ⁇ 2,26
- Model group 10 70 soil 1.53 bicyclic alcohol group 10 2.40 ⁇ 1.07* bicyclol phenylalanine group 10 3.05+2.63
- Bicyclol lysine ester group 10 2.80 ⁇ 2.07
- the bicyclic alcohol amino acid ester test drug of the invention has a significant reducing effect on the elevation of ALT and AST caused by D-galactosamine-induced acute liver injury in rats, and can all reduce the degree of liver damage to varying degrees, wherein the double ring
- the effects of alcohol leucine ester, bicyclic alcohol isoleucine ester, bicyclol glycine ester, and bicyclol alcohol cysteate were particularly remarkable, and the mitigating effect was more obvious than that of the ffl drug bicyclol group, and statistically compared with the model group. Significant difference.
- Serum biochemical indicators A T, AST, and lesion scores reflect the degree of liver damage from different sides, and there may be a degree of inconsistency between them.
- the bicyclic alcohol tryptophan ester and bicyclol aspartate lesion scores increased the degree of liver damage compared with the model group, but to some extent reduced the ALT and AST indicators compared with the model group.
- the water solubility of the bicyclic alcohol amino acid ester of the present invention is significantly improved compared with bicyclol, and the alanine aminotransferase and aspartate aminotransferase caused by D-galactosamine-induced acute liver injury in rats.
- Elevated enzymes have a significant reduction effect, can alleviate the degree of liver damage to varying degrees, and can be used as a drug for the treatment of liver damage.
Abstract
本发明公开了一类可用于医药的双环醇氨基酸酯,结构通式如式(I)。与双环醇相比,该类双环醇氨基酸酯水溶性好、口服利用率高。
Description
双环醇, 化学名为 4, 4'-二甲氧基- 5, 6, 5', 6'-二次甲二氧基 -2-羟甲基 -2'- ¥氧羰基联 苯, 其结构式为 (Me表示甲基):
双环醇为人工合成的一种多功能多靶点药物, 具有显著的保肝降酶活性。 对该药作 用机制进行多方面的研究表明, 双环醇的保肝降酶机制主要是通过清除自 ffi基, 从而维 持细胞的完整性, 使肝细胞核 DNA免受损伤及减少细胞凋亡的发生, 从而起到保肝作 用。 主要用于治疗各种肝损伤, 例如急性肝损伤。 经国家食品药品监督管理局批准, 双 环醇片 (商品名: 百赛诺)亍 2001年上市, 现已列入《国家基本医疗保险和工伤保险药品 目录》 乙类。
双环醇的一个重要物理化学性质是溶解性差, 口服生物利用率较低 (<9%) , 吸收 易受胃肠环境及以及食物等影响。 因此, 有必要对双环醇的分子结构进行优化, 以改善 其药物性质。巳有报道,通过对双环醇苯环上的 2-羟 ¥基进行改造,来改善其分子特性。 发明内容 本发明的目的是提供一类水溶性好、 口服利用率高的双环醇氨基酸衍生物, 以及该 类双环醇氨基酸酯的制备方法及其应用。
发明人在双环醇苯环上的 2-羟甲基位点引入了各种氨基酸片段, 并且进行了大量的 研究和对比, 发现某些氨基酸片段结构可以有效改善分子水溶性, 进而提高药物生物利 用度, 对提高药物活性意义重大, 从而完成了本发明创造。
本发明提供的双环醇氨基酸酯, 其结构式如下 :
OMe
0、
0一
,。、 COOMe
、 0"
OMe 苴 Φ
本发明还提供了双环醇氨基酸衍生物的制备方法- 当 R.是硒代蛋氨酸、 蛋氨酸、 亮氨酸、 色氨酸、 异亮氨酸、 苯丙氨酸、 氨酸、 脯 氨酸、 丙氨酸残基时, 包括以下步骤;
( ! ) 氨基保护的氨基酸与双环醇酯化反应, 得到保护的双环醇氨基酸酯;
(2 ) 保护的双环醇氨基酸酯经脱保护基反应, 即得双环醇氨基酸酯。
当 R是鸟氨酸、 赖氨酸残基时, 包括以下步骤;
( 1 ) 直链与侧链氨基均保护的赖氨酸、 鸟氨酸分别与双环醇酯化反应, 得到保护的双 环醇-赖氨酸酯和保护的双环醇-鸟氨酸酯;
(2 )保护的双环醇 -赖氨酸酯和保护的双环醇 -鸟氨酸酯分别经脱保护基反应, 即得双环 醇-赖氨酸酯和双环醇-鸟氨酸酯。
