CN1288147C - 氟立班丝氨(flibanserin)的稳定多晶体,其制备的技术法及其在药物制备的用途 - Google Patents
氟立班丝氨(flibanserin)的稳定多晶体,其制备的技术法及其在药物制备的用途 Download PDFInfo
- Publication number
- CN1288147C CN1288147C CNB028152263A CN02815226A CN1288147C CN 1288147 C CN1288147 C CN 1288147C CN B028152263 A CNB028152263 A CN B028152263A CN 02815226 A CN02815226 A CN 02815226A CN 1288147 C CN1288147 C CN 1288147C
- Authority
- CN
- China
- Prior art keywords
- flibanserin
- polycrystal
- water
- disease
- potassium
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 229960002053 flibanserin Drugs 0.000 title claims abstract description 38
- PPRRDFIXUUSXRA-UHFFFAOYSA-N flibanserin Chemical compound FC(F)(F)C1=CC=CC(N2CCN(CCN3C(NC4=CC=CC=C43)=O)CC2)=C1 PPRRDFIXUUSXRA-UHFFFAOYSA-N 0.000 title claims abstract description 37
- 239000003814 drug Substances 0.000 title claims abstract description 23
- 238000000034 method Methods 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- 230000008569 process Effects 0.000 title abstract description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 39
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 23
- 229910001868 water Inorganic materials 0.000 claims description 23
- 239000000203 mixture Substances 0.000 claims description 16
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims description 11
- 239000003513 alkali Substances 0.000 claims description 10
- 201000010099 disease Diseases 0.000 claims description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- 238000006243 chemical reaction Methods 0.000 claims description 9
- 125000006239 protecting group Chemical group 0.000 claims description 9
- 150000001298 alcohols Chemical class 0.000 claims description 7
- 150000001875 compounds Chemical class 0.000 claims description 7
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 6
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 6
- 239000000460 chlorine Substances 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 238000005336 cracking Methods 0.000 claims description 6
- 229910052744 lithium Inorganic materials 0.000 claims description 6
- 239000011591 potassium Substances 0.000 claims description 6
- 229910052700 potassium Inorganic materials 0.000 claims description 6
- 239000011734 sodium Substances 0.000 claims description 6
- 229910052708 sodium Inorganic materials 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 4
- 150000001342 alkaline earth metals Chemical class 0.000 claims description 4
- 229910052728 basic metal Inorganic materials 0.000 claims description 4
- 150000003818 basic metals Chemical class 0.000 claims description 4
- 239000011575 calcium Substances 0.000 claims description 4
- 229910052791 calcium Inorganic materials 0.000 claims description 4
- 208000035475 disorder Diseases 0.000 claims description 4
- 230000000694 effects Effects 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- 208000019901 Anxiety disease Diseases 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- 208000018737 Parkinson disease Diseases 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 208000024732 dysthymic disease Diseases 0.000 claims description 3
- 230000003340 mental effect Effects 0.000 claims description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 3
- 235000015320 potassium carbonate Nutrition 0.000 claims description 3
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- 201000000980 schizophrenia Diseases 0.000 claims description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 2
- 208000026139 Memory disease Diseases 0.000 claims description 2
- MYONAGGJKCJOBT-UHFFFAOYSA-N benzimidazol-2-one Chemical compound C1=CC=CC2=NC(=O)N=C21 MYONAGGJKCJOBT-UHFFFAOYSA-N 0.000 claims description 2
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 claims description 2
- 239000000920 calcium hydroxide Substances 0.000 claims description 2
- 229910001861 calcium hydroxide Inorganic materials 0.000 claims description 2
- 239000012442 inert solvent Substances 0.000 claims description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 2
- 235000012204 lemonade/lime carbonate Nutrition 0.000 claims description 2
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims description 2
- 239000011777 magnesium Substances 0.000 claims description 2
- 229910052749 magnesium Inorganic materials 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 238000004458 analytical method Methods 0.000 claims 1
- 125000001309 chloro group Chemical group Cl* 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 17
- 239000013543 active substance Substances 0.000 description 16
- -1 FLIBANSERIN compound Chemical class 0.000 description 12
- 239000007864 aqueous solution Substances 0.000 description 10
- 239000000243 solution Substances 0.000 description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 229940125782 compound 2 Drugs 0.000 description 6
- 238000000113 differential scanning calorimetry Methods 0.000 description 6
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 208000030047 Sexual desire disease Diseases 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 239000000825 pharmaceutical preparation Substances 0.000 description 4
- 230000035946 sexual desire Effects 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-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
- 239000004480 active ingredient Substances 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 3
- 238000000227 grinding Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 238000013019 agitation Methods 0.000 description 2
- 238000001949 anaesthesia Methods 0.000 description 2
- 230000037005 anaesthesia Effects 0.000 description 2
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 230000008676 import Effects 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 229940068968 polysorbate 80 Drugs 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- 239000011877 solvent mixture Substances 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 238000009827 uniform distribution Methods 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- 206010013786 Dry skin Diseases 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 206010057671 Female sexual dysfunction Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerol Natural products OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 1
- 229920000084 Gum arabic 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
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- 125000000066 S-methyl group Chemical group [H]C([H])([H])S* 0.000 description 1
- 241000978776 Senegalia senegal Species 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- OCBHHZMJRVXXQK-UHFFFAOYSA-M benzyl-dimethyl-tetradecylazanium;chloride Chemical compound [Cl-].CCCCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 OCBHHZMJRVXXQK-UHFFFAOYSA-M 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 229940125904 compound 1 Drugs 0.000 description 1
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- 239000012043 crude product Substances 0.000 description 1
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- 239000008298 dragée Substances 0.000 description 1
- 239000013583 drug formulation Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- JMANVNJQNLATNU-UHFFFAOYSA-N glycolonitrile Natural products N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 210000003928 nasal cavity Anatomy 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 229940097496 nasal spray Drugs 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 150000004885 piperazines Chemical class 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
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- 239000000843 powder Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
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- 238000003756 stirring Methods 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
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- 229940066771 systemic antihistamines piperazine derivative Drugs 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
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- 229910052623 talc Inorganic materials 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D233/20—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D233/26—Radicals substituted by carbon atoms having three bonds to hetero atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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- 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
- A61P25/20—Hypnotics; Sedatives
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- 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
- A61P25/22—Anxiolytics
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- 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
- A61P25/24—Antidepressants
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- 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
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
- C07D235/26—Oxygen atoms
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
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Abstract
本发明是关于氟立班丝氨(FLIBANSERIN)(1)的多晶体A，其制备的技术方法及其在制备药物中的用途。
Description
化合物1[2-(4-(3-三氟甲基-苯基)哌嗪-1-基)乙基]-2，3-二氢-1H-苯并咪唑-2-酮(氟立班丝氨)，是以其盐酸盐形式公开于欧洲专利申请EP-A-526434中，并且其具有以下的化学结构：
氟立班丝氨显示其对5-HT1A与5-HT2受体具有亲和力，因此对治疗多种疾病是有希望的治疗剂，例如抑郁症、精神分裂症、帕金森氏症、焦虑症、睡眠障碍、性及精神异常以及与年龄相关的记忆障碍。
在被准许上市作为药物之前，某种医药活性当然要通过药物活性剂满足其基本先决条件。但，药物活性剂还须符合各种其他必要条件。这些必要条件基于与该活性物质本身的性质相关的各种参数。这些参数的非限制性实例有：活性剂在各种环境条件下的稳定性，在制造药物制剂期间的稳定性，以及活性剂在最终药物组合物中的稳定性。被用于制备药物组合物的药物活性物质应该尽可能纯，并在各种环境条件下必须确保长期贮存的稳定性。例如，绝对要避免使用除了真正的活性物质外，还含有活性物质的裂解产物的药物组合物。在这种情况下，药剂中的活性物质的含量可能比指定的低。
在制剂中药物的均匀分布是关键因素，当药剂必须以低剂量给与时尤其如此。为确保均匀分布，活性物质的颗粒大小，例如可通过研磨而减小至适合的程度。因为药物活性物质的裂解作为研磨(或微粒化)的一种副作用，必需尽可能地避免，尽管在制程中需要严格的条件，但是在整个研磨过程中活性物质的高度稳定性是绝对必需的。只有当活性物质在研磨过程中具有足够的稳定性，才可能产生一种均质化的药物制剂，总是可以以再现方式含有指定量的活性物质。
在用于制备药物制剂的研磨过程中可能产生的另一问题是由这过程所引起的能量输入与施加在晶体表面的应力。在某种状态下，这可能导致多晶体的改变、在无定形结构中的改变或晶格中的改变。由于药物制剂的药物品质的需要，活性物质应总是具有同样的形态，由这观点而言，晶体活性物质的稳定性与特性要有严格的要求。
药物活性物质的稳定性在药物组合物中也是重要的，因为其决定该药剂的适用期；适用期为该药剂可没有任何风险地给予的时间长度。在各种贮存条件下，上述药物组合物中的药物的高度稳定性，对于患者与制造商而言都是额外的优点。
除了上述必要条件外，一般仍要记住，对于药物组合物的固态的任何改变若能增进其物理与化学稳定性，将显著优于该相同药物的较不稳定的形式。
因此本发明的目标是提供一种氟立班丝氨化合物的新颖且稳定的晶状体，其能符合上述加于药物活性物质的严格要求。
发明的详细说明
惊异地发现氟立班丝氨游离碱的一种特定多晶体符合上述的必要条件。
再者，已发现视氟立班丝氨合成期间所选择的条件，游离碱是可以产生不同的结晶变体(多晶形A与多晶形B)。
已惊异地发现这些不同的变体，可通过适当选择制程的所用条件而产生。
惊人地，已发现多晶体A(通过选择特定的反应条件可以获得的结晶形式)符合上述严格的必要条件，因此可以解决本发明所针对的问题。因此本发明涉及氟立班丝氨多晶体A，氟立班丝氨的多晶体A是以其熔点约161℃为其特点(由DSC测定；加热速率10K/min)。
多晶体B(氟立班丝氨的较不稳定的形式)表明其熔点约120℃(由DSC测定；加热速率10K/min)。虽然多晶体B因研磨产生机械应力的影响下，表示较低的稳定性，但多晶体A证实可以符合上面提及的稳定性的要求。
本发明的另一方面是关于以工业规模制造氟立班丝氨的多晶体A的方法。依照本发明的方法以流程1说明。
流程1：
将苯并咪唑酮
2与哌嗪衍生物
3于适合的溶剂中，在碱性反应条件下反应，而生成
1。在
2中，R代表一氨基保护基。所使用的保护基可以是任何一种用以保护氨基官能所用的保护基。其实例选自烷基，取代的烷基，杂取代的烷基，不饱和烷基，烷基取代的杂原子，取代或未取代的苯基，取代或未取代的苄基，烷氧羰基及芳氧羰基。优选的保护基可选自丁基、1，1-二苯甲基、甲氧甲基、苄氧甲基、三氯乙氧甲基，吡咯烷基甲基、氰甲基、新戊酰氧甲基、烯丙基、2-丙烯基，叔丁基二甲基硅烷基、甲氧基、硫甲基、4-甲氧苯基、苄基、4-甲氧苄基、2，4-二甲氧苄基、2-硝基苄基、叔丁氧羰基、苄氧羰基、苯氧羰基、4-氯苯氧羰基、4-硝基苯氧羰基、甲氧羰基及乙氧羰基。其中优选的保护基可选自叔丁氧羰基、乙氧羰基、甲氧羰基、苄氧羰基、苯氧羰基及2-丙烯基，以后者为最佳。在
3中的X表示一可脱离基，其可选自氯、溴、碘、甲磺酸酯基、三氟甲磺酸酯基、或对-甲苯磺酸酯基。X优选表示氯、溴或碘，以氯为最佳。合适的溶剂可选自水、醇类、水与醇类的混合物，极性质子惰性溶剂以及其与水的混合物。优选的溶剂可选自二甲基甲酰胺、二甲亚砜、乙腈、四氢呋喃、二烷、甲醇、乙醇、异丙醇以及上述溶剂中的一种或数种和水的混合物。优选的溶剂是易于与水混溶。优选使用水与醇类之一诸如甲醇、乙醇、异丙醇的混合物作为溶剂。在一优选实施方案中，使用水与异丙醇的混合物作为溶剂。所使用的碱可以是碱金属或碱土金属，如锂，钠，钾，钙的碳酸盐，例如：碳酸钠，碳酸锂，碳酸钾，碳酸钙，以碳酸钾为较佳。也可使用锂、钠及钾的碳酸氢盐。优选的也可使用碱金属或碱土金属诸如锂，钠，钾，镁及钙的氢氧化物，优选的是在醇类或水中的氢氧化钠，氢氧化钾，氢氧化锂及氢氧化钙。最佳的碱为氢氧化钠。碱优选是其水溶液的形式，优选是以浓的水溶液形式(例如30％～50％重量/体积)加入。在一最佳实施方案中，使用浓度为约45％重量/体积的氢氧化钠。
化合物
2与
3，是以介于1∶1至1∶2间的摩尔比例导入反应中。优选摩尔比是介于1∶1.1至1∶1.5之间。如上述水与异丙醇的混合物为进行本发明制程的最佳溶剂。在这溶剂混合物中，水与异丙醇的重量比优选为10∶1与1∶1之间，更佳为8∶1与3∶1之间，特佳为7∶1与5∶1之间。对于每摩尔化合物
2，优选使用约2-10公斤的上述溶剂混合物，更佳为3-8公斤，最佳为4-7公斤。在一优选实施方案中，该反应是使用浓度为约45％重量/体积的氢氧化钠作为碱而进行。对于每摩尔化合物
2，使用约0.1-1.5公斤的上述氢氧化钠水溶液，优选使用0.2-1.0公斤，以使用0.3-0.6公斤为特佳。在上述适当溶剂中含有化合物
2，
3及碱的反应混合物优选加热到至少50℃。在一优选实施方案中，该反应温度是在60℃至溶剂沸点的范围内，特佳为介于70～90℃之间。该反应混合物在上述温度下加热至少约10分钟至约12小时，优选约15分钟至约6小时，更佳约30分钟至约3小时。该反应混合物优选在上述温度下加热至少约45分钟至60分钟。
接着将该保护基R裂去，该裂去条件视R基的选择而定。若R为苄基，则裂解是在有适当的催化剂(例如：钯/碳)存在下，在醋酸中通过氢化反应而进行，或在氢溴酸水溶液中进行。如果R为甲氧羰基、乙氧羰基、苯氧羰基及4-硝基苯氧羰基，则可通过使用碱性水溶液诸如NaOH水溶液或KOH水溶液而进行裂解。如果R为叔丁氧羰基，则其可在例如盐酸或氢溴酸水溶液中进行裂解。如果R为2-丙烯基(按本发明为特佳保护基)时，则R的裂去可通过酸性反应条件下实施。在本发明的一特佳制程中，该2-丙烯基是通过使用一强的无机酸而进行裂解，该强的无机酸优选选自氢溴酸，盐酸及硫酸，其中以盐酸为更佳。盐酸可以以气态或水溶液的形式加入，优选是以水溶液形式加入，特佳为以浓的水溶态形式加入(约36％重量/体积)，对于每摩尔化合物
2，需加入1摩尔的盐酸。最佳的浓盐酸(36％重量/体积)加入量，对于每摩尔化合物
2而言，为50-500克，更佳为80-250克。特佳为对于每摩尔化合物
2，加入浓盐酸水溶液(36％重量/体积)约120-160克。视情况可加入额外的水。在温度约70-90℃下，将约30-70％，优选约35-60％的溶剂通过蒸馏而移除。在温度约60-80℃下，通过加入氢氧化钠水溶液(45％w/v)将残余物的pH值调整至约5-9，优选调整至约6-8。在温度约40-55℃下，可通过加入氢氧化钠水溶液(45％w/v)，而将pH值调整至约8-9。接着将该混合物冷却至约20-40℃，优选约30-35℃并离心。对于导入的每摩尔化合物
2，将这样得到的残余物用约100至750毫升，优选约200至500毫升，特佳约300至400毫升的水清洗，然后用异丙醇(每摩尔化合物
2用约50至250克；较佳用约100至200克)，及水相继冲洗直到清除氯为止。视情况可使该产物再进行纯化步骤。该纯化优选通过将化合物
1从例如丙酮中结晶而进行。
本发明的另一方面是关于通过上述方法获得的氟立班丝氨的多晶体A。
下面的合成实例，说明制备氟立班丝氨的多晶体A的方法。其只应视为例示的可能方法，而不应将本发明限于该内容。
实施例：
将375公斤的1-[(3-三氟甲基)苯基]-4-(2-氯乙基)哌嗪与2500公斤水及200公斤45％氢氧化钠水溶液，在一反应器中，在搅拌下加入169.2公斤的1-(2-丙烯基)-1，3-二氢-苯并咪唑-2H-酮，780公斤异丙醇，2000公斤水及220公斤45％氢氧化钠水溶液。将该反应混合物加热至75-85℃，接着加入160公斤的浓盐酸与200公斤水。将反应混合物在恒温下搅拌约45分钟。水与异丙醇的混合物(约3000公斤)通过蒸馏除去后，将残余物冷却至约65-75℃，通过加入125公斤氢氧化钠水溶液(45％w/v)，将pH值调整至约6.5-7.5。冷却至约45-50℃后，通过加入4公斤氢氧化钠水溶液(45％w/v)，将pH值调整至约8-9。接着将该混合物冷却至约30-35℃并离心。将如此得到的残余物以约340升水及126升异丙醇进行清洗，然后用水清洗直到清除氯为止。将该湿产物于温度约45-55℃下真空干燥，生成358公斤粗制氟立班丝氨的多晶体A。将这样得到的粗产物与1750公斤丙酮置于反应器中，并且将生成的混合物在搅拌下加热，直到回流。将所得的溶液过滤，并且通过蒸馏将滤液浓缩。维持温度于0-5℃约1小时，接着通过过滤分离出沉淀固体，并且于55℃干燥至少12小时。最后产量为280公斤的纯氟立班丝氨的多晶体A。
上述氟立班丝氨的多晶体A是通过DSC(差示扫描热量测定法)定性。对于多晶体A所测得的峰温度约为161℃。为了通过DSC鉴定特性，应用配备有TC 10-A处理器与DSC 20电池的Mettler TA 3000系统。其加热速率为10K/min。
此外，氟立班丝氨的多晶体A还通过粉末X射线衍射仪进行定性。根据下列条件，获得多晶体A的X射线粉末衍射图。
设备：配备有一数字microvax 2000的Philips PW 1800/10衍射仪
设定参数：X射线
管型： Cu(长细焦距)
波长(λ)： Kα1＝1.54060A
Kα2＝1.54439A
强度比(α2/α1)： 0.500
起始角度[°2Θ]： 2.000
结束角度[°2Θ]： 60.000
间距大小[°2Θ]： 0.020
最大强度[s]： 7310.250
扫描型式： 持续
最小峰顶端宽度： 0.00
最大峰顶端宽度： 1.00
峰底部宽度： 2.00
最小有效数： 0.75
峰数： 69
发生器：高电压： 50KV
管电流： 30mA
由多晶体A获得的粉末X射线衍射图被说明于图1中。其近似值被收集于表1中。
表1
| 角度[°2Θ] | d值α1[A] | d值α2[A] | 峰宽度[°2Θ] | 峰强度[counts] | 回强度[counts] | 相对强度[％] | 有效性 |
| 5.1959.0459.33510.02510.59511.29013.22514.59515.46016.65517.08517.28517.42018.14018.65019.14019.82020.08020.38521.21521.89022.63023.21024.35524.61024.99525.26026.57527.15527.31027.86528.21028.325 | 16.99679.76899.46608.81608.34307.83096.68916.06425.72685.31855.18565.12605.08664.88634.75384.63324.47574.41844.35304.18454.05703.92593.82913.65163.61443.55963.52283.35143.28113.26293.19913.16083.1482 | 17.03909.79319.48968.83798.36377.85036.70586.07935.74105.33175.19855.13885.09924.89844.76564.64474.48694.42964.36384.19494.06703.93573.83863.66073.62343.56843.53163.35973.28933.27103.20713.16863.1560 | 0.9600.1000.0800.1400.1400.1400.1800.1800.1400.2000.1000.0600.1000.1800.1200.1400.1600.1400.1600.1600.2000.2800.1200.0600.1400.1000.1200.2400.1400.1000.1200.1000.140 | 8921144002044675484044186515134713991204104310637310362454022652369773427748427253540529557242167676742014671789 | 699698100102104112121125130132135135139142144146149149154156161164169172174174182185185188190190 | 0.11.31.65.52.86.47.55.557.37.018.419.116.514.314.5100.049.673.936.35.010.658.56.637.348.47.27.633.19.210.55.720.124.5 | 1.050.970.887.183.466.9113.109.1723.2012.382.782.264.7113.140.9132.779.0221.0623.255.783.0974.663.331.1617.081.013.0242.581.322.751.080.794.41 |
| 28.65029.52030.25031.10531.90532.35033.30033.64034.88035.27536.05536.91037.16037.68039.43539.67540.32540.93041.44541.99042.67043.14544.19046.09546.51048.30548.90050.33051.03553.55054.50055.42056.22056.77057.40558.500 | 3.11323.02342.95212.87292.80262.76512.68842.66202.57012.54222.48902.43332.41752.38532.28312.26982.23472.20312.17692.14992.11722.09502.04781.96751.95091.88261.86101.81151.78811.70991.68231.65651.63481.62031.60391.5764 | 3.12103.03092.95942.88002.80962.77202.69502.66862.57652.54862.49522.43932.42352.39122.28882.27552.24032.20862.18232.15522.12252.10022.05291.97241.95581.88721.86571.81601.79251.71411.68651.66061.63891.62431.60791.5804 | 0.1800.2200.1200.3600.1000.1200.1800.1000.2000.2400.2800.3200.1200.2400.2800.0800.1600.1200.2400.1200.1600.1200.1600.1600.2400.2000.2400.1600.0800.4800.4000.3200.3200.2400.2400.240 | 12041011159282339237134740420229920216921624044939652048037253842843337627931050661543741617713013012114211267 | 190196199204207210216216222225228234234237246246250253256259262266269279282292296303306317324328331335339342 | 16.513.82.23.94.63.218.45.52.84.12.82.33.03.36.15.47.16.65.17.45.95.95.13.84.26.98.46.05.72.41.81.81.71.91.50.9 | 11.6515.741.228.140.963.0114.061.451.044.843.780.902.141.582.670.820.952.662.651.311.451.500.890.860.872.061.671.730.932.841.371.720.871.591.191.57 |
在氟立班丝氨的药物功效方面，本发明还涉及氟立班丝氨的多晶体A作为药物的用途。
本发明的再一方面是关于氟立班丝氨的多晶体A的用途，它用于制备治疗其中使用对5-HT1A与5-HT2受体具有亲和力的化合物具有疗效的疾病用的药物组合物。
本发明的又一方面也关于氟立班丝氨的多晶体A的用途，其用于制备一种药物组合物，以治疗选自抑郁症、精神分裂症、帕金森氏症、焦虑症、睡眠障碍、性与精神异常以及与年龄相关的记忆力障碍的疾病。
本发明尤其关于氟立班丝氨的多晶体A在制备治疗性欲异常的药物上的用途。
在一优选实施方案中，本发明是关于氟立班丝氨的多晶体A在制备治疗选自下列疾病的药物中的用途：低度性欲症，性欲失调症，性欲缺乏症，无性欲症，性欲压制症，抑制性欲症，性欲障碍症及性冷感。
在一优选实施方案中，本发明是关于氟立班丝氨的多晶体A在制备治疗选自下列疾病的药物中的用途：低度性欲症，无性欲症，性欲缺乏症，性欲下降症及性欲压制症。
在一特佳的实施例中，本发明关于氟立班丝氨的多晶体A在制备治疗选自低度性欲症及无性欲症中的药物中的用途。
氟立班丝氨的多晶体A的上述治疗功效，对男性与女性都有效。然而，根据本发明的再一方面的氟立班丝氨的多晶体A优选用于制备治疗女性性功能障碍的药剂。
不论障碍是否终生存在或后天获得，氟立班丝氨的多晶体A的效能都可观察到，并与病源无关(器质性-身体及药物引起的；心理因素；器质性(身体及药物引起两者)与心理因素的组合；或不明原因)。
本发明的再一特征是为提供一种药物组合物，其包含氟立班丝氨的多晶体A作为活性成份，以及一种或多种药用载剂、稀释剂或赋形剂。对于投药氟立班丝氨的多晶体A可以固态，液态或喷雾形式结合进入习知药物制剂中。该组合物例如可以适于口服，直肠，肠胃外投药的剂型给予或由鼻腔吸入；优选的剂型包括，例如，胶囊剂、片剂、糖衣片剂、针剂、栓剂及鼻喷雾剂。
该活性成份可结合习知药物组合物中通常使用的赋形剂或载体，例如滑石、阿拉伯胶、乳糖、明胶、硬脂酸镁、玉米淀粉，水性或非水性介质，聚乙烯吡咯烷酮、半合成的脂肪酸甘油酯、氯苄烷铵、磷酸钠、EDTA及聚山梨酸酯80(polysorbate 80)。该组合物有利地配制成剂量单位。每一剂量单位配制成提供单剂量的活性成份。每单剂量单位宜含有0.01至100毫克，优选0.1至50毫克。
Claims (9)
1.一种氟立班丝氨(
1)的结晶的多晶体A
其在使用DSC进行热分析期间，于161℃具有最大吸热，通过粉末X射线衍射，在2Θ角度，长细焦距的Cu管型，波长Kα1＝1.54060A和Kα2＝1.54439A，强度比α2/α1∶0.500，具有下列衍射峰：15.46±0.01，19.14±0.01，19.82±0.01，20.08±0.01，22.63±0.01，24.61±0.01。
2.氟立班丝氨
1，其包含权利要求1的多晶体A。
3.一种制备权利要求1或2的氟立班丝氨
1的多晶体A的方法，
其特征在于：在第一步骤中，将苯并咪唑酮
2与哌嗪
3反应，
式
2中R是代表一适当的氨基保护基，
式
3中X是表示一选自氯，溴，碘，甲磺酸酯基，三氟甲磺酸酯基及对-甲苯磺酸酯基的离去基，在选自水、醇类、水与醇类的混合物、极性质子惰性溶剂及其与水的混合物的适当溶剂中，在有适当碱存在下进行反应；接着在第二反应步骤中，在适当的裂解条件下，将氨基保护基R去除；其中该碱选自碱金属或碱土金属锂、钠、钾、钙的碳酸盐，锂、钠及钾的碳酸氢盐；碱金属或碱土金属锂，钠，钾，镁及钙的氢氧化物。
4.如权利要求3的方法，其特征为，化合物
2与
3的反应是在温度为50℃至90℃下进行。
5.如权利要求4的方法，其特征为，加热进行10分钟至12小时。
6.如权利要求3的方法，其特征为，该碱选自碳酸钠、碳酸锂、碳酸钾、碳酸钙；在醇类或水中的氢氧化钠，氢氧化钾，氢氧化锂及氢氧化钙。
7.如权利要求1或2的氟立班丝氨
1的多晶体A在制备治疗，其中使用能显示对5-HT1A及5-HT2具亲和力的治疗有效量的化合物具有疗效的疾病的药物中的用途。
8.如权利要求1或2的氟立班丝氨
1的多晶体A在制备治疗，选自抑郁症、精神分裂症、帕金森氏症、焦虑症、睡眠障碍、性及精神异常及与年龄相关记忆力障碍疾病的药物中的用途。
9.一种药物组合物，其包含权利要求1或2的氟立班丝氨
1的多晶体A作为活性成分，视情况可与一种或多种药用载剂、稀释剂或赋形剂混合。
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP01118593.1 | 2001-08-02 | ||
| EP01118593 | 2001-08-02 | ||
| EP01130180.1 | 2001-12-19 | ||
| EP01130180 | 2001-12-19 |
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|---|---|
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| CN1288147C true CN1288147C (zh) | 2006-12-06 |
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| EP (2) | EP1414816B1 (zh) |
| JP (1) | JP3822601B2 (zh) |
| KR (1) | KR100899297B1 (zh) |
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| BR (1) | BR0211601A (zh) |
| CA (1) | CA2450093C (zh) |
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| ES (1) | ES2237694T3 (zh) |
| HK (1) | HK1070063A1 (zh) |
| HR (1) | HRP20040107B1 (zh) |
| HU (1) | HU228666B1 (zh) |
| IL (2) | IL159151A0 (zh) |
| MX (1) | MXPA04000913A (zh) |
| MY (1) | MY127294A (zh) |
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| PL (1) | PL210224B1 (zh) |
| PT (1) | PT1414816E (zh) |
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| US7183410B2 (en) | 2001-08-02 | 2007-02-27 | Bidachem S.P.A. | Stable polymorph of flibanserin |
| DE10138273A1 (de) * | 2001-08-10 | 2003-02-27 | Boehringer Ingelheim Pharma | Arzneimittel mit neuroprotektiver Wirkung |
| UA78974C2 (en) | 2001-10-20 | 2007-05-10 | Boehringer Ingelheim Pharma | Use of flibanserin for treating disorders of sexual desire |
| US10675280B2 (en) | 2001-10-20 | 2020-06-09 | Sprout Pharmaceuticals, Inc. | Treating sexual desire disorders with flibanserin |
| SI1511489T1 (sl) * | 2002-05-22 | 2011-06-30 | Boehringer Ingelheim Pharma | Novi farmacevtski sestavki, ki vsebujejo polimorf A flibanserina |
| WO2006119884A2 (en) * | 2005-05-06 | 2006-11-16 | Boehringer Ingelheim International Gmbh | Method for the treatment of drug abuse with flibanserin |
| EP1912650B8 (en) | 2005-08-03 | 2017-10-18 | Sprout Pharmaceuticals, Inc. | Use of flibanserin in the treatment of obesity |
| EP1945214A1 (en) | 2005-10-29 | 2008-07-23 | Boehringer Ingelheim International GmbH | Benzimidazolone derivatives for the treatment of premenstrual and other female sexual disorders |
| US20070105869A1 (en) * | 2005-11-08 | 2007-05-10 | Stephane Pollentier | Use of flibanserin for the treatment of pre-menopausal sexual desire disorders |
| EP1991228A1 (en) * | 2006-02-28 | 2008-11-19 | Boehringer Ingelheim International GmbH | Treatment of prevention of valvular heart disease with flibanserin |
| MX2008013827A (es) * | 2006-05-09 | 2008-11-10 | Boehringer Ingelheim Int | Uso de flibanserina para el tratamiento de trastornos posmenopausicos del deseo sexual. |
| US20090312242A1 (en) | 2006-06-30 | 2009-12-17 | Ramiro Castro | Flibanserin for the treatment of urinary incontinence and related diseases |
| CA2660476C (en) | 2006-08-14 | 2015-11-17 | Boehringer Ingelheim International Gmbh | Formulations of flibanserin and method for manufacturing the same |
| CL2007002214A1 (es) | 2006-08-14 | 2008-03-07 | Boehringer Ingelheim Int | Composicion farmaceutica en la forma de comprimido, donde al menos la longitud del comprimido en el estado anterior de la aplicacion es al menos 7/12 del diametro pilorico del paciente y despues de ingerirlo en estado alimentado, la longitud del comp |
| AR062321A1 (es) | 2006-08-25 | 2008-10-29 | Boehringer Ingelheim Int | Sistema de liberacion controlada y metodo para fabricarlo |
| WO2008061966A2 (en) * | 2006-11-22 | 2008-05-29 | Boehringer Ingelheim International Gmbh | New use of flibanserin |
| CA2672957C (en) | 2006-12-20 | 2015-04-14 | Boehringer Ingelheim International Gmbh | Sulfated benzimidazolone derivatives having mixed serotonine receptor affinity |
| EP1955699A1 (en) * | 2007-02-08 | 2008-08-13 | Boehringer Ingelheim Pharma GmbH & Co. KG | Use of flibanserin for the treatment of insomnia |
| UY31335A1 (es) | 2007-09-12 | 2009-04-30 | Tratamiento de sintomas vasomotores | |
| EP2090297A1 (en) | 2008-02-13 | 2009-08-19 | Boehringer Ingelheim International GmbH | Formulations of flibanserin |
| CA2686480A1 (en) | 2008-12-15 | 2010-06-15 | Boehringer Ingelheim International Gmbh | New salts |
| CN104926734B (zh) * | 2015-07-07 | 2017-04-05 | 苏州立新制药有限公司 | 氟班色林的制备方法 |
| WO2017076356A1 (zh) * | 2015-11-05 | 2017-05-11 | 苏州晶云药物科技有限公司 | 氟班色林的新晶型及其制备方法 |
| US11492343B2 (en) | 2016-01-31 | 2022-11-08 | Xiaoming Meng | Polymorph of flibanserin and preparation method thereof and use of same |
| CN111303043A (zh) * | 2019-04-19 | 2020-06-19 | 武汉万知化工医药有限公司 | 一种氟班色林盐酸盐的制备方法 |
| CN115919860B (zh) * | 2022-12-05 | 2023-11-10 | 中国药科大学 | 氟班色林在制备治疗雄激素脱发药物中的用途 |
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