MXPA00010435A - Paroxetine 10-camphorsulfonate for treatment of cns disorders - Google Patents

Abstract

Paroxetine 10-camphorsulfonates are useful in the treatment of certain CNS disorders.

Description

-ALCANF? PARQXETINE RSULFQNATO FOR TREATMENT OF DISORDERS OF THE CENTRAL NERVOUS SYSTEM DESCRIPTIVE MEMORY The present invention relates to a new compound, to processes for preparing it and to its use in the treatment of medical disorders. Pharmaceutical products with antidepressant and antiParkinson properties are described in US-A-3912743 and US-A-4007196. An especially important compound among those described is paroxetine, the (-) trans isomer of 4- (4'-fluorophenyl) -3- (3 ', 4, -methylenedioxy-phenoxymethyl) piperidine. This compound is used in therapy as a hydrochloride salt for the treatment and prophylaxis of, among other conditions, depression, obsessive-compulsive disorder (OCD, for its acronym in English) and panic. Surprisingly, a new paroxetine salt has now been discovered that can be used as an alternative to the hydrochloride currently marketed, or as an intermediate in the preparation of the hydrochloride. In accordance with this invention, a paroxetine camphor-10-sulfonate is provided. 10-Camphor sulfonic acid exists in enantiomeric forms and this invention includes salts with both D - (+) - 10- acid camphorsulfonic as with (1 R) - (-) - 10-camphorsulfonic acid, as well as racemic mixtures of both salts. In one aspect, the novel salt of this invention is provided in non-crystalline form, which may be a solid or an oil. The oil is preferably absorbed in a solid carrier, especially a vehicle that is usable as a component of a pharmaceutical composition. In another aspect, the new 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-sulfonate can be prepared by contacting stoichiometric amounts of the paroxetine free base and acid. It is preferred that the acid or base be in solution; more preferably, that both are in solution. An elevated temperature can be used to bring the acid to solution, but good salt yields are obtained by evaporating some or all of the solvents, or by controlled cooling, preferably in stages. The most commonly used solvents are suitable for mobilizing the 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 diethyl ether and tetrahydrofuran ether, but the solvents in which camphor-10-sulphonic acids are highly insoluble are preferably avoided. The appropriate solvents for acids Camphor-10-sulfonic acids include water, alcohols, ethyl acetate and acetic acid. The salt can be isolated in solid form by common means of a solution thereof obtained as mentioned above. For example, the non-crystalline salt can be prepared by precipitation, spray drying and lyophilization of solutions, or by vacuum drying oils or solidification of fusions obtained from the reaction of the free base and the acid. The crystalline salt can 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, said solvate constitutes an additional aspect of this invention. The solvates can be returned to the unsolvated salt by heating; for example, by drying in the oven, or by treatment with a displacement solvent that does not form a solvate. Before the isolation of the paroxetine salt, the water can be extracted by azeotropic distillation to avoid the formation of hydrates or obtain the product in anhydrous form. In that case, the appropriate solvents for the salt solution are those that form an azeotrope with water, such as toluene and propan-2-ol. Also, it should be noted that the mixtures of the solvents can also be used to assist the azeotropic extraction of the water. More generally, crystallization can be carried out from any solvent that allows the formation of the crystalline structure desired, using seeds of the desired structure where necessary or desirable. When polymorphs exist, the individual polymorphs are preferably directly crystallized from a solution of the salt, although recrystallization of a polymorph solution using seeds from another polymorph can also be performed. The paroxetine free base can be prepared according to the methods generally described in the US patent. no.

No. 4,007,196 and in European patent EP-B-0 223403. D-10-camphor sulfonic acid and L-10-alconforsulfonic acid are commercially available. The compounds of this invention can 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 Premenstrual syndrome Depression in adolescents (PMS) Dysthymia Trichotillomania Excessive use of substances In the following, these disorders are referred to as 'disorders'.

The present invention also provides a method for treating and / or preventing one or more of the disorders by administering an effective and / or prophylactic amount of a salt of the invention to the patient in need thereof. The present invention further provides a pharmaceutical composition that is used to treat and / or prevent disorders, which consists of a mixture of a salt of the invention with a pharmaceutically acceptable carrier. The present invention also provides the use of a salt of the invention to treat and / or prevent 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 disorders. More appropriately, this invention is applied to the treatment of depression, obsessive-compulsive disorder and panic. The compositions of this invention are generally adapted for oral administration, but formulations for dissolution for parenteral administration also fall within the scope of this invention. The composition is generally presented as a unit dose composition containing from 1 to 200 mg of active ingredient calculated based on a free base, more often from 5 to 100 mg; for example, from 10 to 50 mg, such as 10, 12.5, 15, 20, 25, 30 040 mg per human patient. More preferably, single unit doses contain 20 mg of active ingredient calculated based on a free base.

