CN110407876B - Febuxostat and phosphocreatine derivative, preparation method thereof and application thereof in preparation of anti-myocardial cell injury drugs - Google Patents
Febuxostat and phosphocreatine derivative, preparation method thereof and application thereof in preparation of anti-myocardial cell injury drugs Download PDFInfo
- Publication number
- CN110407876B CN110407876B CN201910620047.0A CN201910620047A CN110407876B CN 110407876 B CN110407876 B CN 110407876B CN 201910620047 A CN201910620047 A CN 201910620047A CN 110407876 B CN110407876 B CN 110407876B
- Authority
- CN
- China
- Prior art keywords
- febuxostat
- phosphocreatine
- preparation
- derivative
- creatine phosphate
- 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.)
- Active
Links
- 229960005101 febuxostat Drugs 0.000 title claims abstract description 72
- BQSJTQLCZDPROO-UHFFFAOYSA-N febuxostat Chemical compound C1=C(C#N)C(OCC(C)C)=CC=C1C1=NC(C)=C(C(O)=O)S1 BQSJTQLCZDPROO-UHFFFAOYSA-N 0.000 title claims abstract description 67
- 239000003814 drug Substances 0.000 title claims abstract description 28
- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- CFPWPNDPUSLDPF-UHFFFAOYSA-N 2-[carbamimidoyl(methyl)amino]-2-phosphonoacetic acid Chemical class NC(=N)N(C)C(C(O)=O)P(O)(O)=O CFPWPNDPUSLDPF-UHFFFAOYSA-N 0.000 title claims abstract 6
- 229940079593 drug Drugs 0.000 title abstract description 14
- 230000005779 cell damage Effects 0.000 title abstract description 5
- 208000037887 cell injury Diseases 0.000 title abstract description 5
- DRBBFCLWYRJSJZ-UHFFFAOYSA-N N-phosphocreatine Chemical compound OC(=O)CN(C)C(=N)NP(O)(O)=O DRBBFCLWYRJSJZ-UHFFFAOYSA-N 0.000 claims abstract description 77
- 230000008065 myocardial cell damage Effects 0.000 claims abstract description 10
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 26
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 16
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 14
- 238000003756 stirring Methods 0.000 claims description 13
- 239000003054 catalyst Substances 0.000 claims description 10
- 239000012024 dehydrating agents Substances 0.000 claims description 10
- -1 ethylene glycol compound Chemical class 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- 230000009471 action Effects 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- 239000000706 filtrate Substances 0.000 claims description 6
- 239000007791 liquid phase Substances 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 4
- 239000002775 capsule Substances 0.000 claims description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene chloride Substances ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- 239000006227 byproduct Substances 0.000 claims description 3
- 238000004587 chromatography analysis Methods 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 230000001376 precipitating effect Effects 0.000 claims description 3
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 abstract description 9
- 208000024172 Cardiovascular disease Diseases 0.000 abstract description 3
- 230000000144 pharmacologic effect Effects 0.000 abstract description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 34
- 210000004027 cell Anatomy 0.000 description 22
- 230000002107 myocardial effect Effects 0.000 description 13
- 210000004413 cardiac myocyte Anatomy 0.000 description 12
- 229940009456 adriamycin Drugs 0.000 description 11
- 230000006378 damage Effects 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- 230000000694 effects Effects 0.000 description 8
- 208000027418 Wounds and injury Diseases 0.000 description 7
- 208000014674 injury Diseases 0.000 description 7
- 238000011282 treatment Methods 0.000 description 7
- 102000004420 Creatine Kinase Human genes 0.000 description 6
- 108010042126 Creatine kinase Proteins 0.000 description 6
- 102000003855 L-lactate dehydrogenase Human genes 0.000 description 6
- 108700023483 L-lactate dehydrogenases Proteins 0.000 description 6
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 5
- 230000001079 digestive effect Effects 0.000 description 5
- 229960004679 doxorubicin Drugs 0.000 description 5
- 210000003722 extracellular fluid Anatomy 0.000 description 5
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 5
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 5
- 239000008101 lactose Substances 0.000 description 5
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 5
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 5
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 5
- 206010048610 Cardiotoxicity Diseases 0.000 description 4
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 4
- 231100000259 cardiotoxicity Toxicity 0.000 description 4
- 239000001963 growth medium Substances 0.000 description 4
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 4
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 4
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical group OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 230000001681 protective effect Effects 0.000 description 4
- 210000002966 serum Anatomy 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 4
- 241000700159 Rattus Species 0.000 description 3
- 150000004056 anthraquinones Chemical class 0.000 description 3
- 230000006907 apoptotic process Effects 0.000 description 3
