WO2014180264A1 - 磷苯妥英稳定的有机胺盐及其制备方法和用途 - Google Patents
磷苯妥英稳定的有机胺盐及其制备方法和用途 Download PDFInfo
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- WO2014180264A1 WO2014180264A1 PCT/CN2014/076326 CN2014076326W WO2014180264A1 WO 2014180264 A1 WO2014180264 A1 WO 2014180264A1 CN 2014076326 W CN2014076326 W CN 2014076326W WO 2014180264 A1 WO2014180264 A1 WO 2014180264A1
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- WO
- WIPO (PCT)
- Prior art keywords
- organic amine
- methyl
- diphenyl
- injection
- fosphenytoin
- Prior art date
Links
- -1 amine salt Chemical class 0.000 title claims abstract description 22
- 229960000693 fosphenytoin Drugs 0.000 title claims abstract 9
- XWLUWCNOOVRFPX-UHFFFAOYSA-N Fosphenytoin Chemical compound O=C1N(COP(O)(=O)O)C(=O)NC1(C=1C=CC=CC=1)C1=CC=CC=C1 XWLUWCNOOVRFPX-UHFFFAOYSA-N 0.000 title claims abstract 7
- 238000002360 preparation method Methods 0.000 title abstract description 30
- 206010015037 epilepsy Diseases 0.000 claims abstract description 6
- 208000024891 symptom Diseases 0.000 claims abstract description 5
- 208000005392 Spasm Diseases 0.000 claims abstract 2
- 230000002920 convulsive effect Effects 0.000 claims abstract 2
- 229960002036 phenytoin Drugs 0.000 claims description 46
- CXOFVDLJLONNDW-UHFFFAOYSA-N Phenytoin Chemical compound N1C(=O)NC(=O)C1(C=1C=CC=CC=1)C1=CC=CC=C1 CXOFVDLJLONNDW-UHFFFAOYSA-N 0.000 claims description 45
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- 238000002347 injection Methods 0.000 claims description 24
- 239000007924 injection Substances 0.000 claims description 24
- LDDMACCNBZAMSG-BDVNFPICSA-N (2r,3r,4s,5r)-3,4,5,6-tetrahydroxy-2-(methylamino)hexanal Chemical compound CN[C@@H](C=O)[C@@H](O)[C@H](O)[C@H](O)CO LDDMACCNBZAMSG-BDVNFPICSA-N 0.000 claims description 18
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 claims description 17
- 229960000281 trometamol Drugs 0.000 claims description 17
- 239000007788 liquid Substances 0.000 claims description 13
- 239000000843 powder Substances 0.000 claims description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- 150000001412 amines Chemical class 0.000 claims description 8
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 7
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 claims description 7
- UJBWLABLIXXPAL-UHFFFAOYSA-N 2,2,2-trichloro-N-(2,5-dioxo-4,4-diphenylimidazolidin-1-yl)-N-methylacetamide Chemical compound O=C1N(C(C(N1)(C1=CC=CC=C1)C1=CC=CC=C1)=O)N(C(C(Cl)(Cl)Cl)=O)C UJBWLABLIXXPAL-UHFFFAOYSA-N 0.000 claims description 6
- QQBKLRXLVRDKEB-UHFFFAOYSA-N 3-(hydroxymethyl)-5,5-diphenylimidazolidine-2,4-dione Chemical compound O=C1N(CO)C(=O)NC1(C=1C=CC=CC=1)C1=CC=CC=C1 QQBKLRXLVRDKEB-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 claims description 4
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- DRUIESSIVFYOMK-UHFFFAOYSA-N Trichloroacetonitrile Chemical compound ClC(Cl)(Cl)C#N DRUIESSIVFYOMK-UHFFFAOYSA-N 0.000 claims description 3
- HDFFVHSMHLDSLO-UHFFFAOYSA-M dibenzyl phosphate Chemical compound C=1C=CC=CC=1COP(=O)([O-])OCC1=CC=CC=C1 HDFFVHSMHLDSLO-UHFFFAOYSA-M 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 239000004475 Arginine Substances 0.000 claims description 2
- 229910015900 BF3 Inorganic materials 0.000 claims description 2
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 2
- 239000005977 Ethylene Substances 0.000 claims description 2
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims description 2
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims description 2
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims description 2
- 239000004472 Lysine Substances 0.000 claims description 2
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 238000005984 hydrogenation reaction Methods 0.000 claims description 2
- NTNWKDHZTDQSST-UHFFFAOYSA-N naphthalene-1,2-diamine Chemical compound C1=CC=CC2=C(N)C(N)=CC=C21 NTNWKDHZTDQSST-UHFFFAOYSA-N 0.000 claims description 2
- 239000012453 solvate Substances 0.000 claims description 2
- GODZNYBQGNSJJN-UHFFFAOYSA-N 1-aminoethane-1,2-diol Chemical compound NC(O)CO GODZNYBQGNSJJN-UHFFFAOYSA-N 0.000 claims 1
- 239000004480 active ingredient Substances 0.000 claims 1
- 150000004677 hydrates Chemical class 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 32
- 238000005352 clarification Methods 0.000 description 23
- 229940090044 injection Drugs 0.000 description 19
- 239000000243 solution Substances 0.000 description 17
- 238000003756 stirring Methods 0.000 description 17
- 239000008215 water for injection Substances 0.000 description 15
- 206010010904 Convulsion Diseases 0.000 description 11
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- 239000001961 anticonvulsive agent Substances 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- 239000002245 particle Substances 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 230000008018 melting Effects 0.000 description 6
- 238000002844 melting Methods 0.000 description 6
- 229940024807 phenytoin injection Drugs 0.000 description 6
- 239000012982 microporous membrane Substances 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 4
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 229960002790 phenytoin sodium Drugs 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- FJPYVLNWWICYDW-UHFFFAOYSA-M sodium;5,5-diphenylimidazolidin-1-ide-2,4-dione Chemical compound [Na+].O=C1[N-]C(=O)NC1(C=1C=CC=CC=1)C1=CC=CC=C1 FJPYVLNWWICYDW-UHFFFAOYSA-M 0.000 description 4
- 238000003860 storage Methods 0.000 description 4
- 238000005261 decarburization Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000010255 intramuscular injection Methods 0.000 description 3
- 239000007927 intramuscular injection Substances 0.000 description 3
- 239000008176 lyophilized powder Substances 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 206010001497 Agitation Diseases 0.000 description 2
- 239000005909 Kieselgur Substances 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- 229910000577 Silicon-germanium Inorganic materials 0.000 description 2
- LEVVHYCKPQWKOP-UHFFFAOYSA-N [Si].[Ge] Chemical group [Si].[Ge] LEVVHYCKPQWKOP-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 229960000623 carbamazepine Drugs 0.000 description 2
- FFGPTBGBLSHEPO-UHFFFAOYSA-N carbamazepine Chemical compound C1=CC2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 FFGPTBGBLSHEPO-UHFFFAOYSA-N 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 239000008367 deionised water Substances 0.000 description 2
- 229910021641 deionized water Inorganic materials 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000005108 dry cleaning Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- COTNUBDHGSIOTA-UHFFFAOYSA-N meoh methanol Chemical compound OC.OC COTNUBDHGSIOTA-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 229960002695 phenobarbital Drugs 0.000 description 2
- DDBREPKUVSBGFI-UHFFFAOYSA-N phenobarbital Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NC(=O)NC1=O DDBREPKUVSBGFI-UHFFFAOYSA-N 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
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- OGNSCSPNOLGXSM-UHFFFAOYSA-N (+/-)-DABA Natural products NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- MSWZFWKMSRAUBD-IVMDWMLBSA-N 2-amino-2-deoxy-D-glucopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-IVMDWMLBSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 1
- AHCDZZIXAMDCBJ-UHFFFAOYSA-N CCC[Na] Chemical compound CCC[Na] AHCDZZIXAMDCBJ-UHFFFAOYSA-N 0.000 description 1
- 208000021965 Glossopharyngeal Nerve disease Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 206010024264 Lethargy Diseases 0.000 description 1
- 206010036790 Productive cough Diseases 0.000 description 1
- 208000037012 Psychomotor seizures Diseases 0.000 description 1
- 208000008765 Sciatica Diseases 0.000 description 1
- 206010041235 Snoring Diseases 0.000 description 1
- 208000003443 Unconsciousness Diseases 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- FELMSRDKUFGXSF-UHFFFAOYSA-L [Na+].[Na+].P(=O)([O-])([O-])O.OCN1C(NC(C1=O)(C1=CC=CC=C1)C1=CC=CC=C1)=O Chemical compound [Na+].[Na+].P(=O)([O-])([O-])O.OCN1C(NC(C1=O)(C1=CC=CC=C1)C1=CC=CC=C1)=O FELMSRDKUFGXSF-UHFFFAOYSA-L 0.000 description 1
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 238000011047 acute toxicity test Methods 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000003556 anti-epileptic effect Effects 0.000 description 1
- 229960003965 antiepileptics Drugs 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 210000004958 brain cell Anatomy 0.000 description 1
- 230000005978 brain dysfunction Effects 0.000 description 1
- 210000005013 brain tissue Anatomy 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 230000036461 convulsion Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- NIJJYAXOARWZEE-UHFFFAOYSA-N di-n-propyl-acetic acid Natural products CCCC(C(O)=O)CCC NIJJYAXOARWZEE-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- GQPXYJNXTAFDLT-UHFFFAOYSA-L disodium;(2,5-dioxo-4,4-diphenylimidazolidin-1-yl)methyl phosphate Chemical compound [Na+].[Na+].O=C1N(COP([O-])(=O)[O-])C(=O)NC1(C=1C=CC=CC=1)C1=CC=CC=C1 GQPXYJNXTAFDLT-UHFFFAOYSA-L 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000008098 formaldehyde solution Substances 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 1
- 201000005442 glossopharyngeal neuralgia Diseases 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
- 238000009776 industrial production Methods 0.000 description 1
- 230000004941 influx Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 230000001314 paroxysmal effect Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 238000006303 photolysis reaction Methods 0.000 description 1
- 230000015843 photosynthesis, light reaction Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000000284 resting effect Effects 0.000 description 1
- 238000005096 rolling process Methods 0.000 description 1
- AEQFSUDEHCCHBT-UHFFFAOYSA-M sodium valproate Chemical compound [Na+].CCCC(C([O-])=O)CCC AEQFSUDEHCCHBT-UHFFFAOYSA-M 0.000 description 1
- 229940084026 sodium valproate Drugs 0.000 description 1
- 208000024794 sputum Diseases 0.000 description 1
- 210000003802 sputum Anatomy 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 231100000901 systemic toxic effect Toxicity 0.000 description 1
- 231100000378 teratogenic Toxicity 0.000 description 1
- 230000003390 teratogenic effect Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 206010044652 trigeminal neuralgia Diseases 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 210000004885 white matter Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C215/04—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated
- C07C215/06—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic
- C07C215/10—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and acyclic with one amino group and at least two hydroxy groups bound to the carbon skeleton
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
- C07F9/6503—Five-membered rings
- C07F9/6506—Five-membered rings having the nitrogen atoms in positions 1 and 3
Definitions
- the invention relates to the field of medicines of compounds, in particular to an organic salt of phenytoin, and a preparation method of the phenytoin organic amine salt, a sputum symptom for controlling a patient with primary epilepsy, and the use of preventing and treating convulsions in neurosurgery .
- Background technique
- Anti-epileptic drugs are used to prevent and treat paroxysmal or transient brain dysfunction caused by epileptic seizures, but currently used anti-epileptic drugs are ineffective in about 25 to 30% of patients, and appear in the treatment of diseases. Systemic toxic effects, epilepsy, teratogenic risk, and adverse effects associated with dose.
- Antiepileptic drugs can eliminate or alleviate seizures in two ways. One is to affect central neurons to prevent or reduce their pathological transitional discharges; the other is to increase the threshold of excitability of normal brain tissue and reduce the spread of excitability. Prevent recurrence of epilepsy.
- Antiepileptic drugs synthesized before the 1960s such as: phenytoin, carbamazepine, ethosuxamine, sodium valproate, etc., are called old antiepileptic drugs, of which phenobarbital, phenytoin, carbamazepine, and propyl Sodium is a first-line anti-epileptic drug widely used at present.
- Phenytoin (Dalendin): strong effect; high curative effect; preferred for large seizures, followed by psychomotor seizures, and also effective for localized seizures, but ineffective or even worse for small seizures; no lethargy; safety The scope is large; the effect is slow, oral usually takes 3 to 4 days to be effective, used to prevent seizures and maintain treatment; while the symptoms are controlled by phenobarbital. Phenytoin inhibits Na+ influx, which increases the negative resting potential of the cell, increases the distance from the threshold potential, increases the threshold of brain cells, stabilizes the membrane potential, and prevents the spread of lesion discharge. It also increases the content of the inhibitory transmitter ⁇ -aminobutyric acid in the brain, which is also related to its antiepileptic effect. Phenytoin has an analgesic effect on trigeminal neuralgia, sciatica and glossopharyngeal neuralgia.
- Phosphenytoin is a phosphate prodrug of phenytoin, developed by Warner-Lambert, listed in the US in 1996, and listed in the UK and France in 1999. It is the world's first approved phenytoin sodium prodrug. It can be administered intravenously or intramuscularly to treat episodes of epileptic seizures, prevent and treat seizures in neurosurgery, and is effective, safe and tolerable. It can completely replace phenytoin, and broaden its clinical indications and improve the medical care for acute development.
- Phosphenytoin is 3-hydroxymethyl-5,5-diphenylhydantoin disodium phosphate.
- the drug is a white or light yellow crystalline powder with a solubility of 7.4 x 10 mg/ml in water at 37 °C.
- the melting point is about 237 ° C, and its structural formula is as follows: Instruction manual
- phenytoin injection can be injected intramuscularly.
- Rapid intramuscular injection of phenytoin injection in these patients can maintain the concentration of anti-epileptic drugs in patients and reduce the risk of their onset.
- phenytoin is a water injection with a specification of 50 mg/ml.
- normal temperature and strong light irradiation have a significant impact on the stability of phenytoin injection, so the temperature required in the preparation process should be lower than 25 V, need to be stored at 2 ⁇ 8 ° C, while storage It is also prone to fine precipitation and should not be placed at room temperature for more than 48 hours to prevent hydrolysis or photolysis.
- These special requirements are not conducive to large-scale industrial production, but also cause inconvenience in storage and transportation, which limits the promotion and application of drugs.
- Phosphenytoin injection can easily produce two toxic impurities such as 2,2-biphenylaminoacetic acid and phenytoin during storage at 2 ⁇ 8 °C.
- the structural formula is as follows, which poses a great safety hazard for clinical use. .
- the object of the present invention is to remedy the deficiencies in the prior art and to provide a stable phenytoin organic amine salt and a preparation method and use thereof.
- M is a pharmaceutically acceptable organic amine adjusted to the charge balance according to the number of organic amines.
- the phosphorus phenytoin-stabilized organic amine salt wherein the organic amine refers to N-methyl-D-glucosamine, tromethamine, lysine, arginine, ethanolamine, ethylene Alcoholamine, ethylenediamine, naphthalene diamine.
- the phosphorus phenytoin-stabilized organic amine salt refers to phenytoin N-methyl-D-glucosamine salt, phenytoin tromethamine salt, and has the following structural formula:
- the process flow for preparing the present invention is:
- a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a formula of the invention
- the salt of the formula (I) of the present invention may be formulated into an injection solution, a sterile powder for injection or a lyophilized powder for injection by adding a suitable excipient.
- a fourth aspect of the present invention there is provided the use of the inventive pharmaceutical composition for controlling snoring symptoms in a patient with primary epilepsy, preventing and treating seizures during neurosurgery
- the column is an 18-inch silicon germanium bonded silica gel column (Shimpack, CLC-ODS, 150mm X 4.6 mm, 5 ⁇ m); the mobile phase is 0.01 mol/U 1 disodium hydrogen phosphate solution (weighed disodium hydrogen phosphate) 3.58 g Add 1000 ml of water to dissolve, adjust pH to 3.0) with methanol - methanol (55: 45); detection wavelength is 215 nm; flow rate is 1.0 ml/min_ injection volume is 20 ⁇ l. The number of theoretical plates is not less than 3,000 based on the peak of phenytoin.
- the column is an 18-inch silicon germanium bonded silica gel column (Shimpack, CLC-ODS, 150mm X 4.6 mm, 5 ⁇ m); the mobile phase is 0.01 mol/U 1 disodium hydrogen phosphate solution (weighed disodium hydrogen phosphate) 3.58 g Add 1000 ml of water to dissolve, adjust pH to 3.0) with methanol - methanol (55: 45); detection wavelength is 215 nm; flow rate is 1.0 ml/min_ injection volume is 20 ⁇ l. The number of theoretical plates is not less than 3,000 based on the peak of phenytoin.
- Example 4 Preparation of aseptic powder of phenytoin and tromethamine for injection
- phenytoin N-methyl-D-glucosamine aseptic powder of solvent crystal was prepared in a sterile GMP workshop and packed by a screw dispenser. The volume of each bottle was 1.102g, which was stoppered, rolled and packaged. Sterile powder of phenytoin and tromethamine for injection.
- Example 5 Preparation of phenytoin for injection N-methyl-D-glucosamine freeze-dried powder needle
- the water temperature is controlled at 651 ⁇ 51, add 1102g of phenytoin tromethamine, stir well until all dissolved, determine the pH value, the pH value is 8.79, add activated carbon 3g, 65 ° C ⁇ 5 ° C, stirring for 30 min, suction decarburization, adding water for injection to the full amount, sterilizing and filtering with 0.22 ⁇ ⁇ microporous membrane filter, after determining the intermediate content, the solution is dispensed into a 10 ml size vial Medium, each bottle is 5ml.
- the prepared vial filled with phenytoin was placed in a lyophilization box, and then the temperature in the lyophilizer was lowered to below 45 ° C within 2 h to allow rapid freezing. Vacuum the inside air pressure to 2. 66pa in 30min. The temperature is programmed to dry at a temperature of -45 ° C to 30 ° C. After drying, the plug is garnished and rolled to obtain a lyophilized powder for injection of phenytoin.
- the water temperature is controlled at 65 ° ⁇ ⁇ 5 ° ⁇ , add 1362 g of phenytoin N-methyl-D-glucosamine, stir well until all dissolved, determine the pH value, pH value at this time 8.93, adding 6g of activated carbon to the needle, 65 °C ⁇ 5 °C, stirring for 30min, degumming by suction filtration, adding water for injection to the whole amount, sterilizing and filtering with 0.22 ⁇ ⁇ microporous membrane, after determining the content of the intermediate, The solution was aseptically dispensed into a 10 ml vial of 10 ml bottle, and the amount of each bottle was 10 ml. The plug was garnished and capped to obtain a phenytoin N-methyl-D-glucosamine injection.
- the water temperature is controlled at 651 ⁇ 51, add 1102g of phenytoin tromethamine, stir well until all dissolved, determine the pH value, the pH value is 8.80, add 6g of activated carbon for needle, 65 ° C ⁇ 5 ° C, stirring for 30 min, filter decarburization, add water for injection to the full amount, sterilize and filter with 0.22 ⁇ ⁇ microporous membrane filter, determine the intermediate content after passing, the solution is aseptically dispensed in 10ml specification In the vial, the amount of each bottle is 10ml, and the plug is garnished and rolled to obtain phenytoin tromethamine injection.
- the samples prepared according to Examples 3 to 9 were placed at a temperature of 40 ° C ⁇ 2 ° C and a relative humidity of 75% ⁇ 5%, and the relevant indexes were measured at 1, 2, 3, and 6 months. See the table below for the results.
- Example 3 and Example 4 of the present invention are quite stable, the preparations of Examples 5 and 6 are stable, the preparations of Examples 7 and 8 are relatively stable, and Example 9 is unstable. .
- Example 11 Physicochemical parameters test and acute toxicity test results of the example compounds Description
- Example 1 -1.01 ⁇ -2.53 8.6-8.9 83 mg/ml 175°C ⁇ 182°C 982
- Example 2 -1.23 ⁇ - 2.17 8.5-8.7 80 mg/ml 190°C ⁇ 195°C 657
- Phosphate Phenytoin- 1.10 ⁇ - 3.06 8.3-8.9 74 mg/ml approximately 237 °C 234
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Abstract
本发明涉及一种稳定的磷苯妥英有机胺盐及其制备方法和用途,涉及的磷苯妥英有机胺盐的结构通式如通式(I)所示,用于控制原发性癫痫病人的痉挛症状,预防并治疗神经外科手术中惊厥发作的用途。
Description
i ^ 磷苯妥英稳定的有机胺盐及其制备方法和用途 技术领域
本发明涉及化合物的医药领域, 具体涉及磷苯妥英的有机盐,及该磷苯妥英有机胺盐的制 备方法与用于控制原发性癫痫病人的痉挛症状, 预防并治疗神经外科手术中惊厥发作的用途。 背景技术
抗癫痫药物是预防和治疗由癫痫病发作引起的阵发性或暂时性脑功能失调,但目前临床上 使用的抗癫痫药物对约 25〜30%的病人无效, 并在治疗疾病的同时, 出现全身性的毒性作用、 致痫作用、 致畸风险及与剂量呈正相关的不良反应等。
在癫痫发作的治疗中,抗癫痫药物有特殊重要的意义。抗癫痫药物可通过两种方式来消除 或减轻癫痫发作, 一是影响中枢神经元, 以防止或减少他们的病理性过渡放电; 其二是提高正 常脑组织的兴奋阈, 减弱病灶兴奋的扩散, 防止癫痫复发。 一般将 60年代前合成的抗癫痫药 如: 苯妥英钠、 卡马西平、 乙琥胺、 丙戊酸钠等称为老抗癫痫药, 其中苯巴比妥、 苯妥英钠、 卡马西平、 丙戊酸钠是目前广泛应用的一线抗癫痫药。
苯妥英钠 (大仑丁): 作用较强; 疗效高; 为大发作首选, 对精神运动性发作次之, 对局 限性发作也有较好疗效, 但对小发作无效甚至恶化; 无嗜睡作用; 安全范围大; 作用缓慢, 口 服一般需 3〜4天才显效, 用于预防发作及维持治疗; 而控制症状则以苯巴比妥为主。 苯妥英 钠抑制了 Na+内流, 从而使细胞静息电位负值增大, 加大与阈电位的距离, 提高了脑细胞的兴 奋阈,稳定膜电位,从而阻止了病灶放电的扩散。还能使脑中抑制性递质 γ-氨基丁酸的含量升高, 这也与其抗癫痫作用有一定关系。 苯妥英钠对三叉神经痛、 坐骨神经痛及舌咽神经痛有止痛 作用。
磷苯妥英钠是苯妥英钠的磷酸酯前药, 由华纳一兰伯特公司开发, 1996 年在美国上市, 1999 年在英国、 法国上市。 是全世界第一个被批准的苯妥英钠前体药。 可通过静脉或肌肉给 药, 用于治疗癫痫病人的痉挛症状, 预防并治疗神经外科手术中惊厥的发作, 具有较好的有效 性、 安全性和耐受性。 完全可以替代苯妥英钠应用, 且拓宽了其临床适应症, 并改善了急性发 作的医疗护理方法。
磷苯妥英钠注射液的优点:
1、 静注磷苯妥英钠注射液注射过程较易接收。 使必须用苯妥英钠注射液的患者又快又好 地接受治疗、 耐受性好、 中断治疗少, 不良反应少。
2、 磷苯妥英钠注射液可以肌内注射。 许多难以口服给药患者, 如失去知觉、 严重呕吐或 需立即快速给药的患者,本品可以肌内注射给药就具有突出的长处。上述患者快速肌内注射磷 苯妥英钠注射液, 可以保持患者体内的抗癫痫药物浓度而降低其发作的危险。 肌注 30分钟, 药物即被吸收并达到治疗效果。 肌肉注射时, 不需要心脏监控。
磷苯妥英钠及磷苯妥英钠七水合物均易吸湿, 给本品的生产及储存过程带来了很多的困 难, 很难长期保持, 同时室温稳定性差。
目前, 磷苯妥英钠的国外上市剂型为水针剂, 规格为 50mg/ml。 经大量的实验证实: 常温 及强光照射对磷苯妥英钠注射液的稳定性均有明显影响, 所以制备过程中要求温度应低于 25 V,需要在 2〜8°C贮藏, 同时储存过程中也极易发生细微沉淀,常温放置不能超过 48小时, 以防止发生水解或光解反应。 这些特殊的要求既不利于大规模的工业化生产, 也造成了贮藏和 运输上的不便, 限制了药品的推广和应用。
磷苯妥英钠注射液在 2〜8°C储存过程中, 也极易产生 2,2-联苯基氨基乙酸及苯妥英酸两个 毒性杂质, 其结构式如下, 二者给临床使用造成极大安全隐患。
2,2-联苯基氨基乙酸
i ^ 发明内容
本发明的目的在于弥补现有技术中存在的不足之处,提供一种稳定的磷苯妥英有机胺盐及 其制备方法和用途。
在本发明的第一方面, 提供了一种通式 (I) 所示的稳定磷苯妥英的有机胺盐化合物及其 水合物、 溶剂化物:
在另一优选例中, 磷苯妥英稳定的有机胺盐, 所述是有机胺指的是 N-甲基 -D-葡萄糖胺、 氨丁 三醇、 赖氨酸、 精氨酸、 乙醇胺、 乙二醇胺、 乙二胺、 萘二胺。
在另一优选例中, 所述的磷苯妥英稳定的有机胺盐, 指的是磷苯妥英 N-甲基 -D-葡萄糖胺盐、 磷苯妥英氨丁三醇盐, 其结构式如下:
本发明的第二方面, 提供了通式 (I) 稳定磷苯妥英的有机胺盐化合物的制备方法, 其特 征在于, 包含步骤:
a) 5,5-二苯基 -2,4-咪唑二酮 (苯妥英)於室温条件下用碳酸钠作碱用 40%甲醛处理得到 3-羟 甲基 -5,5-二苯基 -咪唑 -2,4-二酮
b) 3-羟甲基 -5,5-二苯基 -咪唑 -2,4-二酮溶于四氢呋喃中, 在碳酸钠作用下, 室温用三氯乙 腈处理得到 (2,5-二氧代 -4,4-二苯基 -咪唑 -1-基) -甲基 -2,2,2-三氯乙酰胺
c) (2,5-二氧代 -4,4-二苯基 -咪唑 -1-基) -甲基 -2,2,2-三氯乙酰胺溶于乙腈, 在 45%三氟化硼 乙醚络合物作用下, 与磷酸二苄酯反应, 处理得到 2,4-咪唑啉二酮 -5,5-二苯基 -3- [(膦酰氧基)-
i ^ 甲基] -二苄基酯
d) 2,4-咪唑啉二酮 -5,5-二苯基 -3- [(膦酰氧基) -甲基] -二苄基酯溶于甲醇, 加入上述有机胺, 用 5% Pt/C作催化剂, 氢化, 压力维持在 3〜3.5kg/cm2, 处理得到通式 (I) 化合物
制备本发明的工艺流程为:
本发明的第三方面,提供了一种药物组合物,它含有药学上可接受的载体以及本发明通式
(I) 的盐。
本发明通式 (I) 的盐加入适宜的辅料可以制成注射液、 注射用无菌粉或注射用冻干粉。 本发明的第四方面,提供了所发明的药物组合物用途,用于控制原发性癫痫病人的痉挛症 状, 预防并治疗神经外科手术中惊厥发作
具体实施方式
下面的实施例可以对本发明进行进一步的描述,然而,这些实施例不应作为对本发明范围 的限制。
实施例 1: 磷苯妥英 N-甲基 -D-葡萄糖胺的制备
a) 3-羟甲基 -5,5-二苯基 -咪唑 -2,4-二酮的制备
於 50L反应釜中, 加去离子水 39L, 碳酸钾 64g, 搅拌, 温度升至 33°C, 大约 15min, 溶液 澄清, 加 40%甲醛溶液 1.47kg, 搅拌 15min后加 5,5-二苯基 -2,4-咪唑二酮 (苯妥英) 1.3kg, 去离 子水 7.8L, 搅拌 2h, 反应完毕后离心, 固体先用水 5.2L洗涤, 真空 70°C干燥 6h, 得 1.35kg3-羟 甲基 -5,5-二苯基 -咪唑 -2,4-二酮。
说 明 书
b) (2,5-二氧代 -4,4-二苯基 -咪唑 -1-基) -甲基 -2,2,2-三氯乙酰胺的制备
於 30L干燥清洁反应釜中加 3-羟甲基 -5,5-二苯基 -咪唑 -2,4-二酮 1200g,四氢呋喃 12L,搅拌, 温度升至 27°C, 加碳酸钾 600g, 缓慢滴入三氯乙腈 520ml, 维持温度 27°C, 搅拌 4h, 反应完毕, 过滤, 滤液在 50°C下减压浓缩得 1.25kg(2,5-二氧代 -4,4-二苯基 -咪唑 -1-基) -甲基 -2,2,2-三氯乙酰 胺。
c) 2,4-咪唑啉二酮 -5,5-二苯基 -3- [(膦酰氧基)-甲基] -二苄基酯的制备
於 50L干燥清洁反应釜中, 加磷酸二苄酯 935g, 乙腈 5000ml, 搅拌, 温度在 28°C, 维持 lOmin , 在?^保护下, 缓慢滴入 45%三氟化硼乙醚络合物 160ml, 维持温度 25°C, 搅拌 15min, 缓慢滴入含 (2,5-二氧代 -4,4-二苯基 -咪唑 -1-基) -甲基 -2,2,2-三氯乙酰胺 1.25kg的二氯甲垸 6000ml 的溶液, 升温度至 28°C, 搅拌维持 lh, 滴入水 20L及二氯甲垸 20L, 分离, 水层用二氯甲垸 10L 萃取, 合并有机层, 用水 2x5000ml洗涤, 有机层在 50°C下减压浓缩得 2,4-咪唑啉二酮 -5,5-二苯 基 -3- [(膦酰氧基) -甲基] -二苄基酯 1542g
d) 磷苯妥英 N-甲基 -D-葡萄糖胺的制备
於 50L干燥清洁高压反应釜中, 加甲醇 21L, 2,4-咪唑啉二酮 -5,5-二苯基 -3- [(膦酰氧基) -甲 基] -二苄基酯 1500g及 N-甲基 -D-葡萄糖胺 1200g溶于 10L水的溶液, 温度在 30°C, 维持 20min , 加含 5% Pt/C 15g的 6L甲醇溶液,用 N2置换空气三次,用 ¾置换 N2三次,通入 ¾,压力维持在 3〜 3.5kg/cm2, 温度维持在 35°C, 搅拌 5h, 薄层鉴别反应终点, 反应完毕, 用硅藻土过滤, 硅藻土 用 10L甲醇洗涤, 滤液在 40°C下减压浓缩, 残余物加甲醇 6L溶解, 往该溶液中加入异丙醇 30L, 将混合物於室温陈化 30min。 析出固体, 过滤, 用 5L异丙醇及 5L石油醚洗涤, 在 50°C下减压真 空干燥 6h, 得磷苯妥英 N-甲基 -D-葡萄糖胺 1685g, 收率 81.5%, 熔点: 175°C〜182°C, 熔融时 同时分解。
H— NMR ( 500MHz,CD3OD/TMS , ppm) :
52.78 ( s, 6H); 52.89 (d, lH,J=14.5Hz); 53.21 (d, lH,J=10.6Hz); δ3.38〜3.56 (m, 4H); δ3.72〜4.14 (m, 14H); δ4.32〜4.57 (m, 3H); 55.96 ( s, 2H); 57.25 (d, 4H,J=12.6Hz); 57.29(t, 2H, J=8.5Hz); 57.38 (t, 4H, J=9.4Hz)
13C— NMR ( 125MHz,CD3OD/TMS, ppm):
δ: 33.9, 52.1, 65.7, 67.3, 69.3, 70.7, 73.1, 122.3, 124.6, 128.7, 132.4, 141.9, 157.2, 161.8
i ^
MS(ESI) : 361 [M+H,100%]
HPLC分析: 99.7%
色谱柱为十八垸基硅垸键合硅胶柱( Shimpack, CLC-ODS, 150mm X 4.6 mm, 5 μ m); 流动 相为 0.01 mol/U 1磷酸氢二钠溶液(称取磷酸氢二钠 3.58 g 加水 1000 ml 使溶解, 以磷酸调 pH 至 3.0) -甲醇(55: 45) ; 检测波长为 215 nm; 流量为 1.0 ml/min_ 进样体积为 20 μ 1。 理论塔 板数按磷苯妥英钠峰计算不低于 3000。
实施例 2: 磷苯妥英氨丁三醇的制备
於 10L干燥清洁高压反应釜中,加甲醇 5L、 2,4-咪唑啉二酮 -5,5-二苯基 -3- [(膦酰氧基)-甲基] - 二苄基酯 108g及氨丁三醇 51g溶于 150ml水的溶液, 室温搅拌, 加含 10% Pt/C 3g的 50ml甲醇溶 液,用 ^置换空气三次,用¾置换 N2三次,通入 ¾,压力维持在 3〜3.5kg/cm2,温度维持在 35°C, 搅拌 4h, 反应完毕, 用硅藻土过滤, 硅藻土用 500ml甲醇洗涤, 滤液在 50°C下减压浓缩, 残余 物加甲醇 300ml溶解, 往该溶液中加入丙酮 3L, 将混合物於室温陈化 30min。 析出固体, 过滤, 用 1L异丙醇及 300ml乙醚洗涤, 在 50°C下减压真空干燥 6h, 得磷苯妥英氨丁三醇 103g, 收率 84.6%, 熔点: 190°C〜195°C, 熔融时同时分解。
1H— NMR ( 500MHz,CD3OD/TMS , ppm) :
54.23 ( s, 12H); 56.01 ( s, 2H); 57.29 (d, 4H,J=13.1Hz); 57.35(t, 2H, J=8.9Hz); 57.51
(t, 4H, J=11.2Hz)
MS(ESI) : 361 [M+H,100%]
HPLC分析: 99.8%
色谱柱为十八垸基硅垸键合硅胶柱( Shimpack, CLC-ODS, 150mm X 4.6 mm, 5 μ m); 流动 相为 0.01 mol/U 1磷酸氢二钠溶液(称取磷酸氢二钠 3.58 g 加水 1000 ml 使溶解, 以磷酸调 pH 至 3.0) -甲醇(55: 45) ; 检测波长为 215 nm; 流量为 1.0 ml/min_ 进样体积为 20 μ 1。 理论塔 板数按磷苯妥英钠峰计算不低于 3000。
实施例 3: 注射用磷苯妥英 Ν-甲基 -D-葡萄糖胺无菌分装粉的制备
处方:
磷苯妥英 Ν-甲基 -D-葡萄糖胺 (无菌) 1372g
1000支
i ^ 制备工艺:
取溶媒结晶的磷苯妥英 N-甲基 -D-葡萄糖胺无菌粉 1372g, 於无菌分装 GMP车间, 采用螺 杆分装机分装, 每瓶装量为 1.372g, 加塞、 轧盖, 包装即得注射用磷苯妥英 N-甲基 -D-葡萄糖 胺无菌粉。
实施例 4: 注射用磷苯妥英氨丁三醇无菌分装粉的制备
处方:
磷苯妥英氨丁三醇 (无菌) 1102g
1000支
制备工艺:
取溶媒结晶的磷苯妥英 N-甲基 -D-葡萄糖胺无菌粉 1102g,於无菌分装 GMP车间,采用螺杆 分装机分装, 每瓶装量为 1.102g, 加塞、 轧盖, 包装即得注射用磷苯妥英氨丁三醇无菌粉。 实施例 5: 注射用磷苯妥英 N-甲基 -D-葡萄糖胺冻干粉针的制备
处方:
磷苯妥英 N-甲基 -D-葡萄糖胺 1372g
注射用水 5000ml
1000支
制备工艺:
取处方总量 95%左右的注射用水, 水温控制在65°〇± 5°〇, 加入磷苯妥英 N-甲基 -D-葡萄糖 胺 1372g,充分搅拌至全部溶解,测定 pH值,此时 pH值为 8.92,加入针用活性炭 3g, 65°C ± 5°C, 搅拌 30min, 抽滤脱碳, 加入注射用水至全量, 用 0.22 μ ηι微孔滤膜除菌过滤, 测定中间体含量 合格后, 溶液分装于 10ml规格的西林瓶中, 每瓶装量为 5ml。
将制备好的已灌装磷苯妥英 N-甲基 -D-葡萄糖胺的西林瓶放入冻干箱内, 然后将冻干机内 温度在 2h内降低到一 45°C以下, 使其迅速冻结。抽真空, 在 30min内使箱内大气压达到 2. 66pa。 按板温 -45°C升到 30°C的开始程序升温干燥。 干燥完后加塞、 轧盖得到注射用磷苯妥英 N-甲基 -D-葡萄糖胺冻干粉针。
实施例 6: 注射用磷苯妥英氨丁三醇冻干粉针的制备
说 明 书 处方:
磷苯妥英氨丁三醇 1102g
注射用水 5000ml
1000支
制备工艺:
取处方总量 95%左右的注射用水, 水温控制在651 ±51, 加入磷苯妥英氨丁三醇 1102g, 充分搅拌至全部溶解,测定 pH值,此时 pH值为 8.79,加入针用活性炭 3g, 65°C ±5°C,搅拌 30min, 抽滤脱碳, 加入注射用水至全量, 用 0.22 μ ηι微孔滤膜除菌过滤, 测定中间体含量合格后, 溶 液分装于 10ml规格的西林瓶中, 每瓶装量为 5ml。
将制备好的已灌装磷苯妥英氨丁三醇的西林瓶放入冻干箱内, 然后将冻干机内温度在 2h 内降低到一 45°C以下, 使其迅速冻结。 抽真空, 在 30min内使箱内大气压达到 2. 66pa。 按板温 -45°C升到 30°C的开始程序升温干燥。 干燥完后加塞、 轧盖得到注射用磷苯妥英氨丁三醇冻干 粉针。
实施例 7: 磷苯妥英 N-甲基 -D-葡萄糖胺注射液的制备
处方:
磷苯妥英 N-甲基 -D-葡萄糖胺 1372g
注射用水 10000ml
1000支
制备工艺:
取处方总量 95%左右的注射用水, 水温控制在65°〇±5°〇, 加入磷苯妥英 N-甲基 -D-葡萄糖 胺 1372g,充分搅拌至全部溶解,测定 pH值,此时 pH值为 8.93,加入针用活性炭 6g, 65°C ±5°C, 搅拌 30min, 抽滤脱碳, 加入注射用水至全量, 用 0.22 μ ηι微孔滤膜除菌过滤, 测定中间体含量 合格后, 溶液无菌分装于 10ml规格的西林瓶中, 每瓶装量为 10ml, 加塞、 轧盖得到磷苯妥英 N-甲基 -D-葡萄糖胺注射液。
实施例 8: 磷苯妥英氨丁三醇注射液的制备
处方:
磷苯妥英氨丁三醇 1102g
注射用水 10000ml
1000支
说 明 书
施例 3 制备工艺:
取处方总量 95%左右的注射用水, 水温控制在651 ± 51, 加入磷苯妥英氨丁三醇 1102g, 充分搅拌至全部溶解,测定 pH值,此时 pH值为 8.80,加入针用活性炭 6g, 65°C ± 5°C,搅拌 30min, 抽滤脱碳, 加入注射用水至全量, 用 0.22 μ ηι微孔滤膜除菌过滤, 测定中间体含量合格后, 溶 液无菌分装于 10ml规格的西林瓶中, 每瓶装量为 10ml, 加塞、 轧盖得到磷苯妥英氨丁三醇注 射液。
实施例 9: 磷苯妥英钠注射液的制备
处方:
磷苯妥英钠七水合物 982.8g
氨丁三醇 121. lg
注射用水 10000ml
1000支
制备工艺:
取处方总量 90%左右的注射用水,水温控制在 65°C ± 5°C,加入磷苯妥英钠七水合物 982.8g, 氨丁三醇 121.1g,充分搅拌至全部溶解,用稀盐酸调节 pH值 8.5〜9.1,加入针用活性炭 6g, 65 °C ± 5°C, 搅拌 30min, 抽滤脱碳, 加入注射用水至全量, 用 0.22 μ m微孔滤膜除菌过滤, 测定中 间体含量合格后, 溶液无菌分装于 10ml规格的西林瓶中, 每瓶装量为 10ml, 加塞、 轧盖得到 磷苯妥英钠注射液。
实施例 10、 稳定性研究结果
加速试验
将按实施例 3〜实施例 9制备的样品, 分别放置于温度 40°C ± 2°C, 相对湿度 75%± 5%的 条件下, 于第 1、 2、 3、 6月测定有关指标, 结果见下表。
考察项目: 外观性状、 pH值、 澄清度与颜色、 不溶性微粒、 有关物质和含量
批号 项目 0月 1月 月 3月 6月
外观性状 白色结晶粉末 白色结晶粉末 白色结晶粉末 白色结晶粉末 白色结晶粉末 pH值 8. 91 8. 91 8. 91 8. 91 8. 91 澄清度 澄清 澄清 澄清 澄清 澄清 颜色 <Y#1 <Υ#1 <Υ#1 <Υ#1 <Υ#1 不溶性微粒 符合规定 符合规定 符合规定 符合规定 符合规定 有关物质 (%) 0. 04 0. 04 0. 04 0. 05 0. 05 含量(%) 99. 54 100. 1 99. 08 99. 54 101. 0
说 明 书
施施施例例例 456
批号 项目 0月 1月 月 3月 6月 外观性状 白色结晶粉末 白色结晶粉末 白色结晶粉末 白色结晶粉末 白色结晶粉末 pH值 8. 78 8. 78 8. 78 8. 78 8. 78 澄清度 澄清 澄清 澄清 澄清 澄清 颜色 <Y#1 <Υ#1 <Υ#1 <Υ#1 <Υ#1 不溶性微粒 符合规定 符合规定 符合规定 符合规定 符合规定 有关物质 (%) 0. 05 0. 05 0. 05 0. 06 0. 06 含量(%) 99. 98 99. 54 99. 12 100. 03 99. 73 批号 项目 0月 1月 月 3月 6月 外观性状 类白色块状物 类白色块状物 类白色块状物 类白色块状物 类白色块状物 pH值 8. 92 8. 92 8. 86 8. 87 8. 79 澄清度 澄清 澄清 澄清 澄清 澄清 颜色 <Υ#1 <Υ#1 <Υ#1 <Υ#1 <Υ#1 不溶性微粒 符合规定 符合规定 符合规定 符合规定 符合规定 有关物质 (%) 0. 06 0. 06 0. 07 0. 08 1. 03 含量(%) 99. 99 99. 01 99. 10 100. 03 98. 98 批号 项目 0月 1月 月 3月 6月 外观性状 类白色块状物 类白色块状物 类白色块状物 类白色块状物 类白色块状物 pH值 8. 79 8. 79 8. 76 8. 70 8. 65 澄清度 澄清 澄清 澄清 澄清 澄清 颜色 <Υ#1 <Υ#1 <Υ#1 <Υ#1 <Υ#1 不溶性微粒 符合规定 符合规定 符合规定 符合规定 符合规定 有关物质 (%) 0. 05 0. 06 0. 08 0. 08 0. 09 含量(%) 100. 03 99. 93 99. 01 98. 93 98. 79
说 明 书
施施例例 89
批号 项目 0月 1月 月 3月 6月 外观性状 无色澄明液体 无色澄明液体 无色澄明液体 无色澄明液体 无色澄明液体 pH值 8. 93 8. 90 8. 87 8. 73 8. 61 澄清度 澄清 澄清 澄清 澄清 澄清 颜色 <Υ#1 <Υ#1 <Υ#1 <Υ#1 <Υ#1 不溶性微粒 符合规定 符合规定 符合规定 符合规定 符合规定 有关物质 (%) 0. 04 0. 07 0. 09 1. 05 1. 31 含量(%) 99. 32 100. 4 99. 23 98. 71 97. 81 批号 项目 0月 1月 月 3月 6月 外观性状 无色澄明液体 无色澄明液体 无色澄明液体 无色澄明液体 无色澄明液体 pH值 8. 80 8. 80 8. 75 8. 73 8. 60 澄清度 澄清 澄清 澄清 澄清 澄清 颜色 <Y#1 <Υ#1 <Υ#1 <Υ#1 <Υ#1 不溶性微粒 符合规定 符合规定 符合规定 符合规定 符合规定 有关物质 (%) 0. 05 0. 06 0. 09 1. 12 1. 25 含量(%) 100. 02 99. 38 99. 01 98. 23 97. 06 批号 项目 0月 1月 月 3月 6月 外观性状 无色澄明液体 淡黄色澄明液 淡黄色浑浊 淡黄色浑浊 淡黄色浑浊 pH值 8. 93 8. 02 7. 45 7. 12 7. 04 澄清度 澄清 澄清 浑浊清 浑浊 浑浊 颜色 <Υ#1 不符合规定 不符合规定 不符合规定 不符合规定 不溶性微粒 符合规定 不符合规定 不符合规定 不符合规定 不符合规定 有关物质 (%) 0. 05 1. 03 2. 71 2. 98 3. 86 含量(%) 99. 97 97. 82 93. 06 90. 15 85. 39 结果表明,本发明实施例 3与实施例 4的制剂相当稳定,实施例 5与实施例 6的制剂很稳 定, 实施例 7与实施例 8的制剂相对稳定, 而实施例 9很不稳定。
实施例 11: 实施例化合物理化参数试验及急性毒性试验结果
说 明 书
^目
LogP值 溶液 pH值 水 溶 性 熔 点 LD50值( mg/kg ) 编号
实施例 1 -1.01〜- 2.53 8.6—8.9 83 mg/ml 175°C〜182°C 982 实施例 2 -1.23〜- 2.17 8.5—8.7 80 mg/ml 190°C〜195°C 657 磷苯妥英钠 -1.10〜- 3.06 8.3—8.9 74 mg/ml 约 237 °C 234
Claims
1、 通式 (I) 稳定磷苯妥英的有机胺盐化合物及其水合物、 溶剂化物:
其中 M为药学上可接受的有机胺, 根据有机胺数目调整, 以达到电荷平衡。
2、 根据权利要求 1所述的磷苯妥英稳定的有机胺盐, 其特征是有机胺指的是 N-甲基 -D-葡萄糖胺、 氨丁三醇、 赖氨酸、 精氨酸、 乙醇胺、 乙二醇胺、 乙二胺、 萘二胺。
3、 根据权利要求 1或 2所述的磷苯妥英稳定的有机胺盐, 其特征是有机胺盐指的是磷苯妥英 N-甲基 -D-葡萄糖胺盐、 磷苯妥英氨丁三醇盐, 其结构式如下:
4、 通式 (I) 稳定磷苯妥英的有机胺盐化合物的制备方法, 其特征在于, 包含步骤:
a) 5,5-二苯基 -2,4-咪唑二酮 (苯妥英)於室温条件下用碳酸钠作碱用 40%甲醛处理得到 3-羟 甲基 -5,5-二苯基 -咪唑 -2,4-二酮
b) 3-羟甲基 -5,5-二苯基 -咪唑 -2,4-二酮溶于四氢呋喃中, 在碳酸钠作用下, 室温用三氯乙 腈处理得到 (2,5-二氧代 -4,4-二苯基 -咪唑 -1-基) -甲基 -2,2,2-三氯乙酰胺
c) (2,5-二氧代 -4,4-二苯基 -咪唑 -1-基) -甲基 -2,2,2-三氯乙酰胺溶于乙腈, 在 45%三氟化硼 乙醚络合物作用下, 与磷酸二苄酯反应, 处理得到 2,4-咪唑啉二酮 -5,5-二苯基 -3- [(膦酰氧基) - 甲基] -二苄基酯
d) 2,4-咪唑啉二酮 -5,5-二苯基 -3- [(膦酰氧基) -甲基] -二苄基酯溶于甲醇, 加入上述有机胺, 用 5% Pt/C作催化剂, 氢化, 压力维持在 3〜3.5kg/cm2, 处理得到通式 (I) 化合物
5、 一种药物组合物, 其特征在于, 含有治疗或预防有效剂量如权利要求 1或 2所述的化合物
权 利 要 求 书 作为活性成分以及药学上可接受的载体。
6、 如权利要求 5所述的药物组合物, 其特征是为注射剂型, 包括注射液、 注射用无菌粉或注 射用冻干粉。
7、 如权利要求 5所述的药物组合物用途, 用于控制原发性癫痫病人的痉挛症状, 预防并治疗 神经外科手术中惊厥发作。
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US4260769A (en) * | 1977-04-22 | 1981-04-07 | Interx Research Corporation | 5,5-Diphenylhydantoins |
WO1990014080A1 (en) * | 1989-05-25 | 1990-11-29 | The Du Pont Merck Pharmaceutical Company | Stable pharmaceutical composition of 3-(hydroxymethyl)-5,5-diphenylhydantoin disodium phosphate ester |
CN1379032A (zh) * | 2002-04-10 | 2002-11-13 | 国家药品监督管理局天津药物研究院 | 磷苯妥英七水合物及其制备方法 |
CN1608626A (zh) * | 2003-10-17 | 2005-04-27 | 天津药物研究院 | 磷苯妥英钠粉针剂及其制备方法 |
BRPI0704450A2 (pt) * | 2007-11-30 | 2012-03-20 | Nortec Química S.a. | processo para preparação de sal disódico do 5,5-difenil-[(3-fosfonoxi) metil]-2,4-imidazolidinediona |
CN103288877A (zh) * | 2013-05-10 | 2013-09-11 | 安徽省先锋制药有限公司 | 磷苯妥英稳定的有机胺盐及其制备方法和用途 |
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CA2022842A1 (en) * | 1989-08-10 | 1991-02-11 | Peter Alan Boxer | Use of prophenytoin for treating stroke |
CN1555805A (zh) * | 2004-01-08 | 2004-12-22 | 陈庆财 | 注射用磷苯妥英钠冻干粉针剂及制备方法 |
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US4260769A (en) * | 1977-04-22 | 1981-04-07 | Interx Research Corporation | 5,5-Diphenylhydantoins |
WO1990014080A1 (en) * | 1989-05-25 | 1990-11-29 | The Du Pont Merck Pharmaceutical Company | Stable pharmaceutical composition of 3-(hydroxymethyl)-5,5-diphenylhydantoin disodium phosphate ester |
CN1379032A (zh) * | 2002-04-10 | 2002-11-13 | 国家药品监督管理局天津药物研究院 | 磷苯妥英七水合物及其制备方法 |
CN1608626A (zh) * | 2003-10-17 | 2005-04-27 | 天津药物研究院 | 磷苯妥英钠粉针剂及其制备方法 |
BRPI0704450A2 (pt) * | 2007-11-30 | 2012-03-20 | Nortec Química S.a. | processo para preparação de sal disódico do 5,5-difenil-[(3-fosfonoxi) metil]-2,4-imidazolidinediona |
CN103288877A (zh) * | 2013-05-10 | 2013-09-11 | 安徽省先锋制药有限公司 | 磷苯妥英稳定的有机胺盐及其制备方法和用途 |
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