当 R为丝氨酸残基时, 包括以下步骤;
( 1 ) 羟基与氨基均保护的丝氨酸与双环醇酯化反应, 得保护的双环醇-丝氨酸酯;
(2) 保护的双环醇 -赖氨酸衍生物脱羟基保护基, 得氨基保护的双环醇 -丝氨酸酯。
(3 ) 氨基保护的双环醇-赖氨酸衍生物脱氨基保护基, 即得双环醇-丝氨酸酯。
当 R为天冬氨酸残基时, 包括以下歩骤:
( I ) 氨基与侧链羧基均保护的天冬氨酸与双环醇酯化反应, 得保护的双环醇-天冬氨酸
酯;
(2) 保护的双环醇-天冬氨酸衍生物经脱保护基反应, 既得双环醇-天冬氨酸酯。
当 R是半胱氨酸残基时, 包括以下步骤:
(1) 巯基与氨基均保护的半腕氨酸与双环醇酯化反应, 得保护的双环醇-半腕氨酸酯;
(2) 保护的双环醇 -半胱氨酸衍生物脱巯基保护基, 得氨基保护的双环醇-半胱氨酸酯。
(3) 氨基保护的双环醇 -半胱氨酸衍生物脱氨基保护基, 即得双环醇-半胱氨酸酯。
作为制备双环醇氨基酸衍生物方法的一种优选方法, 当所用氨基酸为保护的硒代蛋 氨酸、 蛋氨酸、 亮氨酸、 色氨酸、 异亮氨酸、 苯 W氨酸、 甘氨酸、 脑氨酸、 丙氨酸、 鸟 氨酸、 赖氨酸、 丝氨酸 ^所用氨基保护基均为芴甲氧羰基 (Fmoc), 所用羟基保护基为 三苯甲基(Trt)。 当所用氨基酸为保护的天冬氨酸时, 所用羧基保护基为苄基(Bzl/Bn), 所用氨基保护基为苄氧羰基(Cbz)。 当所 ^氨基酸为保护的半胱氨酸所时, 所用巯基保 护基为三苯 Ψ基 (TVt), 所用氨基保护基均为芴甲氧羰基 (Fm0C)。
保护的氨基酸的对应结构为 -
N-芴甲氧羰基-脯氨酸
本发明还优化了制备双环醇氨基酸衍生物的反应条件;
当 R是硒代蛋氨酸、 蛋氨酸、 亮氨酸、 色氨酸、 异亮氨酸、 苯丙氨酸、 甘氨酸、 脯 氨酸、 W氨酸、 鸟氨酸、 赖氨酸残基时, 所对应的
步骤 (1) 中, 酯化反应温度为 540C; 反应时间为 2-10h; 酯化反应体系中还包括 二 ^氨基吡啶(DMAP)和 1- (3-二 φ基氨基丙基) -3-乙基碳化二亚胺盐酸盐(EDC'HCi); 双环醇与保护的氨基酸的摩尔比为 1: (l~L2)o
步骤(2) 中, 脱保护基反应温度为 反应 B寸间为 0.5-2h; 所述脱保护基反应 体系为哌啶和二氯甲烷 (DCM) 的混合物。
当 R为丝氨酸残基 -, 所对应
步骤 (1) 中, 酯化反应温度为 540C; 反应时间为 2-10h; 酯化反应体系中还包括 二 ^氨基吡啶(DMAP)和 1- (3-二 ¥基氨基 W基)- 3-乙基碳化二亚胺盐酸盐(EDC'HCl); 双环醇与保护的氨基酸的摩尔比为 1: (1-L2),
歩骤(2) 中, 脱保护基反应温度为 5- 40Ό; 反应^间为 0.5- 2h; 所述脱保护基反应 体系为三.氟乙酸和二氯甲垸(DCM)的混合物,反应体系中还包括捕获剂三异 W基硅垸。
步骤(3) 中, 脱保护基反应温度为 5-40Ό; 反应^间为 0,5-2h; 所述脱保护基反应 体系为哌啶和二氯甲垸 (DCM) 的混合物。
当 R是天冬氨酸残基时, 所对应
步骤 (1) 中, ―酯化反应温度为 5-4CTC; 反应时间为 2- 10h; 酯化反应体系中还包括 二甲氨基吡啶(DMAP)和 1- (3-二¥基氨基丙基) -3-乙基碳化二亚胺盐酸盐(ED HC1); 双环醇与保护的氨基酸的摩尔比为 1: (1—1.2)。
步骤 (2) 中, 脱保护基反应温度为 5- 40"C; 反应时间为 2-6h; 所述脱保护基反应 体系为钯碳 (Pd/C); 所用溶剂为甲醇。
当 R半胱氨酸残基时, 所对应
步骤 (1) 中, ―酯化反应温度为 5-4CTC; 反应时间为 2- 10h; 酯化反应体系中还包括 二¥氨基吡啶(DMAP)和 1- (3-二甲基氨基丙基)- 3-乙基碳化二亚胺盐酸盐(EDOHCl); 双环醇与保护的氨基酸的摩尔比为 1: (1—1.2)。
步骤(2 ) 中, 脱保护基反应温度为 5-401:; 反应时间为 0.5-2h; 所述脱保护基反应 体系为三氟乙酸和二氯 φ烷(DCM )的混合物,反应体系中还包括捕获剂 异丙基硅烷。
步骤(3 ) 中, 脱保护基反应温度为 5- 40'C : 反应^ "间为 0.5- 2h; 所述脱保护基反应 体系为哌啶和二氯甲烷 (DCM) 的混合物。
本发明提供的双环醇氨基酸酯的制备方法操作简便、 成本低、 收率高。
本发明还提供一种药物组合物, 含有一种或多种上述双环醇氨基酸酯。 本发明双环 醇氨基酸酯或其盐,可以与一种或多种药用辅料,制成各种液体或固体别型,例如片别、 粉针剂、 悬浮剂、 颗粒齐 il等。 给药途径包括肠道或非肠道给药, 例如口服、 注射等, 优 选口服。
本发明还涉及到上述双环醇氨基酸酯在制备治疗肝损伤药物中的应用。 药理实验表 明, 本发明提供的双环醇氨基酸衍生物, 能显著减轻 D-氨基半乳糖胺诱导的大鼠急性 肝损伤程度。 而 , 该类双环醇氨基酸酯容易成盐, 水溶性好 ·, 很容易制成片剂、 注射 剂等各种剂型, 口服利用率高。 注射剂对治疗急性肝损伤具有特别重要的意义。 具体实施方式
根据下述实施例, 可以更好地理解本发明。 然而, 本领域的技术人员容易理解, 实 施例所描述的具体的物料配比、 工艺条件及其结果仅用于说明本发明, 而不应当也不会 限制权利要求书中所详细描述的本发明。 实施例 1 双环醇 西代蛋氨酸酯的制备
( I ) 酯化反应
称取 503mg N-芴甲氧羰基-硒代蛋氨酸 (1.2mmol) 溶于 15 mL无水二氯甲烷 (DCM) 中,冰浴冷却, 加入 13mg 4二甲氨基吡啶 ( DMAP ) ( O.lmmol) 和 230 mg 1- (3-二甲基 氨基丙基)— 3-乙基碳化二亚胺盐酸 ¾ ( EDOHC1) ( 1.2mnioI),搅拌 0 min,加入 390 mg 双环醇 (Immol), 反应 3 h。 反应液依次用饱和碳酸氢钠溶液、 饱和氯化钠溶液洗涤,
干燥, 得固体。
将步骤(1 )所得固体溶于 10 1111_, 20%哌啶/0(〕^[混合体系中,室温反应 30 mill, TLC 检测反应完全。 反应液依次用稀醋酸溶液, 饱和氯化钠溶液洗涤, 干燥, 硅胶柱梯度洗 脱, 流动相为 DCM:: MeOH===,50:I , 旋干得 450mg白色泡状固体, 即为双环醇-硒代蛋氨 酸酯。
