CN102079715A - Lysine salt compound of binary ester acid, preparation method and medicinal application - Google Patents
Lysine salt compound of binary ester acid, preparation method and medicinal application Download PDFInfo
- Publication number
- CN102079715A CN102079715A CN2010105700806A CN201010570080A CN102079715A CN 102079715 A CN102079715 A CN 102079715A CN 2010105700806 A CN2010105700806 A CN 2010105700806A CN 201010570080 A CN201010570080 A CN 201010570080A CN 102079715 A CN102079715 A CN 102079715A
- Authority
- CN
- China
- Prior art keywords
- compound
- lysine
- solvent
- hydrate
- solvate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 32
- -1 Lysine salt compound Chemical class 0.000 title abstract description 28
- 239000002253 acid Substances 0.000 title abstract description 8
- 150000002148 esters Chemical class 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 260
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 44
- 239000012453 solvate Substances 0.000 claims abstract description 41
- 150000003839 salts Chemical class 0.000 claims abstract description 30
- 239000004472 Lysine Substances 0.000 claims description 58
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims description 49
- 239000002904 solvent Substances 0.000 claims description 40
- 239000003814 drug Substances 0.000 claims description 33
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 24
- 238000003756 stirring Methods 0.000 claims description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 22
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 18
- 239000008194 pharmaceutical composition Substances 0.000 claims description 17
- KDXKERNSBIXSRK-RXMQYKEDSA-N D-lysine Chemical compound NCCCC[C@@H](N)C(O)=O KDXKERNSBIXSRK-RXMQYKEDSA-N 0.000 claims description 16
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 16
- 238000004108 freeze drying Methods 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 15
- 238000002156 mixing Methods 0.000 claims description 12
- 239000003937 drug carrier Substances 0.000 claims description 11
- 239000000203 mixture Substances 0.000 claims description 11
- 238000002425 crystallisation Methods 0.000 claims description 10
- 230000008025 crystallization Effects 0.000 claims description 10
- 238000001035 drying Methods 0.000 claims description 9
- 239000002552 dosage form Substances 0.000 claims description 8
- 238000001704 evaporation Methods 0.000 claims description 7
- 238000001914 filtration Methods 0.000 claims description 7
- 206010008190 Cerebrovascular accident Diseases 0.000 claims description 6
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 6
- 208000006011 Stroke Diseases 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 6
- 208000029028 brain injury Diseases 0.000 claims description 5
- 208000030886 Traumatic Brain injury Diseases 0.000 claims description 4
- 230000001154 acute effect Effects 0.000 claims description 4
- 230000002490 cerebral effect Effects 0.000 claims description 4
- 238000006243 chemical reaction Methods 0.000 claims description 4
- 238000001356 surgical procedure Methods 0.000 claims description 4
- 230000009529 traumatic brain injury Effects 0.000 claims description 4
- 208000024827 Alzheimer disease Diseases 0.000 claims description 3
- 208000018737 Parkinson disease Diseases 0.000 claims description 3
- 230000015572 biosynthetic process Effects 0.000 claims description 3
- 239000013078 crystal Substances 0.000 claims description 3
- 230000000302 ischemic effect Effects 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 201000001119 neuropathy Diseases 0.000 claims description 3
- 230000007823 neuropathy Effects 0.000 claims description 3
- 208000033808 peripheral neuropathy Diseases 0.000 claims description 3
- 239000007924 injection Substances 0.000 abstract description 51
- 238000002347 injection Methods 0.000 abstract description 51
- NVGBPTNZLWRQSY-UWVGGRQHSA-N Lys-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@H](C(O)=O)CCCCN NVGBPTNZLWRQSY-UWVGGRQHSA-N 0.000 abstract description 47
- 108010054155 lysyllysine Proteins 0.000 abstract description 46
- 230000002792 vascular Effects 0.000 abstract description 8
- 206010067484 Adverse reaction Diseases 0.000 abstract description 5
- 230000006838 adverse reaction Effects 0.000 abstract description 5
- 210000003205 muscle Anatomy 0.000 abstract description 5
- 229910052751 metal Inorganic materials 0.000 abstract description 4
- 239000002184 metal Substances 0.000 abstract description 4
- 238000004088 simulation Methods 0.000 abstract 2
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 65
- 235000018977 lysine Nutrition 0.000 description 41
- 239000000243 solution Substances 0.000 description 22
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 16
- 239000002775 capsule Substances 0.000 description 16
- 239000000126 substance Substances 0.000 description 14
- 239000003826 tablet Substances 0.000 description 12
- 239000000843 powder Substances 0.000 description 11
- 238000001228 spectrum Methods 0.000 description 11
- 206010061218 Inflammation Diseases 0.000 description 10
- 238000001816 cooling Methods 0.000 description 10
- 230000004054 inflammatory process Effects 0.000 description 10
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 9
- 238000010521 absorption reaction Methods 0.000 description 9
- 239000011259 mixed solution Substances 0.000 description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 8
- 238000005481 NMR spectroscopy Methods 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 229910052799 carbon Inorganic materials 0.000 description 8
- 150000004677 hydrates Chemical class 0.000 description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 7
- 210000004204 blood vessel Anatomy 0.000 description 7
- 239000012153 distilled water Substances 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 238000010438 heat treatment Methods 0.000 description 7
- 229910052739 hydrogen Inorganic materials 0.000 description 7
- 239000001257 hydrogen Substances 0.000 description 7
- 230000000638 stimulation Effects 0.000 description 7
- 235000019766 L-Lysine Nutrition 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 239000000546 pharmaceutical excipient Substances 0.000 description 6
- 210000003462 vein Anatomy 0.000 description 6
- 208000027418 Wounds and injury Diseases 0.000 description 5
- 239000004480 active ingredient Substances 0.000 description 5
- 230000006378 damage Effects 0.000 description 5
- 230000008020 evaporation Effects 0.000 description 5
- 230000002496 gastric effect Effects 0.000 description 5
- 239000008187 granular material Substances 0.000 description 5
- 208000014674 injury Diseases 0.000 description 5
- 239000012528 membrane Substances 0.000 description 5
- 239000000825 pharmaceutical preparation Substances 0.000 description 5
- 238000010183 spectrum analysis Methods 0.000 description 5
- 238000013268 sustained release Methods 0.000 description 5
- 239000012730 sustained-release form Substances 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 241000283973 Oryctolagus cuniculus Species 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 210000002808 connective tissue Anatomy 0.000 description 4
- 239000007919 dispersible tablet Substances 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 4
- 239000007938 effervescent tablet Substances 0.000 description 4
- 239000000839 emulsion Substances 0.000 description 4
- 239000002662 enteric coated tablet Substances 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 238000011049 filling Methods 0.000 description 4
- 238000007710 freezing Methods 0.000 description 4
- 230000008014 freezing Effects 0.000 description 4
- 239000006191 orally-disintegrating tablet Substances 0.000 description 4
- 229940124531 pharmaceutical excipient Drugs 0.000 description 4
- 239000007939 sustained release tablet Substances 0.000 description 4
- 238000001291 vacuum drying Methods 0.000 description 4
- 239000008215 water for injection Substances 0.000 description 4
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 229930195725 Mannitol Natural products 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- JHECKPXUCKQCSH-UHFFFAOYSA-J calcium;disodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate;hydrate Chemical compound O.[Na+].[Na+].[Ca+2].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O JHECKPXUCKQCSH-UHFFFAOYSA-J 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000008367 deionised water Substances 0.000 description 3
- 229910021641 deionized water Inorganic materials 0.000 description 3
- QYMFNZIUDRQRSA-UHFFFAOYSA-N dimethyl butanedioate;dimethyl hexanedioate;dimethyl pentanedioate Chemical compound COC(=O)CCC(=O)OC.COC(=O)CCCC(=O)OC.COC(=O)CCCCC(=O)OC QYMFNZIUDRQRSA-UHFFFAOYSA-N 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 238000010253 intravenous injection Methods 0.000 description 3
- 230000001788 irregular Effects 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 210000004698 lymphocyte Anatomy 0.000 description 3
- 239000008176 lyophilized powder Substances 0.000 description 3
- 239000000594 mannitol Substances 0.000 description 3
- 235000010355 mannitol Nutrition 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000000967 suction filtration Methods 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 239000005715 Fructose Substances 0.000 description 2
- 229930091371 Fructose Natural products 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
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 2
