CN116041418A - Hydroxyproline-serine compound, and preparation method and application thereof - Google Patents
Hydroxyproline-serine compound, and preparation method and application thereof Download PDFInfo
- Publication number
- CN116041418A CN116041418A CN202111261378.3A CN202111261378A CN116041418A CN 116041418 A CN116041418 A CN 116041418A CN 202111261378 A CN202111261378 A CN 202111261378A CN 116041418 A CN116041418 A CN 116041418A
- Authority
- CN
- China
- Prior art keywords
- compound
- hydroxyproline
- serine
- acid
- dissolving
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- -1 Hydroxyproline-serine compound Chemical class 0.000 title claims abstract description 16
- 150000001875 compounds Chemical class 0.000 claims abstract description 108
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims abstract description 23
- 239000003814 drug Substances 0.000 claims abstract description 18
- 150000003839 salts Chemical class 0.000 claims abstract description 14
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 10
- BCPPKUFKSJSTMK-PPKHZWRWSA-N (2s)-2-amino-3-hydroxypropanoic acid;(2s,4r)-4-hydroxypyrrolidine-2-carboxylic acid Chemical compound OC[C@H](N)C(O)=O.O[C@H]1CN[C@H](C(O)=O)C1 BCPPKUFKSJSTMK-PPKHZWRWSA-N 0.000 claims abstract description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 87
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 26
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 26
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 22
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 22
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 20
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 13
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 12
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 11
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 11
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- 238000002390 rotary evaporation Methods 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- 239000007810 chemical reaction solvent Substances 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 7
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 6
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 5
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 5
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 5
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 3
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 claims description 3
- 235000019253 formic acid Nutrition 0.000 claims description 3
- 239000004310 lactic acid Substances 0.000 claims description 3
- 235000014655 lactic acid Nutrition 0.000 claims description 3
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 3
- 239000011976 maleic acid Substances 0.000 claims description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 239000000825 pharmaceutical preparation Substances 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- 229960001153 serine Drugs 0.000 description 19
- 239000007864 aqueous solution Substances 0.000 description 16
- 238000001914 filtration Methods 0.000 description 16
- 238000005406 washing Methods 0.000 description 16
- 241000699666 Mus <mouse, genus> Species 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 238000004440 column chromatography Methods 0.000 description 8
- 229920003045 dextran sodium sulfate Polymers 0.000 description 8
- 238000007865 diluting Methods 0.000 description 8
- 238000001704 evaporation Methods 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- 238000004108 freeze drying Methods 0.000 description 8
- 238000002156 mixing Methods 0.000 description 8
- 229920006395 saturated elastomer Polymers 0.000 description 8
- 239000000741 silica gel Substances 0.000 description 8
- 229910002027 silica gel Inorganic materials 0.000 description 8
- 238000010898 silica gel chromatography Methods 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 210000001072 colon Anatomy 0.000 description 7
- 241000699670 Mus sp. Species 0.000 description 6
- 201000010099 disease Diseases 0.000 description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
- 230000008859 change Effects 0.000 description 5
- 230000003285 pharmacodynamic effect Effects 0.000 description 5
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 4
- 206010009900 Colitis ulcerative Diseases 0.000 description 4
- 201000006704 Ulcerative Colitis Diseases 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 230000009266 disease activity Effects 0.000 description 4
- 230000004580 weight loss Effects 0.000 description 4
- 238000011740 C57BL/6 mouse Methods 0.000 description 3
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- NCEXYHBECQHGNR-QZQOTICOSA-N sulfasalazine Chemical compound C1=C(O)C(C(=O)O)=CC(\N=N\C=2C=CC(=CC=2)S(=O)(=O)NC=2N=CC=CC=2)=C1 NCEXYHBECQHGNR-QZQOTICOSA-N 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- DQXKOHDUMJLXKH-PHEQNACWSA-N (e)-n-[2-[2-[[(e)-oct-2-enoyl]amino]ethyldisulfanyl]ethyl]oct-2-enamide Chemical compound CCCCC\C=C\C(=O)NCCSSCCNC(=O)\C=C\CCCCC DQXKOHDUMJLXKH-PHEQNACWSA-N 0.000 description 2
- JBDOSUUXMYMWQH-UHFFFAOYSA-N 1-naphthyl isothiocyanate Chemical compound C1=CC=C2C(N=C=S)=CC=CC2=C1 JBDOSUUXMYMWQH-UHFFFAOYSA-N 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- 229940126062 Compound A Drugs 0.000 description 2
- 208000011231 Crohn disease Diseases 0.000 description 2