- 230000000747 cardiac effect Effects 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 230000036542 oxidative stress Effects 0.000 description 3
- 239000013641 positive control Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000013268 sustained release Methods 0.000 description 3
- 239000012730 sustained-release form Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 2
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 description 2
- 229930091371 Fructose Natural products 0.000 description 2
- 239000005715 Fructose Substances 0.000 description 2
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 description 2
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 206010028851 Necrosis Diseases 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- KMSKQZKKOZQFFG-HSUXVGOQSA-N Pirarubicin Chemical compound O([C@H]1[C@@H](N)C[C@@H](O[C@H]1C)O[C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1CCCCO1 KMSKQZKKOZQFFG-HSUXVGOQSA-N 0.000 description 2
- 108010093894 Xanthine oxidase Proteins 0.000 description 2
- 102100033220 Xanthine oxidase Human genes 0.000 description 2
- 230000002776 aggregation Effects 0.000 description 2
- 238000004220 aggregation Methods 0.000 description 2
- PYKYMHQGRFAEBM-UHFFFAOYSA-N anthraquinone Natural products CCC(=O)c1c(O)c2C(=O)C3C(C=CC=C3O)C(=O)c2cc1CC(=O)OC PYKYMHQGRFAEBM-UHFFFAOYSA-N 0.000 description 2
- 238000007664 blowing Methods 0.000 description 2
- 244000309466 calf Species 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 230000003833 cell viability Effects 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- CVSVTCORWBXHQV-UHFFFAOYSA-N creatine Chemical compound NC(=[NH2+])N(C)CC([O-])=O CVSVTCORWBXHQV-UHFFFAOYSA-N 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- 229960000975 daunorubicin Drugs 0.000 description 2
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 239000001177 diphosphate Substances 0.000 description 2
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 description 2
- 235000011180 diphosphates Nutrition 0.000 description 2
- 229960001904 epirubicin Drugs 0.000 description 2
- 229930195712 glutamate Natural products 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229960000908 idarubicin Drugs 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- RQHZAASWYUEYCJ-NFJBMJLVSA-N methyl (1r,2r,4s)-4-[(2r,4s,5s,6s)-5-[[(2s,4as,5as,7s,9s,9ar,10ar)-2,9-dimethyl-3-oxo-4,4a,5a,6,7,9,9a,10a-octahydrodipyrano[4,2-a:4',3'-e][1,4]dioxin-7-yl]oxy]-4-(dimethylamino)-6-methyloxan-2-yl]oxy-2-ethyl-2,5,7-trihydroxy-6,11-dioxo-3,4-dihydro-1h-tet Chemical compound O=C1C2=C(O)C=CC=C2C(=O)C2=C1C(O)=C1[C@@H](O[C@@H]3O[C@@H](C)[C@@H](O[C@@H]4O[C@@H](C)[C@H]5O[C@@H]6O[C@@H](C)C(=O)C[C@@H]6O[C@H]5C4)[C@H](C3)N(C)C)C[C@@](CC)(O)[C@H](C(=O)OC)C1=C2 RQHZAASWYUEYCJ-NFJBMJLVSA-N 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 229960001156 mitoxantrone Drugs 0.000 description 2
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 208000010125 myocardial infarction Diseases 0.000 description 2
- 230000017074 necrotic cell death Effects 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 229950007002 phosphocreatine Drugs 0.000 description 2
- 229960001221 pirarubicin Drugs 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 238000007619 statistical method Methods 0.000 description 2
- 229960005322 streptomycin Drugs 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 229960000653 valrubicin Drugs 0.000 description 2
- ZOCKGBMQLCSHFP-KQRAQHLDSA-N valrubicin Chemical compound O([C@H]1C[C@](CC2=C(O)C=3C(=O)C4=CC=CC(OC)=C4C(=O)C=3C(O)=C21)(O)C(=O)COC(=O)CCCC)[C@H]1C[C@H](NC(=O)C(F)(F)F)[C@H](O)[C@H](C)O1 ZOCKGBMQLCSHFP-KQRAQHLDSA-N 0.000 description 2
- 230000035899 viability Effects 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- SMNNBONTPYNICF-UHFFFAOYSA-N Aclacinomycin B Natural products CCC1(O)CC(OC2CC(C(OC3CC(O)C(OC4CCC(=O)CO4)C(C)O3)C(C)O2)N(C)C)c5c(O)c6C(=O)c7ccccc7C(=O)c6cc5C1C(=O)OC SMNNBONTPYNICF-UHFFFAOYSA-N 0.000 description 1
- 108010043137 Actomyosin Proteins 0.000 description 1
- 229910002012 Aerosil® Inorganic materials 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- 201000005569 Gout Diseases 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 201000001431 Hyperuricemia Diseases 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
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 108010019160 Pancreatin Proteins 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 229940045799 anthracyclines and related substance Drugs 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 238000003149 assay kit Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- NPAKNKYSJIDKMW-UHFFFAOYSA-N carvedilol Chemical compound COC1=CC=CC=C1OCCNCC(O)COC1=CC=CC2=NC3=CC=C[CH]C3=C12 NPAKNKYSJIDKMW-UHFFFAOYSA-N 0.000 description 1
- 229960004195 carvedilol Drugs 0.000 description 1
- 210000002390 cell membrane structure Anatomy 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 239000013256 coordination polymer Substances 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 229960003624 creatine Drugs 0.000 description 1
