WO1999055699A1 - Paroxetine 10-camphorsulfonate for treatment of cns disorders - Google Patents
Paroxetine 10-camphorsulfonate for treatment of cns disorders Download PDFInfo
- Publication number
- WO1999055699A1 WO1999055699A1 PCT/GB1999/001246 GB9901246W WO9955699A1 WO 1999055699 A1 WO1999055699 A1 WO 1999055699A1 GB 9901246 W GB9901246 W GB 9901246W WO 9955699 A1 WO9955699 A1 WO 9955699A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- paroxetine
- camphorsulfonate
- solution
- salt
- treatment
- Prior art date
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- AHOUBRCZNHFOSL-UHFFFAOYSA-N Paroxetine hydrochloride Natural products C1=CC(F)=CC=C1C1C(COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-UHFFFAOYSA-N 0.000 title claims abstract description 32
- 229960002296 paroxetine Drugs 0.000 title claims abstract description 32
- AHOUBRCZNHFOSL-YOEHRIQHSA-N (+)-Casbol Chemical compound C1=CC(F)=CC=C1[C@H]1[C@H](COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-YOEHRIQHSA-N 0.000 title claims description 29
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 title claims description 15
- 238000011282 treatment Methods 0.000 title abstract description 7
- 239000012458 free base Substances 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 9
- 238000002360 preparation method Methods 0.000 claims description 9
- 150000001875 compounds Chemical class 0.000 claims description 8
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 claims description 6
- 239000003921 oil Substances 0.000 claims description 5
- 238000002425 crystallisation Methods 0.000 claims description 3
- 230000008025 crystallization Effects 0.000 claims description 3
- 238000004108 freeze drying Methods 0.000 claims description 2
- 239000000155 melt Substances 0.000 claims description 2
- 238000001556 precipitation Methods 0.000 claims description 2
- 230000000069 prophylactic effect Effects 0.000 claims description 2
- 238000001953 recrystallisation Methods 0.000 claims description 2
- 238000007711 solidification Methods 0.000 claims description 2
- 230000008023 solidification Effects 0.000 claims description 2
- 238000001694 spray drying Methods 0.000 claims description 2
- 238000001291 vacuum drying Methods 0.000 claims description 2
- -1 Paroxetine 10-camphorsulfonates Chemical class 0.000 abstract description 3
- 208000015114 central nervous system disease Diseases 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 27
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
- 150000003839 salts Chemical class 0.000 description 19
- 239000002904 solvent Substances 0.000 description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 239000000203 mixture Substances 0.000 description 13
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 9
- 208000035475 disorder Diseases 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 239000002585 base Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 208000021384 Obsessive-Compulsive disease Diseases 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- RBLGLDWTCZMLRW-UHFFFAOYSA-K dicalcium;phosphate;dihydrate Chemical compound O.O.[Ca+2].[Ca+2].[O-]P([O-])([O-])=O RBLGLDWTCZMLRW-UHFFFAOYSA-K 0.000 description 4
- 235000019359 magnesium stearate Nutrition 0.000 description 4
- 229940080313 sodium starch Drugs 0.000 description 4
- 239000012453 solvate Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- MIOPJNTWMNEORI-MHPPCMCBSA-N [(4r)-7,7-dimethyl-3-oxo-4-bicyclo[2.2.1]heptanyl]methanesulfonic acid Chemical compound C1C[C@]2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-MHPPCMCBSA-N 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
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- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- 206010036618 Premenstrual syndrome Diseases 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 239000000935 antidepressant agent Substances 0.000 description 2
- 238000010533 azeotropic distillation Methods 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 2
- 229940038472 dicalcium phosphate Drugs 0.000 description 2
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- DSSYKIVIOFKYAU-XCBNKYQSSA-N (R)-camphor Chemical compound C1C[C@@]2(C)C(=O)C[C@@H]1C2(C)C DSSYKIVIOFKYAU-XCBNKYQSSA-N 0.000 description 1
- MIOPJNTWMNEORI-XVKPBYJWSA-N (R)-camphorsulfonic acid Chemical compound C1C[C@]2(CS(O)(=O)=O)C(=O)C[C@H]1C2(C)C MIOPJNTWMNEORI-XVKPBYJWSA-N 0.000 description 1
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- 208000007848 Alcoholism Diseases 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 229920003084 Avicel® PH-102 Polymers 0.000 description 1
- 208000032841 Bulimia Diseases 0.000 description 1
- 206010006550 Bulimia nervosa Diseases 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- 208000000094 Chronic Pain Diseases 0.000 description 1
- 241000723346 Cinnamomum camphora Species 0.000 description 1
- 208000020401 Depressive disease Diseases 0.000 description 1
- 208000019695 Migraine disease Diseases 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 206010039966 Senile dementia Diseases 0.000 description 1
- 206010041250 Social phobia Diseases 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- MIOPJNTWMNEORI-ZDFGOMNRSA-N [2,2,3,3,4,5,5-heptadeuterio-7-methyl-6-oxo-7-(trideuteriomethyl)-1-bicyclo[2.2.1]heptanyl]methanesulfonic acid Chemical compound C12(C(=O)C(C(C(C1([2H])[2H])([2H])[2H])(C2(C([2H])([2H])[2H])C)[2H])([2H])[2H])CS(=O)(=O)O MIOPJNTWMNEORI-ZDFGOMNRSA-N 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 201000007930 alcohol dependence Diseases 0.000 description 1
- 208000022531 anorexia Diseases 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 230000000648 anti-parkinson Effects 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 239000000939 antiparkinson agent Substances 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 229960000846 camphor Drugs 0.000 description 1
- 229930008380 camphor Natural products 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
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- 238000006243 chemical reaction Methods 0.000 description 1
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- 239000013078 crystal Substances 0.000 description 1
- 206010061428 decreased appetite Diseases 0.000 description 1
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- 238000004090 dissolution Methods 0.000 description 1
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- 208000024732 dysthymic disease Diseases 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
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- 238000009472 formulation Methods 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 206010027599 migraine Diseases 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000001483 mobilizing effect Effects 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 238000000643 oven drying Methods 0.000 description 1
- 208000019906 panic disease Diseases 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 208000002271 trichotillomania Diseases 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
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- A—HUMAN NECESSITIES
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- 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
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/14—Drugs for dermatological disorders for baldness or alopecia
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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
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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
- A61P25/04—Centrally acting analgesics, e.g. opioids
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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
- A61P25/06—Antimigraine agents
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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
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- 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
-
- 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
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/32—Alcohol-abuse
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring 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 to atoms of the carbocyclic ring
- C07D317/64—Oxygen atoms
Definitions
- the present invention relates to a novel compound, to processes for preparing it and to its use in treating medical disorders.
- 10-camphorsulfonic acid exists in enantiomeric forms and this invention includes salts with both D-(+)-10-camphorsulfonic acid and (lR)-(-)-10-camphorsulfonic acid and racemic mixtures of both salts.
- novel salt of this invention is provided in non-crystalline form, which may a solid or an oil.
- the oil is preferably absorbed on a solid carrier, especially a carrier that is usable as a component of a pharmaceutical composition
- novel salt of this invention is provided in crystalline form.
- each polymorph forms another aspect of this invention.
- Paroxetine camphor- 10-sulfonates may be prepared by contacting stoichiometric amounts of the acid and paroxetine free base.
- the acid or base is in solution, more preferably both are in solution. Elevated temperature can be used to bring the acid into
- ⁇ 1 - solution but good yields of the salt are obtained by evaporation of some or all of the solvent or by controlled cooling, preferably in stages.
- Most commonly used solvents are suitable for mobilising paroxetine free base, for example toluene, alcohols such as methanol, ethanol, propan-2-ol, esters such as ethyl acetate, ketones such as acetone and butanone, halogenated hydrocarbons such as dichloromethane, and ethers such as tetrahydrofuran and diethyl ether, but solvents in which camphor- 10-sulfonic acids are very insoluble are preferably avoided.
- Suitable solvents for camphor- 10-sulfonic acids include water, alcohols, ethyl acetate and acetic acid.
- the salt may be isolated in solid form by conventional means from a solution thereof obtained as above.
- the non-crystalline salt may be prepared by precipitation, spray drying, and freeze drying of solutions, or vacuum drying of oils, or solidification of melts obtained from reaction of the free base and the acid.
- the crystalline salt may be prepared by crystallization or recrystallization from appropriate solvents.
- Solvates may be returned to the unsolvated salt by heating, for example by oven-drying, or by treatment with a displacement solvent which does not form a solvate.
- water Prior to the isolation of the paroxetine salt, water may be removed by azeotropic distillation to avoid the formation of hydrates or to obtain the product in anhydrous form.
- suitable solvents for the solution of the salt are those which form an azeotrope with water such as toluene and propan-2-ol. It should also be appreciated that mixtures of solvents can also be used to aid the azeotropic removal of water.
- crystallization may be carried out from any solvent which allows formation of the desired crystal structure, using seeds of the desired structure where necessary or desirable.
- individual polymorphs are preferably crystallized directly from a solution of the salt, although recrystallizing a solution of one polymorph using seeds of another polymorph may also be carried out.
- -2- Paroxetine free base may be prepared according to the procedures generally outlined in US Patent No 4,007,196 and EP-B-0 223403. D-10-camphorsulfonic acid and L-10- camphorsulfonic acid are commercially available.
- the compounds of this invention may be used to treat and prevent the following disorders:
- the present invention further provides a method for treating and/or preventing any one or more of the Disorders by administering an effective and/or prophylactic amount of a salt of the invention to a sufferer in need thereof.
- the present invention further provides a pharmaceutical composition for use in the treatment and/or prevention of the Disorders which comprises an admixture of a salt of the invention with a pharmaceutically acceptable carrier.
- the present invention also provides the use of a salt of the invention for treating and/or preventing the Disorders.
- the present invention also provides the use of a salt of the invention in the manufacture of a medicament for treating and/or preventing the Disorders.
- the present invention is applied to the treatment of depression, OCD and panic.
- compositions of this invention are usually adapted for oral administration, but formulations for dissolution for parental administration are also within the scope of this invention.
- composition is usually presented as a unit dose composition containing from 1 to 200mg of active ingredient calculated on a free base basis, more usually from 5 to lOOmg, for example 10 to 50mg such as 10, 12.5, 15, 20, 25, 30 or 40mg by a human patient. Most preferably unit doses contain 20mg of active ingredient calculated on a free base basis. Such a composition is normally taken from 1 to 6 times daily, for example 2, 3 or 4 times daily so that the total amount of active agent administered is within the range 5 to 400mg of active ingredient calculated on a free base basis. Most preferably the unit dose is taken once a day.
- Preferred unit dosage forms include tablets or capsules.
- compositions of this invention may be formulated by conventional methods of admixture such as blending, filling and compressing.
- Suitable carriers for use in this invention include a diluent, a binder, a disintegrant, a colouring agent, a flavouring agent and/or preservative. These agents may be utilized in conventional manner, for example in a manner similar to that already used for marketed anti-depressant agents.
- compositions include those described EP-B-0- 223403, and US 4,007,196 in which the products of the present invention may be used as the active ingredients.
- Example 2 Larger scale preparation of crystalline salt.
- Example 4 Larger scale preparation of crystalline salt.
- the tablets are made satisfactorily on a single punch or a Rotary press.
- Paroxetine 10-camphorsulfonate, Sodium Starch Glycollate and Dicalcium Phosphate Dihydrate are screened and mixed together in a suitable mixer. (Planetary, Cuble or High Energy Shear mixer.)
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Abstract
Paroxetine 10-camphorsulfonates are useful in the treatment of certain CNS disorders.
Description
PAROXETINE 10-CAMPHORSULFONATE FOR TREATMENT OF CNS
DISORDERS
The present invention relates to a novel compound, to processes for preparing it and to its use in treating medical disorders.
Pharmaceutical products with antidepressant and anti-Parkinson properties are described in US-A-3912743 and US-A-4007196. An especially important compound among those disclosed is paroxetine, the (-)trans isomer of 4-(4'-fluorophenyl)-3-(3',4'-methylenedioxy- phenoxymethyl)-piperidine. This compound is used in therapy as the hydrochloride salt for the treatment and prophylaxis of inter alia depression, obsessive compulsive disorder (OCD) and panic.
We have now surprisingly discovered a novel salt of paroxetine which may be used as an alternative to the currently marketed hydrochloride, or as an intermediate in the preparation of the hydrochloride.
According to the present invention there is provided a paroxetine camphor 10-sulfonate. 10-camphorsulfonic acid exists in enantiomeric forms and this invention includes salts with both D-(+)-10-camphorsulfonic acid and (lR)-(-)-10-camphorsulfonic acid and racemic mixtures of both salts.
In one aspect the novel salt of this invention is provided in non-crystalline form, which may a solid or an oil. The oil is preferably absorbed on a solid carrier, especially a carrier that is usable as a component of a pharmaceutical composition
In another aspect the novel salt of this invention is provided in crystalline form. When the crystalline form exists as more than one polymorph, each polymorph forms another aspect of this invention.
Paroxetine camphor- 10-sulfonates may be prepared by contacting stoichiometric amounts of the acid and paroxetine free base. Preferably either the acid or base is in solution, more preferably both are in solution. Elevated temperature can be used to bring the acid into
■ 1 -
solution, but good yields of the salt are obtained by evaporation of some or all of the solvent or by controlled cooling, preferably in stages. Most commonly used solvents are suitable for mobilising paroxetine free base, for example toluene, alcohols such as methanol, ethanol, propan-2-ol, esters such as ethyl acetate, ketones such as acetone and butanone, halogenated hydrocarbons such as dichloromethane, and ethers such as tetrahydrofuran and diethyl ether, but solvents in which camphor- 10-sulfonic acids are very insoluble are preferably avoided. Suitable solvents for camphor- 10-sulfonic acids include water, alcohols, ethyl acetate and acetic acid.
The salt may be isolated in solid form by conventional means from a solution thereof obtained as above. For example, the non-crystalline salt may be prepared by precipitation, spray drying, and freeze drying of solutions, or vacuum drying of oils, or solidification of melts obtained from reaction of the free base and the acid. The crystalline salt may be prepared by crystallization or recrystallization from appropriate solvents.
When the salt is obtained as a solvate, by association with the solvent in which it is dissolved, such solvate forms a further aspect of this invention. Solvates may be returned to the unsolvated salt by heating, for example by oven-drying, or by treatment with a displacement solvent which does not form a solvate.
Prior to the isolation of the paroxetine salt, water may be removed by azeotropic distillation to avoid the formation of hydrates or to obtain the product in anhydrous form. In that case, suitable solvents for the solution of the salt are those which form an azeotrope with water such as toluene and propan-2-ol. It should also be appreciated that mixtures of solvents can also be used to aid the azeotropic removal of water.
More generally, crystallization may be carried out from any solvent which allows formation of the desired crystal structure, using seeds of the desired structure where necessary or desirable. When polymorphs exist, individual polymorphs are preferably crystallized directly from a solution of the salt, although recrystallizing a solution of one polymorph using seeds of another polymorph may also be carried out.
-2-
Paroxetine free base may be prepared according to the procedures generally outlined in US Patent No 4,007,196 and EP-B-0 223403. D-10-camphorsulfonic acid and L-10- camphorsulfonic acid are commercially available.
The compounds of this invention may be used to treat and prevent the following disorders:
Alcoholism Anxiety
Depression Obsessive Compulsive Disorder
Panic Disorder Chronic Pain
Obesity Senile Dementia
Migraine Bulimia
Anorexia Social Phobia
Pre-Menstrual Syndrome (PMS) Adolescent Depression
Trichotillomania Dysthymia
Substance Abuse
These disorders are herein after referred to as "the Disorders"
The present invention further provides a method for treating and/or preventing any one or more of the Disorders by administering an effective and/or prophylactic amount of a salt of the invention to a sufferer in need thereof.
The present invention further provides a pharmaceutical composition for use in the treatment and/or prevention of the Disorders which comprises an admixture of a salt of the invention with a pharmaceutically acceptable carrier.
The present invention also provides the use of a salt of the invention for treating and/or preventing the Disorders.
The present invention also provides the use of a salt of the invention in the manufacture of a medicament for treating and/or preventing the Disorders.
Most suitably the present invention is applied to the treatment of depression, OCD and panic.
The compositions of this invention are usually adapted for oral administration, but formulations for dissolution for parental administration are also within the scope of this invention.
-4-
The composition is usually presented as a unit dose composition containing from 1 to 200mg of active ingredient calculated on a free base basis, more usually from 5 to lOOmg, for example 10 to 50mg such as 10, 12.5, 15, 20, 25, 30 or 40mg by a human patient. Most preferably unit doses contain 20mg of active ingredient calculated on a free base basis. Such a composition is normally taken from 1 to 6 times daily, for example 2, 3 or 4 times daily so that the total amount of active agent administered is within the range 5 to 400mg of active ingredient calculated on a free base basis. Most preferably the unit dose is taken once a day.
Preferred unit dosage forms include tablets or capsules.
The compositions of this invention may be formulated by conventional methods of admixture such as blending, filling and compressing.
Suitable carriers for use in this invention include a diluent, a binder, a disintegrant, a colouring agent, a flavouring agent and/or preservative. These agents may be utilized in conventional manner, for example in a manner similar to that already used for marketed anti-depressant agents.
Specific examples of pharmaceutical compositions include those described EP-B-0- 223403, and US 4,007,196 in which the products of the present invention may be used as the active ingredients.
The following Examples illustrate the present invention:
Example 1: Preparation of crystalline paroxetine D-(+)-10-camphorsulfonate
A solution of paroxetine base in toluene (5 ml, 6.38 mmol) was added to a solution of D(+)-10-camphorsulfonic acid (1.48 g, 6.38 mmol) in methanol (20 ml). The mixture was allowed to stand at room temperature for 20 min. and the solvent was removed in vacuo. The residue was diluted with toluene (20 ml) and the solvent removed in vacuo.
-5-
Trituration with diethyl ether (c. 50 ml) and filtration under nitrogen gave a white solid which was washed with diethyl ether (2 x 20 ml) and dried in a vacuum desiccator.
Yield 3.50g.
Example 2: Larger scale preparation of crystalline salt.
A solution of paroxetine base in toluene (75 ml, 95.7 mmol) was added to a solution of D(+)-10-camphorsulfonic acid (22.2 g, 95.7 mmol) in methanol (300 ml). The solvent was removed in vacuo, the residue diluted with toluene (100 ml), and the solvent removed in vacuo. Trituration with diethyl ether (c. 350 ml) gave a white solid which was filtered, washed with diethyl ether (2 x 100 ml) and vacuum dried.
Yield 54.46g
H NMR (CDCI3) showed a ratio between D(+)-10-camphorsulfonic acid and paroxetine of l:l.
m. p. 109°C (phase change).
IR nujol mull:
Bands at 1740, 1501, 1464, 1376, 1183, 1034, 828, 768, 601, 515 cm"1.
X-ray diffractogram major peaks (CuK.2α):
Angle [°2Θ] ReUnt [%]
5.965 39.9
6.400 56.5
6.665 36.8
11.880 44.0
-6-
13.765 31.5
15.055 29.1
16.200 38.4
16.945 68.0
17.970 39.2
19.360 28.5
20.825 32.8
21.630 43.0
22.270 36.8
23.365 21.2
24.255 100.0
25.190 75.4
27.105 35.1
29.720 15.5
30.360 18.6
32.360 15.7
32.800 14.9
Example 3: Preparation of crystalline paroxetine (lR)-(-)-10-camphorsulfonate
A solution of paroxetine base in toluene (5 ml, 6.38 mmol) was added to a solution of (1R)- (-)-lO-camphorsulfonic acid (1.48 g, 6.38 mmol) in methanol (20 ml). The mixture was allowed to stand at room temperature for 20 minutes and the solvent was then removed in vacuo. The residual solid was diluted with toluene (20 ml) and the solvent removed in vacuo. Trituration with diethyl ether (c. 50 ml) and filtration under nitrogen gave a white solid which was washed with diethyl ether (2 x 20 ml) and dried at reduced pressure.
Yield 3.18g.
Example 4: Larger scale preparation of crystalline salt.
-7-
A solution of paroxetine base in toluene (66 ml, 84.16 mmol) was added to a solution of (lR)-(-)-10-camphorsulfonic acid (19.5g, 83.94 mmol) in methanol (200 ml). The mixture was allowed to stand at ambient temperature for 40 min. and then the solvent was removed by evaporation. The residual solid was triturated with diethyl ether (c. 350 ml), stirred at ambient temperature for 16 hours and filtered to give a white solid which was washed with diethyl ether (2 x 100 ml) and dried at reduced pressure.
Yield 43.77g
! H NMR (CDC13) showed a ratio between ( 1 R)-(-)- 10-camphorsulfonic acid and paroxetine of 1 : 1.
m. p. 136 - 139°C.
IR nujol mull:
Bands at 1736, 1604, 1503, 1462, 1376, 1278, 1194, 1037, 827, 670, 602, 538 cm"1.
-8-
X-ray diffractogram major peaks (CuK.2 ):
Angle [°2Θ] ReLInt [%]
6.105 19.0
6.645 14.2
13.615 10.0
15.715 17.0
16.785 100.0
17.175 53.2
17.735 16.7
19.205 10.5
19.550 18.9
20.050 13.6
20.430 13.0
21.200 25.5
21.760 14.3
22.270 16.4
23.350 13.2
24.345 42.7
24.905 19.8
25.160 26.1
25.925 19.4
29.015 10.8
30.860 10.6
Example 5: preparation of tablets
INGREDIENTS 20 mg Tablet 30mg Tablet
-9-
Paroxetine 10-camphorsulfonate 20.00 mg 30.0 mg
(based on free base) (based on free base)
Dicalcium Phosphate (DCP) 83.34 mg 125.0 mg
Microcrystalline Cellulose 50.67 mg 76.0 mg
Sodium Starch Glycollate 8.34 mg 12.5 mg
Magnesium Stearate 1.67 mg 2.5 mg
Commercial source of the ingredients
Dicalcium Phosphate Dihydrate Emcompress or Ditab* Microcrystalline Cellulose Avicel PH 102* Sodium Starch Glycollate Explotab.*
* Tradenames
Method
1. Pass DCP through a screen and weigh it into a Planetary mixer.
2. Add 30 mesh Paroxetine 10-camphorsulfonate to the bowl.
3. Add 20 mesh Avicel and Explotab and mix all the powders for 10 minutes. 4. Add magnesium stearate and mix for 5 minutes.
Tablet into Pentagonal Tablets using the following punches:
30 mg Tablet 9.5 mm Circumcircle 20 mg Tablet 8.25 mm Circumcircle
The tablets are made satisfactorily on a single punch or a Rotary press.
■10-
Example 6: preparation of tablets
INGREDIENTS 10 mg Tablet 20 mg Tablet 30mg Tablet
Paroxetine 10- 10 mg 20 mg 30 mg camphorsulfonate (as on free base) (as on free base) (as on free base)
Sodium Starch Glycollate 2.98 mg 5.95 mg 8.93 mg
Granular Dicalcium
Phosphate 158.88 mg 317.75 mg 476.63 mg
(DITAB) or Dicafos
Magnesium Stearate 1.75 mg 3.50 mg 5.25 mg
Method
Paroxetine 10-camphorsulfonate, Sodium Starch Glycollate and Dicalcium Phosphate Dihydrate are screened and mixed together in a suitable mixer. (Planetary, Cuble or High Energy Shear mixer.)
Add Magnesium Stearate and compress it into a tablet using a single punch or Rotary Tablet machine.
-1 1-
Claims
1. A paroxetine 10-camphorsulfonate.
2. Paroxetine (D)-(+)- 10-camphorsulfonate.
3. Paroxetine ( 1 R)-(-)- 10-camphorsulfonate .
4. A compound according to claim 1 , 2 or 3 in non-crystalline form.
5. A compound according to claim 1, 2 or 3 in crystalline form.
6. A process for the preparation of a compound as claimed in claim 1 , 2, 3 or 4 by precipitation, spray drying or freeze drying a solution of a paroxetine 10-camphorsulfonate, or by vacuum drying of oils of paroxetine 10-camphorsulfonate, or solidification of melts of a paroxetine 10-camphorsulfonate.
7. A process for the preparation of a compound as claimed in claim 1, 2, 3 or 5 by crystallization or re-crystallization from a solution of a paroxetine 10-camphorsulfonate.
8. A process according to claim 6 or 7 in which the solution, oil or melt of a paroxetine 10-camphorsulfonate is prepared by treating paroxetine free base with 10- camphorsulfonic acid.
9. A method for treating and/or preventing any one or more of the Disorders by administering an effective and/or prophylactic amount of a paroxetine 10- camphorsulfonate to a sufferer in need thereof.
-12-
Priority Applications (13)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| BR9909878-4A BR9909878A (en) | 1998-04-25 | 1999-04-23 | 10-paroxetine camphosulfonate for treatment of central nervous system disorders |
| SK1590-2000A SK15902000A3 (en) | 1998-04-25 | 1999-04-23 | Paroxetine 10-camphorsulfonate for treatment of cns disorders |
| EA200001105A EA200001105A1 (en) | 1998-04-25 | 1999-04-23 | 10-Camforsulfonat Paroxetine for the treatment of CNS disorders |
| CA002329913A CA2329913A1 (en) | 1998-04-25 | 1999-04-23 | Paroxetine 10-camphorsulfonate for treatment of cns disorders |
| AU36186/99A AU3618699A (en) | 1998-04-25 | 1999-04-23 | Paroxetine 10-camphorsulfonate for treatment of cns disorders |
| IL13901899A IL139018A0 (en) | 1998-04-25 | 1999-04-23 | Paroxetine 10-camphorsulfonate for treatment of cns disorders |
| APAP/P/2000/001958A AP2000001958A0 (en) | 1998-04-25 | 1999-04-23 | Paroxetine 10-camphorsulfornate for treatment of CNS disorders. |
| PL99343596A PL343596A1 (en) | 1998-04-25 | 1999-04-23 | Paroxetine 10-camphorsulfonate for treatment of cns disorders |
| KR1020007011750A KR20010042929A (en) | 1998-04-25 | 1999-04-23 | Paroxetine 10-Camphorsulfonate For Treatment Of CNS Disorders |
| EP99918153A EP1076659A1 (en) | 1998-04-25 | 1999-04-23 | Paroxetine 10-camphorsulfonate for treatment of cns disorders |
| JP2000545859A JP2002513020A (en) | 1998-04-25 | 1999-04-23 | Paroxetine 10-camphorsulfonate for the treatment of CNS diseases |
| NO20005351A NO20005351L (en) | 1998-04-25 | 2000-10-24 | Paroxetine 10-camphor sulfonate for the treatment of CNS disorders |
| BG104973A BG104973A (en) | 1998-04-25 | 2000-11-21 | Paroxetine 10-camphorsulfonate for treatmnent of cns disorders |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9808894.1A GB9808894D0 (en) | 1998-04-25 | 1998-04-25 | Novel compound |
| GB9808894.1 | 1998-04-25 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1999055699A1 true WO1999055699A1 (en) | 1999-11-04 |
Family
ID=10831007
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/GB1999/001246 WO1999055699A1 (en) | 1998-04-25 | 1999-04-23 | Paroxetine 10-camphorsulfonate for treatment of cns disorders |
Country Status (18)
| Country | Link |
|---|---|
| EP (1) | EP1076659A1 (en) |
| JP (1) | JP2002513020A (en) |
| KR (1) | KR20010042929A (en) |
| CN (1) | CN1306530A (en) |
| AP (1) | AP2000001958A0 (en) |
| AU (1) | AU3618699A (en) |
| BG (1) | BG104973A (en) |
| BR (1) | BR9909878A (en) |
| CA (1) | CA2329913A1 (en) |
| EA (1) | EA200001105A1 (en) |
| GB (1) | GB9808894D0 (en) |
| HU (1) | HUP0102298A2 (en) |
| IL (1) | IL139018A0 (en) |
| NO (1) | NO20005351L (en) |
| PL (1) | PL343596A1 (en) |
| SK (1) | SK15902000A3 (en) |
| TR (1) | TR200003083T2 (en) |
| WO (1) | WO1999055699A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7229980B2 (en) | 2004-09-21 | 2007-06-12 | Chong Kun Dang Pharmaceutical Corp. | Paroxetine cholate or cholic acid derivative salts, and composition comprising paroxetine and cholic acid or derivative thereof |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104402708A (en) * | 2014-12-07 | 2015-03-11 | 河南领先科技药业有限公司 | Production method for sodium camphorate |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0188081A2 (en) * | 1984-12-04 | 1986-07-23 | Novo Nordisk A/S | Use of paroxetine for the manufacture of a medicament for the treatment of obesity |
| EP0223403A2 (en) * | 1985-10-25 | 1987-05-27 | Beecham Group Plc | Piperidine derivative, its preparation, and its use as medicament |
| WO1998001424A1 (en) * | 1996-07-08 | 1998-01-15 | Richter Gedeon Vegyészeti Gyár Rt. | N-benzylpiperidine and tetrahydropyridine derivatives |
-
1998
- 1998-04-25 GB GBGB9808894.1A patent/GB9808894D0/en not_active Ceased
-
1999
- 1999-04-23 SK SK1590-2000A patent/SK15902000A3/en unknown
- 1999-04-23 AP APAP/P/2000/001958A patent/AP2000001958A0/en unknown
- 1999-04-23 JP JP2000545859A patent/JP2002513020A/en active Pending
- 1999-04-23 IL IL13901899A patent/IL139018A0/en unknown
- 1999-04-23 AU AU36186/99A patent/AU3618699A/en not_active Abandoned
- 1999-04-23 PL PL99343596A patent/PL343596A1/en not_active Application Discontinuation
- 1999-04-23 KR KR1020007011750A patent/KR20010042929A/en not_active Withdrawn
- 1999-04-23 WO PCT/GB1999/001246 patent/WO1999055699A1/en not_active Application Discontinuation
- 1999-04-23 TR TR2000/03083T patent/TR200003083T2/en unknown
- 1999-04-23 HU HU0102298A patent/HUP0102298A2/en unknown
- 1999-04-23 EA EA200001105A patent/EA200001105A1/en unknown
- 1999-04-23 EP EP99918153A patent/EP1076659A1/en not_active Withdrawn
- 1999-04-23 BR BR9909878-4A patent/BR9909878A/en not_active Application Discontinuation
- 1999-04-23 CN CN99807798A patent/CN1306530A/en active Pending
- 1999-04-23 CA CA002329913A patent/CA2329913A1/en not_active Abandoned
-
2000
- 2000-10-24 NO NO20005351A patent/NO20005351L/en not_active Application Discontinuation
- 2000-11-21 BG BG104973A patent/BG104973A/en unknown
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0188081A2 (en) * | 1984-12-04 | 1986-07-23 | Novo Nordisk A/S | Use of paroxetine for the manufacture of a medicament for the treatment of obesity |
| EP0223403A2 (en) * | 1985-10-25 | 1987-05-27 | Beecham Group Plc | Piperidine derivative, its preparation, and its use as medicament |
| WO1998001424A1 (en) * | 1996-07-08 | 1998-01-15 | Richter Gedeon Vegyészeti Gyár Rt. | N-benzylpiperidine and tetrahydropyridine derivatives |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7229980B2 (en) | 2004-09-21 | 2007-06-12 | Chong Kun Dang Pharmaceutical Corp. | Paroxetine cholate or cholic acid derivative salts, and composition comprising paroxetine and cholic acid or derivative thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| KR20010042929A (en) | 2001-05-25 |
| NO20005351D0 (en) | 2000-10-24 |
| IL139018A0 (en) | 2001-11-25 |
| EA200001105A1 (en) | 2001-04-23 |
| AU3618699A (en) | 1999-11-16 |
| BR9909878A (en) | 2000-12-26 |
| BG104973A (en) | 2001-09-28 |
| NO20005351L (en) | 2000-10-24 |
| JP2002513020A (en) | 2002-05-08 |
| PL343596A1 (en) | 2001-08-27 |
| EP1076659A1 (en) | 2001-02-21 |
| HUP0102298A2 (en) | 2002-05-29 |
| TR200003083T2 (en) | 2001-02-21 |
| AP2000001958A0 (en) | 2000-12-31 |
| SK15902000A3 (en) | 2001-05-10 |
| GB9808894D0 (en) | 1998-06-24 |
| CA2329913A1 (en) | 1999-11-04 |
| CN1306530A (en) | 2001-08-01 |
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