MS(ESI+)OT Z:570.0[M+H]+。 两步总产率 79.2%。 实施例 2
本实施例的制备方法与实施例 1基本相同, 不同之处仅在亍: 所选用的保护的氨基 酸分别为 N-芴甲氧羰基-蛋氨酸, N-芴甲氧羰基-亮氨酸, N-芴甲氧羰基-色氨酸, N-芴 甲氧羰基 -异亮氨酸, N-芴 Ψ氧羰基苯丙氨酸, Ν-芴 ¥氧羰基 -甘氨酸, Ν-芴 Ψ氧羰基- 脯氨酸, Ν-芴 ^氧羰基 -丙氨酸, 侧链氨基为芴 ¥氧羰基保护的 氧羰基 -赖氨酸, 侧链氨基为芴甲氧羰基保护的 Ν-芴甲氧羰基鸟氨酸, 分别制得双环醇—蛋氨酸酯、 双环 醇 亮氨酸酯、 双环醇 -色氨酸酯、 双环醇-异亮氨酸酯、 双环醇苯丙氨酸酯、 双环醇- 氨酸酯、 双环醇 -誧氨酸酯、 双环醇 -丙氨酸酯、 双环醇 -赖氨酸酯、 双环醇 -鸟氨酸酯。 实施例 3 双环醇 -丝氨酸酯的制备
( 1 ) 酯化反应
称取 l„25g羟基为三苯 ¥基保护的 N-芴甲氧羰基-丝氨酸 (2.2mmol) 溶于 30 mL无 水二氯 ^烷 (DCM)中,冰浴冷却,加入 24mg 4-二 ¥氨基 Ρ比啶( DMAP) (0.2mmoi)和 460 mg 1- (3-二¥基氨基 W基)- 3-乙基碳化二亚胺盐酸盐 (EDC'HCl) ( 2.4mmol), 搅拌 0 min, 加入 780 ffig双环醇 (2mffioi), 反应 2 h。 反应液依次用饱和碳酸氢钠溶液、 饱和 氯化钠溶液洗涤, 干燥, 旋千得 1.79g白色泡状固体。
将步骤(1)所得白色泡状固体溶于 50mL (体积比: 二氯甲烷 /三异丙基硅烷 /三氟 乙酸 =94/1/5) 溶液, 反应 1.5h, TLC检测反应完全, 反应液依次用饱和碳酸氢钠溶液、 饱和氯化钠溶液浼涤, 千燥, 过滤, 浓缩, 硅胶柱梯度洗脱, 流动相为 PE: ΕΑ=1:ΐ,
将步骤 (2,2)所得 1,19g白色固体溶于 10111[ 20%哌啶/〕(〕1^混合体系中, 室温反 应 30mi TLC检测反应完全。反应液依次用稀醋酸溶液,饱和氯化钠溶液洗涤,千燥, 浓缩, 硅胶柱梯度洗脱, 流动相为 DCM: MeOH=50:l, 旋干得 480mg白色泡状固体, 即为双环醇-丝氨酸酯。
MS(ESI+)m/z:578.2[M+H 三歩总产率 50.5% 实施例 4 双环醇 -天冬氨酸酯的制备
称取 430mg支链羧基为苄基保护的 N-苄氧羰基-丝氨酸 (l,2mmoi) 溶亍 25 mL 无水二氯甲烷 (DCM)中,冰浴冷却, 加入 13mg4-二 氨基吡啶 (DMAP) (O.lmmol) 和 230 mg 1- (3-二甲基氨基丙基)- 3乙基碳化二亚胺盐酸盐 (EDC'HCi) ( 1.2mmol), 搅拌 10 min, 加入 390 mg双环醇 (Immol), 反应 2 h。 反应液依次用饱和碳酸氢铀溶液、 饱 和氯化钠溶液洗涤, 干燥, 硅胶柱梯度洗脱, 流动相为 PE; EA=1:2, 旋干得 630mg白 色泡状固体。
(2) 应
将步骤( 1 )所得 630mg固体溶于 7 mL 四氢呋喃和 30niL甲醇,加入 10% Pd/C 150mg 氢气保护, 室温反应 5h, TLC检测反应完全。 过滤, 千燥, 硅胶柱梯度洗脱, 流动相 为 PE: EA==4:1, 旋干得 200mg白色泡状固体, 即为双环醇-天冬氨酸酯。
MS(ESI+)m/z:505.9[M+H]+o 两步总产率 39.6%。 实施例 5 双环醇 -半胱氨酸酯的制备
(1) 酯化反应
称取 l,76g巯基为三:苯 ^基保护的 Ν-芴甲氧羰基-半胱氨酸氨酸 (3mmol) 溶于 30
mL无水二氯甲垸 (DCM)中,冰浴冷却,加入 30mg4-二甲氨基吡 ®(:DMAP) (0.25mmol) 和 624mg 1- (3-二 φ基氨基丙基) -3-乙基碳化二亚胺盆酸盐(EDC。HCi) ( 3,25nimol), 搅 拌 lO mi 加入 976mg双环醇 (2.5mmol), 反应 21ι。反应液依次用饱和碳酸氢钠溶液、 饱和氯化钠溶液洗涤, 千燥, 旋千得 2.48g白色泡状固体。
(2) 脱保护基反应
(2,1) 脱氨基保护基
将歩骤(2.1)所得 2.48g白色固体溶于 1()!«1_ 20%哌啶/1)(:^混合体系中, 室温反 应 30 min, TLC检测反应完全。反应液依次用稀醋酸溶液,饱和氯化铀溶液洗涤,千燥, 浓缩, 硅胶柱梯度洗脱, 流动相为 DCM: MeOH=50:l, 旋千得 1.74g 白色泡状固体, 即为双环醇-丝氨酸酯。
(2.2) 脱巯基保护基
将歩骤 (2.1) 所得白色泡状固体溶于 30mL (体积比: 二氯甲烷 /三异丙基硅垸 /三 氟乙酸 ==94/1/5)溶液,反应 1.5h, TLC检测反应完全,反应液依次用饱和碳酸氢钠溶液, 饱和氯化钠溶液洗涤, 千燥, 过滤, 浓缩, 硅胶柱梯度洗脱, 流动相为 PE: EA=1:1, 旋干得 560m 淡绿色固体, 即为双环醇半胱氨酸酯。
ES1-MS: m/'z
:三歩总产率 48.3%。 实施例 1、 2、 3、 4、 5所得双环醇氨基酸酯具体实验及质谱核磁数据如下- 双环醇硒代蛋氨酸酯: 0.45g白色泡状固体, 收率 79,2%。
jH-NMR(500MHz, CDC13) δ: 7.35- 7.36(d, IH, ArH), 6,66- 6,67(d, IH, ArH), 5.97-6,08(m,
2H, OCH20), 5.90- 5.92(m, 2H, OCH20), 4.79- 4.96(m, 2H, ArCH20), 3.94- 3.96(m, 3H, OCH3), 3,91-3,93(ni, 3H, OCH3), 3,65-3,70(ni, 3H, COOCH3), 3.58(s, 1H, CH), — 1.93-— 1.95(m, 2H, CH2), — 1.89(m, 2H, CH2), 1.25(s, 3H, C¾)。
ESI- MS: m/z [; M+H]+=570.0。
双环醇蛋氨酸酯: 0.42g白色泡状固体, 收率 81.3%。