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 229920000881 Modified starch Polymers 0.000 description 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 2
- 206010030113 Oedema Diseases 0.000 description 2
- 229910019142 PO4 Inorganic materials 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
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 108010039918 Polylysine Proteins 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 230000017531 blood circulation Effects 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000007910 chewable tablet Substances 0.000 description 2
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 2
- 150000004691 decahydrates Chemical class 0.000 description 2
- 238000004455 differential thermal analysis Methods 0.000 description 2
- 150000004683 dihydrates Chemical class 0.000 description 2
- 239000003221 ear drop Substances 0.000 description 2
- 229940047652 ear drops Drugs 0.000 description 2
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 2
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 2
- 230000003203 everyday effect Effects 0.000 description 2
- 239000003889 eye drop Substances 0.000 description 2
- 229940012356 eye drops Drugs 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 2
- 210000004051 gastric juice Anatomy 0.000 description 2
- 150000004688 heptahydrates Chemical class 0.000 description 2
- 150000004687 hexahydrates Chemical class 0.000 description 2
- 229940071826 hydroxyethyl cellulose Drugs 0.000 description 2
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound 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 2
- 229940071676 hydroxypropylcellulose Drugs 0.000 description 2
- 230000000968 intestinal effect Effects 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 150000004682 monohydrates Chemical class 0.000 description 2
- 239000007923 nasal drop Substances 0.000 description 2
- 229940100662 nasal drops Drugs 0.000 description 2
- 210000000440 neutrophil Anatomy 0.000 description 2
- 150000004690 nonahydrates Chemical class 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 150000004689 octahydrates Chemical class 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- 150000004686 pentahydrates Chemical class 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 239000000049 pigment Substances 0.000 description 2
- 210000004180 plasmocyte Anatomy 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229920000656 polylysine Polymers 0.000 description 2
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 229940068968 polysorbate 80 Drugs 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 150000004685 tetrahydrates Chemical class 0.000 description 2
- 150000004684 trihydrates Chemical class 0.000 description 2
- FTLYMKDSHNWQKD-UHFFFAOYSA-N (2,4,5-trichlorophenyl)boronic acid Chemical compound OB(O)C1=CC(Cl)=C(Cl)C=C1Cl FTLYMKDSHNWQKD-UHFFFAOYSA-N 0.000 description 1
- VMKOFRJSULQZRM-UHFFFAOYSA-N 1-bromooctane Chemical compound CCCCCCCCBr VMKOFRJSULQZRM-UHFFFAOYSA-N 0.000 description 1
- CHHHXKFHOYLYRE-UHFFFAOYSA-M 2,4-Hexadienoic acid, potassium salt (1:1), (2E,4E)- Chemical compound [K+].CC=CC=CC([O-])=O CHHHXKFHOYLYRE-UHFFFAOYSA-M 0.000 description 1
- YJSATLBWFLERNZ-UHFFFAOYSA-N 2-[2-(2-aminophenyl)ethenyl]aniline Chemical compound NC1=CC=CC=C1C=CC1=CC=CC=C1N YJSATLBWFLERNZ-UHFFFAOYSA-N 0.000 description 1
- FTEDXVNDVHYDQW-UHFFFAOYSA-N BAPTA Chemical compound OC(=O)CN(CC(O)=O)C1=CC=CC=C1OCCOC1=CC=CC=C1N(CC(O)=O)CC(O)=O FTEDXVNDVHYDQW-UHFFFAOYSA-N 0.000 description 1
- XUTPNPHQVUXJIW-UHFFFAOYSA-N CCCCCCCCOCCOC(CN(CC(O)=O)c(cccc1)c1OCCOc(cccc1)c1N(CC(OC)OCCOCCCCCCCC)CC(O)=O)OC Chemical compound CCCCCCCCOCCOC(CN(CC(O)=O)c(cccc1)c1OCCOc(cccc1)c1N(CC(OC)OCCOCCCCCCCC)CC(O)=O)OC XUTPNPHQVUXJIW-UHFFFAOYSA-N 0.000 description 1
- 206010048610 Cardiotoxicity Diseases 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 150000008564 D-lysines Chemical class 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 235000016623 Fragaria vesca Nutrition 0.000 description 1
- 240000009088 Fragaria x ananassa Species 0.000 description 1
- 235000011363 Fragaria x ananassa Nutrition 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 229920002907 Guar gum Polymers 0.000 description 1
- 208000032382 Ischaemic stroke Diseases 0.000 description 1
- 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 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 206010053615 Thermal burn Diseases 0.000 description 1
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 description 1
- 206010047095 Vascular pain Diseases 0.000 description 1
- 229930003268 Vitamin C Natural products 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 239000008351 acetate buffer Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000002421 anti-septic effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 210000004958 brain cell Anatomy 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000003715 calcium chelating agent Substances 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 231100000259 cardiotoxicity Toxicity 0.000 description 1
- 230000007681 cardiovascular toxicity Effects 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 230000009920 chelation Effects 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 229960000913 crospovidone Drugs 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 1
- 210000000416 exudates and transudate Anatomy 0.000 description 1
- 239000007888 film coating Substances 0.000 description 1
- 238000009501 film coating Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229960002737 fructose Drugs 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229940014259 gelatin Drugs 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000000665 guar gum Substances 0.000 description 1
- 235000010417 guar gum Nutrition 0.000 description 1
- 229960002154 guar gum Drugs 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 1
- 229940031574 hydroxymethyl cellulose Drugs 0.000 description 1
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 1
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 210000004969 inflammatory cell Anatomy 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N iron oxide Inorganic materials [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 1
- 235000013980 iron oxide Nutrition 0.000 description 1
- VBMVTYDPPZVILR-UHFFFAOYSA-N iron(2+);oxygen(2-) Chemical class [O-2].[Fe+2] VBMVTYDPPZVILR-UHFFFAOYSA-N 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000845 maltitol Substances 0.000 description 1
- 235000010449 maltitol Nutrition 0.000 description 1
- VQHSOMBJVWLPSR-WUJBLJFYSA-N maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 description 1
- 229940035436 maltitol Drugs 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 230000001338 necrotic effect Effects 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 230000004112 neuroprotection Effects 0.000 description 1
- 230000000324 neuroprotective effect Effects 0.000 description 1
- 229910052755 nonmetal Inorganic materials 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000008183 oral pharmaceutical preparation Substances 0.000 description 1
- 239000007935 oral tablet Substances 0.000 description 1
- 238000000643 oven drying Methods 0.000 description 1
- 239000006174 pH buffer Substances 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000004302 potassium sorbate Substances 0.000 description 1
- 235000010241 potassium sorbate Nutrition 0.000 description 1
- 229940069338 potassium sorbate Drugs 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- XTUSEBKMEQERQV-UHFFFAOYSA-N propan-2-ol;hydrate Chemical compound O.CC(C)O XTUSEBKMEQERQV-UHFFFAOYSA-N 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 230000004224 protection Effects 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 229940085605 saccharin sodium Drugs 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical class O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 150000003385 sodium Chemical class 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 229960003885 sodium benzoate Drugs 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- 229940001482 sodium sulfite Drugs 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000007962 solid dispersion Substances 0.000 description 1
- 239000007944 soluble tablet Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 239000001069 triethyl citrate Substances 0.000 description 1
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 description 1
- 235000013769 triethyl citrate Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
Images
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a lysine salt compound of a derivative (compound D) of a binary ester acid. The lysine salt compound comprises compound D dilysine, compound D monolysine, a hydrate of the compound D dilysine, a hydrate of the compound D monolysine, a solvate of the compound D dilysine and a solvate of the compound D monolysine. The lysine salt compound has high water solubility and stability; moreover, the lysine salt compound improves adverse reactions such as vascular simulation, muscle simulation and the like of the metal salts thereof when in injection use. The invention also provides a preparation method and medicinal application of the lysine salt compound.
Description
The invention belongs to the technical field of pharmacy, and relates to a derivative salt compound of dibasic ester acid, in particular to a lysine salt compound thereof, a preparation method thereof and application thereof in medicaments.