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- UETNIIAIRMUTSM-UHFFFAOYSA-N Jacareubin Natural products CC1(C)OC2=CC3Oc4c(O)c(O)ccc4C(=O)C3C(=C2C=C1)O UETNIIAIRMUTSM-UHFFFAOYSA-N 0.000 description 2
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 2
- 210000000436 anus Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 210000004534 cecum Anatomy 0.000 description 2
- 206010009887 colitis Diseases 0.000 description 2
- JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000002550 fecal effect Effects 0.000 description 2
- 208000035861 hematochezia Diseases 0.000 description 2
- 208000006454 hepatitis Diseases 0.000 description 2
- 229960002591 hydroxyproline Drugs 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 230000000968 intestinal effect Effects 0.000 description 2
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 229960001940 sulfasalazine Drugs 0.000 description 2
- NCEXYHBECQHGNR-UHFFFAOYSA-N sulfasalazine Natural products C1=C(O)C(C(=O)O)=CC(N=NC=2C=CC(=CC=2)S(=O)(=O)NC=2N=CC=CC=2)=C1 NCEXYHBECQHGNR-UHFFFAOYSA-N 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 2
- NBGAYCYFNGPNPV-UHFFFAOYSA-N 2-aminooxybenzoic acid Chemical class NOC1=CC=CC=C1C(O)=O NBGAYCYFNGPNPV-UHFFFAOYSA-N 0.000 description 1
- NUIURNJTPRWVAP-UHFFFAOYSA-N 3,3'-Dimethylbenzidine Chemical compound C1=C(N)C(C)=CC(C=2C=C(C)C(N)=CC=2)=C1 NUIURNJTPRWVAP-UHFFFAOYSA-N 0.000 description 1
- 208000004998 Abdominal Pain Diseases 0.000 description 1
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 1
- 206010008609 Cholangitis sclerosing Diseases 0.000 description 1
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 1
- 108010036949 Cyclosporine Proteins 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 108010016626 Dipeptides Proteins 0.000 description 1
- 208000004232 Enteritis Diseases 0.000 description 1
- 206010015226 Erythema nodosum Diseases 0.000 description 1
- 208000005016 Intestinal Neoplasms Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- FQISKWAFAHGMGT-SGJOWKDISA-M Methylprednisolone sodium succinate Chemical compound [Na+].C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@](O)(C(=O)COC(=O)CCC([O-])=O)CC[C@H]21 FQISKWAFAHGMGT-SGJOWKDISA-M 0.000 description 1
- 206010028116 Mucosal inflammation Diseases 0.000 description 1
- 101000964435 Mus musculus Z-DNA-binding protein 1 Proteins 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000000941 bile Anatomy 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 229960001265 ciclosporin Drugs 0.000 description 1
- 229930182912 cyclosporin Natural products 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 230000035622 drinking Effects 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 230000007760 free radical scavenging Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 210000003405 ileum Anatomy 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000010832 independent-sample T-test Methods 0.000 description 1
- 210000004969 inflammatory cell Anatomy 0.000 description 1
- 230000006749 inflammatory damage Effects 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 201000002313 intestinal cancer Diseases 0.000 description 1
- 201000004614 iritis Diseases 0.000 description 1
- 230000003859 lipid peroxidation Effects 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 210000005229 liver cell Anatomy 0.000 description 1
- 210000005228 liver tissue Anatomy 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 229960004584 methylprednisolone Drugs 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 208000010157 sclerosing cholangitis Diseases 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 238000004467 single crystal X-ray diffraction Methods 0.000 description 1
- 229940037128 systemic glucocorticoids Drugs 0.000 description 1
- 229960001967 tacrolimus Drugs 0.000 description 1
- QJJXYPPXXYFBGM-SHYZHZOCSA-N tacrolimus Natural products CO[C@H]1C[C@H](CC[C@@H]1O)C=C(C)[C@H]2OC(=O)[C@H]3CCCCN3C(=O)C(=O)[C@@]4(O)O[C@@H]([C@H](C[C@H]4C)OC)[C@@H](C[C@H](C)CC(=C[C@@H](CC=C)C(=O)C[C@H](O)[C@H]2C)C)OC QJJXYPPXXYFBGM-SHYZHZOCSA-N 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06139—Dipeptides with the first amino acid being heterocyclic
- C07K5/06165—Dipeptides with the first amino acid being heterocyclic and Pro-amino acid; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/05—Dipeptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/14—Extraction; Separation; Purification
- C07K1/16—Extraction; Separation; Purification by chromatography
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06139—Dipeptides with the first amino acid being heterocyclic
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Pain & Pain Management (AREA)
- Immunology (AREA)
- Epidemiology (AREA)
- Rheumatology (AREA)
- Gastroenterology & Hepatology (AREA)
- Analytical Chemistry (AREA)
- Pyrrole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the technical field of medicines, relates to a hydroxyproline-serine compound and a preparation method thereof, and also relates to a pharmaceutical composition containing the compound and application of the compound in treating inflammatory bowel diseases. The invention provides a hydroxyproline-serine compound with different spatial configurations, a preparation method thereof, a pharmaceutical composition containing the compound, and application of the hydroxyproline-serine with different spatial configurations in preparation of medicines for treating IBD. The structural formula of the hydroxyproline-serine compound or the salt thereof is shown as follows.
