CN1660817A - Alkaline amino acid salt of Glycididazole acid, preparation and application - Google Patents
Alkaline amino acid salt of Glycididazole acid, preparation and application Download PDFInfo
- Publication number
- CN1660817A CN1660817A CN 200410091991 CN200410091991A CN1660817A CN 1660817 A CN1660817 A CN 1660817A CN 200410091991 CN200410091991 CN 200410091991 CN 200410091991 A CN200410091991 A CN 200410091991A CN 1660817 A CN1660817 A CN 1660817A
- Authority
- CN
- China
- Prior art keywords
- glycididazole
- acid
- salt
- ornithine
- preparation
- 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
- 239000002253 acid Substances 0.000 title claims abstract description 93
- -1 amino acid salt Chemical class 0.000 title claims abstract description 25
- AWSWJRUMDBPELJ-UHFFFAOYSA-N 2-[bis[2-[2-(2-methyl-5-nitroimidazol-1-yl)ethoxy]-2-oxoethyl]amino]acetic acid Chemical compound CC1=NC=C([N+]([O-])=O)N1CCOC(=O)CN(CC(O)=O)CC(=O)OCCN1C([N+]([O-])=O)=CN=C1C AWSWJRUMDBPELJ-UHFFFAOYSA-N 0.000 title claims description 125
- 238000002360 preparation method Methods 0.000 title claims description 26
- 150000001413 amino acids Chemical class 0.000 claims abstract description 16
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 15
- 150000003839 salts Chemical class 0.000 claims abstract description 15
- 239000007788 liquid Substances 0.000 claims abstract description 12
- 238000001959 radiotherapy Methods 0.000 claims abstract description 6
- 235000001014 amino acid Nutrition 0.000 claims description 27
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 claims description 24
- 239000004475 Arginine Substances 0.000 claims description 18
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 18
- 229960003104 ornithine Drugs 0.000 claims description 16
- XUYPXLNMDZIRQH-LURJTMIESA-N N-acetyl-L-methionine Chemical compound CSCC[C@@H](C(O)=O)NC(C)=O XUYPXLNMDZIRQH-LURJTMIESA-N 0.000 claims description 15
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 claims description 15
- 229930182817 methionine Natural products 0.000 claims description 15
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 claims description 14
- 239000003814 drug Substances 0.000 claims description 14
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 claims description 11
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 claims description 9
- BMFMQGXDDJALKQ-BYPYZUCNSA-N Argininic acid Chemical class NC(N)=NCCC[C@H](O)C(O)=O BMFMQGXDDJALKQ-BYPYZUCNSA-N 0.000 claims description 8
- 150000002411 histidines Chemical class 0.000 claims description 8
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims description 5
- 238000002512 chemotherapy Methods 0.000 claims description 5
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical class NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 239000002552 dosage form Substances 0.000 claims description 2
- 229940124531 pharmaceutical excipient Drugs 0.000 claims description 2
- 239000002131 composite material Substances 0.000 abstract description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical class NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 abstract 2
- 239000004471 Glycine Substances 0.000 abstract 1
- 229940024606 amino acid Drugs 0.000 description 19
- FWYUJENICVGSJH-UHFFFAOYSA-M sodium;2-[bis[2-[2-(2-methyl-5-nitroimidazol-1-yl)ethoxy]-2-oxoethyl]amino]acetate Chemical compound [Na+].CC1=NC=C([N+]([O-])=O)N1CCOC(=O)CN(CC([O-])=O)CC(=O)OCCN1C([N+]([O-])=O)=CN=C1C FWYUJENICVGSJH-UHFFFAOYSA-M 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 239000000243 solution Substances 0.000 description 13
- 239000007924 injection Substances 0.000 description 10
- 238000002347 injection Methods 0.000 description 10
- 230000000694 effects Effects 0.000 description 9
- 239000000843 powder Substances 0.000 description 9
- 229960002885 histidine Drugs 0.000 description 8
- 235000014304 histidine Nutrition 0.000 description 8
- 238000000034 method Methods 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 230000005855 radiation Effects 0.000 description 6
- 238000001914 filtration Methods 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 description 4
- 229960000282 metronidazole Drugs 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- 206010070834 Sensitisation Diseases 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 229960000935 dehydrated alcohol Drugs 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 230000005251 gamma ray Effects 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 230000001678 irradiating effect Effects 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 230000008313 sensitization Effects 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 159000000000 sodium salts Chemical class 0.000 description 3