- 239000006046 creatine Substances 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000000249 desinfective effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000037149 energy metabolism Effects 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 239000006481 glucose medium Substances 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 238000000589 high-performance liquid chromatography-mass spectrometry Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 238000011866 long-term treatment Methods 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000004118 muscle contraction Effects 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 230000004792 oxidative damage Effects 0.000 description 1
- 229940055695 pancreatin Drugs 0.000 description 1
- 238000005502 peroxidation Methods 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 238000004080 punching Methods 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000012679 serum free medium Substances 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6536—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and sulfur atoms with or without oxygen atoms, as the only ring hetero atoms
- C07F9/6539—Five-membered rings
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Heart & Thoracic Surgery (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Cardiology (AREA)
- Biochemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Molecular Biology (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the field of biological medicines, and discloses febuxostat and phosphocreatine derivatives, a preparation method thereof and application thereof in preparing a medicine for resisting myocardial cell injury. The derivative has a structure shown as a formula (I). The invention discloses the application of febuxostat and phosphocreatine derivatives in preparing anti-myocardial cell injury medicaments, belongs to the first disclosure, and discloses that the compounds can become promising innovative medicament candidate compounds; the febuxostat and the creatine phosphate which are the source compounds are clinically verified medicines, the sources are wide, the price is low, the pharmacological effect is strong, the safety is high, the new medicine application which is improved from old medicines belongs to, and an economic and safe medicine selection is provided for vast patients with cardiovascular diseases.
Description
Technical Field
The invention belongs to the field of biological medicines, and particularly relates to febuxostat and phosphocreatine derivatives, a preparation method thereof and application thereof in preparing a medicine for resisting myocardial cell injury.
Background
The cardiomyocytes, also known as cardiac fibers, are the most important cells for maintaining the heart beat. Studies have shown that cardiomyocyte injury is associated with the development of many cardiac diseases, such as coronary heart disease, heart failure, myocardial infarction, etc., with myocardial infarction still being the leading cause of death worldwide. During human life's operation, oxidative stress can trigger cardiomyocyte apoptosis, resulting in cardiomyocyte injury necrosis, and massive cardiomyocyte necrosis and apoptosis further aggravate the severity of the disease. Meanwhile, the cardiotoxicity caused by clinical chemotherapy of anthraquinones and other drugs is still a very serious medical problem, such as clinically used doxorubicin (doxorubicin, DOX), Daunorubicin (DNR), epirubicin (epirubicin), pirarubicin (pirarubicin), aclarubicin b (aclacinomycin b), idarubicin (idarubicin), valrubicin (valrubicin), mitoxantrone (mitoxantrone), and the like, wherein doxorubicin is the most commonly used antitumor drug. And the dose-dependent and cumulative cardiotoxicity of anthracyclines, cardiac complications occur in nearly 10% of patients treated with DOX after stopping chemotherapy for nearly 10 years, which limits its clinical use, and its cardiotoxicity may even be life threatening. Therefore, the method has important significance for relieving oxidative stress injury, reducing myocardial apoptosis and treating cardiovascular diseases and preventing and treating cardiotoxicity of tumor chemotherapy drugs.
Febuxostat (FBS) and non-buzostat, which have the chemical name of 2- [ (3-cyano-4-isobutoxy) phenyl ] -4-methyl-5-thiazolecarboxylic acid, are Xanthine Oxidase (XO) inhibitors, are suitable for long-term treatment of hyperuricemia with gout symptoms, and are remarkably and safely used clinically.
Creatine Phosphate (CP) plays an important role in the energy metabolism of muscle contraction, it is a chemical energy reserve of cardiac and skeletal muscles and is used for the re-synthesis of ATP, the hydrolysis of ATP providing energy for the actomyosin contraction process. Creatine phosphate sodium as a myocardial protection and energy supplement is an FDP (fructose diphosphate) replacement product, the energy efficiency is about 3.16 times of that of fructose diphosphate, the clinical curative effect is exact, and the safety is high.
Disclosure of Invention
In order to overcome the defects and shortcomings in the prior art, the invention mainly aims to provide febuxostat and phosphocreatine derivatives.
The invention also aims to provide a preparation method of the febuxostat and phosphocreatine derivatives.
The invention further aims to provide the application of the febuxostat and the phosphocreatine derivative in preparing the anti-myocardial cell injury medicine, overcomes the defects of the current myocardial cell injury treatment, and plays a treatment role in resisting peroxidation.