jH-NMR(500MHz, CDC13) δ: 7.33- 7.40(d, 1H, ArH), 6,66- 6,69(d, 1H, ArH), 5.97-6,07(m, 2H, OCH20), 5.90- 5.92(m, 2H, OCH20), 4.74- 4.96(m, 2H, ArCH20), 3.95- 4.02(m, 3H, OCH3), 3,91- 3,94(m, 3H, OCH3), 3,65- 3,70(m, 3H, COOCH3), 3.57(s, 1H, CH), 3.153.51(m, 2H, CH2), 2.32- 2.65(m, 2H, CH2), 1.99- 2.05(m, 3H, SCH3)。
ESI- MS: m/z [M+H]+-522.1 , [M+Na]+=544.1。
双环醇亮氨酸酯: 0,40g白色泡状固体, 收率 79.4%。
jH-NMR(500MHz, CDC13) δ: 7.35- 7.36(d, 1H, ArH), 6,65- 6,67(d, 1H, ArH), 5.97-6,04(m, 2H, OCH20), 5.90- 5.92(m, 2H, ()(::¾()), 4.76- 4.94(m, 2H, ArCH20), 3.93- 3.96(m, 3H, OCH3), 3,90- 3,92(m, 3H, OCH3), 3,64- 3,67(m, 3H, COOCH3), 3.55(s, 1H, CH), 1.51 1.56(m, 1H, CH), 1.22 1.25(m, 2H, CH2), 0.840.86(m, 3H, CH3), 0.830.84(m, 3H, CH3).
ESI MS; m/z [M+H]+=504.1 , [M+Na]+=526, 1。
双环醇色氨酸酯: 0.41g白色固体, 收率 71.2%。
5H-NMR(300MHz, CDC13)6: 7.51- 7.74(d, J===7.86Hz, H, H), 7.36-7.37(d, J==3,54Hz, 1H, ArH), 7.30-7.3 l(m, 1H, ArH), 7.14 7.19(m, 2H, ArH), 7.04-7.10(ni, 1H, ArH), 6.906.94(dd, J3=2,16Hz, J2=9.37Hz, ArH), 6.60(ώ J-2.22Hz, 1H, ArH), 5.96- 6.02(m, 2H, OCH20), 5.92(m, 2H, OCH20), 4.84- 4.99(m, 2H, ArC¾0), 4,08-4, 15(m, 2H, NH2), 3,93- 3,95(d, J=4.17Hz, 3H, OCH3), 3.86- 3.88(d, J=3.84Hz, 3H, OCH3), 3.69(m, 1H, CH), 3.65-3.66(d, J===3,42Hz, 3H, COOC ), 3,II-3,20(m, 1H, CH2), 2.91- 3.00(m, 1H, CH2)。
ESI- MS; m/z; M+H]+=577。2。
双环醇异亮氨酸酯: 0.35g白色黏状物, 收率 69.6%。
NMR(500MHz, CDC13) δ: 7.36- 7.37(d, 1H, ArH), 6,65- 6,68(d, 1H, ArH), 5.99~6,04(m, 2H, OCH20), 5.90- 5.93(m, 2H, OCH20), 4.85- 4.97(m, 2H, ArCH20), 3.94- 3.96(m, 3H, OCH3), 3.90- 3.93(m, 3H, OCH3), 3.63-3.67(m, 3H, COOCH3)? 3,45(m, 1H,
CH), 3,19- 3,31(m, IH, CH), 1.53(br, 2H, C¾), 1.25(s, 3H, C¾), 0.83- 0.88(m, 3H, C¾)。
双环醇赖氨酸酯: 0.45g白色泡状固体, 收率 86.8%。
-i- NMR(3()()MHz, CDCi3) δ: 7.31- 7.39(m, IH, ArH), 6.62-6.71 (m, IH, ArH), 5.99-6.17(m, 2H' OCH20), 5.89- 5.94(m, 2H, OC¾0), 4,82- 5,16(m, 2H, ArH and N¾), 3.94- 3。97(m, 3H, OCH3), 3.87-3.93(m, 3H, OCH3), 3.50-3.73(m, 3H, COOCH3), 2.93(br, IH, CH), 1.61- 1.96(m, 3H, CH2), 1.26- 1.40(m, 4H, C¾), 0.86- 0.90(m, IH, C¾)。 ESI- MS; mlz [M+H]"=519.2, [M+Na]+=541.2。
双环醇丝氨酸酯: 0.48g白色泡状固体, 收率 50.5%。
NMR(500MHz, CDCI3) δ: 7.35(d, — IH, ArH), 6.68(s, — IH, ArH), 6.01-6.05(m, 2H, OCH20), 5.92(s, 2H, OCH20), 4.914.98(m, 2H, ArCH20), 3,97(m, 3H, OCH3), 3.93- 3.94(m, 3H, OCH3), 3.66-3.70(m, 4H, C00C1¾ and CH ), 3.56- 3.6()(m, IH, CE2), 3.44-35(m, IH, C¾)。
ESI- MS: m/z [; M+H]+=578.2。
双环醇天冬氨酸酯: 0.2g白色固体, 收率 39.6%。
jH-NMR(300MHz, CDC13) δ: 7.30- 7.31(m, IH, ArH), 6.66(s, IH, ArH), 5.88~6.05(m, 4H, OCH20), 4.91- 4.94(m, 2H, ArCH2), 4,08-4, 13(m, 2H, N¾), 3,86- 3,97(m, 9H, OCH3 andCOOCH3), 3,62(s, IH, CH), 2.46- 2.68(ra, 2H, (〕¾)。
ESI- MS; m/z [M+H]+=505。9。