- 239000008215 water for injection Substances 0.000 description 3
- GZCWLCBFPRFLKL-UHFFFAOYSA-N 1-prop-2-ynoxypropan-2-ol Chemical class CC(O)COCC#C GZCWLCBFPRFLKL-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 2
- 206010027476 Metastases Diseases 0.000 description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- 206010041277 Sodium retention Diseases 0.000 description 2
- 230000003187 abdominal effect Effects 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- SHWNNYZBHZIQQV-UHFFFAOYSA-L calcium;disodium;2-[2-[bis(carboxylatomethyl)azaniumyl]ethyl-(carboxylatomethyl)azaniumyl]acetate Chemical compound [Na+].[Na+].[Ca+2].[O-]C(=O)C[NH+](CC([O-])=O)CC[NH+](CC([O-])=O)CC([O-])=O SHWNNYZBHZIQQV-UHFFFAOYSA-L 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- FLKPEMZONWLCSK-UHFFFAOYSA-N diethyl phthalate Chemical compound CCOC(=O)C1=CC=CC=C1C(=O)OCC FLKPEMZONWLCSK-UHFFFAOYSA-N 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000002662 enteric coated tablet Substances 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 201000005202 lung cancer Diseases 0.000 description 2
- 208000020816 lung neoplasm Diseases 0.000 description 2
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 2
- JGSARLDLIJGVTE-UHFFFAOYSA-N 3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-UHFFFAOYSA-N 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 1
- 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 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- 229930195722 L-methionine Natural products 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
- 229930195725 Mannitol Natural products 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 240000002853 Nelumbo nucifera Species 0.000 description 1
- 235000006508 Nelumbo nucifera Nutrition 0.000 description 1
- 235000006510 Nelumbo pentapetala Nutrition 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical class [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 229910000831 Steel Inorganic materials 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 229940046011 buccal tablet Drugs 0.000 description 1
- 239000006189 buccal tablet Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000005779 cell damage Effects 0.000 description 1
- 208000037887 cell injury Diseases 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- 230000003750 conditioning effect Effects 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 239000013583 drug formulation Substances 0.000 description 1
- 210000001198 duodenum Anatomy 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 229960004756 ethanol Drugs 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 235000021050 feed intake Nutrition 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229910021645 metal ion Inorganic materials 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
- 239000011259 mixed solution Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- MGFYIUFZLHCRTH-UHFFFAOYSA-N nitrilotriacetic acid Chemical compound OC(=O)CN(CC(O)=O)CC(O)=O MGFYIUFZLHCRTH-UHFFFAOYSA-N 0.000 description 1
- 229910052755 nonmetal Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 230000010355 oscillation Effects 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229940023488 pill Drugs 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 238000000247 postprecipitation Methods 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 238000011127 radiochemotherapy Methods 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 230000001235 sensitizing effect Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000014347 soups Nutrition 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 239000010959 steel Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000011003 system suitability test Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 229940005605 valeric acid Drugs 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 235000020985 whole grains Nutrition 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
A series of composite salts of glycine biazolic acid and amino acid, such as Arg glycinebiazolate, lys glycinebiazolate, etc is prepared through contacting glycinebiazolic acid with alkaline amino acid in liquid to generate salt and removing liquid. Said composite salt can be used as the sensitizer for chemicotherapy and radiotherapy of tumor.
Description
Technical fieldThe invention belongs to medical technical field, relate to basic aminoacids compound salt and the method for making and the purposes of a kind of chemicotherapy sensitizer----glycididazole acid.