Description
Technical Field
The invention belongs to the technical field of medicines, relates to a hydroxyproline-serine compound and a preparation method thereof, and also relates to a pharmaceutical composition containing the compound and application of the compound in treating inflammatory bowel diseases.
Background
Inflammatory Bowel Disease (IBD) is a chronic, idiopathic enteritis that affects the entire gastrointestinal tract, increasing the risk of intestinal cancer. IBD mainly includes both Ulcerative Colitis (UC) and Crohn's Disease (CD), and is clinically manifested mainly as diarrhea, abdominal pain, mucopurulent stool, weight loss, etc., accompanied by parenteral diseases such as arthritis, erythema nodosum, iritis, ankylosing spondylitis, sclerosing cholangitis, etc.
Currently, IBD is treated with an emphasis on controlling mucosal inflammation and suppressing overactive immune response, and common medications mainly include aminosalicylic acids (such as sulfasalazine), glucocorticoids (such as methylprednisolone), and immunosuppressants (such as cyclosporine, tacrolimus, etc.). The medicines have the defects of long administration time, low overall response rate, serious side effects and the like. Therefore, there is a great need to develop highly effective and low-toxic IBD drugs.
trans-L-hydroxyproline-L-serine is a useful anti-hepatitis drug
The dipeptide isolated from the injection has a certain anti-inflammatory activity. Bile induced by trans-L-hydroxyproline-L-serine to alpha-naphthyl isothiocyanate (ANIT)The stasis hepatitis has liver protection function, and the action mechanism is as follows: (1) Enhancing free radical scavenging ability of liver tissue and inhibiting lipid peroxidation damage of liver cells; (2) Reducing the aggregation of inflammatory cells in areas of inflammation and tissue damage; (3) inhibiting the release of inflammatory cytokines. At present, no report on the use of trans-L-hydroxyproline-L-serine for the treatment of IBD has been found.
In recent years, research on chiral drugs has become a hotspot in the development of new drugs. The spatial configuration of chiral drugs is closely related to the therapeutic effect of the drugs, and the research on the drug effect difference between enantiomers of chiral drugs is particularly important. trans-L-hydroxyproline-L-serine is composed of two amino acids, trans-L-hydroxyproline and L-serine, where hydroxyproline and serine share 3 chiral carbon atoms and 8 stereoisomers exist. There is no report in the prior art of the use of stereoisomer compounds for the treatment of IBD. And the therapeutic effect on IBD is different due to the different configuration of the compounds.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a hydroxyproline-serine compound with different spatial configurations, a preparation method thereof, a pharmaceutical composition containing the compound and application of the hydroxyproline-serine with different spatial configurations in preparing medicines for treating IBD.
The invention is realized by the following technical scheme:
the present invention provides, first of all, a hydroxyproline-serine compound having the following structure:
the invention further provides hydroxyproline-serine compounds or salts thereof of the following structure:
the invention also provides a preparation method of the hydroxyproline-serine compound, which comprises the following steps:
the preparation method of the hydroxyproline-serine compound comprises the following steps:
the first step: dissolving a compound I, a compound II and N, N' -dicyclohexyl carbodiimide (DCC) in a reaction solvent, charging nitrogen, reacting at 25-30 ℃, and performing rotary evaporation to obtain a compound III; the molar ratio of the compound I to the compound II is 0.1-10:1.