Said composition is usually taken 1 to 6 times a day; for example, 2, 3 or 4 times a day, such that the total amount of active agent administered falls on the scale of 5 to 400 mg of active ingredient calculated based on free base. More preferably, the dose of a unit is taken once a day. Preferred dosage forms of a unit include tablets or capsules. The compositions of this invention can be formulated by common mixing methods, such as mixing, filling and compression. Suitable vehicles for use in this invention comprise a diluent, a binder, a disintegrant, a coloring agent, a flavoring agent and / or a preservative. These agents can be used in a common way; for example, in a manner similar to that already used for commercial antidepressant agents. Specific examples of pharmaceutical compositions include those described in European Patent EP-B-0-223403, and in that of US Pat. No. 4,007,196, in which the products of this invention can be used as active ingredients. The following examples illustrate this invention: EXAMPLE 1 Preparation of crystalline paroxetine D - (+) - 10-camphor sulfonate 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 minutes and the solvent was removed in vacuo. The residue was diluted with toluene (20 ml) and the solvent was 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 in a desiccator in vacuo. Yield: 3.50 g.

EXAMPLE 2 Preparation on a larger scale of the 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 was diluted with toluene (100 ml) and the solvent was 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 dried in vacuo. Yield: 54.46 g The 1 H NMR resonance (CDCl 3) showed a ratio of 1: 1 between D (+) - 10-camphor sulfonic acid and paroxetine. p.f. 109 ° C (phase change). Nujol mordente for IR: Bands in 1740, 1501, 1464, 1376, 1183, 1034, 828, 768, 601, 515 cm "1. Greater peaks of the X-ray diffractogram (CuK2a): EXAMPLE 3 Preparation of crystalline paroxetine (1 RM -) - 10-camphor sulfonate A solution of paroxetine base in toluene (5 ml, 6.38 mmol) was added to a solution of (1 R) - (-) - 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 then the solvent was removed in vacuo. The residual solid was diluted with toluene (20 ml) and the solvent was 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 under reduced pressure. Yield: 3.18 g.

EXAMPLE 4 Preparation on a larger scale of the crystalline salt A solution of paroxetine base in toluene (66 ml, 84.16 mmol) was added to a solution of (1 R) - (-) - 10-camphorsulfonic acid (19.5 g, 83.94 mmol) in methanol (200 ml). The mixture was allowed to stand at room temperature for 40 minutes and then the solvent was removed by evaporation. The residual solid was triturated with diethyl ether (0. 350 ml), stirred at room temperature for 16 hours and filtered to give a white solid which was washed with diethyl ether (2 x 100 ml) and dried under reduced pressure.

Yield: 43.77g. The 1 H NMR magnetic resonance (CDCI) showed a 1: 1 ratio between (1 R) - (-) - 10-camphor sulfonic acid and paroxetine. p.f. 136-139 ° C. IR mordant of nujol: Bands in 1736, 1604, 1503, 1462, 1376, 1278, 1194, 1037, 827, 670, 602, 538 crn 1. Greater peaks of the X-ray diffractogram (CuK2a): EXAMPLE 5 Preparation of tablets Commercial origin of the ingredients Dicalcium phosphate dihydrate - Emcompress or Ditab * Microcrystalline cellulose - Avicel PH 102 * Sodium starch glycolate - Explotab * * Trade names.

Method 1. Pass DCP through the sieve and weigh it in a planetary mixer. 2. Add 30 mesh paroxetine 10-camphor sulfonate to the bowl. 3. Add Avicel and Explotab of 20 mesh and mix all the powders for 10 minutes. 4. Add magnesium stearate and mix for 5 minutes.

Formation of pentagonal tablets using the following dies: 30 mg tablet 9.5 mm Circumscribed circle 20 mg tablet 8.25 mm Circumscribed circle The tablets were successfully processed in a single die or rotary press.

EXAMPLE 6 Preparation of tablets Method 1. Paroxetine 10-camphorsulfonate, sodium starch glycolate and dicalcium phosphate dihydrate are sieved and mixed together in an appropriate mixer (planetary, Cuble mixer or high energy shear mixer). 2. Magnesium stearate is added and compressed into a tablet using a single die or rotary tablet machine.

Claims (9)

NOVELTY OF THE INVENTION CLAIMS

1. - A paroxetine 10-camphor sulfonate. 2.- (D) - (+) - 10-camphor sulfonate paroxetine. 3.- (1 R) - (-) - 10-camphor sulfonate paroxetine. 4. A compound according to claim 1, 2 6 3 in non-crystalline form. 5. A compound according to claim 1, 2 or 3 in crystalline form. 6. A process for preparing a compound according to claim 1, 2, 3 or 4, by precipitation, spray drying or lyophilization of a paroxetine 10-camphor sulfonate solution, or by vacuum drying oils of 10- paroxetine camphor sulfonate, or solidification of melted materials of paroxetine 10-camphorsulfonate. 7. A process for preparing compounds according to claim 1, 2, 3 or 5, by crystallization or recrystallization of a solution of paroxetine 10-camphor sulfonate. 8. A process according to claim 6 or 7, wherein the solution, oil or fusion of a paroxetine 10-camphor sulfonate is prepared by treating the paroxetine free base with 10-camphor sulfonic acid. 9. The use of a paroxetine 10-camphor sulfonate for the manufacture of a medicament to treat and / or prevent alcoholism, depression, panic disorder, obesity, migraine, anorexia, premenstrual syndrome (PMS), trichotillomania, excessive use of substances , anxiety, obsessive-compulsive disorder, chronic pain, senile dementia, bulimia, social phobia, depression in adolescents and dysthymia.