CN102250066A - Fasudil derivative and preparation method thereof - Google Patents
Fasudil derivative and preparation method thereof Download PDFInfo
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- CN102250066A CN102250066A CN2011100493486A CN201110049348A CN102250066A CN 102250066 A CN102250066 A CN 102250066A CN 2011100493486 A CN2011100493486 A CN 2011100493486A CN 201110049348 A CN201110049348 A CN 201110049348A CN 102250066 A CN102250066 A CN 102250066A
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- fasudil
- derivative
- salt
- pharmaceutical composition
- acid
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- NGOGFTYYXHNFQH-UHFFFAOYSA-N fasudil Chemical class C=1C=CC2=CN=CC=C2C=1S(=O)(=O)N1CCCNCC1 NGOGFTYYXHNFQH-UHFFFAOYSA-N 0.000 title claims abstract description 71
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 229960002435 fasudil Drugs 0.000 claims abstract description 32
- 150000003839 salts Chemical class 0.000 claims abstract description 13
- 239000007800 oxidant agent Substances 0.000 claims abstract description 3
- 230000001590 oxidative effect Effects 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims abstract 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 16
- 239000008194 pharmaceutical composition Substances 0.000 claims description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- 239000000243 solution Substances 0.000 claims description 9
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical group OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 8
- 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 claims description 7
- 229930195725 Mannitol Natural products 0.000 claims description 7
- ZBIKORITPGTTGI-UHFFFAOYSA-N [acetyloxy(phenyl)-$l^{3}-iodanyl] acetate Chemical compound CC(=O)OI(OC(C)=O)C1=CC=CC=C1 ZBIKORITPGTTGI-UHFFFAOYSA-N 0.000 claims description 7
- 239000000594 mannitol Substances 0.000 claims description 7
- 235000010355 mannitol Nutrition 0.000 claims description 7
- MEIRRNXMZYDVDW-MQQKCMAXSA-N (2E,4E)-2,4-hexadien-1-ol Chemical compound C\C=C\C=C\CO MEIRRNXMZYDVDW-MQQKCMAXSA-N 0.000 claims description 6
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 6
- 239000008215 water for injection Substances 0.000 claims description 6
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 claims description 4
- 238000006243 chemical reaction Methods 0.000 claims description 4
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims 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 claims description 3
- 239000004471 Glycine Substances 0.000 claims description 3
- 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 claims description 3
- 239000008103 glucose Substances 0.000 claims description 3
- LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 229940124531 pharmaceutical excipient Drugs 0.000 claims description 3
- FIYYMXYOBLWYQO-UHFFFAOYSA-N ortho-iodylbenzoic acid Chemical compound OC(=O)C1=CC=CC=C1I(=O)=O FIYYMXYOBLWYQO-UHFFFAOYSA-N 0.000 claims description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims 1
- 150000003016 phosphoric acids Chemical class 0.000 claims 1
- 229950004288 tosilate Drugs 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 12
- 239000012535 impurity Substances 0.000 abstract description 5
- 238000001514 detection method Methods 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 4
- 230000003647 oxidation Effects 0.000 abstract description 4
- 238000007254 oxidation reaction Methods 0.000 abstract description 4
- 238000004458 analytical method Methods 0.000 abstract description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 11
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 5
- 230000014759 maintenance of location Effects 0.000 description 5
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000000523 sample Substances 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 3
- 229920000747 poly(lactic acid) Polymers 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Natural products CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- -1 poly(lactic acid) Polymers 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000012488 sample solution Substances 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical class [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 235000019890 Amylum Nutrition 0.000 description 1
- 201000006474 Brain Ischemia Diseases 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 206010008120 Cerebral ischaemia Diseases 0.000 description 1
- 206010008190 Cerebrovascular accident Diseases 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 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
- 102000016349 Myosin Light Chains Human genes 0.000 description 1
- 108010067385 Myosin Light Chains Proteins 0.000 description 1
- VTIUKEAFYDHRHB-UHFFFAOYSA-N NO.N1CCNCC1 Chemical compound NO.N1CCNCC1 VTIUKEAFYDHRHB-UHFFFAOYSA-N 0.000 description 1
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 239000004141 Sodium laurylsulphate Substances 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 208000032851 Subarachnoid Hemorrhage Diseases 0.000 description 1
- 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 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 208000001286 intracranial vasospasm Diseases 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000000463 material Substances 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
- 238000012544 monitoring process Methods 0.000 description 1
- 210000002464 muscle smooth vascular Anatomy 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 229960000502 poloxamer Drugs 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229950008882 polysorbate Drugs 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 239000001253 polyvinylpolypyrrolidone Substances 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 229960001866 silicon dioxide Drugs 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 230000016160 smooth muscle contraction Effects 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
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Abstract
The invention discloses a fasudil derivative and a preparation method thereof. The fasudil derivative I is an oxidation product of fasudil, and is one of the main impurities of fasudil medicaments or preparations thereof. I is applicable to the analysis and detection of fasudil purity, and can be used to control the quality of fasudil. The invention discloses a method for preparing the derivative I which is prepared by fasudil or its salts under the action of an oxidant. The invention also discloses a fasudil composition with an I content of not more than 5%, and the composition can be used to prepare a fasudil medicinal preparation with high quality.
Description
Technical field
The invention belongs to biomedicine field, be specifically related to a kind of fasudil derivative and preparation method thereof, also related to a kind of pharmaceutical composition that contains the aforementioned fasudil derivative of minute quantity.
Background technology
Fasudil is the medicine of a kind of prevention and treatment cerebral apoplexy, fasudil can suppress the myosin light chain phosphorylation of smooth muscle contraction terminal stage, make the vascular smooth muscle diastole, vasodilation can be used for improving and prevents the cerebral vasospasm of subarachnoid hemorrhage postoperative and the symptoms of cerebral ischemia that thereupon causes.
Discover that fasudil or its salt are unstable in solution or air, the solution of fasudil hydrochloride or mesylate is carried out the HPLC analysis and research, find that high polar impurity can appear in solution.Yet which kind of impurity unexposed this impurity of document is at present, also unknown its concrete structure.
Have bibliographical information the compound of piperazine or high piperazine structure to be arranged because the relation of structure is easily oxidized, existing bibliographical information piperazine after the oxidation of hydrogen peroxide, can make the piperazine azanol.
Summary of the invention
The present invention has disclosed a kind of fasudil derivative I first by research, and I is shown below:
Compound shown in the above-mentioned formula I is the product after the oxidation of fasudil, is solution high polar impurity in the solution after oxidation of fasudil salt through structural confirmation and mass analysis checking I.
The fasudil derivative I can form pharmacy acceptable salt with acid, and described acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, methylsulfonic acid, tosic acid and trifluoroacetic acid, preferred hydrochloric acid or methylsulfonic acid.
The invention provides a kind of preparation method of fasudil derivative I; fasudil or its salt and oxidant reaction are made; described oxygenant is selected from hydrogen peroxide, metachloroperbenzoic acid, Peracetic Acid, 2-iodoxy phenylformic acid and iodobenzene diacetate, preferred iodobenzene diacetate.Use hydrogen peroxide and metachloroperbenzoic acid yield low, the product of acquisition is less, improves a lot with the yield of iodobenzene diacetate as oxygenant, and product is more easily separated.
The fasudil derivative I can be used for further preparing the derivative of other fasudil, also can be used for monitoring or controlling the quality of fasudil or its salt and medicament thereof.
The present invention also provides a kind of pharmaceutical composition, contains fasudil or its salt and pharmaceutical excipient, and described pharmaceutical composition contains the fasudil derivative I and is no more than 5%, preferably is no more than 1%, is most preferably not exceeding 0.5%.
Described fasudil salt is selected from hydrochloric acid, sulfuric acid, phosphoric acid, methylsulfonic acid, tosic acid and trifluoroacetic acid, preferred hydrochloric acid or methylsulfonic acid.
Described pharmaceutical composition can or be a liquid composition for solids composition, preferred liquid composition, and fasudil or its salt are soluble in water, and preparation is convenient.Pharmaceutical excipient can be auxiliary material commonly used on the technology of pharmaceutics, thinner as is known to the person skilled in the art, lubricant, tackiness agent etc., for example tween-80, polysorbate, lipid acid sorb are smooth, sodium lauryl sulphate, poloxamer, phosphatide, polyoxyethylenated castor oil, water for injection, poly(lactic acid) (PLA), polylactic acid poly ethanol copolymer (PLGA), N.F,USP MANNITOL, glycine, glucose, lactose, starch, sodium starch glycolate, polyvinylpolypyrrolidone, croscarmellose sodium, Microcrystalline Cellulose, amylum pregelatinisatum, silicon-dioxide etc.
The fasudil derivative I is no more than 5% in the above-mentioned fasudil pharmaceutical composition, and composition quality is stable, and during with the preparation of compositions pharmaceutical preparation, stablizing of said preparation is beneficial to safe medication.
The invention provides a kind of pharmaceutical composition, contain fasudil salt 1～10%, vehicle 3～50%, all the other are water for injection.Described vehicle is selected from N.F,USP MANNITOL, glucose, sorbyl alcohol glycine, preferred N.F,USP MANNITOL or sorbyl alcohol, and the pH of described solution is 3～7, and is preferred 3.5～5.0, contains the fasudil derivative in the described composition and is no more than 5%, preferably is no more than 1%.Described fasudil salt preferably salt hydrochlorate or mesylate.
Description of drawings
Fig. 1 is the HPLC figure of embodiment 3 fasudil derivative Is.
Fig. 2 is the HPLC figure of embodiment 3 methylsulfonic acid fasudils.
Fig. 3 is the HPLC figure of embodiment 3 fasudil derivative Is and methylsulfonic acid fasudil biased sample.
Embodiment
The preparation one of embodiment 1 fasudil derivative I
Get 5g(0.013mol) the methylsulfonic acid fasudil is dissolved in the 50mL water disposable adding 8.31g(0.026mol) iodobenzene diacetate, stirring at room 1.5h, filter, filter residue 50mL water washing, filtrate is yellow-green colour, adds an amount of saturated sodium sulfite cancellation reaction in filtrate.Solution concentration after the cancellation to doing, is obtained the 0.7g white solid through column chromatography, be the fasudil derivative I.
MS(m/z)：308（M+H）
+。
1H?NMR?(400?MHz,?DMSO)：?δ?11.70?(d,?J?=?5.3?Hz,?1H),?8.96?(s,?2H),?8.47?(d,?J?=?7.8?Hz,?1H),?8.16?(dd,?J?=?7.7,?1.2?Hz,?1H),?7.60?(t,?J?=?7.9?Hz,?1H),?7.36?(dd,?J?=?7.4,?6.0?Hz,?1H),?7.05?(d,?J?=?7.5?Hz,?1H),?3.64-3.54?(m,?2H),?3.42?(t,?J?=?6.0?Hz,?3H),?3.17?(d,?J?=?4.3?Hz,?4H),?2.03-?1.91?(m,?2H)。
The preparation two of embodiment 2 fasudil derivative Is
Get the 5g Fasudil Hydrochloride and be dissolved in the 50mL water, disposable adding 7.5g iodobenzene diacetate, stirring at room 1.5h filters, filter residue 50mL water washing, filtrate is yellow-green colour, adds an amount of saturated sodium sulfite cancellation reaction in filtrate.Solution concentration after the cancellation to doing, is obtained the 0.5g white solid through column chromatography, be the fasudil derivative I.
MS(m/z)：308（M+H）
+。
The separation detection of embodiment 3 fasudil derivative Is
The HPLC condition:
With octadecylsilane chemically bonded silica is weighting agent (end group sealing, BDS post); With 0.18 mol/L primary ammonium phosphate-methyl alcohol-triethylamine-phosphoric acid (85:15:0.5:0.1) is moving phase, measures wavelength 274 nm, flow velocity 0.80 mL/min, and theoretical plate number is calculated by methylsulfonic acid fasudil peak should be not less than 4000.
Get the methylsulfonic acid fasudil respectively and the fasudil derivative I is an amount of, use distilled water diluting, be mixed with the 0.2mg/mL sample solution, respectively get 20uL and inject sample introduction, separation detection under above HPLC condition.
It is an amount of to get the methylsulfonic acid fasudil, adds an amount of fasudil derivative I, uses distilled water diluting, and preparation is got 20uL and injected sample introduction, separation detection under above HPLC condition into about the biased sample solution of 0.2mg/mL.
Analytical results: the HPLC of fasudil derivative I schemes as shown in Figure 1, and the peak of retention time 4.946 is the fasudil derivative I.The HPLC of methylsulfonic acid fasudil figure as shown in Figure 2, retention time is that 4.942 peak is the fasudil derivative I, the peak of retention time 8.450 is a fasudil.In the HPLC of biased sample figure, the peak of retention time 4.939 is the fasudil derivative I, and the peak of retention time 8.434 is a fasudil.
Embodiment 4-7 fasudil preparation of compositions
The according to the form below prescription is got fasudil salt, N.F,USP MANNITOL or sorbyl alcohol, with being diluted to 1000mL after an amount of dissolving of water for injection, regulate the pH scope shown in pH to the embodiment 4-7 with sodium hydroxide or hydrochloric acid, analysis HPLC condition with embodiment 3, each composition of analyzing and testing is with the content of external standard method calculating fasudil derivative I.
Preparation of compositions:
Take by weighing Fasudil Hydrochloride or methylsulfonic acid fasudil, add N.F,USP MANNITOL or sorbyl alcohol,, add the proper amount of active carbon decolouring, be diluted to volume 1000mL with water for injection again, promptly make composition with water for injection 700～900mL dissolving, adjust pH.
Claims (10)
1. a fasudil derivative I or its pharmacy acceptable salt, I is shown below:
2. fasudil derivative I pharmacy acceptable salt according to claim 1 is characterized in that described pharmacy acceptable salt is selected from hydrochloride, vitriol, phosphoric acid salt, mesylate, tosilate, trifluoroacetate.
3. the preparation method of a fasudil derivative I is characterized in that and will make behind fasudil or its salt and the oxidant reaction that described oxygenant is selected from hydrogen peroxide, metachloroperbenzoic acid, Peracetic Acid, 2-iodoxy phenylformic acid and iodobenzene diacetate.
4. method according to claim 3 is characterized in that described oxygenant is an iodobenzene diacetate.
5. method according to claim 3 is characterized in that described fasudil salt is hydrochloride or mesylate.
6. a pharmaceutical composition contains fasudil or its salt and pharmaceutical excipient, it is characterized in that described pharmaceutical composition contains the fasudil derivative I and is no more than 5%.
7. pharmaceutical composition according to claim 6 is characterized in that described pharmaceutical composition contains the fasudil derivative I and is no more than 1%.
8. according to claim 6 or 7 described pharmaceutical compositions, it is characterized in that containing fasudil salt 1～10%, vehicle 3～50%, all the other are water for injection, and described vehicle is selected from N.F,USP MANNITOL, glucose, sorbyl alcohol glycine, and the pH of described solution is 3～7.
9. pharmaceutical composition according to claim 8 is characterized in that described vehicle is N.F,USP MANNITOL or sorbyl alcohol.
10. pharmaceutical composition according to claim 8 is characterized in that described pH is 3.5～5.0.
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|---|---|---|---|
| CN 201110049348 CN102250066B (en) | 2011-03-02 | 2011-03-02 | Fasudil derivative and preparation method thereof |
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| CN 201110049348 CN102250066B (en) | 2011-03-02 | 2011-03-02 | Fasudil derivative and preparation method thereof |
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| CN102250066B CN102250066B (en) | 2013-05-01 |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107987059A (en) * | 2018-01-09 | 2018-05-04 | 深圳市祥根生物科技有限公司 | The preparation method of Fasudil impurity I |
| CN108593831A (en) * | 2018-05-08 | 2018-09-28 | 山东新华制药股份有限公司 | HPLC detection method of the Fasudic hydrochloride in relation to substance |
| CN111440150A (en) * | 2020-05-12 | 2020-07-24 | 中国药科大学 | Nitric oxide donor type fasudil derivative and preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005087237A1 (en) * | 2004-03-16 | 2005-09-22 | Asahi Kasei Pharma Corporation | Fasudil-containing preparation and method of improving stability thereof |
| CN101812051A (en) * | 2010-01-25 | 2010-08-25 | 海南美兰史克制药有限公司 | High purity fasudil hydrochloride compound |
-
2011
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005087237A1 (en) * | 2004-03-16 | 2005-09-22 | Asahi Kasei Pharma Corporation | Fasudil-containing preparation and method of improving stability thereof |
| CN101812051A (en) * | 2010-01-25 | 2010-08-25 | 海南美兰史克制药有限公司 | High purity fasudil hydrochloride compound |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107987059A (en) * | 2018-01-09 | 2018-05-04 | 深圳市祥根生物科技有限公司 | The preparation method of Fasudil impurity I |
| CN108593831A (en) * | 2018-05-08 | 2018-09-28 | 山东新华制药股份有限公司 | HPLC detection method of the Fasudic hydrochloride in relation to substance |
| CN108593831B (en) * | 2018-05-08 | 2020-05-19 | 山东新华制药股份有限公司 | HPLC detection method of fasudil hydrochloride related substances |
| CN111440150A (en) * | 2020-05-12 | 2020-07-24 | 中国药科大学 | Nitric oxide donor type fasudil derivative and preparation method and application thereof |
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| CN102250066B (en) | 2013-05-01 |
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Application publication date: 20111123 Assignee: WUHAN ZHONGYOU PHARMACEUTICAL Co.,Ltd. Assignor: SHANGHAI MEIYUE BIOTECH DEVELOPMENT Co.,Ltd.|WUHAN QR PHARMACEUTICALS Co.,Ltd. Contract record no.: 2014420000081 Denomination of invention: Fasudil derivative and preparation method thereof Granted publication date: 20130501 License type: Exclusive License Record date: 20140529 |
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