And a second step of: dissolving a compound III and a compound IV in a reaction solvent containing N, N-Diisopropylethylamine (DIPEA), and reacting at 25-30 ℃ for 2-24 hours to obtain a compound V; the molar ratio of the compound III to the compound IV is 0.1-10:1.
And a third step of: and (3) dissolving the compound V in different acids to obtain the target compound M.
Wherein the reaction solvent in the first step is one or a combination of two or more of dichloromethane, N-dimethylformamide, tetrahydrofuran, dioxane and N, N-dimethylacetamide.
The reaction solvent in the second step is one or a combination of two or more of dichloromethane, N-dimethylformamide, tetrahydrofuran, dioxane and N, N-dimethylacetamide.
The acid in the third step is one or a combination of two or more of hydrochloric acid, acetic acid, formic acid, maleic acid, lactic acid, carbonic acid, trifluoroacetic acid, phosphoric acid and p-toluenesulfonic acid.
The synthetic route is as follows:
b: n, N-Diisopropylethylamine (DIPEA), a reaction solvent (dichloromethane, N-dimethylformamide, tetrahydrofuran, dioxane, N-dimethylacetamide);
c: acid: hydrochloric acid, acetic acid, formic acid, maleic acid, lactic acid, carbonic acid, trifluoroacetic acid, phosphoric acid, and p-toluenesulfonic acid.
The following compounds were obtained, respectively, according to their different reactant configurations: one of (a) trans-4-L-hydroxyproline-L-serine, (B) trans-4-L-hydroxyproline-D-serine, (C) trans-4-D-hydroxyproline-L-serine, (D) trans-4-D-hydroxyproline-D-serine, (E) cis-4-L-hydroxyproline-L-serine, (F) cis-4-L-hydroxyproline-D-serine, (G) cis-4-D-hydroxyproline-L-serine, and (H) cis-4-D-hydroxyproline-D-serine:
the invention also provides a pharmaceutical composition comprising the hydroxyproline-serine compound or the salt thereof and a pharmaceutically acceptable carrier or excipient.
The invention provides application of the hydroxyproline-serine compound or the salt thereof in preparing medicines for treating inflammatory bowel diseases.
The invention also provides application of the pharmaceutical composition in preparing medicines for treating inflammatory bowel diseases.
The inflammatory bowel disease is colitis.
The beneficial effects of the invention are as follows: based on that hydroxyproline has 2 chiral carbon atoms and serine has 1 chiral carbon atom, the interaction between chiral medicine and organism has stereo selectivity difference, so that the stereo configuration and pharmacodynamics relation of chiral medicine are compact. According to the invention, 4 different-configuration compounds III are respectively reacted with 2 different-configuration compounds IV to form 8 different-configuration hydroxyproline-serine, and the effect of different enantiomers in treating IBD is examined. In a mouse inflammatory bowel disease model caused by Dextran Sodium Sulfate (DSS), each compound has the effect of improving the disease state of colonitis to different degrees, wherein the compound of the embodiment 1, the compound of the embodiment 2, the compound of the embodiment 4 and the compound of the embodiment 8 can effectively improve the disease state of colonitis, and the compound is particularly characterized by improving the weight loss caused by the disease, improving the survival rate, reducing the Disease Activity Index (DAI) score and prolonging the colon length. Among them, the compound of example 8 showed the most excellent pharmacodynamic effect, providing possibility for treating DSS-induced IBD.
Drawings
FIG. 1 is a single crystal X-ray diffraction pattern of the compound of example 1.
Figure 2 is a diagram of a pharmacodynamic dosing regimen of the compounds of examples 1-8.
Figure 3 is a graph of changes in mouse body weight of the compounds of examples 1-8 before and after treatment for mouse IBD.
Figure 4 is a graph of the mouse DAI scores of the compounds of examples 1-8 following treatment for mouse IBD.
Figure 5 is a graph comparing colon length of mice treated with the compounds of examples 1-8.
Detailed Description
Example 1: preparation of trans-4-L-hydroxyproline-L-serine (Compound A):
the first step: dissolving a compound I-1 and a compound II, N' -dicyclohexyl carbodiimide (DCC) in tetrahydrofuran, charging nitrogen, reacting for 2 hours at 25 ℃, and performing rotary evaporation to obtain a compound III-1;
and a second step of: dissolving the compound III-1 and the compound IV-1 in dichloromethane containing N, N-Diisopropylethylamine (DIPEA), reacting for 2 hours at 25 ℃, evaporating the solvent under reduced pressure, diluting the residue with dichloromethane, washing with 5% phosphoric acid aqueous solution, aqueous solution and saturated salt in sequence, filtering, mixing the filtrate with silica gel, performing silica gel column chromatography, performing gradient elution on dichloromethane and methanol (100:1-1:100), collecting column chromatography, and concentrating to obtain the compound V-1;
and a third step of: dissolving the compound V-1 in hydrochloric acid, filtering, washing, and freeze-drying to obtain the compound A (trans-4-L-hydroxyproline-L-serine).
Example 2: preparation of trans-4-L-hydroxyproline-D-serine (Compound B):
the first step: dissolving a compound I-1 and a compound II, N' -dicyclohexyl carbodiimide (DCC) in tetrahydrofuran, charging nitrogen, reacting for 2 hours at 25 ℃, and performing rotary evaporation to obtain a compound III-1;
and a second step of: dissolving the compound III-1 and the compound IV-2 in dichloromethane containing N, N-Diisopropylethylamine (DIPEA), reacting for 2 hours at 25 ℃, evaporating the solvent under reduced pressure, diluting the residue with dichloromethane, washing with 5% phosphoric acid aqueous solution, aqueous solution and saturated salt in sequence, filtering, mixing the filtrate with silica gel, performing silica gel column chromatography, performing gradient elution on dichloromethane and methanol (100:1-1:100), collecting column chromatography, and concentrating to obtain the compound V-2;
and a third step of: dissolving the compound V-2 in hydrochloric acid, filtering, washing, and freeze-drying to obtain the compound B (trans-4-L-hydroxyproline-D-serine).
Example 3: preparation of trans-4-D-hydroxyproline-L-serine (Compound C):
the first step: dissolving a compound I-2 and a compound II, N' -dicyclohexyl carbodiimide (DCC) in tetrahydrofuran, charging nitrogen, reacting for 2 hours at 25 ℃, and performing rotary evaporation to obtain a compound III-2;
and a second step of: dissolving the compound III-2 and the compound IV-1 in dichloromethane containing N, N-Diisopropylethylamine (DIPEA), reacting for 2 hours at 25 ℃, evaporating the solvent under reduced pressure, diluting the residue with dichloromethane, washing with 5% phosphoric acid aqueous solution, aqueous solution and saturated salt in sequence, filtering, mixing the filtrate with silica gel, performing silica gel column chromatography, gradient eluting with dichloromethane and methanol (100:1-1:100), collecting column chromatography, and concentrating to obtain a compound V-3;
and a third step of: dissolving the compound V-3 in hydrochloric acid, filtering, washing, and freeze-drying to obtain the compound C (trans-4-D-hydroxyproline-L-serine).
Example 4: preparation of trans-4-D-hydroxyproline-D-serine (Compound D):
the first step: dissolving a compound I-2 and a compound II, N' -dicyclohexyl carbodiimide (DCC) in tetrahydrofuran, charging nitrogen, reacting for 2 hours at 25 ℃, and performing rotary evaporation to obtain a compound III-2;
and a second step of: dissolving the compound III-2 and the compound IV-2 in dichloromethane containing N, N-Diisopropylethylamine (DIPEA), reacting for 2 hours at 25 ℃, evaporating the solvent under reduced pressure, diluting the residue with dichloromethane, washing with 5% phosphoric acid aqueous solution, aqueous solution and saturated salt in sequence, filtering, mixing the filtrate with silica gel, performing silica gel column chromatography, gradient eluting with dichloromethane and methanol (100:1-1:100), collecting column chromatography, and concentrating to obtain a compound V-4;
and a third step of: dissolving the compound V-4 in hydrochloric acid, filtering, washing, and freeze-drying to obtain the compound D (trans-4-D-hydroxyproline-D-serine).
Example 5: preparation of cis-4-L-hydroxyproline-L-serine (Compound E):
the first step: dissolving a compound I-3 and a compound II, N' -dicyclohexyl carbodiimide (DCC) in tetrahydrofuran, charging nitrogen, reacting for 2 hours at 25 ℃, and performing rotary evaporation to obtain a compound III-3;
and a second step of: dissolving the compound III-3 and the compound IV-1 in dichloromethane containing N, N-Diisopropylethylamine (DIPEA), reacting for 2 hours at 25 ℃, evaporating the solvent under reduced pressure, diluting the residue with dichloromethane, washing with 5% phosphoric acid aqueous solution, aqueous solution and saturated salt in sequence, filtering, mixing the filtrate with silica gel, performing silica gel column chromatography, gradient eluting with dichloromethane and methanol (100:1-1:100), collecting column chromatography, and concentrating to obtain a compound V-5;
and a third step of: dissolving the compound V-5 in hydrochloric acid, filtering, washing, and freeze-drying to obtain the compound E (cis-4-L-hydroxyproline-L-serine).
Example 6: preparation of cis-4-L-hydroxyproline-D-serine (Compound F):
the first step: dissolving a compound I-3 and a compound II, N' -dicyclohexyl carbodiimide (DCC) in tetrahydrofuran, charging nitrogen, reacting for 2 hours at 25 ℃, and performing rotary evaporation to obtain a compound III-3;
and a second step of: dissolving the compound III-3 and the compound IV-2 in dichloromethane containing N, N-Diisopropylethylamine (DIPEA), reacting for 2 hours at 25 ℃, evaporating the solvent under reduced pressure, diluting the residue with dichloromethane, washing with 5% phosphoric acid aqueous solution, aqueous solution and saturated salt in sequence, filtering, mixing the filtrate with silica gel, performing silica gel column chromatography, gradient eluting with dichloromethane and methanol (100:1-1:100), collecting column chromatography, and concentrating to obtain a compound V-6;
and a third step of: dissolving the compound V-6 in hydrochloric acid, filtering, washing, and freeze-drying to obtain the compound F (cis-4-L-hydroxyproline-D-serine).
Example 7: preparation of cis-4-D-hydroxyproline-L-serine (Compound G):
the first step: dissolving a compound I-4 and a compound II, N' -dicyclohexyl carbodiimide (DCC) in tetrahydrofuran, charging nitrogen, reacting for 2 hours at 25 ℃, and performing rotary evaporation to obtain a compound III-4;
and a second step of: dissolving the compound III-4 and the compound IV-1 in dichloromethane containing N, N-Diisopropylethylamine (DIPEA), reacting for 2 hours at 25 ℃, evaporating the solvent under reduced pressure, diluting the residue with dichloromethane, washing with 5% phosphoric acid aqueous solution, aqueous solution and saturated salt in sequence, filtering, mixing the filtrate with silica gel, performing silica gel column chromatography, gradient eluting with dichloromethane and methanol (100:1-1:100), collecting column chromatography, and concentrating to obtain a compound V-7;
and a third step of: dissolving the compound V-7 in hydrochloric acid, filtering, washing, and freeze-drying to obtain the compound G (cis-4-D-hydroxyproline-L-serine).
Example 8: cis-4-D-hydroxyproline-D-serine (compound H):
the first step: dissolving a compound I-4 and a compound II, N' -dicyclohexyl carbodiimide (DCC) in tetrahydrofuran, charging nitrogen, reacting for 2 hours at 25 ℃, and performing rotary evaporation to obtain a compound III-4;
and a second step of: dissolving a compound III-4 and a compound IV-2 in dichloromethane containing N, N-Diisopropylethylamine (DIPEA), reacting for 2 hours at 25 ℃, evaporating the solvent under reduced pressure, diluting the residue with dichloromethane, washing with 5% phosphoric acid aqueous solution, aqueous solution and saturated salt in sequence, filtering, mixing the filtrate with silica gel, performing silica gel column chromatography, performing gradient elution on dichloromethane and methanol (100:1-1:100), collecting column chromatography, and concentrating to obtain a compound V-8;
and a third step of: dissolving the compound V-8 in hydrochloric acid, filtering, washing, and freeze-drying to obtain the compound H (cis-4-D-hydroxyproline-D-serine).