双环醇苯丙氨酸酯: 0.31g白色固体, 收率 73.0%。 ESI MS: m/z〖M+H]+=538.2。
双环醇甘氨酸酯: 0,27g白色固体, 收率 67 %。 ESI- MS: m/z [Μ+Η]+=448.2 双环醇脯鍾酯: 0.29g白色固体, 收率 59.3%。 ESI-MS: m/z [M+H]+=488.2 双环醇丙氨酸酯: 0.27g淡黄色固体, 收率 67.2%。 ES】-MS: ιη/'ζ [M+H]+=== 62.2 双环醇鸟氨酸酯: 0.43g淡黄色固体, 收率 65.8%。 ESI- MS: m/z [M+H]+=504.2 双环醇半腕氨酸酯: 0.56g淡绿色固体, 收率 48„3%。 ESI-MS: m/z [M+H]+=494.1。 实施例 6 双环醇氨基酸酯的水溶性
以蒸馏水为溶剂, 采用超声 2h或加热后放至室温, 使溶液达到饱和状态。分别测定 25Ό和 37Ό下双环醇及其衍生物的饱和溶解度, 结果如下-
25 °C时双环醇的溶解度约为 28 g/mL , 双环醇氨基酸酯衍生物的溶解度范围为 2-30mg/mL;
37°C if 双环醇的溶解度约为 56 g/mL, 双环醇氨基酸酯衍生物的溶解度范围为 5- 52mg/mL。
通常认为, 当药物的水溶性^!!^/!^ ., 其水溶性可能成为药物吸收的限速步骤。 实验结果表明, 双环醇氨基酸酯衍生物的水溶性明显优亍双环醇, 有利于药物吸收。 实施例 7 双环醇氨基酸酯对大鼠 D-氨基半乳糖胺肝损伤模型的影响
1. 实验材料
1.1动物
SPF级 SD大鼠, 体重 180g〜220g, 雌雄各半, 由南京军区总医院比较医学中心提 供。
实施例 1、 2、 3 , 4、 5提供的双环醇氨基酸酯供试样品较多, 动物实验分两批进行; 第一批: 隨机分为 9 , 每组 10只, 即 (1)空白对照组, (2)模型对照组, (3)双环醇 组, (4)双环醇蛋氨酸酯组, (5)双环醇亮氨酸酯组, (6)双环醇异亮氨酸酯组, (7) 双环醇 fi西代蛋氨酸酯组, (8)双环醇丝氨酸酯组, (9) 双环醇缬氨酸酯组。
第二批: 随机分为 12组, 每组 10只, 即 (1)空白对照组, (2)模型对照组, (3)双环 醇组, (4)双环醇苯丙氨酸酯组, (5) 双环醇 t'氨酸酯组, (6) 双环醇誧氨酸酯组, (7)双 环醇丙氨酸酯组, (8)双环醇色氨酸酯组, (9)双环醇赖氨酸酯组, (10) 双环醇半胱氨酸 酯组, (11)双环醇天冬氨酸酯组, (12)双环醇鸟氨酸酯组。
1.2 药物
实施例 1、 2、 3、 4、 5的双环醇氨基酸酯, 双环醇。
1.3 药物配制、 别量及分组
第一批实验分九组, 包括:
(1) 空白对照组;
(2) 模型对照组;
(3) 双环醇组: 给药双环醇, 剂量为 6.75 mg kg (按照临床人日服用量 75mg按体表 面积折算成大鼠给药剂量);
(4) 双环醇蛋氨酸酯组: 给药双环醇代蛋氨酸酯, 剂量为 6.75 mg/kg;
(5) 双环醇亮氨酸酯组; 给药双环醇亮氨酸酯, 齐 ij量为 6,75 mg/kg。
(6) 双环醇异亮氨酸酯组: 给药双环醇异亮氨酸酯, 剂量为 6.75 ffig/kg。
(7) 双环醇硒代蛋氨酸酯组: 给药双环醇硒代蛋氨酸酯, 剂量为 6.75 nig/k¾。
(8) 双环醇丝氨酸酯组: 给药双环醇丝氨酸酯, 剂量为 6.75 mg/kg。
9) 双环醇缬氨酸酯组: 给药双环醇缬氨酸酯, 剂量为 6.75 ffig/kg。
(1) 空白对照组;
(2) 模型对照组;
(3) 双环醇组: 给药双环醇, 剂量为 6.75 mg kg (按照临床人日服用量 75mg按体表 面积折算成大鼠给药剂量);
(4) 双环醇苯 R氨酸酯组: 给药双环醇苯丙氨酸酯, 剂量为 6.75 mg/kg。
(5) 双环醇 It氨酸酯组; 给药双环醇甘氨酸酯, 齐 ij量为 6,75 mg/kg。
(6) 双环醇脯氨酸酯组; 给药双环醇脯氨酸酯, 剂量为 6.75 mg/kg。
(7) 双环醇丙氨酸酯组: 给药双环醇丙氨酸酯, 剂量为 6.75 mg/kg;
(8) 双环醇色氨酸酯组: 给药双环醇色氨酸酯, 剂量为 6.75 mg/kg。
(9) 双环醇赖氨酸酯组: 给药双环醇赖氨酸酯, 剂量为 6.75 ffig/kg。
(10) 双环醇半胱氨酸酯组: 给药双环醇半胱氨酸酯, 剂量为 6.75 mg/kg。
(11)双环醇天冬氨酸酯组; 给药双环醇天冬氨酸酯, 剂量为 6.75 mgZkg。
(12) 双环醇鸟氨酸酯组: 给药双环醇鸟氨酸酯, 别量为 6.75 mg/kg。
空白对照组, 模型组给予等容积溶媒, 上述各组药物使用时用 DMSO溶解, 调节 浓度至 6.75 mg/ml,用含 10% β环糊精的 PBS 1:10稀释后灌胃。给药体积为 l.O mL/100 g
L4 试剂
D-氨基半乳糖胺, 南京博源医药科技有限公司。
B-cyclodextrin, 中国医药集团上海化学试剂公司。
W氨酸氨基转移鷗 (AUT) IFCC法检测试剂盒, 四川迈克科技有限责任公司。
天冬氨酸氨基转移酶 (AST) IFCC法检测试剂盒, 四川迈克科技有限责任公司。
1 .5 仪器
DK-8D型恒温水浴槽, 上海精宏实验设备有限公司;
Sartorius电子大平, 德国 Sartorius公— e'J ;
OLYMPUS AU2700全自动生化分析仪。
2 实验方法
2.1 实验歩骤
建模: 除空白对照组外, 其余各组大鼠于第七次给药后 24小 ^"腹腔注射 D-氨基半 乳糖胺 600 mg/kg, 注射体积为 1.0 mL/100 g体重; 空白组注射等量生理 &水。
给药: 各组大鼠每天灌胃分别按剂量给药一次, 连续给药七天。
检测; 大鼠腹腔注射 D-氨基半乳糖胺 24小^后, 称体重, 眼眶采愈并分离愈清, 测定 AUi'和 AST。 颈椎脱臼处死大鼠后, 进行尸检, 取肝、 脾、 胸腺, 称量并计算脏 器系数 (脏器重量 /体重 χΐοο%), 并对肝脏组织进行病理组织学检查。
2.2 病理学检查
实验结束后剖取肝脏, 经 10%福尔马林溶液固定, 常规取材, 脱水, 石蜡包埋, 制 片 (4μη 厚), HE染色, 在光学显微镜下阅片, 检査有无下列病变: (1 )有无肝细胞脂
(2 )有无肝细胞索断裂; (3 )有无肝细胞坏死, 嗜酸性小体形成; (4) 肝窦有无扩张、 充血; (5 )肝小叶内有无炎细胞浸润; (6) 门管区有无炎症或纤维组织增生。 根据病变 由轻到重的程度标记为 0.5分 (轻微), 1分 (轻度), 2分 (中度), 3分 (重度), 0分
(基本正常), 累加所有分数, 并计算出每组每例动物的均分 ( ±SD), 结果进行两个 样本比较的秩和检验。
23 数据处理
对所有数据使用 Microsoft Excel软件进行数据处理, 对病理学 i 分采用秩和检测, 并统 分析结果。
3 实验结果
3.1 受试双环醇氨基酸酯对 D-氨基半乳糖胺诱导的大鼠急性肝损伤血清生化指标的影 响
从表 1-1和表 1-2可以看出, D-氨基半乳糖胺造模组大鼠血清 AL 和 AST显著升 高 (P<0.01 ), 表明: D-氨基半乳糖胺可造成大鼠急性肝损伤。 不同受试药物给药后 AL 和 AST数据见表 1-1和表 1-2。 表 1-1 第一批不同药物对 D-氨基半乳糖胺诱导的大鼠急性肝损伤血清生化指标的影响 ( ±sd, n= 10)
¾| 漏(mg/kg) 血清生化指标
ALT(U/L) AST(U/L) 空白对照组 ― 58, 3士 13,0 272.7±55.2 模型组 ― 4350, 1士 1941.1ΔΔ 6032,4士 1944.2ΔΔ 双环醇组 6,75 2246,8士 1458, 2 3921 ,2±2433.8* 双环醇蛋氨酸酯组 6.75 2357,8士 1746.3* 4229,6士 1842.5* 双环醇亮氨酸酯组 6,75 2162.7±2047.0* 3005. ±2349.4" 双环醇异亮氨酸酯组 6,75 1985.5±1003.0** 3855.2.士 1910.7* 双环醇硒代蛋氨酸酯组 6.75 2981.6±1771 .5 3586,6±2339.0* 双环醇 έ氨酸酯组 6.75 3256.8士 2386.1 4393.9士 2177.8 双环醇缬氨酸酯组 6,75 2784,3士 1629.0 4542,2士 2082.8 与模型组比较, <0.05, * <0.01; 与空白对照组比较, POOL
表 1-2 第二批不同药物对 D-氨基半乳糖胺诱导的大鼠急性肝损伤血清生化指标的影响 ( X士 sd, n= 10 )
血清生化指标
组别 齐 [!量 (mg/kg)
ALT(U/L) AST(U/L) 空白对照组 ― 35,5士 8.6 187,9土 40.2 模型组 162.7±85.5ΔΔ 504.1±191.1ΔΔ 双环醇组 6.75 74.6±58,4* 238.5±91 .2** 双环醇苯丙氨酸酯组 6.75 156,9士167.5 448 J土 254.0 双环醇 氨酸酯组 6.75 82,0±72.4* 267.2±67.0** 双环醇脯氨酸酯组 6.75 149,0±88.0 396.7±〗〗9,6 双环醇丙氨酸酯组 6.75 166.8士 212,0 381.7±310.8 双环醇色氨酸酯组 6.75 252,2±403.8 465, 5土 443.1 双环醇赖氨酸酯组 6.75 133,0士 103.6 452。4±269.5 双环醇半胱氨酸酯组 6.75 45.3±:! 8,广 256,5土 96.9** 双环醇天冬氨酸酯组 6.75 142.6士 144,0 360.7±155.7 双环醇鸟氨酸酯组 6.75 132,6±109.4 455, 8土 217.8
与模型组比较, <0.05, * <0.01; 与空白对照组比较, ΔΔΡ<0,01。
32 双环醇氨基酸酯对 D-氨基半乳糖胺诱导的大鼠急性肝损伤病理组织学检查的影响 受试双环醇氨基酸酯对 D-氨基半乳糖胺诱导的大鼠急性肝脏损伤的组织病理组织 学研究表明, 两批实验中 D-氨基半乳糖胺引起的大鼠肝损伤模型主要表现为 (1) 肝细 胞明显脂变; (2) 出现较多的嗜酸性小体; (3)肝小叶内有多灶性炎细胞浸润, 肝窦淤 血。 不同受试药物应用后均能减轻肝脏损伤程度, 其中双环醇亮氨酸酯, 双环醇异亮 氨酸酯, 双环醇蛋氨酸酯, 双环醇 t'氨酸酯, 双环醇半胱氨酸酯的效果尤为显著, 其减 轻效果较阳性药双环醇组明显, 与模型组相比具有统计学显著性差异 (见表 2-1,2-2)。 表 2-1第一批不同药物对大鼠 [)-氨基半乳糖胺肝损伤影响的病变评分结果 ( ±SD) 组 另 t] 动物数 (只) 病变评分
正常组 10 0,10±0.21** 模型组 10 5.70+0.92
阳性药双环醇组 10 4.35±1.40* 双环醇蛋氨酸酯组 10 4.2.5±1,32#
双环醇亮氨酸酯组 10 3,5士 1.65" 双环醇异亮氨酸酯组 10 3.75士]— ,27** 双环醇硒代蛋氨酸酯组 10 4.35±2.12 双环醇 氨酸酯 10 5.20±2.39 双环醇缬氨酸酯组 10 5,35 ±2,26
注: 各组与模型组比较 * Ρ < 0.05 , **Ρ < 0,0 表 2-2第二批不同药物对大鼠 D-氨基半乳糖胺肝损伤影响的病变评分结果 ( ±S:D)
组 另 u 动物数 (只) 病变评分
正常组 10 0,05土 0,16**
模型组 10 3, 70土 1.53 双环醇组 10 2.40±1.07* 双环醇苯丙氨酸酯组 10 3.05+2.63
双环醇甘氨酸酯组 10 1.55±1.77**
双环醇脯氨酸酯组 10 2.20±2.02
双环醇丙氨酸酯组 10 3.45+2,73
双环醇色氨酸酯组 10 3.95±3,20
双环醇赖氨酸酯组 10 2.80±2.07
双环醇半胱酸酯组 10 1 ,40土 0,74**
双环醇天冬氨酸酯组 10 4.00±2.59
双环醇鸟氨酸酯组 10 3.00±1 ,96
注: 各组与模型组比较 * P < 0.05 , < 0.01
4 结论
本发明的双环醇氨基酸酯受试药物对 D-氨基半乳糖胺诱导的大鼠急性肝损伤引起 的 ALT和 AST升高均有明显的降低作用,均能不同程度地减轻肝脏损伤程度, 其中双 环醇亮氨酸酯、双环醇异亮氨酸酯、双环醇甘氨酸酯、双环醇半胱酸酯的效果尤为显著, 其减轻效果较 ffl性药双环醇组明显, 与模型组相比具有统计学显著性差异。