Background technologyRadiation and chemotherapy are the important method in the neoplastic disease treatment, the quality of chemicotherapy effect directly affects rehabilitation of patients and lifetime, the factor of influence radiation and chemotherapeutical curative effect is a lot, one of them major reason is to contain 10～50% anoxic cell in the tumor tissues, these anoxic cells to the tolerance of ray and chemotherapeutics than powerful about 3 times of the aerobic cell in the tumour and normal cell, ray and chemotherapeutics there is obvious resistance effect, therefore, when conventional chemicotherapy dosage treatment, anoxic cell can not effectively be killed and be become metastases and survival " keep away and protect institute ", this is the unfavorable major cause of tumor chemoradiotherapy effect, also is the root that causes or quicken to cause metastases and recurrence.Chemicotherapy sensitizer a kind of chemical substance that comes to this, it can strengthen ray and the chemotherapeutics killing action to the anoxic cell of tumour, and less to the general damage of healthy tissues of aerobic.
Chinese invention patent numbers 89102182.5 discloses the preparation method of a kind of chemicotherapy sensitizer----Glycididazole, adopts nitrilotriacetic acid(NTA) and metronidazole to carry out double esterification reaction and generate Glycididazole (being called glycididazole acid) under certain condition and environment; In addition, Chinese invention patent application number 99116128.9 also discloses metal-salt and the method for making and the purposes of glycididazole acid, especially the sodium salt of glycididazole acid is a sodium glycididazole, owing to have better water solubility and safety thereof, chemicotherapy sensitization efficiently, sodium glycididazole is by State Food and Drug Administration's approval listing, the chemistry of sodium glycididazole is by name: N, two [(2-methyl-5-nitro-1H-imidazoles-1-yl)-ethoxy carbonyl methyl] Sodium glycocollates of N-, its molecular structure is as follows:
Molecular formula is C
18H
22N
7O
10Na, the injection sodium glycididazole of approved listing is the sodium Metal 99.5 salt compound of glycididazole acid, belong to the ion salt compound, instil with the physiological saline solution posterior vein during use, its metabolism principal product in vivo is a metronidazole, but it should be noted that, metronidazole can cause metabolism disorders such as sodium retention under the too much situation of intaking amount of sodium-salt, sodium glycididazole itself promptly is the sodium salt structure, and needing use physiological saline solution again when using, this just might produce some potential, unpredictalbe side effect when the use sodium glycididazole.
The poorly water-soluble of glycididazole acid, water-soluble hardly, very inconvenient in medication preparation and application, and the metal ion salt compound of glycididazole acid has certain shortcoming, in addition, glycididazole acid itself belongs to the diester-type compound, less stable, sodium glycididazole plasma salt compound is ionized solution in the aqueous solution, facile hydrolysis produces impurity such as metronidazole, and it is very inconvenient to make in medicinal application, Given this, the non-metal salt that the purpose of this invention is to provide glycididazole acid makes it not only have stability in the better water solubility and the aqueous solution, and when having avoided using medicine too much take in sodium and some side effect of producing.
Contain in the molecular structure of summary of the invention glycididazole acid carboxyl (COOH), be acidic-group, involved in the present invention is the compound salt of chemicotherapy sensitizer glycididazole acid and basic aminoacids, with and its production and use.
Basic aminoacids of the present invention comprises arginine, Methionin, ornithine and Histidine, and this four seed amino acid is alkalescence at the aqueous solution, is easy to form double salt soluble in water with glycididazole acid.
Amino acid is the chemical substance that self just exists in the human body, also be the nutrition of safety non-toxic pharmaceutically commonly used, the double salt of glycididazole acid of the present invention and these four kinds of basic aminoacidss is respectively: glycididazole acid arginic acid salt, glycididazole acid lysine salt, glycididazole acid ornithine salt, glycididazole acid Histidine salt.
Its chemical name of arginine is 2-amino-5-guanidine radicals valeric acid, is the optically active form structure, its levo form structure commonly used on the pharmacology, and the molecular structural formula of glycididazole acid arginic acid salt is as follows:
Especially, glycididazole acid and arginine be with 1: 1 molecule number proportioning salify, i.e. one-tenth salt form during a=1, and at this moment its molecular formula is C
18H
23N
7O
10.C
6H
14N
4O
2, molecular structural formula is as follows:
Its chemical name of Methionin is 2, and the 6-diaminocaproic acid is the optically active form structure, its levo form structure commonly used on the pharmacology, and the molecular structural formula of glycididazole acid lysine salt is as follows:
Molecular formula is: C
18H
23N
7O
10.aC
6H
14N
2O
2Wherein a is the molecule number with the salifiable Methionin of glycididazole acid, that is the ratio of two active centre Methionin and the mole number of glycididazole acid in the glycididazole acid lysine salt, the span of a is 0.01～20, and the value of a can be a decimal, also can be integer, in the preparation, the reacting weight that feeds intake of control glycididazole acid and Methionin, the value difference of may command a makes the glycididazole acid lysine salt of different salify ratios.
Especially, glycididazole acid and Methionin is with 1: 1 molecule number proportioning salify, i.e. one-tenth salt form during a=1, and at this moment its molecular formula is C
18H
23N
7O
10.C
6H
14N
2O
2, molecular structural formula is as follows:
Its chemical name of ornithine is 2, and the 5-Ornithine is the optically active form structure, its levo form structure commonly used on the pharmacology, and the molecular structural formula of glycididazole acid ornithine salt is as follows:
Molecular formula is: C
18H
23N
7O
10.aC
5H
12N
2O
2Wherein a is the molecule number with the salifiable ornithine of glycididazole acid, that is the ratio of two active centre ornithines and the mole number of glycididazole acid in the glycididazole acid ornithine salt, the span of a is 0.01～20, and the value of a can be a decimal, also can be integer, in the preparation, the reacting weight that feeds intake of control glycididazole acid and ornithine, the value difference of may command a makes the glycididazole acid ornithine salt of different salify ratios.
Especially, glycididazole acid and ornithine be with 1: 1 molecule number proportioning salify, i.e. one-tenth salt form during a=1, and at this moment its molecular formula is C
18H
23N
7O
10.C
5H
12N
2O
2, molecular structural formula is as follows:
Histidine is the carboxy derivatives that contains of histamine, molecular formula C
6H
9N
3O
2, be the optically active form structure, its levo form structure commonly used on the pharmacology, the molecular structural formula structural formula of glycididazole acid Histidine salt is as follows:
Molecular formula is: C
18H
23N
7O
10.aC
6H
9N
3O
2Wherein a is the molecule number with the salifiable Histidine of glycididazole acid, that is the ratio of two active centre Histidines and the mole number of glycididazole acid in the glycididazole acid Histidine salt, the span of a is 0.01～20, and the value of a can be a decimal, also can be integer, in the preparation, the reacting weight that feeds intake of control glycididazole acid and Histidine, the value difference of may command a makes the glycididazole acid Histidine salt of different salify ratios.
Especially, glycididazole acid and Histidine be with 1: 2 molecule number proportioning salify, i.e. one-tenth salt form during a=2, and at this moment its molecular formula is C
18H
23N
7O
10.2C
6H
9N
3O
2, molecular structural formula is as follows:
The invention provides the composite salt compound of four kinds of glycididazole acids, be respectively: glycididazole acid arginic acid salt, glycididazole acid lysine salt, glycididazole acid ornithine salt, glycididazole acid Histidine salt.Glycididazole acid all belongs to the composite salt structure with the salt of above-mentioned four kinds of basic aminoacidss respectively, its preparation method is thorough mixing in suitable solvent with glycididazole acid and basic aminoacids, glycididazole acid is contacted and salify in liquid environment with basic aminoacids, again solvent is removed by methods such as filtration or evaporation or lyophilizes, promptly obtained the basic aminoacids double salt of the glycididazole acid of solid form.In the preparation, the feed intake reacting weight and the working method of regulation and control glycididazole acid and basic aminoacids can make the glycididazole acid of different salify ratios and the compound salt of basic aminoacids.
In addition, those of skill in the art of the present invention are appreciated that the alkaline amino acid salt of glycididazole acid of the present invention is in preparation process, for keeping distinctive crystalline structure, can contain crystal water, therefore, the alkaline amino acid salt of glycididazole acid of the present invention also comprises its crystalline hydrate.
The blocking effect of the basic aminoacids salt pair specific tumors anoxic cell injury repairing of glycididazole acid of the present invention can be used for making sensitizer in radiotherapy and the chemotherapy.
The alkaline amino acid salt of glycididazole acid of the present invention is used for preparing the medicine that sensitizer is made in tumour radiotherapy and chemotherapy, adopt appropriate pharmaceutical excipient and preparation method, can be made into acceptable pharmaceutical dosage form on any medicine, comprise powder ampoule agent for injection, injection liquid that injection is used; The tablet that orally uses, capsule, granule, pill, oral fluid agent; The emulsion of external application, cream creme; Through the oral cavity or the buccal tablet of sublingual administration etc.In above-mentioned preparation, also comprise by using or do not use apparatus, perhaps make and strengthen or the delay drug effect by other carrier, reach and promptly release or the purpose of slowly-releasing, also comprise preparation or using method that medicine is absorbed at the human body privileged site, as absorption at positions such as duodenum, intestines, stomaches.
The positively effect of the alkaline amino acid salt of glycididazole acid of the present invention is with the double salt ligand of basic aminoacids composition as safety, for the application of glycididazole acid on medicine provides new compound form, to have opened up the range of application of glycididazole acid; And the alkaline amino acid salt of glycididazole acid water-soluble and stable better, be used to prepare medicament and use more convenient; Moreover the alkaline amino acid salt of glycididazole acid belongs to non-sodium ion salt, has avoided causing owing to the absorption of excess sodium the generation of the untoward reaction of metabolic disturbance of electrolyte such as sodium retention.
EmbodimentFurther specify the present invention by embodiment, but do not represent the embodiment limitation of the present invention.
Embodiment one: the arginic preparation of Glycididazole (1: 1)
Getting glycididazole acid 8 gram (about 0.016mol) adds the 30ml dehydrated alcohol and is modulated into suspension, after other gets L-arginase 12 .8 gram (about 0.016mol) and adds the 20ml water dissolution, under the room temperature arginine solution is slowly dropped in the suspension of glycididazole acid, adding follow-up persistent oscillation fully shakes up and occurs white emulsion when mixed solution being add behind the faint yellow clear and bright liquid the about 150ml of dehydrated alcohol again, this emulsion is put the refrigerator freeze overnight makes its post precipitation remove supernatant liquid, with light yellow precipitate in vacuum-drying below 45 ℃ to constant weight, obtain the faint yellow solid powder, with absolute ethanol washing 2～3 times, promptly get the salify ratio behind the pressure reducing and steaming ethanol and be 1: 1 glycididazole acid arginic acid salt (being called for short the Glycididazole arginine) elaboration, yield is about 93.1%, is faint yellow solid-state powder.
Embodiment two: the arginic water capacity liquid of Glycididazole stability experiment
The arginic water-soluble of Glycididazole by embodiment one preparation is fabulous, and solubleness can satisfy the application on the preparation medicament fully greater than 30%.Verify the aqueous stability of Glycididazole arginine and sodium glycididazole by experiment.
Experimental technique: precision takes by weighing Glycididazole arginine and sodium glycididazole, make concentration respectively with distilled water and be about 5% solution, and regulator solution pH=7.5 ± 0.2, measure the concentration of two kinds of solution respectively every 5hr, observe the wherein content of Glycididazole arginine and sodium glycididazole.
Content assaying method: according to high effective liquid chromatography for measuring.The system suitability test is a weighting agent with octadecylsilane chemically bonded silica, acetonitrile-0.05mol/L ammonium acetate (pH7.1) (15: 85) is a moving phase, the detection wavelength is 316nm, number of theoretical plate should be not less than 1200 by the Glycididazole peak, precision measures trial-product and each 20 μ l of two kinds of solution of reference substance inject liquid phase look general instrument, and record Se Putu presses external standard method with the glycididazole acid calculated by peak area, promptly get content, convert to such an extent that data are as follows:
Can find out by last table data, the Glycididazole arginine is higher than the stability of sodium glycididazole in the aqueous solution, and significant difference (p＜0.01) is arranged, this has the significance of two aspects for the Glycididazole arginine, and the one, in useful in preparing drug formulations with use and can guarantee its steady quality more aspect the preservation; The 2nd, medicine also enough keeps relative stability after entering human body, can accumulate in the tumour entity with the original shape medicine more, reaches better radiation or chemotherapy sensitizing effect.
Embodiment three: further observe the arginic drug action of Glycididazole of the present invention with experimentation on animals.
Experimental technique: (1) animal model adopts the C of lotus Lewis lung cancer
57/ BL inbred mouse transplants the tumour cell suspension in mouse hind leg, cultivates tumour and grows up to 200～400mm
3In time, be used for testing.
(2) 8 every group of laboratory animal are divided into four groups, are respectively blank group, independent radiation group, sodium glycididazole+radiation group, Glycididazole arginine+radiation group.Its empty group is not done any disposal; The radiation group gives irradiating gamma-ray, dosage 8Gy/ time/3 days separately; After sodium glycididazole+radiation group gives abdominal injection sodium glycididazole 0.3mmol/kg, carry out irradiating gamma-ray again, dosage 8Gy/ time/3 days; Glycididazole arginine+radiation group is carried out irradiating gamma-ray after giving abdominal injection Glycididazole arginine 0.3mmol/kg again, dosage 8Gy/ time/3 days.
(3) observe testing index: measure the variation of each treated animal at the gross tumor volume of day part, wherein gross tumor volume adopts the millimeter vernier callipers to measure the length of mouse tumor and wide one by one, press the Steel formula (V=grows * wide
2/ 2) calculate gross tumor volume;
The data that record are as follows: (x ± s, n=8)
By last table data as can be seen, sodium glycididazole+radiation group and Glycididazole arginine+radiation group all have good inhibition effect to the growth of mice lung cancer transplantation tumor, compare with independent radiation group, significant difference (p＜0.05) is arranged, the sensitization of Glycididazole arginine+radiation group is better than sodium glycididazole+radiation group, demonstrates the outstanding radiation sensitization effect of Glycididazole arginine.
Embodiment four: the preparation of Glycididazole arginine lyophilized injectable powder
It is an amount of to get water for injection, add an amount of freeze-dried excipient N.F,USP MANNITOL and Glycididazole arginine 30 grams, be stirred to whole dissolvings, left standstill 15 minutes after adding the needle-use activated carbon mixing, about 7.5 behind the filtering gac with hydrochloric acid conditioning solution pH value, millipore filtration is smart filter after, divide and be filled in 100 bottles of cillin bottles, move into freeze drier and carry out freeze-drying by freeze-drying preparation technology, promptly make injection Glycididazole arginine lyophilized injectable powder, every bottle contains Glycididazole arginine 300mg.
Embodiment five: the preparation of Glycididazole Methionin (1: 1)
Get L-Methionin 2.9 and restrain in the adding 40ml water, add 10 gram glycididazole acids after heating is dissolved it fully again, after fully stirring makes solution clear and bright, smart filter, filtrate is adopted freeze-dry process that it is carried out lyophilize and is got pale yellow powder, i.e. Glycididazole Methionin (1: 1), molecular formula C
18H
23N
7O
10.C
6H
14N
2O
2
Embodiment six: the preparation of Glycididazole Methionin injection liquid
Prescription: Glycididazole Methionin 30g
Calcium disodium edathamil 0.1g
The acid phosphatase salt buffer is an amount of
Polyoxyethylene glycol-300 60ml
Water for injection adds to 200ml
With an amount of water for injection 30g Glycididazole Methionin and 0.1g calcium disodium edathamil dissolving back are added 60ml polyoxyethylene glycol-300, regulate PH about 8.5 with the acid phosphatase salt buffer again, add the needle-use activated carbon decolouring, add the injection water to 200ml after coarse filtration, the smart filter, divide and be filled to 100 brown ampoules, the sealing by fusing bottleneck promptly gets every Glycididazole Methionin injection liquid that contains the 2ml soup, contains Glycididazole Methionin 300mg in wherein every bottle liquid medicine.
Embodiment seven: the preparation of Glycididazole ornithine (1: 1)
Getting L-ornithine 4 grams adds in the 35ml water, after dissolving it fully, heating adds 15 gram glycididazole acids again, after fully stirring makes solution clear and bright fully, add gac and stir decolouring, with sand core funnel filtering gac, the filtrate spraying drying is got buff powder, i.e. Glycididazole ornithine (1: 1), molecular formula C
18H
23N
7O
10.C
5H
12N
2O
2
Embodiment eight: the preparation of Glycididazole ornithine enteric coated tablet
Prescription: Glycididazole ornithine 150g
Lactose 35g
Starch 15g
Microcrystalline Cellulose 40g
Magnesium Stearate 2g
With above-mentioned material powder abundant mixing except that Magnesium Stearate, with dehydrated alcohol wetting after, wet granulation, dry whole grain back and add Magnesium Stearate, mixing is pressed into 1000, promptly get the plain sheet of Glycididazole ornithine, plain sheet is wrapped up with enteric coated solution, promptly get Glycididazole ornithine enteric coated tablet, every contains Glycididazole ornithine 150mg.Wherein, enteric coated solution can be selected the dressing solution of following prescription: cellulose acetate-phthalate 10g, stearyl alcohol 4.0g, diethyl phthalate 1.0ml, Virahol 40ml, acetone 45ml for use.
Embodiment nine: the preparation of glycididazole acid Histidine (1: 2)
Get L-Histidine 5 and restrain in the adding 40ml water, add 8 gram glycididazole acids after heating is dissolved it fully again, after fully stirring makes solution clear and bright, smart filter, filtrate is adopted freeze-dry process that it is carried out lyophilize and is got pale yellow powder, i.e. glycididazole acid Histidine (1: 2), molecular formula C
18H
23N
7O
10.2C
6H
9N
3O
2
Claims (10)
1. the compound salt of glycididazole acid and basic aminoacids is characterized in that basic aminoacids comprises arginine, Methionin, ornithine, Histidine.
2. according to claim 1, it is characterized in that compound salt is respectively glycididazole acid arginic acid salt, glycididazole acid lysine salt, glycididazole acid ornithine salt, glycididazole acid Histidine salt.
3. glycididazole acid arginic acid salt according to claim 2 is characterized in that having following molecular structural formula:
The salifiable arginic molecule number of glycididazole acid, the span of a is 0.01～20, preferred a=1.
4. glycididazole acid lysine salt according to claim 2 is characterized in that having following molecular structural formula:
The molecule number of the salifiable Methionin of glycididazole acid, the span of a are 0.01～20, preferred a=1.
5. glycididazole acid ornithine salt according to claim 2 is characterized in that having following molecular structural formula:
The molecule number of the salifiable ornithine of glycididazole acid, the span of a are 0.01～20, preferred a=1.
6. glycididazole acid Histidine salt according to claim 2 is characterized in that having following molecular structural formula:
Wherein a be with
The molecule number of the salifiable Histidine of glycididazole acid, the span of a are 0.01～20, preferred a=2.
7. according to the double salt of any one described glycididazole acid in the claim 3 to 6, its preparation method comprise make glycididazole acid and basic aminoacids contacts salify in liquid environment after, again liquid is removed.
8. according to any one is described in the claim 3 to 6, the alkaline amino acid salt of glycididazole acid also comprises its crystalline hydrate.
9. according to the alkaline amino acid salt of any one described glycididazole acid in the claim 3 to 6, it is characterized in that adopting appropriate pharmaceutical excipient and preparation method, can be made into acceptable pharmaceutical dosage form on any medicine.
10. the compound salt of glycididazole acid and basic aminoacids is used for tumour radiotherapy and chemotherapy and makes the purposes that sensitizer uses.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100919915A CN100560572C (en) | 2004-12-29 | 2004-12-29 | The alkaline amino acid salt of glycididazole acid and preparation thereof and purposes |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100919915A CN100560572C (en) | 2004-12-29 | 2004-12-29 | The alkaline amino acid salt of glycididazole acid and preparation thereof and purposes |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1660817A true CN1660817A (en) | 2005-08-31 |
| CN100560572C CN100560572C (en) | 2009-11-18 |
Family
ID=35010416
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2004100919915A Expired - Fee Related CN100560572C (en) | 2004-12-29 | 2004-12-29 | The alkaline amino acid salt of glycididazole acid and preparation thereof and purposes |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN100560572C (en) |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1270062A (en) * | 1999-04-08 | 2000-10-18 | 广州山河药业股份有限公司 | Glycobiazole metal salt as synergist for radiotherapy or chemicotherapy and its preparing process and application |
-
2004
- 2004-12-29 CN CNB2004100919915A patent/CN100560572C/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CN100560572C (en) | 2009-11-18 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108601791A (en) | Method for crystallising and bioavilability | |
| CN112716936B (en) | Preparation method of puerarin nanoparticles | |
| CN110054624A (en) | Berberine hydrochloride and caffeic acid eutectic object and preparation method and its composition and purposes | |
| CN100451023C (en) | Levo-ornidazole phosphate, preparing process and use thereof | |
| CN101947234A (en) | Preparation method for preparation containing glucosamine and application thereof | |
| CN102906077A (en) | Use of metformin in combination with glucokinase activator and compositions comprising metformin and glucokinase activator | |
| CN103893247A (en) | Pharmaceutical composition as well as preparation method and application thereof | |
| CN110041326A (en) | Berberine hydrochloride and fumaric acid eutectic object and preparation method and its composition and purposes | |
| CN106631957A (en) | Antitumor compound targeting FAP-alpha enzyme and preparation method and application thereof | |
| CN1383815A (en) | Compound prepn of ornithine and asparagic acid for preventing and treating hepatosis and hepatic encephalopathy and its prepn process | |
| CN105055363A (en) | Acotiamide hydrochloride sustained-release drug and preparation method thereof | |
| CN100537593C (en) | Glycyrrhizic acid double salt and preparation thereof | |
| JP3061898B2 (en) | Solid oral ifosfamide pharmaceutical composition and process for its preparation | |
| CN102351722B (en) | L-carnitine compound and composite thereof | |
| CN1939893A (en) | Lysine-ketoprofen and its production | |
| CN1762341A (en) | Salvianolic acid compound for treating cardiovascular and cerebrovascular disease and liver disease, and application thereof | |
| CN100560572C (en) | The alkaline amino acid salt of glycididazole acid and preparation thereof and purposes | |
| WO2020040296A1 (en) | Pegylated boron cluster compound, antitumor agent including pegylated boron cluster compound, and sensitizer including pegylated boron cluster | |
| CN101514189B (en) | Glycin diazole tromethamine compound as well as preparation method and medicament application thereof | |
| CN1903869A (en) | Tibifudine derivative salt and its preparation method and pharmaceutical application | |
| CN1785212A (en) | Novel cinobufogenin freeze-drying powder injection, its prepn. method and quality control method | |
| JPH0859485A (en) | Maillard reaction inhibitor consisting mainly of 3-oxygermylpropionic acid compound | |
| CN1810790A (en) | Non-metal salt of Glicididazole and its prepn | |
| CN113402390B (en) | Aspirin medicine eutectic and preparation method and application thereof | |
| CN115124532B (en) | Rhein and matrine eutectic crystal, preparation method, composition and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| EE01 | Entry into force of recordation of patent licensing contract |
Assignee: Shenzhen Hepalink Pharmaceutical Co., Ltd. Assignor: Yang Xihong Contract record no.: 2011990001119 Denomination of invention: Alkaline amino acid salt of Glycididazole acid, preparation and application Granted publication date: 20091118 License type: Exclusive License Open date: 20050831 Record date: 20111226 |
|
| ASS | Succession or assignment of patent right |
Owner name: SHENZHEN HEPALINK PHARMACEUTICAL CO., LTD. Free format text: FORMER OWNER: YANG XIHONG Effective date: 20120302 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| COR | Change of bibliographic data |
Free format text: CORRECT: ADDRESS; FROM: 721006 BAOJI, SHAANXI PROVINCE TO: 518057 SHENZHEN, GUANGDONG PROVINCE |
|
| TR01 | Transfer of patent right |
Effective date of registration: 20120302 Address after: 518057 Guangdong city of Shenzhen province Nanshan District Pine Hill Lang Road No. 21 Patentee after: Shenzhen Hepalink Pharmaceutical Co., Ltd. Address before: 721006 two sets of Zhao Jia Zhuang, Shigu Town, Weibin District, Shaanxi, Baoji Patentee before: Yang Xihong |
|
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20091118 Termination date: 20151229 |
|
| EXPY | Termination of patent right or utility model |