The identification information for the compounds of examples 1-8 is shown in Table 1:
TABLE 1 information about the compounds of examples 1-8
Example 9: in vivo pharmacodynamics study of C57BL/6 mice
Dosing regimen
Healthy C57BL/6 mice are taken as model animals, 8 mice in each group are randomly grouped, dextran sodium sulfate (DSS, 3%) is used for modeling, and the rest groups are free to drink 3% DSS solution for 5 days except for free drinking of blank groups, so that an experimental colonitis model of the mice is established, and the administration scheme is shown in figure 2. The experiment was divided into 11 groups, which were blank group, model group, positive drug sulfasalazine group, example 1 compound group, example 2 compound group, example 3 compound group, example 4 compound group, example 5 compound group, example 6 compound group, example 7 compound group, example 8 compound group. Wherein sulfasalazine (250 mg/kg) was orally administered once a day and the compounds of examples 1-8 (25 mg/kg) were orally administered twice a day. Both the normal control and model groups were given the same amount of physiological saline instead of the compound of the example to C57BL/6 mice.
Detection index and method
Rate of change in body weight
Mice were weighed daily during the course of the experiment. The rate of change of the body weight of the mice was calculated.
Mouse weight change rate (%) = (mouse weight-mouse initial weight)/mouse initial weight×100% of the total weight of the mouse
Disease activity index scoring
Mice were observed daily for body weight, stool character, and blood stool status during the experiment and scored for scoring requirements as shown in table 2. The DAI index is the sum of the weight loss score, fecal trait score, and blood stool score. Wherein the blood and stool fraction is scored based on the color development condition measured by the fecal occult blood kit, and the specific steps are as follows: firstly, a mung bean-sized stool sample is picked up and placed on a whiteboard, and O-tolidine Solution drops (about 0.1 mL) are added dropwise to different positions of the stool. Then 2 drops (about 0.1 mL) of freshly prepared oxidant are added dropwise, the time is immediately counted and the color change is observed, and the judgment is carried out according to the color change within 2 minutes.
TABLE 2 disease Activity index scoring
Determination of colon length
DSS induces ulcerative colitis models are mainly characterized by shortening of the colon and concomitant edema. The length of the colon can be used to some extent as an indicator of the severity of inflammation. The method comprises the following specific steps: the abdominal cavity was rapidly dissected, the colon and distal ileum were freed, the entire intestinal segment from the anus to the cecum end was removed, and the entire intestinal segment length from each group of anus to the cecum end was measured.
Statistical treatment
Data were processed with GraphPad prism5.0 and analyzed using independent sample t-test. The results are shown in fig. 3, 4 and 5, # #, p <0.005 compared to the blank; * P <0.05 compared to the modeling group; * P <0.01 compared to modeling; * P <0.005 compared to modeling.
Results
TABLE 3 Experimental results for the treatment of ulcerative colitis with the Compounds of examples 1-8
Conclusion(s)
The results are shown in figures 3, 4 and 5, and it is clear from the results that each of the compounds of examples 1-8 has a therapeutic effect on IBD when administered. The compounds of example 1, example 2, example 4, and example 8 were effective in ameliorating the disease state of colitis, as compared to the model group, and were characterized by ameliorating weight loss due to disease (fig. 3), increasing survival, decreasing Disease Activity Index (DAI) score (fig. 4), and increasing colon length (fig. 5). Among them, the compound of example 8 showed the most excellent pharmacodynamic effect, providing possibility for treating DSS-induced IBD.
Claims (10)
1. A hydroxyproline-serine compound having the structure:
2. the hydroxyproline-serine compound of claim 1, having the structural formula:
3. a process for the preparation of hydroxyproline-serine compounds according to claim 1, characterized in that:
the first step: dissolving a compound I, a compound II and N, N' -dicyclohexyl carbodiimide in a reaction solvent, filling nitrogen, reacting, and performing rotary evaporation to obtain a compound III;
and a second step of: dissolving a compound III and a compound IV in a reaction solvent containing N, N-diisopropylethylamine, and reacting to obtain a compound V;
and a third step of: dissolving the compound V in acid to obtain a target compound M;
wherein ,
4. The process according to claim 3, wherein the reaction solvent used in the first or second step is one or a combination of two or more of dichloromethane, N-dimethylformamide, tetrahydrofuran, dioxane, and N, N-dimethylacetamide.
5. The process according to claim 3, wherein the acid in the third step is hydrochloric acid, acetic acid, formic acid, maleic acid, lactic acid, carbonic acid, trifluoroacetic acid, phosphoric acid, or p-toluenesulfonic acid.
6. A process according to claim 3, wherein in the first step the molar ratio of compound i to compound ii is from 0.1 to 10:1.
7. a process according to claim 3, wherein in the second step the molar ratio of compound iii to compound iv is from 0.1 to 10:1.