DP-BAPTA-99 is a novel compound, a compound of dibasic ester acid structure, referred to herein as "Compound D", having the following molecular formula:
international publication WO99/16741 discloses the chemical formula of Compound D.
The compound D is used as a novel neuroprotective drug for acute cerebral apoplexy and has been applied to clinical research. Disadvantageously, however, on the one hand, compound D is poorly water-soluble, disadvantageous for the preparation of pharmaceutical preparations and not easily dissolved in pharmaceutical preparations; on the other hand, the metal ionic salt has the decomposition promoting effect on two ester group structures in the compound D structure, and is not beneficial to the stability and the application of the medicine; on the other hand, the metal salts such as disodium salt of the compound D often cause strong adverse reactions such as vascular stimulation and muscle stimulation when being injected.
In general, formation of a target compound into a salt form is a preferred method for improving the target compound. For applications in the production of pharmaceutical preparations, it is often advantageous to employ pharmaceutically active compounds in the form of specific salts containing acid or base groups, which have, for example, better solubility, better dissolution and absorption behavior, better stability or generally better performance profiles, and the use of specific salts may also be advantageous for the preparation of active compounds or pharmaceutical preparations or for complying with the requirements of the regulatory authorities of pharmaceuticals, for example, for facilitating the clinical use of pharmaceuticals, for increasing the compliance of patients with drugs, for facilitating the therapeutic effect of pharmaceuticals.
The invention content is important and meaningful for improving the water solubility and stability of the compound D and improving adverse reactions such as vascular stimulation, muscle stimulation and the like during injection use on the premise of not changing the pharmacological action of the compound D. The inventor finds through experiments that the non-metal salt of the compound D can improve the defects of the compound D or the metal salt thereof.
The molecular structure of the compound D contains two carboxyl groups, and the inventor finds that the water solubility of the compound D can be obviously improved by adopting a basic substance with good water solubility, namely lysine, to coordinate with the carboxyl group of the compound D to form a salt through experiments. However, when the improvement of the water solubility is considered, it is also considered that the pharmacological action of the compound D cannot be changed and destroyed, and the basic coordination compound to be salified with the compound D is not only suitable in alkalinity but also safe and nontoxic to human body, and it is also considered that the salified compound should have good stability and physical appearance to facilitate the application of the derivative salt of the compound D as a pharmaceutically active ingredient in pharmaceutical preparations. In addition, the stability of the compound D is required to be well promoted; in addition, adverse reactions such as vascular pain, muscle stimulation and the like during injection and use can be improved.
Lysine is a safe and nontoxic free alkali compound, the aqueous solution of the compound is alkaline, the compound can be used as an auxiliary material in various medicament formulas, and the molecular formula is C6H14N2O2In general, L-lysine is preferred.
Based on the above considerations and requirements, the present inventors completed the compound D lysine salt of the present invention, which includes compound D dilysine, compound D mono lysine, a hydrate thereof or a solvate thereof, through experiments and screening.
Further, the present invention provides a method for preparing a lysine salt of compound D; the invention also provides the pharmaceutical application of the compound D lysine salt.
The invention provides a compound shown as a formula I, a hydrate thereof or a solvate thereof:
(I) molecular formula C42H64N2O12.n(C6H14N2O2) Wherein n ═ 2 or 1, represents a dilysine salt, a monolysine salt, respectively, of compound D, wherein:
compound D-lysine:
Compound D, dilysine:
Specifically, the salt compound of the compound D and lysine provided by the invention comprises the compound D-lysine, the compound D-dilysine, and hydrates or solvates thereof.
It should be noted, and will be familiar and understood by those skilled in the art, that since the compounds as salts of the present invention are not externally charged or electrically charged, the compounds as salts of the present invention may also be represented by the following chemical structure of formula II-1 or formula III-1:
it should be noted, and will be familiar and understood by those skilled in the art, that since the number of lysine molecules coordinated to form a salt with a molecule of compound D in the compounds of the invention is 1 or 2, the molecular number of lysine molecules indicated in the molecular formula above the molecular formula of lysine is the same as the suffix indicated in the molecular formula, for example, the compounds of the invention may also be represented by the following chemical structure of formula II-2 or formula III-2:
molecular formula C42H64N2O12.C6H14N2O2，
Molecular formula C42H64N2O12.(C6H14N2O2)2，
The formula II-1, the formula II-2 and the formula II represent the same compound, namely the compound D-lysine;
the formula III-1, the formula III-2 and the formula III represent the same compound, namely the compound D-dilysine.
The lysine salt compound of the compound D of the invention is a solid compound with good physical appearance, and may contain a certain amount of water molecules or solvent molecules in order to maintain a specific structural form in the preparation process, so the invention also comprises a hydrate or solvate of the compound D lysine.
For example, the compound D of the present invention is a hemihydrate, monohydrate, sesquihydrate, dihydrate, disesquihydrate, trihydrate, triple hemihydrate, tetrahydrate, quadruplehemihydrate, pentahydrate, quintuple hemihydrate, hexahydrate, hexahemihydrate, heptahydrate, heptahemihydrate, octahydrate, octahemihydrate, nonahydrate, nonahemihydrate or decahydrate of dilysine, etc.;
for example, the compound D of the present invention is a hemihydrate, monohydrate, sesquihydrate, dihydrate, disesquihydrate, trihydrate, triple hemihydrate, tetrahydrate, quadruplehemihydrate, pentahydrate, quintuple hemihydrate, hexahydrate, hexahemihydrate, heptahydrate, heptahemihydrate, octahydrate, nonahydrate, nonahemihydrate or decahydrate of lysine, and the like.
For another example, compound D of the present invention contains a solvent molecule of a half molecule, 1 molecule, 1.5 molecule, 2 molecule, 2.5 molecule, 3 molecule, 3.5 molecule, 4 molecule, 4.5 molecule, 5 molecule, 5.5 molecule, 6 molecule, 6.5 molecule, 7 molecule, 7.5 molecule, 8 molecule, 8.5 molecule, 9 molecule, 9.5 molecule or 10 molecule, etc.;
for another example, the compound D-lysine of the present invention contains a solvent molecule of a half molecule, 1 molecule, 1.5 molecule, 2 molecule, 2.5 molecule, 3 molecule, 3.5 molecule, 4 molecule, 4.5 molecule, 5 molecule, 5.5 molecule, 6 molecule, 6.5 molecule, 7 molecule, 7.5 molecule, 8 molecule, 8.5 molecule, 9 molecule, 9.5 molecule or 10 molecule, and the like.
It should be noted that many of the above listed hydrates or solvates of the compound D-dilysine or the compound D-dilysine of the present invention are only the possible situations during the crystallization or purification process of the compound D-lysine of the present invention, and any of them is only the existing form of the compound D derivative substance of the present invention, and the contained water of crystallization or crystallization solvent is usually controllable or removable, for example, by thermal burn or crystal transformation to remove the water of crystallization or crystallization solvent, therefore, many of the above listed hydrates or solvates of the compound D derivative still belong to the technical scheme and patent protection scope of the present invention.
The invention also provides a preparation method of the compound D lysine, the hydrate thereof or the solvate thereof, which comprises the steps of contacting the compound D with the lysine in a solvent to react and form salt, wherein the solvent is selected from one or a mixture of several solvents of ethanol, methanol, isopropanol, acetone, acetonitrile, ethyl acetate, water, dimethylacetamide and dimethylformamide; and the reaction temperature is that the compound D and the lysine react to form salt under the condition from room temperature to the reflux temperature of the solvent.
In the embodiment of the invention, the compound D lysine, its hydrate or solvate is as described in the non-limiting examples of the compound of the invention, and in the information described herein, lysine is added to a solution containing the compound D, or the compound D is added to a solution containing lysine, or the solution containing the compound D is mixed with a solution containing lysine by a method similar to that described above, so as to achieve the purpose of contacting the compound D with lysine and reacting to form a salt.
For the preparation of compound D-lysine, a hydrate or solvate thereof, specifically,
under the condition from room temperature to the reflux temperature of a solvent, contacting a compound D and lysine in a molar ratio of 1: 1 (1-1.1) in the solvent, reacting to form a salt, crystallizing the salt at room temperature or below, filtering, washing, draining, and drying to obtain the compound D-lysine, or a hydrate and a solvate thereof, wherein the solvent is selected from one or a mixture of several of ethanol, methanol, isopropanol, acetone, acetonitrile, ethyl acetate, water, dimethylacetamide and dimethylformamide, and part of the solvent can be removed by evaporation to accelerate the formation of crystals if necessary; or,
and (2) completely dissolving the compound D and the lysine in a molar ratio of 1: 1 in a proper amount of water at 5-80 ℃, stirring, and freeze-drying to obtain the compound D-lysine or the hydrate thereof.
For the preparation of compound D, dilysine, hydrates or solvates thereof, in particular,
under the condition from room temperature to the reflux temperature of a solvent, contacting a compound D and lysine in a molar ratio of 1: 2-2.2 in the solvent, reacting to form a salt, crystallizing the salt at room temperature or below, filtering, washing, draining, and drying to obtain a compound D-dilysine, or a hydrate and a solvate thereof, wherein the solvent is selected from one or a mixture of several of ethanol, methanol, isopropanol, acetone, acetonitrile, ethyl acetate, water, dimethylacetamide and dimethylformamide, and the crystallization can be accelerated by reducing the crystallization temperature or/and removing part of the solvent by evaporation as required; or,
and (3) completely dissolving the compound D and the lysine in a molar ratio of 1: 2 in a proper amount of water at 5-80 ℃, stirring, and freeze-drying to obtain the compound D dilysine or a hydrate thereof.
For compound D, it can be synthesized according to the following process route, mainly using the calcium chelating agent BAPTA (chemical name: 1, 2-bis (o-aminophenyl) ethane-N, N' -tetraacetoacetic acid) and octyl bromide as raw materials:
for lysine, it is generally commercially available.
Further, the present invention provides a pharmaceutical composition comprising compound D-dilysine, hydrates or solvates thereof, and a pharmaceutically acceptable carrier.
Compound D lysine salt according to the present invention may be administered by any suitable route, but is generally administered by parenteral or oral route, preferably by injection. For such applications, the salts of compound D according to the invention are generally used in the form of pharmaceutical compositions containing a pharmaceutically acceptable carrier, although the exact form of the composition naturally depends on the form of administration.
Specifically, the invention also provides a pharmaceutical composition containing the compound D-dilysine, the hydrate thereof or the solvate thereof, and one or more pharmaceutically acceptable carriers, wherein the content of the compound D-dilysine, the hydrate thereof or the solvate thereof is 0.1-500 mg, such as 0.1mg, 0.2mg, 0.5mg, 0.7mg, 1mg, 2mg, 3mg, 4mg, 5mg, 7mg, 10mg, 15mg, 20mg, 25mg, 30mg, 40mg, 41mg, 42mg, 43mg, 45mg, 47mg, 48.5mg, 50mg, 60mg, 62mg, 70mg, 80mg, 82mg, 83mg, 85mg, 88mg, 90mg, 92mg, 95mg, 98mg, 100mg, 110mg, 116mg, 120mg, 125mg, 130mg, 132mg, 135mg, 140mg, 150mg, 166mg, 250mg, 25mg, 30mg, 40mg, 41mg, 42mg, 45mg, 25mg, 350mg, 400mg, 450mg, 500 mg.
The compound D dilysine, the compound D polylysine, the hydrate thereof or the solvate thereof are taken as active ingredients, and one or more pharmaceutically acceptable medicinal carriers are contained, so that the compound D dilysine, the compound D polylysine, the hydrate thereof or the solvate thereof can be prepared into any pharmaceutically acceptable medicinal preparation form, including injection preparations, oral preparations, non-oral liquid preparations and the like, such as injection preparations, including powder injection for injection and injection liquid, and the like; also, for example, oral tablets, capsules, granules, oral solutions, powders, pills, sublingual buccal formulations, and the like; such as non-oral eye drops, nasal drops, ear drops, transdermal emulsions, and the like. Or the preparation can be the quick release, sustained release, controlled release and other preparations of the above various preparations, such as oral dispersible tablets, sustained release tablets, chewable tablets, sustained release capsules, enteric coated tablets, effervescent tablets, orally disintegrating tablets, special-shaped tablets, effervescent granules and the like. In particular, the compound preparation is prepared according to a method known in the field, and is preferably used for preparing tablets (including dispersible tablets, sustained release tablets, chewable tablets, enteric-coated tablets, effervescent tablets, orally disintegrating tablets and irregular tablets) used in pharmaceutics, capsules (including gastric soluble, enteric-coated and sustained release capsules), granules, oral solutions, injections (including powder injections and injection solutions for injection) and the like so as to meet various requirements in clinical use.
It will be understood that the pharmaceutically acceptable carrier is a matrix or excipient which holds the pharmaceutical dosage form, generally selected or combined according to the particular pharmaceutical agent, and may optionally include excipients or diluents such as one or more of microcrystalline cellulose, lactose, pregelatinized starch, dextrin, calcium phosphate, sucrose, dextran, mannitol, sorbitol, glucose, fructose, water, polyethylene glycol, propylene glycol, glycerol, cyclodextrin derivatives, and the like; binders such as one or more of povidone (polyvinylpyrrolidone), methylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, gelatin, guar gum, xanthan gum, and the like; also comprises lubricant, such as one or more of magnesium stearate, stearic acid, talcum powder, sodium stearyl fumarate and sodium lauryl sulfate, etc.; disintegrating agents such as sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, crospovidone, croscarmellose sodium, sodium croscarmellose, pregelatinized starch, and one or more of the like; also comprises a surfactant, such as one or more of sodium dodecyl sulfate, polysorbate-80, etc.; may also include pH regulator or buffer, such as phosphate buffer, citric acid, sodium citrate, acetate buffer, dilute hydrochloric acid, sodium carbonate, sodium hydroxide, etc.; optionally antiseptic, such as one or more of sodium benzoate, potassium sorbate, methyl paraben, propyl paraben, etc.; optionally stabilizer and antioxidant, such as one or more of calcium disodium edetate, sodium sulfite, vitamin C, etc.; optionally taste modifier such as one or more of maltitol, fructose, sucrose, saccharin sodium, orange essence, strawberry essence, etc.; other conventional, appropriate additives may also be included.
It should be understood that the term "optionally included" as described above means either optional or non-optional.
It will also be appreciated that where the dosage form is a tablet or capsule, it may be film coated. Materials for film coating including suitable coating agents such as hydroxypropylmethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose phthalate, and the like; plasticizers such as polyethylene glycol, triethyl citrate, and the like; suitable solubilizers, such as polysorbate-80; suitable pigments such as titanium dioxide, various iron oxides, pink pigments, and the like may also be included.
The pharmaceutical composition as described above, which contains one or more pharmaceutically acceptable carriers, is formulated into any form for administration by any suitable route, and can be prepared into any pharmaceutically acceptable pharmaceutical dosage form, wherein the compound D dilysine, the compound D monolysine, hydrates thereof or solvates thereof are the active substances, and the pharmaceutical composition can also contain other substances with pharmaceutical activity, so as to form a compound pharmaceutical composition for combination therapy.
Further, the preparation method of the pharmaceutical composition comprises the step of fully mixing the compound D-dilysine, the hydrate or the solvate thereof and a pharmaceutically acceptable carrier to prepare any pharmaceutically acceptable pharmaceutical dosage form, wherein the preferred pharmaceutical dosage forms are injections (including powder injections and injections for injection), tablets (including dispersible tablets, sustained-release tablets, enteric-coated tablets, effervescent tablets, orally disintegrating tablets, irregular tablets and the like), capsules (including gastric-soluble tablets, enteric-coated capsules and sustained-release capsules), granules, oral solutions and the like.
Specifically, the method for preparing the pharmaceutical composition comprises the step of fully mixing the compound D dilysine, the compound D monolysine, the hydrate thereof or the solvate thereof with pharmaceutically acceptable pharmaceutical carriers to prepare any pharmaceutically acceptable pharmaceutical dosage form, wherein the preferred pharmaceutical dosage forms are injections (including powder injections and injections for injection), tablets (including dispersible tablets, sustained-release tablets, enteric-coated tablets, effervescent tablets, orally disintegrating tablets, irregular tablets and the like), capsules (including gastric-soluble capsules, enteric-coated capsules and sustained-release capsules), granules, oral solutions, non-oral liquid preparations, such as non-oral eye drops, nasal drops, ear drops, transdermally absorbed emulsions, transdermally absorbed transdermal absorbents (including transdermally absorbed creams, gels, emulsions, emulsion agents, patches and the like), and the like.
In addition, the pharmaceutical composition of the salt of the present invention may be formed by mixing the compounds, and in particular, the composition of the present invention may be formed by mixing the compound D including the following structural formula:
it will be appreciated that mixing compound D and lysine may be carried out in a solvent, for example in an aqueous environment, such as: preferably mixing with purified water (such as deionized water or distilled water) or/and ethanol, dissolving, and oven drying, drying with rotary evaporator, drying under reduced pressure or vacuum drying, and lyophilizing to obtain pharmaceutical composition; alternatively, a solid powder of compound D and a solid powder of lysine may be mixed, for example, by a method for producing a solid dispersion to obtain a pharmaceutical composition.
The invention also relates to the application of the compound D-dilysine, the hydrate thereof or the solvate thereof in the following aspects:
the application in preparing the medicine for treating acute ischemic cerebral apoplexy;
the application in preparing the medicine for treating the brain injury and traumatic brain injury caused by open heart surgery;
the application in preparing the medicament for treating the neuropathy;
the application in preparing the medicine for treating Parkinson's disease and Alzheimer's disease.
Description of the drawings: the invention provides the following related drawings:
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of Compound D1H NMR(DMSO-d6)；
FIG. 2 is a nuclear magnetic resonance carbon spectrum of Compound D13C NMR(DMSO-d6)。
Advantages of the salts of the compound D derivatives of the invention:
1. the compound D dilysine, the compound D mono lysine, the hydrate thereof or the solvate thereof has safe and reliable basic ligand, belongs to endogenous substances of human bodies, and has no additional side effect on the human bodies.
And (3) stability test:
the compound D is usually decomposed at high temperature to generate monoester analogues and other impurities, which are collectively called total related substances, and the content of the total related substances is measured under the high temperature condition to analyze the stability of the compound D.
Taking a proper amount of compound D dilysine, compound D mono lysine and compound D disodium, respectively, placing in a weighing bottle, placing in an oven at 50 ℃, sampling on the 5 th day and the 10 th day respectively, and determining the total related substances in the samples.
The results of the analysis by HPLC are shown in Table 1.
TABLE 1
The determination result shows that the content of the total related substances is increased when the compound D dilysine, the compound D mono-lysine and the compound D disodium are placed at a high temperature of 50 ℃ for 10 days, the content of the total related substances of the compound D disodium is far greater than that of the compound D dilysine and the compound D mono-lysine, the percentage content net value of the total related substances is increased at the 10 th day, and the compound D disodium is more than 1.4 times of the compound D mono-lysine and more than 1.7 times of the compound D dilysine. It can be seen that the stability of compound D dilysine and compound D mono lysine is significantly improved compared to compound D disodium.
2. The compound D dilysine, the compound D mono lysine, the hydrate thereof or the solvate thereof have good water solubility, and the water solubility of the compound D is improved.
Through preliminary comparison, the water solubility characteristics (normal temperature and pressure) of the compound D dilysine, the compound D mono lysine and the compound D are compared as shown in the following table 2.
TABLE 2
As can be seen from table 1, compound D dilysine and compound D mono lysine of the present invention have much higher water solubility than compound D, and exhibit excellent water solubility.
3. The compound D dilysine, the compound D monolysine, a hydrate thereof, or a solvate thereof according to the present invention has an excellent water solubility, and has a good effect of promoting dissolution of the compound D in a preparation. Especially for oral preparations.
It should be understood that oral administration of a drug requires absorption from the gastrointestinal tract to enter the blood of a human body to achieve a therapeutic effect, and the therapeutic effect of the drug is directly influenced by the quality of oral administration. Bioavailability (Bioavailability) refers to the degree and rate of utilization of a drug absorbed into the blood circulation, in terms of the concept of pharmacology. Compared with the compound D, the lysine salt of the compound D has excellent water solubility, and has important promotion effect and significance on the degree and speed of absorption into blood circulation of oral pharmaceutical preparations taking the lysine salt as an active ingredient. The absorption process of the medicament after entering the stomach and intestine is divided into two stages, namely, disintegration and dispersion and gastrointestinal wall absorption, wherein the medicament is firstly disintegrated and dispersed in gastric juice or intestinal juice and then contacted with and attached to the gastrointestinal wall for absorption and enters the blood, the two stages can influence the absorption and utilization of the medicament and the exertion of the medicament effect, the compound D is prepared into a derivative form with good water solubility, the medicament dissolution speed is obviously accelerated, the disintegration and dispersion degree and the dispersion speed of the compound D in the gastric juice or the intestinal juice are greatly improved, the contact between the active ingredients of the medicament and the gastrointestinal wall is more sufficient, the active ingredients attached to the gastrointestinal wall for absorption and enter the blood are more sufficient, and the medicament has important significance for improving the bioavailability of the medicament effect ingredient D-lysine salt.
4. The compound D dilysine, the compound D mono lysine, the hydrate thereof or the solvate thereof has less moisture absorption compared with the compound D sodium/potassium salt.
5. When the compound D dilysine, the compound D monolysine, the hydrate thereof or the solvate thereof is used for injection, adverse reactions such as vascular stimulation, muscle stimulation and the like are improved, and the compound D dilysine is obviously superior to the compound D disodium and potassium salt.
Vascular irritation test:
taking 32 rabbits with the body mass of 1.8-2.2 kg, and randomly dividing male and female halves into four groups, namely a compound D-lysine injection group (dissolved by normal saline, the pH value of which is adjusted by phosphate is 7 +/-0.5 and 1mg/ml), a compound D-disodium injection group (dissolved by normal saline, the pH value of which is adjusted by phosphate is 7 +/-0.5 and 1mg/ml) and a normal saline injection group, wherein 8 rabbits in each group are shaved off by a stainless steel blade to cover the auricular vein, and the left ear of the rabbit is disinfected by alcohol,
group 1 ear margin intravenous injection of compound D-lysine injection 1.1mg/kg, 1 times/D;
group 2 compound D dilysine injection for intravenous injection at the edge of ear 1.3mg/kg, 1 times/D;
compound D disodium injection 1.0mg/kg, 1 times/D for group 3 ear margin intravenous injection;
1.0ml/kg of physiological saline injection is injected into the ear margin of the group 4 at a dose/day;
the injection speed is 2.0ml/min, the injection is carried out for 14 days continuously, the injection is carried out at the same position every day, the general reaction of the animals and the congestion and edema reaction of blood vessels at the injection position are observed every day, the animals are killed at the 14 th day, and the materials are taken for pathological examination.
Determination of degree of inflammatory reaction venous inflammatory reaction degree criteria: under the light mirror, the inflammatory reaction degree is divided into 4 grades,
no inflammatory reaction (-): congestion and edema of connective tissue surrounding veins;
mild inflammation (+): the connective tissue around the blood vessel is infiltrated by lymphocytes and plasma cells, and inflammatory cells are not seen in the blood vessel wall and the blood vessel cavity;
moderate inflammation (++): the connective tissue around the blood vessel and each layer of the blood vessel wall are infiltrated by lymphocytes, plasma cells and a few neutrophils;
severe inflammation (+++): the connective tissue around the blood vessel, the vascular wall layers and the vascular cavity can be infiltrated by diffuse lymphocytes and neutrophils, and more exudates and necrotic cell debris can be seen in the vascular cavity. The results of inflammatory responses in rabbits of each group are shown in Table 3.
TABLE 3
The results show that the normal saline injection group has no vein injury basically, the compound D-dilysine injection group has 1 case of mild vein injury, the compound D-dilysine injection group has 3 cases of mild vein injury and no moderate to severe inflammation, the compound D-dilysine injection group has severe vein injury and only 1 case of mild inflammation, and the rest are moderate to severe inflammation, which shows that the comparison difference between the compound D-lysine salt injection group and the compound D-dilysine injection group has statistical significance (P is less than 0.01).
Detailed description of the inventionvarious embodiments and modifications in the practice of the invention will be apparent to and can be readily made by those skilled in the art without departing from the scope and spirit of the invention, which is not limited to the particular embodiments described herein, and indeed, various modifications of the invention other than those described can be understood by those skilled in the art from the foregoing description. The salt compounds of the derivatives of compound D of the present invention, the preparation method thereof and the use thereof in medicine are further illustrated by the following examples, which are not intended to limit the present invention.
In the embodiment of the present invention, the derivative salt compound of the compound D described below is as described in the non-limiting examples of the compound of the present invention, and in the information described herein, the desired lysine is added to the compound D, or the desired compound D is added to a solution containing lysine, or the solution containing the compound D is mixed with a solution containing lysine by a method similar to that described below, for the purpose of contacting the compound D with lysine and reacting to form a salt.
Firstly, compound D can be synthesized according to the process route of the present invention, and the nuclear magnetic resonance hydrogen spectrum and nuclear magnetic resonance carbon spectrum data of compound D are as follows:
1HNMR(DMSO-d6)δ(ppm)：0.834～0.860(6H，t)，1.231(20H，d)，1.420～1.444(4H，m)，3.294～3.411(8H，m)，3.988～4.205(16H，m)，6.724～6.955(8H，m)。
13CNMR(DMSO-d6)δ(ppm)：13.965，22.086，25.581，28.679，28.832，29.107，31.259，53.068，53.251，63.263，67.093，67.643，70.222，113.901，118.159，121.135，139.068，149.614，170.935，172.171。
mass spectrometry analysis: ESI-MS (M/z), excimer ion peak [ M +1 ]]790.4, and C in its molecular formula42H64N2O12And (6) matching.
Example 1 Compound D Dilysine and preparation thereof
Adding 1g (1.267mmol) of the compound D into 100ml of isopropanol, stirring and heating to completely dissolve the compound D, adding a solution of 0.37g (2.55mmol) of L-lysine in 10ml of distilled water, slowly adding the solution and stirring, keeping the temperature and stirring at 40 ℃ for more than 30min after the addition is finished, cooling to room temperature, removing part of the solvent by evaporation by using a rotary evaporator as required, cooling in a refrigerator to fully crystallize the solvent, performing suction filtration, washing a filter cake by using 7ml of cold isopropanol or acetone, and performing vacuum drying to constant weight to obtain the compound D-dilysine.
1HNMR(DMSO-d6)δ(ppm)：0.830～0.853(6H，t)，1.224～1.268(22H，m)，1.416～1.437(4H，m)，3.290～3.312(4H，t)，3.382～3.399(4H，m)，3.411～3.445(8H，m)，3.978～3.994(8H，m)，4.130(4H，s)，4.200(4H，s)，4.392(6H，broad s)，6.719～6.736(2H，m)，6.821～6.852(4H，m)，6.933～6.948(2H，m)。
13CNMR(DMSO-d6)δ(ppm)：13.982，18.576，22.132，25.505，25.627，28.725，28.878，29.137，31.304，53.129，53.312，56.090，63.324，67.154，67.704，70.278，113.962，118.220，121.197，121.227，139.114，149.660，170.996，172.278。
Example 2 Compound D Dilysine and preparation thereof
Adding 1g (1.267mmol) of the compound D into 80ml of methanol, stirring and heating to completely dissolve the compound D, adding a solution of 0.37g (2.55mmol) of L-lysine in 10ml of distilled water, slowly adding the solution and stirring, keeping the temperature and stirring at 40 ℃ for more than 30min after the addition is finished, cooling to room temperature, removing part of the solvent by evaporation by using a rotary evaporator as required, cooling in a refrigerator to fully crystallize, performing suction filtration, washing a filter cake by using 7ml of acetone, and performing vacuum drying to constant weight to obtain the compound D dilysine.
The hydrogen spectrum and carbon spectrum analysis of the compound D dilysine or its hydrate prepared as described above were consistent with those of example 1.
Example 3 Compound D Dilysine or hydrate thereof and preparation thereof
Adding 1g (1.267mmol) of compound D into 28ml of distilled water, stirring to obtain a suspension, adding a solution of 2.534mmol of L-lysine in 7ml of distilled water under stirring, slowly adding the suspension and stirring, preserving the temperature at 30-45 ℃ after the addition, stirring for more than 10min to form a clear solution, cooling to room temperature, freeze-drying in a sterilized freeze-drying box according to a conventional freeze-drying process, pre-freezing for 5 hours, cooling to-35 ℃, sublimating for 8 hours for the first time, and raising the temperature to-5 ℃; sublimating for 7 hours for the second time, raising the temperature to 25 ℃, and drying in vacuum to constant weight to obtain the compound D-dilysine and hydrates thereof through nuclear magnetic resonance hydrogen spectrum, nuclear magnetic resonance carbon spectrum and differential thermal analysis TG-DTA spectrum.
Optionally, the compound D-dilysine and its hydrate are further recrystallized for purification, and the solvent for recrystallization can be isopropanol-water mixed solution, acetone-water mixed solution, ethanol-water mixed solution, methanol-water mixed solution or diethyl ether-water mixed solution.
The hydrogen spectrum and carbon spectrum analysis of the compound D dilysine or its hydrate prepared as described above were consistent with those of example 1.
Example 4 Compound D-lysine and preparation thereof
Adding 1g (1.267mmol) of the compound D into 55ml of methanol, stirring and heating to 50 ℃ for complete dissolution, adding a solution of 0.185g (1.267mmol) of L-lysine in 400ml of methanol, slowly adding the mixture and stirring, preserving the temperature and stirring for more than 50min after the addition is finished, cooling to room temperature, removing part of the solvent by evaporation by using a rotary evaporator as required, cooling in a refrigerator to fully crystallize the solvent, performing suction filtration, washing a filter cake by using 4ml of cold methanol, and performing vacuum drying to constant weight to obtain the compound D-lysine salt.
1HNMR(DMSO-d6)δ(ppm)：0.837～0.842(6H，t)，1.230～1.270(22H，m)，1.414～1.435(4H，m)，3.282～3.322(4H，t)，3.362～3.391(4H，m)，3.417～3.455(8H，m)，3.988～4.002(8H，m)，4.151(4H，s)，4.209(4H，s)，4.398(6H，broad s)，6.720～6.741(2H，m)，6.829～6.860(4H，m)，6.939～6.950(2H，m)。
13CNMR(DMSO-d6)δ(ppm)：13.937，18.621，22.086，25.516，25.711，28.664，28.817，29.092，31.259，53.083，53.251，56.192，63.263，67.109，67.623，70.207，113.947，118.159，121.151，121.310，139.068，149.599，170.935，172.202。
Example 5 Compound D-lysine or hydrate thereof and preparation thereof
Adding 1g (1.267mmol) of compound D into 35ml of distilled water, stirring to obtain a suspension, adding 1.267mmol of L-lysine aqueous solution under stirring, slowly adding and stirring, keeping the temperature at 30-45 ℃ after the addition, stirring for more than 10min to form a clear solution, cooling to room temperature, freeze-drying in a sterilized freeze-drying box according to a conventional freeze-drying process for 5 hours, pre-freezing for 5 hours, cooling to-35 ℃, sublimating for 8 hours for the first time, and raising the temperature to-5 ℃; sublimating for 7 hours for the second time, raising the temperature to 25 ℃, and drying in vacuum to constant weight to obtain the compound D-lysine and the hydrate thereof through nuclear magnetic resonance hydrogen spectrum, nuclear magnetic resonance carbon spectrum and differential thermal analysis TG-DTA spectrum.
Optionally, the compound D-lysine and its hydrate are further recrystallized for purification, and the solvent for recrystallization can be acetone-water mixed solution, ethanol-water mixed solution, methanol-water mixed solution or diethyl ether-water mixed solution.
The hydrogen spectrum and carbon spectrum analysis of the compound D-lysine or its hydrate prepared above were consistent with those of example 4.
EXAMPLE 6 lyophilized powder for injection of Compound D-Dilysine
Compound D dilysine 30g (compound D dilysine hydrate is calculated as compound D dilysine)
Mannitol 120g
Appropriate amount of pH buffer
Adding 2500ml of water for injection
Taking compound D dilysine and mannitol in a prescription amount, adding 2300ml of injection water for dissolving, adjusting the pH to 7-8, adding the injection water to 2500ml, filtering and sterilizing by using a microporous filter membrane, aseptically filling under hundred-grade conditions into 1000 penicillin bottles, adding a rubber plug after checking the filling amount, reserving holes, sending glass bottles into a sterilized freeze-drying box for freeze-drying, pre-freezing for 5 hours, reducing the temperature to-35 ℃, sublimating for 8 hours for the first time, and increasing the temperature to-5 ℃; sublimating for 7 hours for the second time, raising the temperature to 25 ℃, vacuum capping or nitrogen-filled capping, taking out, pressing an aluminum cap label to obtain a finished product, wherein each bottle of the freeze-dried powder contains 30mg of the compound D-dilysine.
EXAMPLE 7 lyophilized powder for injection of Compound D-Dilysine
Compound D Dilysine 25g (compound D Dilysine hydrate in terms of Compound D Dilysine)
18g of sodium chloride
Glucose 30g
Calcium disodium edetate 0.15g
proper amount of pH regulator
Adding water for injection to 2000ml
Taking compound D dilysine, sodium chloride and glucose according to the prescription amount, adding 1800ml of water for injection to dissolve, adding calcium disodium edetate to dissolve, adjusting the pH to 8-9, adding water for injection to 2000ml, stirring with 0.3% (w/v) of active carbon, stirring at 45 ℃ for 30 minutes, decarburizing with a sterilized 0.6 mu m filter membrane, filtering and sterilizing with a 0.22 mu m filter membrane, measuring and adjusting the pH to 8-9, filling the filtrate into 1000 tube penicillin bottles, freeze-drying in a freeze-drying machine, capping with a cap or filling with nitrogen, taking out the bottles, and labeling to obtain the compound D dilysine, wherein the freeze-drying curve is as follows:
| procedure (ii) | Rate of temperature rise | Temperature (. degree.C.) | |
| 1 | Prefreezing | Freezing at room temperature to-40 deg.C | |
| 2 | Heat preservation | -35℃ | |
| 3 | Vacuum pumping | -35℃ | |
| 4 | Temperature rise | 6 ℃/hour | Heating to-5 deg.C |
| 5 | Temperature rise | Heating to 0 ℃ at the temperature of minus 5 |
|
| 6 | Temperature rise | Heating to 10 deg.C at 0 deg.C |
| 7 | Temperature rise | Heating to 25 ℃ at 10 DEG C | |
| 8 | Heat preservation | 25℃ |
The content of compound D-dilysine in each bottle of the prepared freeze-dried powder injection is 25 mg.
Example 8 the method of example 6 or example 7 is followed to adjust the prescribed amounts of compound D dilysine and/or pharmaceutical carrier (or adjuvant) to prepare lyophilized powder for injection containing 5-100 mg of compound D dilysine per vial, e.g., 5mg, 10mg, 15mg, 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, or 100mg of compound D dilysine per vial.
Example 9 injection of Compound D-Dilysine, Compound D-Monolysine, hydrate thereof or solvate thereof
Selecting conventional pharmaceutical excipients from the compound D lysine salt, hydrate or solvate thereof in any one of the embodiments 1 to 5, mixing the conventional pharmaceutical excipients with the pharmaceutical excipients, and preparing freeze-dried powder injection or injection according to the preparation method of the injection, wherein each bottle of the freeze-dried powder injection or injection contains 0.1 to 500mg of the compound D lysine salt.
Example 10 tablets/capsules of Compound D-Dilysine, Compound D-Monolysine, hydrates or solvates thereof
Mixing the compound D lysine salt, hydrate or solvate thereof as described in any one of embodiments 1 to 5 with conventional pharmaceutical excipients, and preparing tablets or capsules according to the preparation method of the tablets or capsules, wherein each tablet or capsule contains 0.1 to 500mg of the compound D lysine salt.
Example 11. mixing 0.1mol of Compound D with 0.2mol of lysine in 1 liter of deionized water gave a clear solution, which was filtered and then rotary evaporated to give a pharmaceutical composition containing Compound D and lysine.
EXAMPLE 12A pharmaceutical composition containing Compound D and lysine was obtained by mixing 0.1mol of Compound D and 0.1mol of lysine in 1 liter of deionized water to obtain a clear solution, filtering and then drying by a rotary evaporator.
Example 13 acid reversible reduction experiment
Taking about 0.1g of each of the compound D dilysine, the compound D mono lysine, the hydrate thereof or the solvate thereof prepared in the above examples, dissolving the compound D dilysine, the compound D mono lysine, the hydrate thereof or the solvate thereof in 25ml of distilled water, dripping hydrochloric acid to adjust the pH to about 1, and precipitating, collecting, analyzing, wherein the precipitates are consistent with the spectrogram of the compound D, and the compound D is confirmed to be the compound D, which indicates that the lysine salt of the compound D of the invention only changes the pharmaceutical properties of the compound D, but not the pharmacological action of the compound D.
Example 14.
The lysine salt of compound D and its formulation prepared in examples 1 to 10, for use as follows:
the application in preparing the medicine for treating acute ischemic cerebral apoplexy;
the application in preparing the medicine for treating the brain injury and traumatic brain injury caused by open heart surgery;
the application in preparing the medicament for treating the neuropathy;
the application in preparing the medicine for treating Parkinson's disease and Alzheimer's disease.
Claims (10)
1. A compound of formula I, a hydrate thereof, or a solvate thereof:
wherein n is 2 or 1.
2. The compound, hydrate or solvate thereof according to claim 1, which comprises:
or is or
3. A process for producing a compound, a hydrate thereof or a solvate thereof according to claim 1 or 2, which comprises contacting compound D with lysine in a solvent, optionally adding lysine to a solution containing compound D, or adding compound D to a solution containing lysine, or mixing a solution containing compound D with a solution containing lysine, and reacting to form a salt, wherein the solvent is one or a mixture of solvents selected from the group consisting of ethanol, methanol, isopropanol, acetone, acetonitrile, ethyl acetate, water, dimethylacetamide and dimethylformamide; the reaction temperature is between room temperature and the reflux temperature of the solvent.
4. The preparation method of the compound, the hydrate thereof or the solvate thereof according to claim 1 or 2, which comprises the steps of contacting the compound D and the lysine in a molar ratio of 1 to (1-1.1) in a solvent at a temperature ranging from room temperature to the reflux temperature of the solvent, reacting to form a salt, crystallizing the salt at room temperature or below, filtering, and drying, wherein the solvent is one or a mixture of several solvents selected from ethanol, methanol, isopropanol, acetone, acetonitrile, ethyl acetate, water, dimethylacetamide and dimethylformamide, and the crystallization can be accelerated by reducing the crystallization temperature or/and evaporating part of the solvent if necessary; or,
and (3) completely dissolving the compound D and the lysine in a molar ratio of 1: 1 in a proper amount of water at 5-80 ℃, stirring, and freeze-drying to obtain the compound D.
5. A method for preparing the compound, the hydrate thereof or the solvate thereof according to claim 1 or 2, which comprises the steps of contacting the compound D and the lysine in a molar ratio of 1 to (2-2.2) in a solvent at a temperature ranging from room temperature to the reflux temperature of the solvent, reacting to form a salt, crystallizing the salt at room temperature or below, filtering, and drying, wherein the solvent is one or a mixture of several solvents selected from ethanol, methanol, isopropanol, acetone, acetonitrile, ethyl acetate, water, dimethylacetamide and dimethylformamide, and if necessary, part of the solvent can be removed by reducing the crystallization temperature or/and evaporating to accelerate the formation of crystals; or,
and (3) completely dissolving the compound D and the lysine in a molar ratio of 1: 2 in a proper amount of water at 5-80 ℃, stirring, and freeze-drying to obtain the compound D.
6. A pharmaceutical composition comprising a compound of any one of claims 1 or 2 and a pharmaceutically acceptable carrier.
7. A pharmaceutical composition comprising any one of the compounds of claim 1 or 2 and a pharmaceutically acceptable carrier, wherein the amount of any one of the compounds of claim 1 or 2 is 0.1 to 500 mg.
8. The process for preparing a pharmaceutical composition according to claim 6 or 7, which comprises mixing the compound D-lysine, the hydrate thereof or the solvate thereof with a pharmaceutically acceptable carrier to prepare any pharmaceutically acceptable dosage form.
9. A pharmaceutical composition formed by combining a compound comprising a compound having the formula:
10. use of a compound according to claim 1 or 2, a hydrate thereof or a solvate thereof:
the application in preparing the medicine for treating acute ischemic cerebral apoplexy;
the application in preparing the medicine for treating the brain injury and traumatic brain injury caused by open heart surgery;
the application in preparing the medicament for treating the neuropathy;
the application in preparing the medicine for treating Parkinson's disease and Alzheimer's disease.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201010570080.6A CN102079715B (en) | 2009-11-26 | 2010-11-24 | Lysine salt compound of binary ester acid, preparation method and medicinal application |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910224894.1 | 2009-11-26 | ||
| CN200910224894 | 2009-11-26 | ||
| CN201010570080.6A CN102079715B (en) | 2009-11-26 | 2010-11-24 | Lysine salt compound of binary ester acid, preparation method and medicinal application |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102079715A true CN102079715A (en) | 2011-06-01 |
| CN102079715B CN102079715B (en) | 2014-07-23 |
Family
ID=44085940
Family Applications (4)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201010571246.6A Expired - Fee Related CN102093234B (en) | 2009-11-26 | 2010-11-24 | Tromethamine salt compound of dibasic ester acid, preparation method and medicinal application thereof |
| CN2010105709656A Pending CN102126973A (en) | 2009-11-26 | 2010-11-24 | Meglumine compound of dibasic ester acid and preparation method and medicinal application thereof |
| CN201010570080.6A Expired - Fee Related CN102079715B (en) | 2009-11-26 | 2010-11-24 | Lysine salt compound of binary ester acid, preparation method and medicinal application |
| CN201010571076.1A Expired - Fee Related CN102079717B (en) | 2009-11-26 | 2010-11-24 | Arginine salt compound of dibasic ester acids and preparation method and medicinal application thereof |
Family Applications Before (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201010571246.6A Expired - Fee Related CN102093234B (en) | 2009-11-26 | 2010-11-24 | Tromethamine salt compound of dibasic ester acid, preparation method and medicinal application thereof |
| CN2010105709656A Pending CN102126973A (en) | 2009-11-26 | 2010-11-24 | Meglumine compound of dibasic ester acid and preparation method and medicinal application thereof |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201010571076.1A Expired - Fee Related CN102079717B (en) | 2009-11-26 | 2010-11-24 | Arginine salt compound of dibasic ester acids and preparation method and medicinal application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (4) | CN102093234B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103373957A (en) * | 2012-04-12 | 2013-10-30 | 成都苑东药业有限公司 | Chelate with functions of protecting nerve cells |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR102200892B1 (en) * | 2019-05-13 | 2021-01-12 | 대원제약주식회사 | Novel salts of pelubiprofen, preparation method thereof and pharmaceutical compositions comprising thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999016741A2 (en) * | 1997-09-28 | 1999-04-08 | D-Pharm Limited | Lipophilic diesters of chelating agents |
| CN1899275A (en) * | 2005-07-11 | 2007-01-24 | 江苏联创医药技术有限公司 | Composition of rheinic acid or rheinic acid compounds, its preparing method and its use in preparing medicine for treating osteoarthritis |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1923798A (en) * | 2005-08-30 | 2007-03-07 | 陈亦林 | Preparation method of dexibuprofen amino acid salt and application |
| CN1944378A (en) * | 2006-10-23 | 2007-04-11 | 广东中科药物研究有限公司 | Biphenyl ammonia acetate butantriol salt and its preparing method |
| CN101514189B (en) * | 2008-02-18 | 2012-07-04 | 杨喜鸿 | Glycin diazole tromethamine compound as well as preparation method and medicament application thereof |
| CN101486644B (en) * | 2009-02-24 | 2012-07-25 | 合肥工业大学 | Preparation of arginine acetylsalicylate |
-
2010
- 2010-11-24 CN CN201010571246.6A patent/CN102093234B/en not_active Expired - Fee Related
- 2010-11-24 CN CN2010105709656A patent/CN102126973A/en active Pending
- 2010-11-24 CN CN201010570080.6A patent/CN102079715B/en not_active Expired - Fee Related
- 2010-11-24 CN CN201010571076.1A patent/CN102079717B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999016741A2 (en) * | 1997-09-28 | 1999-04-08 | D-Pharm Limited | Lipophilic diesters of chelating agents |
| CN1899275A (en) * | 2005-07-11 | 2007-01-24 | 江苏联创医药技术有限公司 | Composition of rheinic acid or rheinic acid compounds, its preparing method and its use in preparing medicine for treating osteoarthritis |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103373957A (en) * | 2012-04-12 | 2013-10-30 | 成都苑东药业有限公司 | Chelate with functions of protecting nerve cells |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102079717B (en) | 2014-01-22 |
| CN102093234B (en) | 2014-06-18 |
| CN102079715B (en) | 2014-07-23 |
| CN102126973A (en) | 2011-07-20 |
| CN102093234A (en) | 2011-06-15 |
| CN102079717A (en) | 2011-06-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US10201519B2 (en) | Stabilized pediatric suspension of carisbamate | |
| ES2743699T3 (en) | Ketamine oral dosage form | |
| EP3505161B1 (en) | Sublingual pharmaceutical composition of edaravone and (+)-2-borneol | |
| EP0424028B1 (en) | S(+)-ibuprofen-L-amino acid and S(+)-ibuprofen-D-amino acid as onset hastened enhanced analgesics | |
| CN101633662A (en) | Prasugrel pharmaceutical acid addition salt as well as preparation method and pharmaceutical application thereof | |
| JP2003530321A (en) | Novel crystals of N- [4- [2- (2-amino-4,7-dihydro-4-oxo-3H-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] benzoyl] -L-glutamic acid Shape and manufacturing method thereof | |
| EP3785698B1 (en) | Edaravone pharmaceutical composition | |
| CN101712692A (en) | Medicinal acid addition salt of tenofovir disoproxil fumarate and preparation method and medicinal application thereof | |
| CN113336768B (en) | Multi-target tyrosine kinase inhibitor | |
| KR20060103336A (en) | Pregabalin composition | |
| CN114423752A (en) | Non-hygroscopic crystalline salts of pyrazole compounds, pharmaceutical compositions and uses thereof | |
| JP4854158B2 (en) | Formulations containing benzamide derivatives as active ingredients | |
| CN100584835C (en) | Novel medicinal salt for cinepazide and preparation method thereof | |
| WO1996010405A1 (en) | Antitumor agent | |
| CN102079715A (en) | Lysine salt compound of binary ester acid, preparation method and medicinal application | |
| CN111349111A (en) | Pentazocine prodrug, preparation method and application thereof | |
| CN116262698A (en) | Novel 2- (1-hydroxypentyl) benzoic acid naphthenamine salt | |
| WO2007143895A1 (en) | Supersaturated solution of gemcitabine hydrochloride and prepraration method thereof | |
| CN102351881B (en) | Stable levofloxacin hydrochloride compound | |
| CN101781300B (en) | Entecavir salt compound, preparation method and medicine application thereof | |
| CN101514189B (en) | Glycin diazole tromethamine compound as well as preparation method and medicament application thereof | |
| CN105367622B (en) | A kind of argatroban compound | |
| CN115124419B (en) | Rhein and cytisine eutectic crystal, preparation method, composition and application thereof | |
| WO2020003107A1 (en) | Low dose oral pharmaceutical composition of pirfenidone or salt thereof | |
| JPH10338634A (en) | Medicinal composition |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| ASS | Succession or assignment of patent right |
Owner name: ZHANG BITING Free format text: FORMER OWNER: ZHAO HAIJING Effective date: 20140619 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| COR | Change of bibliographic data |
Free format text: CORRECT: ADDRESS; FROM: 234000 SUZHOU, ANHUI PROVINCE TO: 350001 FUZHOU, FUJIAN PROVINCE |
|
| TA01 | Transfer of patent application right |
Effective date of registration: 20140619 Address after: Hualin Road, Jinan District of Fuzhou city in Fujian province 350001 No. 330 Building No. second room 1505 Jinghua collar Applicant after: Zhang Biting Address before: 234000, No. 10, building 126, Town God's Temple, Anhui, Suzhou Applicant before: Zhao Haijing |
|
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20140723 Termination date: 20151124 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |