CN1067392C - 稳定结晶的四氢叶酸盐 - Google Patents
稳定结晶的四氢叶酸盐 Download PDFInfo
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- CN1067392C CN1067392C CN96112040A CN96112040A CN1067392C CN 1067392 C CN1067392 C CN 1067392C CN 96112040 A CN96112040 A CN 96112040A CN 96112040 A CN96112040 A CN 96112040A CN 1067392 C CN1067392 C CN 1067392C
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- tetrahydrofolate
- crystalline
- water
- calcium
- magnesium
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- MSTNYGQPCMXVAQ-KIYNQFGBSA-N 5,6,7,8-tetrahydrofolic acid Chemical class N1C=2C(=O)NC(N)=NC=2NCC1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 MSTNYGQPCMXVAQ-KIYNQFGBSA-N 0.000 title description 5
- MSTNYGQPCMXVAQ-NEPJUHHUSA-N 6R-Tetrahydrofolic acid Chemical compound C([C@@H]1CNC=2N=C(NC(=O)C=2N1)N)NC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 MSTNYGQPCMXVAQ-NEPJUHHUSA-N 0.000 claims abstract description 35
- 238000000034 method Methods 0.000 claims abstract description 16
- 239000003814 drug Substances 0.000 claims abstract description 9
- 238000004519 manufacturing process Methods 0.000 claims abstract description 4
- 239000000825 pharmaceutical preparation Substances 0.000 claims abstract description 4
- MSTNYGQPCMXVAQ-RYUDHWBXSA-N (6S)-5,6,7,8-tetrahydrofolic acid Chemical class C([C@H]1CNC=2N=C(NC(=O)C=2N1)N)NC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 MSTNYGQPCMXVAQ-RYUDHWBXSA-N 0.000 claims description 35
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 28
- 239000005460 tetrahydrofolate Substances 0.000 claims description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- 159000000003 magnesium salts Chemical class 0.000 claims description 12
- 238000002425 crystallisation Methods 0.000 claims description 10
- 230000008025 crystallization Effects 0.000 claims description 10
- 159000000007 calcium salts Chemical class 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- 229910052791 calcium Inorganic materials 0.000 claims description 5
- 239000011575 calcium Substances 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 4
- 239000004615 ingredient Substances 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 abstract description 8
- 238000002360 preparation method Methods 0.000 abstract description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 20
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 13
- 229910052757 nitrogen Inorganic materials 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 238000001035 drying Methods 0.000 description 9
- 239000002002 slurry Substances 0.000 description 9
- 235000019152 folic acid Nutrition 0.000 description 7
- 239000011724 folic acid Substances 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 229960000304 folic acid Drugs 0.000 description 6
- PJUIMOJAAPLTRJ-UHFFFAOYSA-N monothioglycerol Chemical compound OCC(O)CS PJUIMOJAAPLTRJ-UHFFFAOYSA-N 0.000 description 6
- 229940035024 thioglycerol Drugs 0.000 description 6
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 5
- WUPYWCAWYJNPBS-UJFGJZBHSA-L [Ca+2].C(CC[C@@H](C(=O)O)NC(=O)C1=CC=C(NC[C@@H]2CNC=3N=C(N)NC(=O)C3N2)C=C1)(=O)[O-].C(CC[C@@H](C(=O)O)NC(=O)C1=CC=C(NC[C@@H]2CNC=3N=C(N)NC(=O)C3N2)C=C1)(=O)[O-] Chemical compound [Ca+2].C(CC[C@@H](C(=O)O)NC(=O)C1=CC=C(NC[C@@H]2CNC=3N=C(N)NC(=O)C3N2)C=C1)(=O)[O-].C(CC[C@@H](C(=O)O)NC(=O)C1=CC=C(NC[C@@H]2CNC=3N=C(N)NC(=O)C3N2)C=C1)(=O)[O-] WUPYWCAWYJNPBS-UJFGJZBHSA-L 0.000 description 5
- 235000011114 ammonium hydroxide Nutrition 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 239000001110 calcium chloride Substances 0.000 description 3
- 229910001628 calcium chloride Inorganic materials 0.000 description 3
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 3
- 239000000347 magnesium hydroxide Substances 0.000 description 3
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000011282 treatment Methods 0.000 description 3
- VVIAGPKUTFNRDU-QWHCGFSZSA-N 5-formyl-5,6,7,8-tetrahydrofolate Chemical compound C([C@@H]1N(C=O)C=2C(=O)N=C(NC=2NC1)N)NC1=CC=C(C(=O)N[C@H](CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-QWHCGFSZSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000002708 enhancing effect Effects 0.000 description 2
- 239000004052 folic acid antagonist Substances 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- UEGPKNKPLBYCNK-UHFFFAOYSA-L magnesium acetate Chemical compound [Mg+2].CC([O-])=O.CC([O-])=O UEGPKNKPLBYCNK-UHFFFAOYSA-L 0.000 description 2
- 239000011654 magnesium acetate Substances 0.000 description 2
- 229940069446 magnesium acetate Drugs 0.000 description 2
- 235000011285 magnesium acetate Nutrition 0.000 description 2
- 229910001629 magnesium chloride Inorganic materials 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical compound O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 description 2
- 238000000634 powder X-ray diffraction Methods 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- SGUBKELXCDHQHX-FXMYHANSSA-N (2s)-2-[[4-[[(6s)-2-amino-4-oxo-5,6,7,8-tetrahydro-1h-pteridin-6-yl]methylamino]benzoyl]amino]pentanedioic acid;sulfuric acid Chemical compound OS(O)(=O)=O.C([C@H]1CNC=2N=C(NC(=O)C=2N1)N)NC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 SGUBKELXCDHQHX-FXMYHANSSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- WZRJTRPJURQBRM-UHFFFAOYSA-N 4-amino-n-(5-methyl-1,2-oxazol-3-yl)benzenesulfonamide;5-[(3,4,5-trimethoxyphenyl)methyl]pyrimidine-2,4-diamine Chemical compound O1C(C)=CC(NS(=O)(=O)C=2C=CC(N)=CC=2)=N1.COC1=C(OC)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 WZRJTRPJURQBRM-UHFFFAOYSA-N 0.000 description 1
- TVZGACDUOSZQKY-LBPRGKRZSA-N 4-aminofolic acid Chemical compound C1=NC2=NC(N)=NC(N)=C2N=C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 TVZGACDUOSZQKY-LBPRGKRZSA-N 0.000 description 1
- VVIAGPKUTFNRDU-UHFFFAOYSA-N 6S-folinic acid Natural products C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-UHFFFAOYSA-N 0.000 description 1
- -1 Alkaline earth metal salts Chemical class 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- WWYVZQJFYPAYMT-UJFGJZBHSA-L C1[C@H](NC2=C(N1)N=C(NC2=O)N)CNC3=CC=C(C=C3)C(=O)N[C@@H](CCC(=O)[O-])C(=O)O.C1[C@H](NC2=C(N1)N=C(NC2=O)N)CNC3=CC=C(C=C3)C(=O)N[C@@H](CCC(=O)[O-])C(=O)O.[Mg+2] Chemical class C1[C@H](NC2=C(N1)N=C(NC2=O)N)CNC3=CC=C(C=C3)C(=O)N[C@@H](CCC(=O)[O-])C(=O)O.C1[C@H](NC2=C(N1)N=C(NC2=O)N)CNC3=CC=C(C=C3)C(=O)N[C@@H](CCC(=O)[O-])C(=O)O.[Mg+2] WWYVZQJFYPAYMT-UJFGJZBHSA-L 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 229960003896 aminopterin Drugs 0.000 description 1
- 230000003432 anti-folate effect Effects 0.000 description 1
- 239000000729 antidote Substances 0.000 description 1
- 229940127074 antifolate Drugs 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- VSGNNIFQASZAOI-UHFFFAOYSA-L calcium acetate Chemical compound [Ca+2].CC([O-])=O.CC([O-])=O VSGNNIFQASZAOI-UHFFFAOYSA-L 0.000 description 1
- 239000001639 calcium acetate Substances 0.000 description 1
- 235000011092 calcium acetate Nutrition 0.000 description 1
- 229960005147 calcium acetate Drugs 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 229940047766 co-trimoxazole Drugs 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 229940014144 folate Drugs 0.000 description 1
- VVIAGPKUTFNRDU-ABLWVSNPSA-N folinic acid Chemical compound C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-ABLWVSNPSA-N 0.000 description 1
- 235000008191 folinic acid Nutrition 0.000 description 1
- 239000011672 folinic acid Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 229960002989 glutamic acid Drugs 0.000 description 1
- 125000000291 glutamic acid group Chemical group N[C@@H](CCC(O)=O)C(=O)* 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229960001691 leucovorin Drugs 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000000590 parasiticidal effect Effects 0.000 description 1
- 239000002297 parasiticide Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- CPNGPNLZQNNVQM-UHFFFAOYSA-N pteridine Chemical compound N1=CN=CC2=NC=CN=C21 CPNGPNLZQNNVQM-UHFFFAOYSA-N 0.000 description 1
- 125000001747 pteroyl group Chemical group [H]C1=C([H])C(C(=O)[*])=C([H])C([H])=C1N([H])C([H])([H])C1=C([H])N=C2N([H])C(N([H])[H])=NC(=O)C2=N1 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- UQDJGEHQDNVPGU-UHFFFAOYSA-N serine phosphoethanolamine Chemical compound [NH3+]CCOP([O-])(=O)OCC([NH3+])C([O-])=O UQDJGEHQDNVPGU-UHFFFAOYSA-N 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/24—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having more than one carboxyl group bound to the carbon skeleton, e.g. aspartic acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D475/00—Heterocyclic compounds containing pteridine ring systems
- C07D475/02—Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4
- C07D475/04—Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4 with a nitrogen atom directly attached in position 2
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/02—Antidotes
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Toxicology (AREA)
- Tropical Medicine & Parasitology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Steroid Compounds (AREA)
- Pyridine Compounds (AREA)
Abstract
本发明涉及(6R，S)-，(6S)-和(6R)-四氢叶酸的稳定结晶盐，涉及制备这些盐的方法以及涉及它们作为生产药物和药物制剂的应用。
Description
本发明涉及结晶的N-〔4-〔〔2-氨基-1,4,5,6,7,8-六氢-4-氧代-(6S)-,-(6R)-和-(6R,S)-蝶啶基)甲基〕氨基〕苯甲酰基〕-L-谷氨酸盐(下文称四氢叶酸盐)，涉及它们的应用以及涉及制备它们的方法。
四氢叶酸衍生物含有两个不对称中心。在这方面，由于这些衍生物由叶酸、N-(蝶酰基)-L-谷氨酸合成，在谷氨酸基中所含有的光学活性碳原子以L-形式存在，而通常由蝶酰基5,6位中的双键加氢在6位中形成的光学活性碳原子以外消旋(6R,S)形式存在。因此四氢叶酸的合成衍生物由2种非对映异构体的1∶1混合物组成。
作为药物,四氢叶酸盐主要使用5-甲酰基-5,6,7,8-四氢叶酸(甲酰四氢叶酸)的钙盐或5-甲基-5,6,7,8-四氢叶酸的钙盐，用于治疗巨红细胞叶酸盆血症，作为解毒药以提高叶酸拮抗物特别是氨基蝶呤和氨甲蝶呤在癌症治疗中的相容性(“抗叶酸盐援救”)，用于提高氟化嘧唑的治疗效果和用于治疗自身免疫疾病，如牛皮癣和风湿性关节炎，用于提高某些杀寄生虫药如三甲氧苄二氮嘧啶-磺胺甲氧唑的相容性以及用于降低二去氮杂四氢叶酸盐(dideazatetrahydrofalates)在化疗中的毒性。在人体中，单个四氢叶酸盐可相互转化(叶酸盐循环)。四氢叶酸在这样的过程中起主要作用。四氢叶酸也用作制备各种四氢叶酸衍生物的基础物质。
迄今，由于难以生产药物有效成分合格纯度的四氢叶酸盐以及由四于氢叶酸极不稳定，特别是对氧化作用高的敏感性，四氢叶酸盐直接用作药物或用作制备各种四氢叶酸衍生物的基础物质都失败了[有关这点参见A.L.Fitzhugh,Pteridine 4(4),187～191(1993)]。在这方面，应当指出，对于四氢叶酸盐的肠胃外应用(在药物领域它是最常用的)，给药的溶液至少接近中性pH值是必须遵循的先决条件。对于这一应用来说，四氢叶酸盐因此是优选的应用形式。为了克服四氢叶酸的不稳定性，已采用了各种方法，例如尽可能完全的排除氧，或者加入抗氧剂如抗坏血酸。但是，对于药物使用来说，完全排除氧几乎是不可能的，既使可能做到也需很高的费用；同样加抗氧剂也未必可能用于药品应用。因此，迄今仍未找到适合在商业上用于制备高纯度的和足够稳定性的四氢叶酸盐，从而使四氢叶酸盐的药物应用成为可能的可行方法。
令人吃惊的是，现已发现，可通过相应的光学纯(6S)-或光学纯(6R)-四氢叶酸盐，富含(6S)-或富含(6R)-四氢叶酸盐，或(6R,S)四氢叶酸盐结晶，得到有极好稳定性的高纯度(6S)-、(6R)-或(6R,S)-四氢叶酸盐。如此得到的结晶(6S)-，(6R)-和/或(6R,S)-四氢叶酸盐实际上在室温下，在适合的形式中是极稳定的。它们适合作药物的成分或生产药物的原料，或者作工业生产高纯度的其他四氢叶酸衍生物的原料。
因此，本发明涉及(6R,S)-,(6S)-和(6R)-四氢叶酸结晶的盐。碱土金属盐，特别是钙盐或镁盐优选用作结晶的四氢叶酸盐。
本发明还涉及一种制备结晶的(6R,S)-,(6S)-和(6R)-四氢叶酸盐的方法，其特征在于相应的四氢叶酸盐进行结晶。在这方面，四氢叶酸盐优选在pH值7～10下从极性介质中进行结晶。
最适合作极性介质的物质是水或水与其相混溶的有机溶剂的混合物，如水溶性醇如甲醇、乙醇、正丙醇、异丙醇、乙二醇，低分子量脂族水溶性羧酸如甲酸、乙酸或乳酸，或者水溶性酰胺如甲酰胺、二甲基甲酰胺、二甲基乙酰胺、1-甲基吡咯烷酮、2-甲基吡咯烷酮或2-哌啶酮。对于所用溶剂的类型和混合比没有具体的限制，因为结晶四氢叶酸盐通常比相应的无定形形式有更低的溶解度。
结晶优选在升温下特别是在50～90℃下进行，或从稀溶液特别是1～10％溶液中结晶。
(6S)-,(6R)-和(6R,S)-四氢叶酸盐的晶化自发产生，或者用相应的结晶四氢叶酸盐接种进行晶化。
无定形的或结晶的纯(6S)-或(6R)-四氢叶酸优选用作晶化的原料。但是，外消旋(6R,S)-四氢叶酸也可使用，因为可富集(6S)-或(6R)-四氢叶酸。在这里适合的原料包括两种分离的固体，如根据EP-495204制备的(6R,S)-四氢叶酸、(6S)-四氢叶酸-硫酸和磺酸加成盐，以及通过催化加氢或氢硼化物还原由叶酸就地制备的四氢叶酸。
由于无定形或部分结晶的光学纯四氢叶酸或其盐作为晶化的原料，用所述的方法可得到在此以前不能达到的纯度(＞98％)和稳定性的盐。
本发明还涉及结晶(6S)-,(6R)-和/或(6R,S)-四氢叶酸盐作为生产药物的成分或用于制备其他四氢叶酸衍生物的应用，因为结晶的(6S)-,(6R)-和(6R,S)-四氢叶酸盐可保持很好的质量，由于其固体形式有极好的稳定性，实际上在无限制的时间内质量不变。本发明还涉及含有结晶(6S)-,(6R)-和/或(6R,S)-四氢叶酸盐的药物制剂。该药物制剂可用已知的方法生产，如冷冻-干燥法。在20℃下结晶四氢叶酸盐在水中的溶解度小于1mg/ml。为类似于四氢叶酸盐领域已知物质(如5-甲酰基-5,6,7,8-四氢叶酸)来应用。
此外，本发明涉及一种用分步结晶将(6R,S)-四氢叶酸的镁盐分离成两种非对映异构体的方法，即(6S)-和(6R)-四氢叶酸的镁盐。该法很简单且有效。即使在粗外消旋(6R,S)-四氢叶酸镁盐第一次结晶后，可得到(6R)-部分大于95％的结晶(6R)-四氢叶酸镁盐，其对映异构体的产率大于50％。通过在类似条件下进一步结晶，可得到更高异构体纯度的结晶(6S)-和(6R)-四氢叶酸镁盐。
在每一情况下，在实施例中给出的四氢叶酸盐和异构体部分的含量由HPLC法测定。
实施例19(稳定性)
为了测定结晶(6S)-和(6R)-四氢叶酸盐的稳定性，将这些物质与对比样一起在25℃、60％相对温度、氮气下或4℃的空气下贮存。在一定时间间隔下测量四氢叶酸盐的剩余含量，并与最初值比较。
| 暴露时间，月 | ||||||
| 0 | 1/2 | 1 | 2 | 6 | 9 | |
| 结晶的(6S)-四氩 25℃，60%，N2叶酸的钙盐 4℃，空气 | 100%100% | 98.5%95.5% | 97.2%92.4% | 96.8%89.2% | 97.7%82.3% | 97.7%76.0% |
| 结晶的(6R)-四氩 25℃，60%，N2叶酸的钙盐 4℃，空气 | 100%100% | 97.8%85.9% | 96.1%79.0% | 98.0%73.0% | 97.1%69.3% | 96.8%69.2% |
| 结晶的(6R，S)-四氩 25℃，60%，N2叶酸的钙盐 4℃，空气 | 100%100% | 99.3%96.5% | 98.0%94.2% | 99.0%89.0% | 97.8%86.6% | 98.7%86.2% |
长时间贮存后，结晶四氢叶酸盐仍有很浅的颜色。相反，无定形样品迅速强烈变色。
在4℃、空气中暴露1月后，无定形(6R,S)-四氢叶酸钙盐的含量比结晶(6R,S)-四氢叶酸钙盐的含量低8％。
实施例2(X射线粉末衍射谱)
为了表征结晶四氢叶酸盐的结构性质(结晶度)，测定了这些物质的X射线粉末衍射谱。
结晶(6S)-,(6R)-和(6R,S)-四氢叶酸盐得到有良好分辨率、狭窄谱带和低背景度的图谱。图谱表明有高的结晶含量。
实施例3[TE1423]
将8.2g(6R,S)-四氢叶酸在氮气下浆化在含有1g硫甘油的100ml水中，用30％氢氧化钠水溶液将pH值调节到3.3，然后用3.8g氯化钙于4g水中的溶液处理浆液。生成溶液的pH值为9.3。在室温下搅拌20h后，生成悬浮液的pH为10.0，将其在吸滤下过滤，并用少量水洗涤残留物。
干燥后，得到7.7g微红色的结晶(6R,S)-四氢叶酸钙盐，其(6S)部分为51.1％，含量为96％。
实施例[TE1418]
将28.6g(6R,S)-四氢叶酸在氮气下浆化在114ml水中，用30％氢氧化钠水溶液将pH值调节到7.5，然后用48.5g氯化钙于500ml水中的溶液处理该浆液。将生成的类橡胶质加热到90℃。搅拌1h后，得到亮黄色的悬浮液，在吸滤下将它热过滤，并用少量水洗涤。
干燥后，得到17.3g米色结晶(6R,S)-四氢叶酸钙盐，其(6S)部分为50.9％，含量为94％。
实施例5[Am593]
将4.0g(6R,S)-四氢叶酸在氮气下浆化在含有0.4g硫甘油的40ml水中，用30％氢氧化钠水溶液将pH值调节到8.5，然后用2.0g乙酸钙在50℃下处理浆液。在吸滤下过滤缓慢从生成的溶液中结晶出的米色产物，并用水洗涤残留物。
干燥后，得到3.64g结晶(6R,S)-四氢叶酸钙盐，其(6S)部分为50.5％，含量为94.6％(为盐，相对于干燥物质)。钙含量为1.12当量。
实施例6[Am592]
将12.0g(6S)-四氢叶酸在氮气下浆化在含有0.6g硫甘油的60ml水中，用50％氢氧化钠水溶液将pH值调节到7.5，然后用22.5g氯化钙于20ml水的溶液在85℃下处理浆液。在85℃下搅拌2h后，在吸滤下过滤结晶出的产物，用水洗涤。
干燥后，得到12.9g结晶(6S)-四氢叶酸钙盐，其(6S)部分为99.9％，含量为96.8％。如此得到的产物在50℃、pH值6下在水中的溶解度为0.12％。
实施例7[Am602]
使用12.0g(6R)-四氢叶酸和类似实施例6描述的处理方法，得到13.8g结晶(6R)-四氢叶酸钙盐，其(6R)部分为99.0％，含量为93％。如此得到的产物在50℃、pH值6下在水中的溶解度为0.07％。
实施例8[Am482]
将40.0g(6S)-四氢叶酸在氮气下浆化在160ml水中，用25％氨水在0～5℃下将pH值调节到9.8。将34g氯化镁于34ml水中的溶液加到生成的溶液中。将pH值调节到7.0并加入200ml乙醇后，在吸滤下过滤结晶出的米色产物，并用乙醇/水洗涤。
干燥后，得到37.0g结晶(6S)-四氢叶酸镁盐，其(6S)部分为99.4％，含量为91.7％。
实施例9[Am583]
将40.0g(6R)-四氢叶酸在氮气下浆化在含有4g硫甘油的400ml水中，用6.0g氢氧化镁和60.0g乙酸镁处理。在50℃下用25％氨水将pH值调节到9.0。冷却到20℃后，得到胶状物质，在加热到35℃下将它转移到流体悬浮液中。在35℃下，吸滤下过滤悬浮液，用水洗涤。
干燥后，得到18.0g结晶(6R)-四氢叶酸镁盐，其(6R)部分为99.4％，含量为92.0％。
实施例10[Am590]
将20.0g(6R,S)-四氢叶酸在氮气下浆化在含有2g硫甘油的200ml水中，用2.7g氢氧化镁处理，加热到50℃。加入30g乙酸镁后，用25％氨水将pH值调节到7.3，然后将溶液冷却到20℃并搅拌过夜。在吸滤下过滤出得到的悬浮液，用水洗涤。
干燥后，得到5.0g结晶(6R)-四氢叶酸镁盐，其(6R)部分为94.8％，含量为97.1％。
实施例11[Am506]
将28.0g(6R,S)-四氢叶酸在氮气下浆化在含有18g硫甘油的110ml水和75ml甲醇中，用9.5g氢氧化镁处理，然后用25％氨水在50℃下将pH值调节到9.3。在吸滤下过滤出在冷却到-5℃后得到的细悬浮液，用冷的甲醇/水混合物洗涤。
干燥后，得到10.5g结晶(6R,S)-四氢叶酸镁盐，其(6S)部分为49.5％，含量为95.9％。
实施例12[Am497]
将4.0g(6R,S)-四氢叶酸在氮气下浆化在16ml水中，用25％氨水将pH值调节到9.7，然后用3.2g氯化镁于3.2ml水中的溶液处理浆液。将生成的透明溶液加到200ml乙醇中。搅拌2h后，在5℃下，在吸滤下过滤得到的浅黄色悬浮液，然后用冷的乙醇/水混合物洗涤。
干燥后，得到4.5g结晶(6R,S)-四氢叶酸镁盐，其(6S)部分为49.3％，含量90.3％。
Claims (8)
1．一种结晶的(6R,S)-,(6S)-和(6R)-四氢叶酸钙盐。
2．一种结晶的(6R,S)-,(6S)-和(6R)-四氢叶酸镁盐。
3．一种制备结晶的(6R,S)-,(6S)-和/或(6R)-四氢叶酸的钙盐或镁盐的方法，其特征在于，(6R,S)-,(6R)-或(6S)-四氢叶酸在pH值7～10下,在极性介质中晶化。
4．根据权利要求3的方法，其特征在于，在升温下和/或从稀溶液中进行晶化。
5．根据权利要求4的方法，其特征在于，在水中或在水与其混溶的有机溶剂的混合物中进行晶化。
6．根据权利要求5的方法，其特征在于，乙酸或低分子量有机醇用作与水混溶的溶剂。
7．结晶(6R,S)-,(6S)-或(6R)-四氢叶酸的钙盐或镁盐作为生产药物的成分的应用。
8．含有结晶(6R,S)-,(6S)-或(6R)-四氢叶酸的钙盐或镁盐的药物制剂。
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| EP0600460A1 (de) * | 1992-12-01 | 1994-06-08 | Cerbios-Pharma S.A. | Verfahren zur Herstellung von (6S)-5,6,7,8-Tetrahydrofolsäure |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5124452A (en) * | 1978-07-10 | 1992-06-23 | Bioresearch S.P.A. | Process for producing d,1-5-methyltetrahydrofolic acid and its salts |
| MX169933B (es) * | 1987-09-18 | 1993-08-02 | Hideaki Yamada | Procedimiento para la produccion biologica de amidas |
| DE3821875C1 (zh) * | 1988-06-29 | 1990-02-15 | Eprova Ag, Forschungsinstitut, Schaffhausen, Ch | |
| CH681303A5 (zh) * | 1991-01-16 | 1993-02-26 | Eprova Ag | |
| CH684270A5 (de) * | 1991-10-04 | 1994-08-15 | Sapec Fine Chemicals | Verfahren zur Herstellung von Erdalkalimetallsalzen von (6R)-N(10)-Formyl-5,6,7,8-tetrahydrofolsäure. |
| GEP20012441B (en) * | 1993-04-02 | 2001-05-25 | Lonza Ag | Process for Preparing 3-Methylpiperidine and 3-Methylpyridine |
| CH686369A5 (de) * | 1994-05-09 | 1996-03-15 | Eprova Ag | Stabile kristalline (6S)- und (6R)-Tetrahydrofolseure. |
| CN1086311C (zh) * | 1994-05-23 | 2002-06-19 | 隆萨股份公司 | 烷基吡啶的氧化氨解 |
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1995
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1996
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- 1996-10-14 AT AT96116403T patent/ATE191482T1/de not_active IP Right Cessation
- 1996-10-14 ES ES96116403T patent/ES2145360T3/es not_active Expired - Lifetime
- 1996-10-14 EP EP96116403A patent/EP0773221B1/de not_active Expired - Lifetime
- 1996-10-14 PT PT96116403T patent/PT773221E/pt unknown
- 1996-10-14 DE DE59604878T patent/DE59604878D1/de not_active Expired - Lifetime
- 1996-10-14 DK DK96116403T patent/DK0773221T3/da active
- 1996-10-30 KR KR1019960050318A patent/KR100296162B1/ko not_active Expired - Fee Related
- 1996-10-31 AU AU70533/96A patent/AU707443B2/en not_active Ceased
- 1996-11-05 CN CN96112040A patent/CN1067392C/zh not_active Expired - Fee Related
- 1996-11-05 ZA ZA969284A patent/ZA969284B/xx unknown
- 1996-11-06 NO NO964699A patent/NO964699L/no not_active Application Discontinuation
- 1996-11-06 KR KR1019960052354A patent/KR100702201B1/ko not_active Expired - Fee Related
- 1996-11-06 JP JP29416096A patent/JP3382103B2/ja not_active Expired - Fee Related
- 1996-11-06 HU HU9603072A patent/HUP9603072A3/hu unknown
- 1996-11-06 RU RU96121625/04A patent/RU2187508C2/ru active
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2000
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0600460A1 (de) * | 1992-12-01 | 1994-06-08 | Cerbios-Pharma S.A. | Verfahren zur Herstellung von (6S)-5,6,7,8-Tetrahydrofolsäure |
Also Published As
| Publication number | Publication date |
|---|---|
| PT773221E (pt) | 2000-09-29 |
| HUP9603072A2 (en) | 1997-08-28 |
| TW533214B (en) | 2003-05-21 |
| KR970027056A (ko) | 1997-06-24 |
| CN1153176A (zh) | 1997-07-02 |
| EP0773221B1 (de) | 2000-04-05 |
| CH689831A5 (de) | 1999-12-15 |
| JPH09169759A (ja) | 1997-06-30 |
| CA2187409C (en) | 2000-08-22 |
| NO964699D0 (no) | 1996-11-06 |
| HU9603072D0 (en) | 1996-12-30 |
| GR3033727T3 (en) | 2000-10-31 |
| KR100702201B1 (ko) | 2007-11-12 |
| AU707443B2 (en) | 1999-07-08 |
| AU7053396A (en) | 1997-05-15 |
| ZA969284B (en) | 1997-05-07 |
| KR970027048A (ko) | 1997-06-24 |
| DK0773221T3 (da) | 2000-07-10 |
| DE59604878D1 (de) | 2000-05-11 |
| NO964699L (no) | 1997-05-09 |
| EP0773221A1 (de) | 1997-05-14 |
| US5817659A (en) | 1998-10-06 |
| RU2187508C2 (ru) | 2002-08-20 |
| HUP9603072A3 (en) | 1998-01-28 |
| CA2187409A1 (en) | 1997-05-08 |
| ATE191482T1 (de) | 2000-04-15 |
| JP3382103B2 (ja) | 2003-03-04 |
| KR100296162B1 (ko) | 2001-09-10 |
| ES2145360T3 (es) | 2000-07-01 |
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