8. a pharmaceutical composition comprising one or more of the hydroxyproline-serine compounds or salts thereof according to claim 1 or 2 and a pharmaceutically acceptable carrier or excipient thereof.
9. A pharmaceutical preparation comprising one or more of the hydroxyproline-serine compounds or salts thereof according to claim 1 or 2 or the pharmaceutical composition according to claim 8.
10. Use of one or more of the hydroxyproline-serine compounds of claim 1 or 2 or the pharmaceutical composition of claim 8 or the pharmaceutical formulation of claim 9 for the preparation of a medicament for the treatment of inflammatory bowel disease.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111261378.3A CN116041418A (en) | 2021-10-28 | 2021-10-28 | Hydroxyproline-serine compound, and preparation method and application thereof |
| PCT/CN2022/126293 WO2023071895A1 (en) | 2021-10-28 | 2022-10-19 | Hydroxyprolyl-serine compound, preparation method therefor and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111261378.3A CN116041418A (en) | 2021-10-28 | 2021-10-28 | Hydroxyproline-serine compound, and preparation method and application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN116041418A true CN116041418A (en) | 2023-05-02 |
Family
ID=86122489
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202111261378.3A Pending CN116041418A (en) | 2021-10-28 | 2021-10-28 | Hydroxyproline-serine compound, and preparation method and application thereof |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN116041418A (en) |
| WO (1) | WO2023071895A1 (en) |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050233974A1 (en) * | 2003-12-01 | 2005-10-20 | John Randle | Treating infectious diseases using ice inhibitors |
| CN106749611B (en) * | 2016-12-29 | 2021-07-16 | 陕西慧康生物科技有限责任公司 | Preparation method of exenatide and product thereof |
-
2021
- 2021-10-28 CN CN202111261378.3A patent/CN116041418A/en active Pending
-
2022
- 2022-10-19 WO PCT/CN2022/126293 patent/WO2023071895A1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| WO2023071895A1 (en) | 2023-05-04 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| WO2018196805A1 (en) | Polymorph of compound, preparation method therefor and use thereof | |
| EA021897B1 (en) | Melanocortin-1 receptor-specific cyclic peptides | |
| AU2016253911B2 (en) | Carboxylic acid URAT1 inhibitor containing diarylmethane structure, preparation method and use thereof | |
| US9487539B2 (en) | Compounds and therapeutic use thereof for protein kinase inhibition | |
| CA2913194A1 (en) | Bisulfate of janus kinase (jak) inhibitor and preparation method therefor | |
| CN109912598B (en) | Nucleoside derivative for preventing and treating inflammatory reaction and application thereof | |
| CN115515944A (en) | Benzothiazole derivative and application thereof | |
| JP2020500205A (en) | Piperidine-2,6-dione derivative and treatment of ulcerative colitis | |
| CN114805478A (en) | Deuterated peptidomimetic compound and application thereof | |
| CN114404415A (en) | Use of indazoles for treating psoriasis | |
| CN103626826A (en) | Azo bond contained glycogen phosphorylase inhibitor cholic acid derivative and preparation method and medical application thereof | |
| CN116041418A (en) | Hydroxyproline-serine compound, and preparation method and application thereof | |
| CN115518065A (en) | Application of imidazole derivatives in preparation of antitumor pharmaceutical composition | |
| CN111902398B (en) | Salts of URAT-1 inhibitors | |
| CN114957270A (en) | S (+) -pranoprofen derivative and preparation method and application thereof | |
| CN107619428B (en) | Acylated derivative of ornithine and aspartate dipeptide compound and application thereof | |
| WO2018068696A1 (en) | Pegylated sinomenine and derivative thereof and preparation method and use of same | |
| CN117003771B (en) | Anti-influenza virus derivative and application thereof | |
| CN112574160B (en) | Galangin derivative and preparation method and application thereof | |
| CN110092799B (en) | Cyclic compound, preparation method and application thereof | |
| WO2023202554A1 (en) | Chiral aryl propionic acid derivative and pharmaceutical composition thereof, and use | |
| US20200369594A1 (en) | Compounds comprising short-chain fatty acid moieties and compositions and methods thereof | |
| CA3235452A1 (en) | Novel crystalline forms | |
| CN115244054A (en) | Crystals of hypoxanthine compound | |
| CN113185492A (en) | Synthesis and application of novel tetrahydrobenzothiophene-2-urea derivative |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |