KR20060054386A - 2-methoxymethyl-3-(3,4-dichlorophenyl)-8-azabicyclo[3.2.1]octane tartrate salts - Google Patents

Abstract

This invention relates to novel (1R,2R,3S,5S)-2-methoxymethyl-3-(3, 4dichlorophenyl)-8-azabicyclo[3.2. 1 ]octane tartrate salts, such as L- tartrate monohydrates and anhydrates. The salts are useful as monoamine neurotransmitter re-uptake inhibitors. In other aspects the invention relates to the use of these salts in a method for therapy and to pharmaceutical compositions comprising the salts of the invention.

Description

2-methoxymethyl-3- (3,4-dichlorophenyl) -8-azabicyclo [3.2.1] octane tartrate salt {2-Methoxymethyl-3- (3,4-dichlorophenyl) -8-azabicyclo [3.2 .1] octane tartrate salts}

The invention provides novel (1R, 2R, 3S, 5S) -2-methoxymethyl-3- (3,4-dichlorophenyl) -8-azabicyclo [3.2.1] octane tartrate salts, for example, It relates to L-tartrate monohydrate and anhydride. The salts are useful as monoamine neurotransmitter reuptake inhibitors.

In another aspect the invention relates to the use of the salts in a method of treatment and to a pharmaceutical composition comprising the salts of the invention.

Compound (1R, 2R, 3S, 5S) -2-methoxymethyl-3- (3,4-dichlorophenyl) -8-azabicyclo [3.2.1] octane is disclosed in WO 97/30997 (NeuroSearch). A / S). In this document, citrate salts were prepared (Example 15).

However, for commercial use, it is important to use physiologically acceptable salts that optimally combine stability, solubility, nonhygroscopicity, bioavailability and good handling properties such as clear melting point and reproducible crystal forms.

Summary of the Invention

In a first aspect, the invention provides an anhydride form of (1R, 2R, 3S, 5S) -2-methoxymethyl-3- (3,4-dichlorophenyl) -8-azabicyclo [3.2.1] octane tartrate And salts selected from hydrate forms.

In a second aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a salt of the invention in combination with one or more pharmaceutically acceptable carriers, excipients or diluents.

In a further aspect, the present invention provides a pharmaceutical composition for the treatment, prevention or alleviation of diseases, disorders or conditions in mammals, including humans, which is responsive to the inhibition of monoamine neurotransmitter reuptake in the central nervous system. The use of the salt of this invention is provided.

In a further aspect, the present invention is directed to a human, in need of treating, preventing or alleviating a therapeutically effective amount of a salt of the present invention that is responsive to inhibition of monoamine neurotransmitter reuptake in the central nervous system. It provides a method for treating, preventing or alleviating a disease, disorder or condition of the animal living body, comprising the step of administering to the animal living body comprising a.

Other objects of the present invention will become apparent to those skilled in the art from the following detailed description and examples.

(1R, 2R, 3S, 5S) -2- Methoxymethyl -3- (3,4- Dichlorophenyl )-8- Azabicyclo [3.2. 1] octane Tartrate

In a first aspect the invention provides anhydrides and hydrates of (1R, 2R, 3S, 5S) -2-methoxymethyl-3- (3,4-dichlorophenyl) -8-azabicyclo [3.2.1] octane tartrate It provides a salt selected from the form.

In one embodiment, the salt is an anhydride of (1R, 2R, 3S, 5S) -2-methoxymethyl-3- (3,4-dichlorophenyl) -8-azabicyclo [3.2.1] octane L-tartrate And hydrate forms.

In a second embodiment, the salt is (1R, 2R, 3S, 5S) -2-methoxymethyl-3- (3,4-dichlorophenyl) -8-azabicyclo [3.2.1] octane L-tartrate monohydrate to be.

In a further embodiment, the salt is an anhydride of (1R, 2R, 3S, 5S) -2-methoxymethyl-3- (3,4-dichlorophenyl) -8-azabicyclo [3.2.1] octane L-tartrate Form.

In a further embodiment, the salt is (1R, 2R, 3S, 5S) -2-methoxymethyl-3- (3,4-dichlorophenyl) -8- with major peaks in the X-ray powder diffraction pattern as follows: It is a polymorphic form (form II) of azabicyclo [3.2.1] octane L-tartrate.

Peak number One 2 3 4 5 6 7 8 9 10 2 θ ° (Cu Kα) 10.35 11.68 12.53 14.81 15 15.77 16.82 17.41 17.77 18.87 d space 8.5 7.6 7.1 6.0 5.9 5.6 5.3 5.1 5.0 4.7 peak 11 12 13 14 15 16 17 18 19 2 θ ° (Cu Kα) 20.29 21.26 21.66 23.44 23.73 25.44 25.99 27.58 28.14 d space 4.4 4.2 4.1 3.8 3.7 3.5 3.4 3.2 3.2

In a further embodiment, the salt is (1R, 2R, 3S, 5S) -2-methoxymethyl-3- (3,4-dichlorophenyl) -8- with major peaks in the X-ray powder diffraction pattern as follows: It is a polymorphic form (type III) of azabicyclo [3.2.1] octane L-tartrate anhydride.

Peak number One 2 3 4 5 6 7 8 9 10 2 θ ° (Cu Kα) 5.37 10.6 10.82 11.58 11.88 12.79 14.78 16.27 16.5 17.03 d space 16.4 8.3 8.2 7.6 7.4 6.9 6.0 5.4 5.4 5.2 peak 11 12 13 14 15 16 17 18 19 2 θ ° (Cu Kα) 17.84 19.29 20.01 21.2 22.99 23.46 24.54 25.15 26.59 d space 5.0 4.6 4.4 4.2 3.9 3.8 3.6 3.5 3.3

In a further embodiment, the salt is (1R, 2R, 3S, 5S) -2-methoxymethyl-3- (3,4-dichlorophenyl) -8- with major peaks in the X-ray powder diffraction pattern as follows: It is a polymorphic form (type IV) of azabicyclo [3.2.1] octane L-tartrate.

Peak number One 2 3 4 5 6 7 8 9 10 2 θ ° (Cu Kα) 5.31 10.19 11.23 12.13 12.35 12.69 14.31 14.55 14.77 16.43 d space 16.6 8.7 7.9 7.3 7.2 7.0 6.2 6.1 6.0 5.4 peak 11 12 13 14 15 16 17 18 19 20 2 θ ° (Cu Kα) 17.48 18.21 18.43 18.81 19.36 19.61 20.26 20.5 21.29 21.46 d space 5.1 4.9 4.8 4.7 4.6 4.5 4.4 4.3 4.2 4.1 peak 21 22 23 24 25 26 27 28 29 30 2 θ ° (Cu Kα) 21.95 22.53 22.77 23.38 23.59 23.9 24.45 25.02 25.56 26.19 d space 4.0 3.9 3.9 3.8 3.8 3.7 3.6 3.6 3.5 3.4 peak 31 32 2 θ ° (Cu Kα) 26.83 27.21 d space 3.3 3.3

Any combination of two or more of the embodiments described above is contemplated within the scope of the present invention.

Luggage form

Salts of the present invention may be provided in anhydride or hydrate form. Hydrate forms include monohydrate, dihydrate, hemihydrate, trihydrate, tetrahydrate, and the like.

Labeling compound

Salts of the invention can be used in labeled or unlabeled form. In the context of the present invention, "label" refers to the binding of a marker to the desired salt allowing for easy quantitative detection of the salt.

Label salts of the invention may be useful as diagnostic tools, radiotracers or monitoring agents in various diagnostic methods and for in vivo receptor imaging.

The labeling salt of the present invention preferably contains one or more radionuclides as labels. Positrons emitting radionuclides are all candidates for use. Radionuclides in the context of the present invention are preferably selected from ² H (deuterium), ³ H (tritium), ¹³ C and ¹⁴ C.

Manufacturing method

Salts of the present invention can be prepared by conventional chemical synthesis methods, for example the methods described in the Examples. Starting materials for the processes described herein can be readily prepared by conventional methods from known or commercially available chemicals.

In addition, one salt of the present invention may be converted to another salt of the present invention using conventional methods.

The final products of the invention described herein can be separated by conventional techniques such as extraction, crystallization, distillation, chromatography and the like.

Biological activity

Salts of the present invention can be tested for their ability to prevent reabsorption of monoamine dopamine, noradrenaline and serotonin in synaptosomes, for example as described in WO 97/30997. Based on the balanced activity observed in this test, the salts of the present invention can be used to treat, prevent or alleviate diseases, disorders or conditions in mammals, including humans, which are responsive to inhibition of neurotransmitter reuptake in the central nervous system. Is considered useful.

In a particular embodiment, the salts of the present invention are mood disorders, depression, atypical depression, pain caused by depression, major depressive disorders, mood modulation disorders, bipolar disorders, bipolar I disorders, bipolar II disorders, cyclic mood disorders, general medicine Mood disorders caused by conditions, substance-induced mood disorders, pseudodementia, Ganser's syndrome, obsessive-compulsive disorder, panic disorder, panic disorder without agoraphobia, panic disorder with agoraphobia, plaza without panic disorder Phobias, panic attacks, memory deficits, memory loss, attention deficit hypermotor disorders, obesity, anxiety, panic disorder, eating disorders, Parkinson's disease, Parkinson's disease, dementia, aging dementia, senile dementia, Alzheimer's disease, AIDS Complications, aging memory disorders, specific phobias, social phobias, post-traumatic stress disorder, acute stress disorder, drug addiction, substance abuse, cocaine Abuse, nicotine abuse, tobacco abuse, alcohol use, alcoholism, pain, chronic pain, inflammatory pain, nervous pain, migraine, tension headache, chronic tension headache, depression-related pain, fibromyalgia, arthritis, osteoarthritis, rheumatoid arthritis, back pain, Cancer pain, irritable bowel pain, irritable bowel syndrome, postoperative pain, post-seizure pain, drug-induced neuropathy, diabetic neuropathy, sympathetic persistent pain, tertiary neuralgia, toothache, facial muscle pain, ring pain, macrophages, premenstrual syndrome, Late luteal phase syndrome, post-traumatic syndrome, chronic fatigue syndrome, incontinence, stress incontinence, urge incontinence, night incontinence, sexual dysfunction, premature ejaculation, erectile dysfunction, erectile dysfunction, eating disorders, anorexia nervosa, sleep disorders, autism, narcosis, Treatment of hair wall, narcolepsy, post seizure depression, seizure-induced brain injury, seizure-induced nerve injury or Gilles de la Tourettes disease, It believed to be useful in a room or in relief.

At present, a suitable dosage range of the pharmaceutically active ingredient (API) is dependent on the exact mode of administration, dosage form, signs to be considered, the weight of the subject, in particular the subject concerned and in addition to the preferences and experience of the attending vet or veterinarian, A daily API of about 0.1 to about 100 mg, more preferably about 0.1 to about 10 mg, most preferably about 0.5 to about 5 mg.

Pharmaceutical composition

In another aspect, the invention provides a novel pharmaceutical composition comprising a pharmaceutically effective amount of a salt of the invention.

Salts of the present invention for use in therapy may be administered in the form of raw salts, but the pharmaceutical composition may be incorporated with one or more adjuvants, excipients, carriers, buffers, diluents and / or other conventional pharmaceutical adjuvants. It is preferable.

In a preferred embodiment, the present invention provides a pharmaceutical composition comprising a salt of the present invention in combination with one or more pharmaceutically acceptable carriers and optionally other therapeutic and / or prophylactic components known in the art. . The carrier (s) should be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the recipient thereof.

The pharmaceutical compositions of the invention may be oral, rectal, bronchial, nasal, lung, topical (including oral and sublingual), transdermal, vaginal or parenteral (dermal, subcutaneous, intramuscular, intraperitoneal, intravenous, intraarterial, intracranial , Intraocular injection or infusion), or in a form suitable for administration by inhalation or aeration or by a sustained release system comprising powder or liquid aerosol administration. Suitable examples of sustained-release systems include semipermeable matrices of solid hydrophobic polymers containing the salts of the present invention, which matrices may be in the form of shaped articles, eg films, or microcapsules.

Salts of the present invention should be placed into pharmaceutical composition forms and unit dosage forms thereof in combination with conventional adjuvants, carriers or diluents. These forms are in the form of solids, in particular tablets, filled capsules, powders and pellets, and liquids, in particular aqueous or non-aqueous liquids, suspensions, emulsions, elixirs and capsules filled with them (both orally), suppositories for rectal administration and parenteral use. Sterile injectables are included. Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or elements, such unit dosage forms being equivalent to the intended daily dosage range used. It may contain any suitable effective amount of phosphorus, active ingredient.

Salts of the invention can be administered in a wide variety of oral and parenteral dosage forms.

For preparing pharmaceutical compositions from the salts of the present invention, the pharmaceutically acceptable carrier may be a solid or a liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. Solid carriers can be one or more substances that can also function as diluents, flavors, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrants, or encapsulant materials.

In powders, the carrier is a finely divided solid, which is mixed with the finely divided active ingredient.

In tablets, the active component is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired.

Powders and tablets preferably contain from 5 or 10 to about 70% of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugars, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting wax, cocoa butter and the like. The term “formulation” is intended to include formulations of the active compound with the encapsulating material as a carrier which provides a capsule in which the active ingredient, with or without carriers, is surrounded by and bound to the carrier. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, keshes, and lozenges can be used in solid forms suitable for oral administration.

To prepare suppositories, low melting waxes, such as mixtures of fatty acid glycerides or cocoa butter, are first melted and the active ingredients are stirred and dispersed homogeneously therein. The molten homogeneous mixture is then introduced into a convenient sized mold, cooled and solidified.

Compositions suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing such carriers known in the art as well as the active ingredient.

Liquid formulations include solvents, suspensions and emulsions, such as water or water-propylene glycol solvents. For example, parenteral injection solution formulations may be formulated as a solvent in an aqueous polyethylene glycol solution.

The salts according to the invention can thus be formulated for parenteral administration (injection, for example, by mass injection or continuous infusion), and are multi-dose containers containing ampoules, prefilled syringes, small volume infusions or additional preservatives. It may be provided in the form of a single dose in. The composition may take this form as a suspending agent, solvent or emulsion in an oily or aqueous vehicle and may contain formulating agents such as suspending agents, stabilizers and / or dispersing agents. Alternatively, the active ingredient may be in powder form obtained by aseptic separation of sterile solid or by lyophilization from solution for constitution with a suitable vehicle, eg, sterile pyrogen-free water, before use.

Aqueous solutions suitable for oral use can be prepared by dissolving the active ingredient in water and adding as appropriate colorants, flavors, stabilizers and thickeners as necessary.

Aqueous suspensions suitable for oral use can be prepared by dispersing the finely divided active component in water with viscous substances such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose or other well known suspending agents. have.

Also included are solid preparations for converting to oral preparations immediately prior to use. Such liquid forms include solvents, suspending agents and emulsions. In addition to the active ingredient, the preparations may include colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers and the like.

Salts of the present invention can be formulated as ointments, creams or lotions or as transdermal patches for topical administration to the epidermis. Ointments and creams may, for example, be formulated with the addition of suitable thickening and / or gelling agents to an aqueous or oily base. Lotions are formulated with an aqueous or oily base and generally contain one or more emulsifiers, stabilizers, dispersants, suspensions, thickeners or colorants.

Compositions suitable for topical administration in the mouth are tablets comprising the active ingredient in an inert base such as lozenges, gelatin and glycerin or sucrose and acacia, including the active agent in a flavor base that is typically sucrose and acacia or tragacanth ( pastille and mouthwashes comprising the active ingredient in a suitable liquid carrier.

Solvents or suspensions are applied directly to the nasal cavity by conventional means, such as by means of a dropper, pipette or sprayer. The composition may be provided in single or multidose form.

Administration to the airway is a pressurized pack in which the active ingredient comprises a suitable propellant such as chlorofluorocarbon (CFC), for example dichlorofluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane, carbon dioxide or other suitable gas. It may also be achieved by an aerosol formulation, provided for. The aerosol may further contain a surfactant such as lecithin for convenience. The dose of medication can be adjusted by providing a metered valve.

Alternatively, the active ingredient may be in the form of a powder mixture in a dry powder, such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP), etc. It may be provided as. Conveniently, the powder carrier forms a gel in the nasal cavity. The powder composition may be provided in the form of a single dose in a blister pack containing a powder, which may be administered by, for example, a capsule or cartridge, eg gelatin or an inhaler.

In compositions for introduction into the airways, including nasal compositions, the active compounds generally have a small particle size of, for example, 5 μm or less. Such particle size can be obtained by means known in the art, for example micronization.

If desired, compositions adapted to provide sustained release of the active ingredient can be used.

The pharmaceutical preparation is preferably in unit dosage form. In this form, the formulation is subdivided into unit doses containing the required amount of the active ingredient. The unit dosage form can be a packaged preparation, a package containing separate amounts of the preparation, such as packaged tablets, capsules and powders in vials or ampoules. In addition, the unit dosage form may be capsule, tablet, cachey or lozenge itself, or any of the required number thereof in packaged form.

Tablets or capsules for oral administration and liquids for intravenous administration and continuous infusion are preferred compositions.

Further details on formulation and administration techniques can be found in the latest edition of Remington's Pharmaceutical Sciences (Maack Publishing Co., Easton, Pa.).

A therapeutically effective amount refers to the amount of active ingredient which improves a symptom or condition. Therapeutic efficacy and toxicity, such as ED ₅₀ and LD _50, can be measured by cell culture or by standard pharmacological procedures in experimental animals. The dose ratio between therapeutic and toxic effects is the therapeutic index and can be expressed as the ratio LD ₅₀ / ED ₅₀ . Pharmaceutical compositions that exhibit large therapeutic indices are preferred.

The dose administered, of course, must be carefully adjusted to the age, weight and condition of the individual being treated as well as the route of administration, dosage form and regimen, and the desired result and exact dosage will, of course, be determined by the practitioner.

The actual dosage depends on the nature and severity of the disease being treated, at the discretion of the physician, and can be varied by varying the dosage to the particular circumstances of the invention that produce the desired therapeutic effect. However, it is presently contemplated that pharmaceutical compositions containing from about 0.1 to about 10 mg, preferably from about 0.5 to about 5 mg of active ingredient per individual dose are suitable for treatment.

The active ingredient may be administered in one or more doses per day. Satisfactory results can be obtained in dosages as low as 0.1 μg / kg intravenous and 1 μg / kg oral administration in certain cases. The upper limit of the dosage range is currently considered to be about 10 mg / kg intravenous and 100 mg / kg orally. Preferred ranges are from 0.1 μg / kg to about 10 mg / kg of daily intravenous injection and from about 1 μg / kg to about 100 mg / kg of oral administration.

Treatment method

In another aspect, the invention provides a method of treating, preventing or alleviating a disease, disorder or condition of an animal body, including a human, which is responsive to inhibition of monoamine neurotransmitter reuptake in the central nervous system. The method comprises administering an effective amount of a salt of the invention to such animal living body, including a person in need thereof.

Suitable dosage ranges typically depend on the exact mode of administration, the form administered, the indications that led to the administration, the weight of the subject and related subjects and further the preferences and experience of the attending or veterinarian.

The invention is further illustrated with reference to the following examples, which are not intended to limit the scope of the claims of the invention in any way.

Example  One

(1R, 2R, 3S, 5S) -2- Methoxymethyl -3- (3,4- Dichlorophenyl )-8- Azabicyclo [3.2.1] octane Citrate  salt

(1R, 2R, 3S, 5S) -2-methoxymethyl-3- (3,4-dichlorophenyl) -8-azabicyclo [3.2.1 as described in WO 97/30997 (Example 15) ] Citrate salts of octane were synthesized.

(1R, 2R, 3S, 5S) -2- Methoxymethyl -3- (3,4- Dichlorophenyl )-8- Azabicyclo [3.2.1] octane

The citrate salt was dissolved in water and the pH was adjusted to 10-13 with aqueous base, then toluene was extracted to give free base. The toluene phase is recovered, dried and evaporated to dryness. From this the free base remains as an oil.

Example  2

(1R, 2R, 3S, 5S) -2-methoxymethyl-3- (3,4-dichlorophenyl) -8-azabicyclo [3.2.1] octane L- Tartrate  Monohydrate (I type)

L- to a heated solution of (1R, 2R, 3S, 5S) -2-methoxymethyl-3- (3,4-dichlorophenyl) -8-azabicyclo [3.2.1] octane (free base) in aqueous ethanol. Tartic acid was added. The warm mixture was treated with activated charcoal and filtered. Cool the filtrate and convert L-tartrate monohydrate to (1R, 2R, 3S, 5S) -2-methoxymethyl-3- (3,4-dichlorophenyl) -8-azabicyclo- [3.2.1] -octane Separated as.

Form I is characterized by the following main peaks in its X-ray powder diffraction pattern shown below.

Peak number One 2 3 4 5 6 7 8 9 10 2 θ ° (Cu Kα) 12.05 14.21 16.37 17.4 18.34 19.29 19.58 20.27 23.3 23.75 d space 7.3 6.2 5.4 5.1 4.8 4.6 4.5 4.4 3.8 3.7 peak 11 12 13 14 15 16 17 2 θ ° (Cu Kα) 24.37 26.11 26.76 28.25 28.72 29.25 29.82 d space 3.6 3.4 3.3 3.2 3.1 3.1 3.0

Example  3

(1R, 2R, 3S, 5S) -2- Methoxymethyl -3- (3,4- Dichlorophenyl )-8- Azabicyclo [3.2.1] Octane L- Tartrate  Anhydride (Type II)

This form was prepared by thermal dehydration. (1R, 2R, 3S, 5S) -2-methoxymethyl-3- (3,4-dichlorophenyl) -8-azabicyclo [3.2.1] octane L-tartrate monohydrate (Type I) was converted to TGA AlO. Heated to 125 ° C. and 10 ° C./min in ₂ crucibles. The furnace was purged with 50 ml / min dry nitrogen during heating and cooling.

Form II is characterized by the following main peaks in its X-ray diffraction pattern shown below:

Peak number One 2 3 4 5 6 7 8 9 10 2 θ ° (Cu Kα) 10.35 11.68 12.53 14.81 15 15.77 16.82 17.41 17.77 18.87 d space 8.5 7.6 7.1 6.0 5.9 5.6 5.3 5.1 5.0 4.7 peak 11 12 13 14 15 16 17 18 19 2 θ ° (Cu Kα) 20.29 21.26 21.66 23.44 23.73 25.44 25.99 27.58 28.14 d space 4.4 4.2 4.1 3.8 3.7 3.5 3.4 3.2 3.2

Example  4

(1R, 2R, 3S, 5S) -2- Methoxymethyl -3- (3,4- Dichlorophenyl )-8- Azabicyclo [3.2.1] Octane L- Tartrate  Anhydride (Type III)

The form was prepared by thermal dehydration. (1R, 2R, 3S, 5S) -2-methoxymethyl-3- (3,4-dichlorophenyl) -8-azabicyclo [3.2.1] octane L-tartrate monohydrate in a TGA AlO ₂ crucible ( Form I) was heated to 10 ° C / min and 160 ° C. The salt was cooled and then the TGA furnace was opened. The furnace was purged with 50 ml / min of dry nitrogen during heating and cooling.

Form III is characterized by the following main peaks in its X-ray powder diffraction pattern shown below:

Peak No. One 2 3 4 5 6 7 8 9 10 2 θ ° (Cu Kα) 5.37 10.6 10.82 11.58 11.88 12.79 14.78 16.27 16.5 17.03 d space 16.4 8.3 8.2 7.6 7.4 6.9 6.0 5.4 5.4 5.2 peak 11 12 13 14 15 16 17 18 19 2 θ ° (Cu Kα) 17.84 19.29 20.01 21.2 22.99 23.46 24.54 25.15 26.59 d space 5.0 4.6 4.4 4.2 3.9 3.8 3.6 3.5 3.3

Example 5

(1R, 2R, 3S, 5S) -2- Methoxymethyl -3- (3,4- Dichlorophenyl )-8- Azabicyclo [3.2.1] Octane L- Tartrate  Anhydride (Type IV)

The newly prepared form II was suspended in anhydrous ethanol to prepare the form. The suspended material was separated after 24 hours and dried under vacuum.

Form IV can also be obtained by a process as described using Form II.

Clearly, type IV was physically metastable. Successive preparations of type IV have been found to be mixtures of type IV and type III, indicating difficulty in preparing type IV.

Form IV is characterized by the following main peaks in the X-ray powder diffraction pattern shown below:

Peak number One 2 3 4 5 6 7 8 9 10 2 θ ° (Cu Kα) 5.31 10.19 11.23 12.13 12.35 12.69 14.31 14.55 14.77 16.43 d space 16.6 8.7 7.9 7.3 7.2 7.0 6.2 6.1 6.0 5.4 peak 11 12 13 14 15 16 17 18 19 20 2 θ ° (Cu Kα) 17.48 18.21 18.43 18.81 19.36 19.61 20.26 20.5 21.29 21.46 d space 5.1 4.9 4.8 4.7 4.6 4.5 4.4 4.3 4.2 4.1 peak 21 22 23 24 25 26 27 28 29 30 2 θ ° (Cu Kα) 21.95 22.53 22.77 23.38 23.59 23.9 24.45 25.02 25.56 26.19 d space 4.0 3.9 3.9 3.8 3.8 3.7 3.6 3.6 3.5 3.4 peak 31 32 2 θ ° (Cu Kα) 26.83 27.21 d space 3.3 3.3

Claims (12)

Salt selected from anhydride and hydrate forms of (1R, 2R, 3S, 5S) -2-methoxymethyl-3- (3,4-dichlorophenyl) -8-azabicyclo [3.2.1] octane tartrate. The anhydride according to claim 1, wherein the anhydride of (1R, 2R, 3S, 5S) -2-methoxymethyl-3- (3,4-dichlorophenyl) -8-azabicyclo [3.2.1] octane L-tartrate and Salts selected from hydrate forms. The compound according to claim 1, which is (1R, 2R, 3S, 5S) -2-methoxymethyl-3- (3,4-dichlorophenyl) -8-azabicyclo [3.2.1] octane L-tartrate monohydrate salt. The anhydride form of claim 1, wherein (1R, 2R, 3S, 5S) -2-methoxymethyl-3- (3,4-dichlorophenyl) -8-azabicyclo [3.2.1] octane L-tartrate Phosphorus salts. The method according to claim 4, wherein the main peaks in the X-ray powder diffraction pattern are (1R, 2R, 3S, 5S) -2-methoxymethyl-3- (3,4-dichlorophenyl) -8-azabi Salt in polymorphic form (form II) of cyclo [3.2.1] octane L-tartrate anhydride. Peak number One 2 3 4 5 6 7 8 9 10 2 θ ° (Cu Kα) 10.35 11.68 12.53 14.81 15 15.77 16.82 17.41 17.77 18.87 d space 8.5 7.6 7.1 6.0 5.9 5.6 5.3 5.1 5.0 4.7 peak 11 12 13 14 15 16 17 18 19 2 θ ° (Cu Kα) 20.29 21.26 21.66 23.44 23.73 25.44 25.99 27.58 28.14 d space 4.4 4.2 4.1 3.8 3.7 3.5 3.4 3.2 3.2 The method according to claim 4, wherein the main peaks in the X-ray powder diffraction pattern are (1R, 2R, 3S, 5S) -2-methoxymethyl-3- (3,4-dichlorophenyl) -8-azabi Salt in polymorphic form (Type III) of cyclo [3.2.1] octane L-tartrate anhydride. Peak number One 2 3 4 5 6 7 8 9 10 2 θ ° (Cu Kα) 5.37 10.6 10.82 11.58 11.88 12.79 14.78 16.27 16.5 17.03 d space 16.4 8.3 8.2 7.6 7.4 6.9 6.0 5.4 5.4 5.2 peak 11 12 13 14 15 16 17 18 19 2 θ ° (Cu Kα) 17.84 19.29 20.01 21.2 22.99 23.46 24.54 25.15 26.59 d space 5.0 4.6 4.4 4.2 3.9 3.8 3.6 3.5 3.3 The method according to claim 4, wherein the main peaks in the X-ray powder diffraction pattern are (1R, 2R, 3S, 5S) -2-methoxymethyl-3- (3,4-dichlorophenyl) -8-azabi Salt in polymorphic form (Type IV) of cyclo [3.2.1] octane L-tartrate anhydride. Peak number One 2 3 4 5 6 7 8 9 10 2 θ ° (Cu Kα) 5.31 10.19 11.23 12.13 12.35 12.69 14.31 14.55 14.77 16.43 d space 16.6 8.7 7.9 7.3 7.2 7.0 6.2 6.1 6.0 5.4 peak 11 12 13 14 15 16 17 18 19 20 2 θ ° (Cu Kα) 17.48 18.21 18.43 18.81 19.36 19.61 20.26 20.5 21.29 21.46 d space 5.1 4.9 4.8 4.7 4.6 4.5 4.4 4.3 4.2 4.1 peak 21 22 23 24 25 26 27 28 29 30 2 θ ° (Cu Kα) 21.95 22.53 22.77 23.38 23.59 23.9 24.45 25.02 25.56 26.19 d space 4.0 3.9 3.9 3.8 3.8 3.7 3.6 3.6 3.5 3.4 peak 31 32 2 θ ° (Cu Kα) 26.83 27.21 d space 3.3 3.3 A pharmaceutical composition comprising a therapeutically effective amount of a salt according to any one of claims 1 to 7 together with one or more pharmaceutically acceptable carriers, excipients or diluents. Use of a salt according to any one of claims 1 to 7 for the manufacture of a medicament. The method of claim 9 for preparing a pharmaceutical composition for the treatment, prevention or alleviation of a disease, disorder or condition in a mammal, including human, which is responsive to the inhibition of reuptake of monoamine neurotransmitter of the central nervous system. Usage. 11. The method of claim 10, wherein the disease, disorder or condition is mood disorder, depression, atypical depression, depression caused by pain, major depressive disorder, mood modulation disorder, bipolar disorder, bipolar I disorder, bipolar II disorder, cyclic mood disorder , Mood disorders due to general medical conditions, substance-induced mood disorders, pseudodementia, Ganser's syndrome, obsessive-compulsive disorder, panic disorder, panic disorder without agoraphobia, panic disorder with agoraphobia, panic disorder Agoraphobia, Panic Attack, Memory Deficit, Memory Loss, Attention Deficit Hyperactivity Disorder, Obesity, Anxiety, General Anxiety Disorder, Eating Disorder, Parkinson's Disease, Parkinson's Disease, Dementia, Dementia With Aging, Senile Dementia, Alzheimer's Disease, Acquired Immunodeficiency complex dementia, aging memory disorders, specific phobias, social phobias, post-traumatic stress disorder, acute stress disorder, drug addiction, substance abuse, Cocaine Abuse, Nicotine Abuse, Tobacco Abuse, Alcoholism, Alcoholism, Pain, Chronic Pain, Inflammatory Pain, Nervous Pain, Migraine, Tension Headache, Chronic Tension Headache, Depression-Related Pain, Fibromyalgia, Arthritis, Osteoarthritis, Rheumatoid Arthritis, Low Back Pain , Cancer pain, irritable bowel pain, irritable bowel syndrome, postoperative pain, pain after seizures, drug-induced neuropathy, diabetic neuropathy, sympathetic persistent pain, tertiary neuralgia, toothache, facial muscle pain, ring pain, macrophages, premenstrual syndrome , Late luteal syndrome, post-traumatic syndrome, chronic fatigue syndrome, incontinence, stress incontinence, urge incontinence, night incontinence, sexual dysfunction, premature ejaculation, erectile dysfunction, erectile dysfunction, eating disorders, anorexia nervosa, sleep disorders, autism, narcosis , Hair growth, narcolepsy, post-seizure depression, seizure-induced brain injury, seizure-induced nerve damage, or Gillette de la Tourettes disease Applications. A therapeutically effective amount of a salt according to any one of claims 1 to 7 is necessary to treat, prevent or alleviate a disease, disorder or condition responsive to the inhibition of monoamine neurotransmitter reuptake in the central nervous system. A method of treating, preventing or alleviating a disease, disorder or condition of an animal living body comprising a human, comprising administering to an animal living body comprising a human.