The purpose of the invention is realized by the following technical scheme:
a febuxostat and creatine phosphate derivative has a structure shown as a formula (I):
the preparation method of the febuxostat and phosphocreatine derivative comprises the following operation steps:
(1) dissolving febuxostat in a solvent a, and stirring and reacting for 1-6 h at 0 ℃ under the action of a dehydrating agent N, N' -dicyclohexylcarbodiimide or 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and a catalyst p-dimethylaminopyridine; then adding ethylene glycol into the mixture in an equimolar ratio with febuxostat, raising the temperature to room temperature from an ice bath, and stirring the mixture overnight in a dark place; filtering to remove by-products, concentrating the filtrate, precipitating with glacial ethyl ether, recrystallizing or purifying by liquid phase preparation, and lyophilizing to obtain febuxostat coupled ethylene glycol compound;
(2) dissolving creatine phosphate in a solvent a, and stirring and reacting for 1-6 h at 0 ℃ under the action of a dehydrating agent N, N' -dicyclohexylcarbodiimide or 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and a catalyst on dimethylaminopyridine; adding the febuxostat coupled ethylene glycol compound obtained in the step (1) according to the molar ratio of 1:1-3 times of creatine phosphate, raising the temperature to room temperature from an ice bath, and stirring overnight in a dark place; concentrating the filtrate, recrystallizing with ethyl acetate or isopropanol, purifying by chromatography or liquid phase preparation, and lyophilizing to obtain febuxostat and creatine phosphate derivatives with structure shown in formula (I).
The solvent a in the step (1) is CH2Cl2DMSO or DMF; the stirring reaction time is 2.5 h; the room temperature is 25 ℃;
the solvent a in the step (2) is CH2Cl2DMSO or DMF; the stirring reaction time is 2.5 h; the room temperature was 25 ℃.
The molar ratio of the febuxostat, the dehydrating agent and the catalyst in the step (1) is 1:1: 1-1: 30: 30; the molar ratio of the creatine phosphate, the dehydrating agent and the catalyst in the step (2) is 1:1: 1-1: 25: 25.
The febuxostat and phosphocreatine derivative or pharmaceutically acceptable salt thereof and any pharmaceutically acceptable preparation are used for preparing the anti-myocardial cell injury medicine.
The pharmaceutically acceptable salt may be: the chemical structures of the febuxostat and the phosphocreatine derivative form sodium, magnesium, calcium or other salts from phosphate.
The medicine contains therapeutically effective dose of febuxostat for resisting myocardial cell injury, phosphocreatine derivatives or pharmaceutically acceptable salts thereof, pharmaceutically acceptable carriers and pharmaceutically acceptable preparations.
The preparation of the medicine is a tablet or a capsule.
Preferably, the preparation comprises febuxostat, phosphocreatine derivatives, a sustained release agent, polyvinylpyrrolidone and micropowder silica gel.
Preferably, the sustained release agent is hydroxypropyl methylcellulose and lactose.
Preferably, the preparation comprises the following components in parts by weight: 5-15 parts of febuxostat and creatine phosphate derivatives, 70-90 parts of hydroxypropyl methyl cellulose, 70-100 parts of lactose, 80-120 parts of superfine silica powder and 80-120 parts of polyvinylpyrrolidone.
Preferably, the preparation comprises the following components in parts by weight: 10 parts of febuxostat and creatine phosphate derivatives, 90 parts of hydroxypropyl methyl cellulose, 75 parts of lactose, 100 parts of superfine silica powder and 100 parts of polyvinylpyrrolidone.
Compared with the prior art, the invention has the following outstanding advantages and beneficial effects:
(1) the inventor discovers that febuxostat can resist myocardial cell injury by inhibiting oxidative damage of primary suckling mouse myocardial cells induced by hydrogen peroxide through previous medicinal chemical synthesis and screening research, and febuxostat and a creatine phosphate derivative (FBS-CP) can effectively improve myocardial cell injury, and the febuxostat and the creatine phosphate derivative are not reported at present.
(2) The invention synthesizes febuxostat and phosphocreatine derivatives with the effect of resisting myocardial cell injury and uses the febuxostat and phosphocreatine derivatives in the preparation of medicines for resisting myocardial cell injury, and opens up the application field of the medicines.
(3) The febuxostat and the creatine phosphate which are raw materials for synthesizing the medicament have wide sources and definite pharmacological action, and the safety is proved to be high clinically for many years, so that the FBS-CP compound can provide a more economic and safe innovative medicament selection for vast cardiovascular disease patients.
Drawings
FIG. 1 is a diagram of the process of synthesizing febuxostat and a creatine phosphate derivative (FBS-CP compound) according to the present invention.
FIG. 2 shows H increase of febuxostat and phosphocreatine derivatives2O2Cell viability map of induced primary cardiomyocyte injury.
FIG. 3 is a diagram showing the enzymatic activities of febuxostat and phosphocreatine derivatives in protecting adriamycin from damaging myocardial cells.
Detailed Description
The present invention will be described in further detail with reference to examples and drawings, but the present invention is not limited thereto.
Example 1 Synthesis of febuxostat and creatine phosphate derivatives
1) Preparation of febuxostat-ethylene glycol: dissolving a proper amount of febuxostat (2.3mmol) in 40ml of DMSO, and stirring for 4h at 0 ℃ under the action of a dehydrating agent (N, N' -dicyclohexylcarbodiimide, DCC, 0.47g/2.3mmol) and a catalyst (p-dimethylaminopyridine, DMAP, 0.29g/2.3 mmol); then adding ethylene glycol (HOCH) according to the equal molar ratio of febuxostat2CH2OH), raised from ice bath to 25 ℃ and stirred overnight for 24h in the dark. Filtering to remove by-product, concentrating the filtrate, precipitating with glacial ethyl ether, recrystallizing or purifying by liquid phase, and lyophilizing to obtain febuxostat-ethylene glycol coupled product (HOCH)2CH2OCO-FBS)。
2) Preparation of febuxostat-ethylene glycol-creatine phosphate: appropriate amount of creatine phosphate (0.15mmol) was dissolved in 60ml of DMSO inStirring at 0 ℃ for 6h under the action of dehydrating agent DCC (3.0mmol) and catalyst DMAP (3.0 mmol); then, according to the molar ratio of the phosphocreatine to the creatine of 1:3 times of the febuxostat-ethylene glycol coupled product obtained in the step 1) is added, the temperature is raised to 25 ℃ from an ice bath, and the mixture is stirred overnight in a dark place. Concentrating the filtrate, recrystallizing with glacial ethyl ether or isopropanol, purifying by chromatography or preparative liquid phase, and lyophilizing to obtain febuxostat and creatine phosphate derivative (FBS-COOCH)2CH2OCO-CP, yield about 60%), and M in positive charge mode by HPLC-MS identification+The molecular weight was 554.6(M + H), consistent with the theoretical molecular weight of 553.5.
1H-NMR (500MHz, DMSO): delta 3.6 and 4.2 are about the peak of hydrogen on ethylene glycol, the other peaks are the peak of hydrogen on febuxostat and creatine phosphate, delta 0.90-0.93 (FBS: 2 CH)3，6H)，δ1.86-1.91 (FBS:CH,1H)，δ1.96-2.10(CP:NH2，2H)，δ2.46-2.50(FBS:CH3,3H)，δ3.03-3.11(CP：CH3，3H)，δ3.90-3.99(FBS：1CH2，2H)，δ4.21-4.35 (CP：CH22H), δ 7.24-8.02 (FBS: 3CH, 3H) on the phenyl ring, δ 11.95-12.15 (CP: 2OH, 2H).
IR: the infrared spectrum is obviously increased by 1728cm-1The ester carbonyl peak shows that the febuxostat and the creatine phosphate are connected through the ester bond of the ethylene glycol, and have the structure shown in the formula (I).
Example 2 preparation and culture of Primary cardiomyocytes in suckling mice
Selecting newborn Wista suckling mouse for 1-3 days, disinfecting skin with 75% alcohol, and taking out heart by killing. Hearts were plated on ice on plates containing DMEM high-glucose medium, blood was removed from the hearts and excess tissue was trimmed off. Transferring heart to another plate, and cutting into 1-2mm3The tissue pieces were sized and transferred to a 15mL centrifuge tube. Discarding DMEM high sugar culture medium, adding appropriate amount of pancreatin cell digestive juice, digesting in 37 deg.C constant temperature water bath for 3-5min, taking out, and discarding the first digestive juice. Then adding the digestive juice, repeatedly blowing and sucking the digestive juice by a dropper, sucking the upper digestive juice into a 15mL centrifuge tube containing 7mL of cell culture solution, and stopping digestion. Repeatedly digesting according to the steps until the tissue blocks are completely digested. Culture in each centrifuge tubeFiltering the nutrient solution with 200 mesh filter screen, subpackaging again, and centrifuging at 1000rpm for 5 min. Discarding the supernatant, adding new cell culture solution, repeatedly blowing with dropper to disperse into single cells, and processing at 1 × 105cells/mL were seeded in 96-well plates at 37 ℃ with 5% CO2Culturing in a cell incubator for 2 h. Transferring the cell suspension containing the myocardial cells to a new culture flask, adding Brdu to inhibit the proliferation of the fibroblasts, and continuing to culture for 72 h.
Example 3 Activity of febuxostat and phosphocreatine derivative antigen on myocardial cell injury
The primary cardiomyocytes obtained in example 2 were randomly divided into 4 groups: blank control group, H2O2The kit comprises an oxidative stress injury model group, a compound group and a positive control group, wherein carvedilol is selected as a positive control drug, and each group is provided with 3 multiple holes. Blank control group and H2O2The model group was incubated for 24 hours with the compound at a concentration of 10. mu.M in advance on the cells of the compound group, with the normal serum-free medium replaced and without any treatment factors added. After 24H, H2O2Model group, compound group (three groups, febuxostat group, phosphocreatine group, and febuxostat and phosphocreatine derivative group obtained in example 1), and positive control group cells were each administered to a final concentration of 600 μ M H2O2After 24 hours of action, the normal control group only changes the normal serum-containing culture solution.
600μM H2O2After 24h, changing the serum-containing high-sugar culture solution to 100 μ L per well, adding 5mg/mL MTT solution into the culture plate, and keeping away from light, wherein the concentration of the MTT solution is 20 μ L per well, 37 deg.C, and 5% CO2Incubate in incubator for 4 h. The culture medium was discarded, 150. mu.L of DMSO was added to each well, the shaker was shaken for 10min, and the OD at 490nm was measured with a microplate reader while setting the zero-setting well. And recording the absorbance values of all groups, and performing data statistical analysis. The experimental results were expressed as cell survival (%) that is (%) (measured OD value-zero well OD value)/(blank group OD value-zero well OD value) × 100. Statistical analysis the experimental results are expressed as mean ± standard deviation (X ± SD), analyzed with one-way variance, processed with SPSS 20.0 statistical software, p<0.05 is considered to haveStatistical significance.
And H2O2Compared with the group, the febuxostat phosphocreatine derivative with 5 mu M and 10 mu M obviously improves H2O2Cell viability of induced primary cardiomyocyte injury in suckling mice (p)<0.05) and has more remarkable curative effect than the raw materials of febuxostat or creatine phosphate (see table 1).
TABLE 1 protective Effect of febuxostat on Primary cardiomyocyte injury
P < 0.05, p < 0.01, and model H2O2Comparing the groups; # p < 0.05, # p < 0.01, compared to the positive group;
example 4 Activity protection of febuxostat and phosphocreatine derivatives against anthraquinone drug-induced myocardial cytotoxicity
Rat cardiac muscle cell line H9c2, cultured in DMEM medium (containing 10% newborn calf serum, 2mM glutamate, 1% streptomycin/penicillin) at 37 deg.C and 5% CO2The sterile environment of (a). The culture medium is replaced every 2-3 days, and when the cells are cultured for 24h and reach 80% aggregation degree, the cells are transferred into a 96-well plate, wherein the cell density is 1 multiplied by 105And culturing for 24h, and then carrying out drug treatment. After treating for 24 hours, the control group, the model group (containing 5. mu.M adriamycin) and the experimental group (containing 5. mu.M adriamycin and 5 to 50. mu.M febuxostat and phosphocreatine derivatives obtained in example 1) were each treated, and the cell viability was measured by the MTT method. The experimental results show that as shown in fig. 2, the H9c2 cell viability was significantly reduced to 62.12% of that of normal cells by treating with 5 μ M doxorubicin for 24H (p < 0.001); the febuxostat can obviously inhibit myocardial cell activity damage (p is less than 0.001) caused by adriamycin, the adriamycin and 5-50 mu M of febuxostat phosphocreatine derivative are co-treated for 24 hours, and the cell activity is 75.02-95.61% of that of normal myocardial cells. Say thatTherefore, the febuxostat and the phosphocreatine derivative have obvious protective effect on myocardial cell activity damage caused by adriamycin.
Example 5 protective Effect of febuxostat and phosphocreatine derivatives on anthraquinone drug-induced myocardial cells in rats
Rat cardiac muscle cell line H9c2, cultured in DMEM medium (containing 10% newborn calf serum, 2mM glutamate, 1% streptomycin/penicillin) at 37 deg.C and 5% CO2The sterile environment of (a). The culture medium is replaced every 2-3 days, and the drug treatment is carried out when the cells are cultured for 24 hours and reach 80% aggregation degree. After 24 hours of treatment with a control group, a model group (containing 5. mu.M adriamycin) and a febuxostat phosphocreatine derivative group (containing 5. mu.M adriamycin and 5 to 50. mu.M of the derivative prepared in example 1), extracellular fluid was collected, and the levels of LDH and CK in the extracellular fluid were measured using a Lactate Dehydrogenase (LDH) kit and a Creatine Kinase (CK) assay kit. The results of the experiment showed that LDH and CK levels in the extracellular fluid of H9c2 increased 2.65-fold and 2.87-fold, respectively, that of normal cells by 20 μ M doxorubicin treatment for 24H (p < 0.001), as shown in FIG. 3; the febuxostat and the phosphocreatine derivative can obviously inhibit LDH and CK levels in the myocardial extracellular fluid from being increased (p is less than 0.001) caused by adriamycin, the adriamycin and 5-50 mu M of febuxostat and the phosphocreatine derivative are co-treated for 24 hours, and the LDH and CK levels in the myocardial extracellular fluid are respectively 1.5-2.4 times and 1.3-2.1 times of those of normal cells. The febuxostat and the phosphocreatine derivative have obvious protective effect on myocardial cell membrane structure damage caused by adriamycin.
Example 6 prescription compatibility
15g of febuxostat and creatine phosphate derivatives obtained in example 1, 70g of hydroxypropyl methylcellulose, 100g of polyvinylpyrrolidone, 65g of lactose and 110g of aerosil.
Uniformly mixing the febuxostat phosphocreatine derivative with a sustained release agent (hydroxypropyl methyl cellulose and lactose) according to the prescription amount, adding a binding agent polyvinylpyrrolidone plasmid, drying at the temperature of 40-80 ℃, preparing dry granules, adding the lubricant micropowder silica gel according to the prescription amount into the dry granules, uniformly mixing, and performing irregular punching to obtain the finished product.
Example 7 prescription compatibility
30g of the febuxostat phosphocreatine derivative obtained in the example 1, 280g of microcrystalline cellulose and 15g of superfine silica gel powder are crushed, sieved by a 100-mesh sieve, mixed uniformly and directly filled into capsules.
Example 8 prescription compatibility
70g of the febuxostat phosphocreatine derivative obtained in the example 1, 300g of microcrystalline cellulose and 30g of superfine silica gel powder are crushed, sieved by a 100-mesh sieve, mixed uniformly and directly filled into capsules.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the present invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Claims (6)
1. A febuxostat and phosphocreatine derivative is characterized in that: the derivative has a structure shown as a formula (I):
2. the method for preparing febuxostat and phosphocreatine derivatives according to claim 1, which is characterized by comprising the following steps:
(1) dissolving febuxostat in a solvent a, and stirring and reacting for 1-6 h at 0 ℃ under the action of a dehydrating agent N, N' -dicyclohexylcarbodiimide or 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and a catalyst p-dimethylaminopyridine; then adding ethylene glycol into the mixture in an equimolar ratio with febuxostat, raising the temperature to room temperature from an ice bath, and stirring the mixture overnight in a dark place; filtering to remove by-products, concentrating the filtrate, precipitating with glacial ethyl ether, recrystallizing or purifying by liquid phase preparation, and lyophilizing to obtain febuxostat coupled ethylene glycol compound;
(2) dissolving creatine phosphate in a solvent a, and stirring and reacting for 1-6 h at 0 ℃ under the action of a dehydrating agent N, N' -dicyclohexylcarbodiimide or 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and a catalyst on dimethylaminopyridine; adding the febuxostat coupled ethylene glycol compound obtained in the step (1) according to the molar ratio of 1:1-3 times of creatine phosphate, raising the temperature to room temperature from an ice bath, and stirring overnight in a dark place; concentrating the filtrate, recrystallizing with ethyl acetate or isopropanol, purifying by chromatography or liquid phase preparation, and lyophilizing to obtain febuxostat and creatine phosphate derivatives with structure shown in formula (I).
3. The method of claim 2, wherein: the solvent a in the step (1) is CH2Cl2DMSO or DMF; the stirring reaction time is 2.5 h; the room temperature is 25 ℃;
the solvent a in the step (2) is CH2Cl2DMSO or DMF; the stirring reaction time is 2.5 h; the room temperature was 25 ℃.
4. The method of claim 2, wherein: the molar ratio of the febuxostat, the dehydrating agent and the catalyst in the step (1) is 1:1: 1-1: 30: 30; the molar ratio of the creatine phosphate, the dehydrating agent and the catalyst in the step (2) is 1:1: 1-1: 25: 25.
5. The use of the febuxostat and phosphocreatine derivative or the pharmaceutically acceptable salt and the pharmaceutically acceptable preparation thereof according to claim 1 in the preparation of a medicament for resisting myocardial cell injury.
6. Use according to claim 5, characterized in that: the preparation of the medicine is a tablet or a capsule.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910620047.0A CN110407876B (en) | 2019-07-10 | 2019-07-10 | Febuxostat and phosphocreatine derivative, preparation method thereof and application thereof in preparation of anti-myocardial cell injury drugs |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910620047.0A CN110407876B (en) | 2019-07-10 | 2019-07-10 | Febuxostat and phosphocreatine derivative, preparation method thereof and application thereof in preparation of anti-myocardial cell injury drugs |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN110407876A CN110407876A (en) | 2019-11-05 |
| CN110407876B true CN110407876B (en) | 2021-07-23 |
Family
ID=68360878
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910620047.0A Active CN110407876B (en) | 2019-07-10 | 2019-07-10 | Febuxostat and phosphocreatine derivative, preparation method thereof and application thereof in preparation of anti-myocardial cell injury drugs |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110407876B (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102643249A (en) * | 2011-02-18 | 2012-08-22 | 苏州波锐生物医药科技有限公司 | 2-arylthiazole derivative and medicinal salt and application thereof |
| CN104341450A (en) * | 2013-08-09 | 2015-02-11 | 付翌秋 | Synthesis and pharmaceutical application of sulfamide derivative |
| WO2015196323A1 (en) * | 2014-06-23 | 2015-12-30 | 北京新天宇科技开发有限公司 | New derivatives of 2-(3-cyano-4-isobutyloxyphenyl)-4-methylthiazole-5-formate, preparation method therefor and application thereof |
| CN105218479A (en) * | 2014-06-23 | 2016-01-06 | 北京新天宇科技开发有限公司 | The new derivatives of 2-[3-cyano-4-isobutoxy phenyl]-4-methylthiazol-5-formic acid, its preparation method and application |
-
2019
- 2019-07-10 CN CN201910620047.0A patent/CN110407876B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102643249A (en) * | 2011-02-18 | 2012-08-22 | 苏州波锐生物医药科技有限公司 | 2-arylthiazole derivative and medicinal salt and application thereof |
| CN104341450A (en) * | 2013-08-09 | 2015-02-11 | 付翌秋 | Synthesis and pharmaceutical application of sulfamide derivative |
| WO2015196323A1 (en) * | 2014-06-23 | 2015-12-30 | 北京新天宇科技开发有限公司 | New derivatives of 2-(3-cyano-4-isobutyloxyphenyl)-4-methylthiazole-5-formate, preparation method therefor and application thereof |
| CN105218479A (en) * | 2014-06-23 | 2016-01-06 | 北京新天宇科技开发有限公司 | The new derivatives of 2-[3-cyano-4-isobutoxy phenyl]-4-methylthiazol-5-formic acid, its preparation method and application |
Also Published As
| Publication number | Publication date |
|---|---|
| CN110407876A (en) | 2019-11-05 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP2762522B2 (en) | Angiogenesis inhibitor | |
| JP4451660B2 (en) | Paclitaxel solvate | |
| KR101073985B1 (en) | Anticancer Composition Comprising Plant Stem Cell Line Derived from Taxus Cambium or Procambium, Lysate, Extract or Media Thereof | |
| JP5294509B2 (en) | Cycloastragenol monoglucoside, process for its production and use as a pharmaceutical composition | |
| JP6517206B2 (en) | Novel therapeutic agent for pulmonary fibrosis, method of adjusting the same | |
| JP2012522022A (en) | Novel salvianolic acid compound L, its preparation and use | |
| CN110420315A (en) | Application of the Lycium chinense glycopeptide in preparation three high drugs for the treatment of | |
| JP2017537092A (en) | Formulation containing chlorogenic acid crystal form and use thereof | |
| CN101033245A (en) | Preparation method and application of pedunculoside | |
| JP6389958B2 (en) | Medicinal use of anti-tumor for rutile pentacyclic triterpene saponins | |
| US20210353580A1 (en) | Application of chlorogenic acid and compositions thereof in preparation of drugs for treating squamous cell carcinoma | |
| CN110407876B (en) | Febuxostat and phosphocreatine derivative, preparation method thereof and application thereof in preparation of anti-myocardial cell injury drugs | |
| CN102002081B (en) | 9-O-beta-D-glucosyl nandinine as well as preparation method and application thereof | |
| CN1883498A (en) | Compound puerarin for treating cardiovascular and cerebrovascular disease | |
| CN107056874A (en) | A kind of compound of asiatic acid tenofovir dipivoxil and preparation method thereof | |
| KR100573375B1 (en) | Composition having an extract of Akebia quinata Seed for treating or preventing cancer, and preparation method thereof | |
| CN102558128A (en) | Extract containing prodelphinidin and procyanidin of ginkgo and its preparation method and application | |
| CN113214209A (en) | Hesperetin and carbamazepine eutectic compound, preparation method, composition and application thereof | |
| CN113521078A (en) | Aged cell killing agent and application thereof | |
| WO2013189229A1 (en) | New use of 20(s)-protopanoxadiol | |
| CN114652740B (en) | Leonurine, polygonatum polysaccharide and deoxynojirimycin pharmaceutical composition and application thereof | |
| TW201836612A (en) | A compound for treating cancer extracted from Bitter gourd | |
| CN112110987B (en) | 5-fluorouracil modified by asparaginyl theanine and phenylalanine, synthesis, activity and application thereof | |
| CN101036637A (en) | Application of salvia miltiorrhiza bge I sodium sulfonate in the preparation of medicine and its medicine made by the same | |
| CN115124419A (en) | Rhein and cytisine eutectic crystal, preparation method, composition and application thereof |
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 | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |