AU3618699A - Paroxetine 10-camphorsulfonate for treatment of cns disorders - Google Patents

Paroxetine 10-camphorsulfonate for treatment of cns disorders Download PDF

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AU3618699A
AU3618699A AU36186/99A AU3618699A AU3618699A AU 3618699 A AU3618699 A AU 3618699A AU 36186/99 A AU36186/99 A AU 36186/99A AU 3618699 A AU3618699 A AU 3618699A AU 3618699 A AU3618699 A AU 3618699A
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paroxetine
camphorsulfonate
solution
salt
free base
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AU36186/99A
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Michael Urquhart
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SmithKline Beecham Ltd
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SmithKline Beecham Ltd
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    • 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
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    • 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
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    • 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
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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
    • 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
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    • 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

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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Neurology (AREA)
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  • Hospice & Palliative Care (AREA)
  • Child & Adolescent Psychology (AREA)
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  • Hematology (AREA)
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Description

WO 99/55699 PCT/GB99/01246 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. 5 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 10 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 15 of the hydrochloride. According to the present invention there is provided a paroxetine camphor 1 0-sulfonate. 1 0-camphorsulfonic acid exists in enantiomeric forms and this invention includes salts with both D-(+)-10-camphorsulfonic acid and (1R)-(-)-10-camphorsulfonic acid and racemic 20 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 25 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. 30 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
-I-
WO 99/55699 PCT/GB99/01246 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 5 butanone, halogenated hydrocarbons such as dichloromethane, and ethers such as tetrahydrofuran and diethyl ether, but solvents in which camphor-i 0-sulfonic acids are very insoluble are preferably avoided. Suitable solvents for camphor-10-sulfonic acids include water, alcohols, ethyl acetate and acetic acid. 10 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. 15 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. 20 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 25 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 30 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- WO 99/55699 PCT/GB99/01246 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. 5 The compounds of this invention may be used to treat and prevent the following disorders: -3- WO 99/55699 PCT/GB99/01246 Alcoholism Anxiety Depression Obsessive Compulsive Disorder Panic Disorder Chronic Pain Obesity Senile Dementia 5 Migraine Bulimia Anorexia Social Phobia Pre-Menstrual Syndrome (PMS) Adolescent Depression Trichotillomania Dysthymia Substance Abuse 10 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 15 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. 20 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 25 a medicament for treating and/or preventing the Disorders. Most suitably the present invention is applied to the treatment of depression, OCD and panic. 30 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- WO 99/55699 PCT/GB99/01246 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 100mg, for example 10 to 50mg such as 10, 12.5, 15, 20, 25, 30 or 40mg by a human patient. Most 5 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. 10 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. 15 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. 20 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. 25 The following Examples illustrate the present invention: Example 1: Preparation of crystalline paroxetine D-(+)- 1 0-camphorsulfonate A solution of paroxetine base in toluene (5 ml, 6.38 mmol) was added to a solution of 30 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- WO 99/55699 PCT/GB99/01246 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. 5 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 10 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 15 1 H NMR (CDCl 3 ) showed a ratio between D(+)-10-camphorsulfonic acid and paroxetine of 1:1. m. p. 109*C (phase change). 20 IR nujol mull: Bands at 1740, 1501, 1464, 1376, 1183, 1034, 828, 768, 601, 515 cm-l. 25 X-ray diffractogram major peaks (CuK2a): Angle [*201 Rel.Int [%] 5.965 39.9 6.400 56.5 6.665 36.8 11.880 44.0 -6- WO 99/55699 PCT/GB99/01246 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 (1R)-(-)-10-camphorsulfonate 5 A solution of paroxetine base in toluene (5 ml, 6.38 mmol) was added to a solution of (1R) (-)-10-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 10 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. 15 -7- WO 99/55699 PCT/GB99/01246 A solution of paroxetine base in toluene (66 ml, 84.16 mmol) was added to a solution of (1R)-(-)-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 5 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 10 H NMR (CDCl 3 ) showed a ratio between (1 R)-(-)- 1 0-camphorsulfonic acid and paroxetine of 1:1. m. p. 136 - 139"C. 15 IR nujol mull: Bands at 1736, 1604, 1503, 1462, 1376, 1278, 1194, 1037, 827, 670, 602, 538 cm-l. -8- WO 99/55699 PCT/GB99/01246 X-ray diffractogram major peaks (CuK 2 a): Angle [201 Rel.Int [%] 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 5 Example 5: preparation of tablets INGREDIENTS 20 mg Tablet 30mg Tablet -9- WO 99/55699 PCT/GB99/01246 Paroxetine 1 0-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* 5 Microcrystalline Cellulose - Avicel PH 102* Sodium Starch Glycollate - Explotab.* * Tradenames 10 Method 1. Pass DCP through a screen and weigh it into a Planetary mixer. 2. Add 30 mesh Paroxetine 1 0-camphorsulfonate to the bowl. 3. Add 20 mesh Avicel and Explotab and mix all the powders for 10 minutes. 15 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 20 mg Tablet 8.25 mm Circumcircle The tablets are made satisfactorily on a single punch or a Rotary press. -10- WO 99/55699 PCT/GB99/01246 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 5 Method 1. Paroxetine 10-camphorsulfonate, Sodium Starch Glycollate and Dicalcium Phosphate Dihydrate are screened and mixed together in a suitable mixer. 10 (Planetary, Cuble or High Energy Shear mixer.) 2. Add Magnesium Stearate and compress it into a tablet using a single punch or Rotary Tablet machine. -11-

Claims (9)

1. A paroxetine 1 0-camphorsulfonate. 5
2. Paroxetine (D)-(+)-10-camphorsulfonate.
3. Paroxetine (1 R)-(-)- 1 0-camphorsulfonate.
4. A compound according to claim 1, 2 or 3 in non-crystalline form. 10
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 1 0-camphorsulfonate, 15 or by vacuum drying of oils of paroxetine 1 0-camphorsulfonate, or solidification of melts of a paroxetine 1 0-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 1 0-camphorsulfonate. 20
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 25 camphorsulfonate to a sufferer in need thereof. -12-
AU36186/99A 1998-04-25 1999-04-23 Paroxetine 10-camphorsulfonate for treatment of cns disorders Abandoned AU3618699A (en)

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Application Number Priority Date Filing Date Title
GBGB9808894.1A GB9808894D0 (en) 1998-04-25 1998-04-25 Novel compound
GB9808894 1998-04-25
PCT/GB1999/001246 WO1999055699A1 (en) 1998-04-25 1999-04-23 Paroxetine 10-camphorsulfonate for treatment of cns disorders

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AP (1) AP2000001958A0 (en)
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KR100672184B1 (en) 2004-09-21 2007-01-19 주식회사종근당 Paroxetine cholate or cholic acid derivative salts
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

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GB8430581D0 (en) * 1984-12-04 1985-01-09 Ferrosan As Treatment
ES2058061T3 (en) * 1985-10-25 1994-11-01 Beecham Group Plc DERIVED FROM PIPERIDINE, ITS PREPARATION AND ITS USE AS A MEDICINAL PRODUCT.
HU221921B1 (en) * 1996-07-08 2003-02-28 Richter Gedeon Vegyészeti Gyár Rt. N-benzyl-piperidine or tetrahydro-pyridine derivatives and processes for producing them

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CA2329913A1 (en) 1999-11-04
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IL139018A0 (en) 2001-11-25

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