血清生化指标 A T、 AST以及病变评分从不同侧面反应了肝脏损伤程度,它们之间 可能存在着一定程度的不一致性。双环醇色氨酸酯和双环醇天冬氨酸酯病变评分指标较 模型组加重了肝脏损伤程度, 但在一定程度上较模型组降低了 ALT和 AST指标。
综上所述, 本发明的双环醇氨基酸酯的水溶性较双环醇明显改善, 对 D-氨基半乳 糖胺诱导的大鼠急性肝损伤引起的丙氨酸氨基转移酶和天门冬氨酸氨基转移酶升高均 有明显的降低作用, 均能不同程度地减轻肝脏损伤程度, 可以作为治疗肝损伤的药物应 用。
Claims
1. 双环醇氨基酸酯, 其结构式如下:
其中 Me代表甲基, 并且 R= «代蛋氨酸残基、 蛋氨酸残基、 亮氨酸残基、 异亮氨 酸残基、 苯丙氨酸残基、 甘氨酸残基、 誧氨酸残基、 丙氨酸残基、 鸟氨酸残基、 赖氨酸 残基、 天冬氨酸残基、 色氨酸残基、 丝氨酸残基或半胱氨酸残基。
2. 根据权利要求 1所述的双环醇氨基酸酯, 其中1 =亮氨酸残基、 异亮氨酸残基、 甘氨酸残基或半胱氨酸残基。
3. 权利要求 1所述的双环醇氨基酸酯的制备方法, 当 R是硒代蛋氨酸、 蛋氨酸、 亮氨酸、 异亮氨酸、 苯丙氨酸、 甘氨酸、 脯氨酸、 丙氨酸、 色氨酸残基时, 包括以 T歩 骤:
( 1 ) 氨基保护的氨基酸与双环醇酯化反应, 得保护的双环醇氨基酸酯, 氨基保护 基为芴甲氧羰基;
(2) 保护的双环醇氨基酸酯经脱保护基反应, 即得双环醇氨基酸酯。
4. 权利要求 1所述的双环醇氨基酸酯的制备方法, 当: R是鸟氨酸或赖氨酸残基时, 包括以下歩骤:
( 1 ) 直链与侧链氨基均保护的赖氨酸、 鸟氨酸分别与双环醇酯化反应, 得保护的 双环醇—赖氨酸衍生物和保护的双环醇—鸟氨酸衍生物, 氨基酸直链与侧链氨基保护基均 为芴甲氧羰基;
(2 )保护的双环醇 -赖氨酸和双环醇-鸟氨酸衍生物分别经脱保护基反应, 即得双环 醇-赖氨酸衍生物和双环醇-鸟氨酸衍生物。
5. 权利要求 1所述的双环醇氨基酸酯的制备方法, 当 R是丝氨酸残基时, 包括以 下步骤:
( 1 ) 羟基与氨基均保护的丝氨酸与双环醇酯化反应, 得保护的双环醇-丝氨酸酯, 氨基酸羟基保护基为三.苯甲基、 氨基酸氨基保护基为芴甲氧羰基;
(2) 保护的双环醇-赖氨酸衍生物脱羟基保护基, 得氨基保护的双环醇 -丝氨酸酯;
(3 ) 氨基保护的双环醇-赖氨酸衍生物脱氨基保护基, 即得双环醇-丝氨酸酯。
6. 权利要求 1所述的双环醇氨基酸酯的制备方法, 当 R是天冬氨酸残基时, 包括 以下步骤:
( 1 ) 氨基与侧链羧基均保护的天冬氨酸与双环醇酯化反应, 得保护的双环醇-天冬 氨酸酯, 氨基酸羧基保护基为苄基, 所选用氨基酸氨基保护基为苄氧羰基;
(2) 保护的双环醇-天冬氨酸衍生物经脱保护基反应, 既得双环醇-天冬氨酸酯。
7. 权利要求 1所述的双环醇氨基酸酯的制备方法, 当 R是半胱氨酸残基时, 包括 以下步骤:
( ! ) 巯基与氨基均保护的半胱氨酸与双环醇酯化反应, 得保护的双环醇-半胱氨酸 酯, 氨基酸巯基保护基为三.苯甲基, 氨基酸氨基保护基为芴甲氧羰基;
(2)保护的双环醇半胱氨酸衍生物脱巯基保护基, 得氨基保护的双环醇 -半銑氨酸 酯;
(3 ) 氨基保护的双环醇 -半胱氨酸衍生物脱氨基保护基, 即得双环醇-半胱氨酸酯。
8. 一种药物组合物, 含有权利要求 1所述的任意一种或多种双环醇氨基酸酯。
9. 一种药物组合物, 含有权利要求 2所述的任意一种或多种双环醇氨基酸酯。
10. 权利要求 1或 2所述双环醇氨基酸酯在制备治疗肝损伤药物中的应用。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201310104047.8A CN103214451B (zh) | 2013-03-27 | 2013-03-27 | 双环醇氨基酸酯及其制备方法与应用 |
CN201310104047.8 | 2013-03-27 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2014154122A1 true WO2014154122A1 (zh) | 2014-10-02 |
Family
ID=48812668
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2014/073998 WO2014154122A1 (zh) | 2013-03-27 | 2014-03-25 | 双环醇氨基酸酯及其制备方法与应用 |
Country Status (2)
Country | Link |
---|---|
CN (1) | CN103214451B (zh) |
WO (1) | WO2014154122A1 (zh) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103214451B (zh) * | 2013-03-27 | 2015-05-20 | 南京工业大学 | 双环醇氨基酸酯及其制备方法与应用 |
CN105713035A (zh) * | 2015-12-25 | 2016-06-29 | 北京协和药厂 | 双环醇磷酸酯化合物、制备方法、制剂及用途 |
CN107245069A (zh) * | 2017-06-13 | 2017-10-13 | 佛山科学技术学院 | 一种双环醇‑乙酰半胱氨酸偶联物及其制备方法和用途 |
CN112250658B (zh) * | 2020-12-21 | 2021-05-07 | 北京鑫开元医药科技有限公司 | 一种甲酰化双环醇及其制备方法 |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101104629A (zh) * | 2007-07-23 | 2008-01-16 | 中国海洋大学 | 一种双环醇糖苷化合物及其制备方法和应用 |
CN102180861A (zh) * | 2010-05-27 | 2011-09-14 | 武汉大学 | 双环醇缬氨酸酯及其制备方法和其药物组合物与用途 |
CN102911251A (zh) * | 2012-10-09 | 2013-02-06 | 南京工业大学 | 双环醇-谷胱甘肽缀合物及其制备方法与应用 |
CN102964332A (zh) * | 2012-12-13 | 2013-03-13 | 南京工业大学 | 双环醇-硫普罗宁酯及其制备方法与应用 |
CN103214451A (zh) * | 2013-03-27 | 2013-07-24 | 南京工业大学 | 双环醇氨基酸酯及其制备方法与应用 |
-
2013
- 2013-03-27 CN CN201310104047.8A patent/CN103214451B/zh not_active Expired - Fee Related
-
2014
- 2014-03-25 WO PCT/CN2014/073998 patent/WO2014154122A1/zh active Application Filing
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101104629A (zh) * | 2007-07-23 | 2008-01-16 | 中国海洋大学 | 一种双环醇糖苷化合物及其制备方法和应用 |
CN102180861A (zh) * | 2010-05-27 | 2011-09-14 | 武汉大学 | 双环醇缬氨酸酯及其制备方法和其药物组合物与用途 |
CN102911251A (zh) * | 2012-10-09 | 2013-02-06 | 南京工业大学 | 双环醇-谷胱甘肽缀合物及其制备方法与应用 |
CN102964332A (zh) * | 2012-12-13 | 2013-03-13 | 南京工业大学 | 双环醇-硫普罗宁酯及其制备方法与应用 |
CN103214451A (zh) * | 2013-03-27 | 2013-07-24 | 南京工业大学 | 双环醇氨基酸酯及其制备方法与应用 |
Also Published As
Publication number | Publication date |
---|---|
CN103214451A (zh) | 2013-07-24 |
CN103214451B (zh) | 2015-05-20 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2022143473A1 (zh) | 一种核苷类化合物及其用途 | |
WO2020030143A1 (zh) | 酮酰胺类化合物及其制备方法、药物组合物和用途 | |
TW200914460A (en) | Proteasome inhibitors | |
CN106470975A (zh) | 多环氨基甲酰基吡啶酮化合物的合成 | |
WO2011083304A1 (en) | Prodrugs of opioids and uses thereof | |
WO2014154122A1 (zh) | 双环醇氨基酸酯及其制备方法与应用 | |
CN109310674A (zh) | 醛糖还原酶抑制剂及其使用方法 | |
CN106458857A (zh) | AHU‑377结晶型游离酸、半钙盐、α﹣苯乙胺盐及其制备方法和应用 | |
CN114805478A (zh) | 氘代拟肽类化合物及其用途 | |
CN105873922A (zh) | 9,9,10,10-四氟-9,10二氢菲类丙型肝炎病毒抑制剂及其应用 | |
US20220002306A1 (en) | Crystal form of upadacitinib and preparation method and use thereof | |
CN111491937A (zh) | 作为精氨酸酶抑制剂的杂环化合物 | |
ES2880391T3 (es) | Compuesto de ciclofosfato de nucleósido de fármaco precursor antivírico y uso del mismo | |
CN105820130A (zh) | 三氮唑正丙酸类urat1抑制剂、制备方法及其在高尿酸血症和痛风治疗上的用途 | |
CN107129517A (zh) | 一种具有α,β‑不饱和酮结构片段的孕烯醇酮衍生物及其用途 | |
CN106631957A (zh) | 一种靶向FAP‑alpha酶的抗肿瘤化合物及其制备方法与应用 | |
CN115572298A (zh) | 一种核苷类似物及其盐的晶型、制备方法和应用 | |
WO2021180023A1 (zh) | 一种弹性蛋白酶抑制剂前药及其用途 | |
CN113024557B (zh) | 一种Peganumine A生物碱结构简化物及其应用 | |
WO2018227886A1 (zh) | 新型吲哚胺2,3-双加氧化酶抑制剂 | |
US6784315B2 (en) | Stilbene derivative crystal and method for producing the same | |
NZ582850A (en) | 5'-substituted adenosynes, preparation thereof and use as inhibitors of s-adenosylmethionine decarboxylase | |
CN112384494A (zh) | 一种稠合三环γ-氨基酸衍生物的组合物及其制备 | |
CN102993161B (zh) | 双环醇-亮氨酰胺及其制备方法与应用 | |
CN109651377A (zh) | 一种治疗癌症的化合物及其用途 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 14775076 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 14775076 Country of ref document: EP Kind code of ref document: A1 |